Use of cyclopamine in the treatment of psoriasis

• US 20040072913A1
• Filed: 10/09/2003
• Published: 04/15/2004
• Est. Priority Date: 07/02/2001
• Status: Active Grant

• Current Assignee: Sinan Tas
• Original Assignee: Sinan Tas
• Inventors: Tas, Sinan, Avci, Oktay
• Granted Patent: US 7,605,167 B2
• Time in Patent Office: Days
• US Class Current: 514/649
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 8/63 Steroids; Derivatives thereof
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61Q 19/02 for chemically bleaching or whitening the skin

Abstract

This invention concerns the use of cyclopamine, a naturally occurring steroidal alkaloid known for over thirty years, for the treatment of psoriasis and achievement of rapid clearance of the psoriatic skin lesions together with the reversion of the histopathological signs of disease to normalcy with no detectable side effects. The cyclopamine-induced clearance of psoriatic lesions from the skin of patients is associated with the causation of cellular differentiation in lesional epidermis and with the rapid disappearance of CD4(+) lymphocytes and other inflammatory cells from lesional skin. Therapeutic compositions comprising of cyclopamine and a corticosteroid and/or the pre-treatment of lesions with a corticosteroid provide significantly further increased therapeutic effectiveness over the use of cyclopamine alone or a corticosteroid alone.

Claims

1. A method of inducing differentiation of the epidermal cells of skin comprising administering a medicament comprising cyclopamine or a pharmaceutically acceptable salt or derivative thereof.

2. A method as in claim 1 wherein the medicament is administered for treating a skin disorder associated with impairment of the differentiation of epidermal cells.

3. A method as in claim 2 wherein the skin disorder is psoriasis.

4. The method of claim 3 wherein the amount of said cyclopamine or a pharmaceutically acceptable salt or derivative thereof administered is an amount effective for clearing CD4 positive lymphocytes from psoriatic lesions.

5. The method of claim 3 wherein the amount of said cyclopamine or a pharmaceutically acceptable salt or derivative thereof administered is an amount effective for normalizing the decreased or lost cytokeratin 15 expression in the epidermal basal layer of psoriatic lesional skin.

6. The method of claim 3 wherein the amount of said cyclopamine or a pharmaceutically acceptable salt or derivative thereof administered is an amount effective for attaining decrease or disappearance of erythema from psoriatic lesional skin within 12 hours of administration.

7. The method of claim 3 wherein the amount of said cyclopamine or a pharmaceutically acceptable salt or derivative thereof administered is an amount effective for obtaining rapid regression and clearance of psoriatic skin lesions within 8 days, without harming the nonlesional skin.

8. The method of claim 2 wherein said medicament is a pharmaceutical composition comprising, in combination, cyclopamine or pharmaceutically acceptable salt or derivative thereof, and a corticosteroid in a pharmaceutically acceptable carrier.

9. A method according to claim 8, characterized in that the concentration of cyclopamine or a pharmaceutically acceptable salt or derivative thereof in the composition is in the range of 9 mM to 24 mM, and the corticosteroid is clobetasol 17-propionate having a concentration range in the composition of 0.2 mM to 1.5 mM.

10. A method according to claim 8, characterized in that the concentration of cyclopamine or a pharmaceutically acceptable salt or derivative thereof in the composition is in the range of 9 mM to 24 mM, and the corticosteroid is hydrocortisone having a concentration range in the composition of 10 mM to 20 mM.

11. A method as in claim 2 wherein, prior to administering said medicament comprising cyclopamine or a pharmaceutically acceptable salt or derivative thereof, skin lesions are pretreated with a corticosteroid.

12. A medicament for inducing differentiation of the epidermal cells of skin comprising cyclopamine or a pharmaceutically acceptable salt or derivative thereof.

13. A medicament as in claim 12 characterized in that said medicament is a pharmaceutical form enabling controlled release.

14. A medicament as in claim 12 characterized that said medicament is adsorbed onto a dermal patch.

15. A medicament as in claim 12 characterized in that said medicament is manufactured in the form of a cream, ointment, gel or hydrogel.

16. A medicament as in claim 15 comprising 18 mM cyclopamine.

17. A medicament as in claim 12 characterized in that cyclopamine or a pharmaceutically acceptable salt or derivative thereof is entrapped in liposomes or is in the form of an aqueous solution for systemic administration.

18. A pharmaceutical composition comprising cyclopamine or a pharmaceutically acceptable salt or derivative thereof and a corticosteroid in a pharmaceutically acceptable carrier.

19. A pharmeceutical composition according to claim 18, characterized in that the cyclopamine concentration is in the range of 9 mM to 24 mM.

20. A pharmaceutical composition according to claim 19, wherein the corticosteroid is either clobetasol 17-propionate in the concentration range of 0.2 mM to 1.5 mM or hydrocortisone in the concentration range of 10 mM to 50 mM.

21. A pharmaceutical composition according to claim 18, characterized in that, said composition is a pharmaceutical form enabling controlled release.

22. A pharmaceutical composition according to claim 18, characterized in that said composition is adsorbed onto a dermal patch.

23. A pharmaceutical composition according to claim 18, characterized in that said composition is in the form of a cream, ointment, gel or hydrogel.

24. A pharmaceutical composition according to claim 18, characterized in that said composition is entrapped in liposomes or is in the form of an aqueous solution for systemic administration.