Method of modifying the release profile of sustained release compositions

• US 6,558,702 B2
• Filed: 04/13/2001
• Issued: 05/06/2003
• Est. Priority Date: 04/13/2001
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Riley, M. Gary I., Dasch, James R.
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/835,001
• Publication Number:
  US 20030004100A1
• Time in Patent Office: 753 Days
• Field of Search: 514/2, 514/12, 514/21, 514/44, 514/89, 514/107, 514/108, 514/772, 514/788, 514/964, 514/965, 424/851, 424/422, 424/423, 424/424, 424/425, 424/426, 424/484, 424/485, 424/486, 424/487, 424/488, 424/489, 424/490, 424/491, 424/492, 424/493, 424/494, 424/495, 424/496, 424/497, 424/498, 424/499, 424/500, 424/501, 424/502
• US Class Current: 424/484
• 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 31/663 Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• 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 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

The present invention relates to a method for the sustained release in vivo of a biologically active 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 agent incorporated therein, and a bisphosphonate wherein the bisphosphonate compound is present in an amount sufficient to modify the release profile of the biologically active 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 agent selected from a biologically active protein, peptide or nucleic acid 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 protein, peptide or nucleic acid incorporated therein, and a bisphosphonate compound wherein the bisphosphonate compound is present in an amount sufficient to modify the release profile of the biologically active protein, peptide or nucleic acid from the sustained release composition.

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

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

12. The method of claim 1 wherein the biologically active agent is a protein.

13. The method of claim 12 wherein the protein is erythropoietin.

27. The method of claim 1, wherein the bisphosphonate compound is separately incorporated into a second biocompatible polymer.

28. The method of claim 27, wherein the second biocompatible polymer is the same as the biocompatible polymer of the sustained release composition.

29. The method of claim 27, wherein the second biocompatible polymer is different from the biocompatible polymer of the sustained release composition.

30. The method of claim 1, wherein the bisphosphonate compound is unencapsulated but comingled with the sustained release composition.

31. The method of claim 1 wherein the biocompatible polymer of the sustained release composition is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanhydrides, 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 method of claim 31 wherein the biocompatible polymer is a poly(lactide-co-glycolide).

33. The method of claim 1 wherein the bisphosphonate compound is alendronate, risendronate, pamidronate, etidronate, tiludronate or a combination thereof.

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

3. A method for the sustained release in vivo of a biologically active 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 agent incorporated therein, and a bisphosphonate compound wherein the bisphosphonate compound is separately incorporated into a second biocompatible polymer and is present in an amount sufficient to modify the release profile of the biologically active agent from the sustained release composition.

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 3, wherein the second biocompatible polymer is different from the biocompatible polymer of the sustained release composition.

7. The method of claim 3 wherein the biocompatible polymer of the sustained release composition is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends thereof, and copolymers thereof.

8. The method of claim 7 wherein the biocompatible polymer is a poly(lactide-co-glycolide).

9. The method of claim 3 wherein the bisphosphonate compound is alendronate, risendronate, pamidronate, etidronate, tiludronate or a combination thereof.

10. The method of claim 3, wherein the sustained release composition is in the form of microparticles.

35. The method of claim 3, wherein the biologically active agent is a protein.

36. The method of claim 3, wherein the biologically active agent is peptide.

6. A method for the sustained release in vivo of a biologically active 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 agent incorporated therein, and a bisphosphonate compound wherein the bisphosphonate compound is unencapsulated but comingled with the sustained release composition and is present in an amount sufficient to modify the release profile of the biologically active agent from the sustained release composition.

37. The method of claim 6 wherein the biocompatible polymer of the sustained release composition is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends thereof, and copolymers thereof.

38. The method of claim 37 wherein the biocompatible polymer is a poly(lactide-co-glycolide).

39. The method of claim 6 wherein the bisphosphonate compound is alendronate, risendronate, pamidronate, etidronate, tiludronate or a combination thereof.

