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Claims for Patent: 6,194,006

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Claims for Patent: 6,194,006

Title: Preparation of microparticles having a selected release profile
Abstract:An improved method for preparing microparticles that exhibit controlled release of an effective amount of an active agent over an extended period of time. More particularly, a method is provided for preparing microparticles having a selected release profile for release of active agent contained in the microparticles. By adjusting the degree of drying that is performed during the preparation of the microparticles, the release profile can be controlled. By performing no intermediate drying, an initial burst and a substantially linear release profile is achieved. By performing substantially complete intermediate drying, an initial lag phase and a substantially sigmoidal release profile is achieved.
Inventor(s): Lyons; Shawn L. (Cincinnati, OH), Ramstack; J. Michael (Lebanon, OH), Wright; Steven G. (Madeira, OH)
Assignee: Alkermes Controlled Therapeutics Inc. II (Cambridge, MA)
Application Number:09/223,276
Patent Claims: 1. A method for preparing microparticles having a selected release profile for release of active agent contained in the microparticles, comprising:

(a) preparing an emulsion that comprises a first phase and a second phase, wherein the first phase comprises the active agent, a polymer, and a solvent for the polymer;

(b) quenching the emulsion in a quench liquid to form microparticles containing the active agent;

(c) selecting a degree of intermediate drying of the microparticles to be performed so that the selected release profile is achieved;

(d) washing the microparticles; and

(e) final drying the microparticles.

2. The method of claim 1, wherein the selecting step (c) is carried out to select no intermediate drying, thereby resulting in microparticles having an initial burst and a substantially linear release profile.

3. The method of claim 1, wherein the selecting step (c) is carried out to select substantially complete intermediate drying, thereby resulting in microparticles having an initial lag phase and a substantially sigmoidal release profile.

4. The method of claim 3, further comprising after step (c):

(f) performing the selected degree of intermediate drying.

5. The method of claim 4, wherein the substantially complete intermediate drying results in the microparticles having a moisture content of less than about 0.2% after step (f).

6. The method of claim 4, wherein the substantially complete intermediate drying comprises a step of drying under vacuum and a step of drying with a gas sweep.

7. The method of claim 4, wherein the substantially complete intermediate drying comprises drying under vacuum with a gas sweep for a period in the range of approximately 16-48 hours.

8. The method of claim 6, wherein the gas sweep is performed using air.

9. The method of claim 6, wherein the gas sweep is performed using nitrogen.

10. The method of claim 1, wherein step (a) comprises:

(1) preparing the first phase by dissolving the polymer in the solvent, and dissolving or dispersing the active agent in the solvent; and

(2) combining the first phase and the second phase under the influence of mixing means to form the emulsion in which the first phase is discontinuous and the second phase is continuous.

11. The method of claim 10, wherein the mixing means comprises a static mixer.

12. The method of claim 4, wherein step (a) comprises:

(1) preparing the first phase by dissolving the polymer in the solvent to form a polymer solution, dissolving or dispersing the active agent in another solvent to form an active agent solution, and combining the polymer solution and the active agent solution to form the first phase; and

(2) combining the first phase and the second phase under the influence of mixing means to form the emulsion in which the first phase is discontinuous and the second phase is continuous.

13. The method of claim 12, wherein the mixing means comprises a static mixer.

14. The method of claim 4, wherein the degree of intermediate drying performed in step (f) is carried out at a temperature of less than about 10.degree. C.

15. The method of claim 4, wherein the degree of intermediate drying performed in step (f) is carried out in a drying device for a time period greater than about four hours after substantially zero absolute humidity is reached in the drying device.

16. The method of claim 1, wherein the washing step (d) comprises:

(1) introducing the microparticles into a vessel containing an extraction medium having a temperature lower than the glass transition temperature (T.sub.g) of the microparticles; and

(2) agitating the vessel contents to disperse the microparticles in the extraction medium.

17. The method of claim 1, further comprising after step (c):

(f) performing the selected degree of intermediate drying.

18. A method for controlling a release profile of an active agent contained in microparticles, comprising:

(a) forming microparticles containing the active agent by quenching an emulsion in a quench liquid, the emulsion comprising a first phase and a second phase, wherein the first phase comprises the active agent, a polymer, and a solvent for the polymer;

(b) selecting a degree of drying of the microparticles to be performed, wherein the degree of drying affects the release profile of the active agent from the microparticles; and

(c) performing the selected degree of drying.

