Details for Patent: 5,916,598
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Title: | Preparation of biodegradable, biocompatible microparticles containing a biologically active agent |
Abstract: | A method for preparing biodegradable, biocompatible microparticles. A first phase is prepared that includes a biodegradable, biocompatible polymer, an active agent, and a solvent. An immiscible second phase is prepared. The first and second phases are combined to form an emulsion in which the first phase is discontinuous and the second phase is continuous. The two phases are immersed in a quench liquid that includes a quench medium and a quantity of the solvent. The quantity of the solvent is selected to control a rate of extraction of the solvent from the first phase. The first phase is isolated in the form of microparticles. Also disclosed is a microencapsulated active agent prepared by the method for preparing biodegradable, biocompatible microparticles. |
Inventor(s): | Rickey; Michael E. (Loveland, OH), Ramstack; J. Michael (Lebanon, OH), Lewis; Danny H. (Hartselle, AL) |
Assignee: | Alkermes Controlled Therapeutics Inc. II (Cambridge, MA) |
Filing Date: | May 04, 1998 |
Application Number: | 09/071,865 |
Claims: | 1. A method of preparing biodegradable, biocompatible microparticles, comprising: (A) preparing a first phase, said first phase comprising an active agent, a biodegradable, biocompatible polymer, and a solvent; (B) preparing a second phase, wherein said first phase is substantially immiscible in said second phase; (C) combining said first phase and said second phase under the influence of mixing means to form an emulsion in which said first phase is discontinuous and said second phase is continuous; (D) immersing said first phase and said second phase in a quench liquid that comprises a quench medium and a quantity of said solvent, wherein the quantity of said solvent is selected to control a rate of extraction of said solvent from said discontinuous first phase; and (E) isolating said discontinuous first phase in the form of microparticles. 2. The method of claim 1, wherein said mixing means comprises a static mixer. 3. The method of claim 1, wherein said solvent is a solvent blend of at least two mutually miscible organic solvents. 4. The method of claim 3, wherein one of said at least two organic solvents has a rate of extraction from said discontinuous first phase that is more rapid than a rate of extraction from said discontinuous first phase of another of said at least two organic solvents. 5. The method of claim 4, wherein said quantity of said solvent in said quench liquid comprises a quantity of said one of said at least two organic solvents having the more rapid rate of extraction and is free from said another of said at least two organic solvents. 6. The method of claim 1, wherein said 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. A method of preparing biodegradable, biocompatible microparticles, comprising: (A) preparing a first phase, said first phase comprising an active agent, a biodegradable, biocompatible polymer, and a solvent blend comprising a first solvent and a second solvent; (B) preparing a second phase, wherein said first phase is substantially immiscible in said second phase; (C) combining said first phase and said second phase under the influence of mixing means to form an emulsion in which said first phase is discontinuous and said second phase is continuous; (D) immersing said first phase and said second phase in a quench liquid that comprises a quench medium and a quantity of said first solvent, wherein said first solvent has a rate of extraction from said discontinuous first phase that is more rapid than a rate of extraction from said discontinuous first phase of said second solvent, said quench liquid being free from said second solvent; and (E) isolating said discontinuous first phase in the form of microparticles. 8. The method of claim 7, wherein said first solvent is ethyl acetate and said second solvent is benzyl alcohol. 9. The method of claim 8, wherein said active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof. 10. The method of claim 7, wherein said quench liquid has a concentration of said first solvent of from about 20% to about 70% of a saturation point of said first solvent in said quench medium. 11. The method of claim 8, wherein said quench liquid has a concentration of ethyl acetate of from about 20% to about 70% of a saturation point of ethyl acetate in said quench medium. 12. The method of claim 11, wherein said quench medium is water. 13. The method of claim 7, wherein said mixing means comprises a static mixer. 14. The method of claim 7, wherein said 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. 15. A microencapsulated active agent prepared by a method for preparing biodegradable, biocompatible microparticles, said method comprising: (A) preparing a first phase, said first phase comprising an active agent, a biodegradable, biocompatible polymer, and a solvent; (B) preparing a second phase, wherein said first phase is substantially immiscible in said second phase; (C) combining said first phase and said second phase under the influence of mixing means to form an emulsion in which said first phase is discontinuous and said second phase is continuous; (D) immersing said first phase and said second phase in a quench liquid that comprises a quench medium and a quantity of said solvent, wherein the quantity of said solvent is selected to control a rate of extraction of said solvent from said discontinuous first phase; and (E) isolating said discontinuous first phase in the form of microparticles. 16. A microencapsulated active agent prepared by a method for preparing biodegradable, biocompatible microparticles, said method comprising: (A) preparing a first phase, said first phase comprising an active agent, a biodegradable, biocompatible polymer, and a solvent blend comprising a first solvent and a second solvent; (B) preparing a second phase, wherein said first phase is substantially immiscible in said second phase; (C) combining said first phase and said second phase under the influence of mixing means to form an emulsion in which said first phase is discontinuous and said second phase is continuous; (D) immersing said first phase and said second phase in a quench liquid that comprises a quench medium and a quantity of said first solvent, wherein said first solvent has a rate of extraction from said discontinuous first phase that is more rapid than a rate of extraction from said discontinuous first phase of said second solvent, said quench liquid being free from said second solvent; and (E) isolating said discontinuous first phase in the form of microparticles. 17. The method of claim 1, further comprising: (F) adjusting a temperature of said quench medium to control solubility of said solvent in said quench medium. 18. The method of claim 7, further comprising: (F) adjusting a temperature of said quench medium to control solubility of said first solvent in said quench medium. 19. The method of claim 8, further comprising: (F) adjusting a temperature of said quench medium to control solubility of said ethyl acetate in said quench medium. 20. The method of claim 19, wherein the temperature of said quench medium is in the range of 0-10.degree. C. |