NZ561128A

NZ561128A - Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the gastrointestinal tract or urinary tract

Info

Publication number: NZ561128A
Application number: NZ561128A
Authority: NZ
Inventors: Harry A Dugger
Original assignee: Velcera Pharmaceuticals Inc
Priority date: 2002-08-29
Filing date: 2003-08-27
Publication date: 2007-11-30

Abstract

Disclosed is a propellant free buccal spray composition for transmucosal administration of a pharmacologically active compound comprising an active compound in an amount between 0.005 and 55 percent by weight of the total composition selected from the group consisting of anti-spasmodics, agents for treating urinary incontinence, anti-diarrheal agents selected from the group consisting of palnosetron, tropisetron, attapulgite, atropine, bismuth, diphenoxylate, loperamide, and mixtures thereof, agents for treating nausea and/or vomiting selected from the group consisting of alosetron, dolasetron, granisetron, meclizine, metoclopramide, palnosetron, prochloperazine, promethazine, trimethobenzamide, tropisetron, and mixtures thereof, smooth muscle contractile agents, anti-secretory agents, enzymes, anti- diuretics selected from the group consisting of benzthiazide, bendroflumethazide, bumetanide, chlorthalidone, chIomthiazide, ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, methyclothiazlde, polythiazide, quinethazone, spironolactone, triamterene, torsemide, trichlomethiazide, and mixtures thereof, anti-ulcerants selected from the group consisting of ranitidine, misoprostol, sucralfate, pantoprazole, lansoprazole, orneprazole, and mixtures thereof, bile acid replacement and/or gallstone solubilizing drugs, and mixtures thereof; and a non-polar solvent in an amount between 30 and 99 percent by weight of the total composition.

Description

New Zealand Paient Spedficaiion for Paient Number 56112Q 03-Sep-2Q07 03:52 PM AAR Sydney 0 2/34 *10053880230* Patent Form No 5 New Zealand Patents Act 1953 56 112s Complete Specification Divisional Application Parent of Divisional Application Details: Application No: 539285 Country: New Zealand Date of Application: 27 August 2003 Title of invention: Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the gastrointesti nal tract or urinary tract We VELCERA PHARMACEUTICALS, INC, hereby declare the invention, for which we pray that a patent may be granted to us, arid the method by which it is to be performed, to be particularly described in and by the following statement Signature(s) of applicant(s) Dr Kathryn Sunn Registered New Zealand Patent Attorney Kathryn .Sunn@aar.com .au Tel 61 2 9230 4284 Dated; 3 September 2QQ7 kkss AQ10S0S3726V1 205903296 3.9.2007 '""^^Sivomcr " 3 SEP 2007 I SMCE2VEDI 03-Sep-2007 03:53 PH AAR Sydney 0 4/34 561128 BUCCAL, POLAR AND NON-POLAR SPRAY OR CAPSULE CONTAINING DRUGS FOR TREATING DISORDERS OF THE GASTROINTESTINAL TRACT OR URTNARY TRACT CROSS REFERENCE TO RELATED APPLICATIONS This application is a contionation-iii-part of application no. 09/537,118, filed March 29,2000 which is a coniirniatiott-in-part of Hie U.S. national phase designation of PCT/US97/17899 filed October 1,1997, the disclosures of which are mcaipoiated by reference herein in their entirety.

BACKGROUND GP TflTK 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 fee stomach or intestine. However, formulations suitable for such administration by these latter 15 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.P. 4,689,233, Dvorsky et al, describes a soft gelatin capsule for the administration of the anli-coronaiy drug nifedipine dissolved in a mixture of polyefher alcohols. U.S.?. 4,755,389, Jones et aL, 20 describes a hard gelatin chewable capsule containing nifedipine. A chewabls gelatin capsule containing a solution or dispersion of a drag is described in U.S.P. 4,935,243, Borkaa et al. U.S J. 4,919,919, Aouda et al, andTLS-P. 5,370,862, Klokkers-BetMce, describe a nitroglycerin spray for administration to the oral mucosa comprising nitroglycerin, ethanol, and other components. An orally administered ptirap spray is 25 described by Cholcha in U.S.F. 5,186,925, Aerosol compositions contarmng a hydrocarbon propellaat and a drug for administration to a mucosal surface are described mUX. 2,082,457, Su, U.S.P, 3,155,574, Silson et aL, U.SJP. 5,011,678, Wang et al., and by ParneJl itt U.S JP. 5,128,132. It should he noted that these references discuss bioavailability of solutions by inhalation rather than through the membranes to which they are administered.

SUMMARY OF THE INVENTION A buccal aerosol spray or soft bite gelatin capsule using a polar or non-polar solvent has now been developed which provides biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect. -1.- 03-Sep-2007 03:53 PM AAR Sydney 0 /34 The buccal am>sol spray compositions of lie present invention, far transmucossl administration of a pharmacologically active compound soluble in a pharmacologically acceptable non-polar solvent comprise in weight % of total composition: pharmaceutically acceptable propefflant 5-80 %, nonpolar solvent 19-85 %, active compound 5 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 propellent 20-70 %, non-polar solvent 25-74.75 %, active compound 0.25-35 %, flavoring agent 2-7.5 %.

