Nonsteroidal immunomodulating kit and composition and uses thereof

• US 20050232869A1
• Filed: 03/11/2005
• Published: 10/20/2005
• Est. Priority Date: 10/25/2002
• Status: Active Grant

• Current Assignee: VYNE Therapeutics, Inc.
• Original Assignee: Foamix Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Friedman, Doron, Tamarkin, Dov, Eini, Meir
• Granted Patent: US 9,668,972 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/07 Retinol compounds, e.g. vitamin A retinoic acids A61K31/203
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 8/046 Aerosols; Foams
• CPC Class Codes: A61K 8/671 Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/122 Foams; Dry foams edible foams A61K9/0056
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin

Abstract

A composition and therapeutic kit including an aerosol packaging assembly including a container accommodating a pressurized product and an outlet capable of releasing a foamable composition, including a nonsteroidal immunomodulating agent as a foam. The pressurized product includes a foamable composition including: a) a container accommodating a pressurized product; and b) an outlet capable of releasing the pressurized product as a foam; wherein the pressurized product comprises a foamable composition including: i. a nonsteroidal immunomodulating agent; ii. at least one organic carrier selected from the group consisting of a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight; iii. a surface-active agent; iv. about 0.1% to about 5% by weight of a therapeutically active foam adjuvant, selected from the group consisting of a fatty alcohol, a fatty acid, a hydroxyl fatty acid; and mixtures thereof; v. about 0.01 % to about 5% by weight of at least one polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; vi. water; and vii. liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.

Claims

1. A therapeutic kit to provide a safe and effective dosage of a nonsteroidal immunomodulating agent, including an aerosol packaging assembly including:

a) a container accommodating a pressurized product; and

b) an outlet capable of releasing the pressurized product as a foam;

wherein the pressurized product comprises a foamable composition including;

i. a nonsteroidal immunomodulating agent;

ii. at least one organic carrier selected from the group consisting of a hydrophobic organic carrier, an organic polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight;

iii. a surface active agent;

iv. about 0.01% to about 5% by weight of at least one polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;

v. water; and

vi. liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.

2. The kit 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.

3. The kit of claim 1, wherein the outlet comprises a valve.

4. The kit of claim 3, wherein the valve comprises a stem with 1 to 4 apertures formed in the stem.

5. The kit of claim 4, wherein each aperture formed in the stem has a diameter, selected from the group consisting of (i) about 0.2 mm to about 1 mm;

(ii) about 0.3 mm to about 0.8 mm; and

(iii) about 0.01 mm² and 1 mm².

6. The kit of claim 4, wherein the sum of areas of all apertures in the stem is between about 0.04 mm² and 0.5 mm².

7. The kit of claim 1, wherein the at least one organic carrier is present in an amount selected from the group consisting of (i) about 2% to about 5%;

(ii) about 5% to about 10%;

(iii) about 10% to about 20%; and

(iv) about 20% to about 50%.

8. The kit of claim 1, further including about 0.1% to about 5% by weight of a therapeutically active 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 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;

1 2-hydroxy stearic acid and mixtures thereof.

9. The kit of claim 1, wherein the foamable composition is substantially alcohol-free.

10. The kit of claim 1, wherein the nonsteroidal immunomodulating agent is selected from the group consisting of:

(i) a COX-1 inhibitor, a COX-2 inhibitor or a non-selective nonsteroidal immunomodulating agent, which simultaneously inhibits both COX-1 and COX-2.

(ii) salicylic acid, an indole, an indende acetic acid, a heteraryl acetic acid, an arylpropionic acid, an anthranilic acids, a fenamate, an enolic acid, a pyrazolidinediones and an alkanones; and

salts and derivatives thereof.

(iii) salicylic acid, aspirin, sodium salicylate, choline magnesium trislicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, esters of salicylic acid with a carboxylic acid, esters of salicylic acid with a dicarboxylic acid, esters of salicylic acid with a fatty acid, esters of salicylic acid with a hydroxyl fatty acid, esters of salicylic acid with an essential fatty acid, esters of salicylic acid with a polycarboxylic acid, para-aminophenol, indole, indomethacin, sulindac, etodolac, tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flubiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, meclofenamic acid, oxicams, piroxicam, tenoxicam, pyrazolidinediones, phenylbutazone, oxyphenthratrazone, nabumetone, diaryl-substituted furanones, Rofecoxib), diaryl-substituted pyrazoles, Celecoxib, indole acetic acids, Etodolac, sulfonanilides, Nimesulide and salts, derivatives and analogs thereof.

(iv) an imidazole or triazole compounds which possess anti-inflammatory properties

(v) ketoconazole.

(vi) An agents, which inhibits pro-inflammatory cytokines from T cells and/or pro-inflammatory mediators from mast cells.

(vii) An agents, which inhibits TNF-alpha, TNF-beta, interleukin-1, interleukin-4, interleukin-6, interleukin-10, interleukin-12 and IFN-gamma.

