US 2005O271596A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0271596A1 Friedman et al. (43) Pub. Date: Dec. 8, 2005

(54) VASOACTIVE KIT AND COMPOSITION AND (30) Foreign Application Priority Data USES THEREOF Oct. 24, 2003 (IB)...... IB03/005527 (75) Inventors: Doron Friedman, Karmei Yosef (IL); Oct. 25, 2002 (IL)...... 1524.86 Alex Besonov, Rehovet (IL); Dov Tamarkin, Maccabim (IL); Meir Eini, Publication Classification Ness Ziona (IL) (51) Int. Cl." ...... A61L 9/04 Correspondence Address: (52) U.S. Cl...... 424/45 WILMER CUTLER PICKERING HALE AND DORR LLP 60 STATE STREET (57) ABSTRACT BOSTON, MA 02109 (US) (73) Assignee: Foamix Ltd. The present invention relates to a therapeutic kit to provide a Safe and effective dosage of a vasoactive agent, including (21) Appl. No.: 11/124,676 an aeroSol packaging assembly including: a container accommodating a pressurized product; and an outlet capable (22) Filed: May 9, 2005 of releasing the pressurized product as a foam, wherein the Related U.S. Application Data preSSurized product comprises a foamable composition including: a vasoactive agent; at least one organic carrier (63) Continuation-in-part of application No. 10/532,618, Selected from the group consisting of a hydrophobic organic filed as 371 of international application No. PCT/ carrier, an organic polar Solvent, an emollient and mixtures IB03/05527, filed on Oct. 24, 2003. thereof, at a concentration of about 2% to about 50% by Continuation-in-part of application No. 10/911,367, weight, a surface-active agent, about 0.01% to about 5% by filed on Aug. 4, 2004. weight of at least one polymeric additive Selected from the group consisting of a bioadhesive agent, a gelling agent, a (60) Provisional application No. 60/429,546, filed on Nov. film forming agent and a phase change agent, Water, and 29, 2002. Provisional application No. 60/492,385, liquefied or compressed gas propellant at a concentration of filed on Aug. 4, 2003. about 3% to about 25% by weight of the total composition.

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VASOACTIVE KIT AND COMPOSITION AND 0009 a) a container accommodating a pressurized USES THEREOF product; and CROSS REFERENCE TO RELATED 0010 b) an outlet capable of releasing the pressur APPLICATIONS ized product as a foam; 0001. This application is a continuation-in-part applica 0011 wherein the pressurized product comprises a tion of co-pending International Patent Application No. foamable composition including: IB03/005527, designating the United States and filed on Oct. i. a vasoactive agent; 24, 2003, which claims the benefit of priority under 35 0012) U.S.C. S.119(e) to U.S. Patent Application Ser. No. 60/492, 0013 ii. at least one organic carrier selected from 546, filed on Nov. 29, 2002, both entitled “Cosmetic and the group consisting of a hydrophobic organic Pharmaceutical Foam,” and which claims the benefit of carrier, an organic polar Solvent, an emollient and priority under 35 USCS119 (a) to Israeli Patent Application mixtures thereof, at a concentration of about 2% to No. 152486, filed Oct. 25, 2002, all of which are hereby about 50% by weight; incorporated in their entirety by reference. 0.014) iii. a surface-active agent; 0002 This application is a continuation-in-part applica 0015 iv. about 0.01% to about 5% by weight of at tion of co-pending U.S. patent application Ser. No. 10/911, least one polymeric additive Selected from the 367, filed on Aug. 4, 2004, which claims the benefit of group consisting of a bioadhesive agent, a gelling priority under 35 U.S.C. S119(e) to U.S. Patent Application agent, a film forming agent and a phase change Ser. No. 60/492,385, filed on Aug. 4, 2003, both entitled “Foam Carrier Containing Amphiphilic Copolymer Gelling agent, Agent” and both hereby incorporated in their entirety by 0016 v. water; and reference. 0017 vi. liquefied or compressed gas propellant BACKGROUND OF THE INVENTION at a concentration of about 3% to about 25% by weight of the total composition. 0.003 Vasoactive agents have been used to relieve various Systemic and Superficial disorders. Classical treatment appli 0018. In one or more embodiments, the composition is cations include skin redness, varicose veins, hemorrhage, Selected from the group consisting of an oil-in-water emul hair growth disorders and Sexual disfunction. sion and a water-in-oil emulsion. 0004 Vasoactive agents are available in topical dosage 0019. In one or more embodiments the kit contains a form. Compositions containing vasoactive agents for topical Valve, which is optionally attached to metered dose device. treatment of dermatological disorders are available prima 0020. In one or more preferred embodiments the kit rily in cream, lotion gel and ointment forms. While Semi further includes a therapeutically active foam adjuvant is Solid compositions, Such as creams, lotions, gels and oint Selected from the group consisting of a fatty alcohol having ments are commonly used by consumers, new forms are 15 or more carbons in their carbon chain; a fatty acid having desirable in order to achieve better control of the application, 16 or more carbons in their carbon chain; fatty alcohols, while maintaining or bestowing the skin beneficial proper derived from beeswax and including a mixture of alcohols, ties of Such products. Thus, the development of new com a majority of which has at least 20 carbon atoms in their positions, having breakable foam consistency when released carbon chain; a fatty alcohol having at least one double from a container and liquid properties when applied onto the bond; a fatty acid having at least one double bond; a skin is advantageous. branched fatty alcohol; a branched fatty acid and a fatty acid 0005 Foams and, in particular, foam emulsions are com Substituted with a hydroxyl group. plicated Systems which do not form under all circumstances. Slight Shifts in foam emulsion composition, Such as by the 0021. In one or more embodiments, the composition addition of active ingredients, may destabilize the foam. further contains a penetration enhancer. 0022. The kit according to the present invention can 0006 PCT/AU99/00735 teaches a pharmaceutical foam optionally further contain at least one additional therapeutic composition including (a) an active ingredient; (b) an occlu agent Selected from the group consisting of an anti-infective, Sive agent; (c) an aqueous Solvent; and (d) an organic an antibiotic, an antibacterial agent, an antifungal agent, an coSolvent, in which the active ingredient is insoluble in antiviral agent, an antiparasitic agent, a Steroidal antiinflam water and insoluble in both water and the occlusive agent, matory agent, an immunosuppressive agent, an immuno and wherein there is Sufficient occlusive agent to form an modulator, an immunoregulating agent, a hormonal agent, occlusive layer on the skin. vitamin A, a vitamin A derivative, vitamin B, a vitamin B 0007 US Patent Application No. 20050079139 describes derivative, vitamin C, a vitamin C derivative, vitamin D, a an aqueous pharmaceutical foam formulation in a dosage vitamin D derivative, vitamin E, a vitamin E derivative, form which comprises an active ingredient Selected from the vitamin F, a vitamin F derivative, vitamin K, a vitamin K group consisting of minoxidil, minoxidil Sulphate, other derivative, a wound healing agent, a disinfectant, an anes Soluble minoxidil Salts, and mixtures thereof. thetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, SUMMARY OF THE INVENTION a neuropeptide, a allergen, an immunogenic Substance, a 0008. The present invention relates to a therapeutic kit to haptene, an oxidizing agent, an antioxidant, a dicarboxylic provide a Safe and effective dosage of a vasoactive agent, acid, azelaic acid, Sebacic acid, adipic acid, fumaric acid, a including an aerosol packaging assembly including: retinoid, an antiproliferative agent, an anticancer agent, a US 2005/0271596 A1 Dec. 8, 2005 photodynamic therapy agent, benzoyl chloride, calcium 0032 FIG. 1 is a schematic illustration of an aerosol hypochlorite, magnesium hypochlorite, an anti-wrinkle Valve Suitable for use in the aerosol packaging assembly agent, a radical Scavenger, a metal, Silver, a metal oxide, according to in one or more embodiments of the invention. titanium dioxide, Zinc oxide, Zirconium oxide, iron oxide, Silicone oxide, talc, carbon, an anti wrinkle agent, a skin DETAILED DESCRIPTION OF THE Whitening agent, a skin protective agent, a masking agent, an INVENTION anti-Wart agent, a refatting agent, a lubricating agent and 0033. The present invention provides a therapeutic kit mixtures thereof. including a vasoactive agent. The kit includes an aeroSol packaging assembly having a container accommodating a 0023. In further embodiments, the present invention pro preSSurized product and an outlet capable of releasing the vides a method of treating, alleviating or preventing disor preSSurized product as a foam. ders of the skin, body cavity or mucosal Surface, wherein the disorder involves inflammation as one of its etiological 0034 Aerosol Packaging Assembly factors, including administering topically to a Subject having 0035. The aerosol packaging assembly typically includes the disorder, a foamed composition including: a container Suitable for accommodating a pressurized prod 0024 (1) a vasoactive agent; uct and an outlet capable of releasing a foam. The outlet is typically a valve. FIG. 1 illustrates a typical aerosol valve 0025 (2) at least one organic carrier selected from a 100. The valve is made up of the valve cup 110 typically hydrophobic organic carrier, a polar Solvent, an constructed from tinplated Steel, or aluminum, an outer emollient and mixtures thereof, at a concentration of gasket 120, which is the seal between the valve cup and the about 2% to about 50% by weight; aerosol can (not shown), a valve housing 130, which con 0026 (3) about 0.1% to about 5% by weight of a tains the valve stem 132, spring 134 and inner gasket 136, Surface-active agent; and a dip tube 140, which allows the liquid to enter valve. The valve stem is the tap through which the product flows. 0027 (4) about 0.01% to about 5% by weight of a The inner gasket 136 covers the aperture 150 (hole) in the polymeric additive selected from a bioadhesive valve stem. The valve spring 134 is usually made of stainless agent, a gelling agent, a film forming agent and a Steel. phase change agent, and 0036) The valve stem is fitted with small apertures 150 0028 (5) water, (also termed “orifices” and “holes”), through which the product flows. Valves may contain one, two, three, four or 0029 wherein the vasoactive agent is administered in a more apertures, depending on the nature of the product to be therapeutically effective amount. dispensed. In the closed position, the aperture(s) is covered 0.030. In one or more embodiments, the disorder to be by the inner gasket. When the actuator is depressed it pushes treated is Selected from the group consisting of a dermatose, the valve stem through the inner gasket, and the aperture(s) a dermatitis, a vaginal disorder, a Vulvar disorder, an anal is uncovered, allowing liquid to pass through the valve and disorder, a disorder of a body cavity, an ear disorder, a into the actuator. disorder of the nose, a disorder of the respiratory System, a bacterial infection, fungal infection, Viral infection, derma 0037. The valve can have a stem with 1 to 4 apertures, or tosis, dermatitis, parasitic infections, disorders of hair fol 1 to 2 apertures. Each aperture can have a diameter of about licles and Sebaceous glands, Scaling papular diseases, benign 0.2 mm to about 1 mm, or a diameter of about 0.3 mm to tumors, malignant tumors, reactions to Sunlight, bullous about 0.8 mm. The total aperture area, i.e., the Sum of areas diseases, pigmentation disorders, disorders of cornification, of all apertures in a given stem, is between about 0.01 mm preSSure Sores, disorders of Sweating, inflammatory reac and 1 mm or the total aperture area is between about 0.04 tions, Xerosis, ichthyosis, allergy, burn, wound, cut, chlamy mm and 0.5 mm . dia infection, gonorrhea infection, hepatitis B, herpes, HIV/ 0038. In order to provide proper therapy, precise dosing AIDS, human papillomavirus (HPV), genital warts, bacterial is desired. According to one or more embodiments, the valve Vaginosis, candidiasis, chancroid, granuloma Inguinale, is attached, directly, or through a tube, to a metered dose lymphogranloma Venereum, mucopurulent cerviciitis device, which for dispensing an accurate dose of drug in the (MPC), molluscum contagiosum, nongonococcal urethritis form of a foam. The metered dose valve is selected to release (NGU), trichomoniasis, vulvar disorders, vulvodynia, Vulvar a foam in a Volume that provides an adequate therapeutic pain, yeast infection, Vulvar dystrophy, Vulvar intraepithelial dose to the target Site of the Skin, a body Surface, a body neoplasia (VIN), contact dermatitis, osteoarthritis, joint cavity or mucosal Surface, e.g., the mucosa of the nose, pain, hormonal disorder, pelvic inflammation, endometritis, mouth, eye, ear, respiratory System, vagina or rectum. Salpingitis, oophoritis, genital cancer, cancer of the cervix, 0039. In one or more embodiments, the meter dose valve cancer of the Vulva, cancer of the vagina, Vaginal dryness, provides a unit dose of between about 10 till and about 1000 dySpareunia, anal and rectal disease, anal absceSS/fistula, AiL. ASSuming a representative foam density (specific grav anal cancer, anal fissure, anal warts, Crohn's disease, hem ity) of 0.06 g/mL, a 10 uL valve provides a volume of about orrhoids, anal itch, pruritus ani, fecal incontinence, consti 0.17 mL of foam, and a 1000 till metered dose valve pation, polyps of the colon and rectum; provides about 17 mL of foam. Thus, by Selecting a specific metered dosing valve and adjusting the foam density by fine BRIEF DESCRIPTION OF THE DRAWING tuning formulation parameters and adjusting the ratio 0031. The invention is described with reference to the between the liquid components of the composition and the figure which is presented for the purpose of illustration and propellant, one can design an adequate dosage form accord are not intended to be limiting of the invention. ing to the Specific target Site. US 2005/0271596 A1 Dec. 8, 2005

