High concentration antibody-containing liquid formulation

Abstract

The problem to be solved is to provide a humanized anti-IL-6 receptor antibody MRA-containing formulation which is suitable for subcutaneous administration, wherein dimerization or deamidation is prevented during long-term storage. The present application is directed to a stable antibody-containing liquid formulation characterized by containing arginine and histidine buffer. A method of inhibiting deamidation or dimerization of such an antibody in a concentrated liquid formulation includes histidine buffer in the liquid formulation.

1 . An antibody-containing lyophilized formulation free from reducing sugars, non-reducing sugars, sugar alcohols or polysaccharides as fillers and including one or more amino acid selected from the group consisting of arginine, histidine, lysine, serine, proline, glycine, alanine and threonine or a salt thereof. 
     
     
         2 . The formulation of  claim 1  wherein the antibody concentration of the lyophilized formulation after reconstitution is 10 mg/mL or more. 
     
     
         3 . The formulation of  claim 2  wherein the antibody concentration of the lyophilized formulation after reconstitution is 50 mg/mL or more. 
     
     
         4 . The formulation of  claim 3  wherein the antibody concentration of the lyophilized formulation after reconstitution is 100 mg/mL or more. 
     
     
         5 . The formulation of any one of  claims 1  to  4  wherein the content of the amino acid or a salt thereof is 270 moles or more per mole of the antibody. 
     
     
         6 . The formulation of  claim 5  wherein the content of the amino acid or a salt thereof is 380 moles or more per mole of the antibody. 
     
     
         7 . The formulation of  claim 6  wherein the content of the amino acid or a salt thereof is 540 moles or more per mole of the antibody. 
     
     
         8 . The formulation of any one of  claims 1  to  7  wherein the pH of the solution after reconstitution is 4-8. 
     
     
         9 . The formulation of  claim 8  wherein the pH of the solution after reconstitution is 5.0-7.5. 
     
     
         10 . The formulation of any one of  claims 1  to  9  wherein the antibody is a chimeric antibody, humanized antibody or human antibody. 
     
     
         11 . The formulation of  claim 10  wherein the antibody is an anti-IL-6 receptor antibody. 
     
     
         12 . The formulation of any one of  claims 1  to  11  wherein the amino acid or a salt thereof is one or more amino acid selected from the group consisting of arginine, histidine and lysine or a salt thereof. 
     
     
         13 . The formulation of  claim 12  wherein the amino acid or a salt thereof is arginine or a salt thereof. 
     
     
         14 . The formulation of any one of  claims 1  to  13  wherein the viscosity after reconstitution is 20 mPa·s or less. 
     
     
         15 . The formulation of  claim 14  wherein the viscosity after reconstitution is 15 mPa·s or less. 
     
     
         16 . The formulation of  claim 15  wherein the viscosity after reconstitution is 12 mPa·s or less. 
     
     
         17 . An antibody-containing lyophilized formulation including one or more amino acid selected from the group consisting of arginine, histidine, lysine, serine, proline, glycine, alanine and threonine or a salt thereof as a lyoprotectant or a filler characterized in that it includes 25 mg/ml or more of the amino acid or a salt thereof when the antibody concentration of the lyophilized formulation is 20 mg/mL or more, or it includes 12.5 mg/ml or more of the amino acid or a salt thereof when the antibody concentration is 30 mg/mL or more, or it includes 6.25 mg/ml or more of the amino acid or a salt thereof when the antibody concentration is 40 mg/mL or more. 
     
     
         18 . The formulation of  claim 17  characterized in that it includes 25 mg/ml or more of the amino acid or a salt thereof when the antibody concentration of the lyophilized formulation is 30 mg/mL or more, or it includes 12.5 mg/ml or more of the amino acid or a salt thereof when the antibody concentration is 40 mg/mL or more. 
     
     
         19 . A process for preparing an antibody-containing lyophilized formulation including one or more amino acid selected from the group consisting of arginine, histidine, lysine, serine, proline, glycine, alanine and threonine or a salt thereof as a lyoprotectant or a filler, comprising the step of lyophilizing a solution before lyophilization having a total concentration of reducing sugars, non-reducing sugars, sugar alcohols and polysaccharides of less than 20 mg/mL. 
     
     
         20 . An antibody-containing lyophilized formulation including one or more amino acid selected from the group consisting of arginine, histidine, lysine, serine, proline, glycine, alanine and threonine or a salt thereof as a lyoprotectant or a filler, wherein the ratio per vial of antibody weight to the total weight of reducing sugars, non-reducing sugars, sugar alcohols and polysaccharides is less than 1:0.5. 
     
     
         21 . A protein-containing lyophilized formulation free from reducing sugars, non-reducing sugars, sugar alcohols or polysaccharides as fillers and including one or more amino acid selected from the group consisting of arginine, histidine, lysine, serine, proline, glycine, alanine and threonine or a salt thereof. 
     
     
         22 . A process for preparing a protein-containing lyophilized formulation including one or more amino acid selected from the group consisting of arginine, histidine, lysine, serine, proline, glycine, alanine and threonine or a salt thereof as a lyoprotectant or a filler, comprising the step of lyophilizing a solution before lyophilization having a total concentration of reducing sugars, non-reducing sugars, sugar alcohols and polysaccharides of less than 20 mg/mL. 
     
     
         23 . A protein-containing lyophilized formulation including one or more amino acid selected from the group consisting of arginine, histidine, lysine, serine, proline, glycine, alanine and threonine or a salt thereof as a lyoprotectant or a filler, wherein the ratio per vial of protein weight to the total weight of reducing sugars, non-reducing sugars, sugar alcohols and polysaccharides is less than 1:0.5.