(viii) A xanthine, pentoxifylline, propentofylline, torbafylline, amiloride, chloroquine, thalidomide and salts, derivatives and analogs thereof.

(ix) An immunosuppressant agents, immunoregulating agents and immunomodulators.

(x) An immunomodulating cyclic peptide, cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus, laquinimod and imiquimod.

(xi) a calcineurin inhibitor.

(xii) a nitric oxide synthase inhibitor.

(xiii) a leucocyte chemotaxis inhibitor.

(xiv) a dicarboxylic acid, having between about 6 and about 14 carbon atoms its carbon atom skeleton, and salts and derivatives thereof.

(xv) adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, 1,11-undecanedioic acid, 1,12-dodecanedioic acid, 1,13-tridecanedioic acid and 1,14-tetradecanedioic acid.

(xvi) azelaic acid.

(xvii) A dicarboxylic acid is covalently linked with at least one moiety, selected from the group consisting of alpha-hydroxy acid, beta-hydroxy acid, hydroxybenzoic acid, alkylhydroxybenzoate, dihydroxy benzene, cresol, alcohol derivatives of Vitamin A (retinoic acid), retinal, steroid hormones, corticosteroids, vitamin E and vitamin D, and derivatives and analogs thereof.

11. The kit of claim 1, wherein the concentration range of the nonsteroidal immunomodulating agent is selected from the group of (i) about 0.05% and about 2%;

(ii) about 2% and about 5%;

(iii) about 5% and about 12%; and

(iv) about 12% and about 24%.

12. The kit of claim 2, wherein the nonsteroidal immunomodulating agent is soluble in the aqueous phase of the emulsion.

13. The kit of claim 2, wherein the nonsteroidal immunomodulating agent is soluble in the oil phase of the emulsion.

14. The kit of claim 1, wherein 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 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, a 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 mixtures thereof.

15. The kit of claim 1, wherein the concentration of the surface active agent is between about 0.1% and about 5%.

16. The kit 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.

17. The kit of claim 1, wherein the surface active agent comprises a combination of a non-ionic surfactant and an ionic surfactant, at a ratio of between 1:

1 and 20;

1.

18. The kit 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.

19. The kit 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.

20. The kit of claim 1, wherein the surface active agent comprises 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, wherein 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.

21. The kit of claim 1, wherein the polymeric agent is selected from the group consisting of a water-soluble cellulose ether and naturally-occurring polymeric material.

22. The kit of claim 21, 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.

27. The kit of claim 1 or the composition of claim 23, wherein the composition does not contain petrolatum.

23. A therapeutic foamable composition including:

i. a nonsteroidal immunomodulating agent;

ii. a therapeutically active oil;

iii. a surface active agent;

iv. about 0.01% to about 5% by weight of at least one polymeric additive selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent;

v. water; and

vi. liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.

24. The composition of claim 23, further including about 0.1% to about 5% by weight of a therapeutically active 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 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 mixtures thereof

25. The composition of claim 23, wherein the foamable composition further comprises at least one additional therapeutic agent.

26. The composition of claim 24, wherein 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, an 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, a 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 mixtures thereof.

28. A method of treating, alleviating or preventing a disorders of the skin, a body cavity or mucosal surface, wherein the disorder involves inflammation as one of its etiological factors, including:

administering topically to a subject having the disorder, a foamed composition including;

a) a nonsteroidal immunomodulating agent;

b) at least one organic carrier selected from a hydrophobic organic carrier, a polar solvent, an emollient and mixtures thereof, at a concentration of about 2% to about 50% by weight;

c) about 0.1% to about 5% by weight of a surface-active agent;

d) about 0.01% to about 5% by weight of a polymeric additive selected from a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent; and

e) water,

wherein the nonsteroidal immunomodulating agent is administered in a therapeutically effective amount.

29. The method of claim 28, wherein the composition further comprises about 0.1% to about 5% by weight of a therapeutically active 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 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 mixtures thereof.

30. The method of claim 28, wherein 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, dermatosis, dermatitis, parasitic infections, disorders of hair follicles and sebaceous glands, scaling papular diseases, benign tumors, malignant tumors, reactions to sunlight, bullous diseases, pigmentation disorders, disorders of cornification, pressure sores, disorders of sweating, inflammatory reactions, xerosis, ichthyosis, allergy, burn, wound, cut, chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis, osteoarthritis, joint pain, hormonal disorder, pelvic inflammation, endometritis, salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal and rectal disease, anal abscess/fistula, anal cancer, anal fissure, anal warts, Crohn'"'"'s disease, hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation, polyps of the colon and rectum;

and wherein the disorder is responsive to treatment with the nonsteroidal immunomodulating agent.

31. The method of claim 29, wherein the composition further comprises at least one additional therapeutic agent.

32. The method of claim 29, wherein the organic carrier comprises at least one therapeutically active oil.