AU2006201878A1 - Foamable composition for hyperhidrosis - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Foamix Ltd Actual Inventor(s): Dov Tamarkin, Doron Friedman, Meir Eini Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: r i C /1 ~O j) u-c~ FOAMABLE COMPOSITION FOR HYPERHIDROSIS Our Ref 770931 POF Code: 128985/468584 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- 6006q FOAMABLE COMPOSITION FOR HYPERHIDROSIS This application claims priority from US Patent Application No.60/781,868 filed on 13 March 2006, the contents of which are to be taken as incorporated herein by this reference.

[0001] This application is a continuation-in-part application of co-pending United States Patent Application Serial No. 10/532618, filed on April 25, 2005, which is an Sapplication filed under 35 U.S.C. §371 of International Patent Application No.

0 IB03/005527 designating the United States and filed on October 24, 2003, which claims the benefit of priority under 35 U.S.C. §119(e) to United States Patent Application Serial No. 60/492,546, filed on November 29, 2002, both entitled "Cosmetic and oo Pharmaceutical Foam," and which also claims the benefit of priority under g USC§119(a) to Israeli Patent App. No. 152486, filed October 25, 2002, all of which are O hereby incorporated in their entirety by reference.

[0002] This application is a continuation-in-part application of co-pending United States Patent Application Serial No. 10/911,367, filed on August 4, 2004, which claims the benefit of priority under 35 U.S.C. §119(e) to United States Patent Application Serial No. 60/492,385, filed on August 4, 2003, both entitled "Foam Carrier Containing Amphiphilic Copolymer Gelling Agent" and both hereby incorporated in their entirety by reference.

BACKGROUND OF THE INVENTION [0003] Foams and, in particular, foam emulsions are complex dispersion systems which do not form under all circumstances. Slight shifts in foam emulsion composition, such as by the addition of active ingredients, may destabilize the foam.

[0004] Hyperhidrosis is a medical condition characterized by excessive sweating in the armpits, palms, soles of the feet, face, scalp, and/or torso. Hyperhidrosis involves sweating in excess of the amount required normally for the body's level of activity and temperature. There are two types of hyperhidrosis-primary and secondary. In primary hyperhidrosis, the cause is unknown and excessive sweating is localized in the armpits, hands, face, and/or feet. Primary hyperhidrosis begins during childhood or early adolescence, gets worse during puberty, and lasts a lifetime. In secondary hyperhidrosis, which is less common than primary hyperhidrosis, excessive sweating is 1A US1DOCS 5559587v1 IN caused by another medical condition and usually occurs over the entire body. Medical conditions that can cause secondary hyperhidrosis include hyperthyroidism, menopause, obesity, psychiatric disorders, and diabetes. Secondary hyperhidrosis may Salso be caused by use of certain medications.

[0005] Topical agents applied to the skin in the affected area are the first course of treatment for hyperhidrosis. Topical applications include anticholinergic drugs, boric 00 acid, tannic acid, resorcinol, potassium permanganate, formaldehyde, glutaraldehyde 00 and methenamine. Antiperspirant actives currently used in the industry are Lewis acids.

STypically, such antiperspirant actives are partially neutralized chloride salts of metal ions I such as aluminum and zirconium.

0 [0006] US Pat. No. 6,433,003 discloses methods for treating hyperhidrosis involving the topical administration of glycopyrrolate compounds to humans. US Pat. No.

5,730,964 and 5,512,555 teach methods of treating sweat related conditions with compounds that are 5-alpha-reductase inhibitors, such as finasteride, epristeride and cholestan-3-one, alone or in combination with other active agents to treat conditions such as apocrine gland sweating, hyperhidrosis, and hydradenitis suppurativa. US Pat.

No. 4,885,282 describes a method for the treatment of skin suffering from hyperhidrosis, ichthyosis or wrinkling, comprising applying to the affected area of a compound selected from the group consisting of mono- and dicarboxylic acids having 4 to 18 carbon atoms, a mercapto derivative thereof, a salt thereof, and an ester thereof.

[0007] US Pat. Application No. 20050196414 describes a method of administering a botulinum toxin to a subject comprising topically applying to the skin or epithelium of the subject the botulinum toxin for prevention or reduction of symptoms associated with subjective or clinical hyperhidrosis. US Pat. App. No. 20040192754 teaches compounds that can ameliorate symptoms of idiopathic hyperhidrosis and associated conditions include 5-HT2C receptor antagonists ketanserin, ritanserin, mianserin, mesulergine, cyproheptadine, fluoxetine, mirtazapine, olanzapine, and ziprasidone) as well as 5-HT2C receptor modulators inverse agonists, partial agonists, and allosteric modulators).

2 US1 DOCS 5559587v1 SUMMARY OF THE INVENTION [0008] According to preferred embodiments of the present invention, there is provided a composition geared towards treating hyperhidrosis or any condition involving and/or promoting excessive sweating, typically involving the whole body, include Shyperthyroidism or similar endocrine disorders; endocrine treatment for prostatic cancer or other types of malignant disorder; severe psychiatric disorders; obesity and oo menopause. The foamable composition of the present invention is suitable for treating 00 palmar hyperhidrosis; axillary hyperhidrosis; plantar hyperhidrosis; hyperhidrosis of the trunk and/or the thighs; and facial hyperhidrosis; and any combination of them consisting of a therapeutic foamable composition including: an active agent, suitable for the treatment or prevention of hyperhidrosis, about 2% to about 50% of organic carrier selected from the group consisting of a hydrophobic organic carrier, a polar solvent, an emollient and any mixture thereof, about 0.1% to about 5% of a surface-active agent, about 0.01% to about 5% of at least one polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent, and water; and a liquefied or compressed gas propellant at a concentration of about 3% to about 25% of the total composition.

[0009] According to further embodiments of the present invention, the foamable composition is selected from the group consisting of an oil-in-water emulsion and a water-in-oil emulsion.