The buccal polar aerosol spray compositions of the present invention, for transmucosal administration of a pharmacologically active compound soluble in a pharmacologically acceptable polar solvent are also admimstrable in aerosol £bnu driven by a propeHant In this case, the composition comprises in weight % of total composition; aqueous polar solvent 10-97 %, active compound 0.1-25 %, suitably additionally 15 comprising, by weight of total composition a flavoring agent 0.05-10 % and propellant: 2 -10 %. Preferably the composition comprises: polar solvent 20-97 %, active compound 0.1-15%, flavoring agent 0,1-5 % and propellant 2-5 %; most suitably polar solvent 25-97 %, active compound 0.2-25 %, flavoring agent 0.1-2.5 % and propellant 2-4 %.

The buccal proof* spray composition of the present invention, i. e., the 20 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 agcsni: 0.1-10 %.

The buccal polar pump spray compositions of the present invention, i. a, the 25 propellant 'ftee cqmpositioh, for transraucosal 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 30 %, flavoring agent 0.5-8 %; most suitably polar solvent 60.9-97.06 %, active compound 0.01-40 %, flavoring agent 0.75-7.5 %.

The soft bite gelatin capsules of the present invention for transmucosal administration of a pharmacologically active compound, at least partially soluble in a 03-Sep-2007 03:53 PM AAR Sydney 0 6/34 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 weigh! of the composition: flavoring agent 0.01-5 10 %. Preferably, the soft bite gelatin capsule comprises: non-polar solvent 21.5-99,975 %, emulsifier 0-15 %, active compound 0.025-70 %D flavoring agent 1-8 %; most suitably; nonpolar solvent 28.5-97.9 %} emulsifier 0-10 %, active compound 0.1 "65.0 %, flavoring agent 2-6%.

The soft bite polar gelatin capsules of the present invention for transmucosal 10 administration of a pharmacologically active compound, at least partially soluble in a pharmacologically acceptable polar solvent, having charged thereto a (^imposition comprising in weight % of total composition: polar solvent 25-99.89 %, emulsifier 0-20 %, active compound 0.01-65 %, provided that said wrapojation contains ltss than 10 % of water, suitably additionally comprising, by weight of the ccppositicm: flavoring agent 01-10 15 %. Preferably, the soft bite gelatin capsule comprises: polar solvent 37-99.95 %, emulsifier 0-15 %, active compound 0.025-55 %, flavoring agent 1-S %; most suitably: polar solvent 44-96.925 %, emulsifier 0-10 %, active compound 0.075-50 %, flavoring agent 2-6 %, It is an object of Hie invention to coat the mucosal membranes either with extremely fine droplets of spray containing die active compounds or a solution or paste 20 thereof from bite capsules.

It is also an object of the invention to administer to the cral mucosa of a mammalian in need of same, preferably man, by spray or bite capsule, a predetermined amount of a biologically active compound by this method or from a soft gelatin capsule.

A further object is a sealed aerosol spray container contirfiiing a composition 25 of the non polar or polar aerosol spray fonnulatiom, and a metered valve suitable for releasing from said container a predetermined amount of said composition.

As the propellant evaporates after activation of the aerosol valve, a mist of fine droplets is formed which contains solvent and active cranpoond.

The propellant is a non-Freon material, preferably a hydrocarbon of a 30 linear or branched configuration. Thepropellant 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 solve&t from the container when the valve is activated but not excessive pressure such as to damage the container or valve seals. 03-Sep-2007 03:54 PM AAR Sydney 0 7/34 The non-polar solvent is a non-polar hydrocarbon, preferably a Cj.ls hydrocarbon of a linear or branched configuration, fatty acid esters, god triglycerides, such as miglyol. The solvent must dissolve the active compound and be miscMe -with the propellant, Le., solvent and propellant must foim a single phase at a temperature of 0-40°C 5 a pressure range of between 1-3 atm.

The polar end 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 10 released by activation of a metered valve, which does not allow entry of atmospheric gasses with each activation. Such containers are commercially available.

A farther object is a pump spray container containing a composition of the pump spray fbimulation, 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 foixa of a viscous solution ot 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 20 % thereof (All percentages herein are by weight unless otherwise indicated) The polar or non-polar solvent is chosen such that it is compatible with the gelatin shell and the active compound- The solvent preferably dissolves the active compound. However, other components wherein the active compound La oat soluble or only slightly soluble may be used and will form a paste filL 25 Soft gelatin capsules are well known in the art Sec, for example, U.S.P. 4,935,243, Borkan etaL,fbrits teaching of such circles. 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 30 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 change of a first pass effect, use of the bite capsules of the invention will eliminate much of the lag time, resulting in 03-Sep-2007 03:54 PM AAR Sydney 0 8/3-4 hastened onset ofbiological effect. The shell of a soft gelatin capsule of the invention may comprise, for example: gelatin: 50-75 %, glycerin 20-30 % colorants 0,5-1.5 %, water 5-10 %, and sorbitol 2-10%.

