Nonsteroidal immunomodulating kit and composition and uses thereof

• US 9,668,972 B2
• Filed: 03/11/2005
• Issued: 06/06/2017
• Est. Priority Date: 10/25/2002
• Status: Active Grant

• Current Assignee: VYNE Therapeutics, Inc.
• Original Assignee: Foamix Pharmaceuticals, Ltd. (VYNE Therapeutics, Inc.)
• Inventors: Tamarkin, Dov, Eini, Meir, Friedman, Doron
• Primary Examiner(s): THAKOR, DEVANG K
• Application Number:
  US11/078,902
• Publication Number:
  US 20050232869A1
• Time in Patent Office: 4,470 Days
• Field of Search: 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

Compositions and therapeutic kits including an aerosol container containing a foamable composition that includes a nonsteroidal immunomodulating agent are described. The foamable composition includes a liquid hydrophobic carrier; a surface-active agent; polymeric additive; water; and a propellant.

Claims

1. A therapeutic kit comprising an aerosol packaging assembly comprising:

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) a foamable emulsion composition comprising;

i. a nonsteroidal immunomodulating agent;

ii. at least one liquid hydrophobic carrier at a concentration of about 20% to about 50% by weight;

iii. about 0.1% to about 5% by weight of surface active agent;

iv. 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

v. water; and

(B) a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight;

wherein the pressurized product includes less than 5% or about 5% by weight of ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol, and pentanol, or mixtures of two or more thereof;

wherein the surface active agent comprises a non-ionic surface active agent and optionally an ionic surface active agent at a maximum amount of less than about 0.72% by weight;

wherein if ionic surfactant is present the ratio of non-ionic to ionic surface active agent is about 6;

1 or greater than 6;

1;

wherein the nonsteroidal immunomodulating agent is substantially or completely dissolved in the oil phase of the emulsion; and

wherein the pressurized product is released from the container as an expanded, breakable foam that collapses upon application of shear force.

3. The kit of claim 1, wherein the polymeric agent is a gelling agent and wherein the propellant is selected from the group consisting of a hydrocarbon, a fluorocarbon, and mixtures thereof.

5. The kit of claim 3, wherein the foamable composition is selected from the group consisting of an oil-in-water emulsion and a water-in-oil emulsion.

6. The kit of claim 5, wherein the outlet comprises a valve.

7. The kit of claim 6, wherein the valve comprises a stem with 1 to 4 apertures formed in the stem.

8. The kit of claim 7, 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;

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

9. The kit of claim 7, wherein the sum of areas of all apertures in the stem is selected from the group consisting of (i) between about 0.01 mm² and 1 mm²;

and (ii) between about 0.04 mm² and 0.5 mm².

10. The kit of claim 5, further comprising about 0.1% to about 5% by weight of a therapeutically active foam adjuvant selected from the group consisting of a fatty alcohol having 15 or more carbons in its carbon chain;

a fatty acid having 16 or more carbons in its carbon chain;

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 of two or more thereof.

11. The kit of claim 10, wherein the pressurized product includes less than 2% or about 2% by weight of ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol and pentanol, or mixtures of two or more thereof.

13. The kit of claim 10, wherein the concentration range of the nonsteroidal immunomodulating agent is selected from the group consisting of (i) between about 0.05% and about 2% by weight;

(ii) between about 2% and about 5% by weight;

(iii) between about 5% and about 12% by weight; and

(iv) between about 12% and about 24% by weight.

14. The kit of claim 5, 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, a vitamin A, a vitamin B, a vitamin C, a vitamin D, a vitamin E, a vitamin F, a vitamin K, 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 of two or more thereof.

15. The kit of claim 3, wherein the concentration of the surface active agent is between about 0.2% and about 2% by weight.

16. The kit of claim 11, 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 3, wherein the surface active agent is non-ionic.

18. The kit of claim 5, wherein the emulsion is a water-in-oil emulsion.

19. The kit of claim 5, wherein the emulsion is an oil-in-water emulsion.

20. The kit of claim 5, wherein the surface active agent comprises a combination of at least one non-ionic surfactant having a hydrophilic/lipophilic balance (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 10, wherein the polymeric agent is selected from the group consisting of a water-soluble cellulose ether and a naturally-occurring polymeric material.

22. The kit of claim 10, wherein the polymeric agent is selected from the group consisting of methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose, xanthan gum, guar gum, carrageenin gum, locust bean gum, tragacanth gum, and mixtures of any two or more thereof.

26. The kit of claim 10, further comprising at least one organic carrier selected from the group consisting of a polar solvent, an emollient, and mixtures of two or more thereof.

