US20030185761A1 - Buccal, polar and non-polar spray or capsule containing drugs for treating pain - Google Patents
Buccal, polar and non-polar spray or capsule containing drugs for treating pain Download PDFInfo
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- US20030185761A1 US20030185761A1 US10/230,059 US23005902A US2003185761A1 US 20030185761 A1 US20030185761 A1 US 20030185761A1 US 23005902 A US23005902 A US 23005902A US 2003185761 A1 US2003185761 A1 US 2003185761A1
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- 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
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- 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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
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Definitions
- Aerosol compositions containing a hydrocarbon propellant and a drug for administration to a mucosal surface are described in U.K. 2,082,457, Su, U.S. Pat. No. 3,155,574, Silson et al., U.S. Pat. No. 5,011,678, Wang et al., and by Parnell in U.S. Pat. No. 5,128,132. It should be noted that these references discuss bioavailability of solutions by inhalation rather than through the membranes to which they are administered.
- a buccal aerosol spray or soft bite gelatin capsule using a polar or non-polar solvent has now been developed which provides biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect.
- the composition comprises: propellant 10-70%, non-polar solvent 25-89.9%, active compound 0.01-40%, flavoring agent 1-8%; most suitably propellant 20-70%, non-polar solvent 25-74.75%, active compound 0.25-35%, flavoring agent 2-7.5%.
- compositions of the present invention for transmucosal administration of a pharmacologically active compound soluble in a pharmacologically acceptable polar solvent are also administrable in aerosol form driven by a propellant.
- the composition comprises in weight % of total composition: aqueous polar solvent 10-97%, active compound 0.1-25%, suitably additionally comprising, by weight of total composition a flavoring agent 0.05-10% and propellant: 2-10%.
- the composition comprises: polar solvent 20-97%, active compound 0.1-15%, flavoring agent 0.1-5% and propellant 2-5%; most suitably polar solvent 25-97%, active compound 0.2-25%, flavoring agent 0.1-2.5% and propellant 2-4%.
- the buccal pump spray composition of the present invention i.e., the propellant free composition, for transmucosal administration of a pharmacologically active compound wherein said active compound is soluble in a pharmacologically acceptable non-polar solvent comprises in weight % of total composition: non-polar solvent 30-99.69%, active compound 0.005-55%, and suitably additionally, flavoring agent 0.1-10%.
- the composition comprises: polar solvent 37-98.58%, active compound 0.005-55%, flavoring agent 0.5-8%; most suitably polar solvent 60.9-97.06%, active compound 0.01-40%, flavoring agent 0.75-7.5%.
- the soft bite gelatin capsules of the present invention for transmucosal administration of a pharmacologically active compound, at least partially soluble in a pharmacologically acceptable non-polar solvent, having charged thereto a fill composition comprise in weight % of total composition: non-polar solvent 4-99.99%, emulsifier 0-20%, active compound 0.01-80%, provided that said fill composition contains less than 10% of water, suitably additionally comprising, by weight of the composition: flavoring agent 0.01-10%.
- the soft bite gelatin capsule comprises: non-polar solvent 21.5-99.975%, emulsifier 0-15%, active compound 0.025-70%, flavoring agent 1-8%; most suitably: nonpolar solvent 28.5-97.9%, emulsifier 0-10%, active compound 0.1-65.0%, flavoring agent 2-6%.
- the soft bite gelatin capsule comprises: polar solvent 37-99.95%, emulsifier 0-15%, active compound 0.025-55%, flavoring agent 1-8%; most suitably: polar solvent 44-96.925%, emulsifier 0-10%, active compound 0.075-50%, flavoring agent 2-6%.
- a further object is a sealed aerosol spray container containing a composition of the non polar or polar aerosol spray formulation, and a metered valve suitable for releasing from said container a predetermined amount of said composition.
- the propellant is a non-Freon material, preferably a C 3-8 hydrocarbon of a linear or branched configuration.
- the propellant should be substantially non-aqueous.
- the propellant produces a pressure in the aerosol container such that under expected normal usage it will produce sufficient pressure to expel the solvent from the container when the valve is activated but not excessive pressure such as to damage the container or valve seals.
- the non-polar solvent is a non-polar hydrocarbon, preferably a C 7-18 hydrocarbon of a linear or branched configuration, fatty acid esters, and triglycerides, such as miglyol.
- the solvent must dissolve the active compound and be miscible with the propellant, i.e., solvent and propellant must form a single phase at a temperature of 0-40° C. a pressure range of between 1-3 atm.
- the polar and non-polar aerosol spray compositions of the invention are intended to be administered from a sealed, pressurized container. Unlike a pump spray, which allows the entry of air into the container after every activation, the aerosol container of the invention is sealed at the time of manufacture. The contents of the container are released by activation of a metered valve, which does not allow entry of atmospheric gasses with each activation.
- a metered valve which does not allow entry of atmospheric gasses with each activation.
- a further object is a pump spray container containing a composition of the pump spray formulation, and a metered valve suitable for releasing from said container a predetermined amount of said composition.
- a further object is a soft gelatin bite capsule containing a composition of as set forth above.
- the formulation may be in the form of a viscous solution or paste containing the active compounds. Although solutions are preferred, paste fills may also be used where the active compound is not soluble or only partially soluble in the solvent of choice. Where water is used to form part of the paste composition, it should not exceed 10% thereof. (All percentages herein are by weight unless otherwise indicated.)
- the polar or non-polar solvent is chosen such that it is compatible with the gelatin shell and the active compound.
- the solvent preferably dissolves the active compound.
- other components wherein the active compound is not soluble or only slightly soluble may be used and will form a paste fill.
- Soft gelatin capsules are well known in the art. See, for example, U.S. Pat. No. 4,935,243, Borkan et al., for its teaching of such capsules.
- the capsules of the present invention are intended to be bitten into to release the low viscosity solution or paste therein, which will then coat the buccal mucosa with the active compounds.
- the shell of a soft gelatin capsule of the invention may comprise, for example: gelatin: 50-75%, glycerin 20-30%, colorants 0.5-1.5%, water 5-10%, and sorbitol 2-10%.
- the active compound may include, biologically active peptides, central nervous system active amines, sulfonyl ureas, antibiotics, antifungals, antivirals, sleep inducers, antiasthmatics, bronchial dilators, antiemetics, histamine H-2 receptor antagonists, barbiturates, prostaglandins and neutraceuticals.
- the active compounds may also include antihistamines, alkaloids, hormones, benzodiazepines and narcotic analgesics. While not limited thereto, these active compounds are particularly suitable for non-polar pump spray formulation and application.
- the active compounds may also include nerve impulse inhibitors, anti-opioid agents, anti-migraine agents, anti-muscle spasm agents, pain control agents, anesthetics, anti-inflammatory drugs, or mixtures thereof.
- FIG. 1. is a schematic diagram showing routes of absorption and processing of pharmacologically active substances in a mammalian system.