0040 Pharmaceutical Composition 0055 Alteration in the release and action of endothelium derived vasoactive factorS is responsible for changes in 0041 All % values are provided on a weight (w/w) basis. vascular reactivity early in the course of vascular disease. 0042. According to one or more embodiments of the These factors include nitric oxide, eicosanoids, endothe present invention, the foamable therapeutic composition for lium-derived hyperpolarizing factor, endothelin, and angio administration to the Skin, body Surface, body cavity or tensin II. mucosal Surface, e.g., the mucosa of the nose, mouth, eye, 0056 Nitric oxide (NO) has been recognized as an ear, respiratory System, vagina or rectum (Severally and important messenger molecule having a broad spectrum of interchangeably termed herein “target site') includes: functions in many biological Systems ranging from physi 0043 (1) a vasoactive agent, wherein the amount of ological control to pathological cytotoxic effect 1-3. Along the amount of the vasoactive agent is effective in the with prostacyclin, NO is responsible for endothelium treatment of a disorder of the target Site, derived tonic relaxation of all types of blood vessels. NO is 0044) (2) at least one organic carrier selected from a formed from L-arginine through the action of a family of hydrophobic organic carrier, a polar Solvent, an isoenzymes, the nitric oxide synthases (NOS). Thus, in one emollient and mixtures thereof, at a concentration of or more embodiments, the vasoactive agent is Selected from about 2% to about 5%, or about 5% to about 10%; or the group of therapeutic agents that modulate the production about 10% to about 20%; or about 20% to about 50% of nitric oxide or otherwise modulate or activate the effect of by weight; nitric oxide. In one or more embodiments, the vasoactive agent is Selected from the group of therapeutic agents that 0.045 (3) about 0.1% to about 5% by weight of a modulate the activity of the enzyme nitric oxide Synthase. In Surface-active agent; one or more embodiments, the vasoactive agent is Selected 0046) (4) about 0.01% to about 5% by weight of at from the group of therapeutic agents that enhance the effect least one polymeric agent Selected from a bioadhe of NO by inhibiting enzymes from the phosphodiesterase Sive agent, a gelling agent, a film forming agent and group, Such as phosphodiesterase type 5 (PDE5). a phase change agent; and 0057. In one or more embodiments, the vasoactive agent 0047 (5) a liquefied or compressed gas propellant at is Selected from the group including nitrites, nitrates and a concentration of about 3% to about 25% by weight their analogs, esters and Salts. In one or more embodiments of the total composition. the vasoactive agent possesses a moiety Selected from the 0.048 Water and optional ingredients are added to com group consisting of ONO, and ONO2. plete the total mass to 100%. Upon release from an aerosol 0058 Exemplary vasodilators include, but are not limited container, the foamable composition forms an expanded to, amyl nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, foam Suitable for topical administration. isobutyl nitrite, glyceryl trinitrate, also known as nitroglyc erin, octyl nitrite, Sodium nitrite, Sodium nitroprusSide, 0049 According to one or more embodiments, the foam clonitrate, erythrityl tetranitrate, isosorbide mononitrate, able composition is Substantially alcohol-free, i.e., free of isosorbide dinitrate, mannitol heXanitrate, pentaerythritol Short chain alcohols. Short chain alcohols, having up to 5 tetranitrate, penetrinitol, triethanolamine trinitrate, trolni carbon atoms in their carbon chain Skeleton and one trate phosphate (triethanolamine trinitrate diphosphate), pro hydroxyl group, Such as ethanol, propanol, isopropanol, patylnitrate, nitrite esters of Sugars, nitrite esters of polyols, butanol, iso-butanol, t-butanol and pentanol, are considered nitrate esters of Sugars, nitrate esters of polyols, nicorandil, less desirable Solvents or polar Solvents due to their skin apresoline, diaZOxide, hydralazine, hydrochlorothiazide, irritating effect. Thus, the composition is Substantially alco minoxidil, pentaerythritol, tolazoline, Scoparone (6,7- hol-free and includes less than about 5% final concentration dimethoxycoumarin) and salts, isomers, analogs and deriva of lower alcohols, preferably less than about 2%, more tives thereof. preferably less than about 1%. 0059. In one or more embodiments, the vasoactive agent 0050. In one or more embodiments, at least a portion of belongs to a class of drugs that are known of possess the vasoactive agent is Suspended in the composition, yet, in vasodilator properties. Non limiting examples of drug other embodiments, the vasoactive agent is dissolved in the classes that possess vasodilator properties include, but are composition. not limited to, beta-adrenergic blockers, alpha-adrenoceptor 0051. In one or more embodiments, the foam composi blockers, prostaglandin and prostaglandin-like compounds, tion is formulated as an oil-in-water emulsion or oil-in-water inhibitors of type 5 phosphodiesterase (PDE-5), angiotensin microemulsion. converting enzyme inhibitors, calcium antagonists, angio tensin II receptor antagonists, direct acting Smooth muscle 0.052 In one or more embodiments, the concentration of vasodilators, adrenergic inhibitors, endothelin antagonists, surface-active agent about 0.1% to about 5%, or from about mineralocorticoid receptor antagonists, vasopeptidase 0.2% to about 2%. inhibitors and renin inhibitors. Active agents belonging to 0053. In the context of the present invention, a vasoactive Such drug classes, as well as active agents belonging to other agent is a Substance that changes the diameter of a blood classes, which cause a vasodilator effect are also included in vessel. the Scope of vasoactive agents according to the present 0054. In one or more embodiments, the vasoactive agent invention. is a vasodilator. A vasodilator is any of various agents that 0060) Non-nitrate vasodilators from different classes relax or widen blood vessels and thereby maintain or lower include, but are not limited to Sildenafil, dipyridamole, blood pressure. catecholamine, isoproternol, furosemide, prostaglandin, US 2005/0271596 A1 Dec. 8, 2005 prostacyclin, enalaprilat (ACE-inhibitor), morphine (opi 0066 Other descriptive names of the vasoconstrictor ate), acepromazine (C.-blocker), prazosin (C-blocker), enala group include vasoactive agonists, Vasopressor agents and pril.(ACE-inhibitor), captopril (ACE-inhibitor), amlodipine vasoconstrictor drugs. Certain vasoconstrictors act on Spe (Ca channel blocker), minoxidil, tadalafil, Vardenafil, phe cific receptors, Such as Vasopressin receptorS or adrenore nylephrin, etillefein, caffeine, capsaicin and Salts, isomers, ceptorS. analogs and derivatives thereof. 0067. In one or more embodiments, the vasoconstrictor is 0061. In one or more embodiments, the vasoactive agent a calcium channel agonist. Calcium channel agonists are is Selected from the group of vasodilator peptides and agents that increase calcium influx into calcium channels of proteins. Non-limiting examples of vasodilator paprides excitable tissues, thereby causing vasoconstriction. include, but are not limited to bradykinin, bradykinin-like peptide I, bradykinin-like peptide III Phyllokinin (bradyki 0068. Non limiting examples of vasoconstrictors include nyl-isoleucyl-tyrosine O-Sulfate), megaScoliakinin (Thr6 ephedrine, epinephrine, phenylephrine, angiotensin, Vaso bradykinin-Lys-Ala), lysyl-bradykinin-like waspkinin, pressin, and and analogs and derivatives thereof. lysyl-bradykinin, maximakinin (Bombinakinin M), bombi 0069. In one or more embodiments, the vasoactive agent nakinin-GAP, kininogen-1 associated peptides, kininogen-2 is a Substance derived or extracted from herbs, having a asSociated peptides, T-kinin, thiostatin, prolixin-S, Vespula vasoconstrictor effect. kinin 2, Vespakinin X, relaxin, adrenomedullin, ghrelin, maXadilan, Substance P, calcitonin gene-related peptide 0070 Thus, in one or more embodiments, the vasoactive (CGRP), Natriuretic peptides (NPs), e.g., atrial natriuretic agent is a Substance derived or extracted from a herbal peptide (ANP), C-type natriuretic peptide (CNP), and Source, Selected from the group including ephedra Sinica adrenomedullin (ADM), adrenomedullin, ovine corticotro (ma huang), polygonum bistorta (bistort root), hamamelis pin-releasing factor, Sauvagine, urotensin and Salts, isomers, virginiana (witch hazel), hydrastis Canadensis (goldenseal), analogs and derivatives thereof. lycopus virginicus (bugleweed), aspidosperma quebracho 0.062. In one or more embodiments, the vasoactive agent (quebracho blanco), cytisus Scoparius (Scotch broom), is Selected from the group of therapeutic agents that induce cypress and Salts, isomers, analogs and derivatives thereof. the production of a vasodilator peptide or otherwise enhance 0071. Yet, in additional embodiments, the vasoactive or activate the effect of a vasodilator peptide. agent is a metal oxide or a mineral, Such as Zinc oxide and 0.063. In one or more embodiments, the vasoactive agent bismuth Subgallate. is a Substance derived or extracted from herbs having a 0072 The McKenzie vasoconstrictor assay, as described, vasodilator effect. Non limiting examples of herbs that for example, in the British Journal of Dermatology contain vasoactive agents include achillea millefolium (Yar 1975;93:563-71 and versions thereof, has been the primary row), allium Sativum (garlic), amoracia rusticana (horse method used for classifying the Strength of a vasoconstrictor radish), berberis vulgaris (barberry), cimicifuga racemosa clinical efficacy. Thus, in one or more embodiments, the (black cohosh), coleus forskholii (coleus), copiis (Gold vasoactive agent is an agent that positively affects the enthread), Crataegus (hawthorn), eleutherOCOccuS Sentico SuS (Siberian ginseng), ginkgo biloba(ginkgo), melissa Ofi vasoconstrictor assay. icinalis (lemon balm), Olea europaea (olive leaf), panax 0073 Mixtures of these vasoactive agents may also be ginseng (Chinese ginseng), petroSelinum crispum (parsley), employed according to the present invention. Scutellaria baica lensis (baical skullcap), tilia europaea (lin 0074 Solubility of the vasoactive agent is an important den flower), trigOnella foenum-graecum (fenugreek), urtica factor in the development of a Stable foamable composition dioica (nettles), Valeriana Officinalis (Valerian), viburnum according to the present invention. (cramp, bark, black haw), veratrum viride (American helle bore), verbena officinalis (vervain), xanthoxylum ameri 0075 For definition purposes, in the context of the canum (prickly ash), Zingiber officinale (ginger), rauwolfia present invention, the descriptive terminology for Solubility Serpentina (Indian Snakeroot), viscum album, wild yam, according to the US Pharmacopoeia (USP23, 1995, p. 10), Sasparilla, licorice, damiana, yucca, Saw palmetto, gotu kola the European Pharmacopoeia (EP, 5" Edition (2004), page (centella asiatica), yohimbine and Salts, hazel nut, brazil 7) and several other textbooks used in the art of pharma nut, walnut and analogs and derivatives thereof. ceutical Sciences (see for example, Martindale, The Extra 0064. According to one or more embodiments, the foam Pharmacopoeia,30" Edition (1993), page xiv. of the Preface; able composition includes a vasodilator and a vasoactive and Remington's Pharmaceutical Sciences, 18" Edition agent Such that the vasodilator can have a Synergistic effect (1990), page 208) is adapted: by readily facilitating facile penetration of the vasoactive agent. 0065. In one or more embodiments, the vasoactive agent Parts of Solvent Required is a vasoconstrictor. A vasoconstrictor is any of various Descriptive Term for 1 Part of Solute agents that narrow blood vessels and thereby maintain or Very soluble Less than 1 increase blood pressure, and/or decrease blood flow. There Freely soluble From 1 to 10 are many disorders that can benefit from treatment using a Soluble From 10 to 30 vasoconstrictor. For example, redness of the skin (e.g., Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1,000 erythema or cuperose), which typically involves dilated Very slightly soluble From 1,000 to 10,000 blood vessels, benefit from treatment with a vasoconstrictor, Practically insoluble or Insoluble 10,000 and over which shrinks the capillaries thereby decreasing the unto ward redness. US 2005/0271596 A1 Dec. 8, 2005

