US20040136914A1 - Buccal, polar and non-polar spray containing ondansetron - Google Patents

Buccal, polar and non-polar spray containing ondansetron Download PDF

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US20040136914A1
US20040136914A1 US10/671,717 US67171703A US2004136914A1 US 20040136914 A1 US20040136914 A1 US 20040136914A1 US 67171703 A US67171703 A US 67171703A US 2004136914 A1 US2004136914 A1 US 2004136914A1
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amount
composition
patient
percent
weight
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US10/671,717
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Harry Dugger
Mohammed Abd El-Shafy
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Flemington Pharmaceutical Corp
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Flemington Pharmaceutical Corp
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Priority claimed from PCT/US1997/017899 external-priority patent/WO1999016417A1/en
Priority claimed from US10/230,085 external-priority patent/US20030095926A1/en
Priority to US10/671,717 priority Critical patent/US20040136914A1/en
Application filed by Flemington Pharmaceutical Corp filed Critical Flemington Pharmaceutical Corp
Assigned to NOVADEL PHARMA, INC. reassignment NOVADEL PHARMA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DUGGER, HARRY A., EL-SHAFY, III, MOHAMMED ABD
Publication of US20040136914A1 publication Critical patent/US20040136914A1/en
Priority to EP04789153A priority patent/EP1682090A1/en
Priority to KR1020067008480A priority patent/KR20060090997A/en
Priority to JP2006534019A priority patent/JP2007507509A/en
Priority to CA002554954A priority patent/CA2554954A1/en
Priority to PCT/US2004/031801 priority patent/WO2005032520A1/en
Priority to IL174623A priority patent/IL174623A0/en
Priority to US11/429,953 priority patent/US20060198790A1/en
Assigned to PROQUEST INVESTMENTS III, L.P. AS COLLATERAL AGENT FOR SECURED PARTIES reassignment PROQUEST INVESTMENTS III, L.P. AS COLLATERAL AGENT FOR SECURED PARTIES SECURITY AGREEMENT Assignors: NOVADEL PHARMA INC.
Priority to US12/350,602 priority patent/US20090162297A1/en
Priority to US12/632,719 priority patent/US20100152262A1/en
Assigned to NOVADEL PHARMA INC. reassignment NOVADEL PHARMA INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: PROQUEST INVESTMENTS III, L.P. AS COLLATERAL AGENT
Priority to US13/445,331 priority patent/US9078816B2/en
Priority to US13/450,987 priority patent/US20120202866A1/en
Abandoned legal-status Critical Current

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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 Pamell 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.
  • Ondansetron is a 5-HT 3 receptor antagonist.
  • the structure of ondansetron is depicted below:
  • Ondansetron is an anti-emetic used to treat nausea and/or vomiting, especially chemotherapy and radiation induced nausea and/or vomiting ( Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 th ed., pp. 260). Ondansetron is also used as a pre-operative anti-emetic ( Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 th ed., pp. 304). Administration of ondansetron in combination with a corticosteroid, such as phenothiazine or butyrophenone, can increase efficacy as an anti-emetic ( Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 th ed., pp. 928). Ondansetron can also be used to treat anxiety ( Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 th ed., pp. 427).
  • Ondansetron can be administered orally, intravenously, or intramuscularly.
  • Ondansetron when administered as an anti-emetic for severe chemotherapy-induced emesis, is typically administered at a single daily dose of 32 mg by intravenous infusion over about 15 minutes about 30 minutes prior to chemotherapy or intravenously in 3 divided doses of 0.1 to 0.15 mg/kg with the first dose given about 30 minutes prior to chemotherapy and the following doses given 4 and 8 hours after the initial dose.
  • ondansetron can be administered at a daily dose of 32 mg in combination with a daily dose of 20 mg dexamethasone, each administered by intravenous infusion.
  • ondansetron is typically administered orally (as a tablet or solution) at a dose of 8 mg (tablet) or 10 mg (solution) about 30 minutes prior to chemotherapy followed by a second dose 8 hours later. The dose can then be repeated twice per day for 1 to 2 days following chemotherapy ( Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 th ed., pp. 928-930).
  • ondansetron The oral bioavailability of ondansetron is about 60 percent with effective blood levels appearing 30 to 60 minutes after administration. Ondansetron is extensively metabolized by the liver with a plasma half-life of about 3 to 4 hours. Adverse effects of ondansetron are mild and include headaches, constipation, and dizziness ( Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 th ed., pp. 928-930).
  • 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 polar aerosol spray compositions of the present invention for transmucosal administration of a pharmacologically active compound comprises a mixture of a polar solvent and a non-polar solvent comprising in weight % of total composition: solvent 10-97%, active compound 0.05-50%, propellant 5-80%, and optionally a taste mask and/or flavoring agent 0.01-10%.
  • the composition comprises: solvent 20-97%, active compound 0.1-40%, propellant 10-70%, and taste mask and/or flavoring agent 1-8%; most suitably solvent 25-97%, active compound 0.25-35%, propellant 20-70%, and taste mask and/or flavoring agent 2-7.5%.
  • the ratio of the polar solvent to the non-polar solvent can range from about 1:99 to about 99:1, preferable from about 60:40 to about 40:60, and more preferably about 50:50.
  • 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 composition comprises: solvent 37-98.58%, active compound 0.005-55%, taste mask and/or flavoring agent 0.5-8%; more preferably the composition comprises solvent 60.9-97.06%, active compound 0.01-40%, and taste mask and/or flavoring agent 0.75-7.5%.
  • the ratio of the polar solvent to the non-polar solvent can range from about 1:99 to about 99:1, preferable about 60:40 to about 40:60, and more preferably about 50:50.
  • 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 anti-diuretics, anti-muscle spasm agents, anti-spasmodics, agents for treating urinary incontinence, anti-diarrheal agents, agents for treating nausea and/or vomiting, smooth muscle contractile agents, anti-secretory agents, enzymes, anti-diuretics, anti-ulcerants, bile acid replacement and/or gallstone solubilizing drugs, or mixtures thereof.
  • the active compound is ondansetron or a pharmaceutically acceptable salt 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
  • 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.
  • compositions may further include a taste mask.
  • taste mask as used herein means an agent that can hide or minimize an undesirable flavor such as a bitter or sour flavor.
  • a representative taste mask is a combination of vanillin, ethyl vanillin, maltol, iso-amyl acetate, ethyl oxyhydrate, anisic aldehyde, and propylene glycol (commercially available as “PFC 9885 Bitter Mask” from Pharmaceutical Flavor Clinic of Camden, N.J.).