The active compound may include, biologically active peptides, central 5 nervous system active amines, sulfcttiyl ureas, antibiotics, antifungals, antivirals, sleep inducers, antiasthmatics, bronchial dilators, antiemetics, histamine H-2 receptor antagonists, barfjiturateSj prostaglandins aod neateaceuticds.

The active compounds may also include antihistamines, alkaloids, hormones, benzodiazepines and narcotic analgesics. While not limited thereto, these active compounds 10 are particularly suitable for non-polar pump spray formulation and application.

The active compounds may also include anti-diuretics, ajati-muscle spasm agents, antispasmodics, agents for treating urinary incontinaice, anti-diarrheal agents, agents for treating nausea and/or vomiting, smooth muscle contractile agents, anti-secretory agents, enzymes, anti-diuretics, airtt-utasaals, bile acid replacement and/or gallstone 15 solubilizmg drugs, or mixtures thereof.

BRTKF DESCRIPTION OF THE DRAWING FIG 1. is a schematic diagram showing routes of absoiption and processing of pharmacologically active substances in a mammalian system.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The preferred active compounds of the present invention are in an ionized, salt form or as the free base of the phaimaceutically acceptable salts thereof (provided, for the aerosol or pump spray compositions, they are soluble in the spray solvent). These 25 compounds are soluble in the non-polar solvents of the invention at useful concentrations or can be prepared as pastes at useful confutations. 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 30 As propellants for the non polar sprays, propane, N-butane, iso-butane, N- peotane, iso-pentane, and neo-pentane, and-mixtures thereof may be usesd, N-butoce 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 03-Sep-20Q7 03:55 PM AAR Sydney 0 9/34 ate 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 exclude oxidizing agents, reducing ageois, Lewis acids or bases, and water. The concentration of each of these should be less than 0.1 %, 5 except that water may be as high as 0.2%.

Suitable non-polar solvents for the Castries and the non-polar sprays include (CVC™) frtty acid (Cj-Cj) esters, Cy-C^ hydrocarbon, alkanoyl esters, and the triglycerides of the cotresponding acids. When the capsule fill is a paste, other liquid components may be osedinstead of the above low molecular weight solvents. These 10 include soya oil, com oil, other vegetable oils.

As solvents for the polar capsules or sprays there may be used low molecular weight poiyethyleneglycols (PEG) of4004000 Mw (preferably 400-600), low molecular weight (CjrCg) mono and pofyois and alcohols of Cj-Cls linear or branch chain hydrocarbons, glycerin may also be present and water may also be used in the sprays, bnt 15 only in limited amount in the capsules.

It is expected that same glycerin and water used to make the gelatin shell will migrate from the shell to the £11 during the curing of the M likewise, there may be some migration of components from the fill to the shell during curing and even throughout the shelf-life of the capsule.

Therefore, the values given herein are for the compositions as prepared, it being within the scope of .the invention that minor variations will occur.

The preferred flavoring agents are synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners (sugars, aspartame, saccharin, etc.), and combinations thereof.

The active substances include the active compounds selected from the group consisting of cyclosporins, sermorelm, octreotide acetate, calcitonm-salman, insulin lispro, sumatriptan succinate, clozapine, cyclobanzaprine, derfenfluramme hydrochloride, glyburide, zidovudine, erythromycin, ciprofloxacin, ondansetron hydrochloride, dimenhydonale, cimetidine hydrochloride, famotidine, phenytoin sodium, phanytoin, 30 carboprost tbromethamine, caiboprost, diphenhydramine hydrochloride, isoproterenol hydrochloride, terbutaline sulfite, tarbutaline, theophylline, albuterol sulfate and neutraceuticals, that is to say nutrients with pharmacological action such as but not limited to carnitine, valerian, echinacea, and the Bee. 03-Sep-2007 03:55 PM AAR Sydney 0 /34 In another embodiment, the active compound is an anti-diuretic, anti-muscle spam 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-nlcerant, tile acid replacement and/01 gallstone 5 solubilizing drug, or a mixture thereof In ana embodiment the active compound is an. anti-diuretic. Suitable antidiuretics for use in the buccal sprays of the invention include, but are not limited to, acetazolamide, benzthiazide, bmdroflumefhaaide,bumetamde, chlorthalidone, chlorothiazide, ethacrynic acid, fhrosemide, hydrochlorothiazide, hydroftamethiazide, 10 mefliyclothiazdde, polythiazide, qvtinefhazons, spironolactone, triamterene, torsemide, trichlomethiazide, and mixtures thereof.

In one embodiment the active compound is an anti-muscle spasm agent Suitable anti-muscle spasm agents for use in the buccal sprays of the invention include, bul arc not limited to, baclofen, botulinum toxin, carisoprodol, chloipheciesm, chlorzoxazone, 15 cyclobenzaprine, dantrolene, diazepam, metaxalone, methocarbamol, oiphenadrine, tizanidine, and mixtures thereof In one embodiment the active compound is an anti-spasmodic. Suitable antispasmodics for use in the buccal sprays of the invention include, but are not limited to, atropine, baclofen, dicyclomine, hyoscine, piopatheline, oxybutynin, S-oxybutymn, 20 tizanidine, and mixtures thereof.

