Pharmaceutical microparticles

Abstract

Microparticles consisting of (a) a matrix with a mixture of (a 1 )) at least one hydrophobic, biologically degradable polymer and (a 2 ) optionally at least one water-soluble polymer, (b) a pharmaceutical active ingredient distributed in the matrix, and (c) in addition at least one water-insoluble, surface-active substance from the group of lecithins and phospholipids, distributed in the matrix, and a three-phase emulsion process for their preparation.

1 - 15 . (canceled) 
     
     
         16 . A process for producing microparticles comprising the steps of:
 a) dissolving at least one peptide, polypeptide, and/or protein in an aqueous buffer to produce an active ingredient solution,   b) dissolving at least one biologically degradable polymer, at least one water-soluble polymer, and lecithin in an organic solvent to produce a polymer solution containing about 20% lecithin,   c) mixing the active ingredient solution of a) and the polymer solution of b) using a gear pump to form an emulsion,   d) pumping the emulsion of c) and an aqueous solution with a gear pump to a static mixer and mixing the same in the static mixer to form a water in oil in water emulsion,   e) removing the solvent from the emulsion of d), and   f) separating the microparticles,   wherein the microparticles do not exhibit an initial burst release of the therapeutic polypeptide contained therein.   
     
     
         17 . The method of  claim 16  wherein the aqueous solution of c) comprises an aqueous buffer and at least one surfactant and/or water-soluble polymer. 
     
     
         18 . The process of  claim 16  further comprising circulating the emulsion of d) through a membrane. 
     
     
         19 . The process of  claim 16  wherein the aqueous buffer is a phosphate buffer. 
     
     
         20 . The process of  claim 16  wherein the organic solvent is methylenechloride. 
     
     
         21 . The process of  claim 17  wherein the surfactant is polyvinyl alcohol. 
     
     
         22 . The process of  claim 16  wherein the solvent is removed in e) by vacuum and/or evaporation, optionally further comprising heating. 
     
     
         23 . The process of  claim 16  wherein the amount of lecithin is from 0.01 to 90% w/w of the final microparticle weight. 
     
     
         24 . The process of  claim 16  wherein the biologically degradable polymer is selected from the group consisting of a polycarbonate; a polyester of an aliphatic hydroxycarboxylic acid; a polyester of an aminocarboxylic acid; a polyamide of an aliphatic hydroxycarboxylic acid; a polyamide of an aminocarboxylic acids; a homo-condensate of α-hydroxycarboxylic acid; a copolycondensate of α-hydroxycarboxylic acid; glycolic acid; lactic acid; poly-L-lactic acid; poly-D,L-lactic acid; a copolycondensate of poly-D,L-lactide/glycolide with a monomer ratio selected from the group consisting of 10:1 to 1:10. 1:4 to 4:1, and 1:1, and a molecular weight of 5000 to 100,000 daltons; and mixtures thereof. 
     
     
         25 . The process of  claim 24  wherein the biologically degradable polymer is a copolycondensate of D,L-lactic acid and glycolic acid (1:1). 
     
     
         26 . The process of  claim 18  wherein the membrane is selected from the group consisting of a polymer membrane, ceramic membrane, hollow fiber, and spiral wound system. 
     
     
         27 . A microparticle prepared by the process of  claim 16 . 
     
     
         28 . The microparticle of  claim 27  comprising an amount of lecithin selected from the group consisting of about 0.01 to about 90%, about 0.1 to about 70%, and about 0.1 to about 20% w/w. 
     
     
         29 . The microparticle of  claim 27  having a diameter of 0.1 to 200 μm. 
     
     
         30 . The microparticle of  claim 27  comprising a biologically degradable polymer comprising homo- or copolyester of dicarboxylic acid, alkylene diol, polyalkylene glycol and/or aliphatic hydroxycarboxylic acid; homo- or copolyamide of dicarboxylic acids, alkylene diamine and/or aliphatic aminocarboxylic acid; corresponding polyester-polyamide copolymer; polyanhydride; polyorthoester; polyphosphazene; and polycarbonates. 
     
     
         31 . The microparticle of  claim 30 , in which the biologically degradable polymer is poly-L- or poly-D,L-lactic acid or poly-D,L-lactide/glycolide with a monomer ratio of ca. 1:1 and a molecular weight of 5000 to 100,000 daltons. 
     
     
         32 . The microparticle of  claim 27  comprising at least one water-soluble polymer. 
     
     
         33 . The microparticle of  claim 32  wherein the water-soluble polymer is polyvinyl pyrrolidone. 
     
     
         34 . The microparticle of  claim 29  in which the amount of biologically degradable polymer is 1 to 99% by weight. 
     
     
         35 . The microparticle of  claim 27  wherein the at least one peptide, polypeptide, and/or protein is selected from the group consisting of an antibody, growth hormones, insulin, interferon, erythropoietin, calcitonin, heparin, somatostatin, cell-stimulating factors and parathyroid hormones. 
     
     
         36 . The microparticle of  claim 35  wherein the interferon is interferon alpha 2b. 
     
     
         37 . The microparticle of  claim 26  wherein the amount of the at least one peptide, polypeptide, and/or protein is about 1 to about 20% (w/w) of the microparticle.