WO2012101242A1 - Novel pharmaceutical suspension for parenteral application - Google Patents
Novel pharmaceutical suspension for parenteral application Download PDFInfo
- Publication number
- WO2012101242A1 WO2012101242A1 PCT/EP2012/051288 EP2012051288W WO2012101242A1 WO 2012101242 A1 WO2012101242 A1 WO 2012101242A1 EP 2012051288 W EP2012051288 W EP 2012051288W WO 2012101242 A1 WO2012101242 A1 WO 2012101242A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drugs
- injectable pharmaceutical
- suspension
- pharmaceutical suspension
- eudragit
- Prior art date
Links
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- 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
- A61K9/5089—Processes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an injectable pharmaceutical suspension comprising a polyelectrolyte and a nanoparticular, poorly soluble pharmaceutically active compound, wherein said polyelectrolyte comprises a methacrylate polymer. Furthermore, the present invention relates to a method for stabilizing a poorly soluble active pharmaceutical compound in an injectable pharmaceutical suspension comprising the steps of: a) suspending in a liquid dispersion medium a poorly soluble pharmaceutically active compound without the presence of a detergent, b) mechanically treating said suspension to obtain particles comprising the active compound with an effective average size of less than about 5000 nm, preferably less than about 4000 nm, more preferably less than about 3000 nm, even more preferably less than about 1000 nm and most preferably less than about 800 nm, c) contacting said active compound or suspension with a methacrylate polymer or with a polyelectrolyte complex comprising a methacrylate polymer during and/or before mechanically treating. The present invention also relates to the injectable pharmaceutical suspension according to the invention for use of the in the treatment of a disease.
Description
Novel pharmaceutical suspension for parenteral application
Technical field of the Invention
The present invention is in the field of drug formulation. In particular the present invention relates to improved nanoparticulate suspensions of poorly soluble compounds and nanoparticulate pharmaceutical compositions. More particularly the present invention relates to injectable nanoparticular suspensions of poorly soluble compounds comprising a methacrylate polymer.
Background of the Invention
The application of drugs with a poor solubility in water is a general problem in pharmaceutics. Poor solubility, inter alia, leads to poor bioavailability of these drugs. In general, bioavailability of active compounds can be improved by increasing particle surfaces, e.g. by the provision of small particles of these active compounds (i.e. micro- or nanoparticulate pharmaceutical compositions). Another problem is the stabilization of pharmaceutical compositions. Solubility and stability of pharmaceutical compositions is often mediated by the addition of additives such as surfactants (detergents). A method for reducing the particle size and encapsulating nanoparticulate compounds using polyelectrolytes is disclosed in EP-Al 2 172 193. Furthermore, for parenteral application of the poorly soluble drugs it is necessary to provide a suspension with high viscosity to facilitate application through even small needle of a syringe, e.g. a 28 gauge needle. Another problem is the provision of the pharmaceutically active compound in a high concentration while providing a suspension viscose enough for application with small needles.
The inventors interestingly found that the provision of an injectable pharmaceutical suspension according to the present invention overcomes these problems. The inventors especially found that the use of methacrylate polymers allows the provision of a stable, injectable and highly concentrated pharmaceutical suspension. Furthermore, the injectable pharmaceutical suspensions according to the present inventions exhibit a high bioavailability
of the pharmaceutically active compound after injection and moreover serve as a depot, resulting in a release of the drug over a longer period after single administration.
Summary of the Invention
The inventors unexpectedly found that encapsulating a nanoparticular, poorly soluble pharmaceutically active compound (API) with a polyelectrolyte comprising a methacrylate polymer allows providing a suspension with a high concentration of the API while being easily injectable with small syringe. Hence, the present invention relates to an injectable pharmaceutical suspension comprising a polyelectrolyte and a nanoparticular, poorly soluble pharmaceutically active compound, wherein said polyelectrolyte comprises a methacrylate polymer.
Methods for encapsulating nanoparticular, poorly soluble pharmaceutical compounds are disclosed in EP-A1 2 172 193. However, the inventors unexpectedly found that encapsulating nanoparticular, poorly soluble pharmaceutically active compounds with a methacrylate polymer leads to a greatly increased stabilisation of the suspension. Hence, the present invention further relates to a method for stabilizing a poorly soluble active pharmaceutical compound in a n injectable anoparticulate pharmaceutical suspension comprising the steps of: a) suspending in a liquid dispersion medium a poorly soluble pharmaceutically active compound without the presence of a detergent,
b) mechanically treating said suspension to obtain particles comprising the active compound with an effective average size of less than about 5000 nm, preferably less than about 4000 nm, more preferably less than about 3000 nm, even more preferably less than about 1000 nm and most preferably less than about 800 nm,
c) contacting said active compound or suspension with a methacrylate polymer or with a polyelectrolyte complex comprising a methacrylate polymer during and/or before mechanically treating.
However, the inventors also found that the provision of the poorly soluble pharmaceutically
active compound as a dry powder and contacting it with a liquid solution comprising the methacrylate polymer before the mechanical treatment. Hence, in a further embodiment the present invention relates to a method for stabilizing a poorly soluble active pharmaceutical compound in a injectable nanoparticulate pharmaceutical suspension comprising the steps of:
a) contacting the poorly soluble pharmaceutically active compound with a solution of methacrylate polymer without the presence of a detergent;
b) mechanically treating the mixture to obtain particles comprising the active compound with an effective average size of less than about 5000 nm, preferably less than about 4000 nm, more preferably less than about 3000 nm, even more preferably less than about 1000 nm and most preferably less than about 800 nm, and optionally c) contacting said active compound or suspension with a methacrylate polymer or with one or more further polyelectrolytes during, before and/or after mechanically treating;
The present invention also relates to a method for stabilizing two or more poorly soluble pharmaceutically active in an injectable pharmaceutical suspension comprising the steps of: a) contacting two or more poorly soluble pharmaceutically active compound with a solution of methacrylate polymer without the presence of a detergent;
b) mechanically treating the mixture to obtain particles comprising the active compound with an effective average size of less than about 5000 nm, preferably less than about 4000 nm, more preferably less than about 3000 nm, even more preferably less than about 1000 nm and most preferably less than about 800 nm, and optionally c) contacting said active compound or suspension with a methacrylate polymer or with one or more further polyelectrolytes during, before and/or after mechanically treating.
