Etanercept formulations stabilized with meglumine

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 about 25 to about 75 mg/ml etanercept, comprising combining about 25 to about 75 mg/ml etanercept with 0.5-5 wt. % meglumine, a buffer, and optionally a sugar, sodium chloride, or a sugar and sodium chloride, wherein the composition is free or essentially free of arginine, and wherein the composition has a monomer content greater than 85 wt. % after two weeks of storage. 
     
     
         2 . The method of  claim 1 , wherein the buffer is selected from the group consisting of phosphate, histidine, citrate, maleate, tartrate, succinate, acetate, tris-(hydroxymethyl)-aminomethane and bicarbonate. 
     
     
         3 . The method of  claim 1 , where the composition has at M 3  or T 2  or T 4  no more than, on average, about 10,000 subvisible particles per mL having a size greater than 5 μm. 
     
     
         4 . The method of  claim 1 , where the composition comprises about 10 to 30 mM phosphate. 
     
     
         5 . The method of  claim 1 , where the composition comprises about 1 to about 5 wt. % sucrose. 
     
     
         6 . The method of  claim 1 , where the composition comprises about 100 to about 150 mM sodium chloride. 
     
     
         7 . The method of  claim 1 , where the composition comprises about 50 mg/ml etanercept; about 5 wt. % meglumine; about 10 to 30 mM phosphate. 
     
     
         8 . The method of  claim 7 , where the composition is free of sucrose, is free of sodium chloride, or is free of sucrose and sodium chloride. 
     
     
         9 . The method of  claim 1 , where the composition elicits long term storage stability as characterized by SEC analysis at M 3  or T 2  or T 4  of: aggregates content of less than about 3 wt %. 
     
     
         10 . The method of  claim 1 , where the composition has a pH of 6.0 to 6.6. 
     
     
         11 . The method of  claim 1 , wherein the composition eliciting 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 %: and   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 composition is characterized by SEC analysis at M 3  or T 2  or T 4  in which: the monomer content is greater than about 80 wt. %;
 aggregates content is less than about 3 wt. %, and fragment 3 content less than about 10 wt. %.   
     
     
         13 . The method of  claim 1 , wherein the 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 composition represented by peak 2 of the HIC chromatogram is greater than or equal to about 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. %. 
     
     
         14 . The method of  claim 1 , wherein the sugar is sucrose, trehalose, dextrose, or a combination thereof. 
     
     
         15 . The method of  claim 1 , wherein the composition has an osmolality from about 180 to about 420 mOsM. 
     
     
         16 . The method of  claim 1 , wherein the composition further comprises lactose, a glycerol, xylitol, sorbitol, mannitol, maltose, inositol, trehalose, glucose, bovine serum albumin (BSA), human serum albumin (HSA), a recombinant albumin, a dextran, a polyviny alcohol (PVA), a hydroxypropyl methylcellulose (HPMC), a polyethyleneimine, gelatin, polyvinylpyrrolidone (PVP), hydroxyethylcellulose (HEC), a polyethylene glycol, an ethylene glycol, a glycerol, alanine, glycine, lysine, sarcosine, sodium dodecylsulfate (SDS), polysorbate 20, polysorbate 80, poloxamer 188, trimethylamine N-oxide, betaine, zinc ions, calcium ions, magnesium ions, CHAPS, 2-O-beta-mannoglycerate, or a combination thereof. 
     
     
         17 . A method of treating a patient in need of treatment with etanercept, comprising administering to said patient a composition containing about 25 to about 75 mg/ml etanercept, 0.5-5 wt. % meglumine, a buffer, and optionally a sugar, sodium chloride, or a sugar and sodium chloride, wherein the composition is free or essentially free of arginine, and wherein the composition has a monomer content greater than 85 wt. % after two weeks of storage. 
     
     
         18 . The method of  claim 17 , comprising administering 25-100 mg etanercept per dose to the subject. 
     
     
         19 . The method of  claim 17 , comprising injecting the composition subcutaneously or intramuscularly. 
     
     
         20 . The method of  claim 17 , wherein the patient is 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, atopic dermatitis, or a combination thereof. 
     
     
         21 . A vial, syringe, or injector pen containing a composition containing about 25 to about 75 mg/ml etanercept, 0.5-5 wt. % meglumine, a buffer, and optionally a sugar, sodium chloride, or a sugar and sodium chloride, wherein the composition is free or essentially free of arginine, and wherein the composition has a monomer content greater than 85 wt. % after two weeks of storage.