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 stable aqueous etanercept formulation comprising about 25 to about 75 mg/ml of etanercept, wherein the etanercept is stabilized by a stabilizing component having 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 formulation is free of arginine. 
     
     
         2 . The formulation of  claim 1  wherein the formulation 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. %. 
 
     
     
         3 . The formulation of  claim 1 , wherein etanercept is at a concentration of 50 mg/ml. 
     
     
         4 . The formulation of  claim 1 , further comprising an aqueous buffer. 
     
     
         5 . The formulation of  claim 1 , wherein the aqueous etanercept formulation has a pH of about 6.0 to about 6.6. 
     
     
         6 . The formulation of  claim 1 , wherein the stable aqueous etanercept formulation 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 etanercept formulation 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 formulation represented by peak 3 is less than or equal to about 3 wt. %. 
     
     
         7 . The formulation of  claim 1 , wherein the stable aqueous etanercept formulation has no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μm. 
     
     
         8 . The formulation of  claim 1 , wherein the stable aqueous formulation formulation 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 formulation represented by peak 1 of the HIC chromatogram is less than about 3 wt. %; the amount of the formulation represented by peak 2 of the HIC chromatogram is greater than 80 wt. %; and the amount of the formulation represented by peak 3 of the HIC chromatogram is less than about 20 wt. %. 
     
     
         9 . The formulation of  claim 1 , wherein the stable aqueous formulation is free of cysteine. 
     
     
         10 . The formulation of  claim 1 , wherein the stable aqueous formulation 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 formulation of  claim 1 , wherein the stable aqueous formulation 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 formulation of  claim 1 , wherein the stable aqueous formulation 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 in need of treatment by injection of etanercept comprising administering to the subject a stable aqueous etanercept composition comprising 25 to 75 mg/ml etanercept, wherein the etanercept is stabilized by a stabilizing component having 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. 
     
     
         14 . The method of  claim 13 , comprising administering 25-100 mg etanercept per dose to the subject. 
     
     
         15 . The method of  claim 13 , comprising injecting the stable aqueous etanercept composition subcutaneously or intramuscularly. 
     
     
         16 . The method of  claim 13 , 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. 
     
     
         17 . The method of  claim 13 , 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. 
     
     
         18 . The method of  claim 13 , 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. 
     
     
         19 . The method of  claim 13 , wherein subject suffers from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or a psoriasis. 
     
     
         20 . A vial, syringe, or injector pen containing a stable aqueous etanercept composition comprising 25 to 75 mg/ml etanercept, wherein the etanercept is stabilized by an aqueous buffer and a stabilizing component having 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 etanercept composition has a pH of about 6.0 to about 6.6.