Compositions with modulating agents

• US 8,795,693 B2
• Filed: 11/29/2007
• Issued: 08/05/2014
• Est. Priority Date: 08/04/2003
• Status: Active Grant

• Current Assignee: VYNE Therapeutics, Inc.
• Original Assignee: Foamix Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Tamarkin, Dov, Eini, Meir, Friedman, Doron, Berman, Tal, Schuz, David
• Primary Examiner(s): Desai, Anand
• Assistant Examiner(s): MERCIER, MELISSA S
• Application Number:
  US11/947,751
• Publication Number:
  US 20080206159A1
• Time in Patent Office: 2,441 Days
• Field of Search: None
• US Class Current: 424/401
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/375 Ascorbic acid, i.e. vitamin C; Salts thereof
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0046 Ear
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0056 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
• CPC Class Codes: A61K 9/122 Foams; Dry foams edible foams A61K9/0056
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents

Abstract

The present invention relates to a waterless composition and foam as a vehicle in which an active pharmaceutical or cosmetic agent, when added is stable or stabilized by or its destabilization is impeded by the presence of a modulating agent. The pharmaceutical or cosmetic composition and foam, includes: a waterless solvent, a modulating agent and one or more active pharmaceutical or cosmetic agents. The present invention also relates to a method of treatment administering the waterless composition and foam.

Claims

1. A waterless composition comprising one or more active agents and a carrier for topical delivery of the one or more active agents suitable for stabilizing at least one of said one or more active agents, said carrier comprising:

a) about 25% to about 98% of at least one polar solvent selected from the group consisting of a polyol, a polyethylene glycol, and combinations thereof;

b) a modulating agent;

c) about 0.01% to about 5% by weight of at least one polymeric agent;

d) a surface active agent; and

e) a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in its carbon chain, a fatty acid having 16 or more carbons in its carbon chain and mixtures of any two or more thereof;

wherein the at least one active agent is chemically unstable in the carrier in the absence of a modulating agent;

wherein the modulating agent is capable of and is selected to modulate or adjust the artificial pH of the carrier to an artificial pH or to provide an artificial pH buffering effect such that the chemical stability of the at least one active agent is increased as compared to its stability in the carrier without the modulating agent; and

wherein if the waterless composition is packaged in an aerosol container and a liquefied or compressed gas propellant is added at a concentration of about 3% to about 25% by weight of the waterless composition, then the composition will be capable upon release from the aerosol container to expand to form a breakable foam that collapses upon application of shear force.

2. The waterless composition of claim 1 further comprising one or more agents that additionally are capable of a function selected from the group consisting of chelating an available metal ion, impeding ionization, and impeding oxidation.

3. The waterless composition of claim 1, wherein the polymeric agent is selected from the group consisting of a locust bean gum, sodium alginate, sodium caseinate, an egg albumin, a gelatin agar, a carrageenin gum, a xanthan gum, a quince seed extract, a tragacanth gum, a guar gum, a cationic guar, a hydroxypropyl guar gum, a starch, an amine-bearing polymer, a chitosan, an alginic acid, a hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, a polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, a polyvinyl acetate, a polyvinyl chloride polymer, a polyvinylidene chloride polymer, a methylcellulose, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a methylhydroxyethylcellulose, a hydroxyethyl carboxymethyl cellulose, a carboxymethyl cellulose, a cationic cellulose, a PEG 1000, a PEG 4000, a PEG 6000, a PEG 8000 and a carbomer.

4. The waterless composition of claim 3, wherein the polymeric agent is about 0.2% to about 3% by weight of a gelling agent.

5. The waterless composition of claim 1 wherein the modulating agent is between about 5% to about 0.01% by weight of the composition and wherein if the active agent itself has a modulating effect, the amount of active agent used to obtain an effective modulating effect is less than the amount of active agent used to obtain an effective therapeutic effect.

6. The waterless composition of claim 5 wherein the modulating agent is between about 1% to about 0.02% by weight of the composition.

7. The waterless composition of claim 1 wherein the modulating agent is between about 0.6% to about 0.04% by weight of the composition.

61. The waterless composition of claim 4, wherein the concentration of the polymeric agent is selected such that the viscosity of the composition is less than 12,000 CPs, or less than 10,000 CPs.

62. The waterless composition of claim 1, wherein the modulating agent is an acid.

63. The waterless composition of claim 62, wherein the acid is a fatty acid selected from the group consisting of stearic acid, lauric acid, myristic acid, valproic acid, and mixtures of any two or more thereof.

