US20090186099A1 - Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system - Google Patents

Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system Download PDF

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US20090186099A1
US20090186099A1 US12/351,275 US35127509A US2009186099A1 US 20090186099 A1 US20090186099 A1 US 20090186099A1 US 35127509 A US35127509 A US 35127509A US 2009186099 A1 US2009186099 A1 US 2009186099A1
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active compound
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Harry A. Dugger, III
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    • A—HUMAN NECESSITIES
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
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    • A61K31/075—Ethers or acetals
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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Definitions

  • 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.
  • 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 soil 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 p-FOX (fatty acid oxidation) inhibitors, acetylcholinesterase inhibitors, nerve impulse inhibitors, anti-cholinergics, anti-convulsants, anti-psychotics, anxiolytic agents, dopamine metabolism inhibitors, agents to treat post stroke sequelae, neuroprotectants, agents to treat Alzheimer's disease, neurotransmitters, neurotransmitter agonists, sedatives, agents for treating attention deficit disorder, agents for treating narcolepsy, central adregenic antagonists, anti-depression agents, agents for treating Parkinson's disease, benzodiazepine antagonists, stimulants, neurotransmitter antagonists, tranquilizer, or a mixture thereof.
  • p-FOX fatty acid oxidation
  • 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 isobutane, 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 an 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 maybe 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, elozepine; cyclobenzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine, erythromycin, ciprofloxacin ondansetron hydrochloride, dimenhydrinate, cimetidine hydrochloride, famotidine, phenyloin sodium, phenyloin, 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 p-FOX (fatty acid oxidation) inhibitor, acetylcholinesterase inhibitor, nerve impulse inhibitor, anti-cholinergic, anti-convulsant, anti-psychotic, anixiolytic agent, dopamine metabolism inhibitor, agent to treat post stroke sequelae, neuroprotectant, agent to treat Alzheimer's disease, neurotransmitter, neurotransmitter agonist, sedative, agent for treating attention deficit disorder, agent for treating narcolepsy, central adregenic antagonist, anti-expression agent, agent for treating Parkinson's disease, benzodiazepine antagonist, stimulant, neurotransmitter antagonist, tranquilizer, or a mixture thereof.
  • p-FOX fatty acid oxidation
  • the active compound is a p-FOX inhibitor.
  • a suitable p-FOX inhibitor for use in the buccal sprays of the invention includes, but is not limited to, ranolazine.
  • the active compound is an acetylcholinesterase inhibitor.
  • Suitable acetylcholinesterase inhibitors for use in the buccal sprays of the invention include, but are not limited to, galantamine, neostigmine, physostigmine, and edrophonium.
  • 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, doxaurim, mivacurium, pancuronium, vercuronium, pipecuronium, and rocuronium.
  • the active compound is an anti-cholinergic.
  • Suitable anti-cholinergics for use in the buccal sprays of the invention include, but are not limited to, amantadine, ipratropium, oxitropium, and dicycloverine.
  • the active compound is an anti-convulsant
  • Suitable anti-convulsants for use in the buccal sprays of the invention include, but are not limited to, acetazolamide, carbamazepine, clonazepam, diazepam, divalproex (valproic acid), ethosuximide, lamotrignine acid, levetriacetam, oxcarbazepine, phenobarbital, phenyloin, pregabalin, primidone, remacemide, trimethadione, topiramate, vigabatrin, and zonisamide.
  • the active compound is an anti-psychotic.
  • Suitable anti-psychotics for use in the buccal sprays of the invention include, but are not limited to, amisulpride, aripiprazole bifemelane, bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone loperidone, olanzapine, quetiapine, fluphenazine, fumarate, risperidone, thiothixene, thioridazine, sulpride, and ziprasidone,
  • the active compound is an anxiolytic agent.
  • suitable anxiolytic agents for use in the buccal sprays of the invention include, but are not limited to, amitryptiline, atracurium, buspirone, chlorzoxazone, clorazepate, cisatracurium, cyclobenzaprine, eperisone, esopiclone hydroxyzine, mirtazapine, mivacurium, pagoclone, sulperide, zaleplon, and zopiclone.
  • the active compound is a dopamine metabolism inhibitor.
  • Suitable dopamine metabolism inhibitors for use in the buccal sprays of the invention include, but are not limited to, entacapone, lazebemide, selegiline, and tolcapone.
  • the active compound is an agent to treat post stroke sequelae.
  • Suitable agents to treat post stroke sequelae for use in the buccal sprays of the invention include, but are not limited to, glatiramer, interferon beta 1A, interferon beta 1B, estradiol, and progesterone.
  • the active compound is a neuroprotectant.
  • Suitable neuroprotectants for use in the buccal sprays of the invention include, but are not limited to, donepezil, memanine, nimodipine, riluzole, rivastigmine, tacrine, TAK147, and xaliproden.
  • the active compound is an agent to treat Alzheimer's disease.
  • Suitable agents to treat Alzheimer's disease for use in the buccal sprays of the invention include, but are not limited to, carbidopa, levodopa, tacrine, donezepil, rivastigmine, and galantamine.