27. The kit of claim 26, wherein the polar solvent comprises propylene glycol.

28. The kit of claim 26, wherein the polar solvent comprises a polyethylene glycol.

29. The kit of claim 10, wherein the foamable composition comprises the ionic surface active agent and the ratio of non-ionic to ionic surface active agent is about 8:

1 or greater than 8;

1.

30. The kit of claim 11, wherein the foamable composition comprises an ionic surface active agent and the ratio of non-ionic to ionic surface active agent is greater than 16:

1.

31. The kit of claim 5, wherein the ratio of non-ionic to ionic surface active agent is about 14:

1 or greater than 14;

1.

35. The kit of claim 3, wherein the nonsteroidal immunomodulating agent is selected from the group consisting of salsalate, salicylsalicylic acid, sulindac, fenoprofen, oxaprozin, meclofenamic acid sirolimus, everolimus, and mixtures of any two or more thereof.

2. A therapeutic foamable composition comprising:

(a) an emulsion composition comprising;

i. a nonsteroidal immunomodulating agent;

ii. about 20% to about 50% by weight of a therapeutically active oil;

iii. about 0.1% to about 5% by weight of surface active agent;

iv. 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

v. water; and

(b) a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight;

wherein the foamable composition includes less than 5% or about 5% by weight of ethanol, propanol, isopropanol, butanol, iso-butanol, t-butanol and pentanol or mixtures thereof;

wherein the surface active agent comprises non-ionic surface active agent and optionally ionic surface active agent at a maximum amount of less than about 0.72% by weight;

wherein if ionic surfactant is present the ratio of non-ionic to ionic surface active agent is about 6;

1 or greater than 6;

1;

wherein the nonsteroidal immunomodulating agent is substantially or completely dissolved in the oil phase of the emulsion; and

wherein upon release from a pressurized canister the foamable composition forms an expanded, breakable foam that collapses upon application of shear force.

4. The kit of claim 2, wherein the polymeric agent is a gelling agent and wherein the propellant is selected from the group consisting of a hydrocarbon, a fluorocarbon, or mixtures thereof.

12. The kit of claim 4, wherein the nonsteroidal immunomodulating agent is selected from the group consisting of:

i. an indole, an indende acetic acid, a heteraryl acetic acid, an arylpropionic acid, an anthranilic acids, a fenamate, an enolic acid, a pyrazolidinedione, and an alkanone; and

salts thereof;

ii. salicylic acid, aspirin, sodium salicylate, choline magnesium trisalicylate, 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 and analogs thereof;

iii. an imidazole or triazole compound;

iv. ketoconazole;

v. a xanthine, pentoxifylline, propentofylline, torbafylline, amiloride, chloroquine, thalidomide, and salts and analogs thereof;

vi. a cyclic peptide, cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus, laquinimod, and imiquimod;

vii. a dicarboxylic acid having between about 6 and about 14 carbon atoms in its carbon atom skeleton, and salts thereof;

viii. 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;

ix. azelaic acid; and

x. a dicarboxylic acid 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 analogs thereof.

23. The foamable composition of claim 4, further comprising about 0.1% to about 5% by weight of a therapeutically active foam adjuvant 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 of two or more thereof.

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

25. The foamable 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, a vitamin A, a vitamin B, a vitamin C, a vitamin D, a vitamin E, a vitamin F, a vitamin K, 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 of two or more thereof.

32. The foamable composition of claim 2, wherein the foamable composition comprises the ionic surface active agent and the ratio of non-ionic to ionic surface active agent is about 16:

1 or greater than about 16;

1.

33. The foamable composition of claim 24, wherein foamable composition comprises the ionic surface active agent and the ratio of non-ionic to ionic surface active agent is about 20:

1 or greater than about 20;

1.

34. The foamable composition of claim 4, wherein the therapeutically active oil is selected from the group consisting of a polyunsaturated oil, a polyunsaturated fatty acid, an omega-3 fatty acid, an omega-6 fatty acid, linoleic acid, linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), an essential oil containing an active biologically occurring molecule, a liquid hydrophobic plant-derived oil possessing therapeutic benefits, and mixtures of any two or more thereof.

36. The kit of claim 4, wherein the nonsteroidal immunomodulating agent is selected from the group consisting of an indende acetic acid, a heteraryl acetic acid, an arylpropionic acid, an anthranilic acids, olsalazine, tolmetin, oxyphenthratrazone, Rofecoxib, indole acetic acid, nimesulide, a xanthine, pentoxifylline, propentofylline, torbafylline, amiloride, chloroquine, tresperimus, pimecrolimus, laflunimus, laquinimod, and mixtures of any two or more thereof.