Pharmeutical microparticles

Abstract

Microparticles consisting of (a) a matrix with a mixture of (a1) at least one hydrophobic, biologically degradable polymer and (a2) 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 - 21 . (canceled)  
     
     
         22 . A process for the preparation of microparticles comprising the steps 
 a) preparing an aqueous solution of at least one pharmacologically active ingredient;    b) preparing a solution of a biodegradable polymer, a water soluble polymer, and a surface active substance in an organic solvent which is insoluble in water;    c) preparing an aqueous solution of a surfactant;    d) mixing solutions of a) and b) using a gear pump to form an emulsion;    e) pumping emulsion d) and the aqueous solution c) with a gear pump to a static mixer and mixing them in the static mixer to form a water in oil in water emulsion;    f) removing the organic solvent from emulsion e); and    g) separating the microparticles.    
     
     
         23 .The process of  claim 22 , wherein the surface active substance of step b) is a phospholipid or lecithin.  
     
     
         24 . The process of  claim 22 , wherein a phosphate buffer is used for the preparation of the aqueous solutions of step a) and c).  
     
     
         25 . The process of  claim 22 , wherein the organic solvent of step c) is methylene chloride.  
     
     
         26 . The process of  claim 22 , wherein the surfactant of step c) is polyvinyl alcohol.  
     
     
         27 . The process of  claim 22 , wherein the organic solvent in step f) is removed by evaporation.  
     
     
         28 . The process of  claim 22 , wherein the microparticles of step g) are separated by sedimentation or filtration.  
     
     
         29 . The process of  claim 22 , wherein the obtained microparticles are freeze-dried.  
     
     
         30 . The process of claim  23 , wherein the amount of phospholipid or lecithin is from about 0.01 to about 90% w/w of the final microparticle weight.  
     
     
         31 . The process of  claim 22 , wherein the biodegradable polymer is chosen from at least one of 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-polyaminde copolymer; polyanhydride; polyorthoester; polyphosphazene; and 
 polycarbonates.    
     
     
         32 . The process of  claim 31 , wherein the biodegradable 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.  
     
     
         33 . The process of  claim 22 , wherein the water soluble polymer is polyvinyl pyrrolidone.  
     
     
         34 . The process of claim  23 , wherein the phospholipid is phosphatidyl choline.  
     
     
         35 . The process of  claim 22 , wherein the active ingredient is a peptide, a polypeptide or a protein.  
     
     
         36 . The process of  claim 35 , wherein the active ingredient is selected from at least one of antibodies, growth hormones, insulin, interferons, erythropoietin, calcitonin, heparin, somatostatins, cell-stimulating factors and parathyroid hormones.  
     
     
         37 . The process of  claim 36 , wherein the interferon is interferon alpha 2b.  
     
     
         38 . The process of  claim 22 , wherein the organic solvent is removed from the microparticles using cross-filtration technology by circulating emulsion e) tangentially to a membrane at a constant flow wherein the organic solvent, salts and excipients are removed through the membrane, replacing water removed through the membrane by fresh water.  
     
     
         39 . Microparticles comprising 
 a pharmaceutically active ingredient;    at biodegradable polymer;    a water soluble polymer;    a phospholipid or lecithin;    wherein the microparticles are obtained by the process of  claim 22 .    
     
     
         40 . The microparticles of  claim 39  having a diameter of 0.1 to 200 μm.  
     
     
         41 . The microparticles of  claim 39  comprising 1 to 20% by weight active agent, based on the weight of the microparticles.