8. A foamable waterless composition comprising:

a. a therapeutically effective concentration of one or more active agents;

b. a carrier for topical delivery of the one or more active agents suitable for stabilizing at least one of said one or more active agents, comprising

i. about 25% to about 98% of at least polar solvent selected from the group consisting of (1) a polyol; and

(2) a polyethylene glycol (PEG);

ii. 0% to about 75% of a secondary polar solvent;

iii. a modulating agent

iv. about 0.01% to about 5% by weight of at least one polymeric agent and mixtures of any two or more thereof, wherein the polymeric agent is selected from the group consisting of a locust bean gum, sodium alginate, sodium caseinate, an egg albumin, a gelatin agar, a carrageenin gum, a xanthan gum, a quince seed extract, a tragacanth gum, a guar gum, a cationic guar, a hydroxypropyl guar gum, a starch, an amine-bearing polymer, a chitosan, an alginic acid, a hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, a polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, a polyvinyl acetate, a polyvinyl chloride polymer, a polyvinylidene chloride polymer, a methylcellulose, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a methylhydroxyethylcellulose, a hydroxyethyl carboxymethyl cellulose, a carboxymethyl cellulose, a cationic cellulose, a PEG 1000, a PEG 4000, a PEG 6000, a PEG 8000 and a carbomer;

v. a surface active agent;

vi. a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in its carbon chain, a fatty acid having 16 or more carbons in its carbon chain and mixtures of any two or more thereof; and

vii. a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the foamable waterless composition wherein the gas propellant is essentially free of chlorofluorocarbons;

wherein the at least one active agent is chemically unstable in the carrier in the absence of a modulating agent;

wherein the modulating agent is capable of and is selected to modulate or adjust the artificial pH of the carrier to an artificial pH or to provide an artificial pH buffering effect such that the chemical stability of the at least one active agent is increased as compared to its stability in the carrier without the modulating agent

wherein the carrier is shakable or flowable; and

wherein the composition is stored in an aerosol container and upon release expands to form a breakable foam that collapses upon application of shear force.

9. The foamable waterless composition of claim 8, wherein the breakable foam is of about good quality.

10. The foamable waterless composition of claim 8, wherein the modulating agent is selected from the group consisting of sodium citrate, citric acid, lactic acid, glutamic acid, ascorbic acid, azelaic acid, stearic acid, triethanolamine, lysine, lidocaine, prilocalne, carbomer, formic acid, acetic acid, propionic acid, butyric acid, butyric acid, caproic acid, caprylic acid, nonanoic acid, capric acid, lauric acid, myristic acid, valproic acid, and mixtures of any two or more thereof.

11. The foamable waterless composition of claim 8, wherein the polyol is selected from the group consisting of a diol;

a triol;

at least one diol and at least one triol, wherein the ratio between the diol and triol is between 9;

1 and 1;

1;

a saccharide; and

mixtures of any two or more thereof.

12. The foamable waterless composition of claim 11, wherein the diol is selected from the group consisting of propylene glycol, butanediol, butenediol, butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and dibutylene glycol;

and or

wherein the triol is selected from the group consisting of glycerin, butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol.

13. The foamable waterless composition of claim 8, wherein the PEG is selected from the group consisting of a PEG 200, a PEG 300, a PEG 400, a PEG 600, a PEG 1000, a PEG 4000, a PEG 6000 and a PEG 8000.

14. The foamable waterless composition of claim 8, wherein the carrier comprises one or more PEGs in a concentration to provide viscosity of less than 12,000 CPs.

15. The foamable waterless composition of claim 8, wherein the carrier comprises a mixture of at least one polyol and at least one PEG.

16. The foamable waterless composition of claim 8, wherein the secondary polar solvent is selected from the group consisting of dimethyl isosorbide, tetrahydrofurfuryl alcohol polyethyleneglycol ether, DMSO, a pyrrolidone, N-Methyl-2-pyrrolidone, 1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG-type surfactant, an alpha hydroxy acid, lactic acid and glycolic acid.

17. The foamable waterless composition of claim 8, wherein the carrier comprises (1) at least one polar solvent selected from a diol, a triol and PEG, and (2) at least one secondary polar solvent.

18. The foamable waterless composition of claim 8, wherein the ratio between the polyol and/or PEG and the secondary polar solvent is between 9:

1 and 1;

4.

19. The foamable waterless composition of claim 8, wherein the composition is substantially alcohol-free.

20. The foamable waterless composition of claim 8, wherein the modulating agent is selected from the group consisting of an alpha hydroxy acid, an aliphatic beta hydroxy acid, an aromatic acid, an aromatic hydroxy acid, an alpha ketoacid, an aliphatic carboxylic acid, a branched aliphatic carboxylic acid, a short chain carboxylic acid, a fatty acid, an omega-3 fatty acid, an omega-6 fatty acid, an omega-9 fatty acid, a dicarboxylic acid, a branched dicarboxylic acid, an unsaturated dicarboxylic acid, an amino acid, a dimer or oligomer of amino acids, a retinoid, a nitrogen-containing organic compound, a primary, secondary, tertiary and quaternary amine, an amide, an amine oxide and a lactam.

