Pharmaceutical compositions for the treatment of transplant rejection or autoimmune or inflammatory conditions comprising cyclosporin A and 40-0-(2-hydroxyethyl)-rapamycin

• US 6,239,124 B1
• Filed: 01/28/1999
• Issued: 05/29/2001
• Est. Priority Date: 07/30/1996
• Status: Expired due to Term

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Zenke, Gerhard, Meinzer, Armin, Haeberlin, Barbara, Schuurman, Hendrik
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/230,618
• Time in Patent Office: 852 Days
• Field of Search: 514/183, 514/516
• US Class Current: 514/183
• 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 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/45 having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A synergistic combination of an IL-2 transcription inhibitor (e.g., cyclosporin A or FK506) and 40-O-(2-hydroxyethyl)-rapamycin is provided, which is useful in the treatment and prevention of transplant rejection and also certain autoimmune and inflammatory diseases, together with novel pharmaceutical compositions comprising an IL-2 transcription inhibitor in combination with a rapamycin, e.g., 40-O-(2-hydroxyethyl)-rapamycin.

Claims

1. A pharmaceutical composition comprising (I) cyclosporin A and (II) 40-O-(2-hydroxyethyl)-rapamycin, wherein the weight ratio I:

II is 2;

1 to 180;

1, in combination or association with a pharmaceutically acceptable diluent of carrier.

2. A composition of claim 1 in the form of a microemulsion or a microemulsion preconcentrate or a solid dispersion.

3. A composition of claim 2 which is a microemulsion preconcentrate formulation.

4. A composition of claim 2 which is a solid dispersion formulation.

5. A composition of claim 1 wherein I and II are present in an oil-in-water microemulsion preconcentrate comprising a hydrophilic phase, a lipophilic phase, and a surfactant.

6. Cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin as a combined pharamceutical preparation in the weight ratio 2:

1 to 180;

1 for simultaneous, separate, or sequential use in synergistically effective amounts.

7. A method of treating or preventing an autoimmune or inflammatory condition or transplant rejection in a subject suffering from or at risk for such condition or rejection, comprising co-administering synergistically effective amounts of (I) cyclosporin A and (II) 40-O-(2-hydroxyethyl)-rapamycin in the weight ratio 2:

1 to 180;

1.

8. The method of claim 7 wherein the ratio is 5:

1 to 60;

1.

9. The method of claim 7 wherein the ratio is 10:

1 to 20;

1.

10. The method of claim 9 wherein the ratio is 16:

1.

11. A method of treating or preventing chronic rejection of a heart or kidney transplant in a subject suffering from or at risk for such rejection, comprising co-administering together or at substantially the same time synergistically effective amounts of (I) cyclosporin A and (II) 40-O-)2-hydroxyethyl)-rapamycin.

12. The method of claim 11 wherein the compounds are administered as a fixed combination.

13. The method of claim 11 wherein the weight ratio 1:

11 is 5;

1 to 50;

1.

14. The method of claim 11 wherein the weight ratio is 10:

1 to 20;

1.

15. The method of claim 11 wherein the weight ratio is 16:

1.

16. The method of claim 11 wherein compounds I and II are co-administered in combination or association with a pharmaceutically acceptable diluent or carrier.

17. The method of claim 16 wherein compounds I and II are co-administered in the form of a microemulsion, a microemulsion preconcentrate, or a solid dispersion.

18. A kit comprising (I) cyclosporin A and (II) 40-O-(2-hydroxyethyl)-rapamycin in separate unit dosage forms, wherein said unit dosage forms are suitable for administrating I and II in synergistically effective amounts, wherein the weight ratio I:

II is 2;

1 to 180;

1.

19. The method of using cyclosporin A in the manufacture of a pharmaceutical kit of claim 18.

20. The method of using 40-O-(2-hydroxyethyl)-rapamycin in the manufacture of a pharmaceutical kit of claim 18.