- the preferred active compounds of the present invention are in an ionized, salt form or as the free base of the pharmaceutically acceptable salts thereof (provided, for the aerosol or pump spray compositions, they are soluble in the spray solvent). These compounds are soluble in the non-polar solvents of the invention at useful concentrations or can be prepared as pastes at useful concentrations. These concentrations may be less than the standard accepted dose for these compounds since there is enhanced absorption of the compounds through the oral mucosa. This aspect of the invention is especially important when there is a large (40-99.99%) first pass effect.
- propellants for the non polar sprays propane, N-butane, iso-butane, N-pentane, iso-pentane, and neo-pentane, and mixtures thereof may be used.
- N-butane and iso-butane, as single gases, are the preferred propellants. It is permissible for the propellant to have a water content of no more than 0.2%, typically 0.1-0.2%. All percentages herein are by weight unless otherwise indicated. It is also preferable that the propellant be synthetically produced to minimize the presence of contaminants which are harmful to the active compounds. These contaminants include oxidizing agents, reducing agents, Lewis acids or bases, and water. The concentration of each of these should be less than 0.1%, except that water may be as high as 0.2%.
- Suitable non-polar solvents for the capsules and the non-polar sprays include (C 2 -C 24 ) fatty acid (C 2 -C 6 ) esters, C 7 -C 18 hydrocarbon, C 2 -C 6 alkanoyl esters, and the triglycerides of the corresponding acids.
- other liquid components may be used instead of the above low molecular weight solvents. These include soya oil, corn oil, other vegetable oils.
- solvents for the polar capsules or sprays there may be used low molecular weight polyethyleneglycols (PEG) of 400-1000 Mw (preferably 400-600), low molecular weight (C 2 -C 8 ) mono and polyols and alcohols of C 7 -C 18 linear or branch chain hydrocarbons, glycerin may also be present and water may also be used in the sprays, but only in limited amount in the capsules.
- PEG polyethyleneglycols
- C 2 -C 8 low molecular weight mono and polyols and alcohols of C 7 -C 18 linear or branch chain hydrocarbons
- glycerin may also be present and water may also be used in the sprays, but only in limited amount in the capsules.
- the preferred flavoring agents are synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners (sugars, aspartame, saccharin, etc.), and combinations thereof.
- the active substances include the active compounds selected from the group consisting of cyclosporine, sermorelin, octreotide acetate, calcitonin-salmon, insulin lispro, sumatriptan succinate, clozepine, cyclobenzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine, erythromycin, ciprofloxacin, ondansetron hydrochloride, dimenhydrinate, cimetidine hydrochloride, famotidine, phenytoin sodium, phenytoin, carboprost thromethamine, carboprost, diphenhydramine hydrochloride, isoproterenol hydrochloride, terbutaline sulfate, terbutaline, theophylline, albuterol sulfate and neutraceuticals, that is to say nutrients with pharmacological action such as but not limited to carnitine
- the active compound is a nerve impulse inhibitor, anti-opioid agent, anti-migraine agent, anti-muscle spasm agent, pain control agent, anesthetic, anti-inflammatory drug, or a mixture thereof.
- the active compound is a nerve impulse inhibitor.
- Suitable nerve impulse inhibitors for use in the buccal sprays of the invention include, but are not limited to levobupivacaine, lidocaine, prilocaine, mepivacaine, propofol, rapacuronium bromide, ropivacaine, tubocurarine, atracurium, doxacurium, mivacurium, pancuronium, vecuronium, pipecuronium, rocuronium, and mixtures thereof.
- the active compound is an anti-opioid agent.
- Suitable anti-opioid agents for use in the buccal sprays of the invention include, but are not limited to, naloxone, nalmefene, naltrexone, cholecystokinin, nociceptin, neuropeptide FF, oxytocin, vasopressin, and mixtures thereof.
- the active compound is an anti-migraine agent.
- Suitable anti-migraine agents for use in the buccal sprays of the invention include, but are not limited to, frovatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, naratriptan, almotriptan, ergotamine, diethylergotamine, sumatriptan, and mixtures thereof.
- the active compound is an anti-muscle spasm agent.
- Suitable anti-muscle spasm agents for use in the buccal sprays of the invention include, but are not limited to, baclofen, botulinum toxin, carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, metaxalone, methocarbamol, orphenadrine, tizanidine, and mixtures thereof.
- the active compound is a pain control agent.
- Suitable pain control agents for use in the buccal sprays of the invention include, but are not limited to, non-steroidal anti-inflammatory drugs, alfentanil, butorphanol, codeine, dezocine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, propoxyphene, pentazocine, sufentanil, tramadol, and mixtures thereof.
- the active compound is an anesthetic.
- Suitable anesthetics for use in the buccal sprays of the invention include, but are not limited to, benzonatate, bupivacaine, desflurane, enflurane, isoflurane, levobupivacaine, lidocaine, mepivacaine, prilocaine, propofol, rapacuronium bromide, ropivacaine, sevoflurane, ketamine, and mixtures thereof.
- the active compound is an anti-inflammatory drug.
- Suitable anti-inflammatory drugs for use in the buccal sprays of the invention include, but are not limited to, alosetron, anakinra, beclomethasone, betamethasone, budesonide, clobetasol, celecoxib, cromolyn, desoximetasone, dexamethasone, epinastic, etanercept, etoricoxib, flunisolide, fluocinonide, fluticasone, formoterol, hydrocortisone, hydroxychloroquine, ibudilast, ketotifen, meloxicam, mesalamine, methotrexate, methylprednisolone, mometasone, montelukast, nedocromil, olsalazine, prednisone, ramatroban, rofecoxib, salsalate, terbutaline, triamcino
- compositions of the present invention comprise an active compound or a pharmaceutically acceptable salt thereof.
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including organic and inorganic acids or bases.
- salts may be prepared from pharmaceutically acceptable non-toxic bases.
- Salts derived from all stable forms of inorganic bases include aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, etc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethyl-aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methyl-glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc.
- basic ion-exchange resins such as arginine, betaine, caffeine, choline
- salts may be prepared from pharmaceutically acceptable non-toxic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc.
- Particularly preferred are citric, hydrobromic, maleic, phosphoric, sulfuric, and tartaric acids.