21. The foamable waterless composition of claim 20,

wherein the alpha hydroxy acid and beta hydroxyl acid are selected from the group consisting of alpha-hydroxybutyric acid, alpha-hydroxyisobutyric acid, alpha-hydroxyisocaproic acid, alpha-hydroxyisovaleric acid, atrolactic acid, beta-hydroxybutyric acid, beta-phenyl lactic acid, beta-phenylpyruvic acid, citric acid, pyruvic acid, galacturonic acid, glucoheptonic acid, glucoheptono 1,4-lactone, gluconic acid, gluconolactone, glucuronic acid, glucuronolactone, glycolic acid, lactic acid, mandelic acid, mucic acid, pyruvic acid, saccharic acid, saccharic acid 1,4-lactone, tartaric acid and tartronic acid, 3-Hydroxybutanoic acid, quinic acid, isocitric acid, tropic acid, trethocanic acid, chlorolactic acid, citramalic acid, agaricic acid, aleuritic acid, pantoic acid, lactobionic acid, piscidic acid, hexylosonic acid or the anhydride thereof, and salicylic acids and derivatives thereof;

wherein the aromatic acid is selected from the group consisting of benzoic acid, toluic acid, dimethyl benzoic acid and phthalic acid;

wherein the alpha ketoacid has the molecular structure of (Ra)COCOO(Rb);

wherein Ra and Rb are independently selected from the group consisting of H and saturated or unsaturated, isomeric or non-isomeric, straight, branched, or cyclic C1-C25 alkyl, aralkyl, or aryl groups, wherein Ra may be optionally substituted with an F, Cl, Br, I, OH, CHO, COOH, or alkoxy group having 1 to 9 carbon atoms;

wherein the aliphatic carboxylic acid is selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, butyric acid, caproic acid, caprylic acid, nonanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, octacosanoic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, erucic acid, valproic acid and 12-hydroxy stearic acid;

wherein the dicarboxylic acid is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, dodecanedioic acid, brassylic acid, thapsic acid, 14-methylnonacosanedioic acid, 14,15-dimethyltriacontanedioic acid (C30) undecylenic acid, maleic acid and fumaric acid;

wherein the carbon atom skeleton of the branched dicarboxylic acid is substituted with at least one group selected from the group consisting of R, F, Cl, Br, OH, OR, SH, CHO, COOH, and NRaRb, and wherein R, Ra and Rb are independently selected from the group consisting of H, saturated or unsaturated, isomeric or non-isomeric, straight, branched, or cyclic C1-C25 alkyl, aralkyl, or aryl groups;

wherein the branched dicarboxylic acid is selected from the group consisting of aspartic acid, alpha-ketoglutaric acid, adipic acid 2-amino, aconitic acid, benzene dicarboxylic acid, citramalic acid, citric acid, cystathionine, glucuronic acid, glutamic acid, itaconic acid, malic acid, mucic acid, oxalacetic acid, diamino pimelic acid, saccharic acid, dimethyl succinic acid, tartaric acid and tartronic acid;

wherein the carboxylic acid is selected from the group consisting retinoic acid, isotretinoin, ascorbic acid, isoascorbic acid, ethanesulfonic acid, glycerophosphoric acid, acetohydroxamic acid, aconitic acid, alpha-ketocaproic acid, aminomalonic acid, hippuric acid, hydrochloric acid, methanesulfonic acid, oxalic acid, phosphoric acid, sorbic acid, iminodiacetic acid and carnitine; and

wherein the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, lysine, histidine, phenylalanine, tyrosine, tryptophan, praline, B-alanine (3-alanine), 4-aminobutyrate (GABA), 3-cyanoalanine (B-cyanoalanine), 2-aminobutyric acid, 2-methylene-4-aminobutyric acid, 3-methylene-4-aminobutyric acid, 2-aminoisobutyric acid, 5-aminolevulinic acid, 2-amino-4-methylhexanoic acid (homoisoleucine), 2-amino-4-methylhex-4-enoic acid, 2-amino-4-methylhex-5-ynoic acid, 2-amino-3-methylpentanoic acid, 2-aminoadipic acid, 4-ethylideneglutamic acid, 3-aminoglutaric acid, 2-aminopimelic acid, N4-ethylasparagine, N4-methylasparagine, erythro-4-methylglutamic acid, 4-methyleneglutamic acid, 4-methyleneglutamine, N5-methylglutamine, N5-ethylglutamine (theanine), N5-isopropylglutamine, 2-amino-4-(aminoxy)butyric acid (canaline), 2,4-diaminobutyrate, N4-acetyl-2,4-diaminobutyrate, N4-lactyl-2,4-diaminobutyrate, N4-oxalyl-2,4-diaminobutyrate, 2,3-diaminopropionic acid, N3-acetyl-2,3-diaminopropionic acid, N3-methyl-2,3-diaminopropionic acid, N3-oxalyl-2,3-diaminopropionic acid, N6-acetyllysine, N6-methyllysine, N6-trimethyllysine (laminine), ornithine (2,5-diaminopentanoic acid), saccharopine (N6-(2′

