Topical formulations for delivery of hedgehog inhibitor compounds and use thereof

• US 10,695,344 B2
• Filed: 01/03/2019
• Issued: 06/30/2020
• Est. Priority Date: 06/04/2015
• Status: Active Grant

• Current Assignee: Sol-Gel Technologies Ltd.
• Original Assignee: PellePharm, Inc.
• Inventors: Brown, Marc Barry, Stevenson, Cameron Robert, Evans, Charles Rodney Greenaway
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US16/239,457
• Publication Number:
  US 20190134027A1
• Time in Patent Office: 544 Days
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• 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 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Compositions for topical administration of a hedgehog inhibitor compound are described. In one embodiment, the hedgehog inhibitor compound is patidegib and the topical composition comprises the compound in a solvent system of a monohydric primary alcohol and a polyol in a w/w ratio of between about 0.9-1.8. In another embodiment, the hedgehog inhibitor is itraconazole and the topical composition comprises the compound in a solvent system comprising a monohydric primary alcohol and an optionally lower alkyl end-capped oligomeric alkylene glycol in a w/w ratio of between about 0.8 and 2.6 and a fused bicyclic ether. Method of using the compositions are also described, where in one embodiment, the compositions are topically applied for treating or preventing basal cell carcinoma.

Claims

1. A method for treating basal cell carcinoma, comprising:

topically applying a composition or a topical delivery system comprising the composition to a subject in need thereof,

wherein the composition comprises

a hedgehog inhibitor compound and a solvent system comprising (i) a monohydric primary alcohol and a polyol in a w/w ratio of between about 0.9-1.8 and (ii) a buffer or a fatty acid comprising between 13-22 carbon atoms, wherein the hedgehog inhibitor compound is present in the solvent system between about 0.1-10 wt %, wherein the hedgehog inhibitor compound is patidegib or itraconazole,

whereby said topically applying achieves intracutaneous delivery of patidegib or itraconazole in an amount sufficient for treating basal cell carcinoma, with a non-therapeutic concentration of patidegib or itraconazole present in the blood of the subject.

2. The method of claim 1, wherein the monohydric alcohol is of the form R—

OH, where R is selected from methyl, ethyl, propyl, butyl, and pentyl.

3. The method of claim 2, wherein the monohydric alcohol is ethanol.

4. The method of claim 1, wherein the solvent system further comprises diethylene glycol monoethyl ether.

5. The method of claim 1, wherein the solvent system comprises a buffer at pH 7.5.

6. The method of claim 1, wherein the hedgehog inhibitor compound is patidegib.

7. The method of claim 1, wherein the composition comprises patidegib and a solvent system comprising (i) ethanol and propylene glycol in a w/w ratio of between about 0.9-1.8, (ii) diethylene glycol monoethyl ether, and (iii) a buffer, wherein patidegib is present in the solvent system in an amount between about 0.1-10 wt %.

8. The method of claim 7, wherein the ratio (w/w) of ethanol to diethylene glycol monoethyl ether is within about 10-20% of the ratio (w/w) of ethanol to propylene glycol.

9. The method of claim 7, wherein the ratio (w/w) of ethanol to diethylene glycol monoethyl ether is the same as the ratio (w/w) of ethanol to propylene glycol.

10. The method of claim 1, wherein the subject has Gorlin syndrome.

11. A method for treating basal cell carcinoma, comprising:

providing a composition or a topical delivery system comprising the composition to a subject in need thereof,

wherein the composition comprises

a hedgehog inhibitor compound and a solvent system comprising (i) a monohydric primary alcohol and a polyol in a w/w ratio of between about 0.9-1.8 and (ii) a buffer or a fatty acid comprising between 13-22 carbon atoms, wherein the hedgehog inhibitor compound is present in the solvent system between about 0.1-10 wt %, wherein the hedgehog inhibitor compound is patidegib or itraconazole,

whereby said providing comprises instructions to topically apply the composition or the delivery system and wherein said topically applying achieves intracutaneous delivery of patidegib or itraconazole in an amount sufficient for treating basal cell carcinoma, with a non-therapeutic concentration of the compound present in the blood of the subject.

12. The method of claim 11, wherein the monohydric alcohol is of the form R—

OH, where R is selected from methyl, ethyl, propyl, butyl, and pentyl.

13. The method of claim 12, wherein the monohydric alcohol is ethanol.

14. The method of claim 11, wherein the solvent system further comprises diethylene glycol monoethyl ether.

15. The method of claim 11, wherein the solvent system comprises a buffer at pH 7.5.

16. The method of claim 11, wherein the hedgehog inhibitor compound is patidegib.

17. The method of claim 11, wherein the composition comprises patidegib and a solvent system comprising (i) ethanol and propylene glycol in a w/w ratio of between about 0.9-1.8, (ii) diethylene glycol monoethyl ether, and (iii) a buffer, wherein patidegib is present in the solvent system in an amount between about 0.1-10 wt %.

18. The method of claim 17, wherein the ratio (w/w) of ethanol to diethylene glycol monoethyl ether is within about 10-20% of the ratio (w/w) of ethanol to propylene glycol.

19. The method of claim 17, wherein the ratio (w/w) of ethanol to diethylene glycol monoethyl ether is the same as the ratio (w/w) of ethanol to propylene glycol.

20. The method of claim 11, wherein the subject has Gorlin syndrome.