0.076 Thus, in one or more embodiments, the vasoactive would be beneficial. Likewise, chronic ulcers involve poor agent is “soluble”, “freely soluble” or “very soluble” (as blood Supply and potential bacterial, fungal and Viral infec defined above) in the aqueous phase of the emulsion. In tions, which warrants a beneficial effect of a combination of other embodiments, where the agent possesses hydrophobic a vasoactive agent and an antiinfective agent. Hence, in characteristics, the vasoactive agent is “Soluble”, “freely many cases, the inclusion of an additional therapeutic agent soluble' or “very soluble” in the oil phase of the emulsion. in the foamable pharmaceutical composition of the present In other cases, the vasoactive agent is “very slightly invention, contributes to the clinical activity of the vasoac soluble”, “slightly soluble” or “sparingly soluble” in either tive agent. Thus, in one or more embodiments, the foamable the water phase or oil phase of the emulsion. composition further includes at least one additional thera 0077. In other embodiments, the vasoactive agent is peutic agent, in a therapeutically effective concentration. insoluble i.e., “requires 10,000 parts or more of a solvent to 0086. In one or more embodiments, the at least one be solubilized”, in either the water phase of the composition, additional therapeutic agent is Selected from the group or the oil phase of the composition, but not in both. consisting of an anti-infective, an antibiotic, an antibacterial 0078. In yet other embodiments, the vasoactive agent is agent, an antifungal agent, an antiviral agent, an antiparasitic not fully dissolved in both the aqueous phase of the oil phase agent, a Steroidal antiinflammatory agent, a nonsteroidal of the emulsion concurrently, and thus, it is Suspended in the anti-inflammatory drug, an immunosuppressive agent, an emulsion (i.e., at least a portion of the vasoactive agent immunomodulator, an immunoregulating agent, a hormonal portion remains in Solid State in the final composition). In agent, Vitamin A, a Vitamin A derivative, Vitamin B, a Such a case, the polymeric agents that are listed herein Serve vitamin B derivative, vitamin C, a vitamin C derivative, as Suspension-Stabilizing agents to Stabilize the composition. vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a 0079. In certain embodiments of the present invention, Vitamin K derivative, a wound healing agent, a disinfectant, the composition and properties of the aqueous phase of the an anesthetic, an antiallergic agent, an alpha hydroxyl acid, emulsion (e.g., pH, electrolyte concentration and chelating lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a agents) and/or the composition of the oil phase of the peptide, a neuropeptide, a allergen, an immunogenic Sub emulsion are adjusted to attain a desirable Solubility profile Stance, a haptene, an oxidizing agent, an antioxidant, a of the active agent. dicarboxylic acid, azelaic acid, Sebacic acid, adipic acid, 0080. The vasoactive agent is included in the composi fumaric acid, a vasoactive agent, an antiproliferative agent, tion of the present invention in a concentration that provides an anticancer agent, a photodynamic therapy agent, an a desirable ratio between the efficacy and Safety. Typically, anti-Wrinkle agent, a radical Scavenger, a metal oxide (e.g., vasoactive agents are included in the composition in a titanium dioxide, Zinc oxide, Zirconium oxide, iron oxide), concentration between about 0.005% and about 12%. How Silicone oxide, an anti wrinkle agent, a skin whitening agent, ever, in Some embodiments, the concentration of between a skin protective agent, a masking agent, an anti-Wart agent, about 0.005% and about 0.5%, in other embodiment a refatting agent, a lubricating agent and mixtures thereof. between about 0.5% and about 2%, and in additional 0087. In certain cases, the disorder to be treated involves embodiments between about 2% and about 5% or between unaesthetic lesions that need to be masked. For example, about 5% and about 12%. rosacea involves papules and pustules, which can be treated 0081. In one or more embodiments, the vasoactive agent with a vasoactive agent, as well as erythema, telangiectasia is encapsulated in particles, microparticles, nanoparticles, and redness, which partially respond to treatment with a microcapsules, Spheres, microSphres, nanocapsules, nano vasoactive agent. Thus, in one or more embodiments, the Spheres, liposomes, nioSomes, polymer matrix, nanocrystals additional active agent is a masking agent, i.e., a pigment. or microSponges. Non limiting examples of Suitable pigments include brown, yellow or red iron oxide or hydroxides, chromium oxides or 0082 In one or more embodiments, the vasoactive agent hydroxides, titanium oxides or hydroxides, Zinc oxide, is a vasoactive agent precursor present at a concentration FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 between about 0.05% and about 12%. aluminum lake and FD&C Yellow No. 6 aluminum lake. 0.083. In one or more embodiments, the vasoactive agent 0088. The foamable composition of the present invention is a compound that is positively identified using a laboratory can be an emulsion, or microemulsion, including an aqueous method, Suitable of detecting a vasoactive agent. phase and an organic carrier phase. The organic carrier is 0084. In one or more embodiments, the vasoactive agent Selected from a hydrophobic organic carrier (also termed is a Substance that is positively identified using a competi herein “hydrophobic Solvent'), an emollient, a polar Solvent, tive nuclear retinoic acid receptor binding assay. and a mixture thereof. 0085. Several disorders of the skin, a body cavity or 0089. A “hydrophobic organic carrier” as used herein mucosal Surface (e.g., the mucosa of the nose, mouth, eye, refers to a material having Solubility in distilled water at ear, vagina or rectum), involve a combination of etiological ambient temperature of less than about 1 gm per 100 mL, factors, Some of which are related to the state of blood more preferable less than about 0.5gm per 100 mL, and circulation (that can be affected by a vasoactive agent); and most preferably less than about 0.1 gm per 100 mL. It is other etiological factors that require an additional therapeu liquid at ambient temperature. The identification of a hydro tic modality. For example, hair loSS involves inacququate phobic organic carrier or “hydrophobic Solvent', as used blood circulation as well as cell growth abnormalities and herein, is not intended to characterize the Solubilization disruption of hair growth cycle, and therefore combined capabilities of the Solvent for any Specific active agent or any treatment with a vasoactive agent and a hormonal agent other component of the foamable composition. Rather, Such US 2005/0271596 A1 Dec. 8, 2005

