Etanercept formulations exhibiting marked reduction in sub-visible particles

Abstract

The invention provides stabilized aqueous pharmaceutical etanercept compositions suitable for long-term storage of etanercept, with substantial reduction in sub-visible particles, and methods of manufacture of these compositions, methods of administration, and articles of manufacture.

What is claimed is: 
     
         1 . A method of treating a subject suffering from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, granulomatosis, Crohn's disease, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, or atopic dermatitis, comprising administering to the subject an aqueous pharmaceutical composition comprising:
 etanercept at 25 to 75 mg/ml;   a surfactant at 0.01 to 0.05% w/v;   a metal ion selected from the group consisting of calcium, magnesium and zinc, wherein the metal ion is present at 2 mM to 20 mM;   a buffer selected from the group consisting of phosphate, histidine, citrate, maleate, tartrate, succinate, tris-(hydroxymethyl)-aminomethane, and bicarbonate;   wherein the aqueous pharmaceutical composition has a pH of between 6 and 7, and the aqueous pharmaceutical composition is free of arginine.   
     
     
         2 . The method of  claim 1 , wherein the surfactant is polysorbate 80, polysorbate 60, polysorbate 40, or polysorbate 20. 
     
     
         3 . The method of  claim 1 , wherein the surfactant comprises polysorbate 80. 
     
     
         4 . The method of  claim 1 , wherein the aqueous pharmaceutical composition has (i) less than 2500 particles/ml having a size of 5-10 μm, (ii) less than 3500 particles having size of about 2-5 μm, and (iii) less than 700 particles/ml having size of about 1-2 μm. 
     
     
         5 . The method of  claim 1 , wherein etanercept is present at 25 to 50 mg/ml, the metal ion is magnesium, and wherein the aqueous pharmaceutical composition further comprises sucrose or trehalose at 0.5 to 6 wt %, NaCl at 25 to 150 mM, and the buffer is sodium phosphate at 1 to 30 mM. 
     
     
         6 . The method of  claim 1 , wherein the metal ion is magnesium and wherein the aqueous pharmaceutical composition further comprises NaCl at 0 to 100 mM; and the buffer is sodium phosphate at 1 to 30 mM. 
     
     
         7 . The method of  claim 1 , wherein the aqueous pharmaceutical composition is characterized by:
 (a) an SEC analysis at T 4  of greater than 90 wt % monomer content; and less than 3 wt % aggregate(s) content; and   (b) an HIC analysis at T 2  wherein the amount of the aqueous pharmaceutical composition represented by peak 1 of the HIC chromatogram is less than 4 wt %; the amount of the aqueous pharmaceutical composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and the amount of the aqueous pharmaceutical composition represented by peak 3 of the HIC chromatogram is less than 20 wt %; and   (c) an HIC analysis at T 4  wherein the amount of the aqueous pharmaceutical composition represented by peak 1 of the HIC chromatogram is less than 3 wt %; the amount of the aqueous pharmaceutical composition represented by peak 2 of the HIC chromatogram is greater than 80, wt %; and the amount of the aqueous pharmaceutical composition represented by peak 3 of the HIC chromatogram is less than 20 wt %.   
     
     
         8 . The method of  claim 1 , wherein the aqueous pharmaceutical composition is administered subcutaneously. 
     
     
         9 . The method of  claim 1 , wherein the aqueous pharmaceutical composition is administered intramuscularly or intravenously. 
     
     
         10 . The method of  claim 1 , wherein the aqueous pharmaceutical composition is administered once weekly. 
     
     
         11 . The method of  claim 1 , wherein the aqueous pharmaceutical composition is administered twice weekly. 
     
     
         12 . The method of  claim 1 , wherein the aqueous pharmaceutical composition has about 1 wt % aggregate content or less than 1 wt % aggregate content as determined by size exclusion chromatography after 4 weeks storage at 25° C. 
     
     
         13 . The method of  claim 1 , comprising administering 25-100 mg etanercept in the aqueous pharmaceutical composition. 
     
     
         14 . A method of treating a subject suffering from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, granulomatosis, Crohn's disease, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), Hepatitis C, endometriosis, asthma, cachexia, psoriasis, or atopic dermatitis, comprising administering to the subject an aqueous pharmaceutical composition comprising:
 etanercept at or about 50 mg/ml;   up to 0.05% w/v surfactant;   2 mM to 20 mM metal ion;   about 25 mM to about 100 mM NaCl;   10 mM to 200 mM of a phosphate or citrate buffer;   wherein the aqueous pharmaceutical composition has a pH of 6 to 7,   wherein the aqueous pharmaceutical composition is free of arginine,   wherein said aqueous pharmaceutical composition has about 1 wt % aggregate content or less than 1 wt % aggregate content as determined by size exclusion chromatography after 4 weeks storage at 25° C., and   wherein the aqueous pharmaceutical composition has:
 (i) less than 2500 particles/ml having a size of about 5-10 μm; 
 (ii) less than 3500 particles having size of about 2-5 μm, and 
 (iii) less than 700 particles/ml having size of about 1-2 μm. 
   
     
     
         15 . The method of  claim 14 , wherein the aqueous pharmaceutical composition further comprises sucrose or trehalose at 0.5 to 6 wt %. 
     
     
         16 . The method of  claim 14 , wherein the aqueous pharmaceutical composition is administered subcutaneously. 
     
     
         17 . The method of  claim 14 , wherein the aqueous pharmaceutical composition is administered intramuscularly or intravenously. 
     
     
         18 . The method of  claim 14 , wherein the aqueous pharmaceutical composition is administered once weekly. 
     
     
         19 . The method of  claim 14 , wherein the aqueous pharmaceutical composition is administered twice weekly. 
     
     
         20 . The method of  claim 14 , comprising administering 25-100 mg etanercept in the aqueous pharmaceutical composition.