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 . A stable pharmaceutically acceptable aqueous formulation of human growth hormone comprising: 
 a) human growth hormone,    b) a buffer    c) a non-ionic surfactant,    d) optionally, mannitol,    e) optionally, a neutral salt, and    f) optionally, a preservative.    
   
   
       2 . The formulation of  claim 1  wherein the non-ionic, surfactant is present in the range of about 0.1% (w/v) to about 1% (w/v).  
   
   
       3 . The formulation of  claim 1  wherein the non-ionic surfactant is a poloxamer.  
   
   
       4 . The formulation of  claim 1  wherein the non-ionic surfactant is a polysorbate.  
   
   
       5 . The formulation of  claim 3  wherein the poloxamer is poloxamer 188 or poloxamer 184.  
   
   
       6 . The formulation of  claim 4  wherein the polysorbate is polysorbate 20 or polysorbate 80.  
   
   
       7 . The formulation of  claim 1  wherein the concentration of mannitol is about 5 mg/ml to about 50 mg/ml.  
   
   
       8 . The formulation of  claim 1  wherein the buffer is a citrate buffer.  
   
   
       9 . The formulation of  claim 1  wherein the buffer concentration is about 2 mM to about So mM.  
   
   
       10 . The formulation of  claim 1  wherein the buffer is selected from the group consisting of phosphate, Tris, succinate, acetate, at histidine buffers.  
   
   
       11 . The formulation-of  claim 1  wherein the formulation is sterile.  
   
   
       12 . The formulation of  claim 1  wherein the formulation is isotonic.  
   
   
       13 . The formulation of  claim 1  wherein the neutral salt is sodium chloride.  
   
   
       14 . The formulation of  claim 1  wherein the preservative is selected from the group consisting of phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, benzalconium chloride, and benzethonium chloride.  
   
   
       15 . An aqueous hGH formulation comprising 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.  
   
   
       16 . A method of preventing denaturation of human growth hormone aqueous formulations comprising mixing human growth hormone and a non-ionic surfactant in the range of 0.1-5% (w/v).  
   
   
       17 . The method of  claim 16  wherein the non-ionic surfactant is a poloxamer.  
   
   
       18 . The method of  claim 16  wherein the non-ionic surfactant is a polysorbate.  
   
   
       19 . The method of  claim 17  wherein the poloxamer is poloxamer 188 or 184.  
   
   
       20 . The method of  claim 16  wherein the polysorbate is polysorbate 20 or polysorbate 80.  
   
   
       21 . A method of preventing denaturation of human growth hormone aqueous formulations stored for six to 18 months at 2-8° C. comprising mixing human growth hormone and a non-ionic surfactant in the range of 0.1-5% (w/v).