GLYCEROL ETHERS VEHICLE AND PHARMACEUTICAL COMPOSITIONS THEREOF

• US 20090130029A1
• Filed: 11/21/2008
• Published: 05/21/2009
• Est. Priority Date: 11/21/2007
• Status: Abandoned Application

• Current Assignee: Foamix Pharmaceuticals, Ltd. (VYNE Therapeutics, Inc.)
• Original Assignee: Foamix Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Besonov, Alex, TAMARKIN, Dov
• Application Number:
  US12/275,532
• Publication Number:
  US 20090130029A1
• Time in Patent Office: Days
• US Class Current: 424/47
• CPC Class Codes: A61K 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• CPC Class Codes: A61K 8/046 Aerosols; Foams
• CPC Class Codes: A61K 8/345 containing more than one hydroxy group
• CPC Class Codes: A61K 8/67 Vitamins
• CPC Class Codes: A61K 9/12 Aerosols; Foams A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present disclosure teaches unique foamable vehicles or carriers comprising at least one glycerol ether, a stabilizer, and water; pharmaceutical and cosmetic compositions with potentially enhanced skin delivery and their uses.

Claims

1. A pharmaceutical or cosmetic vehicle composition comprising:

(a) less than or equal to about 75% by weight of at least one glycerol ether;

(b) at least one stabilizer selected from the group consisting of a surface-active agent, a polymeric agent and mixtures thereof;

(c) water; and

(d) about 3% to about 35% by weight of a liquefied hydrocarbon gas propellant;

wherein the polymeric agent, if present, is about 0.1% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;

wherein the composition is contained in a pressurized container; and

wherein the composition is substantially flowable and provides a breakable and thermolabile foam of fairly good to excellent quality upon release from the container.

2. The composition of claim 1, wherein the composition further comprises a carrier or solvent selected from the group consisting of an organic carrier, a hydrophilic solvent, a hydrophobic solvent, a potent solvent, a polar solvent, a silicone, an emollient, a liquid wax and mixtures thereof;

wherein the organic carrier is selected from the group consisting of mineral oil, a therapeutic oil, triglycerides, medium chain triglyceride (MCT) oil, capric/caprylic triglyceride, cocoglycerides, alkyl esters of fatty acids such as isopropyl palmitate, isopropyl myristate, isopropyl isostearate, poly propylene glycol 15-stearyl ether, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, maleated soybean oil, unsaturated or polyunsaturated oils, such as 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, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose oils;

essential oils; and

silicone oils, such as dimethicone, cyclomethicone, polyalkyl siloxane, polyaryl siloxane, polyalkylaryl siloxane, a polyether siloxane copolymer and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer and a polypropylene glycol alkyl ether;

wherein the polar solvent is selected from the group consisting of dimethyl isosorbide, glycerol, propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, other glycols, oleyl alcohol, alpha-hydroxy acids, such as lactic acid and glycolic acid, sulfoxides, such as dimethylsulfoxide (DMSO), dimethylformanide, methyl dodecyl sulfoxide, dimethylacetamide, azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, alkanols, such as dialkylamino acetates, and admixtures thereof;

wherein the silicone is selected from the group consisting of a volatile silicone and non-volatile silicone; and

wherein the liquid wax is selected from the group consisting of isostearic acid, oleyl alcohol, and capric alcohol, capryl alcohol, isostearic acid, caprylic acid, caproic acid, and butyric acid, jojoba oil.

3. The composition of claim 1 wherein the surface-active agent is a liquid or a combination comprising a solid and a liquid.