In one embodiment the active compound is an agent for iTcating urinary incontinence. Suitable agents for treating urinary incontinence for use in the buccal spiays of the invention include, but are not limited to, darifenacin, vamicamide, detrol, ditropan, imipramine, and mixtures tbeieof..

In one embodiment the active compound is an anti-diaixheal agent. Suitable anti-diarrhea! agents for use in the buccal sprays of the invention include, but are not limited to, ondansetron, palnosetron, tropisetron, attapnlgite, atropine, bismuth, diphenoxylate, loperamide, and mixtures thereof. lb one embodiment the active compound is an agent for treating nausea 30 and/W 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, dolaseixoo, granisetron, meclizine, mstocloprami.de, ondansetron, palnosetron, prochloperazins, promethazine, trimethobenzamiode, tropisetron, and mixtures thereof.

Q3-Sep-20Q7 03:55 PM AAR Sydney 0 11/34 Ea 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 fruited to hyoscine.

In one embodiment the active compound is an anti-secretory agent Suitable 5 anti-secretory agents for use in the buccal sprays of the invention include, but are not limited to, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabepxazole, tenctoprazole, ecabet, misoprostol, teprenone. and mixtures thereof.

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-galacfcosidase, 10 alpha-L-iduromdase, foughicerase/alglucerase, amylase, lipase, protease, pancreatin, olsalazine, and mixtures thereof In one embodiment the active compound is an anti-diuretic. Suitable antidiuretics for use in the buccal sprays of the invention include, but are not limited tQ, desmopressin, oxytocins mixtures thereot 15 In one embodiment the active compound is an turfi-nlcerant. Suitable anti- ulceranfs for use in the buccal sprays of the invention include, but are not limited to, cimstidine, ranitidhie, famotidine, misoprostol, sucralfate, pantoprazole, lansoprazole, omqirazole, and mixtures thereof! la one embodiment the active compound is a bile acid replacement and/or 20 gaflstntie 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 msodioL The formulations of the present invention comprise an active confound or a phanaaceutically acceptable salt thereof The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including 25 organic and inorganic acids or bases.

When an active compound of the present invention is acidic, salts maybe prepared from phatmaoenitically acceptable non-toxic bases. Salts derived irom all stable farms of inorganic bases include aluminum, ammonium, calcium, coppea:, iron, lithium, magnesium, manganese, potassium, sodium, zinc, etc. Particularly prefiaxed are the 30 ammonium, calcium, magnesium, potassium, and sodium salts. Salts dtsrived 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 argoiine, betaine, caffeine, choline, 03-Sep-2007 03:56 PH AAR Sydney 0 12/34 NJN dibenzyie&ylenerii amine, diethylamide, 2Kttethylainmodlianol, 2-dimethyl-anmv>ethanoI, ethanolamine, elhyltmediamine., N-ethylmorpholiue, N^thylpiperidine, glucamine, glucosamine, histidine, isopropylaiijine, lysine, methyl-^ucosamhie, morpholine, piperazmc, piperidine, polyamiae resins, procaine, purine, ti^bromme, 5 trietiiylamine, trimetibtylamine, topropylamine, etc.

When an active compound of the present invention is basic, salts may be prepared front pbamiaceutically acceptable non-toxic acids. Such acids include acetic, benzeaesul&mc, benzoic, camphazstrifbtuc, citric, ethane-salfoiiic, fumaric, gluconic, ghitamic, hydrobromic, hydrochloric, tee&iomc, lactic, maleic, mandelic, me^hsacsulfcuic, 10 raucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- tohienesalfbitic, etc. Particularly preferred are citric, hydrobromic., maleic, phosphoric, sulfuric, tartaric acids. la the discussion of methods of treatment herein, reference to the active compounds is meant to also include the pharmaceutical^ acceptable sails thereof White 15 certain formulations ate set forth herein, the acttiiil amounts to be administered to the mammal or mm in need of same are to be determined by the treating physician.

The invention is farther defined by reference to the following examples, which are intended to be illustrative and not limiting.

