Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent

A method for preparing biodegradable, biocompatible microparticles comprising:

• A) preparing a first phase comprising
• 1) a biodegradable, biocompatible polymeric encapsulating binder selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing, and
• 2) an active agent selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof dissolved or dispersed in a blend comprising ethyl acetate and benzyl alcohol, said blend being free from halogenated hydrocarbons;
• B) preparing a second phase comprising polyvinyl alcohol dissolved in water;
• C) combining said first phase and said second phase in a static mixer to form an emulsion in which said first phase is discontinuous and said second phase is continuous;
• D) immersing said first and said second phases in a quench liquid;
• E) isolating said discontinuous first phase in the form of microparticles;
• and
• F) washing said discontinuous first phase with an aqueous solution comprising water and ethanol, thereby reducing the level of benzyl alcohol to less than about 2% by weight of said microparticles.

A microencapsulated drug prepared by a method for preparing biodegradable, biocompatible microparticles comprising:

• A) preparing a first phase comprising:
• (1) a biodegradable, biocompatible polymeric encapsulating binder, and
• (2) an active agent having limited water solubility, dissolved or dispersed in a first solvent;
• B) preparing an aqueous 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) separating said discontinuous first phase from said continuous second phase;
• and
• E) washing said discontinuous first phase with
• (1) water at a temperature in the range of from about 25.degree. C. to about 40.degree. C., or
• (2) an aqueous solution comprising water and a second solvent for residual first solvent in said first phase,
• thereby reducing the level of residual first solvent to less than about 2% by weight of said microparticles.

Microencapsulated risperidone, 9-hydroxyrisperidone, or pharmaceutically acceptable salts thereof prepared by a process comprising:

• A) preparing a first phase comprising:
• 1) a biodegradable, biocompatible polymeric encapsulating binder selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing, and
• 2) an active agent selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof, dissolved or dispersed in a blend comprising ethyl acetate and benzyl alcohol, said blend being free from halogenated hydrocarbons;
• B) preparing a second phase comprising polyvinyl alcohol dissolved in water;
• C) combining said first phase and said second phase in a static mixer to form an emulsion in which said first phase is discontinuous and said second phase is continuous;
• D) immersing said first and second phases in a quench liquid;
• E) isolating said discontinuous first phase in the form of microparticles;
• and
• F) washing said discontinuous first phase with an aqueous solution comprising water and ethanol, thereby reducing the level of benzyl alcohol to less than about 2% by weight of said microparticles.

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 first solvent;
• B) preparing a second phase, wherein said first phase is substantially immiscible in said second phase;
• C) flowing said first phase through a static mixer at a first flow rate;
• D) flowing said second phase through said static mixer at a second flow rate so that said first phase and said second phase flow simultaneously through said static mixer thereby forming microparticles containing said active agent;
• E) isolating said microparticles;
• and
• F) washing said microparticles with water at an elevated temperature or with an aqueous solution comprising water and a second solvent for residual first solvent in said microparticles, thereby reducing the level of residual first solvent to less than about 2% by weight of said microparticles.