Also encompassed herein is an injectable pharmaceutical suspension according to the present invention derivable by a method according to the present invention as disclosed herein.
Furthermore the present invention relates to an injectable pharmaceutical suspension according to the present invention, for use in the treatment of a disease in a subject, wherein the composition is provided in a form to be administered parenterally to said subject.
The present invention also relates to a dosage form comprising an injectable pharmaceutical suspension according to the present invention.
Furthermore, the present invention relates to a method of treating comprising the parenteral application of an injectable pharmaceutical suspension according to the present invention.
Detailed Description of the Invention
"Injectable" in the context with the present invention means that the suspension can be easily handled and applied using syringes and needles. The skilled artisan is aware of the properties such a suspension has to have. He knows that the suspension has to be of a viscosity that allows application event through thin needles, e.g. a 28 gauge needle. Even nanosuspensions with 10% solid content are of a viscosity similar to water and therefore i.v. injectable. Viscosities range from 1-20 mPas for very low viscous systems, up to 100 mPas for nanosuspensions with similar viscosity to injectable oils. For nanosuspensions with viscosities above 100 mPas to 1.000 mPas the viscosity goes to more cream-like flow behaviour. For such systems larger bore injection needles have to be used. This is no problem, because with injection needles with diameter 1 mm and more even solids can be injected, e.g. implants such as the commercial injectable implant Zoladex (injectable rod, about 1 mm in diameter, company Zeneca). Therefore even nanosuspensions of high viscosity of > 1.000 mPas to 30,000 mPas are injectable. In a preferred embodiment of the present invention the injectable pharmaceutical suspension has a viscosity of 1 to 30,000 mPas, preferably of 1 to 1,000 mPas, more preferably 1 to 100 mPas, even more preferably 1 to 20 mPa s. Since the suspension is to be applied parenterally, the skilled artisan will recognize that the suspension also has to possess properties that allow the direct application into the animal or human body. Theses properties may vary for different routes of application, e.g. intravenous or intramuscular application. Among these properties the pH
and osmolarity are relevant, they are preferably physiological. In one embodiment of the present invention the injectable pharmaceutical suspension has a pH between 5 and 9, preferably between 6 and 8, more preferably between 7,0 and 7,5. The osmolarity of the injectable pharmaceutical suspension according to the present invention is in one embodiment isotonic, preferably 308 mosmol/1.
The average size of the particles is preferably less than about 5000 nm, more preferably less than about 3000 nm, even more preferably less than about 1000 nm, most preferably less than about 800 nm.
The average size of the particles is measured by the following procedure: Photon Correlation Spectroscopy (PCS) for expected average sizes below 3 μπι, or by Laser Diffractometry (LD) for expected larger particle sizes. A polyelectrolyte according to the present invention is a polymer whose repeating units bear an electrolyte group. These groups will dissociate in aqueous solutions, making the polymers charged. Methacrylate polymers are examples of such polyelectrolytes.
"Methacrylate polymer" in the context with the present invention is a polymer comprising a methacrylate and/or methacrylate derivative as a repeating unit. The polymer may be a homopolymer or copolymer. Preferred methacrylate polymers in context of the present invention are selected from the group of poly-(methyl methacrylate), poly-(methyl acrylate), poly-(methacylic acid-co-methyl methacrylate), poly-(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate), and poly-(dimethylaminoethyl methacrylate. In a preferred embodiment of the present invention the methacrylate polymer is Eudragit, preferably selected from the group comprising Eudragit L 100-55®, Eudragit L- 100®, Eudragit S-100®, Eudragit E-100®, and Eudragit E PO®.
The poorly soluble pharmaceutically active compound has preferably a solubility in the liquid dispersion medium, e.g. in water of less than 10 g/L, preferably 1 g/L, more preferably less than about 250 mg/L, most preferably less than 100 mg/L at processing temperature,
e.g. room temperature. The preferred liquid dispersion medium is water; however other liquid media in which the active compound is poorly soluble and dispersible including aqueous salt solutions or aqueous mixtures of solvents such as ethanol, benzyl alcohol, dimethyl sulfoxide, chlorobutanol, glycerin, thioglycerol and polyethylene glycol, preferably ethanol.The pH of the aqueous dispersion media can be adjusted by techniques known in the art.
In another preferred embodiment of the present invention the poorly soluble active compound is a poorly soluble drug according to groups II or IV of the Biopharmaceutics Classification System (BCS) (FDA). In a preferred embodiment of the present invention the nanoparticular, poorly soluble, pharmaceutically active compound is selected from the group consisting of:
Atorvastatin, Amiodarone, Candesartan-Cilexetil, Carvedilol, Clopidogrel bisulfate, Dipyridamole, Eprosartan mesylate, Epierenone, Ezetimibe, Felodipine, Furosemide, Isradipine, Lovastatin, Metolazone, Nicardipine, Nisoldipine Olmesartan medoxomil, Propafenone HC1, Qinapril, Ramipril, Simvastatin, Telmisartan, Trandolapril, Valsartan and other cardio-vascular active drugs;
Cisplatin, Carboplatin, Paclitaxel, Docetaxel, Vincristine, Etoposide and other antineoplastic compounds used to treat cancer;
Acyclovir, Adefovir, Dipivoxil, Amphotericin, Amprenavir, Cefixime, Ceftazidime, Clarithromycin, Clotrimazole, Efavirenz, Ganciclovir, Itraconazole, Norfloxacin, Nystatin, Ritonavir, Saquinavir, Monepantel, Doramectin and other anti-infective drugs including anti-bacterial, anti fungal and anti-parasitic drugs;
Cisplatin, Docetaxel, Etoposide, Exemestane, Idarubicin, Irinotecan, Melphalan, Mercaptopurine, Mitotane, Paclitaxel, Valrubicin and other drugs used in oncology; Azathioprine, Tacrolimus, Cyclosporine, Pimecrolimus, Sirolimus and other immonosupressive drugs;
Clozapine, Entacapone, Fluphenazine, Imipramine, Nefazodone, Olanzapine, Paroxetine, Pimozide, Sertraline, Triazolam, Zaleplon, Ziprasidoneand, Risperidone, Carbamazepine and other drugs for CNS indications;
Danazol, Dutasteride, Medroxyprogesterone, Estradiol, Raloxifene, Sildenafil,
Tadalafil, Testosterone, Vardenafil and other drugs used for reproductive health; Celecoxib, Dihydroergotamine Mesylate, Eletriptan, Ergoloidmesylates, Ergotamine- tartrate, Nabumetone, Ibuprofen, Ketoprofen, Triamcinolone, Triamcinolone acetonide and other anti-inflammatory and analgesic drugs;
Bosentan, Budesonide, Desloratadine, Fexofenadin, Fluticasone, Loratadine, Mometasone, Salmeterol Xinafoate, Triamcinolon Acetonide, Zafirlukast and other drugs for respiratory indications; and
Dronabinol, Famotidine, Glyburide, Hyoscyamine, Isotretinoin, Megestrol, Mesalamine, Modafmil, Mosapride, Nimodipine, Perphenazine, Propofol, Sucralfate, Thalidomide, Trizanidine hydrochloride and other drugs for various indications including in particular gastro-intestinal disorders, diabetes and dermatology indications.