The following are examples of certain classes. All values unless otherwise 20 specified are in weight percent. 03-Sep-2007 03:56 PM AAR Sydney 0 13/34 EXAMPLES cyclosporins water ethanol polyethylene glycol flavors EXAMPLE 1 Biologically active peptides including peptide hormones Cyclosporins lingual sprav Amounts preferred amount -50 10-35 -20 7.5-50 -60 7.5-50 -60 30-45 0.1-5 14 most preferred amount -25 9,5-1.2 -2G -40 2-3 B. Cvclosnorine Non-Polar lingual spray Amounts preferred smoimt most preferred amount cyclosporins 1-50 3-40 5-30 Migylol 20 25 30-40 Polyoxyethylated castor oil 20 25 30-40 Butane flavors -80 0.1-5 -70 1-4 1 ' 33-50 2-3 C. Cvclospoajne non^okr bite caosnle Amounts preferred amount most preferred amount cyclosporin 1-35 5-25 10-20 olive oil 25-60 35-55 30-45 polyoxyethylated olfiic gtyosides 25-30 35-55 flavors 0.1-5 1-4 -45 2-3 03-Sep-2007 03:56 PM AAR Sydney 0 14/34 D. Cvdosoadoe bite capsule Amounts preferred amoimt most preferred amount cydosparins -50 -35 -25 | i -60 -45 -40 glycerin -30 7,5-25 -20 propylene glycol -30 7.5-25 -20 flavore 0.1-10 1-8 3-6 E. Sftraoreljn fas the aceta*^ linpual gpmv Amounts preferred amount most] sennfirelki (as the acetate) .01-5 .1-3 .2-1.0 mancitol 1-25 -20 -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 -30 7,5-25 9.5-15 polyethylene glycol -60 3045 -40 propylene glycol -25 -20 12-17 flavors 0.1-5 1-4 2-3 F. Octreotide acetate fSaadostatirrt linpnal gppy 'Amounts preferred amount most preferred amount octreotide acetate 0.001-0.5 0.005-0^50 0.01-0.10 acetic acid M0 2-8 4-6 sodium acetate 1-10 2-8 4-6 sodium chloride 3-30 .5-25 -20 flavors 0.1-5 0.5-.4 2-3 ethanol . -30 7.5-20 9.5-15 water -95 -90' 65-85 flavors 0.1-5 1-4 2-3 03-Sep-2007 03:56 PH AAR Sydney 0 /34 Q. r!aldtnntn-sa1mrm Unpnal spray Amounts preferred amount most preferred amount (^titoain-aalffi&n 0.001-5 0,005-2 01-1.5 ethanol 245. 3-10 7-9.5 viwtei -95 50-90 60^80 polyethylene glycol 2-15 3-10 7-9.5 sodium chloride 2.5-20 -15 -12.5 flavors 0.1-5 1-4 2-3 H. TnaiHn lisnro. ljnp"^ y*** Amounts prefixed amount most preferred amount itistllirt -&0 4-55 -50 glycerin- 0.1-10 0.25-5 0.1-1.5 dibasic sodium phosphate 1-15 2.5-10 4-8 m-cresol, 1-25 -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 traoa amounts ethanol -20 7.5-15 9-12 water -90 40-80 50-75 propylene glycol -20 7.5-15 9-12 flavors 0.1-5 0.5-3 6.75-2 adjust pH to 7.0-7.8 with HCI or NaOH 03-Sep-2007 03:57 PM AAR Sydney 0 16/34 EXAMPLE 2 CNS active ami-nes and their salts: including but not limited to tricyclic amines, GABA analogues, thiazides, phenotbiazine derivative^ serotonin antagonists and. sejotoain A. Sumatantai) snccinatB Ungual sprav Amounts preferred amount most preferred amount sumatriptan succinate 0.5-30 1-20 -15 ethanol -60 7.5-50 -20 propylene glycol -30 .7.5-20 -15 polyethylene glycol 0-60 -45 -40 water -30 7-5-20 -15 flavors 0.1-5 1-4 2-3 ■R Sumatriptan Rnnsfnate bite caosule Amounts preferred amount most preferred amount sumatriptan, succinate 0.01-5 0.05-3.5 0.075-1.75 polyethylene glycol -70 -60 -50 glycerin -70 -60 -50 flavors 0.1-10 1-8 3-6 C. Clozeoine lineual Bpiay Amounts preferred amount most preferred amount clozepine 0.5-30 1-20 -15 rfhanol -60 7.5-50 -20 propylene glycol -30 7.5-20 -15 polyethylene glycol 0-60 -45 -40 water -30 7.5-20 -15 flavors 0.1-5 1-4 2-3 03-Sep-2QQ7 03:57 PM AAR Sydney 0 D. Clozetane non-polar lingual spray Amounts preferred .amount most preferred amount clozepine 0.5-3Q 1-20 10-15 Mlgylol 20-85 25-70 30-40 Buianol 5-SO 30-75 60-70 flavors 0.1-5 1-4 2-3 E. Clozapine non-polar lingaal spravwithflnt propellant Amounts preferred amount most preferred amount clozepine 0.5-30 1-20 10-15 Migytol 70-99.5 80-99 85-90 flavors 0.1-5 1-4 2-3 F, Cvclotenzamme noa-nolar lingual snrav Amounts preferred amount most preferred amount cyclobanzaprine (base) 0.5-30 1-20 10-15 Migybl • 20-85 25-70 30-40 Iso-butane 15-80 30-75 60-70 flavors 0-1-5 1-4 2-3 G. Dexfaifturgmitii-t livrfrncMoride lingual apiav Amounts preferred amount most preferred amount dexfenflttramine 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 03-Sep-2007 03:57 PM AAK Sydney 0 EXAMPLE 3 Sulfonylureas A. rrlvhilride linmial spray Amounts preferred awiminf glyburide 0.25-25 0.5-20 e&anol -60 -7.5-50 propylene glycol -30 7.5-20 polyethylene glycol 0-60 -45 water 2.5-30 -20 flavors 0.1-5 1-4 B. GMmride non-nokr bite cacsule Amounts preferred amount glyburide 0.01-10 0.025-7.5 olive oil -60 -55 polyoxyefhylated oleic glycerides -60 -55 flavors 0.1-5 1-4 most 0.75-15 10-20 10-15. 35-40 6-15 3-3 most preferred amount 0.1-4 -50 -50 2-3 Q3-Sep-2007 03:57 PM AAR Sydney 0 19/34 EXAMPLE 4 Antibiotics anti-ftngals and anti-virals Zidovudine rfonmedv called azidoflivtaidine (AZT) feetrovMI non-polar lineaal snrav Amounts preferred amount most preferred amount zidovudine -50 -40 -35 Soya Oil -85 -70 -40 Butane -80 -75 60-70 flavors 0.1-5 1-4 2-3 B.