information is provided to aid in the identification of mate oils are also considered therapeutically active oil, due to rials Suitable for use as a hydrophobic carrier in the foamable their barrier retaining and protective properties. compositions described herein. 0096. In one or more embodiments, the hydrophobic 0090. In one or more embodiments, the hydrophobic carrier includes at least 2% by weight Silicone oil or at least organic carrier is an oil, Such as mineral oil. Mineral oil 5% by weight. (Chemical Abstracts Service Registry number 8012-95-1) is a mixture of aliphatic, naphthalenic, and aromatic liquid 0097. The solvent may be a mixture of two or more of the hydrocarbons that derive from petroleum. It is typically above hydrophobic Solvents in any proportion. liquid; its viscosity is in the range of between about 35 CST 0098. A further class of solvents includes “emollients” and about 100 CST (at 40°C.), and its pour point (the lowest that have a Softening or Soothing effect, especially when temperature at which an oil can be handled without exces applied to body areas, Such as the skin and mucosal Surfaces. Sive amounts of wax crystals forming So preventing flow) is Emollients are not necessarily hydrophobic. Examples of below 0° C. The hydrophobic organic carrier does not Suitable emollients include hexyleneglycol, propylene gly include thick or Semi-Solid materials, Such as white petro col, isoStearic acid derivatives, isopropyl palmitate, isopro latum, also termed “Vaseline', which, in certain composi pyl isoStearate, diisopropyl adipate, diisopropyl dimerate, tions is disadvantageous due to its waxy nature and Semi maleated Soybean oil, octyl palmitate, cetyl lactate, cetyl Solid texture. ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, 0.091 According to one or more embodiments, hydro cetyl acetate, phenyl trimethicone, glyceryl oleate, toco phobic Solvents are liquid oils originating from Vegetable, pheryl linoleate, wheat germ glycerides, arachidyl propi marine or animal Sources. Suitable liquid oil includes Satu onate, myristyl lactate, decyl oleate, propylene glycol rici rated, unsaturated or polyunsaturated oils. By way of noleate, isopropyl lanolate, pentaerythrityl tetrastearate, example, the unsaturated oil may be olive oil, corn oil, neopentylglycol dicaprylate/dicaprate, isononyl Soybean oil, canola oil, cottonseed oil, coconut oil, Sesame isononanoate, isotridecyl isononanoate, myristyl myristate, oil, Sunflower oil, borage Seed oil, SyZigium aromaticum oil, triisocetyl citrate, octyl dodecanol, Sucrose esters of fatty hempseed oil, herring oil, cod-liver oil, Salmon oil, flaxseed acids, octyl hydroxyStearate and mixtures thereof. oil, wheat germ oil, evening primrose oils or mixtures 0099. According to one or more embodiments of the thereof, in any proportion. present invention, the hydrophobic organic carrier includes 0092 Suitable hydrophobic solvents also include poly a mixture of a hydrophobic solvent and an emolient. unsaturated oils containing poly-unsaturated fatty acids. In According to one or more embodiments, the foamable one or more embodiments, the unsaturated fatty acids are composition is a mixture of mineral oil and an emollient in Selected from the group of omega-3 and omega-6 fatty acids. a ratio between 2:8 and 8:2 on a weight basis. Examples of Such polyunsaturated fatty acids are linoleic 0100. A “polar solvent' is an organic solvent, typically and linolenic acid, gamma-linoleic acid (GLA), eicosapen soluble in both water and oil. Examples of polar solvents taenoic acid (EPA) and docosahexaenoic acid (DHA). Such include polyols, Such as glycerol (glycerin), propylene gly unsaturated fatty acids are known for their skin-conditioning col, heXylene glycol, diethylene glycol, propylene glycol effect, which contribute to the therapeutic benefit of the n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, present foamable composition. Thus, the hydrophobic Sol limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, vent can include at least 6% of an oil Selected from omega-3 other glycols, Sulfoxides, Such as dimethylsulfoxide oil, omega-6 oil, and mixtures thereof. In the context of the (DMSO), dimethylformamide, methyl dodecyl sulfoxide, present invention, oils that possess therapeutically-benefi dimethylacetamide, monooleate of ethoxylated glycerides cial properties are termed “therapeutically active oil'. (with 8 to 10 ethylene oxide units), azone (1-dodecylazacy 0093. Another class of hydrophobic solvents is the essen cloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, esters, Such as tial oils, which are also considered therapeutically active oil, isopropyl myristate/palmitate, ethyl acetate, butyl acetate, which contain active biologically occurring molecules and, methyl proprionate, capric/caprylic triglycerides, upon topical application, exert a therapeutic effect, which is octylmyristate, dodecyl-myristate, myristyl alcohol, lauryl conceivably Synergistic to the beneficial effect of the vaso alcohol, lauric acid, lauryl lactate ketones, amides, Such as active agent in the composition. acetamide oleates Such as triolein; various alkanoic acids Such as caprylic acid; lactam compounds, Such as aZone; 0094. Another class of therapeutically active oils alkanols, Such as dialkylamino acetates, and admixtures includes liquid hydrophobic plant-derived oils, which are thereof. known to possess therapeutic benefits when applied topi cally. 0101 According to one or more embodiments, the polar solvent is a polyethylene glycol (PEG) or PEG derivative 0.095 Silicone oils also may be used and are desirable that is liquid at ambient temperature, including PEG200 due to their known skin protective and occlusive properties. (MW (molecular weight) about 190-210 kD), PEG300 (MW Suitable Silicone oils include non-volatile Silicones, Such as about 285-315 kD), PEG400 (MW about 380-420 kD), polyalkyl siloxanes, polyaryl Siloxanes, polyalkylaryl Silox PEG600 (MW about 570-630 kD) and higher MW PEGs anes and polyether Siloxane copolymers, polydimethylsilox Such as PEG 4000, PEG 6000 and PEG 10000 and mixtures anes (dimethicones) and poly(dimethylsiloxane)-(diphenyl thereof. Siloxane) copolymers. These are chosen from cyclic or linear polydimethylsiloxanes containing from about 3 to about 9, 0102) The polymeric agent serves to stabilize the foam preferably from about 4 to about 5, silicon atoms. Volatile composition and to control drug residence in the target Silicones Such as cyclomethicones can also be used. Silicone organ. Exemplary polymeric agents, are classified below in US 2005/0271596 A1 Dec. 8, 2005 a non-limiting manner. In certain cases, a given polymer can 0.108 Mucoadhesive/bioadhesion has been defined as the belong to more than one of the classes provided below. attachment of Synthetic or biological macromolecules to a 0103) In one or more embodiments, the composition of biological tissue. Mucoadhesive agents are a class of poly the present invention includes at least one gelling agent. A meric biomaterials that exhibit the basic characteristic of a gelling agent controls the residence of a therapeutic com hydrogel, i.e. Swell by absorbing water and interacting by position in the target Site of treatment by increasing the means of adhesion with the mucous that covers epithelia. Viscosity of the composition, thereby limiting the rate of its Compositions of the present invention may contain a clearance from the Site. Many gelling agents are known in mucoadhesive macromolecule or polymer in an amount the art to possess mucoadhesive properties. sufficient to confer bioadhesive properties. The bioadhesive macromolecule enhances the delivery of biologically active 0104. The gelling agent can be a natural gelling agent, a agents on or through the target Surface. The mucoadhesive Synthetic gelling agent and an inorganic gelling agent. macromolecule may be selected from acidic Synthetic poly Exemplary gelling agents that can be used in accordance mers, preferably having at least one acidic group per four with one or more embodiments of the present invention repeating or monomeric Subunit moieties, Such as poly include, for example, naturally-occurring polymeric mate (acrylic)- and/or poly(methacrylic) acid (e.g., CarbopolE), rials, Such as locust bean gum, Sodium alginate, Sodium Carbomer(R), poly(methylvinyl ether/maleic anhydride) caseinate, egg albumin, gelatin agar, carrageenin gum, copolymer, and their mixtures and copolymers, acidic Syn Sodium alginate, Xanthan gum, quince Seed extract, traga thetically modified natural polymers, Such as carboxymeth canth gum, guar gum, Starch, chemically modified Starches ylcellulose (CMC); neutral synthetically modified natural and the like, Semi-Synthetic polymeric materials Such as polymers, Such as (hydroxypropyl)methylcellulose, basic cellulose ethers (e.g. hydroxyethyl cellulose, methyl cellu amine-bearing polymerS Such as chitosan; acidic polymers lose, carboxymethyl cellulose, hydroxy propylmethyl cellu obtainable from natural Sources, Such as alginic acid, hyalu lose), guar gum, hydroxypropyl guar gum, Soluble starch, ronic acid, pectin, gum tragacanth, and karaya gum, and cationic celluloses, cationic guars, and the like, and Syn neutral Synthetic polymers, Such as polyvinyl alcohol or thetic polymeric materials, Such as carboxyvinyl polymers, their mixtures. An additional group of mucoadhesive poly polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid mers includes natural and chemically modified cyclodextrin, polymers, polymethacrylic acid polymers, polyvinyl acetate especially hydroxypropyl-3-cyclodextrin. Such polymers polymers, polyvinyl chloride polymers, polyvinylidene may be present as free acids, bases, or Salts, usually in a final chloride polymers and the like. Mixtures of the above compounds are contemplated. concentration of about 0.01% to about 0.5% by weight. 0109) A suitable bioadhesive macromolecule is the fam 0105. Further exemplary gelling agents include the ily of acrylic acid polymers and copolymers, (e.g., Car acrylic acid/ethyl acrylate copolymers and the carboxyvinyl bopolE). These polymers contain the general structure polymers sold, for example, by the B.F. Goodrich Company -CH-CH(COOH)-). Hyaluronic acid and other bio under the trademark of CarbopolE resins. These resins logically-derived polymers may be used. consist essentially of a colloidal water-Soluble polyalkenyl polyether crosslinked polymer of acrylic acid crosslinked 0110 Exemplary bioadhesive or mucoadhesive macro with from 0.75% to 2% of a crosslinking agent such as molecules have a molecular weight of at least 50 kDa, or at polyallyl Sucrose or polyallyl pentaerythritol. Examples least 300 kDa, or at least 1,000 kDa. Favored polymeric include Carbopol(R) 934, Carbopol(R) 940, Carbopol® 950, ionizable macromolecules have not less than 2 mole percent Carbopol(R) 980, Carbopol(R) 951 and Carbopol(R 981. Car acidic groups (e.g., COOH, SO3H) or basic groups (NH2, bopolE 934 is a water-soluble polymer of acrylic acid NRH, NR2), relative to the number of monomeric units. The crosslinked with about 1% of a polyallyl ether of sucrose acidic or basic groups can constitute at least 5 mole percent, having an average of about 5.8 allyl groups for each Sucrose or at least 10 mole percent, or at least 25, at least 50 more molecule. percent, or even up to 100 mole percent relative to the number of monomeric units of the macromolecule. 0106. In one or more embodiment, the composition of the present invention includes at least one polymeric agent, 0111. Yet, another group of mucoadhesive agent includes which is a water-soluble cellulose ether. Preferably, the inorganic gelling agents such as Silicon dioxide (fumed water-Soluble cellulose ether is Selected from the group silica), including but not limited to, AEROSIL 200 consisting of methylcellulose, hydroxypropyl cellulose, (DEGUSSA). hydroxypropyl methylcellulose (Methocel), hydroxyethyl 0112 Many mucoadhesive agents are known in the art to cellulose, methylhydroxyethylcellulose, methylhydroxypro also possess gelling properties. pylcellulose, hydroxyethylcarboxymethylcellulose, car 0113. The foam composition may contain a film forming boxymethylcellulose and carboxymethylhydroxyethylcel component. The film forming component may include at lulose. More preferably, the water-soluble cellulose ether is least one water-insoluble alkyl cellulose or hydroxyalkyl Selected from the group consisting of methylcellulose, cellulose. Exemplary alkyl cellulose or hydroxyalkyl cellu hydroxypropyl cellulose and hydroxypropyl methylcellu lose polymers include ethyl cellulose, propyl cellulose, butyl lose (Methocel). In one or more embodiments, the compo cellulose, cellulose acetate, hydroxypropyl cellulose, Sition includes a combination of a water-Soluble cellulose hydroxybutyl cellulose, and ethylhydroxyethyl cellulose, ether; and a naturally-occurring polymeric materials, alone or in combination. In addition, a plasticizer or a croSS Selected from the group including Xanthan gum, guar gum, linking agent may be used to modify the polymer's charac carrageenan gum, locust bean gum and tragacanth gum. teristics. For example, esterS Such as dibutyl or diethyl 0107 Yet, in other embodiments, the gelling agent phthalate, amides Such as diethyldiphenyl urea, vegetable includes inorganic gelling agents, Such as Silicone dioxide oils, fatty acids and alcohols Such as oleic and myristyl acid (fumed Silica). may be used in combination with the cellulose derivative. US 2005/0271596 A1 Dec. 8, 2005