[0010] According to still further embodiments of the present invention, the foamable composition further includes about 0.1% to about 5% by weight of a foam adjuvant is selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid having 16 or more carbons in their carbon chain; a fatty alcohol, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain; a fatty alcohol having at least one double bond; a fatty acid having at least one double bond; a branched fatty alcohol; a branched fatty acid; a fatty acid substituted with a hydroxyl group; cetyl alcohol; stearyl alcohol; arachidyl alcohol; behenyl alcohol; 1-triacontanol; hexadecanoic acid; stearic 3 US1DOCS 5559587v1 I acid; arachidic acid; behenic acid; octacosanoic acid; 12-hydroxy stearic acid and any mixture thereof.

[0011] According to yet further embodiments of the present invention, the foamable composition is substantially alcohol-free.

[0012] According to further embodiments of the present invention, the active agent is 00 selected from the group consisting of: an anticholinergic drugs, an agent, selected from r the group consisting of boric acid, tannic acid, resorcinol, potassium permanganate, Sformaldehyde, glutaraldehyde and methenamine, a Lewis acid, a salt or a complex of a \O metal ion, capable of treating hyperhidrosis, a salt or a complex of a metal ion such as 0 aluminum and zirconium, a salt or a complex of a metal selected from the group consisting of aluminum and zirconium, a 5-alpha-reductase inhibitor, an agent, selected from the group consisting of finasteride, flutamide, spironolactone, saw palmetto extract, epristeride and cholestan-3-one, an agent, capable of treating hyperhidrosis, selected from the group consisting of mono- and dicarboxylic acids having 4 to 18 carbon atoms, a mercapto derivative thereof, a salt thereof, and an ester thereof, botulinum toxin, a HT2C receptor antagonist, an agent, selected from the group consisting of ketanserin, ritanserin, mianserin, mesulergine, cyproheptadine, fluoxetine, mirtazapine, olanzapine, and ziprasidone, and a 5-HT2C receptor modulator, an antiperspirant.

[0013] According to still further embodiments of the present invention, the foamable composition further comprises at least one additional therapeutic agent selected from the group consisting of an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, a steroid, a non-steroidal antiinflammatory agent, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, an allergen, an immunogenic substance, a 4 US1DOCS 5559587v1 I haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid, sebacic O acid, adipic acid, fumaric acid, a retinoid, an antiproliferative agent, an anticancer agent, a photodynamic therapy agent, benzoyl chloride, calcium hypochlorite, magnesium hypochlorite, an anti-wrinkle agent, a radical scavenger, a metal, silver, a metal oxide, titanium dioxide, zinc oxide, zirconium oxide, iron oxide, silicone oxide, talc, carbon, an 0 anti wrinkle agent, a skin whitening agent, a skin protective agent, a masking agent, an anti-wart agent, a refatting agent, a lubricating agent and any mixture thereof.

00 00 [0014] According to yet further embodiments of the present invention, the Sconcentration of the surface active agent is between about 0.1% and about [0015] According to further embodiments of the present invention, the polymeric agent is selected from the group consisting of a water-soluble cellulose ether and a naturally-occurring polymeric material.

[0016] According to yet further embodiments of the present invention, the watersoluble cellulose ether is selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (Methocel), hydroxyethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose, xanthan gum, guar gum, carrageenin gum, locust bean gum and tragacanth gum.

[0017] According to further embodiments of the present invention, there is provided a method of treating, alleviating or preventing a disorder of the skin, a body cavity or mucosal surface, wherein the disorder involves excessive sweating as one of its symptoms, including: administering topically to a subject having the disorder, a foamed composition including: an active agent, suitable for the treatment or prevention of hyperhidrosis, about 2% to about 50% by weight of an organic carrier selected from the group consisting of a hydrophobic organic carrier, a polar solvent, an emollient and any mixture thereof, about 0.1% to about 5% by weight of a surface-active agent, about 0.01% to about 5% by weight of a polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent, US1DOCS 5559587v1 Sand water, wherein the active agent is administered in a therapeutically effective Samount.

[0018] According to further embodiments of the method according present invention, the composition further comprises about 0.1% to about 5% by weight of a foam adjuvant is selected from the group consisting of a fatty alcohol having 15 or more carbons in Stheir carbon chain, a fatty acid having 16 or more carbons in their carbon chain, fatty alcohols, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain, a fatty alcohol having at least one double bond, a fatty acid having at least one double bond, a branched fatty alcohol, a branched fatty acid, a fatty acid substituted with a hydroxyl group, cetyl alcohol, stearyl Salcohol, arachidyl alcohol, behenyl alcohol, 1-triacontanol, hexadecanoic acid, stearic Sacid, arachidic acid, behenic acid, octacosanoic acid, 12-hydroxy stearic acid and any mixture thereof.

[0019] According to still further embodiments of the method according present invention, the composition further comprises at least one additional therapeutic agent.

[0020] According to still further embodiments of the method according present invention, the disorder is selected from the group consisting of a dermatose, a dermatitis, a vaginal disorder, a vulvar disorder, an anal disorder, a disorder of a body cavity, an ear disorder, a disorder of the nose, a disorder of the respiratory system, a bacterial infection, fungal infection, viral infection, dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, post-operative or post-surgical skin conditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, erythema nodosum, grannuloma annulare, epidermal necrolysis, sunburn, photosensitivity, 6 US1DOCS 5559587v1 pemphigus, bullous pemphigoid, dermatitis herpetiformis, keratosis pilaris, callouses, 0 corns, ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi's Ssarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact dermatitis, atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, baldness, alopecia, Behcet's syndrome, Scholesteatoma, Dercum disease, ectodermal dysplasia, gustatory sweating, nail patella Ssyndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical or thermal skin burns, scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis, necrotizing 00oo Smyositis, gangrene, scarring, and vitiligo.

(N

I DETAILED DESCRIPTION OF THE INVENTION [0021] The present invention provides a foamable therapeutic composition for administration to the skin, a body surface, a body cavity or mucosal surface, the mucosa of the nose, mouth, eye, ear, respiratory system, vagina or rectum (severally and interchangeably termed herein "target site") includes: an active agent, suitable for the treatment or prevention of hyperhidrosis; at least one organic carrier selected from the group consisting of a hydrophobic organic carrier, a polar solvent, an emollient and any mixture thereof, at a concentration of about 2% to about 50% by weight; about 0.1% to about 5% by weight of a surface-active agent; about 0.01% to about 5% by weight of at least one polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; and a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.

