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Last Updated: March 29, 2024

Details for Patent: 6,379,704


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Title: Method for preparing microparticles having a selected polymer molecular weight
Abstract:A method for preparing microparticles having a selected polymer molecular weight. The hold time and temperature of a solution containing a nucleophilic compound and a polymer having a starting molecular weight are controlled in order to control the molecular weight of the polymer in the finished microparticle product. In this manner, a selected polymer molecular weight in the finished microparticle product can be achieved from a variety of starting material molecular weights.
Inventor(s): Wright; Steven G. (Madeira, OH), Rickey; Michael E. (Loveland, OH), Ramstack; J. Michael (Lebanon, OH), Lyons; Shawn L. (Cincinnati, OH), Hotz; Joyce M. (Cincinnati, OH)
Assignee: Alkermes Controlled Therapeutics Inc. II (Cambridge, MA)
Filing Date:Jun 01, 2001
Application Number:09/870,751
Claims:1. A method of preparing microparticles having a selected microparticle polymer molecular weight, comprising:

(a) preparing a first phase, the first phase comprising a nucleophilic compound, a polymer having a starting molecular weight, and a solvent for the polymer;

(b) combining the first phase with a second phase to form an emulsion;

(c) extracting solvent from the emulsion, thereby forming microparticles; and

(d) maintaining the first phase at a hold temperature for a hold period prior to step (b), the hold period of sufficient duration to allow the starting molecular weight of the polymer to reduce so that the selected microparticle polymer molecular weight is achieved.

2. The method of claim 1, further comprising:

(e) increasing the hold temperature, thereby increasing molecular weight decay of the polymer to reduce a duration of the hold period.

3. The method of claim 1, further comprising:

(e) decreasing the hold temperature, thereby decreasing molecular weight decay of the polymer to increase a duration of the hold period.

4. The method of claim 1, wherein the starting molecular weight is in the range of from about 50 kD to about 250 kD.

5. The method of claim 1, wherein the hold period is in the range of from about 0.05 hour to about 6 hours.

6. The method of claim 1, wherein the hold temperature is in the range of from about 15.degree. C. to about 35.degree. C.

7. The method of claim 1, wherein step (c) comprises combining the emulsion and an extraction medium.

8. The method of claim 1, wherein the nucleophilic compound is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

9. The method of claim 8, wherein the solvent comprises benzyl alcohol and ethyl acetate.

10. The method of claim 1, wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, and copolymers of the foregoing.

11. The method of claim 10, wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.

12. The method of claim 1, further comprising:

(e) mixing the first phase during the hold period.

13. The method of claim 1, wherein the selected microparticle polymer molecular weight is in the range of from about 10 kD to about 185.0 kD.

14. The method of claim 4, wherein the selected microparticle polymer molecular weight is in the range of from about 10 kD to about 185.0 kD.

15. The method of claim 1, wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.

16. The method of claim 4, wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.

17. The method of claim 13, wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.

18. A method of preparing microparticles, comprising:

(a) providing a polymer having a starting molecular weight;

(b) dissolving the polymer and a nucleophilic compound in a solvent to form a first phase;

(c) combining the first phase with a second phase to form an emulsion;

(d) extracting solvent from the emulsion, thereby forming microparticles; and

(e) maintaining the first phase at a hold temperature for a hold period prior to step (c), wherein the hold period is selected so that the starting molecular weight reduces so that a selected microparticle polymer molecular weight is achieved.

19. The method of claim 18, further comprising:

(f) increasing the hold temperature, thereby increasing molecular weight decay of the polymer to reduce a duration of the hold period.

20. The method of claim 18, further comprising:

(f) decreasing the hold temperature, thereby decreasing molecular weight decay of the polymer to increase a duration of the hold period.

21. The method of claim 18, wherein the starting molecular weight is in the range of from about 50 kD to about 250 kD.

22. The method of claim 18, wherein the hold period is in the range of from about 0.05 hour to about 6 hours.

23. The method of claim 18, wherein the hold temperature is in the range of from about 15.degree. C. to about 35.degree. C.

24. The method of claim 18, wherein step (d) comprises combining the emulsion and an extraction medium.

25. The method of claim 18, further comprising:

(f) adding an active agent to the first phase.

26. The method of claim 18, wherein the nucleophilic compound is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

27. The method of claim 26, wherein the solvent comprises benzyl alcohol and ethyl acetate.

28. The method of claim 18, wherein the polymer is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, and copolymers of the foregoing.

29. The method of claim 28, wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.

30. The method of claim 18, further comprising:

(f) mixing the first phase during the hold period.

31. The method of claim 18, wherein the selected microparticle polymer molecular weight is in the range of from about 10 kD to about 185.0 kD.

32. The method of claim 21, wherein the selected microparticle polymer molecular weight is in the range of from about 10 kD to about 185.0 kD.

33. The method of claim 18, wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.

34. The method of claim 21, wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.

35. The method of claim 31, wherein the starting molecular weight reduces by an amount in the range of from about 10% to about 50% to reach the selected microparticle polymer molecular weight.

36. Microparticles having a selected microparticle polymer molecular weight prepared by the method of claim 1.

37. Microparticles prepared by the method of claim 18.

38. The method of claim 1, wherein the nucleophilic compound is an active agent.

39. The method of claim 1, wherein the nucleophilic compound is an inactive agent.

40. The method of claim 1, further comprising:

(e) adding an active agent to the first phase.

41. The method of claim 1, further comprising:

(e) adding an inactive agent to the first phase.

42. The method of claim 1, wherein the nucleophilic compound is basic.

43. The method of claim 18, wherein the nucleophilic compound is an active agent.

44. The method of claim 18, wherein the nucleophilic compound is an inactive agent.

45. The method of claim 18, further comprising:

(f) adding an inactive agent to the first phase.

46. The method of claim 18, wherein the nucleophilic compound is basic.

47. The method of claim 1, wherein the nucleophilic compound is naltrexone.

48. The method of claim 1, wherein the nucleophilic compound is oxybutynin.

49. The method of claim 18, wherein the nucleophilic compound is naltrexone.

50. The method of claim 18, wherein the nucleophilic compound is oxybutynin.

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