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Claims for Patent: 6,331,317

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Claims for Patent: 6,331,317

Title: Apparatus and method for preparing microparticles
Abstract:Apparatus and method for preparing microparticles. An emulsion is formed by combining two phases in a static mixing assembly. The static mixing assembly preferably includes a preblending static mixer and a manifold. The emulsion flows out of the static mixing assembly into a quench liquid whereby droplets of the emulsion form microparticles. The residence time of the emulsion in the static mixing assembly is controlled to obtain a predetermined particle size distribution of the resulting microparticles.
Inventor(s): Lyons; Shawn L. (Cincinnati, OH), Wright; Steven G. (Madeira, OH)
Assignee: Alkermes Controlled Therapeutics II Inc. (Cambridge, MA)
Application Number:09/438,659
Patent Claims: 1. A method of preparing microparticles, comprising:

preparing a first phase, the first phase comprising an active agent and a polymer;

preparing a second phase;

preparing a quench liquid;

pumping the first phase and the second phase through a first static mixer to form an emulsion; and

flowing the emulsion through a manifold that includes a plurality of static mixers into the quench liquid whereby droplets of the emulsion form microparticles.

2. The method of claim 1, wherein a diameter of the first static mixer is greater than a diameter of each of the plurality of static mixers in the manifold.

3. The method of claim 1, wherein the pumping step is performed wherein the first phase is pumped at a first flow rate and the second phase is pumped at a second flow rate greater than the first flow rate.

4. The method of claim 3, wherein a ratio of the second flow rate to the first flow rate is from about 4:1 to about 5:1.

5. The method of claim 3, wherein the flowing step is performed by flowing a portion of a total flow rate through each of the plurality of static mixers in the manifold, wherein the total flow rate is the sum of the first flow rate and the second flow rate.

6. The method of claim 5, wherein the plurality of static mixers in the manifold is two.

7. The method of claim 1, wherein the first static mixer comprises a plurality of static mixing elements received within a conduit.

8. The method of claim 7, wherein each of the plurality of static mixers in the manifold comprises a plurality of static mixing elements received within a conduit.

9. The method of claim 1, wherein the step of preparing the first phase comprises:

dissolving the active agent in a first solvent to form an active agent solution;

dissolving the polymer in a second solvent to form a polymer solution; and

blending the active agent solution and the polymer solution.

10. The method of claim 9, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

11. The method of claim 10, wherein the first solvent is benzyl alcohol.

12. 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 85:15 to about 50:50.

13. The method of claim 12, wherein the second solvent is ethyl acetate.

14. A method of preparing microparticles, comprising:

preparing a first phase, the first phase comprising an active agent and a polymer;

preparing a second phase;

preparing a quench liquid;

combining the first phase and the second phase in a first static mixer to form an emulsion, the emulsion forming an outflow of the first static mixer;

dividing the outflow of the first static mixer to form at least two flow streams;

flowing each of the at least two flow streams through a separate second static mixer; and

combining the at least two flow streams with the quench liquid whereby droplets of the emulsion form microparticles.

15. The method of claim 14, wherein a diameter of the first static mixer is greater than a diameter of each separate second static mixer.

16. The method of claim 14, wherein the step of preparing the first phase comprises:

dissolving the active agent in a first solvent to form an active agent solution;

dissolving the polymer in a second solvent to form a polymer solution; and

blending the active agent solution and the polymer solution.

17. The method of claim 16, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.

18. The method of claim 17, wherein the first solvent is benzyl alcohol.

19. The method of claim 16, wherein the polymer is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 85:15 to about 50:50.

20. The method of claim 19, wherein the second solvent is ethyl acetate.

21. The method of claim 14, wherein the at least two flow streams have substantially equal flow rates.

22. A microencapsulated active agent prepared by a method for preparing microparticles, the method comprising:

preparing a first phase, the first phase comprising an active agent and a polymer;

preparing a second phase;

preparing a quench liquid;

pumping the first phase and the second phase through a first static mixer to form an emulsion; and

flowing the emulsion through a manifold that includes a plurality of static mixers into the quench liquid whereby droplets of the emulsion form microparticles.