In one embodiment the injectable pharmaceutical suspension may comprise a solubilizer selected from the group consisting of polyvinyl pyrrolidone, polyethylene glycol, polypropylen glycol, polyethylene glycol 660 hydroxystearate, polysorbat, benzyl alcohol, ethanol, polyvinyl alcohol, Lipoid, ethyl oleate, transcutol, glycofurol, miglyol. However, in a preferred embodiment of the injectable pharmaceutical suspension solublizers are absent. In one embodiment the injectable pharmaceutical suspension may comprise additional compounds to confer desired properties to the suspension, e.g. the desired osmolality. Hence, in one embodiment the suspension further comprises excipients selected from the group comprising NaCl. In one embodiment of the present invention the injectable pharmaceutical suspension comprises a second or further polyelectrolyte(s) in addition to the methacrylate polymer. In one embodiment of the present invention the second or further polyelectrolyte(s) are selected for the group consisting of water-soluble cationic or anionic polysaccharides, peptides, proteins, nucleic acids and corresponding salts thereof, xylan polysulfates, dextran sulfates, poly(amino acids) such as polyaspartic acid, poly-arginine, poly-lysine or polyglutamic acid, polysaccharide polysulfates such as sulfates of starch hydrolysates, inulin, hydroxyethylstarches, polysaccharide polysulfonates, polysaccharide polyphosphates, polyphosphates, methacrylate polymers, Eudragits, Eudragit L 100-55®, Eudragit L-100® and Eudragit S-100®, Eudragit E-100®, Eudragit E PO®, protamine,
albumins, casein, gelatine, collagen, oligonucleotides, polymethacrylate, polyacrylic acid, chitosan, pectin, carboxymethylcellulose, alginate, carrageenan, hyaluronic acid, chondroitin sulfate, dextrane sulphate, heparine, poly-a,P-(2-dimethylaminoethyl)-D,L-aspartamide, chitosan, lysine octadecyl ester, aminated dextrans, aminated cyclodextrins, aminated cellulose ethers, aminated pectins, polystyrenesulfonate and corresponding salts thereof and in each case partially hydrophobized derivatives of xylan polysulfate, polysulfates of other polysaccharides such as, for example, starch hydrolysates, inulin, hydroxyethylstarches, dextrans; of poly(amino acids) such as polyaspartic acid or polyglutamic acid, and of polysaccharide polysulfonates, polysaccharide polyphosphonates, polyphosphates, albumins (like human serum albumin (HSA) or bovine serum albumin (BSA)). In one embodiment the second polyelectrolyte is oppositely charged to the methacrylate polymer, i.e. since methyl acrylic acid compounds are polyanions, the second polyelectrolyte is a polycation and vice versa. In one embodiment, when two or more further polyelectrolytes are used, it is preferred that the third (and if applicable the other odd-numbered polyelectrolytes) polyelectrolyte have the same charge as the methacrylate polymer, i.e. they are polyanions, and the second (and if applicable the other even-numbered polyelectrolytes) have opposite charges as compared to the methacrylate polymer. In one preferred embodiment, the suspension is contacted with a second polyelectrolyte and no further polyelectrolytes. In a preferred embodiment the second polyelectrolyte is a further methacrylate polymer. In an also preferred embodiment the second polyelectrolyte is human serum albumin (HSA) or bovine serum albumin (BSA). Furthermore, in one embodiment of the present invention the methacrylate polymer is Eudragit S and the second polyelectrolyte is Eudragit E. In another preferred embodiment, the methacrylate polymer is Eudragit E and the second polyelectrolyte is Eudragit S. In another preferred embodiment the first polyelectrolyte is Eudragit S and the second polyelectrolyte is Eudragit E. In an also preferred embodiment the methacrylate polymer is Eudragit and the second polyelectrolyte is bovine serum albumin (BSA). In yet another preferred embodiment the methacrylate polymer is Eudragit.
The methacrylate polymer and/or the second or further polyelectrolytes according to the present invention in the methods for stabilizing may be provided in a solution. In a preferred embodiment methacrylate polymer has a concentration in the solution of between 5% and 0,5%, preferably between 5% and 2,5%.
It will be readily understood that the solution comprising methacrylate polymer or polyelectrolyte is liquid. In a preferred embodiment the solution is an aqueous solution, optionally comprising excipients or solubilizers. In one embodiment the aqueous solution further comprises Lipoid. In another embodiment the aqueous solution comprises NaCl, preferably in a concentration of 0,2M.
In one embodiment of according to the present invention the method for stabilizing a poorly soluble active pharmaceutical compound comprises the step of: contacting said suspension with a one or more further polyelectrolytes during, before and/or after mechanically treating. It might be desireable to dilute the suspension obtained by the method according to the present invention, due to the high concentrations of pharmaceutically active compounds in the suspension obtainable by using the method according to the present invention. Hence, in one embodiment of the present invention, the method for stabilizing a poorly soluble active pharmaceutical compound comprises the step of diluting the suspension to the desired concentration.