Ervthromvcin bite capsule ttte capsule Amounts preferred amount most preferred amount erythromycin -65 -50 -45 polyoxyethylene glycol 5-70 30-60 45-55 glycerin 5-20 7.5-15 10-12,5 flavora 1-10 2-S 3-6 C. Cmrofloxadn hydrochloride bite capsule Amounts preferred amount most preferred amount ciprofloxacin hydrochloride 25-65 35-55 40-50 glycerin 5-20 7.5-1S 10-12.5 polyethylene glycol 120-75 30-65 40-60 flaws 1-10 2-S 3-6 D. zidovudine rfivrmerlv called azidrrth wilding fAZP fRetrovirVl zidovudine water efhanol 30 polyethylene glycol Amounts preferred amount most preferred amount -50 -40 -35 -80 40-75 45-70 -20 7.5-15 9.5-12.5 -2 0 7-5-15 9.5-12.5 03-Sep-2007 03:57 PM AAR Sydney 0 /34 flavors 0.1-5 1-4 2-3 IS EXAMPLES.

Anti-emetics A, Ondansetron hydrochloride lingnal spray Amounts preferred amount most preferred amount ondansetron hydrochloride 1-25 2-20 2.5-15 citric acidmonohydiate 140 2-8 2.5-5 sodium citrate dihydrate 0,5-5 M 1.25-2.5 water 1-90 -8 5 -75 . etfaanol -30 7.5-20 9.5-15 propylene glycol -30 7.5-20 9.5-15 polyethylene glycol -30 7.5-20 9.5-15 flavors 1-10 3-8 -7.5 • B. iHmenhvdritiate bite capsule Amounts preferred, amount dimaihydriiia.te 0.5-30 2-25 glycerin 5-20 7.5-15 polyeflryleae glycol 45-95 50-90 flavors 1-10 2-8 most preferred amount 3-15 -1 2.5 55-85 3-6 C TVmmhviirrnfftB fnHftf lingnal SPraV Amounts preferred amount most preferred amount dimenliydrinale 3-50 4-40 -35 water -90 -80 -75 ethanal 1-80 3-50 -10 polyethylene glycol 1-80 3-50 -15 sorbitol 0.1-5 O.2-40 0.4-1.0 aspartame 0.01-0.5 0.02-0,4 . 0.04-0.1 03-Sep-2007 03:58 PM AAR Sydney 0 21/34 flavors 0.1-5 1-4 EXAMPLES 2-3 [Histamine H-2 receptor antagonists ■ A ritmffrirliiift hyrfmnhlfflidB bite Cflnsble Amounts preferred amount most preferred amount cimefcdineHCl -60 -55 -50 glycerin -20 7.5-15 -12.5 polyethylene glycol -90 -85 -75 flavors 1-10 2-8 3-6 B. Famotidiri& linzual snrav Amounts preferred amount most preferred amount famotidiae 1-35 -30 7-20 water 2.5-25 3-20 -10 L-aspartle acid 0.1-20 1-15 -10 polyethylene glycol -97 -95 50-85 flavors 0.1-10 1-7.5 2-5 C. Famotidine noiMiolar linenal sorzv Amounts preferred amount most preferred amount famotidine 1-35 -30 7-20 Soya oil -50 -40 -20 Butansl -80 -75 45-70 polyoxyethylated oleic glyosrides -50 -40 -20 flavors 0.1-5 1-4 2-3 03-Sep-2007 03:58 PM AAR Sydney 0 22/34 EXAMPLE 7 Barbiturates Phmvtoin gntiimn Ktipnal sprav Amounts prefetred mount most preferred amount phenytoin sodium -60 -55 -40 water 2.5-25 3-20 -10 ethanol -30 ' 7.5-20 9.5-15 piojpyleiie glycol -30 7.5-20 9.5-15 polyethylene glycol -30 7.5-20 9.5-15 flavors 1-10 3-8 -7.5 B. Phenvtoin oon-yolar lingual stnav Amounts preferred amount most preferred pheoytoin 15 migjdol Butane polyoxyethylated oleic glyeerides flavors -45 -50 -80 -50 0.1-1() -40 15^0 30-75 -40 1-8 amount 15-35 15-20 60-70 , -20 5-7.5 03-Sep-2007 03:58 PM AAR Sydney 0 23/34 carboprost tlmroiotiiflmine •water ethanol polyefliyleae glycol sodium chloride flavors EXAMPLES Prostaglandins CaAonrost thromeftiamms lingnal antsy Amounts preferred amount 0.05-5 0,1-3 50-95 60-80 -20 7.5-15 -20 7.5-15 1-20 3-15 0.1-5 1-4 most preferred amount 025-2.5 65-75 9.5-12,5 9.5-12.5 4-8 2-3 pH is adjusted with sodium hydroxide and/or hydrochloric acid B. carboprost migylol Butane polyoxyethylated oleic glyeerides flavors Carboprost non-polar Knpaal spray Amounts preferred amount most preferred amoxmt 0.05-5 25-50 5-60 -50 0.1-10 0.1-3 30*45 10-50 -45 1-8 0,25-2.5 -40 -35 *40 5-7.5 03-Sep-2007 03:58 PM AAR Sydney 0 24/34 