CA2706113A1 - Solid carriers for improved delivery of active ingredients in pharmaceutical compositions - Google Patents
Solid carriers for improved delivery of active ingredients in pharmaceutical compositions Download PDFInfo
- Publication number
- CA2706113A1 CA2706113A1 CA2706113A CA2706113A CA2706113A1 CA 2706113 A1 CA2706113 A1 CA 2706113A1 CA 2706113 A CA2706113 A CA 2706113A CA 2706113 A CA2706113 A CA 2706113A CA 2706113 A1 CA2706113 A1 CA 2706113A1
- Authority
- CA
- Canada
- Prior art keywords
- peg
- active ingredient
- surfactants
- oil
- nikko
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/927—Diagnostic contrast agent
Abstract
The present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered. In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides. The compositions of the present invention can be used for improved delivery of hydrophilic or hydrophobic pharmaceutical active ingredients, such as drugs, nutrionals, cosmecueticals and diagnostic agents.
Description
SOLID CARRIERS FOR IMPROVED DELIVERY
OF ACTIVE INGREDIENTS IN PHARMACEUTICAL COMPOSITIONS
TECHNICAL FIELD
The present invention relates to pharmaceutical delivery systems for pharmaceutical active ingredients, such as drugs, nutritionals, cosmeceuticals, and diagnostic agents. In particular, the present invention provides compositions and dosage forms including solid carriers for improved delivery of pharmaceutical active ingredients.
BACKGROUND ART
Hydrophobic active ingredients, such as progesterone, cyclosporine, itraconazole and glyburide present delivery challenges due to their poor aqueous solubility and slow dissolution rate. Several commercial products of these hydrophobic drugs are available, the various products using different methods to try to enhance in vivo performance. One approach is size reduction by micronization, such as in Prometrium (micronized progesterone) and Micronase (micronized glyburide). Other approaches include size reduction in emulsion formulations, such as in Sandimmune (cyclosporine emulsion) and NeOral (cyclosporine microemulsion). These approaches suffer from several disadvantages. Micronization/nanonization presents processing and stability challenges, as well as dissolution limitations, since the micronized/nanosized drug still possesses a high degree of crystallinity. Liquid formulations present drug precipitation and packaging challenges, due to solvent evaporation. Moreover, non-solid formulations are more prone to chemical instability and capsule-shell incompatibility, leading to the possibility of leakage upon storage.
For hydrophilic active ingredients, the formulation challenges are different.
Although these compounds are readily soluble in the aqueous gastrointestinal environment, they are poorly absorbed, due to poor membrane permeability and/or enzymatic degradation. Surfactants and lipophilic additives have been reported to improve membrane permeability; see, e.g., LeCluyse and Sutton, "In vitro models for .2-selection of development candidates. Permeability studies to define mechanisms of absorption enhancement", Advanced Drug Delivery Reviews, 23, 163-183 (1997).
However, these compositions fail to maintain effective levels and type of enhancers for bioacceptable absorption enhancement. Most solid dosage forms of hydrophilic active ingredients exhibit poor or no absorption of the active. Moreover, these non-solid formulations suffer from the disadvantages of chemical instability, leakage and capsule shell incompatibility as discussed above.
Solid carriers for pharmaceutical active ingredients offer potential advantages over micronized drugs, emulsions or solubilized formulations. Solid carriers, typically of size less than about 2 mm, can easily pass through the stomach, thus making the performance less prone to gastric emptying variability. Further, the problems of leakage and other disadvantages of liquid formulations are not present in solid carrier formulations. To date, however, such solid carrier formulations generally have been limited to a few specific drugs, due to difficulties in formulating appropriate 6 drug/excipient compositions to effectively coat the active ingredient onto a carrier particle.
Conventional solid dosage forms of hydrophobic active ingredients, such as tablets, or multiparticulates in capsules, often exhibit slow and incomplete dissolution and subsequent absorption. These formulations often show a high propensity for biovariability and food interactions of the active ingredient, resulting in restrictive compliancellabeling requirements.
Due to the slow dissolution and dependence on gastric emptying, solid dosage forms often delay the onset of some hydrophobic active ingredients.
Thus, there is a need for pharmaceutical compositions and dosage forms, and methods therefor, that do not suffer from the foregoing disadvantages.
DISCLOSURE OF THE INVENTION
It is an object of the invention to provide solid pharmaceutical compositions having active ingredients in a rapid dissolvable and more solubilized state therein.
It is another object of the invention to provide solid pharmaceutical compositions having more rapid dissolution upon administration to a patient.
It is another object of the invention to provide solid pharmaceutical compositions having more sustained and complete solubilization upon administration to a patient.
It is another object of the invention to provide solid pharmaceutical compositions capable of delivery a wide variety of pharmaceutical active ingredients.
It is another object of the invention to provide solid pharmaceutical compositions of coated substrate materials without the need for binders.
It is another object of the invention to provide solid pharmaceutical compositions having increased chemical stability of the active ingredient.
It is another object of the invention to provide solid pharmaceutical compositions capable of improving the absorption and/or bioavailability of a pharmaceutical active ingredient.
It is another object of the invention to provide solid pharmaceutical compositions having better protection of the upper gastrointestinal tract from untoward effects of the active ingredient.
It is another object of the present invention to provide solid pharmaceutical compositions capable of improving the palatability of or masking the taste of unpalatable pharmaceutical active ingredients.
In accordance with these and other objects, the present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered.
In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant.
Optionally, the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a lipophilic component, such as a lipophilic surfactant or a triglyceride. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
In other aspects, the present invention also provides dosage forms of any of the solid pharmaceutical compositions, and methods of using the solid pharmaceutical compositions.
These and other objects and features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to illustrate the manner in which the above-recited and other advantages and objects of the invention are obtained, a more particular description of the invention briefly described above will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore to be considered to be limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:
Figure 1 is a graph showing the extent of dissolution/release of glyburide as a function of time for a composition according to the present invention and two prior art compositions.
Figure 2A is a graph showing the extent of dissolution/release of progesterone as a function of.time for two compositions according to the present invention and the pure bulk drug.
Figure 2B is a graph showing the extent of dissolution/release of progesterone as a function of time for two compositions of the present invention, a conventional commercial formulation of progesterone, and the pure bulk drug.
to Figure 3 is a graph showing the extent of dissolution/release of omeprazole as a function of time for two compositions according to the present invention and a prior art composition.
MODES FOR CARRYING OUT THE INVENTION
The present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered. In one embodiment; the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. These and other embodiments, as well as preferred aspects thereof, are described in more detail below.
It should be appreciated that any of the components of the compositions of the present invention can be used as supplied commercially, or can be preprocessed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The various components can also be pre-coated or encapsulated. These various processes and coatings are described in more detail below.
1. Pharmaceutical Active Ingredients In the embodiments of the present invention which include active ingredients, the active ingredients suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of effectively delivering a wide variety of active ingredients. The active ingredient can be hydrophilic, lipophilic, amphiphilic or hydrophobic, and can be solubilized, dispersed, or partially solubilized and dispersed, in the encapsulation coat.
Alternatively, the active ingredient can be.provided separately from the solid pharmaceutical composition, such as for co-administration. Such active ingredients can be any compound or mixture of compounds having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, cosmeceuticals, diagnostic agents, nutritional agents, and the like. It should be appreciated that the categorization of an active ingredient as hydrophilic or hydrophobic may change, depending upon the particular salts, isomers, analogs and derivatives used.
In one embodiment, the active ingredient agent is hydrophobic. Hydrophobic active ingredients are compounds with little or no water solubility. Intrinsic water solubilities (i. e., water solubility of the unionized form) for hydrophobic active ingredients are less than about 1% by weight, and typically less than about 0.1% or 0.01 % by weight. In a particular aspect of this embodiment, the active ingredient is a hydrophobic drug. In other particular aspects, the active ingredient is a nutrient, a cosmeceutical, a diagnostic agent or a nutritional agent.
Suitable hydrophobic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, a-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
Specific, non-limiting examples of suitable hydrophobic active ingredients are:
acutretin, albendazole, albuterol, aminogluthemide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethsone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulphan, butenafine, calcifediol, calciprotiene, calcitriol, camptothecan, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, cetrizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, oinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidrogel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, dicoumarol, digoxin, dihydro epiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenytion, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone, mefloquine, megesterol acetate, methadone, methoxsalen, metronidazole, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratiptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, -- --- - -------nizatidine, omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel, paricalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terzosin, tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of course, salts, isomers and derivatives of the above-listed hydrophobic active ingredients may also be used, as well as mixtures.
Among the above-listed hydrophobic active ingredients, preferred active ingredients include: acutretin, albendazole, albuterol, aminogluthenlide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, benzonatate, bicalutanide, busulphan, butenafine, calcifediol, calciprotiene, calcitrioI, camptothecan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, ciprofloxacin, cisapride, citrizine, clarithromycin, clemastine, clomiphene, codeine, coenzyme Q10, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, digoxin, dihydro epiandrosterone, dihydroergotamine, dihyrotachysterol, dirithromycin, donepezil, efavirenz, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenytion, frovatriptan, furzolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irinotecan, isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, mefepristone, mefloquine, megesterol acetate, methdone, methoxsalen, metronidazole, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, mmedroxyprogesterone, montelukast, nabumetone, nalbuphine, naratiptan, nelfinavir, nilutanide, nitrofurantoin, nizatidine, omeprazole, osteradiol, oxaprozin, paclitaxel, paricalcitol, pentazocine, pioglitazone, pizofetin, pravastatin, probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tetrahydrocannabinol, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
Particularly preferred hydrophobic active ingredients include: acutretin, albuterol, aminogluthemide, amiodarone, amlodipine, amprenavir, atorvastatin, atovaquone, baclofen, benzonatate, bicalutanide, busulphan, calcifediol, calciprotiene, calcitriol, camptothecan, capsaicin, carbamezepine, carotenes, celecoxib, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, cisapride, citrizine, clemastine, coenzyme Q10, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, dihydro epiandrosterone, dihydroergotamine, dihyrotachysterol, efavirenz, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fexofenadine, finasteride, flucanazole, flurbiprofen, fosphenytion, frovatriptan, furzolidone, glibenclamide, glipizide, glyburide, glymepride, ibuprofen, irinotecan, isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone, megesterol acetate, methoxsalen, metronidazole, metronidazole, miconazole, miglitol, mitoxantrone, montelukast, nabumetone, naratiptan,.nelfinavir, nilutanide, nitrofurantoin, nizatidine, omeprazole, osteradiol, oxaprozin, paclitaxel, paricalcitol, pioglitazone, pizofetin, pranlukast, probucol, progesterone, pseudo-ephedrine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sildenafil citrate, simvastatin, sirolimus, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbenafine, tetrahydrocannabinol, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, pharmaceutically acceptable salts, isomers and derivative thereof, and mixtures thereof.
Most preferred hydrophobic active ingredients include: amlodipine, amprenavir, atorvastatin, atovaquone, celecoxib, cisapride, coenzyme Q10, cyclosporine, famotidine, fenofibrate, fexofenadine, fmasteride, ibuprofen, itraconazole, lanosprazole, Ioratadine, lovastatin, megesterol acetate, montelukast, nabumetone, nizatidine, omeprazole, oxaprozin, paclitaxel, paricalcitol, pioglitazone, pranlukast, progesterone, pseudo-ephedrine, rabeprazole, rapamycin, refocoxib, repaglinide, rimexolone, ritanovir, rosiglitazone, saquinavir, sildenafil citrate, simvastatin, sirolimus, tacrolimus, 1o tamsulosin, teniposide, terbenafine, tetrahydrocannabinol, tiagabine, tizanidine, tramadol, troglitazone, vitamin A, vitamin D, vitamin E, zafirlukast, zileuton, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
In another embodiment, the active ingredient is hydrophilic. Amphiphilic compounds are also included within the class of hydrophilic active ingredients.
Apparent water solubilities for hydrophilic active ingredients are greater than about 0.1 %
by weight, and typically greater than about 1% by weight. Ina particular aspect of this embodiment, the hydrophilic active ingredient is a hydrophilic drug. In other particular aspects, the hydrophilic active ingredient is a cosmeceutical, a diagnostic agent, or a nutritional agent.
= Suitable hydrophilic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-=25 neoplastic agents, erectile dysfunction improvement agents, -immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, Q-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, -- - - --------cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
Likewise, the hydrophilic active ingredient can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof.
Specific, non-limiting examples of suitable hydrophilic active ingredients include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride;
alatrofloxacin;
alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine;
amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human);
antihemophilic factor (porcine); antihemophilic factor (recombinant);
aprotinin;
asparaginase; atenolol; atracurium besylate; atropine; azithromycin;
aztreonam; BCG
vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate;
calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate;
is cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime;
cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium;
ceftizoxime;
ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chrionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium;
colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium;
danaproid; deforoxamine; denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride;
dornase alpha; doxacurium chloride; doxorubicin; editronate disodium;
elanaprilat;
enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha;
erythromycin; esmol hydrochloride; factor IX; famiciclovir; fludarabine;
fluoxetine;
foscamet sodium; ganciclovir; granulocyte colony stimulating factor;
granulocyte-macrophage stimulating factor; growth hormones- recombinant human; growth hormone- bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B
conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine;
interleukin-2;
interleukin-3; insulin-human; insulin lispro; insulin procine; insulin NPH;
insulin aspart;
insulin glargine; insulin detemir; interferon alpha; interferon beta;
ipratropium bromide;
isofosfamide; japanese encephalitis virus vaccine; lamivudine; leucovorin calcium;
leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives;
lobucavir, lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine;
menotropins; mephenzolate bromide; mesalmine; methanamine; methotrexate;
methscopolamine; metformin hydrochloride; metroprolol; mezocillin sodium;
mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide;
neostigmine methyl sulfate; neutontin; norfloxacin; octreotide acetate;
ofloxacin;
olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine;
pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline;
periciclovir;
pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate;
plague vaccine; piperacillin sodium; platelet derived growth factor-human;
pneumococcal vaccine polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live (OPV);
polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin;
propofenone;
propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate;
ribavarin;
rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide;
small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine;
streptokinase;
streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate;
thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc;
TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin;
trovafloxacin;
tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea;
urokinase;
vancomycin; valaciclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecoronium bromide; vinblastin; vincristine;
vinorelbine;
vitamin B12 ; warfarin sodium; yellow fever vaccine; zalcitabine; zanamavir;
zolandronate; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
Among the above-listed hydrophilic active ingredients, preferred active ingredients include acarbose; acyclovir; atracurium besylate; alendronate;
alglucerase;
3o amantadine hydrochloride; amphotericin B; antihemophilic factor (human);
antihemopliilic factor (porcine); antihemophilic factor (recombinant;
azithromycin;
calcitonin human; calcitonin salmon; capecitabine; cefazolin sodium; cefonicid sodium;
cefoperazone; cefoxitin sodium; ceflizoxime; ceftriaxone; cefuroxime axetil;
cephalexin;
chrionic gonadotropin; cidofovir; cladribine ; clindamycin and clindamycin derivatives;
cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium;
danaproid;
desmopressin; didanosine; dirithromycin; editronate disodium; enoxaprin sodium;
epoetin alpha; factor IX; famiciclovir, fludarabine; foscarnet sodium;
ganciclovir;
granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor;
growth hormones- recombinant human; growth hormone-Bovine; gentamycin;
glucagon;
gonadotropin releasing hormone and synthetic analogs thereof; GnRH;
gonadorelin;
hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated;
Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine;
interleukin-2; interleukin-3; insulin-human; insulin lispro; insulin procine;
insulin NPH;
insulin aspart; insulin glargine; insulin detemir; interferon alpha;
interferon beta;
ipratropium bromide; isofosfamide; lamivudine; leucovorin calcium; leuprolide acetate;
lincomycin and lincomycin derivatives; metformin hydrochloride; nedocromil sodium;
neostigmine bromide; neostigmine methyl sulfate; neutontin; octreotide acetate;
olpadronate; panlidronate disodium; pancuronium bromide; pentamindine isethionate;
pentagastrin; physostigmine salicylate; poliovirus vaccine live (OPV);
pyridostigmine bromide; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine;
salmetrol xinafoate; somatostatin; spectinomycin; stavudine; streptokinase; ticarcillin;
tiludronate;
tissue type plasminogen activator, TNFR:Fc; TNK-1PA; trimetrexate gluconate;
trospectinomycin; tumor necrosis factor; typhoid vaccine live; urokinase;
vancomycin;
valaciclovir; vasopressin and vasopressin derivatives; vinblastin;
vincristine; vinorelbine;
warfarin sodium; zalcitabine; zanamavir; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
Most preferred hydrophilic active ingredients include acarbose; alendronate;
amantadine hydrochloride; azithromycin; calcitonin human; calcitonin salmon;
ceftriaxone; cefuroxime axetil; chrionic gonadotropin; cromalyn sodium;
daltaperin sodium; danaproid; desmopressin; didanosine; editronate disodium; enoxaprin sodium;
epoetin alpha; factor IX; famiciclovir; foscarnet sodium; ganciclovir;
granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; growth hormones-recombinant human; growth hormone- Bovine; glucagon; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; heparin sodium;
indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin-human;
insulin lispro; insulin procine interferon alpha; interferon beta; leuprolide acetate;
metformin hydrochloride; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate;
neutontin; octreotide acetate; olpadronate; pamidronate disodium; residronate;
rimantadine hydrochloride; salmetrol xinafoate; somatostatin; stavudine;
ticarcillin;
tiludronate; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; tumor necrosis factor; typhoid vaccine live; vancomycin; valaciclovir; vasopressin and vasopressin derivatives; zalcitabine; zanamavir; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
OF ACTIVE INGREDIENTS IN PHARMACEUTICAL COMPOSITIONS
TECHNICAL FIELD
The present invention relates to pharmaceutical delivery systems for pharmaceutical active ingredients, such as drugs, nutritionals, cosmeceuticals, and diagnostic agents. In particular, the present invention provides compositions and dosage forms including solid carriers for improved delivery of pharmaceutical active ingredients.
BACKGROUND ART
Hydrophobic active ingredients, such as progesterone, cyclosporine, itraconazole and glyburide present delivery challenges due to their poor aqueous solubility and slow dissolution rate. Several commercial products of these hydrophobic drugs are available, the various products using different methods to try to enhance in vivo performance. One approach is size reduction by micronization, such as in Prometrium (micronized progesterone) and Micronase (micronized glyburide). Other approaches include size reduction in emulsion formulations, such as in Sandimmune (cyclosporine emulsion) and NeOral (cyclosporine microemulsion). These approaches suffer from several disadvantages. Micronization/nanonization presents processing and stability challenges, as well as dissolution limitations, since the micronized/nanosized drug still possesses a high degree of crystallinity. Liquid formulations present drug precipitation and packaging challenges, due to solvent evaporation. Moreover, non-solid formulations are more prone to chemical instability and capsule-shell incompatibility, leading to the possibility of leakage upon storage.
For hydrophilic active ingredients, the formulation challenges are different.
Although these compounds are readily soluble in the aqueous gastrointestinal environment, they are poorly absorbed, due to poor membrane permeability and/or enzymatic degradation. Surfactants and lipophilic additives have been reported to improve membrane permeability; see, e.g., LeCluyse and Sutton, "In vitro models for .2-selection of development candidates. Permeability studies to define mechanisms of absorption enhancement", Advanced Drug Delivery Reviews, 23, 163-183 (1997).
However, these compositions fail to maintain effective levels and type of enhancers for bioacceptable absorption enhancement. Most solid dosage forms of hydrophilic active ingredients exhibit poor or no absorption of the active. Moreover, these non-solid formulations suffer from the disadvantages of chemical instability, leakage and capsule shell incompatibility as discussed above.
Solid carriers for pharmaceutical active ingredients offer potential advantages over micronized drugs, emulsions or solubilized formulations. Solid carriers, typically of size less than about 2 mm, can easily pass through the stomach, thus making the performance less prone to gastric emptying variability. Further, the problems of leakage and other disadvantages of liquid formulations are not present in solid carrier formulations. To date, however, such solid carrier formulations generally have been limited to a few specific drugs, due to difficulties in formulating appropriate 6 drug/excipient compositions to effectively coat the active ingredient onto a carrier particle.
Conventional solid dosage forms of hydrophobic active ingredients, such as tablets, or multiparticulates in capsules, often exhibit slow and incomplete dissolution and subsequent absorption. These formulations often show a high propensity for biovariability and food interactions of the active ingredient, resulting in restrictive compliancellabeling requirements.
Due to the slow dissolution and dependence on gastric emptying, solid dosage forms often delay the onset of some hydrophobic active ingredients.
Thus, there is a need for pharmaceutical compositions and dosage forms, and methods therefor, that do not suffer from the foregoing disadvantages.
DISCLOSURE OF THE INVENTION
It is an object of the invention to provide solid pharmaceutical compositions having active ingredients in a rapid dissolvable and more solubilized state therein.
It is another object of the invention to provide solid pharmaceutical compositions having more rapid dissolution upon administration to a patient.
It is another object of the invention to provide solid pharmaceutical compositions having more sustained and complete solubilization upon administration to a patient.
It is another object of the invention to provide solid pharmaceutical compositions capable of delivery a wide variety of pharmaceutical active ingredients.
It is another object of the invention to provide solid pharmaceutical compositions of coated substrate materials without the need for binders.
It is another object of the invention to provide solid pharmaceutical compositions having increased chemical stability of the active ingredient.
It is another object of the invention to provide solid pharmaceutical compositions capable of improving the absorption and/or bioavailability of a pharmaceutical active ingredient.
It is another object of the invention to provide solid pharmaceutical compositions having better protection of the upper gastrointestinal tract from untoward effects of the active ingredient.
It is another object of the present invention to provide solid pharmaceutical compositions capable of improving the palatability of or masking the taste of unpalatable pharmaceutical active ingredients.
In accordance with these and other objects, the present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered.
In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant.
Optionally, the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a lipophilic component, such as a lipophilic surfactant or a triglyceride. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a lipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
In other aspects, the present invention also provides dosage forms of any of the solid pharmaceutical compositions, and methods of using the solid pharmaceutical compositions.
These and other objects and features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to illustrate the manner in which the above-recited and other advantages and objects of the invention are obtained, a more particular description of the invention briefly described above will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore to be considered to be limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:
Figure 1 is a graph showing the extent of dissolution/release of glyburide as a function of time for a composition according to the present invention and two prior art compositions.
Figure 2A is a graph showing the extent of dissolution/release of progesterone as a function of.time for two compositions according to the present invention and the pure bulk drug.
Figure 2B is a graph showing the extent of dissolution/release of progesterone as a function of time for two compositions of the present invention, a conventional commercial formulation of progesterone, and the pure bulk drug.
to Figure 3 is a graph showing the extent of dissolution/release of omeprazole as a function of time for two compositions according to the present invention and a prior art composition.
MODES FOR CARRYING OUT THE INVENTION
The present invention provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered. In one embodiment; the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. These and other embodiments, as well as preferred aspects thereof, are described in more detail below.
It should be appreciated that any of the components of the compositions of the present invention can be used as supplied commercially, or can be preprocessed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The various components can also be pre-coated or encapsulated. These various processes and coatings are described in more detail below.
1. Pharmaceutical Active Ingredients In the embodiments of the present invention which include active ingredients, the active ingredients suitable for use in the pharmaceutical compositions and methods of the present invention are not particularly limited, as the compositions are surprisingly capable of effectively delivering a wide variety of active ingredients. The active ingredient can be hydrophilic, lipophilic, amphiphilic or hydrophobic, and can be solubilized, dispersed, or partially solubilized and dispersed, in the encapsulation coat.
Alternatively, the active ingredient can be.provided separately from the solid pharmaceutical composition, such as for co-administration. Such active ingredients can be any compound or mixture of compounds having therapeutic or other value when administered to an animal, particularly to a mammal, such as drugs, nutrients, cosmeceuticals, diagnostic agents, nutritional agents, and the like. It should be appreciated that the categorization of an active ingredient as hydrophilic or hydrophobic may change, depending upon the particular salts, isomers, analogs and derivatives used.
In one embodiment, the active ingredient agent is hydrophobic. Hydrophobic active ingredients are compounds with little or no water solubility. Intrinsic water solubilities (i. e., water solubility of the unionized form) for hydrophobic active ingredients are less than about 1% by weight, and typically less than about 0.1% or 0.01 % by weight. In a particular aspect of this embodiment, the active ingredient is a hydrophobic drug. In other particular aspects, the active ingredient is a nutrient, a cosmeceutical, a diagnostic agent or a nutritional agent.
Suitable hydrophobic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, a-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
Specific, non-limiting examples of suitable hydrophobic active ingredients are:
acutretin, albendazole, albuterol, aminogluthemide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethsone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulphan, butenafine, calcifediol, calciprotiene, calcitriol, camptothecan, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, cetrizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, oinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidrogel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, dicoumarol, digoxin, dihydro epiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenytion, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate, isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone, mefloquine, megesterol acetate, methadone, methoxsalen, metronidazole, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratiptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, -- --- - -------nizatidine, omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel, paricalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terzosin, tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of course, salts, isomers and derivatives of the above-listed hydrophobic active ingredients may also be used, as well as mixtures.
Among the above-listed hydrophobic active ingredients, preferred active ingredients include: acutretin, albendazole, albuterol, aminogluthenlide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, benzonatate, bicalutanide, busulphan, butenafine, calcifediol, calciprotiene, calcitrioI, camptothecan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, ciprofloxacin, cisapride, citrizine, clarithromycin, clemastine, clomiphene, codeine, coenzyme Q10, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, digoxin, dihydro epiandrosterone, dihydroergotamine, dihyrotachysterol, dirithromycin, donepezil, efavirenz, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenytion, frovatriptan, furzolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irinotecan, isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, mefepristone, mefloquine, megesterol acetate, methdone, methoxsalen, metronidazole, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, mmedroxyprogesterone, montelukast, nabumetone, nalbuphine, naratiptan, nelfinavir, nilutanide, nitrofurantoin, nizatidine, omeprazole, osteradiol, oxaprozin, paclitaxel, paricalcitol, pentazocine, pioglitazone, pizofetin, pravastatin, probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tetrahydrocannabinol, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
Particularly preferred hydrophobic active ingredients include: acutretin, albuterol, aminogluthemide, amiodarone, amlodipine, amprenavir, atorvastatin, atovaquone, baclofen, benzonatate, bicalutanide, busulphan, calcifediol, calciprotiene, calcitriol, camptothecan, capsaicin, carbamezepine, carotenes, celecoxib, chlorpheniramine, cholecaliferol, cimetidine, cinnarizine, cisapride, citrizine, clemastine, coenzyme Q10, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, dihydro epiandrosterone, dihydroergotamine, dihyrotachysterol, efavirenz, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fexofenadine, finasteride, flucanazole, flurbiprofen, fosphenytion, frovatriptan, furzolidone, glibenclamide, glipizide, glyburide, glymepride, ibuprofen, irinotecan, isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone, megesterol acetate, methoxsalen, metronidazole, metronidazole, miconazole, miglitol, mitoxantrone, montelukast, nabumetone, naratiptan,.nelfinavir, nilutanide, nitrofurantoin, nizatidine, omeprazole, osteradiol, oxaprozin, paclitaxel, paricalcitol, pioglitazone, pizofetin, pranlukast, probucol, progesterone, pseudo-ephedrine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sildenafil citrate, simvastatin, sirolimus, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbenafine, tetrahydrocannabinol, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, ubidecarenone, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, pharmaceutically acceptable salts, isomers and derivative thereof, and mixtures thereof.
Most preferred hydrophobic active ingredients include: amlodipine, amprenavir, atorvastatin, atovaquone, celecoxib, cisapride, coenzyme Q10, cyclosporine, famotidine, fenofibrate, fexofenadine, fmasteride, ibuprofen, itraconazole, lanosprazole, Ioratadine, lovastatin, megesterol acetate, montelukast, nabumetone, nizatidine, omeprazole, oxaprozin, paclitaxel, paricalcitol, pioglitazone, pranlukast, progesterone, pseudo-ephedrine, rabeprazole, rapamycin, refocoxib, repaglinide, rimexolone, ritanovir, rosiglitazone, saquinavir, sildenafil citrate, simvastatin, sirolimus, tacrolimus, 1o tamsulosin, teniposide, terbenafine, tetrahydrocannabinol, tiagabine, tizanidine, tramadol, troglitazone, vitamin A, vitamin D, vitamin E, zafirlukast, zileuton, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
In another embodiment, the active ingredient is hydrophilic. Amphiphilic compounds are also included within the class of hydrophilic active ingredients.
Apparent water solubilities for hydrophilic active ingredients are greater than about 0.1 %
by weight, and typically greater than about 1% by weight. Ina particular aspect of this embodiment, the hydrophilic active ingredient is a hydrophilic drug. In other particular aspects, the hydrophilic active ingredient is a cosmeceutical, a diagnostic agent, or a nutritional agent.
= Suitable hydrophilic active ingredients are not limited by therapeutic category, and can be, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-=25 neoplastic agents, erectile dysfunction improvement agents, -immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, Q-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, -- - - --------cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
Likewise, the hydrophilic active ingredient can be a cytokine, a peptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, or a mixture thereof.
Specific, non-limiting examples of suitable hydrophilic active ingredients include: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride;
alatrofloxacin;
alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine;
amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human);
antihemophilic factor (porcine); antihemophilic factor (recombinant);
aprotinin;
asparaginase; atenolol; atracurium besylate; atropine; azithromycin;
aztreonam; BCG
vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate;
calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate;
is cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime;
cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium;
ceftizoxime;
ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chrionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium;
colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium;
danaproid; deforoxamine; denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride;
dornase alpha; doxacurium chloride; doxorubicin; editronate disodium;
elanaprilat;
enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha;
erythromycin; esmol hydrochloride; factor IX; famiciclovir; fludarabine;
fluoxetine;
foscamet sodium; ganciclovir; granulocyte colony stimulating factor;
granulocyte-macrophage stimulating factor; growth hormones- recombinant human; growth hormone- bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B
conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine;
interleukin-2;
interleukin-3; insulin-human; insulin lispro; insulin procine; insulin NPH;
insulin aspart;
insulin glargine; insulin detemir; interferon alpha; interferon beta;
ipratropium bromide;
isofosfamide; japanese encephalitis virus vaccine; lamivudine; leucovorin calcium;
leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives;
lobucavir, lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine;
menotropins; mephenzolate bromide; mesalmine; methanamine; methotrexate;
methscopolamine; metformin hydrochloride; metroprolol; mezocillin sodium;
mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide;
neostigmine methyl sulfate; neutontin; norfloxacin; octreotide acetate;
ofloxacin;
olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine;
pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline;
periciclovir;
pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate;
plague vaccine; piperacillin sodium; platelet derived growth factor-human;
pneumococcal vaccine polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live (OPV);
polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin;
propofenone;
propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate;
ribavarin;
rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide;
small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine;
streptokinase;
streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate;
thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc;
TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomycin;
trovafloxacin;
tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea;
urokinase;
vancomycin; valaciclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecoronium bromide; vinblastin; vincristine;
vinorelbine;
vitamin B12 ; warfarin sodium; yellow fever vaccine; zalcitabine; zanamavir;
zolandronate; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
Among the above-listed hydrophilic active ingredients, preferred active ingredients include acarbose; acyclovir; atracurium besylate; alendronate;
alglucerase;
3o amantadine hydrochloride; amphotericin B; antihemophilic factor (human);
antihemopliilic factor (porcine); antihemophilic factor (recombinant;
azithromycin;
calcitonin human; calcitonin salmon; capecitabine; cefazolin sodium; cefonicid sodium;
cefoperazone; cefoxitin sodium; ceflizoxime; ceftriaxone; cefuroxime axetil;
cephalexin;
chrionic gonadotropin; cidofovir; cladribine ; clindamycin and clindamycin derivatives;
cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium;
danaproid;
desmopressin; didanosine; dirithromycin; editronate disodium; enoxaprin sodium;
epoetin alpha; factor IX; famiciclovir, fludarabine; foscarnet sodium;
ganciclovir;
granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor;
growth hormones- recombinant human; growth hormone-Bovine; gentamycin;
glucagon;
gonadotropin releasing hormone and synthetic analogs thereof; GnRH;
gonadorelin;
hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated;
Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine;
interleukin-2; interleukin-3; insulin-human; insulin lispro; insulin procine;
insulin NPH;
insulin aspart; insulin glargine; insulin detemir; interferon alpha;
interferon beta;
ipratropium bromide; isofosfamide; lamivudine; leucovorin calcium; leuprolide acetate;
lincomycin and lincomycin derivatives; metformin hydrochloride; nedocromil sodium;
neostigmine bromide; neostigmine methyl sulfate; neutontin; octreotide acetate;
olpadronate; panlidronate disodium; pancuronium bromide; pentamindine isethionate;
pentagastrin; physostigmine salicylate; poliovirus vaccine live (OPV);
pyridostigmine bromide; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine;
salmetrol xinafoate; somatostatin; spectinomycin; stavudine; streptokinase; ticarcillin;
tiludronate;
tissue type plasminogen activator, TNFR:Fc; TNK-1PA; trimetrexate gluconate;
trospectinomycin; tumor necrosis factor; typhoid vaccine live; urokinase;
vancomycin;
valaciclovir; vasopressin and vasopressin derivatives; vinblastin;
vincristine; vinorelbine;
warfarin sodium; zalcitabine; zanamavir; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
Most preferred hydrophilic active ingredients include acarbose; alendronate;
amantadine hydrochloride; azithromycin; calcitonin human; calcitonin salmon;
ceftriaxone; cefuroxime axetil; chrionic gonadotropin; cromalyn sodium;
daltaperin sodium; danaproid; desmopressin; didanosine; editronate disodium; enoxaprin sodium;
epoetin alpha; factor IX; famiciclovir; foscarnet sodium; ganciclovir;
granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; growth hormones-recombinant human; growth hormone- Bovine; glucagon; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; heparin sodium;
indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin-human;
insulin lispro; insulin procine interferon alpha; interferon beta; leuprolide acetate;
metformin hydrochloride; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate;
neutontin; octreotide acetate; olpadronate; pamidronate disodium; residronate;
rimantadine hydrochloride; salmetrol xinafoate; somatostatin; stavudine;
ticarcillin;
tiludronate; tissue type plasminogen activator; TNFR:Fc; TNK-tPA; tumor necrosis factor; typhoid vaccine live; vancomycin; valaciclovir; vasopressin and vasopressin derivatives; zalcitabine; zanamavir; zidovudine; pharmaceutically acceptable salts, isomers and derivatives thereof; and mixtures thereof.
2. Surfactants Various embodiments of the invention, as described in more detail below, include a hydrophilic surfactant. Hydrophilic surfactants can be used to provide any of several advantageous characteristics to the compositions, including: increased solubility of the active ingredient in the solid carrier; improved dissolution of the active ingredient;
improved solubilization of the active ingredient upon dissolution; enhanced absorption and/or bioavailability of the active ingredient, particularly a hydrophilic active ingredient; and improved stability, both physical and chemical, of the active ingredient.
The hydrophilic surfactant can be a single hydrophilic surfactant or a mixture of hydrophilic surfactants, and can be ionic or non-ionic.
Likewise, various embodiments of the invention include a lipophilic component, which can be a lipophilic surfactant, including a mixture of lipophilic surfactants, a = triglyceride, or a mixture thereof. The lipophilic surfactant can provide any of the advantageous characteristics listed above for hydrophilic surfactants, as well as further enhancing the function of the surfactants. These various embodiments are described in more detail below. For convenience, the surfactants are described in this section, and the triglycerides in the section that follows.
As is well known in the art, the terms "hydrophilic" and "lipophilic" are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and lipophilicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (the "HLB" value). Surfactants with lower HLB values are more lipophilic, and have greater solubility in oils, whereas surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic surfactants are compounds having an HLB
value less than about 10.
It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. For many important surfactants, including several polyethoxylated surfactants, it has been reported that HLB values can differ by as much as about 8 HLB
units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide containing block copolymers (poloxamers, available commercially as PLURONIC
surfactants, BASF Corp.), the HLB values may not accurately reflect the true physical chemical nature of the compounds. Finally, commercial surfactant products are generally not pure compounds, but are often complex mixtures of compounds, and the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component. Different commercial products having the same primary surfactant component can, and typically do, have different HLB values. In addition, a certain amount of lot-to-lot variability is expected even for a single commercial surfactant product. Keeping these inherent difficulties in mind, and using HLB values as a guide, one skilled in the art can readily identify surfactants having suitable hydrophilicity or lipophilicity for use in the present invention, as described herein.
Surfactants can be any surfactant suitable for use in pharmaceutical compositions.
Suitable surfactants can be anionic, cationic, zwitterionic or non-ionic. Such surfactants can be grouped into the following general chemical classes detailed in the Tables herein.
The HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable.
It should be emphasized that the invention is not limited to the surfactants in the Tables, which show representative, but not exclusive, lists of available surfactants. In addition, refined, distilled or fractionated surfactants, purified fractions thereof, or re-esterified fractions, are also within the scope of the invention, although not specifically listed in the Tables.
2.1. Polyethoxylated Fatty Acids Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have useful surfactant properties. Examples of polyethoxylated fatty acid monoester surfactants commercially available are shown in Table 1.
Table 1: PEG-Fatty Acid Monoester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 4-100 monolaurate Crodet L series (Croda) >9 PEG 4-100 monooleate Crodet 0 series (Croda) >8 PEG 4-100 monostearate Crodet S series (Croda), Myrj Series (Atlas/ICI) >6 PEG 400 distearate Cithrol 4DS series (Croda) >10 PEG 100,200,300 Cithrol ML series (Croda) >10 monolaurate PEG 100,200,300 Cithrol MO series (Croda) >10 monooleate COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 400 dioleate Cithrol 4D0 series (Croda) >10 PEG 400-1000 Cithrol MS series (Croda) >10 monostearate PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster K1 (Condea) 2 PEG-2 stearate Nikkol MYS-2 (Nikko) 4 PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5 PEG-4 laurate Mapeg 200 ML (PPG), Kessco PEG 200ML 9.3 (Stepan), LIPOPEG 2L (LIPO Chem.) PEG-4 oleate MapegE 200 MO (PPG), Kessco PEG200 MO 8.3 (Stepan), PEG-4 stearate Kessco PEG 200 MS (Stepan), Hodag 20 S 6.5 (Calgene), Nikkol MYS-4 (Nikko) PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleate Nikkol TMGO-5 (Nikko) 9.5 PEG-6 oleate Algon OL 60 (Auschem SpA), Kessco PEG 300 8.5 MO (Stepan), Nikko] MYO-6 (Nikko), Emulgante A6 (Condea) PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4 PEG-6 laurate Kessco PEG300 ML (Stepan) 11.4 PEG-7 laurate Lauridac 7 (Condea) 13 PEG-6 stearate Kessco PEG00 MS (Stepan) 9.7 PEG-8 laurate Mapeg 400 ML (PPG), LIPOPEG 4DL(Lipo 13 Chem.) PEG-8 oleate Mapeg 400 MO (PPG), Emulgante AS (Condea); 12 Kessco PEG 400 MO (Stepan) PEG-8 stearate Mapeg 400 MS (PPG), Myrj 45 12 PEG-9 oleate Emulgante A9 (Condea) >10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-9 stearate Cremophor S9 (BASF) >10 PEG-10 laurate Nikkol MYL-1 0 (Nikko), Lauridac 10 (Croda) 13 PEG-10 oleate Nikkol MYO-10 (Nikko) I 1 PEG-10 stearate Nikkol MYS-10 (Nikko), Coster K100 (Condea) 11 PEG-I2 laurate Kessco PEG 600ML (Stepan) 15 PEG-12 oleate Kessco PEG 600MO (Stepan) 14 PEG-12 ricinoleate (CAS # 9004-97-1) >10 PEG-12 stearate Mapeg 600 MS (PPG), Kessco PEG 60OMS 14 (Stepan) PEG-15 stearate Nikkol TMGS-15 (Nikko), Koster K15 (Condea) 14 PEG-15 oleate Nikkol TMGO-1 5 (Nikko) 15 PEG-20 laurate Kessco PEG 1000 ML (Stepan) 17 PEG-20 oleate Kessco PEG 1000 MO (Stepan) 15 PEG-20 stearate Mapeg 1000 MS (PPG), Kessco PEG 1000 MS 16 (Stepan), Myrj 49 PEG-25 stearate Nikkol MYS-25 (Nikko) 15 PEG-32 laurate Kessco PEG 1540 ML (Stepan) 16 PEG-32 oleate Kessco PEG 1540 MO (Stepan) 17 PEG-32 stearate Kessco PEG 1540 MS (Stepan) 17 PEG-30 stearate Myrj 51 >10 PEO-40 laurate Crodet L40 (Croda) 17.9 PEG-40 oleate Crodet 040 (Croda) 17.4 PEG-40 stearate Myrj 52, Emerest 2715 (Henkel), Nikkol MYS- >10 40 (Nikko) PEG-45 stearate Nikko] MYS-45 (Nikko) 18 PEG-50 stearate Myrj 53 >10 WO 01/37808 PCT/tJS00/32255 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-55 stearate Nikkol MYS-55 (Nikko) 18 PEG-100 oleate Crodet 0-100 (Croda) 18.8 PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19 PEG-200 oleate Albunol 200 MO (Taiwan Surf:) >10 PEG-400 oleate LACTOMUL (Henkel), Albunol 400 MO (Taiwan >10 Surf.) PEG-600 oleate Albunol 600 MO (Taiwan Surf.) >10 2.2 PEG-Fatty Acid Diesters Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention. Representative PEG-fatty acid diesters are shown in Table 2.
Table 2: PEG-Fatty Acid Diester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-4 dilaurate Mapeg 200 DL (PPG), Kessco PEG 200 DL 7 (Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4 dioleate Mapeg 200 DO (PPG), 6 PEG-4 distearate Kessco 200 DS (Stepan) 5 PEG-6 dilaurate Kessco PEG 300 DL (Stepan) 9.8 PEG-6 dioleate Kessco PEG 300 DO (Stepan) 7.2 PEG-6 distearate Kessco PEG 300 DS (Stepan) 6.5 PEG-8 dilaurate Mapeg 400 DL (PPG), Kessco PEG 400 DL 11 (Stepan), LIPOPEG 4 DL (Lipo Chem.) PEG-8 dioleate Mapeg 400 DO (PPG), Kessco PEG 400 DO 8.8 (Stepan), LIPOPEG 4 DO(Lipo Chem.) -------------COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-8 distearate Mapeg 400 DS (PPG), CDS 400 (Nikkol) 11 PEG-10 dipalmitate Polyaldo 2PKFG >10 PEG-12 dilaurate Kessco PEG 600 DL (Stepan) 11.7 PEG-12 distearate Kessco PEG 600 DS (Stepan) 10.7 PEG-12 dioleate Mapeg D 600 DO (PPG), Kessco 600 10 DO(Stepan) PEG-20 dilaurate Kessco PEG 1000 DL (Stepan) 15 PEG-20 dioleate Kessco PEG 1000 DO (Stepan) 13 PEG-20 distearate Kessco PEG 1000 DS (Stepan) 12 PEG-32 dilaurate Kessco PEG 1540 DL (Stepan) 16 PEG-32 dioleate Kessco PEG 1540 DO (Stepan) 15 PEG-32 distearate Kessco PEG 1540 DS (Stepan) 15 PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series (Croda) >10 2.3 PEG-Fatty Acid Mono- and Di-ester Mixtures In general, mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products. Several PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters.
Representative surfactant mixtures are shown in Table 3.
Table 3: PEG-Fatty Acid Mono- and Diester Mixtures COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 4-150 mono, dilaurate Kessco PEG 200-6000 mono, dilaurate (Stepan) PEG 4-150 mono, dioleate Kessco PEG 200-6000 mono, dioleate (Stepan) PEG 4-150 mono, Kessco 200-6000 mono, distearate (Stepan) distearate 2.4 Polyethylene Glycol Glycerol Fatty Acid Esters Suitable PEG glycerol fatty acid esters are shown in Table 4.
Table 4: PEG Glycerol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-20 glyceryl laurate Tagat L (Goldschmidt) 16 PEG-30 glyceryl laurate Tagat L2 (Goldschmidt) 16 PEG-15 glyceryl laurate Glycerox L series (Croda) 15 PEG-40 glyceryl laurate Glycerox L series (Croda) 15 PEG-20 glyceryl stearate Capmul EMG (ABITEC), Aldo MS-20 KFG (Lonna) 13 PEG-20 glyceryl oleate Tagat 0 (Goldschmidt) >10 PEG-30 glyceryl oleate Tagat 02 (Goldschmidt) >10 2.5. Alcohol - Oil Transesterification Products A large number of surfactants of different degrees of lipophilicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils. Most commonly, the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil. Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol.
Representative surfactants of this class suitable for use in the present invention are shown in Table 5.
Table 5: Transesterification Products of Oils and Alcohols COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-3 castor oil Nikkol CO-3 (Nikko) 3 PEG-5, 9, and 16 castor oil ACCONON CA series (ABITEC) 6-7 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikko! CO-20 i 1 TX (Nikko) PEG-23 castor oil Emulgante EL23 >10 PEG-30 castor oil Emalex C-30 (Nihon Emulsion), Alkamuls EL 11 620 (Rhone-Poulenc), Incrocas 30 (Croda) PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulgin RO 35 (Henkel) PEG-38 castor oil Emulgante EL 65 (Condea) PEG-40 castor oil Emalex C-40 (Nihon Emulsion), Alkamuls EL 13 719 (Rhone-Poulenc) PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14 PEG-56 castor oil Eumulgin PRT 56 (Pulcra SA) >10 PEG-60 castor oil Nikko! CO-60TX (Nikko) 14 PEG-100 castor oil Thornley >10 PEG-200 castor oil Eumulgin PRT 200 (Pulcra SA) >10 PEG-5 hydrogenated castor Nikkol HCO-5 (Nikko) 6 oil PEG-7 hydrogenated castor Simusol 989 (Seppic), Cremophor WO7 6 oil (BASF) PEG-10 hydrogenated castor Nikkol HCO-10 (Nikko) 6.5 oil PEG-20 hydrogenated castor Nikkol HCO-20 (Nikko) 11 oil PEG-25 hydrogenated castor Simulsol 1292 (Seppic), Cerex ELS 250 11 oil (Auschem SpA) PEG-30 hydrogenated castor Nikkol HCO-30 (Nikko) 11 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
oil PEG-40 hydrogenated castor Cremophor RH 40 (BASF), Croduret (Croda), 13 oil Emulgin HRE 40 (Henkel) PEG-45 hydrogenated castor Cerex ELS 450 (Auschem Spa) 14 oil PEG-50 hydrogenated castor Emalex HC-50 (Nihon Emulsion) 14 oil PEG-60 hydrogenated castor Nikkol HCO-60 (Nikko); Cremophor RH 60 15 oil (BASF) PEG-80 hydrogenated castor Nikkol HCO-80 (Nikko) 15 oil PEG-100 hydrogenated castor Nikkol HCO -100 (Nikko)' 17 oil PEG-6 corn oil Labrafil M 2125 CS (Gattefosse) 4 PEG-6 almond oil Labrafil M 1966 CS (Gattefosse) 4 PEG-6 apricot kernel oil Labrafil M 1944 CS (Gattefosse) 4 PEG-6 olive oil Labrafil M 1980 CS (Gattefosse) 4 PEG-6 peanut oil Labrafil M 1969 CS (Gattefosse) 4 PEG-6 hydrogenated palm Labrafil M 2130 BS (Gattefosse) 4 kernel oil PEG-6 palm kernel oil Labrafil M 2130 CS (Gattefosse) 4 PEG-6 triolein Labrafil M 2735 CS (Gattefosse) 4 PEG-8 corn oil Labrafil WL 2609 BS (Gattefosse) 6-7 PEG-20 corn glycerides Crovol M40 (Croda) 10 PEG-20 almond glycerides Crovol A40 (Croda) 10 PEG-25 trioleate TAGAT TO (Goldschmidt) 11 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-40 palm kernel oil Crovol PK-70 >10 PEG-60 corn glycerides Crovol M70(Croda) 15 PEG-60 almond glycerides Crovol A70 (Croda) 15 PEG-4 caprylic/capric Labrafac Hydro (Gattefosse), 4-5 triglyceride PEG-8 caprylic/capric Labrasol (Gattefosse),Labrafac CM 10 >10 glycerides (Gattefosse) PEG-6 caprylic/capric SOFTIGEN 767 (Hills), Glycerox 767 (Croda) 19 glycerides ' Lauroyl macrogol-32 GELUCIRE 44/14 (Gattefosse) 14 glyceride Stearoyl macrogol glyceride GELUCIRE 50/13 (Gattefosse) 13 Mono, di, tri, tetra esters of SorbitoGlyceride (Gattefosse) <10 vegetable oils and sorbitol Pentaerythrityl tetraisostearate Crodamol PTIS (Croda) <10 Pentaerythrityl distearate Albunol DS (Taiwan Surf.) <10 Pentaerythrityl tetraoleate Liponate P0-4 (Lipo Chem.) <10 Pentaerythrityl tetrastearate Liponate PS-4 (Lipo Chem.) <10 Pentaerythrityl Liponate PE-810 (Lipo Chem.), Crodamol PTC <10 tetracaprylate/tetracaprate (Croda) Pentaerythrityl tetraoctanoate Nikkol Pentarate 408 (Nikko) 2.6. Polyglycerized Fatty Acids Polyglycerol esters of fatty acids are also suitable surfactants for the present invention. Examples of suitable polyglyceryl esters are shown in Table 6.
CA
Table 6: Polyglycerized Fatty. Acids COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7 Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 isostearate Nikkol DGMIS (Nikko) 5-7 Polyglyceryl-3 oleate Caprol 3G0 (ABITEC), Drewpol 3-1-0 (Stepan) 6.5 Polyglyceryl-4 oleate Nikkol Tetraglyn 1-0 (Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6-1-0 (Stepan), Nikkol Hexaglyn 1-0 9 (Nikko) Polyglyceryl-10 laurate Nikkol Decaglyn i -L (Nikko) 15 Polyglyceryl-10 oleate Nikkol Decaglyn 1-0 (Nikko) 14 Polyglyceryi-10 stearate Nikkol Decaglyn 1-S (Nikko) 12 Polyglyceryl-6 ricinoleate Nikkol Hexaglyn PR-15 (Nikko) >8 Polyglyceryl- 10 linoleate Nikkol Decaglyn I -LN (Nikko) 12 Polyglyceryi-6 pentaoleate Nikkol Hexaglyn 5-0 (Nikko) <10 Polyglyceryl-3 dioleate Cremophor 0032 (BASF) <10 Polyglyceryl-3 distearate Cremophor GS32 (BASF) <10 PolygIyceryl-4 pentaoleate Nikkol Tetraglyn 5-0 (Nikko) <10 Polyglyceryl-6 dioleate Caprol 6G20 (ABITEC); Hodag PGO-62 (Calgene), 8.5 PLUROL OLEIQUE CC 497 (Gattefosse) Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7 Polyglyceryl-10 trioleate Nikkol Decaglyn 3-0 (Nikko) 7 Polyglyceryl-10 Nikkol Decaglyn 5-0 (Nikko) 3.5 pentaoleate Polyglyceryl-10 Nikkol Decaglyn 7-0 (Nikko) 3 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
septaoleate Polyglyceryl-10 tetraoleate Caprol 1OG40 (ABITEC); Hodag POO-62 6.2 (CALGENE), Drewpol 10-4-0 (Stepan) Polyglyceryl-10 ikkol Decaglyn 10-IS (Nikko) <10 decaisostearate Polyglyceryl-101 Drewpol 10-10-0 (Stepan), Caprol IOG100 . 3.5 decaoleate (ABITEC), Nikkol Decaglyn 10-0 PolyglyceryI-10 mono, Caprol PGE 860 (ABITEC) 1 I
dioleate Polyglyceryl Polymuls (Henkel) 3-20 polyricinoleate 2.7. Propylene Glycol Fatty Acid Esters Esters of propylene glycol and fatty acids are suitable surfactants for use in the present invention. Examples of surfactants of this class are given in Table 7.
Table 7: Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Propylene glycol Capryol 90 (Gattefosse), Nikko! Sefsol 218 (Nikko) <10 monocaprylate Propylene glycol Lauroglycol 90 (Gattefosse), Lauroglycol FCC <10 monolaurate (Gattefosse) Propylene glycol oleate Lutrol OP2000 (BASF) <10 Propylene glycol myristate Mirpyl <10 Propylene glycol ADM PGME-03 (ADM), LIPO PGMS (Lipo 3-4 monostearate Chem.), Aldo PGHMS (Lonza) Propylene glycol hydroxy stearate <10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Propylene glycol PROPYMULS (Henkel) <10 ricinoleate Propylene glycol <10 isostearate Propylene glycol Myverol P-06 (Eastman) <10 monooleate Propylene glycol Captex 200 (ABITEC), Miglyol 840 (Hills), >6 dicaprylate/dicaprate Neobee M-20 (Stepan) Propylene glycol Captex 800 (ABITEC) >6 dioctanoate Propylene glycol LABRAFAC PG (Gattefosse) >6 caprylate/caprate Propylene glycol dilaurate >6 Propylene glycol distearate Kessco PGDS (Stepan) >6 Propylene glycol Nikkol Sefsol 228 (Nikko) >6 dicaprylate Propylene glycol dicaprate Nikkol PDD (Nikko) >6 2.8. Mixtures of Propylene Glycol Esters - Glycerol Esters In general, mixtures of surfactants are also suitable for use in the present invention. In particular, mixtures of propylene glycol fatty acid esters and glycerol fatty acid esters are suitable and are commercially available. Examples of these surfactants are shown in Table 8.
Table 8: Glycerol/Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB=
Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4 Stearic ATMOS 150 3-4 2.9. Mono- and Diglycerides A particularly important class of surfactants is the class of mono- and diglycerides. These surfactants are generally lipophilic. Examples of these surfactants are given in Table 9.
Table 9: Mono- and Diglyceride Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Monopalmitolein (C16:1) (Larodan) <10 Monoelaidin (C18:1) (Larodan) <10 Monocaproin (C6) (Larodan) <10 Monocaprylin (Larodan) <10 Monocaprin (Larodan) <10 Monolaurin (Larodan) <10 Glyceryl monomyristate Nikkol MGM (Nikko) 3-4 (C14) Glyceryl monooleate PECEOL (Gattefosse), Hodag GMO-D, Nikkol 3-4 (C18:1) MGO (Nikko) Glyceryl monooleate RYLO series (Danisco), DIMODAN series 3-4 (Danisco), EMULDAN (Danisco), ALDOO
MO FG (Loma), Kessco GMO (Stepan), MONOMULSO series (Henkel), TEGIN 0, DREWMULSE GMO (Stepan), Atlas 0-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
40, 70, and 100 (ADM), Myverol (Eastman) Glycerol OLICINE (Gattefosse) 3-4 monooleate/linoleate Glycerol monolinoleate Maisine (Gattefosse), MYVEROL 18-92, 3-4 Myverol 18-06 (Eastman) Glyceryl ricinoleate Softigen 701 (Hills), HODAG GMR-D 6 (Calgene), ALDO MR (Lonza) Glyceryl monolaurate ALDO MLD (Loma), Hodag GML (Calgene) 6.8 Glycerol monopalmitate Emalex GMS-P (Nihon) 4 Glycerol monostearate Capmul GMS (ABITEC), Myvaplex 5-9 (Eastman), IMWITOR 191 (Hills), CUTINA GMS, Aldo MS (Loma), Nikko]
MGS series (Nikko) Glyceryl mono-,dioleate Capmul GMO-K (ABITEC) <10 Glyceryl palmitic/stearic CUTINA MD-A, ESTAGEL-G 18 <10 Glyceryl acetate Lamegin EE (Grunau GmbH) <10 Glyceryl laurate Imwitor 312 (Hills), Monomuls 90-45 4 (Griinau GmbH), Aldo MLD (Lonna) Glyceryl Imwitor 375 (Hills) <10 citrate/lactate/oleate/
linoleate Glyceryl caprylate Imwitor 308 (Hills), Capmul MCMCB 5-6 (ABITEC) Glyceryl caprylate/caprate Capmul MCM (ABITEC) 5-6 Caprylic acid Imwitor 988 (Hills) 5-6 mono,diglycerides Caprylic/capric glycerides Imwitor 742 (Hills) <10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Mono-and diacetylated Myvacet 9-45, Myvacet 9-40, Myvacet 9- 3.8-4 monoglycerides 08 (Eastman), Lamegin (Grunau) Glyceryl monostearate Aldo MS, Arlacel 129 (ICI), LIPO GMS (Lipo 4.4 Chem.), Imwitor 191 (Hills), Myvaplex (Eastman) Lactic acid esters of . LAMEGIN GLP (Henkel) <10 mono,diglycerides Dicaproin (C6) (Larodan) <10 Dicaprin (C10) (Larodan) <10 Dioctanoin (C8) (Larodan) <10 Dimyristin (C14) (Larodan) <10 Dipalmitin (CI6) (Larodan) <10 Distearin (Larodan) <10 Glyceryl dilaurate (C12) Capmul GDL (ABITEC) 3-4 GlyeeryI dioleate Capmul GDO (ABITEC) 3-4 Glycerol esters of fatty GELUCIRE 39/01 (Gattefosse), GELUCIRE I
acids 43/01 (Gattefosse) .
GELUCIRE 37/06 (Gattefosse) 6 Dipalmitolein (C 16:1) (Larodan) <10 1,2 and 1,3-diolein (C18:1) (Larodan) <10 Dielaidin (C 18:1) (Larodan) <10 Dilinolein (C 18:2) (Larodan) <10 2.10. Sterol and Sterol Derivatives Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or lipophilic. Examples of surfactants of this class are shown in Table 10.
Table 10: Sterol and Sterol Derivative Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Cholesterol, sitosterol, <10 lanosterol PEG-24 cholesterol ether Solulan C-24 (Amerchol) >10 PEG-30 cholestanol Nikkol DHC (Nikko) >10 Phytosterol GENEROL series (Henkel) <10 PEG-25 phyto sterol Nikkol BPSH-25 (Nikko) >10 PEG-5 soya sterol Nikkol BPS-5 (Nikko) <10 PEG-10 soya sterol Nikkol BPS-I0 (Nikko) <10 PEG-20 soya sterol Nikkol BPS-20 (Nikko) <10 PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10 2.11. Polyethylene Glycol Sorbitan Fatty Acid Esters A variety of PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention. In general, these surfactants are hydrophilic, although several lipophilic surfactants of this class can be used. Examples of these surfactants are shown in Table 11.
Table 11: PEG-Sorbitan Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10 PEG-20 sorbitan Tween-20 (Atlas/ICI), Crillet I (Croda), DACOL 17 monolaurate MLS 20 (Condea) PEG-4 sorbitan Tween-21 (Atlas/ICI), Crillet l 1 (Croda) 13 monolaurate PEG-80 sorbitan Hodag PSML-80 (Calgene); T-Maz 28 >10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
monolaurate PEG-6 sorbitan Nikko! GL-1 (Nikko) 16 monolaurate PEG-20 sorbitan Tween-40 (Atlas/ICI), Crillet 2 (Croda) 16 monopalmitate PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 (Croda) 15 monostearate PEG-4 sorbitan Tween-61 (Atlas/ICI), Crillet 31 (Croda) 9.6 monostearate PEG-8 sorbitan DACOL MSS (Condea) >10 monostearate PEG-6 sorbitan Nikkol TS 106 (Nikko) 11 monostearate PEG-20 sorbitan tristearate Tween-65 (Atlas/ICI), Crillet 35 (Croda) 11 PEG-6 sorbitan Nikkol GS-6 (Nikko) 3 tetrastearate PEG-60 sorbitan Nikko! GS-460 (Nikko) 13 tetrastearate PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), Crillet 41 (Croda) 10 PEG-6 sorbitan monooleate Nikkol TO- 106 (Nikko) 10 PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 (Croda) 15 monooleate PEG-40 sorbitan oleate Emalex ET 8040 (Nihon Emulsion) 18 PEG-20 sorbitan trioleate Tween-85 (Atlas/ICI), Crillet 45 (Croda) 11 PEG-6 sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleate Nikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikko! GO-440 (Nikko) 13 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-20 sorbitan Tween-120 (Atlas/ICI), Crillet 6 (Croda) >10 monoisostearate PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10 PEG-6 sorbitol Nikko] GS-6 (Nikko) 3 hexastearate 2.12. Polyethylene Glycol Alkyl Ethers Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 12.