0114. In one or more embodiments, the composition of including Sensitive tissue Such as found in most mucosal the present invention includes a phase change polymer, tissues, especially when they are infected or inflamed. We which alters the composition behavior from fluid-like prior have Surprisingly found that non-ionic Surfactants alone to administration to Solid-like upon contact with the target provide foams of excellent quality, i.e. a Score of “E” mucosal Surface. Such phase change results from external according to the grading Scale discussed herein below. Stimuli, Such as changes in temperature or pH and exposure 0121. In one or more embodiments, the surface active to specific ions (e.g., Ca"). agent includes a mixture of at least one non-ionic Surfactant 0115 Non-limiting examples of phase change polymers and at least one ionic Surfactant in a ratio in the range of include poly(N-isopropylamide) and Poloxamer 407(R). about 100:1 to 6:1. In one or more embodiments, the non-ionic to ionic Surfactant ratio is greater than about 6:1, 0116. The polymeric agent is present in an amount in the or greater than about 8:1; or greater than about 14:1, or range of about 0.01% to about 5.0% by weight of the foam greater than about 16:1, or greater than about 20:1. composition. In one or more embodiments, it is typically less than about 1 wt % of the foamable composition. 0122) In one or more embodiments of the present inven tion, a combination of a non-ionic Surfactant and an ionic 0117 Surface-active agents (also termed “surfactants”) Surfactant (Such as Sodium lauryl Sulphate and cocamidopro include any agent linking oil and water in the composition, pylbetaine) is employed, at a ratio of between 1:1 and 20:1, in the form of emulsion. A surfactants hydrophilic/lipo or at a ratio of 4:1 to 10:1. The resultant foam has a low philic balance (HLB) describes the emulsifier's affinity Specific gravity, e.g., less than 0.1 g/ml. toward water or oil. The HLB scale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic), with 10 representing 0123. It has been surprisingly discovered that the stability an equal balance of both characteristics. Lipophilic emulsi of the composition is especially pronounced when a com fiers form water-in-oil (w/o) emulsions, hydrophilic Surfac bination of at least one non-ionic Surfactant having HLB of tants form oil-in-water (o/w) emulsions. The HLB of a blend less than 9 and at least one non-ionic Surfactant having HLB of two emulsifiers equals the weight fraction of emulsifier A of equal or more than 9 is employed. The ratio between the times its HLB value plus the weight fraction of emulsifier B at least one non-ionic surfactant having HLB of less than 9 times its HLB value (weighted average). and the at least one non-ionic Surfactant having HLB of equal or more than 9, is between 1:8 and 8:1, or at a ratio of 0118 According to one or more embodiments of the 4:1 to 1:4. The resultant HLB of Such a blend of at least two present invention, the Surface-active agent has a hydrophilic emulsifiers is between about 9 and about 14. lipophilic balance (HLB) between about 9 and about 14, which is the required HLB (the HLB required to stabilize an 0.124 Thus, in an exemplary embodiment, a combination O/W emulsion of a given oil) of most oils and hydrophobic of at least one non-ionic Surfactant having HLB of less than Solvents. Thus, in one or more embodiments, the composi 9 and at least one non-ionic Surfactant having HLB of equal tion contains a single Surface active agent having an HLB or more than 9 is employed, at a ratio of between 1:8 and 8:1, value between about 9 and 14, and in one or more embodi or at a ratio of 4:1 to 1:4, wherein the HLB of the combi ments, the composition contains more than one Surface nation of emulsifiers is between about 9 and about 14. active agent and the weighted average of their HLB values 0.125. In one or more embodiments of the present inven is between about 9 and about 14. Yet, in other embodiments, tion, the Surface-active agent includes mono-, di- and tri when a water in oil emulsion is desirable, the composition esters of Sucrose with fatty acids (sucrose esters), prepared contains one or more Surface active agents, having an HLB from Sucrose and esters of fatty acids or by extraction from value between about 2 and about 9. Sucro-glycerides. Suitable Sucrose esters include those hav 0119) The surface-active agent is selected from anionic, ing high monoester content, which have higher HLB values. cationic, nonionic, Zwitterionic, amphoteric and ampholytic 0.126 The total Surface active agent is in the range of Surfactants, as well as mixtures of these Surfactants. Such about 0.1 to about 5% of the foamable composition, and is Surfactants are well known to those skilled in the therapeutic typically less than about 2% or less than about 1%. and cosmetic formulation art. Nonlimiting examples of possible Surfactants include polySorbates, Such as polyoxy 0127 Preferably, a therapeutically effective foam adju ethylene (20) Sorbitan monostearate (Tween 60) and poly Vant is included in the foamable compositions of the present (oxyethylene) (20) Sorbitan monooleate (Tween 80); poly invention to increase the foaming capacity of Surfactants (oxyethylene) (POE) fatty acid esters, such as Myri 45, Myri and/or to stabilize the foam. In one or more embodiments of 49, Myri 52 and Myri 59; poly(oxyethylene) alkylyl ethers, the present invention, the foam adjuvant agent includes fatty Such as poly(Oxyethylene) cetyl ether, poly(Oxyethylene) alcohols having 15 or more carbons in their carbon chain, palmityl ether, polyethylene oxide hexadecyl ether, polyeth Such as cetyl alcohol and Stearyl alcohol (or mixtures ylene glycol cetyl ether, brij 38, bri 52, brij 56 and bri W1; thereof). Other examples of fatty alcohols are arachidyl Sucrose esters, partial esters of Sorbitol and its anhydrides, alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), Such as Sorbitan monolaurate and Sorbitan monolaurate; as well as alcohols with longer carbon chains (up to C50). mono or diglycerides, isoceteth-20, Sodium methyl cocoyl Fatty alcohols, derived from beeSWax and including a mix taurate, Sodium methyl oleoyl taurate, Sodium lauryl Sulfate, ture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain, are especially well Suited as triethanolamine lauryl Sulfate and betaines. foam adjuvant agents. The amount of the fatty alcohol 0120 In one or more embodiments of the present inven required to Support the foam System is inversely related to tion, the Surface-active agent includes at least one non-ionic the length of its carbon chains. Foam adjuvants, as defined Surfactant. Ionic Surfactants are known to be irritants. There herein are also useful in facilitating improved spreadability fore, non-ionic Surfactants are preferred in applications and absorption of the composition. US 2005/0271596 A1 Dec. 8, 2005

0128. In one or more embodiments of the present inven of the formulation, protect the formulation components from tion, the foam adjuvant agent includes fatty acids having 16 degradation and oxidation and modify their consistency. or more carbons in their carbon chain, Such as hexadecanoic Such excipients may be selected, for example, from Stabi acid (C16) stearic acid (C18), arachidic acid (C20), behenic lizing agents, antioxidants, humectants, preservatives, colo acid (C22), octacosanoic acid (C28), as well as fatty acids rant and odorant agents and other formulation components, with longer carbon chains (up to C50), or mixtures thereof. used in the art of formulation. AS for fatty alcohols, the amount of fatty acids required to 0.136 Aerosol propellants are used to generate and Support the foam System is inversely related to the length of administer the foamable composition as a foam. The total its carbon chain. composition including propellant, foamable compositions 0129. In one or more embodiments, a combination of a and optional ingredients is referred to as the foamable fatty acid and a fatty ester is employed. carrier. The propellant makes up about 3% to about 25 wt % of the foamable carrier. Examples of Suitable propellants 0130 Optionally, the carbon atom chain of the fatty include Volatile hydrocarbons Such as butane, propane, alcohol or the fatty acid may have at least one double bond. isobutane or mixtures thereof, and fluorocarbon gases. A further class of foam adjuvant agent includes a branched fatty alcohol or fatty acid. The carbon chain of the fatty acid 0.137 Composition and Foam Physical Characteristics or fatty alcohol also can be substituted with a hydroxyl 0.138 A pharmaceutical or cosmetic composition manu group, Such as 12-hydroxy Stearic acid. factured using the foam carrier according to one or more embodiments of the present invention is very easy to use. 0131) An important property of the fatty alcohols and When applied onto the afflicted body surface of mammals, fatty acids used in context of the composition of the present i.e., humans or animals, it is in a foam State, allowing free invention is related to their therapeutic properties per Se. application without Spillage. Upon further application of a Long chain Saturated and mono unsaturated fatty alcohols, mechanical force, e.g., by rubbing the composition onto the e.g., Stearyl alcohol, erucyl alcohol, arachidyl alcohol and body Surface, it freely spreads on the Surface and is rapidly behenyl alcohol (docosanol) have been reported to possess absorbed. antiviral, antiinfective, antiproliferative and antiinflamma tory properties (see, U.S. Pat. No. 4,874,794). Longer chain 0.139. The foam composition of the present invention fatty alcohols, e.g., tetracosanol, hexacosanol, heptacosanol, creates a Stable emulsion having an acceptable shelf-life of octacosanol, triacontanol, etc., are also known for their at least one year, or at least two years at ambient tempera metabolism modifying properties and tissue energizing ture. A feature of a product for cosmetic or medical use is long term stability. Propellants, which are a mixture of low properties. Long chain fatty acids have also been reported to molecular weight hydrocarbons, tend to impair the Stability possess anti-infective characteristics. of emulsions. It has been observed, however, that emulsion 0132) Thus, in preferred embodiments of the present foam compositions according to the present invention are invention, a combined and enhanced therapeutic effect is Surprisingly stable. Following accelerated Stability Studies, attained by including both a vasoactive agent and a thera they demonstrate desirable texture; they form fine bubble peutically effective foam adjuvant in the same composition, Structures that do not break immediately upon contact with thus providing a simultaneous anti-inflammatory and anti a Surface, spread easily on the treated area and absorb infective effect from both components. Furthermore, in a quickly. further preferred embodiment, the composition concurrently 0140. The composition should also be free flowing, to comprises a vasoactive agent, a therapeutically effective allow it to flow through the aperture of the container, e.g., foam adjuvant and a therapeutically active oil, as detailed and aeroSol container, and create an acceptable foam. Com above. Such combination provides an even more enhanced positions containing Semi-Solid hydrophobic Solvents, e.g., therapeutic benefit. Thus, the foamable carrier, containing white petrolatum, as the main ingredients of the oil phase of the foam adjuvant provides an extra therapeutic benefit in the emulsion, exhibit high Viscosity and poor flowability and comparison with currently used vehicles, which are inert and are inappropriate candidates for a foamable composition. non-active. 0141 Foam quality can be graded as follows: 0133. The foam adjuvant according to one or more pre 0142 Grade E (excellent): very rich and creamy in ferred embodiments of the present invention includes a appearance, does not show any bubble Structure or shows a mixture of fatty alcohols, fatty acids and hydroxy fatty acids very fine (small) bubble structure; does not rapidly become and derivatives thereof in any proportion, providing that the dull; upon Spreading on the skin, the foam retains the total amount is 0.1% to 5% (w/w) of the carrier mass. More creamineSS property and does not appear watery. preferably, the total amount is 0.4%-2.5% (w/w) of the carrier mass. 0.143 Grade G (good): rich and creamy in appearance, very small bubble size, “dulls' more rapidly than an excel 0134. Optionally, the composition further contains a pen lent foam, retains creamineSS upon spreading on the skin, etration enhancer. Non limiting examples of penetration and does not become watery. enhancers include propylene glycol, butylene glycols, glyc 014.4 Grade FG (fairly good): a moderate amount of erol, pentaerythritol, Sorbitol, mannitol, oligosaccharides, creamineSS noticeable, bubble Structure is noticeable; upon dimethyl isosorbide, monooleate of ethoxylated glycerides Spreading on the skin the product dulls rapidly and becomes having about 8 to 10 ethylene oxide units, polyethylene Somewhat lower in apparent Viscosity. glycol 200-600, transcutol, glycofurol and cyclodextrins. 0145 Grade F (fair): very little creaminess noticeable, 0135 The therapeutic foam of the present invention may larger bubble Structure than a “fairly good' foam, upon further optionally include a variety of formulation excipi Spreading on the Skin it becomes thin in appearance and ents, which are added in order to fine-tune the consistency watery. US 2005/0271596 A1 Dec. 8, 2005