EXAMPLES Neutrscecticals A- Carnitine as bite capsule (contents are a paste) Amounts preferred amount most preferred amount camitiiiB fanlarafe 6-80 45-65 soya oil 7.5-50 1G-40 12.5-35 soya lecithin 0.001-1.0 0.005-0.5 .01-0.1 Soya fats 7.5-50 -40 12.5-35 flavors 140 2-8 3-6 B. Valerian as lineual surav Amounts preferred amount most preferred amount valerian extract 0.1-10 0.2-7 0.25-5 water 50-95 60-80 65-75 ethaaol -20 7.5-15 9.5-12.5 polye&ylene glycol -20 7.5-15 9.5-12.5 flavors 1-10 2-8 3-6 C. Echinacea as bite caosule ■ Amounts preferred amount tnost preferred amount echinacea extract -85 40-75 45-55 soya oil 7.5-50 -40 . 12.5-35 soya lecithin 0.001-1.0 0.005-0.5 .01-0.1 Soya fats 7.5-50 -40 12.5-35 flavors 1-10 2-8 3-6 03-Sep-2007 03:58 PM AAR Sydney 0 25/34 D. Mixtures of ingredients Amounts preferred amount magnesium oxide 15-40 20-35 citromiuna picolinate 0.01-1.0 0.02-0.5 foHcacid .025-3.0 0.05-2.0 vitamin B-12 0.01-1.0 0.02-0.5 vitamin E 15-40 20-35 Soya oil 10-40 12,5-35 soya lecithin 0.1-5 0.2-4 soyafet 10-40 15-35 most {referred amount -30 .025-0.75 0.25-0.5 .025-0.75 -30 -20 0.5-1.5 17.5-20 03-Sep-2007 03:59 PM AAR Sydney 0 26/34 EXAMPLE 10 Sleep Inducers (also CNS active amioe) A. Diphenhydramine hvdiqchloiidelinemal gprav Amouats preferred amount most preferred amount diphfi^ydraniine 3-50. 4-40 5-35 HQ water 5-90 10-80 50-75 ettianol 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 v • 03-Sep-2007 03:59 PM AAR Sydney 0 27/34 EXAMPLE 11 Aiti-Asta^c^Brondhodilatow Isoproterenol Hydiochlaridfi as polar lingnal stnav Amounts preferred amount most preferred amount isoproterenol Hydrochloride 04-10 0.2-7.5 0.5-6 water .5-90 -80 50-75 ethaaol 1-80 3-50 -10 polyethylene glycol 1-80 3-50 -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. Terijtttalia.fr sulfate as polar lingual sprav Amounts prefenred amorant most pruned amount terbutaiine sulfate 0.1-10 02-7.5 0.5-6 water -90 -80 50-75 ethaaol 1-10 2-8 2.5-5 Sorbitol. 0.1-5 02-4 0.4-1.0 1 aspartame 0.01-0.5 0.02-0.4 0.04-0.1. 1 flavors 0.1-5 1-4 2-3 I C. Terbctaline as non-polar lingual sorav Amounts preferred amount terbutaOne migylol isolmtane polyoxyethylated oleic glycerides flavors 0.1-10 0.2-7.5 25-50 30-45 5-60 10-50 -50 0:1-10 -45 1-8 most preferred amount 0.5-6 35-40 -35 -40 5-7-5 Q3-Sep-2007 03:59 PM AAR Sydney 0 28/34 D. ThaftpTiylline polar bite capanle Amounts preferred amount most preferred amount theophylline -50 *40 -30 polyethylene glycol -60 -50 -40 gfyceda -50 -45 -40 propylene glycol 23-50 -45 3040 flavors 0.1-5 1-4 2-3 E. ATbnterol sulfate as pfilar linfliiftl gprav Amounts preferred atnoiifit; most preferred amount albuterol sulfate 0.1-10 0.2-7,5 0.5-6 water -90 -S0 50-75 sthanol M0 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 03-Sep-2007 03:59 PM AAR Sydney 0 29/34 Example 12 Polar solvent formulations using a propellant: A, Sulfiinvhirga Amount Preferred Amount Most-Preferred Amount glytniride 0.1-25% 0.5-15% 0.6-10% Ethanol 40-99% (50-97% 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) Amount Preferred Amount Most-Preferred Amount prostaglandin E, 0.01-10% 0,1-5% 0.2-3% Ethanol -90% -75% -50% Propylene! glycol 1-90% -80% -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. Promethamnefa^tieineH^ sleep inducer, and CNS active amine! Amount Preferred Amount Most-Pref&red Amount promethazine 1-25% 3-15% -12% EUiasol -90% -75% ■25-50% Propylene glycol' 1-90% -80% -75% Water 0.01-5% 0.1-4% 0.2-2% Flavors 0.05-10% 0.1-5% 0.1-2.5% Propellant 240% 3-5% 3-4%

