Human growth hormone aqueous formulation

Abstract

A stable pharmaceutically acceptable aqueous formulation containing human growth hormone, a buffer, a non-ionic surfactant, and, optionally, a neutral salt, mannitol, or, a preservative, is disclosed. Also disclosed are associated means and methods for preparing, storing, and using such formulations.

1 - 21 . (canceled) 
     
     
         22 . An aqueous formulation of human growth hormone comprising:
 a) at least about 0.1 mg/ml of human growth hormone;   b) a buffer having a concentration in the range of about 2 mM to about 50 mM;   c) a non-ionic surfactant in the range of from a 0.1% (w/v) to about 5% (w/v);   d) optionally, mannitol,   e) optionally, a neutral salt at a concentration adjusted to near isotonicity, and   f) optionally, a preservative.   
     
     
         23 . The formulation of  claim 22  wherein amount of buffer is adjusted to provide a pH of from about 4 to 8. 
     
     
         24 . The formulation of  claim 22  wherein the non-ionic surfactant is a poloxamer. 
     
     
         25 . The formulation of  claim 22  wherein the non-ionic surfactant is polysorbate. 
     
     
         26 . The formulation of  claim 24  wherein the poloxamer is poloxamer 188 or poloxamer 184 in the range of from a 0.1% (w/v) to about 1% (w/v). 
     
     
         27 . The formulation of  claim 25  wherein the polysorbate is polysorbate 20 or polysorbate 80 in the range of from a 0.1% (w/v) to about 1% (w/v). 
     
     
         28 . The formulation of claim  1  wherein the concentration of mannitol is about 5 mg/ml to about 50 mg/ml. 
     
     
         29 . The formulation of  claim 23  wherein the buffer is an alkali metal citrate buffer. 
     
     
         30 . The formulation of  claim 23  wherein the buffer is selected from the group consisting of phosphate, Tris, succinate, acetate, or histidine buffers. 
     
     
         31 . The formulation of  claim 22  wherein the formulation is sterile filtered using a 0.2 micron pore size sterilized membrane filter. 
     
     
         32 . The formulation of  claim 22  wherein the preservative is selected from phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, benzalconium chloride and benzethonium chloride. 
     
     
         33 . The formulation of  claim 22  wherein the neutral salt is an alkali metal halide. 
     
     
         34 . The formulation of  claim 22  wherein the preservative is phenol in the range of 0.2-0.4% (w/v). 
     
     
         35 . The formulation of  claim 22  wherein the preservative is benzyl alcohol in the range of 0.7-1% (w/v). 
     
     
         36 . The formulation of  claim 22 , wherein the formulation comprises 5 mg/ml hGH, 8.8 mg/ml sodium chloride, 2.0 mg/ml polysorbate 20, 2.5 mg/ml sodium citrate, and 2.5 mg/ml phenol, at pH 6.0. 
     
     
         37 . A method of preventing denaturation of a human growth hormone formulation, the method comprising mixing an aqueous solution of human growth hormone and a non-ionic surfactant in the range of 0.1-5% (w/v). 
     
     
         38 . The method of  claim 37  wherein the non-ionic surfactant is a poloxamer. 
     
     
         39 . The method of  claim 37  wherein the non-ionic surfactant is a polysorbate. 
     
     
         40 . The method of  claim 38  wherein the poloxamer is poloxamer 188 or 184. 
     
     
         41 . The method of  claim 39  wherein the polysorbate is polysorbate 20 or polysorbate 80.