Pharmaceutical formulations of tnf-alpha antibodies

Abstract

The present invention provides certain improved formulations of proteins. Specifically, the present invention provides use of certain excipients that are useful for stabilization of antibody preparations. Additionally, the novel formulation of the present invention prevents the formation of aggregates or fragments or modification of protein in solution.

We claim: 
     
         1 .- 41 . (canceled) 
     
     
         42 . A liquid pharmaceutical formulation comprising an antibody or antigen binding portion thereof directed to TNFα wherein the antibody is adalimumab or its antigen binding portion, at a concentration of 1 mg/mL to 160 mg/mL, and an amino acid, wherein the pH of the formulation is between 4 to 8. 
     
     
         43 . The formulation as claimed in  claim 42 , wherein the concentration of antibody is 100 mg/mL. 
     
     
         44 . The formulation as claimed in  claim 42 , wherein the pH of the formulation is between pH 5.0 and pH 5.5, preferably at pH 5.2. 
     
     
         45 . The formulation as claimed in  claim 42 , further comprising a buffer system, wherein the buffer system is selected from histidine-buffers, citrate-buffers, succinate-buffers, acetate-buffers, phosphate-buffers, phosphate buffered saline, citrate and phosphate buffer, tromethamine buffers and suitable mixtures thereof, and/or wherein the buffer is present in the concentration of 1 mM to about 100 mM, preferably 5 mM to 50 mM. 
     
     
         46 . The formulation as claimed in  claim 45 , wherein the buffer system is a succinate-buffer or acetate-buffer or histidine buffer or suitable mixture thereof. 
     
     
         47 . The formulation as claimed in  claim 42 , wherein the amino acid is selected from arginine, glycine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophane, methionine, serine, proline, cysteine/cystine and suitable combination thereof and/or wherein the amino acid is present in the concentration of 0.5% to 10%. 
     
     
         48 . The formulation as claimed in  claim 47 , wherein the amino acid is arginine or glycine or histidine alone or in combination with other suitable amino acids. 
     
     
         49 . The formulation as claimed in  claim 42 , further comprising a stabilizer, wherein stabilizer is selected from a sugar and a polyol, including their suitable combination. 
     
     
         50 . The formulation as claimed in  claim 49 , wherein the sugar is selected from glucose, fructose, galactose, mannose, sorbose, ribose, deoxyribose, sucrose, trehalose, lactose, maltose, raffinose and suitable mixtures thereof or wherein the polyol is selected from mannitol, sorbitol, dextran, glycerol, arabitol, propylene glycol, polyethylene glycol and suitable combinations thereof. 
     
     
         51 . The formulation as claimed in  claim 42 , which further comprises suitable excipients selected from surfactants and tonicity agents. 
     
     
         52 . The formulation as claimed in  claim 51 , wherein the surfactant is selected from polyoxyethylensorbitan fatty acid esters (Tween), polyoxyethylene alkyl ethers, alkylphenylpolyoxyethylene ethers, polyoxyethylene-polyoxypropylene copolymer and sodium dodecyl sulphate (SDS) and the tonicity agent is selected from sodium chloride and potassium chloride. 
     
     
         53 . The formulation as claimed in  claim 52 , wherein the surfactant is selected from polysorbate 20 or polysorbate 80. 
     
     
         54 . The formulation as claimed in  claim 51 , wherein the surfactant is present at 0.001% to about 1% and/or wherein the tonicity agent is sodium chloride and is present in an amount between about 10 mM to about 150 mM. 
     
     
         55 . A lyophilized formulation comprising the composition as claimed in  claim 42 . 
     
     
         56 . A formulation comprising
 a. 1-160 mg/mL of adalimumab,   b. 0.5-10% of amino acid, and   c. a buffer system with a pH of 4 to 8.   
     
     
         57 . The formulation as claimed in  claim 56 , wherein the concentration of adalimumab is 100 mg/mL. 
     
     
         58 . The formulation as claimed in  claim 56 , wherein the pH of the formulation is between pH 5.0 and pH 5.5, preferably at pH 5.2. 
     
     
         59 . The formulation as claimed in  claim 56 , wherein the buffer system is selected from histidine-buffers, citrate-buffers, succinate-buffers, acetate-buffers, phosphate-buffers, phosphate buffered saline, citrate and phosphate buffer, tromethamine buffers and suitable mixtures thereof, and/or wherein the buffer is present in the concentration of 1 mM to about 100 mM, preferably 5 mM to 50 mM. 
     
     
         60 . The formulation as claimed in  claim 59 , wherein the buffer system is a succinate-buffer or acetate-buffer or histidine buffer or suitable mixture thereof. 
     
     
         61 . The formulation as claimed in  claim 56 , wherein the amino acid is selected from arginine, glycine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophane, methionine, serine, proline, cysteine/cystine and suitable combination thereof. 
     
     
         62 . The formulation as claimed in  claim 61 , wherein the amino acid is arginine or glycine or histidine alone or in combination with other suitable amino acids. 
     
     
         63 . The formulation as claimed in  claim 56  further comprising a stabilizer, wherein stabilizer is selected from a sugar and a polyol, including their suitable combination. 
     
     
         64 . The formulation as claimed in  claim 63 , wherein the sugar is selected from glucose, fructose, galactose, mannose, sorbose, ribose, deoxyribose, sucrose, trehalose, lactose, maltose, raffinose and suitable mixtures thereof or wherein the polyol is selected from mannitol, sorbitol, dextran, glycerol, arabitol, propylene glycol, polyethylene glycol and suitable combinations thereof. 
     
     
         65 . The formulation as claimed in  claim 56 , further comprising a suitable excipient selected from a surfactant and a tonicity agent. 
     
     
         66 . The formulation as claimed in  claim 65 , wherein the surfactant is selected from polyoxyethylensorbitan fatty acid ester (Tween), polyoxyethylene alkyl ether, alkylphenylpolyoxyethylene ether, polyoxyethylene-polyoxypropylene copolymer and sodium dodecyl sulphate (SDS) and the tonicity agent is selected from sodium chloride and potassium chloride. 
     
     
         67 . The formulation as claimed in  claim 66 , wherein the surfactant is selected from polysorbate 20 and polysorbate 80. 
     
     
         68 . The formulation as claimed in  claim 65 , wherein the surfactant is present at 0.001% to about 1% and/or wherein the tonicity agent is sodium chloride and is present in an amount between about 10 mM to about 150 mM. 
     
     
         69 . A lyophilized formulation comprising the composition as claimed in  claim 56 .