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 producing a storage stable single-dose etanercept product comprising filling a syringe or injector pen with about 1 mL of a composition containing 25 to 75 mg/ml etanercept in an aqueous buffer that is stabilized with a stabilizing formulation 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 forming a filled syringe or injector pen containing 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 in the storage stable single-dose etanercept product 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 , wherein the aqueous buffer is an aqueous citrate buffer. 
     
     
         6 . The method of  claim 1 , wherein the stable aqueous etanercept composition elicits long term storage stability in the storage stable single-dose etanercept product 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 in the storage stable single-dose etanercept product 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 . The method of  claim 1 , wherein the composition containing 25 to 75 mg/ml etanercept comprises greater than 90 wt. % correctly folded etanercept. 
     
     
         14 . The method of  claim 1 , wherein the composition containing 25 to 75 mg/ml etanercept comprises contains less than 5 wt. % incorrectly folded etanercept. 
     
     
         15 . The method of  claim 1 , wherein the stable aqueous pharmaceutical composition has less immunogenicity than commercially available etanercept. 
     
     
         16 . The method of  claim 1 , further comprising storing the storage stable single-dose etanercept product at about 5° C. 
     
     
         17 . The method of  claim 1 , further comprising storing the storage stable single-dose etanercept product at about 25° C. 
     
     
         18 . The method of  claim 1 , further comprising combining the storage stable single-dose etanercept product with instructions for once weekly administration of the storage stable single-dose etanercept product to a human subject in a kit. 
     
     
         19 . A method of treating a subject suffering from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, a psoriasis, or atopic dermatitis comprising administering a once weekly dose of about 50 mg/ml etanercept to the subject using a storage stable single-dose etanercept product comprising about 50 mg/ml etanercept in an aqueous buffer that is stabilized with a stabilizing formulation 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 product is free of arginine. 
     
     
         20 . The method of  claim 19 , wherein 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 is administered subcutaneously from a syringe or injector pen.