A typical wet mill configuration involves slurry circulated through a high shear mixer (ULTRA-TURRAX® and Mills from IKA® Werke GmbH&Co.KG), or using beads or basket mills (DISPERMAT® and TOROUSMILL® from VMA-Getzmann GmbH), or planetary micro mills (PULVERISETTE 7, 6, 5, 4, 0, Classic Line/Premium Line from Fritsch GmbH) at rotation speeds of up to 1100 rpm. In preferred embodiments 2.5 mm zirconium oxide milling beads, 2.0 mm zirconium oxide milling beads, 1.8 mm zirconium oxide milling beads, 1.5 mm zirconium oxide milling beads and/or 0.5 mm zirconium oxide milling beads are used (diameters of the beads). Preferably, milling beads with a diameter of from about 1.5 mm to about 1.8 mm are used. During milling, the beads may be exchanged, for instance when adding the further (e.g. second) polyelectrolyte the beads are changed from 2.5 to 0.5 mm zirconium beads. In another preferred embodiment, the milling beads are not exchanged during the milling process. Milling times may be varied. Preferred milling times are for example 10, 20, 30, 40, 50 or 60 minutes independently for each milling step.
Preferably the method according to the present invention is carried out without any
intermediate washing steps. In a preferred embodiment of the method for the production of a nanoparticulate pharmaceutical composition according to the present invention, the method comprises a dilution step at the end of the process to obtain the formed injectable pharmaceutical suspension.
In a preferred method according to the present invention, step a) suspending a poorly soluble active compound is carried out without the presence of a detergent.
In a preferred embodiment of the method according to the invention the method is carried out without a detergent selected from the group comprising soaps, fatty acid salts, sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl sulfate salts, sodium lauryl sulfate, sodium laureth sulfate (also known as sodium lauryl ether sulfate (SLES)), Alkyl benzene sulfonate, cetyl trimethylammonium bromide (CTAB) also known as (a.k.a.) hexadecyl trimethyl ammonium bromide, and other alkyltrimethylammonium salts, cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzethonium chloride (BZT), dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine, coco ampho glycinate, alkyl polyglucosides, including: octyl glucoside, decyl maltoside and cocamide MEA, cocamide DEA. In another preferred embodiment of the invention mechanically treating is selected from the group comprising wet milling, high-shear mixing and high-pressure homogenization. Most preferred is wet milling as mechanically treating. According to the invention several improvements may be applied to the milling process as outlined in the following. The skilled artisan knows that the hydrodynamics during milling can be influenced by the addition of methacrylate polymer, improving the yield of milling and thus the control of the particle size. The inventors now unexpectedly found that the addition of a methacrylate polymer greatly improves the hydrodynamics and allows the provision of injectable suspension with a high concentration of the nanoparticular, poorly soluble pharmaceutically active compound. The methacrylate polymer or methacrylate polymer and a second or further polyelectrolyte(s) may serve as additional nanoparticulate abrasive agents during milling. The presence of methacrylate polymer or methacrylate polymer and a second or
further polyelectrolyte(s) during the milling process may lead to transitional coating of the grist, the walls of the mill and the grinding balls, respectively, thereby improving the grinding process and the milling results. The methacrylate polymer and/or the second or further polyelectrolyte(s) also serve as lubricants during milling resulting in a reduction of abrasion of the milling equipment and a decrease in contamination of the grist.
In one embodiment of the present invention more than one nanoparticular, poorly soluble, pharmaceutically active compound is present in the injectable pharmaceutical suspension. In a preferred embodiment of the present invention the injectable pharmaceutical suspension comprises two or more nanoparticular, poorly soluble, pharmaceutically active compound. Hence, in one embodiment of the present invention the injectable pharmaceutical suspension comprises a second nanoparticular, poorly soluble, pharmaceutically active compound. In one embodiment of the present invention the second nanoparticular, poorly soluble, pharmaceutically active compound is selected from the group consisting of:
Atorvastatin, Amiodarone, Candesartan-Cilexetil, Carvedilol, Clopidogrel bisulfate, Dipyridamole, Eprosartan mesylate, Epierenone, Ezetimibe, Felodipine, Furosemide, Isradipine, Lovastatin, Metolazone, Nicardipine, Nisoldipine Olmesartan medoxomil, Propafenone HC1, Qinapril, Ramipril, Simvastatin, Telmisartan, Trandolapril, Valsartan and other cardio-vascular active drugs;
Cisplatin, Carboplatin, Paclitaxel, Docetaxel, Vincristine, Etoposide and other antineoplastic compounds used to treat cancer;
Acyclovir, Adefovir, Dipivoxil, Amphotericin, Amprenavir, Cefixime, Ceftazidime, Clarithromycin, Clotrimazole, Efavirenz, Ganciclovir, Itraconazole, Norfloxacin, Nystatin, Ritonavir, Saquinavir, Monepantel, Doramectin and other anti-infective drugs including anti-bacterial, anti fungal and anti-parasitic drugs;
Cisplatin, Docetaxel, Etoposide, Exemestane, Idarubicin, Irinotecan, Melphalan, Mercaptopurine, Mitotane, Paclitaxel, Valrubicin and other drugs used in oncology; Azathioprine, Tacrolimus, Cyclosporine, Pimecrolimus, Sirolimus and other immonosupressive drugs;
Clozapine, Entacapone, Fluphenazine, Imipramine, Nefazodone, Olanzapine, Paroxetine, Pimozide, Sertraline, Triazolam, Zaleplon, Ziprasidoneand, Risperidone,
Carbamazepine and other drugs for CNS indications;
Danazol, Dutasteride, Medroxyprogesterone, Estradiol, Raloxifene, Sildenafil, Tadalafil, Testosterone, Vardenafil and other drugs used for reproductive health; Celecoxib, Dihydroergotamine Mesylate, Eletriptan, Ergoloidmesylates, Ergotamine- tartrate, Nabumetone, Ibuprofen, Ketoprofen, Triamcinolone, Triamcinolone acetonide and other anti-inflammatory and analgesic drugs;
Bosentan, Budesonide, Desloratadine, Fexofenadin, Fluticasone, Loratadine, Mometasone, Salmeterol Xinafoate, Triamcinolon Acetonide, Zafirlukast and other drugs for respiratory indications; and
- Dronabinol, Famotidine, Glyburide, Hyoscyamine, Isotretinoin, Megestrol, Mesalamine, Modafinil, Mosapride, Nimodipine, Perphenazine, Propofol, Sucralfate, Thalidomide, Trizanidine hydrochloride and other drugs for various indications including in particular gastro-intestinal disorders, diabetes and dermatology indications.