- Cyclosporine Lingual Spray preferred most preferred Amounts amount amount amount cyclosporine 5-50 10-35 15-25 water 5-20 7.5-50 9.5-12 ethanol 5-60 7.5-50 10-20 polyethylene glycol 20-60 30-45 35-40 flavors 0.1-5 1-4 2-3
- Cyclosporine Non-Polar Lingual Spray preferred most preferred Amounts amount amount amount cyclosporine 1-50 3-40 5-30 Migylol 20 25 30-40 Polyoxyethylated castor oil 20 25 30-40 Butane 25-80 30-70 33-50 flavors 0.1-5 1-4 2-3
- Cyclosporine Non-polar Bite Caosule preferred most preferred Amounts amount amount cyclosporine 1-35 5-25 10-20 olive oil 25-60 35-55 30-45 polyoxyethylated 25-60 35-55 30-45 oleic glycerides flavors 0.1-5 1-4 2-3
- CNS Active Amines and their Salts Including but not Limited to Tricyclic Amines, GABA Analogues, Thiazides, Phenothiazine Derivatives, Serotonin Antagonists and Serotonin Reuptake Inhibitors
- Clozepine Lingual Spray preferred most preferred Amounts amount amount amount clozepine 0.5-30 1-20 10-15 ethanol 5-60 7.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 5-30 7.5-20 10-15 flavors 0.1-5 1-4 2-3
- Glyburide Lingual Spray preferred most preferred Amounts amount amount amount glyburide 0.25-25 0.5-20 0.75-15 ethanol 5-60 ⁇ 7.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 2.5-30 5-20 6-15 flavors 0.1-5 1-4 2-3
- Glyburide Non-polar Bite Capsule preferred most preferred Amounts amount amount amount glyburide 0.01-10 0.025-7.5 0.1-4 olive oil 30-60 35-55 30-50 polyoxyethylated oleic 30-60 35-55 30-50 glycerides flavors 0.1-5 1-4 2-3
- Zidovudine Formally Called Azidothymidine (AZT) (Retrovir)
- Non-polar Lingual Spray preferred most preferred Amounts amount amount amount zidovudine 10-50 15-40 25-35 Soya oil 20-85 25-70 30-40 Butane 15-80 30-75 60-70 flavors 0.1-5 1-4 2-3
- D. zidovudine [Formerly Called Azidothymidine (AZT) (Retrovir)] Lingual Spray most Amounts preferred amount preferred amount zidovudine 10-50 15-40 25-35 water 30-80 40-75 45-70 ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5 flavors 0.1-5 1-4 2-3
- Ondansetron Hydrochloride Lingual Spray most Amounts preferred amount preferred amount ondansetron 1-25 2-20 2.5-15 hydrochloride citric acid 1-10 2-8 2.5-5 monohydrate sodium citrate 0.5-5 1-4 1.25-2.5 dihydrate water 1-90 5-85 10-75 ethanol 5-30 7.5-20 9.5-15 propylene glycol 5-30 7.5-20 9.5-15 polyethylene glycol 5-30 7.5-20 9.5-15 flavors 1-10 3-8 5-7.5
- C. Dimenhydrinate Polar Lingual Spray most Amounts preferred amount preferred amount dimenhydrinate 3-50 4-40 5-35 water 5-90 10-80 15-75 ethanol 1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15 sorbitol 0.1-5 0.2-40 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3
- Cimetidine Hydrochloride Bite Capsule most Amounts preferred amount preferred amount cimetidine HCl 10-60 15-55 25-50 glycerin 5-20 7.5-15 10-12.5 polyethylene glycol 20-90 25-85 30-75 flavors 1-10 2-8 3-6
- Famotidine Lingual Spray most Amounts preferred amount preferred amount famotidine 1-35 5-30 7-20 water 2.5-25 3-20 5-10 L-aspartic acid 0.1-20 1-15 5-10 polyethylene glycol 20-97 30-95 50-85 flavors 0.1-10 1-7.5 2-5
- Famotidine Non-polar Lingual Spray most Amounts preferred amount preferred amount famotidine 1-35 5-30 7-20 Soya oil 10-50 15-40 15-20 Butanel 5-80 30-75 45-70 polyoxyethylated 10-50 15-40 15-20 oleic glycerides flavors 0.1-5 1-4 2-3
- Phenytoin Sodium Lingual Spray most Amounts preferred amount preferred amount phenytoin sodium 10-60 15-55 20-40 water 2.5-25 3-20 5-10 ethanol 5-30 7.5-20 9.5-15 propylene glycol 5-30 7.5-20 9.5-15 polyethylene glycol 5-30 7.5-20 9.5-15 flavors 1-10 3-8 5-7.5
- Phenytoin Non-polar Lingual Spray most Amounts preferred amount preferred amount phenytoin 5-45 10-40 15-35 migylol 10-50 15-40 15-20 Butane 15-80 30-75 60-70 polyoxyethylated 10-50 15-40 15-20 oleic glycerides flavors 0.1-10 1-8 5-7.5
- Carboprost Thromethamine Lingual Spray most Amounts preferred amount preferred amount carboprost 0.05-5 0.1-3 0.25-2.5 thromethamine water 50-95 60-80 65-75 ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5 sodium chloride 1-20 3-15 4-8 flavors 0.1-5 1-4 2-3
- valerian as Lingual Spray most preferred Amounts preferred amount amount valerian extract 0.1-10 0.2-7 0.25-5 water 50-95 60-80 65-75 ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5 flavors 1-10 2-8 3-6
- Echinacea as Bite Capsule most preferred Amounts preferred amount amount echinacea extract 30-85 40-75 45-55 soya oil 7.5-50 10-40 12.5-35 soya lecithin 0.001-1.0 0.005-0.5 .01-0.1 Soya fats 7.5-50 10-40 12.5-35 flavors 1-10 2-8 3-6
- A. Diphenhydramine Hydrochloride Lingual Spray most preferred Amounts preferred amount amount diphenhydramine 3-50. 4-40 5-35 HCl water 5-90 10-80 50-75 ethanol 1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3
- Isoproterenol Hydrochloride as Polar Lingual Spray most preferred Amounts preferred amount amount isoproterenol Hydrochloride 0.1-10 0.2-7.5 0.5-6 water 5-90 10-80 50-75 ethanol 1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3
- C. Terbutaline as Non-polar Lingual Spray most preferred Amounts preferred amount amount terbutaline 0.1-10 0.2-7.5 0.5-6 migylol 25-50 30-45 35-40 isobutane 5-60 10-50 20-35 polyoxyethylated 25-50 30-45 35-40 oleic glycerides flavors 0.1-10 1-8 5-7.5
- Theophylline Polar Bite Capsule most preferred Amounts preferred amount amount theophylline 5-50 10-40 15-30 polyethylene glycol 20-60 25-50 30-40 glycerin 25-50 35-45 30-40 propylene glycol 25-50 35-45 30-40 flavors 0.1-5 1-4 2-3
- Prostaglandin E (Vasodilator) Most-Preferred Amount Preferred Amount Amount prostaglandin E 1 0.01-10% 0.1-5% 0.2-3% Ethanol 10-90% 20-75% 25-50% Propylene glycol 1-90% 5-80% 10-75% Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4%
- Promethazine Antiemetic, Sleep Inducer, and CNS Active Amine
Abstract
Description
- This application is a continuation-in-part of application No. 09/537,118, filed Mar. 29, 2000 which is a continuation-in-part of the U.S. national phase designation of PCT/US97/17899 filed Oct. 1, 1997, the disclosures of which are incorporated by reference herein in their entirety.