4. The composition of claim 1, wherein the surface active agent is selected from the group consisting of a polysorbate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, a polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59, a polyoxyethylene alkylyl ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1, a sucrose ester, a partial ester of sorbitol, sorbitan monolaurate, sorbitan monolaurate a monoglyceride, a diglyceride, isoceteth-20, a sucrose ester, or selected from the group consisting of steareth 2, glyceryl monostearate/PEG 100 stearate, Glyceryl Stearate, Steareth-21, peg 40 stearate, polysorbate 40, polysorbate 60, polysorbate 80, sorbitan stearate, laureth 4, Sorbitan monooleate, ceteareth 20, steareth 20, ceteth 20, Macrogol Cetostearyl Ether, ceteth 2, PEG-30 Dipolyhydroxystearate, sucrose distearate, polyoxyethylene (100) stearate, PEG 100 stearate, PEG 40 stearate, laureth 4, cetomacrogol ether, Cetearyl alcohol, Cetearyl glucoside, Oleyl alcohol, Steareth-2, Diisopropyl adipate, Capric/caprilic triglicerides, Polysorbate 20;

Montanov 68 (cetearyl alcohol and cetearyl glucoside), Sharonmix 824 (a liquid blend of methyl paraben, ethyl paraben and propyl paraben—

in phenoxyethanol), Simusol 165 (Glyceryl stearate and PEG-100 stearate), methyl glucose sequistearate, PEG 30 dipolyhydroxystearate, sucrose stearic acid esters, sorbitan laureth, sorbitan stearate and mixtures thereof.

5. The composition of claim 1 wherein the polymeric agent is selected from the group consisting of avicel, carbopol 934, pemulen TR2, klucel EF, xanthan gum, methocel A4M, carboxy methyl cellulose, locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, an amine-bearing polymer, chitosan, alginic acid, hyaluronic acid, a chemically modified starch, a carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, polyvinyl acetate, a polyvinyl chloride polymer, a polyvinylidene chloride polymer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose, methyl hydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose, carboxymethylcellulose carboxymethylhydroxyethylcellulose, a cationic cellulose, PEG 1000, PEG 4000, PEG 6000, PEG 8000, a derivatized polymeric emulsifier, aluminum starch octenylsuccinate (ASOS), sodium starch octenylsuccinate.

6. The composition of claim 1, wherein the glycerol ether is a volatile glycerol ether, and wherein the glycerol ether evaporates upon application to a topical surface at about 37°

C.

7. The composition of claim 1, wherein the glycerol ether is selected from the group consisting of glycerol propyl ether, glycerol hexyl ether, glycerol nonyl ether and mixtures thereof.

8. The composition of claim 1, further containing a non-volatile ether.

9. The composition of claim 8, wherein the non-volatile ether is selected from the group consisting of Glycerol, 1(2-chlorophenyl)ether;

glycerol, 1-(4-chlorophenyl)ether;

glycerol, 1,2-dimethyl ether;

glycerol, 1,3-dimethyl ether;

glycerol, 1,3-diphenylether;

glycerol, 1-(2-methoxyphenyl)ether;

glycerol, 1-methyl ether;

glycerol, 2-methyl ether;

glycerol, 1-octadecyl ether;

glycerol, 1-phenyl ether; and

polyoxypropylene glyceryl ether.

10. The composition of claim 1, further containing a foam adjuvant.

11. The composition of claim 1, wherein the ratio of glycerol ether to stabilizer and water ranges from about 9:

1 to about 1;

100.

12. The composition of claim 11, wherein the ratio of glycerol ether to stabilizer and water ranges from about 5:

1 to about 1;

2.

13. The composition of claim 1, further comprising an additional component selected from the group consisting of a modulating agent, a polar solvent, an antiperspirant, an anti-static agent, a buffering agent, a bulking agent, a chelating agent, a colorant, a conditioner, a deodorant, a diluent, a dye, an emollient, fragrance, a humectant, an occlusive agent, a penetration enhancer, a perfuming agent, a permeation enhancer, a pH-adjusting agent, a preservative, a skin penetration enhancer, a sunscreen, a sun blocking agent, a sunless tanning agent, an antioxidant, an antiseptive, a flavonoid, and a vitamin.