Table 12: Polyethylene Glycol Alkyl Ethers COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-2 oleyl ether,oleth-2 Brij 92/93 (Atlas/ICI) . 4.9 PEG-3 oleyl ether,oleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether,oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl ether,oleth- Volpo 10 (Croda), Brij 96/97 (Atlas/ICI) 12 PEG-20 oleyl ether,oleth- Volpo 20 (Croda), Brij 98/99 (Atlas/ICI) 15 PEG-4 lauryl ether, Brij 30 (Atlas/ICI) 9.7 laureth-4 PEG-9 lauryl ether >10 PEG-23 lauryl ether, Brij 35 (Atlas/ICI) 17 laureth-23 PEG-2 cetyl ether Brij 52 (ICI) 5.3 C
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-10 cetyl ether Brij 56 (ICI) 13 PEG-20 cetyl ether Brij 58 (ICI) 16 PEG-2 stearyl ether Brij 72 (ICI) 4.9 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-20 stearyl ether Brij 78 (ICI) 15 PEG-100 stearyl ether Brij 700 (IC1) >10 2.13. Sugar Esters Esters of sugars are suitable surfactants for use in the present invention.
Examples of such surfactants are shown in Table 13.
Table 13: Sugar Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Sucrose distearate SUCRO ESTER 7 (Gattefosse), Crodesta F-10 3 (Croda) Sucrose SUCRO ESTER I 1 (Gattefosse), Crodesta F-110 12 distearate/monostearate (Croda) Sucrose dipalmitate 7.4 Sucrose monostearate Crodesta F-160 (Croda) 15 Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10 Sucrose monolaurate Saccharose monolaurate 1695 (Mitsubishi-Kasei) 15 2.14. Polyethylene Glycol Alkyl Phenols Several hydrophilic PEG-alkyl phenol surfactants are available, and are suitable 1o for use in the present invention. Examples of these surfactants are shown in Table 14.
Table 14: Polyethylene Glycol Alkyl Phenol Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-10-100 nonyl phenol Triton X series (Rohm & Haas), Igepal CA series >10 (GAF, USA), Antarox CA series (GAF, UK) PEG-15-100 octyl phenol Triton N-series (Rohm & Haas), Igepal CO series >10 ether (GAF, USA), Antarox CO series (GAF, UK) 2.15. Polyoxyethylene-Polyoxypropylene Block Copolymers The POE-POP block copolymers are a unique class of polymeric surfactants.
The unique structure of the surfactants, with hydrophilic POE and lipophilic POP
moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention. These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these polymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula:
HO(C2H40)a(C3H60)b(C2H40)aH
where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene units, respectively.
Examples of suitable surfactants of this class are shown in Table 15. Since the compounds are widely available, commercial sources are not listed in the Table. The compounds are listed by generic name, with the corresponding "a" and "b"
values.
Table 15: POE-POP Block Copolymers COMPOUND a, b values in HO(C2mO).(C3H6O)b(C2H4O).H HLB
Poloxamer 105 a=11 b=16 8 Poloxamer 108 a=46 b=16 >10 Poloxamer 122 a=5 b=21 3 Poloxamer 123 a=7 b=21 COMPOUND a, b values in HO(C2H40)a(C3H6O)b(C2H40)aH HLB
Poloxamer 124 a= 11 b=21 >7 Poloxamer 181 a=3 b=30 Poloxamer 1 82 a=8 b=30 2 Poloxamer 183 a*=10 b=30 Poloxamer 184 a-13 b=30 Poloxamer 185 a=19 b=30 Poloxamer 188 a = 75 b=30 29 Poloxamer 212 a=8 b=35 Poloxamer 215 a=24 b=35 Poloxamer 217 a=52 b=35 Poloxamer 231 a= 16 b=39 Poloxamer 234 a = 22 b=39 Poloxamer 235 a = 27 b=39 Poloxamer 237 a = 62 b=39 24 Poloxamer 238 a = 97 b=39 Poloxamer 282 a= 10 b=47 Poloxamer 284 a = 21 b=47 Poloxamer 288 a= 122 b=47 >10 Poloxamer 331 a=7 b = 54 0.5 Poloxamer 333 a = 20 b=54 Poloxamer 334 a=31 b = 54 Poloxamer 335 a=38 b=54 Poloxamer 338 a= 128 b = 54 Poloxamer 401 a=6 b=67 Poloxamer 402 a =13 b=67 COMPOUND a, b values in HO(C2H4O)a(C3H6O)b(C2H4O)aH HLB
Poloxamer 403 a=21 b=67 Poloxamer 407 a=98 b=67 2.16. Sorbitan Fatty Acid Esters Sorbitan esters of fatty acids are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 16.
Table 16: Sorbitan Fatty Acid Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Sorbitan monolaurate Span-20 (Atlas/ICI), Crill I (Croda), Arlacel 20 8.6 (ICJ) Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), Nikko! SP- 6.7 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Cri114 (Croda), Cri1150 4.3 (Croda) Sorbitan monostearate Span-60 (Atlas/ICI), Cri113 (Croda), Nikko! SS- 4.7 10 (Nikko) Sorbitan trioleate Span-85 (Atlas/ICI), Cri1145 (Croda), Nikko! SO- 4.3 30 (Nikko) Sorbitan sesquioleate Arlacel-C (ICI), Cri1143 (Croda), Nikko! SO-15 3.7 (Nikko) Sorbitan tristearate Span-65 (Atlas/ICI) Crill 35 (Croda), Nikkol SS- 2.1 30 (Nikko) Sorbitan monoisostearate Crill 6 (Croda), Nikko! SI-10 (Nikko) 4.7 Sorbitan sesquistearate Nikko! SS-15 (Nikko) 4.2 2.17. Lower Alcohol Fatty Acid Esters Esters of lower alcohols (C2 to C4) and fatty acids (C$ to C,$) are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 17.
Table 17: Lower Alcohol Fatty Acid Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Ethyl oleate Crodamol EO (Croda), Nikkol EOO (Nikko) <10 Isopropyl myristate Crodamol IPM (Croda) <10 Isopropyl palmitate Crodamol IPP (Croda) <10 Ethyl linoleate Nikkol VF-E (Nikko) <10 Isopropyl linoleate Nikkol VF-IP (Nikko) <10 2.18. Ionic Surfactants Ionic surfactants, including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention. Preferred anionic surfactants include fatty acid salts and bile salts. Preferred cationic surfactants include carnitines. Specifically, preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl camitine; palmitoyl carnitine; and myristoyl camitine.
Examples of such surfactants are shown in Table 18. For simplicity, typical counterions are shown in the entries in the Table. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium. Unlike typical non-ionic surfactants, these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table.
-------- ---- -- --Table 18: Ionic Surfactants COMPOUND HLB
FATTY ACID SALTS >10 Sodium caproate Sodium caprylate Sodium caprate Sodium laurate Sodium myristate Sodium myristolate Sodium palmitate Sodium palmitoleate Sodium oleate 18 Sodium ricinoleate Sodium linoleate Sodium linolenate Sodium stearate Sodium lauryl sulfate (dodecyl) 40 Sodium tetradecyl sulfate Sodium lauryl sarcosinate Sodium dioctyl sulfosuccinate [sodium docusate (Cytec)]
BILE SALTS >10 Sodium cholate Sodium taurocholate Sodium glycocholate Sodium deoxycholate COMPOUND HLB
Sodium taurodeoxycholate Sodium glycodeoxycholate Sodium ursodeoxycholate Sodium chenodeoxycholate Sodium taurochenodeoxycholate Sodium glyco cheno *deoxycholate Sodium cholylsarcosinate Sodium N-methyl taurocholate Sodium lithocholate PHOSPHOLIPIDS
Egg/Soy lecithin [EpikuronTM (Lucas Meyer), OvothinTM
(Lucas Meyer)]
Lyso egg/soy lecithin Hydroxylated lecithin Lysophosphatidylcholine Cardiolipin Sphingomyelin Phosphatidylcholine Phosphatidyl ethanolamine Phosphatidic acid Phosphatidyl glycerol Phosphatidyl serine PHOSPHORIC ACID ESTERS
Diethanolammonium polyoxyethylene-10 oleyl ether phosphate Esterification products of fatty alcohols or fatty alcohol COMPOUND HLB
ethoxylates with phosphoric acid or anhydride CARBOXYLATES
Ether carboxylates (by oxidation of terminal OH group of fatty alcohol ethoxylates) Succinylated monoglycerides [LAMEGIN ZE (Henkel)]
Sodium stearyl fumarate Stearoyl propylene glycol hydrogen succinate Mono/diacetylated tartaric acid esters of mono- and diglycerides Citric acid esters of mono-, diglycerides Glyceryl-lacto esters of fatty acids (CFR ref. 172.852) Acyl lactylates:
lactylic esters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate salts Propylene glycol alginate SULFATES AND SULFONATES
Ethoxylated alkyl sulfates Alkyl benzene sulfones a-olefin sulfonates Acyl isethionates Acyl taurates Alkyl glyceryl ether sulfonates Octyl sulfosuccinate disodium Disodium undecylenamideo-MEA-sulfosuccinate COMPOUND HLB
CATIONIC Surfactants >10 Lauroyl carnitine Palmitoyl carnitine Myristoyl carnitine Hexadecyl triammonium bromide Decyl trimethyl ammonium bromide Cetyl trimethyl ammonium bromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium salts Diisobutyl phenoxyethoxydimethyl benzylammonium salts Alkylpyridinium salts Betaines (trialkylglycine):
Lauryl betaine (N-lauryl,N,N-dimethylglycine) Ethoxylated amines:
Polyoxyethyl ene-15 coconut amine 2.19 Unionized Ionizable Surfactants Ionizable surfactants, when present in their unionized (neutral, non-salt) form, are lipophilic surfactants suitable for use in the compositions of the present invention.
Particular examples of such surfactants include free fatty acids, particularly C6-C22 fatty acids, and bile acids. More specifically, suitable unionized ionizable surfactants include the free fatty acid and bile acid forms of any of the fatty acid salts and bile salts shown in Table 18.
2.20 Derivatives of Fat-Soluble Vitamins Derivatives of oil-soluble vitamins, such as vitamins A, D, E, K, etc., are also useful surfactants for the compositions of the present invention. An example of such a derivative is tocopheryl PEG-1000 succinate (TPGS, available from Eastman).
2.21 Preferred Surfactants Among the above-listed surfactants, several surfactants are preferred. In general, surfactants or mixtures of surfactants that solidify at ambient room temperature are most preferred. Also preferred are surfactants or mixtures of surfactants that solidify at ambient room temperature in combination with particular lipophilic components, such as triglycerides, or with addition of appropriate additives, such as viscosity modifiers, binders, thickeners, and the like.
Preferred non-ionic hydrophilic surfactants include alkylglucosides;
alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;
polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters;
polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters;
polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof;
polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils;
reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides;
polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.
More preferably, the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters;
polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters;
polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. The glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.
Also preferred are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols.
These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products. The polyol is s preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
The hydrophilic surfactant can also be, or include as a component, an ionic surfactant. Preferred ionic surfactants include alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids;
sodium docusate; carnitines; and mixtures thereof.
More preferable ionic surfactants include bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate;-acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides;
succinylated monoglycerides; citric acid esters of mono-,diglycerides; carnitines; and mixtures thereof.
More specifically, preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
Particularly preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof, with the most preferred ionic surfactants being lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
Preferred lipophilic surfactants are alcohols; polyoxyethylene alkylethers;
fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters;
lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives;
sugar esters;
sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
As with the hydrophilic surfactants, lipophilic surfactants can be reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
Preferably, the lipophilic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters;
polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides;
sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; potyoxyethylene vegetable oils;
polyoxyethylene hydrogenated vegetable oils; and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
More preferred are lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters;
acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides;
sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof, with glycerol fatty acid esters and acetylated glycerol fatty acid esters being most preferred. Among the glycerol fatty acid esters, the esters are preferably mono- or diglycerides, or mixtures of mono-and diglycerides, where the fatty acid moiety is a C6 to C22 fatty acid.
Also preferred are lipophilic surfactants which are the reaction mixture of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
Preferred polyols are polyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.
improved solubilization of the active ingredient upon dissolution; enhanced absorption and/or bioavailability of the active ingredient, particularly a hydrophilic active ingredient; and improved stability, both physical and chemical, of the active ingredient.
The hydrophilic surfactant can be a single hydrophilic surfactant or a mixture of hydrophilic surfactants, and can be ionic or non-ionic.
Likewise, various embodiments of the invention include a lipophilic component, which can be a lipophilic surfactant, including a mixture of lipophilic surfactants, a = triglyceride, or a mixture thereof. The lipophilic surfactant can provide any of the advantageous characteristics listed above for hydrophilic surfactants, as well as further enhancing the function of the surfactants. These various embodiments are described in more detail below. For convenience, the surfactants are described in this section, and the triglycerides in the section that follows.
As is well known in the art, the terms "hydrophilic" and "lipophilic" are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and lipophilicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (the "HLB" value). Surfactants with lower HLB values are more lipophilic, and have greater solubility in oils, whereas surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic surfactants are compounds having an HLB
value less than about 10.
It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. For many important surfactants, including several polyethoxylated surfactants, it has been reported that HLB values can differ by as much as about 8 HLB
units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide containing block copolymers (poloxamers, available commercially as PLURONIC
surfactants, BASF Corp.), the HLB values may not accurately reflect the true physical chemical nature of the compounds. Finally, commercial surfactant products are generally not pure compounds, but are often complex mixtures of compounds, and the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component. Different commercial products having the same primary surfactant component can, and typically do, have different HLB values. In addition, a certain amount of lot-to-lot variability is expected even for a single commercial surfactant product. Keeping these inherent difficulties in mind, and using HLB values as a guide, one skilled in the art can readily identify surfactants having suitable hydrophilicity or lipophilicity for use in the present invention, as described herein.
Surfactants can be any surfactant suitable for use in pharmaceutical compositions.
Suitable surfactants can be anionic, cationic, zwitterionic or non-ionic. Such surfactants can be grouped into the following general chemical classes detailed in the Tables herein.
The HLB values given in the Tables below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable.
It should be emphasized that the invention is not limited to the surfactants in the Tables, which show representative, but not exclusive, lists of available surfactants. In addition, refined, distilled or fractionated surfactants, purified fractions thereof, or re-esterified fractions, are also within the scope of the invention, although not specifically listed in the Tables.
2.1. Polyethoxylated Fatty Acids Although polyethylene glycol (PEG) itself does not function as a surfactant, a variety of PEG-fatty acid esters have useful surfactant properties. Examples of polyethoxylated fatty acid monoester surfactants commercially available are shown in Table 1.
Table 1: PEG-Fatty Acid Monoester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 4-100 monolaurate Crodet L series (Croda) >9 PEG 4-100 monooleate Crodet 0 series (Croda) >8 PEG 4-100 monostearate Crodet S series (Croda), Myrj Series (Atlas/ICI) >6 PEG 400 distearate Cithrol 4DS series (Croda) >10 PEG 100,200,300 Cithrol ML series (Croda) >10 monolaurate PEG 100,200,300 Cithrol MO series (Croda) >10 monooleate COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 400 dioleate Cithrol 4D0 series (Croda) >10 PEG 400-1000 Cithrol MS series (Croda) >10 monostearate PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster K1 (Condea) 2 PEG-2 stearate Nikkol MYS-2 (Nikko) 4 PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5 PEG-4 laurate Mapeg 200 ML (PPG), Kessco PEG 200ML 9.3 (Stepan), LIPOPEG 2L (LIPO Chem.) PEG-4 oleate MapegE 200 MO (PPG), Kessco PEG200 MO 8.3 (Stepan), PEG-4 stearate Kessco PEG 200 MS (Stepan), Hodag 20 S 6.5 (Calgene), Nikkol MYS-4 (Nikko) PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleate Nikkol TMGO-5 (Nikko) 9.5 PEG-6 oleate Algon OL 60 (Auschem SpA), Kessco PEG 300 8.5 MO (Stepan), Nikko] MYO-6 (Nikko), Emulgante A6 (Condea) PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4 PEG-6 laurate Kessco PEG300 ML (Stepan) 11.4 PEG-7 laurate Lauridac 7 (Condea) 13 PEG-6 stearate Kessco PEG00 MS (Stepan) 9.7 PEG-8 laurate Mapeg 400 ML (PPG), LIPOPEG 4DL(Lipo 13 Chem.) PEG-8 oleate Mapeg 400 MO (PPG), Emulgante AS (Condea); 12 Kessco PEG 400 MO (Stepan) PEG-8 stearate Mapeg 400 MS (PPG), Myrj 45 12 PEG-9 oleate Emulgante A9 (Condea) >10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-9 stearate Cremophor S9 (BASF) >10 PEG-10 laurate Nikkol MYL-1 0 (Nikko), Lauridac 10 (Croda) 13 PEG-10 oleate Nikkol MYO-10 (Nikko) I 1 PEG-10 stearate Nikkol MYS-10 (Nikko), Coster K100 (Condea) 11 PEG-I2 laurate Kessco PEG 600ML (Stepan) 15 PEG-12 oleate Kessco PEG 600MO (Stepan) 14 PEG-12 ricinoleate (CAS # 9004-97-1) >10 PEG-12 stearate Mapeg 600 MS (PPG), Kessco PEG 60OMS 14 (Stepan) PEG-15 stearate Nikkol TMGS-15 (Nikko), Koster K15 (Condea) 14 PEG-15 oleate Nikkol TMGO-1 5 (Nikko) 15 PEG-20 laurate Kessco PEG 1000 ML (Stepan) 17 PEG-20 oleate Kessco PEG 1000 MO (Stepan) 15 PEG-20 stearate Mapeg 1000 MS (PPG), Kessco PEG 1000 MS 16 (Stepan), Myrj 49 PEG-25 stearate Nikkol MYS-25 (Nikko) 15 PEG-32 laurate Kessco PEG 1540 ML (Stepan) 16 PEG-32 oleate Kessco PEG 1540 MO (Stepan) 17 PEG-32 stearate Kessco PEG 1540 MS (Stepan) 17 PEG-30 stearate Myrj 51 >10 PEO-40 laurate Crodet L40 (Croda) 17.9 PEG-40 oleate Crodet 040 (Croda) 17.4 PEG-40 stearate Myrj 52, Emerest 2715 (Henkel), Nikkol MYS- >10 40 (Nikko) PEG-45 stearate Nikko] MYS-45 (Nikko) 18 PEG-50 stearate Myrj 53 >10 WO 01/37808 PCT/tJS00/32255 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-55 stearate Nikkol MYS-55 (Nikko) 18 PEG-100 oleate Crodet 0-100 (Croda) 18.8 PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19 PEG-200 oleate Albunol 200 MO (Taiwan Surf:) >10 PEG-400 oleate LACTOMUL (Henkel), Albunol 400 MO (Taiwan >10 Surf.) PEG-600 oleate Albunol 600 MO (Taiwan Surf.) >10 2.2 PEG-Fatty Acid Diesters Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention. Representative PEG-fatty acid diesters are shown in Table 2.
Table 2: PEG-Fatty Acid Diester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-4 dilaurate Mapeg 200 DL (PPG), Kessco PEG 200 DL 7 (Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4 dioleate Mapeg 200 DO (PPG), 6 PEG-4 distearate Kessco 200 DS (Stepan) 5 PEG-6 dilaurate Kessco PEG 300 DL (Stepan) 9.8 PEG-6 dioleate Kessco PEG 300 DO (Stepan) 7.2 PEG-6 distearate Kessco PEG 300 DS (Stepan) 6.5 PEG-8 dilaurate Mapeg 400 DL (PPG), Kessco PEG 400 DL 11 (Stepan), LIPOPEG 4 DL (Lipo Chem.) PEG-8 dioleate Mapeg 400 DO (PPG), Kessco PEG 400 DO 8.8 (Stepan), LIPOPEG 4 DO(Lipo Chem.) -------------COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-8 distearate Mapeg 400 DS (PPG), CDS 400 (Nikkol) 11 PEG-10 dipalmitate Polyaldo 2PKFG >10 PEG-12 dilaurate Kessco PEG 600 DL (Stepan) 11.7 PEG-12 distearate Kessco PEG 600 DS (Stepan) 10.7 PEG-12 dioleate Mapeg D 600 DO (PPG), Kessco 600 10 DO(Stepan) PEG-20 dilaurate Kessco PEG 1000 DL (Stepan) 15 PEG-20 dioleate Kessco PEG 1000 DO (Stepan) 13 PEG-20 distearate Kessco PEG 1000 DS (Stepan) 12 PEG-32 dilaurate Kessco PEG 1540 DL (Stepan) 16 PEG-32 dioleate Kessco PEG 1540 DO (Stepan) 15 PEG-32 distearate Kessco PEG 1540 DS (Stepan) 15 PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series (Croda) >10 2.3 PEG-Fatty Acid Mono- and Di-ester Mixtures In general, mixtures of surfactants are also useful in the present invention, including mixtures of two or more commercial surfactant products. Several PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters.
Representative surfactant mixtures are shown in Table 3.
Table 3: PEG-Fatty Acid Mono- and Diester Mixtures COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG 4-150 mono, dilaurate Kessco PEG 200-6000 mono, dilaurate (Stepan) PEG 4-150 mono, dioleate Kessco PEG 200-6000 mono, dioleate (Stepan) PEG 4-150 mono, Kessco 200-6000 mono, distearate (Stepan) distearate 2.4 Polyethylene Glycol Glycerol Fatty Acid Esters Suitable PEG glycerol fatty acid esters are shown in Table 4.
Table 4: PEG Glycerol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-20 glyceryl laurate Tagat L (Goldschmidt) 16 PEG-30 glyceryl laurate Tagat L2 (Goldschmidt) 16 PEG-15 glyceryl laurate Glycerox L series (Croda) 15 PEG-40 glyceryl laurate Glycerox L series (Croda) 15 PEG-20 glyceryl stearate Capmul EMG (ABITEC), Aldo MS-20 KFG (Lonna) 13 PEG-20 glyceryl oleate Tagat 0 (Goldschmidt) >10 PEG-30 glyceryl oleate Tagat 02 (Goldschmidt) >10 2.5. Alcohol - Oil Transesterification Products A large number of surfactants of different degrees of lipophilicity or hydrophilicity can be prepared by reaction of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils. Most commonly, the oils used are castor oil or hydrogenated castor oil, or an edible vegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, or almond oil. Preferred alcohols include glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, and pentaerythritol.
Representative surfactants of this class suitable for use in the present invention are shown in Table 5.
Table 5: Transesterification Products of Oils and Alcohols COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-3 castor oil Nikkol CO-3 (Nikko) 3 PEG-5, 9, and 16 castor oil ACCONON CA series (ABITEC) 6-7 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikko! CO-20 i 1 TX (Nikko) PEG-23 castor oil Emulgante EL23 >10 PEG-30 castor oil Emalex C-30 (Nihon Emulsion), Alkamuls EL 11 620 (Rhone-Poulenc), Incrocas 30 (Croda) PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulgin RO 35 (Henkel) PEG-38 castor oil Emulgante EL 65 (Condea) PEG-40 castor oil Emalex C-40 (Nihon Emulsion), Alkamuls EL 13 719 (Rhone-Poulenc) PEG-50 castor oil Emalex C-50 (Nihon Emulsion) 14 PEG-56 castor oil Eumulgin PRT 56 (Pulcra SA) >10 PEG-60 castor oil Nikko! CO-60TX (Nikko) 14 PEG-100 castor oil Thornley >10 PEG-200 castor oil Eumulgin PRT 200 (Pulcra SA) >10 PEG-5 hydrogenated castor Nikkol HCO-5 (Nikko) 6 oil PEG-7 hydrogenated castor Simusol 989 (Seppic), Cremophor WO7 6 oil (BASF) PEG-10 hydrogenated castor Nikkol HCO-10 (Nikko) 6.5 oil PEG-20 hydrogenated castor Nikkol HCO-20 (Nikko) 11 oil PEG-25 hydrogenated castor Simulsol 1292 (Seppic), Cerex ELS 250 11 oil (Auschem SpA) PEG-30 hydrogenated castor Nikkol HCO-30 (Nikko) 11 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
oil PEG-40 hydrogenated castor Cremophor RH 40 (BASF), Croduret (Croda), 13 oil Emulgin HRE 40 (Henkel) PEG-45 hydrogenated castor Cerex ELS 450 (Auschem Spa) 14 oil PEG-50 hydrogenated castor Emalex HC-50 (Nihon Emulsion) 14 oil PEG-60 hydrogenated castor Nikkol HCO-60 (Nikko); Cremophor RH 60 15 oil (BASF) PEG-80 hydrogenated castor Nikkol HCO-80 (Nikko) 15 oil PEG-100 hydrogenated castor Nikkol HCO -100 (Nikko)' 17 oil PEG-6 corn oil Labrafil M 2125 CS (Gattefosse) 4 PEG-6 almond oil Labrafil M 1966 CS (Gattefosse) 4 PEG-6 apricot kernel oil Labrafil M 1944 CS (Gattefosse) 4 PEG-6 olive oil Labrafil M 1980 CS (Gattefosse) 4 PEG-6 peanut oil Labrafil M 1969 CS (Gattefosse) 4 PEG-6 hydrogenated palm Labrafil M 2130 BS (Gattefosse) 4 kernel oil PEG-6 palm kernel oil Labrafil M 2130 CS (Gattefosse) 4 PEG-6 triolein Labrafil M 2735 CS (Gattefosse) 4 PEG-8 corn oil Labrafil WL 2609 BS (Gattefosse) 6-7 PEG-20 corn glycerides Crovol M40 (Croda) 10 PEG-20 almond glycerides Crovol A40 (Croda) 10 PEG-25 trioleate TAGAT TO (Goldschmidt) 11 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-40 palm kernel oil Crovol PK-70 >10 PEG-60 corn glycerides Crovol M70(Croda) 15 PEG-60 almond glycerides Crovol A70 (Croda) 15 PEG-4 caprylic/capric Labrafac Hydro (Gattefosse), 4-5 triglyceride PEG-8 caprylic/capric Labrasol (Gattefosse),Labrafac CM 10 >10 glycerides (Gattefosse) PEG-6 caprylic/capric SOFTIGEN 767 (Hills), Glycerox 767 (Croda) 19 glycerides ' Lauroyl macrogol-32 GELUCIRE 44/14 (Gattefosse) 14 glyceride Stearoyl macrogol glyceride GELUCIRE 50/13 (Gattefosse) 13 Mono, di, tri, tetra esters of SorbitoGlyceride (Gattefosse) <10 vegetable oils and sorbitol Pentaerythrityl tetraisostearate Crodamol PTIS (Croda) <10 Pentaerythrityl distearate Albunol DS (Taiwan Surf.) <10 Pentaerythrityl tetraoleate Liponate P0-4 (Lipo Chem.) <10 Pentaerythrityl tetrastearate Liponate PS-4 (Lipo Chem.) <10 Pentaerythrityl Liponate PE-810 (Lipo Chem.), Crodamol PTC <10 tetracaprylate/tetracaprate (Croda) Pentaerythrityl tetraoctanoate Nikkol Pentarate 408 (Nikko) 2.6. Polyglycerized Fatty Acids Polyglycerol esters of fatty acids are also suitable surfactants for the present invention. Examples of suitable polyglyceryl esters are shown in Table 6.
CA
Table 6: Polyglycerized Fatty. Acids COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7 Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 isostearate Nikkol DGMIS (Nikko) 5-7 Polyglyceryl-3 oleate Caprol 3G0 (ABITEC), Drewpol 3-1-0 (Stepan) 6.5 Polyglyceryl-4 oleate Nikkol Tetraglyn 1-0 (Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6-1-0 (Stepan), Nikkol Hexaglyn 1-0 9 (Nikko) Polyglyceryl-10 laurate Nikkol Decaglyn i -L (Nikko) 15 Polyglyceryl-10 oleate Nikkol Decaglyn 1-0 (Nikko) 14 Polyglyceryi-10 stearate Nikkol Decaglyn 1-S (Nikko) 12 Polyglyceryl-6 ricinoleate Nikkol Hexaglyn PR-15 (Nikko) >8 Polyglyceryl- 10 linoleate Nikkol Decaglyn I -LN (Nikko) 12 Polyglyceryi-6 pentaoleate Nikkol Hexaglyn 5-0 (Nikko) <10 Polyglyceryl-3 dioleate Cremophor 0032 (BASF) <10 Polyglyceryl-3 distearate Cremophor GS32 (BASF) <10 PolygIyceryl-4 pentaoleate Nikkol Tetraglyn 5-0 (Nikko) <10 Polyglyceryl-6 dioleate Caprol 6G20 (ABITEC); Hodag PGO-62 (Calgene), 8.5 PLUROL OLEIQUE CC 497 (Gattefosse) Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7 Polyglyceryl-10 trioleate Nikkol Decaglyn 3-0 (Nikko) 7 Polyglyceryl-10 Nikkol Decaglyn 5-0 (Nikko) 3.5 pentaoleate Polyglyceryl-10 Nikkol Decaglyn 7-0 (Nikko) 3 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
septaoleate Polyglyceryl-10 tetraoleate Caprol 1OG40 (ABITEC); Hodag POO-62 6.2 (CALGENE), Drewpol 10-4-0 (Stepan) Polyglyceryl-10 ikkol Decaglyn 10-IS (Nikko) <10 decaisostearate Polyglyceryl-101 Drewpol 10-10-0 (Stepan), Caprol IOG100 . 3.5 decaoleate (ABITEC), Nikkol Decaglyn 10-0 PolyglyceryI-10 mono, Caprol PGE 860 (ABITEC) 1 I
dioleate Polyglyceryl Polymuls (Henkel) 3-20 polyricinoleate 2.7. Propylene Glycol Fatty Acid Esters Esters of propylene glycol and fatty acids are suitable surfactants for use in the present invention. Examples of surfactants of this class are given in Table 7.
Table 7: Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Propylene glycol Capryol 90 (Gattefosse), Nikko! Sefsol 218 (Nikko) <10 monocaprylate Propylene glycol Lauroglycol 90 (Gattefosse), Lauroglycol FCC <10 monolaurate (Gattefosse) Propylene glycol oleate Lutrol OP2000 (BASF) <10 Propylene glycol myristate Mirpyl <10 Propylene glycol ADM PGME-03 (ADM), LIPO PGMS (Lipo 3-4 monostearate Chem.), Aldo PGHMS (Lonza) Propylene glycol hydroxy stearate <10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Propylene glycol PROPYMULS (Henkel) <10 ricinoleate Propylene glycol <10 isostearate Propylene glycol Myverol P-06 (Eastman) <10 monooleate Propylene glycol Captex 200 (ABITEC), Miglyol 840 (Hills), >6 dicaprylate/dicaprate Neobee M-20 (Stepan) Propylene glycol Captex 800 (ABITEC) >6 dioctanoate Propylene glycol LABRAFAC PG (Gattefosse) >6 caprylate/caprate Propylene glycol dilaurate >6 Propylene glycol distearate Kessco PGDS (Stepan) >6 Propylene glycol Nikkol Sefsol 228 (Nikko) >6 dicaprylate Propylene glycol dicaprate Nikkol PDD (Nikko) >6 2.8. Mixtures of Propylene Glycol Esters - Glycerol Esters In general, mixtures of surfactants are also suitable for use in the present invention. In particular, mixtures of propylene glycol fatty acid esters and glycerol fatty acid esters are suitable and are commercially available. Examples of these surfactants are shown in Table 8.
Table 8: Glycerol/Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB=
Oleic ATMOS 300, ARLACEL 186 (ICI) 3-4 Stearic ATMOS 150 3-4 2.9. Mono- and Diglycerides A particularly important class of surfactants is the class of mono- and diglycerides. These surfactants are generally lipophilic. Examples of these surfactants are given in Table 9.
Table 9: Mono- and Diglyceride Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Monopalmitolein (C16:1) (Larodan) <10 Monoelaidin (C18:1) (Larodan) <10 Monocaproin (C6) (Larodan) <10 Monocaprylin (Larodan) <10 Monocaprin (Larodan) <10 Monolaurin (Larodan) <10 Glyceryl monomyristate Nikkol MGM (Nikko) 3-4 (C14) Glyceryl monooleate PECEOL (Gattefosse), Hodag GMO-D, Nikkol 3-4 (C18:1) MGO (Nikko) Glyceryl monooleate RYLO series (Danisco), DIMODAN series 3-4 (Danisco), EMULDAN (Danisco), ALDOO
MO FG (Loma), Kessco GMO (Stepan), MONOMULSO series (Henkel), TEGIN 0, DREWMULSE GMO (Stepan), Atlas 0-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
40, 70, and 100 (ADM), Myverol (Eastman) Glycerol OLICINE (Gattefosse) 3-4 monooleate/linoleate Glycerol monolinoleate Maisine (Gattefosse), MYVEROL 18-92, 3-4 Myverol 18-06 (Eastman) Glyceryl ricinoleate Softigen 701 (Hills), HODAG GMR-D 6 (Calgene), ALDO MR (Lonza) Glyceryl monolaurate ALDO MLD (Loma), Hodag GML (Calgene) 6.8 Glycerol monopalmitate Emalex GMS-P (Nihon) 4 Glycerol monostearate Capmul GMS (ABITEC), Myvaplex 5-9 (Eastman), IMWITOR 191 (Hills), CUTINA GMS, Aldo MS (Loma), Nikko]
MGS series (Nikko) Glyceryl mono-,dioleate Capmul GMO-K (ABITEC) <10 Glyceryl palmitic/stearic CUTINA MD-A, ESTAGEL-G 18 <10 Glyceryl acetate Lamegin EE (Grunau GmbH) <10 Glyceryl laurate Imwitor 312 (Hills), Monomuls 90-45 4 (Griinau GmbH), Aldo MLD (Lonna) Glyceryl Imwitor 375 (Hills) <10 citrate/lactate/oleate/
linoleate Glyceryl caprylate Imwitor 308 (Hills), Capmul MCMCB 5-6 (ABITEC) Glyceryl caprylate/caprate Capmul MCM (ABITEC) 5-6 Caprylic acid Imwitor 988 (Hills) 5-6 mono,diglycerides Caprylic/capric glycerides Imwitor 742 (Hills) <10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Mono-and diacetylated Myvacet 9-45, Myvacet 9-40, Myvacet 9- 3.8-4 monoglycerides 08 (Eastman), Lamegin (Grunau) Glyceryl monostearate Aldo MS, Arlacel 129 (ICI), LIPO GMS (Lipo 4.4 Chem.), Imwitor 191 (Hills), Myvaplex (Eastman) Lactic acid esters of . LAMEGIN GLP (Henkel) <10 mono,diglycerides Dicaproin (C6) (Larodan) <10 Dicaprin (C10) (Larodan) <10 Dioctanoin (C8) (Larodan) <10 Dimyristin (C14) (Larodan) <10 Dipalmitin (CI6) (Larodan) <10 Distearin (Larodan) <10 Glyceryl dilaurate (C12) Capmul GDL (ABITEC) 3-4 GlyeeryI dioleate Capmul GDO (ABITEC) 3-4 Glycerol esters of fatty GELUCIRE 39/01 (Gattefosse), GELUCIRE I
acids 43/01 (Gattefosse) .
GELUCIRE 37/06 (Gattefosse) 6 Dipalmitolein (C 16:1) (Larodan) <10 1,2 and 1,3-diolein (C18:1) (Larodan) <10 Dielaidin (C 18:1) (Larodan) <10 Dilinolein (C 18:2) (Larodan) <10 2.10. Sterol and Sterol Derivatives Sterols and derivatives of sterols are suitable surfactants for use in the present invention. These surfactants can be hydrophilic or lipophilic. Examples of surfactants of this class are shown in Table 10.
Table 10: Sterol and Sterol Derivative Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Cholesterol, sitosterol, <10 lanosterol PEG-24 cholesterol ether Solulan C-24 (Amerchol) >10 PEG-30 cholestanol Nikkol DHC (Nikko) >10 Phytosterol GENEROL series (Henkel) <10 PEG-25 phyto sterol Nikkol BPSH-25 (Nikko) >10 PEG-5 soya sterol Nikkol BPS-5 (Nikko) <10 PEG-10 soya sterol Nikkol BPS-I0 (Nikko) <10 PEG-20 soya sterol Nikkol BPS-20 (Nikko) <10 PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10 2.11. Polyethylene Glycol Sorbitan Fatty Acid Esters A variety of PEG-sorbitan fatty acid esters are available and are suitable for use as surfactants in the present invention. In general, these surfactants are hydrophilic, although several lipophilic surfactants of this class can be used. Examples of these surfactants are shown in Table 11.
Table 11: PEG-Sorbitan Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10 PEG-20 sorbitan Tween-20 (Atlas/ICI), Crillet I (Croda), DACOL 17 monolaurate MLS 20 (Condea) PEG-4 sorbitan Tween-21 (Atlas/ICI), Crillet l 1 (Croda) 13 monolaurate PEG-80 sorbitan Hodag PSML-80 (Calgene); T-Maz 28 >10 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
monolaurate PEG-6 sorbitan Nikko! GL-1 (Nikko) 16 monolaurate PEG-20 sorbitan Tween-40 (Atlas/ICI), Crillet 2 (Croda) 16 monopalmitate PEG-20 sorbitan Tween-60 (Atlas/ICI), Crillet 3 (Croda) 15 monostearate PEG-4 sorbitan Tween-61 (Atlas/ICI), Crillet 31 (Croda) 9.6 monostearate PEG-8 sorbitan DACOL MSS (Condea) >10 monostearate PEG-6 sorbitan Nikkol TS 106 (Nikko) 11 monostearate PEG-20 sorbitan tristearate Tween-65 (Atlas/ICI), Crillet 35 (Croda) 11 PEG-6 sorbitan Nikkol GS-6 (Nikko) 3 tetrastearate PEG-60 sorbitan Nikko! GS-460 (Nikko) 13 tetrastearate PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), Crillet 41 (Croda) 10 PEG-6 sorbitan monooleate Nikkol TO- 106 (Nikko) 10 PEG-20 sorbitan Tween-80 (Atlas/ICI), Crillet 4 (Croda) 15 monooleate PEG-40 sorbitan oleate Emalex ET 8040 (Nihon Emulsion) 18 PEG-20 sorbitan trioleate Tween-85 (Atlas/ICI), Crillet 45 (Croda) 11 PEG-6 sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleate Nikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikko! GO-440 (Nikko) 13 COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-20 sorbitan Tween-120 (Atlas/ICI), Crillet 6 (Croda) >10 monoisostearate PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10 PEG-6 sorbitol Nikko] GS-6 (Nikko) 3 hexastearate 2.12. Polyethylene Glycol Alkyl Ethers Ethers of polyethylene glycol and alkyl alcohols are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 12.
Table 12: Polyethylene Glycol Alkyl Ethers COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-2 oleyl ether,oleth-2 Brij 92/93 (Atlas/ICI) . 4.9 PEG-3 oleyl ether,oleth-3 Volpo 3 (Croda) <10 PEG-5 oleyl ether,oleth-5 Volpo 5 (Croda) <10 PEG-10 oleyl ether,oleth- Volpo 10 (Croda), Brij 96/97 (Atlas/ICI) 12 PEG-20 oleyl ether,oleth- Volpo 20 (Croda), Brij 98/99 (Atlas/ICI) 15 PEG-4 lauryl ether, Brij 30 (Atlas/ICI) 9.7 laureth-4 PEG-9 lauryl ether >10 PEG-23 lauryl ether, Brij 35 (Atlas/ICI) 17 laureth-23 PEG-2 cetyl ether Brij 52 (ICI) 5.3 C
COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-10 cetyl ether Brij 56 (ICI) 13 PEG-20 cetyl ether Brij 58 (ICI) 16 PEG-2 stearyl ether Brij 72 (ICI) 4.9 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-20 stearyl ether Brij 78 (ICI) 15 PEG-100 stearyl ether Brij 700 (IC1) >10 2.13. Sugar Esters Esters of sugars are suitable surfactants for use in the present invention.
Examples of such surfactants are shown in Table 13.
Table 13: Sugar Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Sucrose distearate SUCRO ESTER 7 (Gattefosse), Crodesta F-10 3 (Croda) Sucrose SUCRO ESTER I 1 (Gattefosse), Crodesta F-110 12 distearate/monostearate (Croda) Sucrose dipalmitate 7.4 Sucrose monostearate Crodesta F-160 (Croda) 15 Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10 Sucrose monolaurate Saccharose monolaurate 1695 (Mitsubishi-Kasei) 15 2.14. Polyethylene Glycol Alkyl Phenols Several hydrophilic PEG-alkyl phenol surfactants are available, and are suitable 1o for use in the present invention. Examples of these surfactants are shown in Table 14.
Table 14: Polyethylene Glycol Alkyl Phenol Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
PEG-10-100 nonyl phenol Triton X series (Rohm & Haas), Igepal CA series >10 (GAF, USA), Antarox CA series (GAF, UK) PEG-15-100 octyl phenol Triton N-series (Rohm & Haas), Igepal CO series >10 ether (GAF, USA), Antarox CO series (GAF, UK) 2.15. Polyoxyethylene-Polyoxypropylene Block Copolymers The POE-POP block copolymers are a unique class of polymeric surfactants.
The unique structure of the surfactants, with hydrophilic POE and lipophilic POP
moieties in well-defined ratios and positions, provides a wide variety of surfactants suitable for use in the present invention. These surfactants are available under various trade names, including Synperonic PE series (ICI); Pluronic series (BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these polymers is "poloxamer" (CAS 9003-11-6). These polymers have the formula:
HO(C2H40)a(C3H60)b(C2H40)aH
where "a" and "b" denote the number of polyoxyethylene and polyoxypropylene units, respectively.
Examples of suitable surfactants of this class are shown in Table 15. Since the compounds are widely available, commercial sources are not listed in the Table. The compounds are listed by generic name, with the corresponding "a" and "b"
values.
Table 15: POE-POP Block Copolymers COMPOUND a, b values in HO(C2mO).(C3H6O)b(C2H4O).H HLB
Poloxamer 105 a=11 b=16 8 Poloxamer 108 a=46 b=16 >10 Poloxamer 122 a=5 b=21 3 Poloxamer 123 a=7 b=21 COMPOUND a, b values in HO(C2H40)a(C3H6O)b(C2H40)aH HLB
Poloxamer 124 a= 11 b=21 >7 Poloxamer 181 a=3 b=30 Poloxamer 1 82 a=8 b=30 2 Poloxamer 183 a*=10 b=30 Poloxamer 184 a-13 b=30 Poloxamer 185 a=19 b=30 Poloxamer 188 a = 75 b=30 29 Poloxamer 212 a=8 b=35 Poloxamer 215 a=24 b=35 Poloxamer 217 a=52 b=35 Poloxamer 231 a= 16 b=39 Poloxamer 234 a = 22 b=39 Poloxamer 235 a = 27 b=39 Poloxamer 237 a = 62 b=39 24 Poloxamer 238 a = 97 b=39 Poloxamer 282 a= 10 b=47 Poloxamer 284 a = 21 b=47 Poloxamer 288 a= 122 b=47 >10 Poloxamer 331 a=7 b = 54 0.5 Poloxamer 333 a = 20 b=54 Poloxamer 334 a=31 b = 54 Poloxamer 335 a=38 b=54 Poloxamer 338 a= 128 b = 54 Poloxamer 401 a=6 b=67 Poloxamer 402 a =13 b=67 COMPOUND a, b values in HO(C2H4O)a(C3H6O)b(C2H4O)aH HLB
Poloxamer 403 a=21 b=67 Poloxamer 407 a=98 b=67 2.16. Sorbitan Fatty Acid Esters Sorbitan esters of fatty acids are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 16.
Table 16: Sorbitan Fatty Acid Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Sorbitan monolaurate Span-20 (Atlas/ICI), Crill I (Croda), Arlacel 20 8.6 (ICJ) Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), Nikko! SP- 6.7 (Nikko) Sorbitan monooleate Span-80 (Atlas/ICI), Cri114 (Croda), Cri1150 4.3 (Croda) Sorbitan monostearate Span-60 (Atlas/ICI), Cri113 (Croda), Nikko! SS- 4.7 10 (Nikko) Sorbitan trioleate Span-85 (Atlas/ICI), Cri1145 (Croda), Nikko! SO- 4.3 30 (Nikko) Sorbitan sesquioleate Arlacel-C (ICI), Cri1143 (Croda), Nikko! SO-15 3.7 (Nikko) Sorbitan tristearate Span-65 (Atlas/ICI) Crill 35 (Croda), Nikkol SS- 2.1 30 (Nikko) Sorbitan monoisostearate Crill 6 (Croda), Nikko! SI-10 (Nikko) 4.7 Sorbitan sesquistearate Nikko! SS-15 (Nikko) 4.2 2.17. Lower Alcohol Fatty Acid Esters Esters of lower alcohols (C2 to C4) and fatty acids (C$ to C,$) are suitable surfactants for use in the present invention. Examples of these surfactants are shown in Table 17.
Table 17: Lower Alcohol Fatty Acid Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB
Ethyl oleate Crodamol EO (Croda), Nikkol EOO (Nikko) <10 Isopropyl myristate Crodamol IPM (Croda) <10 Isopropyl palmitate Crodamol IPP (Croda) <10 Ethyl linoleate Nikkol VF-E (Nikko) <10 Isopropyl linoleate Nikkol VF-IP (Nikko) <10 2.18. Ionic Surfactants Ionic surfactants, including cationic, anionic and zwitterionic surfactants, are suitable hydrophilic surfactants for use in the present invention. Preferred anionic surfactants include fatty acid salts and bile salts. Preferred cationic surfactants include carnitines. Specifically, preferred ionic surfactants include sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate; lauroyl camitine; palmitoyl carnitine; and myristoyl camitine.
Examples of such surfactants are shown in Table 18. For simplicity, typical counterions are shown in the entries in the Table. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used, such as alkali metal cations or ammonium. Unlike typical non-ionic surfactants, these ionic surfactants are generally available as pure compounds, rather than commercial (proprietary) mixtures. Because these compounds are readily available from a variety of commercial suppliers, such as Aldrich, Sigma, and the like, commercial sources are not generally listed in the Table.
-------- ---- -- --Table 18: Ionic Surfactants COMPOUND HLB
FATTY ACID SALTS >10 Sodium caproate Sodium caprylate Sodium caprate Sodium laurate Sodium myristate Sodium myristolate Sodium palmitate Sodium palmitoleate Sodium oleate 18 Sodium ricinoleate Sodium linoleate Sodium linolenate Sodium stearate Sodium lauryl sulfate (dodecyl) 40 Sodium tetradecyl sulfate Sodium lauryl sarcosinate Sodium dioctyl sulfosuccinate [sodium docusate (Cytec)]
BILE SALTS >10 Sodium cholate Sodium taurocholate Sodium glycocholate Sodium deoxycholate COMPOUND HLB
Sodium taurodeoxycholate Sodium glycodeoxycholate Sodium ursodeoxycholate Sodium chenodeoxycholate Sodium taurochenodeoxycholate Sodium glyco cheno *deoxycholate Sodium cholylsarcosinate Sodium N-methyl taurocholate Sodium lithocholate PHOSPHOLIPIDS
Egg/Soy lecithin [EpikuronTM (Lucas Meyer), OvothinTM
(Lucas Meyer)]
Lyso egg/soy lecithin Hydroxylated lecithin Lysophosphatidylcholine Cardiolipin Sphingomyelin Phosphatidylcholine Phosphatidyl ethanolamine Phosphatidic acid Phosphatidyl glycerol Phosphatidyl serine PHOSPHORIC ACID ESTERS
Diethanolammonium polyoxyethylene-10 oleyl ether phosphate Esterification products of fatty alcohols or fatty alcohol COMPOUND HLB
ethoxylates with phosphoric acid or anhydride CARBOXYLATES
Ether carboxylates (by oxidation of terminal OH group of fatty alcohol ethoxylates) Succinylated monoglycerides [LAMEGIN ZE (Henkel)]
Sodium stearyl fumarate Stearoyl propylene glycol hydrogen succinate Mono/diacetylated tartaric acid esters of mono- and diglycerides Citric acid esters of mono-, diglycerides Glyceryl-lacto esters of fatty acids (CFR ref. 172.852) Acyl lactylates:
lactylic esters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate Alginate salts Propylene glycol alginate SULFATES AND SULFONATES
Ethoxylated alkyl sulfates Alkyl benzene sulfones a-olefin sulfonates Acyl isethionates Acyl taurates Alkyl glyceryl ether sulfonates Octyl sulfosuccinate disodium Disodium undecylenamideo-MEA-sulfosuccinate COMPOUND HLB
CATIONIC Surfactants >10 Lauroyl carnitine Palmitoyl carnitine Myristoyl carnitine Hexadecyl triammonium bromide Decyl trimethyl ammonium bromide Cetyl trimethyl ammonium bromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium salts Diisobutyl phenoxyethoxydimethyl benzylammonium salts Alkylpyridinium salts Betaines (trialkylglycine):
Lauryl betaine (N-lauryl,N,N-dimethylglycine) Ethoxylated amines:
Polyoxyethyl ene-15 coconut amine 2.19 Unionized Ionizable Surfactants Ionizable surfactants, when present in their unionized (neutral, non-salt) form, are lipophilic surfactants suitable for use in the compositions of the present invention.
Particular examples of such surfactants include free fatty acids, particularly C6-C22 fatty acids, and bile acids. More specifically, suitable unionized ionizable surfactants include the free fatty acid and bile acid forms of any of the fatty acid salts and bile salts shown in Table 18.
2.20 Derivatives of Fat-Soluble Vitamins Derivatives of oil-soluble vitamins, such as vitamins A, D, E, K, etc., are also useful surfactants for the compositions of the present invention. An example of such a derivative is tocopheryl PEG-1000 succinate (TPGS, available from Eastman).
2.21 Preferred Surfactants Among the above-listed surfactants, several surfactants are preferred. In general, surfactants or mixtures of surfactants that solidify at ambient room temperature are most preferred. Also preferred are surfactants or mixtures of surfactants that solidify at ambient room temperature in combination with particular lipophilic components, such as triglycerides, or with addition of appropriate additives, such as viscosity modifiers, binders, thickeners, and the like.
Preferred non-ionic hydrophilic surfactants include alkylglucosides;
alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides;
polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters;
polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters;
polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof;
polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils;
reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides;
polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.
More preferably, the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters;
polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters;
polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils. The glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture.
Also preferred are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols.
These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products. The polyol is s preferably glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
The hydrophilic surfactant can also be, or include as a component, an ionic surfactant. Preferred ionic surfactants include alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids;
sodium docusate; carnitines; and mixtures thereof.
More preferable ionic surfactants include bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate;-acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides;
succinylated monoglycerides; citric acid esters of mono-,diglycerides; carnitines; and mixtures thereof.
More specifically, preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
Particularly preferred ionic surfactants are lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof, with the most preferred ionic surfactants being lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
Preferred lipophilic surfactants are alcohols; polyoxyethylene alkylethers;
fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters;
lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives;
sugar esters;
sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
As with the hydrophilic surfactants, lipophilic surfactants can be reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
Preferably, the lipophilic surfactant is selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters;
polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides;
sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene-polyoxypropylene block copolymers; potyoxyethylene vegetable oils;
polyoxyethylene hydrogenated vegetable oils; and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
More preferred are lower alcohol fatty acids esters; polypropylene glycol fatty acid esters; propylene glycol fatty acid esters; glycerol fatty acid esters;
acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides;
sorbitan fatty acid esters; polyoxyethylene vegetable oils; and mixtures thereof, with glycerol fatty acid esters and acetylated glycerol fatty acid esters being most preferred. Among the glycerol fatty acid esters, the esters are preferably mono- or diglycerides, or mixtures of mono-and diglycerides, where the fatty acid moiety is a C6 to C22 fatty acid.
Also preferred are lipophilic surfactants which are the reaction mixture of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
Preferred polyols are polyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.
3. Triglycerides For compositions of the present invention that include a lipophilic component, the lipophilic component can be a lipophilic surfactant or a triglyceride.
Preferred triglycerides are those which solidify at ambient room temperature, with or without addition of appropriate additives, or those which in combination with particular surfactants and/or active ingredients solidify at room temperature. Examples of triglycerides suitable for use in the present invention are shown in Table 19.
In general, these triglycerides are readily available from commercial sources. For several triglycerides, representative commercial products and/or commercial suppliers are listed.
Table 19: Triglycerides Triglyceride Commercial Source Aceituno oil Almond oil Super Refined Almond Oil (Croda) Araehis oil Babassu oil Beeswax Blackcurrant seed oil Borage oil Buffalo ground oil Candlenut oil Canola oil Lipex 108 (Abitec) Castor oil Chinese vegetable tallow oil Cocoa butter Coconut oil Pureco 76 (Abitec) Coffee seed oil Corn oil Super Refined Corn Oil (Croda) Cottonseed oil Super Refined Cottonseed Oil (Croda) Crambe oil Cuphea species oil Evening primrose oil Grapeseed oil Groundnut oil Hemp seed oil Illipe butter a Triglyceride Commercial Source Kapok seed oil Linseed oil Menhaden oil Super Refined Menhaden Oil (Croda) Mowrah butter Mustard seed oil Oiticica oil Olive oil Super Refined Olive Oil (Croda) Palm oil Palm kernel oil Peanut oil Super Refined Peanut Oil (Croda) Poppy seed oil Rapeseed oil Rice bran oil Safflower oil Super Refined Safflower Oil (Croda) {
Sal fat Sesame oil Super Refined Sesame Oil (Croda) Shark liver oil Super Refined Shark Liver Oil (Croda) Shea nut oil Soybean oil Super Refined Soybean Oil (Croda) Stillingia oil Sunflower oil Tall oil Tea seed oil Tobacco seed oil Tung oil (China wood oil) Triglyceride Commercial Source Ucuhuba Vernonia oil Wheat germ oil Super Refined Wheat Germ Oil (Croda) Hydrogenated castor oil Castorwax Hydrogenated coconut oil Pureco 100 (Abitec) Hydrogenated cottonseed oil Dritex C (Abitec) Hydrogenated palm oil Dritex PST (Abitec); Softisan 154 (Hills) Hydrogenated soybean oil Sterotex HM NF (Abitec); Dritex S (Abitec) Hydrogenated vegetable oil Sterotex NF (Abitec); Hydrokote M (Abitec) Hydrogenated cottonseed and castor Sterotex K (Abitec) oil Partially hydrogenated soybean oil Hydrokote AP5 (Abitec) Partially hydrogenated soy and Apex B (Abitec) cottonseed oil Glyceryl mono-, di-, tri-behenate Compritol 888 Glyceryl tributyrate (Sigma) Glyceryl tricaproate (Sigma) Glyceryl tricaprylate (Sigma) Glyceryl tricaprate Captex 1000 (Abitec) Glyceryl triundecanoate Captex 8227 (Abitec) Glyceryl trilaurate (Sigma) Glyceryl trimyristate Dynasan 114 (Hills) Glyceryl tripalmitate Dynasan 116 (Huts) Glyceryl tristearate Dynasan 118 (Hills) Glyceryl triarchidate (Sigma) Glyceryl trimyristoleate (Sigma) S
Triglyceride Commercial Source Glyceryl tripalmitoleate (Sigma) Glyceryl trioleate (Sigma) Glyceryl trilinoleate (Sigma) Glyceryl trilinolenate (Sigma) Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355 (Abitec);
Miglyol 810 (Hills); Miglyol 812 (Hills) Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec) Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec); Miglyol 818 (Hills) Glyceryl tricaprylate/caprate/stearate Softisan 378 (Hills); (Larodan) Glyceryl tricaprylate/laurate/stearate (Larodan) GIyceryl1,2-caprylate-3-linoleate (Larodan) Glyceryl 1,2-caprate-3-stearate (Larodan) Glyceryl 1,2-laurate-3-myristate (Larodan) Glyceryl 1,2-myristate-3-laurate (Larodan) Glyceryl 1,3-palmitate-2-butyrate (Larodan) Glyceryl 1,3-stearate-2-caprate (Larodan) Glyceryl 1,2-linoleate-3-caprylate (Larodan) Fractionated triglycerides, modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention.
Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long-chain triglycerides, and structured triglycerides. It should be appreciated that several commercial surfactant compositions contain small to moderate amounts of triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a transesterification reaction. Such commercial surfactant compositions, while nominally referred to as "surfactants", may be suitable to provide all or part of the triglyceride component for the compositions of the present invention. Examples of commercial surfactant compositions containing triglycerides include some members of the surfactant families Gelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (Hills). Specific examples of these compositions are:
Gelucire 44/14 (saturated polyglycolized glycerides) Gelucire 50/13 (saturated polyglycolized glycerides) Gelucire 53/10 (saturated polyglycolized glycerides) Gelucire 33/01 (semi-synthetic triglycerides of CB-C)8 saturated fatty acids) Gelucire 39/01 (semi-synthetic glycerides) other Gelucires, such as 37/06, 43/01, 35/10, 37/02, 46/07,48/09, 50/02, 62/05, etc.
Maisine 35-1(linoleic glycerides) lmwitor 742 (caprylic/capric glycerides) Still other commercial surfactant compositions having significant triglyceride content are known to those skilled in the art. It should be appreciated that such compositions, which contain triglycerides as well as surfactants, may be suitable to provide all or part of the triglyceride component of the compositions of the present invention, as well as all or part of the surfactant component.
Preferred triglycerides are those which solidify at ambient room temperature, with or without addition of appropriate additives, or those which in combination with particular surfactants and/or active ingredients solidify at room temperature. Examples of triglycerides suitable for use in the present invention are shown in Table 19.
In general, these triglycerides are readily available from commercial sources. For several triglycerides, representative commercial products and/or commercial suppliers are listed.
Table 19: Triglycerides Triglyceride Commercial Source Aceituno oil Almond oil Super Refined Almond Oil (Croda) Araehis oil Babassu oil Beeswax Blackcurrant seed oil Borage oil Buffalo ground oil Candlenut oil Canola oil Lipex 108 (Abitec) Castor oil Chinese vegetable tallow oil Cocoa butter Coconut oil Pureco 76 (Abitec) Coffee seed oil Corn oil Super Refined Corn Oil (Croda) Cottonseed oil Super Refined Cottonseed Oil (Croda) Crambe oil Cuphea species oil Evening primrose oil Grapeseed oil Groundnut oil Hemp seed oil Illipe butter a Triglyceride Commercial Source Kapok seed oil Linseed oil Menhaden oil Super Refined Menhaden Oil (Croda) Mowrah butter Mustard seed oil Oiticica oil Olive oil Super Refined Olive Oil (Croda) Palm oil Palm kernel oil Peanut oil Super Refined Peanut Oil (Croda) Poppy seed oil Rapeseed oil Rice bran oil Safflower oil Super Refined Safflower Oil (Croda) {
Sal fat Sesame oil Super Refined Sesame Oil (Croda) Shark liver oil Super Refined Shark Liver Oil (Croda) Shea nut oil Soybean oil Super Refined Soybean Oil (Croda) Stillingia oil Sunflower oil Tall oil Tea seed oil Tobacco seed oil Tung oil (China wood oil) Triglyceride Commercial Source Ucuhuba Vernonia oil Wheat germ oil Super Refined Wheat Germ Oil (Croda) Hydrogenated castor oil Castorwax Hydrogenated coconut oil Pureco 100 (Abitec) Hydrogenated cottonseed oil Dritex C (Abitec) Hydrogenated palm oil Dritex PST (Abitec); Softisan 154 (Hills) Hydrogenated soybean oil Sterotex HM NF (Abitec); Dritex S (Abitec) Hydrogenated vegetable oil Sterotex NF (Abitec); Hydrokote M (Abitec) Hydrogenated cottonseed and castor Sterotex K (Abitec) oil Partially hydrogenated soybean oil Hydrokote AP5 (Abitec) Partially hydrogenated soy and Apex B (Abitec) cottonseed oil Glyceryl mono-, di-, tri-behenate Compritol 888 Glyceryl tributyrate (Sigma) Glyceryl tricaproate (Sigma) Glyceryl tricaprylate (Sigma) Glyceryl tricaprate Captex 1000 (Abitec) Glyceryl triundecanoate Captex 8227 (Abitec) Glyceryl trilaurate (Sigma) Glyceryl trimyristate Dynasan 114 (Hills) Glyceryl tripalmitate Dynasan 116 (Huts) Glyceryl tristearate Dynasan 118 (Hills) Glyceryl triarchidate (Sigma) Glyceryl trimyristoleate (Sigma) S
Triglyceride Commercial Source Glyceryl tripalmitoleate (Sigma) Glyceryl trioleate (Sigma) Glyceryl trilinoleate (Sigma) Glyceryl trilinolenate (Sigma) Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355 (Abitec);
Miglyol 810 (Hills); Miglyol 812 (Hills) Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec) Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec); Miglyol 818 (Hills) Glyceryl tricaprylate/caprate/stearate Softisan 378 (Hills); (Larodan) Glyceryl tricaprylate/laurate/stearate (Larodan) GIyceryl1,2-caprylate-3-linoleate (Larodan) Glyceryl 1,2-caprate-3-stearate (Larodan) Glyceryl 1,2-laurate-3-myristate (Larodan) Glyceryl 1,2-myristate-3-laurate (Larodan) Glyceryl 1,3-palmitate-2-butyrate (Larodan) Glyceryl 1,3-stearate-2-caprate (Larodan) Glyceryl 1,2-linoleate-3-caprylate (Larodan) Fractionated triglycerides, modified triglycerides, synthetic triglycerides, and mixtures of triglycerides are also within the scope of the invention.