0146 Grade P (poor): no creaminess noticeable, large pattern baldness, alopecia areata, alopecia universa bubble Structure, and when spread on the Skin it becomes lis and alopecia totalis, pseudofolliculitis barbae, very thin and watery in appearance. keratinous cyst; 0147 Grade VP (very poor): dry foam, large very dull 0160 Scalingg papularpap diseases including9. psoriasis,P bubbles, difficult to spread on the skin. pityriasis rosea, lichen planus, pityriasis rubra 0148 Topically administratable foams are typically of pilaris, quality grade E or G, when released from the aeroSol 0.161 Benign tumors including moles, dysplastic container. Smaller bubbles are indicative of more stable nevi, Skin tags, lipomas, angiomas, pyogenic granu foam, which does not collapse Spontaneously immediately loma, Seborrheic keratoses, dermatofibroma, kera upon discharge from the container. The finer foam Structure toacanthoma, keloid; looks and feels Smoother, thus increasing its usability and appeal. 0162 Malignant tumors including basal cell carcinoma, Squamous cell carcinoma, malignant melanoma, paget's 0149. A further aspect of the foam is breakability. The disease of the nipples, kaposi's Sarcoma; breakable foam is thermally stable, yet breaks under sheer force. Sheer-force breakability of the foam is clearly advan 0163 Reactions to Sunlight including Sunburn, chronic tageous over thermally-induced breakability. Thermally Sen effects of Sunlight, photosensitivity; Sitive foams immediately collapse upon exposure to skin 0.164 Bullous diseases including pemphigus, temperature and, therefore, cannot be applied on the hand bullous pemphigoid, dermatitis herpetiformis, linear and afterwards delivered to the afflicted area. immunoglobulin A disease; 0150. Another property of the foam is specific gravity, as 0.165 Pigmentation disorders including hypopig measured upon release from the aeroSol can. Typically, mentation Such as Vitiligo, albinism and postinflam foams have specific gravity of less than 0.1 g/mL or less than matory hypopigmentation and hyperpigmentation 0.05 g/mL. Such as melasma (chloasma), drug-induced hyper 0151 Fields of Pharmaceutical Applications pigmentation, postinflammatory hyperpigmentation; 0152 Vasoactive agents are initially thought to affect 0166 Disorders of comification including ichthyo disorders that involve blood circulation abnormalities, yet, sis, keratosis pilaris, calluses and corns, actinic kera in many case, circulation layS a Secondary, yet influential tosis, role, which must be taken into account in order to optimize treatment. For example, cutaneous malignant tumors are 0167) Pressure Sores, characterized by poor blood circulation, which make them leSS responsive to drug treatment, and therefore usage of a 0168) Disorders of Sweating, and vasoactive agent would be beneficial to the cancer therapy. 0169 Inflammatory reactions including drug erup 0153. Thus, by including an appropriate vasoactive agent tions, toxic epidermal necrolysis, erythema multi and optionally, additional active agents in the compositions forme, erythema nodosum, granuloma annulare. of the present invention, the composition are useful in 0170 According to one or more embodiments of the treating an animal or a patient having any one of a variety present invention, the compositions are also useful in the of dermatological disorders (also termed "dermatoses”), therapy of non-dermatological disorders by providing trans Such as classified in a non-limiting exemplary manner dermal delivery of an active vasoactive agent that is effective according to the following groups: against non-dermatological disorders. 0154 Disorders that involve peripheral blood flow 0171 The same advantage is expected when the compo abnormality, or disorders that respond to treatment Sition is topically applied to a body cavity or mucosal with a vasoactive agent, Surface (e.g., the mucosa of the nose, mouth, eye, ear, Vagina or rectum) to treat conditions Such as peripheral blood flow O155 Dermatitis including contact dermatitis, disorders, chlamydia infection, gonorrhea infection, hepati atopic dermatitis, Seborrheic dermatitis, nummular tis B, herpes, HIV/AIDS, human papillomavirus (HPV), dermatitis, chronic dermatitis of the hands and feet, genital warts, bacterial vaginosis, candidiasis, chancroid, generalized exfoliative dermatitis, Stasis dermatitis, granuloma Inguinale, lymphogranloma Venereum, mucopu lichen simplex chronicus, diaper rash; rulent cerviciitis (MPC), molluscum contagiosum, nongono 0156 Bacterial infections including cellulitis, acute coccal urethritis (NGU), trichomoniasis, vulvar disorders, lymphangitis, lymphadenitis, erysipelas, cutaneous Vulvodynia, Vulvar pain, yeast infection, Vulvar dystrophy, abscesses, necrotizing Subcutaneous infections, Sta Vulvar intraepithelial neoplasia (VIN), contact dermatitis, phylococcal Scalded skin Syndrome, folliculitis, pelvic inflammation, endometritis, Salpingitis, oophoritis, furuncles, hidradenitis Suppurativa, carbuncles, genital cancer, cancer of the cervix, cancer of the Vulva, paronychial infections, erythrasma; cancer of the vagina, Vaginal dryneSS, dySpareunia, anal and rectal disease, anal absceSS/fistula, anal cancer, anal fissure, O157 Fungal Infections including dermatophyte anal warts, Crohn's disease, hemorrhoids, anal itch, pruritus infections, yeast Infections, parasitic Infections ani, fecal incontinence, constipation, polyps of the colon and including Scabies, pediculosis, creeping eruption; rectum. 0172 The following examples exemplify the therapeutic 0158 Viral Infections; kits and pharmacological compositions and methods 0159. Disorders of hair follicles and sebaceous described herein. The examples are for the purposes of glands including acne, rosacea, perioral dermatitis, illustration only and are not intended to be limiting of the hypertrichosis (hirsutism), alopecia, including male invention. US 2005/0271596 A1 Dec. 8, 2005

EXAMPLE 1. -continued Oil in Water Foamable Emulsion Compositions Comprising Minoxidil with and Without an Foam Properties Additional Active Agent Emulsion uniformity Uniform Uniform 0173 Emulsion color White White pH 6.34 6.75 Foam quality E E Density O.O38 O.O44 Composition No: Centrifugation: Stable Stable MN1 MN2 MN3 MN4 Composition No: Ingredient % MN5 Minoxidil (vasoactive agent) 2.OO 2.OO 2.OO 2.OO Ingredient % MN6 SL1 SL2 Salicylic acid (additional 2.OO active agent) Azelaic acid (additional active 1O.OO Minoxidil (vasoactive agent) 2.OO 2.OO agent) Sildenafil (vasoactive agent) 1O.OO 1O.OO Propylene glycol (penetration S.OO S.OO Propylene glycol (penetration 2.OO 2.OO enhancer) enhancer) Mineral oil 5.60 5.60 Mineral oil 5.60 5.60 5.60 5.60 Isopropyl myristate 5.60 5.60 Isopropyl palmitate 5.60 5.60 5.60 Glyceryl monostearate O.45 O.45 Capric-caprylic triglyceride 5.60 Xanthan gum 0.25 O.25 Sorbitan stearate (Span 60) 2.OO 2.OO 2.OO 2.OO Methocel K10OM 0.25 O.25 PPG15-stearyl ether 1.OO 1.OO 1.OO 1.OO Avice RC581 2.OO 2.OO Stearic acid O.85 O.85 O.85 O.85 Polysorbate 60 O.85 O.85 O.85 O.85 Glyceryl monostearate O.45 O.45 O.45 O.45 PEG-100 stearate (MyrjS9) 2.50 2.50 2.50 2.50 Xanthan gum O.26 O.26 O.26 O.26 Preservative 0.25 O.25 O.25 0.25 Foam Properties Propellant 1O.OO 1O.OO 1O.OO 1O.OO Water TO 100 TO 1 OO TO 1 OO TO 100 Foam Properties Methocel K10OM O.26 O.26 O O Preservative O.25 O.25 0.25 O.25 Emulsion uniformity Uniform Uniform Propellant 1O.OO 1O.OO 1O.OO 1O.OO pH 6.34 6.75 Water To 1 OO TO 100 T 1 OO TO 100 Foam quality E E Density O.O38 O.O44 Centrifugation Stable Stable EXAMPLE 3 0174 As shown above, Compositions MN1 and MN2 were further examined for emulsion uniformity, emulsion Oil in Water Foamable Emulsion Compositions Stability, foam quality and density and found Stable, and Comprising Caffeine meeting the requirements of density between 0.01 and 0.1 g/mL and excellent (E) quality. 0176) EXAMPLE 2 Additional Oil in Water Foamable Emulsion Composition No: CF1 Compositions Comprising Minoxidil and Sildenafil Ingredient % 0175) Caffeine (Vasoactive agent) S.OO Mineral Oil 8.OO Hexylenglycol (penetration enhancer) S.OO Phophtydilcholina 50% (phosal 50 PG) 2.OO Composition No: Cyclomethicone or Cyclopentasiloxane 1.OO Stearic Acid 2.OO MN5 Polyoxyl 2 Stearyl Ether (Brij 72) 1.OO Ingredient % MN6 Polyoxiethylene 21 Stearyl Ether (Brij 721) 3.OO Acrylates/C10-30 Alkylacrilate Crospolimer O.OS Minoxidil 2.OO 2.OO (Pemulen TR2) Mineral oil 5.60 Glyceryl Monoestearate NE 1.OO Isopropyl myristate 5.60 3.OO Bis. PEG/PPG-18Methyl Ether Dimethyl Silane 1.OO Glyceryl monostearate O.45 (Dow 2501) Stearyl alcohol O.85 Glycerin 3.OO Xanthan gum O.25 Sodium benzoate 4.OO Methocel K10OM O.25 Water TO 100 Avice RC581 2.OO Foam Properties Polysorbate 60 O.85 O.85 PEG-100 stearate (MyrjS9) 2.50 2.50 Density Propylene glycol S.OO S.OO foam quality Preservative O.25 O.25 centrifugation Stable Propellant 1O.OO 1O.OO Ph 6.29 Water TO 100 TO 100 US 2005/0271596 A1 Dec. 8, 2005 12

EXAMPLE 4 EXAMPLE 6 Oil in Water Vasoactive Agent Foamable Emulsion Compositions with Hammamelis Extract as Compositions (-30% oil) Vasoactive Agent 0177) 0180

Composition No: Composition No:

MNT HM1 HM2 Ingredient % SL2 SL3 MN8 Ingredient % Minoxidil (vasoactive agent) S.OO S.OO Hamamelis Extract 1O.OO 1O.OO Sildenafil (vasoactive agent) 1O.OO Mineral oil 6.OO 6.OO Amyl nitrate (NO donor - 2.OO Isopropyl myristate 6.OO 6.OO vasoactive agent) Glyceryl monostearate OSO O.SO Azelaic acid (additional active 1O.OO Stearyl alcohol 1.OO 1.OO agent) Xanthan gum O.30 MCT oil 3OOO 3OOO 3O.OO 3O.OO Methocel K10OM O.30 O.30 Glyceryl monostearate OSO OSO OSO OSO Polysorbate 80 1.OO 1.OO Stearyl alcohol 1.OO 1.OO 1.OO 1.OO PEG-40 stearate 3.OO 3.00 Xanthan gum O.30 O.30 O.30 O.30 EDTA disodium O.2O O.2O Methocel K10OM O.30 O.30 O.30 O.30 Preservative O.25 0.25 Polysorbate 80 1.OO 1.OO 1.OO 1.OO Propellant 8.OO 8.00 PEG-40 stearate 3.OO 3.OO 3.OO 3.OO Water TO 100 TO 100 Cocamidopropyl betaine OSO OSO OSO OSO Foam Properties Preservative O.25 O.25 O.25 O.25 Propellant 16.00 16.00 16.OO 16.OO Emulsion uniformity Uniform Uniform Water TO 100 TO 100 TO 100 TO 100 pH 4.99 4.25 Foam quality E E Density O.04 O.04 Centrifugation: Stable. Stable. EXAMPLE 5

Compositions with Vasoactive Herbal Extracts EXAMPLE 7 0178) Compositions with a Vasoactive Herbal Extract and an Additional Active Agent Composition No: 0181)

UL1 GK1 Ingredient % Composition No: Eleutherococci. Extract 1.OO Ginkgo extract 1.OO Mineral oil 5.60 5.60 Ingredient % Isopropyl myristate 5.60 5.60 Glyceryl monostearate O.45 O.45 Hamamelis Extract (Vasoactive herbal 1. Polyoxyl 2 Stearyl Ether (Brij 72) 3.00 3.OO extract) Polyoxiethylene 21 Stearyl Ether (Brij 721) 2.OO 2.OO Hydrocortisone propionate (Additional 1.OO Stearic acid O.85 O.85 active agent) Methocel E15 O.26 O.26 Lidocaine base (Additional active agent) 4.OO Preservative 0.25 O.25 Mineral oil 5.60 5.60 Propellant 8.00 8.OO Isopropyl myristate 5.60 5.60 Water To 100 TO 100 Glyceryl monostearate O.45 O.45 Foam Properties Stearyl alcohol O.85 O.85 Xanthan gum O.2O O.2O Emulsion uniformity Uniform Uniform Methocel K10OM O.2O O.2O pH 4.99 4.25 Polysorbate 80 O.90 O.90 Foam quality E E PEG-40 stearate 2.60 2.60 Density O.04 O.04 EDTA disodium O.2O O.2O Centrifugation: Stable Stable Foam Properties Emulsion uniformity Uniform Uniform Color Brown Brown 0179 Compositions UL1 and GK1 were further exam pH 7.6O ined for emulsion uniformity, emulsion Stability, foam qual Foam quality FG Density O.O41 ity and density and found Stable, and meeting the require Centrifugation: Stable Stable ments of density between 0.01 and 0.1 g/mL and excellent (E) quality. US 2005/0271596 A1 Dec. 8, 2005 13