In one embodiment of the present invention one or more solubilizer and/or excipient selected from the group consisting of polyvinyl pyrrolidone, polyethylene glycol, polypropylen glycol, polyethylene glycol 660 hydroxystearate, polysorbat, benzyl alcohol, ethanol, polyvinyl alcohol, Lipoid, ethyl oleate, transcutol, glycofurol, miglyol, and NaCl is present in said suspension. In one embodiment the one or more solubilizers and/or excipients is present during mechanical treatment of the suspension. In a preferred embodiment a solubilizer and one excipient is present, preferably Lipoid and NaCl. In a preferred embodiment the concentration of NaCl, present in the injectable pharmaceutical suspension is 0.2M.
The skilled artisan knows that parenteral application may be performed in different ways. "Parenteral application" in the context with the present invention means subcutaneous administration, intramuscular administration, intraorbital administration, intracapsular administration, intraspinal administration, intrasternal administration, intravenous administration, intradermal administration, intraperitoneal administration, and intraportal administration. In a preferred embodiment of the present invention the injectable pharmaceutical suspension for use in the treatment of a disease, the suspension is provided
in a form to be administered by injection, preferably by subcutaneous, intramuscular, intraarterial or intravenous injection to said subject.
The injectable pharmaceutical suspension for use in the treatment of a disease according to the present invention is suited for the application of poorly soluble pharmaceutically active compounds to different animals and humans. However, the skilled person is aware of the fact that methacrylate polymers are not biodegradable. Hence, it might be desirable that the injectable pharmaceutical suspension is only administered to non-human animals. The inventors unexpectedly found that even if the non-human animal is an animal for slaughter and subsequent consumption, the residual methacrylate polymer in the meat of the animal is passaged through the intestinal tract without interfering with the human organism. However, in one embodiment of the present invention the subject is selected from the group of human and non-human animals, preferably non-human animals. Non-human animals include but are not limited to pets, zoo animals, farm animals and animals for production; preferably selected from the group comprising alpacas, including mules, miniature donkeys, donkeys, burros, cats, dogs, ferrets, hedgehogs, horses, goats, pygmy goats, llamas, pigs, rabbits, rodents (including hamsters, guinea pigs, mice, gerbils, chinchillas, plains viscachas, and rats), sheep (including ewes and lambs), skunks or any pets, cattle, elephants, camels, lions, tigers, rhinoceroses or any other zoo animals.
The present invention relates to dosage forms of the injectable pharmaceutical suspension. The skilled artisan knows forms suited for dosage. However, since the injectable pharmaceutical suspension is primarily used for parenteral application, preferably through injection by syringes, in one embodiment of the dosage form according to the present invention the injectable pharmaceutical suspension is provided in a syringe or transferable to a syringe, preferably provided in a pharmaceutical phial.
In one embodiment the present invention relates to a method for treating a disease, comprising administering an injectable pharmaceutical suspension according to the present invention to a subject, wherein the administration is performed parenterally.
The presence of the methacrylate polymer leads to an increase in stability of the suspension
against Ostwald ripening. The inventors unexpectedly found that suspensions according to the present invention are stable for more than 3 years without flocculation and/or creaming, and/or coalescence. In a preferred embodiment the injectable pharmaceutical suspension exhibits a zeta potential of between -10 mV and -80 mV, preferably between -30 mV and - 70 mV. If the second or further polyelectrolyte is a polykation, the skilled artisan will recognize that the zeta potential may also be positive. Hence, in one embodiment of the present invention the injectable pharmaceutical suspension exhibits a zet potential of between 10 mV and 80 mV, preferably between 30 mV and 70 mV.
The mean distance between individual particles of active agent is increased by the presence of polyelectrolyte complexes adsorbed to the drug surface and in the dispersion medium, thereby increasing their surface stability and preventing aggregation. Also the stability of the suspension is increased during sterilisation procedures (e.g. autoclaving, gamma radiation treatment) when the methacrylate polymer is present. It will be apparent that the methods and suspension of the present invention, as well as the uses as substantially described herein or illustrated in the description and the examples, are also subject of the present invention and claimed herewith. In this respect, it is also understood that the embodiments as described in the description and/or any one of the examples, can be independently used and combined with any one of the embodiments described hereinbefore and claimed in the appended claims set. Thus, these and other embodiments are disclosed and encompassed by the description and examples of the present invention.
EXAMPLES
Example 1
The purpose of this example was to prepare an injectable nanoparticular suspensions of a poorly soluble pharmaceutically active compound (API 1) exclusively stabilized by a charged methacrylate polyelectrolyte. Concretely, Eudragit S, an anionic polymer with methacrylate as a functional group, was incorporated to the drug suspension during the mechanical treatment for size reduction.
An alkaline aqueous solution of 5 % Eudragit S was prepared in water containing 0.2 M sodium chloride with a pH of 8.5 g of API 1 was transferred to the 45 ml chamber of a planetary mill (Pulverisette 7 premium line, manufactured by Fritsch GmbH, Germany). 12 ml of the Eudragit S solution was added. Suspension and milling of the API 1 were performed with 2.5 mm zirconium oxide beads for 2x10 min at 800 rpm. The resulting suspension was removed from the bowls and characterized regarding particle size (laser diffraction), zetapotential, drug content (HPLC) and microscopy. LD values were: dgo of 2.9 μιη, d5o of 1.3 μηι and d10 of 600 nm. Zeta potential measured at -50.5 mV. Drug content in the high concentrated suspension were 32.2 % (w/v) of API 1.
The resulting suspension was diluted with the Eudragit S solution as described above to a target concentration of 12.5 % (w/v) of API 1. When stored at room temperature, the characterized data remained unchanged. And no aggregation of particles could be observed macro- and microscopically.
The suspension was administered subcutaneously to mammalians and performance was measured with regard to the concentration of the API 1 in blood, indicating a fast onset of action showing the high bioavailability. The results are shown in Figure 1. Furthermore, the concentration of API 1 in the blood was constant over a longer period, i.e. for several days. This clearly shows that the injected suspension has very good properties as a depot.