[0022] Water and optional ingredients are added to complete the total mass to 100%. Upon release from an aerosol container, the foamable composition forms an expanded foam suitable for topical administration.

7 US1DOCS 5559587v1 [0023] According to one or more embodiments, the foamable composition is 0 substantially alcohol-free, free of short chain alcohols. Short chain alcohols, having

(N

up to 5 carbon atoms in their carbon chain skeleton and one hydroxyl group, such as ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol and pentanol, are considered less desirable solvents or polar solvents due to their skin-irritating effect.

0 Thus, the composition is substantially alcohol-free and includes less than about 5% final concentration of lower alcohols, preferably less than about more preferably less than about 1%.

[0024] The active agent, suitable for the treatment or prevention of hyperhidrosis, is selected from the group consisting of an anticholinergic drug, a boric acid, a tannic acid, c- a resorcinol, a potassium permanganate, a formaldehyde, a glutaraldehyde and a methenamine. In one or more embodiments the agents for the treatment of hyperhidrosis is a Lewis acid. Typically, the Lewis acid is a partially neutralized salt of metal ions such as aluminum and zirconium. Exemplary metal ion salts, suitable to reduce hyperhidrosis are aluminum chloride; aluminum and/or zirconium chlorohydrates; aluminum-zirconium-Glycine (AZG) complexes; and aluminum hydroxybromide, which are typicall included in antiperspirant preparations. The aluminum ions act by penetrating into eccrine-gland ducts at the opening of the epidermis. When the aluminum ions are drawn into the cells, water passes in with them.

As more water flows in, the cells begin to swell, squeezing the ducts closed so that sweat cannot get out. In one or more embodiments, the agents for the treatment of hyperhidrosis is a glycopyrrolate compound. In one or more embodiments, the agents for the treatment of hyperhidrosis is a 5-alpha-reductase inhibitor. Examples of reductase inhibitors include, but are not limited to finasteride, epristeride, flutamide, spironolactone, saw palmetto extract, and cholestan-3-one. In one or more embodiments, the agents for the treatment of hyperhidrosis is selected from the group consisting of a mono- and dicarboxylic acid having 4 to 18 carbon atoms, a mercapto derivative thereof, a salts thereof, and an ester thereof. In one or more embodiments, the agents for the treatment of hyperhidrosis is botulinum toxin. In one or more embodiments, the agents for the treatment of hyperhidrosis consists of a 5-HT2C receptor antagonist. Examples of 5-HT2C receptor antagonist include, but are not 8 US1DOCS 5559587v1 limited to ketanserin, ritanserin, mianserin, mesulergine, cyproheptadine, fluoxetine,

O

0 mirtazapine, olanzapine, and ziprasidone. Yet, another class of agents for the treatment of hyperhidrosis includes 5-HT2C receptor modulators inverse agonists, partial Sagonists, and allosteric modulators).

S[0025] The foamable composition of the present invention can be an emulsion, or microemulsion, including an aqueous phase and an organic carrier phase. The organic 00 carrier is selected from the group consisting of a hydrophobic organic carrier (also Stermed herein "hydrophobic solvent"), an emollient, a polar solvent, and any mixture N thereof. The identification of a organic carrier or "solvent", as used herein, is not Sintended to characterize the solubilization capabilities of the solvent for any specific c active agent or any other component of the foamable composition. Rather, such information is provided to aid in the identification of materials suitable for use as an organic carrier in the foamable compositions described herein.

[0026] A "hydrophobic organic carrier" as used herein refers to a material having solubility in distilled water at ambient temperature of less than about 1 gm per 100 mL, more preferable less than about 0.5 gm per 100 mL, and most preferably less than about 0.1 gm per 100 mL. It is liquid at ambient temperature.

[0027] In one or more embodiments, the hydrophobic organic carrier is an oil, such as mineral oil. According to one or more embodiments, hydrophobic solvents are liquid oils originating from vegetable, marine or animal sources. Suitable liquid oil includes saturated, unsaturated or polyunsaturated oils. By way of example, the unsaturated oil may be olive oil, corn oil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil, codliver oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose oils or any mixture thereof, in any proportion.

[0028] Suitable hydrophobic solvents also include polyunsaturated oils containing poly-unsaturated fatty acids. In one or more embodiments, the unsaturated fatty acids are selected from the group consisting of an omega-3 fatty acid and a omega-6 fatty acid. Examples of such polyunsaturated fatty acids are linoleic and linolenic acid, 9 US1DOCS 5559587v1 Sgamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid C (DHA). Such unsaturated fatty acids are known for their skin-conditioning effect, which contribute to the therapeutic benefit of the present foamable composition. Thus, the Shydrophobic solvent can include at least 6% of an oil selected from the group consisting of an omega-3 oil, an omega-6 oil, and any mixture thereof. In the context of the present invention, oils that possess therapeutically-beneficial properties are termed "therapeutically active oil".

r- 0 [0029] Another class of hydrophobic solvents is the essential oils, which are also considered therapeutically active oil, which contain active biologically occurring molecules and, upon topical application, exert a therapeutic effect, which is conceivably synergistic to the beneficial effect of the NSAID in the composition.

[0030] Another class of therapeutically active oils includes liquid hydrophobic plantderived oils, which are known to possess therapeutic benefits when applied topically.

[0031] Silicone oils also may be used and are desirable due to their known skin protective and occlusive properties. Suitable silicone oils include non-volatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers, polydimethylsiloxanes (dimethicones) and poly(dimethylsiloxane)- (diphenyl-siloxane) copolymers. These are chosen from cyclic or linear polydimethylsiloxanes containing from about 3 to about 9. Volatile silicones such as cyclomethicones can also be used. Silicone oils are also considered therapeutically active oil, due to their barrier retaining and protective properties.

[0032] In one or more embodiments, the hydrophobic carrier includes at least 2% by weight silicone oil or at least 5% by weight.

[0033] The solvent may be a mixture of two or more of the above hydrophobic solvents in any proportion.

[0034] A further class of solvents includes "emollients" that have a softening or soothing effect, especially when applied to body areas, such as the skin and mucosal surfaces. Emollients are not necessarily hydrophobic. Examples of suitable emollients US1DOCS 5559587v1 include hexyleneglycol, propylene glycol, isostearic acid derivatives, isopropyl palmitate, 0 isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin Salcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat .germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol Sricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol 0dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, sucrose esters of fatty acids, octyl 00o g hydroxystearate and any mixture thereof.