Preferred triglycerides include vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, medium and long-chain triglycerides, and structured triglycerides. It should be appreciated that several commercial surfactant compositions contain small to moderate amounts of triglycerides, typically as a result of incomplete reaction of a triglyceride starting material in, for example, a transesterification reaction. Such commercial surfactant compositions, while nominally referred to as "surfactants", may be suitable to provide all or part of the triglyceride component for the compositions of the present invention. Examples of commercial surfactant compositions containing triglycerides include some members of the surfactant families Gelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (Hills). Specific examples of these compositions are:
Gelucire 44/14 (saturated polyglycolized glycerides) Gelucire 50/13 (saturated polyglycolized glycerides) Gelucire 53/10 (saturated polyglycolized glycerides) Gelucire 33/01 (semi-synthetic triglycerides of CB-C)8 saturated fatty acids) Gelucire 39/01 (semi-synthetic glycerides) other Gelucires, such as 37/06, 43/01, 35/10, 37/02, 46/07,48/09, 50/02, 62/05, etc.
Maisine 35-1(linoleic glycerides) lmwitor 742 (caprylic/capric glycerides) Still other commercial surfactant compositions having significant triglyceride content are known to those skilled in the art. It should be appreciated that such compositions, which contain triglycerides as well as surfactants, may be suitable to provide all or part of the triglyceride component of the compositions of the present invention, as well as all or part of the surfactant component.
4. Substrates The substrate of the compositions of the present invention can be a powder or a multiparticulate, such as a granule, a pellet, a bead, a spherule, a beadlet, a microcapsule, a millisphere, a nanocapsule, a nanosphere, a microsphere, a platelet, a minitablet, a tablet or a capsule. A powder constitutes a finely divided (milled, micronized, nanosized, precipitated) form of an active ingredient or additive molecular aggregates or a compound aggregate of multiple components or a physical mixture of aggregates of an active ingredient and/or additives. Such substrates can be formed of various materials known in the art, such as, for example:
Sugars, such as lactose, sucrose or dextrose;
Polysaccharides, such as maltodextrin or dextrates;
Starches;
Cellulosics, such as microcrystalline cellulose or microcrystalline cellulose/sodium carboxymethyl cellulose;
Inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; and Polyols, such as mannitol, xylitol, sorbitol or cyclodextrin.
The substrate can also be formed of any of the active ingredients, surfactants, triglycerides or additives described herein. In one particular embodiment, the substrate is a solid form of an additive, an active ingredient, a surfactant, or a triglyceride; a complex of an additive, surfactant or triglyceride and an active ingredient; a coprecipitate of an additive, surfactant or triglyceride and an active ingredient, or a mixture thereof.
It should be emphasized that the substrate need not be a solid material, although often it will be a solid. For example, the encapsulation coat on the substrate may act as a solid "shell" surrounding and encapsulating a liquid or semi-liquid substrate material.
Such substrates are also within the scope of the present invention, as it is ultimately the carrier, of which the substrate is a part, which must be a solid.
Sugars, such as lactose, sucrose or dextrose;
Polysaccharides, such as maltodextrin or dextrates;
Starches;
Cellulosics, such as microcrystalline cellulose or microcrystalline cellulose/sodium carboxymethyl cellulose;
Inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; and Polyols, such as mannitol, xylitol, sorbitol or cyclodextrin.
The substrate can also be formed of any of the active ingredients, surfactants, triglycerides or additives described herein. In one particular embodiment, the substrate is a solid form of an additive, an active ingredient, a surfactant, or a triglyceride; a complex of an additive, surfactant or triglyceride and an active ingredient; a coprecipitate of an additive, surfactant or triglyceride and an active ingredient, or a mixture thereof.
It should be emphasized that the substrate need not be a solid material, although often it will be a solid. For example, the encapsulation coat on the substrate may act as a solid "shell" surrounding and encapsulating a liquid or semi-liquid substrate material.
Such substrates are also within the scope of the present invention, as it is ultimately the carrier, of which the substrate is a part, which must be a solid.
5. Additives The solid pharmaceutical compositions of the present invention can optionally include one or more additives, sometimes referred to as excipients. The additives can be contained in an encapsulation coat in compositions which include an encapsulation coat, or can be part of the solid carrier, such as coated to an encapsulation coat, or contained within the components forming the solid carrier. Alternatively, the additives can be contained in the pharmaceutical composition but not part of the solid carrier itself Specific, non-limiting examples of additives are described below.
Suitable additives are those commonly utilized to facilitate the processes involving the preparation of the solid carrier, the encapsulation coating, or the pharmaceutical dosage form. These processes include agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The additive can also be pre-coated or encapsulated. Appropriate coatings are well known in the art, and are further described in the sections below. Based on the functionality of the additives, examples of the additives are as follows:
5.1. Solubilizers The pharmaceutical compositions of the present invention can optionally include one or more solubilizers, i.e., additives to increase the solubility of the pharmaceutical active ingredient or other composition components in the solid carrier.
Suitable solubilizers for use in the compositions of the present invention include:
alcohols and polvols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methyicellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives;
ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide);
amides, such as 2-pyrrolidone, 2-piperidone, e-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone;
esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, s-caprolactone and isomers thereof, S-valerolactone and isomers thereof, ji-butyrolactone and isomers thereof;
and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water.
Mixtures of solubilizers are also within the scope of the invention. Except as indicated, these compounds are readily available from standard commercial sources.
Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrroli-done, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
The amount of solubilizer that can be included in compositions of the present invention is not particularly limited. Of course, when such compositions are ultimately administered to a patient, the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example, to maximize the concentration of active ingredient, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation.
5.2. Enzyme Inhibitors When the active ingredient is subject to enzymatic degradation, the compositions can include an enzyme inhibiting agent. Enzyme inhibiting agents are shown for example, in Bernskop-Schnurch, A., "The use of inhibitory agents to overcome enzymatic barrier to perorally administered therapeutic peptides and proteins", J.
Controlled Release 52, 1-16 (1998), the disclosure of which is incorporated herein by reference.
Generally, inhibitory agents can be divided into the following classes:
Inhibitors that are not based on amino acids, such as P-aminobenzamidine, FK-448, camostat mesylate, sodium glycocholate;
Amino acids and modified amino acids, such as aminoboronic acid derivatives and n-acetylcysteine;
Peptides and modified peptides, such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, hosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin;
Polypeptide=protese inhibitors, such as aprotinin (bovine pancreatic trypsin inhibitor), Bowman-Birk inhibitor and soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor.
Complexing agents, such as EDTA, EGTA, 1,10- phenanthroline and hydroxychinoline; and Mucoadhesive polymers and polymer-inhibitor conjugates, such as polyacrylate derivatives, chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-pepstatin, polyacrylic acid-Bwoman-Birk inhibitor.
The choice and levels of the enzyme inhibitor are based on toxicity, specificity of the proteases and the potency of the inhibition. The inhibitor can be suspended or solubilized in the composition preconcentrate, or added to the aqueous diluent or as a beverage.
Without wishing to be bound by theory, it is believed that an inhibitor can function solely or in combination as:
a competitive inhibitor, by binding at the substrate binding site of the enzyme, thereby preventing the access to the substrate; examples of inhibitors believed to operate by this mechanism are antipain, elastatinal and the Bowman Birk inhibitor;
a non-competitive inhibitor which can be simultaneously bound to the enzyme site along with the substrate, as their binding sites are not identical;
and/or a complexing agent due to loss in enzymatic activity caused by deprivation of essential metal ions out of the enzyme structure.
5.3. Other Additives Other additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art. Such additives include:
anti-adherents (anti-sticking agents, glidants, flow promoters, lubricants) such as talc, magnesium stearate, fumed silica (Carbosil, Aerosil), micronized silica (Syloid No.
FP 244, Grace U.S.A.), polyethylene glycols, surfactants, waxes, stearic acid, stearic acid salts, stearic acid derivatives, starch, hydrogenated vegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000 and magnesium lauryl sulfate;
anticoagulants, such as acetylated monoglycerides;
antifoaming agents, such as long-chain alcohols and silicone derivatives;
antioxidants. such as BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbyl palmitate, 4-hydroxymethyl-2,6-di-tert-butyl phenol, and tocopherol;
binders (adhesives), i.e., agents that impart cohesive properties to powdered materials through particle-particle bonding, such as matrix binders (dry starch, dry sugars), film binders (PVP, starch paste, celluloses, bentonite, sucrose), and chemical binders (polymeric cellulose derivatives, such as carboxy methyl cellulose, HPC and HPMC; sugar syrups; corn syrup; water soluble polysaccharides such as acacia, tragacanth, guar and alginates; gelatin; gelatin hydrolysate; agar; sucrose;
dextrose; and non-cellulosic binders, such as PVP, PEG, vinyl pyrrolidone copolymers, pregelatinized starch, sorbitol, and glucose);
bufferants, where the acid is a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid, and where the base is a pharmaceutically acceptable base, such as an amino acid, an amino acid ester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, or a salt of a pharmaceutically acceptable cation and acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, a fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid;
chelatin a ents such as EDTA and EDTA salts;
coagulants , such as alginates;
is colorants or opaouants, such as titanium dioxide, food dyes, lakes, natural vegetable colorants, iron oxides, silicates,. sulfates, magnesium hydroxide and aluminum hydroxide;
coolants, such as halogenated hydrocarbons (e.g., trichloroethane, trichloroethylene, dichloromethane, fluorotrichloromethane), diethylether and liquid nitrogen;
cryoprotectants, such as trehelose, phosphates, citric acid, tartaric acid, gelatin, dextran and mannitol;
diluents or fillers, such as lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starches, directly compressible starch, microcrystalline cellulose, cellulosics, sorbitol, sucrose, sucrose-based materials, calcium sulfate, dibasic calcium phosphate and dextrose;
disintegrants or super disintegrants, such as croscarmellose sodium, starch, starch derivatives, clays, gums, cellulose, cellulose derivatives, alginates, crosslinked polyvinypyrrolidone, sodium starch glycolate and microcrystalline cellulose;
hydrogen bonding agents, such as magnesium oxide;
flavorants or desensitizers, such as spray-dried flavors, essential oils and ethyl vanillin;
ion-exchange resins, such as styrene/divinyl benzene copolymers, and quaternary ammonium compounds;
plasticizers, such as polyethylene glycol, citrate esters (e.g., triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin, propylene glycol, phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl seccate;
preservatives, such as ascorbic acid, boric acid, sorbic acid, benzoic acid, and salts thereof, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds;
solvents, such as alcohols, ketones, esters, chlorinated hydrocarbons and water;
sweeteners, including natural sweeteners such as maltose, sucrose, glucose, sorbitol, glycerin and dextrins, and artificial sweeteners, such as aspartame, saccharine and saccharine salts; and thickeners (viscosity modifiers, thickening agents), such as sugars, polyvinylpyrrolidone, cellulosics, polymers and alginates.
Additives can also be materials such as proteins (e.g., collagen, gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates (e.g., alginates, carrageenan, cellulose derivatives, pectin, starch, chitosan); gums (e.g., xanthan gum, gum arabic);
spermaceti;
natural or synthetic waxes; carnuaba wax; fatty, acids (e.g., stearic acid, hydroxystearic acid); fatty alcohols; sugars; shellacs, such as those based on sugars (e.g., lactose, sucrose, dextrose) or starches; polysaccharide-based shellacs (e.g., maltodextrin and maltodextrin derivatives, dextrates, cyclodextrin and cyclodextrin derivatives);
cellulosic-based shellacs (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, cellulose acetate butyrate, cellulose acetate trimellitate, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate);
inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc and titania; polyols, such as -mannito], xylitol and sorbitol; polyethylene glycol esters; and polymers, such as alginates, poly(lactide coglycolide), gelatin, crosslinked gelatin, and agar-agar.
It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
Suitable additives are those commonly utilized to facilitate the processes involving the preparation of the solid carrier, the encapsulation coating, or the pharmaceutical dosage form. These processes include agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The additive can also be pre-coated or encapsulated. Appropriate coatings are well known in the art, and are further described in the sections below. Based on the functionality of the additives, examples of the additives are as follows:
5.1. Solubilizers The pharmaceutical compositions of the present invention can optionally include one or more solubilizers, i.e., additives to increase the solubility of the pharmaceutical active ingredient or other composition components in the solid carrier.
Suitable solubilizers for use in the compositions of the present invention include:
alcohols and polvols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methyicellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives;
ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide);
amides, such as 2-pyrrolidone, 2-piperidone, e-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone;
esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, s-caprolactone and isomers thereof, S-valerolactone and isomers thereof, ji-butyrolactone and isomers thereof;
and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water.
Mixtures of solubilizers are also within the scope of the invention. Except as indicated, these compounds are readily available from standard commercial sources.
Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrroli-done, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
The amount of solubilizer that can be included in compositions of the present invention is not particularly limited. Of course, when such compositions are ultimately administered to a patient, the amount of a given solubilizer is limited to a bioacceptable amount, which is readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example, to maximize the concentration of active ingredient, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation.
5.2. Enzyme Inhibitors When the active ingredient is subject to enzymatic degradation, the compositions can include an enzyme inhibiting agent. Enzyme inhibiting agents are shown for example, in Bernskop-Schnurch, A., "The use of inhibitory agents to overcome enzymatic barrier to perorally administered therapeutic peptides and proteins", J.
Controlled Release 52, 1-16 (1998), the disclosure of which is incorporated herein by reference.
Generally, inhibitory agents can be divided into the following classes:
Inhibitors that are not based on amino acids, such as P-aminobenzamidine, FK-448, camostat mesylate, sodium glycocholate;
Amino acids and modified amino acids, such as aminoboronic acid derivatives and n-acetylcysteine;
Peptides and modified peptides, such as bacitracin, phosphinic acid dipeptide derivatives, pepstatin, antipain, leupeptin, chymostatin, elastatin, bestatin, hosphoramindon, puromycin, cytochalasin potatocarboxy peptidase inhibitor, and amastatin;
Polypeptide=protese inhibitors, such as aprotinin (bovine pancreatic trypsin inhibitor), Bowman-Birk inhibitor and soybean trypsin inhibitor, chicken egg white trypsin inhibitor, chicken ovoinhibitor, and human pancreatic trypsin inhibitor.
Complexing agents, such as EDTA, EGTA, 1,10- phenanthroline and hydroxychinoline; and Mucoadhesive polymers and polymer-inhibitor conjugates, such as polyacrylate derivatives, chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid-bacitracin, carboxymethyl cellulose-pepstatin, polyacrylic acid-Bwoman-Birk inhibitor.
The choice and levels of the enzyme inhibitor are based on toxicity, specificity of the proteases and the potency of the inhibition. The inhibitor can be suspended or solubilized in the composition preconcentrate, or added to the aqueous diluent or as a beverage.
Without wishing to be bound by theory, it is believed that an inhibitor can function solely or in combination as:
a competitive inhibitor, by binding at the substrate binding site of the enzyme, thereby preventing the access to the substrate; examples of inhibitors believed to operate by this mechanism are antipain, elastatinal and the Bowman Birk inhibitor;
a non-competitive inhibitor which can be simultaneously bound to the enzyme site along with the substrate, as their binding sites are not identical;
and/or a complexing agent due to loss in enzymatic activity caused by deprivation of essential metal ions out of the enzyme structure.
5.3. Other Additives Other additives conventionally used in pharmaceutical compositions can be included, and these additives are well known in the art. Such additives include:
anti-adherents (anti-sticking agents, glidants, flow promoters, lubricants) such as talc, magnesium stearate, fumed silica (Carbosil, Aerosil), micronized silica (Syloid No.
FP 244, Grace U.S.A.), polyethylene glycols, surfactants, waxes, stearic acid, stearic acid salts, stearic acid derivatives, starch, hydrogenated vegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000 and magnesium lauryl sulfate;
anticoagulants, such as acetylated monoglycerides;
antifoaming agents, such as long-chain alcohols and silicone derivatives;
antioxidants. such as BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbyl palmitate, 4-hydroxymethyl-2,6-di-tert-butyl phenol, and tocopherol;
binders (adhesives), i.e., agents that impart cohesive properties to powdered materials through particle-particle bonding, such as matrix binders (dry starch, dry sugars), film binders (PVP, starch paste, celluloses, bentonite, sucrose), and chemical binders (polymeric cellulose derivatives, such as carboxy methyl cellulose, HPC and HPMC; sugar syrups; corn syrup; water soluble polysaccharides such as acacia, tragacanth, guar and alginates; gelatin; gelatin hydrolysate; agar; sucrose;
dextrose; and non-cellulosic binders, such as PVP, PEG, vinyl pyrrolidone copolymers, pregelatinized starch, sorbitol, and glucose);
bufferants, where the acid is a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid, and where the base is a pharmaceutically acceptable base, such as an amino acid, an amino acid ester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, or a salt of a pharmaceutically acceptable cation and acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, a fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid;
chelatin a ents such as EDTA and EDTA salts;
coagulants , such as alginates;
is colorants or opaouants, such as titanium dioxide, food dyes, lakes, natural vegetable colorants, iron oxides, silicates,. sulfates, magnesium hydroxide and aluminum hydroxide;
coolants, such as halogenated hydrocarbons (e.g., trichloroethane, trichloroethylene, dichloromethane, fluorotrichloromethane), diethylether and liquid nitrogen;
cryoprotectants, such as trehelose, phosphates, citric acid, tartaric acid, gelatin, dextran and mannitol;
diluents or fillers, such as lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starches, directly compressible starch, microcrystalline cellulose, cellulosics, sorbitol, sucrose, sucrose-based materials, calcium sulfate, dibasic calcium phosphate and dextrose;
disintegrants or super disintegrants, such as croscarmellose sodium, starch, starch derivatives, clays, gums, cellulose, cellulose derivatives, alginates, crosslinked polyvinypyrrolidone, sodium starch glycolate and microcrystalline cellulose;
hydrogen bonding agents, such as magnesium oxide;
flavorants or desensitizers, such as spray-dried flavors, essential oils and ethyl vanillin;
ion-exchange resins, such as styrene/divinyl benzene copolymers, and quaternary ammonium compounds;
plasticizers, such as polyethylene glycol, citrate esters (e.g., triethyl citrate, acetyl triethyl citrate, acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin, propylene glycol, phthalate esters (e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol and dibutyl seccate;
preservatives, such as ascorbic acid, boric acid, sorbic acid, benzoic acid, and salts thereof, parabens, phenols, benzyl alcohol, and quaternary ammonium compounds;
solvents, such as alcohols, ketones, esters, chlorinated hydrocarbons and water;
sweeteners, including natural sweeteners such as maltose, sucrose, glucose, sorbitol, glycerin and dextrins, and artificial sweeteners, such as aspartame, saccharine and saccharine salts; and thickeners (viscosity modifiers, thickening agents), such as sugars, polyvinylpyrrolidone, cellulosics, polymers and alginates.
Additives can also be materials such as proteins (e.g., collagen, gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates (e.g., alginates, carrageenan, cellulose derivatives, pectin, starch, chitosan); gums (e.g., xanthan gum, gum arabic);
spermaceti;
natural or synthetic waxes; carnuaba wax; fatty, acids (e.g., stearic acid, hydroxystearic acid); fatty alcohols; sugars; shellacs, such as those based on sugars (e.g., lactose, sucrose, dextrose) or starches; polysaccharide-based shellacs (e.g., maltodextrin and maltodextrin derivatives, dextrates, cyclodextrin and cyclodextrin derivatives);
cellulosic-based shellacs (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, cellulose acetate butyrate, cellulose acetate trimellitate, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate);
inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc and titania; polyols, such as -mannito], xylitol and sorbitol; polyethylene glycol esters; and polymers, such as alginates, poly(lactide coglycolide), gelatin, crosslinked gelatin, and agar-agar.
It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
6. Dosage Forms The compositions of the present invention can be processed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, coating, comminution, compression, cryopelletization, encapsulation, extrusion, wet granulation, dry granulation, homogenization, inclusion complexation, lyophilization, melting, microencapsulation, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The compositions can be provided in the form of a minicapsule, a capsule, a .tablet, an implant, a troche, a lozenge (minitablet), a temporary or permanent suspension, an ovule, a suppository, a wafer, a chewable tablet, a quick or fast dissolving tablet, an effervescent tablet, a buccal or sublingual solid, a granule, a film, a sprinkle, a pellet, a bead, a pill, a powder, a triturate, a platelet, a strip or a sachet.
Compositions can also be administered as a "dry syrup", where the finished dosage form is placed directly on the tongue and swallowed or followed with a drink or beverage. These forms are well known in the art and are packaged appropriately. The compositions can be formulated for oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal delivery, although oral delivery is presently preferred.
The pharmaceutical composition and/or the solid carrier particles can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, or enzyme degradable coatings. Multiple coatings can be applied for desired performance. Further, the dosage form can be designed for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release. For release/absorption control, solid carriers can be made of various component types and levels or thicknesses of coats, with or without an active ingredient. Such diverse solid carriers can be blended in a dosage form to achieve a desired performance. The definitions of these terms are known to those skilled in the art. In addition, the dosage form release profile can be effected by a polymeric matrix composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition. Without wishing to be bound by theory, it is believed that the release may be effected through favorable diffusion, dissolution, erosion, ion-exchange, osmosis or combinations thereof.
When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule. Although not limited to capsules, such dosage forms can further be coated with, for example, a seal coating, an enteric coating, an extended release coating, or a targeted delayed release coating. These various coatings are known in the art, but for clarity, the following brief descriptions are provided:
Seal coating, or coating with isolation layers: Thin layers of up to 20 microns in thickness can be applied for variety of reasons, including for particle porosity reduction, to reduce dust, for chemical protection, to mask taste, to reduce odor, to minimize gastrointestinal irritation, etc. The isolating effect is proportional to the thickness of the coating. Water soluble cellulose ethers are preferred for this application.
HPMC and ethyl cellulose in combination, or Eudragit E100, may be particularly suitable for taste masking applications. Traditional enteric coating materials listed elsewhere can also be applied to form an isolating layer.
Extended release coating: The term "extended release coating" as used herein means a coating designed to effect delivery over an extended period of time.
Preferably, the extended release coating is a pH-independent coating formed of, for example, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic esters, or sodium carboxymethyl cellulose.
Various extended release dosage forms can be readily designed by one skilled in art to achieve delivery to both the small and large intestines, to only the small intestine, or to only the large intestine, depending upon the choice of coating materials and/or coating thickness.
Enteric coating: The term "enteric coating" as used herein relates to a mixture of pharmaceutically acceptable excipients which is applied to, combined with, mixed with or otherwise added to the carrier or composition. The coating may be applied to a compressed or molded or extruded tablet, a gelatin capsule, and/or pellets, beads, granules or particles of the carrier or composition. The coating may be applied through an aqueous dispersion or after dissolving in appropriate solvent. Additional additives and their levels, and selection of a primary coating material or materials will depend on the following properties:
1. resistance to dissolution and disintegration in the stomach;
2. impermeability to gastric fluids and drug/carrier/enzyme while in the stomach;
3. ability to dissolve or disintegrate rapidly at the target intestine site;
4. physical and chemical stability during storage;
5. non-toxicity;
6. easy application as a coating (substrate friendly); and 7. economical practicality.
Dosage forms of the compositions of the present invention can also be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to effect release in the lower gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablettmold (coated or uncoated) containing granules, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
The term "delayed release" as used herein refers to the delivery so that the release can be accomplished at some generally predictable location in the lower intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. The preferred method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH
about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. The preferred polymers for use in the present invention are anionic carboxylic polymers. The more preferred polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:
Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7.
Acrylic polymers (preferred). The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution.
Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonio methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE
(Rohm is Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for extended release. The Eudragit series E
dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine.
Cellulose Derivatives (also preferred). Examples of suitable cellulose derivatives are:
ethyl cellulose;
reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH > 6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles < I m. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides;
cellulose acetate trimellitate (Eastman);
methylcellulose (Pharmacoat, Methocel);
hydroxypropyl methyl cellulose phthalate (HPMCP).
The performance can vary based on the degree and type of substitution. HP-50, HP-55, HP-55S, HP-55F grades are suitable;
hydroxypropyl methyl cellulose succinate (HPMCS; AQOAT (Shin Etsu)).
The performance can vary based on the degree and type of substitution.
Suitable grades include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions;
Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids; and Cotteric (by Colorcon).
Combinations of the above materials can also be used.
The coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well 1s known in the art. Suitable plasticizers include: triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the lower intestinal tract is reached.
Colorants, detackifiers, surfactants, antifoaming agents, lubricants, stabilizers such as hydroxy propyl cellulose, acid/base may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
A particularly suitable methacrylic copolymer is Eudragit L.RTM, particularly L-30D.RTM and Eudragit 100-55.RTM, manufactured by Rohm Phanna, Germany. In Eudragit L-30 D.RTM, the ratio of free carboxyl groups to ester groups is approximately 1: 1. Further, the copolymer is known to be insoluble in gastrointestinal fluids having pH
below 5.5, generally 1.5-5.5, i.e., the pH generally present in the fluid of the upper gastrointestinal tract, but readily soluble or partially soluble at pH above 5.5, i.e., the pH
generally present in the fluid of lower gastrointestinal tract.
Another methacrylic acid polymer which is suitable for use in coating the composition or solid carrier which can be employed in the compositions and methods described herein, either alone or in combination with other coatings, is Eudragit S.RTM, manufactured by Rohm Pharma, Germany. Eudragit S® differs from Eudragit L=
D.RTM only insofar as the ratio of free carboxyl groups to ester groups is approximately io 1:2. Eudragit S.RTM is insoluble at pH below 5.5, but unlike Eudragit L-30-D.RTM, is poorly soluble in gastrointestinal fluids having pH of 5.5-7.0, such as is present in the small intestine media. This copolymer is soluble at pH 7.0 and above, i.e., the pH
generally found in the colon. Eudragit S.RTM can be used alone as a coating to provide delivery of beginning at the large intestine via a delayed release mechanism.
In addition, Eudragit S.RTM, being poorly soluble in intestinal fluids below pH 7, can be used in combination with Eudragit L-30-D.RTM, soluble in intestinal fluids above pH
5.5, in order to effect a delayed release composition. The more Eudragit L-30 D.RTM
used the more proximal realease and delivery begins, and the more Eudragit S.RTM used, the more distal release and delivery begins Both Eudragit L-30-D-RTM and Eudragit S.RTM can be substituted with other pharmaceutically acceptable polymers with similar pH solubility characteristics.
Preferred materials include shellac, acrylic polymers, cellulosic derivatives, polyvinyl acetate phthalate, and mixtures thereof. More preferred materials include Eudragit series E, L, S, RL, RS, NE, L.RTM, L300.RTM, S.RTM, 100-55RTM, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric. Most preferred materials include Eudragit series L.RTM, L300.RTM, S.RTM, L100-55RTM, cellulose acetate phthalate, Aquateric, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric.
WO 01/37808 PCT[US00132255 Extended release. and targeted delayed release coatings for dosage forms of the compositions of the present invention are described more completely in U.S.
Patent Nos.
5,622,721 and 5,686,105, the disclosures of which are incorporated herein by reference in their entirety.
Fast-Disintegrating Coatings for Immediate Release: Immediate release coating of solid carriers is commonly used to improve product elegance as well as for a moisture barrier, and taste and odor masking. Rapid breakdown of the film in gastric media is important, leading to effective disintegration and dissolution. Eudragit RD]
00 (Rohm) is an example of such a coating. It is a combination of a water insoluble cationic to methacrylate copolymer with a water soluble cellulose ether. In powder form, it is readily dispensible into an easily sprayable suspension that dries to leave a smooth film.
Such films rapidly disintegrate in aqueous media at a rate that is independent of pH and film thickness.
7. Processes The compositions of the present invention can be prepared by a variety of processes to apply an encapsulation coat onto a substrate or to forma substrate-free solid carrier such as a multiparticulate or a powder. The commonly utilized coating and pelletization processes include balling, spheronization, extrusion, spray congealing, spray drying, pan coating, fluidized bed coating, melt extrusion, crystallization, cryopelletization, nanoencapsulation, coacervation, etc. It is also clear to one skilled in the art that appropriate additives can also be introduced to the composition or during the processes to facilitate the preparation of the solid carrier or the dosage forms, depending on the need of the individual process.
A coating process frequently involves spraying a coating solution onto a substrate. The coating solution can be a molten solution of the encapsulation coat composition free of a dispersing medium. The coating solution can also be prepared by solubilizing or suspending the composition of the encapsulation coat in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. At the end of the coating process, the residual dispersing medium can be further removed to a desirable level utilizing appropriate drying processes, such as vacuum evaporation, heating, freeze drying, etc.
A pelletization process typically involves preparing a molten solution of the composition of the solid carrier or a dispersion of the composition of the solid carrier solubilized or suspended in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. Such solution or dispersion is then passed through a certain opening to achieve the desired shape, size, and other properties. Similarly, appropriate drying processes can be adopted to control the level of the residual dispersing medium, if necessary.
The processes described above, the combination of the processes, or the modification of the processes are well know in the art. Some of the processes are briefly described herein for reference.
Balling, Spheronization or Extrusion In a broad sense, pellets are very much like granules and bead; the techniques for producing pellets can also produce granules, beads, etc. Pellets, granules or beads are formed with the aid of a pelletizer, spheronizer or extruder. The pelletizer, spheronizer or extruder is able to form approximately spherical bodies from a mass of finely divided particles continuously, by a rolling or tumbling action on a flat or curved surface with the addition of a liquid.
Pelletizers can be classified based on the angle of their axis as horizontal drum or inclined dish pelletizers. Rotary fluidized granulators can also be used for pelletization.
A standard fluidized drier bowl can be replaced with a rotating plate as an air distributor.
For granulation, a binder liquid is sprayed from via one or two binary nozzles located axially to the rotational movement of the powder bed. This operation results in rounding of the granules to approximately spherical pellets. Such balling or agitation techniques can be influenced by operating conditions, such as bridging/binding liquid requirements, residence time of the material in the pelletizer, speed and angle of inclination of the pelletizer, amount of material fed to the pelletizer, choice and levels of binder, etc. One skilled in the art can readily adjust such factors to produce a satisfactory product.
_67-The components of the invention can also be self binding. Liquid components can be pelletized with an the aid of suitable solidifying, binding or thickening agents.
Similarly, the choice of an appropriate binder for a given application is readily determined by one skilled in the art. At a minimum, the binder must be capable of wetting the surfaces of the particle being pelletized or granulated. Binders must have sufficient wet strength to allow agglomerates to be handled, and sufficient dry strength to make them suitable for their intended purposes. Each process, however, makes use of a different system of forces and may require a different agglomerate strength.
The final selection of the binder should be made on the basis of the type of equipment that is used.
The size and size distribution of pellets, bulk density, strength and flow properties also affect the performance of the pellets, and these properties can be adjusted by one skilled in the art by the inclusion of additives, choice of equipment, and processing conditions.
Extrusion Extrusion is a well-known method of applying pressure to a composition (damp or melted) until it flows through an orifice or a defined opening. The extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion.
Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders.
Encapsulation by Extrusion: In this method, the lipid composition in the form of an emulsion is added to a low moisture melt of low maltodextrin, or sugar, or modified edible starch, mixed and extruded into a cold bath. The solidified composition can be further ground down. Optionally, centrifugal extrusion can be utilized for efficiency.
Melt Extrusion: Components of the invention can be melted and extruded with a continuous, solvent free extrusion process, with or without inclusion of additives. Such a process is well-established and well-known to skilled practitioners in the art.
Spheronization Spheronization is the process of converting material into spheres, the shape with the lowest surface area to volume ratio. Spheronization typically begins with damp extruded particles. The extruded particles are broken into uniform lengths instantaneously and gradually transformed into spherical shapes. In addition, powdered raw materials, which require addition of either liquid or material from a mixer, can be processed in an air-assisted spheronizer.
Spray Congealing Spray congealing is method that is generally used in changing the structure of the materials, to obtain free flowing powders- from liquids and to provide pellets ranging in size from about 0.25 to 2.0 mm. Spray congealing is process in which a substance of interest is allowed to melt, disperse, or dissolve in a hot melt of other additives, and is then sprayed into an air chamber wherein the temperature is below the melting point of the formulation components, to provide spherical congealed pellets. The air removes the latent heat of fusion. The temperature of the cooled air used depends on the freezing point of the product. The particles are held together by solid bonds formed from the congealed melts. Due to the absence of solvent evaporation in most spray congealing processes, the particles are generally non porous and strong, and remain intact upon agitation. The characteristics of the final congealed product depend in part on the properties of the additives used. The rate of feeding and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet. The feed should have adequate viscosity to ensure homogeneity. The conversion of molten feed into powder is a single, continuous step. Proper atomization and a controlled cooling rate are critical to obtain high surface area, uniform and homogeneous congealed pellets.
Adjustment of these parameters is readily achieved by one skilled in the art.
The spray congealing method is particularly suitable for heat labile substances, since ambient temperature is used to dry, and for moisture sensitive substances, since non-aqueous compositions can be utilized. Spray congealing is similar to spray drying, except that no solvent is utilized- Spray congealing is a uniform and rapid process, and is completed before the product comes in contact with any equipment surface. Most additives that are solid at room temperature and melt without decomposition are suitable for this method.
Conventional spray dryers operating with cool inlet air have been used for spray congealing. Several methods of atomization of molten mass can be employed, such as pressure, or pneumatic or centrifugal atomization. For persons skilled in the spray congealing art, it is well known that several formulation aspects, such as matrix materials, viscosity, and processing factors, such as temperature, atomization and cooling rate affect the quality (morphology, particle size distribution, polymophism and dissolution characteristics) of spray congealed pellets. The spray congealed particles may be used in tablet granulation form, encapsulation form, or can be incorporated into a liquid suspension form.
Solvent Dehydration (Spray Drying) For compositions that are oily in nature, the spray drying technique is commonly employed. The oily material is commonly mixed with a polymeric material, such as gelatin, vegetable gum, modified starch, dextrin, or other appropriate additives. An emulsifier is added, if needed, to form an oil-in-water emulsion. The emulsion is atomized into a column of heated air in a drying chamber, resulting in rapid evaporation of water. Alternatively, the emulsion is atomized directly into a polar solvent, such as isopropanol, ethanol, glycerol or polyglycols, to dehydrate the aerosolized particle. This method is particularly suitable for compositions containing lipophilic actives or additives that result in lipophilic cores. Spray drying/solvent dehydration can also be applied to hydrophilic active ingredients or additives to form an oil in water emulsion which is spray dried. This results in a homogenous solid composition. Furthermore, water or organic solvent based formulations can be spray dried by using inert process gas, such as nitrogen, argon and the like.
Crystallization Components of the present invention can be dissolved in appropriate solvents and subjected to spherical crystallization techniques well-known in the art.
Nanoencapsulation Nanoencapsulation involves solubilizing an aqueous solution of an active ingredient and other components in a weakly polar vehicle. Micelles are formed with the active in an organic outer phase. Then, an amphiphilic monomer is added to the lipophilic external phase. The mixed micelles thus formed are then polymerized with the aid of a suitable procedure, such as UV or gamma radiation, heat, or chemical agents.
the hardened solidified micelles are made to undergo phase exchange by replacing an outer lipophilic vehicle by water. By selecting appropriate monomers, networking agents and auxiliary materials, nanoncapsules as small as 80 to 250 nm can be prepared.
Supercritical Fluid Processes Components of the present invention can be dispersed in a supercritical fluid and crystallized as needed. Current techniques involving supercritical fluids include precipitation by rapid expansion of supercritical solutions, gas anti-solvent processes, and precipitation from gas saturated solutions.
Coacervation Coacervation is a transfer of macromolecules with film properties from a solvated state in a coacervation phase into a phase in which there is a film around each particle.
The coacervation method involves dispersing the composition in a dispersion of a polymeric colloid, such as gelatin alginate, and shock treating the mixture with temperature or pH, etc., to generate a two-phase system. The desired phase is then hardened with a cross-linking agent, such as glutaraldehyde.
- - - ------ ------ -CA
Cryopelletization The cryopelletization procedure allows conversion of a molten mass, aqueous solution or suspension into solid, bead-like particles. The molten mass solutions or suspensions are dripped by means of an appropriately designed device into liquid nitrogen. The production of small drops and liquid nitrogen cooling permit very rapid and uniform freezing of the material processed. The pellets are further dried in conventional freeze dryers. Cryopelletization can also be carried out under aseptic conditions for sterile processing. The most critical step producing spherical particles by globulization is the droplet formation. Droplet formation is influenced by formulation related variables, such as the nature of the active ingredient and additives, viscosity, total solid content, surface tension, etc. Extra care must be undertaken with processing of suspensions to ensure homogeneity. In addition, equipment design and processing variable also play an important role. One skilled in the art can readily balance the various factors to produce a satisfactory product. Enteric matrix pellets can be formed that include polyacrylic acid (e.g. Carbopol) with a high molecular weight polyethylene (such as PEG-20,000).
Other processes suitable for producing solid compositions of the pharmaceutical compositions of the present invention include extrusion and spray chilling.
These processes are described in detail in U.S. Patent Nos. 5,965,161 and 5,539,000 respectively.
For processing of encapsulated compositions, various methods can be used. The term "microencapsulation" applies to enclosure or encasement in microcapsules.
Microencapsulation is a means of applying coatings to small particles of solids or droplets of liquids and dispersions. The terms "coated", "protected" or "layered" are commonly used interchangeably with the term "encapsulated". All of these terms can be used to refer to practically any core material that is encased or enclosed in an outer shell.
Typical equipment used to apply coating includes a conventional pan (Pellegrini; Italy), a modified perforated pan (multicoater, Thomas Eng., IL) or a Wurster coater in a Glatt powder doater/granulator (Glatt Airtechniques).
Solvent Based Solution Coating Solvent-based coating is when the components of the invention are solubilized and/or dispersed in a solvent. The solvent can be aqueous. When the solvent is aqueous-based, the components can be emulsified with an appropriate emulsifier, organic solvent, or a supercritical fluid. Solvents with a-lower melting point than water and higher evaporation numbers are preferred. Solvent mixtures with other organic solvents or water are often employed to get appropriate viscosity and component solubilization.
Typical solvents include ethanol, methanol, isopropanol, acetone, dichloromethane, trichloromethane and ethyl acetate. Appropriate polymers can also be added as needed.
Cellulosic derivatives and polymethacrylates are particularly suitable additives for organic solvent coating. Dissolution and solubilization of the components is facilitated by rigorous stirring or heating. Plasticizers may be also be added to stimulate dissolution.
Colorants and antisticking agents can be employed as needed.
Substrate surface area, shape, porosity and stability are important determinants of good coating. Spherical particles are preferred, and these may be produced through spheronization or a spherical crystallization process. Crystals or compact granules from dry compaction or extrusion processes, often available commercially, serve as good substrates.
Encapsulation can be conducted by traditional pan coating or fluidized bed techniques. Several process (air supply, temperature, spray rate, spray system, powder feed, attrition) and formulation factors determine the quality of the end product, and one skilled in the art can readily adjust such parameters as needed.
Air suspension in a rotary fluidized bed granulator can used to deposit the encapsulation coat on to a substrate, thus allowing a high rate of drug application with low drug loss. Furthermore, both aqueous and organic solvents can be used. The Wurster process, an air suspension technique, is more suitable for encapsulations involving very fine powders.
CA
Solvent-Free Coating This process entails using coating materials that can be applied in a molten state.
The selection of proper coating materials depends on melting point, melting point range and the viscosity in the liquid state. A fluidized bed is ideal for molten coatings of substrates that range from about 100 microns to about 2000 microns in size.
Fluidized bed coating, spraying molten materials, involves achieving a proper balance of process parameters that allow proper encapsulation to occur. Substrate particles that are suspended and separated from each other by. the fluidization air enter a zone of finely atomized coating liquid. Coating occurs as the liquid droplets, which are substantially smaller in size than substrate, impact the particles, spread, and solidify.
Multiple layers can be coated, and the completion of spraying is followed by a product stabilization or cooling step. Some critical success parameters include bed temperature, atomization, atomization fluid temperature, or droplet size, spray type, spray rate, rate of coating droplet solidification on particle surfaces, particle size, shape, etc: Inert materials such as sodium chloride, citric acid, potassium chloride can serve as substrates.
One skilled in the art can readily adjust such parameters to achieve a satisfactory product.
The processes described above are suitable for treating substrate-based compositions or non-substrate-based compositions of the present invention.
Thus, in one embodiment, pharmaceutical compositions of the present invention do not include a seed particle, such as a conventional drug or other additive aggregate starch or sugar bead.
Instead, the compositions are processed, and the components are chosen, such that a solid composition is formed without the need to coat the composition onto a substrate bead. Such compositions can be in the form of beadlets, beads, granules, pellets, etc., that have an approximately homogenous distribution of active ingredient, surfactant, triglyceride and/or additives. These compositions can be produced by means of balling in pelletizers or fluid bed granulators, and compaction or extrusion/spheronization. In addition, these compositions can be produced using solvent-free spray congealing processes or dropping (globulization) methods. Dropping procedures involve conversion of aqueous solutions or suspensions to a solid form. Congealing of the liquid droplets in cooling baths can aided by a chemical reaction (e.g., insoluble salt or complex formation), a sol/gel transition, or by freezing in a coolant bath of liquid nitrogen or halogenated hydrocarbons.
8. Specific Formulations In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant.
Optionally, the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
Prior art has used surfactants in formulating coated bead compositions to provide a wetting function, to enable hydrophobic drugs to properly adhere to beads and/or water-soluble binders. For example, U.S. Patent No. 4,717,569 to Harrison et al.
discloses coated bead compositions of hydrophobic steroid compounds wetted by a hydrophilic surfactant and adhered to the beads by a water-soluble binder. The steroid compound is present as finely divided particles, held to the beads by the binder. The present inventors have surprisingly found that proper choice of surfactants and other components allows compositions to be prepared with a wide variety of hydrophilic or hydrophobic active ingredients. For example, while the Harrison reference discloses the use of surfactants as wetting agents, the present inventors have found that surfactants at higher levels, i.e., in amounts far in excess of the amounts necessary or appropriate for a wetting function, enable a pharmaceutical active ingredient to be fully or at least partially solubilized in the encapsulation coating material itself, rather than merely physically bound in a binder matrix. In fact, while binders can optionally be used in the 25-- compositions of the present invention, the higher surfactant concentrations of the present invention, i.e., solubilizing amounts, obviate the need for binders and render them optional instead of necessary.
The amount of hydrophilic surfactant used in this embodiment can be adjusted so as to at least partially solubilize the pharmaceutical active ingredient, with the optional lipophilic surfactants and triglycerides *chosen to further increase the pharmaceutical active ingredient's solubility.
A further advantage believed to accrue from the pharmaceutical compositions of the present invention is that upon administration of the composition to a patient, the high levels of surfactants and other components present in the composition facilitate the rapid solubilization of the pharmaceutical active ingredient. Thus, while the prior art composition of Harrison contains a drug in a form which requires further solubilization in vivo, such as by emulsification and micellization in the gastrointestinal tract, the active ingredient in compositions of the present invention is at least partially solubilized in the composition itself, and is further provided with surfactants and other components in the composition to facilitate rapid dispersion (emulsification/micellization) and sustained solubilization of the active ingredient upon administration.
It should be noted that in this embodiment, the encapsulation coat can alternatively be formulated without an active ingredient. In this aspect, an active ingredient can be provided in the composition itself but not in the encapsulation coat, if desired. While not presently preferred, such a formulation delivers the active ingredient to the patient along with the surfactants and other components to facilitate dispersion (emulsification/micellization), thus still providing more rapid active ingredient presentation to the absorption site. Alternatively, the active ingredient can be administered in a separate dosage form, including a conventional dosage form, prior to, concurrently with, or subsequent to administration of the present compositions, to achieve similar advantages.
The optional lipophilic surfactant and triglycerides can be used as desired to further enhance solubilization of the active ingredient, or to promote dispersion (emulsification/micellization) in vivo, or to promote in vivo absorption at the absorption site.
.For more hydrophilic active ingredients, the materials of the encapsulation coat provides components to promote efficient transport of the active ingredient across the barrier membrane to promote more effective absorption. For these active ingredients, it is preferable to include a lipophilic component in the encapsulation coat.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a lipophilic component, such as a lipophilic surfactant or a triglyceride. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant. In this embodiment, the lipophilic surfactant or triglyceride can be present in amounts to enable at least partial solubilization of an active ingredient in the encapsulation coat, in the composition, or separately administered.
In another embodiment, the solid pharmaceutical composition effectively presents a lipophilic component with or without an active ingredient to help promote absorption of a hydrophilic active.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a iipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
In this embodiment, the solid pharmaceutical composition is formulated without the need for a substrate seed particle. The active ingredient, surfactants and triglycerides in the chosen combination are processed, with appropriate excipients if necessary, to form solid carriers in the absence of a seed substrate. Preferably, the components are chosen to at least partially solubilize the active ingredient, as described above.
Compositions can also be administered as a "dry syrup", where the finished dosage form is placed directly on the tongue and swallowed or followed with a drink or beverage. These forms are well known in the art and are packaged appropriately. The compositions can be formulated for oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal delivery, although oral delivery is presently preferred.
The pharmaceutical composition and/or the solid carrier particles can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, or enzyme degradable coatings. Multiple coatings can be applied for desired performance. Further, the dosage form can be designed for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release. For release/absorption control, solid carriers can be made of various component types and levels or thicknesses of coats, with or without an active ingredient. Such diverse solid carriers can be blended in a dosage form to achieve a desired performance. The definitions of these terms are known to those skilled in the art. In addition, the dosage form release profile can be effected by a polymeric matrix composition, a coated matrix composition, a multiparticulate composition, a coated multiparticulate composition, an ion-exchange resin-based composition, an osmosis-based composition, or a biodegradable polymeric composition. Without wishing to be bound by theory, it is believed that the release may be effected through favorable diffusion, dissolution, erosion, ion-exchange, osmosis or combinations thereof.
When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule. Although not limited to capsules, such dosage forms can further be coated with, for example, a seal coating, an enteric coating, an extended release coating, or a targeted delayed release coating. These various coatings are known in the art, but for clarity, the following brief descriptions are provided:
Seal coating, or coating with isolation layers: Thin layers of up to 20 microns in thickness can be applied for variety of reasons, including for particle porosity reduction, to reduce dust, for chemical protection, to mask taste, to reduce odor, to minimize gastrointestinal irritation, etc. The isolating effect is proportional to the thickness of the coating. Water soluble cellulose ethers are preferred for this application.
HPMC and ethyl cellulose in combination, or Eudragit E100, may be particularly suitable for taste masking applications. Traditional enteric coating materials listed elsewhere can also be applied to form an isolating layer.
Extended release coating: The term "extended release coating" as used herein means a coating designed to effect delivery over an extended period of time.
Preferably, the extended release coating is a pH-independent coating formed of, for example, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic esters, or sodium carboxymethyl cellulose.
Various extended release dosage forms can be readily designed by one skilled in art to achieve delivery to both the small and large intestines, to only the small intestine, or to only the large intestine, depending upon the choice of coating materials and/or coating thickness.
Enteric coating: The term "enteric coating" as used herein relates to a mixture of pharmaceutically acceptable excipients which is applied to, combined with, mixed with or otherwise added to the carrier or composition. The coating may be applied to a compressed or molded or extruded tablet, a gelatin capsule, and/or pellets, beads, granules or particles of the carrier or composition. The coating may be applied through an aqueous dispersion or after dissolving in appropriate solvent. Additional additives and their levels, and selection of a primary coating material or materials will depend on the following properties:
1. resistance to dissolution and disintegration in the stomach;
2. impermeability to gastric fluids and drug/carrier/enzyme while in the stomach;
3. ability to dissolve or disintegrate rapidly at the target intestine site;
4. physical and chemical stability during storage;
5. non-toxicity;
6. easy application as a coating (substrate friendly); and 7. economical practicality.
Dosage forms of the compositions of the present invention can also be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to effect release in the lower gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablettmold (coated or uncoated) containing granules, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
The term "delayed release" as used herein refers to the delivery so that the release can be accomplished at some generally predictable location in the lower intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. The preferred method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH
about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. The preferred polymers for use in the present invention are anionic carboxylic polymers. The more preferred polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:
Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7.
Acrylic polymers (preferred). The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution.
Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonio methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE
(Rohm is Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for extended release. The Eudragit series E
dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine.
Cellulose Derivatives (also preferred). Examples of suitable cellulose derivatives are:
ethyl cellulose;
reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH > 6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles < I m. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides;
cellulose acetate trimellitate (Eastman);
methylcellulose (Pharmacoat, Methocel);
hydroxypropyl methyl cellulose phthalate (HPMCP).
The performance can vary based on the degree and type of substitution. HP-50, HP-55, HP-55S, HP-55F grades are suitable;
hydroxypropyl methyl cellulose succinate (HPMCS; AQOAT (Shin Etsu)).
The performance can vary based on the degree and type of substitution.
Suitable grades include AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions;
Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids; and Cotteric (by Colorcon).
Combinations of the above materials can also be used.
The coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well 1s known in the art. Suitable plasticizers include: triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the lower intestinal tract is reached.
Colorants, detackifiers, surfactants, antifoaming agents, lubricants, stabilizers such as hydroxy propyl cellulose, acid/base may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.
A particularly suitable methacrylic copolymer is Eudragit L.RTM, particularly L-30D.RTM and Eudragit 100-55.RTM, manufactured by Rohm Phanna, Germany. In Eudragit L-30 D.RTM, the ratio of free carboxyl groups to ester groups is approximately 1: 1. Further, the copolymer is known to be insoluble in gastrointestinal fluids having pH
below 5.5, generally 1.5-5.5, i.e., the pH generally present in the fluid of the upper gastrointestinal tract, but readily soluble or partially soluble at pH above 5.5, i.e., the pH
generally present in the fluid of lower gastrointestinal tract.
Another methacrylic acid polymer which is suitable for use in coating the composition or solid carrier which can be employed in the compositions and methods described herein, either alone or in combination with other coatings, is Eudragit S.RTM, manufactured by Rohm Pharma, Germany. Eudragit S® differs from Eudragit L=
D.RTM only insofar as the ratio of free carboxyl groups to ester groups is approximately io 1:2. Eudragit S.RTM is insoluble at pH below 5.5, but unlike Eudragit L-30-D.RTM, is poorly soluble in gastrointestinal fluids having pH of 5.5-7.0, such as is present in the small intestine media. This copolymer is soluble at pH 7.0 and above, i.e., the pH
generally found in the colon. Eudragit S.RTM can be used alone as a coating to provide delivery of beginning at the large intestine via a delayed release mechanism.
In addition, Eudragit S.RTM, being poorly soluble in intestinal fluids below pH 7, can be used in combination with Eudragit L-30-D.RTM, soluble in intestinal fluids above pH
5.5, in order to effect a delayed release composition. The more Eudragit L-30 D.RTM
used the more proximal realease and delivery begins, and the more Eudragit S.RTM used, the more distal release and delivery begins Both Eudragit L-30-D-RTM and Eudragit S.RTM can be substituted with other pharmaceutically acceptable polymers with similar pH solubility characteristics.
Preferred materials include shellac, acrylic polymers, cellulosic derivatives, polyvinyl acetate phthalate, and mixtures thereof. More preferred materials include Eudragit series E, L, S, RL, RS, NE, L.RTM, L300.RTM, S.RTM, 100-55RTM, cellulose acetate phthalate, Aquateric, cellulose acetate trimellitate, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric. Most preferred materials include Eudragit series L.RTM, L300.RTM, S.RTM, L100-55RTM, cellulose acetate phthalate, Aquateric, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, poly vinyl acetate phthalate, and Cotteric.
WO 01/37808 PCT[US00132255 Extended release. and targeted delayed release coatings for dosage forms of the compositions of the present invention are described more completely in U.S.
Patent Nos.
5,622,721 and 5,686,105, the disclosures of which are incorporated herein by reference in their entirety.
Fast-Disintegrating Coatings for Immediate Release: Immediate release coating of solid carriers is commonly used to improve product elegance as well as for a moisture barrier, and taste and odor masking. Rapid breakdown of the film in gastric media is important, leading to effective disintegration and dissolution. Eudragit RD]
00 (Rohm) is an example of such a coating. It is a combination of a water insoluble cationic to methacrylate copolymer with a water soluble cellulose ether. In powder form, it is readily dispensible into an easily sprayable suspension that dries to leave a smooth film.
Such films rapidly disintegrate in aqueous media at a rate that is independent of pH and film thickness.
7. Processes The compositions of the present invention can be prepared by a variety of processes to apply an encapsulation coat onto a substrate or to forma substrate-free solid carrier such as a multiparticulate or a powder. The commonly utilized coating and pelletization processes include balling, spheronization, extrusion, spray congealing, spray drying, pan coating, fluidized bed coating, melt extrusion, crystallization, cryopelletization, nanoencapsulation, coacervation, etc. It is also clear to one skilled in the art that appropriate additives can also be introduced to the composition or during the processes to facilitate the preparation of the solid carrier or the dosage forms, depending on the need of the individual process.
A coating process frequently involves spraying a coating solution onto a substrate. The coating solution can be a molten solution of the encapsulation coat composition free of a dispersing medium. The coating solution can also be prepared by solubilizing or suspending the composition of the encapsulation coat in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. At the end of the coating process, the residual dispersing medium can be further removed to a desirable level utilizing appropriate drying processes, such as vacuum evaporation, heating, freeze drying, etc.
A pelletization process typically involves preparing a molten solution of the composition of the solid carrier or a dispersion of the composition of the solid carrier solubilized or suspended in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. Such solution or dispersion is then passed through a certain opening to achieve the desired shape, size, and other properties. Similarly, appropriate drying processes can be adopted to control the level of the residual dispersing medium, if necessary.
The processes described above, the combination of the processes, or the modification of the processes are well know in the art. Some of the processes are briefly described herein for reference.
Balling, Spheronization or Extrusion In a broad sense, pellets are very much like granules and bead; the techniques for producing pellets can also produce granules, beads, etc. Pellets, granules or beads are formed with the aid of a pelletizer, spheronizer or extruder. The pelletizer, spheronizer or extruder is able to form approximately spherical bodies from a mass of finely divided particles continuously, by a rolling or tumbling action on a flat or curved surface with the addition of a liquid.
Pelletizers can be classified based on the angle of their axis as horizontal drum or inclined dish pelletizers. Rotary fluidized granulators can also be used for pelletization.
A standard fluidized drier bowl can be replaced with a rotating plate as an air distributor.
For granulation, a binder liquid is sprayed from via one or two binary nozzles located axially to the rotational movement of the powder bed. This operation results in rounding of the granules to approximately spherical pellets. Such balling or agitation techniques can be influenced by operating conditions, such as bridging/binding liquid requirements, residence time of the material in the pelletizer, speed and angle of inclination of the pelletizer, amount of material fed to the pelletizer, choice and levels of binder, etc. One skilled in the art can readily adjust such factors to produce a satisfactory product.
_67-The components of the invention can also be self binding. Liquid components can be pelletized with an the aid of suitable solidifying, binding or thickening agents.
Similarly, the choice of an appropriate binder for a given application is readily determined by one skilled in the art. At a minimum, the binder must be capable of wetting the surfaces of the particle being pelletized or granulated. Binders must have sufficient wet strength to allow agglomerates to be handled, and sufficient dry strength to make them suitable for their intended purposes. Each process, however, makes use of a different system of forces and may require a different agglomerate strength.
The final selection of the binder should be made on the basis of the type of equipment that is used.
The size and size distribution of pellets, bulk density, strength and flow properties also affect the performance of the pellets, and these properties can be adjusted by one skilled in the art by the inclusion of additives, choice of equipment, and processing conditions.
Extrusion Extrusion is a well-known method of applying pressure to a composition (damp or melted) until it flows through an orifice or a defined opening. The extrudable length varies with the physical characteristics of the material to be extruded, the method of extrusion, and the process of manipulation of the particles after extrusion.
Various types of extrusion devices can be employed, such as screw, sieve and basket, roll, and ram extruders.
Encapsulation by Extrusion: In this method, the lipid composition in the form of an emulsion is added to a low moisture melt of low maltodextrin, or sugar, or modified edible starch, mixed and extruded into a cold bath. The solidified composition can be further ground down. Optionally, centrifugal extrusion can be utilized for efficiency.
Melt Extrusion: Components of the invention can be melted and extruded with a continuous, solvent free extrusion process, with or without inclusion of additives. Such a process is well-established and well-known to skilled practitioners in the art.
Spheronization Spheronization is the process of converting material into spheres, the shape with the lowest surface area to volume ratio. Spheronization typically begins with damp extruded particles. The extruded particles are broken into uniform lengths instantaneously and gradually transformed into spherical shapes. In addition, powdered raw materials, which require addition of either liquid or material from a mixer, can be processed in an air-assisted spheronizer.
Spray Congealing Spray congealing is method that is generally used in changing the structure of the materials, to obtain free flowing powders- from liquids and to provide pellets ranging in size from about 0.25 to 2.0 mm. Spray congealing is process in which a substance of interest is allowed to melt, disperse, or dissolve in a hot melt of other additives, and is then sprayed into an air chamber wherein the temperature is below the melting point of the formulation components, to provide spherical congealed pellets. The air removes the latent heat of fusion. The temperature of the cooled air used depends on the freezing point of the product. The particles are held together by solid bonds formed from the congealed melts. Due to the absence of solvent evaporation in most spray congealing processes, the particles are generally non porous and strong, and remain intact upon agitation. The characteristics of the final congealed product depend in part on the properties of the additives used. The rate of feeding and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet. The feed should have adequate viscosity to ensure homogeneity. The conversion of molten feed into powder is a single, continuous step. Proper atomization and a controlled cooling rate are critical to obtain high surface area, uniform and homogeneous congealed pellets.
Adjustment of these parameters is readily achieved by one skilled in the art.
The spray congealing method is particularly suitable for heat labile substances, since ambient temperature is used to dry, and for moisture sensitive substances, since non-aqueous compositions can be utilized. Spray congealing is similar to spray drying, except that no solvent is utilized- Spray congealing is a uniform and rapid process, and is completed before the product comes in contact with any equipment surface. Most additives that are solid at room temperature and melt without decomposition are suitable for this method.
Conventional spray dryers operating with cool inlet air have been used for spray congealing. Several methods of atomization of molten mass can be employed, such as pressure, or pneumatic or centrifugal atomization. For persons skilled in the spray congealing art, it is well known that several formulation aspects, such as matrix materials, viscosity, and processing factors, such as temperature, atomization and cooling rate affect the quality (morphology, particle size distribution, polymophism and dissolution characteristics) of spray congealed pellets. The spray congealed particles may be used in tablet granulation form, encapsulation form, or can be incorporated into a liquid suspension form.