Example 2
The purpose of this example was to prepare an injectable nanoparticular suspensions of a further poorly soluble pharmaceutically active compound (API 2), which is typically given at lower concentrations. The method was performed as in Example 1 with the following amendments:
An alkaline aqueous solution of 5 % Eudragit S was prepared in water containing 0.2 M sodium chloride with a pH of 8. An aqueous solution of BSA with a concentration of 5 % was prepared with MilliQ-water. This solution contains of 0.5 % Lipoid SI 00. 0.4 g of API 2 was transferred to the 45 ml chamber of a planetary mill (Pulverisette 7 premium line,
manufactured by Fritsch GmbH, Germany). 3 ml of the Eudragit S solution and 3 ml of BSA solution were added to the solid substance. Suspension and milling of the API 2 were performed with 2.5 mm zirconium oxide beads for 2 10 min at 800 rpm. After the second lO min milling another 2 ml of the Eudragit S solution and 2 ml of BSA solution were added. The milling process was continued for another 2 10 min at 800 rpm.
The resulting suspension was removed from the bowls and characterized regarding particle size (laser diffraction), zeta potential, drug content (HPLC) and microscopy. LD values were: dg0 of 2.6 μπι, d50 of 1.1 μτα and d10 of 486 nm. Zeta potential measured at -42.7 mV. Drug contents in the high concentrated suspension were 2.85 % (w/V) API 2. The resulting dispersion was diluted with Eudragit solution as described above to a target concentration of 1 % (w/v) API 2. When stored at room temperature, the characterized data remained unchanged. And no aggregation of particles could be observed macro- and microscopically. The suspension was administered subcutaneously to a non-human mammal and compared to the performance of a control formulation of API 2 from prior art (without polyelectrolytes) with regard to the concentrations of the API 2 in blood. The results are shown in Figure 2. The fast onset of high concentrations of API 2 in the blood indicates a high bioavailability.
Claims
1. An injectable pharmaceutical suspension comprising a polyelectrolyte and a nanoparticular, poorly soluble pharmaceutically active compound, wherein said polyelectrolyte is a methacrylate polymer.
2. The injectable pharmaceutical suspension according to claim 1, wherein the methacrylate polymer is selected from the group comprising Eudragit L 100-55®, Eudragit L-100® and Eudragit S-100®, Eudragit E-100®, and Eudragit E PO®..
3. The injectable pharmaceutical suspension according to claim 1 or 2, wherein the nanoparticular, poorly soluble, pharmaceutically active compound is selected from the group consisting of:
Atorvastatin, Amiodarone, Candesartan-Cilexetil, Carvedilol, Clopidogrel bisulfate, Dipyridamole, Eprosartan mesylate, Epierenone, Ezetimibe, Felodipine, Furosemide, Isradipine, Lovastatin, Metolazone, Nicardipine, Nisoldipine Olmesartan medoxomil, Propafenone HC1, Qinapril, Ramipril, Simvastatin, Telmisartan, Trandolapril, Valsartan and other cardio-vascular active drugs;
Cisplatin, Carboplatin, Paclitaxel, Docetaxel, Vincristine, Etoposide and other antineoplastic compounds used to treat cancer;
Acylcovir, Adefovir, Dipivoxil, Amphotericin, Amprenavir, Cefixime, Ceftazidime, Clarithromycin, Clotrimazole, Efavirenz, Ganciclovir, Itraconazole, Norfloxacin, Nystatin, Ritonavir, Saquinavir, Monepantel, Doramectin and other anti-infective drugs including anti-bacterial, antifungal and anti-parasitic drugs;
Cisplatin, Docetaxel, Etoposide, Exemestane, Idarubicin, Irinotecan, Melphalan, Mercaptopurine, Mitotane, Paclitaxel, Valrubicin and other drugs
used in oncology;
Azathioprine, Tacrolimus, Cyclosporine, Pimecrolimus, Sirolimus and other immonosupressive drugs;
Clozapine, Entacapone, Fluphenazine, Imipramine, Nefazodone, Olanzapine, Paroxetine, Pimozide, Sertraline, Triazolam, Zaleplon, Ziprasidoneand, Risperidone, Carbamazepine and other drugs for CNS indications;
Danazol, Dutasteride, Medroxyprogesterone, Estradiol, Raloxifene, Sildenafil, Tadalafil, Testosterone, Vardenafil and other drugs used for reproductive health;
Celecoxib, Dihydroergotamine Mesylate, Eletriptan, Ergoloidmesylates, Ergotamine-tartrate, Nabumetone, Ibuprofen, Ketoprofen, Triamcinolone, Triamcinolone acetonide and other anti-inflammatory and analgesic drugs; Bosentan, Budesonide, Desloratadine, Fexofenadin, Fluticasone, Loratadine, Mometasone, Salmeterol Xinafoate, Triamcinolon Acetonide, Zafirlukast and other drugs for respiratory indications; and
Dronabinol, Famotidine, Glyburide, Hyoscyamine, Isotretinoin, Megestrol, Mesalamine, Modafmil, Mosapride, Nimodipine, Perphenazine, Propofol, Sucralfate, Thalidomide, Trizanidine hydrochloride and other drugs for various indications including in particular gastro-intestinal disorders, diabetes and dermatology indications.
4. The injectable pharmaceutical suspension according to any one of claims 1 to 3, wherein a solubilizer selected from the group comprising polyvinyl pyrrolidone, polyethylene glycol, polypropylen glycol, polyethylene glycol 660 hydroxystearate, polysorbat, benzyl alcohol, ethanol, polyvinyl alcohol, Lipoid, ethyl oleate, transcutol, glycofurol, and miglyol is present in said suspension.
5. The injectable pharmaceutical suspension according ot any one of claims 1 to 4, further comprising a second or further polyelectrolyte.
6. The injectable pharmaceutical suspension according to claim 5, wherein the second polyelectrolyte is selected from the group comprising bovine serum albumine (BSA),
Eudragit L 100-55®, Eudragit L-100® and Eudragit S-100®, Eudragit E-100®, and Eudragit E PO®.