- It is known that certain biologically active compounds are better absorbed through the oral mucosa than through other routes of administration, such as through the stomach or intestine. However, formulations suitable for such administration by these latter routes present their own problems. For example, the biologically active compound must be compatible with the other components of the composition such as propellants, solvents, etc. Many such formulations have been proposed. For example, U.S. Pat. No. 4,689,233, Dvorsky et al., describes a soft gelatin capsule for the administration of the anti-coronary drug nifedipine dissolved in a mixture of polyether alcohols. U.S. Pat. No. 4,755,389, Jones et al., describes a hard gelatin chewable capsule containing nifedipine. A chewable gelatin capsule containing a solution or dispersion of a drug is described in U.S. Pat. No. 4,935,243, Borkan et al. U.S. Pat. No. 4,919,919, Aouda et al, and U.S. Pat. No. 5,370,862, Klokkers-Bethke, describe a nitroglycerin spray for administration to the oral mucosa comprising nitroglycerin, ethanol, and other components. An orally administered pump spray is described by Cholcha in U.S. Pat. No. 5,186,925. Aerosol compositions containing a hydrocarbon propellant and a drug for administration to a mucosal surface are described in U.K. 2,082,457, Su, U.S. Pat. No. 3,155,574, Silson et al., U.S. Pat. No. 5,011,678, Wang et al., and by Parnell in U.S. Pat. No. 5,128,132. It should be noted that these references discuss bioavailability of solutions by inhalation rather than through the membranes to which they are administered.
- A buccal aerosol spray or soft bite gelatin capsule using a polar or non-polar solvent has now been developed which provides biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect.
- The buccal aerosol spray compositions of the present invention, for transmucosal administration of a pharmacologically active compound soluble in a pharmacologically acceptable non-polar solvent comprise in weight % of total composition: pharmaceutically acceptable propellant 5-80%, nonpolar solvent 19-85%, active compound 0.05-50%, suitably additionally comprising, by weight of total composition a flavoring agent 0.01-10%. Preferably the composition comprises: propellant 10-70%, non-polar solvent 25-89.9%, active compound 0.01-40%, flavoring agent 1-8%; most suitably propellant 20-70%, non-polar solvent 25-74.75%, active compound 0.25-35%, flavoring agent 2-7.5%.
- The buccal polar aerosol spray compositions of the present invention, for transmucosal administration of a pharmacologically active compound soluble in a pharmacologically acceptable polar solvent are also administrable in aerosol form driven by a propellant. In this case, the composition comprises in weight % of total composition: aqueous polar solvent 10-97%, active compound 0.1-25%, suitably additionally comprising, by weight of total composition a flavoring agent 0.05-10% and propellant: 2-10%. Preferably the composition comprises: polar solvent 20-97%, active compound 0.1-15%, flavoring agent 0.1-5% and propellant 2-5%; most suitably polar solvent 25-97%, active compound 0.2-25%, flavoring agent 0.1-2.5% and propellant 2-4%.
- The buccal pump spray composition of the present invention, i.e., the propellant free composition, for transmucosal administration of a pharmacologically active compound wherein said active compound is soluble in a pharmacologically acceptable non-polar solvent comprises in weight % of total composition: non-polar solvent 30-99.69%, active compound 0.005-55%, and suitably additionally, flavoring agent 0.1-10%.
- The buccal polar pump spray compositions of the present invention, i.e., the propellant free composition, for transmucosal administration of a pharmacologically active compound soluble in a pharmacologically acceptable polar solvent comprises in weight % of total composition: aqueous polar solvent 30-99.69%, active compound 0.001-60%, suitably additionally comprising, by weight of total composition a flavoring agent 0.1-10%. Preferably the composition comprises: polar solvent 37-98.58%, active compound 0.005-55%, flavoring agent 0.5-8%; most suitably polar solvent 60.9-97.06%, active compound 0.01-40%, flavoring agent 0.75-7.5%.
- The soft bite gelatin capsules of the present invention for transmucosal administration of a pharmacologically active compound, at least partially soluble in a pharmacologically acceptable non-polar solvent, having charged thereto a fill composition comprise in weight % of total composition: non-polar solvent 4-99.99%, emulsifier 0-20%, active compound 0.01-80%, provided that said fill composition contains less than 10% of water, suitably additionally comprising, by weight of the composition: flavoring agent 0.01-10%. Preferably, the soft bite gelatin capsule comprises: non-polar solvent 21.5-99.975%, emulsifier 0-15%, active compound 0.025-70%, flavoring agent 1-8%; most suitably: nonpolar solvent 28.5-97.9%, emulsifier 0-10%, active compound 0.1-65.0%, flavoring agent 2-6%.
- The soft bite polar gelatin capsules of the present invention for transmucosal administration of a pharmacologically active compound, at least partially soluble in a pharmacologically acceptable polar solvent, having charged thereto a composition comprising in weight % of total composition: polar solvent 25-99.89%, emulsifier 0-20%, active compound 0.01-65%, provided that said composition contains less than 10% of water, suitably additionally comprising, by weight of the composition: flavoring agent 01-10%. Preferably, the soft bite gelatin capsule comprises: polar solvent 37-99.95%, emulsifier 0-15%, active compound 0.025-55%, flavoring agent 1-8%; most suitably: polar solvent 44-96.925%, emulsifier 0-10%, active compound 0.075-50%, flavoring agent 2-6%.
- It is an object of the invention to coat the mucosal membranes either with extremely fine droplets of spray containing the active compounds or a solution or paste thereof from bite capsules.
- It is also an object of the invention to administer to the oral mucosa of a mammalian in need of same, preferably man, by spray or bite capsule, a predetermined amount of a biologically active compound by this method or from a soft gelatin capsule.
- A further object is a sealed aerosol spray container containing a composition of the non polar or polar aerosol spray formulation, and a metered valve suitable for releasing from said container a predetermined amount of said composition.
- As the propellant evaporates after activation of the aerosol valve, a mist of fine droplets is formed which contains solvent and active compound.
- The propellant is a non-Freon material, preferably a C3-8 hydrocarbon of a linear or branched configuration. The propellant should be substantially non-aqueous. The propellant produces a pressure in the aerosol container such that under expected normal usage it will produce sufficient pressure to expel the solvent from the container when the valve is activated but not excessive pressure such as to damage the container or valve seals.
- The non-polar solvent is a non-polar hydrocarbon, preferably a C7-18 hydrocarbon of a linear or branched configuration, fatty acid esters, and triglycerides, such as miglyol. The solvent must dissolve the active compound and be miscible with the propellant, i.e., solvent and propellant must form a single phase at a temperature of 0-40° C. a pressure range of between 1-3 atm.
- The polar and non-polar aerosol spray compositions of the invention are intended to be administered from a sealed, pressurized container. Unlike a pump spray, which allows the entry of air into the container after every activation, the aerosol container of the invention is sealed at the time of manufacture. The contents of the container are released by activation of a metered valve, which does not allow entry of atmospheric gasses with each activation. Such containers are commercially available.
- A further object is a pump spray container containing a composition of the pump spray formulation, and a metered valve suitable for releasing from said container a predetermined amount of said composition.
- A further object is a soft gelatin bite capsule containing a composition of as set forth above. The formulation may be in the form of a viscous solution or paste containing the active compounds. Although solutions are preferred, paste fills may also be used where the active compound is not soluble or only partially soluble in the solvent of choice. Where water is used to form part of the paste composition, it should not exceed 10% thereof. (All percentages herein are by weight unless otherwise indicated.)