EXAMPLE 8 organic polar Solvent, an emolient and mixtures thereof, at a concentration of about 2% to about 50% Comparative Study, to ASSeSS the Organoleptic by weight; Properties of Foamable Composition According to the Present Invention, VS. Foams According to iii. a Surface-active agent; PCT/AU99/00735 iv. about 0.01% to about 5% by weight of at least one 0182. Usability of a pharmaceutical composition and its polymeric additive Selected from the group consist ease of use is a primary determinant in high treatment ing of a bioadhesive agent, a gelling agent, a film compliance and Subsequently, favorable therapeutic results. forming agent and a phase change agent; The present Study was performed in order to assess the V. water, and organoleptic properties of foamable compositions according Vi. liquefied or compressed gas propellant at a concen to the present invention, vs. foams according to PCT/AU99/ tration of about 3% to about 25% by weight of the 00735 (735). total composition. 0183) The vehicle of Composition MN1 (oil in water 2. The kit of claim 1, wherein the foamable composition emulsion; ~12% oil) according the Examples 1 hereinabove is Selected from the group consisting of an oil-in-water were compared with Composition No. 1 according to the emulsion and a water-in-oil emulsion. example of PCT/AU99/00735 (oil in water emulsion; which 3. The kit of claim 1, wherein the outlet comprises a valve, contains 10% petrolatum, but does not contain a foam containing a stem with 1 to 4 apertures formed in the Stem. adjuvant and a polymeric agent), in a consumer test panel of 4. The kit of claim 3, wherein each aperture formed in the Six Subjects. The panelists were asked to assess the follow Stem has a diameter, Selected from the group consisting of (i) ing parameters: appearance, physical disintegration, fluidity, about 0.2 mm to about 1 mm; (ii) about 0.3 mm to about 0.8 ease of spreading (spreadability), absorbency, residual feel mm; and (iii) about 0.01 mm and 1 mm . ing and oily feeling. AS presented in the following table, the 5. The kit of claim 3, wherein the Sum of areas of all majority of panelists determined that the MN1 foam was apertures in the stem is between about 0.04 mm and 0.5 better than Composition No. 1 according to the example of mm. 735 patent. 6. The kit of claim 3, wherein the valve is attached to metered dose device. 7. The kit of claim 1, wherein the at least one organic MN1 Better than 735 Better than MN1 Equals carrier is present in an amount Selected from the group 735 MN1 735 consisting of (i) about 2% to about 5%; (ii) about 5% to about 10%; (iii) about 10% to about 20%; and (iv) about Appearance 5 O 1. 20% to about 50%. Physical disintegration 3 1. 2 Easy to spread 2 O 3 8. The kit of claim 1, wherein the foamable composition Absorbency 3 1. 2 is Substantially alcohol-free. Residual feeling 5 O 1. 9. The kit of claim 1, further including about 0.1% to Oily feeling 4 1. 1. about 5% by weight of a therapeutically active foam adju Vant is Selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid 0184 The multiple advantageous features of composition having 16 or more carbons in their carbon chain; fatty MN1 are presumably attained due to (1) the presence of a alcohols, derived from beeswax and including a mixture of foam adjuvant and a polymeric agent in MN1, which con alcohols, a majority of which has at least 20 carbon atoms tributes to the Sensory profile and to the facile spreading and in their carbon chain; a fatty alcohol having at least one absorbency; and (2) absence of petrolatum in MN1, which double bond; a fatty acid having at least one double bond; a avoids the residual and oily feeling, typical to petrolatum branched fatty alcohol; a branched fatty acid; a fatty acid containing products. This difference is meaningful in terms Substituted with a hydroxyl group, cetyl alcohol, Stearyl of usability, compliance and consequently treatment Suc alcohol, arachidyl alcohol; behenyl alcohol, 1-triacontanol; CCSS. hexadecanoic acid, Stearic acid, arachidic acid; behenic acid; octacosanoic acid; 12-hydroxy Stearic acid and mixtures What is claimed is: thereof. 1. A therapeutic kit to provide a safe and effective dosage 10. The kit of claim 1 or 9, wherein the vasoactive agent of a vasoactive agent, including an aerosol packaging is a vasodilator. assembly including: 11. The kit of claim 10, wherein the vasodilator is selected from the group consisting of a) a container accommodating a pressurized product; and i. agents that modulate the production of nitric oxide or b) an outlet capable of releasing the pressurized product otherwise modulate or activate the effect of nitric oxide, as a foam; ii. agents that modulate the activity of the enzyme nitric wherein the pressurized product comprises a foamable Oxide Synthase; composition including: iii. agents that enhance the effect of NO by inhibiting i. a vasoactive agent; enzymes from the phosphodiesterase group; ii. at least one organic carrier Selected from the group iv. a vasodilator including nitrites, nitrates and their consisting of a hydrophobic organic carrier, an analogs, esters and Salts, US 2005/0271596 A1 Dec. 8, 2005 14

V. agents possessing a moiety Selected from the group flower), trigonella foenum-graecum (fenugreek), urtica consisting of ONO, and ONO; dioica (nettles), valeriana Oficinalis (Valerian), vibur vi. a vasodilator Selected from the group including amyl num (cramp, bark, blackhaw), veratrum viride (Ameri nitrite, amyl nitrate, ethyl nitrite, butyl nitrite, isobutyl can hellebore), verbena Officinalis (Vervain), xanthoxy nitrite, glyceryl trinitrate, octyl nitrite, Sodium nitrite, lum americanum (prickly ash), Zingiber Oficinale Sodium nitroprusside, clonitrate, erythrityl tetranitrate, (ginger), rauwolfia Serpentina (Indian Snakeroot), vis isosorbide mononitrate, isosorbide dinitrate, mannitol cum album, wild yam, Sasparilla, licorice, damiana, heXanitrate, pentaerythritol tetranitrate, penetrinitol, yucca, Saw palmetto, gotu kola (centella asiatica), triethanolamine trinitrate, trolnitrate phosphate (trietha yohimbine and Salts, hazel nut, brazil nut and walnut, nolamine trinitrate diphosphate), propatylnitrate, nitrite and Salts thereof. esters of Sugars, nitrite esters of polyols, nitrate esters 12. The kit of claim 1 or 9, wherein the vasoactive agent of Sugars, nitrate esters of polyols, nicorandil, apreSo is a vasoconstrictor. line, diazoxide, hydralazine, hydrochlorothiazide, 13. The kit of claim 12, wherein the vasoconstrictor is minoxidil, pentaerythritol, tolaZoline and Scoparone Selected from the group consisting of: (6,7-dimethoxycoumarin); i. the group of vasoactive agonists, vasopressor agents and vii. the group including beta-adrenergic blockers, alpha vasoconstrictor drugs, adrenoceptor blockers, prostaglandin and prostaglan ii. an agent that acts on Vasopressin receptors or adreno din-like compounds, inhibitors of type 5 phosphodi receptors, esterase (PDE-5), angiotensin converting enzyme inhibitors, calcium antagonists, angiotensin II receptor iii. a calcium channel agonist, antagonists, direct acting Smooth muscle vasodilators, iv. a vasoconstrictor Selected from the group including adrenergic inhibitors, endothelin antagonists, mineralo ephedrine, epinephrine, phenylephrine, angiotensin and corticoid receptor antagonists, vasopeptidase inhibitors Vasopressin; and renin inhibitors, which cause a vasodilator effect; V. a vasoconstrictor Selected from the group including viii. the group including Sildenafil, dipyridamole, cat ephedra Sinica (mahuang), polygonum bistorta (bistort echolamine, isoproternol, furosemide, prostaglandin, root), hamamelis virginiana (witch hazel), hydrastis prostacyclin, enalaprilat (ACE-inhibitor), morphine Canadensis (goldenseal), lycopus virginicus (opiate), acepromazine (C.-blocker), praZOsin (bugleweed), aspidosperma quebracho (quebracho (C.-blocker), enalapril.(ACE-inhibitor), Captopril blanco), cytisus Scoparius (Scotch broom) and cypress; (ACE-inhibitor), amlodipine (Ca channel blocker), and minoxidil, tadalafil, Vardenafil, phenylephrin, etillefein, caffeine and capsaicin; vi. an agent that positively affects the McKenzie vaso constrictor assay. and Salts thereof. ix. the group including bradykinin, bradykinin-like pep 14. The kit of claim 1 or 9, wherein the concentration tide I, bradykinin-like peptide III Phyllokinin (Bradyki range of the vasoactive agent is Selected from the group of nyl-isoleucyl-tyrosine O-Sulfate), megascoliakinin (i) between about 0.005% and about 0.5%; (ii) between (Thr6bradykinin-Lys-Ala), lysyl-bradykinin-like about 0.5% and about 2%; (iii) between about 2% and about waspkinin, lysyl-bradykinin, maximakinin (Bombina 5%; and (iv) between about 5% and about 12%. kinin M), bombinakinin-GAP, kininogen-1 associated 15. The kit of claim 1 or 9, wherein the vasoactive agent peptides, kininogen-2 associated peptides, T-kinin, is a vasodilator; and wherein upon release from the con thiostatin, prolixin-S, Vespulakinin 2, Vespakinin X, tainer, a Shear-Sensitive foam, having a density range relaxin, adrenomedulin, ghrelin, maXadilan, Substance selected from (1) between about 0.02 gr/mL and about 0.1 P. calcitonin gene-related peptide (CGRP), Natriuretic gr/mL, and (2) between about 0.02 gr/mL and about 0.1 peptides (NPS), e.g., atrial natriuretic peptide (ANP), gr/mL, is produced. C-type natriuretic peptide (CNP), and adrenomedullin 16. The kit of claim 2, wherein the graded of solubility of (ADM), adrenomedullin, Ovine corticotropin-releasing the vasoactive agent in the aqueous phase of the emulsion is factor, Sauvagine and urotensin; Selected from the groups consisting of: ... an agent that induces the production of a vasodilator (i) “soluble”, “freely soluble” or “very soluble” peptide or otherwise enhance or activate the effect of a vasodilator peptide; (ii) “very slightly soluble", slightly soluble' or “spar ingly soluble” Xi. a vasodilator derived or extracted from herbs, and (iii) insoluble i.e., “requires 10,000 parts or more of a Xii. a vasodilator derived or extracted Selected from the Solvent to be solubilized' group of herbs including achillea millefolium (Yarrow), allium Sativum (garlic), amoracia rusticana (horserad where the descriptive grade of solubility is defined ish), berberis vulgaris (barberry), cimicifuga racemosa according to the US Pharmacopoeia. (black cohosh), Coleus forSkholii (coleus), copiis 17. The kit of claim 2, wherein the grade of solubility of (Golden thread), crataegus (hawthorn), eleutherococ the vasoactive agent in the oil phase of the emulsion is cus SenticOSuS (Siberian ginseng), ginkgo bilo Selected from the groups consisting of: ba(ginkgo), melissa Oficinalis (lemon balm), Olea europaea (olive leaf), panax ginseng (Chinese gin (i) “soluble”, “freely soluble” or “very soluble” Seng), petroSelinum crispum (parsley), Scutellaria (ii) “very slightly soluble", slightly soluble' or “spar baica lensis (baical skullcap), tilia europaea (linden ingly soluble” US 2005/0271596 A1 Dec. 8, 2005 15