(N

S[0035] According to one or more embodiments of the present invention, the Shydrophobic organic carrier includes a mixture of a hydrophobic solvent and an emollient. According to one or more embodiments, the foamable composition is a mixture of mineral oil and an emollient in a ratio between 2:8 and 8:2 on a weight basis.

[0036] A "polar solvent" is an organic solvent, typically soluble in both water and oil.

Examples of polar solvents include polyols, such as glycerol (glycerin), propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, other glycols, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, dimethylisosorbide, monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide units), azone (1 -dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, esters, such as isopropyl myristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate, capric/caprylic triglycerides, octylmyristate, dodecylmyristate; myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketones; amides, such as acetamide oleates such as triolein; various alkanoic acids such as caprylic acid; lactam compounds, such as azone; alkanols, such as dialkylamino acetates, and admixtures thereof.

[0037] According to one or more embodiments, the polar solvent is a polyethylene glycol (PEG) or PEG derivative that is liquid at ambient temperature.

11 US1DOCS 5559587v1 [0038] The polymeric agent serves to stabilize the foam composition and to control 0 drug residence in the target organ. Exemplary polymeric agents, are classified below in a non-limiting manner. In certain cases, a given polymer can belong to more than one Sof the classes provided below.

C [0039] In one or more embodiments, the polymeric agent is a gelling agent. A gelling agent controls the residence of a therapeutic composition in the target site of 00 treatment by increasing the viscosity of the composition, thereby limiting the rate of its r'- 0 clearance from the site. Many gelling agents are known in the art to possess mucoadhesive properties.

O

0 [0040] The gelling agent can be a natural gelling agent, a synthetic gelling agent and an inorganic gelling agent. Exemplary gelling agents that can be used in accordance with one or more embodiments of the present invention include, for example, naturallyoccurring polymeric materials, such as locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, starch, chemically modified starches and the like, semi-synthetic polymeric materials such as cellulose ethers (e.g.

hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy propylmethyl cellulose), guar gum, hydroxypropyl guar gum, soluble starch, cationic celluloses, cationic guars, and the like, and synthetic polymeric materials, such as carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like. Mixtures of the above compounds are contemplated.

[0041] Further exemplary gelling agents include the acrylic acid/ethyl acrylate copolymers and the carboxyvinyl polymers sold, for example, by the B.F. Goodrich Company under the trademark of Carbopol® resins. These resins consist essentially of a colloidal water-soluble polyalkenyl polyether crosslinked polymer of acrylic acid crosslinked with from 0.75% to 2% of a crosslinking agent such as polyallyl sucrose or polyallyl pentaerythritol. Examples include Carbopol® 934, Carbopol® 940, Carbopol® 12 US1DOCS 5559587v1 IN 950, Carbopol® 980, Carbopol® 951 and Carbopol® 981. Carbopol® 934 is a watersoluble polymer of acrylic acid crosslinked with about 1% of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each sucrose molecule.

[0042] In one or more embodiment, the composition of the present invention includes Sat least one polymeric agent, which is a water-soluble cellulose ether. Preferably, the water-soluble cellulose ether is selected from the group consisting of methylcellulose, 00 hydroxypropyl cellulose, hydroxypropyl methylcellulose (Methocel), hydroxyethyl 0 cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethylcellulose and O carboxymethylhydroxyethylcellulose. More preferably, the water-soluble cellulose ether is selected from the group consisting of methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose (Methocel). In one or more embodiments, the composition includes a combination of a water-soluble cellulose ether; and a naturallyoccurring polymeric materials, selected from the group consisting of a xanthan gum, guar gum, carrageenan gum, locust bean gum and tragacanth gum.

[0043] Yet, in other embodiments, the gelling agent includes inorganic gelling agents, such as silicone dioxide (fumed silica).

[0044] Mucoadhesive/bioadhesion has been defined as the attachment of synthetic or biological macromolecules to a biological tissue. Mucoadhesive agents are a class of polymeric biomaterials that exhibit the basic characteristic of a hydrogel, i.e. swell by absorbing water and interacting by means of adhesion with the mucous that covers epithelia. Compositions of the present invention may contain a mucoadhesive macromolecule or polymer in an amount sufficient to confer bioadhesive properties.

The bioadhesive macromolecule enhances the delivery of biologically active agents on or through the target surface. The mucoadhesive macromolecule may be selected from the group consisting of an acidic synthetic polymer, preferably including at least one acidic group per four repeating or monomeric subunit moieties, such as poly(acrylic)and/or poly(methacrylic) acid Carbopol®, Carbomer®), poly(methylvinyl ether/maleic anhydride) copolymer, a mixture thereof and copolymers copylmers; acidic 13 US1DOCS 5559587v1 Ssynthetically modified natural polymers, such as carboxymethylcellulose (CMC); neutral synthetically modified natural polymers, such as (hydroxypropyl)methylcellulose; basic Samine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth, and karaya gum; and neutral synthetic polymers, such as polyvinyl alcohol or their mixtures. An O additional group of mucoadhesive polymers includes natural and chemically modified 0cyclodextrin, especially hydroxypropyl-P-cyclodextrin. Such polymers may be present r- as free acids, bases, or salts, usually in a final concentration of about 0.01% to about by weight.

O [0045] A suitable bioadhesive macromolecule is the family of acrylic acid polymers Sand copolymers, Carbopol®). These polymers contain the general structure

[CH

2 -CH(COOH)-]n. Hyaluronic acid and other biologically-derived polymers may be used.

[0046] Exemplary bioadhesive or mucoadhesive macromolecules have a molecular weight of at least 50 kDa, or at least 300 kDa, or at least 1,000 kDa. Favored polymeric ionizable macromolecules have not less than 2 mole percent acidic groups COOH, SO 3 H) or basic groups (NH 2 NRH, NR 2 relative to the number of monomeric units. The acidic or basic groups can constitute at least 5 mole percent, or at least mole percent, or at least 25, at least 50 more percent, or even up to 100 mole percent relative to the number of monomeric units of the macromolecule.