- The polar or non-polar solvent is chosen such that it is compatible with the gelatin shell and the active compound. The solvent preferably dissolves the active compound. However, other components wherein the active compound is not soluble or only slightly soluble may be used and will form a paste fill.
- Soft gelatin capsules are well known in the art. See, for example, U.S. Pat. No. 4,935,243, Borkan et al., for its teaching of such capsules. The capsules of the present invention are intended to be bitten into to release the low viscosity solution or paste therein, which will then coat the buccal mucosa with the active compounds. Typical capsules, which are swallowed whole or bitten and then swallowed, deliver the active compounds to the stomach, which results in significant lag time before maximum blood levels can be achieved or subject the compound to a large first pass effect. Because of the enhanced absorption of the compounds through the oral mucosa and no chance of a first pass effect, use of the bite capsules of the invention will eliminate much of the lag time, resulting in hastened onset of biological effect. The shell of a soft gelatin capsule of the invention may comprise, for example: gelatin: 50-75%, glycerin 20-30%, colorants 0.5-1.5%, water 5-10%, and sorbitol 2-10%.
- The active compound may include, biologically active peptides, central nervous system active amines, sulfonyl ureas, antibiotics, antifungals, antivirals, sleep inducers, antiasthmatics, bronchial dilators, antiemetics, histamine H-2 receptor antagonists, barbiturates, prostaglandins and neutraceuticals.
- The active compounds may also include antihistamines, alkaloids, hormones, benzodiazepines and narcotic analgesics. While not limited thereto, these active compounds are particularly suitable for non-polar pump spray formulation and application.
- The active compounds may also include nerve impulse inhibitors, anti-opioid agents, anti-migraine agents, anti-muscle spasm agents, pain control agents, anesthetics, anti-inflammatory drugs, or mixtures thereof.
- FIG. 1. is a schematic diagram showing routes of absorption and processing of pharmacologically active substances in a mammalian system.
- The preferred active compounds of the present invention are in an ionized, salt form or as the free base of the pharmaceutically acceptable salts thereof (provided, for the aerosol or pump spray compositions, they are soluble in the spray solvent). These compounds are soluble in the non-polar solvents of the invention at useful concentrations or can be prepared as pastes at useful concentrations. These concentrations may be less than the standard accepted dose for these compounds since there is enhanced absorption of the compounds through the oral mucosa. This aspect of the invention is especially important when there is a large (40-99.99%) first pass effect.
- As propellants for the non polar sprays, propane, N-butane, iso-butane, N-pentane, iso-pentane, and neo-pentane, and mixtures thereof may be used. N-butane and iso-butane, as single gases, are the preferred propellants. It is permissible for the propellant to have a water content of no more than 0.2%, typically 0.1-0.2%. All percentages herein are by weight unless otherwise indicated. It is also preferable that the propellant be synthetically produced to minimize the presence of contaminants which are harmful to the active compounds. These contaminants include oxidizing agents, reducing agents, Lewis acids or bases, and water. The concentration of each of these should be less than 0.1%, except that water may be as high as 0.2%.
- Suitable non-polar solvents for the capsules and the non-polar sprays include (C2-C24) fatty acid (C2-C6) esters, C7-C 18 hydrocarbon, C2-C6 alkanoyl esters, and the triglycerides of the corresponding acids. When the capsule fill is a paste, other liquid components may be used instead of the above low molecular weight solvents. These include soya oil, corn oil, other vegetable oils.
- As solvents for the polar capsules or sprays there may be used low molecular weight polyethyleneglycols (PEG) of 400-1000 Mw (preferably 400-600), low molecular weight (C2-C8) mono and polyols and alcohols of C7-C18 linear or branch chain hydrocarbons, glycerin may also be present and water may also be used in the sprays, but only in limited amount in the capsules.
- It is expected that some glycerin and water used to make the gelatin shell will migrate from the shell to the fill during the curing of the shell. Likewise, there may be some migration of components from the fill to the shell during curing and even throughout the shelf-life of the capsule.
- Therefore, the values given herein are for the compositions as prepared, it being within the scope of the invention that minor variations will occur.
- The preferred flavoring agents are synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners (sugars, aspartame, saccharin, etc.), and combinations thereof.
- The active substances include the active compounds selected from the group consisting of cyclosporine, sermorelin, octreotide acetate, calcitonin-salmon, insulin lispro, sumatriptan succinate, clozepine, cyclobenzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine, erythromycin, ciprofloxacin, ondansetron hydrochloride, dimenhydrinate, cimetidine hydrochloride, famotidine, phenytoin sodium, phenytoin, carboprost thromethamine, carboprost, diphenhydramine hydrochloride, isoproterenol hydrochloride, terbutaline sulfate, terbutaline, theophylline, albuterol sulfate and neutraceuticals, that is to say nutrients with pharmacological action such as but not limited to carnitine, valerian, echinacea, and the like.
- In another embodiment, the active compound is a nerve impulse inhibitor, anti-opioid agent, anti-migraine agent, anti-muscle spasm agent, pain control agent, anesthetic, anti-inflammatory drug, or a mixture thereof.
- In one embodiment the active compound is a nerve impulse inhibitor. Suitable nerve impulse inhibitors for use in the buccal sprays of the invention include, but are not limited to levobupivacaine, lidocaine, prilocaine, mepivacaine, propofol, rapacuronium bromide, ropivacaine, tubocurarine, atracurium, doxacurium, mivacurium, pancuronium, vecuronium, pipecuronium, rocuronium, and mixtures thereof.
- In one embodiment the active compound is an anti-opioid agent. Suitable anti-opioid agents for use in the buccal sprays of the invention include, but are not limited to, naloxone, nalmefene, naltrexone, cholecystokinin, nociceptin, neuropeptide FF, oxytocin, vasopressin, and mixtures thereof.
- In one embodiment the active compound is an anti-migraine agent. Suitable anti-migraine agents for use in the buccal sprays of the invention include, but are not limited to, frovatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, naratriptan, almotriptan, ergotamine, diethylergotamine, sumatriptan, and mixtures thereof.
- In one embodiment the active compound is an anti-muscle spasm agent. Suitable anti-muscle spasm agents for use in the buccal sprays of the invention include, but are not limited to, baclofen, botulinum toxin, carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, metaxalone, methocarbamol, orphenadrine, tizanidine, and mixtures thereof.
- In one embodiment the active compound is a pain control agent. Suitable pain control agents for use in the buccal sprays of the invention include, but are not limited to, non-steroidal anti-inflammatory drugs, alfentanil, butorphanol, codeine, dezocine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, propoxyphene, pentazocine, sufentanil, tramadol, and mixtures thereof.
- In one embodiment the active compound is an anesthetic. Suitable anesthetics for use in the buccal sprays of the invention include, but are not limited to, benzonatate, bupivacaine, desflurane, enflurane, isoflurane, levobupivacaine, lidocaine, mepivacaine, prilocaine, propofol, rapacuronium bromide, ropivacaine, sevoflurane, ketamine, and mixtures thereof.