  • the active compound is a neurotransmitter.
  • Suitable neurotransmitters for use in the buccal sprays of the invention include, but are not limited to, acetylcholine, serotonin, 5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate, glycine, histamine, epinephrine, norpinephrine, dopamine, adenosine, ATP, and nitric oxide.
  • the active compound is a neurotransmitter agonist.
  • Suitable neurotransmitter agonists for use in the buccal sprays of the invention include, but are not limited to, almotriptan, aniracetam, atomoxetine, benserazide, bromocriptine bupropion, cabergoline, citalopram, clomipramine, desipramine, diazepam, dihydroergotamine, doxepin duloxetine, eletriptan, escitalopram, fluvoxamine, gabapentin, imipramine, moclobemide, naratriptan, nefazodone, nefiracetam acamprosate, nicergoline, nortyptiline, paroxetine, pergolide, pramipexole, rizatriptan, ropinirole, sertraline, sibutramine, sumatriptan, tiagabine, trazodone, ven
  • the active compound is a sedative.
  • Suitable sedatives for use in the buccal sprays of the invention include, but are not limited to, dexmedetomidine, eszopiclone, indiplon, zolpidem, and zaleplon.
  • the active compound is an agent for treating attention deficit disorder.
  • Suitable agents for treating attention deficit disorder for use in the buccal sprays of the invention include, but are not limited to, amphetamine, dextroamphetamine, methylphenidate, and pemoline.
  • the active compound is an agent for treating narcolepsy.
  • Suitable agents for treating narcolepsy for use in the buccal sprays of the invention include, but are not limited to, modafinil and mazindol.
  • the active compound is a central adregenic antagonists.
  • a suitable central adregenic antagonists for use in the buccal sprays of the invention includes, but is not limited to, mesoridazine.
  • the active compound is an anti-depression agent.
  • Suitable anti-depression agents for use in the buccal sprays of the invention include, but are not limited to, amitriptyline, amoxapine, bupropion, clomipramine, clomipramine, clorgyline, desipramine, doxepin, fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, sertraline, tranylcypromine, trazodone, and venlafaxine.
  • the active compound is an agent for treating Parkinson's disease.
  • Suitable agents for treating Parkinson's disease for use in the buccal sprays of the invention include, but are not limited to, amantadine, bromocriptine, carvidopa, levodopa, pergolide, and selegiline.
  • the active compound is a benzodiazepine antagonist
  • a suitable benzodiazepine antagonist for use in the buccal sprays of the invention includes, but is not limited to, flumazenil.
  • the active compound is a neurotransmitter antagonist.
  • a suitable neurotransmitter antagonist for use in the buccal sprays of the invention includes, but is not limited, to deramciclane.
  • the active compound is a stimulant.
  • Suitable stimulants for use in the buccal sprays of the invention include, but are not limited to, amphetamine, dextroamphetamine, dinoprostone, methylphenidate, methylphenidate, modafinil, and pemoline.
  • the active compound is a tranquilizer.
  • a suitable tranquilizer for use in the buccal sprays of the invention includes, but is not limited to, mesoridazine.
  • 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-dimethylaminoethanol, 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.
  • Calcitonin-salmon lingual spray 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.
  • CNS active amines and their salts including but not limited to tricyclic amines, GABA analogues, thiazides, phenothiazine derivatives, serotonin antagonists and serotonin reuptake inhibitors
  • Sumatriptan succinate lingual spray 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
  • Sumatriptan succinate bite capsule 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 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
  • Clozepine non-polar lingual spray with propellant 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
  • Cyclobenzaprine non-polar lingual spray 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.
  • Glyburide lingual spray 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 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 (formerly called azidothymidine (AZT) (Retrovir)] non-polar lingual spray 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
  • Erythromycin bite capsule bite capsule 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 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 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 ondansetron hydrochloride 1-25 2-20 2.5-15 citric acid monohydrate 1-10 2-8 2.5-5 sodium citrate dihydrate 0.5-5 1-4 1.25-2.5 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 9.5-1 flavors 1-10 3-8 5-7.5
  • Cimetidine hydrochloride bite capsule cimetidine HCl 10-60 15-55 25-50 glycerin 5-20 7.5-15 10-12.5 polyethylene 20-90 25-85 30-75 glycol flavors 1-10 2-8 3-6
  • Carboprost thromethamine lingual spray carboprost thromethamine 0.05-5 0.1-3 0.25-2.5 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 sodium chloride 1-20 3-15 4-8 flavors 0.1-5 1-4 2-3
  • Carboprost non-polar lingual spray carboprost 0.05-5 0.1-3 0.25-2.5 migylol 25-50 30-45 35-40
  • Carnitine as bite capsule contents are a paste
  • 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
  • Valerian as lingual spray 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.
  • 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
  • Diphenhydramine hydrochloride lingual spray preferred most Amounts amount preferred 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 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.