A method for stabilizing a poorly soluble active pharmaceutical compound in an injectable pharmaceutical suspension comprising the steps of: a) contacting, without the presence of a detergent, a poorly soluble pharmaceutically active compound with a solution comprising methacrylate polymer;
b) mechanically treating the mixture of step a) to obtain particles comprising the active compound with an effective average size of less than about 5000 nm, preferably less than about 4000 nm, more preferably less than about 3000 nm, even more preferably less than about 1000 nm and most preferably less than about 800 nm, and optionally
c) contacting said active compound or suspension with a methacrylate polymer or with one or more further polyelectrolytes during, before and/or after mechanically treating;
The method according to claim 7, wherein the further polyelectrolytes are selected from the group comprising water-soluble cationic or anionic polysaccharides, peptides, proteins, nucleic acids and corresponding salts thereof, xylan polysulfates, dextran sulfates, poly(amino acids) such as polyaspartic acid, poly-arginine, poly- lysine or polyglutamic acid, polysaccharide polysulfates such as sulfates of starch hydrolysates, inulin, hydroxyethylstarches, polysaccharide polysulfonates, polysaccharide polyphosphates, polyphosphates, Eudragits, protamine, albumins, casein, gelatine, collagen, oligonucleotides, polymethacrylate, polyacrylic acid, chitosan, pectin, carboxymethylcellulose, alginate, carrageenan, hyaluronic acid, chondroitin sulfate, dextrane sulphate, heparine, poly-a,p-(2-dimethylaminoethyl)- D,L-aspartamide, chitosan, lysine octadecyl ester, aminated dextrans, aminated cyclodextrins, aminated cellulose ethers, aminated pectins, polystyrenesulfonate and corresponding salts thereof and in each case partially hydrophobized derivatives of xylan polysulfate, polysulfates of other polysaccharides such as, for example, starch
hydrolysates, inulin, hydroxyethylstarches, dextrans; of poly(amino acids) such as polyaspartic acid or polyglutamic acid, and of polysaccharide polysulfonates, polysaccharide polyphosphonates, polyphosphates.
9. The method according to any one of claims 7 to 8, wherein the nanoparticular, poorly soluble, pharmaceutically active compound is selected from the group consisting of:
Atorvastatin, Amiodarone, Candesartan-Cilexetil, Carvedilol, Clopidogrel bisulfate, Dipyridamole, Eprosartan mesylate, Epierenone, Ezetimibe, Felodipine, Furosemide, Isradipine, Lovastatin, Metolazone, Nicardipine, Nisoldipine Olmesartan medoxomil, Propafenone HC1, Qinapril, Ramipril, Simvastatin, Telmisartan, Trandolapril, Valsartan and other cardio-vascular active drugs;
Cisplatin, Carboplatin, Paclitaxel, Docetaxel, Vincristine, Etoposide and other antineoplastic compounds used to treat cancer;
Acyclovir, Adefovir, Dipivoxil, Amphotericin, Amprenavir, Cefixime, Ceftazidime, Clarithromycin, Clotrimazole, Efavirenz, Ganciclovir, Itraconazole, Norfloxacin, Nystatin, Ritonavir, Saquinavir, Monepantel, Doramectin and other anti-infective drugs including anti-bacterial, anti fungal and anti-parasitic drugs;
Cisplatin, Docetaxel, Etoposide, Exemestane, Idarubicin, Irinotecan, Melphalan, Mercaptopurine, Mitotane, Paclitaxel, Valrubicin and other drugs used in oncology;
Azathioprine, Tacrolimus, Cyclosporine, Pimecrolimus, Sirolimus and other immonosupressive drugs;
Clozapine, Entacapone, Fluphenazine, Imipramine, Nefazodone, Olanzapine, Paroxetine, Pimozide, Sertraline, Triazolam, Zaleplon, Ziprasidoneand, Risperidone, Carbamazepine and other drugs for CNS indications;
Danazol, Dutasteride, Medroxyprogesterone, Estradiol, Raloxifene, Sildenafil, Tadalafil, Testosterone, Vardenafil and other drugs used for reproductive health;
Celecoxib, Dihydroergotamine Mesylate, Eletriptan, Ergoloidmesylates,
Ergotamine-tartrate, Nabumetone, Ibuprofen, Ketoprofen, Triamcinolone, Triamcinolone acetonide and other anti-inflammatory and analgesic drags; Bosentan, Budesonide, Desloratadine, Fexofenadin, Fluticasone, Loratadine, Mometasone, Salmeterol Xinafoate, Triamcinolon Acetonide, Zafirlukast and other drugs for respiratory indications; and
Dronabinol, Famotidine, Glyburide, Hyoscyamine, Isotretinoin, Megestrol, Mesalamine, Modafmil, Mosapride, Nimodipine, Perphenazine, Propofol, Sucralfate, Thalidomide, Trizanidine hydrochloride and other drugs for various indications including in particular gastro-intestinal disorders, diabetes and dermatology indications.
10. The method according to any one of claims 7 to 9, wherein a solubilizer selected from the group consisting of polyvinyl pyrrolidone, polyethylene glycol, polypropylen glycol, polyethylene glycol 660 hydroxystearate, polysorbat, benzyl alcohol, ethanol, polyvinyl alcohol, Lipoid, ethyl oleate, transcutol, glycofurol, miglyol is present in said suspension.
11. An injectable pharmaceutical suspension according to any one of claims 1 to 6 derivable by a method according to any one of claims 7 to 10.
12. An injectable pharmaceutical suspension according to any one of claims 1 to 6 or 11, for use in the treatment of a disease in a subject, wherein the composition is provided in a form to be administered parenterally to said subject.
13. The injectable pharmaceutical suspension for use in the treatment of a disease according to claim 12, wherein the suspension is provided in a form to be administered by injection, preferably by subcutaneous, intramuscular, intraarterial or intravenous injection to said subject.
14. The injectable pharmaceutical suspension for use in the treatment of a disease according to claim 12 or 13, wherein the subject is selected from the group of human and non-human animals, preferably non-human animals.
15. A dosage form comprising an injectable pharmaceutical suspension according to any one of claims 1 to 6 or 1 1.
16. The dosage form according to claim 15, wherein the injectable pharmaceutical suspension is provided in a syringe or transferable to a syringe.