  • a taste mask in combination with a flavoring agent is particularly advantageous when the active compound is an alkaloid since alkaloids often have a bitter taste.
  • 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 an anti-diuretic, anti-muscle spasm agent, anti-spasmodic, agent for treating urinary incontinence, anti-diarrheal agent, agent for treating nausea and/or vomiting, smooth muscle contractile agent, anti-secretory agent, enzyme, anti-diuretic, anti-ulcerant, bile acid replacement and/or gallstone solubilizing drug, or a mixture thereof
  • the active compound is an anti-diuretic.
  • Suitable anti-diuretics for use in the buccal sprays of the invention include, but are not limited to, acetazolamide, benzthiazide, bendroflumethazide, bumetanide, chlorthalidone, chlorothiazide, ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, quinethazone, spironolactone, triamterene, torsemide, trichlomethiazide, 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 an anti-spasmodic.
  • Suitable anti-spasmodics for use in the buccal sprays of the invention include, but are not limited to, atropine, baclofen, dicyclomine, hyoscine, propatheline, oxybutynin, S-oxybutynin, tizanidine, and mixtures thereof.
  • the active compound is an agent for treating urinary incontinence.
  • Suitable agents for treating urinary incontinence for use in the buccal sprays of the invention include, but are not limited to, darifenacin, vamicamide, detrol, ditropan, imipramine, and mixtures thereof.
  • the active compound is an anti-diarrheal agent.
  • Suitable anti-diarrheal agents for use in the buccal sprays of the invention include, but are not limited to, ondansetron, palnosetron, tropisetron, attapulgite, atropine, bismuth, diphenoxylate, loperamide, and mixtures thereof.
  • the active compound is an agent for treating nausea and/or vomiting.
  • Suitable agents for treating nausea and/or vomiting for use in the buccal sprays of the invention include, but are not limited to, alosetron, dolasetron, granisetron, meclizine, metoclopramide, ondansetron, palnosetron, prochloperazine, promethazine, trimethobenzamiode, tropisetron, and mixtures thereof.
  • the active compound is a smooth muscle contractile agent.
  • a suitable smooth muscle contractile agents for use in the buccal sprays of the invention includes, but is not limited to hyoscine.
  • the active compound is an anti-secretory agent.
  • Suitable anti-secretory agents for use in the buccal sprays of the invention include, but are not limited to, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, tenetoprazole, ecabet, misoprostol, teprenone, and mixtures thereof.
  • the active compound is an enzyme.
  • Suitable enzymes for use in the buccal sprays of the invention include, but are not limited to, alpha-galactosidase, alpha-L-iduronidase, imiglucerase/alglucerase, amylase, lipase, protease, pancreatin, olsalazine, and mixtures thereof.
  • the active compound is an anti-diuretic.
  • Suitable anti-diuretics for use in the buccal sprays of the invention include, but are not limited to, desmopressin, oxytocin, and mixtures thereof.
  • the active compound is an anti-ulcerant.
  • Suitable anti-ulcerants for use in the buccal sprays of the invention include, but are not limited to, cimetidine, ranitidine, famotidine, misoprostol, sucralfate, pantoprazole, lansoprazole, omeprazole, and mixtures thereof.
  • the active compound is a bile acid replacement and/or gallstone solubilizing drug.
  • a suitable bile acid replacement and/or gallstone solubilizing drug for use in the buccal sprays of the invention includes, but is not limited to ursodiol.
  • the active compound is ondansetron, or a pharmaceutically acceptable salt thereof. In one embodiment, the active compound is ondansetron hydrochloride.
  • the buccal spray contains from about contains form about 0.01 to 20 weight/weight (w/w) percent ondansetron, or a pharmaceutically acceptable salt thereof, preferably, about 0.1 to 15 w/w percent, and more preferably about 0.2 to 10 w/w percent ondansetron, or a pharmaceutically acceptable salt thereof.
  • the invention further relates to a method for treating emesis in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising ondansetron or a pharmaceutically acceptable salt thereof.
  • the emesis is chemotherapy induced emesis.
  • the emesis is radiation induced emesis.
  • the ondansetron or a pharmaceutically acceptable salt thereof, is administered in combination with a corticosteroid, such as phenothiazine or butyrophenone.
  • a corticosteroid such as phenothiazine or butyrophenone.
  • the ondansetron, or a pharmaceutically acceptable salt thereof is administered in combination with dexamethasone.
  • the oral mucosa of the patient is sprayed with ondansetron, or a pharmaceutically acceptable salt thereof, before chemotherapy or radiation therapy begins.
  • ondansetron, or a pharmaceutically acceptable salt thereof is sprayed on the oral mucosa of the patient between about 5 minutes and about 2 hours before chemotherapy or radiation therapy begins, preferably between about 15 minutes and about 1 hour, more preferably between about 30 minutes before chemotherapy or radiation therapy begins.
  • the method further includes administering ondansetron, or a pharmaceutically acceptable salt thereof, after chemotherapy or radiation therapy is ended.
  • the ondansetron, or a pharmaceutically acceptable salt thereof is sprayed on the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy has ended, preferable between about 2 hours and about 5 hours, more preferably about 4 hours after chemotherapy or radiation therapy has ended.
  • the emesis is anesthetic induced emesis. Accordingly, the invention further relates to a method of administering anesthesia by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising ondansetron or a pharmaceutically acceptable salt thereof before the anesthesis is administered.
  • the invention further relates to a method for treating anxiety in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising ondansetron or a pharmaceutically acceptable salt thereof.