  • Theophylline polar bite capsule 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
  • Albuterol sulfate as polar lingual spray 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
  • Promethazine antiemetic, sleep inducer, and CNS active amine 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 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%

Abstract

Buccal aerosol sprays or capsules using polar and non-polar solvent have now been developed which provide biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect. The buccal polar compositions of the invention comprise formulation I: aqueous polar solvent, active compound, and optional flavoring agent; formulation II: aqueous polar solvent, active compound, optionally flavoring agent, and propellant; formulation III: non-polar solvent, active compound, and optional flavoring agent; and formulation IV: non-polar solvent, active compound, optional flavoring agent, and propellant.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation-in-part of application Ser. No. 09/537,118, filed Mar. 29, 2000 which is a continuation-in-part of the U.S. national phase designation of PCT/US97/17399 filed Oct. 1, 1997, the disclosures of which are incorporated by reference herein in their entirety.
    • BACKGROUND OF THE INVENTION
  • 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 anticoronary 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 trough the membranes to which they are administered.
    • SUMMARY OF THE INVENTION
  • 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%. Preferrably 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 soil 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 0.01-45%, provided that si 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 p-FOX (fatty acid oxidation) inhibitors, acetylcholinesterase inhibitors, nerve impulse inhibitors, anti-cholinergics, anti-convulsants, anti-psychotics, anxiolytic agents, dopamine metabolism inhibitors, agents to treat post stroke sequelae, neuroprotectants, agents to treat Alzheimer's disease, neurotransmitters, neurotransmitter agonists, sedatives, agents for treating attention deficit disorder, agents for treating narcolepsy, central adregenic antagonists, anti-depression agents, agents for treating Parkinson's disease, benzodiazepine antagonists, stimulants, neurotransmitter antagonists, tranquilizer, or a mixture thereof.
    • BRIEF DESCRIPTION OF THE DRAWING
  • FIG. 1. is a schematic diagram showing routes of absorption and processing of pharmacologically active substances in a mammalian system.
    •  DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • 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 isobutane, 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 an 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-C18 hydrocarbon, C2-C6 alkanoyl esters, and the triglycerides of the corresponding acids. When the capsule fill is a paste, other liquid components maybe 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, elozepine; cyclobenzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine, erythromycin, ciprofloxacin ondansetron hydrochloride, dimenhydrinate, cimetidine hydrochloride, famotidine, phenyloin sodium, phenyloin, 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 p-FOX (fatty acid oxidation) inhibitor, acetylcholinesterase inhibitor, nerve impulse inhibitor, anti-cholinergic, anti-convulsant, anti-psychotic, anixiolytic agent, dopamine metabolism inhibitor, agent to treat post stroke sequelae, neuroprotectant, agent to treat Alzheimer's disease, neurotransmitter, neurotransmitter agonist, sedative, agent for treating attention deficit disorder, agent for treating narcolepsy, central adregenic antagonist, anti-expression agent, agent for treating Parkinson's disease, benzodiazepine antagonist, stimulant, neurotransmitter antagonist, tranquilizer, or a mixture thereof.
  • In one embodiment the active compound is a p-FOX inhibitor. A suitable p-FOX inhibitor for use in the buccal sprays of the invention includes, but is not limited to, ranolazine.
  • In one embodiment the active compound is an acetylcholinesterase inhibitor. Suitable acetylcholinesterase inhibitors for use in the buccal sprays of the invention include, but are not limited to, galantamine, neostigmine, physostigmine, and edrophonium.
  • 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, doxaurim, mivacurium, pancuronium, vercuronium, pipecuronium, and rocuronium.
  • In one embodiment the active compound is an anti-cholinergic. Suitable anti-cholinergics for use in the buccal sprays of the invention include, but are not limited to, amantadine, ipratropium, oxitropium, and dicycloverine.
  • In one embodiment the active compound is an anti-convulsant Suitable anti-convulsants for use in the buccal sprays of the invention include, but are not limited to, acetazolamide, carbamazepine, clonazepam, diazepam, divalproex (valproic acid), ethosuximide, lamotrignine acid, levetriacetam, oxcarbazepine, phenobarbital, phenyloin, pregabalin, primidone, remacemide, trimethadione, topiramate, vigabatrin, and zonisamide.
  • In one embodiment the active compound is an anti-psychotic. Suitable anti-psychotics for use in the buccal sprays of the invention include, but are not limited to, amisulpride, aripiprazole bifemelane, bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone loperidone, olanzapine, quetiapine, fluphenazine, fumarate, risperidone, thiothixene, thioridazine, sulpride, and ziprasidone,
  • In one embodiment the active compound is an anxiolytic agent. Suitable anxiolytic agents for use in the buccal sprays of the invention include, but are not limited to, amitryptiline, atracurium, buspirone, chlorzoxazone, clorazepate, cisatracurium, cyclobenzaprine, eperisone, esopiclone hydroxyzine, mirtazapine, mivacurium, pagoclone, sulperide, zaleplon, and zopiclone.
