RU98122206A - MICROPARTICLES AND METHOD FOR PRODUCING THEM - Google Patents

Claims (19)

1. A method for producing biodegradable, biocompatible microparticles, said method comprising: contacting microparticles comprising a biodegradable, biocompatible polymer matrix containing an active substance and an organic solvent with an aqueous solvent system, whereby the content of said organic solvent in said microparticles is reduced to 2% or less than the mass of said microparticles, said solvent system being such as to satisfy at least one of the conditions (a) that it at least a portion of the time during which it is in contact with said particles has an elevated temperature and the organic solvent is free of halogenated hydrocarbons and (b) that it contains water and a water-miscible solvent for said organic solvent; and recovering said microparticles from said aqueous solvent system. 2. The method according to p. 1, characterized in that it includes: A) obtaining a first phase comprising: (1) a biodegradable, biocompatible polymer encapsulating binder and (2) having a limited solubility in water, an active substance dissolved or dispersed in a first solvent ; B) obtaining an aqueous second phase; C) combining said first phase and said second phase under the influence of a mixing agent to form an emulsion in which said first phase is dispersed and said second phase is continuous; D) separating said dispersed first phase from said continuous second phase; and E) washing said dispersed first phase (1) with water at a temperature in the range of from about 25 ^° C to about 40 ^° C, or (2) an aqueous solution comprising water and a second solvent for the residual first solvent in said first phase, thereby reducing thus, the level of residual first solvent to less than about 2 wt.% these microparticles.  3. The method according to p. 2, characterized in that it further includes the step of terminating the reaction between step C) and step D).  4. The method according to p. 1, characterized in that it includes: A) obtaining a first phase, said first phase comprising an active substance, a biodegradable, biocompatible polymer and a first solvent; B) obtaining a second phase in which said first phase is substantially immiscible; C) passing the flow of said first phase through a static mixer at a first flow rate; D) passing the flow of 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 substance; 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 the residual first solvent in said microparticles, thereby reducing the level of residual first solvent to less than about 2 wt.% of said microparticles.  5. The method according to any one of paragraphs. 2-4, characterized in that said first solvent is a mixture of at least two mutually miscible organic solvents, and said second phase comprises water and, optionally, a hydrophilic colloid or surfactant.  8. The method according to p. 5, characterized in that one of these organic solvents is an ester, and the second is benzyl alcohol.  7. The method according to any one of paragraphs. 5 and 6, characterized in that said solvent mixture comprises ethyl acetate and benzyl alcohol, said second phase comprises poly (vinyl alcohol), and said polymer or binder is selected from poly (glycolic acid), poly (D, L-lactic acid) , poly (L-lactic acid) and their copolymers.  8. A method according to any one of the preceding claims, characterized in that said active substance comprises at least one main part.  9. A method according to any one of the preceding claims, characterized in that said active substance is selected from the group consisting of risperidone, 9-hydroxyrisperidone and their pharmaceutically acceptable salts. 10. A method according to any one of the preceding claims, characterized in that said aqueous solution or aqueous solvent system comprises water and a C ₁ -C ₄ alcohol. 11. The method according to p. 10, characterized in that said C ₁ -C ₄ alcohol is ethanol.  12. The method according to p. 1, characterized in that it includes: (A) obtaining a first phase comprising: 1) a biodegradable, biocompatible polymer encapsulating binder selected from poly (glycolic acid), poly- (D, L-lactic acid ), poly- (L-lactic acid) and their copolymers, and 2) an active substance selected from risperidone, 9-hydroxyisperidone and their pharmaceutically acceptable salts, dissolved or dispersed in a mixture comprising ethyl acetate and benzyl alcohol, the mixture being free of halogenated hydrocarbons; B) obtaining 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 dispersed and said second phase is continuous; D) immersing said first and said second phases in a coolant to terminate the reaction; E) isolating said particulate first phase in the form of microparticles; and F) washing said dispersed first phase with an aqueous solution comprising water and ethanol, thereby lowering the level of benzyl alcohol to less than 2 wt.% of said microparticles.  13. A particulate material comprising microparticles of a biodegradable, biocompatible polymer matrix containing an active substance and an organic solvent, said organic solvent being present in said microparticles in an amount of 2% or less of the total weight of said microparticles.  14. Microparticles of a biodegradable, biocompatible polymer matrix containing the active substance obtained using the method according to any one of paragraphs. 1-12.  15. A pharmaceutical composition comprising microparticles according to any one of paragraphs. 13 and 14, together with at least one pharmaceutically acceptable carrier or excipient.  16. The composition of claim 15, wherein said polymeric binder is a copolymer of glycolic acid and D, L-lactic acid.  17. The composition according to any one of paragraphs. 15 and 16, characterized in that the content of the specified residual solvent in these microparticles is in the range of 0.5 to 1.5 wt.%, And the specified residual solvent is benzyl alcohol.  18. The composition according to p. 15, characterized in that it includes biodegradable and biocompatible microparticles, the size of which is in the range of 25 - 180 microns, in a pharmaceutically acceptable carrier, and these microparticles include: a copolymer of poly (glycolic acid), poly (D, L -lactic acid), in which the molar ratio of lactide to glycolide is in the range 85:15 - 50:50, and having from 35 to 40% dispersed or dissolved in it an active substance selected from risperidone, 9-hydroxy-risperidone and their pharmaceutically acceptable salts, and 0 5 - 1.5 wt.% Benzyl alcohol.  19. The use of particles obtained using the method according to any one of paragraphs. 1-12, for the manufacture of a medicament for use in a diagnostic or treatment method.