32. The composition of claim 1 in a non-foam state.

14. A therapeutic composition comprising:

i. at least one volatile glycerol ether;

ii. at least one stabilizer selected from the group consisting of a surface-active agent, a polymeric agent and mixtures thereof;

iii. water;

iv. a pharmaceutical or cosmetic agent homogeneously distributed in the composition; and

v. about 3% to about 35% by weight of a liquefied hydrocarbon gas propellant

wherein the polymeric agent, if present is about 0.1% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;

wherein the volatile glycerol ether evaporates upon application to a topical surface at about 37°

C. to deposit the pharmaceutical or cosmetic agent on the target topical surface; and

wherein the composition is contained in a pressurized container; and

wherein the composition is substantially flowable and provides a breakable and thermolabile foam of fairly good to excellent quality upon release from the container.

15. The therapeutic composition of claim 14, wherein the pharmaceutical or cosmetic agent is selected from the group consisting of active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotics, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, antiyeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, coal tar, dicarboxylic acids, disinfectants, fungicides, hair growth regulators, hormones, hydroxy acids, interferons, immunosuppressants, immunoregulating agents, insecticides, insect repellents, keratolytic agents, lactams, metals, metal oxides, mitocides, neuropeptides, steroids, non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides, photodynamic therapy agents, phosphcholines, alkyl phosphoric acids, retinoids, sanatives, scabicides, self tanning agents, skin whitening agents, vasoconstrictors, vasodilators, vitamins, vitamin D derivatives, wound healing agents and wart removers as well as agents having activity against skin and topical lesions, leishmaniasis, superficial basal cell carcinomas, actinic keratoses, Bowen'"'"'s disease and/or other squamous cell carcinomas and molluscum contagiosum.

16. The foamable therapeutic composition of claim 14, wherein the volatile glycerol ether is present in the composition in an amount sufficient to solubilize the active agent.

17. The foamable therapeutic composition of claim 14, wherein the active agent is a phosphocholine or an alkyl phosphoric acid.

18. The foamable therapeutic composition of claim 14, wherein the active agent is hexadecylphosphocholine.

19. The foamable therapeutic composition of claim 14, wherein the active agent is effective against any one or more of skin or topical lesions, cancer, skin cancer and leishmaniasis.

20. The foamable therapeutic composition of claim 17 further comprising at least one excipient compound selected from the group consisting of a petrolatum, a therapeutic oil, a liquid wax, a liquid emollient and mixtures thereof.

21. The composition of claim 14, wherein the composition further comprises a carrier or solvent selected from the group consisting of an organic carrier, a hydrophilic solvent;

a hydrophobic solvent;

a potent solvent;

a polar solvent, a silicone, an emollient, a liquid wax and mixtures thereof.

22. The composition of claim 14, wherein the glycerol ether, stabilizer and water are selected to generate a single phase formulation or substantially homogenous suspension.

23. The composition of claim 14, wherein the glycerol ether, stabilizer and water are selected to generate an emulsion that is substantially resistant to phase reversal.

24. A method of treating, ameliorating or preventing a disorder of a mammalian subject, the method comprising:

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

a. a therapeutically effective amount of a pharmaceutical or cosmetic agent substantially homogenously distributed in the glycerol ether composition;

b. less than or equal to about 75% by weight of at least one glycerol ether;

c. at least one stabilizer selected from the group consisting of a surface-active agent, a polymeric agent and mixtures thereof;

d. about 3% to about 35% by weight of a liquefied hydrocarbon gas propellant and

wherein the polymeric agent is about 0.1% to about 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;

wherein the composition is contained in a pressurized container; and

wherein the composition is substantially flowable and provides a breakable and thermolabile foam of fairly good to excellent quality upon release from the container; and

wherein the glycerol ether evaporates upon application to a topical surface at about 37°

C. to deposit the pharmaceutical or cosmetic agent on the target topical surface.

25. The method of claim 24, wherein the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the ear canal, the vagina and the rectum.