  • 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 most Amounts preferred amount preferred 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 Amounts amount preferred 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 Capsule Amounts preferred amount most preferred 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
  • Cyclosporine Bite Capsule most Amounts preferred amount preferred 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
  • Calcitonin-Salmon Lingual Spray most Amounts preferred amount preferred 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 most preferred Amounts preferred 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
  • CNS Active Amines and their Salts Including But not Limited to Tricyclic Amines, GABA Analogues, Thiazides, Phenothiazine Derivatives, Serotonin Antagonists and Aerotonin Reuptake Inhibitors
  • A. Sumatriptan Succinate Lingual Spray most Amounts preferred amount preferred 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
  • Clozepine Lingual Spray most Amounts preferred amount preferred 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
  • Cyclobenzaprine Non-Polar Lingual Spray most Amounts preferred amount preferred 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
  • Dexfenfluramine Hydrochloride Lingual Spray most Amounts preferred amount preferred 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
  • Glyburide Lingual Spray most Amounts preferred amount preferred 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 most Amounts preferred amount preferred 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 (AZT) (Retrovir)] non-polar lingual spray Amounts preferred amount most preferred 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
  • Erythromycin Bite Capsule Bite Capsule most preferred Amounts preferred 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
  • D. Zidovudine [Formerly Called Azidothymidine (AZT) (Retrovir)] Lingual Spray most preferred Amounts preferred amount 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 preferred most preferred Amounts amount amount amount 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 9.5-15 flavors 1-10 3-8 5-7.5
  • a Propellant Free Ondansetron Formulation in a Polar Solvent can be Made according to the following Formula: Component Percent (w/w) Ondansetron Hydrochloride 4 Tween 80 0.5 EDTA 0.02 Ethanol 10 Glycerol 5 Water QS to 100
  • a Propellant Free Ondansetron Formulation in a Non-Polar Solvent can be Made according to the following Formula Component Percent (w/w) Ondansetron 0.2 Bitter Mask 0.50.1 Alpha-tocopherol Acetate 2 Liquid Paraffin QS to 100
  • a Propellant Free Ondansetron Formulation in a Mixture of a Polar Solvent and a Non-Polar Solvent can be Made according to the following Formula Component Percent (w/w) Ondansetron 0.1 Miglyol 810 20 Polysorbate (span) 1 Lemon Oil 0.1 Ethanol QS to 100
  • An Ondansetron Formulation in a Non-Polar Solvent with a Propellant can be Made according to the following Formula: Component Percent (w/w) Ondansetron 0.1 Lemon Oil 0.2 Miglyol 20 Butane 100
  • Dimenhydrinate Polar Lingual Spray most preferred Amounts preferred amount 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 preferred Amounts preferred amount 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
  • 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
  • A. Carboprost Thromethamine Lingual Spray preferred most preferred Amounts amount amount amount 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
  • Echinacea as Bite Capsule most Amounts preferred amount preferred 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 Amounts preferred 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 most Amounts preferred amount preferred amount isoproterenol 0.1-10 0.2-7.5 0.5-6 Hydrochloride 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 Amounts preferred amount preferred 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- Amount Preferred Amount Preferred 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

Buccal aerosol sprays or capsules using polar and non-polar solvents have now been developed which provide ondansetron 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, ondansetron, and optional flavoring agent; formulation II: aqueous polar solvent, ondansetron, optionally flavoring agent, and propellant; formulation III: non-polar solvent, ondansetron, and optional flavoring agent; formulation IV: non-polar solvent, ondansetron, optional flavoring agent, and propellant; formulation V: a mixture of a polar solvent and a non-polar solvent, ondansetron, and optional flavoring agent; formulation VI: a mixture of a polar solvent and a non-polar solvent, ondansetron, optional flavoring agent, and propellant.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation-in-part of application Ser. No. 10/230,085, filed Aug. 29, 2002, now pending, which 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/US97/17899 filed Oct. 1, 1997, the disclosures of which are incorporated by reference herein in their entirety.[0001]
    • 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 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 Pamell 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. [0002]
  • Ondansetron is a 5-HT[0003] 3 receptor antagonist. The structure of ondansetron is depicted below:
    Figure US20040136914A1-20040715-C00001
  • Ondansetron is an anti-emetic used to treat nausea and/or vomiting, especially chemotherapy and radiation induced nausea and/or vomiting ([0004] Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 260). Ondansetron is also used as a pre-operative anti-emetic (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 304). Administration of ondansetron in combination with a corticosteroid, such as phenothiazine or butyrophenone, can increase efficacy as an anti-emetic (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 928). Ondansetron can also be used to treat anxiety (Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 427).
  • Ondansetron can be administered orally, intravenously, or intramuscularly. Ondansetron, when administered as an anti-emetic for severe chemotherapy-induced emesis, is typically administered at a single daily dose of 32 mg by intravenous infusion over about 15 minutes about 30 minutes prior to chemotherapy or intravenously in 3 divided doses of 0.1 to 0.15 mg/kg with the first dose given about 30 minutes prior to chemotherapy and the following doses given 4 and 8 hours after the initial dose. To treat severe chemotherapy-induced emesis, ondansetron can be administered at a daily dose of 32 mg in combination with a daily dose of 20 mg dexamethasone, each administered by intravenous infusion. For moderate chemotherapy-induced emesis, ondansetron is typically administered orally (as a tablet or solution) at a dose of 8 mg (tablet) or 10 mg (solution) about 30 minutes prior to chemotherapy followed by a second dose 8 hours later. The dose can then be repeated twice per day for 1 to 2 days following chemotherapy ([0005] Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 928-930).
  • The oral bioavailability of ondansetron is about 60 percent with effective blood levels appearing 30 to 60 minutes after administration. Ondansetron is extensively metabolized by the liver with a plasma half-life of about 3 to 4 hours. Adverse effects of ondansetron are mild and include headaches, constipation, and dizziness ([0006] Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 928-930).