- In one embodiment the active compound is an anti-inflammatory drug. Suitable anti-inflammatory drugs for use in the buccal sprays of the invention include, but are not limited to, alosetron, anakinra, beclomethasone, betamethasone, budesonide, clobetasol, celecoxib, cromolyn, desoximetasone, dexamethasone, epinastic, etanercept, etoricoxib, flunisolide, fluocinonide, fluticasone, formoterol, hydrocortisone, hydroxychloroquine, ibudilast, ketotifen, meloxicam, mesalamine, methotrexate, methylprednisolone, mometasone, montelukast, nedocromil, olsalazine, prednisone, ramatroban, rofecoxib, salsalate, terbutaline, triamcinolone, valdecoxib, zafirlukast, and mixtures thereof.
- The formulations of the present invention comprise an active compound or a pharmaceutically acceptable salt thereof. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including organic and inorganic acids or bases.
- When an active compound of the present invention is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases. Salts derived from all stable forms of inorganic bases include aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, etc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins such as arginine, betaine, caffeine, choline, N,N dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethyl-aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methyl-glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc.
- When an active compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc. Particularly preferred are citric, hydrobromic, maleic, phosphoric, sulfuric, and tartaric acids.
- In the discussion of methods of treatment herein, reference to the active compounds is meant to also include the pharmaceutically acceptable salts thereof. While certain formulations are set forth herein, the actual amounts to be administered to the mammal or man in need of same are to be determined by the treating physician.
- The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting.
- The following are examples of certain classes. All values unless otherwise specified are in weight percent.
- A. Cyclosporine Lingual Spray
preferred most preferred Amounts amount amount cyclosporine 5-50 10-35 15-25 water 5-20 7.5-50 9.5-12 ethanol 5-60 7.5-50 10-20 polyethylene glycol 20-60 30-45 35-40 flavors 0.1-5 1-4 2-3 - B. Cyclosporine Non-Polar Lingual Spray
preferred most preferred Amounts amount amount cyclosporine 1-50 3-40 5-30 Migylol 20 25 30-40 Polyoxyethylated castor oil 20 25 30-40 Butane 25-80 30-70 33-50 flavors 0.1-5 1-4 2-3 - C. Cyclosporine Non-polar Bite Caosule
preferred most preferred Amounts amount amount cyclosporine 1-35 5-25 10-20 olive oil 25-60 35-55 30-45 polyoxyethylated 25-60 35-55 30-45 oleic glycerides flavors 0.1-5 1-4 2-3 - D. Cyclosporine Bite Capsule
preferred most preferred Amounts amount amount cyclosporine 5-50 10-35 15-25 polyethylene glycol 20-60 30-45 35-40 glycerin 5-30 7.5-25 10-20 propylene glycol 5-30 7.5-25 10-20 flavors 0.1-10 1-8 3-6 - E. Sermorelin (as the Acetate) Lingual Spray
preferred Amounts amount most preferred sermorelin (as the acetate) .01-5 .1-3 .2-1.0 mannitol 1-25 5-20 10-15 monobasic sodium phosphate, 0.1-5 1-3.1 .5-2.5 dibasic sodium phosphate water 0.01-5 .05-3 0.1-0.5 ethanol 5-30 7.5-25 9.5-15 polyethylene glycol 20-60 30-45 35-40 propylene glycol 5-25 10-20 12-17 flavors 0.1-5 1-4 2-3 - F. Octreotide Acetate (Sandostatin) Lingual Spray
preferred most preferred Amounts amount amount octreotide acetate 0.001-0.5 0.005-0.250 0.01-0.10 acetic acid 1-10 2-8 4-6 sodium acetate 1-10 2-8 4-6 sodium chloride 3-30 .5-25 15-20 flavors 0.1-5 0.5-.4 2-3 ethanol 5-30 7.5-20 9.5-15 water 15-95 35-90 65-85 flavors 0.1-5 1-4 2-3 - G. Calcitonin-salmon Lingual Spray
preferred most preferred Amounts amount amount calcitonin-salmon 0.001-5 0.005-2 01-1.5 ethanol 2-15 3-10 7-9.5 water 30-95 50-90 60-80 polyethylene glycol 2-15 3-10 7-9.5 sodium chloride 2.5-20 5-15 10-12.5 flavors 0.1-5 1-4 2-3 - H. Insulin Lispro, Lingual Spray
preferred most preferred Amounts amount amount insulin 20-60 4-55 5-50 glycerin 0.1-10 0.25-5 0.1-1.5 dibasic sodium 1-15 2.5-10 4-8 phosphate m-cresol, 1-25 5-25 7.5-12.5 zinc oxide 0.01-0.25 .05-0.15 0.075-0.10 m-cresol 0.1-1 0.2-0.8 0.4-0.6 phenol trace amounts trace amounts trace amounts ethanol 5-20 7.5-15 9-12 water 30-90 40-80 50-75 propylene glycol 5-20 7.5-15 9-12 flavors 0.1-5 0.5-3 0.75-2 - A. Sumatriptan Succinate Lingual Spray
preferred most preferred Amounts amount amount sumatriptan succinate 0.5-30 1-20 10-15 ethanol 5-60 7.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 5-30 7.5-20 10-15 flavors 0.1-5 1-4 2-3 - B. Sumatriptan Succinate Bite Capsule
preferred most preferred Amounts amount amount sumatriptan succinate 0.01-5 0.05-3.5 0.075-1.75 polyethylene glycol 25-70 30-60 35-50 glycerin 25-70 30-60 35-50 flavors 0.1-10 1-8 3-6 - C. Clozepine Lingual Spray
preferred most preferred Amounts amount amount clozepine 0.5-30 1-20 10-15 ethanol 5-60 7.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 5-30 7.5-20 10-15 flavors 0.1-5 1-4 2-3 - D. Clozepine Non-polar Lingual Spray with Propellant
preferred most preferred Amounts amount amount clozepine 0.5-30 1-20 10-15 Migylol 20-85 25-70 30-40 Butanol 5-80 30-75 60-70 flavors 0.1-5 1-4 2-3 - E. Clozepine Non-polar Lingual Spray without Propellant
preferred most preferred Amounts amount amount clozepine 0.5-30 1-20 10-15 Migylol 70-99.5 80-99 85-90 flavors 0.1-5 1-4 2-3 - F. Cyclobenzaprine Non-polar Lingual Spray
preferred most preferred Amounts amount amount cyclobenzaprine (base) 0.5-30 1-20 10-15 Migylol 20-85 25-70 30-40 Iso-butane 15-80 30-75 60-70 flavors 0.1-5 1-4 2-3 - G. Dexfenfluramine Hydrochloride Lingual Spray
preferred most preferred Amounts amount amount dexfenfluramine Hcl 5-30 7.5-20 10-15 ethanol 5-60 7.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 5-30 7.5-20 10-15 flavors 0.1-5 1-4 2-3 - A. Glyburide Lingual Spray