40. The method of claim 6, wherein the sustained release composition is in the form of microparticles.

41. The method of claim 6, wherein the biologically active agent is a protein.

42. The method of claim 6, wherein the biologically active agent is a peptide.

14. A pharmaceutical composition comprising:

a) a sustained release composition comprising a biocompatible polymer having an effective amount of a biologically active agent selected from a biologically active protein, peptide or nucleic acid incorporated therein; and

b) a bisphosphonate compound, wherein the bisphosphonate compound is present in an amount sufficient to modify the release profile of the biologically active protein, peptide or nucleic acid from the sustained release composition.

15. The pharmaceutical composition of claim 14, wherein the bisphosphonate compound is co-incorporated into the sustained release composition.

24. The pharmaceutical composition of claim 14, wherein the biologically active agent is a peptide.

25. The pharmaceutical composition of claim 14, wherein the biologically active agent is a protein.

26. The pharmaceutical composition of claim 25, wherein the protein is erythropoietin.

43. The pharmaceutical composition of claim 14, wherein the bisphosphonate compound is separately incorporated into a second biocompatible polymer.

44. The pharmaceutical composition of claim 43, wherein the second biocompatible polymer is the same as the biocompatible polymer of the sustained release composition.

45. The pharmaceutical composition of claim 43, wherein the second biocompatible polymer is different from the biocompatible polymer of the sustained release composition.

46. The pharmaceutical composition of claim 14, wherein the bisphosphonate compound is unencapsulated but comingled with the sustained release composition.

47. The pharmaceutical composition of claim 14 wherein the biocompatible polymer of the sustained release composition is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends thereof, and copolymers thereof.

48. The pharmaceutical composition of claim 47, wherein the biocompatible polymer is a poly(lactide-co-glycolide).

49. The pharmaceutical composition of claim 14, wherein the bisphosphonate compound is alendronate, risendronate, pamidronate, etidronate, tiludronate or a combination thereof.

50. The pharmaceutical composition of claim 14, wherein the sustained release composition is in the form of microparticles.

16. A pharmaceutical composition comprising:

a) a sustained release composition comprising a biocompatible polymer having an effective amount of a biologically active agent incorporated therein; and

b) a bisphosphonate compound, wherein the bisphosphonate compound is separately incorporated into a second biocompatible polymer and present in an amount sufficient to modify the release profile of the biologically active agent from the sustained release composition.

17. The pharmaceutical composition of claim 16, wherein the second biocompatible polymer is the same as the biocompatible polymer of the sustained release composition.

18. The pharmaceutical composition of claim 16, wherein the second biocompatible polymer is different from the biocompatible polymer of the sustained release composition.

20. The pharmaceutical composition of claim 16 wherein the biocompatible polymer of the sustained release composition is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends thereof, and copolymers thereof.

21. The pharmaceutical composition of claim 20 wherein the biocompatible polymer is a poly(lactide-co-glycolide).

22. The pharmaceutical composition of claim 16 wherein the bisphosphonate compound is alendronate, risendronate, pamidronate, etidronate, tiludronate or a combination thereof.

23. The pharmaceutical composition of claim 16, wherein the sustained release composition is in the form of microparticles.

51. The pharmaceutical composition of claim 16, wherein the biologically active agent is a protein.

52. The pharmaceutical composition of claim 16, wherein the biologically active agent is peptide.

19. A pharmaceutical composition comprising:

a) a sustained release composition comprising a biocompatible polymer having an effective amount of a biologically active agent incorporated therein; and

b) a bisphosphonate compound, wherein the bisphosphonate compound is unencapsulated but comingled with the sustained release composition and present in an amount sufficient to modify the release profile of the biologically active agent from the sustained release composition.

53. The pharmaceutical composition of claim 19 wherein the biocompatible polymer of the sustained release composition is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and polyorthoester, polyurethanes, blends thereof, and copolymers thereof.

54. The pharmaceutical composition of claim 53 wherein the biocompatible polymer is a poly(lactide-co-glycolide).

55. The pharmaceutical composition of claim 19 wherein the bisphosphonate compound is alendronate, risendronate, pamidronate, etidronate, tiludronate or a combination thereof.

56. The pharmaceutical composition of claim 19, wherein the sustained release composition is in the form of microparticles.

57. The pharmaceutical composition of claim 19, wherein the biologically active agent is a protein.

58. The pharmaceutical composition of claim 19, wherein the biologically active agent is a peptide.