-glutamyl)lysine, 2,6-diaminopimelic acid, N4-(2-hydroxylethyl)asparagine, erythro-3-hydroxyaspartic acid, 4-hydroxyarginine, 4-hydroxycitrulline, threo-4-hydroxyglutamic acid, 3,4-dihydroxyglutamic acid, 3-hydroxy-4-methylglutamic acid, 3-hydroxy-4-methyleneglutamic acid, 4-hydroxy-4-methylglutamic acid, 4-hydroxy-glutamine, N5-(2-hydroxyethyl)glutamine, 5-hydroxynorleucine, threo-4-hydroxyhomoarginine, homoserine, O-acetylhomoserine, O-oxalylhomoserine, O-phosphohomoserine, 4-hydroxyisoleucine, 5-hydroxymethylhomocysteine, threo-3-hydroxyleucine, 5-hydroxyleucine, 2-hydroxylysine, 4-hydroxylysine, 5-hydroxylysine, N6-acetyl-5-hydroxylysine, N6-trimethyl-5-hydroxylysine, 4-hydroxyornithine, mimosine, 4-hydroxynorvaline, 5-hydroxynorvaline, 2-amino-4,5-dihydroxypentanoic acid, 2-amino-4-hydroxypimelic acid, 4-hydroxyvaline, O-acetylserine, O-phosphoserine, pipecolic acid, (piperidine-2-carboxylic acid), 3-hydroxypipecolic acid, trans-4-hydroxypipecolic acid, trans-5-hydroxypipecolic acid, 5-hydroxy-6-methylpipecolic acid, 4,5-dihydroxypipecolic acid, trans-3-hydroxyproline, trans-4-hydroxyproline, trans-4-hydroxymethylproline, azetidine-2-carboxylic acid, N-(3-amino-3-carboxypropyl)azetidine-2-carboxylic acid, 4,5-dehydropipecolic acid (baikiain), 3-amino-3-carboxypyrrolidone (cucurbitine), 2-(cyclopent-2′

-enyl)glycine, 5-hydroxytryptophan, albizziine (2-amino-3-ureidopropionic acid), arginosuccinic acid, canavinosuccinic acid, citrulline, homoarginine, homocitrulline, indospicine, O-ureidohomoserine, 6-hydroxykynurenine, 3-(4-aminophenyl)alanine, 3-(3-aminomethylphenyl)alanine, 3-(3-carboxyphenyl)alanine, 3-carboxytyrosine, 3-(3-hydroxymethylphenyl)alanine, 3-(3-hydroxyphenyl)alanine, 3-(3,4-dihydroxyphenyl)alanine (L-DOPA), 2-(phenyl)glycine, 2-(3-carboxyphenyl)glycine, 2-(3-carboxy-4-hydroxyphenyl)glycine, 2-(3-hydroxyphenyl)glycine, 2-(3,5-dihydroxyphenyl)glycine, 4-aminopipecolic acid, guvacine, 2-amino-4-(isoxazolin-5-one)-2-yl)butyric acid, lathyrine, tetrahydrolathyrine and ornithin and dimers or oligomers thereof.

22. The foamable waterless composition of claim 20, wherein the modulating agent is a nitrogen-containing organic compound selected from the group consisting of primary amines, methylamine and ethylamine;

an ethanolamine, monoethanolamine, monoisopropanolamines, a diamine, ethylenediamine, 1,2-diaminopropane, a dialkylamine, dimethylamine, diethylamine, diethanolamine, diisopropanolamine, N-methylethanolamine, N-ethylethanolamine, a tertiary amine, a trialkylamine, triethylamine, triethylamine, triethanolamine, N-methyldiethanolamine and tri-isopropanolamine.

23. The foamable waterless composition of claim 8, wherein the polymeric agent is a cellulose polymer or a carbomer.

24. The foamable waterless composition of claim 8, wherein the polymeric agent is dispersible in the polyol or in the mixture of a polyol and an additional polar solvent.

25. The foamable waterless composition of claim 8, wherein the surface active agent comprises at least one surfactant selected from the group consisting of a polyoxyethylene fatty ether, a polyoxyethylene fatty ester, a carbohydrate ester and a sucrose ester, glyceryl stearate, PEG-100 stearate, steareth-2, steareth-20, steareth-21, ceteareth 2, PEG-100 stearyl ether, cetearyl glucoside, methyl glucose sesquistearate, sorbitan monostearate, GMS NE, span 20, glyceryl stearate and PEG 100 stearate, glyceryl stearate and PEG 100 stearate and laureth4;

steareth 2, PEG 100 searate and laureth4, and cetearyl glucoside and cetearyl alcohol.

26. The foamable waterless composition of claim 8, wherein the surface active agent comprises a non-ionic surface active agent.