preferred most preferred Amounts amount amount glyburide 0.25-25 0.5-20 0.75-15 ethanol 5-60 −7.5-50 10-20 propylene glycol 5-30 7.5-20 10-15 polyethylene glycol 0-60 30-45 35-40 water 2.5-30 5-20 6-15 flavors 0.1-5 1-4 2-3 - B. Glyburide Non-polar Bite Capsule
preferred most preferred Amounts amount amount glyburide 0.01-10 0.025-7.5 0.1-4 olive oil 30-60 35-55 30-50 polyoxyethylated oleic 30-60 35-55 30-50 glycerides flavors 0.1-5 1-4 2-3 - A. Zidovudine [Formerly Called Azidothymidine (AZT) (Retrovir)] Non-polar Lingual Spray
preferred most preferred Amounts amount amount zidovudine 10-50 15-40 25-35 Soya oil 20-85 25-70 30-40 Butane 15-80 30-75 60-70 flavors 0.1-5 1-4 2-3 - B. Erythromycin Bite Capsule Bite Capsule
preferred most preferred Amounts amount amount erythromycin 25-65 30-50 35-45 polyoxyethylene glycol 5-70 30-60 45-55 glycerin 5-20 7.5-15 10-12.5 flavors 1-10 2-8 3-6 - C. Ciprofloxacin Hydrochloride Bite Capsule
preferred most preferred Amounts amount amount ciprofloxacin hydrochloride 25-65 35-55 40-50 glycerin 5-20 7.5-15 10-12.5 polyethylene glycol 120-75 30-65 40-60 flavors 1-10 2-8 3-6 - D. zidovudine [Formerly Called Azidothymidine (AZT) (Retrovir)] Lingual Spray
most Amounts preferred amount preferred amount zidovudine 10-50 15-40 25-35 water 30-80 40-75 45-70 ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5 flavors 0.1-5 1-4 2-3 - A. Ondansetron Hydrochloride Lingual Spray
most Amounts preferred amount preferred amount ondansetron 1-25 2-20 2.5-15 hydrochloride citric acid 1-10 2-8 2.5-5 monohydrate sodium citrate 0.5-5 1-4 1.25-2.5 dihydrate water 1-90 5-85 10-75 ethanol 5-30 7.5-20 9.5-15 propylene glycol 5-30 7.5-20 9.5-15 polyethylene glycol 5-30 7.5-20 9.5-15 flavors 1-10 3-8 5-7.5 - B. Dimenhydrinate Bite Capsule
most Amounts preferred amount preferred amount dimenhydrinate 0.5-30 2-25 3-15 glycerin 5-20 7.5-15 10-12.5 polyethylene glycol 45-95 50-90 55-85 flavors 1-10 2-8 3-6 - C. Dimenhydrinate Polar Lingual Spray
most Amounts preferred amount preferred amount dimenhydrinate 3-50 4-40 5-35 water 5-90 10-80 15-75 ethanol 1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15 sorbitol 0.1-5 0.2-40 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3 - A. Cimetidine Hydrochloride Bite Capsule
most Amounts preferred amount preferred amount cimetidine HCl 10-60 15-55 25-50 glycerin 5-20 7.5-15 10-12.5 polyethylene glycol 20-90 25-85 30-75 flavors 1-10 2-8 3-6 - B. Famotidine Lingual Spray
most Amounts preferred amount preferred amount famotidine 1-35 5-30 7-20 water 2.5-25 3-20 5-10 L-aspartic acid 0.1-20 1-15 5-10 polyethylene glycol 20-97 30-95 50-85 flavors 0.1-10 1-7.5 2-5 - C. Famotidine Non-polar Lingual Spray
most Amounts preferred amount preferred amount famotidine 1-35 5-30 7-20 Soya oil 10-50 15-40 15-20 Butanel 5-80 30-75 45-70 polyoxyethylated 10-50 15-40 15-20 oleic glycerides flavors 0.1-5 1-4 2-3 - A. Phenytoin Sodium Lingual Spray
most Amounts preferred amount preferred amount phenytoin sodium 10-60 15-55 20-40 water 2.5-25 3-20 5-10 ethanol 5-30 7.5-20 9.5-15 propylene glycol 5-30 7.5-20 9.5-15 polyethylene glycol 5-30 7.5-20 9.5-15 flavors 1-10 3-8 5-7.5 - B. Phenytoin Non-polar Lingual Spray
most Amounts preferred amount preferred amount phenytoin 5-45 10-40 15-35 migylol 10-50 15-40 15-20 Butane 15-80 30-75 60-70 polyoxyethylated 10-50 15-40 15-20 oleic glycerides flavors 0.1-10 1-8 5-7.5 - A. Carboprost Thromethamine Lingual Spray
most Amounts preferred amount preferred amount carboprost 0.05-5 0.1-3 0.25-2.5 thromethamine water 50-95 60-80 65-75 ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5 sodium chloride 1-20 3-15 4-8 flavors 0.1-5 1-4 2-3 - pH is Adjusted with Sodium Hydroxide and/or Hydrochloric Acid
- B. Carboprost Non-polar Lingual Spray
Amounts preferred amount most preferred amount carboprost 0.05-5 0.1-3 0.25-2.5 migylol 25-50 30-45 35-40 Butane 5-60 10-50 20-35 polyoxyethylated 25-50 30-45 35-40 oleic glycerides flavors 0.1-10 1-8 5-7.5 - A. Carnitine as Bite Capsule (Contents are a Paste)
most preferred Amounts preferred amount amount carnitine fumarate 6-80 30-70 45-65 soya oil 7.5-50 10-40 12.5-35 soya lecithin 0.001-1.0 0.005-0.5 .01-0.1 Soya fats 7.5-50 10-40 12.5-35 flavors 1-10 2-8 3-6 - B. Valerian as Lingual Spray
most preferred Amounts preferred amount amount valerian extract 0.1-10 0.2-7 0.25-5 water 50-95 60-80 65-75 ethanol 5-20 7.5-15 9.5-12.5 polyethylene glycol 5-20 7.5-15 9.5-12.5 flavors 1-10 2-8 3-6 - C. Echinacea as Bite Capsule
most preferred Amounts preferred amount amount echinacea extract 30-85 40-75 45-55 soya oil 7.5-50 10-40 12.5-35 soya lecithin 0.001-1.0 0.005-0.5 .01-0.1 Soya fats 7.5-50 10-40 12.5-35 flavors 1-10 2-8 3-6 - D. Mixtures of Ingredients
most preferred Amounts preferred amount amount magnesium oxide 15-40 20-35 25-30 chromium picolinate 0.01-1.0 0.02-0.5 .025-0.75 folic acid .025-3.0 0.05-2.0 0.25-0.5 vitamin B-12 0.01-1.0 0.02-0.5 .025-0.75 vitamin E 15-40 20-35 25-30 Soya oil 10-40 12.5-35 15-20 soya lecithin 0.1-5 0.2-4 0.5-1.5 soya fat 10-40 15-35 17.5-20 - A. Diphenhydramine Hydrochloride Lingual Spray
most preferred Amounts preferred amount amount diphenhydramine 3-50. 4-40 5-35 HCl water 5-90 10-80 50-75 ethanol 1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3 - A. Isoproterenol Hydrochloride as Polar Lingual Spray
most preferred Amounts preferred amount amount isoproterenol Hydrochloride 0.1-10 0.2-7.5 0.5-6 water 5-90 10-80 50-75 ethanol 1-80 3-50 5-10 polyethylene glycol 1-80 3-50 5-15 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3 - B. Terbutaline Sulfate as Polar Lingual Spray
most preferred Amounts preferred amount amount terbutaline sulfate 0.1-10 0.2-7.5 0.5-6 water 5-90 10-80 50-75 ethanol 1-10 2-8 2.5-5 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3 - C. Terbutaline as Non-polar Lingual Spray