  • In one embodiment the active compound is a dopamine metabolism inhibitor. Suitable dopamine metabolism inhibitors for use in the buccal sprays of the invention include, but are not limited to, entacapone, lazebemide, selegiline, and tolcapone.
  • In one embodiment the active compound is an agent to treat post stroke sequelae. Suitable agents to treat post stroke sequelae for use in the buccal sprays of the invention include, but are not limited to, glatiramer, interferon beta 1A, interferon beta 1B, estradiol, and progesterone.
  • In one embodiment the active compound is a neuroprotectant. Suitable neuroprotectants for use in the buccal sprays of the invention include, but are not limited to, donepezil, memanine, nimodipine, riluzole, rivastigmine, tacrine, TAK147, and xaliproden.
  • In one embodiment the active compound is an agent to treat Alzheimer's disease. Suitable agents to treat Alzheimer's disease for use in the buccal sprays of the invention include, but are not limited to, carbidopa, levodopa, tacrine, donezepil, rivastigmine, and galantamine.
  • In one embodiment the active compound is a neurotransmitter. Suitable neurotransmitters for use in the buccal sprays of the invention include, but are not limited to, acetylcholine, serotonin, 5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate, glycine, histamine, epinephrine, norpinephrine, dopamine, adenosine, ATP, and nitric oxide.
  • In one embodiment the active compound is a neurotransmitter agonist. Suitable neurotransmitter agonists for use in the buccal sprays of the invention include, but are not limited to, almotriptan, aniracetam, atomoxetine, benserazide, bromocriptine bupropion, cabergoline, citalopram, clomipramine, desipramine, diazepam, dihydroergotamine, doxepin duloxetine, eletriptan, escitalopram, fluvoxamine, gabapentin, imipramine, moclobemide, naratriptan, nefazodone, nefiracetam acamprosate, nicergoline, nortyptiline, paroxetine, pergolide, pramipexole, rizatriptan, ropinirole, sertraline, sibutramine, sumatriptan, tiagabine, trazodone, venlafaxine, and zolmitriptan.
  • In one embodiment the active compound is a sedative. Suitable sedatives for use in the buccal sprays of the invention include, but are not limited to, dexmedetomidine, eszopiclone, indiplon, zolpidem, and zaleplon.
  • In one embodiment the active compound is an agent for treating attention deficit disorder. Suitable agents for treating attention deficit disorder for use in the buccal sprays of the invention include, but are not limited to, amphetamine, dextroamphetamine, methylphenidate, and pemoline.
  • In one embodiment the active compound is an agent for treating narcolepsy. Suitable agents for treating narcolepsy for use in the buccal sprays of the invention include, but are not limited to, modafinil and mazindol.
  • In one embodiment the active compound is a central adregenic antagonists. A suitable central adregenic antagonists for use in the buccal sprays of the invention includes, but is not limited to, mesoridazine.
  • In one embodiment the active compound is an anti-depression agent. Suitable anti-depression agents for use in the buccal sprays of the invention include, but are not limited to, amitriptyline, amoxapine, bupropion, clomipramine, clomipramine, clorgyline, desipramine, doxepin, fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, sertraline, tranylcypromine, trazodone, and venlafaxine.
  • In one embodiment the active compound is an agent for treating Parkinson's disease. Suitable agents for treating Parkinson's disease for use in the buccal sprays of the invention include, but are not limited to, amantadine, bromocriptine, carvidopa, levodopa, pergolide, and selegiline.
  • In one embodiment the active compound is a benzodiazepine antagonist A suitable benzodiazepine antagonist for use in the buccal sprays of the invention includes, but is not limited to, flumazenil.
  • In one embodiment the active compound is a neurotransmitter antagonist. A suitable neurotransmitter antagonist for use in the buccal sprays of the invention includes, but is not limited, to deramciclane.
  • In one embodiment the active compound is a stimulant. Suitable stimulants for use in the buccal sprays of the invention include, but are not limited to, amphetamine, dextroamphetamine, dinoprostone, methylphenidate, methylphenidate, modafinil, and pemoline.
  • In one embodiment the active compound is a tranquilizer. A suitable tranquilizer for use in the buccal sprays of the invention includes, but is not limited to, mesoridazine.
  • 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-dimethylaminoethanol, 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.