[0047] Yet, another group of mucoadhesive agent includes inorganic gelling agents such as silicon dioxide (fumed silica), including but not limited to, AEROSIL 200

(DEGUSSA).

[0048] Many mucoadhesive agents are known in the art to also possess gelling properties.

[0049] The foam composition may contain a film forming component. The film forming component may include at least one water-insoluble alkyl cellulose or hydroxyalkyl cellulose. Exemplary alkyl cellulose or hydroxyalkyl cellulose polymers 14 US1DOCS 5559587v1 I include ethyl cellulose, propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropyl O cellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose, alone or in combination. In addition, a plasticizer or a cross linking agent may be used to modify the polymer's characteristics. For example, esters such as dibutyl or diethyl phthalate, amides such as diethyldiphenyl urea, vegetable oils, fatty acids and alcohols such as 0 oleic and myristyl acid may be used in combination with the cellulose derivative.

oo [0050] In one or more embodiments, the composition of the present invention r'- 00 includes a phase change polymer, which alters the composition behavior from fluid-like 0 prior to administration to solid-like upon contact with the target mucosal surface. Such phase change results from external stimuli, such as changes in temperature or pH and Sexposure to specific ions Ca 2 [0051] Non-limiting examples of phase change polymers include poly(Nisopropylamide) and Poloxamer 407®.

[0052] The polymeric agent is present in an amount in the range of about 0.01% to about 5.0% by weight of the foam composition. In one or more embodiments, it is typically less than about 1 wt% of the foamable composition.

[0053] Surface-active agents (also termed "surfactants") include any agent linking oil and water in the composition, in the form of emulsion. A surfactant's hydrophilic/lipophilic balance (HLB) describes the emulsifier's affinity toward water or oil.

The HLB scale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic), with representing an equal balance of both characteristics. Lipophilic emulsifiers form waterin-oil emulsions; hydrophilic surfactants form oil-in-water emulsions. The HLB of a blend of two emulsifiers equals the weight fraction of emulsifier A times its HLB value plus the weight fraction of emulsifier B times its HLB value (weighted average).

[0054] According to one or more embodiments of the present invention, the surfaceactive agent has a hydrophilic lipophilic balance (HLB) between about 9 and about 14, which is the required HLB (the HLB required to stabilize an O/W emulsion of a given oil) US1DOCS 5559587v1 N of most oils and hydrophobic solvents. Thus, in one or more embodiments, the composition contains a single surface active agent having an HLB value between about 9 and 14, and in one or more embodiments, the composition contains more than one surface active agent and the weighted average of their HLB values is between about 9 and about 14. Yet, in other embodiments, when a water in oil emulsion is desirable, the C composition contains one or more surface active agents, having an HLB value between about 2 and about 9.

00 0o [0055] The surface-active agent is selected from group consisting of an anionic Ssurfactant, a cationic surfactant, a nonionic surfactant, a zwitterionic surfactant, an O amphoteric surfactant, an ampholytic surfactant, and an mixture thereof. Such Ssurfactants are well known to those skilled in the therapeutic and cosmetic formulation art. Nonlimiting examples of possible surfactants include polysorbates, such as polyoxyethylene (20) sorbitan monostearate (Tween 60) and poly(oxyethylene) sorbitan monooleate (Tween 80); poly(oxyethylene) (POE) fatty acid esters, such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1; sucrose esters, partial esters of sorbitol and its anhydrides, such as sorbitan monolaurate and sorbitan monolaurate; mono or diglycerides, isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, triethanolamine lauryl sulfate and betaines.

[0056] In one or more embodiments of the present invention, the surface-active agent includes at least one non-ionic surfactant. Ionic surfactants are known to be irritants. Therefore, non-ionic surfactants are preferred in applications including sensitive tissue such as found in most mucosal tissues, especially when they are infected or inflamed. We have surprisingly found that non-ionic surfactants alone provide foams of excellent quality, i.e. a score of according to the grading scale discussed herein below.

16 US1DOCS 5559587v [0057] In one or more embodiments, the surface active agent includes a mixture of Sat least one non-ionic surfactant and at least one ionic surfactant in a ratio in the range Sof about 100:1 to 6:1. In one or more embodiments, the non-ionic to ionic surfactant ratio is greater than about 6:1, or greater than about 8:1; or greater than about 14:1, or Sgreater than about 16:1, or greater than about 20:1.

[0058] In one or more embodiments of the present invention, a combination of a non- 0 ionic surfactant and an ionic surfactant (such as sodium lauryl sulphate and Scocamidopropylbetaine) is employed, at a ratio of between 1:1 and 20:1, or at a ratio of 4:1 to 10:1. The resultant foam has a low specific gravity, less than 0.lg/ml.

IND

S[0059] It has been surprisingly discovered that the stability of the composition is especially pronounced when a combination of at least one non-ionic surfactant having HLB of less than 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed. The ratio between the at least one non-ionic surfactant having HLB of less than 9 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 4:1 to 1:4. The resultant HLB of such a blend of at least two emulsifiers is between about 9 and about 14.

[0060] Thus, in an exemplary embodiment, a combination of at least one non-ionic surfactant having HLB of lessthan 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed, at a ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein the HLB of the combination of emulsifiers is between about 9 and about 14.

[0061] In one or more embodiments of the present invention, the surface-active agent includes mono-, di- and tri-esters of sucrose with fatty acids (sucrose esters), prepared from sucrose and esters of fatty acids or by extraction from sucro-glycerides.

Suitable sucrose esters include those having high monoester content, which have higher HLB values.

[0062] The total surface active agent is in the range of about 0.1 to about 5% of the foamable composition, and is typically less than about 2% or less than about 1%.

17 US1DOCS 5559587vl [0063] Optionally, a foam adjuvant is included in the foamable compositions of the 0 present invention to increase the foaming capacity of surfactants and/or to stabilize the foam. In one or more embodiments of the present invention, the foam adjuvant agent includes fatty alcohols having 15 or more carbons in their carbon chain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof). Other examples of fatty alcohols are 0 arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well as alcohols with longer carbon chains (up to C50). Foam adjuvants, as defined herein are also useful in facilitating improved spreadability and absorption of the composition.

