Method of modifying the release profile of sustained release compositions

• US 20040121009A1
• Filed: 10/08/2003
• Published: 06/24/2004
• Est. Priority Date: 10/17/2002
• Status: Abandoned Application

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Burke, Paul A., Zale, Stephen E., Riley, M. Gary I., Steitz-Abadi, Susan A., Dasch, James R.
• Application Number:
  US10/681,571
• Publication Number:
  US 20040121009A1
• Time in Patent Office: Days
• US Class Current: 424/468
• 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 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to a method for the sustained release in vivo of a biologically active labile agent comprising administering to a subject in need of treatment an effective amount of a sustained release composition comprising a biocompatible polymer having the biologically active labile agent incorporated therein, and a corticosteroid wherein the labile is released for a period of at least about two weeks. It is understood that the corticosteroid is present in an amount sufficient to modify the release profile of the biologically active labile agent from the sustained release composition. Pharmaceutical compositions suitable for use in the method of the invention are also disclosed.

Claims

1. A method for the sustained release in vivo of a biologically active labile agent comprising administering to a subject in need of treatment an effective amount of a sustained release composition comprising a biocompatible polymer having a biologically active labile agent incorporated therein wherein the labile agent is released for a period of at least about two weeks, and a corticosteroid.

2. The method of claim 1, wherein the corticosteroid is co-incorporated into the sustained release composition.

3. The method of claim 1, wherein the corticosteroid is separately incorporated into a second biocompatible polymer.

4. The method of claim 3, wherein the second biocompatible polymer is the same as the biocompatible polymer of the sustained release composition.

5. The method of claim 4, wherein the second biocompatible polymer is different from the biocompatible polymer of the sustained release composition.

6. The method of claim 1, wherein the corticosteroid is unencapusulated but commingled with the sustained release composition.

7. The method of claim 1 wherein the corticosteroid is selected from 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, disflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, flucinolone acetonide, fluocinonide, fluocortin butyl, flucortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone acetonide, triamcinolone acetonide 21-oic acid methyl ester, triamcinolone benetonide, triamcinolone hexacetonide, triamcinolone diacetate, pharmaceutically acceptable mixtures thereof and salts thereof.

8. The method of claim 7, wherein the corticosteroid is selected from triamcinolone acetonide, triamcinolone acetonide 21-oic acid methyl ester, triamcinolone benetonide, triamcinolone hexacetonide, triamcinolone diacetate, pharmaceutically acceptable mixtures thereof.

9. The method of claim 1, wherein the labile agent is released for a period of at least about three weeks.

10. The method of claim 9, wherein the labile agent is release for a period of at least about four weeks.

11. The method of claim 1, wherein the biocompatible polymer is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanydrides, poly(amino acids), polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends thereof, and copolymers thereof.

12. The method of claim 11, wherein the biocompatible polymer is a poly(lactide-co-glycolide).

13. The method of claim 1, wherein the sustained release composition is in the form of microparticles.

14. The method of claim 1, wherein the biologically active labile agent is a peptide.

15. The method claim 14, wherein the peptide is exendin-4.

16. The method of claim 1, wherein the biologically active labile agent is a protein.

17. The method of claim 16, wherein the protein is selected from immunoglobulins, antibodies, cytokines, interleukins, interferons, erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors, insulin, enzymes, tumor suppressors, blood proteins, hormones, vaccines, antigens, blood coagulation factors and growth factors.

18. The method of claim 16, wherein the protein is erythropoietin.

19. The method of claim 16, wherein the protein is follicle stimulating hormone.

20. The method of claim 16, wherein the protein is insulin.

21. A pharmaceutical composition comprising a sustained release composition comprising a biocompatible polymer having an effective amount of a biologically active labile agent incorporated therein wherein the labile is released for a period of at least about two weeks and a corticosteroid.

22. The pharmaceutical of claim 21, wherein the corticosteroid is co-incorporated into the sustained release composition.

23. The pharmaceutical composition of claim 21, wherein the corticosteroid is separately incorporated into a second biocompatible polymer.

24. The pharmaceutical composition of claim 23, wherein the second biocompatible polymer is the same as the biocompatible polymer of the sustained release composition.

25. The pharmaceutical composition of claim 23, wherein the second biocompatible polymer is different from the biocompatible polymer of the sustained release composition.

26. The pharmaceutical composition of claim 21, wherein the corticosteroid is unencapusulated but commingled with the sustained release composition.

27. The pharmaceutical composition of claim 21, wherein the corticosteroid is selected from 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, disflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, flucinolone acetonide, fluocinonide, fluocortin butyl, flucortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone acetonide, triamcinolone acetonide 21-oic acid methyl ester, triamcinolone benetonide, triamcinolone hexacetonide, triamcinolone diacetate, pharmaceutically acceptable mixtures thereof and salts thereof.

28. The pharmaceutical composition of claim 27, wherein the corticosteroid is selected from triamcinolone acetonide, triamcinolone acetonide 21-oic acid methyl ester, triamcinolone benetonide, triamcinolone hexacetonide, triamcinolone diacetate, pharmaceutically acceptable mixtures thereof.

29. The pharmaceutical composition of claim 21, wherein the sustained release composition has a targeted release period for the labile agent of about two weeks or more.

30. The pharmaceutical composition of claim 29, wherein the targeted release period is about three weeks or more.

31. The pharmaceutical composition of claim 21, wherein the biocompatible polymer is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanydrides, poly(amino acids), polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends thereof, and copolymers thereof.

32. The pharmaceutical composition of claim 31, wherein the biocompatible polymer is a poly(lactide-co-glycolide).

33. The pharmaceutical composition of claim 21, wherein the sustained release composition is in the form of microparticles.

34. The pharmaceutical composition of claim 21, wherein the biologically active labile agent is a peptide.

35. The pharmaceutical composition of claim 34, wherein the peptide is exendin-4.

36. The pharmaceutical composition of claim 21, wherein the biologically active labile agent is a protein.

37. The pharmaceutical composition of claim 36, wherein the protein is selected from immunoglobulins, antibodies, cytokines, interleukins, interferons, erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors, insulin, enzymes, tumor suppressors, blood proteins, hormones, vaccines, antigens, blood coagulation factors and growth factors.

38. The pharmaceutical composition of claim 36, wherein the protein is erythropoietin.

39. The pharmaceutical composition of claim 36, wherein the protein is follicle stimulating hormone.

40. The pharmaceutical composition of claim 36, wherein the protein is insulin.