Claims for Patent: 6,495,166

Summary for Patent: 6,495,166

Title:	Apparatus and method for preparing microparticles using in-line solvent extraction
Abstract:	Apparatus and method for preparing microparticles using in-line solvent extraction. An emulsion is formed by combining two phases in a static mixer. The emulsion is combined with an extraction liquid in a blending static mixer. The outflow of the blending static mixer is combined with additional extraction liquid. The additional extraction liquid and the outflow of the blending static mixer can be combined in a vessel, or through the use of a static mixer manifold that includes a plurality of static mixers.
Inventor(s):	Lyons; Shawn L. (Cincinnati, OH), Wright; Steven G. (Madeira, OH)
Assignee:	Alkermes Controlled Therapeutics Inc. (Cambridge, MA)
Application Number:	09/438,656
Patent Claims:	1. A method of preparing microparticles, comprising: preparing a first phase, the first phase comprising an active agent, a polymer, and a solvent; preparing a continuous second phase; combining the first phase and the second phase in a first static mixer to form an emulsion; combining the emulsion and a first extraction liquid for extracting solvent from the emulsion in a second static mixer; and combining an outflow of the second static mixer with a second extraction liquid for extracting solvent from the emulsion. 2. The method of claim 1, wherein the step of combining the outflow of the second static mixer with the second extraction liquid comprises: allowing the outflow of the second static mixer to flow into a vessel containing the second extraction liquid. 3. The method of claim 1, wherein the step of combining the outflow of the second static mixer with the second extraction liquid comprises: combining the outflow of the second static mixer and the second extraction liquid in a third static mixer. 4. The method of claim 3, further comprising: allowing an outflow of the third static mixer to flow into a vessel. 5. The method of claim 4, wherein the vessel is empty prior to allowing the outflow of the third static mixer to flow therein. 6. The method of claim 1, wherein the second static mixer comprises a plurality of individual static mixers configured to provide a plurality of parallel flow streams. 7. The method of claim 6, wherein the plurality of individual static mixers is two. 8. The method of claim 2, wherein the second static mixer comprises a plurality of individual static mixers configured to provide a plurality of parallel flow streams. 9. The method of claim 3, wherein the second static mixer comprises a plurality of individual static mixers configured to provide a plurality of parallel flow streams. 10. The method of claim 1, wherein the step of combining the first phase and the second phase comprises: pumping the first phase at a first flow rate; and pumping the second phase at a second flow rate greater than the first flow rate. 11. The method of claim 10, wherein a ratio of the second flow rate to the first flow rate is approximately 2:1. 12. The method of claim 1, wherein the step of combining the emulsion and the first extraction liquid comprises: pumping the first extraction liquid at a first rate into the emulsion flowing out of the first static mixer to form a first combined stream; and allowing the first combined stream to flow through the second static mixer. 13. The method of claim 12, wherein a volume ratio of the emulsion to the first extraction liquid is approximately 1:1. 14. The method of claim 1, wherein the step of combining the outflow of the second static mixer with the second extraction liquid comprises: pumping the second extraction liquid at a second rate into the outflow of the second static mixer to form a second combined stream; and allowing the second combined stream to flow through a third static mixer. 15. The method of claim 12, wherein the step of combining the outflow of the second static mixer with the second extraction liquid comprises: pumping the second extraction liquid at a second rate into the outflow of the second static mixer to form a second combined stream; and allowing the second combined stream to flow through a third static mixer. 16. The method of claim 15, wherein the second rate is greater than the first rate. 17. The method of claim 15, wherein the first extraction liquid and the second extraction liquid are the same. 18. The method of claim 15, wherein the first extraction liquid and the second extraction liquid are different. 19. The method of claim 1, wherein a volume ratio of the second phase to the first phase is approximately 5:1. 20. The method of claim 1, wherein a volume ratio of the second phase to the first phase is approximately 3:1. 21. The method of claim 1, wherein the first extraction liquid has the same composition as the second extraction liquid. 22. The method of claim 1, wherein the first extraction liquid is different from the second extraction liquid. 23. The method of claim 1, wherein the first extraction liquid has the same composition as the second phase. 24. The method of claim 23, wherein the second extraction liquid has the same composition as the second phase. 25. 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. 