S[0064] In one or more embodiments of the present invention, the foam adjuvant agent includes fatty acids having 16 or more carbons in their carbon chain, such as Shexadecanoic acid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22), octacosanoic acid (C28), as well as fatty acids with longer carbon chains (up to C50), or mixtures thereof. As for fatty alcohols, the amount of fatty acids required to support the foam system is inversely related to the length of its carbon chain.

[0065] In one or more embodiments, a combination of a fatty acid and a fatty ester is employed.

[0066] Optionally, the carbon atom chain of the fatty alcohol or the fatty acid may have at least one double bond. A further class of foam adjuvant agent includes a branched fatty alcohol or fatty acid. The carbon chain of the fatty acid or fatty alcohol also can be substituted with a hydroxyl group, such as 12-hydroxy stearic acid.

[0067] An important property of the fatty alcohols and fatty acids used in context of the composition of the present invention is related to their therapeutic properties per se.

Long chain saturated and mono unsaturated fatty alcohols, stearyl alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol (docosanol) have been reported to possess antiviral, antiinfective, antiproliferative and antiinflammatory properties (see, for example, U.S. Patent No. 4,874,794). Longer chain fatty alcohols, tetracosanol, hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are also known for their metabolism modifying properties and tissue energizing properties. Long chain fatty acids have also been reported to possess anti-infective characteristics.

18 US1DOCS 5559587v1 S[0068] Thus, in preferred embodiments of the present invention, a combined and enhanced therapeutic effect is attained by including both a nonsteroidal immunomodulating agent and a therapeutically effective foam adjuvant in the same composition, thus providing a simultaneous anti-inflammatory and antiinfective effect from both components. Furthermore, in a further preferred embodiment, the Scomposition concurrently comprises an active agent, suitable for the treatment of 0hyperhidrosis and a therapeutically effective foam adjuvant and a therapeutically active oil, as detailed above. Such combination provides an even more enhanced therapeutic 00 benefit. Thus, the foamable carrier, containing the foam adjuvant provides an extra Stherapeutic benefit in comparison with currently used vehicles, which are inert and non- Sactive.

[0069] The foam adjuvant amount is about 0.1% to about 5% of the composition mass.

[0070] Since hyperhidrosis is often associated with an underlying disorder, a combination of an agent, suitable for the treatment of hyperhidrosis and an additional active agent, suitable for the treatment of the underlying disorder or another disorder which substantially concurrently occurs in the same patient is useful for simultaneous therapy of the patient's condition.

[0071] In one or more embodiments, the additional therapeutic agent is selected from the group consisting of an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, a steroidal antiinflammatory agent, a nonsterolidal anti-inflammatory agent, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, vitamin A, a vitamin A derivative, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, a allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic 19 US1DOCS 5559587v1 IND acid, sebacic acid, adipic acid, fumaric acid, a retinoid, an antiproliferative agent, an 0 anticancer agent, a photodynamic therapy agent, an anti-wrinkle agent, a radical scavenger, a metal oxide titanium dioxide, zinc oxide, zirconium oxide, iron oxide), silicone oxide, an anti wrinkle agent, a skin whitening agent, a skin protective agent, a masking agent, an anti-wart agent, a refatting agent, a lubricating agent and any mixture 0 thereof.

00 [0072] The therapeutic foam of the present invention may further optionally include a 00 variety of formulation excipients, which are added in order to fine-tune the consistency of the formulation, protect the formulation components from degradation and oxidation and modify their consistency. Such excipients may be selected, for example, from Sstabilizing agents, antioxidants, humectants, preservatives, colorant and odorant agents and other formulation components, used in the art of formulation.

[0073] Aerosol propellants are used to generate and administer the foamable composition as a foam. The total composition including propellant, foamable compositions and optional ingredients is referred to as the foamable carrier. The propellant makes up about 3% to about 25 wt% of the foamable carrier. Examples of suitable propellants include volatile hydrocarbons such as butane, propane, isobutane or mixtures thereof, and fluorocarbon gases.

Composition and Foam Physical Characteristics [0074] A pharmaceutical or cosmetic composition manufactured using the foam carrier according to one or more embodiments of the present invention is very easy to use. When applied onto the afflicted body surface of mammals, humans or animals, it is in a foam state, allowing free application without spillage. Upon further application of a mechanical force, by gently rubbing the composition onto the body surface, it freely spreads on the surface and is rapidly absorbed.

[0075] The foam composition of the present invention creates a stable emulsion having an acceptable shelf-life of at least one year, or at least two years at ambient temperature. A feature of a product for cosmetic or medical use is long term stability.

US1DOCS 5559587v1 IND Propellants, which are a mixture of low molecular weight hydrocarbons, tend to impair 0 C the stability of emulsions. It has been observed, however, .that emulsion foam compositions according to the present invention are surprisingly stable. Following accelerated stability studies, they demonstrate desirable texture; they form fine bubble structures that do not break immediately upon contact with a surface, spread easily on C the treated area and absorb quickly.

00 [0076] The composition should also be free flowing, to allow it to flow through the r'- 00 aperture of the container, and aerosol container, and create an acceptable foam.

SCompositions containing semi-solid hydrophobic solvents, white petrolatum, as the main ingredients of the oil phase of the emulsion, exhibit high viscosity and poor N flowability and are inappropriate candidates for a foamable composition.

[0077] Foam quality can be graded as follows: Grade E (excellent): very rich and creamy in appearance, does not show any bubble structure or shows a very fine (small) bubble structure; does not rapidly become dull; upon spreading on the skin, the foam retains the creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size, "dulls" more rapidly than an excellent foam, retains creaminess upon spreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable, bubble structure is noticeable; upon spreading on the skin the product dulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubble structure than a "fairly good" foam, upon spreading on the skin it becomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, and when spread on the skin it becomes very thin and watery in appearance.

21 US1DOCS 5559587v IDGrade VP (very poor): dry foam, large very dull bubbles, difficult to spread on 0 Sthe skin.

S[0078] Topically administratable foams are typically of quality grade E or G, when released from the aerosol container. Smaller bubbles are indicative of more stable Sfoam, which does not collapse spontaneously immediately upon discharge from the container. The finer foam structure looks and feels smoother, thus increasing its 00 usability and appeal.