    • EXAMPLES Example 1 Biologically Active Peptides Including Peptide Hormones
  • Amounts preferred amount most preferred amount
    A. Cyclosporine lingual spray
    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
    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
    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
    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
    sermorelin (as the acetate) .01-5   .1-3   .2-1.0
    mannitol 1-25  5-20 10-15
    monobasic sodium phosphate, 0.1-5    1-31  .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
    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
    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
    insulin 20-60   4-55  5-50
    glycerin 0.1-10   0.25-5   0.1-1.5
    dibasic sodium phosphate 1-15 2.5-10  4-8
    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  
    adjust pH to 7.0-7.8 with HCI or NaOH
    • Example 2
  • CNS active amines and their salts: including but not limited to tricyclic amines, GABA analogues, thiazides, phenothiazine derivatives, serotonin antagonists and serotonin reuptake inhibitors
  • most
    Amounts preferred amount preferred amount
    A. Sumatriptan succinate lingual spray
    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
    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
    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
    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
    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
    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
    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
    • Example 3 Sulfonylureas
  • most
    Amounts preferred amount preferred amount
    A. Glyburide lingual spray
    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
    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
    • Example 4 Antibiotics Anti-Fungals and Anti-Virals
  • preferred most
    Amounts amount preferred amount
    A. Zidovudine
    [formerly called azidothymidine (AZT) (Retrovir)]
    non-polar lingual spray
    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
    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
    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
    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
    • Example 5 Anti-Emetics
  • preferred most
    Amounts amount preferred amount
    A. Ondansetron hydrochloride lingual spray
    ondansetron hydrochloride 1-25  2-20 2.5-15 
    citric acid monohydrate 1-10 2-8 2.5-5  
    sodium citrate dihydrate 0.5-5   1-4 1.25-2.5 
    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  9.5-1 
    flavors 1-10 3-8   5-7.5
    B. Dimenhydrinate bite capsule
    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
    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
    • Example 6 Histamine H-2 Receptor Antagonists
  • Amounts preferred amount most preferred amount
    A. Cimetidine hydrochloride bite capsule
    cimetidine HCl 10-60 15-55 25-50
    glycerin  5-20 7.5-15    10-12.5
    polyethylene 20-90 25-85 30-75
    glycol
    flavors  1-10 2-8 3-6
    B. Famotidine lingual spray
    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 20-97 30-95 50-85
    glycol
    flavors 0.1-10    1-7.5 2-5
    C. Famotidine non-polar lingual spray
    famotidine  1-35  5-30  7-20
    Soya oil 10-50 15-40 15-20
    Butane1  5-80 30-75 45-70
    polyoxyethylated 10-50 15-40 15-20
    oleic glycerides
    flavors 0.1-5   1-4 2-3
    • Example 7 Barbiturates
  • Amounts preferred amount most preferred amount
    A. Phenytoin sodium lingual spray
    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 5-30 7.5-20  9.5-15 
    glycol
    flavors 1-10 3-8   5-7.5
    B. Phenytoin non-polar lingual spray
    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
    • Example 8 Prostaglandins
  • preferred most
    Amounts amount preferred amount
    A. Carboprost thromethamine lingual spray
    carboprost thromethamine 0.05-5    0.1-3   0.25-2.5 
    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
    sodium chloride 1-20  3-15 4-8
    flavors 0.1-5   1-4 2-3
    B. Carboprost non-polar lingual spray
    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
    pH is adjusted with sodium hydroxide and/or hydrochloric acid
    • Example 9 Neutraceuticals
  • most
    Amounts preferred amount preferred amount
    A. Carnitine as bite capsule (contents are a paste)
    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
    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
    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
    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  
    • Example 10 Sleep Inducers (also CNS Active Amine)
  • A. Diphenhydramine hydrochloride lingual spray
    preferred most
    Amounts amount preferred 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 
    • Example 11 Anti-Asthmatics-Bronchodilators
  • preferred most
    Amounts amount preferred amount
    A. Isoproterenol Hydrochloride as polar lingual spray
    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
    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
    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
    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
    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
    • Example 12 Polar Solvent Formulations Using a Propellant
  • Most-Preferred
    Amount Preferred Amount Amount
    A. Sulfonylurea
    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)
    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)
    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
    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 (59)

1-134. (canceled)
135. A method for administering an effective amount of a pharmacologically active compound to a mammal to provide transmucosal absorption of a therapeutically effective amount of the active compound through the oral mucosa of the mammal to the systemic circulatory system of the mammal, comprising:
spraying the oral mucosa of the mammal with a propellant free buccal spray composition, containing a pharmacologically active compound dissolved in a pharmacologically acceptable solvent, comprising in weight percent of the composition:
an active compound in an amount between 0.001 and 60 percent by weight of the total composition comprising an acetylcholinesterase inhibitor, a nerve impulse inhibitor, an anti-cholinergic, an anti-convulsant, an anti-psychotic, an anxiolytic agent, a dopamine metabolism inhibitor, an agent for treating post stroke sequelae, a neuroprotectant, an agent treating Alzheimer's disease, a neurotransmitter, a neurotransmitter agonist, a sedative, an agent for treating attention deficit disorder, an agent for treating narcolepsy, a central adregenic antagonist, an anti-depression agent, an agent for treating Parkinson's disease, a benzodiazepine antagonist, a stimulant, a neurotransmitter antagonist, a tranquilizer or a mixture thereof; and
a polar solvent in an amount between 30 and 99.69 percent by weight of the total composition.
136. The method of claim 135, wherein the active compound is an acetylcholinesterase inhibitor comprising galantamine, neostigmine, physostigmine, edrophonium or a mixture thereof.