27. The foamable waterless composition of claim 26, wherein the surface active agent further comprises an ionic surfactant, selected from the group consisting of a cationic surfactant, a zwitterionic surfactant, an amphoteric surfactant and an ampholytic surfactant.

28. The foamable waterless composition of claim 26, wherein the surface active agent comprises a mixture of at least one non-ionic surfactant and at least one ionic surfactant in a ratio selected from

a. about 100:

1 to about 6;

1

b. about 1;

1 to about 20;

1.

29. The foamable waterless composition of claim 8, further comprising a hydrophobic solvent.

30. The foamable waterless composition of claim 29, wherein the hydrophobic solvent is selected from the group consisting of a mineral oil, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, a maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, an acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, unsaturated or polyunsaturated oils, an olive oil, a corn oil, a soybean oil, a canola oil, a cottonseed oil, a coconut oil, a sesame oil, a sunflower oil, a borage seed oil, a Syzygium aromaticum oil, a hempseed oil, a herring oil, a cod-liver oil, a salmon oil, a flaxseed oil, a wheat germ oil, an evening primrose oil, an essential oil, a silicone oil, a dimethicone, a cyclomethicone, a polyalkyl siloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a polyether siloxane copolymer, and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer.

31. The foamable waterless composition of claim 8, wherein the foam adjuvant is selected from the group consisting of cetyl alcohol, stearyl alcohol, behenyl alcohol, stearic acid and any two or more thereof.

32. The foamable waterless composition of claim 8, further comprising an additional component selected from the group consisting of an anti perspirant, an anti-static agent, a buffering agent, a bulking agent, a chelating agent, a colorant, a conditioner, a deodorant, a diluent, a dye, an emollient, a fragrance, a humectant, an occlusive agent, a penetration enhancer, a perfuming agent, a permeation enhancer, a preservative, a skin penetration enhancer, a sunscreen, a sun blocking agent, a sunless tanning agent, and a vitamin.

33. The foamable waterless composition of claim 8, wherein the one or more active agents are selected from the group consisting of active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antiinfective, antibacterials, antibiotics, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antifungal, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antiparasitic agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, anti-yeast agents, agents that control yeast, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, dicarboxylic acids, disinfectants, fungicides, hair growth regulators, hormones, hydroxy acids, immunosuppressants, immunoregulating agents, insecticides, insect repellents, keratolytic agents, lactams, metals, metal oxides, mitocides, neuropeptides, non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides, photodynamic therapy agents, retinoids, sanatives, scabicides, self tanning agents, steroids, skin whitening agents, asoconstrictors, vasodilators, vitamins, vitamin D derivatives, flavonoids, wound healing agents and wart removers.

34. The foamable waterless composition of claim 33, wherein the steroid is selected from the group consisting of alclometasone dipropionate, amcinafel, amcinafide, amcinonide, beclomethasone, beclomethasone dipropionate, betamethsone, betamethasone benzoate, betamethasone dexamethasone-phosphate, dipropionate, betamethasone valerate, budesonide, chloroprednisone, chlorprednisone acetate, clescinolone, clobetasol, clobetasol propionate, clobetasol valerate, clobetasone, clobetasone butyrate, clocortelone, cortisone, cortodoxone, craposone butyrate, desonide, desoxymethasone, dexamethasone, desoxycorticosterone acetate, dichlorisone, diflorasone diacetate, diflucortolone valerate, difluorosone diacetate, diflurprednate, fluadrenolone, flucetonide, flucloronide, fluclorolone acetonide, flucortine butylesters, fludroxycortide, fludrocortisone, flumethasone, flumethasone pivalate, flumethasone pivalate, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluosinolone acetonide, fluperolone, fluprednidene acetate, fluprednisolone hydrocortamate, fluradrenolone, fluradrenolone acetonide, flurandrenolone, fluticasone, halcinonide, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cyclopentylpropionate, hydrocortisone valerate, hydroxyltriamcinolone, medrysone, meprednisone, .alpha.-methyl dexamethasone, methylprednisolone, methylprednisolone acetate, mometasone furoate, paramethasone, prednisolone, prednisone, pregnenolone, progesterone, spironolactone, triamcinolone, triamcinolone acetonide and derivatives, esters and salts thereof;

wherein the antifungal is selected from the group consisting of a polyene, natamycin, nystatin;

an allylamine, naftifine, terbinafine;

an imidazole, bifonazole, clotrimazole, econazole, fenticonazole, ketocanazole, miconazole, oxiconazole;

a diazole, a triazoles, fluconazole, itraconazole, terconazole, tolnaftate, ciclopirox, undecylenic acid, sulbentine, griseofulvin, Amphotericin B, flucytosine (5FC), a morpholine compound, amorolfine, and the related morpholines and analogs, derivatives and salts thereof, and any combination thereof at a therapeutically effective concentration; and

wherein the antibacterial is selected from the group consisting of a beta-lactam antibiotic, an aminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole, metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin, clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxin B, an antibiotic polyene, an antibiotic polyether, an antibiotic quinolone, an antibiotic steroid, fucidic acid, mupirocin, chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal, silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, an oxidizing agent, iodine, iodate, a periodate, a hypochlorite, a permanganate, a substance that release free radicals and/or active oxygen, a cationic antimicrobial agent, a quaternary ammonium compound, a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymeric biguanide, a naturally occurring antibiotic compound and analogs, derivatives, salts, ions and complexes thereof.

