Compositions and methods for treating inflammatory diseases of the skin
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/765
A61K-038/03
A61K-038/16
C07K-007/00
C07K-014/00
출원번호
US-0645689
(2000-08-24)
발명자
/ 주소
Rothbard, Jonathan B.
Wender, Paul A.
McGrane, P. Leo
Sista, Lalitha V. S.
Kirschberg, Thorsten A.
출원인 / 주소
CellGate, Inc.
대리인 / 주소
Townsend and Townsend and Crew LLP
인용정보
피인용 횟수 :
22인용 특허 :
21
초록
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.
대표청구항▼
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
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: R 1—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; R 2is hydrogen, alkyl, aryl, acyl, or allyl; R 3comprises the delivery-enhancing transporter, R 4is substituted or unsubstituted S or N; R 5is NHR6; R 6is 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 R7and R8are each independently selected from the group consisting of H and alkyl.14. The conjugate of claim 1, wherein the conjugate comprises structure 3 and R2is methyl ethyl propyl, butyl, allyl, benzyl or phenyl.15. The conjugate of claim 14, wherein R2is phenyl; k is l, and X is O.16. The conjugate of claim 1, wherein the conjugate comprises structure 4; R4is S; R5is NHR6; and R6is hydrogen, methyl, allyl, butyl or phenyl.17. The conjugate of claim 1, wherein the conjugate comprises structure 4; R5is NHR6, R6is 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 is20. The conjugate of claim 1, wherein the conjugate is21. The conjugate of claim 1, wherein the conjugate is22. The conjugate of claim 1, wherein the conjugate comprises an ascomycin.23. The conjugate of claim 1, wherein the conjugate comprises a glucocorticoid.
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