Production process for polymeric micelle charged therein with drug and polymeric micelle composition

Abstract

Provided are a production process for a polymeric micelle which is stable and has a high drug content and a composition containing such polymeric micelle. Disclosed are a production process for a polymeric micelle, comprising the steps of dissolving a drug and a specific copolymer in a water non-miscible organic solvent to prepare a solution, mixing the resulting solution with water to form an O/W type emulsion and then slowly volatilizing the organic solvent from the solution, and a polymeric micelle composition charged therein with a water-scarcely soluble drug, which can be obtained by the above production process.

1 . A production process for a polymeric micelle charged therein with a water-scarcely soluble drug, comprising the steps of: 
 (A) dissolving a water-scarcely soluble drug and a block copolymer having a hydrophilic segment and a hydrophobic segment in a water non-miscible organic solvent to prepare an organic solution,    (B) mixing the resulting organic solution with an aqueous medium to form an oil-in-water (O/W) type emulsion,    (C) vaporizing and removing the above organic solvent from the resulting emulsion to form a polymeric micelle solution charged therein with the above drug, and    (D) subjecting the resulting polymeric micelle solution, if necessary, to supersonic treatment and ultrafiltration treatment.    
     
     
         2 . The production process as described in    claim 1   , wherein the hydrophilic segment is a segment comprising at least one selected from the group consisting of poly(ethylene oxide), poly(malic acid), poly(saccharide), poly(acrylic acid), poly(vinyl alcohol) and poly(vinylpyrrolidone).  
     
     
         3 . The production process as described in    claim 1    or    2   , wherein the hydrophobic segment is a segment comprising at least one selected from the group consisting of poly(β-benzyl aspartate), poly(γ-benzyl glutamate), poly(β-alkyl aspartate), poly(lactide), poly(ε -caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone) and poly(α-amino acid).  
     
     
         4 . The production process as described in    claim 1   , wherein the hydrophilic segment comprises poly(ethylene oxide), and the hydrophobic segment is selected from the group consisting of poly(β-benzyl aspartate), poly(γ-benzyl glutamate), poly(β -benzyl aspartate-co-aspartic acid) and poly(γ-benzyl glutamate-co-glutamic acid).  
     
     
         5 . The production process as described in    claim 1   , wherein the block copolymer is represented by the following Formula (I) or  
                   
       [wherein R 1  and R 3  each represent a hydrogen atom or a lower alkyl group; R 2  represents a hydrogen atom, a saturated or unsaturated C 1  to C 29  aliphatic carbonyl group or an arylcarbonyl group; R 4  represents a hydroxyl group, a saturated or unsaturated C 1  to C 30  aliphatic oxy group or an aryl-lower alkyloxy group; L 1  represents a linkage group selected from the group consisting of —NH—, —O— and —OCO-Z-NH— (wherein Z represents a C 1  to C 4  alkylene group); L 2  represents a linkage group selected from —OCO-Z-CO— and —NHCO—Z-CO— (wherein Z represents a C 1  to C 4  alkylene group); n represents an integer of 10 to 2500; x and y may be the same or different and represent integers the total of which is 10 to 300; x to y falls in a range of 3:1 to 0:100; and x and y each are present at random].  
     
     
         6 . The production process as described in    claim 5   , wherein x to y in Formula (I) or (II) falls in a range of 7:3 to 1:3.  
     
     
         7 . The production process as described in any of    claims 1    to    6   , wherein the drug and the block copolymer are used in a weight ratio of 1:10 to 3:10.  
     
     
         8 . The production process as described in any of    claims 1    to    7   , wherein the water non-miscible organic solvent is at least one selected from the group consisting of chloroform, methylene chloride, toluene, xylene and n-hexane.  
     
     
         9 . The production process as described in any of    claims 1    to    8   , wherein the drug is selected from the group consisting of paclitaxel, docetaxel and camptothecin and topotecan.  
     
     
         10 . A composition comprising a polymeric micelle originating in a block copolymer charged therein with a drug, wherein the drug is a water-scarcely soluble drug; the block copolymer is represented by the following Formula (I) or (II):  
                   
       [wherein R 1  and R 3  each represent a hydrogen atom or a lower alkyl group; R 2  represents a hydrogen atom, a saturated or unsaturated C 1  to C 29  aliphatic carbonyl group or an arylcarbonyl group; R 4  represents a hydroxyl group, a saturated or unsaturated C 1  to C 30  aliphatic oxy group or an aryl-lower alkyloxy group; L 1  represents a linkage group selected from the group consisting of —NH—, —O— and —OCO-Z-NH— (wherein Z represents a C 1  to C 4  alkylene group); L 2  represents a linkage group selected from —OCO-Z-CO— and — NHCO-Z-CO— (wherein Z represents a C 1  to C 4  alkylene group); n represents an integer of 10 to 2500; x and y may be the same or different and represent integers the total of which is 10 to 300; x to y falls in a range of 7:3 to 1:3; and x and y each are present at random]; a micelle solution prepared by dissolving or dispersing the above micelle in water can stably be maintained in a drug concentration of at least 3 mg per ml of the solution.  
     
     
         11 . The composition as described in    claim 10   , wherein the drug is selected from the group consisting of paclitaxel, docetaxel, camptothecin and topotecan.  
     
     
         12 . The composition as described in    claim 10   , wherein the drug is paclitaxel and an analogue thereof.