35. The foamable waterless composition of claim 8, wherein the one or more active agents are unstable in the presence of water.

36. The foamable waterless composition of claim 8, wherein the one or more active agents are stable at an acidic pH range and the modulating agent is acidic.

37. The foamable waterless composition of claim 8, wherein the active agent is an ester, which undergoes hydrolysis at basic pH.

38. The foamable waterless composition of claim 8, wherein the one or more active agents undergo rearrangement at basic pH.

39. The foamable waterless composition of claim 8, wherein the one or more active agents are stable at a basic pH range and the modulating agent is basic.

40. The foamable waterless composition of claim 39, wherein the active agent is selected from vitamin D, a vitamin D analog, a vitamin D derivative.

41. The foamable waterless composition of claim 8, wherein the modulating agent is a nitrogen-containing modulating agent.

42. The foamable waterless composition of claim 8, wherein the modulating agent is triethanolamine and the active agent is calcipotriol.

43. The foamable waterless composition of claim 8, wherein the modulating agent is selected from the group consisting of sodium citrate, citric acid, lactic acid, glutamic acid, azaleic acid, ascorbic acid, stearic acid, formic acid, acetic acid, propionic acid, butyric acid, butyric acid, caproic acid, caprylic acid, nonanoic acid, capric acid, lauric acid, myristic acid, valproic acid, and mixtures of any two or more thereof and the active agent is betamethasone valerate.

44. The foamable waterless composition of claim 8, wherein the modulating agent is selected from the group consisting of carbomer, and triethanolamine, and mixtures thereof and the active agent is selected from the group consisting of clobetosol proprionate and flucinoline acetonide.

45. The foamable waterless composition of claim 8, wherein the one or more active agents are stable at about neutral pH range and the modulating agent is neutral.

46. The foamable waterless composition of claim 8, wherein the modulating agent is a pharmaceutical or cosmetic active agent.

47. The foamable waterless composition of claim 8, comprising (1) a corticosteroid;

and (2) and active agent selected from the group of an antifungal agent, an antimicrobial agent, an antiviral agent, an anti-acne agent, a vitamin D3 derivative, calcipotriol, and antipsoriasis agent, a keratolytic agent and an antiacne agent.

48. The foamable waterless composition of claim 8, comprising (1) a keratolytic agent;

and (2) an active agent selected from the group of a corticosteroid, an antifungal agent, an antimicrobial agent, an antiviral agent, an anti-acne agent, a vitamin D3 derivative, calcipotriol, an antipsoriasis agent, an immunomodulator, an immunosuppressant and an antiacne agent.

53. The foamable waterless composition of claim 8, comprising a solid, semi solid or waxy surfactant wherein the amount of surfactant or combination of surfactants is between about 0.05% to about 10%.

54. The foamable waterless composition of claim 8, comprising a solid, semi solid or waxy surfactant which is soluble in oil and having a HLB or weighted average HLB of less than about 12.

49. A method of treating a disorder of mammalian subject, comprising:

administering a composition to a target site, the composition comprising;

one or more active agents and a waterless carrier for topical delivery of the one or more active agents, wherein the waterless carrier is suitable for stabilizing at least one of said one or more active agents, said waterless carrier comprising;

a) about 25% to about 98% of at least polar solvent selected from the group consisting of (1) a polyol; and

(2) a polyethylene glycol (PEG) solvent;

b) a modulating agent;

c) about 0.01% to about 5% by weight of at least one polymeric agent;

d) a surface active agent; and

e) a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in its carbon chain, a fatty acid having 16 or more carbons in its carbon chain and mixtures of any two or more thereof;

wherein the at least one active agent is chemically unstable in the carrier in the absence of a modulating agent;

wherein the modulating agent is capable of and is selected to modulate or adjust the artificial pH of the carrier to an artificial pH or to provide an artificial pH buffering effect such that the chemical stability of the at least one active agent is increased as compared to its stability in the carrier without the modulating agent; and

wherein if the composition is packaged in an aerosol container and a liquefied or compressed gas propellant is added at a concentration of about 3% to about 25% by weight of the composition, then the composition will be capable upon release from the aerosol container to expand to form a breakable foam that collapses upon application of shear force.