    • 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. [0007]
  • 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%. [0008]
  • 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%. [0009]
  • In another embodiment, the buccal polar aerosol spray compositions of the present invention for transmucosal administration of a pharmacologically active compound (i.e., those administrable in aerosol form driven by a propellant) comprises a mixture of a polar solvent and a non-polar solvent comprising in weight % of total composition: solvent 10-97%, active compound 0.05-50%, propellant 5-80%, and optionally a taste mask and/or flavoring agent 0.01-10%. Preferably the composition comprises: solvent 20-97%, active compound 0.1-40%, propellant 10-70%, and taste mask and/or flavoring agent 1-8%; most suitably solvent 25-97%, active compound 0.25-35%, propellant 20-70%, and taste mask and/or flavoring agent 2-7.5%. The ratio of the polar solvent to the non-polar solvent can range from about 1:99 to about 99:1, preferable from about 60:40 to about 40:60, and more preferably about 50:50. [0010]
  • 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%. [0011]
  • 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%. [0012]
  • In another embodiment, the buccal pump spray composition (i.e., the propellant free composition) for transmucosal administration of a pharmacologically active compound comprises a mixture of a polar solvent and a non-polar solvent comprising in weight % of total composition solvent 30-99.69%, active compound 0.001-60%, and optionally a taste mask and/or flavoring agent 0.1-10%. Preferably the composition comprises: solvent 37-98.58%, active compound 0.005-55%, taste mask and/or flavoring agent 0.5-8%; more preferably the composition comprises solvent 60.9-97.06%, active compound 0.01-40%, and taste mask and/or flavoring agent 0.75-7.5%. The ratio of the polar solvent to the non-polar solvent can range from about 1:99 to about 99:1, preferable about 60:40 to about 40:60, and more preferably about 50:50. [0013]
  • 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%. [0014]
  • 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%. [0015]
  • 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. [0016]
  • 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. [0017]
  • 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. [0018]
  • As the propellant evaporates after activation of the aerosol valve, a mist of fine droplets is formed which contains solvent and active compound. [0019]
  • The propellant is a non-Freon material, preferably a C[0020] 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[0021] 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. Such containers are commercially available. [0022]
  • 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. [0023]
  • 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.) [0024]
  • 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. [0025]
  • 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%. [0026]
  • 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. [0027]
  • 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. [0028]
  • The active compounds may also include anti-diuretics, anti-muscle spasm agents, anti-spasmodics, agents for treating urinary incontinence, anti-diarrheal agents, agents for treating nausea and/or vomiting, smooth muscle contractile agents, anti-secretory agents, enzymes, anti-diuretics, anti-ulcerants, bile acid replacement and/or gallstone solubilizing drugs, or mixtures thereof. [0029]
  • In one embodiment, the active compound is ondansetron or a pharmaceutically acceptable salt thereof.[0030]
    • 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.[0031]
    • 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. [0032]
  • 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%. [0033]
  • Suitable non-polar solvents for the capsules and the non-polar sprays include (C[0034] 2-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 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 (C[0035] 2-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. [0036]
  • Therefore, the values given herein are for the compositions as prepared, it being within the scope of the invention that minor variations will occur. [0037]
  • 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. [0038]
  • The compositions may further include a taste mask. The term “taste mask” as used herein means an agent that can hide or minimize an undesirable flavor such as a bitter or sour flavor. A representative taste mask is a combination of vanillin, ethyl vanillin, maltol, iso-amyl acetate, ethyl oxyhydrate, anisic aldehyde, and propylene glycol (commercially available as “PFC 9885 Bitter Mask” from Pharmaceutical Flavor Clinic of Camden, N.J.). A taste mask in combination with a flavoring agent is particularly advantageous when the active compound is an alkaloid since alkaloids often have a bitter taste. [0039]
  • 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. [0040]
  • In another embodiment, the active compound is an anti-diuretic, anti-muscle spasm agent, anti-spasmodic, agent for treating urinary incontinence, anti-diarrheal agent, agent for treating nausea and/or vomiting, smooth muscle contractile agent, anti-secretory agent, enzyme, anti-diuretic, anti-ulcerant, bile acid replacement and/or gallstone solubilizing drug, or a mixture thereof [0041]
  • In one embodiment the active compound is an anti-diuretic. Suitable anti-diuretics for use in the buccal sprays of the invention include, but are not limited to, acetazolamide, benzthiazide, bendroflumethazide, bumetanide, chlorthalidone, chlorothiazide, ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, quinethazone, spironolactone, triamterene, torsemide, trichlomethiazide, and mixtures thereof. [0042]
  • 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. [0043]
  • In one embodiment the active compound is an anti-spasmodic. Suitable anti-spasmodics for use in the buccal sprays of the invention include, but are not limited to, atropine, baclofen, dicyclomine, hyoscine, propatheline, oxybutynin, S-oxybutynin, tizanidine, and mixtures thereof. [0044]
  • In one embodiment the active compound is an agent for treating urinary incontinence. Suitable agents for treating urinary incontinence for use in the buccal sprays of the invention include, but are not limited to, darifenacin, vamicamide, detrol, ditropan, imipramine, and mixtures thereof. [0045]
  • In one embodiment the active compound is an anti-diarrheal agent. Suitable anti-diarrheal agents for use in the buccal sprays of the invention include, but are not limited to, ondansetron, palnosetron, tropisetron, attapulgite, atropine, bismuth, diphenoxylate, loperamide, and mixtures thereof. [0046]
  • In one embodiment the active compound is an agent for treating nausea and/or vomiting. Suitable agents for treating nausea and/or vomiting for use in the buccal sprays of the invention include, but are not limited to, alosetron, dolasetron, granisetron, meclizine, metoclopramide, ondansetron, palnosetron, prochloperazine, promethazine, trimethobenzamiode, tropisetron, and mixtures thereof. [0047]
  • In one embodiment the active compound is a smooth muscle contractile agent. A suitable smooth muscle contractile agents for use in the buccal sprays of the invention includes, but is not limited to hyoscine. [0048]
  • In one embodiment the active compound is an anti-secretory agent. Suitable anti-secretory agents for use in the buccal sprays of the invention include, but are not limited to, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, tenetoprazole, ecabet, misoprostol, teprenone, and mixtures thereof. [0049]
  • In one embodiment the active compound is an enzyme. Suitable enzymes for use in the buccal sprays of the invention include, but are not limited to, alpha-galactosidase, alpha-L-iduronidase, imiglucerase/alglucerase, amylase, lipase, protease, pancreatin, olsalazine, and mixtures thereof. [0050]
  • In one embodiment the active compound is an anti-diuretic. Suitable anti-diuretics for use in the buccal sprays of the invention include, but are not limited to, desmopressin, oxytocin, and mixtures thereof. [0051]
  • In one embodiment the active compound is an anti-ulcerant. Suitable anti-ulcerants for use in the buccal sprays of the invention include, but are not limited to, cimetidine, ranitidine, famotidine, misoprostol, sucralfate, pantoprazole, lansoprazole, omeprazole, and mixtures thereof. [0052]