00 [0079] As further aspect of the foam is breakability. The breakable foam is thermally stable, yet breaks under sheer force. Sheer-force breakability of the foam is clearly C advantageous over thermally-induced breakability. Thermally sensitive foams immediately collapse upon exposure to skin temperature and, therefore, cannot be applied on the hand and afterwards delivered to the afflicted area.

[0080] Another property of the foam is specific gravity, as measured upon release from the aerosol can. Typically, foams have specific gravity of less than 0.1 g/mL or less than 0.05 g/mL.

Fields of Pharmaceutical Applications [0081] Hyperhidrosis is excessive sweating. Sweating is a natural phenomenon necessary for the regulation of an individual's body-temperature. The secretion of sweat is mediated by a portion of our vegetative nervous system (the Sympathetic Nervous System). In some people, this system is working at a very high activity level, far higher than needed to keep a constant temperature. This condition is referred to as hyperhidrosis.

[0082] The composition of the present invention is suitable for the treatment of primary hyperhidrosis; hyperhidrosis with an unknown cause (idiopathic). The composition is also useful in secondary hyperhidrosis, wherein the hyperhidrosis is part of an underlying condition. Exemplary conditions that can involve and/or promote excessive sweating, typically involving the whole body, include hyperthyroidism or 22 US1DOCS 5559587v1 similar endocrine disorders; endocrine treatment for prostatic cancer or other types of 0 malignant disorder; severe psychiatric disorders; obesity and menopause.

[0083] Thus, the foamable composition of the present invention is suitable for Streating facial hyperhidrosis (sweat pouring down from the forehead); palmar C hyperhidrosis (excessive sweating of the hands); axillary hyperhidrosis (hyperhidrosis of the armpits); plantar hyperhidrosis; hyperhidrosis of the trunk and/or the thighs; and oo facial hyperhidrosis; and any combination of them.

00 C [0084] According to a survey conducted by the International Hyperhidrosis Society

(N

O (IHHS) other "sweat inducing" circumstances include: eating spicy foods public 0 0 speaking getting test results from a doctor taking an important test flying in an airplane telling a lie and returning a purchase to a store [0085] In one or more embodiments, the foamable composition of the present invention is suitable for preventing or reducing the extent of excessive sweating.

[0086] In one or more embodiments, the foamable composition of the present invention is suitable an antiperspirant. In the context of the present invention, an antiperspirant effect is analogous to an effect against hyperhidrosis.

[0087] In certain embodiments, the foamable composition of the present invention is suitable for alleviating the smell, associated with excessive sweating.

[0088] Since secondary hyperhidrosis is invariably associated with an underlying disorder, a combination of an agent, suitable for the treatment of hyperhidrosis and an additional active agent, suitable for the treatment of the underlying disorder or another disorder which substantially concurrently occurs in the same patient is useful for simultaneous therapy of the patient's condition. By combining an appropriate antihyperhidrosis agent and optional active agents in the composition of the present invention, the composition is useful in treating a patient having any one of a variety of dermatological disorders, which include hyperydrosis as one or their symptoms, such as dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne 23 US1DOCS 5559587v1 I conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin O infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma, C yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, postoperative or post-surgical skin conditions, scabies, pediculosis, creeping eruption, 00 r- eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, erythema nodosum, grannuloma annulare, epidermal necrolysis, c sunburn, photosensitivity, pemphigus, bullous pemphigoid, dermatitis herpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skin ulcers, ischemic necrosis, miliaria, Shyperhidrosis, moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact dermatitis, atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermal dysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical or thermal skin burns, scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis, necrotizing myositis, gangrene, scarring, and vitiligo.

Example 1 -Oil in water foamable compositions including agents suitable for the treatment of hyperhidrosis 24 US1DOCS 5559587v1 Composition No: AZ-1 AC-2 ZC-3 BT-4 Ingredient Azelaic acid 15.00 Aluminum chloride 10.00 Zirconium chloride 10.00 Botulism toxin 2.00 Mineral oil 5.60 5.60 5.60 5.60 Isopropyl palmitate 5.60 5.60 5.60 5.60 Sorbitan stearate (Span 60) 2.00 2.00 2.00 2.00 ether 1.00 1.00 1.00 1.00 Stearic acid 0 0 0.85 0.85 Stearyl alcohol 0.85 0.85 Glyceryl monostearate 0.45 0.45 0.45 0.45 Xanthan gum 0.26 0.26 0.26 0.26 Methocel K100M 0.26 0.26 0 0 Preservative 0.25 0.25 0.25 0.25 Water To 100 To 100 To 100 To 100 Propellant 10.00 10.00 10.00 10.00 US1DOCS 5559587v

Claims (11)

