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 combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially free of arginine, thereby preparing a stable aqueous etanercept composition. 
     
     
         2 . The method of  claim 1 , further comprising adding one or more additional components selected from: a buffer; a tonicity modifier, and an excipient to the aqueous pharmaceutical composition. 
     
     
         3 . The method of  claim 2 , wherein the aqueous pharmaceutical composition has a pH of about 6.0 to about 6.6. 
     
     
         4 . 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 etanercept 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. %. 
     
     
         5 . 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. 
     
     
         6 . 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. %.   
     
     
         7 . The method of  claim 1 , wherein etanercept is at a concentration of 50 mg/ml and wherein sodium chloride is at a concentration of 75 mM. 
     
     
         8 . The method of  claim 1 , wherein the stable aqueous etanercept composition comprises 10 mM or 25 mM sodium phosphate. 
     
     
         9 . The method of  claim 1 , wherein the stable aqueous etanercept composition comprises 25 to 75 mg/ml of etanercept, up to 150 mM sodium chloride, 10 to 25 mM sodium phosphate, and 3 to 5 wt. % trehalose, and is free of arginine. 
     
     
         10 . The method of  claim 1 , wherein the stable aqueous etanercept composition comprises 50 mg/ml etanercept, 75 mM sodium chloride, and 25 mM sodium phosphate. 
     
     
         11 . 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. %. 
     
     
         12 . The method of  claim 1 , wherein the stable aqueous etanercept composition, at M 3  or T 2  or T 4 , elicits long term storage stability that meets the following criteria:
 (A) an SEC analysis of: monomer content greater than about 90%; aggregates content of less than about 3 wt. %; and fragment 3 content less than about 5 wt. %; and   (B) an HIC analysis 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. %.   
     
     
         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, the method comprising combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially 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 . A method of treating a subject in need of treatment for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Wegener's disease (granulomatosis), Crohn's disease (or inflammatory bowel disease), chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, or atopic dermatitis comprising administering to the subject a stable aqueous etanercept composition comprising 25 to 75 mg/ml etanercept, the method comprising combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially free of arginine. 
     
     
         17 . The method of  claim 16 , comprising administering 25-100 mg etanercept per dose to the subject. 
     
     
         18 . The method of  claim 16 , wherein the administering comprises injecting the stable aqueous etanercept composition subcutaneously or intramuscularly. 
     
     
         19 . A vial, syringe, or injector pen containing a stable aqueous etanercept composition comprising 25 to 75 mg/ml etanercept, the method comprising combining 25 to 75 mg/ml etanercept with up to 150 mM sodium chloride, 1 to 30 mM sodium phosphate, and 3 to 5 wt. % sucrose in an aqueous pharmaceutical composition, wherein the aqueous pharmaceutical composition is free or essentially free of arginine. 
     
     
         20 . The vial, syringe, or injector pen of  claim 19 , wherein the stable aqueous pharmaceutical composition has a pH of about 6.0 to about 6.6.