Etanercept Formulations Stabilized with Sodium Chloride

Abstract

The invention provides stabilized aqueous pharmaceutical etanercept compositions suitable for long-term storage of etanercept, methods of manufacture of these compositions, methods of administration, and kits containing same.

What is claimed is: 
     
         1 . A method of reducing formation of etanercept aggregates or fragments in a composition containing 25 to 75 mg/ml etanercept, the method comprising about 25 to about 75 mg/ml of etanercept with a stabilizing composition comprising about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and one or more amino acids selected from the group consisting of L-serine, sodium glutamic acid, alanine, glycine, and lysine, thereby preparing a stable aqueous etanercept composition, wherein the stable aqueous etanercept composition is free of arginine. 
     
     
         2 . The method of  claim 1 , wherein the stable aqueous etanercept composition has a pH of about 6.0 to about 6.6. 
     
     
         3 . The method of  claim 1  wherein the stable aqueous etanercept composition elicits long term storage stability as characterized by at least one of:
 SEC analysis at M 3  or T 2  or T 4  of: monomer content greater than about 90%; 
 aggregates content of less than about 3 wt. %; and 
 fragment 3 content less than about 5 wt. %. 
 
     
     
         4 . The method of  claim 1 , wherein etanercept is at a concentration of 50 mg/ml. 
     
     
         5 . The method of  claim 1 , further comprising an aqueous citrate buffer. 
     
     
         6 . The method of  claim 1 , wherein the stable aqueous etanercept composition elicits long term storage stability as characterized by: an HIC analysis at M 3  or T 2  or T 4  wherein the amount of the stable aqueous pharmaceutical composition represented by peak 2 of the HIC chromatogram is greater than or equal to 95 wt. %; and wherein, if peak 3 is present on the HIC chromatogram, the amount of the composition represented by peak 3 is less than or equal to about 3 wt. %. 
     
     
         7 . The method of  claim 1 , wherein the stable aqueous etanercept composition has no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μm. 
     
     
         8 . The method of  claim 1 , wherein the stable aqueous etanercept composition elicits long term storage stability as characterized by at least one of: HIC analysis at M 3  or T 2  or T 4  wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than about 3 wt. %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt. %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than about 20 wt. %. 
     
     
         9 . The method of  claim 1 , wherein the stable aqueous etanercept composition is free of cysteine. 
     
     
         10 . The method of  claim 1 , wherein the stable aqueous etanercept composition consists of about 50 mg/ml of etanercept stabilized by an aqueous buffer and about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and glycine or lysine. 
     
     
         11 . The method of  claim 1 , wherein the stable aqueous etanercept composition consists of about 50 mg/ml of etanercept stabilized by an aqueous citrate buffer and about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and glycine or lysine. 
     
     
         12 . The method of  claim 1 , wherein the stable aqueous etanercept composition consists of about 50 mg/ml of etanercept stabilized by an aqueous citrate buffer and about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and lysine. 
     
     
         13 . A method of treating a subject with an etanercept-containing composition comprising administering to the subject a stable aqueous pharmaceutical composition containing 25 to 75 mg/ml of an etanercept-containing protein mixture wherein the etanercept-containing protein mixture comprises greater than 90 wt. % correctly folded etanercept, and the stable aqueous pharmaceutical is stabilized with a stabilizing composition comprising about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and one or more amino acids selected from the group consisting of L-serine, sodium glutamic acid, alanine, glycine, and lysine, wherein the stable aqueous etanercept composition is free of arginine, wherein the stable aqueous pharmaceutical composition has less immunogenicity than commercially available etanercept. 
     
     
         14 . The method of  claim 13 , wherein the etanercept-containing protein mixture contains less than 5 wt. % incorrectly folded etanercept. 
     
     
         15 . The method of  claim 13 , wherein the stable aqueous pharmaceutical composition has aggregates content of less than about 3 wt. %. 
     
     
         16 . The method of  claim 13 , comprising administering 25-100 mg etanercept per dose to the subject. 
     
     
         17 . The method of  claim 13 , comprising injecting the stable aqueous pharmaceutical composition subcutaneously or intramuscularly. 
     
     
         18 . The method of  claim 13 , wherein the stable aqueous pharmaceutical composition consists of about 50 mg/ml of etanercept stabilized by an aqueous buffer and about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and glycine or lysine. 
     
     
         19 . The method of  claim 13 , wherein the stable aqueous pharmaceutical composition consists of about 50 mg/ml of etanercept stabilized by an aqueous citrate buffer and about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and glycine or lysine. 
     
     
         20 . The method of  claim 13 , wherein the stable aqueous pharmaceutical composition consists of about 50 mg/ml of etanercept stabilized by an aqueous citrate buffer and about 3 to 5 wt. % of sucrose, sodium chloride, sodium citrate, and lysine.