Solvent Dehydration (Spray Drying) For compositions that are oily in nature, the spray drying technique is commonly employed. The oily material is commonly mixed with a polymeric material, such as gelatin, vegetable gum, modified starch, dextrin, or other appropriate additives. An emulsifier is added, if needed, to form an oil-in-water emulsion. The emulsion is atomized into a column of heated air in a drying chamber, resulting in rapid evaporation of water. Alternatively, the emulsion is atomized directly into a polar solvent, such as isopropanol, ethanol, glycerol or polyglycols, to dehydrate the aerosolized particle. This method is particularly suitable for compositions containing lipophilic actives or additives that result in lipophilic cores. Spray drying/solvent dehydration can also be applied to hydrophilic active ingredients or additives to form an oil in water emulsion which is spray dried. This results in a homogenous solid composition. Furthermore, water or organic solvent based formulations can be spray dried by using inert process gas, such as nitrogen, argon and the like.
Crystallization Components of the present invention can be dissolved in appropriate solvents and subjected to spherical crystallization techniques well-known in the art.
Nanoencapsulation Nanoencapsulation involves solubilizing an aqueous solution of an active ingredient and other components in a weakly polar vehicle. Micelles are formed with the active in an organic outer phase. Then, an amphiphilic monomer is added to the lipophilic external phase. The mixed micelles thus formed are then polymerized with the aid of a suitable procedure, such as UV or gamma radiation, heat, or chemical agents.
the hardened solidified micelles are made to undergo phase exchange by replacing an outer lipophilic vehicle by water. By selecting appropriate monomers, networking agents and auxiliary materials, nanoncapsules as small as 80 to 250 nm can be prepared.
Supercritical Fluid Processes Components of the present invention can be dispersed in a supercritical fluid and crystallized as needed. Current techniques involving supercritical fluids include precipitation by rapid expansion of supercritical solutions, gas anti-solvent processes, and precipitation from gas saturated solutions.
Coacervation Coacervation is a transfer of macromolecules with film properties from a solvated state in a coacervation phase into a phase in which there is a film around each particle.
The coacervation method involves dispersing the composition in a dispersion of a polymeric colloid, such as gelatin alginate, and shock treating the mixture with temperature or pH, etc., to generate a two-phase system. The desired phase is then hardened with a cross-linking agent, such as glutaraldehyde.
- - - ------ ------ -CA
Cryopelletization The cryopelletization procedure allows conversion of a molten mass, aqueous solution or suspension into solid, bead-like particles. The molten mass solutions or suspensions are dripped by means of an appropriately designed device into liquid nitrogen. The production of small drops and liquid nitrogen cooling permit very rapid and uniform freezing of the material processed. The pellets are further dried in conventional freeze dryers. Cryopelletization can also be carried out under aseptic conditions for sterile processing. The most critical step producing spherical particles by globulization is the droplet formation. Droplet formation is influenced by formulation related variables, such as the nature of the active ingredient and additives, viscosity, total solid content, surface tension, etc. Extra care must be undertaken with processing of suspensions to ensure homogeneity. In addition, equipment design and processing variable also play an important role. One skilled in the art can readily balance the various factors to produce a satisfactory product. Enteric matrix pellets can be formed that include polyacrylic acid (e.g. Carbopol) with a high molecular weight polyethylene (such as PEG-20,000).
Other processes suitable for producing solid compositions of the pharmaceutical compositions of the present invention include extrusion and spray chilling.
These processes are described in detail in U.S. Patent Nos. 5,965,161 and 5,539,000 respectively.
For processing of encapsulated compositions, various methods can be used. The term "microencapsulation" applies to enclosure or encasement in microcapsules.
Microencapsulation is a means of applying coatings to small particles of solids or droplets of liquids and dispersions. The terms "coated", "protected" or "layered" are commonly used interchangeably with the term "encapsulated". All of these terms can be used to refer to practically any core material that is encased or enclosed in an outer shell.
Typical equipment used to apply coating includes a conventional pan (Pellegrini; Italy), a modified perforated pan (multicoater, Thomas Eng., IL) or a Wurster coater in a Glatt powder doater/granulator (Glatt Airtechniques).
Solvent Based Solution Coating Solvent-based coating is when the components of the invention are solubilized and/or dispersed in a solvent. The solvent can be aqueous. When the solvent is aqueous-based, the components can be emulsified with an appropriate emulsifier, organic solvent, or a supercritical fluid. Solvents with a-lower melting point than water and higher evaporation numbers are preferred. Solvent mixtures with other organic solvents or water are often employed to get appropriate viscosity and component solubilization.
Typical solvents include ethanol, methanol, isopropanol, acetone, dichloromethane, trichloromethane and ethyl acetate. Appropriate polymers can also be added as needed.
Cellulosic derivatives and polymethacrylates are particularly suitable additives for organic solvent coating. Dissolution and solubilization of the components is facilitated by rigorous stirring or heating. Plasticizers may be also be added to stimulate dissolution.
Colorants and antisticking agents can be employed as needed.
Substrate surface area, shape, porosity and stability are important determinants of good coating. Spherical particles are preferred, and these may be produced through spheronization or a spherical crystallization process. Crystals or compact granules from dry compaction or extrusion processes, often available commercially, serve as good substrates.
Encapsulation can be conducted by traditional pan coating or fluidized bed techniques. Several process (air supply, temperature, spray rate, spray system, powder feed, attrition) and formulation factors determine the quality of the end product, and one skilled in the art can readily adjust such parameters as needed.
Air suspension in a rotary fluidized bed granulator can used to deposit the encapsulation coat on to a substrate, thus allowing a high rate of drug application with low drug loss. Furthermore, both aqueous and organic solvents can be used. The Wurster process, an air suspension technique, is more suitable for encapsulations involving very fine powders.
CA
Solvent-Free Coating This process entails using coating materials that can be applied in a molten state.
The selection of proper coating materials depends on melting point, melting point range and the viscosity in the liquid state. A fluidized bed is ideal for molten coatings of substrates that range from about 100 microns to about 2000 microns in size.
Fluidized bed coating, spraying molten materials, involves achieving a proper balance of process parameters that allow proper encapsulation to occur. Substrate particles that are suspended and separated from each other by. the fluidization air enter a zone of finely atomized coating liquid. Coating occurs as the liquid droplets, which are substantially smaller in size than substrate, impact the particles, spread, and solidify.
Multiple layers can be coated, and the completion of spraying is followed by a product stabilization or cooling step. Some critical success parameters include bed temperature, atomization, atomization fluid temperature, or droplet size, spray type, spray rate, rate of coating droplet solidification on particle surfaces, particle size, shape, etc: Inert materials such as sodium chloride, citric acid, potassium chloride can serve as substrates.
One skilled in the art can readily adjust such parameters to achieve a satisfactory product.
The processes described above are suitable for treating substrate-based compositions or non-substrate-based compositions of the present invention.
Thus, in one embodiment, pharmaceutical compositions of the present invention do not include a seed particle, such as a conventional drug or other additive aggregate starch or sugar bead.
Instead, the compositions are processed, and the components are chosen, such that a solid composition is formed without the need to coat the composition onto a substrate bead. Such compositions can be in the form of beadlets, beads, granules, pellets, etc., that have an approximately homogenous distribution of active ingredient, surfactant, triglyceride and/or additives. These compositions can be produced by means of balling in pelletizers or fluid bed granulators, and compaction or extrusion/spheronization. In addition, these compositions can be produced using solvent-free spray congealing processes or dropping (globulization) methods. Dropping procedures involve conversion of aqueous solutions or suspensions to a solid form. Congealing of the liquid droplets in cooling baths can aided by a chemical reaction (e.g., insoluble salt or complex formation), a sol/gel transition, or by freezing in a coolant bath of liquid nitrogen or halogenated hydrocarbons.
8. Specific Formulations In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant.
Optionally, the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component.
Prior art has used surfactants in formulating coated bead compositions to provide a wetting function, to enable hydrophobic drugs to properly adhere to beads and/or water-soluble binders. For example, U.S. Patent No. 4,717,569 to Harrison et al.
discloses coated bead compositions of hydrophobic steroid compounds wetted by a hydrophilic surfactant and adhered to the beads by a water-soluble binder. The steroid compound is present as finely divided particles, held to the beads by the binder. The present inventors have surprisingly found that proper choice of surfactants and other components allows compositions to be prepared with a wide variety of hydrophilic or hydrophobic active ingredients. For example, while the Harrison reference discloses the use of surfactants as wetting agents, the present inventors have found that surfactants at higher levels, i.e., in amounts far in excess of the amounts necessary or appropriate for a wetting function, enable a pharmaceutical active ingredient to be fully or at least partially solubilized in the encapsulation coating material itself, rather than merely physically bound in a binder matrix. In fact, while binders can optionally be used in the 25-- compositions of the present invention, the higher surfactant concentrations of the present invention, i.e., solubilizing amounts, obviate the need for binders and render them optional instead of necessary.
The amount of hydrophilic surfactant used in this embodiment can be adjusted so as to at least partially solubilize the pharmaceutical active ingredient, with the optional lipophilic surfactants and triglycerides *chosen to further increase the pharmaceutical active ingredient's solubility.
A further advantage believed to accrue from the pharmaceutical compositions of the present invention is that upon administration of the composition to a patient, the high levels of surfactants and other components present in the composition facilitate the rapid solubilization of the pharmaceutical active ingredient. Thus, while the prior art composition of Harrison contains a drug in a form which requires further solubilization in vivo, such as by emulsification and micellization in the gastrointestinal tract, the active ingredient in compositions of the present invention is at least partially solubilized in the composition itself, and is further provided with surfactants and other components in the composition to facilitate rapid dispersion (emulsification/micellization) and sustained solubilization of the active ingredient upon administration.
It should be noted that in this embodiment, the encapsulation coat can alternatively be formulated without an active ingredient. In this aspect, an active ingredient can be provided in the composition itself but not in the encapsulation coat, if desired. While not presently preferred, such a formulation delivers the active ingredient to the patient along with the surfactants and other components to facilitate dispersion (emulsification/micellization), thus still providing more rapid active ingredient presentation to the absorption site. Alternatively, the active ingredient can be administered in a separate dosage form, including a conventional dosage form, prior to, concurrently with, or subsequent to administration of the present compositions, to achieve similar advantages.
The optional lipophilic surfactant and triglycerides can be used as desired to further enhance solubilization of the active ingredient, or to promote dispersion (emulsification/micellization) in vivo, or to promote in vivo absorption at the absorption site.
.For more hydrophilic active ingredients, the materials of the encapsulation coat provides components to promote efficient transport of the active ingredient across the barrier membrane to promote more effective absorption. For these active ingredients, it is preferable to include a lipophilic component in the encapsulation coat.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a lipophilic component, such as a lipophilic surfactant or a triglyceride. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, an ionic or non-ionic hydrophilic surfactant, or both a pharmaceutical active ingredient and a hydrophilic surfactant. In this embodiment, the lipophilic surfactant or triglyceride can be present in amounts to enable at least partial solubilization of an active ingredient in the encapsulation coat, in the composition, or separately administered.
In another embodiment, the solid pharmaceutical composition effectively presents a lipophilic component with or without an active ingredient to help promote absorption of a hydrophilic active.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate.
The encapsulation coat includes a pharmaceutical active ingredient and an ionic or non-ionic hydrophilic surfactant; a pharmaceutical active ingredient and a lipophilic component such as a iipophilic surfactant or a triglyceride; or a pharmaceutical active ingredient and both a hydrophilic surfactant and a lipophilic component.
In another embodiment, the solid pharmaceutical composition includes a solid carrier, wherein the solid carrier is formed of at least two components selected from the group consisting of pharmaceutical active ingredients; ionic or non-ionic hydrophilic surfactants; and lipophilic components such as lipophilic surfactants and triglycerides.
In this embodiment, the solid pharmaceutical composition is formulated without the need for a substrate seed particle. The active ingredient, surfactants and triglycerides in the chosen combination are processed, with appropriate excipients if necessary, to form solid carriers in the absence of a seed substrate. Preferably, the components are chosen to at least partially solubilize the active ingredient, as described above.
9. Methods The present invention also provides methods of using the above-described pharmaceutical composition. In one aspect, the present invention provides a method of treating a patient with a pharmaceutical active ingredient, the method including the steps of providing a dosage form of a pharmaceutical composition as described above, including an active ingredient, and administering the dosage form to the patient. The patient can be an animal, preferably a mammal, and more preferably a human.
In another aspect, the present invention provides a method including the steps of providing a dosage form of a pharmaceutical composition as described above, providing a dosage form of a pharmaceutical active ingredient, and administering the dosage forms to the patient. This method is advantageous when all or part of the active ingredient or an additional active ingredient is to be administered to the patient in a separate dosage form prior to, concurrently with, or subsequent to administration of the pharmaceutical composition.
In another aspect, the present invention provides a method of improving the palatability and/or masking the taste of a pharmaceutical active ingredient, by providing the active ingredient in a pharmaceutical composition as described above.
Since the active ingredient is encapsulated in a lipid coat, it will not instantaneously dissolve in the mouth, but will instead dissolve in a region past the oral cavity, thereby substantially avoiding or at least reducing undesirable contact between the active ingredient and the mouth.
In another aspect of the invention, the compositions enable gastric resistance or acid degradation reduction of the active ingredient.
In another aspect of the invention, the solid carrier improves the chemical stability of the active ingredient.
In another aspect of the invention, the solid carrier protects the upper gastrointestinal tract from the adverse effects of the active ingredient.
In another aspect, the present invention provides a method of improving the dissolution and/or absorption of a pharmaceutical active ingredient, by administering the active ingredient in a composition as described above, or co-administering the active ingredient with a composition as described above.
EXAMPLES
Example 1: Preparation of Coated Beads Compositions according to the present invention were prepared as follows. The specific components used are detailed in Examples 2-5.
A spraying solution of the coating materials was prepared by dissolving the desired amount of the active ingredient and mixing with the hydrophilic and/or lipophilic surfactants in an organic solvent or a mixture of organic solvents. The organic solvent used for the coating solution was a mixture of methylene chloride and isopropyl alcohol in a 3:1 to 1:1 weight ratio.
Commercially available sugar beads (30/35 mesh size) were coated in a conventional coating pan having a spray gun (Campbell Hausfield, DH 7500) with a nozzle diameter of 1.2 mm and an air pressure of 25 psi. The bed temperature was maintained at approximately 32 C during the spraying process. Appropriate amounts of }
talc were sprinkled on the beads during the spraying process to. reduce the agglomeration of coated beads. When the spraying process was completed, the coated beads were allowed to cool to room temperature. The coated beads were then dried under vacuum to minimize residual solvent levels. The dried, coated beads were then sieved and collected.
Example 2: Composition I
A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (glyburide), and a mixture of a hydrophilic surfactant (PEG-40 stearate) and a lipophilic surfactant (glycerol monolaurate). The components and their amounts were as follows:
WO 01/37808 PCr/US00/32255 Component Weight (g) % (w/w) Glyburide 1 0.8 PEG-40 stearate 33 25.2 Glycerol monolaurate 17 13.0 Non-pareil seed (30/35 mesh) 80 61.1 Example 3: Composition 11 A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (progesterone), a mixture of a hydrophilic surfactant (Solulan C-24) and two lipophilic components (deoxycholic acid and distilled monoglycerides). The components and their amounts were as follows:
Component Weight (g) % (w/w) Progesterone 12 8.6 Solulan C-24 (Amerchol)* 32 22.9 Distilled monoglycerides 8 5.7 Deoxycholic acid 8 5.7 Non-pareil seed (30/35 mesh) 80 57.1 * PEG-24 cholesterol ether Example 4: Composition III
A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (itraconazole), a mixture of non-ionic hydrophilic surfactants (Cremophor RH-40 and PEG-150 monostearate), an ionic hydrophilic surfactant (sodium taurocholate) and a lipophilic surfactant (glycerol monolaurate). The components and their amounts were as follows:
Component Weight (g) % (w/w) Itraconazole 20 9.7 Cremophor RH-40 (BASF)* 25 12.1 Glycerol monolaurate 10 4.8 Sodium taurocholate 5 2.4 PEG-150 monostearate 27 13.0 Non-pareil seed (30/35 mesh) 120 58.0 * PEG-40 hydrogenated castor oil Example 5: Composition IV
A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (omeprazole), a mixture of a two hydrophilic surfactants (PEG-150 monostearate and PEG-40 monostearate), and a triglyceride-containing lipophilic component (Maisine 35-1). The components and their amounts were as follows:
Component Weight (g) % (w/w) Omeprazole 16 8.8 PEG-150 monostearate 50.4 27.8 PEG-40 monostearate 25.2 13.9 Maisine 35-1 (Gattefosse)* 8.4 4.6 Magnesium carbonate 1.6 0.9 Non-pareil seed (30/35 mesh) 80 44.1 linoleic glycerides Example 6: Seal Coating The dried, coated beads of Example 3 were further seal coated by a polymer layer. The seal coating polymer layer was applied to the progesterone-coated beads in a Uni-Glatt fluid bed coater. Polyvinylpyrrolidone (PVP-K30) was dissolved in isopropyl alcohol to form a 5% w/w solution. This seal coating solution was sprayed onto the coated beads with a Wurster bottom spray insert. The inlet and outlet air temperature were maintained at 30 and 40 C, respectively. When the spraying process was complete, the beads were further dried by supplying dry air at 50-55 C for 5-15 minutes.
The seal coated beads were then allowed to cool in the apparatus by supplying dry air at 20-25 C for 5-15 minutes. The dried, seal coated beads were collected and stored in a container.
Example 7: Protective Coating The dried, coated beads of Example 5 were further coated with a protective polymer layer. The protective coating was applied to the omeprazole coated beads by spraying with a hydroxypropyl methylcellulose (HPMC) solution. The protective coating HPMC solution was prepared by dissolving 6 grams of HPMC in ethanol.
To this solution, methylene chloride was added followed by 2 mL of triethylcitrate as a plasticizer and I g of talc. the HPMC solution was sprayed on the beads as described in Example 6, and the protective coated beads were then dried and collected.
Example 8: Enteric Coating The dried, coated beads of Example 5 were further coated with an enteric coating layer. The enteric layer was applied to the omeprazole coated beads by spraying a Eudragit L100 solution. Eudragit LI00 is an acrylate polymer commercially available from Rohm Pharma. The spraying solution was prepared by dispersing 15 g of Eudragit L100 in 200 mL of ethanol to give a clear solution. To this solution, 4 g of triethyl citrate was then added as a plasticizer. 2 grams of purified talc was also added to the solution. The solution was then sprayed onto the beads, and the beads were dried, as described in Example 6.
Example 9: Comparative Dissolution Study I
A comparative dissolution study was performed on three forms of an active ingredient: the glyburide coated beads of Example 2, a commercially available glyburide product (Micronase , available from Pharmacia & Upjohn), and the pure glyburide bulk drug. The dissolution study was performed using a USP dissolution type 2 apparatus.
For each of the three forms, material equivalent to 5 mg of glyburide was used for each triplicated dissolution run in 500 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60, 120 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer. The samples were filtered through a 0.45 u filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a glyburide-specific HPLC assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of I
mL/min, at ambient temperature. Glyburide was detected by its UV absorption at 229 nm.
The results of the comparative dissolution measurement were expressed as the percent of glyburide dissolved/released in the dissolution medium at a given time, relative to the initial total glyburide content present in the dissolution medium (5 mg/500 mL). The results are shown in Figure 1, with the error bars representing the standard deviation. As the Figure shows, the glyburide coated beads of the present invention {
showed a superior dissolution profile in the rate, the extent, and the variability of glyburide dissolved/released into the dissolution medium, compared to the commercial Micronase and the pure bulk drug.
Example 10: Comparative Dissolution Study II
A comparative dissolution study was performed on three forms of an active ingredient: the progesterone coated beads of Example 3, the seal coated, progesterone coated beads of Example 6, and the pure progesterone bulk drug. The dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 100 mg of progesterone was used for each duplicated dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer containing 0.5% w/v of Tween 80.
The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 30, 60, 120 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer/Tween solution. The samples were filtered through a 0.45 filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a progesterone-specific HPLC assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 i L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of I
mLlmin, at ambient temperature. Glyburide was detected by its UV absorption at 229 nm.
The results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL). The results are shown in Figure 2A. As the Figure shows, the progesterone coated beads of the present invention, with or without a seal coating, showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the pure bulk drug.
Example 11: Comparative Dissolution Study III
A comparative dissolution study was performed on three forms of an active ingredient: the progesterone coated beads of Example 3, the seal coated, progesterone coated beads of Example 6, and the pure progesterone bulk drug. Prometrium is a capsule dosage form in which micronized progesterone is suspended in a blend of vegetable oils. The dissolution of the Prometrium capsule was performed using a USP
dissolution type 1 apparatus, and the dissolution of the other samples was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 100 mg of progesterone was used for each dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60 and 1 80 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer/Tween solution. The samples were filtered through a 0.45 filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a progesterone-specific HPLC
assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of I
mL/min, at ambient temperature. Glyburide was detected by its UV absorption at 229 am.
The results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL). The results are shown in Figure 2B. As the Figure shows, the progesterone coated beads of the present invention, with or without a seal coating, showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the commercial Prometrium and the pure bulk drug.
Example 12: Comparative Dissolution Study IV
A comparative dissolution study was performed comparing the rate and extent of dissolution of the protective coated, omeprazole coated beads of Example 7, the enteric coated, omeprazole coated beads of Example 8 and a commercially available omeprazole product (Prilosec , available from Astra Zeneca). The dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three dosage forms, material equivalent to 5 mg of omeprazole was used for each dissolution run in 500 mL
of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45 and 60 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer. The samples were filtered through a 0.45 EA filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for an omeprazole-specific HPLC assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 30:70 v/v acetonitrile/phosphate buffer (pH 7.4), at a flow rate of 1.1 mL/min, at ambient temperature. Omeprazole was detected by its UV absorption at 302 rim.
The results of the comparative dissolution measurement were expressed as the percent of omeprazole dissolved in the dissolution medium at a given time, relative to the initial total omeprazole content present in the dissolution medium (5 mg/500 mL). The results are shown in Figure 3. As the Figure shows, the omeprazole coated beads of the t o present invention showed superior dissolution profiles in both the rate and the extent of omeprazole dissolved/released into the dissolution medium, compared to the commercial Prilose product.
The following non-limiting examples 13-28 illustrate compositions that can be prepared according to the present invention. It should be appreciated that the compositions can be prepared in the absence of the active ingredients and appropriate.
amounts of the active ingredients in any given dosage form then can be administered together or separately with the composition. It should also be appreciated that the compositions can further include additional additives, excipients, and other components for the purpose of facilitating the processes involving the preparation of the composition or the pharmaceutical dosage form, as described herein, as is well-known to those skilled in the art.
Example 13 Component Amount (g) Atorvastatin 4 Partially hydrogenated soybean oil 10 Myrj 52 (PEG-40 stearate) 70 Monomuls 90-45 (glyceryl monolaurate) 20 Non-pareil seed (25/30 mesh) 120 Example 14 Component Amount (g) Alendronate sodium 50 Cremophor RH-40 (PEG-40 hydrogenated castor oil) 1 00 Capmul MCM (glyceryl caprylate/caprate) 50 Sodium alginate 2 Water 5 Non-pareil seed (25/30 mesh) 200 Example 15 Component Amount (g) Ganciclovir 100 Tocopheryl PEG-1000 succinate 200 Imwitor 191 (glyceryl monostearate) 30 Water 20 Non-pareil seed (25/30 mesh) 400 Example 16 Component Amount (g) Simvastatin 20 Hydrogenated castor oil 40 Crodet 040 (PEG-40 oleate) 200 Example 17 Component Amount (g) Zafirlukast 7 PEG-I50 monostearate 50 PEG-40 monostearate 80 Peceol (glyceryl monooleate) 15 Example 18 Component Amount Salmon calcitonin 300,000 IU
PEG-40 monostearate 200 g Glycerol monolaurate 100 g Water 5g .88-Example 19 Component Amount (g) Lovastatin 20 Coenzyme Q10 50 PEG-40 stearate 150 Glycerol monolaurate 50 Non-pareil seed (25/30 mesh) 200 Example 20 Component Amount (g) Tacrolimus 5 Solulan C-24 130 Distilled monoglycerides 40 Deoxycholic acid 80 Non-pareil seed (35/40 mesh) 250 Example 21 Component Amount (g) Rapamycin 20 PEG-40 stearate 150 PEG-150 stearate 50 Miglyol 812 20 Example 22 Component Amount (g) Pioglitazone 15 Pureco 76 20 Lutrol OP 2000 30 PEG- 100 hydrogenated castor oil 100 PEG-100 oleate (Crodet 0-100) 100 Non-pareil seed (25/30 mesh) 200 Example 23 Component Amount (g) Oxaprozin 50 Safflower oil 25 PEG- 10 soya sterol (Nikkol BYS-20) 25 Myrj 52 150 Non-pareil seed (25/30 mesh) 300 S
Example 24 Component Amount (g) Tretinoin 50 Capmul GMO-K 50 Sodium taurocholate 100 Example 25 Component Amount (g) Celecoxib 50 Myrj 52 100 Glycerol monolaurate 30 Hydrogenated coconut oil 20 Non-pareil seed (25/30 mesh) 200 Example 26 Component Amount (g) Refocoxib 10 Kessco PEG 1540 MS (PEG-32 stearate) 160 Imwitor 312 20 Hydrogenated palm oil (Softisan 154) 20 Example 27 Component Amount (g) Fenofibrate 100 Imwitor 742 40 Imwitor 988 40 Sodium alginate 4 Crodet 0-40 120 Myrj 51 120 Water 20 Example 28 Component Amount (g) Saquinavir 200 Myrj 52 130 Arlacel 186 20 The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
In another aspect, the present invention provides a method including the steps of providing a dosage form of a pharmaceutical composition as described above, providing a dosage form of a pharmaceutical active ingredient, and administering the dosage forms to the patient. This method is advantageous when all or part of the active ingredient or an additional active ingredient is to be administered to the patient in a separate dosage form prior to, concurrently with, or subsequent to administration of the pharmaceutical composition.
In another aspect, the present invention provides a method of improving the palatability and/or masking the taste of a pharmaceutical active ingredient, by providing the active ingredient in a pharmaceutical composition as described above.
Since the active ingredient is encapsulated in a lipid coat, it will not instantaneously dissolve in the mouth, but will instead dissolve in a region past the oral cavity, thereby substantially avoiding or at least reducing undesirable contact between the active ingredient and the mouth.
In another aspect of the invention, the compositions enable gastric resistance or acid degradation reduction of the active ingredient.
In another aspect of the invention, the solid carrier improves the chemical stability of the active ingredient.
In another aspect of the invention, the solid carrier protects the upper gastrointestinal tract from the adverse effects of the active ingredient.
In another aspect, the present invention provides a method of improving the dissolution and/or absorption of a pharmaceutical active ingredient, by administering the active ingredient in a composition as described above, or co-administering the active ingredient with a composition as described above.
EXAMPLES
Example 1: Preparation of Coated Beads Compositions according to the present invention were prepared as follows. The specific components used are detailed in Examples 2-5.
A spraying solution of the coating materials was prepared by dissolving the desired amount of the active ingredient and mixing with the hydrophilic and/or lipophilic surfactants in an organic solvent or a mixture of organic solvents. The organic solvent used for the coating solution was a mixture of methylene chloride and isopropyl alcohol in a 3:1 to 1:1 weight ratio.
Commercially available sugar beads (30/35 mesh size) were coated in a conventional coating pan having a spray gun (Campbell Hausfield, DH 7500) with a nozzle diameter of 1.2 mm and an air pressure of 25 psi. The bed temperature was maintained at approximately 32 C during the spraying process. Appropriate amounts of }
talc were sprinkled on the beads during the spraying process to. reduce the agglomeration of coated beads. When the spraying process was completed, the coated beads were allowed to cool to room temperature. The coated beads were then dried under vacuum to minimize residual solvent levels. The dried, coated beads were then sieved and collected.
Example 2: Composition I
A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (glyburide), and a mixture of a hydrophilic surfactant (PEG-40 stearate) and a lipophilic surfactant (glycerol monolaurate). The components and their amounts were as follows:
WO 01/37808 PCr/US00/32255 Component Weight (g) % (w/w) Glyburide 1 0.8 PEG-40 stearate 33 25.2 Glycerol monolaurate 17 13.0 Non-pareil seed (30/35 mesh) 80 61.1 Example 3: Composition 11 A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (progesterone), a mixture of a hydrophilic surfactant (Solulan C-24) and two lipophilic components (deoxycholic acid and distilled monoglycerides). The components and their amounts were as follows:
Component Weight (g) % (w/w) Progesterone 12 8.6 Solulan C-24 (Amerchol)* 32 22.9 Distilled monoglycerides 8 5.7 Deoxycholic acid 8 5.7 Non-pareil seed (30/35 mesh) 80 57.1 * PEG-24 cholesterol ether Example 4: Composition III
A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (itraconazole), a mixture of non-ionic hydrophilic surfactants (Cremophor RH-40 and PEG-150 monostearate), an ionic hydrophilic surfactant (sodium taurocholate) and a lipophilic surfactant (glycerol monolaurate). The components and their amounts were as follows:
Component Weight (g) % (w/w) Itraconazole 20 9.7 Cremophor RH-40 (BASF)* 25 12.1 Glycerol monolaurate 10 4.8 Sodium taurocholate 5 2.4 PEG-150 monostearate 27 13.0 Non-pareil seed (30/35 mesh) 120 58.0 * PEG-40 hydrogenated castor oil Example 5: Composition IV
A pharmaceutical composition was prepared according to the method of Example 1, having a substrate particle, an active ingredient (omeprazole), a mixture of a two hydrophilic surfactants (PEG-150 monostearate and PEG-40 monostearate), and a triglyceride-containing lipophilic component (Maisine 35-1). The components and their amounts were as follows:
Component Weight (g) % (w/w) Omeprazole 16 8.8 PEG-150 monostearate 50.4 27.8 PEG-40 monostearate 25.2 13.9 Maisine 35-1 (Gattefosse)* 8.4 4.6 Magnesium carbonate 1.6 0.9 Non-pareil seed (30/35 mesh) 80 44.1 linoleic glycerides Example 6: Seal Coating The dried, coated beads of Example 3 were further seal coated by a polymer layer. The seal coating polymer layer was applied to the progesterone-coated beads in a Uni-Glatt fluid bed coater. Polyvinylpyrrolidone (PVP-K30) was dissolved in isopropyl alcohol to form a 5% w/w solution. This seal coating solution was sprayed onto the coated beads with a Wurster bottom spray insert. The inlet and outlet air temperature were maintained at 30 and 40 C, respectively. When the spraying process was complete, the beads were further dried by supplying dry air at 50-55 C for 5-15 minutes.
The seal coated beads were then allowed to cool in the apparatus by supplying dry air at 20-25 C for 5-15 minutes. The dried, seal coated beads were collected and stored in a container.
Example 7: Protective Coating The dried, coated beads of Example 5 were further coated with a protective polymer layer. The protective coating was applied to the omeprazole coated beads by spraying with a hydroxypropyl methylcellulose (HPMC) solution. The protective coating HPMC solution was prepared by dissolving 6 grams of HPMC in ethanol.
To this solution, methylene chloride was added followed by 2 mL of triethylcitrate as a plasticizer and I g of talc. the HPMC solution was sprayed on the beads as described in Example 6, and the protective coated beads were then dried and collected.
Example 8: Enteric Coating The dried, coated beads of Example 5 were further coated with an enteric coating layer. The enteric layer was applied to the omeprazole coated beads by spraying a Eudragit L100 solution. Eudragit LI00 is an acrylate polymer commercially available from Rohm Pharma. The spraying solution was prepared by dispersing 15 g of Eudragit L100 in 200 mL of ethanol to give a clear solution. To this solution, 4 g of triethyl citrate was then added as a plasticizer. 2 grams of purified talc was also added to the solution. The solution was then sprayed onto the beads, and the beads were dried, as described in Example 6.
Example 9: Comparative Dissolution Study I
A comparative dissolution study was performed on three forms of an active ingredient: the glyburide coated beads of Example 2, a commercially available glyburide product (Micronase , available from Pharmacia & Upjohn), and the pure glyburide bulk drug. The dissolution study was performed using a USP dissolution type 2 apparatus.
For each of the three forms, material equivalent to 5 mg of glyburide was used for each triplicated dissolution run in 500 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60, 120 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer. The samples were filtered through a 0.45 u filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a glyburide-specific HPLC assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of I
mL/min, at ambient temperature. Glyburide was detected by its UV absorption at 229 nm.
The results of the comparative dissolution measurement were expressed as the percent of glyburide dissolved/released in the dissolution medium at a given time, relative to the initial total glyburide content present in the dissolution medium (5 mg/500 mL). The results are shown in Figure 1, with the error bars representing the standard deviation. As the Figure shows, the glyburide coated beads of the present invention {
showed a superior dissolution profile in the rate, the extent, and the variability of glyburide dissolved/released into the dissolution medium, compared to the commercial Micronase and the pure bulk drug.
Example 10: Comparative Dissolution Study II
A comparative dissolution study was performed on three forms of an active ingredient: the progesterone coated beads of Example 3, the seal coated, progesterone coated beads of Example 6, and the pure progesterone bulk drug. The dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 100 mg of progesterone was used for each duplicated dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer containing 0.5% w/v of Tween 80.
The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 30, 60, 120 and 180 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer/Tween solution. The samples were filtered through a 0.45 filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a progesterone-specific HPLC assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 i L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of I
mLlmin, at ambient temperature. Glyburide was detected by its UV absorption at 229 nm.
The results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL). The results are shown in Figure 2A. As the Figure shows, the progesterone coated beads of the present invention, with or without a seal coating, showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the pure bulk drug.
Example 11: Comparative Dissolution Study III
A comparative dissolution study was performed on three forms of an active ingredient: the progesterone coated beads of Example 3, the seal coated, progesterone coated beads of Example 6, and the pure progesterone bulk drug. Prometrium is a capsule dosage form in which micronized progesterone is suspended in a blend of vegetable oils. The dissolution of the Prometrium capsule was performed using a USP
dissolution type 1 apparatus, and the dissolution of the other samples was performed using a USP dissolution type 2 apparatus. For each of the three forms, material equivalent to 100 mg of progesterone was used for each dissolution run in 900 mL of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45, 60 and 1 80 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer/Tween solution. The samples were filtered through a 0.45 filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for a progesterone-specific HPLC
assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 75:25 v/v methanol/phosphate buffer (0.1 M potassium dihydrogen phosphate, pH adjusted to 3.5 using phosphoric acid), at a flow rate of I
mL/min, at ambient temperature. Glyburide was detected by its UV absorption at 229 am.
The results of the comparative dissolution measurement were expressed as the percent of progesterone dissolved/released in the dissolution medium at a given time, relative to the initial total progesterone content present in the dissolution medium (100 mg/900 mL). The results are shown in Figure 2B. As the Figure shows, the progesterone coated beads of the present invention, with or without a seal coating, showed superior dissolution profiles in both the rate and the extent of progesterone dissolved/released into the dissolution medium, compared to the commercial Prometrium and the pure bulk drug.
Example 12: Comparative Dissolution Study IV
A comparative dissolution study was performed comparing the rate and extent of dissolution of the protective coated, omeprazole coated beads of Example 7, the enteric coated, omeprazole coated beads of Example 8 and a commercially available omeprazole product (Prilosec , available from Astra Zeneca). The dissolution study was performed using a USP dissolution type 2 apparatus. For each of the three dosage forms, material equivalent to 5 mg of omeprazole was used for each dissolution run in 500 mL
of isotonic pH 7.4 phosphate buffer. The dissolution medium was maintained at 37 C and constantly stirred at a speed of 100 rpm. The dissolution media were sampled at 15, 30, 45 and 60 minutes. At each time point, 3 mL of the medium was sampled, and the medium was replenished with 3 mL of fresh buffer. The samples were filtered through a 0.45 EA filter immediately after the sampling. The filtrates were then diluted in methanol to an appropriate concentration for an omeprazole-specific HPLC assay.
The HPLC assay was performed on a Varian 9010 system by injecting 50 L of the sample. The sample was separated on a Phenominex C18 column by running a mobile phase of 30:70 v/v acetonitrile/phosphate buffer (pH 7.4), at a flow rate of 1.1 mL/min, at ambient temperature. Omeprazole was detected by its UV absorption at 302 rim.
The results of the comparative dissolution measurement were expressed as the percent of omeprazole dissolved in the dissolution medium at a given time, relative to the initial total omeprazole content present in the dissolution medium (5 mg/500 mL). The results are shown in Figure 3. As the Figure shows, the omeprazole coated beads of the t o present invention showed superior dissolution profiles in both the rate and the extent of omeprazole dissolved/released into the dissolution medium, compared to the commercial Prilose product.
The following non-limiting examples 13-28 illustrate compositions that can be prepared according to the present invention. It should be appreciated that the compositions can be prepared in the absence of the active ingredients and appropriate.
amounts of the active ingredients in any given dosage form then can be administered together or separately with the composition. It should also be appreciated that the compositions can further include additional additives, excipients, and other components for the purpose of facilitating the processes involving the preparation of the composition or the pharmaceutical dosage form, as described herein, as is well-known to those skilled in the art.
Example 13 Component Amount (g) Atorvastatin 4 Partially hydrogenated soybean oil 10 Myrj 52 (PEG-40 stearate) 70 Monomuls 90-45 (glyceryl monolaurate) 20 Non-pareil seed (25/30 mesh) 120 Example 14 Component Amount (g) Alendronate sodium 50 Cremophor RH-40 (PEG-40 hydrogenated castor oil) 1 00 Capmul MCM (glyceryl caprylate/caprate) 50 Sodium alginate 2 Water 5 Non-pareil seed (25/30 mesh) 200 Example 15 Component Amount (g) Ganciclovir 100 Tocopheryl PEG-1000 succinate 200 Imwitor 191 (glyceryl monostearate) 30 Water 20 Non-pareil seed (25/30 mesh) 400 Example 16 Component Amount (g) Simvastatin 20 Hydrogenated castor oil 40 Crodet 040 (PEG-40 oleate) 200 Example 17 Component Amount (g) Zafirlukast 7 PEG-I50 monostearate 50 PEG-40 monostearate 80 Peceol (glyceryl monooleate) 15 Example 18 Component Amount Salmon calcitonin 300,000 IU
PEG-40 monostearate 200 g Glycerol monolaurate 100 g Water 5g .88-Example 19 Component Amount (g) Lovastatin 20 Coenzyme Q10 50 PEG-40 stearate 150 Glycerol monolaurate 50 Non-pareil seed (25/30 mesh) 200 Example 20 Component Amount (g) Tacrolimus 5 Solulan C-24 130 Distilled monoglycerides 40 Deoxycholic acid 80 Non-pareil seed (35/40 mesh) 250 Example 21 Component Amount (g) Rapamycin 20 PEG-40 stearate 150 PEG-150 stearate 50 Miglyol 812 20 Example 22 Component Amount (g) Pioglitazone 15 Pureco 76 20 Lutrol OP 2000 30 PEG- 100 hydrogenated castor oil 100 PEG-100 oleate (Crodet 0-100) 100 Non-pareil seed (25/30 mesh) 200 Example 23 Component Amount (g) Oxaprozin 50 Safflower oil 25 PEG- 10 soya sterol (Nikkol BYS-20) 25 Myrj 52 150 Non-pareil seed (25/30 mesh) 300 S
Example 24 Component Amount (g) Tretinoin 50 Capmul GMO-K 50 Sodium taurocholate 100 Example 25 Component Amount (g) Celecoxib 50 Myrj 52 100 Glycerol monolaurate 30 Hydrogenated coconut oil 20 Non-pareil seed (25/30 mesh) 200 Example 26 Component Amount (g) Refocoxib 10 Kessco PEG 1540 MS (PEG-32 stearate) 160 Imwitor 312 20 Hydrogenated palm oil (Softisan 154) 20 Example 27 Component Amount (g) Fenofibrate 100 Imwitor 742 40 Imwitor 988 40 Sodium alginate 4 Crodet 0-40 120 Myrj 51 120 Water 20 Example 28 Component Amount (g) Saquinavir 200 Myrj 52 130 Arlacel 186 20 The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.
Claims (6)
1. A pharmaceutical composition comprising a solid carrier, the solid carrier comprising at least one pharmaceutical active ingredient, at least one hydrophilic surfactant, and a lipophilic additive selected from the group consisting of lipophilic surfactants, triglycerides, and combinations thereof, and wherein the at least one hydrophilic surfactant is present in an amount that partially or fully solubilizes the at least one pharmaceutical active ingredient.
2. The pharmaceutical composition of claim 1, wherein the active ingredient is hydrophobic and has an intrinsic aqueous solubility of less than about 1 mg/mL.
3. The pharmaceutical composition of claim 1, wherein the active ingredient is a hydrophilic active ingredient having an apparent water solubility of at least about 1 mg/mL.
4. The pharmaceutical composition of claim 1, wherein the at least one hydrophilic surfactant comprises a non-ionic hydrophilic surfactant having an HLB
value of at least about 10.
value of at least about 10.
5. The pharmaceutical composition of claim 1, wherein the at least one hydrophilic surfactant comprises an ionic surfactant.
6. A pharmaceutical composition comprising a solid carrier, the solid carrier comprising an admixture of:
(a) a pharmaceutical active ingredient;
(b) an amount of at least one hydrophilic surfactant sufficient to partially or fully solubilize the pharmaceutical active ingredient, said hydrophilic surfactant being selected from the group consisting of (i) polyoxyethylene sorbitan fatty acid esters, (ii) poloxyethylene-polyoxypropylene block copolymers, (iii) polyglycerol fatty acid esters, (iv) polyoxyethylene glycerides, (v) polyoxyethylene sterols, (vi) polyoxyethylene vegetable oils, (vii) polyoxyethylene hydrogenated vegetable oils, (viii) reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols, (ix) tocopherol polyethylene glycol succinates, (x) sugar esters, (xi) sugar ethers, (xii) sucroglycerides, and (xiii) mixtures thereof, and (c) an additive to provide for controlled release of the active ingredient, said additive being selected from the group consisting of poiyvinylpyrrolidone, polyethylene glycol, hydroxypropoyl methylcellulose, hydroxypropyl ceilulose, and other cellulose derivatives and mixtures thereof.
(a) a pharmaceutical active ingredient;
(b) an amount of at least one hydrophilic surfactant sufficient to partially or fully solubilize the pharmaceutical active ingredient, said hydrophilic surfactant being selected from the group consisting of (i) polyoxyethylene sorbitan fatty acid esters, (ii) poloxyethylene-polyoxypropylene block copolymers, (iii) polyglycerol fatty acid esters, (iv) polyoxyethylene glycerides, (v) polyoxyethylene sterols, (vi) polyoxyethylene vegetable oils, (vii) polyoxyethylene hydrogenated vegetable oils, (viii) reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols, (ix) tocopherol polyethylene glycol succinates, (x) sugar esters, (xi) sugar ethers, (xii) sucroglycerides, and (xiii) mixtures thereof, and (c) an additive to provide for controlled release of the active ingredient, said additive being selected from the group consisting of poiyvinylpyrrolidone, polyethylene glycol, hydroxypropoyl methylcellulose, hydroxypropyl ceilulose, and other cellulose derivatives and mixtures thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/447,690 | 1999-11-23 | ||
US09/447,690 US6248363B1 (en) | 1999-11-23 | 1999-11-23 | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
CA2391923A CA2391923C (en) | 1999-11-23 | 2000-11-22 | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2391923A Division CA2391923C (en) | 1999-11-23 | 2000-11-22 | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2706113A1 true CA2706113A1 (en) | 2001-05-31 |
Family
ID=23777347
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2706113A Abandoned CA2706113A1 (en) | 1999-11-23 | 2000-11-22 | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
CA2391923A Expired - Lifetime CA2391923C (en) | 1999-11-23 | 2000-11-22 | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2391923A Expired - Lifetime CA2391923C (en) | 1999-11-23 | 2000-11-22 | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
Country Status (6)
Country | Link |
---|---|
US (9) | US6248363B1 (en) |
EP (1) | EP1233756A4 (en) |
JP (2) | JP2003517470A (en) |
AU (1) | AU1798101A (en) |
CA (2) | CA2706113A1 (en) |
WO (1) | WO2001037808A1 (en) |
Families Citing this family (1546)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5744500A (en) * | 1990-01-03 | 1998-04-28 | Teva Pharmaceutical Industries, Ltd. | Use of R-enantiomer of N-propargyl-1-aminoindan, salts, and compositions thereof |
US6428771B1 (en) * | 1995-05-15 | 2002-08-06 | Pharmaceutical Discovery Corporation | Method for drug delivery to the pulmonary system |
US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
US6489346B1 (en) * | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
US6699885B2 (en) * | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
US6645988B2 (en) * | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
US20030215507A1 (en) * | 1996-03-25 | 2003-11-20 | Wyeth | Extended release formulation |
FR2754177B1 (en) * | 1996-10-07 | 1999-08-06 | Sanofi Sa | PHARMACEUTICAL MICROSPHERES OF VALPROIC ACID FOR ORAL ADMINISTRATION |
US20050004049A1 (en) * | 1997-03-11 | 2005-01-06 | Elan Pharma International Limited | Novel griseofulvin compositions |
GB9800936D0 (en) * | 1997-05-10 | 1998-03-11 | Univ Nottingham | Biofunctional polymers |
US20030077229A1 (en) * | 1997-10-01 | 2003-04-24 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs |
EP1004305B1 (en) * | 1998-04-20 | 2011-09-28 | Eisai R&D Management Co., Ltd. | Stabilized compositions containing benzimidazole-type compounds |
US20040087512A1 (en) * | 1998-05-12 | 2004-05-06 | Teter Beverly B. | In-situ formation of CLA |
US7022683B1 (en) * | 1998-05-13 | 2006-04-04 | Carrington Laboratories, Inc. | Pharmacological compositions comprising pectins having high molecular weights and low degrees of methoxylation |
KR100314496B1 (en) | 1998-05-28 | 2001-11-22 | 윤동진 | Non-thrombogenic heparin derivatives, process for preparation and use thereof |
