Methods for fabricating polymer-based controlled release devices

• US 6,455,074 B1
• Filed: 08/16/1999
• Issued: 09/24/2002
• Est. Priority Date: 09/24/1997
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Herberger, John D., Tracy, Mark A., Burke, Paul A., Herbert, Paul F.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US09/375,090
• Time in Patent Office: 1,135 Days
• Field of Search: 424/501, 424/502, 424/426, 428/402.21, 264/4.1, 264/4.3, 264/4.33
• US Class Current: 424/501
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• 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 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer

Abstract

The present invention relates to a polymer-based sustained release device, and methods of forming and using the device for the sustained release of an active agent. The improved method of the invention for forming a polymer-based sustained release device comprises forming a polymer/active agent solution by mixing a polymer, a continuous phase, and an active agent. The continuous phase can comprise one or more polymer solvents, a polymer solvent/polymer non-solvent mixture, or a polymer solvent/active agent non-solvent mixture. When the continuous phase comprises a polymer solvent/active agent non-solvent, the active agent can also be present as a microparticulate rather than in solution. The continuous phase is then removed from the polymer/active agent solution, thereby forming a solid polymer/active agent matrix.

Claims

1. A method for forming a polymer-based sustained release device comprising the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, an effective amount of the biologically active and a continuous phase comprising a polymer solvent/polymer non-solvent mixture wherein the polymer and biologically active agent are present in relative concentrations such that the device contains about 50% by weight or more of the biologically active agent and the amount of non-solvent achieves solubilization of the biologically active agent and does not cause substantial precipitation of the polymer;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the continuous phase of step (a) from the polymer/biologically active agent solution, thereby forming a solid polymer/biologically active agent matrix.

2. The method of claim 1 wherein the polymer solvent is DMSO.

3. The method of claim 2 wherein the polymer non-solvent is ethanol.

4. The method of claim 1 wherein the droplets are microdroplets.

5. The method of claim 1 wherein the active agent is a peptide, an antigen or a small molecule drug.

6. The method of claim 1 wherein the active agent is an LHRH analog.

7. The method of claim 6 wherein the LHRH analog is azaline B.

8. The method of claim 1 wherein the polymer is selected from the group consisting of:

poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

9. A method for forming a polymer-based sustained release device comprising the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, an effective amount of the biologically active agent and a continuous phase comprising a polymer solvent/biologically active agent non-solvent mixture wherein the amount of non-solvent achieves solubilization of the biologically active agent and does not cause substantial precipitation of the polymer;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the continuous phase of step (a) from the polymer/biologically active agent solution, thereby forming a solid polymer/biologically active agent matrix.

10. The method of claim 9 wherein the droplets are microdroplets.

11. The method of claim 9 wherein the active agent is a peptide, an antigen or a small molecule drug.

12. The method of claim 9 wherein the active agent is an LHRH analog.

13. The method of claim 12 wherein the LHRH analog is azaline B.

14. The method of claim 9 wherein the polymer is selected from the group consisting of:

poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

15. A method for forming a polymer-based sustained release device comprising the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, an effective amount of the biologically active agent, and a continuous phase comprising a polymer solvent/biologically active agent non-solvent mixture wherein the amount of non-solvent achieves the biologically active agent as a microparticulate in the continuous phase and does not cause substantial precipitation of the polymer;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the continuous phase of step (a) from the polymer/biologically active agent solution, thereby forming a solid polymer/biologically active agent matrix.

16. The method of claim 15 wherein the droplets are microdroplets.

17. The method of claim 15 wherein the active agent is a peptide, an antigen or a small molecule drug.

18. The method of claim 15 wherein the active agent is an LHRH analog.

19. The method of claim 18 wherein the LHRH analog is azaline B.

20. The method of claim 15 wherein the polymer is selected from the group consisting of:

poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

21. The method of claim 19 wherein the continuous phase comprises DMSO.

23. The method of claim 21 wherein the DMSO is removed by extraction with an oil.

24. The method of claim 21 wherein the DMSO is removed by extraction with an alkane/ethanol mixture.

22. A method for forming a polymer-based sustained release device comprising the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, a continuous phase comprising one or more polymer solvents and an effective amount of the biologically active agent wherein the polymer and biologically active agent are present in relative concentrations such that the device contains about 50% by weight or more of biologically active agent;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the DMSO of step (a) thereby forming a solid polymer/active agent matrix.

