Details for Patent: 7,223,440

Title:	Residual solvent extraction method and microparticles produced thereby
Abstract:	Methods for preparing microparticles having reduced residual solvent levels. Microparticles are contacted with a non-aqueous washing system to reduce the level of residual solvent in the microparticles. Preferred non-aqueous washing systems include 100% ethanol and a blend of ethanol and heptane. A solvent blend of a hardening solvent and a washing solvent can be used to harden and wash microparticles in a single step, thereby eliminating the need for a post-hardening wash step.
Inventor(s):	Rickey; Michael E. (Loveland, OH), Ramstack; J. Michael (Lunenburg, MA), Kumar; Rajesh (Marlborough, MA)
Assignee:	Alkermes, Inc. (Cambridge, MA)
Filing Date:	Dec 21, 2005
Application Number:	11/312,371
Claims:	1. A method for preparing microparticles, comprising: preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent; combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase; extracting the halogenated solvent from the combined phase with an extraction medium, that is a non-solvent for the polymer and a solvent for the halogentated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium; rinsing the precipitated microparticles to form finished microparticles; and after said rinsing step, washing the finished microparticles in a non-aquesous washing system comprising 100% heptane to thereby reduce the level of residual halogenated solvent. 2. The method of claim 1, wherein the halogenated solvent is methylene chloride. 3. The method of claim 1, wherein a temperature of the washing is between about 10.degree. and about 26.degree. C. 4. The method of claim 1, wherein the coacervating agent is silicone oil. 5. The method of claim 1, wherein the extraction medium is a 1:9 ratio of ethanol to heptane. 6. The method of claim 1, wherein the biodegradable, biocompatible 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. 7. The method of claim 1, wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight. 8. The method of claim 1, further comprising after said washing step: final drying of the washed microparticles. 9. A method for preparing microparticles, comprising: contacting rinsed finished microparticles comprising a biodegradable, biocompatible polymer matrix comprising a peptide and a halogenated solvent with a non-aqueous washing system to thereby reduce a level of residual halogentated solvent with a non-aqueous washing system to thereby reduce a level of residual halogenated solvent in the rinsed, finished microparticles to formed washed microparticles, wherein the washing system comprises 100% heptane; and recovering the washed microparticles from the washing system. 10. The method of claim 9, wherein the halogenated solvent is methylene chloride. 11. The method of claim 9, wherein a temperature of the washing is between about 10.degree. and about 26.degree. C. 12. The method of claim 9, wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight. 13. Microparticles prepared by the method of claim 1. 14. A method for preparing microparticles, comprising: preparing a first phase comprising a biodegradable, biocompatible polymer and a halogenated solvent; preparing an aqueous second phase comprising a peptide; combining the first phase and the second phase under the influence of a mixer to form an emulsion; combining the emulsion with a coacervating agent that is free from solvent for the polymer to form a combined phase; extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium; rinsing the precipitated microparticle to form finished microparticles; and after said rinsing step washing the finished microparticles in a non-aqueous washing system that comprises 100% heptane to thereby reduce a level of residual halogenated solvent. 15. The method of claim 14, wherein the mixer is a static mixer. 16. The method of claim 14, wherein the halogenated solvent is methylene chloride. 17. The method of claim 14, wherein a temperature of the washing is between about 10.degree. and about 26.degree. C. 18. The method of claim 14, wherein the coacervating agent is silicone oil. 19. The method of claim 14, wherein the extraction medium is a 1:9 ratio of ethanol to heptane. 20. The method of claim 14, wherein the biodegradable, biocompatible 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. 21. The method of claim 14, wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight. 22. A method for preparing microparticles, comprising: preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent; combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase; extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium; rinsing the precipitated microparticles to form finished microparticles; and after said rinsing step, washing the finished microparticles in a non-aqueous washing system that comprises heptane. 23. A method for preparing microparticles, comprising: preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a solvent; combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase; extracting the solvent from the combined phase in an extraction medium that is a non-solvent for the polymer and a solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium; rinsing the precipitated microparticles to form finished microparticles; and after said rinsing step, washing the finished microparticles in 100% heptane.