Solution preparation containing stabilized antibody

Abstract

The present inventors discovered that a significant stabilization effect was achieved by using an acidic amino acid, aspartic acid or glutamic acid as a counter ion species in histidine buffer or tris(hydroxymethyl)aminomethane, specifically by using histidine-aspartate buffer or histidine-glutamate buffer, or tris(hydroxymethyl)aminomethane-aspartate or tris(hydroxy-methyl) aminomethane-glutamate as a buffer. The present inventors also discovered that a significant stabilization effect was achieved by using an acidic amino acid, aspartic acid or glutamic acid, as a counter ion species to a basic amino acid such as arginine, specifically by using arginine-aspartate or arginine-glutamate.

1 .- 23 . (canceled) 
     
     
         24 . A method for suppressing aggregate formation during liquid or frozen storage storage of an antibody-comprising formulation by using aspartic acid or glutamic acid as a counter ion species to a tris(hydroxymethyl) aminomethane buffer in the formulation, wherein the pH of the formulation is 5.5 to 8 and wherein the concentration of the antibody in the formulation is 50 mg/mL or more. 
     
     
         25 . (canceled) 
     
     
         26 . A method for suppressing aggregate formation during liquid or frozen storage of an antibody-comprising formulation by using aspartic acid or glutamic acid as a counter ion species to a stabilizer in the formulation, wherein the concentration of the antibody in the formulation is 50 mg/mL or more. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 24 , wherein the method suppresses aggregate formation during liquid storage. 
     
     
         29 . The method of  claim 24 , wherein the method suppresses aggregate formation during frozen storage. 
     
     
         30 . The method of  claim 24 , wherein the antibody has been modified to have an isoelectric point (pI) of between 5.0 to 8.0. 
     
     
         31 . The method of  claim 24 , wherein the concentration of the antibody in the formulation is 50 to 250 mg/ml. 
     
     
         32 . The method of  claim 24 , wherein formulation contains 5 mM or less, 2 mM or less, or 1 mM or less of chloride and acetate ions. 
     
     
         33 . The method of  claim 24 , wherein the formulation further comprises a sugar. 
     
     
         34 . The method of  claim 24 , wherein the tris(hydroxymethyl) aminomethane buffer concentration is 5 to 100 mM. 
     
     
         35 . The method of  claim 28 , wherein the viscosity of the liquid formulation is 30 mPa s or less. 
     
     
         36 . The method of  claim 28 , wherein the liquid formulation is stable at 2° C. to 8° C. for at least six months. 
     
     
         37 . The method of  claim 29 , wherein the formulation is frozen stored at −30° C. to −10° C. 
     
     
         38 . The method of  claim 24 , wherein the formulation has not been subjected to lyophilization. 
     
     
         39 . The method of  claim 26 , wherein the method suppresses aggregate formation during liquid storage. 
     
     
         40 . The method of  claim 26 , wherein the method suppresses aggregate formation during frozen storage. 
     
     
         41 . The method of  claim 26 , wherein the antibody has been modified to have an isoelectric point (pI) of between 5.0 to 8.0. 
     
     
         42 . The method of  claim 26 , wherein the concentration of the antibody in the formulation is 50 to 250 mg/ml. 
     
     
         43 . The method of  claim 26 , wherein formulation contains 5 mM or less, 2 mM or less, or 1 mM or less of chloride and acetate ions. 
     
     
         44 . The method of  claim 26 , wherein the formulation further comprises a sugar. 
     
     
         45 . The method of  claim 39 , wherein the viscosity of the liquid formulation is 30 mPa s or less. 
     
     
         46 . The method of  claim 39 , wherein the liquid formulation is stable at 2° C. to 8° C. for at least six months. 
     
     
         47 . The method of  claim 40 , wherein the formulation is frozen stored at −30° C. to −10° C. 
     
     
         48 . The method of  claim 26 , wherein the formulation has not been subjected to lyophilization. 
     
     
         49 . The method of  claim 26 , wherein the counter ion species is aspartic acid. 
     
     
         50 . The method of  claim 26 , wherein the counter ion species is glutamic acid. 
     
     
         51 . The method of  claim 26 , wherein the counter ion species is aspartic acid and glutamic acid. 
     
     
         52 . The method of  claim 26 , wherein the stabilizer is selected from argininamide, lysine, meglumine, spermine, spermidine, magnesium, calcium, sodium, potassium, and arginine. 
     
     
         53 . The method of  claim 26 , wherein the concentration of the stabilizer is 5 to 300 mM or 25 to 200 mM. 
     
     
         54 . The method of  claim 26 , wherein the stabilizer is arginine. 
     
     
         55 . The method of  claim 54 , wherein the arginine concentration is 25 to 200 mM or 50 to 150 mM.