  • In one embodiment the active compound is a bile acid replacement and/or gallstone solubilizing drug. A suitable bile acid replacement and/or gallstone solubilizing drug for use in the buccal sprays of the invention includes, but is not limited to ursodiol. [0053]
  • In one embodiment, the active compound is ondansetron, or a pharmaceutically acceptable salt thereof. In one embodiment, the active compound is ondansetron hydrochloride. [0054]
  • Typically, when ondansetron, or a pharmaceutically acceptable salt thereof, is the active compound the buccal spray contains from about contains form about 0.01 to 20 weight/weight (w/w) percent ondansetron, or a pharmaceutically acceptable salt thereof, preferably, about 0.1 to 15 w/w percent, and more preferably about 0.2 to 10 w/w percent ondansetron, or a pharmaceutically acceptable salt thereof. [0055]
  • The invention further relates to a method for treating emesis in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising ondansetron or a pharmaceutically acceptable salt thereof. [0056]
  • In one embodiment, the emesis is chemotherapy induced emesis. [0057]
  • In another embodiment, the emesis is radiation induced emesis. [0058]
  • In another embodiment, the ondansetron, or a pharmaceutically acceptable salt thereof, is administered in combination with a corticosteroid, such as phenothiazine or butyrophenone. [0059]
  • In another embodiment, the ondansetron, or a pharmaceutically acceptable salt thereof, is administered in combination with dexamethasone. [0060]
  • In another embodiment for treating chemotherapy or radiation induced emesis, the oral mucosa of the patient is sprayed with ondansetron, or a pharmaceutically acceptable salt thereof, before chemotherapy or radiation therapy begins. Typically, ondansetron, or a pharmaceutically acceptable salt thereof, is sprayed on the oral mucosa of the patient between about 5 minutes and about 2 hours before chemotherapy or radiation therapy begins, preferably between about 15 minutes and about 1 hour, more preferably between about 30 minutes before chemotherapy or radiation therapy begins. In another embodiment, the method further includes administering ondansetron, or a pharmaceutically acceptable salt thereof, after chemotherapy or radiation therapy is ended. Typically, the ondansetron, or a pharmaceutically acceptable salt thereof, is sprayed on the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy has ended, preferable between about 2 hours and about 5 hours, more preferably about 4 hours after chemotherapy or radiation therapy has ended. [0061]
  • In another embodiment, the emesis is anesthetic induced emesis. Accordingly, the invention further relates to a method of administering anesthesia by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising ondansetron or a pharmaceutically acceptable salt thereof before the anesthesis is administered. [0062]
  • The invention further relates to a method for treating anxiety in a patient by spraying the oral mucosa of the patient with a therapeutically effective amount of a buccal spray comprising ondansetron or a pharmaceutically acceptable salt thereof. [0063]
  • 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. [0064]
  • 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. [0065]
  • 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. [0066]
  • 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. [0067]
  • The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting. [0068]
  • The following are examples of certain classes. All values unless otherwise specified are in weight percent. [0069]
    • EXAMPLES Example 1 Biologically Active Peptides Including Peptide Hormones
  • A. Cyclosporine Lingual Spray [0070]
    most
    Amounts preferred amount preferred 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 [0071]
    preferred most
    Amounts amount preferred 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 Capsule [0072]
    Amounts preferred amount most preferred 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 [0073]
    most
    Amounts preferred amount preferred 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 [0074]
    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    1-31  .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 [0075]
    most
    Amounts preferred amount preferred 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 [0076]
    most
    Amounts preferred amount preferred 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 [0077]
    most preferred
    Amounts preferred 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  
    • Example 2
  • CNS Active Amines and their Salts: Including But not Limited to Tricyclic Amines, GABA Analogues, Thiazides, Phenothiazine Derivatives, Serotonin Antagonists and Aerotonin Reuptake Inhibitors [0078]
  • A. Sumatriptan Succinate Lingual Spray [0079]
    most
    Amounts preferred amount preferred 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 [0080]
    most
    Amounts preferred amount preferred 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 [0081]
    most
    Amounts preferred amount preferred 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 [0082]
    Amounts preferred amount most preferred 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 [0083]
    Amounts preferred amount most preferred 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 [0084]
    most
    Amounts preferred amount preferred 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 [0085]
    most
    Amounts preferred amount preferred 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
    • Example 3 Sulfonylureas
  • A. Glyburide Lingual Spray [0086]
    most
    Amounts preferred amount preferred 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 [0087]
    most
    Amounts preferred amount preferred 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
    • Example 4 Antibiotics Anti-Fungals and Anti-Virals
  • A. Zidovudine [Formerly Called Azidothymidine (AZT) (Retrovir)] Non-Polar Lingual Spray [0088]
    (AZT) (Retrovir)] non-polar lingual spray
    Amounts preferred amount most preferred 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 [0089]
    most preferred
    Amounts preferred 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 [0090]
    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 [0091]
    most preferred
    Amounts preferred amount 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
    • Example 5 Anti-Emetics
  • A. Ondansetron Hydrochloride Lingual Spray [0092]
    preferred most preferred
    Amounts amount amount
    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  9.5-15 
    flavors 1-10 3-8   5-7.5
  • B. A Propellant Free Ondansetron Formulation in a Polar Solvent can be Made According to the Following Formula: [0093]
    Component Percent (w/w)
    Ondansetron Hydrochloride 4
    Tween 80 0.5
    EDTA 0.02
    Ethanol 10
    Glycerol 5
    Water QS to 100
  • C. A Propellant Free Ondansetron Formulation in a Non-Polar Solvent can be Made According to the Following Formula [0094]
    Component Percent (w/w)
    Ondansetron 0.2
    Bitter Mask 0.50.1
    Alpha-tocopherol Acetate 2
    Liquid Paraffin QS to 100
  • D. A Propellant Free Ondansetron Formulation in a Mixture of a Polar Solvent and a Non-Polar Solvent can be Made According to the Following Formula [0095]
    Component Percent (w/w)
    Ondansetron 0.1
    Miglyol 810 20
    Polysorbate (span) 1
    Lemon Oil 0.1
    Ethanol QS to 100
  • E. An Ondansetron Formulation in a Non-Polar Solvent with a Propellant can be Made According to the Following Formula: [0096]
    Component Percent (w/w)
    Ondansetron 0.1
    Lemon Oil 0.2
    Miglyol 20
    Butane 100
  • F. An Ondansetron Formulation in a Polar Solvent with a Propellant can be Made According to the Following Formula: [0097]
    Component Percent (w/w)
    Ondansetron 2
    Bitter mask 0.2
    Ethanol 60
    Butane 100
  • G. An Ondansetron Formulation in a Mixture of a Polar Solvent and a Non-Polar Solvent with a Propellant can be Made According to the Following Formula: [0098]
    Component Percent (w/w)
    Ondansetron 0.1
    Miglyol 20
    Polysorbate (span) 1
    Lemon Oil 0.1
    Ethanol 20
    Butane 100
  • H. Dimenhydrinate Bite Capsule [0099]