50. A method of treating a disorder of mammalian subject, comprising:

administering a foamable composition to a target site, the composition comprising;

a foamable waterless composition comprising;

a. a therapeutically effective concentration of one or more active agents;

b. a carrier for topical delivery of the one or more active agents suitable for stabilizing at least one of said one or more active agents, comprising

i. about 25% to about 98% of at least polar solvent selected from the group consisting of (1) a polyol; and

(2) a polyethylene glycol (PEG);

ii. 0% to about 75% of a secondary polar solvent;

iii. a modulating agent;

iv. about 0.01% to about 5% by weight of at least one polymeric agent;

v. a surface active agent;

vi. a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in its carbon chain, a fatty acid having 16 or more carbons in its carbon chain and mixtures of any two or more thereof; and

vii. a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the foamable waterless composition wherein the gas propellant is essentially free of chlorofluorocarbons;

wherein the at least one active agent is chemically unstable in the carrier in the absence of a modulating agent;

wherein the modulating agent is capable of and is selected to modulate or adjust the artificial pH of the carrier to an artificial pH or to provide an artificial pH buffering effect such that the chemical stability of the at least one active agent is increased as compared to its stability in the carrier without the modulating agent;

wherein the carrier is shakable or flowable; and

wherein the foamable waterless composition is stored in an aerosol container and upon release expands to form a breakable foam that collapses upon application of shear force; and

wherein the polymeric agent is selected from the group consisting of a locust bean gum, sodium alginate, sodium caseinate, an egg albumin, a gelatin agar, a carrageenin gum, a xanthan gum, a quince seed extract, a tragacanth gum, a guar gum, a cationic guar, a hydroxypropyl guar gum, a starch, an amine-bearing polymer, a chitosan, an alginic acid, a hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, a polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, a polyvinyl acetate, a polyvinyl chloride polymer, a polyvinylidene chloride polymer, a methylcellulose, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a methylhydroxyethylcellulose, a hydroxyethyl carboxymethyl cellulose, a carboxymethyl cellulose, a cationic cellulose, a PEG 1000, a PEG 4000, a PEG 6000, a PEG 8000 and a carbomer.

51. The method of claim 50, wherein the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina and the rectum.

52. The method of claim 50, wherein the disorder is selected from the group consisting of dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, eethyma, yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, post-operative or post-surgical skin conditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, erythema nodosum, grannuloma annulare, epidermal necrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid, dermatitis herpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi'"'"'s sarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact dermatitis, atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, baldness, alopecia, Behcet'"'"'s syndrome, cholesteatoma, Dercum disease, ectodermal dysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical or thermal skin burns, scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis, necrotizing myositis, gangrene, scarring, and vitiligo, chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal and rectal disease, anal abscess/fistula, anal cancer, anal fissure, anal warts, Crohn'"'"'s disease, hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation, polyps of the colon and rectum;

and wherein the active agent is suitable for treating said disorder.

55. A foamable waterless composition comprising:

a. a therapeutically effective concentration of one or more active agents;

b. a carrier for topical delivery of the one or more active agents suitable for stabilizing at least one of said one or more active agents, comprising;

i. about 25% to about 98% of at least polar solvent selected from the group consisting of (1) a polyol; and

(2) a polyethylene glycol;

ii. 0% to about 75% of a secondary polar solvent;

iii. a modulating agent;

iv. about 0.01% to about 5% by weight of at least one polymeric agent;

v. a surface active agent;

vi. a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in its carbon chain, a fatty acid having 16 or more carbons in its carbon chain and mixtures of any two or more thereof; and

vii. a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the foamable waterless composition, wherein the gas propellant is essentially free of chlorofluorocarbons;

wherein the at least one active agent is chemically unstable in the carrier in the absence of a modulating agent;

wherein the modulating agent comprises one or more agents that are capable of impeding said destabilization and or are capable of stabilizing the active agent by chelating a metal ion such that the modulating agent is capable of reducing in the carrier the availability of metal ions so the stability of at least one active agent is improved when compared to its stability in the carrier without the modulating agent;

wherein the carrier is shakable or flowable; and

wherein the composition is stored in an aerosol container and upon release expands to form a breakable foam that collapses upon application of shear force; and

wherein the polymeric agent is selected from the group consisting of a locust bean gum, sodium alginate, sodium caseinate, an egg albumin, a gelatin agar, a carrageenin gum, a xanthan gum, a quince seed extract, a tragacanth gum, a guar gum, a cationic guar, a hydroxypropyl guar gum, a starch, an amine-bearing polymer, a chitosan, an alginic acid, a hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, a polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, a polyvinyl acetate, a polyvinyl chloride polymer, a polyvinylidene chloride polymer, a methylcellulose, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a methylhydroxyethylcellulose, a hydroxyethyl carboxymethyl cellulose, a carboxymethyl cellulose, a cationic cellulose, a PEG 1000, a PEG 4000, a PEG 6000, a PEG 8000 and a carbomer.

