Polypeptide formulation

Abstract

The present invention relates to an aqueous pharmaceutical composition suitable for long-term storage of polypeptides containing an Fc domain of an immunoglobulin, methods of manufacture, methods of administration and kits containing same.

What is claimed is:  
     
         1 . A pharmaceutical composition that is a stable aqueous formulation comprising an Fc domain containing polypeptide and an aggregation inhibitor, wherein the aggregation inhibitor is L-arginine.  
     
     
         2 . The composition of  claim 1 , further comprising a buffer.  
     
     
         3 . The composition of  claim 2 , wherein the buffer is selected from the group consisting of sodium phosphate, histidine, potassium phosphate, sodium or potassium citrate, maleic acid, ammonium acetate, tris-(hydroxymethyl)-aminomethane (tris), acetate and diethanolamine.  
     
     
         4 . The composition of  claim 3 , wherein the L-arginine is at a concentration of from about 10 mM to about 100 mM.  
     
     
         5 . The composition of any one of claims  1 ,  2 ,  3  or  4 , further comprising a tonicity modifier.  
     
     
         6 . The composition of  claim 5 , wherein the tonicity modifier is selected from the group consisting of arginine, cysteine, histidine, glycine, sodium chloride, potassium chloride, sodium citrate, sucrose, glucose and Mannitol.  
     
     
         7 . The composition of  claim 6 , wherein the tonicity modifier is sodium chloride.  
     
     
         8 . The composition of any one of claims  1 ,  2 ,  3 , or  4 , further comprising an excipient.  
     
     
         9 . The composition of  claim 6 , further comprising an excipient.  
     
     
         10 . The composition of  claim 7 , further comprising an excipient.  
     
     
         11 . The composition of  claim 8 , wherein the excipient is selected from the group consisting of sucrose, lactose, glycerol, xylitol, sorbitol, Mannitol, maltose, inositol, trehalose, glucose, bovine serum albumin (BSA), human SA or recombinant HA, dextran, PVA, hydroxypropyl methylcellulose (HPMC), polyethyleneimine, gelatin, polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC), polyethylene glycol, ethylene glycol, glycerol, dimethysulfoxide (DMSO), dimethylformamide (DMF), proline, L-serine, sodium glutamic acid, alanine, glycine, lysine hydrochloride, sarcosine, gamma-aminobutyric acid, Tween-20, Tween-80, SDS, polysorbate, polyoxyethylene copolymer, potassium phosphate, sodium acetate, ammonium sulfate, magnesium sulfate, sodium sulfate, trimethylamine N-oxide, betaine, zinc ions, copper ions, calcium ions, manganese ions, magnesium ions, CHAPS, sucrose monolaurate, and 2-O-beta-mannoglycerate.  
     
     
         12 . The composition of  claim 11 , wherein the excipient is sucrose.  
     
     
         13 . A stable pharmaceutical composition comprising about 10 mg/ml to about 100 mg/ml TNFR:Fc, L-arginine, sodium phosphate, sodium chloride and sucrose.  
     
     
         14 . The composition of  claim 13 , wherein L-arginine is about 10 mM to about 75 mM.  
     
     
         15 . The composition of  claim 13 , wherein sodium phosphate is about 5 mM to about 100 mM.  
     
     
         16 . The composition of  claim 13 , wherein sodium chloride is about 5 mM to about 200 mM.  
     
     
         17 . The composition of  claim 13 , wherein sucrose is about 0.5% to about 1.5%.  
     
     
         18 . The composition of  claim 13 , wherein pH is about 5.5 to about 7.8.  
     
     
         19 . The composition of  claim 13 , having 25 mg/ml TNFR:Fc, 25 mM L-arginine, 25 mM sodium phosphate, 98 mM sodium chloride, 1% sucrose at pH 6.2.  
     
     
         20 . The composition of any one of claims  1 ,  13  or  19 , wherein the composition is liquid.  
     
     
         21 . The composition of  claim 20 , wherein the composition is frozen.  
     
     
         22 . A method of formulating a composition comprising combining isolated TNFR:Fc with L-arginine.  
     
     
         23 . The method of  claim 22 , further comprising the steps of combining a buffer, a tonicity modifier, and an excipient with the composition.  
     
     
         24 . The method of  claim 22  or  23 , wherein the composition is liquid.  
     
     
         25 . A kit comprising a composition comprising an Fc domain containing polypeptide and L-arginine, and instructions for use of said composition.  
     
     
         26 . The kit of  claim 25 , wherein the composition is liquid.  
     
     
         27 . The kit of  claim 25  or  26 , wherein the composition is stored in a pre-filled sterile syringe.  
     
     
         28 . The kit of  claim 27 , wherein the syringe is stored at about −20° C. to about −70° C.  
     
     
         29 . A method of treating a mammal in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of any one of claims  4  or  13 .  
     
     
         30 . A method of accelerated stability testing of an Fc domain containing polypeptide in a pharmaceutical composition, wherein the composition comprises L-arginine, the steps of the method comprising storing the composition at 37° C. and measuring the stability of the polypeptide after at least one month at 37° C.