26. The method of claim 24, wherein the disorder is selected from the group consisting of dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, eethyma, yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, post-operative or post-surgical skin conditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, erythema nodosum, granuloma 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;

and wherein the active agent is suitable for treating said disorderm or is selected from the group consisting of chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranuloma venereum, mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis, topical or skin lesions, leishmaniosis, cancer, skin cancer, genital cancer, cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal and rectal disease, anal abscess/fistula, anal cancer, anal fissure, anal warts, Crohn'"'"'s disease, hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation, polyps of the colon and rectum;

warts;

herpes simplex virus infections, other viral infections, skin and topical lesions, leishmaniasis, superficial basal cell carcinomas, actinic keratoses, Bowen'"'"'s disease and/or other squamous cell carcinomas, molluscum contagiosum and eczema, and wherein the active agent is suitable for treating said disorder.

27. The method of claim 24, wherein the disorder is a dermatological disorder which can be treated, ameliorated or prevented by a topical phosphocholine or alkyl phosphoric acid.

28. The method of claim 24 wherein the active agent is selected from the group consisting of active herbal extracts, acaricides, age spot and keratose removing agents, allergen, analgesics, local anesthetics, antiacne agents, antiallergic agents, antiaging agents, antibacterials, antibiotics, antiburn agents, anticancer agents, antidandruff agents, antidepressants, antidermatitis agents, antiedemics, antihistamines, antihelminths, antihyperkeratolyte agents, antiinflammatory agents, antiirritants, antilipemics, antimicrobials, antimycotics, antiproliferative agents, antioxidants, anti-wrinkle agents, antipruritics, antipsoriatic agents, antirosacea agents antiseborrheic agents, antiseptic, antiswelling agents, antiviral agents, antiyeast agents, astringents, topical cardiovascular agents, chemotherapeutic agents, corticosteroids, coal tar, dicarboxylic acids, disinfectants, fungicides, hair growth regulators, hormones, hydroxy acids, interferons, immunosuppressants, immunoregulating agents, insecticides, insect repellents, keratolytic agents, lactams, metals, metal oxides, mitocides, neuropeptides, steroids, non-steroidal anti-inflammatory agents, oxidizing agents, pediculicides, photodynamic therapy agents, phosphcholines, alkyl phosphoric acids, retinoids, sanatives, scabicides, self tanning agents, skin whitening agents, vasoconstrictors, vasodilators, vitamins, vitamin D derivatives, wound healing agents and wart removers as well as agents having activity against skin and topical lesions, leishmaniasis, superficial basal cell carcinomas, actinic keratoses, Bowen'"'"'s disease and/or other squamous cell carcinomas and molluscum contagiosum.

29. The method of claim 24 wherein the glycerol ether is a volatile glycerol ether, wherein the volatile glycerol ether evaporates upon application to a topical surface at about 37°

C.

30. A pharmaceutical composition comprising:

i. a liquid volatile glycerol ether

ii. a stabilizer comprising about 1% to about 5% of at least one surface-active agent and about 0.1% 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;

iii. water;

iv. an active agent substantially homogenously distributed in the composition; and

v. 3% to about 35% by weight of a liquefied hydrocarbon gas propellant

wherein the volatile glycerol ether evaporates upon application to a topical surface at about 37°

C. to deposit the pharmaceutical or cosmetic agent for absorption onto a topical surface; and

wherein the composition is contained in a pressurized container; and

wherein the composition provides a breakable and thermolabile foam of about fairly good to about excellent quality upon release from the container.

31. The pharmaceutical composition of claim 30, wherein a liquid volatile glycerol ether comprises about 1% to about 75% by weight of a volatile glycerol ether selected from the group consisting of glycerol propyl ether, glycerol hexyl ether and glycerol nonyl ether and mixtures thereof.

33. A pharmaceutical or cosmetic vehicle composition comprising:

(a) less than or equal to about 75% by weight of at least one glycerol ether;

(b) at least one stabilizer selected from the group consisting of a surface-active agent, a polymeric agent and mixtures thereof; and

(c) water;

wherein the polymeric agent, if present, is about 0.1% to about 10% by weight of and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;

wherein the composition is contained in a pressurized container; and

wherein the composition is substantially flowable and provides a breakable and thermolabile foam of about fairly good to about excellent quality upon release from the container; and

wherein the composition is able to deposit a pharmaceutical or cosmetic agent for absorption onto a topical surface.