56. The foamable waterless composition of claim 55 further comprising one or more agents that additionally are capable of impeding said destabilization and or are capable of stabilizing the active agent primarily by modulating or adjusting the artificial pH of the carrier such that the modulating agent is capable of producing in the carrier an artificial pH or an artificial pH buffering effect at about a pH or pH range in which the stability of at least one active agent is improved when compared to its stability in the carrier without the modulating agent and or by impeding ionization and or by impeding oxidation.

57. The foamable waterless composition of claim 55, wherein the modulating agent is a chelating agent.

58. The foamable waterless composition of claim 57, wherein the chelating agent is sufficiently soluble or functional in the polar solvent to enable it to “

mop up”

or “

lock”

metal ions.

59. The foamable waterless composition of claim 57, wherein the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (“

EDTA”

) and salts thereof, disodium EDTA, tetrasodium EDTA, calcium disodium EDTA;

diethylenetriaminepentaacetic acid (“

DTPA”

) and salts thereof;

hydroxyethlethylenediaminetriacetic acid (“

HEDTA”

) and salts thereof; and

nitrilotriacetic acid (“

NTA”

) and salts thereof;

acetyl trihexyl citrate, aminotrimethylene phosphonic acid, beta-alanine diacetic acid, bismuth citrate, calcium disodium edta, citric acid, cyclohexanediamine tetraacetic acid, diammonium citrate, dibutyl oxalate, diethyl oxalate, diisobutyl oxalate, diisopropyl oxalate, dilithium oxalate, dimethyl oxalate, dipotassium edta, dipotassium oxalate, dipropyl oxalate, disodium edta, disodium edta-copper, disodium pyrophosphate, edta, etidronic acid, hedta, methyl cyclodextrin, oxalic acid, pentapotassium, triphosphate, pentasodium aminotrimethylene phosphonate, pentasodium pentetate, pentasodium triphosphate, pentetic acid, phytic acid, potassium citrate, sodium citrate, sodium dihydroxyethylglycinate, sodium gluceptate, sodium gluconate, sodium hexametaphosphate, sodium metaphosphate, sodium metasilicate, sodium oxalate, sodium trimetaphosphate, tea-edta, tetrahydroxypropyl ethylenediamine, tetrapotassium etidronate, tetrapotassium pyrophosphate, tetrasodium edta, tetrasodium etidronate, tetrasodium pyrophosphate, tripotassium edta, trisodium edta, trisodium hedta, trisodium nta, trisodium phosphate, malic acid, fumaric acid, maltol, succimer, penicillamine, dimercaprol, and desferrioxamine mesilate.

60. A foamable waterless carrier for use with a therapeutically effective concentration of one or more active agents comprising:

i. about 25% to about 98% of at least polar solvent selected from the group consisting of (1) a polyol; and

(2) a polyethylene glycol;

0% to about 75% of a secondary polar solvent;

ii. a modulating agent;

iii. about 0.01% to about 5% by weight of at least one polymeric agent;

iv. a surface active agent;

v. a foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in its carbon chain, a fatty acid having 16 or more carbons in its carbon chain and mixtures of any two or more thereof; and

vi. a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the foamable waterless carrier, wherein the gas propellant is essentially free of chlorofluorocarbons

wherein at least one active agent if present is susceptible, to one or more of reaction, breakdown, ionization or oxidation;

wherein the modulating agent comprises one or more agents that are capable of impeding said destabilization and or are capable of stabilizing the active agent primarily by modulating or adjusting the artificial pH of the carrier such that the modulating agent is capable of producing in the waterless carrier an artificial pH or an artificial pH buffering effect at about a pH or pH range in which the stability of at least one active agent is improved when compared to its stability in the carrier without the modulating agent and or by chelating a metal ion such that the modulating agent is capable of reducing in the waterless carrier the availability of metal ions so the stability of at least one active agent is improved when compared to its stability in the carrier without the modulating agent;

wherein the foamable waterless carrier is shakable or flowable; and

wherein the foamable waterless carrier is stored in an aerosol container and upon release expands to form a breakable foam that collapses upon application of shear force; and

wherein the polymeric agent is selected from the group consisting of a locust bean gum, sodium alginate, sodium caseinate, an egg albumin, a gelatin agar, a carrageenin gum, a xanthan gum, a quince seed extract, a tragacanth gum, a guar gum, a cationic guar, a hydroxypropyl guar gum, a starch, an amine-bearing polymer, a chitosan, an alginic acid, a hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, a polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, a polyvinyl acetate, a polyvinyl chloride polymer, a polyvinylidene chloride polymer, a methylcellulose, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a methylhydroxyethylcellulose, a hydroxyethyl carboxymethyl cellulose, a carboxymethyl cellulose, a cationic cellulose, a PEG 1000, a PEG 4000, a PEG 6000, a PEG 8000 and a carbomer.