Sustained-release material prepared by dispersing a lyophilized polypeptide in an oil phase

Abstract

Disclosed is a sustained-release preparation characterized in that it is produced by dispersing in an oil phase a rapidly dried product containing a bioactive polypeptide and a surfactant, and subsequent shaping, and a method of its production.

1 . A method of producing a sustained-release preparation, which comprises dispersing a rapidly dried product containing a bioactive polypeptide and a surfactant in an oil phase, followed by shaping of the resulting dispersion.  
     
     
         2 . A method of    claim 1   , wherein the average particle diameter of the rapidly dried product dispersed in the oil phase is about 0.05 μm to about 50 μm.  
     
     
         3 . A method of    claim 1   , wherein the ratio by weight of the bioactive polypeptide and the surfactant is about 1:0.001 to about 1:1,000.  
     
     
         4 . A method of    claim 1   , wherein the oil phase is an organic solvent phase containing a biocompatible polymer.  
     
     
         5 . A method of    claim 4   , wherein the biocompatible polymer concentration in the organic solvent is about 0.01% (w/w) to about 80% (w/w).  
     
     
         6 . A method of    claim 4   , wherein the ratio of the surfactant used to the total amount of the bioactive polypeptide, the surfactant and the biocompatible polymer is about 0.002% (w/w) to about 50% (w/w).  
     
     
         7 . A method of    claim 1   , wherein the bioactive polypeptide is soluble in water.  
     
     
         8 . A method of    claim 1   , wherein the bioactive polypeptide is a hormone.  
     
     
         9 . A method of    claim 8   , wherein the hormone is a growth hormone.  
     
     
         10 . A method of    claim 8   , wherein the hormone is an insulin.  
     
     
         11 . A method of    claim 1   , wherein the bioactive polypeptide is a cytokine.  
     
     
         12 . A method of    claim 11   , wherein the cytokine is an interferon or an interleukin.  
     
     
         13 . A method of    claim 4   , wherein the biocompatible polymer is a biodegradable polymer.  
     
     
         14 . A method of    claim 13   , wherein the biodegradable polymer is a fatty acid polyester.  
     
     
         15 . A method of    claim 14   , wherein the fatty acid polyester is a lactic acid-glycolic acid polymer.  
     
     
         16 . A method of    claim 14   , wherein the molecular weight of the lactic acid-glycolic acid polymer is about 3,000 to 70,000 and the lactic acid/glycolic acid content ratio is about 100/0 to about 30/70.  
     
     
         17 . A method of    claim 14   , wherein the fatty acid polyester is a hydroxybutyric acid-glycolic acid polymer.  
     
     
         18 . A method of    claim 17   , wherein the molecular weight of the hydroxybutyric acid-glycolic acid polymer is about 3,000 to about 70,000 and the hydroxybutyric acid/glycolic acid content ratio is about 100/0 to about 40/60.  
     
     
         19 . A method of    claim 1   , wherein the surfactant is non-ionic.  
     
     
         20 . A method of    claim 19   , wherein the hydrophile/lipophile balance (HLB) of the non-ionic surfactant is not less than 10.  
     
     
         21 . A method of    claim 1   , wherein the surfactant comprises one or more nonionic surfactants selected from the group consisting of polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene hydrogenated castor oils, polyoxyethylene alkyl ethers, and polyvinylpyrrolidones.  
     
     
         22 . A method of    claim 19   , wherein the non-ionic surfactant is a polyoxyethylene-polyoxypropylene copolymer.  
     
     
         23 . A method of    claim 1   , wherein the sustained-release preparation is a microcapsule.  
     
     
         24 . A method of    claim 23   , wherein the average particle diameter of the microcapsule is about 1.0 μm to about 200 μm.  
     
     
         25 . A method of    claim 1   , wherein the sustained-release preparation is an injectable preparation.  
     
     
         26 . A dispersion of a rapidly dried product containing a bioactive polypeptide and a surfactant in an oil phase.  
     
     
         27 . A dispersion of    claim 26   , wherein the average particle diameter of the rapidly dried product dispersed in the oil phase is about 0.05 μm to 50 μm.  
     
     
         28 . A preparation useful as a starting material for sustained-release preparation, which comprises a rapidly dried product of an aqueous solution or suspension comprising a bioactive polypeptide and a surfactant dispersed in an oil phase containing a biocompatible polymer.  
     
     
         29 . A sustained-release preparation produced by the method of    claim 1   .  
     
     
         30 . A sustained-release preparation of    claim 29   , wherein the bioactive polypeptide is a growth hormone.  
     
     
         31 . A medicament for treatment or prevention of growth hormone deficiency, Turner's syndrome, pituitary dwarfism, chronic renal disease, achondroplasia, adult hypopituitarism, Down syndrome, Silver syndrome, hypochondroplasia, osteoporosis and juvenile chronic arthritis, which comprises the sustained-release preparation of    claim 30   .  
     
     
         32 . Use of the sustained-release preparation of    claim 30    for the manufacture of a medicament for treatment or prevention of growth hormone deficiency, Turner's syndrome, pituitary dwarfism, chronic renal disease, achondroplasia, adult hypopituitarism, Down syndrome, Silver syndrome, hypochondroplasia, osteoporosis and juvenile chronic arthritis.  
     
     
         33 . A method of treating or preventing growth hormone deficiency, Turner's syndrome, pituitary dwarfism, chronic renal disease, achondroplasia, adult hypopituitarism, Down syndrome, Silver syndrome, hypochondroplasia, osteoporosis and juvenile chronic arthritis, in a subject, which comprises administrating to the subject in need an effective amount of the sustained-release preparation of    claim 30   .