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, exclusive of the buffer capacity of the antibody, the composition 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,   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, and   wherein the concentration of the antibody is between approximately 20 and 400 mg/ml.   
     
     
         3 . A composition comprising a pharmaceutical protein, wherein
 the pharmaceutical protein is adalimumab,   wherein, exclusive of the buffer capacity of the adalimumab, the composition 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,   wherein at the pH of the composition, 21° C., one atmosphere of pressure, and equilibrium with ambient atmosphere, the adalimumab 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, and   wherein the concentration of the adalimumab is between approximately 20 and 400 mg/ml.   
     
     
         4 . A formulation comprising:
 adalimumab or epratuzumab at a concentration between 20 and 200 mg/ml; and   water, wherein at least 95% of a total amount of buffering agent of the formulation is adalimumab or epratuzumab.   
     
     
         5 . The formulation of  claim 4 , wherein the formulation comprises adalimumab. 
     
     
         6 . The formulation of  claim 5 , wherein the formulation further comprises a polyol. 
     
     
         7 . The formulation of  claim 6 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, and sucrose. 
     
     
         8 . The formulation of  claim 5 , wherein the formulation further comprises a surfactant. 
     
     
         9 . The formulation of  claim 8 , wherein the surfactant is selected from the group consisting of polysorbate 80 and polysorbate 20. 
     
     
         10 . The formulation of  claim 5 , wherein a pH of the formulation is from 4 to 8. 
     
     
         11 . The formulation of  claim 5 , wherein a pH of the formulation is from 4 to 6. 
     
     
         12 . The formulation of  claim 5 , wherein a pH of the formulation is from 5 to 6. 
     
     
         13 . The formulation of  claim 5 , wherein a pH of the formulation is 5. 
     
     
         14 . The formulation of  claim 5 , 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. 
     
     
         15 . The formulation of  claim 5 , 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. 
     
     
         16 . The formulation of  claim 5 , wherein the formulation is substantially free of any buffering agent other than the pharmaceutical protein. 
     
     
         17 . A formulation comprising:
 adalimumab or epratuzumab at a concentration between 20 and 200 mg/ml; and   water, wherein adalimumab provides at least 99% of a buffer capacity of the formulation.   
     
     
         18 . The formulation of  claim 17 , wherein the formulation comprises adalimumab. 
     
     
         19 . The formulation of  claim 18 , wherein the formulation further comprises a polyol. 
     
     
         20 . The formulation of  claim 19 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, and sucrose. 
     
     
         21 . The formulation of  claim 18 , wherein the formulation further comprises a surfactant. 
     
     
         22 . The formulation of  claim 21 , wherein the surfactant is selected from the group consisting of polysorbate 80 and polysorbate 20. 
     
     
         23 . The formulation of  claim 18 , wherein a pH of the formulation is from 4 to 8. 
     
     
         24 . The formulation of  claim 18 , wherein a pH of the formulation is from 4 to 6. 
     
     
         25 . The formulation of  claim 18 , wherein a pH of the formulation is from 5 to 6. 
     
     
         26 . The formulation of  claim 18 , wherein a pH of the formulation is 5. 
     
     
         27 . The formulation of  claim 18 , 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. 
     
     
         28 . The formulation of  claim 18 , 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. 
     
     
         29 . The formulation of  claim 18 , wherein the formulation is substantially free of any buffering agent other than the pharmaceutical protein. 
     
     
         30 . The formulation of  claim 18 , wherein adalimumab provides at least 99.5% of the buffer capacity of the formulation. 
     
     
         31 . The composition of  claim 2 , wherein the antibody is adalimumab.