Compositions and methods for treating inflammatory diseases of the skin

• US 6,730,293 B1
• Filed: 08/24/2000
• Issued: 05/04/2004
• Est. Priority Date: 08/24/1999
• Status: Expired due to Fees

• Current Assignee: Kai Pharmaceuticals, Inc. (Amgen Inc.)
• Original Assignee: Cellgate, Inc. (Tbg Diagnostics Limited)
• Inventors: Wender, Paul A., McGrane, P. Leo, Rothbard, Jonathan B., Kirschberg, Thorsten A., Sista, Lalitha V. S.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/645,689
• Time in Patent Office: 1,349 Days
• Field of Search: 424/78.05, 424/78.06, 424/78.17, 424/78.37, 525/54.11, 530/324-330
• US Class Current: 424/78.05
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/557 the modifying agent being biotin
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

This invention provides compositions and methods for enhancing delivery of glucocorticoids and ascomycins such as hydrocortisone, cyclosporin and FK506 across into and across one or more layers of the skin for the treatment of psoriasis and other inflammatory diseases of the skin.

Claims

1. A conjugate that comprises a) a compound selected from the group consisting of a glucocorticoid, cyclosporin, FK506 and an ascomycin, and b) a delivery-enhancing transporter that comprises 5 to 25 arginine residues, wherein the conjugate is selected from the group consisting of structures 3, 4, 5 and 6, as follows:

wherein;

R₁—

X comprises the glucocorticoid, cyclosporin, FK506, or ascomycin;

X is a functional group on the glucocorticoid, cyclosporin, FK506, or ascomycin to which the remainder of the conjugate is attached;

Ar is an aryl group having the attached radicals arranged in an ortho or para configuration, which aryl group can be substituted or unsubstituted;

Y is N;

R₂ is hydrogen, alkyl, aryl, acyl, or allyl;

R₃ comprises the delivery-enhancing transporter,

R₄ is substituted or unsubstituted S or N;

R₅ is NHR₆;

R₆ is hydrogen, alkyl, aryl, acyl or allyl;

k is selected from 1 and 2; and

n an m are each 1.

2. The conjugate of claim 1, wherein the glucocorticoid is hydrocortisone.

3. The conjugate of claim 1, wherein the conjugate comprises FK506.

4. The conjugate of claim 1, wherein the conjugate comprises a cyclosporin.

5. The conjugate of claim 4, the cyclosporin is cyclosporin A.

6. The conjugate of claim 1, wherein the delivery-enhancing transporter comprises 7 to 15 arginine residues.

7. The conjugate of claim 1, wherein the delivery-enhancing transporter consists essentially of 5 to 50 amino acids, at least 50 percent of which amino acids are arginines.

8. The conjugate of claim 1, wherein the delivery-enhancing transporter comprises at least 5 contiguous arginines.

9. The conjugate of claim 1, wherein the half-life of the conjugate is between 5 minutes and 24 hours upon contact with the skin.

10. The conjugate of claim 1, wherein the conjugate comprises a releasable linker which releases the compound, in biologically active form, from the delivery-enhancing transporter after the compound has passed into and through one or more layers of the skin.

11. The conjugate of claim 1, wherein the compound is released from the linker by solvent-mediated cleavage.

12. The conjugate of claim 1, wherein the conjugate is stable at acidic pH but the compound is released from the delivery-enhancing transporter at physiological pH.

13. The conjugate of claim 1, wherein X is selected from the group consisting of NH, O, S, and CR₇R₈, wherein R₇ and R₈ are each independently selected from the group consisting of H and alkyl.

14. The conjugate of claim 1, wherein the conjugate comprises structure 3 and R₂ is methyl ethyl propyl, butyl, allyl, benzyl or phenyl.

15. The conjugate of claim 14, wherein R₂ is phenyl;

k is l, and X is O.

16. The conjugate of claim 1, wherein the conjugate comprises structure 4;

R₄ is S;

R₅ is NHR₆; and

R₆ is hydrogen, methyl, allyl, butyl or phenyl.

17. The conjugate of claim 1, wherein the conjugate comprises structure 4;

R₅ is NHR₆, R₆ is hydrogen, methyl, allyl, butyl or phenyl; and

k is 1.

18. The conjugate of claim 1, wherein the conjugate comprises:

wherein PH is phenyl.

19. The conjugate of claim 1, wherein the conjugate is

20. The conjugate of claim 1, wherein the conjugate is

21. The conjugate of claim 1, wherein the conjugate is

22. The conjugate of claim 1, wherein the conjugate comprises an ascomycin.

23. The conjugate of claim 1, wherein the conjugate comprises a glucocorticoid.