1. 2. The therapeutic foamable composition of claim 1, wherein the foamable composition is selected from the group consisting of an oil-in-water emulsion and a water-in-oil emulsion.
2. 3. The therapeutic foamable composition of claim 1, further including about 0.1% to about 5% by weight of a foam adjuvant is selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid having 16 or more carbons in their carbon chain; a fatty alcohol, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain; a fatty alcohol having at least one double bond; a fatty acid having at least one double bond; a branched fatty alcohol; a branched fatty acid; a fatty acid substituted with a hydroxyl group; cetyl alcohol; stearyl alcohol; arachidyl alcohol; behenyl alcohol; 1-triacontanol; hexadecanoic acid; stearic acid; arachidic acid; behenic acid; octacosanoic acid; 12-hydroxy stearic acid and any mixture thereof.
3. 4. The therapeutic foamable composition of claim 1, wherein the foamable composition is substantially alcohol-free. 26 US1DOCS 5559587v1 I 5. The therapeutic foamable composition of claim 1, wherein the active agent is O 0 selected from the group consisting of: An anticholinergic drugs; S(ii) An agent, selected from the group consisting of boric acid, tannic acid, resorcinol, potassium permanganate, formaldehyde, glutaraldehyde and oo methenamine; r- (iii) a Lewis acid; I0 (iv) a salt or a complex of a metal ion, capable of treating hyperhidrosis; a salt or a complex of a metal ion such as aluminum and zirconium; (vi) a salt or a complex of a metal selected from the group consisting of aluminum and zirconium; (vii) a 5-alpha-reductase inhibitor. (viii) an agent, selected from the group consisting of finasteride, flutamide, spironolactone, saw palmetto extract, epristeride and cholestan-3-one. (ix) an agent- capable of treating hyperhidrosis, selected from the group consisting of mono- and dicarboxylic acids having 4 to 18 carbon atoms, a mercapto derivative thereof, a salt thereof, and an ester thereof. botulinum toxin; (xi) a 5-HT2C receptor antagonist; (xii) an agent, selected from the group consisting of ketanserin, ritanserin, mianserin, mesulergine, cyproheptadine, fluoxetine, mirtazapine, olanzapine, and ziprasidone; and (xiii) a 5-HT2C receptor modulator. 27 US1DOCS 5559587v1 a a. N (xiv) an antiperspirant O c 6. The therapeutic foamable composition of claim 1, wherein the foamable composition Sfurther comprises at least one additional therapeutic agent selected from the group consisting of an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, a steroid, a non-steroidal antiinflammatory agent, an immunosuppressive agent, an immunomodulator, an 00 immunoregulating agent, a hormonal agent, vitamin A, a vitamin A derivative, 00 vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a 0 vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a disinfectant, c an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, an allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaric acid, a retinoid, an antiproliferative agent, an anticancer agent, a photodynamic therapy agent, benzoyl chloride, calcium hypochlorite, magnesium hypochlorite, an anti-wrinkle agent, a radical scavenger, a metal, silver, a metal oxide, titanium dioxide, zinc oxide, zirconium oxide, iron oxide, silicone oxide, talc, carbon, an anti wrinkle agent, a skin whitening agent, a skin protective agent, a masking agent, an anti-wart agent, a refatting agent, a lubricating agent and any mixture thereof.
4. 7. The therapeutic foamable composition of claim 1, wherein the concentration of the surface active agent is between about 0.1% and about
5. 8. The therapeutic foamable composition of claim 1, wherein the surface active agent includes a mixture of at least one non-ionic surfactant and at least one ionic surfactant in a ratio in the range of about 100:1 to 6:1.
6. 9. The therapeutic foamable composition of claim 1, wherein the surface active agent is exclusively non-ionic. The therapeutic foamable composition of claim 2, wherein the emulsion is a water- in-oil emulsion and wherein the HLB of the surface active agent is between about 9 and about 14. 28 US1DOCS 5559587v IN 11. The therapeutic foamable composition of claim 2, wherein the emulsion is an oil-in- water emulsion and wherein the HLB of the surface active agent is between about 2 and about 9. S12. The therapeutic foamable composition of claim 1, wherein the surface active agent comprises a combination of at least one non-ionic surfactant having HLB of less than 0 9 and at least one non-ionic surfactant having HLB of equal or more than 9, wherein the ratio between the at least one non-ionic surfactant having HLB of less than 9 and oo r the at least one non-ionic surfactant having HLB of equal or more than 9, is between 00oo S 1:8 and 8:1.
7. 13. The therapeutic foamable composition of claim 1, wherein the polymeric agent is 0 selected from the group consisting of a water-soluble cellulose ether and a naturally- occurring polymeric material.
8. 14.The therapeutic foamable composition of claim 13, wherein the water-soluble cellulose ether is selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (Methocel), hydroxyethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose, xanthan gum, guar gum, carrageenin gum, locust bean gum and tragacanth gum. A method of treating, alleviating or preventing a disorders of the skin, a body cavity or mucosal surface, wherein the disorder involves excessive sweating as one of its symptoms, including: administering topically to a subject having the disorder, a foamed composition including: an active agent, suitable for the treatment or prevention of hyperhidrosis; (ii) about 2% to about 50% by weight of an organic carrier selected from the group consisting of a hydrophobic organic carrier, a polar solvent, an emollient and any mixture thereof; (iii) about 0.1% to about 5% by weight of a surface-active agent; 29 US1DOCS 5559587v1 ID (iv) about 0.01% to about 5% by weight of a polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; and water, wherein the active agent is administered in a therapeutically effective amount.
9. 16. A method of treating, alleviating or preventing the symptoms of excessive sweating, 00 including: 00 administering topically to a subject having the disorder, a foamed composition ID including: an active agent, suitable for the treatment or prevention of hyperhidrosis; (ii) about 2% to about 50% by weight of an organic carrier selected from the group consisting of a hydrophobic organic carrier, a polar solvent, an emollient and any mixture thereof; (iii) about 0.1% to about 5% by weight of a surface-active agent; (iv) about 0.01% to about 5% by weight of a polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; and water, wherein the active agent is administered in a therapeutically effective amount.
10. 17. The method of claim 15 and 16, wherein the composition further comprises about 0.1 to about 5% by weight of a foam adjuvant is selected from the group consisting of a fatty alcohol having 15 or more carbons in their carbon chain; a fatty acid having 16 or more carbons in their carbon chain; fatty alcohols, derived from beeswax and including a mixture of alcohols, a majority of which has at least carbon atoms in their carbon chain; a fatty alcohol having at least one double bond; a fatty acid having at least one double bond; a branched fatty alcohol; a branched fatty acid; a fatty acid substituted with a hydroxyl group; cetyl alcohol; stearyl alcohol; arachidyl alcohol; behenyl alcohol; 1 -triacontanol; hexadecanoic acid; US 1DOCS 5559587vl IN0 stearic acid; arachidic acid; behenic acid; octacosanoic acid; 12-hydroxy stearic acid and any mixture thereof.
11. 18. The method of claim 15 and 16, wherein the composition further comprises at least one additional therapeutic agent. S19. The method of claim 18, wherein the disorder is selected from the group consisting of a dermatose, a dermatitis, a vaginal disorder, a vulvar disorder, an anal disorder, 0 a disorder of a body cavity, an ear disorder, a disorder of the nose, a disorder of the r'- 0 respiratory system, a bacterial infection, fungal infection, viral infection, dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory O acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne S conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, post-operative or post-surgical skin conditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, erythema nodosum, grannuloma annulare, epidermal necrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid, dermatitis herpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact dermatitis, atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermal dysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical or thermal skin burns, scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis, necrotizing myositis, gangrene, scarring, and vitiligo. DATED: 2 May 2006 PHILLIPS ORMONDE FITZPATRICK Attorneys for: FOAMIX LTD US1DOCS 5559587v1 z 3