Self-buffering protein formulations

Abstract

The invention herein described, provides, among other things, self-buffering protein formulations. Particularly, the invention provides self-buffering pharmaceutical protein formulations that are suitable for veterinary and human medical use. The self-buffering protein formulations are substantially free of other buffering agents, stably maintain pH for the extended time periods involved in the distribution and storage of pharmaceutical proteins for veterinary and human medical use. The invention further provides methods for designing, making, and using the formulation. In addition to other advantages, the formulations avoid the disadvantages associated with the buffering agents conventionally used in current formulations of proteins for pharmaceutical use. The invention in these and other respects can be productively applied to a wide variety of proteins and is particularly useful for making and using self-buffering formulations of pharmaceutical proteins for veterinary and medical use, especially, in particular, for the treatment of diseases in human subjects.

1 . (canceled) 
     
     
         2 . A composition comprising a pharmaceutical protein, wherein
 the pharmaceutical protein is an antibody,   wherein the antibody has a buffer capacity per unit volume of at least that of approximately 4.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 under the same conditions,   wherein, exclusive of the buffer capacity of said antibody, the buffer capacity per unit volume of the composition under the same conditions is no more than that of 2.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 under the same conditions, and   wherein the concentration of the antibody is between approximately 20 and 400 mg/ml.   
     
     
         3 . A self-buffering protein formulation comprising:
 adalimumab or epratuzumab at a concentration between 20 and 200 mg/ml; and   water, wherein, apart from adalimumab, there is no buffer in the self-buffering formulation.   
     
     
         4 . The self-buffering protein formulation of  claim 3 , wherein the formulation comprises adalimumab. 
     
     
         5 . The self-buffering protein formulation of  claim 4 , wherein the formulation, exclusive of the buffer capacity of the antibody, has a buffer capacity per unit volume of the solution at the pH of the solution, 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere of no more than that of 2.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 at 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere. 
     
     
         6 . The self-buffering protein formulation of  claim 4 , wherein, the formulation, exclusive of the buffer capacity of the antibody, has a buffer capacity per unit volume of the solution at the pH of the solution, 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere of no more than that of 2.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 at 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere, and wherein at the pH of the composition, 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere, the antibody has a buffer capacity per unit volume of at least that of 4.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 at 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere. 
     
     
         7 . The self-buffering protein formulation of  claim 4 , wherein the formulation further comprises a polyol. 
     
     
         8 . The self-buffering protein formulation of  claim 7 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, and sucrose. 
     
     
         9 . The self-buffering protein formulation of  claim 4 , wherein the formulation further comprises a surfactant. 
     
     
         10 . The self-buffering protein formulation of  claim 9 , wherein the surfactant is selected from the group consisting of polysorbate 80 and polysorbate 20. 
     
     
         11 . The self-buffering protein formulation of  claim 4 , wherein a pH of the formulation is from 4 to 8. 
     
     
         12 . The self-buffering protein formulation of  claim 4 , wherein a pH of the formulation is from 4 to 6. 
     
     
         13 . The self-buffering protein formulation of  claim 4 , wherein a pH of the formulation is from 5 to 6. 
     
     
         14 . The self-buffering protein formulation of  claim 4 , wherein a pH of the formulation is 5. 
     
     
         15 . The self-buffering protein formulation of  claim 5 , wherein the formulation has a pH between approximately 4 and 6. 
     
     
         16 . A formulation comprising:
 adalimumab or epratuzumab at a concentration between 20 and 200 mg/ml; and   water, wherein the formulation is substantially free of buffering agents other than adalimumab or epratuzumab.   
     
     
         17 . The formulation of  claim 16 , wherein the formulation comprises adalimumab. 
     
     
         18 . The formulation of  claim 17 , wherein the formulation has a pH between approximately 4 and 6. 
     
     
         19 . The formulation of  claim 17 , wherein the formulation, exclusive of the buffer capacity of the antibody, has a buffer capacity per unit volume of the solution at the pH of the solution, 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere of no more than that of 2.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 at 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere. 
     
     
         20 . The formulation of  claim 17 , wherein, the formulation, exclusive of the buffer capacity of the antibody, has a buffer capacity per unit volume of the solution at the pH of the solution, 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere of no more than that of 2.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 at 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere, and wherein at the pH of the composition, 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere, the antibody has a buffer capacity per unit volume of at least that of 4.0 mM sodium acetate buffer in pure water in the range of pH 5.0 to 4.0 or pH 5.0 to 5.5 at 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere. 
     
     
         21 . The formulation of  claim 17 , wherein the formulation further comprises a polyol. 
     
     
         22 . The formulation of  claim 21 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, and sucrose. 
     
     
         23 . The formulation of  claim 17 , wherein the formulation further comprises a surfactant. 
     
     
         24 . The formulation of  claim 23 , wherein the surfactant is selected from the group consisting of polysorbate 80 and polysorbate 20. 
     
     
         25 . The formulation of  claim 17 , wherein a pH of the formulation is from 4 to 8. 
     
     
         26 . The formulation of  claim 17 , wherein a pH of the formulation is from 4 to 6. 
     
     
         27 . The formulation of  claim 17 , wherein a pH of the formulation is from 5 to 6. 
     
     
         28 . The formulation of  claim 17 , wherein a pH of the formulation is 5. 
     
     
         29 . An aqueous pharmaceutical formulation consisting essentially of:
 an antibody selected from the group consisting of: (a) an anti-tumor necrosis factor alpha antibody comprising a light chain variable region (LCVR) having a CDR3 domain of the CDR3 domain of adalimumab, a CDR2 domain of the CDR2 domain of adalimumab, and a CDR1 domain of the CDR1 domain of adalimumab, and a heavy chain variable region (HCVR) having a CDR3 domain of the CDR3 domain of adalimumab, a CDR2 domain of the CDR2 domain of adalimumab, and a CDR1 domain of the CDR1 domain of adalimumab, wherein the concentration of the antibody is 20 to 200 mg/ml; or (b) epratuzumab; and   water.   
     
     
         30 . The aqueous pharmaceutical formulation of  claim 29 , wherein the antibody is adalimumab. 
     
     
         31 . The composition of  claim 2 , wherein the antibody is adalimumab.