most preferred Amounts preferred amount amount terbutaline 0.1-10 0.2-7.5 0.5-6 migylol 25-50 30-45 35-40 isobutane 5-60 10-50 20-35 polyoxyethylated 25-50 30-45 35-40 oleic glycerides flavors 0.1-10 1-8 5-7.5 - D. Theophylline Polar Bite Capsule
most preferred Amounts preferred amount amount theophylline 5-50 10-40 15-30 polyethylene glycol 20-60 25-50 30-40 glycerin 25-50 35-45 30-40 propylene glycol 25-50 35-45 30-40 flavors 0.1-5 1-4 2-3 - E. Albuterol Sulfate as Polar Lingual Spray
Amounts preferred amount most preferred amount albuterol sulfate 0.1-10 0.2-7.5 0.5-6 water 5-90 10-80 50-75 ethanol 1-10 2-8 2.5-5 Sorbitol 0.1-5 0.2-4 0.4-1.0 aspartame 0.01-0.5 0.02-0.4 0.04-0.1 flavors 0.1-5 1-4 2-3 - A. Sulfonylurea
Amount Preferred Amount Most-Preferred Amount glyburide 0.1-25% 0.5-15% 0.6-10% Ethanol 40-99% 60-97% 70-97% Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4% - B. Prostaglandin E (Vasodilator)
Most-Preferred Amount Preferred Amount Amount prostaglandin E1 0.01-10% 0.1-5% 0.2-3% Ethanol 10-90% 20-75% 25-50% Propylene glycol 1-90% 5-80% 10-75% Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4% - C. Promethazine (Antiemetic, Sleep Inducer, and CNS Active Amine)
Most-Preferred Amount Preferred Amount Amount promethazine 1-25% 3-15% 5-12% Ethanol 10-90% 20-75% 25-50% Propylene glycol 1-90% 5-80% 10-75% Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4% - D. Meclizine
Most-Preferred Amount Preferred Amount Amount meclizine 1-25% 3-15% 5-12% Ethanol 1-15% 2-10% 3-6 Propylene glycol 20-98% 5-90% 10-85% Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 2-10% 3-5% 3-4%
Claims (55)
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/230,059 US20030185761A1 (en) | 1997-10-01 | 2002-08-29 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
NZ539284A NZ539284A (en) | 2002-08-29 | 2003-08-27 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
CA002497268A CA2497268A1 (en) | 2002-08-29 | 2003-08-27 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
AU2003296899A AU2003296899A1 (en) | 2002-08-29 | 2003-08-27 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
JP2004551444A JP2006505611A (en) | 2002-08-29 | 2003-08-27 | Oral, polar and non-polar sprays or capsules containing pain medications |
PCT/US2003/026859 WO2004043428A2 (en) | 2002-08-29 | 2003-08-27 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
EP03811212A EP1539107A2 (en) | 2002-08-29 | 2003-08-27 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US10/671,710 US20040136913A1 (en) | 1997-10-01 | 2003-09-29 | Buccal, polar and non-polar spray containing sumatriptan |
US10/726,625 US6969508B2 (en) | 1997-10-01 | 2003-12-04 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US11/366,663 US20060165604A1 (en) | 1997-10-01 | 2006-03-03 | Buccal, polar and non-polar spray containing sumatriptan |
US12/351,576 US20090162298A1 (en) | 1997-10-01 | 2009-01-09 | Buccal, polar and non-polar spray containing sumatriptan |
US12/351,606 US20090124554A1 (en) | 1997-10-01 | 2009-01-09 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US13/467,441 US20120252846A1 (en) | 1997-10-01 | 2012-05-09 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1997/017899 WO1999016417A1 (en) | 1997-10-01 | 1997-10-01 | Buccal, polar and non-polar spray or capsule |
US53711800A | 2000-03-29 | 2000-03-29 | |
US10/230,059 US20030185761A1 (en) | 1997-10-01 | 2002-08-29 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US53711800A Continuation-In-Part | 1997-10-01 | 2000-03-29 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/671,710 Continuation-In-Part US20040136913A1 (en) | 1997-10-01 | 2003-09-29 | Buccal, polar and non-polar spray containing sumatriptan |
US10/726,625 Division US6969508B2 (en) | 1997-10-01 | 2003-12-04 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US12/351,606 Continuation US20090124554A1 (en) | 1997-10-01 | 2009-01-09 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030185761A1 true US20030185761A1 (en) | 2003-10-02 |
Family
ID=32312002
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/230,059 Abandoned US20030185761A1 (en) | 1997-10-01 | 2002-08-29 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US10/726,625 Expired - Fee Related US6969508B2 (en) | 1997-10-01 | 2003-12-04 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US12/351,606 Abandoned US20090124554A1 (en) | 1997-10-01 | 2009-01-09 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US13/467,441 Abandoned US20120252846A1 (en) | 1997-10-01 | 2012-05-09 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/726,625 Expired - Fee Related US6969508B2 (en) | 1997-10-01 | 2003-12-04 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US12/351,606 Abandoned US20090124554A1 (en) | 1997-10-01 | 2009-01-09 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
US13/467,441 Abandoned US20120252846A1 (en) | 1997-10-01 | 2012-05-09 | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
Country Status (7)
Country | Link |
---|---|
US (4) | US20030185761A1 (en) |
EP (1) | EP1539107A2 (en) |
JP (1) | JP2006505611A (en) |
AU (1) | AU2003296899A1 (en) |
CA (1) | CA2497268A1 (en) |
NZ (1) | NZ539284A (en) |
WO (1) | WO2004043428A2 (en) |
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Also Published As
Publication number | Publication date |
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JP2006505611A (en) | 2006-02-16 |
EP1539107A2 (en) | 2005-06-15 |
WO2004043428A3 (en) | 2004-10-21 |
US20090124554A1 (en) | 2009-05-14 |
US20120252846A1 (en) | 2012-10-04 |
US20040120896A1 (en) | 2004-06-24 |
CA2497268A1 (en) | 2004-05-27 |
US6969508B2 (en) | 2005-11-29 |
WO2004043428A2 (en) | 2004-05-27 |
AU2003296899A1 (en) | 2004-06-03 |
NZ539284A (en) | 2007-07-27 |
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