137. The method of claim 135, wherein the active compound is a nerve impulse inhibitor comprising levobupivacaine, lidocaine, prilocaine, mepivacaine, propofol, rapacuronium bromide, ropivacaine, tubocurarine, atracurium, doxaurium, mivacuium, pancuronium, vercuronium, pipecuronium, rocurronium or a mixture thereof.
138. The method of claim 135, wherein the active compound is an anti-cholinergic comprising amantadine, ipratropium, oxitropium, dicycloverine or a mixture thereof.
139. The method of claim 135, wherein the active compound is an anti-convulsant comprising acetazolamide, carbamazepine, clonazepam, diazepam, divalproex, ethosuximide, lamotrignine acid, levetriacetam, oxcarbazepine, Phenobarbital, phenyloin, pregabalin, primidone, remacemide, trimethadione, topiramate, vigabatrin, zonisamide or a mixture thereof.
140. The method of claim 135, wherein the active compound is an anti-psychotic comprising amisulpride, aripiprazole bifemelane, bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone loperidone, olanzapine, quetiapine, fluphenazine, esperidone, thiothixene, thioridazine, sulpride, ziprasidone or a mixture thereof.
141. The method of claim 135, wherein the active compound is an anxiolytic agent comprising amitryptiline, atracurium, buspirone, chlorzoxazone, clorazepate, cisatracurium, cyclobenzaprine, eperisone, esopiclone, hydroxyzine, mirtazapine, mivacurium, pagoclone, superide, zaleplon, zopiclone or a mixture thereof.
142. The method of claim 135, wherein the active compound is a dopamine metabolism inhibitor comprising entacapone, lazebemide, selegiline, tolcapone or a mixture thereof.
143. The method of claim 135, wherein the active compound is an agent for treating post stroke sequelae comprising glatiramer, estradiol, progesterone or a mixture thereof.
144. The method of claim 135, wherein the active compound is a neuroprotectant comprising donepezil, memanine, nimodipine, riluzole, rivastigmine, tacrine, xaliproden or a mixture thereof.
145. The method of claim 135, wherein the active compound is a agent for treating Alzheimer's disease comprising carbidopa, levodopa, tacrine, donezepil, rivastigmine, galantamine or a mixture thereof.
146. The method of claim 135, wherein the active compound is a neurotransmitter comprising acetylcholine, serotonin, 5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate, glycine, histamine, epinephrine, norpinephrine, dopamine, adenosine, ATP nitric oxide or a mixture thereof.
147. The method of claim 135, wherein the active compound is a neurotransmitter agonist comprising almotriptan, aniracetam, atomoxetine, benserazide, bromocriptine, bupropion, cabergoline, citalopram, clomipramine, desipramine, diazepam, dihydroergotmine, doxepin duloxetine, eletriptan, escitalopram, fluvoxamine, gabapentin, imipramine, moclobemide, naratriptan, nefazodone, nefiracetam acamprosate, nicergoline, nortryptiline, paroxetine, pergolide, pramipexole, rizatriptan, ropinirole, sertraline, sibutramine, sumatriptan, tiagabine, trazodone, venlafaxine, zolmitriptan or a mixture thereof.
148. The method of claim 135, wherein the active compound is a sedative comprising dexmedetomidine, eszopiclone, indiplon, zolpidem, zaleplon or a mixture thereof.
149. The method of claim 135, wherein the active compound is an agent for treating attention deficit disorder comprising amphetamine, dextroamphetamine, methylphenidate, pemoline or a mixture thereof.
150. The method of claim 135, wherein the active compound is an agent for treating narcolepsy comprising modafinil, mazindol or a mixture thereof.
151. The method of claim 135, wherein the active compound is an anti-depression agent comprising amitriptyline, amoxapine, bupropion, clomipramine, clorgyline, despipramine, doxepin, fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, sertraline, tranylcypromine, trazodone, venlafaxine or a mixture thereof.
152. The method of claim 135, wherein the active compound is an agent for treating Parkinson's disease comprising amantadine, bromocriptine, carvidopa, levodopa, pergolide, selegiline or a mixture thereof.
153. The method of claim 135, wherein the active compound comprises flumazenil.
154. The method of claim 135, wherein the active compound comprises deramciclane.
155. The method of claim 135, wherein the active compound is a stimulant comprising amphetamine, dextroamphetamine, dinoprostone, methylphenidate, methylphenidate, modafinil, pemoline or a mixture thereof.
156. The method of claim 135, wherein the active compound comprises mesoridazine.
157. The method of claim 135, wherein the amount of the spray is predetermined.
158. The method of claim 135, further comprising a flavoring agent in an amount between 0.1 and 10 percent by weight of the total composition.
159. The method of claim 158, wherein the flavoring agent comprises a synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavor, sweetener or a mixture thereof.
160. The method of claim 158, wherein the polar solvent is present in an amount between 37 and 98.58 percent by weight of the total composition, the active compound is present in an amount between 0.005 and 55 percent by weight of the total composition, and the flavoring agent is present in an amount between 0.5 and 8 percent by weight of the total composition.
