FENOLDOPAM TOPICAL FORMULATIONS FOR TREATING SKIN DISORDERS

• US 20190328746A1
• Filed: 08/30/2017
• Published: 10/31/2019
• Est. Priority Date: 08/31/2016
• Status: Active Grant

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem), Taro Pharmaceutical Industries Limited (Sun Pharmaceutical Industries Limited)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem), Taro Pharmaceutical Industries Limited (Sun Pharmaceutical Industries Limited)
• Inventors: KHAN, Wahid, SHIFRIN, Helena, SCHLINGER, Ron, AVRAMOFF, Avi, DOMB, Avi
• Granted Patent: US 11,612,607 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/06 Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• 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: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/7038 Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics

Abstract

Embodiments of stable topical compositions for administering fenoldopam (compound (I) or a pharmaceutically acceptable salt or solvate thereof are disclosed for immediate or continued slow release administration, over prolonged periods of time with safe minimal systemic exposure of fenoldopam (reducing the risk for lowering blood pressure). The compositions include those compositions that increase the stability and skin absorption of the drug, particularly anhydrous semi-solid compositions and creams. This is accomplished by incorporating fenoldopam in soluble or dispersed form into semi-solid compositions like ointments or anhydrous gels that are not irritative. Embodiments of methods for using the topical compositions in the treatment of dermatological disorders including psoriasis, alopecia atopic dermatitis and vitiligo are disclosed.

Claims

1. A method of treating skin disorders, comprising topically administering of therapeutically effective amount of fenoldopam or its pharmaceutical acceptable salts, wherein the concentration of fenoldopam is less than 5%.

2. The method of claim 1 further comprising an acidifying agent and/or buffering system.

3. The method of claim 2, wherein the buffering system is selected from molecular or polymeric acidic buffering agents, selected from:

citric acid and sodium citrate, acetic acid and sodium acetate, alginic acid and sodium alginate and polyacrylic acid, and polyacrylic acid sodium salt.

4. The method of claim 2, wherein the acidifying agent is:

citric acid, maleic acid, malonic acid, lactic acid, glycolic acid, acrylic or methacrylic acid, maleic acid-containing polymers or alginate, or sulfate, sulfonate, phosphate or phosphonate acids.

5. The method of claim 1, wherein the therapeutically effective amount of fenoldopam comprises between 0.01-3% w/w.

6. The method of claim 1, wherein the therapeutically effective amount of fenoldopam comprises 0.1% w/w.

7. The method of claim 1, wherein the therapeutically effective amount of fenoldopam comprises 1% w/w.

8. The method of claim 1, wherein the skin disorders is selected from psoriasis, atopic dermatitis, alopecia and vitiligo.

9. A topical composition comprising a therapeutically effective amount of fenoldopam in its base or salt form, for the treatment of T-cell mediated auto-immune inflammatory disorders, wherein at least 80% of fenoldopam is in a solubilized form.

10. A topical composition comprising a therapeutically effective amount of fenoldopam in its base or salt form, for the treatment of D1 receptor-mediated skin disorders.

11. The topical composition of claim 9 or 10, wherein the composition is cream-based composition, anhydrous PEG-based gel, a lipid-based ointment, foam, solid particles, paste, lotion and an adhesive strip or a patch.

12. The topical composition of claim 9 or 10, wherein the disorders are selected from psoriasis, atopic dermatitis, alopecia, vitiligo, basal and squamous cell carcinomas.

13. The topical composition of claim 9 or 10, comprising about 0.01-3% fenoldopam w/w.

14. The anhydrous PEG-based composition of claim 11, wherein the anhydrous PEG composition exhibit higher flux of fenoldopam through the skin compared to the water-based composition.

15. The topical composition of claim 9 or 10, further comprising at least one penetration enhancer in order to improve the penetrability into the skin.

16. The topical composition of claim 15, wherein the penetration enhancer is selected from polyols, alcohols, fatty alcohols, fatty acids, fatty acid esters, anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants.

17. The topical composition of claim 9 or 10, further comprising at least one anti-oxidant to improve the stability of fenoldopam in the composition.

18. The topical composition of claim 17, wherein the anti-oxidant is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid derivatives such as ascorbic acid, erythorbic acid, Sodium ascorbate, thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione, tocopherols, sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate.

19. The topical composition of claim 9 or 10, further comprising at least one preservative to further improve the stability of the aqueous composition.

20. The topical composition of claim 19, wherein the preservative is selected from benzyl alcohol, chlorocresol, hydroxy benzoates, benzoic acid, thiomersal, chloramphenicol and parabens.

21. The topical composition of claim 9 or 10, which is stable for at least nine months at room temperature.

23. A method of treating psoriasis, comprising topically administering the composition of claim 9 or 10 on an affected area of skin at least once or twice daily, thereby treating the disorder.

28. The composition of claim 9 or 10, further comprising anti-inflammatory agents, analgesics, local anasthetics, tars or other actives used for treating T-cell mediated inflammatory skin disorders.

22. A method of treating skin disorders, comprising topically administering of therapeutically effective amount of fenoldopam or its pharmaceutical acceptable salts, wherein at least 80% of fenoldopam is in a solubilized form.

24. A non-irritating topical composition comprising fenoldopam for the treatment of skin disorders, the composition having a pH of not higher than 4, wherein the composition does not cause skin irritation following daily exposure for at least 1 week.

25. A topical fenoldopam composition having a pH above 4, wherein the composition is stable at room temperature for at least 3 months.

27. The topical composition of claim 25, further comprising a polymeric polyacid selected from natural polyacid, alginic acid, poly(acrylic acid) and poly(maleic acid) and their copolymer and crosslinked derivatives.

26. A topical anhydrous pH-independent fenoldopam composition comprising fenoldopam for the treatment of skin disorders, wherein the composition is stable at room temperature for at least 3 months.

29. Method of inhibiting the psoriasis-induced proinflammatory cytokine secretion comprising topical applying an effective amount of fenoldopam, thereby inhibiting the cytokine secretion, wherein the concentration of fenoldopam is less than 5% w/w.