23. A microencapsulated active agent prepared by a method for preparing microparticles, the method comprising:

preparing a first phase, the first phase comprising an active agent and a polymer;

preparing a second phase;

preparing a quench liquid;

combining the first phase and the second phase in a first static mixer to form an emulsion, the emulsion forming an outflow of the first static mixer;

dividing the outflow of the first static mixer to form at least two substantially identical flow streams;

flowing each of the at least two substantially identical flow streams through a separate second static mixer; and

combining the least two substantially identical flow streams with the quench liquid whereby droplets of the emulsion form microparticles.

24. A system for preparing microparticles, comprising:

a first pump;

a second pump;

a first static mixer in fluid communication with said first pump and with said second pump, wherein said first pump is configured to pump an organic phase into said first static mixer, and said second pump is configured to pump a continuous phase into said first static mixer;

a manifold in fluid communication with said first static mixer, said manifold comprising a plurality of static mixers; and

an extraction vessel in fluid communication with said manifold, wherein an outflow of said first static mixer flows through said manifold into said extraction vessel.

25. The system of claim 24, wherein said first pump is configured to operate at a first flow rate, and said second pump is configured to operate at a second flow rate greater than said first flow rate.

26. The system of claim 25, wherein a ratio of said second flow rate to said first flow rate is from about 4:1 to about 5:1.

27. The system of claim 24, wherein a diameter of said first static mixer is greater than a diameter of each of said plurality of static mixers in said manifold.

28. The system of claim 24, wherein said plurality of static mixers in said manifold is two.

29. The system of claim 27, wherein said plurality of static mixers in said manifold is two.

30. The system of claim 24, further comprising:

a first vessel in fluid communication with said first pump; and

a second vessel in fluid communication with said second pump.

31. A method for controlling particle size distribution of microparticles, comprising:

preparing a first phase, the first phase comprising an active agent and a polymer;

preparing a second phase;

preparing a quench liquid;

pumping the first phase and the second phase through a static mixing assembly to form an emulsion;

flowing the emulsion into the quench liquid whereby droplets of the emulsion form microparticles; and

adjusting a residence time of the emulsion in the static mixing assembly to obtain a predetermined particle size distribution of the resulting microparticles, wherein the residence time is equal to a length of the static mixing assembly divided by an average velocity of the emulsion through the static mixing assembly.

32. The method of claim 31, wherein the adjusting step is carried out to increase the residence time, thereby narrowing particle size distribution.

33. The method of claim 31, wherein the adjusting step is carried out to decrease the residence time, thereby broadening particle size distribution.

34. The method of claim 31, wherein the static mixing assembly comprises a plurality of individual static mixers configured so that the emulsion flows sequentially through the plurality of individual static mixers.

35. The method of claim 31, wherein the static mixing assembly comprises:

a first static mixer; and

a manifold that includes a plurality of static mixers, the manifold in fluid communication with the first static mixer.

36. The method of claim 35, wherein a diameter of the first static mixer is greater than a diameter of each of the plurality of static mixers in the manifold.

37. The method of claim 31, wherein the residence time is from about three seconds to about four seconds.

38. The method of claim 35, wherein the residence time is from about three seconds to about four seconds.

39. The method of claim 31, wherein the adjusting step is carried out by changing the length of the static mixing assembly.

40. The method of claim 6, wherein the portion of the total flow rate flowing through each of the two static mixers is one-half.

41. The method of claim 35, wherein the plurality of static mixers in the manifold are configured to provide a plurality of parallel flow streams.

42. The method of claim 36, wherein the plurality of static mixers in the manifold are configured to provide a plurality of parallel flow streams.

43. The system of claim 24, wherein said plurality of static mixers are configured in parallel.

44. The system of claim 24, wherein said plurality of static mixers are configured in series.
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