NZ330726A (en) * | 1998-06-18 | 2000-10-27 | Dec Res | Intra-vaginal delivery unit or composition containing a cyclodextrin which improves absorbtion of 17-beta oestradiol or oestradiol benzoate |
US6413713B1 (en) * | 1998-10-30 | 2002-07-02 | Hyperbaric Systems | Method for preserving blood platelets |
US20070160675A1 (en) * | 1998-11-02 | 2007-07-12 | Elan Corporation, Plc | Nanoparticulate and controlled release compositions comprising a cephalosporin |
US20070122481A1 (en) * | 1998-11-02 | 2007-05-31 | Elan Corporation Plc | Modified Release Compositions Comprising a Fluorocytidine Derivative for the Treatment of Cancer |
US20080113025A1 (en) * | 1998-11-02 | 2008-05-15 | Elan Pharma International Limited | Compositions comprising nanoparticulate naproxen and controlled release hydrocodone |
US20090297597A1 (en) * | 1998-11-02 | 2009-12-03 | Gary Liversidge | Modified Release Ticlopidine Compositions |
EP1133281A1 (en) * | 1998-11-20 | 2001-09-19 | RTP Pharma Inc. | Dispersible phospholipid stabilized microparticles |
GB9903547D0 (en) * | 1999-02-16 | 1999-04-07 | Novartis Ag | Organic compounds |
US7658938B2 (en) * | 1999-02-22 | 2010-02-09 | Merrion Reasearch III Limited | Solid oral dosage form containing an enhancer |
US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
KR20010102370A (en) * | 1999-03-11 | 2001-11-15 | 후지야마 아키라 | Liposome preparations |
US6616942B1 (en) * | 1999-03-29 | 2003-09-09 | Soft Gel Technologies, Inc. | Coenzyme Q10 formulation and process methodology for soft gel capsules manufacturing |
US7164034B2 (en) * | 1999-06-10 | 2007-01-16 | Pfizer Inc. | Alpha2delta ligands for fibromyalgia and other disorders |
US20080207755A1 (en) * | 2000-05-31 | 2008-08-28 | Pfizer Inc | Alpha 2 Delta Ligands For Fibromyalgia and Other Disorders |
CA2374760A1 (en) * | 1999-06-18 | 2000-12-28 | Takeda Chemical Industries, Ltd. | Quickly disintegrating solid preparations |
US7169889B1 (en) * | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
PT1808438E (en) * | 1999-06-29 | 2015-01-14 | Mannkind Corp | Purification and stabilization of peptide and proteins in pharmaceutical agents |
US9006175B2 (en) * | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
US20030236236A1 (en) * | 1999-06-30 | 2003-12-25 | Feng-Jing Chen | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
US20150374826A1 (en) * | 1999-06-30 | 2015-12-31 | Lipocine Inc. | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
US6982281B1 (en) * | 2000-11-17 | 2006-01-03 | Lipocine Inc | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
EP1226138B1 (en) | 1999-10-08 | 2004-12-29 | Affinium Pharmaceuticals, Inc. | Fab i inhibitors |
JP4081273B2 (en) | 1999-10-20 | 2008-04-23 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method for stabilizing benzimidazole compounds |
US7364752B1 (en) | 1999-11-12 | 2008-04-29 | Abbott Laboratories | Solid dispersion pharamaceutical formulations |
WO2001034119A2 (en) * | 1999-11-12 | 2001-05-17 | Abbott Laboratories | Inhibitors of crystallization in a solid dispersion |
US20060034937A1 (en) * | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US20030180352A1 (en) * | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
RU2216319C1 (en) * | 1999-11-30 | 2003-11-20 | Панацея Биотек Лимитед | Quick-soluble pharmaceutical composition as solid medicinal form with prolonged sweet taste and method for it preparing |
FR2803538B1 (en) * | 1999-12-15 | 2002-06-07 | Separex Sa | METHOD AND DEVICE FOR CAPTURING FINE PARTICLES BY PERCOLATION IN A BED OF GRANULES |
IL149792A0 (en) * | 1999-12-16 | 2002-11-10 | Teva Pharma | Novel processes for making and a new crystalline form of leflunomide |
US6632429B1 (en) * | 1999-12-17 | 2003-10-14 | Joan M. Fallon | Methods for treating pervasive development disorders |
US20040062803A1 (en) * | 1999-12-22 | 2004-04-01 | Hedden David B. | Sustained-release formulation of a cyclooxygenase-2 inhibitor |
AP2002002552A0 (en) | 1999-12-23 | 2002-06-30 | Pfizer Prod Inc | Pharmaceutical compositions providing enhanced drug concentrations. |
SK285128B6 (en) * | 1999-12-28 | 2006-07-07 | Zentiva, A. S. | A remedy with controlled release comprising tramadol hydrochloride and method for preparation thereof |
US20040009229A1 (en) * | 2000-01-05 | 2004-01-15 | Unger Evan Charles | Stabilized nanoparticle formulations of camptotheca derivatives |
SE0000090D0 (en) * | 2000-01-13 | 2000-01-13 | Astrazeneca Ab | Method and apparatus for monitoring |
AU2001228454A1 (en) * | 2000-01-13 | 2001-07-24 | Merck Patent G.M.B.H | Pharmaceutical preparations containing 2-pyrrolidone as the dissolving intermediary |
ES2270982T3 (en) * | 2000-02-04 | 2007-04-16 | Depomed, Inc. | DOSAGE FORM OF NUCLEO AND CARCASA THAT IS APPROXIMATE TO A RELEASE OF THE ZERO ORDER PHARMACO. |
DE10007771A1 (en) * | 2000-02-14 | 2001-08-23 | Kleine & Steube Entoxin Gmbh | Immunomodulatory compositions, processes for their preparation and their use |
US6544555B2 (en) | 2000-02-24 | 2003-04-08 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
FR2805761B1 (en) * | 2000-03-02 | 2002-08-30 | Mainelab | LIPID NANOCAPSULES, METHOD OF PREPARATION AND USE AS A MEDICAMENT |
KR20010100194A (en) * | 2000-03-13 | 2001-11-14 | 박호군 | Composition and formulation for solubilization of various compounds and preparation method thereof |
WO2001074397A1 (en) * | 2000-03-31 | 2001-10-11 | Kirin Beer Kabushiki Kaisha | Powdery preparation for transmucosal administration containing a polymeric form of drug and exhibiting improved storage stability |
ES2218338T3 (en) * | 2000-04-13 | 2004-11-16 | Pfizer Products Inc. | SYNERGIC EFFECT OF GLIBURIDE AND MILRINONE. |
AU5066101A (en) * | 2000-04-13 | 2001-10-30 | Synthon B.V. | Modified release formulations containing a hypnotic agent |
US6884778B2 (en) * | 2000-04-14 | 2005-04-26 | William Marsh Rice University | Biocompatible macromers |
GB0010446D0 (en) * | 2000-04-28 | 2000-06-14 | Glaxo Wellcome Kk | Pharmaceutical formulation |
AUPQ761100A0 (en) * | 2000-05-18 | 2000-06-08 | Australian Rural Group Limited | Lipophilic medicament |
KR100381834B1 (en) * | 2000-05-20 | 2003-04-26 | 이상득 | Solid dispersion system of pranlukast with improved dissolution, and the method thereof |
FR2809309B1 (en) * | 2000-05-23 | 2004-06-11 | Mainelab | EXTENDED RELEASE MICROSPHERES FOR INJECTION DELIVERY |
FR2809310B1 (en) * | 2000-05-26 | 2004-02-13 | Centre Nat Rech Scient | USE OF BIGUANIDE DERIVATIVES FOR MANUFACTURING A MEDICINAL PRODUCT HAVING A HEALING EFFECT |
DE10026698A1 (en) | 2000-05-30 | 2001-12-06 | Basf Ag | Self-emulsifying active ingredient formulation and use of this formulation |
GB0015617D0 (en) * | 2000-06-26 | 2000-08-16 | Vectura Ltd | Improved preparations for dermal delivery of active substances |
US6375982B1 (en) * | 2000-07-05 | 2002-04-23 | Capricorn Pharma, Inc. | Rapid-melt semi-solid compositions, methods of making same and method of using same |
AU2001279284A1 (en) * | 2000-07-05 | 2002-01-14 | Capricorn Pharma, Inc | Rapid-melt semi-solid compositions, methods of making same and methods of using same |
US20100010101A1 (en) * | 2000-07-05 | 2010-01-14 | Capricorn Pharma, Inc. | Rapid-Melt Compositions and Methods of Making Same |
USRE44145E1 (en) | 2000-07-07 | 2013-04-09 | A.V. Topchiev Institute Of Petrochemical Synthesis | Preparation of hydrophilic pressure sensitive adhesives having optimized adhesive properties |
US6967028B2 (en) * | 2000-07-31 | 2005-11-22 | Mainelab | Prolonged release microspheres for injectable administration |
PT1311269E (en) * | 2000-08-04 | 2012-05-10 | Dmi Biosciences Inc | Method of using diketopiperazines and composition containing them |
DK2116257T3 (en) * | 2000-08-09 | 2013-02-04 | Alk Abello As | Parenteral vaccine formulations and applications thereof |
US20070053895A1 (en) * | 2000-08-14 | 2007-03-08 | Fallon Joan M | Method of treating and diagnosing parkinsons disease and related dysautonomic disorders |
US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
US20040043061A1 (en) * | 2000-09-15 | 2004-03-04 | Leon Daniel S. | Dissolvable films comprising suspended, non-soluble pharmaceutically active ingredients, apparatus and methods for their manufacture and use |
ATE270544T1 (en) * | 2000-09-22 | 2004-07-15 | Galephar M F | SEMI-SOLID MEDICINAL PREPARATION CONTAINING ISOTRETINOIN |
US20020119192A1 (en) * | 2000-09-22 | 2002-08-29 | Vishwanathan Narayanan Badri | Controlled release formulations for oral administration |
AU2007202061B2 (en) * | 2000-10-06 | 2009-03-05 | Durect Corporation | Devices and methods for management of inflammation |
AU2001296770A1 (en) * | 2000-10-06 | 2002-04-15 | Durect Corporation | Devices and methods for management of inflammation |
US20020068078A1 (en) | 2000-10-13 | 2002-06-06 | Rudnic Edward M. | Antifungal product, use and formulation thereof |
WO2002032427A1 (en) * | 2000-10-20 | 2002-04-25 | Galephar M/F | Stable oral formulation containing benzimidazole derivative |
US20040018228A1 (en) * | 2000-11-06 | 2004-01-29 | Afmedica, Inc. | Compositions and methods for reducing scar tissue formation |
US8030002B2 (en) | 2000-11-16 | 2011-10-04 | Curemark Llc | Methods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions |
MY137726A (en) * | 2000-11-22 | 2009-03-31 | Nycomed Gmbh | Freeze-dried pantoprazole preparation and pantoprazole injection |
DE10058119A1 (en) * | 2000-11-22 | 2002-05-23 | Bayer Ag | Pharmaceutical kit containing repinotan, for use in acute treatment of neurological disorders such as stroke, including assay composition for determining body repinotan levels to optimize dosage |
US20030162733A1 (en) * | 2000-11-27 | 2003-08-28 | Haynes Joel R. | Nucleic acid adjuvants |
AU2002239282A1 (en) * | 2000-11-28 | 2002-06-11 | Transform Pharmaceuticals, Inc. | Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof |
US6599522B2 (en) * | 2000-12-01 | 2003-07-29 | Lakshminarayan Rao V. Mokshagundam | Triglyceride reducing agent |
US8067032B2 (en) | 2000-12-22 | 2011-11-29 | Baxter International Inc. | Method for preparing submicron particles of antineoplastic agents |
US6884436B2 (en) * | 2000-12-22 | 2005-04-26 | Baxter International Inc. | Method for preparing submicron particle suspensions |
US20030096013A1 (en) * | 2000-12-22 | 2003-05-22 | Jane Werling | Preparation of submicron sized particles with polymorph control |
US9700866B2 (en) * | 2000-12-22 | 2017-07-11 | Baxter International Inc. | Surfactant systems for delivery of organic compounds |
US20050048126A1 (en) * | 2000-12-22 | 2005-03-03 | Barrett Rabinow | Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug |
US20040256749A1 (en) * | 2000-12-22 | 2004-12-23 | Mahesh Chaubal | Process for production of essentially solvent-free small particles |
US20030072807A1 (en) * | 2000-12-22 | 2003-04-17 | Wong Joseph Chung-Tak | Solid particulate antifungal compositions for pharmaceutical use |
US6607784B2 (en) * | 2000-12-22 | 2003-08-19 | Baxter International Inc. | Microprecipitation method for preparing submicron suspensions |
US7193084B2 (en) * | 2000-12-22 | 2007-03-20 | Baxter International Inc. | Polymorphic form of itraconazole |
WO2002051428A1 (en) * | 2000-12-25 | 2002-07-04 | Shiseido Company, Ltd. | Sympathetic-activating perfume composition |
US6867183B2 (en) * | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
US7060675B2 (en) * | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
RU2322981C2 (en) | 2001-02-19 | 2008-04-27 | Новартис Аг | Combination and method for prophylaxis of breast cancer |
US6524615B2 (en) * | 2001-02-21 | 2003-02-25 | Kos Pharmaceuticals, Incorporated | Controlled release pharmaceutical composition |
US6534088B2 (en) * | 2001-02-22 | 2003-03-18 | Skyepharma Canada Inc. | Fibrate-statin combinations with reduced fed-fasted effects |
KR100510356B1 (en) * | 2001-02-27 | 2005-08-24 | 룀 게엠베하 운트 콤파니 카게 | Pharmaceutical formulations comprising a coating and binding agent with improved storage stability and process for the preparation thereof |
US7494669B2 (en) * | 2001-02-28 | 2009-02-24 | Carrington Laboratories, Inc. | Delivery of physiological agents with in-situ gels comprising anionic polysaccharides |
US6777000B2 (en) * | 2001-02-28 | 2004-08-17 | Carrington Laboratories, Inc. | In-situ gel formation of pectin |
FR2821747B1 (en) * | 2001-03-09 | 2004-07-02 | Ethypharm Lab Prod Ethiques | SUSPENSION OF TELITHROMYCIN WITH A MASK TASTE |
KR200249057Y1 (en) * | 2001-03-22 | 2001-10-19 | 김진환 | Sewage backflow integrated into the lid and base. Odor Prevention Device |
DE10114178A1 (en) | 2001-03-23 | 2002-10-10 | Aventis Pharma Gmbh | Zinc-free and low-zinc insulin preparations with improved stability |
WO2003088897A2 (en) * | 2001-04-06 | 2003-10-30 | Affinium Pharmaceuticals, Inc. | Fab i inhibitors |
US7431710B2 (en) | 2002-04-08 | 2008-10-07 | Glaukos Corporation | Ocular implants with anchors and methods thereof |
US6503532B1 (en) * | 2001-04-13 | 2003-01-07 | Murty Pharmaceuticals, Inc. | Pharmaceutical composition containing tetrahydrocannabinol and a transdermal/transcutaneous delivery method thereof |
US8206738B2 (en) * | 2001-05-01 | 2012-06-26 | Corium International, Inc. | Hydrogel compositions with an erodible backing member |
US8840918B2 (en) * | 2001-05-01 | 2014-09-23 | A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences | Hydrogel compositions for tooth whitening |
WO2002087543A1 (en) * | 2001-05-01 | 2002-11-07 | Biozone Laboratories, Inc. | Sustained release formulations for nifedipine, dextromethorphan, and danazol |
RU2286801C2 (en) | 2001-05-01 | 2006-11-10 | Институт Нефтехимического Синтеза Имени А.В. Топчиева Российской Академии Наук | Water-absorbing biphase bioadhesive compositions |
RU2276998C2 (en) | 2001-05-01 | 2006-05-27 | Институт Нефтехимического Синтеза Имени А.В. Топчиева Российской Академии Наук | Hydrogel compositions |
US8541021B2 (en) | 2001-05-01 | 2013-09-24 | A.V. Topchiev Institute Of Petrochemical Synthesis | Hydrogel compositions demonstrating phase separation on contact with aqueous media |
US20050215727A1 (en) | 2001-05-01 | 2005-09-29 | Corium | Water-absorbent adhesive compositions and associated methods of manufacture and use |
US20050113510A1 (en) | 2001-05-01 | 2005-05-26 | Feldstein Mikhail M. | Method of preparing polymeric adhesive compositions utilizing the mechanism of interaction between the polymer components |
AU4061702A (en) * | 2001-05-15 | 2003-04-03 | Mcneil-Ppc, Inc. | Dip coating compositions containing starch or dextrin |
US20020183277A1 (en) * | 2001-05-15 | 2002-12-05 | Lise Binderup | Combination of vitamin D analogue and pyrimidine nucleoside analogue |
US20030070584A1 (en) * | 2001-05-15 | 2003-04-17 | Cynthia Gulian | Dip coating compositions containing cellulose ethers |
US20030072731A1 (en) * | 2001-05-15 | 2003-04-17 | Cynthia Gulian | Dip coating compositions containing starch or dextrin |
US6623754B2 (en) * | 2001-05-21 | 2003-09-23 | Noveon Ip Holdings Corp. | Dosage form of N-acetyl cysteine |
JP4865958B2 (en) | 2001-05-23 | 2012-02-01 | 株式会社トクホン | Analgesic anti-inflammatory patch with local action |
JP2002348474A (en) * | 2001-05-23 | 2002-12-04 | Dow Corning Toray Silicone Co Ltd | Polyorganosiloxane microemulsion composition and cosmetic raw material |
US20080058424A1 (en) * | 2002-05-23 | 2008-03-06 | Cephalon, Inc. | Novel pharmaceutical formulations of modafinil |
KR100911779B1 (en) * | 2001-05-25 | 2009-08-12 | 세파론, 인코포레이티드 | Solid Pharmaceutical Formulations Comprising Modafinil |
US20030070679A1 (en) * | 2001-06-01 | 2003-04-17 | Boehringer Ingelheim Pharma Kg | Capsules containing inhalable tiotropium |
US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
US6713452B2 (en) | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6835802B2 (en) | 2001-06-04 | 2004-12-28 | Nobex Corporation | Methods of synthesizing substantially monodispersed mixtures of polymers having polyethylene glycol moieties |
US6828297B2 (en) * | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6828305B2 (en) * | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
GB0114532D0 (en) * | 2001-06-14 | 2001-08-08 | Jagotec Ag | Novel compositions |
US7244703B2 (en) * | 2001-06-22 | 2007-07-17 | Bentley Pharmaceuticals, Inc. | Pharmaceutical compositions and methods for peptide treatment |
ITMI20011337A1 (en) * | 2001-06-26 | 2002-12-26 | Farmatron Ltd | ORAL PHARMACEUTICAL COMPOSITIONS WITH MODIFIED RELEASE OF THE ACTIVE SUBSTANCE |
ITMI20011338A1 (en) * | 2001-06-26 | 2002-12-26 | Farmatron Ltd | ORAL PHARMACEUTICAL COMPOSITIONS WITH IMMEDIATE RELEASE OF THE ACTIVE INGREDIENT |
FR2826549A1 (en) * | 2001-06-28 | 2003-01-03 | Roquette Freres | PROCESS FOR THE PREPARATION OF A COMPRESSED EDULCORANT TABLET AND A COMPRESSED EDULCORANT THUS OBTAINED |
US7014867B2 (en) * | 2001-06-28 | 2006-03-21 | Ucb Farchim Sa | Tablet comprising cetirizine and pseudoephedrine |
CA2452056C (en) * | 2001-07-02 | 2011-11-01 | Elan Corporation, Plc. | Compositions of bioactive material particles dispersed in a continuous solid encapsulating material |
US7737185B2 (en) * | 2001-07-09 | 2010-06-15 | Repros Therapeutics Inc. | Methods and compositions with trans-clomiphene |
WO2003005954A2 (en) * | 2001-07-09 | 2003-01-23 | Zonagen, Inc. | Methods and materials for the treatment of testosterone deficiency in men |
US7173064B2 (en) * | 2001-07-09 | 2007-02-06 | Repros Therapeutics Inc. | Methods and compositions with trans-clomiphene for treating wasting and lipodystrophy |
MXPA04000176A (en) * | 2001-07-10 | 2004-10-27 | Kos Life Sciences Inc | A core formulation. |
CN100335045C (en) * | 2001-07-17 | 2007-09-05 | 出光兴产株式会社 | Preventive agent for ascites in poultry |
AR034813A1 (en) * | 2001-07-20 | 2004-03-17 | Novartis Ag | PHARMACEUTICAL COMPOSITIONS AND USE OF THE SAME |
US6720002B2 (en) * | 2001-07-20 | 2004-04-13 | R.P. Scherer Technologies, Inc. | Antihistamine formulations for soft capsule dosage forms |
GB0118300D0 (en) * | 2001-07-26 | 2001-09-19 | Cortendo Ab | Formulations |
FR2827770B1 (en) * | 2001-07-27 | 2005-08-19 | Gattefosse Ets Sa | ORAL PHARMACEUTICAL COMPOSITION COMPRISING AN ACTIVE INGREDIENT LIKELY TO BE SUBSTANTIALLY EFFECT OF FIRST INTESTINAL PASSAGE |
US20080305173A1 (en) * | 2001-07-31 | 2008-12-11 | Beuford Arlie Bogue | Amorphous drug beads |
US20030068375A1 (en) * | 2001-08-06 | 2003-04-10 | Curtis Wright | Pharmaceutical formulation containing gelling agent |
US20030153590A1 (en) * | 2001-08-14 | 2003-08-14 | Oy Contral Pharma Ltd | Method of treating alcoholism or alcohol abuse |
US7097868B2 (en) * | 2001-08-23 | 2006-08-29 | Bio-Dar Ltd. | Stable coated microcapsules |
US6488952B1 (en) * | 2001-08-28 | 2002-12-03 | John P. Kennedy | Semisolid therapeutic delivery system and combination semisolid, multiparticulate, therapeutic delivery system |
EP1427366A2 (en) * | 2001-08-29 | 2004-06-16 | UMD, Inc. | Vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy |
US20030099711A1 (en) * | 2001-08-29 | 2003-05-29 | David Meadows | Sustained release preparations |
US7338971B2 (en) * | 2001-08-30 | 2008-03-04 | El-Naggar Mawaheb M | Treatment of inflammatory, cancer, and thrombosis disorders |
GB0121436D0 (en) * | 2001-09-04 | 2001-10-24 | Pfizer Ltd | Biomodulated multiparticulate formulations |
US7312192B2 (en) * | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US7196059B2 (en) * | 2001-09-07 | 2007-03-27 | Biocon Limited | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
US6913903B2 (en) * | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
US7166571B2 (en) * | 2001-09-07 | 2007-01-23 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
US20030091634A1 (en) * | 2001-09-14 | 2003-05-15 | Pawan Seth | Delayed release tablet of venlafaxin |
US20060003012A9 (en) | 2001-09-26 | 2006-01-05 | Sean Brynjelsen | Preparation of submicron solid particle suspensions by sonication of multiphase systems |
IL160570A0 (en) | 2001-09-26 | 2004-07-25 | Baxter Int | Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal |
US8309118B2 (en) | 2001-09-28 | 2012-11-13 | Mcneil-Ppc, Inc. | Film forming compositions containing sucralose |
JP2005511521A (en) * | 2001-10-10 | 2005-04-28 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | Powder processing with pressurized gaseous fluid |
US7112340B2 (en) * | 2001-10-19 | 2006-09-26 | Baxter International Inc. | Compositions of and method for preparing stable particles in a frozen aqueous matrix |
US20030152622A1 (en) * | 2001-10-25 | 2003-08-14 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral diuretic |
US20030091630A1 (en) * | 2001-10-25 | 2003-05-15 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data |
CA2409552A1 (en) * | 2001-10-25 | 2003-04-25 | Depomed, Inc. | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
MY148466A (en) | 2001-10-26 | 2013-04-30 | Merck Frosst Canada Ltd | Granule formulation |
CA2465110A1 (en) * | 2001-11-07 | 2003-05-15 | Synthon B.V. | Tamsulosin tablets |
US20040142902A1 (en) * | 2001-11-08 | 2004-07-22 | Struijker- Boudier Harry A.J. | Implant dosage form and use thereof for the delivery of a cholosterol lowering agent |
JP4031232B2 (en) * | 2001-11-09 | 2008-01-09 | カプスゲル・ジャパン株式会社 | New capsule |
ITMI20012366A1 (en) * | 2001-11-09 | 2003-05-09 | Farmatron Ltd | THERAPEUTIC SYSTEMS STABILIZED WITH IMMEDIATE RELEASE AND / OR MODIFIED FOR THE ORAL ADMINISTRATION OF ACTIVE AND / OR EXCIPIENT PRINCIPLES AND / OR WINGS |
US20040092428A1 (en) * | 2001-11-27 | 2004-05-13 | Hongming Chen | Oral pharmaceuticals formulation comprising paclitaxel, derivatives and methods of administration thereof |
US6455557B1 (en) * | 2001-11-28 | 2002-09-24 | Elan Pharmaceuticals, Inc. | Method of reducing somnolence in patients treated with tizanidine |
US20040220240A1 (en) * | 2001-11-28 | 2004-11-04 | Pellegrini Cara A. | Method of increasing the extent of absorption of tizanidine |
KR20050044655A (en) * | 2001-12-03 | 2005-05-12 | 노바세아, 인크. | Pharmaceutical compositions comprising active vitamin d compounds |
CA2469623C (en) * | 2001-12-12 | 2012-05-29 | F H Faulding & Co Limited | Composition for the preservation of viruses |
US6652891B2 (en) | 2001-12-12 | 2003-11-25 | Herbasway Laboratories, Llc | Co-enzyme Q10 dietary supplement |
US7183321B2 (en) * | 2001-12-17 | 2007-02-27 | Bristol-Myers Squibb Company | Antidiabetic formulation and method |
AU2002353659A1 (en) * | 2001-12-18 | 2003-07-15 | Synthon B.V. | Simvastatin dosage forms |
CA2470075A1 (en) * | 2001-12-20 | 2003-07-03 | Teva Pharmaceutical Industries Ltd. | Hydrogenation of precursors to thiazolidinedione antihyperglycemics |
DE60218744T2 (en) * | 2001-12-20 | 2007-12-06 | Alpex Pharma S.A. | PARTICULAR COMPOSITION CONTAINING A LIPOPHILIC LIQUID |
AU2002358717B2 (en) * | 2001-12-20 | 2007-12-20 | Societe Des Produits Nestle S.A. | A food product containing gel capsules or tablets |
US20030139386A1 (en) * | 2001-12-21 | 2003-07-24 | Sophie Cote | Pharmaceutical compositions based on azetidine derivatives |
FR2834212B1 (en) * | 2001-12-27 | 2004-07-09 | Besins Int Belgique | USE OF IMMEDIATE RELEASE POWDER IN PHARMACEUTICAL AND NUTRACEUTICAL COMPOSITIONS |
US20030165566A1 (en) * | 2002-01-10 | 2003-09-04 | O'toole Edel | Sedative non-benzodiazepine formulations |
KR100937113B1 (en) * | 2002-01-16 | 2010-01-18 | 아스텔라스세이야쿠 가부시키가이샤 | Medicinal compositions for improving oral absorption |
SE0200154D0 (en) * | 2002-01-21 | 2002-01-21 | Galenica Ab | New process |
US20030162827A1 (en) * | 2002-01-30 | 2003-08-28 | Suresh Venkataram | HMG CoA reductase inhibiting composition, method of preparation thereof and method for competitively inhibiting HMG CoA reductase using such composition |
JP3665904B2 (en) * | 2002-01-31 | 2005-06-29 | 関西ティー・エル・オー株式会社 | Human cancer prevention composition and human cancer prevention method |
GB0203296D0 (en) * | 2002-02-12 | 2002-03-27 | Glaxo Group Ltd | Novel composition |
ES2302913T3 (en) * | 2002-02-14 | 2008-08-01 | Dsm Ip Assets B.V. | FORMULATIONS BASED ON COENZYME Q-10. |
DE10392164T5 (en) * | 2002-02-20 | 2004-10-28 | Strides Arcolab Ltd. | Oral pharmaceutical formulation |
US20050182056A9 (en) * | 2002-02-21 | 2005-08-18 | Seth Pawan | Modified release formulations of at least one form of tramadol |
US8128957B1 (en) | 2002-02-21 | 2012-03-06 | Valeant International (Barbados) Srl | Modified release compositions of at least one form of tramadol |
PL208114B1 (en) * | 2002-02-26 | 2011-03-31 | Astrazeneca Ab | Pharmaceutical formulation of iressa comprising a water-soluble cellulose derivative |
US20030161875A1 (en) * | 2002-02-27 | 2003-08-28 | Deepak Murpani | Fast dissolving tablets of cyclooxygenase-2 enzyme inhibitors |
CO5400144A1 (en) | 2002-03-11 | 2004-05-31 | Novartis Ag | ORGANIC COMPOUNDS |
GB0205868D0 (en) * | 2002-03-13 | 2002-04-24 | Univ Nottingham | Polymer composite with internally distributed deposition matter |
WO2003080149A2 (en) | 2002-03-20 | 2003-10-02 | Mannkind Corporation | Inhalation apparatus |
US20030219482A1 (en) * | 2002-03-21 | 2003-11-27 | Chaudhari Sunil Sudhakar | Multiparticulate compositions for once-a-day administration |
PT1492511E (en) | 2002-04-09 | 2009-04-09 | Flamel Tech Sa | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
US8100844B2 (en) * | 2002-04-25 | 2012-01-24 | Ultraflex Systems, Inc. | Ambulating ankle and knee joints with bidirectional dampening and assistance using elastomeric restraint |
GB0210397D0 (en) * | 2002-05-07 | 2002-06-12 | Ferring Bv | Pharmaceutical formulations |
US20040043070A1 (en) * | 2002-05-14 | 2004-03-04 | Ayres James W. | Hot melt coating by direct blending and coated substrates |
US20050215552A1 (en) * | 2002-05-17 | 2005-09-29 | Gadde Kishore M | Method for treating obesity |
KR101072885B1 (en) * | 2002-05-17 | 2011-10-17 | 듀크 유니버시티 | Method for treating obesity |
US7229644B2 (en) * | 2002-05-23 | 2007-06-12 | Cephalon, Inc. | Pharmaceutical formulations of modafinil |
US20040033257A1 (en) * | 2002-05-30 | 2004-02-19 | Strides Inc. | Pharmaceutical formulation in a drug delivery system and process for preparing the same |
US6824763B2 (en) | 2002-05-30 | 2004-11-30 | Kimberly-Clark Worldwide, Inc. | Anti-fungal powder having enhanced excipient properties |
US20030224046A1 (en) * | 2002-06-03 | 2003-12-04 | Vinay Rao | Unit-dose combination composition for the simultaneous delivery of a short-acting and a long-acting oral hypoglycemic agent |
US7182950B2 (en) * | 2002-06-12 | 2007-02-27 | Nutralease Ltd. | Nano-sized self-assembled liquid dilutable vehicles |
DE10227232A1 (en) * | 2002-06-18 | 2004-01-15 | Aventis Pharma Deutschland Gmbh | Sour insulin preparations with improved stability |
AR039744A1 (en) * | 2002-06-26 | 2005-03-09 | Alza Corp | METHODS AND DOSAGE FORMS TO INCREASE THE SOLUBILITY OF PHARMACOS COMPOSITIONS FOR CONTROLLED ADMINISTRATION |
US20050175697A1 (en) * | 2003-12-29 | 2005-08-11 | David Edgren | Novel drug compositions and dosage forms of topiramate |
US20040005339A1 (en) * | 2002-06-28 | 2004-01-08 | Shojaei Amir H. | Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability |
CA2490545A1 (en) * | 2002-06-28 | 2004-01-08 | Alza Corporation | Transdermal drug delivery devices having coated microprotrusions |
WO2004002458A1 (en) * | 2002-06-28 | 2004-01-08 | Shire Laboratories Inc. | Formulations of fenofibrate and/or fenofibrate derivatives with improved oral bioavailability |
US10004729B2 (en) | 2002-07-05 | 2018-06-26 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US7771707B2 (en) | 2004-06-12 | 2010-08-10 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
JP2005533846A (en) * | 2002-07-22 | 2005-11-10 | ナノハイブリッド カンパニー リミテッド | Itraconazole, cyclosporine, or a hybrid of carvedilol and layered silicate and method for producing the same |
FR2842736B1 (en) | 2002-07-26 | 2005-07-22 | Flamel Tech Sa | ORAL PHARMACEUTICAL FORMULATION IN THE FORM OF A PLURALITY OF MICROCAPSULES FOR PROLONGED RELEASE OF LOW SOLUBLE ACTIVE (S) PRINCIPLE (S) |
DE10234260A1 (en) * | 2002-07-27 | 2004-02-05 | Beiersdorf Ag | Soap-containing cleaning substrate |
US20050232995A1 (en) | 2002-07-29 | 2005-10-20 | Yam Nyomi V | Methods and dosage forms for controlled delivery of paliperidone and risperidone |
US8637512B2 (en) | 2002-07-29 | 2014-01-28 | Glaxo Group Limited | Formulations and method of treatment |
CA2494233A1 (en) * | 2002-07-29 | 2004-02-05 | Alza Corporation | Formulations and dosage forms for controlled delivery of topiramate |
US20050208132A1 (en) * | 2002-07-29 | 2005-09-22 | Gayatri Sathyan | Methods and dosage forms for reducing side effects of benzisozazole derivatives |
GB2399084B (en) * | 2002-07-30 | 2007-01-31 | Univ Liverpool | Porous beads and method of production thereof |
GB2391472B (en) * | 2002-08-02 | 2004-12-08 | Satishchandra Punambhai Patel | Pharmaceutical compositions |
US7429619B2 (en) * | 2002-08-02 | 2008-09-30 | Mcneil Consumer Healthcare | Polyacrylic film forming compositions |
US20040033262A1 (en) * | 2002-08-19 | 2004-02-19 | Orchid Health Care | Sustained release pharmaceutical composition of a cephalosporin antibiotic |
US6986884B2 (en) * | 2002-09-04 | 2006-01-17 | Rosenberg E William | Composition and method for treating soft nails |
EP1539124B1 (en) | 2002-09-05 | 2018-07-18 | Vanderbilt Royalty Sub L.P. | Compositions and kits for the removal of irritating compounds from bodily surfaces |
US8524200B2 (en) | 2002-09-11 | 2013-09-03 | The Procter & Gamble Company | Tooth whitening products |
US20040116532A1 (en) | 2002-09-13 | 2004-06-17 | Craig Heacock | Pharmaceutical formulations of modafinil |
US8084058B2 (en) | 2002-09-20 | 2011-12-27 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
AU2003272601B2 (en) * | 2002-09-20 | 2009-05-07 | Alpharma Pharmaceuticals, Llc | Sustained-release opioid formulations and methods of use |
US7785627B2 (en) | 2002-09-20 | 2010-08-31 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
US9060941B2 (en) * | 2002-09-20 | 2015-06-23 | Actavis, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
US7959946B2 (en) | 2002-09-20 | 2011-06-14 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
US20040220153A1 (en) * | 2002-09-24 | 2004-11-04 | Jost-Price Edward Roydon | Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines |
US8980870B2 (en) | 2002-09-24 | 2015-03-17 | Boehringer Ingelheim International Gmbh | Solid telmisartan pharmaceutical formulations |
US20040062778A1 (en) * | 2002-09-26 | 2004-04-01 | Adi Shefer | Surface dissolution and/or bulk erosion controlled release compositions and devices |
US6702850B1 (en) | 2002-09-30 | 2004-03-09 | Mediplex Corporation Korea | Multi-coated drug-eluting stent for antithrombosis and antirestenosis |
CA2500652A1 (en) * | 2002-10-02 | 2004-04-15 | Dmi Biosciences, Inc. | Diagnosis and monitoring of diseases |
US6966990B2 (en) | 2002-10-11 | 2005-11-22 | Ferro Corporation | Composite particles and method for preparing |
TWI319713B (en) * | 2002-10-25 | 2010-01-21 | Sustained-release tramadol formulations with 24-hour efficacy | |
US8487002B2 (en) * | 2002-10-25 | 2013-07-16 | Paladin Labs Inc. | Controlled-release compositions |
CA2503150A1 (en) * | 2002-10-31 | 2004-05-21 | Supergen, Inc. | Pharmaceutical formulations targeting specific regions of the gastrointestinal tract |
DE10251963A1 (en) * | 2002-11-08 | 2004-05-19 | Lts Lohmann Therapie-Systeme Ag | Wafer-form transmucosal dosage form, comprising solution of active agent, e.g. for combating drug abuse, in phosphatidyl choline fraction, providing both rapid and constant release via the oral cavity |
KR100801946B1 (en) * | 2002-11-12 | 2008-02-12 | 테바 파마슈티컬 인더스트리즈 리미티드 | Pharmaceutical compositions and dosage forms for buccal and sublingual delivery of tizanidine and methods of administering tizanidine sublingually or buccally |
KR100508518B1 (en) * | 2002-11-13 | 2005-08-17 | 한미약품 주식회사 | Method for the preparation of paclitaxel solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby |
US20040131662A1 (en) | 2003-11-12 | 2004-07-08 | Davidson Robert S. | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
US20040191302A1 (en) | 2003-03-28 | 2004-09-30 | Davidson Robert S. | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
US8999372B2 (en) * | 2002-11-14 | 2015-04-07 | Cure Pharmaceutical Corporation | Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use |
US9561182B2 (en) * | 2003-08-22 | 2017-02-07 | Cure Pharmaceutical Corporation | Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals |
IS6633A (en) * | 2002-11-22 | 2004-05-23 | Omega Farma Ehf. | Compositions of finasteride tablets |
KR100592512B1 (en) * | 2002-11-22 | 2006-07-03 | 서울약품공업(주) | Extended Release Formulation of Tamsulosin or Pharmaceutically Acceptable Salt for Treating Evacuatory Insufficiency |
US20040109927A1 (en) * | 2002-11-27 | 2004-06-10 | Ang Jit Fu | Carbonate-based anti-caking agent with reduced gas release properties |
AU2003278549A1 (en) * | 2002-11-28 | 2004-06-18 | Themis Laboratories Private Limited | Process for manufacturing sustained release microbeads containing venlafaxine hci |
US20050026877A1 (en) * | 2002-12-03 | 2005-02-03 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
ES2518316T3 (en) | 2002-12-06 | 2014-11-05 | Debiopharm International Sa | Heterocyclic compounds, their manufacturing methods and their use in therapy |
US7670627B2 (en) * | 2002-12-09 | 2010-03-02 | Salvona Ip Llc | pH triggered targeted controlled release systems for the delivery of pharmaceutical active ingredients |
US7166671B2 (en) * | 2002-12-10 | 2007-01-23 | Cellresin Technologies, Llc | Grafted cyclodextrin |
US8129450B2 (en) | 2002-12-10 | 2012-03-06 | Cellresin Technologies, Llc | Articles having a polymer grafted cyclodextrin |
US7385004B2 (en) * | 2002-12-10 | 2008-06-10 | Cellresin Technologies, Llc | Enhanced lubrication in polyolefin closure with polyolefin grafted cyclodextrin |
US20040115226A1 (en) * | 2002-12-12 | 2004-06-17 | Wenji Li | Free-flowing solid formulations with improved bio-availability of poorly water soluble drugs and process for making the same |
NZ523128A (en) * | 2002-12-12 | 2006-01-27 | Ashmont Holdings Ltd | Anthelmintic formulations containing avermectins and or milbemycins |
ATE411010T1 (en) | 2002-12-13 | 2008-10-15 | Jagotec Ag | TOPICAL NANOPARTICLE SPIRONOLACTONE FORMULATION |
PL377520A1 (en) * | 2002-12-13 | 2006-02-06 | Warner-Lambert Company Llc | Pregabalin derivatives for the treatment of fibromyalgia and other disorders |
US20040115287A1 (en) * | 2002-12-17 | 2004-06-17 | Lipocine, Inc. | Hydrophobic active agent compositions and methods |
US7160830B2 (en) * | 2002-12-18 | 2007-01-09 | Albemarle Netherlands, B.V. | Process for the preparation of catalyst microspheres |
IN192381B (en) * | 2002-12-20 | 2004-04-10 | Ranbaxy Lab | |
US7381422B2 (en) * | 2002-12-23 | 2008-06-03 | Vical Incorporated | Method for producing sterile polynucleotide based medicaments |
CA2508279A1 (en) * | 2002-12-23 | 2004-07-22 | Vical Incorporated | Method for freeze-drying nucleic acid/block copolymer/cationic surfactant complexes |
US20040127551A1 (en) * | 2002-12-27 | 2004-07-01 | Kai Zhang | Taxane-based compositions and methods of use |
US20040197408A1 (en) * | 2002-12-30 | 2004-10-07 | Angiotech International Ag | Amino acids in micelle preparation |
US20040142903A1 (en) * | 2003-01-16 | 2004-07-22 | Par Pharmaceutical Inc. | Bioavailable fenofibrate compositions, methods for treating hyperlipidemia and hypercholesterolemia and processes for the preparation of such compositions |
US20080213363A1 (en) * | 2003-01-23 | 2008-09-04 | Singh Nikhilesh N | Methods and compositions for delivering 5-HT3 antagonists across the oral mucosa |
US20040162273A1 (en) * | 2003-01-23 | 2004-08-19 | The Procter & Gamble Company | Powder pharmaceutical compositions |
US20040147564A1 (en) * | 2003-01-29 | 2004-07-29 | Rao Vinay U. | Combinations of glimepiride and the thiazolidinedione for treatment of diabetes |
WO2004067001A1 (en) | 2003-01-29 | 2004-08-12 | Takeda Pharmaceutical Company Limited | Process for producing coated preparation |
US20040186155A1 (en) * | 2003-01-30 | 2004-09-23 | Dayno Jeffrey Marc | Combination therapy for the treatment or prevention of migraine |
US7423004B2 (en) * | 2003-01-31 | 2008-09-09 | Smithkline Beecham Corporation | Solid dispersion compositions |
US6931888B2 (en) * | 2003-02-07 | 2005-08-23 | Ferro Corporation | Lyophilization method and apparatus for producing particles |
US7083748B2 (en) * | 2003-02-07 | 2006-08-01 | Ferro Corporation | Method and apparatus for continuous particle production using supercritical fluid |
US20040156894A1 (en) * | 2003-02-07 | 2004-08-12 | Grother Leon Paul | Use of edible acids in fast-dispersing pharmaceutical solid dosage forms |
SI21402A (en) * | 2003-02-12 | 2004-08-31 | LEK farmacevtska dru�ba d.d. | Lined particles and pharmaceutical forms |
US20050220870A1 (en) * | 2003-02-20 | 2005-10-06 | Bonnie Hepburn | Novel formulation, omeprazole antacid complex-immediate release for rapid and sustained suppression of gastric acid |
JP2006518751A (en) * | 2003-02-20 | 2006-08-17 | サンタラス インコーポレイティッド | Novel formulation for rapid and sustained suppression of gastric acid, omeprazole antacid complex-immediate release |
WO2004073729A1 (en) | 2003-02-21 | 2004-09-02 | Translational Research Ltd. | Compositions for nasal administration of drug |
WO2005005010A2 (en) * | 2003-02-21 | 2005-01-20 | Ferro Corporation | Methods and apparatus for producing composite particles using supercritical fluid as plasticizing and extracting agent |
US20040185119A1 (en) * | 2003-02-26 | 2004-09-23 | Theuer Richard C. | Method and compositions for treating gastric hyperacidity while diminishing the likelihood of producing vitamin deficiency |
FR2853831A1 (en) * | 2003-03-05 | 2004-10-22 | Usv Ltd | SOLID DOSAGE FOR ORAL USE OF METFORMIN AND GLYBURIDE AND PROCESS FOR PREPARING THE SAME |
EP1759692A3 (en) * | 2003-03-10 | 2007-09-12 | Novartis AG | Taste-masked solid veterinary compositions |
EP1603540A2 (en) * | 2003-03-14 | 2005-12-14 | Nirmal Mulye | A process for preparing sustained release tablets |
US7858607B2 (en) * | 2003-03-14 | 2010-12-28 | Mamchur Stephen A | System for use by compounding pharmacists to produce hormone replacement medicine customized for each consumer |
JP4880448B2 (en) | 2003-03-17 | 2012-02-22 | アフィナム ファーマシューティカルズ,インコーポレーテッド | Composition comprising a plurality of antibiotics and method of using the same |
US20040185009A1 (en) * | 2003-03-19 | 2004-09-23 | Dexcel Pharma Technologies Ltd. | Composition and device for treating periodontal diseases |
WO2004093866A1 (en) * | 2003-03-25 | 2004-11-04 | Kiel Laboratories, Inc. | Process for preparing phenolic acid salts of gabapentin |
WO2004093827A2 (en) * | 2003-03-25 | 2004-11-04 | Kiel Laboratories, Inc. | Phenolic acid salts of gabapentin in solid dosage forms and methods of use |
US20040191298A1 (en) * | 2003-03-26 | 2004-09-30 | Fredrik Nicklasson | New formulations and use thereof |
WO2004087243A1 (en) | 2003-03-27 | 2004-10-14 | Bioactis Limited | Powder medicine applicator for nasal cavity |
CA2520660C (en) * | 2003-03-28 | 2013-08-20 | Sigmoid Biotechnologies Limited | Solid oral dosage form containing seamless microcapsules |
US20050152967A1 (en) * | 2003-03-28 | 2005-07-14 | Pfab, Lp | Dynamic variable release |
WO2004087175A1 (en) * | 2003-04-04 | 2004-10-14 | Pharmacia Corporation | Oral extended release compressed tablets of multiparticulates |
BRPI0409748A (en) * | 2003-04-08 | 2006-10-24 | Algorx Pharmaceuticals Inc | preparation and purification of synthetic capsaicin |
WO2004091506A2 (en) * | 2003-04-10 | 2004-10-28 | Ivax Research, Inc. | Taxane-based compositions and methods of use |
US20040208932A1 (en) * | 2003-04-17 | 2004-10-21 | Ramachandran Thembalath | Stabilized paroxetine hydrochloride formulation |
TR200300510A2 (en) * | 2003-04-18 | 2004-11-22 | Sanovel �La� Sanay� Ve T�Caret A.�. | Dispersing alendronate microparticle formulation |
EP1619945A2 (en) * | 2003-04-23 | 2006-02-01 | Human BioSystems | Improved methods and solutions for storing donor organs |
KR101167579B1 (en) * | 2003-04-29 | 2012-07-27 | 오렉시젠 세러퓨틱스 인크. | Compositions for affecting weight loss |
ES2277030T3 (en) * | 2003-05-02 | 2007-07-01 | Dexcel Ltd. | FORMULATION IN TABLETS OF VENLAFAXINE OF PROLONGED RELEASE. |
US7030102B1 (en) * | 2003-05-06 | 2006-04-18 | Bioactives, Llc | Highly bioavailable coenzyme Q-10 cyclodextrin complex |
US8507000B2 (en) * | 2003-05-06 | 2013-08-13 | Nostrum Pharmaceuticals, Inc. | Controlled release formulation of erythromycin derivatives |
CL2004000983A1 (en) * | 2003-05-08 | 2005-03-04 | Altana Pharma Ag | ORAL PHARMACEUTICAL COMPOSITION IN THE FORM OF A TABLET THAT INCLUDES DIHYDRATED MAGNETIC PANTOPRAZOL, WHERE THE TABLET FORM IS COMPOSED BY A NUCLEUS, A MIDDLE COAT AND AN OUTER LAYER; AND USE OF PHARMACEUTICAL COMPOSITION IN ULCERAS AND |
US20060008531A1 (en) * | 2003-05-08 | 2006-01-12 | Ferro Corporation | Method for producing solid-lipid composite drug particles |
PE20050150A1 (en) * | 2003-05-08 | 2005-03-22 | Altana Pharma Ag | A DOSAGE FORM CONTAINING (S) -PANTOPRAZOLE AS AN ACTIVE INGREDIENT |
GB0310919D0 (en) * | 2003-05-13 | 2003-06-18 | West Pharm Serv Drug Res Ltd | Pharmaceutical compositions |
US20070141071A1 (en) * | 2003-05-14 | 2007-06-21 | Oregon State University | Hot melt coating by direct blending and coated substrates |
EP2537524B1 (en) * | 2003-05-15 | 2016-07-06 | Ampio Pharmaceuticals, Inc. | Treatment of T-cell mediated diseases |
US20040234579A1 (en) * | 2003-05-22 | 2004-11-25 | Mark D. Finke, Inc. | Dietary supplements and methods of preparing and administering dietary supplements |
IN2003MU00504A (en) * | 2003-06-05 | 2005-05-13 | Alembic Ltd | |
WO2004110492A2 (en) * | 2003-06-06 | 2004-12-23 | Glaxo Group Limited | Composition comprising triptans and nsaids |
US20050020546A1 (en) * | 2003-06-11 | 2005-01-27 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
US7655692B2 (en) * | 2003-06-12 | 2010-02-02 | Pfizer Inc. | Process for forming amorphous atorvastatin |
SE0301880D0 (en) * | 2003-06-25 | 2003-06-25 | Astrazeneca Uk Ltd | New drug delivery composition |
US20060177500A1 (en) * | 2003-07-09 | 2006-08-10 | Hee-Jong Shin | Solid dispersion of tacrolimus |
US7314640B2 (en) * | 2003-07-11 | 2008-01-01 | Mongkol Sriwongjanya | Formulation and process for drug loaded cores |
MXPA06000524A (en) * | 2003-07-18 | 2006-08-11 | Santarus Inc | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders. |
AR045062A1 (en) * | 2003-07-18 | 2005-10-12 | Santarus Inc | PHARMACEUTICAL FORMULATIONS TO INHIBIT THE SECRETION OF ACID AND METHODS TO PREPARE AND USE THEM |
US8993599B2 (en) * | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
US20060246116A1 (en) * | 2003-07-18 | 2006-11-02 | Petworks, Llc | Formula and method for the delivery of medications to animals |
WO2005016253A2 (en) * | 2003-07-18 | 2005-02-24 | Petworks, Llc | Formula nd method for the delivery of oral medications to animals |
EP1498122A1 (en) * | 2003-07-18 | 2005-01-19 | Aventis Pharma S.A. | Semi-solid systems containing azetidine derivatives |
WO2005009368A2 (en) | 2003-07-21 | 2005-02-03 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
JP2006528189A (en) | 2003-07-21 | 2006-12-14 | アドバンシス ファーマスーティカル コーポレイション | Antibiotic products, their use and formulation |
WO2005009364A2 (en) | 2003-07-21 | 2005-02-03 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
CA2534920A1 (en) * | 2003-08-06 | 2005-02-24 | Alza Corporation | Uniform delivery of topiramate over prolonged period of time with enhanced dispersion formulation |
CN1845725A (en) * | 2003-08-06 | 2006-10-11 | 尼马尔·穆利耶 | Pharmaceutical composition containing water soluble drug |
NZ619746A (en) * | 2003-08-06 | 2014-05-30 | Senomyx Inc | Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof |
US20060286037A1 (en) * | 2003-08-08 | 2006-12-21 | Ono Pharmaceutical Co., Ltd. | Heart-slowing drug containing short-acting ß blocker as the active ingredient |
JP2007521231A (en) * | 2003-08-08 | 2007-08-02 | バイオヴェイル ラボラトリーズ インコーポレイテッド | Controlled release tablets of bupropion hydrochloride |
EP1653925A1 (en) | 2003-08-11 | 2006-05-10 | Advancis Pharmaceutical Corporation | Robust pellet |
JP4614139B2 (en) * | 2003-08-12 | 2011-01-19 | キョンドン ファーム カンパニー リミテッド | Method for producing tamsulosin hydrochloride sustained release tablet and tamsulosin hydrochloride sustained release tablet comprising the same |
CA2535398C (en) | 2003-08-12 | 2013-11-12 | Advancis Pharmaceuticals Corporation | Antibiotic product, use and formulation thereof |
WO2005021056A1 (en) * | 2003-08-21 | 2005-03-10 | Cns, Inc. | Effervescent delivery system |
JP2007503389A (en) * | 2003-08-22 | 2007-02-22 | アルザ・コーポレーシヨン | Staged delivery of topiramate over long periods of time |
EP1510208A1 (en) | 2003-08-22 | 2005-03-02 | Fournier Laboratories Ireland Limited | Pharmaceutical composition comprising a combination of metformin and statin |
US20050107350A1 (en) * | 2003-08-22 | 2005-05-19 | Pharmacia Corporation | Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith |
WO2005018651A1 (en) * | 2003-08-26 | 2005-03-03 | Shire Holdings Ag | Pharmaceutical formulation comprising lanthanum compounds |
WO2005020910A2 (en) * | 2003-08-27 | 2005-03-10 | Pharmacia Corporation | Cyclooxygenase-2 selective inhibitor and corticotropin releasing factor antagonist compositions for treating ischemic mediated cns disorders or injuries |
US20050187278A1 (en) * | 2003-08-28 | 2005-08-25 | Pharmacia Corporation | Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors |
US8377952B2 (en) | 2003-08-28 | 2013-02-19 | Abbott Laboratories | Solid pharmaceutical dosage formulation |
US8025899B2 (en) * | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
US20050197512A1 (en) * | 2003-08-29 | 2005-09-08 | Ulrich Beutler | Purification process |
PL1663216T3 (en) * | 2003-08-29 | 2012-03-30 | Veloxis Pharmaceuticals As | Modified release compositions comprising tacrolimus |
GB0503942D0 (en) * | 2005-02-25 | 2005-04-06 | Novartis Ag | Purification process |
SI1663217T1 (en) * | 2003-08-29 | 2010-10-29 | Lifecycle Pharma As | Solid dispersions comprising tacrolimus |
GB0320312D0 (en) * | 2003-08-29 | 2003-10-01 | Novartis Ag | Purification process |
US8246996B2 (en) | 2003-08-29 | 2012-08-21 | Shionogi Inc. | Antibiotic product, use and formulation thereof |
JP2005075804A (en) * | 2003-09-03 | 2005-03-24 | Toyo Capsule Kk | Medicinal composition including menatetrenone |
WO2005023225A1 (en) * | 2003-09-05 | 2005-03-17 | Ranbaxy Laboratories Limited | Cilostazol adsorbate |
US20050058670A1 (en) * | 2003-09-09 | 2005-03-17 | Jong-Soo Woo | Oral itraconazole composition which is not affected by ingested food and process for preparing same |
GB0321256D0 (en) * | 2003-09-11 | 2003-10-08 | Generics Uk Ltd | Novel crystalline compounds |
PL1663182T5 (en) | 2003-09-12 | 2020-07-27 | Amgen Inc. | RAPID DISSOLUTION FORMULATION OF CINACALCET HCl |
US20050059583A1 (en) | 2003-09-15 | 2005-03-17 | Allergan, Inc. | Methods of providing therapeutic effects using cyclosporin components |
CA2538064C (en) | 2003-09-15 | 2013-12-17 | Advancis Pharmaceutical Corporation | Antibiotic product, use and formulation thereof |
GB0322552D0 (en) | 2003-09-26 | 2003-10-29 | Astrazeneca Uk Ltd | Therapeutic treatment |
NZ546349A (en) * | 2003-09-29 | 2010-03-26 | Cipla Ltd | Pharmaceutical formulation with improved stability |
US8124072B2 (en) | 2003-09-29 | 2012-02-28 | Soft Gel Technologies, Inc. | Solubilized CoQ-10 |
EP1670325A1 (en) * | 2003-09-29 | 2006-06-21 | Soft Gel Technologies, Inc. | SOLUBILIZED CoQ-10 |
US20050069590A1 (en) * | 2003-09-30 | 2005-03-31 | Buehler Gail K. | Stable suspensions for medicinal dosages |
BR0318535A (en) * | 2003-09-30 | 2006-09-12 | Lupin Ltd | pharmaceutical composition for controlled drug delivery, process for preparing a pharmaceutical composition and controlled release composition |
TWI372066B (en) * | 2003-10-01 | 2012-09-11 | Wyeth Corp | Pantoprazole multiparticulate formulations |
AR045957A1 (en) * | 2003-10-03 | 2005-11-16 | Novartis Ag | PHARMACEUTICAL COMPOSITION AND COMBINATION |
WO2005034908A2 (en) * | 2003-10-10 | 2005-04-21 | Lifecycle Pharma A/S | A solid dosage form comprising a fibrate and a statin |
WO2005034999A2 (en) * | 2003-10-10 | 2005-04-21 | Bvm Holding Co. | Composition comprising association complex of a pharmaceutical and a poloxamer |
KR20060085686A (en) | 2003-10-10 | 2006-07-27 | 라이프사이클 파마 에이/에스 | A solid dosage form comprising a fibrate |
US20050096390A1 (en) * | 2003-10-10 | 2005-05-05 | Per Holm | Compositions comprising fenofibrate and pravastatin |
US20060172006A1 (en) * | 2003-10-10 | 2006-08-03 | Vincent Lenaerts | Sustained-release tramadol formulations with 24-hour clinical efficacy |
US20070014846A1 (en) * | 2003-10-10 | 2007-01-18 | Lifecycle Pharma A/S | Pharmaceutical compositions comprising fenofibrate and atorvastatin |
US20050096391A1 (en) * | 2003-10-10 | 2005-05-05 | Per Holm | Compositions comprising fenofibrate and rosuvastatin |
US9173847B2 (en) * | 2003-10-10 | 2015-11-03 | Veloxis Pharmaceuticals A/S | Tablet comprising a fibrate |
US20050084531A1 (en) * | 2003-10-16 | 2005-04-21 | Jatin Desai | Tablet with aqueous-based sustained release coating |
GB0324574D0 (en) * | 2003-10-21 | 2003-11-26 | Glaxo Group Ltd | Novel compositions |
WO2005042623A1 (en) * | 2003-10-23 | 2005-05-12 | University Of Nottingham | Preparing active polymer extrudates |
US7338171B2 (en) * | 2003-10-27 | 2008-03-04 | Jen-Chuen Hsieh | Method and apparatus for visual drive control |
US20070092562A1 (en) * | 2003-10-28 | 2007-04-26 | Spi Pharma, Inc. | Product and process for increasing compactibility of carbohydrates |
WO2005044193A2 (en) * | 2003-10-28 | 2005-05-19 | Spi Pharma, Inc. | Product and process for increasing compactibility of carbohydrates |
US20060003002A1 (en) * | 2003-11-03 | 2006-01-05 | Lipocine, Inc. | Pharmaceutical compositions with synchronized solubilizer release |
US20050096365A1 (en) * | 2003-11-03 | 2005-05-05 | David Fikstad | Pharmaceutical compositions with synchronized solubilizer release |
US8987322B2 (en) * | 2003-11-04 | 2015-03-24 | Circ Pharma Research And Development Limited | Pharmaceutical formulations for carrier-mediated transport statins and uses thereof |
US8709476B2 (en) | 2003-11-04 | 2014-04-29 | Supernus Pharmaceuticals, Inc. | Compositions of quaternary ammonium compounds containing bioavailability enhancers |
JP5610663B2 (en) * | 2003-11-04 | 2014-10-22 | スパーナス ファーマシューティカルズ インコーポレイテッド | Trospium once a day dosage form |
SE0302924D0 (en) * | 2003-11-05 | 2003-11-05 | Camurus Ab | Pharmaceutical composition having a cationic excipient |
US20070292498A1 (en) * | 2003-11-05 | 2007-12-20 | Warren Hall | Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers |
US7390504B2 (en) * | 2003-11-07 | 2008-06-24 | Jj Pharma, Inc. | HDL-boosting combination therapy complexes |
US20050101605A1 (en) * | 2003-11-07 | 2005-05-12 | Ahmed Salah U. | Oral liquid formulations of methotrexate |
US8784869B2 (en) | 2003-11-11 | 2014-07-22 | Mattern Pharma Ag | Controlled release delivery system for nasal applications and methods of treatment |
DE60303854T2 (en) | 2003-11-11 | 2006-08-10 | Mattern, Udo | Nose formulation with controlled release of sex hormones |
ES2260563T3 (en) * | 2003-11-13 | 2006-11-01 | Ferring B.V. | BLISTER PACKAGE AND SOLID PHARMACEUTICAL FORM FOR IT. |
US7387793B2 (en) | 2003-11-14 | 2008-06-17 | Eurand, Inc. | Modified release dosage forms of skeletal muscle relaxants |
US7470435B2 (en) * | 2003-11-17 | 2008-12-30 | Andrx Pharmaceuticals, Llc | Extended release venlafaxine formulation |
PT1532975E (en) † | 2003-11-18 | 2007-04-30 | Helm Ag | Process for the manufacture of free-flowing, powdery atorvastatin adsorbates |
WO2005062722A2 (en) * | 2003-11-21 | 2005-07-14 | Sun Pharmaceutical Industries Limited | Fexofenadine containing pharmaceutical formulation |
CZ300438B6 (en) * | 2003-11-25 | 2009-05-20 | Pliva Hrvatska D.O.O. | Process for preparing solid medicament form for oral administration with instantaneous release of active substance and containing as the active substance finasteride polymorphous form |
US7201920B2 (en) | 2003-11-26 | 2007-04-10 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse of opioid containing dosage forms |
WO2005060943A1 (en) * | 2003-11-28 | 2005-07-07 | Glenmark Pharmaceuticals Ltd. | Antifungal oral dosage forms and the methods preparation |
US20050118265A1 (en) * | 2003-11-28 | 2005-06-02 | Anandi Krishnan | Antifungal oral dosage forms and the methods for preparation |
WO2005053727A2 (en) * | 2003-11-29 | 2005-06-16 | Sangstat Medical Corporation | Pharmaceutical compositions for bioactive peptide agents |
CA2547239A1 (en) * | 2003-12-04 | 2005-06-16 | Pfizer Products Inc. | Azithromycin multiparticulate dosage forms by liquid-based processes |
WO2005053639A2 (en) * | 2003-12-04 | 2005-06-16 | Pfizer Products Inc. | Controlled release multiparticulates formed with dissolution enhancers |
WO2005053651A1 (en) * | 2003-12-04 | 2005-06-16 | Pfizer Products Inc. | Multiparticulate compositions with improved stability |
WO2005053652A1 (en) | 2003-12-04 | 2005-06-16 | Pfizer Products Inc. | Multiparticulate crystalline drug compositions containing a poloxamer and a glyceride |
CN1889932A (en) * | 2003-12-04 | 2007-01-03 | 辉瑞产品公司 | Method of making pharmaceutical multiparticulates |
KR20060109481A (en) * | 2003-12-04 | 2006-10-20 | 화이자 프로덕츠 인코포레이티드 | Spray-congeal process using an extruder for preparing multiparticulate azithromycin compositions containing preferably a poloxamer and a glyceride |
JP2007513147A (en) * | 2003-12-04 | 2007-05-24 | ファイザー・プロダクツ・インク | Spray congealing process for producing a multiparticulate crystalline pharmaceutical composition, preferably containing poloxamer and glyceride, using an extruder |
US6984403B2 (en) * | 2003-12-04 | 2006-01-10 | Pfizer Inc. | Azithromycin dosage forms with reduced side effects |
BRPI0418589A (en) | 2003-12-08 | 2008-01-29 | Bentley Pharmaceuticals Inc | pharmaceutical compositions and methods for insulin treatment |
US9359585B2 (en) * | 2003-12-08 | 2016-06-07 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Stable nonaqueous reactive skin care and cleansing compositions having a continuous and a discontinuous phase |
ITMI20032399A1 (en) * | 2003-12-09 | 2005-06-10 | Zambon Spa | PHARMACEUTICAL COMPOSITION CONTAINING GABAPENTIN. |
ATE301455T1 (en) * | 2003-12-09 | 2005-08-15 | Helm Ag | PHARMACEUTICAL PREPARATION CONTAINING VALACICLOVIR |
US6783772B1 (en) * | 2003-12-12 | 2004-08-31 | Sanjeev Khandelwal | Pharmaceutical preparations containing alendronate sodium |