25. The method of claim 22 wherein the polymer is selected from the group consisting of:

poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

26. The method of claim 22 wherein the active agent is a peptide, an antigen or a small molecule drug.

27. The method of claim 22 wherein the active agent is an LHRH analog.

28. The method of claim 27 wherein the LHRH analog is azaline B.

32. The polymer-based sustained release device of claim 28 wherein the active agent is a peptide, an antigen or a small molecule drug.

33. The polymer-based sustained release device of claim 28 wherein the active agent is an LHRH analog.

34. The polymer-based sustained release device of claim 32 wherein the LHRH analog is azaline B.

29. A polymer-based sustained release device produced by the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, a continuous phase comprising one or more polymer solvents and an effective amount of the biologically active agent wherein the polymer and biologically active agent are present in relative concentrations such that the device contains about 50% by weight or more of biologically active agent;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the continuous phase of step (a) thereby forming a solid polymer/biologically active agent matrix.

30. The polymer-based sustained release device of claim 29, wherein the device is in the form of microparticles.

31. The polymer-based sustained release device of claim 29, wherein the polymer is selected from the group consisting of:

poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acids, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

35. A polymer-based sustained release device produced by the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, a continuous phase comprising a polymer solvent/polymer non-solvent mixture and an effective amount of the biologically active agent wherein the polymer and biologically active agent are present in relative concentrations such that the device contains about 50% by weight or more of biologically active agent, and the amount of polymer non-solvent achieves solubilization of the biologically active agent and does not cause substantial precipitation of the polymer;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the continuous phase of step (a) thereby forming a solid polymer/biologically active agent matrix.

36. The polymer-based sustained release device of claim 35, wherein the device is in the form of microparticles.

37. The polymer-based sustained release device of claim 35, wherein the polymer is selected from the group consisting of:

poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

38. The polymer-based sustained release device of claim 35 wherein the active agent is a peptide, an antigen or a small molecule drug.

39. The polymer-based sustained release device of claim 35 wherein the active agent is an LHRH analog.

40. The polymer-based sustained release device of claim 35 wherein the LHRH analog is azaline B.

41. A polymer-based sustained release device produced by the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, a continuous phase comprising a polymer solvent/biologically active agent non-solvent mixture and an effective amount of the biologically active agent wherein the polymer and biologically active agent are present in relative concentrations such that the device contains about 50% by weight or more of biologically active agent, and the amount of polymer non-solvent achieves solubilization of the biologically active agent and does not cause substantial precipitation of the polymer;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the continuous phase of step (a) thereby forming a solid polymer/biologically active agent matrix.

42. The polymer-based sustained release device of claim 41, wherein the device is in the form of microparticles.

43. The polymer-based sustained release device of claim 41, wherein the polymer is selected from the group consisting of:

poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

44. The polymer-based sustained release device of claim 41 wherein the active agent is a peptide, an antigen, or a small molecule drug.

45. The polymer-based sustained release device of claim 41 wherein the active agent is an LHRH analog.

46. The polymer-based sustained release device of claim 41 wherein the LHRH analog is azaline B.

47. A polymer-based sustained release device produced by the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, an effective amount of the biologically active agent and a continuous phase comprising a polymer solvent/biologically active agent non-solvent mixture wherein the polymer and biologically active agent are present in relative concentrations such that the device contains about 50% by weight or more of biologically active agent, and the amount of polymer non-solvent achieves the biologically active agent as a microparticulate in the continuous phase and does not cause substantial precipitation of the polymer;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution; and

d) removing the continuous phase of step (a) thereby forming a solid polymer/biologically active agent matrix.

48. The polymer-based sustained release device of claim 47, wherein the device is in the form of microparticles.

49. The polymer-based sustained release device of claim 47, wherein the polymer is selected from the group consisting of:

poly(lactide)s poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.

50. The polymer-based sustained release device of claim 47 wherein the active agent is a peptide, an antigen or a small molecule drug.

51. The polymer-based sustained release device of claim 47 wherein the active agent is an LHRH analog.

52. The polymer-based sustained release device of claim 47 wherein the LHRH analog is azaline B.