Topical formulations for delivery of hedgehog inhibitor compounds and use thereof

• US 10,369,147 B2
• Filed: 06/03/2016
• Issued: 08/06/2019
• 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:
  US15/173,257
• Publication Number:
  US 20160354368A1
• Time in Patent Office: 1,159 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 composition for intradermal delivery, comprising:

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.

4. The composition of any one of claims 1-3, wherein the monohydric alcohol is represented by the structure CnH2n-OH, where n is 1, 2, 3 or 4.

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

6. A topical delivery system, comprising an intradermal composition according to claim 1.

7. The topical delivery system of claim 6, further comprising a backing member and membrane joined to define a reservoir in which the composition is contained.

8. The topical delivery system of claim 7, wherein the membrane is a non-rate controlling membrane.

2. A composition for intradermal delivery, comprising:

a hedgehog inhibitor compound and a solvent system, the hedgehog inhibitor having a saturation solubility in the solvent system of between about 2.5-8 wt % and the solvent system comprising between about 15-60 wt % of a monohydric primary alcohol and between about 10-50 wt % propylene glycol, wherein the hedgehog inhibitor compound is patidegib or itraconazole.

3. A composition for intradermal delivery, comprising:

a hedgehog inhibitor compound and a solvent system comprising (i) a monohydric alcohol comprised of at least one of ethanol and benzyl alcohol and propylene glycol, the monohydric alcohol and propylene glycol 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 a hedgehog inhibitor compound is present in the solvent system between about 0.1-10 wt %, wherein the hedgehog inhibitor compound is patidegib or itraconazole.

9. A composition for intradermal delivery, consisting essentially of:

patidegib and a solvent system comprising ethanol and propylene glycol in a w/w ratio of between about 0.9-1.8, wherein the patidegib has a saturation solubility in the solvent system of between about 2.5-8 wt % and wherein formulation provides an in vitro concentration of patidegib in each of the dermis and epidermis of greater than about 250 μ

M 48 hours after topical application.

10. The composition of claim 9, wherein the solvent system further comprises a fatty acid comprising between 13-22 carbon atoms.