26. The method of claim 25, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof. 27. The method of claim 25, wherein the first solvent is benzyl alcohol. 28. The method of claim 25, 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. 29. The method of claim 27, wherein the second solvent is ethyl acetate. 30. The method of claim 1, wherein the step of preparing the first phase comprises: dissolving the active agent and the polymer in the solvent to form a solution. 31. The method of claim 30, wherein the active agent is bupivacaine and the solvent is ethyl acetate. 32. The method of claim 31, 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. 33. A method of preparing microparticles, comprising: preparing a first phase, the first phase comprising an active agent, a polymer, and a solvent; preparing a continuous second phase; 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; combining the outflow of the first static mixer and a first portion of a starting volume of an extraction liquid for extracting solvent from the emulsion in a second static mixer to form an outflow of the second static mixer; dividing the outflow of the second static mixer to form at least two flow streams; flowing each of the at least two flow streams through a separate third static mixer; and combining the at least two flow streams with a second portion of the extraction liquid. 34. The method of claim 33, wherein the step of combining the at least two flow streams with the second portion of the extraction liquid comprises: allowing the at least two flow streams to flow into a vessel containing the second portion of the extraction liquid. 35. The method of claim 33, wherein the step of combining the at least two flow streams with the second portion of the extraction liquid comprises: combining the at least two flow streams and the second portion of the extraction liquid in a fourth static mixer. 36. The method of claim 35, further comprising: allowing an outflow of the fourth static mixer to flow into a vessel. 37. The method of claim 33, wherein the step of combining the at least two flow streams with the second portion of the extraction liquid comprises: combining the at least two flow streams and the second portion of the extraction liquid in a fourth static mixer and repeating this combining step until the starting volume of the extraction liquid is depleted. 38. A method of preparing microparticles, comprising: preparing a first phase, the first phase comprising an active agent, a polymer, and a solvent; preparing a continuous second phase; 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; combining the outflow of the first static mixer and a first extraction liquid for extracting solvent from the emulsion in a second static mixer to form an outflow of the second static mixer; dividing the outflow of the second static mixer to form at least two flow streams; flowing each of the at least two flow streams through a separate third static mixer; and combining the at least two flow streams with a second extraction liquid for extracting solvent from the emulsion. 39. The method of claim 38, wherein the second extraction liquid is different from the first extraction liquid. 40. The method of claim 38, wherein the step of combining the at least two flow streams with the second extraction liquid comprises: allowing the at least two flow streams to flow into a vessel containing the second extraction liquid. 41. The method of claim 38, wherein the step of combining the at least two flow streams with the second extraction liquid comprises: combining the at least two flow streams and the second extraction liquid in a fourth static mixer. 42. The method of claim 41, wherein the second extraction liquid is different from the first extraction liquid. 43. The method of claim 41, further comprising: allowing an outflow of the fourth static mixer to flow into a vessel. 44. The method of claim 38, wherein the step of combining the at least two flow streams with the second extraction liquid comprises: combining the at least two flow streams and the second extraction liquid in a fourth static mixer and repeating this combining step until the second extraction liquid is depleted. 45. The method of claim 4, further comprising: continuing the step of combining the outflow of the second static mixer and the second extraction liquid in the third static mixer until the first phase is depleted; and transferring a remainder of the second extraction liquid to the vessel. 46. The method of claim 36, further comprising: continuing the step of combining the at least two flow streams and the second portion of the extraction liquid in the fourth static mixer until the first phase is depleted; and transferring a remainder of the starting volume of the extraction liquid to the vessel. 47. The method of claim 43, further comprising: continuing the step of combining the at least two flow streams and the second extraction liquid in the fourth static mixer until the first phase is depleted; and transferring a remainder of the second extraction liquid to the vessel. 48. Microparticles prepared by the method of claim 1. 49. Microparticles prepared by the method of claim 33. 50. Microparticles prepared by the method of claim 38.