US7446101B1 (en) * | 2003-12-12 | 2008-11-04 | Bioactives, Llc | Bioavailable carotenoid-cyclodextrin formulations for soft-gels and other encapsulation systems |
US20050136121A1 (en) * | 2003-12-22 | 2005-06-23 | Shear/Kershman Laboratories, Inc. | Oral peptide delivery system with improved bioavailability |
US7846462B2 (en) * | 2003-12-22 | 2010-12-07 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Personal care implement containing a stable reactive skin care and cleansing composition |
WO2005061088A1 (en) * | 2003-12-22 | 2005-07-07 | Finlay Warren H | Powder formation by atmospheric spray-freeze drying |
AR046773A1 (en) * | 2003-12-23 | 2005-12-21 | Novartis Ag | PHARMACEUTICAL FORMULATIONS OF BISPHOSPHONATES |
EP1701706A2 (en) * | 2003-12-29 | 2006-09-20 | Alza Corporation | Novel drug compositions and dosage forms |
US20050175696A1 (en) * | 2003-12-29 | 2005-08-11 | David Edgren | Drug granule coatings that impart smear resistance during mechanical compression |
WO2005065645A2 (en) * | 2003-12-31 | 2005-07-21 | Actavis Group Hf | Donepezil formulations |
US20070148232A1 (en) * | 2003-12-31 | 2007-06-28 | Pfizer Inc. | Stabilized pharmaceutical solid compositions of low-solubility drugs and poloxamers, and stabilizing polymers |
BRPI0418330A (en) * | 2003-12-31 | 2007-05-02 | Pfizer Prod Inc | solid compositions of low solubility drugs and poloxamers |
EP1708738B1 (en) * | 2004-01-12 | 2016-05-04 | MannKind Corporation | A method of reducing serum proinsulin levels in type 2 diabetics |
US7713959B2 (en) * | 2004-01-13 | 2010-05-11 | Duke University | Compositions of an anticonvulsant and mirtazapine to prevent weight gain |
BRPI0506829A (en) * | 2004-01-13 | 2007-05-29 | Univ Duke | Anticonvulsant and antipsychotic drug compositions and methods for their use to affect weight loss |
US20050152887A1 (en) * | 2004-01-14 | 2005-07-14 | Doctor's Signature Sales And Marketing International Corp. [Dba Life Force International | Protonic formulation |
US7658721B2 (en) * | 2004-01-16 | 2010-02-09 | Biodel Inc. | Sublingual drug delivery device |
CA2553690C (en) | 2004-01-22 | 2016-05-24 | Sung Lan Hsia | Topical co-enzyme q10 formulations and methods of use |
US20050164952A1 (en) * | 2004-01-23 | 2005-07-28 | Vital Pharmaceuticals, Inc. | Delivery system for growth hormone releasing peptides |
CN102764247B (en) | 2004-01-30 | 2016-04-20 | 考里安国际公司 | The rapidly dissolving film of active agent delivery |
JP2007520555A (en) * | 2004-02-05 | 2007-07-26 | バクスター・インターナショナル・インコーポレイテッド | Dispersants prepared by use of self-stabilizing agents |
CA2554271A1 (en) * | 2004-02-10 | 2005-08-25 | Santarus, Inc. | Combination of proton pump inhibitor, buffering agent, and nonsteroidal anti-inflammatory agent |
EP1715853A4 (en) * | 2004-02-17 | 2012-07-18 | Transcept Pharmaceuticals Inc | Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof |
EP1721619A4 (en) * | 2004-02-17 | 2012-09-05 | Eisai R&D Man Co Ltd | Soft capsule preparation |
KR100582350B1 (en) * | 2004-02-17 | 2006-05-22 | 한미약품 주식회사 | Tamsulosin hydrochloride composition for oral administration and controlled-release granule formulation thereof |
US8642079B2 (en) * | 2004-02-23 | 2014-02-04 | Hormos Medical Corporation | Solid formulations of ospemifene |
US20070269519A1 (en) * | 2004-03-03 | 2007-11-22 | Constantine Georgiades | Whitening products |
US20050196355A1 (en) * | 2004-03-03 | 2005-09-08 | Constantine Georgiades | Film products having controlled disintegration properties |
US20080003248A1 (en) * | 2004-03-03 | 2008-01-03 | Constantine Georgiades | Whitening products |
EP1725217B1 (en) * | 2004-03-10 | 2008-08-06 | Ranbaxy Laboratories, Ltd. | Processes for the preparation of solid dosage forms of amorphous valganciclovir hydrochloride |
PT2319500E (en) * | 2004-03-12 | 2013-01-23 | Biodel Inc | Rapid acting drug delivery compositions |
US20080090753A1 (en) | 2004-03-12 | 2008-04-17 | Biodel, Inc. | Rapid Acting Injectable Insulin Compositions |
US20080096800A1 (en) * | 2004-03-12 | 2008-04-24 | Biodel, Inc. | Rapid mucosal gel or film insulin compositions |
US20080248999A1 (en) * | 2007-04-04 | 2008-10-09 | Biodel Inc. | Amylin formulations |
US20080085298A1 (en) * | 2004-03-12 | 2008-04-10 | Biodel, Inc. | Rapid Mucosal Gel or Film Insulin Compositions |
EP1591114A1 (en) * | 2004-03-12 | 2005-11-02 | Fournier Laboratories Ireland Limited | Use of metformin and orlistat for the treatment or prevention of obesity |
US20050202079A1 (en) * | 2004-03-15 | 2005-09-15 | Mylan Pharmaceuticals Inc. | Novel orally administrable formulation of nitrofurantoin and a method for preparing said formulation |
US7468428B2 (en) | 2004-03-17 | 2008-12-23 | App Pharmaceuticals, Llc | Lyophilized azithromycin formulation |
US20050208145A1 (en) * | 2004-03-19 | 2005-09-22 | Thava Vasanthan | Grain fiber compositions and methods of use |
DE602004023764D1 (en) * | 2004-03-19 | 2009-12-03 | Zentiva Kimyasal Ueruenler San | PREPARATION OF LIPID-COATED CEFUROXIME AXETILE |
WO2005092370A1 (en) | 2004-03-22 | 2005-10-06 | Solvay Pharmaceuticals Gmbh | Oral pharmaceutical compositions of lipase-containing products, in particular of pancreatin, containing surfactants |
US20080039422A1 (en) * | 2004-03-30 | 2008-02-14 | Transition Therapeutics Inc. | Vitamin B12-Containing Compositions and Methods of Use |
WO2005095390A2 (en) * | 2004-03-31 | 2005-10-13 | Sandoz Ag | Novel co-precipitate of amorphous rosiglitazone |
US8003122B2 (en) * | 2004-03-31 | 2011-08-23 | Cordis Corporation | Device for local and/or regional delivery employing liquid formulations of therapeutic agents |
US7989490B2 (en) * | 2004-06-02 | 2011-08-02 | Cordis Corporation | Injectable formulations of taxanes for cad treatment |
WO2005097061A1 (en) * | 2004-04-01 | 2005-10-20 | Procyte Corporation | Encapsulated peptide copper complexes and compositions and methods related thereto |
US20050220873A1 (en) * | 2004-04-02 | 2005-10-06 | Chien-Hsuan Han | Pharmaceutical dosage forms having immediate and controlled release properties that contain a GABAB receptor agonist |
US20050226927A1 (en) * | 2004-04-02 | 2005-10-13 | Impax Laboratories, Inc. | Pharmaceutical dosage forms having immediate release and/or controlled release properties that contain a GABAB receptor agonist |
US8007827B2 (en) * | 2004-04-02 | 2011-08-30 | Impax Laboratories, Inc. | Pharmaceutical dosage forms having immediate release and/or controlled release properties |
US20050226906A1 (en) * | 2004-04-08 | 2005-10-13 | Micro Nutrient, Llc | Nutrient system for individualized responsive dosing regimens |
US7850987B2 (en) * | 2004-04-08 | 2010-12-14 | Micronutrient, Llc | Nutrient composition(s) and system(s) for individualized, responsive dosing regimens |
US7785619B2 (en) * | 2004-04-08 | 2010-08-31 | Micro Nutrient, Llc | Pharmanutrient composition(s) and system(s) for individualized, responsive dosing regimens |
WO2005117870A2 (en) * | 2004-04-16 | 2005-12-15 | Santarus, Inc. | Combination of proton pump inhibitor, buffering agent, and prokinetic agent |
US20050238675A1 (en) * | 2004-04-26 | 2005-10-27 | Wenjie Li | Water-soluble formulations of fat soluble vitamins and pharmaceutical agents and their applications |
RU2006139930A (en) * | 2004-05-03 | 2008-06-10 | Дюк Юниверсити (Сша/Сша) (Us) | COMPOSITIONS FOR PROMOTING WEIGHT LOSS |
US20070237823A1 (en) * | 2004-05-04 | 2007-10-11 | Thomas Bock | Solid Pharmaceutical Form Comprising and Ltb4 Antagonist |
MXPA06012944A (en) * | 2004-05-10 | 2007-02-12 | Lupin Ltd | Novel pharmaceutical formulation of cefixime for enhanced bioavailability. |
US20060127468A1 (en) | 2004-05-19 | 2006-06-15 | Kolodney Michael S | Methods and related compositions for reduction of fat and skin tightening |
US7754230B2 (en) * | 2004-05-19 | 2010-07-13 | The Regents Of The University Of California | Methods and related compositions for reduction of fat |
PL2422789T3 (en) * | 2004-05-19 | 2018-09-28 | Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center | Injectable coposition comprising sodium deoxycholate |
US20080286359A1 (en) * | 2004-05-24 | 2008-11-20 | Richard John Dansereau | Low Dosage Forms Of Risedronate Or Its Salts |
US7645460B2 (en) * | 2004-05-24 | 2010-01-12 | The Procter & Gamble Company | Dosage forms of risedronate |
CN1957039A (en) * | 2004-05-24 | 2007-05-02 | 细胞树脂技术有限责任公司 | Amphoteric grafted barrier materials |
US20080287400A1 (en) * | 2004-05-24 | 2008-11-20 | Richard John Dansereau | Low Dosage Forms Of Risedronate Or Its Salts |
US7645459B2 (en) | 2004-05-24 | 2010-01-12 | The Procter & Gamble Company | Dosage forms of bisphosphonates |
US8815916B2 (en) * | 2004-05-25 | 2014-08-26 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
US8906940B2 (en) * | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
US20050265955A1 (en) * | 2004-05-28 | 2005-12-01 | Mallinckrodt Inc. | Sustained release preparations |
CA2568914C (en) | 2004-06-04 | 2013-09-24 | Affinium Pharmaceuticals, Inc. | Therapeutic agents, and methods of making and using the same |
CA2568640C (en) | 2004-06-04 | 2011-08-09 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical composition containing irbesartan |
US20060002986A1 (en) * | 2004-06-09 | 2006-01-05 | Smithkline Beecham Corporation | Pharmaceutical product |
EP1753398B1 (en) * | 2004-06-10 | 2018-09-19 | Glatt Air Techniques, Inc. | Controlled release matrix pharmaceutical dosage formulation |
US8461187B2 (en) | 2004-06-16 | 2013-06-11 | Takeda Pharmaceuticals U.S.A., Inc. | Multiple PPI dosage form |
US20060002999A1 (en) * | 2004-06-17 | 2006-01-05 | Forest Laboratories, Inc. | Immediate release formulations of 1-aminocyclohexane compounds, memantine and neramexane |
ITMI20041295A1 (en) | 2004-06-25 | 2004-09-25 | Cosmo Spa | ORAL ANTI-MICROBIAL PHARMACEUTICAL COMPOSITIONS |
WO2006005017A2 (en) * | 2004-06-30 | 2006-01-12 | Valeant Research & Development | Oral composition comprising carbamylating agent |
WO2006014427A1 (en) | 2004-07-02 | 2006-02-09 | Advancis Pharmaceutical Corporation | Tablet for pulsed delivery |
KR100553160B1 (en) * | 2004-07-09 | 2006-02-22 | 한국콜마 주식회사 | Nano sized phospholipid liposome composition comprising coenzym Q10 and manufacturing method thereof |
TWI302944B (en) * | 2004-07-12 | 2008-11-11 | Method for removing virus activity from biological materials | |
EP1776098A1 (en) * | 2004-07-14 | 2007-04-25 | Repros Therapeutics Inc. | Trans-clomiphene for the treatment of benign prostate hypertrophy, prostate cancer, hypogonadism, elevated triglycerides and high cholesterol |
RU2393168C2 (en) | 2004-07-19 | 2010-06-27 | Биокон Лимитед | Insulin-oligomer conjugates, preparations and use thereof |
DE102004035938A1 (en) * | 2004-07-23 | 2006-02-16 | Röhm GmbH & Co. KG | Process for the preparation of coated drug forms with stable drug release profile |
WO2006014973A2 (en) * | 2004-07-26 | 2006-02-09 | Teva Pharmaceutical Industries, Ltd. | Pharmaceutical dosage forms including rasagiline |
PT1781264E (en) | 2004-08-04 | 2013-10-16 | Evonik Corp | Methods for manufacturing delivery devices and devices thereof |
AU2005271259B2 (en) | 2004-08-05 | 2012-01-19 | A.V. Topchiev Institute Of Petrochemical Synthesis | Adhesive composition |
WO2006016530A1 (en) * | 2004-08-10 | 2006-02-16 | Translational Research, Ltd. | Transnasal composition having immediate action and high absorbability |
US20060039966A1 (en) * | 2004-08-12 | 2006-02-23 | Miller Bruce A Jr | Dosage delivery apparatus for improving user acceptance of oral supplements and medicaments and methods for manufacturing same |
DE102004039270A1 (en) * | 2004-08-13 | 2006-02-23 | J. S. Staedtler Gmbh & Co. Kg | Moldable mass e.g. in the model building and/or prototype building, comprises dried (by supplying energy source) and hardened (by using microwave equipment) mass |
JP5078014B2 (en) | 2004-08-20 | 2012-11-21 | マンカインド コーポレイション | Catalytic reaction of diketopiperazine synthesis. |
WO2006023347A1 (en) * | 2004-08-20 | 2006-03-02 | Alpharma, Inc. | Paroxetine formulations |
HUE026797T2 (en) | 2004-08-23 | 2016-07-28 | Mannkind Corp | Diketopiperazine salts for drug delivery |
US8119153B2 (en) * | 2004-08-26 | 2012-02-21 | Boston Scientific Scimed, Inc. | Stents with drug eluting coatings |
WO2006024138A1 (en) * | 2004-08-30 | 2006-03-09 | Taro Pharmaceutical Industries Ltd. | A thermoreversible pharmaceutical formulation for anti-microbial agents comprising poloxamer polymers and hydroxy fatty acid ester of polyethylene glycol |
US20060134212A1 (en) * | 2004-09-02 | 2006-06-22 | Forest Laboratories, Inc. | Lercanidipine immediate release compositions |
US20060165789A1 (en) * | 2004-09-09 | 2006-07-27 | Forest Laboratories, Inc. | Lercanidipine modified release compositions |
US20060165788A1 (en) * | 2004-09-09 | 2006-07-27 | Wattanaporn Abramowitz | Lercanidipine pH dependent pulsatile release compositions |
US8750983B2 (en) * | 2004-09-20 | 2014-06-10 | P Tech, Llc | Therapeutic system |
US20060115499A1 (en) * | 2004-09-27 | 2006-06-01 | Alk-Abello A/S | Liquid allergy vaccine formulation for oromucosal administration |
PL1811979T3 (en) * | 2004-09-27 | 2009-04-30 | Sigmoid Pharma Ltd | Microcapsules comprising a methylxanthine and a corticosteroid |
WO2006036982A2 (en) * | 2004-09-28 | 2006-04-06 | Atrium Medical Corporation | Drug delivery coating for use with a stent |
US9801982B2 (en) | 2004-09-28 | 2017-10-31 | Atrium Medical Corporation | Implantable barrier device |
US9012506B2 (en) | 2004-09-28 | 2015-04-21 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US20060198838A1 (en) * | 2004-09-28 | 2006-09-07 | Fallon Joan M | Combination enzyme for cystic fibrosis |
WO2006036969A2 (en) | 2004-09-28 | 2006-04-06 | Atrium Medical Corporation | Formation of barrier layer |
US9000040B2 (en) | 2004-09-28 | 2015-04-07 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US7740875B2 (en) * | 2004-10-08 | 2010-06-22 | Mediquest Therapeutics, Inc. | Organo-gel formulations for therapeutic applications |
US20060078580A1 (en) * | 2004-10-08 | 2006-04-13 | Mediquest Therapeutics, Inc. | Organo-gel formulations for therapeutic applications |
US20060079513A1 (en) * | 2004-10-13 | 2006-04-13 | Preston David M | Methods and compositions including methscopolamine nitrate |
US20060079514A1 (en) * | 2004-10-13 | 2006-04-13 | Victory Pharma Incorporated | Methods and compositions including methscopolamine bromide |
KR100591786B1 (en) * | 2004-10-19 | 2006-06-26 | 휴먼팜 주식회사 | Pharmaceutical composition containing pranlukast and preparation process thereof |
US8835413B2 (en) | 2004-10-20 | 2014-09-16 | Endorecherche, Inc. | Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women |
US20060088591A1 (en) * | 2004-10-22 | 2006-04-27 | Jinghua Yuan | Tablets from a poorly compressible substance |
WO2006047022A1 (en) | 2004-10-25 | 2006-05-04 | Virginia Commonwealth University | Nuclear sulfated oxysterol, potent regulator of cholesterol homeostasis, for therapy of hypercholesterolemia, hyperlipidemia, and atherosclerosis |
KR101086254B1 (en) * | 2004-11-04 | 2011-11-24 | 에스케이케미칼주식회사 | Soild dispersion composition of pranlukast with improved bioavailability and the method of preparing the solid dispersion |
US8586085B2 (en) * | 2004-11-08 | 2013-11-19 | Biokey, Inc. | Methods and formulations for making pharmaceutical compositions containing bupropion |
US20060193908A1 (en) * | 2004-11-09 | 2006-08-31 | Burnside Beth A | Extended release formulations of poorly soluble antibiotics |
US20060099230A1 (en) * | 2004-11-10 | 2006-05-11 | Chin-Chih Chiang | Novel formulations of eprosartan with enhanced bioavailability |
WO2006054175A2 (en) * | 2004-11-18 | 2006-05-26 | Aurobindo Pharma Limited | Stable dosage forms of acid labile drug |
FR2878161B1 (en) * | 2004-11-23 | 2008-10-31 | Flamel Technologies Sa | ORAL MEDICINE FORM, SOLID AND DESIGNED TO AVOID MEASUREMENT |
CA2588296A1 (en) | 2004-11-24 | 2006-06-01 | Neuromolecular Pharmaceuticals, Inc. | Composition comprising an nmda receptor antagonist and levodopa and use thereof for treating neurological disease |
BRPI0516912A2 (en) * | 2004-11-24 | 2009-06-23 | Algorx Pharmaceuticals Inc | capsaicinoid gel formulation and uses |
FR2878158B1 (en) * | 2004-11-24 | 2009-01-16 | Flamel Technologies Sa | ORAL PHARMACEUTICAL FORM, SOLID MICROPARTICULAR DESIGNED TO PREVENT MEASUREMENT |
US9149433B2 (en) * | 2004-11-30 | 2015-10-06 | Basf Corporation | Method for formation of micro-prilled polymers |
EP1827393A4 (en) * | 2004-12-09 | 2012-04-18 | Insys Therapeutics Inc | Room-temperature stable dronabinol formulations |
KR101118199B1 (en) | 2004-12-20 | 2012-03-15 | 주식회사 삼양홀딩스 | Polymeric micelle composition for solubilizing tacrolimus |
US20120269886A1 (en) | 2004-12-22 | 2012-10-25 | Nitto Denko Corporation | Therapeutic agent for pulmonary fibrosis |
HUE048419T2 (en) | 2004-12-22 | 2020-08-28 | Nitto Denko Corp | Drug carrier and drug carrier kit for inhibiting fibrosis |
DE102005042875A1 (en) * | 2004-12-23 | 2006-09-21 | Grünenthal GmbH | Fast-release dosage forms for antibiotics |
US20060246003A1 (en) * | 2004-12-27 | 2006-11-02 | Eisai Co. Ltd. | Composition containing anti-dementia drug |
US20070129402A1 (en) * | 2004-12-27 | 2007-06-07 | Eisai Research Institute | Sustained release formulations |
US20090208579A1 (en) * | 2004-12-27 | 2009-08-20 | Eisai R & D Management Co., Ltd. | Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same |
US20060280789A1 (en) * | 2004-12-27 | 2006-12-14 | Eisai Research Institute | Sustained release formulations |
RU2401125C2 (en) * | 2004-12-27 | 2010-10-10 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Method of antidementia drug stabilisation |
US20060140820A1 (en) | 2004-12-28 | 2006-06-29 | Udo Mattern | Use of a container of an inorganic additive containing plastic material |
CN100434068C (en) * | 2004-12-30 | 2008-11-19 | 天津药物研究院 | Bexarotene gel and its preparation method |
US20060147518A1 (en) * | 2004-12-30 | 2006-07-06 | Pierre Fabre Medicament | Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it |
US7758884B2 (en) * | 2005-01-28 | 2010-07-20 | Kemin Industries, Inc. | Formulation for increasing the deposition of dietary carotenoids in eggs |
AU2006210481B2 (en) | 2005-02-04 | 2011-12-08 | Repros Therapeutics Inc. | Methods and materials with trans-clomiphene for the treatment of male infertility |
US20060198886A1 (en) * | 2005-03-01 | 2006-09-07 | Jenkins Richard B | Medicament having coated methenamine combined with acidifier |
EP2194140A2 (en) * | 2005-03-02 | 2010-06-09 | Metanomics GmbH | Process for the production of fine chemicals |
FR2883179B1 (en) * | 2005-03-18 | 2009-04-17 | Ethypharm Sa | COATED TABLET |
EP1865938A4 (en) | 2005-03-22 | 2008-09-24 | Repros Therapeutics Inc | Dosing regimes for trans-clomiphene |
AU2006230557A1 (en) * | 2005-03-31 | 2006-10-05 | King Pharmaceuticals Research & Development, Inc. | Controlled release pharmaceutical compositions of liothyronine and methods of making and using the same |
CN101189249B (en) | 2005-04-01 | 2013-04-17 | 加利福尼亚大学董事会 | Phosphono-pent-2-en-1-yl nucleosides and analogs |
DE602006017345D1 (en) * | 2005-04-01 | 2010-11-18 | Neurogesx Inc | OILS OF CAPSAICINOIDS AND METHOD FOR THEIR PREPARATION AND USE |
US20090156545A1 (en) * | 2005-04-01 | 2009-06-18 | Hostetler Karl Y | Substituted Phosphate Esters of Nucleoside Phosphonates |
JP5002904B2 (en) * | 2005-04-04 | 2012-08-15 | ブラザー工業株式会社 | Radio tag communication apparatus, communication method thereof, and communication program thereof |
BRPI0607017B8 (en) * | 2005-04-06 | 2021-05-25 | Adamas Pharmaceuticals Inc | pharmaceutical composition comprising memantine and donezepil, and their use for the treatment of snc-related conditions |
US7348027B2 (en) * | 2005-04-08 | 2008-03-25 | Bayer Healthcare Llc | Taste masked veterinary formulation |
JP2008535920A (en) * | 2005-04-12 | 2008-09-04 | エラン・ファルマ・インターナショナル・リミテッド | Modified release composition comprising a fluorocytidine derivative for the treatment of cancer |
US20090252807A1 (en) * | 2005-04-13 | 2009-10-08 | Elan Pharma International Limited | Nanoparticulate and Controlled Release Compositions Comprising Prostaglandin Derivatives |
KR20080009201A (en) | 2005-04-15 | 2008-01-25 | 클라루스 쎄러퓨틱스, 아이엔씨. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US8492369B2 (en) | 2010-04-12 | 2013-07-23 | Clarus Therapeutics Inc | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
MX2007012947A (en) * | 2005-04-18 | 2008-04-09 | Rubicon Res Pvt Ltd | Bioenhanced compositions. |
US20100119607A1 (en) * | 2005-04-18 | 2010-05-13 | Rubicon Research Pvt. Ltd. | Bioenhanced compositions |
PL385455A1 (en) * | 2005-04-22 | 2008-11-24 | Teva Pharmaceuticals Usa,Inc. | Oral disintegrating pharmaceutical tablet of olanzapine preparations |
US20060240108A1 (en) * | 2005-04-26 | 2006-10-26 | Bernard Bobby L | Cellulosic films incorporating a pharmaceutically acceptable plasticizer with enhanced wettability |
US20060240051A1 (en) * | 2005-04-26 | 2006-10-26 | Singleton Andy H | Eutectic blends containing a water soluble vitamin derivative |
BRPI0608780A2 (en) * | 2005-04-28 | 2010-11-09 | Eisai R&D Man Co Ltd | anti-dementia drug-containing composition |
US20070259348A1 (en) * | 2005-05-03 | 2007-11-08 | Handylab, Inc. | Lyophilized pellets |
US20060281783A1 (en) * | 2005-05-25 | 2006-12-14 | Transoral Pharmaceuticals, Inc. | Compositions and methods of treating middle-of-the night insomnia |
US20070287740A1 (en) * | 2005-05-25 | 2007-12-13 | Transcept Pharmaceuticals, Inc. | Compositions and methods of treating middle-of-the night insomnia |
US20070225322A1 (en) * | 2005-05-25 | 2007-09-27 | Transoral Pharmaceuticals, Inc. | Compositions and methods for treating middle-of-the night insomnia |
AU2006249349B2 (en) * | 2005-05-26 | 2012-01-12 | Teva Women's Health, Inc. | Oral dosage forms comprising progesterone and methods of making and using the same |
EP1893180A2 (en) * | 2005-06-07 | 2008-03-05 | Pfizer Products Inc. | Multiparticulates comprising low-solubility drugs and carriers that result in rapid drug release |
ES2326251B1 (en) * | 2005-06-12 | 2010-07-08 | Elan Pharma International Limited | COMPOSITIONS OF MODIFIED LIBERATION TICLOPIDINE. |
US20060280787A1 (en) * | 2005-06-14 | 2006-12-14 | Baxter International Inc. | Pharmaceutical formulation of the tubulin inhibitor indibulin for oral administration with improved pharmacokinetic properties, and process for the manufacture thereof |
MX2007015183A (en) * | 2005-06-14 | 2008-02-19 | Baxter Int | Pharmaceutical formulations for minimizing drug-drug interactions. |
WO2006134610A1 (en) * | 2005-06-16 | 2006-12-21 | Hetero Drugs Limited | Efavirenz pharmaceutical composition having enhanced dissolution profile |
WO2007002125A1 (en) * | 2005-06-23 | 2007-01-04 | Schering Corporation | Rapidly absorbing oral formulations of pde5 inhibitors |
US7981442B2 (en) * | 2005-06-28 | 2011-07-19 | University Of South Florida | Ultrasound enhancement of drug release across non-ionic surfactant membranes |
US8435558B1 (en) | 2005-06-28 | 2013-05-07 | University Of South Florida | Ultrasound enhancement of drug release across non-ionic surfactant membranes |
AR054805A1 (en) * | 2005-06-29 | 2007-07-18 | Stiefel Laboratories | TOPICAL COMPOSITIONS FOR SKIN TREATMENT |
US20070014847A1 (en) * | 2005-07-05 | 2007-01-18 | Ahmed Salah U | Coated capsules and methods of making and using the same |
CN100402035C (en) * | 2005-07-07 | 2008-07-16 | 石药集团中奇制药技术(石家庄)有限公司 | A pharmaceutical composition of microencapsulated cefuroxime axetil |
US20110045065A1 (en) * | 2005-07-11 | 2011-02-24 | Ashok Vasantray Vyas | Substance having antioxidant, geroprotective and anti-ischemic activity and method for the preparation thereof |
US7288520B2 (en) * | 2005-07-13 | 2007-10-30 | Allergan, Inc. | Cyclosporin compositions |
US7297679B2 (en) | 2005-07-13 | 2007-11-20 | Allergan, Inc. | Cyclosporin compositions |
US20070015691A1 (en) | 2005-07-13 | 2007-01-18 | Allergan, Inc. | Cyclosporin compositions |
US7276476B2 (en) * | 2005-07-13 | 2007-10-02 | Allergan, Inc. | Cyclosporin compositions |
US20070015693A1 (en) * | 2005-07-13 | 2007-01-18 | Allergan, Inc. | Cyclosporin compositions |
US7202209B2 (en) | 2005-07-13 | 2007-04-10 | Allergan, Inc. | Cyclosporin compositions |
US8067451B2 (en) * | 2006-07-18 | 2011-11-29 | Horizon Pharma Usa, Inc. | Methods and medicaments for administration of ibuprofen |
US20080020040A1 (en) * | 2006-07-18 | 2008-01-24 | Horizon Therapeutics, Inc. | Unit dose form for administration of ibuprofen |
US20080021078A1 (en) * | 2006-07-18 | 2008-01-24 | Horizon Therapeutics, Inc. | Methods and medicaments for administration of ibuprofen |
NZ565846A (en) * | 2005-07-18 | 2011-12-22 | Horizon Therapeutics Inc | Medicaments containing famotidine and ibuprofen and administration of same |
US20070020333A1 (en) * | 2005-07-20 | 2007-01-25 | Chin-Chih Chiang | Controlled release of hypnotic agents |
US7501393B2 (en) * | 2005-07-27 | 2009-03-10 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
CN101272769B (en) * | 2005-07-28 | 2013-04-24 | Isp投资有限公司 | Benzoquinones of enhanced bioavailability |
EP1913138B1 (en) | 2005-07-29 | 2016-08-24 | Abbott Laboratories GmbH | Processes for the manufacture of pancreatin powder with low virus content |
KR100693461B1 (en) * | 2005-07-29 | 2007-03-12 | 동국제약 주식회사 | Pharmaceutical Composition Comprising a Macrolide Antibiotic As an Active Ingredient, and Preparation Method thereof, and Sustained Release Compositions Comprising the same |
MX2008001520A (en) * | 2005-08-01 | 2008-04-07 | Teva Pharma | Tizanidine compositions and methods of treatment using the compositions. |
EP1749528A1 (en) | 2005-08-05 | 2007-02-07 | Pharma C S.A. | Pharmaceutical combinations containing a mu opioid agonist and an inhibitor of NO production |
US20070036859A1 (en) * | 2005-08-11 | 2007-02-15 | Perry Ronald L | Sustained release antihistamine and decongestant composition |
US11266607B2 (en) | 2005-08-15 | 2022-03-08 | AbbVie Pharmaceuticals GmbH | Process for the manufacture and use of pancreatin micropellet cores |
US9198871B2 (en) | 2005-08-15 | 2015-12-01 | Abbott Products Gmbh | Delayed release pancreatin compositions |
US20070111964A1 (en) * | 2005-08-17 | 2007-05-17 | Fleming And Company, Pharmaceuticals | Vitamin B12 nasal spray and method of use |
US8394812B2 (en) | 2005-08-24 | 2013-03-12 | Penwest Pharmaceuticals Co. | Sustained release formulations of nalbuphine |
PT1931315E (en) | 2005-08-24 | 2014-01-03 | Endo Pharmaceuticals Inc | Sustained release formulations of nalbuphine |
KR101233235B1 (en) * | 2005-08-26 | 2013-02-15 | 에스케이케미칼주식회사 | Pharmaceutical composition of pranlukast solid-dispersion with improved early dissolution rate and the method of preparing the composition |
US20080058282A1 (en) | 2005-08-30 | 2008-03-06 | Fallon Joan M | Use of lactulose in the treatment of autism |
TR200801336T1 (en) | 2005-08-31 | 2008-08-21 | Abraxis Bioscience, Inc. | Compositions and methods for the preparation of drugs with increased stability to poor water solubility. |
ATE469567T1 (en) * | 2005-09-02 | 2010-06-15 | Firmenich & Cie | FREE FLAVOR MICROEMULSIONS WITH SUGAR ESTERS FROM FATTY ACIDS |
RU2005128993A (en) * | 2005-09-08 | 2007-03-20 | Общество С Ограниченной Ответственностью Исследовательский Центр "Комкон" (Ru) | MEANS FOR CORRECTION OF STRESS-INDUCED NEUROMEDIATOR, NEURO-ENDOCRINE AND METABOLIC DISORDERS, AND ALSO THE METHOD FOR PREVENTION AND TREATMENT OF THEIR PATHOLOGICALLY SIMILAR TO THEM |
DK1931346T3 (en) * | 2005-09-09 | 2012-10-22 | Angelini Labopharm Llc | Trazodone composition for once daily administration |
KR20120060245A (en) | 2005-09-14 | 2012-06-11 | 맨카인드 코포레이션 | Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents |
KR100754953B1 (en) | 2005-09-14 | 2007-09-04 | 주식회사 대웅 | A solublized material comprising ubidecarenone, aqueous solution and process for preparation thereof |
US7473684B2 (en) | 2005-09-16 | 2009-01-06 | Selamine Limited | Bisphosphonate formulation |
US20070116695A1 (en) * | 2005-09-21 | 2007-05-24 | Fallon Joan M | Pharmaceutical preparations for attention deficit disorder, attention deficit hyperactivity disorder and other associated disorders |
US9427423B2 (en) | 2009-03-10 | 2016-08-30 | Atrium Medical Corporation | Fatty-acid based particles |
US8574627B2 (en) | 2006-11-06 | 2013-11-05 | Atrium Medical Corporation | Coated surgical mesh |
US9278161B2 (en) | 2005-09-28 | 2016-03-08 | Atrium Medical Corporation | Tissue-separating fatty acid adhesion barrier |
US8084420B2 (en) * | 2005-09-29 | 2011-12-27 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US20070086952A1 (en) * | 2005-09-29 | 2007-04-19 | Biodel, Inc. | Rapid Acting and Prolonged Acting Inhalable Insulin Preparations |
US7713929B2 (en) * | 2006-04-12 | 2010-05-11 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
CA2521272A1 (en) * | 2005-10-04 | 2007-04-04 | Bernard Charles Sherman | Capsules comprising topiramate |
CA2624897C (en) * | 2005-10-12 | 2017-02-14 | Proventiv Therapeutics, Llc | Methods and articles for treating 25-hydroxyvitamin d insufficiency and deficiency |
NO346660B1 (en) | 2005-10-12 | 2022-11-21 | Unimed Pharmaceuticals Llc | Improved testosterone gel and method of use |
US7745400B2 (en) * | 2005-10-14 | 2010-06-29 | Gregg Feinerman | Prevention and treatment of ocular side effects with a cyclosporin |
US9839667B2 (en) | 2005-10-14 | 2017-12-12 | Allergan, Inc. | Prevention and treatment of ocular side effects with a cyclosporin |
CA2626030A1 (en) | 2005-10-15 | 2007-04-26 | Atrium Medical Corporation | Hydrophobic cross-linked gels for bioabsorbable drug carrier coatings |
US20070141106A1 (en) * | 2005-10-19 | 2007-06-21 | Bonutti Peter M | Drug eluting implant |
MX2008005936A (en) * | 2005-11-07 | 2008-10-01 | Perque Llc | Compositions for regulating metabolic disorders and methods of use thereof. |
US8652529B2 (en) | 2005-11-10 | 2014-02-18 | Flamel Technologies | Anti-misuse microparticulate oral pharmaceutical form |
US8497258B2 (en) | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
US8679545B2 (en) | 2005-11-12 | 2014-03-25 | The Regents Of The University Of California | Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract |
US8324192B2 (en) | 2005-11-12 | 2012-12-04 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
AU2006322314A1 (en) * | 2005-11-18 | 2007-06-14 | Synthon B.V. | Zolpidem tablets |
KR20080079646A (en) * | 2005-11-21 | 2008-09-01 | 테바 파마슈티컬 인더스트리즈 리미티드 | Atorvastatin formulation |
ES2761812T3 (en) | 2005-11-22 | 2020-05-21 | Nalpropion Pharmaceuticals Inc | Composition and methods of increasing insulin sensitivity |
JP2009517394A (en) * | 2005-11-28 | 2009-04-30 | オレキシジェン・セラピューティクス・インコーポレーテッド | Sustained release formulation of zonisamide |
JP5334588B2 (en) * | 2005-11-28 | 2013-11-06 | マリナス ファーマシューティカルズ | Ganaxolone preparation, method for producing the same, and use thereof |
JP2009518399A (en) * | 2005-12-05 | 2009-05-07 | アフィニウム ファーマシューティカルズ, インク. | Heterocyclic acrylamide compounds as FABI inhibitors and antibacterial agents |
US8357394B2 (en) | 2005-12-08 | 2013-01-22 | Shionogi Inc. | Compositions and methods for improved efficacy of penicillin-type antibiotics |
US8778924B2 (en) | 2006-12-04 | 2014-07-15 | Shionogi Inc. | Modified release amoxicillin products |
US7700614B2 (en) * | 2005-12-14 | 2010-04-20 | Abbott Laboratories | One pot synthesis of tetrazole derivatives of rapamycin |
US9572886B2 (en) | 2005-12-22 | 2017-02-21 | Nitto Denko Corporation | Agent for treating myelofibrosis |
CA2841386A1 (en) | 2005-12-30 | 2007-07-12 | Zensun (Shanghai) Science & Technology Limited | Extended release of neuregulin for improved cardiac function |
WO2007077581A2 (en) * | 2006-01-02 | 2007-07-12 | Rubicon Research Private Limited | Pharmaceutical compositions |
AR054215A1 (en) | 2006-01-20 | 2007-06-13 | Eriochem Sa | A PHARMACEUTICAL FORMULATION OF A TAXANE, A SOLID COMPOSITION OF A LIOFILIZED TAXAN FROM AN ACETIC ACID SOLUTION, A PROCEDURE FOR THE PREPARATION OF A SOLID COMPOSITION OF A TAXANE, A SOLUBILIZING COMPOSITION OF A LIOFILIZED TAXANE AND AN ELEMENTARY KIT |
US9107844B2 (en) * | 2006-02-03 | 2015-08-18 | Stiefel Laboratories Inc. | Topical skin treating compositions |
CA2882048C (en) * | 2006-02-03 | 2020-03-24 | Proventiv Therapeutics, Llc | Treating vitamin d insufficiency and deficiency with 25-hydroxyvitamin d2 and 25-hydroxyvitamin d3 |
RU2008136208A (en) | 2006-02-09 | 2010-03-20 | Альба Терапьютикс Корпорейшн (Us) | COMPOSITIONS FOR DENSE CONTACT EFFECTOR |
FR2897267A1 (en) * | 2006-02-16 | 2007-08-17 | Flamel Technologies Sa | MULTIMICROPARTICULAR PHARMACEUTICAL FORMS FOR PER OS ADMINISTRATION |
US20070190141A1 (en) * | 2006-02-16 | 2007-08-16 | Aaron Dely | Extended release opiate composition |
EP2497484A3 (en) | 2006-02-22 | 2012-11-07 | MannKind Corporation | A method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent |
BRPI0708191A2 (en) * | 2006-02-24 | 2012-05-29 | Teva Pharma | "fluvastatin sodium pharmaceutical compositions" |
SE528446C2 (en) * | 2006-03-02 | 2006-11-14 | Ferring Int Ct Sa | Pharmaceutical composition comprising desmopressin, silica and starch |
WO2007106468A2 (en) * | 2006-03-13 | 2007-09-20 | Encysive Pharmaceuticals, Inc. | Formulations of sitaxsentan sodium |
AU2007225088B2 (en) | 2006-03-13 | 2012-09-13 | Kyorin Pharmaceutical Co., Ltd | Aminoquinolones as GSK-3 inhibitors |
US20070232671A1 (en) * | 2006-03-13 | 2007-10-04 | Given Bruce D | Methods and compositions for treatment of diastolic heart failure |
CN101400343B (en) | 2006-03-16 | 2012-01-11 | 特瑞斯制药股份有限公司 | Modified release formulations containing drug-ion exchange resin complexes |
BRPI0709410A2 (en) * | 2006-03-20 | 2011-07-12 | Javelin Pharmaceuticals Inc | pharmaceutical composition and method for treating a mammal in need of an analgesic, anti-inflammatory or antipyretic agent |
AU2007230716B2 (en) * | 2006-03-28 | 2012-05-03 | Javelin Pharmaceuticals, Inc. | Formulations of low dose diclofenac and beta-cyclodextrin |
MX2008012526A (en) | 2006-03-31 | 2008-10-14 | Stiefel Res Australia Pyt Ltd | Foamable suspension gel. |
BRPI0710503A2 (en) * | 2006-04-07 | 2011-08-16 | Merrion Res Iii Ltd | use of a pharmaceutical composition, pharmaceutical composition, and oral dosage form |
US7718609B2 (en) * | 2006-04-12 | 2010-05-18 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
JP2007308480A (en) * | 2006-04-20 | 2007-11-29 | Shin Etsu Chem Co Ltd | Solid preparation containing enteric solid dispersion |
ES2640453T3 (en) | 2006-04-21 | 2017-11-03 | Senomyx, Inc. | Processes for preparing solid flavoring compositions |
US20080096819A1 (en) * | 2006-05-02 | 2008-04-24 | Allozyne, Inc. | Amino acid substituted molecules |
EP2581450B1 (en) * | 2006-05-02 | 2018-08-15 | MedImmune Limited | Non-natural amino acid substituted polypeptides |
WO2007131047A2 (en) * | 2006-05-02 | 2007-11-15 | University Of Miami | Topical co-enzyme q10 formulations and treatment of pain, fatigue and wounds |
US8299052B2 (en) | 2006-05-05 | 2012-10-30 | Shionogi Inc. | Pharmaceutical compositions and methods for improved bacterial eradication |
US10072256B2 (en) | 2006-05-22 | 2018-09-11 | Abbott Products Gmbh | Process for separating and determining the viral load in a pancreatin sample |
EP2019679B1 (en) | 2006-05-23 | 2018-06-20 | Theracos, Inc. | Glucose transport inhibitors and methods of use |
US20070281014A1 (en) * | 2006-06-01 | 2007-12-06 | Cima Labs, Inc. | Prednisolone salt formulations |
US8916195B2 (en) | 2006-06-05 | 2014-12-23 | Orexigen Therapeutics, Inc. | Sustained release formulation of naltrexone |
US20070286900A1 (en) * | 2006-06-09 | 2007-12-13 | Catherine Herry | Low dose tablets of opioid analgesics and preparation process |
US7893053B2 (en) | 2006-06-16 | 2011-02-22 | Theracos, Inc. | Treating psychological conditions using muscarinic receptor M1 antagonists |
US8748419B2 (en) | 2006-06-16 | 2014-06-10 | Theracos, Inc. | Treating obesity with muscarinic receptor M1 antagonists |
DK3357496T3 (en) | 2006-06-21 | 2020-05-11 | Opko Ireland Global Holdings Ltd | THERAPY USING VITAMIN D REPLETER AND VITAMIN D HORMON REPLACEMENT |
US20080026061A1 (en) * | 2006-06-22 | 2008-01-31 | Reichwein John F | Crystalline N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4.5-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide |
US20080014257A1 (en) * | 2006-07-14 | 2008-01-17 | Par Pharmaceutical, Inc. | Oral dosage forms |
US8067033B2 (en) | 2007-11-30 | 2011-11-29 | Horizon Pharma Usa, Inc. | Stable compositions of famotidine and ibuprofen |
US8318720B2 (en) * | 2006-07-20 | 2012-11-27 | Affinium Pharmaceuticals, Inc. | Acrylamide derivatives as Fab I inhibitors |
UA96457C2 (en) | 2006-08-03 | 2011-11-10 | Нитек Фарма Аг | Delayed-release glucocorticoid treatment of rheumatoid disease |
AU2007281918A1 (en) * | 2006-08-04 | 2008-02-14 | Insys Therapeutics Inc. | Aqueous dronabinol formulations |
EP2061509A2 (en) * | 2006-08-14 | 2009-05-27 | Wayne State University | Polymer-surfactant nanoparticles for sustained release of compounds |
EP2051696A2 (en) * | 2006-08-18 | 2009-04-29 | Morton Grove Pharmaceuticals, Inc. | Stable liquid levetiracetam compositions and methods |
KR20090065519A (en) * | 2006-08-30 | 2009-06-22 | 자고텍 아게 | Controlled release solid oral dosage formulations comprising nisoldipine |
US9744137B2 (en) * | 2006-08-31 | 2017-08-29 | Supernus Pharmaceuticals, Inc. | Topiramate compositions and methods of enhancing its bioavailability |
US20100297224A1 (en) * | 2006-08-31 | 2010-11-25 | Horizon Therapeutics, Inc. | NSAID Dose Unit Formulations with H2-Receptor Antagonists and Methods of Use |
WO2008028193A2 (en) * | 2006-09-01 | 2008-03-06 | Pharmion Corporation | Colon-targeted oral formulations of cytidine analogs |
JP2010502698A (en) * | 2006-09-05 | 2010-01-28 | アストラゼネカ アクチボラグ | Pharmaceutical composition comprising candesartan cilexetil |
EP2063861B1 (en) * | 2006-09-15 | 2015-02-25 | Echo Pharmaceuticals B.V. | Dosage unit for sublingual, buccal or oral administration of water-insoluble pharmaceutically active substances |
US7879846B2 (en) | 2006-09-21 | 2011-02-01 | Kyorin Pharmaceutical Co.., Ltd. | Serine hydrolase inhibitors |
US20080075785A1 (en) * | 2006-09-22 | 2008-03-27 | San-Laung Chow | Controlled release hydrogel formulation |
US20110165236A1 (en) * | 2006-09-22 | 2011-07-07 | Biokey, Inc. | Controlled release hydrogel formulation |
EP2068825B1 (en) | 2006-10-04 | 2011-01-26 | M & P Patent Aktiengesellschaft | Controlled release delivery system for nasal application of neurotransmitters |
US20090092658A1 (en) * | 2007-10-05 | 2009-04-09 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
US20080085310A1 (en) * | 2006-10-06 | 2008-04-10 | Maria Oksana Bachynsky | Capecitabine rapidly disintegrating tablets |
US20080145411A1 (en) * | 2006-10-06 | 2008-06-19 | Kaneka Corporation | Composition of high absorbability for oral administration comprising oxidized coenzyme q10 |
EP2124556B1 (en) | 2006-10-09 | 2014-09-03 | Charleston Laboratories, Inc. | Pharmaceutical compositions |
DE602007013440D1 (en) | 2006-10-19 | 2011-05-05 | Auspex Pharmaceuticals Inc | SUBSTITUTED INDOLE |
CN101563074B (en) | 2006-10-20 | 2012-11-07 | 麦克内尔-Ppc股份有限公司 | Acetaminophen / ibuprofen combinations |
CN101167697B (en) * | 2006-10-26 | 2011-03-30 | 中国科学院上海药物研究所 | Donepezils compound long-acting slow-releasing and controlled-releasing composition and preparation method thereof |
WO2008054725A2 (en) * | 2006-10-31 | 2008-05-08 | Surmodics Pharmaceuticals, Inc. | Spheronized polymer particles |
US9492596B2 (en) | 2006-11-06 | 2016-11-15 | Atrium Medical Corporation | Barrier layer with underlying medical device and one or more reinforcing support structures |
WO2008057604A2 (en) * | 2006-11-08 | 2008-05-15 | The Regents Of The University Of California | Small molecule therapeutics, syntheses of analogues and derivatives and methods of use |
KR20140088619A (en) | 2006-11-09 | 2014-07-10 | 오렉시젠 세러퓨틱스 인크. | Unit dosage packages |
TWI504419B (en) | 2006-11-09 | 2015-10-21 | Orexigen Therapeutics Inc | Layered pharmaceutical formulations |
DE102006053385B4 (en) | 2006-11-13 | 2014-05-08 | Universitätsklinikum Freiburg | Enterococcus faecalis antigen |
ES2555066T3 (en) | 2006-11-17 | 2015-12-28 | Supernus Pharmaceuticals, Inc. | Topiramate sustained release formulations |
US8414910B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US8998846B2 (en) | 2006-11-20 | 2015-04-07 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
US8414526B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids |
US8430055B2 (en) | 2008-08-29 | 2013-04-30 | Lutonix, Inc. | Methods and apparatuses for coating balloon catheters |
US20080276935A1 (en) | 2006-11-20 | 2008-11-13 | Lixiao Wang | Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs |
US9700704B2 (en) | 2006-11-20 | 2017-07-11 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
US9737640B2 (en) | 2006-11-20 | 2017-08-22 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US8414525B2 (en) * | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
US20080175887A1 (en) | 2006-11-20 | 2008-07-24 | Lixiao Wang | Treatment of Asthma and Chronic Obstructive Pulmonary Disease With Anti-proliferate and Anti-inflammatory Drugs |
CA2670636A1 (en) | 2006-11-27 | 2008-06-05 | H. Lundbeck A/S | Heteroaryl amide derivatives |
US20100041644A1 (en) * | 2006-11-28 | 2010-02-18 | Laboratorios Liconsa, S. A. | Stabilized solid pharmaceutical composition of candesartan cilexetil |
KR20090091321A (en) | 2006-11-28 | 2009-08-27 | 마리누스 파마슈티컬스 | Nanoparticulate formulations and methods for the making and use thereof |
GB0624090D0 (en) * | 2006-12-01 | 2007-01-10 | Selamine Ltd | Ramipril amine salts |
GB0624087D0 (en) * | 2006-12-01 | 2007-01-10 | Selamine Ltd | Ramipril combination salt |
GB0624084D0 (en) * | 2006-12-01 | 2007-01-10 | Selamine Ltd | Ramipril amino acid salts |
US20080131501A1 (en) * | 2006-12-04 | 2008-06-05 | Supernus Pharmaceuticals, Inc. | Enhanced immediate release formulations of topiramate |
JP2010511722A (en) * | 2006-12-05 | 2010-04-15 | ノバルティス アーゲー | Valsartan microemulsion dosage form and process for producing the same |
US20080200890A1 (en) * | 2006-12-11 | 2008-08-21 | 3M Innovative Properties Company | Antimicrobial disposable absorbent articles |
US9555167B2 (en) * | 2006-12-11 | 2017-01-31 | 3M Innovative Properties Company | Biocompatible antimicrobial compositions |
WO2008076780A2 (en) * | 2006-12-14 | 2008-06-26 | Isp Investments Inc. | Amorphous valsartan and the production thereof |
WO2008080037A2 (en) * | 2006-12-21 | 2008-07-03 | Isp Investments Inc. | Carotenoids of enhanced bioavailability |
CA2671766A1 (en) * | 2006-12-22 | 2008-07-03 | Encysive Pharmaceuticals, Inc. | Modulators of c3a receptor and methods of use thereof |
WO2008078730A1 (en) | 2006-12-26 | 2008-07-03 | Translational Research, Ltd. | Preparation for transnasal application |
MX2009006912A (en) * | 2006-12-28 | 2009-08-12 | Repros Therapeutics Inc | Methods and formulations for improved bioavalability of antiprogestins. |
US20130150943A1 (en) | 2007-01-19 | 2013-06-13 | Elixir Medical Corporation | Biodegradable endoprostheses and methods for their fabrication |
US20080177373A1 (en) | 2007-01-19 | 2008-07-24 | Elixir Medical Corporation | Endoprosthesis structures having supporting features |
US8814930B2 (en) * | 2007-01-19 | 2014-08-26 | Elixir Medical Corporation | Biodegradable endoprosthesis and methods for their fabrication |
US20080181961A1 (en) * | 2007-01-26 | 2008-07-31 | Isp Investments, Inc. | Amorphous oxcarbazepine and the production thereof |
US10189957B2 (en) * | 2007-01-26 | 2019-01-29 | Isp Investments Llc | Formulation process method to produce spray dried products |
EP1958617B1 (en) * | 2007-02-14 | 2010-09-08 | Laboratorios Lesvi, S.L. | Pharmaceutical compositions containing quetiapine fumarate |
KR100868295B1 (en) | 2007-02-15 | 2008-11-11 | 풍림무약주식회사 | Solid dispersion containing leflunomide and preparation method thereof |
WO2008098374A1 (en) | 2007-02-16 | 2008-08-21 | Affinium Pharmaceuticals, Inc. | Salts, prodrugs and polymorphs of fab i inhibitors |
WO2008106167A1 (en) * | 2007-02-28 | 2008-09-04 | Conatus Pharmaceuticals, Inc. | Combination therapy comprising matrix metalloproteinase inhibitors and caspase inhibitors for the treatment of liver diseases |
DK2144604T3 (en) * | 2007-02-28 | 2011-10-17 | Conatus Pharmaceuticals Inc | Methods for the treatment of chronic viral hepatitis C using RO 113-0830 |
SI2125698T1 (en) | 2007-03-15 | 2016-12-30 | Auspex Pharmaceuticals, Inc. | DEUTERATED d9-VENLAFAXINE |
US8343541B2 (en) | 2007-03-15 | 2013-01-01 | Soft Gel Technologies, Inc. | Ubiquinol and alpha lipoic acid compositions |
US20100143471A1 (en) * | 2007-03-21 | 2010-06-10 | Lupin Limited | Novel reduced dose pharmaceutical compositions of fexofenadine and pseudoephedrine |
UA93148C2 (en) | 2007-03-29 | 2011-01-10 | Панасэа Биотэк Лимитэд | modified release dosage form of tacrolimus |
TWI407971B (en) | 2007-03-30 | 2013-09-11 | Nitto Denko Corp | Cancer cells and tumor-related fibroblasts |
RU2492175C2 (en) | 2007-04-02 | 2013-09-10 | Теракос, Инк. | Benzyl derivatives of glycosides and methods of their application |
EP2380564B1 (en) | 2007-04-04 | 2014-10-22 | Sigmoid Pharma Limited | An oral pharmaceutical composition |
DK2148661T3 (en) | 2007-04-25 | 2013-03-25 | Cytochroma Inc | Controlled-release oral preparations comprising vitamin D compound and waxy carrier |
CA2684778C (en) * | 2007-04-25 | 2017-09-05 | Cytochroma Inc. | Methods and compounds for vitamin d therapy |
ES2401914T3 (en) | 2007-04-25 | 2013-04-25 | Concert Pharmaceuticals Inc. | Cilostazol analogues |
CA2683628C (en) | 2007-04-25 | 2018-03-06 | Cytochroma Inc. | Method of treating vitamin d insufficiency and deficiency |
JP2010525080A (en) | 2007-04-25 | 2010-07-22 | プロヴェンティヴ セラピュティックス リミテッド ライアビリティ カンパニー | Safe and effective treatment and prevention method for secondary hyperparathyroidism in chronic kidney disease |
EP2061587A1 (en) | 2007-04-26 | 2009-05-27 | Sigmoid Pharma Limited | Manufacture of multiple minicapsules |
DK2152078T3 (en) | 2007-04-27 | 2021-02-08 | Cydex Pharmaceuticals Inc | FORMULATIONS CONTAINING CLOPIDOGREL AND SULFOALKYLETHERCYCLODEXTRINE AND USE PROCEDURES |
US20100215737A1 (en) * | 2007-05-01 | 2010-08-26 | Ivan Coulter | Combination pharmaceutical compositions |
US7892776B2 (en) | 2007-05-04 | 2011-02-22 | The Regents Of The University Of California | Screening assay to identify modulators of protein kinase A |
US7537532B2 (en) * | 2007-05-16 | 2009-05-26 | Young Carl D | Handle for implement and method |
US20080286357A1 (en) * | 2007-05-17 | 2008-11-20 | Balchem Corporation | Multi-functional particulate delivery system for pharmacologically active ingredients |
US8426467B2 (en) | 2007-05-22 | 2013-04-23 | Baxter International Inc. | Colored esmolol concentrate |
US8722736B2 (en) | 2007-05-22 | 2014-05-13 | Baxter International Inc. | Multi-dose concentrate esmolol with benzyl alcohol |
KR20100017928A (en) * | 2007-05-25 | 2010-02-16 | 더 유니버시티 오브 브리티쉬 콜롬비아 | Formulations for the oral administration of therapeutic agents and related methods |
DK2167033T3 (en) | 2007-05-30 | 2017-08-14 | Veloxis Pharmaceuticals As | Once daily oral dosage form comprising tacrolism |
US20090004284A1 (en) * | 2007-06-26 | 2009-01-01 | Watson Pharmaceuticals, Inc. | Controlled release tamsulosin hydrochloride formulation |
GB0712316D0 (en) * | 2007-06-26 | 2007-08-01 | Entripneur Ltd | A novel powder and its method of manufacture |
US20090004285A1 (en) * | 2007-06-29 | 2009-01-01 | Liangping Yu | Stable non-disintegrating dosage forms and method of making same |
FR2918277B1 (en) * | 2007-07-06 | 2012-10-05 | Coretecholding | NOVEL PROCESS FOR THE PRODUCTION OF HYDRODISPERSIBLE DRY PHARMACEUTICAL FORMS AND THE HYDRODISPERSIBLE COMPOSITIONS THUS OBTAINED |
MX2010000465A (en) * | 2007-07-12 | 2010-08-30 | Tragara Pharmaceuticals Inc | Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders. |
US8110226B2 (en) * | 2007-07-20 | 2012-02-07 | Mylan Pharmaceuticals Inc. | Drug formulations having inert sealed cores |
CN101091890A (en) * | 2007-07-26 | 2007-12-26 | 沈阳药科大学 | Composite type emulsifier, and emulsion prepared by using the emulsifier, and preparation method |
US20090036414A1 (en) * | 2007-08-02 | 2009-02-05 | Mutual Pharmaceutical Company, Inc. | Mesalamine Formulations |
EP2184983A1 (en) * | 2007-08-06 | 2010-05-19 | Insys Therapeutics Inc. | Oral cannabinoid liquid formulations and methods of treatment |
CA2988753A1 (en) | 2007-08-06 | 2009-02-12 | Serenity Pharmaceuticals, Llc | Methods and devices for desmopressin drug delivery |
US8268806B2 (en) | 2007-08-10 | 2012-09-18 | Endorecherche, Inc. | Pharmaceutical compositions |
CA2707840A1 (en) | 2007-08-20 | 2009-02-26 | Allozyne, Inc. | Amino acid substituted molecules |
EP3318562A3 (en) | 2007-08-23 | 2018-09-12 | Theracos Sub, LLC | Benzylbenzene derivatives and methods of use |
US20090060983A1 (en) * | 2007-08-30 | 2009-03-05 | Bunick Frank J | Method And Composition For Making An Orally Disintegrating Dosage Form |
CA2699151A1 (en) * | 2007-09-11 | 2009-03-19 | Activx Biosciences, Inc. | Cyanoaminoquinolones and tetrazoloaminoquinolones as gsk-3 inhibitors |
MX2010002662A (en) | 2007-09-12 | 2010-04-09 | Activx Biosciences Inc | Spirocyclic aminoquinolones as gsk-3 inhibitors. |
KR100790954B1 (en) * | 2007-09-13 | 2008-01-04 | 영남대학교 산학협력단 | Novel composite of gelatin ultra-micro capsule containing itraconazole |
EP2207570A2 (en) | 2007-09-14 | 2010-07-21 | Nitto Denko Corporation | Drug carriers |
EP2200613B1 (en) | 2007-09-21 | 2018-09-05 | The Johns Hopkins University | Phenazine derivatives and uses thereof |
AR063111A1 (en) | 2007-10-03 | 2008-12-30 | Eriochem Sa | A PHARMACEUTICAL FORMULATION OF TAXANO |
WO2009048929A1 (en) | 2007-10-08 | 2009-04-16 | Lux Biosciences, Inc. | Ophthalmic compositions comprising calcineurin inhibitors or mtor inhibitors |
MX2010003979A (en) | 2007-10-16 | 2010-06-02 | Biocon Ltd | An orally administerable solid pharmaceutical composition and a process thereof. |
CN102940619A (en) | 2007-10-16 | 2013-02-27 | 利普生物药剂公司 | Trans-clomiphene for metabolic syndrome |
GB0720967D0 (en) * | 2007-10-25 | 2007-12-05 | Protophama Ltd | Anti-material pharmaceutical composition |
TW200932240A (en) * | 2007-10-25 | 2009-08-01 | Astellas Pharma Inc | Pharmaceutical composition containing lipophilic substance which inhibits IL-2 production |
US20090111736A1 (en) * | 2007-10-29 | 2009-04-30 | Sri International | Orally-Absorbed Solid Dose Formulation for Vancomycin |
KR101560176B1 (en) * | 2007-10-31 | 2015-10-14 | 맥네일-피피씨, 인코포레이티드 | Orally disintegrated dosage form |
US20100216754A1 (en) * | 2007-11-13 | 2010-08-26 | Meritage Pharma, Inc. | Compositions for the treatment of inflammation of the gastrointestinal tract |
US20090123551A1 (en) * | 2007-11-13 | 2009-05-14 | Meritage Pharma, Inc. | Gastrointestinal delivery systems |
US20090123390A1 (en) * | 2007-11-13 | 2009-05-14 | Meritage Pharma, Inc. | Compositions for the treatment of gastrointestinal inflammation |
CN101969956B (en) * | 2007-11-13 | 2014-03-05 | 梅里蒂奇制药公司 | Corticosteroid compositions |
GB2458403B (en) * | 2007-11-13 | 2010-01-13 | Meritage Pharma Inc | Stabilised corticosteroid compositions |
US8802156B2 (en) | 2007-11-14 | 2014-08-12 | Laboratorios Farmacéuticos Rovi, S.A. | Pharmaceutical forms for the release of active compounds |
KR100920106B1 (en) * | 2007-11-14 | 2009-10-01 | 경북대학교 산학협력단 | Controlled drug carrier for deliverying sildenafil citrate transdermally and patch containing the same |
TWI592159B (en) * | 2007-11-16 | 2017-07-21 | 威佛(國際)股份有限公司 | Pharmaceutical compositions |
WO2009066299A2 (en) * | 2007-11-23 | 2009-05-28 | Rappaport Family Institute For Research | Use of haptoglobin genotyping in diagnosis and treatment of cardiovascular disease |
DE102007057395A1 (en) * | 2007-11-27 | 2009-05-28 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Encapsulated microparticles with a virulent core and method of making the microparticles |
JP2011506319A (en) * | 2007-12-06 | 2011-03-03 | デュレクト コーポレーション | Useful methods for the treatment of pain, joint inflammation symptoms, or inflammation associated with chronic diseases |
JP5502751B2 (en) | 2007-12-20 | 2014-05-28 | エボニック コーポレイション | Process for preparing microparticles with low residual solvent concentration |
CA2739668C (en) | 2008-01-04 | 2016-10-11 | Schabar Research Associates Llc | The use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound |
US20110020519A1 (en) * | 2008-01-04 | 2011-01-27 | Aveka, Inc. | Encapsulation of oxidatively unstable compounds |
WO2009089117A1 (en) * | 2008-01-04 | 2009-07-16 | Hormel Foods Corporation | Encapsulation of oxidatively unstable compounds |
MX2010007342A (en) * | 2008-01-04 | 2010-08-26 | Biodel Inc | Insulin formulations for insulin release as a function of tissue glucose levels. |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
EP2240022B1 (en) | 2008-01-09 | 2016-12-28 | Charleston Laboratories, Inc. | Bilayered tablets comprising oxycodone and promethazine |
JP2011511674A (en) | 2008-02-07 | 2011-04-14 | ユニヴァーシティ オブ ワシントン | Circumferential aerosol device |
US20100021538A1 (en) * | 2008-02-29 | 2010-01-28 | Youngro Byun | Pharmaceutical compositions containing heparin derivatives |
EP2280694A1 (en) * | 2008-03-10 | 2011-02-09 | Dexcel Pharma Technologies Ltd. | Humidity-resistant drug formulations and methods of preparation thereof |
NZ588407A (en) | 2008-03-11 | 2012-07-27 | Takeda Pharmaceutical | Orally-disintegrating solid preparation |
CA2718416C (en) * | 2008-03-13 | 2018-01-02 | Mallinckrodt Inc. | Multi-function, foot-activated controller for imaging system |
US8658163B2 (en) * | 2008-03-13 | 2014-02-25 | Curemark Llc | Compositions and use thereof for treating symptoms of preeclampsia |
MY161576A (en) | 2008-03-17 | 2017-04-28 | Ambit Biosciences Corp | Quinazoline derivatives as raf kinase modulators and methods of use thereof |
EP2268160B1 (en) | 2008-03-20 | 2012-12-05 | Virun, Inc. | Emulsions including a peg-derivative of tocopherol |
US8420110B2 (en) * | 2008-03-31 | 2013-04-16 | Cordis Corporation | Drug coated expandable devices |
US8409601B2 (en) | 2008-03-31 | 2013-04-02 | Cordis Corporation | Rapamycin coated expandable devices |
EP3112476B1 (en) | 2008-04-02 | 2023-08-02 | EirGen Pharma Ltd. | Methods, compositions, uses, and kits useful for vitamin d deficiency and related disorders |