    most preferred
    Amounts preferred amount 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
  • I. Dimenhydrinate Polar Lingual Spray [0100]
    most preferred
    Amounts preferred amount 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 
    • Example 6 Histamine H-2 Receptor Antagonists
  • A. Cimetidine Hydrochloride Bite Capsule [0101]
    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 [0102]
    most preferred
    Amounts preferred amount 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 [0103]
    Amounts preferred amount most 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
    • Example 7 Barbiturates
  • A. Phenytoin Sodium Lingual Spray [0104]
    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 [0105]
    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
    • Example 8 Prostaglandins
  • A. Carboprost Thromethamine Lingual Spray [0106]
    preferred most preferred
    Amounts amount amount
    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 [0107]
    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
    • Example 9 Neutraceuticals
  • A. Carnitine as Bite Capsule (Contents are a Paste) [0108]
    most
    Amounts preferred amount preferred 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 [0109]
    most
    Amounts preferred amount preferred 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 [0110]
    most
    Amounts preferred amount preferred 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 [0111]
    most
    Amounts preferred amount preferred 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  
    • Example 10 Sleep Inducers Also CNS Active Amine
  • A. Diphenhydramine Hydrochloride Lingual Spray [0112]
    most
    Amounts preferred 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
  • A. Isoproterenol Hydrochloride as Polar Lingual Spray [0113]
    most
    Amounts preferred amount preferred amount
    isoproterenol 0.1-10  0.2-7.5 0.5-6  
    Hydrochloride
    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 [0114]
    Amounts preferred amount most preferred 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 [0115]
    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 [0116]
    most
    Amounts preferred amount preferred 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 [0117]
    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
    • Example 12 Polar Solvent Formulations Using a Propellant
  • A. Sulfonylurea [0118]
    Preferred
    Amount 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) [0119]
    Most-
    Amount Preferred Amount Preferred 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) [0120]
    Most-
    Amount Preferred Amount Preferred 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 [0121]
    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 (104)

What is claimed is:
1. A propellant free buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount of between 0.001 and 60 percent by weight of the total composition; and
a polar solvent in an amount between 30 and 99 percent by weight of the total composition.
2. The composition of claim 1, further comprising a taste mask and/or flavoring agent in an amount of between 0.1 and 10 percent by weight of the total composition.
3. The composition of claim 2, wherein the polar solvent is present in an amount between 37 and 98 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount between 0.005 and 55 percent by weight of the total composition, and the taste mask and/or flavoring agent is present in an amount between 0.5 and 8 percent by weight of the total composition.
4. The composition of claim 3, wherein the polar solvent is present in an amount between 60 and 97 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount between 0.01 and 40 percent by weight of the total composition, and the taste mask and/or flavoring agent is present in an amount between 0.75 and 7.5 percent by weight of the total composition.
5. The composition of claim 1, wherein the polar solvent is selected from the group consisting of polyethylene glycols having a molecular weight between 400 and 1000, C2 to C8 mono- and poly-alcohols, and C7 to C18 alcohols of linear or branched configuration.
6. The composition of claim 1, wherein the polar solvent comprises polyethylene glycol.
7. The composition of claim 1, wherein the polar solvent comprises ethanol.
8. The composition of claim 2, wherein the flavoring agent is selected from the group consisting of synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners, and mixtures thereof.
9. A method of administering ondansetron or a pharmaceutically acceptable salt thereof to a mammal, comprising spraying the oral mucosa of the mammal with the composition of claim 1.
10. The method of claim 9, wherein the amount of the spray is predetermined.
11. A buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount of between 0.1 and 25 percent by weight of the total composition;
a polar solvent in an amount between 10 and 97 percent by weight of the total composition; and
a propellant in an amount between 2 and 10 percent by weight of the total composition, wherein said propellant is a C3 to C8 hydrocarbon of linear or branched configuration.
12. The composition of claim 11, further comprising a taste mask and/or flavoring agent in an amount between 0.05 and 10 percent by weight of the total composition.
13. The composition of claim 12, wherein the polar solvent is present in an amount between 20 and 97 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount between 0.1 and 15 percent by weight of the total composition, the propellant is present in an amount between 2 and 5 percent by weight of the composition, and the taste mask and/or flavoring agent is present in an amount between 0.1 and 5 percent by weight of the total composition.
14. The composition of claim 13, wherein the polar solvent is present in an amount between 25 and 97 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount between 0.2 and 25 percent by weight of the total composition, the propellant is present in an amount between 2 and 4 percent by weight of the composition, and taste mask and/or flavoring agent is present in an amount between 0.1 and 2.5 percent by weight of the total composition.
15. The composition of claim 11, wherein the polar solvent is selected from the group consisting of polyethyleneglycols having a molecular weight between 400 and 1000, C2 to C8 mono- and poly-alcohols, and C7 to C18 alcohols of linear or branched configuration.
16. The composition of claim 15, wherein the polar solvent comprises polyethylene glycol.
17. The composition of claim 15, wherein the polar solvent comprises ethanol.
18. The composition of claim 12, wherein the flavoring agent is selected from the group consisting of synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners, and mixtures thereof.
19. The composition of claim 11, wherein the propellant is selected from the group consisting of propane, N-butane, iso-butane, N-pentane, iso-pentane, neo-pentane, and mixtures thereof.
20. A method of administering ondansetron or a pharmaceutically acceptable salt thereof to a mammal, comprising spraying the oral mucosa of the mammal with the composition of claim 11.
21. The method of claim 20, wherein the amount of the spray is predetermined.
22. A propellant free buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount between 0.005 and 55 percent by weight of the total composition; and
a non-polar solvent in an amount between 30 and 99 percent by weight of the total composition.
23. The composition of claim 22, further comprising a taste mask and/or flavoring agent in an amount between 0.1 and 10 percent by weight of the total composition.
24. The composition of claim 23, wherein the flavoring agent is selected from the group consisting of synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners, and mixtures thereof.
25. The composition of claim 22, wherein the solvent is selected from the group consisting of (C2-C24) fatty acid (C2-C6) esters, C7-C18 hydrocarbons of linear or branched configuration, C2-C6 alkanoyl esters, and triglycerides of C2-C6 carboxylic acids.
26. The composition of claim 25, wherein the solvent is a triglyceride.
27. A method of administering ondansetron or a pharmaceutically acceptable salt thereof to a mammal, comprising spraying the oral mucosa of the mammal with the composition of claim 22.