17. The dosage form according to claim 15 or 16, wherein the injectable pharmaceutical suspension is provided in a pharmaceutical phial.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11152405.4 | 2011-01-27 | ||
| EP11152405 | 2011-01-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2012101242A1 true WO2012101242A1 (en) | 2012-08-02 |
Family
ID=45566984
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2012/051288 WO2012101242A1 (en) | 2011-01-27 | 2012-01-27 | Novel pharmaceutical suspension for parenteral application |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2012101242A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103239399A (en) * | 2013-05-30 | 2013-08-14 | 苏州普罗达生物科技有限公司 | Sirolimus nanoparticle suspension agent and preparation method thereof |
| CN103263385A (en) * | 2013-05-17 | 2013-08-28 | 江苏正大清江制药有限公司 | Celecoxib long-acting nano injection and preparation method thereof |
| US20150335753A1 (en) * | 2012-12-19 | 2015-11-26 | Kashiv Pharma, Llc | Supersaturated stabilized nanoparticles for poorly soluble drugs |
| US20170128380A1 (en) * | 2014-07-03 | 2017-05-11 | Pfizer Inc. | Targeted Therapeutic Nanoparticles And Methods Of Making And Using Same |
| CN107216445A (en) * | 2017-05-03 | 2017-09-29 | 南京大学 | A kind of nano-complex and preparation method and application |
| WO2018055615A1 (en) * | 2016-09-22 | 2018-03-29 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Injectable implants |
| CN109310643A (en) * | 2016-05-12 | 2019-02-05 | 株式会社柳柳制药 | The dutasteride and Tadalafei compound formulation of ester derivant containing glycerine fatty acid or methyl glycol fatty acid ester derivative and the oral capsule preparation comprising it |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070082838A1 (en) * | 2005-08-31 | 2007-04-12 | Abraxis Bioscience, Inc. | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
| EP2172193A1 (en) | 2008-10-02 | 2010-04-07 | Capsulution Nanoscience AG | Improved nanoparticulate compositions of poorly soluble compounds |
-
2012
- 2012-01-27 WO PCT/EP2012/051288 patent/WO2012101242A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070082838A1 (en) * | 2005-08-31 | 2007-04-12 | Abraxis Bioscience, Inc. | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
| EP2172193A1 (en) | 2008-10-02 | 2010-04-07 | Capsulution Nanoscience AG | Improved nanoparticulate compositions of poorly soluble compounds |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150335753A1 (en) * | 2012-12-19 | 2015-11-26 | Kashiv Pharma, Llc | Supersaturated stabilized nanoparticles for poorly soluble drugs |
| US10500282B2 (en) * | 2012-12-19 | 2019-12-10 | Kashiv Biosciences, Llc | Supersaturated stabilized nanoparticles for poorly soluble drugs |
| CN103263385A (en) * | 2013-05-17 | 2013-08-28 | 江苏正大清江制药有限公司 | Celecoxib long-acting nano injection and preparation method thereof |
| CN103239399A (en) * | 2013-05-30 | 2013-08-14 | 苏州普罗达生物科技有限公司 | Sirolimus nanoparticle suspension agent and preparation method thereof |
| RU2706791C2 (en) * | 2014-07-03 | 2019-11-21 | Пфайзер Инк. | Directed deliverable therapeutic nanoparticles and methods for preparing and use thereof |
| US10182996B2 (en) * | 2014-07-03 | 2019-01-22 | Pfizer Inc. | Targeted therapeutic nanoparticles and methods of making and using same |
| CN107072962A (en) * | 2014-07-03 | 2017-08-18 | 辉瑞公司 | Targeted therapeutic nano particle and its preparation and application |
| US20170128380A1 (en) * | 2014-07-03 | 2017-05-11 | Pfizer Inc. | Targeted Therapeutic Nanoparticles And Methods Of Making And Using Same |
| CN109310643A (en) * | 2016-05-12 | 2019-02-05 | 株式会社柳柳制药 | The dutasteride and Tadalafei compound formulation of ester derivant containing glycerine fatty acid or methyl glycol fatty acid ester derivative and the oral capsule preparation comprising it |
| WO2018055615A1 (en) * | 2016-09-22 | 2018-03-29 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Injectable implants |
| US11439587B2 (en) | 2016-09-22 | 2022-09-13 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Injectable implants |
| CN107216445A (en) * | 2017-05-03 | 2017-09-29 | 南京大学 | A kind of nano-complex and preparation method and application |
| CN107216445B (en) * | 2017-05-03 | 2020-02-21 | 南京大学 | Nano composite and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20120058151A1 (en) | nanoparticulate compositions of poorly soluble compounds | |
| Mohammad et al. | Drug nanocrystals: Fabrication methods and promising therapeutic applications | |
| WO2012101242A1 (en) | Novel pharmaceutical suspension for parenteral application | |
| EP3076951B1 (en) | Process for the production of drug formulations for oral administration | |
| Alam et al. | Commercially bioavailable proprietary technologies and their marketed products | |
| Maged et al. | Nano spray drying technique as a novel approach to formulate stable econazole nitrate nanosuspension formulations for ocular use | |
| JP2012504550A (en) | Stabilization of amorphous drugs using a sponge-like carrier matrix. | |
| JP5778667B2 (en) | Nanoparticulate telmisartan composition and method for its preparation | |
| SK68193A3 (en) | Surface modified anticancer nanoparticles | |
| CN101212954A (en) | Nanoparticulate clopidogrel formulations | |
| WO2016049360A1 (en) | Shear-thinning self-healing networks | |
| Ren et al. | Recent perspectives in hot melt extrusion-based polymeric formulations for drug delivery: applications and innovations | |
| Lucena et al. | In vivo vaginal fungal load reduction after treatment with itraconazole-loaded polycaprolactone-nanoparticles | |
| KR20190005183A (en) | Full Best Land formulation and its use | |
| WO2004030649A2 (en) | Methods for producing and stabilising microsuspensions and nanosuspensions by means of amphiphiles and polyelectrolytes | |
| EP3254699B1 (en) | Solid dispersion containing dutasteride, and composition containing same | |
| AU2012324911B2 (en) | Pharmaceutical nanosuspension | |
| EP3220894B1 (en) | Nanosuspension formulation | |
| Palani et al. | Enhancement of rosuvastatin calcium bioavailability applying nanocrystal technology and in-vitro, in-vivo evaluations | |
| EP3621659A1 (en) | Drug delivery composition and method of fabrication | |
| KR101794032B1 (en) | Method for preparing nanoparticles | |
| WO2005060361A2 (en) | Pharmaceutical formulations for itraconazole | |
| KR101730865B1 (en) | Pharmaceutical compositions comprising revaprazan-containing nanoparticles and processes for the preparation thereof | |
| Marques et al. | Factors affecting the preparation of nanocrystals: characterization, surface modifications and toxicity aspects | |
| Samuel et al. | Optimization of PLGA nanoparticles for delivery of Novel anticancer CK-10 peptide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12702786 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 12702786 Country of ref document: EP Kind code of ref document: A1 |