US8222272B2 (en) | 2008-04-11 | 2012-07-17 | Roxane Laboratories, Inc. | Pharmaceutical formulation and process comprising a solid dispersion of macrolide (tacrolimus) |
KR20100136997A (en) | 2008-04-11 | 2010-12-29 | 싸이토테크 랩스, 엘엘씨 | Methods and use of inducing apoptosis in cancer cells |
US8084025B2 (en) | 2008-04-18 | 2011-12-27 | Curemark Llc | Method for the treatment of the symptoms of drug and alcohol addiction |
US20090264392A1 (en) * | 2008-04-21 | 2009-10-22 | Meritage Pharma, Inc. | Treating eosinophilic esophagitis |
WO2009131537A1 (en) * | 2008-04-25 | 2009-10-29 | Karolinska Institutet Innovations Ab | New therapy of treatment of the irritable bowel syndrome. |
MX2010012201A (en) * | 2008-05-07 | 2011-05-30 | Merrion Res Iii Ltd | Compositions of peptides and processes of preparation thereof. |
JP2010043063A (en) | 2008-05-09 | 2010-02-25 | Agency For Science Technology & Research | Diagnosis and treatment of kawasaki disease |
WO2009139880A1 (en) * | 2008-05-13 | 2009-11-19 | Celgene Corporation | Thioxoisoindoline compounds and compositions and methods of using the same |
CA2724594A1 (en) * | 2008-05-20 | 2009-11-26 | John R. Wetterau | Niacin and nsaid combination therapy |
EP2296686B2 (en) * | 2008-05-21 | 2017-11-01 | Ferring B.V. | Orodispersible desmopressin for increasing initial period of sleep undisturbed by nocturia |
US11963995B2 (en) | 2008-05-21 | 2024-04-23 | Ferring B.V. | Methods comprising desmopressin |
US20100286045A1 (en) | 2008-05-21 | 2010-11-11 | Bjarke Mirner Klein | Methods comprising desmopressin |
EP2300011A4 (en) | 2008-05-27 | 2012-06-20 | Dmi Life Sciences Inc | Therapeutic methods and compounds |
EP2288355A1 (en) * | 2008-05-30 | 2011-03-02 | Fairfield Clinical Trials LLC | Method and composition for skin inflammation and discoloration |
EP2303025A4 (en) | 2008-05-30 | 2012-07-04 | Orexigen Therapeutics Inc | Methods for treating visceral fat conditions |
US9045262B2 (en) * | 2008-06-10 | 2015-06-02 | General Mills, Inc. | Packages for dispensing liquid and dry food |
US8485378B2 (en) * | 2009-04-08 | 2013-07-16 | General Mills, Inc. | Multi-container packages for dispensing liquid and dry food |
EP2300329A4 (en) * | 2008-06-10 | 2011-07-27 | Gen Mills Inc | Packages for dispensing liquid and dry food |
US8815318B2 (en) * | 2008-06-10 | 2014-08-26 | General Mills, Inc. | Packages for dispensing liquid and dry food |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
EP3281663B8 (en) | 2008-06-13 | 2022-09-21 | MannKind Corporation | Breath powered dry powder inhaler for drug delivery |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
FR2932387B1 (en) * | 2008-06-16 | 2010-09-17 | Cll Pharma | ORAL COMPOSITION CONTAINING AN ANTIPLATELET AGENT OF THE FAMILY OF THIENOPYRIDINES IN THE BASIC FORM. |
GB2460915B (en) | 2008-06-16 | 2011-05-25 | Biovascular Inc | Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor |
US9364619B2 (en) | 2008-06-20 | 2016-06-14 | Mannkind Corporation | Interactive apparatus and method for real-time profiling of inhalation efforts |
WO2009155612A2 (en) * | 2008-06-20 | 2009-12-23 | Genvault Corporation | Sample collection and storage devices and methods of use thereof |
FR2932682B1 (en) * | 2008-06-23 | 2013-07-12 | Bionetwork | NOVEL PHARMACEUTICAL FORMS WITH RAPID EFFECT AND USES OF PHARMACEUTICAL COMPOSITIONS THUS OBTAINED. |
WO2010008475A2 (en) * | 2008-06-23 | 2010-01-21 | Virun, Inc. | Compositions containing nono-polar compounds |
US20090324730A1 (en) * | 2008-06-26 | 2009-12-31 | Fallon Joan M | Methods and compositions for the treatment of symptoms of complex regional pain syndrome |
US9320780B2 (en) * | 2008-06-26 | 2016-04-26 | Curemark Llc | Methods and compositions for the treatment of symptoms of Williams Syndrome |
EP2318035B1 (en) * | 2008-07-01 | 2019-06-12 | Curemark, Llc | Methods and compositions for the treatment of symptoms of neurological and mental health disorders |
US20100003319A1 (en) * | 2008-07-02 | 2010-01-07 | Glenmark Generics Ltd. | Raloxifene immediate release tablets |
TW201004632A (en) | 2008-07-02 | 2010-02-01 | Idenix Pharmaceuticals Inc | Compounds and pharmaceutical compositions for the treatment of viral infections |
GB0812742D0 (en) * | 2008-07-11 | 2008-08-20 | Critical Pharmaceuticals Ltd | Process |
UA104594C2 (en) | 2008-07-15 | 2014-02-25 | Теракос, Инк. | Deuterated benzylbenzole derivatives and using thereof |
EP2315571A4 (en) * | 2008-07-16 | 2013-05-01 | Surmodics Pharmaceuticals Inc | Process for preparing microparticles containing bioactive peptides |
CN102099015B (en) * | 2008-07-18 | 2015-05-06 | 拜奥莫达概念公司 | Articles of manufacture releasing an active ingredient |
EP2314277B1 (en) * | 2008-07-28 | 2017-04-19 | Kao Corporation | External preparation for skin, and wrinkle-repairing agent |
US10776453B2 (en) * | 2008-08-04 | 2020-09-15 | Galenagen, Llc | Systems and methods employing remote data gathering and monitoring for diagnosing, staging, and treatment of Parkinsons disease, movement and neurological disorders, and chronic pain |
WO2010017056A1 (en) * | 2008-08-07 | 2010-02-11 | Merck & Co., Inc. | Orally administered solid formulations containing a hydrophobic drug and tpgs |
TWI494123B (en) | 2008-08-11 | 2015-08-01 | Mannkind Corp | Use of ultrarapid acting insulin |
DK2324002T3 (en) | 2008-08-22 | 2016-12-19 | Theracos Sub Llc | Methods of making of sglt2 inhibitors |
CA2638240C (en) * | 2008-08-29 | 2010-02-02 | Alexander Macgregor | Method of treating dysglycemia and glucose excursions |
JP2012501681A (en) * | 2008-09-12 | 2012-01-26 | ジェンボールト コーポレイション | Matrix and media for storage and stabilization of biomolecules |
WO2010033812A1 (en) * | 2008-09-18 | 2010-03-25 | Variation Biotechnologies, Inc. | Compositions and methods for treating hepatitis a. |
US20100092447A1 (en) | 2008-10-03 | 2010-04-15 | Fallon Joan M | Methods and compositions for the treatment of symptoms of prion diseases |
KR101939557B1 (en) | 2008-10-17 | 2019-01-17 | 사노피-아벤티스 도이칠란트 게엠베하 | Combination of an insulin and a GLP-1 agonist |
EP2349201B1 (en) * | 2008-10-30 | 2014-10-29 | Medlite As | Formulation for treatment of vaginal dryness |
WO2010053487A1 (en) | 2008-11-07 | 2010-05-14 | Cydex Pharmaceuticals, Inc. | Composition containing sulfoalkyl ether cyclodextrin and latanoprost |
US20120064143A1 (en) * | 2008-11-11 | 2012-03-15 | The Board Of Regents Of The University Of Texas System | Inhibition of mammalian target of rapamycin |
EP3037421A3 (en) | 2008-11-25 | 2016-11-30 | University Of Rochester | Mlk inhibitors and methods of use |
IT1392214B1 (en) * | 2008-11-28 | 2012-02-22 | Sila S R L | PROCESS FOR THE PRODUCTION OF A COMPOUND OF N-BUTIRRIC ACID IN MICROCAPSULATED FORM, INTENDED FOR ANIMAL OR HUMAN POWER |
WO2010065492A1 (en) * | 2008-12-02 | 2010-06-10 | Sciele Pharma, Inc. | Alpha2-adrenergic agonist a calcium channel blocker composition |
CA2748034A1 (en) | 2008-12-23 | 2010-07-01 | Pharmasset, Inc. | Purified 2'-deoxy'2'-fluoro-2'-c-methyl-nucleoside-phosphoramidate prodrugs for the treatment of viral infections |
PA8855601A1 (en) | 2008-12-23 | 2010-07-27 | NUCLEOSID FORFORMIDATES | |
CN102325783A (en) | 2008-12-23 | 2012-01-18 | 法莫赛特股份有限公司 | Synthesis of purine nucleosides |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
US20100221328A1 (en) * | 2008-12-31 | 2010-09-02 | Wertz Christian F | Sustained-release formulations |
CN102307892A (en) | 2008-12-31 | 2012-01-04 | 西尼克斯公司 | Derivatives of cyclosporin A |
AU2010203709B2 (en) | 2009-01-06 | 2014-05-22 | Galenagen, Llc | Compositions and methods for the treatment or prevention of Staphylococcus Aureus infections and for the Eradication or reduction of Staphylococcus Aureus on surfaces |
NZ593823A (en) | 2009-01-06 | 2013-09-27 | Curelon Llc | Compositions and methods for the treatment or the prevention of infections by e. coli |
US11304960B2 (en) | 2009-01-08 | 2022-04-19 | Chandrashekar Giliyar | Steroidal compositions |
WO2010083035A2 (en) | 2009-01-14 | 2010-07-22 | Corium International, Inc. | Transdermal administration of tamsulosin |
EP2391369A1 (en) * | 2009-01-26 | 2011-12-07 | Nitec Pharma AG | Delayed-release glucocorticoid treatment of asthma |
NZ593622A (en) * | 2009-01-28 | 2013-12-20 | Novartis Ag | Galenic formulations of organic compounds |
WO2010088450A2 (en) | 2009-01-30 | 2010-08-05 | Celladon Corporation | Methods for treating diseases associated with the modulation of serca |
NZ582836A (en) * | 2009-01-30 | 2011-06-30 | Nitec Pharma Ag | Delayed-release glucocorticoid treatment of rheumatoid arthritis by improving signs and symptoms, showing major or complete clinical response and by preventing from joint damage |
US8568793B2 (en) | 2009-02-11 | 2013-10-29 | Hope Medical Enterprises, Inc. | Sodium nitrite-containing pharmaceutical compositions |
CA2750242C (en) | 2009-02-12 | 2018-05-22 | Incept, Llc | Drug delivery through hydrogel plugs |
US20100209475A1 (en) * | 2009-02-19 | 2010-08-19 | Biomet Manufacturing Corp. | Medical implants having a drug delivery coating |
CA2751854A1 (en) * | 2009-02-25 | 2010-09-02 | Merrion Research Iii Limited | Composition and drug delivery of bisphosphonates |
WO2010099379A1 (en) | 2009-02-27 | 2010-09-02 | Ambit Biosciences Corporation | Jak kinase modulating quinazoline derivatives and methods of use thereof |
US9060927B2 (en) * | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
US8101593B2 (en) | 2009-03-03 | 2012-01-24 | Kythera Biopharmaceuticals, Inc. | Formulations of deoxycholic acid and salts thereof |
WO2010101967A2 (en) | 2009-03-04 | 2010-09-10 | Idenix Pharmaceuticals, Inc. | Phosphothiophene and phosphothiazole hcv polymerase inhibitors |
CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
EP2406266B1 (en) * | 2009-03-11 | 2013-12-25 | Kyorin Pharmaceutical Co., Ltd. | 7-cycloalkylaminoquinolones as gsk-3 inhibitors |
JP2012520314A (en) | 2009-03-11 | 2012-09-06 | アムビト ビオスシエンセス コルポラチオン | Combination of indazolylaminopyrrolotriazine and taxane for cancer treatment |
EP3138603A1 (en) * | 2009-03-20 | 2017-03-08 | Incube Labs, Llc | Solid drug delivery apparatus, formulations and methods of use |
WO2010110686A1 (en) | 2009-03-27 | 2010-09-30 | Pathway Therapeutics Limited | Pyrimidinyl and 1,3,5 triazinyl benzimidazoles and their use in cancer therapy |
MX2011010105A (en) | 2009-03-27 | 2012-01-12 | Pathway Therapeutics Inc | Pyrimidinyl and 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy. |
US9056050B2 (en) | 2009-04-13 | 2015-06-16 | Curemark Llc | Enzyme delivery systems and methods of preparation and use |
US20130274352A1 (en) * | 2009-04-14 | 2013-10-17 | The Regents Of The University Of California | Oral Drug Devices and Drug Formulations |
US20120045504A1 (en) * | 2009-04-14 | 2012-02-23 | Kathryn Whitehead | oral drug devices and drug formulations |
PE20120811A1 (en) | 2009-04-22 | 2012-07-08 | Axikin Pharmaceuticals Inc | CCR3 ARYLSULFONAMIDE ANTAGONISTS |
EP2421829B1 (en) | 2009-04-22 | 2015-09-30 | Axikin Pharmaceuticals, Inc. | 2,5-disubstituted arylsulfonamide ccr3 antagonists |
MX357611B (en) | 2009-04-22 | 2018-07-17 | Axikin Pharmaceuticals Inc | 2,5-disubstituted arylsulfonamide ccr3 antagonists. |
ES2350075B1 (en) * | 2009-05-11 | 2011-11-10 | Maria Pilar Mateo Herrero | MICROENCAPSULATED COMPOSITION BASED ON SAPONIFIED EUROPEAN OLEA, SUUSO AND ITS OBTAINING PROCEDURE. |
AU2010247750B2 (en) | 2009-05-11 | 2016-09-22 | Berg Llc | Methods for treatment of metabolic disorders using epimetabolic shifters, multidimensional intracellular molecules, or environmental influencers |
SG176000A1 (en) * | 2009-05-13 | 2011-12-29 | Protein Delivery Solutions Llc | Pharmaceutical system for trans-membrane delivery |
KR101991367B1 (en) | 2009-05-13 | 2019-06-21 | 사이덱스 파마슈티칼스, 인크. | Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same |
WO2010131486A1 (en) * | 2009-05-15 | 2010-11-18 | Shin Nippon Biomedical Laboratories, Ltd. | Intranasal pharmaceutical compositions with improved pharmacokinetics |
GB2483815B (en) | 2009-05-18 | 2013-12-25 | Sigmoid Pharma Ltd | Composition comprising oil drops |
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
TWI576352B (en) | 2009-05-20 | 2017-04-01 | 基利法瑪席特有限責任公司 | Nucleoside phosphoramidates |
US9498440B2 (en) | 2009-05-22 | 2016-11-22 | Inventia Healthcare Private Limited | Extended release pharmaceutical compositions |
US20100310726A1 (en) | 2009-06-05 | 2010-12-09 | Kraft Foods Global Brands Llc | Novel Preparation of an Enteric Release System |
US9968564B2 (en) * | 2009-06-05 | 2018-05-15 | Intercontinental Great Brands Llc | Delivery of functional compounds |
US20100307542A1 (en) * | 2009-06-05 | 2010-12-09 | Kraft Foods Global Brands Llc | Method of Reducing Surface Oil on Encapsulated Material |
US8859003B2 (en) * | 2009-06-05 | 2014-10-14 | Intercontinental Great Brands Llc | Preparation of an enteric release system |
EP2266546A1 (en) * | 2009-06-08 | 2010-12-29 | Advancell Advanced in Vitro Cell Technologies,S.A. | Process for the preparation of colloidal systems for the delivery of active compounds |
MX338355B (en) | 2009-06-09 | 2016-04-13 | Aurinia Pharmaceuticals Inc | Topical drug delivery systems for ophthalmic use. |
US8937150B2 (en) | 2009-06-11 | 2015-01-20 | Abbvie Inc. | Anti-viral compounds |
DK2455376T3 (en) | 2009-06-11 | 2015-03-02 | Abbvie Bahamas Ltd | Heterocyclic compounds as inhibitors of hepatitis C virus (HCV) |
WO2010144789A2 (en) | 2009-06-12 | 2010-12-16 | Mannkind Corporation | Diketopiperazine microparticles with defined specific surface areas |
WO2010144865A2 (en) | 2009-06-12 | 2010-12-16 | Meritage Pharma, Inc. | Methods for treating gastrointestinal disorders |
CN108295241A (en) | 2009-06-18 | 2018-07-20 | 宁静制药公司 | The desmopressin administration of safety |
WO2011003870A2 (en) | 2009-07-06 | 2011-01-13 | Creabilis S.A. | Mini-pegylated corticosteroids, compositions including same, and methods of making and using same |
CA2767392C (en) | 2009-07-06 | 2017-03-14 | Variation Biotechnologies, Inc. | Methods for preparing vesicles and formulations produced therefrom |
US9907746B2 (en) | 2009-07-06 | 2018-03-06 | Variation Biotechnologies, Inc. | Methods for preparing vesicles and formulations produced therefrom |
AR080945A1 (en) | 2009-07-07 | 2012-05-23 | Pathway Therapeutics Inc | PIRIMIDINIL AND 1,3,5-TRIAZINIL BENZIMIDAZOLES AND ITS USE IN THERAPY AGAINST CANCER |
HUE035519T2 (en) | 2009-07-08 | 2018-05-02 | Hope Medical Entpr Inc D B A Hope Pharmaceuticals | Sodium thiosulfate-containing pharmaceutical compositions |
EP2451274B1 (en) | 2009-07-08 | 2017-10-04 | Charleston Laboratories, Inc. | Pharmaceutical compositions |
WO2011006147A1 (en) | 2009-07-10 | 2011-01-13 | Scott Iii Linzy O | Methods and compositions for treating thyroid-related medical conditions with reduced folates |
AU2010276404A1 (en) * | 2009-07-20 | 2012-02-02 | Vetegen, Llc | A stable pharmaceutical omeprazole formulation for oral administration |
EP2467144A1 (en) | 2009-07-24 | 2012-06-27 | ViroLogik GmbH | Combination of proteasome inhibitors and anti-hepatitis medication for treating hepatitis |
US8951558B2 (en) * | 2009-07-30 | 2015-02-10 | Evonik Röhm Gmbh | Aqueous carbonated medium containing an amino(meth)acrylate polymer or copolymer |
US8735374B2 (en) * | 2009-07-31 | 2014-05-27 | Intelgenx Corp. | Oral mucoadhesive dosage form |
GB2472327B (en) * | 2009-07-31 | 2013-03-13 | Shin Nippon Biomedical Lab Ltd | Intranasal granisetron and nasal applicator |
WO2011017389A1 (en) | 2009-08-05 | 2011-02-10 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors useful against viral infections, particularly hcv |
US20110038910A1 (en) | 2009-08-11 | 2011-02-17 | Atrium Medical Corporation | Anti-infective antimicrobial-containing biomaterials |
EP2464341B1 (en) | 2009-08-12 | 2022-07-06 | Sublimity Therapeutics Limited | Immunomodulatory compositions comprising a polymer matrix and an oil phase |
BR112012003661A2 (en) | 2009-08-19 | 2017-04-25 | Ambit Biosciences Corp | "Biaryl compounds and methods of use thereof." |
HUE034235T2 (en) | 2009-08-31 | 2018-02-28 | Zynerba Pharmaceuticals Inc | Use of cannabidiol prodrugs in topical and transdermal administration with microneedles |
KR101636958B1 (en) * | 2009-09-11 | 2016-07-06 | 주식회사 대웅제약 | Ursodesoxycholic Acid-Synthetic Hydrotalcite-Eudragit Nanohybrid, Pharmaceutical Composition Containing the Same and Method for Preparing the Same |
KR20120102598A (en) * | 2009-09-17 | 2012-09-18 | 에보닉 데구사 코포레이션 | Implant devices that differ by release profile and methods of making and using same |
CN102596184B (en) * | 2009-09-18 | 2015-03-11 | 赛诺菲 | (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluormethylphenyl)-amide tablet formulations with improved stability |
US20110318411A1 (en) | 2010-06-24 | 2011-12-29 | Luber Joseph R | Multi-layered orally disintegrating tablet and the manufacture thereof |
US8871263B2 (en) * | 2009-09-24 | 2014-10-28 | Mcneil-Ppc, Inc. | Manufacture of tablet in a die utilizing radiofrequency energy and meltable binder |
US20110070286A1 (en) * | 2009-09-24 | 2011-03-24 | Andreas Hugerth | Process for the manufacture of nicotine-comprising chewing gum and nicotine-comprising chewing gum manufactured according to said process |
US8313768B2 (en) | 2009-09-24 | 2012-11-20 | Mcneil-Ppc, Inc. | Manufacture of tablet having immediate release region and sustained release region |
AU2010300641B2 (en) | 2009-09-30 | 2016-03-17 | Acura Pharmaceuticals, Inc. | Methods and compositions for deterring abuse |
EP2486918A4 (en) * | 2009-10-09 | 2014-02-26 | Yungjin Pharmaceutical Co Ltd | Pharmaceutical composition with both immediate and extended release characteristics |
US8357398B2 (en) * | 2009-10-21 | 2013-01-22 | Alitair Pharmaceuticals Inc. | Benzonatate compositions and methods of use |
WO2011050135A1 (en) | 2009-10-21 | 2011-04-28 | Curemark Llc | Methods and compositions for the prevention and treatment of influenza |
US8470817B2 (en) * | 2009-10-26 | 2013-06-25 | Sunesis Pharmaceuticals, Inc. | Compounds and methods for treatment of cancer |
WO2011050457A1 (en) | 2009-10-26 | 2011-05-05 | The University Of British Columbia | Stabilized formulation for oral administration of therapeutic agents and related methods |
CA2778698A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
WO2011056764A1 (en) | 2009-11-05 | 2011-05-12 | Ambit Biosciences Corp. | Isotopically enriched or fluorinated imidazo[2,1-b][1,3]benzothiazoles |
US8663671B2 (en) | 2009-11-05 | 2014-03-04 | Philip Morris Usa Inc. | Methods and compositions for producing hydrogel capsules coated for low permeability and physical integrity |
US20110112125A1 (en) * | 2009-11-09 | 2011-05-12 | Tritech Biopharmaceuticals Co., Ltd. | Novel hair growth composition |
US9283211B1 (en) | 2009-11-11 | 2016-03-15 | Rapamycin Holdings, Llc | Oral rapamycin preparation and use for stomatitis |
WO2015103447A1 (en) | 2013-12-31 | 2015-07-09 | Rapamycin Holdings, Llc | Oral rapamycin nanoparticle preparations and use |
RU2537239C2 (en) | 2009-11-13 | 2014-12-27 | Санофи-Авентис Дойчланд Гмбх | Pharmaceutical composition containing agonist glp-1, insulin and methionine |
AU2010317994B2 (en) | 2009-11-13 | 2014-03-06 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical composition comprising a GLP-1 agonist and methionine |
PL2501234T3 (en) * | 2009-11-20 | 2018-01-31 | Tonix Pharma Holdings Ltd | Methods and compositions for treating symptoms associated with post-traumatic stress disorder using cyclobenzaprine |
WO2011064769A1 (en) | 2009-11-24 | 2011-06-03 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Methods and pharmaceutical compositions for the treatment of hot flashes |
CN106389381A (en) | 2009-12-02 | 2017-02-15 | 阿达玛斯医药公司 | Amantadine compositions and methods of use |
US20110301235A1 (en) | 2009-12-02 | 2011-12-08 | Alquest Therapeutics, Inc. | Organoselenium compounds and uses thereof |
CA2782285A1 (en) * | 2009-12-02 | 2011-06-09 | Luigi Mapelli | Fexofenadine microcapsules and compositions containing them |
US10610528B2 (en) | 2009-12-08 | 2020-04-07 | Intelgenx Corp. | Solid oral film dosage forms and methods for making same |
US20110136815A1 (en) * | 2009-12-08 | 2011-06-09 | Horst Zerbe | Solid oral film dosage forms and methods for making same |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
AR079528A1 (en) | 2009-12-18 | 2012-02-01 | Idenix Pharmaceuticals Inc | 5,5-FUSIONED ARYLENE OR HETEROARYLENE INHIBITORS OF HEPATITIS C VIRUS |
US8710092B2 (en) * | 2009-12-23 | 2014-04-29 | Map Pharmaceuticals, Inc. | Substituted indolo 4,3 FG quinolines useful for treating migraine |
CN102834409A (en) | 2009-12-30 | 2012-12-19 | 西尼克斯公司 | Cyclosporine analogues |
EP2682111A1 (en) * | 2009-12-31 | 2014-01-08 | Differential Drug Development Associates LLC | Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols |
EP2521537A2 (en) | 2010-01-04 | 2012-11-14 | Wockhardt Limited | Pharmaceutical composition for modified delivery of actives |
CN102724878A (en) | 2010-01-11 | 2012-10-10 | 奥雷西根治疗公司 | Methods of providing weight loss therapy in patients with major depression |
US8603568B2 (en) * | 2010-01-15 | 2013-12-10 | Kemin Industries, Inc. | Hydrolyzed lecithin product to improve digestibility |
EP2359812A1 (en) * | 2010-01-18 | 2011-08-24 | Cephalon France | Oral lyophilised compositions |
WO2011089167A1 (en) | 2010-01-19 | 2011-07-28 | Virologik Gmbh | Kombination of proteasome inhibitors and anti -hepatitis medication for treating retroviral diseases |
US20110182985A1 (en) * | 2010-01-28 | 2011-07-28 | Coughlan David C | Solid Pharmaceutical Composition with Enhancers and Methods of Preparing thereof |
WO2011094890A1 (en) | 2010-02-02 | 2011-08-11 | Argusina Inc. | Phenylalanine derivatives and their use as non-peptide glp-1 receptor modulators |
WO2011097525A1 (en) | 2010-02-05 | 2011-08-11 | Tragara Pharmaceuticals, Inc. | Solid state forms of macrocyclic kinase inhibitors |
SI2536706T1 (en) | 2010-02-11 | 2017-10-30 | Celgene Corporation | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same |
US20110200669A1 (en) * | 2010-02-15 | 2011-08-18 | Winston Laboratories, Inc. | Method and compositions of civamide to treat disease of the intestines |
PL2575769T3 (en) | 2010-02-17 | 2016-12-30 | Stabilized tacrolimus composition | |
AU2011223873B2 (en) | 2010-03-02 | 2015-06-25 | Axikin Pharmaceuticals, Inc. | Isotopically enriched arylsulfonamide CCR3 antagonists |
US20130273154A1 (en) * | 2011-03-02 | 2013-10-17 | Joseph M. Fayad | Oral formulations Mimetic of Roux-en-Y gastric bypass actions on the ileal brake; Compositions, Methods of Treatment, Diagnostics and Systems for treatment of metabolic syndrome manifestations including insulin resistance, fatty liver disease, hpperlipidemia, and type 2 diabetes |
US20140294951A1 (en) * | 2011-10-26 | 2014-10-02 | Joseph M. Fayad | Oral formulations mimetic of Roux-en-Y gastric bypass actions on the ileal brake; Compositions, methods of treatment, diagnostics and systems for treatment of metabolic syndrome manifestations including insulin resistance, fatty liver disease, hyperlipidemia, and T2D |
EP2544707B1 (en) * | 2010-03-09 | 2018-11-21 | Dignity Health | Methods for inhibiting preterm labor and uterine contractility disorders and preventing cervical ripening |
WO2011112689A2 (en) | 2010-03-11 | 2011-09-15 | Ambit Biosciences Corp. | Saltz of an indazolylpyrrolotriazine |
SG10201501872XA (en) | 2010-03-12 | 2015-05-28 | Berg Llc | Intravenous formulations of coenzyme q10 (coq10) and methods of use thereof |
EP2547655B1 (en) | 2010-03-17 | 2016-03-09 | Axikin Pharmaceuticals, Inc. | Arylsulfonamide ccr3 antagonists |
CN103037708B (en) | 2010-03-23 | 2015-05-20 | 维尔恩公司 | Nanoemulsion including sucrose fatty acid ester |
WO2011120033A1 (en) * | 2010-03-26 | 2011-09-29 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor xa inhibitors for oral administration |
WO2011123476A1 (en) | 2010-03-29 | 2011-10-06 | Cytochroma Inc. | Methods and compositions for reducing parathyroid levels |
WO2011123479A1 (en) | 2010-03-29 | 2011-10-06 | Academia Sinica | Quantitative measurement of nano / micro particle endocytosis with cell mass spectrometry |
TW201136945A (en) | 2010-03-31 | 2011-11-01 | Pharmasset Inc | Purine nucleoside phosphoramidate |
SG184323A1 (en) | 2010-03-31 | 2012-11-29 | Gilead Pharmasett Llc | Stereoselective synthesis of phosphorus containing actives |
US8563530B2 (en) | 2010-03-31 | 2013-10-22 | Gilead Pharmassel LLC | Purine nucleoside phosphoramidate |
US8581001B2 (en) | 2010-04-16 | 2013-11-12 | Codman & Shurtleff | Metformin-cysteine prodrug |
US20110268809A1 (en) | 2010-04-28 | 2011-11-03 | Paul Andrew Brinkley | Nicotine-Containing Pharmaceutical Compositions |
US20110274628A1 (en) | 2010-05-07 | 2011-11-10 | Borschke August J | Nicotine-containing pharmaceutical compositions |
WO2011149950A2 (en) | 2010-05-24 | 2011-12-01 | University Of Rochester | Bicyclic heteroaryl kinase inhibitors and methods of use |
CA2798323A1 (en) | 2010-05-26 | 2011-12-01 | Selecta Biosciences, Inc. | Dose selection of adjuvanted synthetic nanocarriers |
WO2011150198A1 (en) | 2010-05-27 | 2011-12-01 | Ambit Biosciences Corporation | Azolyl urea compounds and methods of use thereof |
WO2011150201A2 (en) | 2010-05-27 | 2011-12-01 | Ambit Biosciences Corporation | Azolyl amide compounds and methods of use thereof |
CA2801001A1 (en) | 2010-06-01 | 2011-12-08 | Biotheryx, Inc. | Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases |
EP2585063A1 (en) | 2010-06-01 | 2013-05-01 | Biotheryx Inc. | Methods of treating hematologic malignancies using 6-cyclohexyl-1-hydroxy-4-methyl-2(1h)-pyridone |
MX2012014273A (en) | 2010-06-07 | 2013-03-22 | Novomedix Llc | Furanyl compounds and the use thereof. |
NZ605440A (en) * | 2010-06-10 | 2014-05-30 | Abbvie Bahamas Ltd | Solid compositions comprising an hcv inhibitor |
WO2011153712A1 (en) | 2010-06-12 | 2011-12-15 | Theracos, Inc. | Crystalline form of benzylbenzene sglt2 inhibitor |
CN102277748A (en) * | 2010-06-12 | 2011-12-14 | 罗莱家纺股份有限公司 | Using method of nanometer vitamin microcapsule finishing agent |
US9375437B2 (en) | 2010-06-18 | 2016-06-28 | Lipocine Inc. | Progesterone containing oral dosage forms and kits |
WO2011161666A2 (en) * | 2010-06-21 | 2011-12-29 | White Innovation Ltd. | Enclosed liquid capsules |
US8741373B2 (en) | 2010-06-21 | 2014-06-03 | Virun, Inc. | Compositions containing non-polar compounds |
AU2011271097B2 (en) | 2010-06-21 | 2014-11-27 | Mannkind Corporation | Dry powder drug delivery system and methods |
WO2011161236A1 (en) * | 2010-06-24 | 2011-12-29 | Prayon S.A. | Stabilized active compound |
US20110319389A1 (en) | 2010-06-24 | 2011-12-29 | Tonix Pharmaceuticals, Inc. | Methods and compositions for treating fatigue associated with disordered sleep using very low dose cyclobenzaprine |
GB201010954D0 (en) * | 2010-06-29 | 2010-08-11 | Edko Pazarlama Tanitim Ticaret | Compositions |
CN103096922B (en) | 2010-07-06 | 2019-08-06 | 变异生物技术公司 | For treating the composition and method of influenza |
CN102309461B (en) * | 2010-07-09 | 2013-08-14 | 重庆医科大学 | Pyridostigmine bromide odor masking dispersible tablets and preparation method thereof |
US20120015913A1 (en) | 2010-07-15 | 2012-01-19 | Delansorne Remi | Formulations of 14-EPI-Analogues of Vitamin D |
SG187071A1 (en) * | 2010-07-15 | 2013-02-28 | Hybrigenics Sa | New formulations of 14 - epi -analogues of vitamin d |
US10322213B2 (en) | 2010-07-16 | 2019-06-18 | Atrium Medical Corporation | Compositions and methods for altering the rate of hydrolysis of cured oil-based materials |
US20130178522A1 (en) | 2010-07-19 | 2013-07-11 | James M. Jamison | Vitamin c and chromium-free vitamin k, and compositions thereof for treating an nfkb-mediated condition or disease |
CN101953822B (en) * | 2010-07-30 | 2012-05-30 | 合肥立方制药股份有限公司 | Venlafaxine hydrochloride controlled release tablets and preparation method thereof |
IT1405012B1 (en) * | 2010-08-06 | 2013-12-16 | Sofar Spa | COMPOSITIONS OF BECLOMETASONE DIPROPIONIONATO IN GASTRORESISTANT MICROSPHERES WITH MODIFIED RELEASE AND PROCESS FOR THEIR OBJECTION |
CN103179978A (en) | 2010-08-30 | 2013-06-26 | 赛诺菲-安万特德国有限公司 | Use of ave0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2 |
EP2611794A1 (en) | 2010-09-01 | 2013-07-10 | Ambit Biosciences Corporation | 4-azolylaminoquinazoline derivatives and methods of use thereof |
EP2611502A1 (en) | 2010-09-01 | 2013-07-10 | Ambit Biosciences Corporation | Adenosine a3 receptor modulating compounds and methods of use thereof |
WO2012030924A1 (en) | 2010-09-01 | 2012-03-08 | Ambit Biosciences Corporation | Azolopyridine and azolopyrimidine compounds and methods of use thereof |
US20130225578A1 (en) | 2010-09-01 | 2013-08-29 | Ambit Biosciences Corporation | 7-cyclylquinazoline derivatives and methods of use thereof |
EP2611792B1 (en) | 2010-09-01 | 2017-02-01 | Ambit Biosciences Corporation | Hydrobromide salts of a pyrazolylaminoquinazoline |
WO2012030894A1 (en) | 2010-09-01 | 2012-03-08 | Ambit Biosciences Corporation | Thienopyridine and thienopyrimidine compounds and methods of use thereof |
KR20130102060A (en) | 2010-09-01 | 2013-09-16 | 암비트 바이오사이언시즈 코포레이션 | Quinazoline compounds and methods of use thereof |
WO2012030913A1 (en) | 2010-09-01 | 2012-03-08 | Ambit Biosciences Corporation | An optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof |
US20130296363A1 (en) | 2010-09-01 | 2013-11-07 | Ambit Biosciences Corporation | Quinoline and isoquinoline derivatives for use as jak modulators |
WO2012030910A1 (en) | 2010-09-01 | 2012-03-08 | Ambit Biosciences Corporation | 2-cycloquinazoline derivatives and methods of use thereof |
WO2012033792A2 (en) | 2010-09-07 | 2012-03-15 | Dmi Acquisition Corp. | Treatment of diseases |
US8933055B2 (en) * | 2010-09-22 | 2015-01-13 | Ecolab Usa Inc. | Antimicrobial compositions containing cationic active ingredients and quaternary sugar derived surfactants |
WO2012044641A1 (en) | 2010-09-29 | 2012-04-05 | Pathway Therapeutics Inc. | 1,3,5-triazinyl benzimidazole sulfonamides and their use in cancer therapy |
MX2013003954A (en) | 2010-10-11 | 2013-08-01 | Axikin Pharmaceuticals Inc | Salts of arylsulfonamide ccr3 antagonists. |
US8808743B2 (en) * | 2010-10-20 | 2014-08-19 | William Wayne Howard | Benzonatate compositions and methods of use |
US8865198B2 (en) | 2010-10-25 | 2014-10-21 | Dexcel Pharma Technologies Ltd. | Method for treating a periodontal disease |
EP2632471B1 (en) | 2010-10-27 | 2019-05-01 | Dignity Health | Trimegestone (tmg) for treatment of preterm birth |
US11202831B2 (en) | 2010-10-29 | 2021-12-21 | Infirst Healthcare Limited | Solid solution compositions and use in cardiovascular disease |
US10695431B2 (en) | 2010-10-29 | 2020-06-30 | Infirst Healthcare Limited | Solid solution compositions and use in cardiovascular disease |
US10695432B2 (en) | 2010-10-29 | 2020-06-30 | Infirst Healthcare Limited | Solid solution compositions and use in severe pain |
US9271950B2 (en) | 2010-10-29 | 2016-03-01 | Infirst Healthcare Limited | Compositions for treating chronic inflammation and inflammatory diseases |
US9308213B2 (en) | 2010-10-29 | 2016-04-12 | Infirst Healthcare Limited | Solid solution compositions and use in chronic inflammation |
US9737500B2 (en) | 2010-10-29 | 2017-08-22 | Infirst Healthcare Limited | Compositions and methods for treating severe pain |
US8895536B2 (en) | 2010-10-29 | 2014-11-25 | Infirst Healthcare Ltd. | Compositions and methods for treating chronic inflammation and inflammatory diseases |
US9504664B2 (en) | 2010-10-29 | 2016-11-29 | Infirst Healthcare Limited | Compositions and methods for treating severe pain |
US11730709B2 (en) | 2010-10-29 | 2023-08-22 | Infirst Healthcare Limited | Compositions and methods for treating severe pain |
US11224659B2 (en) | 2010-10-29 | 2022-01-18 | Infirst Healthcare Limited | Solid solution compositions and use in severe pain |
US9744132B2 (en) | 2010-10-29 | 2017-08-29 | Infirst Healthcare Limited | Solid solution compositions and use in chronic inflammation |
US9994443B2 (en) | 2010-11-05 | 2018-06-12 | Selecta Biosciences, Inc. | Modified nicotinic compounds and related methods |
EP2637669A4 (en) | 2010-11-10 | 2014-04-02 | Infinity Pharmaceuticals Inc | Heterocyclic compounds and uses thereof |
US10238684B2 (en) | 2010-11-18 | 2019-03-26 | Foundational Biosystems, Llc | Micro- and nano-quantity sleep enhancing nutrient composition and method of enhancing central nervous system protein clearance using same |
GB201020032D0 (en) | 2010-11-25 | 2011-01-12 | Sigmoid Pharma Ltd | Composition |
US20180153904A1 (en) | 2010-11-30 | 2018-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9358241B2 (en) | 2010-11-30 | 2016-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9034858B2 (en) | 2010-11-30 | 2015-05-19 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
CA2818853A1 (en) | 2010-11-30 | 2012-06-07 | Gilead Pharmasset Llc | 2'-spirocyclo-nucleosides for use in therapy of hcv or dengue virus |
AU2011338530B2 (en) | 2010-12-06 | 2017-06-15 | Follica, Inc. | Methods for treating baldness and promoting hair growth |
US20120148675A1 (en) | 2010-12-10 | 2012-06-14 | Basawaraj Chickmath | Testosterone undecanoate compositions |
WO2012080050A1 (en) | 2010-12-14 | 2012-06-21 | F. Hoffmann-La Roche Ag | Solid forms of a phenoxybenzenesulfonyl compound |
CA2824197C (en) | 2011-01-10 | 2020-02-25 | Michael Martin | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
EP2663327A4 (en) | 2011-01-13 | 2015-12-02 | Variation Biotechnologies Inc | Compositions and methods for treating viral infections |
JP2014503597A (en) | 2011-01-31 | 2014-02-13 | セルジーン コーポレイション | Pharmaceutical composition of cytidine analogue and method of use thereof |
US9353100B2 (en) | 2011-02-10 | 2016-05-31 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections |
EP3502236B1 (en) | 2011-02-18 | 2023-08-23 | The Scripps Research Institute | Directed differentiation of oligodendrocyte precursor cells to a myelinating cell fate |
CA2827643C (en) | 2011-02-18 | 2019-05-07 | Kythera Biopharmaceuticals, Inc. | Treatment of submental fat |
CN103813786A (en) | 2011-02-25 | 2014-05-21 | 南达科他州立大学 | Protein nanocarriers for topical delivery |
AU2012223528A1 (en) | 2011-03-02 | 2013-10-24 | Joseph M. Fayad | Compositions, methods of treatment and diagnostics for treatment of hepatic steatosis alone or in combination with a Hepatitis C virus infection |
CA2865791C (en) | 2011-03-03 | 2019-10-08 | Cidara Therapeutics, Inc. | Antifungal agents and uses thereof |
BR112013022249B8 (en) | 2011-03-03 | 2022-10-25 | Impel Neuropharma Inc | NASAL DRUG DISTRIBUTION DEVICE |
US20120232159A1 (en) | 2011-03-07 | 2012-09-13 | Tonix Pharmaceuticals, Inc. | Methods and Compositions for Treating Depression using Cyclobenzaprine |
MX2013010217A (en) | 2011-03-11 | 2013-10-25 | Celgene Corp | Use of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2- 6-dione in treatment of immune-related and inflammatory diseases. |
BR112013024907A2 (en) | 2011-03-28 | 2016-12-20 | Mei Pharma Inc | compound, pharmaceutical composition, method for treating, preventing or attenuating one or more symptoms of a pi3k-mediated disorder, disease or condition in a subject, method for modulating pi3k enzymatic activity |
WO2012135166A1 (en) | 2011-03-28 | 2012-10-04 | Pathway Therapeutics Inc. | (fused ring arylamino and heterocyclylamino) pyrimidynyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases |
CA2831590A1 (en) | 2011-03-28 | 2012-10-04 | Mei Pharma, Inc. | (alpha-substituted cycloalkylamino and heterocyclylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases |
US20120252721A1 (en) | 2011-03-31 | 2012-10-04 | Idenix Pharmaceuticals, Inc. | Methods for treating drug-resistant hepatitis c virus infection with a 5,5-fused arylene or heteroarylene hepatitis c virus inhibitor |
CA2843324A1 (en) | 2011-03-31 | 2012-11-15 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
CN105667994B (en) | 2011-04-01 | 2018-04-06 | 曼金德公司 | Blister package for pharmaceutical kit |
JP6092844B2 (en) | 2011-04-04 | 2017-03-08 | バーグ エルエルシー | Treatment of central nervous system tumors |
US8653058B2 (en) | 2011-04-05 | 2014-02-18 | Kythera Biopharmaceuticals, Inc. | Compositions comprising deoxycholic acid and salts thereof suitable for use in treating fat deposits |
DK2701733T3 (en) | 2011-04-21 | 2019-05-27 | Curemark Llc | CONNECTIONS FOR TREATMENT OF NEUROPSYCIATRIC DISORDERS |
CN107376071B (en) | 2011-05-09 | 2021-07-09 | 英倍尔药业股份有限公司 | Nozzle for delivering a compound to the upper olfactory region of a user |
US20130040923A1 (en) | 2011-05-13 | 2013-02-14 | Trimel Pharmaceuticals Corporation | Intranasal lower dosage strength testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder |
US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
US20130045958A1 (en) | 2011-05-13 | 2013-02-21 | Trimel Pharmaceuticals Corporation | Intranasal 0.15% and 0.24% testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder |
US9757388B2 (en) | 2011-05-13 | 2017-09-12 | Acerus Pharmaceuticals Srl | Intranasal methods of treating women for anorgasmia with 0.6% and 0.72% testosterone gels |
US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
EP2526971A1 (en) * | 2011-05-25 | 2012-11-28 | ArisGen SA | Mucosal delivery of drugs |
US8524664B2 (en) | 2011-06-02 | 2013-09-03 | Colorado Seminary, Which owns and Operates The Univeristy of Denver | Methods of treating overproduction of cortisol using ACTH antagonist peptides |
PE20180414A1 (en) | 2011-06-17 | 2018-03-01 | Berg Llc | INHALABLE PHARMACEUTICAL COMPOSITIONS |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
CN103827113A (en) | 2011-06-23 | 2014-05-28 | Map药物公司 | Novel fluoroergoline analogs |
CA2842190A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
US8969363B2 (en) | 2011-07-19 | 2015-03-03 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US8951996B2 (en) | 2011-07-28 | 2015-02-10 | Lipocine Inc. | 17-hydroxyprogesterone ester-containing oral compositions and related methods |
UA113291C2 (en) | 2011-08-04 | 2017-01-10 | TRANSCLOMYPHENE METABOLITES AND THEIR APPLICATIONS | |
JP6016343B2 (en) | 2011-09-08 | 2016-10-26 | 株式会社ロッテ | Oral composition |
RU2014111823A (en) | 2011-08-29 | 2015-10-10 | Инфинити Фармасьютикалз, Инк. | HETEROCYCLIC COMPOUNDS AND THEIR APPLICATIONS |
JP6367115B2 (en) | 2011-08-29 | 2018-08-01 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Combination medicine used for blood glucose control in patients with type 2 diabetes |
AR087744A1 (en) | 2011-09-01 | 2014-04-16 | Sanofi Aventis Deutschland | PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OF A NEURODEGENERATIVE DISEASE |
AR088441A1 (en) | 2011-09-12 | 2014-06-11 | Idenix Pharmaceuticals Inc | SUBSTITUTED CARBONYLOXYMETHYLPHOSPHORAMIDATE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF VIRAL INFECTIONS |
EP2755985B1 (en) | 2011-09-12 | 2017-11-01 | Idenix Pharmaceuticals LLC | Compounds and pharmaceutical compositions for the treatment of viral infections |
US10226417B2 (en) | 2011-09-16 | 2019-03-12 | Peter Jarrett | Drug delivery systems and applications |
US9629392B2 (en) | 2011-09-22 | 2017-04-25 | R.J. Reynolds Tobacco Company | Translucent smokeless tobacco product |
US20130078307A1 (en) | 2011-09-22 | 2013-03-28 | Niconovum Usa, Inc. | Nicotine-containing pharmaceutical composition |
US9474303B2 (en) | 2011-09-22 | 2016-10-25 | R.J. Reynolds Tobacco Company | Translucent smokeless tobacco product |
US9084439B2 (en) | 2011-09-22 | 2015-07-21 | R.J. Reynolds Tobacco Company | Translucent smokeless tobacco product |
JP6368645B2 (en) | 2011-09-29 | 2018-08-01 | ピーエルエックス オプコ インコーポレーテッド | PH-dependent carriers for targeted release of drugs along the gastrointestinal tract, compositions thereby, and their manufacture and use |
US9630979B2 (en) | 2011-09-29 | 2017-04-25 | Infinity Pharmaceuticals, Inc. | Inhibitors of monoacylglycerol lipase and methods of their use |
EP2763679A4 (en) * | 2011-10-07 | 2016-06-01 | Univ Florida State Res Found | Prophylactic and post-acute use of progesterone to better outcomes associated with concussion |
US8980834B2 (en) | 2011-10-10 | 2015-03-17 | Ampio Pharmaceuticals, Inc. | Treatment of degenerative joint disease |
WO2013055749A1 (en) | 2011-10-10 | 2013-04-18 | Ampio Pharmaceuticals, Inc. | Implantable medical devices with increased immune tolerance, and methods for making and implanting |
WO2013056070A2 (en) | 2011-10-14 | 2013-04-18 | Ambit Biosciences Corporation | Heterocyclic compounds and methods of use thereof |
AR089650A1 (en) | 2011-10-14 | 2014-09-10 | Idenix Pharmaceuticals Inc | PHOSPHATES 3,5-REPLACED CYCLES OF PURINE NUCLEOTIDE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF VIRAL INFECTIONS |
US9907748B2 (en) | 2011-10-21 | 2018-03-06 | Niconovum Usa, Inc. | Excipients for nicotine-containing therapeutic compositions |
WO2013059664A1 (en) * | 2011-10-21 | 2013-04-25 | Seachaid Pharmaceuticals, Inc. | Pharmaceutical compositions and uses thereof |
KR20140095483A (en) | 2011-10-24 | 2014-08-01 | 맨카인드 코포레이션 | Methods and compositions for treating pain |
BR112014008036A2 (en) | 2011-10-28 | 2017-04-11 | Ampio Pharmaceuticals Inc | rhinitis treatment |
EP3936133A1 (en) | 2011-11-23 | 2022-01-12 | TherapeuticsMD, Inc. | Natural combination hormone replacement formulations and therapies |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
WO2013086015A1 (en) | 2011-12-05 | 2013-06-13 | Incept, Llc | Medical organogel processes and compositions |
US8912215B2 (en) | 2011-12-13 | 2014-12-16 | Everon Biosciences, Inc. | Rapamycin composition |
SG10201509139QA (en) | 2011-12-19 | 2015-12-30 | Map Pharmaceuticals Inc | Novel iso-ergoline derivatives |
CN102423299B (en) * | 2011-12-20 | 2013-06-19 | 中国热带农业科学院农产品加工研究所 | Preparation method for drug-loaded chitosan nano-microspheres |
US8946420B2 (en) | 2011-12-21 | 2015-02-03 | Map Pharmaceuticals, Inc. | Neuromodulatory compounds |
US9034832B2 (en) | 2011-12-29 | 2015-05-19 | Abbvie Inc. | Solid compositions |
US11285040B2 (en) | 2012-01-04 | 2022-03-29 | Sight Sciences, Inc. | Combination treatment systems |
US10973680B2 (en) | 2012-01-04 | 2021-04-13 | Sight Sciences, Inc. | Controller for dry eye treatment systems |
US9724230B2 (en) | 2012-01-04 | 2017-08-08 | Sight Sciences, Inc. | Dry eye treatment apparatus and methods |
US9510972B2 (en) * | 2012-01-04 | 2016-12-06 | Sight Sciences, Inc. | Dry eye treatment systems |
CL2012000047A1 (en) * | 2012-01-06 | 2012-07-20 | Cultivos Hidrobiologicos Y Biotecnologia Aguamarina S A | Method for reducing particulate matter suspended in air or water, which comprises agglomerating the particulate matter suspended with negatively charged exopolysaccharides (eps). |
AU2013208693B2 (en) | 2012-01-12 | 2017-12-07 | Variation Biotechnologies Inc. | Compositions and methods for treating viral infections |
EP2806894A4 (en) | 2012-01-27 | 2015-11-04 | Variation Biotechnologies Inc | Methods and compositions for therapeutic agents |
MY167560A (en) * | 2012-02-06 | 2018-09-14 | Merial Inc | Parasiticidal oral veterinary compositions comprising systemically-acting active agents, methods and uses thereof |
US9763928B2 (en) | 2012-02-10 | 2017-09-19 | Niconovum Usa, Inc. | Multi-layer nicotine-containing pharmaceutical composition |
WO2013130600A1 (en) | 2012-02-29 | 2013-09-06 | Ambit Biosciences Corporation | Solid forms comprising optically active pyrazolylaminoquinazoline, compositions thereof, and uses therewith |
US8916555B2 (en) | 2012-03-16 | 2014-12-23 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
KR102236462B1 (en) | 2012-03-19 | 2021-04-08 | 시다라 세라퓨틱스, 인코포레이티드 | Dosing regimens for echinocandin class compounds |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US9687445B2 (en) | 2012-04-12 | 2017-06-27 | Lts Lohmann Therapie-Systeme Ag | Oral film containing opiate enteric-release beads |
JP6577865B2 (en) | 2012-04-25 | 2019-09-18 | エスピーアイ ファーマ,インコーポレイテッド | Process for producing crystalline microspheres and the same |
US9233491B2 (en) | 2012-05-01 | 2016-01-12 | Johnson & Johnson Consumer Inc. | Machine for production of solid dosage forms |
US9511028B2 (en) | 2012-05-01 | 2016-12-06 | Johnson & Johnson Consumer Inc. | Orally disintegrating tablet |
US9445971B2 (en) | 2012-05-01 | 2016-09-20 | Johnson & Johnson Consumer Inc. | Method of manufacturing solid dosage form |
CN104427976B (en) | 2012-05-10 | 2018-04-24 | 佩因拉佛姆有限公司 | Hydrophobic depot formulations of active ingredient and preparation method thereof |
US9296778B2 (en) | 2012-05-22 | 2016-03-29 | Idenix Pharmaceuticals, Inc. | 3′,5′-cyclic phosphate prodrugs for HCV infection |
PE20150132A1 (en) | 2012-05-22 | 2015-02-14 | Idenix Pharmaceuticals Inc | D-AMINO ACID COMPOUNDS FOR HEPATIC DISEASE |
WO2013177188A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
CN102657626B (en) * | 2012-05-23 | 2013-07-17 | 重庆康刻尔制药有限公司 | Medicinal composite tablet of pioglitazone medicine |
US10350278B2 (en) | 2012-05-30 | 2019-07-16 | Curemark, Llc | Methods of treating Celiac disease |
DK3730132T3 (en) | 2012-06-06 | 2022-08-08 | Nalpropion Pharmaceuticals Llc | COMPOSITION FOR USE IN A METHOD FOR TREATING OVERWEIGHT AND OBESITY IN PATIENTS WITH HIGH CARDIOVASCULAR RISK |
US9867880B2 (en) | 2012-06-13 | 2018-01-16 | Atrium Medical Corporation | Cured oil-hydrogel biomaterial compositions for controlled drug delivery |
US9078925B2 (en) | 2012-06-18 | 2015-07-14 | Galephar Pharmaceutical Research, Inc. | Pharmaceutical semi-solid composition of isotretinoin |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
MX356695B (en) | 2012-06-19 | 2018-06-11 | Debiopharm Int Sa | Prodrug derivatives of (e)-n-methyl-n-((3-methylbenzofuran-2-yl)m ethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylam ide. |
US9012640B2 (en) | 2012-06-22 | 2015-04-21 | Map Pharmaceuticals, Inc. | Cabergoline derivatives |
GB201212010D0 (en) | 2012-07-05 | 2012-08-22 | Sigmoid Pharma Ltd | Formulations |
DK2872205T3 (en) | 2012-07-12 | 2017-02-27 | Mannkind Corp | DRY POWDER FORMAL ADMINISTRATION SYSTEM |
WO2014011830A1 (en) | 2012-07-12 | 2014-01-16 | Mallinckrodt Llc | Extended release, abuse deterrent pharmaceutical compositions |
PL2882441T3 (en) | 2012-08-09 | 2020-09-21 | Celgene Corporation | Treatment of immune-related and inflammatory diseases |
UA114521C2 (en) | 2012-08-09 | 2017-06-26 | Селджин Корпорейшн | Salts and solid forms of (s)-3-(4-((4-morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and compositions comprising and methods of using the same |
EP2884961B1 (en) | 2012-08-15 | 2019-03-06 | Tris Pharma Inc. | Methylphenidate extended release chewable tablet |
US9029320B2 (en) * | 2012-08-27 | 2015-05-12 | Red Mountain Med Spa, LLC | Formulations and methods for weight loss and body contouring |
CA2922849A1 (en) | 2012-08-31 | 2014-03-06 | Ixchel Pharma, Llc | Agents useful for treating obesity, diabetes and related disorders |
TW201414721A (en) | 2012-09-07 | 2014-04-16 | Axikin Pharmaceuticals Inc | Isotopically enriched arylsulfonamide CCR3 antagonists |
US9789063B2 (en) * | 2012-09-27 | 2017-10-17 | Basf Se | Storage-stable dust-free homogeneous particulate formulation |
WO2014055647A1 (en) | 2012-10-03 | 2014-04-10 | Mei Pharma, Inc. | (sulfinyl and sulfonyl benzimidazolyl) pyrimidines and triazines, pharmaceutical compositions thereof, and their use for treating proliferative diseases |
AP2015008384A0 (en) | 2012-10-08 | 2015-04-30 | Univ Montpellier Ct Nat De La Rech Scient | 2'-Chloro nucleoside analogs for hcv infection |
US20140112886A1 (en) | 2012-10-19 | 2014-04-24 | Idenix Pharmaceuticals, Inc. | Dinucleotide compounds for hcv infection |
WO2014066239A1 (en) | 2012-10-22 | 2014-05-01 | Idenix Pharmaceuticals, Inc. | 2',4'-bridged nucleosides for hcv infection |
WO2014066856A1 (en) | 2012-10-26 | 2014-05-01 | Mannkind Corporation | Inhalable influenza vaccine compositions and methods |
PT2914296T (en) | 2012-11-01 | 2018-10-30 | Infinity Pharmaceuticals Inc | Treatment of cancers using pi3 kinase isoform modulators |
WO2014070523A1 (en) | 2012-11-02 | 2014-05-08 | Repros Therapeutics Inc. | Trans-clomiphene for use in cancer therapy |
CA2890177A1 (en) | 2012-11-08 | 2014-05-15 | Summa Health System | Vitamin c, vitamin k, a polyphenol, and combinations thereof for wound healing |
EP2919903B1 (en) | 2012-11-14 | 2020-07-22 | W.R. Grace & CO. - CONN. | Compositions containing a biologically active material and a non-ordered inorganic oxide |
US20140140952A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-Alanine Ester of Sp-Nucleoside Analog |
US20140140951A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-Alanine Ester of Rp-Nucleoside Analog |
EP2925304B1 (en) | 2012-11-30 | 2018-09-05 | Acura Pharmaceuticals, Inc. | Self-regulated release of active pharmaceutical ingredient |
WO2014085633A1 (en) | 2012-11-30 | 2014-06-05 | Novomedix, Llc | Substituted biaryl sulfonamides and the use thereof |
WO2014085795A1 (en) | 2012-11-30 | 2014-06-05 | University Of Rochester | Mixed lineage kinase inhibitors for hiv/aids therapies |
US8859005B2 (en) | 2012-12-03 | 2014-10-14 | Intercontinental Great Brands Llc | Enteric delivery of functional ingredients suitable for hot comestible applications |
JP2014114247A (en) * | 2012-12-11 | 2014-06-26 | Capsugel Belgium Nv | Oil-in-water type emulsion and method for producing the same |
FR2999432B1 (en) * | 2012-12-17 | 2014-12-12 | Ethypharm Sa | ORODISPERSIBLE COMPRESSES OBTAINED BY COMPRESSION MOLDING |
BR112015014523A2 (en) | 2012-12-19 | 2017-07-11 | Kashiv Pharma Llc | stabilized nanosuspension, pharmaceutical composition, and method of treatment of a patient |
US9211300B2 (en) | 2012-12-19 | 2015-12-15 | Idenix Pharmaceuticals Llc | 4′-fluoro nucleosides for the treatment of HCV |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9271951B2 (en) | 2012-12-21 | 2016-03-01 | Mylan Inc. | Levothyroxine formulation with acacia |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
EP2934143A4 (en) | 2012-12-21 | 2016-06-15 | Map Pharmaceuticals Inc | Novel methysergide derivatives |
US20140179784A1 (en) * | 2012-12-21 | 2014-06-26 | Mylan Inc. | Levothyroxine formulation with carrageenan |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
WO2014110305A1 (en) | 2013-01-11 | 2014-07-17 | Mayo Foundation For Medical Education And Research | Vitamins c and k for treating polycystic diseases |
JP6474732B2 (en) | 2013-01-14 | 2019-02-27 | インファースト ヘルスケア リミテッド | Extreme pain treatment composition and method |
ES2829904T3 (en) * | 2013-01-14 | 2021-06-02 | Infirst Healthcare Ltd | Solid solution compositions and use in severe pain |
CN103040788A (en) * | 2013-01-19 | 2013-04-17 | 南京正宽医药科技有限公司 | Cefuroxime axetil capsule and preparation method thereof |
KR101644837B1 (en) * | 2013-01-30 | 2016-08-03 | 주식회사 대웅 | Pharmaceutical composition for protecting wounds, providing hemostasis, or preventing adhesion in the gastrointestinal tract |
WO2014117999A1 (en) | 2013-02-04 | 2014-08-07 | Biocopea Limited | Compositions and methods for treating chronic inflammation and inflammatory diseases |
GB201304662D0 (en) | 2013-03-14 | 2013-05-01 | Sigmoid Pharma Ltd | Compositions |
WO2014137930A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
US9309275B2 (en) | 2013-03-04 | 2016-04-12 | Idenix Pharmaceuticals Llc | 3′-deoxy nucleosides for the treatment of HCV |
US20140255452A1 (en) | 2013-03-11 | 2014-09-11 | Niconovum Usa, Inc. | Method and apparatus for differentiating oral pouch products |
DK2968281T3 (en) | 2013-03-13 | 2020-11-02 | Univ Texas | MTOR INHIBITORS FOR PREVENTING THE GROWTH OF THE INTESTINAL POLYPH |
US11484534B2 (en) | 2013-03-14 | 2022-11-01 | Abbvie Inc. | Methods for treating HCV |
RU2719579C2 (en) * | 2013-03-14 | 2020-04-21 | Сидара Терапьютикс, Инк. | Dosing regimens for echinocandin class compounds |
AU2014233277B2 (en) | 2013-03-15 | 2019-04-04 | Tonix Pharma Holdings Limited | Eutectic formulations of cyclobenzaprine hydrochloride and amitriptyline hydrochloride |
NZ629037A (en) | 2013-03-15 | 2017-04-28 | Infinity Pharmaceuticals Inc | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
SG10201707619RA (en) | 2013-03-15 | 2017-10-30 | Ampio Pharmaceuticals Inc | Compositions for the mobilization, homing, expansion and differentiation of stem cells and methods of using the same |
KR101847947B1 (en) | 2013-03-15 | 2018-05-28 | 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 | Stabilized modified release vitamin d formulation |
US9351517B2 (en) | 2013-03-15 | 2016-05-31 | Virun, Inc. | Formulations of water-soluble derivatives of vitamin E and compositions containing same |
US11744838B2 (en) | 2013-03-15 | 2023-09-05 | Acerus Biopharma Inc. | Methods of treating hypogonadism with transnasal testosterone bio-adhesive gel formulations in male with allergic rhinitis, and methods for preventing an allergic rhinitis event |
EP2968137B1 (en) | 2013-03-15 | 2021-11-10 | Marius Pharmaceuticals LLC | Emulsion formulations |
KR102499439B1 (en) | 2013-03-15 | 2023-02-13 | 맨카인드 코포레이션 | Microcrystalline diketopiperazine compositions and methods |
WO2014167439A1 (en) | 2013-03-26 | 2014-10-16 | Wockhardt Limited | Modified release pharmaceutical compositions of topiramate or salts thereof |
WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
SG11201508272YA (en) | 2013-04-08 | 2015-11-27 | Berg Llc | Treatment of cancer using coenzyme q10 combination therapies |
JP6589086B2 (en) * | 2013-04-12 | 2019-10-16 | ビョーメ セラピューティクス リミテッド | Composition and formulation of antibacterial agent, method for producing the same and method for treating microbial infection |
WO2014172572A1 (en) * | 2013-04-18 | 2014-10-23 | Board Of Regents, The University Of Texas System | Antimicrobial wraps for medical implants |
CA2946832A1 (en) * | 2013-04-25 | 2014-10-30 | Seachaid Pharmaceuticals, Inc. | Oral cefepime compositions and uses thereof |
JP2016520378A (en) | 2013-04-28 | 2016-07-14 | インペル ニューロファーマ インコーポレイテッド | Medical unit dose container |
US20140335153A1 (en) * | 2013-05-09 | 2014-11-13 | Cure Pharmaceutical Corporation | Thin film with high load of active ingredient |
KR20160013204A (en) | 2013-05-30 | 2016-02-03 | 인피니티 파마슈티칼스, 인코포레이티드 | Treatment of cancers using pi3 kinase isoform modulators |
EP3004130B1 (en) | 2013-06-05 | 2019-08-07 | Idenix Pharmaceuticals LLC. | 1',4'-thio nucleosides for the treatment of hcv |
WO2014204933A1 (en) | 2013-06-17 | 2014-12-24 | Adamas Pharmaceuticals, Inc. | Amantadine compositions and methods of use |