28. The method of claim 27, wherein the amount of the spray is predetermined.
29. A buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount between 0.05 and 50 percent by weight of the total composition; and
a non-polar solvent in an amount between 19 and 85 percent by weight of the total composition; and
a propellant in an amount between 5 and 80 percent by weight of the total composition, wherein said propellant is a C3 to C8 hydrocarbon of linear or branched configuration.
30. The composition of claim 29, further comprising a taste mask and/or flavoring agent in an amount of between 0.1 and 10 percent by weight of the total composition.
31. The composition of claim 30, wherein the flavoring agent is selected from the group consisting of synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners, and mixtures thereof.
32. A buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount between 0.01 and 40 percent by weight of the total composition;
a non-polar solvent in an amount between 25 and 89 percent by weight of the total composition;
a propellant in an amount between 10 and 70 percent by weight of the total composition, wherein said propellant is a C3 to C8 hydrocarbon of linear or branched configuration; and
a taste mask and/or flavoring agent is present in an amount between 1 and 8 percent by weight of the total composition.
33. The composition of claim 32, wherein the propellant is present in an amount between 20 and 70 percent by weight of the total composition, the non-polar solvent is present in an amount between 25 and 75 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount from between 0.25 and 35 percent by weight of the total composition, and the taste mask and/or flavoring agent is present in an amount between 2 and 7.5 percent by weight of the total composition.
34. The composition of claim 29, wherein the propellant is selected from the group consisting of propane, n-butane, iso-butane, n-pentane, iso-pentane, neo-pentane, and mixtures thereof.
35. The composition of claim 34, wherein the propellant is n-butane or iso-butane and has a water content of not more than 0.2 percent and a concentration of oxidizing agents, reducing agents, Lewis acids, and Lewis bases of less than 0.1 percent.
36. The composition of claim 29, wherein the solvent is selected from the group consisting of (C2-C24) fatty acid (C2-C6) esters, C7-C18 hydrocarbons of linear or branched configuration, C2-C6 alkanoyl esters, and triglycerides of C2-C6 carboxylic acids.
37. The composition of claim 36, wherein the solvent is a triglyceride.
38. A method of administering ondansetron or a pharmaceutically acceptable salt thereof to a mammal, comprising spraying the oral mucosa of the mammal with the composition of claim 29.
39. The method of claim 38, wherein the amount of the spray is predetermined.
40. A buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount between 0.2 and 10 percent by weight of the total composition; and
a polar solvent comprising propylene glycol and ethanol in an amount between 50 and 99 percent by weight of the total composition.
41. A propellant free buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount of between 0.001 and 60 percent by weight of the total composition; and
a mixture of a polar solvent and a non-polar solvent in an amount of between 30 and 99.69 percent by weight of the total composition, wherein the ratio of the polar solvent to the non-polar solvent ranges from 1:99 to 99:1.
42. The composition of claim 40, further comprising a taste mask and/or flavoring agent in an amount of between 0.1 and 10 percent by weight of the total composition.
43. The composition of claim 42, wherein the polar solvent is present in an amount between 37 and 98 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount between 0.005 and 55 percent by weight of the total composition, and the taste mask and/or flavoring agent is present in an amount between 0.5 and 8 percent by weight of the total composition.
44. The composition of claim 43, wherein the polar solvent is present in an amount between 60 and 97 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount between 0.01 and 40 percent by weight of the total composition, and the taste mask and/or flavoring agent is present in an amount between 0.75 and 7.5 percent by weight of the total composition.
45. The composition of claim 41, wherein the polar solvent is selected from the group consisting of polyethylene glycols having a molecular weight between 400 and 1000, C2 to C8 mono- and poly-alcohols, and C7 to C18 alcohols of linear or branched configuration and the non-polar solvent is selected from the group consisting of (C2-C24) fatty acid (C2-C6) esters, C7-C18 hydrocarbons of linear or branched configuration, C2-C6 alkanoyl esters, and triglycerides of C2-C6 carboxylic acids.
46. The composition of claim 42, wherein the flavoring agent is selected from the group consisting of synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners, and mixtures thereof.
47. A method of administering ondansetron or a pharmaceutically acceptable salt thereof to a mammal, comprising spraying the oral mucosa of the mammal with the composition of claim 41.
48. The method of claim 47, wherein the amount of the spray is predetermined.
49. A buccal spray composition for transmucosal administration of ondansetron or a pharmaceutically acceptable salt thereof comprising:
ondansetron or a pharmaceutically acceptable salt thereof in an amount between 0.05 and 50 percent by weight of the total composition;
a mixture of a polar solvent and a non-polar solvent in an amount between 10 and 97 percent by weight of the total composition, wherein the ratio of the polar solvent to the non-polar solvent ranges from 1:99 to 99:1; and
a propellant in an amount between 5 and 80 percent by weight of the total composition, wherein said propellant is a C3 to C8 hydrocarbon of linear or branched configuration.
50. The composition of claim 49, further comprising a taste mask and/or flavoring agent is present in an amount between 0.01 and 10 percent by weight of the total composition.
51. The composition of claim 50, wherein the propellant is present in an amount between 10 and 70 percent by weight of the total composition, the solvent is present in an amount between 20 and 97 percent by weight of the total composition, the ondansetron or a pharmaceutically acceptable salt thereof is present in an amount from between 0.1 and 40 percent by weight of the total composition, and the taste mask and/or flavoring agent is present in an amount between 1 and 8 percent by weight of the total composition.
52. The composition of claim 49, wherein the propellant is selected from the group consisting of propane, n-butane, iso-butane, n-pentane, iso-pentane, neo-pentane, and mixtures thereof.
53. The composition of claim 52, wherein the propellant is n-butane or iso-butane and has a water content of not more than 0.2 percent and a concentration of oxidizing agents, reducing agents, Lewis acids, and Lewis bases of less than 0.1 percent.
54. The composition of claim 49, wherein the polar solvent is selected from the group consisting of polyethylene glycols having a molecular weight between 400 and 1000, C2 to C8 mono- and poly-alcohols, and C7 to C18 alcohols of linear or branched configuration and the non-polar solvent is selected from the group consisting of (C2-C24) fatty acid (C2-C6) esters, C7-C18 hydrocarbons of linear or branched configuration, C2-C6 alkanoyl esters, and triglycerides of C2-C6 carboxylic acids.
55. A method of administering ondansetron or a pharmaceutically acceptable salt thereof to a mammal, comprising spraying the oral mucosa of the mammal with the composition of claim 49.