161. The method of claim 160, wherein the polar solvent is present in an amount between 60.9 and 97.06 percent by eight of the total composition, the active compound is present in an amount between 0.01 and 40 percent by weight of the total composition, and the flavoring agent is present in an amount between 0.75 and 7.5 percent by weight of the total composition.
162. The method of claim 135, wherein the polar solvent comprises a polyethylene glycol having a molecular weight between 400 and 1000, a C2 to C8 mono- and polyalcohol, or a C7 to C18 alcohol of linear or branched configuration.
163. The method of claim 135, wherein the polar solvent comprises aqueous polyethylene glycol.
164. The method of claim 135, wherein the polar solvent comprises aqueous ethanol.
165. A method for administering an effective amount of a pharmacologically active compound to a mammal to provide transmucosal absorption of a therapeutically effective amount of the active compound through the oral mucosa of the mammal to the systemic circulatory system of the mammal, comprising:
spraying the oral mucosa of the mammal with a propellant free buccal spray composition, containing a pharmacologically active compound dissolved in a pharmacologically acceptable solvent, comprising in weight percent of the composition:
an active compound in an amount between 0.005 and 55 percent by weight of the total composition comprising an acetylcholinesterase inhibitor, a nerve impulse inhibitor, an anti-cholinergic, an anti-convulsant, an anti-psychotic, an anxiolytic agent, a dopamine metabolism inhibitor, an agent for treating post stroke sequelae, a neuroprotectant, an agent treating Alzheimer's disease, a neurotransmitter, a neurotransmitter agonist, a sedative, an agent for treating attention deficit disorder, an agent for treating narcolepsy, a central adregenic antagonist, an anti-depression agent, an agent for treating Parkinson's disease, a benzodiazepine antagonist, a stimulant, a neurotransmitter antagonist, a tranquilizer or a mixture thereof; and
a non-polar solvent in an amount between 30 and 99.69 percent by weight of the total composition.
166. The method of claim 165, further comprising a flavoring agent in an amount between 0.1 and 10 percent by weight of the total composition.
167. The method of claim 165, wherein the active compound is an acetylcholinesterase inhibitor comprising galantamine, neostigmine, physostigmine, and edrophonium or a mixture thereof.
168. The method of claim 165, wherein the active compound is a nerve impulse inhibitor comprising levobapivacaine, lidocaine, prilocaine, mepivacaine, propofol, rapacuronium bromide, ropivacaine, tubocurarine, atracurium, doxaurium, mivacuium, pancuronium, vercuronium, pipecuronium, rocuronium or a mixture thereof.
169. The method of claim 165, wherein the active compound is an anti-cholinergic comprising amantadine, ipretropium, oxitropium, dicycloverine or a mixture thereof.
170. The method of claim 165, wherein the active compound is an anti-convulsant comprising acetazloamide, earbamazepine, clonazepatn, diazepam, divalproex, ethosuximide, lamotrignine acid, levetriacetam, oxcarbazepine, phenobarbital, phenyloin, pregabalin, primidone, remacemide, trimethadione, topiramate, vigabatrin, zonisamide or a mixture thereof.
171. The method of claim 165, wherein the active compound is an anti-psychotic comprising amisulpride, aripiprazole bifemelane, bromperidol, clozapine, chlorpromazine, haloperidol, iloperidone loperidone, olanzapine, quetiapine, fluphenazine, risperidone, thiothixene, thioridazine, sulpride, ziprasidone or a mixture thereof.
172. The method of claim 165, wherein the active compound is an anxiolytic agent comprising amitryptiline, atracurium, buspirone, chlorzoxazone, clorazepate, cisatracurium, cyclobenzaprine, eperisone, esopiclone, hydroxyzine, mirtazapine, mivacurium, pagoclone, sulperide, zaleplon, zopiclone or a mixture thereof.
173. The method of claim 165, wherein the active compound is a dopamine metabolism inhibitor comprising entacapone, lazebemide, selegiline, tolcapone or a mixture thereof.
174. The method of claim 165, wherein the active compound is an agent for treating post stroke sequelae comprising glatiramer, estradiol, progesterone or a mixture thereof.
175. The method of claim 165, wherein the active compound is a neuroprotectant comprising donepezil, memanine, nimodipine, riluzole, rivastigmine, tacrine, xaliproden or a mixture thereof.
176. The method of claim 165, wherein the active compound is an agent for treating Alzheimer's disease comprising carbidopa, lelvodopa, tacrine, donezepil, rivastigmine, galantamine or a mixture thereof.
177. The method of claim 165, wherein the active compound is a neurotransmitter comprising acetylcholine, serotonin, 5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate, glycine, histamine, epinephrine, norpinephrine, dopamine, adenosine, ATP, nitric oxide or a mixture thereof.