WO2015010092A1 (en) | 2013-07-18 | 2015-01-22 | Mannkind Corporation | Heat-stable dry powder pharmaceutical compositions and methods |
WO2015017713A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
JP2016530930A (en) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | Ventilation device and method |
US10195153B2 (en) | 2013-08-12 | 2019-02-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
KR20160055170A (en) | 2013-08-30 | 2016-05-17 | 암비트 바이오사이언시즈 코포레이션 | Biaryl acetamide compounds and methods of use thereof |
EA034143B1 (en) | 2013-09-04 | 2020-01-09 | Берг Ллк | Methods of treatment of cancer by continuous infusion of coenzyme q10 |
NZ631142A (en) | 2013-09-18 | 2016-03-31 | Axikin Pharmaceuticals Inc | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
BR112016005768B1 (en) | 2013-09-19 | 2021-09-21 | Microvention, Inc | POLYMER FILMS |
BR112016005770B1 (en) | 2013-09-19 | 2021-07-27 | Terumo Corporation | POLYMER PARTICLES |
EP3046924A1 (en) | 2013-09-20 | 2016-07-27 | IDENIX Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
US9700549B2 (en) | 2013-10-03 | 2017-07-11 | David Wise | Compositions and methods for treating pelvic pain and other conditions |
BR112016007467B1 (en) | 2013-10-04 | 2022-09-20 | Infinity Pharmaceuticals, Inc | HETEROCYCLIC COMPOUNDS AND USES THEREOF |
US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US9757330B2 (en) | 2013-10-18 | 2017-09-12 | Industrial Technology Research Institute | Recipe for in-situ gel, and implant, drug delivery system formed thereby |
US20160244452A1 (en) | 2013-10-21 | 2016-08-25 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
WO2015061683A1 (en) | 2013-10-25 | 2015-04-30 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate and d-alanine thiophosphoramidate pronucleotides of nucleoside compounds useful for the treatment of hcv |
US20160271162A1 (en) | 2013-11-01 | 2016-09-22 | Idenix Pharmacueticals, Llc | D-alanine phosphoramide pronucleotides of 2'-methyl 2'-fluro guanosine nucleoside compounds for the treatment of hcv |
WO2015070094A1 (en) | 2013-11-08 | 2015-05-14 | Microvention, Inc. | Polymer particles |
GB201319792D0 (en) * | 2013-11-08 | 2013-12-25 | Sigmoid Pharma Ltd | Formulations |
GB201319791D0 (en) | 2013-11-08 | 2013-12-25 | Sigmoid Pharma Ltd | Formulations |
US10064905B1 (en) * | 2013-11-11 | 2018-09-04 | Ilysm, LLC | Pharmaceutical preparation |
US10022337B2 (en) * | 2013-11-15 | 2018-07-17 | Dsm Ip Assets B.V. | Formulation of sparingly soluble compounds by hot-melt extrusion |
EP3074399A1 (en) | 2013-11-27 | 2016-10-05 | Idenix Pharmaceuticals LLC | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
WO2015081133A2 (en) | 2013-11-27 | 2015-06-04 | Idenix Pharmaceuticals, Inc. | Nucleotides for the treatment of liver cancer |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
EP3083654A1 (en) | 2013-12-18 | 2016-10-26 | Idenix Pharmaceuticals LLC | 4'-or nucleosides for the treatment of hcv |
EP3639828B8 (en) | 2013-12-24 | 2022-01-05 | Virginia Commonwealth University | Use of oxygenated cholesterol sulfates (ocs) for treating acute liver failure |
US9700544B2 (en) | 2013-12-31 | 2017-07-11 | Neal K Vail | Oral rapamycin nanoparticle preparations |
EP3089757A1 (en) | 2014-01-03 | 2016-11-09 | AbbVie Inc. | Solid antiviral dosage forms |
WO2015105992A1 (en) | 2014-01-10 | 2015-07-16 | Mcneil-Ppc, Inc. | Process for making tablet using radiofrequency and lossy coated particles |
CA2933202C (en) * | 2014-01-21 | 2022-05-31 | Jason Teckoe | Immediate release film coatings containing medium chain glycerides and substrates coated therewith |
US20170066779A1 (en) | 2014-03-05 | 2017-03-09 | Idenix Pharmaceuticals Llc | Solid forms of a flaviviridae virus inhibitor compound and salts thereof |
NO2723977T3 (en) | 2014-03-19 | 2018-03-10 | ||
CN113620958A (en) | 2014-03-19 | 2021-11-09 | 无限药品股份有限公司 | Heterocyclic compounds for the treatment of PI 3K-gamma mediated disorders |
US10005765B2 (en) | 2014-03-20 | 2018-06-26 | Capella Therapeutics, Inc. | Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer |
CA2943231C (en) | 2014-03-20 | 2023-10-24 | Capella Therapeutics, Inc. | Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer |
WO2015145459A1 (en) | 2014-03-26 | 2015-10-01 | Sun Pharma Advanced Research Company Ltd. | Abuse deterrent immediate release coated reservoir solid dosage form |
WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
RU2016136666A (en) * | 2014-03-28 | 2018-05-03 | Терапьютиксмд, Инк. | PROGESTERON BASED COMPOSITIONS |
CA2944549A1 (en) | 2014-04-09 | 2015-10-15 | Siteone Therapeutics, Inc. | 10',11'-modified saxitoxin useful for the treatment of pain |
WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
WO2015168079A1 (en) | 2014-04-29 | 2015-11-05 | Infinity Pharmaceuticals, Inc. | Pyrimidine or pyridine derivatives useful as pi3k inhibitors |
SG11201609256SA (en) | 2014-05-12 | 2016-12-29 | Conatus Pharmaceuticals Inc | Treatment of the complications of chronic liver disease with caspase inhibitors |
KR20170005819A (en) | 2014-05-22 | 2017-01-16 | 쎄러퓨틱스엠디, 인코퍼레이티드 | Natural combination hormone replacement formulations and therapies |
AU2015265607A1 (en) | 2014-05-28 | 2016-11-17 | Idenix Pharmaceuticals Llc | Nucleoside derivatives for the treatment of cancer |
WO2015184173A1 (en) | 2014-05-29 | 2015-12-03 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
WO2015195474A1 (en) | 2014-06-18 | 2015-12-23 | Biotheryx, Inc. | Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating inflammatory, neurodegenerative, or immune-mediated diseases |
GEP20197011B (en) | 2014-06-19 | 2019-08-12 | Ariad Pharma Inc | Heteroaryl compounds for kinase inhibition |
WO2016005994A2 (en) | 2014-07-06 | 2016-01-14 | Gattefosse India Pvt. Ltd. | Pharmaceutical composition comprising solid dispersion of bcs class ii drugs with gelucires |
US9855234B2 (en) | 2014-07-08 | 2018-01-02 | Insys Development Company, Inc. | Diclofenac sublingual spray |
US9499514B2 (en) | 2014-07-11 | 2016-11-22 | Celgene Corporation | Antiproliferative compounds and methods of use thereof |
ES2809458T3 (en) | 2014-07-17 | 2021-03-04 | Pharmaceutical Manufacturing Res Services Inc | Liquid filled, abuse deterrent and immediate release dosage form |
JP2017523138A (en) | 2014-07-29 | 2017-08-17 | セラピューティックスエムディー インコーポレーテッドTherapeuticsmd, Inc. | Transdermal cream |
US9850521B2 (en) * | 2014-08-01 | 2017-12-26 | Agilent Technologies, Inc. | In vitro assay buffer for Cas9 |
US9956153B2 (en) | 2014-08-01 | 2018-05-01 | Ecolab Usa Inc. | Antimicrobial foaming compositions containing cationic active ingredients |
SG10201911274TA (en) | 2014-08-07 | 2020-02-27 | Opko Ireland Global Holdings Ltd | Adjunctive therapy with 25-hydroxyvitamin d |
US9480588B2 (en) | 2014-08-15 | 2016-11-01 | Elixir Medical Corporation | Biodegradable endoprostheses and methods of their fabrication |
US9855156B2 (en) | 2014-08-15 | 2018-01-02 | Elixir Medical Corporation | Biodegradable endoprostheses and methods of their fabrication |
US9259339B1 (en) | 2014-08-15 | 2016-02-16 | Elixir Medical Corporation | Biodegradable endoprostheses and methods of their fabrication |
US9730819B2 (en) | 2014-08-15 | 2017-08-15 | Elixir Medical Corporation | Biodegradable endoprostheses and methods of their fabrication |
EP4066836A1 (en) | 2014-08-18 | 2022-10-05 | Ampio Pharmaceuticals, Inc. | Treatment of joint conditions |
WO2016033549A2 (en) | 2014-08-28 | 2016-03-03 | Lipocine Inc. | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
WO2016033556A1 (en) | 2014-08-28 | 2016-03-03 | Lipocine Inc. | BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS |
US20170319548A1 (en) | 2014-09-12 | 2017-11-09 | Tobira Therapeutics, Inc. | Cenicriviroc combination therapy for the treatment of fibrosis |
US10016363B2 (en) | 2014-09-18 | 2018-07-10 | Virun, Inc. | Pre-spray emulsions and powders containing non-polar compounds |
AU2015317336B2 (en) | 2014-09-18 | 2021-01-21 | Tonix Pharma Holdings Limited | Eutectic formulations of Cyclobenzaprine hydrochloride |
US9861611B2 (en) | 2014-09-18 | 2018-01-09 | Virun, Inc. | Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same |
CN107405306A (en) * | 2014-09-19 | 2017-11-28 | 奥叙拉尔有限公司 | Ophthalmic pharmaceutical compositions |
BR112017006778A2 (en) * | 2014-10-01 | 2018-01-09 | Als Mountain Llc | pharmaceutical composition comprising aspirin, metformin and serotonin with nonionic surfactant |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
JP2017531026A (en) | 2014-10-20 | 2017-10-19 | ファーマシューティカル マニュファクチュアリング リサーチ サービシズ,インコーポレーテッド | Sustained release abuse deterrent liquid filler form |
RS60737B1 (en) | 2014-10-21 | 2020-09-30 | Ariad Pharma Inc | Crystalline forms of 5-chloro-n4-[-2-(dimethylphosphoryl) phenyl]-n2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl) piperidin-1-yl]pyrimidine-2,4-diamine |
US20170354639A1 (en) | 2014-10-24 | 2017-12-14 | Biogen Ma Inc. | Diterpenoid derivatives and methods of use thereof |
PT3215127T (en) | 2014-11-07 | 2021-02-10 | Sublimity Therapeutics Ltd | Compositions comprising cyclosporin |
DK3220916T3 (en) * | 2014-11-17 | 2023-06-26 | Epizyme Inc | METHOD FOR TREATMENT OF CANCER WITH N-((4,6-DIMETHYL-2-OXO-1,2-DIHYDROPYRIDIN-3-YL)METHYL)-5-(ETHYL(TETRAHYDRO-2H-PYRAN-4-YL)AMINO) -4-METHYL-4'-(MORPHOLINOMETHYL)-[1,1'-BIPHENYL]-3-CARBOXAMIDE |
NZ733670A (en) | 2014-12-12 | 2021-12-24 | Sanofi Aventis Deutschland | Insulin glargine/lixisenatide fixed ratio formulation |
HUE049801T2 (en) | 2014-12-23 | 2020-10-28 | Sma Therapeutics Inc | 3,5-diaminopyrazole kinase inhibitors |
JP2018502889A (en) | 2015-01-20 | 2018-02-01 | エックスオーシー ファーマシューティカルズ インコーポレイテッドXoc Pharmaceuticals, Inc | Isoergoline compounds and uses thereof |
CA2974117A1 (en) | 2015-01-20 | 2016-07-28 | Xoc Pharmaceuticals, Inc. | Ergoline compounds and uses thereof |
EP3250191B1 (en) | 2015-01-29 | 2024-01-17 | Novo Nordisk A/S | Tablets comprising glp-1 agonist and enteric coating |
US10987328B2 (en) | 2015-02-20 | 2021-04-27 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US9579289B2 (en) | 2015-02-20 | 2017-02-28 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
US10300032B2 (en) | 2015-02-20 | 2019-05-28 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form |
CN107847496A (en) * | 2015-02-20 | 2018-03-27 | 英仕柏集团有限责任公司 | Perle containing Fexofenadine fourth |
US10172800B2 (en) | 2015-02-20 | 2019-01-08 | Osmotica Kereskedelmi Es Szolgaltato Kft | Controlled release dosage form with enhanced pharmacokinetics |
GB201505938D0 (en) | 2015-04-08 | 2015-05-20 | Reckitt Benckiser Llc | Compositions comprising C0-Q10, krill oil and vitamin D |
TWI748945B (en) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | Treatment type 2 diabetes mellitus patients |
TW201705975A (en) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | Treatment of type 2 diabetes mellitus patients |
US9907880B2 (en) | 2015-03-26 | 2018-03-06 | Microvention, Inc. | Particles |
GB201505527D0 (en) * | 2015-03-31 | 2015-05-13 | Jmedtech Pte Ltd | Composition |
EP3288556A4 (en) | 2015-04-29 | 2018-09-19 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
WO2016187355A1 (en) * | 2015-05-20 | 2016-11-24 | Glaukos Corporation | Therapeutic drug compositions and implants for delivery of same |
CN108368147A (en) | 2015-05-27 | 2018-08-03 | 南方研究院 | Nucleotide for treating cancer |
AU2016267685A1 (en) | 2015-05-28 | 2017-12-07 | Dr. Reddy's Laboratories Ltd. | Oral composition of celecoxib for treatment of pain |
US20160346221A1 (en) | 2015-06-01 | 2016-12-01 | Autotelic Llc | Phospholipid-coated therapeutic agent nanoparticles and related methods |
US10631564B2 (en) | 2015-06-19 | 2020-04-28 | University Of Southern California | Enterically coated microparticle compositions and methods for modified nutrient delivery |
US10744070B2 (en) | 2015-06-19 | 2020-08-18 | University Of Southern California | Enteral fast access tract platform system |
WO2016209969A1 (en) | 2015-06-22 | 2016-12-29 | Ampio Pharmaceuticals, Inc. | Use of low molecular weight fractions of human serum albumin in treating diseases |
MX2017016823A (en) | 2015-06-22 | 2018-03-12 | Lipocine Inc | 17-hydroxyprogesterone ester-containing oral compositions and related methods. |
AU2016282790B9 (en) | 2015-06-23 | 2020-01-30 | Neurocrine Biosciences, Inc. | VMAT2 inhibitors for treating neurological diseases or disorders |
JP2018524346A (en) | 2015-07-02 | 2018-08-30 | サイヴィタス セラピューティックス,インコーポレイテッド | Triptan powder for pulmonary delivery |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
US9585867B2 (en) | 2015-08-06 | 2017-03-07 | Charles Everett Ankner | Cannabinod formulation for the sedation of a human or animal |
HUE057306T2 (en) | 2015-08-17 | 2022-04-28 | Kura Oncology Inc | Methods of treating cancer patients with farnesyl transferase inhibitors |
WO2017040607A1 (en) | 2015-08-31 | 2017-03-09 | Acura Pharmaceuticals, Inc. | Methods and compositions for self-regulated release of active pharmaceutical ingredient |
US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
US11590228B1 (en) | 2015-09-08 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine compositions |
WO2017044897A1 (en) | 2015-09-10 | 2017-03-16 | Impel Neuropharma Inc. | In-line nasal delivery device |
US11564833B2 (en) | 2015-09-25 | 2023-01-31 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
WO2017059385A1 (en) | 2015-09-30 | 2017-04-06 | Siteone Therapeutics, Inc. | 11,13-modified saxitoxins for the treatment of pain |
AU2016343633B2 (en) | 2015-10-30 | 2021-07-01 | Neurocrine Biosciences, Inc. | Valbenazine salts and polymorphs thereof |
WO2017079566A1 (en) | 2015-11-05 | 2017-05-11 | Conatus Pharmaceuticals, Inc. | Caspase inhibitors for use in the treatment of liver cancer |
US10112924B2 (en) | 2015-12-02 | 2018-10-30 | Astraea Therapeutics, Inc. | Piperdinyl nociceptin receptor compounds |
US20170165252A1 (en) | 2015-12-10 | 2017-06-15 | Niconovum Usa Inc. | Protein-enriched therapeutic composition |
PT3394057T (en) | 2015-12-23 | 2022-04-21 | Neurocrine Biosciences Inc | Synthetic methods for preparation of (s)-(2r,3r,11br)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1h-pyrido[2,1,-a]lsoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) |
JP2019500397A (en) | 2015-12-31 | 2019-01-10 | クオナトウス ファーマシューティカルズ,インコーポレイテッド | Methods of using caspase inhibitors for the treatment of liver disease |
CN108712904B (en) | 2016-01-08 | 2022-08-02 | 细胞基因公司 | Solid forms of 2- (4-chlorophenyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 2-difluoroacetamide and pharmaceutical compositions and uses thereof |
EP3399980A4 (en) | 2016-01-08 | 2019-09-04 | Celgene Corporation | Methods for treating cancer and the use of biomarkers as a predictor of clinical sensitivity to therapies |
EP3399995A4 (en) | 2016-01-08 | 2019-08-21 | Cidara Therapeutics, Inc. | Methods for preventing and treating pneumocystis infections |
ES2957477T3 (en) | 2016-01-08 | 2024-01-19 | Celgene Corp | Antiproliferative compounds for use in the treatment of leukemia |
TN2018000293A1 (en) | 2016-02-26 | 2020-01-16 | Debiopharm Int Sa | Medicament for treatment of diabetic foot infections |
EP3430400B1 (en) | 2016-03-16 | 2023-06-21 | Cidara Therapeutics, Inc. | Dosing regimens for treatment of fungal infections |
US10759806B2 (en) | 2016-03-17 | 2020-09-01 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors |
KR20180123100A (en) | 2016-03-28 | 2018-11-14 | 옵코 아일랜드 글로벌 홀딩스 리미티드 | How to Treat Vitamin D |
AU2017239645A1 (en) | 2016-04-01 | 2018-10-18 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical composition |
US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
WO2017168174A1 (en) | 2016-04-02 | 2017-10-05 | N4 Pharma Uk Limited | New pharmaceutical forms of sildenafil |
CN108884019A (en) | 2016-04-11 | 2018-11-23 | 克雷西奥生物科技有限公司 | Deuterated chloramines ketone derivatives |
US10047077B2 (en) | 2016-04-13 | 2018-08-14 | Skyline Antiinfectives, Inc. | Deuterated O-sulfated beta-lactam hydroxamic acids and deuterated N-sulfated beta-lactams |
CN109937025B (en) | 2016-04-20 | 2022-07-29 | 多斯医学公司 | Delivery device for bioabsorbable ocular drugs |
US20190119758A1 (en) | 2016-04-22 | 2019-04-25 | Kura Oncology, Inc. | Methods of selecting cancer patients for treatment with farnesyltransferase inhibitors |
WO2017190086A1 (en) | 2016-04-29 | 2017-11-02 | Fgh Biotech, Inc. | Di-substituted pyrazole compounds for the treatment of diseases |
US11622872B2 (en) | 2016-05-16 | 2023-04-11 | Elixir Medical Corporation | Uncaging stent |
TWI753910B (en) | 2016-05-16 | 2022-02-01 | 美商拜歐斯瑞克斯公司 | Pyridinethiones, pharmaceutical compositions thereof, and their therapeutic use for treating a proliferative, inflammatory, neurodegenerative, or immune-mediated disease |
EP3861961A1 (en) | 2016-05-16 | 2021-08-11 | Elixir Medical Corporation | Uncaging stent |
WO2017203365A1 (en) * | 2016-05-26 | 2017-11-30 | Dr. Reddy's Laboratiories Ltd. | Pharmaceutical compositions for treating acne |
WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
WO2017222575A1 (en) | 2016-06-23 | 2017-12-28 | Collegium Pharmaceutical, Inc. | Process of making more stable abuse-deterrent oral formulations |
CN109922796B (en) | 2016-06-23 | 2023-04-07 | 考里安有限责任公司 | Adhesive matrix with hydrophilic and hydrophobic domains and therapeutic agents |
US10143706B2 (en) | 2016-06-29 | 2018-12-04 | Cannscience Innovations, Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
WO2018002673A1 (en) | 2016-07-01 | 2018-01-04 | N4 Pharma Uk Limited | Novel formulations of angiotensin ii receptor antagonists |
US9993466B2 (en) | 2016-07-27 | 2018-06-12 | Corium International, Inc. | Donepezil transdermal delivery system |
EP3490544A1 (en) | 2016-07-27 | 2019-06-05 | Corium International, Inc. | Memantine transdermal delivery systems |
US20180028461A1 (en) | 2016-07-27 | 2018-02-01 | Corium International, Inc. | Transdermal delivery systems with pharmacokinetics bioequivalent to oral delivery |
US20200222430A1 (en) * | 2016-08-02 | 2020-07-16 | Durect Corporation | Compositions comprising oxygenated cholesterol sulfate and at least one of polyalkylene glycol, carboxymethyl cellulose and polyoxylglyceride |
US20190269695A1 (en) | 2016-08-02 | 2019-09-05 | Virginia Commonwealth University | Compositions comprising 5-cholesten-3, 25-diol, 3-sulfate (25hc3s) or pharmaceutically acceptable salt thereof and at least one cyclic oligosaccharide |
WO2018027001A1 (en) * | 2016-08-03 | 2018-02-08 | Temple University-Of The Commonwealth System Of Higher Education | Microencapsulation of active agents |
EP3481387A4 (en) | 2016-08-11 | 2020-04-08 | Ovid Therapeutics Inc | Methods and compositions for treatment of epileptic disorders |
CN110072861B (en) | 2016-09-07 | 2022-11-11 | Fgh生物科技公司 | Disubstituted pyrazoles for the treatment of diseases |
US10391105B2 (en) | 2016-09-09 | 2019-08-27 | Marinus Pharmaceuticals Inc. | Methods of treating certain depressive disorders and delirium tremens |
AU2017326558B2 (en) | 2016-09-19 | 2022-01-06 | Mei Pharma, Inc. | Combination therapy |
EP3518983B1 (en) | 2016-09-28 | 2024-04-24 | Terumo Corporation | Polymer particles |
EP3300724B1 (en) * | 2016-09-30 | 2019-08-21 | Erber Aktiengesellschaft | Particle containing at least a volatile substance and process for its preparation |
EP3525765A1 (en) * | 2016-10-13 | 2019-08-21 | Catalent U.K. Swindon Zydis Limited | Lyophilized pharmaceutical compositions for vaginal delivery |
EA201991091A1 (en) | 2016-11-03 | 2019-11-29 | WAYS OF TREATMENT OF PATIENTS WITH MALIGNANT NEW FORMATIONS USING PHARNESYL TRANSFERASE INHIBITORS | |
US10988442B2 (en) | 2016-11-09 | 2021-04-27 | Novomedix, Llc | Nitrite salts of 1,1-dimethylbiguanide, pharmaceutical compositions, and methods of use |
US10106521B2 (en) | 2016-11-09 | 2018-10-23 | Phloronol, Inc. | Eckol derivatives, methods of synthesis and uses thereof |
WO2018098501A1 (en) | 2016-11-28 | 2018-05-31 | Lipocine Inc. | Oral testosterone undecanoate therapy |
EP3548007A4 (en) | 2016-12-01 | 2020-08-12 | Ignyta, Inc. | Methods for the treatment of cancer |
US20200078352A1 (en) | 2016-12-02 | 2020-03-12 | Neurocrine Biosciences, Inc. | Use of Valbenazine for Treating Schizophrenia or Schizoaffective Disorder |
CN110430889B (en) * | 2017-01-20 | 2023-09-19 | 堪萨斯大学 | Macrocyclic peptides that reduce C-MYC protein levels and slow cancer cell growth |
WO2018140092A1 (en) | 2017-01-27 | 2018-08-02 | Obrien Christopher F | Methods for the administration of certain vmat2 inhibitors |
GB2573933B (en) | 2017-01-31 | 2022-07-13 | Kimberly Clark Co | Antibacterial composition including benzoic acid ester and methods of inhibiting bacterial growth utilizing the same |
CN114796218A (en) | 2017-02-21 | 2022-07-29 | 库拉肿瘤学公司 | Methods of treating cancer using farnesyl transferase inhibitors |
US9956215B1 (en) | 2017-02-21 | 2018-05-01 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
CN110545821A (en) * | 2017-02-21 | 2019-12-06 | Ico治疗公司 | Solid oral formulations of amphotericin B |
WO2018164996A1 (en) | 2017-03-06 | 2018-09-13 | Neurocrine Biosciences, Inc. | Dosing regimen for valbenazine |
JP6908769B2 (en) * | 2017-03-15 | 2021-07-28 | セレシン・インコーポレーテッド | Pharmaceutical Compositions with High Drug Filling Medium Chain Triglycerides and Related Methods |
EP3601326A4 (en) | 2017-03-20 | 2020-12-16 | The Broad Institute, Inc. | Compounds and methods for regulating insulin secretion |
US10493026B2 (en) | 2017-03-20 | 2019-12-03 | Johnson & Johnson Consumer Inc. | Process for making tablet using radiofrequency and lossy coated particles |
WO2018183782A1 (en) | 2017-03-29 | 2018-10-04 | Siteone Therapeutics, Inc. | 11,13-modified saxitoxins for the treatment of pain |
CN110831945B (en) | 2017-03-29 | 2023-08-08 | 赛特温治疗公司 | 11, 13-modified saxitoxins for the treatment of pain |
WO2018200605A1 (en) | 2017-04-26 | 2018-11-01 | Neurocrine Biosciences, Inc. | Use of valbenazine for treating levodopa-induced dyskinesia |
JOP20190219A1 (en) | 2017-05-09 | 2019-09-22 | Cardix Therapeutics LLC | Pharmaceutical compositions and methods of treating cardiovascular diseases |
US10085999B1 (en) | 2017-05-10 | 2018-10-02 | Arixa Pharmaceuticals, Inc. | Beta-lactamase inhibitors and uses thereof |
US20190224275A1 (en) | 2017-05-12 | 2019-07-25 | Aurinia Pharmaceuticals Inc. | Protocol for treatment of lupus nephritis |
BR112019024116A2 (en) | 2017-05-17 | 2020-06-02 | Berg Llc | USE OF COENZYME Q10 FORMULATIONS IN THE TREATMENT AND PREVENTION OF BULLY EPIDERMOLYSIS |
MX2019013561A (en) | 2017-05-19 | 2022-02-09 | Nflection Therapeutics Inc | Pyrrolopyridine-aniline compounds for treatment of dermal disorders. |
ES2913213T3 (en) | 2017-05-19 | 2022-06-01 | Nflection Therapeutics Inc | Condensed Aniline Heteroaromatic Compounds for the Treatment of Skin Disorders |
CA3064274A1 (en) | 2017-06-01 | 2018-12-06 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
US11197909B2 (en) | 2017-07-12 | 2021-12-14 | Cidara Therapeutics, Inc. | Compositions and methods for the treatment of fungal infections |
CN110996932A (en) | 2017-07-13 | 2020-04-10 | 托尼克斯医药控股公司 | Cyclobenzaprine and amitriptyline analogs |
SG11202000894TA (en) | 2017-08-07 | 2020-02-27 | Kura Oncology Inc | Methods of treating cancer with farnesyltransferase inhibitors |
US10806730B2 (en) | 2017-08-07 | 2020-10-20 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
WO2019040748A1 (en) | 2017-08-24 | 2019-02-28 | Adamas Pharma, Llc | Amantadine compositions, preparations thereof, and methods of use |
EP3681469A1 (en) | 2017-09-15 | 2020-07-22 | Oxular Limited | Ophthalmic drug compositions |
AU2018335259A1 (en) | 2017-09-21 | 2020-04-09 | Neurocrine Biosciences, Inc. | High dosage valbenazine formulation and compositions, methods, and kits related thereto |
US11744967B2 (en) | 2017-09-26 | 2023-09-05 | Shin Nippon Biomedical Laboratories, Ltd. | Intranasal delivery devices |
US10993941B2 (en) | 2017-10-10 | 2021-05-04 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
AU2017435893B2 (en) | 2017-10-10 | 2023-06-29 | Neurocrine Biosciences, Inc | Methods for the administration of certain VMAT2 inhibitors |
JP2018043990A (en) * | 2017-10-11 | 2018-03-22 | カプスゲル・ベルギウム・ナムローゼ・フェンノートシャップCapsugel Belgium NV | Oil-in-water emulsion and method for producing the same |
JP2021503988A (en) | 2017-11-21 | 2021-02-15 | インペル ニューロファーマ インコーポレイテッド | Intranasal device with inlet interface |
US11571532B2 (en) | 2017-11-21 | 2023-02-07 | Impel Pharmaceuticals Inc. | Intranasal device with dip tube |
WO2019113269A1 (en) | 2017-12-08 | 2019-06-13 | Kura Oncology, Inc. | Methods of treating cancer patients with farnesyltransferase inhibitors |
US11826321B2 (en) | 2017-12-11 | 2023-11-28 | Tonix Pharma Holdings Limited | Cyclobenzaprine treatment for agitation, psychosis and cognitive decline in dementia and neurodegenerative conditions |
US11173132B2 (en) | 2017-12-20 | 2021-11-16 | Corium, Inc. | Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point |
KR20200118034A (en) | 2018-01-05 | 2020-10-14 | 임펠 뉴로파마 인코포레이티드 | Intranasal delivery of olanzapine by a precision olfactory organ device |
US20190209463A1 (en) | 2018-01-05 | 2019-07-11 | Impel Neuropharma, Inc. | Intranasal delivery of dihydroergotamine by precision olfactory device |
TW201929847A (en) | 2018-01-10 | 2019-08-01 | 美商克拉治療有限責任公司 | Pharmaceutical compositions comprising dicarboxylic acids and their therapeutic applications |
WO2019139869A1 (en) | 2018-01-10 | 2019-07-18 | Cura Therapeutics Llc | Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications |
MX2018000963A (en) | 2018-01-22 | 2018-12-13 | Federico Amezcua Amezcua | Synergistic pharmaceutical composition originated from the active enantiomer s-ketorolac tromethamine and tramadol hydrochloride. |
US10231931B1 (en) | 2018-03-23 | 2019-03-19 | Genus Lifesciences Inc. | Thyroid hormone oral dosage forms and methods of using the same |
WO2019241555A1 (en) | 2018-06-14 | 2019-12-19 | Neurocrine Biosciences, Inc. | Vmat2 inhibitor compounds, compositions, and methods relating thereto |
WO2019239356A1 (en) | 2018-06-15 | 2019-12-19 | R. J. Reynolds Tobacco Company | Purification of nicotine |
KR102145853B1 (en) * | 2018-06-19 | 2020-08-19 | 한국유나이티드제약 주식회사 | Pharma ceutical Composition Comprising Cilostazol and Statin derivatives |
US11447497B2 (en) | 2018-06-29 | 2022-09-20 | Histogen, Inc. | (S)-3-(2-(4-(benzyl)-3-oxopiperazin-1-yl)acetamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid derivatives and related compounds as caspase inhibitors for treating cardiovascular diseases |
WO2020009560A1 (en) | 2018-07-04 | 2020-01-09 | AMÉZCUA AMÉZCUA, Federico | Synergic pharmaceutical composition of the active enantiomer (s)-ketorolac and gabapentin for the treatment of neuropathic pain |
WO2020018959A1 (en) | 2018-07-19 | 2020-01-23 | Impel Neuropharma, Inc. | Respiratory tract delivery of levodopa and dopa decarboxylase inhibitor for treatment of parkinson's disease |
US11350657B2 (en) * | 2018-08-06 | 2022-06-07 | Pharmavite, Llc | Protein gummy composition |
AU2019322863A1 (en) | 2018-08-15 | 2021-03-11 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
AU2019334202A1 (en) | 2018-09-06 | 2021-03-25 | Innopharmascreen, Inc. | Methods and compositions for treatment of asthma or parkinson's disease |
EP3860714B1 (en) | 2018-10-03 | 2023-09-06 | Siteone Therapeutics, Inc. | 11,13-modified saxitoxins for the treatment of pain |
SG11202104296TA (en) | 2018-11-01 | 2021-05-28 | Kura Oncology Inc | Methods of treating cancer with farnesyltransferase inhibitors |
JP7406264B2 (en) | 2018-11-20 | 2023-12-27 | エヌフレクション セラピューティクス インコーポレイテッド | Cyanoaryl-aniline compounds for the treatment of skin disorders |
CN113645964A (en) | 2018-11-20 | 2021-11-12 | 恩福莱克逊治疗有限公司 | Arylaniline and heteroarylaniline compounds for use in fetal marker therapy |
EP4233865A3 (en) | 2018-11-20 | 2023-09-27 | NFlection Therapeutics, Inc. | Aryl-aniline and heteroaryl-aniline compounds for treatment of skin cancers |
MA55144A (en) | 2018-11-20 | 2021-09-29 | Nflection Therapeutics Inc | NAPHTHYRIDINONE-ANILINE COMPOUNDS FOR THE TREATMENT OF SKIN CONDITIONS |
US11266662B2 (en) | 2018-12-07 | 2022-03-08 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in prophylaxis and treatment of postpartum depression |
US20230078755A1 (en) | 2018-12-19 | 2023-03-16 | Shy Therapeutics, Llc | Compounds that Interact with the RAS Superfamily for the Treatment of Cancers, Inflammatory Diseases, Rasopathies, and Fibrotic Disease |
WO2020132700A1 (en) | 2018-12-21 | 2020-06-25 | Fgh Biotech Inc. | Methods of using inhibitors of srebp in combination with niclosamide and analogs thereof |
US20220071941A1 (en) | 2018-12-21 | 2022-03-10 | Kura Oncology, Inc. | Therapies for squamous cell carcinomas |
SG11202107019VA (en) | 2019-01-03 | 2021-07-29 | Impel Neuropharma Inc | Nasal drug delivery device |
CN113874080A (en) | 2019-02-06 | 2021-12-31 | 戴斯阿尔法公司 | IL-17A modulators and uses thereof |
WO2020180663A1 (en) | 2019-03-01 | 2020-09-10 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
JP2022524049A (en) | 2019-03-07 | 2022-04-27 | クオナトウス ファーマシューティカルズ,インコーポレイテッド | Caspase inhibitors and how to use them |
US20220143006A1 (en) | 2019-03-15 | 2022-05-12 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
GR1009790B (en) | 2019-03-20 | 2020-08-03 | Φαρματεν Α.Β.Ε.Ε. | Prolonged release formulation comprising tacrolimus |
CA3134825A1 (en) | 2019-03-29 | 2020-10-08 | Kura Oncology, Inc. | Methods of treating squamous cell carcinomas with farnesyltransferase inhibitors |
WO2020205387A1 (en) | 2019-04-01 | 2020-10-08 | Kura Oncology, Inc. | Methods of treating cancer with farnesyltransferase inhibitors |
US20220305001A1 (en) | 2019-05-02 | 2022-09-29 | Kura Oncology, Inc. | Methods of treating acute myeloid leukemia with farnesyltransferase inhibitors |
CA3140374A1 (en) | 2019-05-17 | 2020-11-26 | Impel Neuropharma, Inc. | Single-use nasal delivery device |
US11298336B2 (en) | 2019-05-30 | 2022-04-12 | Soluble Technologies, Inc. | Water soluble formulation |
CN114007617A (en) * | 2019-05-31 | 2022-02-01 | 葡瑞慕生物技术有限公司 | Unit dosage form for transmucosal administration of pharmaceutically active ingredients |
CA3146159A1 (en) | 2019-07-11 | 2021-01-14 | Cura Therapeutics, Llc | Phenyl compounds and pharmaceutical compositions thereof, and their therapeutic applications |
US20220274922A1 (en) | 2019-07-11 | 2022-09-01 | Cura Therapeutics, Llc | Sulfone compounds and pharmaceutical compositions thereof, and their therapeutic applications |
EP4003314A4 (en) | 2019-07-26 | 2023-09-20 | Espervita Therapeutics, Inc. | Functionalized long-chain hydrocarbon mono- and di-carboxylic acids useful for the prevention or treatment of disease |
JP2022543837A (en) | 2019-08-05 | 2022-10-14 | マリナス ファーマシューティカルズ, インコーポレイテッド | Ganaxolone for use in treating status epilepticus |
US10940141B1 (en) | 2019-08-23 | 2021-03-09 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
IL291345B2 (en) | 2019-09-16 | 2024-04-01 | Dice Alpha Inc | Il-17a modulators and uses thereof |
WO2021059023A1 (en) | 2019-09-26 | 2021-04-01 | Abionyx Pharma Sa | Compounds useful for treating liver diseases |
KR20220091488A (en) | 2019-10-01 | 2022-06-30 | 몰레큘러 스킨 테라퓨틱스, 인코포레이티드 | Benzoxazinone Compounds as KLK5/7 Dual Inhibitors |
CA3158280A1 (en) | 2019-12-06 | 2021-06-10 | Alex Aimetti | Ganaxolone for use in treating tuberous sclerosis complex |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
US20210251947A1 (en) * | 2020-02-10 | 2021-08-19 | TRYAGx Labs Inc. | Stable formulations of dronabinol |
AU2021244695A1 (en) | 2020-03-26 | 2022-11-10 | Plx Opco Inc. | Pharmaceutical carriers capable of pH dependent reconstitution and methods for making and using same |
US11529331B2 (en) | 2020-05-29 | 2022-12-20 | Boulder Bioscience Llc | Methods for improved endovascular thrombectomy using 3,3′-diindolylmethane |
EP4168414A1 (en) | 2020-06-18 | 2023-04-26 | Shy Therapeutics LLC | Substituted thienopyrimidines that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease |
AU2021310264A1 (en) | 2020-07-15 | 2023-02-09 | Schabar Research Associates Llc | Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn |
CA3124579A1 (en) | 2020-07-15 | 2022-01-15 | Schabar Research Associates Llc | Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn |
US11786475B2 (en) | 2020-07-22 | 2023-10-17 | Soluble Technologies Inc. | Film-based dosage form |
CA3188924A1 (en) | 2020-08-14 | 2022-02-17 | Hassan Pajouhesh | Non-hydrated ketone inhibitors of nav1.7 for the treatment of pain |
WO2022040584A1 (en) * | 2020-08-21 | 2022-02-24 | Neuronasal, Inc. | Methods of administering glutathione precursors |
US11541009B2 (en) | 2020-09-10 | 2023-01-03 | Curemark, Llc | Methods of prophylaxis of coronavirus infection and treatment of coronaviruses |
WO2022165000A1 (en) | 2021-01-27 | 2022-08-04 | Shy Therapeutics, Llc | Methods for the treatment of fibrotic disease |
EP4284377A1 (en) | 2021-01-27 | 2023-12-06 | Shy Therapeutics LLC | Methods for the treatment of fibrotic disease |
US11452690B1 (en) | 2021-01-27 | 2022-09-27 | ECI Pharmaceuticals, LLC | Oral liquid compositions comprising amlodipine besylate and methods of using the same |
WO2022189856A1 (en) | 2021-03-08 | 2022-09-15 | Abionyx Pharma Sa | Compounds useful for treating liver diseases |
BR112023018290A2 (en) | 2021-03-10 | 2023-12-12 | Dice Molecules Sv Inc | ALPHA V BETA 6 AND ALPHA V BETA 1 INTEGRIN INHIBITORS AND USES THEREOF |
EP4062907A1 (en) * | 2021-03-23 | 2022-09-28 | Substipharm | Formulation for oral administration of ivermectin and uses thereof |
US11197819B1 (en) * | 2021-04-09 | 2021-12-14 | Drug Delivery Company, Llc | Extended release bioabsorbable subcutaneous medicinal dosage delivery implant system |
WO2022226166A1 (en) | 2021-04-22 | 2022-10-27 | Protego Biopharma, Inc. | Spirocyclic imidazolidinones and imidazolidinediones for treatment of light chain amyloidosis |
US11866639B2 (en) | 2021-04-29 | 2024-01-09 | Saudi Arabian Oil Company | Method and material to reduce acid-carbonate reaction rate by endothermic reaction |
WO2022251533A1 (en) | 2021-05-27 | 2022-12-01 | Protego Biopharma, Inc. | Heteroaryl diamide ire1/xbp1s activators |
TW202327590A (en) | 2021-11-30 | 2023-07-16 | 美商庫拉腫瘤技術股份有限公司 | Macrocyclic compounds and compositions, and methods of preparing and using the same |
WO2023129577A1 (en) | 2022-01-03 | 2023-07-06 | Lilac Therapeutics, Inc. | Cyclic thiol prodrugs |
WO2023150345A1 (en) * | 2022-02-04 | 2023-08-10 | Intact Therapeutics, Inc. | Mesalamine pharmaceutical formulations and methods of use thereof |
WO2023192817A1 (en) | 2022-03-28 | 2023-10-05 | Isosterix, Inc. | Inhibitors of the myst family of lysine acetyl transferases |
TW202342070A (en) | 2022-03-30 | 2023-11-01 | 美商拜奧馬林製藥公司 | Dystrophin exon skipping oligonucleotides |
GB2619907A (en) | 2022-04-01 | 2023-12-27 | Kanna Health Ltd | Novel crystalline salt forms of mesembrine |
US20230331693A1 (en) | 2022-04-14 | 2023-10-19 | Bristol-Myers Squibb Company | Gspt1 compounds and methods of use of the novel compounds |
WO2023201348A1 (en) | 2022-04-15 | 2023-10-19 | Celgene Corporation | Methods for predicting responsiveness of lymphoma to drug and methods for treating lymphoma |
WO2023211990A1 (en) | 2022-04-25 | 2023-11-02 | Siteone Therapeutics, Inc. | Bicyclic heterocyclic amide inhibitors of na v1.8 for the treatment of pain |
WO2023215781A1 (en) | 2022-05-05 | 2023-11-09 | Biomarin Pharmaceutical Inc. | Method of treating duchenne muscular dystrophy |
WO2024054832A1 (en) | 2022-09-09 | 2024-03-14 | Innovo Therapeutics, Inc. | CK1α AND DUAL CK1α / GSPT1 DEGRADING COMPOUNDS |
WO2024073473A1 (en) | 2022-09-30 | 2024-04-04 | Boulder Bioscience Llc | Compositions comprising 3,3'-diindolylmethane for treating non-hemorrhagic closed head injury |
Family Cites Families (122)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3164520A (en) * | 1962-10-29 | 1965-01-05 | Olin Mathieson | Injectable steroid compositions containing at least 75% benzyl benzoate |
US3510561A (en) * | 1965-05-20 | 1970-05-05 | Canada Packers Ltd | Sulfone-enhanced heparin absorption through mucous membranes |
US4147783A (en) * | 1974-02-28 | 1979-04-03 | Akzona Incorporated | Oral pharmaceutical preparation |
JPS5266616A (en) * | 1975-11-29 | 1977-06-02 | Sawai Seiyaku Kk | Manufacturing of solidified oily liquid substance |
FR2408345A1 (en) * | 1976-11-30 | 1979-06-08 | Besins Jean Louis | NEW COMPOSITION WITH ANTI-CONCEPTIONAL ACTION |
JPS53107408A (en) * | 1977-02-28 | 1978-09-19 | Yamanouchi Pharmaceut Co Ltd | Micellar preparation for rectal infusion |
JPS5770824A (en) * | 1980-10-20 | 1982-05-01 | Nippon Saafuakutanto Kogyo Kk | Vehicle for medicine |
US4439432A (en) * | 1982-03-22 | 1984-03-27 | Peat Raymond F | Treatment of progesterone deficiency and related conditions with a stable composition of progesterone and tocopherols |
US4654327A (en) * | 1982-04-21 | 1987-03-31 | Research Corp. | Quaternary ammonium complexes of heparin |
IL68769A (en) * | 1983-05-23 | 1986-02-28 | Hadassah Med Org | Pharmaceutical compositions containing insulin for oral administration |
US4731384A (en) * | 1983-07-01 | 1988-03-15 | Troponwerke Gmbh & Co, Kg | Etofenamate formulation |
US4832952A (en) * | 1983-07-07 | 1989-05-23 | American Home Products Corporation | Pharmaceutical composition containing a liquid lubricant |
DE3331009A1 (en) * | 1983-08-27 | 1985-03-14 | Basf Ag, 6700 Ludwigshafen | METHOD FOR INCREASING THE ENTERAL RESORBABILITY OF HEPARIN OR. HEPARINOIDS AND THE SO AVAILABLE HEPARIN OR HEPARINOID PREPARATION |
DE3406497A1 (en) * | 1984-02-23 | 1985-09-05 | Mueller Bernhard Willi Werner | HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION |
US4795327A (en) * | 1984-03-26 | 1989-01-03 | Forest Laboratories, Inc. | Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactants |
US4572915A (en) * | 1984-05-01 | 1986-02-25 | Bioglan Laboratories | Clear micellized solutions of fat soluble essential nutrients |
GB8414221D0 (en) | 1984-06-04 | 1984-07-11 | Sterwin Ag | Unit dosage form |
DE3421468A1 (en) * | 1984-06-08 | 1985-12-19 | Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim | LIPID NANOPELLETS AS A CARRIER SYSTEM FOR MEDICINAL PRODUCTS FOR PERORAL USE |
GB8903804D0 (en) * | 1989-02-20 | 1989-04-05 | Sandoz Ltd | Improvements in or relating to organic compounds |
US4897269A (en) * | 1984-09-24 | 1990-01-30 | Mezei Associates Limited | Administration of drugs with multiphase liposomal delivery system |
US4867984A (en) | 1984-11-06 | 1989-09-19 | Nagin K. Patel | Drug in bead form and process for preparing same |
DE3500103A1 (en) * | 1985-01-04 | 1986-07-10 | R.P. Scherer GmbH, 6930 Eberbach | PHARMACEUTICAL PREPARATION WITH AN INTENSIVE SOLUTION IN WATER AND DIGESTIVE JUICES |
FR2585246A1 (en) * | 1985-07-26 | 1987-01-30 | Cortial | PROCESS FOR OBTAINING SOLID PHARMACEUTICAL FORMS WITH PROLONGED RELEASE |
US4717596A (en) * | 1985-10-30 | 1988-01-05 | International Business Machines Corporation | Method for vacuum vapor deposition with improved mass flow control |
US5023108A (en) | 1986-01-13 | 1991-06-11 | Research Corporation | Aqueous dispersions of waxes and lipids for pharmaceutical coating |
US5433959A (en) * | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
CA1327010C (en) * | 1986-02-13 | 1994-02-15 | Tadashi Makino | Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production |
US4849227A (en) | 1986-03-21 | 1989-07-18 | Eurasiam Laboratories, Inc. | Pharmaceutical compositions |
ES2053549T3 (en) * | 1986-08-11 | 1994-08-01 | Innovata Biomed Ltd | A PROCESS FOR THE PREPARATION OF AN APPROPRIATE PHARMACEUTICAL FORMULATION FOR INHALATION. |
NL194638C (en) * | 1986-12-19 | 2002-10-04 | Novartis Ag | Hydrosol containing solid particles of a pharmaceutically active substance and pharmaceutical preparation containing this hydrosol. |
US4900734A (en) * | 1987-08-27 | 1990-02-13 | Maxson Wayne S | Novel pharmaceutical composition containing estradiol and progesterone for oral administration |
GB8730011D0 (en) * | 1987-12-23 | 1988-02-03 | Smithkline Dauelsberg | Pharmaceutical compositions |
FR2627696B1 (en) * | 1988-02-26 | 1991-09-13 | Fournier Innovation Synergie | NEW GALENIC FORM OF FENOFIBRATE |
DE3807895A1 (en) * | 1988-03-10 | 1989-09-21 | Knoll Ag | PRODUCTS CONTAINING A CALCIUM ANTAGONIST AND A LIPID DOWNER |
GB2222770B (en) * | 1988-09-16 | 1992-07-29 | Sandoz Ltd | Pharmaceutical compositions containing cyclosporins |
US4994439A (en) * | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
US5014656A (en) * | 1990-04-25 | 1991-05-14 | General Motors Corporation | Internal combustion engine having a permanent ground electrode and replaceable center electrode element |
US5091188A (en) * | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
US5091187A (en) * | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
US5298497A (en) * | 1990-05-15 | 1994-03-29 | E. R. Squibb & Sons, Inc. | Method for preventing onset of hypertension employing a cholesterol lowering drug |
DE69109297T2 (en) * | 1990-08-13 | 1995-11-09 | David W Yesair | MIXED LIPID-BICARBONATE-COLLOIDAL PARTICLES FOR THE DELIVERY OF MEDICINAL PRODUCTS AND CALORIES. |
US5300529A (en) * | 1991-02-12 | 1994-04-05 | Isp Investments Inc. | Stable, clear, efficacious aqueous microemulsion compositions containing a high loading of a water-insoluble, agriculturally active chemical |
US5403593A (en) * | 1991-03-04 | 1995-04-04 | Sandoz Ltd. | Melt granulated compositions for preparing sustained release dosage forms |
TW212139B (en) | 1991-04-15 | 1993-09-01 | Yamanouchi Pharma Co Ltd | |
US5223268A (en) | 1991-05-16 | 1993-06-29 | Sterling Drug, Inc. | Low solubility drug-coated bead compositions |
US5380535A (en) | 1991-05-28 | 1995-01-10 | Geyer; Robert P. | Chewable drug-delivery compositions and methods for preparing the same |
JPH0597672A (en) * | 1991-10-08 | 1993-04-20 | Terumo Corp | Amide derivative-containing solid preparation and its production |
ATE195075T1 (en) * | 1991-11-22 | 2000-08-15 | Procter & Gamble Pharma | DELAYED-RELEASE MEDICINAL PRODUCTS CONTAINING RISEDRONATE |
US5206219A (en) * | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
US5571533A (en) * | 1992-02-07 | 1996-11-05 | Recordati, S.A., Chemical And Pharmaceutical Company | Controlled-release mucoadhesive pharmaceutical composition for the oral administration of furosemide |
SE9200951D0 (en) * | 1992-03-27 | 1992-03-27 | Kabi Pharmacia Ab | PHARMACEUTICAL COMPOSITION CONTAINING A DEFINED LIPID SYSTEM |
GB9212511D0 (en) * | 1992-06-12 | 1992-07-22 | Cortecs Ltd | Pharmaceutical compositions |
PH30929A (en) | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
GB9300875D0 (en) * | 1993-01-18 | 1993-03-10 | Ucb Sa | Nanocapsule containing pharmaceutical compositions |
BE1006990A5 (en) * | 1993-04-22 | 1995-02-07 | Univ Gent | METHOD AND COMPOSITION TO MAKE AN ACTIVE INGREDIENT IN A solid dosage form. |
SE9302135D0 (en) * | 1993-06-18 | 1993-06-18 | Kabi Pharmacia Ab | NEW PHARMACEUTICAL COMPOSITION |
ES2068762B1 (en) * | 1993-07-21 | 1995-12-01 | Lipotec Sa | A NEW PHARMACEUTICAL PREPARATION TO IMPROVE THE BIOAVAILABILITY OF DRUGS OF DIFFICULT ABSORPTION AND PROCEDURE FOR THEIR OBTAINING. |
US6022852A (en) * | 1993-10-22 | 2000-02-08 | Hexal Ag | Pharmaceutical composition containing cyclosporin A |
ATE317397T1 (en) * | 1993-11-17 | 2006-02-15 | Athena Neurosciences Inc | TRANSPARENT LIQUID FOR ADMINISTRATION OF ENCAPSULATED MEDICATIONS |
DE4340781C3 (en) * | 1993-11-30 | 2000-01-27 | Novartis Ag | Liquid preparations containing cyclosporin and process for their preparation |
KR0146671B1 (en) * | 1994-02-25 | 1998-08-17 | 김충환 | Cyclosporin-containing powder composition |
US5811120A (en) | 1994-03-02 | 1998-09-22 | Eli Lilly And Company | Solid orally administerable raloxifene hydrochloride pharmaceutical formulation |
GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
US5731356A (en) * | 1994-03-22 | 1998-03-24 | Zeneca Limited | Pharmaceutical compositions of propofol and edetate |
GB9409778D0 (en) * | 1994-05-16 | 1994-07-06 | Dumex Ltd As | Compositions |
US6692766B1 (en) * | 1994-06-15 | 2004-02-17 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Controlled release oral drug delivery system |
US5616330A (en) * | 1994-07-19 | 1997-04-01 | Hemagen/Pfc | Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same |
US5858398A (en) * | 1994-11-03 | 1999-01-12 | Isomed Inc. | Microparticular pharmaceutical compositions |
US5629021A (en) * | 1995-01-31 | 1997-05-13 | Novavax, Inc. | Micellar nanoparticles |
FR2730231B1 (en) * | 1995-02-02 | 1997-04-04 | Fournier Sca Lab | COMBINATION OF FENOFIBRATE AND VITAMIN E, USE IN THERAPEUTICS |
US5573783A (en) | 1995-02-13 | 1996-11-12 | Nano Systems L.L.C. | Redispersible nanoparticulate film matrices with protective overcoats |
SI9500173B (en) * | 1995-05-19 | 2002-02-28 | Lek, | Three-phase pharmaceutical form with constant and controlled release of amorphous active ingredient for single daily application |
US5726181A (en) * | 1995-06-05 | 1998-03-10 | Bionumerik Pharmaceuticals, Inc. | Formulations and compositions of poorly water soluble camptothecin derivatives |
DE19527661C2 (en) * | 1995-07-28 | 1998-02-19 | Optrex Europ Gmbh | Carrier comprising electrical conductors with an electronic component and method for contacting conductors of a substrate with contact warts of an electronic component |
US6645988B2 (en) * | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
US5858401A (en) * | 1996-01-22 | 1999-01-12 | Sidmak Laboratories, Inc. | Pharmaceutical composition for cyclosporines |
DE19619045C1 (en) * | 1996-05-02 | 1997-11-13 | Jenapharm Gmbh | Use of combination products for the treatment of hypogonadal men and men with pituitary disorders |
EP0914100A1 (en) * | 1996-06-28 | 1999-05-12 | Schering Corporation | Oral composition comprising a triazole antifungal compound |
US5846971A (en) | 1996-06-28 | 1998-12-08 | Schering Corporation | Oral antifungal composition |
US5883109A (en) * | 1996-07-24 | 1999-03-16 | Bristol-Myers Squibb Company | Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drug |
SE9603077D0 (en) * | 1996-08-29 | 1996-08-29 | Tetra Laval Holdings & Finance | An apparatus for and method of performing an animal-related action regarding at least a portion of the body of an animal |
US5891469A (en) | 1997-04-02 | 1999-04-06 | Pharmos Corporation | Solid Coprecipitates for enhanced bioavailability of lipophilic substances |
US6361796B1 (en) * | 1996-10-25 | 2002-03-26 | Shire Laboratories, Inc. | Soluble form osmotic dose delivery system |
FR2758459B1 (en) * | 1997-01-17 | 1999-05-07 | Pharma Pass | FENOFIBRATE PHARMACEUTICAL COMPOSITION HAVING HIGH BIODAVAILABILITY AND PROCESS FOR PREPARING THE SAME |
GB9700878D0 (en) * | 1997-01-17 | 1997-03-05 | Scherer Ltd R P | Dosage forms and method for ameliorating male erectile dysfunction |
WO1998038984A2 (en) * | 1997-03-05 | 1998-09-11 | Sugen, Inc. | Formulations for hydrophobic pharmaceutical agents |
US5874418A (en) * | 1997-05-05 | 1999-02-23 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use |
US6046177A (en) * | 1997-05-05 | 2000-04-04 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations |
US6531139B1 (en) * | 1997-07-29 | 2003-03-11 | Pharmacia & Upjohn Company | Self-emulsifying formulation for lipophilic compounds |
IT1294760B1 (en) * | 1997-09-03 | 1999-04-12 | Jagotec Ag | PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL TABLETS ABLE TO RELEASE, ACCORDING TO PREDETERMINABLE SCHEMES, LITTLE ACTIVE INGREDIENTS |
US20020013304A1 (en) * | 1997-10-28 | 2002-01-31 | Wilson Leland F. | As-needed administration of an androgenic agent to enhance female sexual desire and responsiveness |
US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
US5891845A (en) * | 1997-11-21 | 1999-04-06 | Fuisz Technologies Ltd. | Drug delivery systems utilizing liquid crystal structures |
US6013665A (en) * | 1997-12-16 | 2000-01-11 | Abbott Laboratories | Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides |
ID25908A (en) * | 1998-03-06 | 2000-11-09 | Novartis Ag | EMULSION PRACTONCENTRATES CONTAINING CYCLOSPORINE OR MACROLIDES |
DK173431B1 (en) * | 1998-03-20 | 2000-10-23 | Gea Farmaceutisk Fabrik As | Pharmaceutical formulation comprising a 2 - [[(2-pyridinyl) methyl] sulfinyl] benzimidazole with anti-ulcer activity and progress |
ES2157731B1 (en) * | 1998-07-21 | 2002-05-01 | Liconsa Liberacion Controlada | ORAL PHARMACEUTICAL PREPARATION OF AN ANTIFUNGIC ACTIVITY COMPOUND AND PROCEDURE FOR PREPARATION. |
US6174547B1 (en) * | 1999-07-14 | 2001-01-16 | Alza Corporation | Dosage form comprising liquid formulation |
US5993880A (en) * | 1998-10-01 | 1999-11-30 | Kraft Foods Inc. | Non-staining, acid-stable, cold-water-soluble, edible green color and compositions for preparing acidic foods and beverages |
US6383517B1 (en) * | 1999-01-29 | 2002-05-07 | Abbott Laboratories | Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption |
US6180138B1 (en) * | 1999-01-29 | 2001-01-30 | Abbott Laboratories | Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption |
US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US7374779B2 (en) * | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
US6982281B1 (en) * | 2000-11-17 | 2006-01-03 | Lipocine Inc | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
US6720001B2 (en) * | 1999-10-18 | 2004-04-13 | Lipocine, Inc. | Emulsion compositions for polyfunctional active ingredients |
US20060034937A1 (en) * | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
ATE297194T1 (en) * | 1999-12-16 | 2005-06-15 | Medinfar Produtos Farmaceutico | NEW STABLE MULTI-UNIT SUBSTITUTED PHARMACEUTICAL PREPARATIONS CONTAINING BENZIMIDAZOLES |
AU782469B2 (en) * | 1999-12-23 | 2005-08-04 | Mayne Pharma International Pty Ltd | Improved pharmaceutical compositions for poorly soluble drugs |
AP2002002552A0 (en) * | 1999-12-23 | 2002-06-30 | Pfizer Prod Inc | Pharmaceutical compositions providing enhanced drug concentrations. |
US6340471B1 (en) * | 1999-12-30 | 2002-01-22 | Alvin Kershman | Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals |
US20020102301A1 (en) * | 2000-01-13 | 2002-08-01 | Joseph Schwarz | Pharmaceutical solid self-emulsifying composition for sustained delivery of biologically active compounds and the process for preparation thereof |
US7025979B2 (en) * | 2000-02-15 | 2006-04-11 | Schering Ag | Male contraceptive formulation comprising norethisterone |
US6503894B1 (en) * | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
US20030022875A1 (en) * | 2001-07-27 | 2003-01-30 | Wilson Leland F. | As-needed administration of orally active androgenic agents to enhance female sexual desire and responsiveness |
US20040002445A1 (en) * | 2002-03-28 | 2004-01-01 | Rajneesh Taneja | Enhancement of endogenous gonadotropin production |
ATE540671T1 (en) * | 2003-08-04 | 2012-01-15 | Bend Res Inc | PHARMACEUTICAL COMPOSITIONS OF AMORPHOUS DRUG ADSORBATES AND LIPOPHILIC MICROPHASE-FORMING MATERIALS |
US20050080075A1 (en) * | 2003-08-25 | 2005-04-14 | Nichols M. James | Formulations, conjugates, and combinations of drugs for the treatment of neoplasms |
KR20060085686A (en) * | 2003-10-10 | 2006-07-27 | 라이프사이클 파마 에이/에스 | A solid dosage form comprising a fibrate |
US20060003002A1 (en) * | 2003-11-03 | 2006-01-05 | Lipocine, Inc. | Pharmaceutical compositions with synchronized solubilizer release |
US20060051406A1 (en) * | 2004-07-23 | 2006-03-09 | Manjeet Parmar | Formulation of insoluble small molecule therapeutics in lipid-based carriers |
US20060134210A1 (en) * | 2004-12-22 | 2006-06-22 | Astrazeneca Ab | Solid dosage form comprising proton pump inhibitor and suspension made thereof |
GB0807605D0 (en) * | 2008-04-28 | 2008-06-04 | Diurnal Ltd | Lipid composition |
-
1999
- 1999-11-23 US US09/447,690 patent/US6248363B1/en not_active Expired - Lifetime
-
2000
- 2000-11-22 AU AU17981/01A patent/AU1798101A/en not_active Abandoned
- 2000-11-22 CA CA2706113A patent/CA2706113A1/en not_active Abandoned
- 2000-11-22 CA CA2391923A patent/CA2391923C/en not_active Expired - Lifetime
- 2000-11-22 JP JP2001539423A patent/JP2003517470A/en active Pending
- 2000-11-22 WO PCT/US2000/032255 patent/WO2001037808A1/en active Application Filing
- 2000-11-22 EP EP00980761A patent/EP1233756A4/en not_active Ceased
-
2001
- 2001-03-06 US US09/800,593 patent/US6569463B2/en not_active Expired - Lifetime
-
2003
- 2003-05-01 US US10/428,341 patent/US6923988B2/en not_active Expired - Lifetime
-
2008
- 2008-12-02 US US12/326,711 patent/US20090074859A1/en not_active Abandoned
-
2012
- 2012-02-14 JP JP2012029635A patent/JP2012116863A/en active Pending
-
2014
- 2014-08-14 US US14/460,188 patent/US20150224130A9/en not_active Abandoned
-
2015
- 2015-05-15 US US14/713,692 patent/US20150273067A1/en not_active Abandoned
-
2017
- 2017-06-16 US US15/625,764 patent/US20180125978A1/en not_active Abandoned
-
2019
- 2019-02-28 US US16/289,565 patent/US20200061191A1/en not_active Abandoned
-
2020
- 2020-06-30 US US16/917,731 patent/US20210008212A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US6923988B2 (en) | 2005-08-02 |
JP2012116863A (en) | 2012-06-21 |
US6248363B1 (en) | 2001-06-19 |
AU1798101A (en) | 2001-06-04 |
US20180125978A1 (en) | 2018-05-10 |
EP1233756A4 (en) | 2007-12-26 |
US6569463B2 (en) | 2003-05-27 |
EP1233756A1 (en) | 2002-08-28 |
US20200061191A1 (en) | 2020-02-27 |
US20140357586A1 (en) | 2014-12-04 |
CA2391923C (en) | 2011-05-17 |
WO2001037808A1 (en) | 2001-05-31 |
CA2391923A1 (en) | 2001-05-31 |
US20210008212A1 (en) | 2021-01-14 |
US20030215496A1 (en) | 2003-11-20 |
US20090074859A1 (en) | 2009-03-19 |
US20030064097A1 (en) | 2003-04-03 |
US20150273067A1 (en) | 2015-10-01 |
US20150224130A9 (en) | 2015-08-13 |
JP2003517470A (en) | 2003-05-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210008212A1 (en) | Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions | |
US20060034937A1 (en) | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions | |
US7374779B2 (en) | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents | |
US20030180352A1 (en) | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions | |
US11052096B2 (en) | Steroidal compositions | |
US6267985B1 (en) | Clear oil-containing pharmaceutical compositions | |
AU2010203457B2 (en) | Steroidal compositions | |
US20030104048A1 (en) | Pharmaceutical dosage forms for highly hydrophilic materials | |
AU6083800A (en) | Compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Discontinued |
Effective date: 20131205 |