(iii) insoluble i.e., “requires 10,000 parts or more of a 27. The kit of claim 1 or 9, wherein the foamable Solvent to be solubilized' composition contains at least one therapeutically active oil. where the descriptive grade of solubility is defined 28. The kit of claim 27, wherein the foamable composi according to the US Pharmacopoeia. tion further contains at least one therapeutically effective 18. The kit of claim 2, wherein the vasoactive agent is foam adjuvant. dissolved in at least one phase of the emulsion. 29. The kit of claim 1 or 9, wherein the composition 19. The kit of claim 1, wherein the foamable composition further contains a penetration enhancer. further contains at least one additional therapeutic agent 30. The kit of claim 29, wherein the penetration enhancer Selected from the group consisting of an anti-infective, an is Selected from the group consisting of propylene glycol, antibiotic, an antibacterial agent, an antifungal agent, an butylene glycols, hexylene glycol, glycerol, pentaerythritol, antiviral agent, an antiparasitic agent, a Steroidal antiinflam Sorbitol, mannitol, oligosaccharides, dimethyl isosorbide, matory agent, an immunosuppressive agent, an immuno monooleate of ethoxylated glycerides having about 8 to 10 modulator, an immunoregulating agent, a hormonal agent, ethylene oxide units, polyethylene glycol 200-600, transcu vitamin A, a vitamin A derivative, vitamin B, a vitamin B tol, glycofurol and cyclodextrins. derivative, vitamin C, a vitamin C derivative, vitamin D, a 31. A therapeutic foamable composition including: vitamin D derivative, vitamin E, a vitamin E derivative, i. a vasoactive agent; vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, an anes ii. a therapeutically active oil; thetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, iii. a Surface-active agent; a neuropeptide, a allergen, an immunogenic Substance, a iv. about 0.01% to about 5% by weight of at least one haptene, an oxidizing agent, an antioxidant, a dicarboxylic polymeric additive Selected from the group consisting acid, azelaic acid, Sebacic acid, adipic acid, fumaric acid, a of a bioadhesive agent, a gelling agent, a film forming retinoid, an antiproliferative agent, an anticancer agent, a agent and a phase change agent; photodynamic therapy agent, benzoyl chloride, calcium hypochlorite, magnesium hypochlorite, an anti-wrinkle V. water, and agent, a radical Scavenger, a metal, Silver, a metal oxide, Vi. liquefied or compressed gas propellant at a concentra titanium dioxide, Zinc oxide, Zirconium oxide, iron oxide, tion of about 3% to about 25% by weight of the total Silicone oxide, talc, carbon, an anti Wrinkle agent, a skin composition. Whitening agent, a skin protective agent, a masking agent, an 32. The composition of claim 31, further including about anti-Wart agent, a refatting agent, a lubricating agent and 0.1% to about 5% by weight of a therapeutically active foam mixtures thereof. adjuvant is Selected from the group consisting of a fatty 20. The kit of claim 1, wherein the concentration of the alcohol having 15 or more carbons in their carbon chain; a surface active agent is between about 0.1% and about 5%. fatty acid having 16 or more carbons in their carbon chain; 21. The kit of claim 1, wherein the Surface active agent fatty alcohols, derived from beeswax and including a mix includes a mixture of at least one non-ionic Surfactant and at ture of alcohols, a majority of which has at least 20 carbon least one ionic Surfactant in a ratio in the range of about atoms in their carbon chain; a fatty alcohol having at least 100:1 to 6:1. one double bond; a fatty acid having at least one double 22. The kit of claim 1, wherein the Surface active agent bond; a branched fatty alcohol; a branched fatty acid; a fatty comprises a combination of a non-ionic Surfactant and an acid Substituted with a hydroxyl group, cetyl alcohol; Stearyl ionic Surfactant, at a ratio of between 1:1 and 20:1. alcohol, arachidyl alcohol; behenyl alcohol, 1-triacontanol; 23. The kit of claim 2, wherein the emulsion is a water in hexadecanoic acid, Stearic acid, arachidic acid; behenic acid; oil emulsion and wherein the HLB range of the surface octacosanoic acid; 12-hydroxy Stearic acid and mixtures active agent is selected from (1) between about 2 and about thereof. 9; and (2) between about 9 and about 14. 33. The composition of claim 31, wherein the foamable 24. The kit of claim 1, wherein the Surface active agent composition further comprises at least one additional thera comprises a combination of at least one non-ionic Surfactant peutic agent. having HLB of less than 9 and at least one non-ionic 34. The composition of claim 31, wherein the additional surfactant having HLB of equal or more than 9, wherein the therapeutic agent is Selected from the group consisting of an ratio between the at least one non-ionic Surfactant having anti-infective, an antibiotic, an antibacterial agent, an anti HLB of less than 9 and the at least one non-ionic Surfactant fungal agent, an antiviral agent, an antiparasitic agent, an having HLB of equal or more than 9, is between 1:8 and 8:1. Steroidal antiinflammatory agent, an immunosuppressive 25. The kit of claim 1, wherein the polymeric agent is agent, an immunomodulator, an immunoregulating agent, a Selected from the group consisting of a water-Soluble cel hormonal agent, Vitamin A, a Vitamin A derivative, Vitamin lulose ether and a naturally-occurring polymeric material. B, a vitamin B derivative, vitamin C, a vitamin C derivative, 26. The kit of claim 25, wherein the water-soluble cellu vitamin D, a vitamin D derivative, vitamin E, a vitamin E lose ether is Selected from the group consisting of methyl derivative, vitamin F, a vitamin F derivative, vitamin K, a cellulose, hydroxypropyl cellulose, hydroxypropyl methyl Vitamin K derivative, a wound healing agent, a disinfectant, cellulose (Methocel), hydroxyethyl cellulose, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, methylhydroxyethylcellulose, methylhydroxypropylcellu lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a lose, hydroxyethylcarboxymethylcellulose, carboxymethyl peptide, a neuropeptide, a allergen, an immunogenic Sub cellulose, carboxymethylhydroxyethylcellulose, Xanthan Stance, a haptene, an oxidizing agent, an antioxidant, a gum, guar gum, carrageenin gum, locust bean gum and dicarboxylic acid, azelaic acid, Sebacic acid, adipic acid, tragacanth gum. fumaric acid, a vasoactive agent, an antiproliferative agent, US 2005/0271596 A1 Dec. 8, 2005 an anticancer agent, a photodynamic therapy agent, benzoyl of the nose, a disorder of the respiratory System, a bacterial chloride, calcium hypochlorite, magnesium hypochlorite, an infection, fungal infection, Viral infection, dermatosis, der anti-wrinkle agent, a radical Scavenger, a metal, Silver, a matitis, parasitic infections, disorders of hair follicles and metal oxide, titanium dioxide, Zinc oxide, Zirconium oxide, Sebaceous glands, Scaling papular diseases, benign tumors, iron oxide, Silicone oxide, talc, carbon, an anti wrinkle malignant tumors, reactions to Sunlight, bullous diseases, agent, a skin whitening agent, a skin protective agent, a pigmentation disorders, disorders of cornification, preSSure masking agent, an anti-Wart agent, a refatting agent, a Sores, disorders of Sweating, inflammatory reactions, Xero lubricating agent and mixtures thereof. sis, ichthyosis, allergy, burn, wound, cut, chlamydia infec 35. The foamable composition of claim 31, wherein the tion, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, foamable composition contains at least one therapeutically human papillomavirus (HPV), genital warts, bacterial vagi active oil. nosis, candidiasis, chancroid, granuloma Inguinale, lym 36. The foamable composition of claim 35, wherein the phogranloma Venereum, mucopurulent cerviciitis (MPC), foamable composition further contains at least one thera molluscum contagiosum, nongonococcal urethritis (NGU), peutically effective foam adjuvant. trichomoniasis, Vulvar disorders, Vulvodynia, Vulvar pain, 37. The foamable composition of claim 31, wherein the yeast infection, Vulvar dystrophy, Vulvar intraepithelial neo composition further contains a penetration enhancer. plasia (VIN), contact dermatitis, osteoarthritis, joint pain, 38. The foamable composition of claim 37, wherein the hormonal disorder, pelvic inflammation, endometritis, Salp penetration enhancer is Selected from the group consisting of ingitis, oophoritis, genital cancer, cancer of the cervix, propylene glycol, butylene glycols, heXylene glycol, glyc cancer of the Vulva, cancer of the vagina, Vaginal dryness, erol, pentaerythritol, Sorbitol, mannitol, oligosaccharides, dySpareunia, anal and rectal disease, anal absceSS/fistula, dimethyl isosorbide, monooleate of ethoxylated glycerides anal cancer, anal fissure, anal warts, Crohn's disease, hem having about 8 to 10 ethylene oxide units, polyethylene orrhoids, anal itch, pruritus ani, fecal incontinence, consti glycol 200-600, transcutol, glycofurol and cyclodextrins. pation, polyps of the colon and rectum; 39. A method of treating, alleviating or preventing disor and wherein the disorder is responsive to treatment with ders of the skin, body cavity or mucosal Surface, wherein the the vasoactive agent. disorder involves inflammation as one of its etiological 42. The method of claim 39, wherein the foamable factors, including: composition contains at least one therapeutically active oil. 43. The method of claim 42, wherein the foamable administering topically to a Subject having the disorder, a composition further contains at least one therapeutically foamed composition including: effective foam adjuvant. (6) a vasoactive agent; 44. The method of claim 39, wherein the composition further comprises at least one additional therapeutic agent, (7) at least one organic carrier Selected from a hydro Selected from the group consisting of an anti-infective, an phobic organic carrier, a polar Solvent, an emollient antibiotic, an antibacterial agent, an antifungal agent, an and mixtures thereof, at a concentration of about 2% antiviral agent, an antiparasitic agent, an Steroidal antiin to about 50% by weight; flammatory agent, an immunosuppressive agent, an immu nomodulator, an immunoregulating agent, a hormonal agent, (8) about 0.1% to about 5% by weight of a surface vitamin A, a vitamin A derivative, vitamin B, a vitamin B active agent, derivative, vitamin C, a vitamin C derivative, vitamin D, a (9) about 0.01% to about 5% by weight of a polymeric vitamin D derivative, vitamin E, a vitamin E derivative, additive Selected from a bioadhesive agent, a gelling vitamin F, a vitamin F derivative, vitamin K, a vitamin K agent, a film forming agent and a phase change derivative, a wound healing agent, a disinfectant, an anes agent, and thetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, (10) water, a neuropeptide, a allergen, an immunogenic Substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic wherein the vasoactive agent is administered in a thera acid, azelaic acid, Sebacic acid, adipic acid, fumaric acid, a peutically effective amount. vasoactive agent, an antiproliferative agent, an anticancer 40. The method of claim 39, wherein the composition agent, a photodynamic therapy agent, benzoyl chloride, further comprises about 0.1% to about 5% by weight of a calcium hypochlorite, magnesium hypochlorite, an anti therapeutically active foam adjuvant is Selected from the Wrinkle agent, a radical Scavenger, a metal, Silver, a metal group consisting of a fatty alcohol having 15 or more oxide, titanium dioxide, Zinc oxide, Zirconium oxide, iron carbons in their carbon chain; a fatty acid having 16 or more oxide, Silicone oxide, talc, carbon, an anti wrinkle agent, a carbons in their carbon chain; fatty alcohols, derived from Skin whitening agent, a skin protective agent, a masking beeswax and including a mixture of alcohols, a majority of agent, an anti-Wart agent, a refatting agent, a lubricating which has at least 20 carbon atoms in their carbon chain; a agent and mixtures thereof. fatty alcohol having at least one double bond; a fatty acid 45. The method of claim 39, wherein the composition having at least one double bond; a branched fatty alcohol; a further contains a penetration enhancer. branched fatty acid; a fatty acid substituted with a hydroxyl 46. The method of claim 45, wherein the penetration group, cetyl alcohol; Stearyl alcohol, arachidyl alcohol; enhancer is Selected from the group consisting of propylene behenyl alcohol, 1-triacontanol; hexadecanoic acid; Stearic glycol, butylene glycols, hexylene glycol, glycerol, pen acid, arachidic acid; behenic acid; octacosanoic acid; 12-hy droxy Stearic acid and mixtures thereof. taerythritol, Sorbitol, mannitol, oligosaccharides, dimethyl 41. The method of claim 39, wherein the disorder is isosorbide, monooleate of ethoxylated glycerides having Selected from the group consisting of a dermatose, a der about 8 to 10 ethylene oxide units, polyethylene glycol matitis, a vaginal disorder, a Vulvar disorder, an anal disor 200-600, transcutol, glycofurol and cyclodextrins. der, a disorder of a body cavity, an ear disorder, a disorder k k k k k