178. The method of claim 165, wherein the active compound is a neurotransmitter agonist comprising almotriptan, aniracetam, atomoxetine, benserazide, bromociptine, bupropion, cabergoline, citalopram, clomipramine, desipramine, diazepam, dihydroergotamine, doxepin duloxetine, eletriptan, escitalopram, fluvoxamine, gabapentin, imipramine, moclobemide, naratriptan, nefazodone, nefiracetam, acamprosate, nicergoline, nortryptiline, paroxetine, pergolide, pramipexole, rizatriptan, ropinirole, sertraline, sibutramine, sumatriptan, tiagabine, trazodone, venlafaxine, zolmitriptan or a mixture thereof.
179. The method of claim 165, wherein the active compound is a sedative comprising dexmedetomidine, eszopiclone, indiplon, zolpidem, zaleplon or a mixture thereof.
180. The method of claim 165, wherein the active compound is an agent for treating attention deficit disorder comprising amphetamine, dextroamphetamine, methylphenidate, pemoline or a mixture thereof.
181. The method of claim 165, wherein the active compound is an agent for treating narcolepsy comprising modafinil, mazindol or a mixture thereof.
182. The method of claim 165, wherein the active compound is an anti-depression agent comprising amitriptyline, amoxapine, bupropion, clomipramine, clomipramine, clorgyline, despipramine, doxepin, fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, sentraline, tranylcyporomine, trazodone, venlafaxine or a mixture thereof.
183. The method of claim 165, wherein the active compound is an agent for treating Parkinson's disease comprising amantadine, bromocriptine, carvidopa, levodopa, pergolide, selegiline or a mixture thereof.
184. The method of claim 165, wherein the active compound comprises flumazenil.
185. The method of claim 165, wherein the active compound comprises deramciclane.
186. The method of claim 165, wherein the active compound is a stimulant comprising amphetamine, dextroamphetamine, dinoprostone, methylphenidate, methylphenidate, modafinil, pemoline or a mixture thereof.
187. The method of claim 165, wherein the active compound comprises mesoridazine.
188. The method of claim 165, wherein the amount of the spray is predetermined.
189. The method of claim 165, further comprising a flavoring agent which comprises a synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavor, sweetener or a mixture thereof.
190. The method of claim 165, wherein the solvent comprises a (C2-C24) fatty acid (C2-C6) ester, a C7-C18 hydrocarbon of linear or branched configuration, a C2-C6 alkanoyl ester, or a triglyceride of C2-C6 carboxylic acid.
191. The method of claim 190, wherein the solvent comprises one or more fatty acid esters.
192. A method for administering an effective amount of a pharmacologically active sedative to a mammal to provide transmucosal absorption of a therapeutically effective amount of the sedative through the oral mucosa of the mammal to the systemic circulatory system of the mammal, comprising:
spraying the oral mucosa of the mammal with a propellant free buccal spray composition, containing a pharmacologically active sedative dissolved in a pharmacologically acceptable solvent, comprising in weight percent of the composition:
zolpidem in an amount between 0.001 and 60 percent by weight of the total composition; and
propylene glycol in an amount between 30 and 99.69 percent by weight of the total composition;
wherein a therapeutically effective amount of zolpidem is absorbed through the oral mucosa to the systemic circulatory system to the mammal.
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US20090162298A1 (en) * 1997-10-01 2009-06-25 Dugger Iii Harry A Buccal, polar and non-polar spray containing sumatriptan
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US20090186035A1 (en) * 1997-10-01 2009-07-23 Dugger Iii Harry A Buccal, polar and non-polar spray or capsule containing drugs for treating an infectious disease or cancer
US6037346A (en) * 1997-10-28 2000-03-14 Vivus, Inc. Local administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction
US20040191178A1 (en) * 2001-07-05 2004-09-30 R.T. Alamo Ventures I, Inc. Administration of dihydroergotamine as a sublingual spray or aerosol for the treatment of migraine

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US20080170995A1 (en) * 1997-10-01 2008-07-17 Novadel Pharma Inc. Buccal, polar and non-polar spray or capsule containing cardiovascular or renal drugs
US20090118170A1 (en) * 1997-10-01 2009-05-07 Dugger Iii Harry A Buccal, polar and non-polar spray or capsule
US20090123387A1 (en) * 1997-10-01 2009-05-14 Dugger Iii Harry A Buccal, polar and non-polar spray or capsule containing cardiovascular or reneal drugs
US20090124554A1 (en) * 1997-10-01 2009-05-14 Dugger Iii Harry A Buccal, polar and non-polar spray or capsule containing drugs for treating pain
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US20090162297A1 (en) * 1997-10-01 2009-06-25 Dugger Iii Harry A Buccal, polar and non-polar spray containing ondansetron
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US20040120895A1 (en) 2004-06-24
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WO2004035021A2 (en) 2004-04-29
EP2277506A1 (en) 2011-01-26
US6977070B2 (en) 2005-12-20
EP2283814A1 (en) 2011-02-16
US20030077227A1 (en) 2003-04-24
CA2497262A1 (en) 2004-04-29
EP2283813A1 (en) 2011-02-16
EP2283815A1 (en) 2011-02-16
WO2004035021A3 (en) 2004-11-11
AU2003298564A1 (en) 2004-05-04
EP1539106A2 (en) 2005-06-15

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