19. The method of claim 18, wherein the selecting step (b) is carried out to select final drying and no intermediate drying, thereby resulting in an initial burst of the active agent and a substantially linear release of the active agent.

20. The method of claim 18, wherein the selecting step (b) is carried out to select final drying and substantially complete intermediate drying, thereby resulting in an initial lag in release of the active agent, and a substantially sigmoidal release of the active agent.

21. The method of claim 20, wherein the cumulative release of active agent from the microparticles is less than about 15% after 15 days.

22. The method of claim 19, wherein the cumulative release of active agent from the microparticles is greater than about 10% after 24 hours.

23. The method of claim 18, wherein performing step (c) comprises:

(1) performing a degree of intermediate drying of the microparticles;

(2) washing the microparticles; and

(3) performing final drying of the microparticles.

24. The method of claim 23, wherein washing step (2) comprises:

(i) introducing the microparticles into a vessel containing an extraction medium having a temperature lower than the glass transition temperature (T.sub.g) of the microparticles; and

(ii) agitating the vessel contents to disperse the microparticles in the extraction medium.

25. The method of claim 18, wherein performing step (c) comprises:

(1) performing a substantially complete intermediate drying of the microparticles;

(2) washing the microparticles; and

(3) performing a substantially complete final drying of the microparticles.

26. The method of claim 25, wherein the substantially complete intermediate drying step results in the microparticles having a moisture content of less than about 0.2% after step (1).

27. The method of claim 25, wherein the substantially complete intermediate drying step is carried out at a temperature of less than about 10.degree. C.

28. The method of claim 25, wherein the substantially complete intermediate drying step is carried out in a drying device for a time period greater than about four hours after substantially zero absolute humidity is reached in the drying device.

29. The method of claim 25, wherein washing step (2) comprises:

(i) introducing the microparticles into a vessel containing an extraction medium having a temperature lower than the glass transition temperature (T.sub.g) of the microparticles; and

(ii) agitating the vessel contents to disperse the microparticles in the extraction medium.

30. A microencapsulated active agent having a selected release profile prepared by a method for preparing microparticles, the method comprising:

(a) preparing an emulsion that comprises a first phase and a second phase, wherein the first phase comprises the active agent, a polymer, and a solvent for the polymer;

(b) quenching the emulsion in a quench liquid to form microparticles containing the active agent;

(c) selecting a degree of intermediate drying of the microparticles to be performed so that the selected release profile is achieved;

(d) washing the microparticles; and

(e) final drying the microparticles.

31. The microencapsulated active agent of claim 30, wherein the method further comprises after step (c):

(f) performing the selected degree of intermediate drying.

32. The microencapsulated active agent of claim 30, wherein the selecting step (c) is carried out to select no intermediate drying, thereby resulting in microparticles having an initial burst and a substantially linear release profile.

33. The microencapsulated active agent of claim 30, wherein the selecting step (c) is carried out to select substantially complete intermediate drying, thereby resulting in microparticles having an initial lag phase and a substantially sigmoidal release profile.

34. The microencapsulated active agent of claim 31, wherein the substantially complete intermediate drying results in the microparticles having a moisture content of less than about 0.2% after step (f).

35. The microencapsulated active agent of claim 33, wherein the cumulative release of active agent from the microparticles is less than about 15% after 15 days.

36. The method of claim 24, wherein washing step (2) further comprises:

(iii) transferring the microparticles from the vessel to an extraction tank having another extraction medium, wherein the temperature of the another extraction medium is higher than the glass transition temperature (T.sub.g) of the microparticles at the time of transfer of the microparticles into the another extraction medium.

37. The method of claim 16, wherein washing step (d) further comprises:

(3) transferring the microparticles from the vessel to an extraction tank having another extraction medium, wherein the temperature of the another extraction medium is higher than the glass transition temperature (T.sub.g) of the microparticles at the time of transfer of the microparticles into the another extraction medium.

38. The method of claim 36, wherein the temperature of the another extraction medium is greater than about 18.degree. C.

39. The method of claim 37, wherein the temperature of the another extraction medium is greater than about 18.degree. C.

40. The method of claim 24, wherein the temperature of the extraction medium is less than about 10.degree. C.

41. The method of claim 16, wherein the temperature of the extraction medium is less than about 10.degree. C.

42. The method of claim 12, wherein the solvent used to form the polymer solution is ethyl acetate and the solvent used to form the active agent solution is benzyl alcohol.

43. The microencapsulated active agent of claim 30, wherein the solvent is a solvent blend comprising ethyl acetate and benzyl alcohol.
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