Claims

03-Sep-2007 03:59 PM AAR Sydney 0 30/34 D, Mwntmnft Acaount Preferred Amount Most-Preferred 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% Propellaot 2-10% 3-5% 3-4%, •27 - 03-Sep-2007 03:59 PM AAR Sydney 0 31/34 What is claimed is:

1. A propellant free buccal spray composition for transmucosal administration of a pharmacologically active compound comprising art active compound in an amount between 0.005 and 55 percent by weight of the total composition 5 selected from the group consisting of antispasmodics, agents for treating urinary incontinence, anti-diarrheal agents selected from the group consisting of palnosetron, tropisetron, attapulgite, atropine, bismuth, diphenoxylate, loperamide, and mixtures thereof, agents for treating nausea and/or vomiting selected from the group consisting of alosetron, dolasetron, granisetron, 10 meclizine, metoclopramide, palnosetron, prochloperazine, promethazine, trimethobenzamide, tropisetron, and mixtures thereof, smooth muscle contractile agents, anti-secretory agents, enzymes, anti- diuretics selected from the group consisting of benzthiazide, bendroflumethazide, bumetanide, chlorthalidone, chlorothiazide, ethacrynic acid, furosetnide, hydrochlorothiazide, 15 hydroflumethiazide, methyetotbiazide, polythiazide, quinethazone, spironolactone, triamterene, torsemide, trichiomethiazide, and mixtures thereof, anti-ulcerants selected from the group consisting of ranitidine, misoprostol, sucralfate, pantoprazole, lansoprazole, omeprazole, and mixtures thereof, bile acid replacement and/or gallstone solubilizing drugs, and mixtures thereof; and a 20 non-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 flavoring agent in an amount between 0.1 and 10 percent by weight of the total composition. j

3. The composition of claim 1, wherein the active compound is an anti- diuretic 25 selected from the group consisting of benzthiazide, bendroflumethazide, bumetanide, chlorthalidone, chlorothiazide, ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, quinethazone, spironolactone, triamterene, torsemide, trichiomethiazide, and mixtures thereof. 30

4. The composition of claim 1, wherein the active compound is an anti- spasmodic selected from the group consisting of atropine, baclofen, dicyclomine, hyoscine, propatheiine, oxybutynin, S-oxybutynin, tizanidine, and mixtures thereof.

5. The composition of claim 1, wherein the active compound is ari agent for treating urinary incontinence selected from the group consisting of darit:enacin, 35 vamicamide, detrol, ditropan, imipramine, and mixtures thereof. 28 03-Sep-2007 04:00 PM AAR Sydney 0 32/34

6. The composition of claim 1, wherein the active compound is an anti- diarrheal selected from the group consisting of palnosetron, tropisetron, attapulgite, atropine, bismuth, diphenoxylate, loperamide, and mixtures thereof.

7. The composition of claim 1, wherein the active compound is an agent for treating 5 nausea or vomiting selected from the group consisting of alosetron, dolasetron, granisetron, meclizine, metoclopramide, palnosetron, prcchloperazine, promethazine, trimethobenzamiode, tropisetron, and mixtures thereof.

8. The composition of claim 1, .wherein the active compound is the smooth muscle contractile agent hyoscine. 10

9. The composition of claim 1, wherein the active compound is an anti- secretory agent selected from the group consisting of esomeprazole, lansoprazole, omeprazole,' pantoprazole, rabeprazole, tenetoprazole, ecabet, misoprostol, teprenone, and mixtures thereof.

10. The composition of claim 1, wherein the active compound is an enzyme selected 15 from the group consisting of alpha-galactosidase, alpha-L-iduronidase, imiglucerase/alglucerase, amylase, lipase, protease, pancreatin, olsalazine, and mixtures thereof.

11. The composition of claim 1, wherein the active compound is an anti- diuretic selected from the group consisting of desmopressin, oxytocin, and mixtures 20 thereof

12. The composition of claim 1, wherein the active compound is a anti-ulcerant selected from the group consisting of ranitidine, misoprostol, sucralfate, pantoprazole, lansoprazole, omeprazole, and mixtures thereof

13. The composition of claim 1, wherein the active compound is the bile acid 25 replacement and/or gallstone solubilizing agent ursodiol.

14. 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.

15. The composition of claim 1, wherein the solvent is selected from the group 30 consisting (CrCa) fatty acid (CrC6) esters, C7-C18 hydrocarbons of linear or branched configuration, Ca-C§ alkanoyl esters, and triglycerides of Cz-C@ carboxyilc acids. 29 03-Sep-2007 04:00 PM AAR Sydney 0 33/34 561 12s

16. The composition of claim 15, wherein the solvent is miglyol. 17, Use of a composition according to claim 1 for the manufacture of a medicament for the administration of a pharmacologically active compound to the oral mucosa of a mammal. 5 18. Use according to claim 17, wherein the amount of the composition is predetermined.