56. The method of claim 55, wherein the amount of the spray is predetermined.
57. A method of treating emesis in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 1.
58. The method of claim 57, wherein the emesis is caused by chemotherapy or radiation.
59. The method of claim 58, further comprising administering to the patient a corticosteroid.
60. The method of claim 58, further comprising administering to the patient dexamethasone.
61. The method of claim 58, wherein the oral mucosa of the patient is sprayed between about 5 minutes and 2 hours before chemotherapy or radiation therapy begins.
62. The method of claim 61, further comprising spraying the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy ends.
63. A method of administering anesthesia to a patient comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 1 before the anesthesia is administered.
64. A method of treating anxiety in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 1.
65. A method of treating emesis in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 11.
66. The method of claim 65, wherein the emesis is caused by chemotherapy or radiation.
67. The method of claim 66, further comprising administering to the patient a corticosteroid.
68. The method of claim 66, further comprising administering to the patient dexamethasone.
69. The method of claim 66, wherein the oral mucosa of the patient is sprayed between about 5 minutes and 2 hours before chemotherapy or radiation therapy begins.
70. The method of claim 69, further comprising spraying the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy ends.
71. A method of administering anesthesia to a patient comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 11 before the anesthesia is administered.
72. A method of treating anxiety in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 11.
73. A method of treating emesis in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 22.
74. The method of claim 73, wherein the emesis is caused by chemotherapy or radiation.
75. The method of claim 74, further comprising administering to the patient a corticosteroid.
76. The method of claim 74, further comprising administering to the patient dexamethasone.
77. The method of claim 74, wherein the oral mucosa of the patient is sprayed between about 5 minutes and 2 hours before chemotherapy or radiation therapy begins.
78. The method of claim 77, further comprising spraying the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy ends.
79. A method of administering anesthesia to a patient comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 22 before the anesthesia is administered.
80. A method of treating anxiety in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 22.
81. A method of treating emesis in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 29.
82. The method of claim 81, wherein the emesis is caused by chemotherapy or radiation.
83. The method of claim 82, further comprising administering to the patient a corticosteroid.
84. The method of claim 82, further comprising administering to the patient dexamethasone.
85. The method of claim 82, wherein the oral mucosa of the patient is sprayed between about 5 minutes and 2 hours before chemotherapy or radiation therapy begins.
86. The method of claim 85, further comprising spraying the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy ends.
87. A method of administering anesthesia to a patient comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 29 before the anesthesia is administered.
88. A method of treating anxiety in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 29.
89. A method of treating emesis in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 41.
90. The method of claim 89, wherein the emesis is caused by chemotherapy or radiation.
91. The method of claim 90, further comprising administering to the patient a corticosteroid.
92. The method of claim 90, further comprising administering to the patient a dexamethasone.
93. The method of claim 90, wherein the oral mucosa of the patient is sprayed between about 5 minutes and 2 hours before chemotherapy or radiation therapy begins.
94. The method of claim 93, further comprising spraying the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy ends.
95. A method of administering anesthesia to a patient comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 41 before the anesthesia is administered.
96. A method of treating anxiety in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 41.
97. A method of treating emesis in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 49.
98. The method of claim 97, wherein the emesis is caused by chemotherapy or radiation.
99. The method of claim 98, further comprising administering to the patient a corticosteroid.
100. The method of claim 98, further comprising administering to the patient dexamethasone.
101. The method of claim 98, wherein the oral mucosa of the patient is sprayed between about 5 minutes and 2 hours before chemotherapy or radiation therapy begins.
102. The method of claim 101, further comprising spraying the oral mucosa of the patient between about 1 hour and 6 hours after chemotherapy or radiation therapy ends.
103. A method of administering anesthesia to a patient comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 49 before the anesthesia is administered.
104. A method of treating anxiety in a patient, comprising spraying the oral mucosa of the patient with a therapeutically effective amount of the buccal spray of claim 49.
US10/671,717 1997-10-01 2003-09-29 Buccal, polar and non-polar spray containing ondansetron Abandoned US20040136914A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US10/671,717 US20040136914A1 (en) 1997-10-01 2003-09-29 Buccal, polar and non-polar spray containing ondansetron
JP2006534019A JP2007507509A (en) 2003-09-29 2004-09-27 Ordanpolar and nonpolar sprays containing ondansetron
KR1020067008480A KR20060090997A (en) 2003-09-29 2004-09-27 Buccal, polar and non-polar spray containing ondansetron
PCT/US2004/031801 WO2005032520A1 (en) 2003-09-29 2004-09-27 Buccal, polar and non-polar spray containing ondansetron
EP04789153A EP1682090A1 (en) 2003-09-29 2004-09-27 Buccal, polar and non-polar spray containing ondansetron
CA002554954A CA2554954A1 (en) 2003-09-29 2004-09-27 Buccal, polar and non-polar spray containing ondansetron
IL174623A IL174623A0 (en) 2003-09-29 2006-03-29 Buccal, polar and non-polar spray containing ondansetron
US11/429,953 US20060198790A1 (en) 1997-10-01 2006-05-09 Buccal, polar and non-polar spray containing ondansetron
US12/350,602 US20090162297A1 (en) 1997-10-01 2009-01-08 Buccal, polar and non-polar spray containing ondansetron
US12/632,719 US20100152262A1 (en) 1997-10-01 2009-12-07 Buccal, polar and non-polar spray containing ondansetron
US13/445,331 US9078816B2 (en) 1997-10-01 2012-04-12 Buccal, polar and non-polar spray containing ondansetron
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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
US10/230,085 US20030095926A1 (en) 1997-10-01 2002-08-29 Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the gastrointestinal tract or urinary tract
US10/671,717 US20040136914A1 (en) 1997-10-01 2003-09-29 Buccal, polar and non-polar spray containing ondansetron

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US12/350,602 Abandoned US20090162297A1 (en) 1997-10-01 2009-01-08 Buccal, polar and non-polar spray containing ondansetron
US12/632,719 Abandoned US20100152262A1 (en) 1997-10-01 2009-12-07 Buccal, polar and non-polar spray containing ondansetron
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US12/632,719 Abandoned US20100152262A1 (en) 1997-10-01 2009-12-07 Buccal, polar and non-polar spray containing ondansetron
US13/445,331 Expired - Fee Related US9078816B2 (en) 1997-10-01 2012-04-12 Buccal, polar and non-polar spray containing ondansetron
US13/450,987 Abandoned US20120202866A1 (en) 1997-10-01 2012-04-19 Buccal, polar and non-polar spray containing ondansetron

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