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 arc 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 adalimumab, wherein at the pH of the composition, 21° C., one atmosphere, and equilibrium with ambient atmosphere, the adalimumab has a buffer capacity per unit volume of at least 1.50 mEq/liter-pH unit, wherein further, exclusive of the buffer capacity of the adalimumab, the buffer capacity per unit volume of the composition is less than 0.5 mEq/liter-pH unit, and wherein the concentration of the adalimumab is between approximately 20 and 400 mg/ml. 
     
     
         3 . The composition of  claim 2 , wherein a pH maintained by the antibody is between approximately 4 and 6. 
     
     
         4 . The composition of  claim 2 , wherein a pH maintained by the antibody is between approximately 3.5 and 8. 
     
     
         5 . A composition comprising a pharmaceutical protein, wherein at the pH of the composition, 21° C., one atmosphere, and equilibrium with ambient atmosphere, the protein has a buffer capacity per unit volume of at least 1,50 mEq/liter-pH unit, wherein further, exclusive of the buffer capacity of the protein, the buffer capacity per unit volume of the composition is less than 0.5 mEq/liter-pH unit, wherein the pharmaceutical protein is adalimumab, and wherein the concentration of adalimumab is between approximately 20 and 400 mg/ml. 
     
     
         6 . The composition of  claim 5 , wherein a pH maintained by the antibody is between approximately 4 and 6. 
     
     
         7 . The composition of  claim 5 , wherein a pH maintained by the antibody is between approximately 3.5 and 8. 
     
     
         8 . An aqueous pharmaceutical formulation consisting 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.   
     
     
         9 . The aqueous pharmaceutical formulation of  claim 8 , wherein the antibody has a LCVR consisting of a LCVR of adalimumab, and a HCVR consisting of a HCVR of adalimumab, 
     
     
         10 . The aqueous pharmaceutical formulation of  claim 8 , wherein the antibody is adalimumab. 
     
     
         11 . The aqueous pharmaceutical formulation of  claim 10 , wherein a pH of the formulation is from 5 to 6. 
     
     
         12 . The aqueous pharmaceutical formulation of  claim 10 , wherein a pH of the formulation is from 4 to 8. 
     
     
         13 . The aqueous pharmaceutical formulation of  claim 10 , wherein a pH of the formulation is from 4 to 6. 
     
     
         14 . The aqueous pharmaceutical formulation of  claim 10 , wherein a pH of the formulation is from 4 to 6. 
     
     
         15 . The aqueous pharmaceutical formulation of  claim 9 , wherein a pH of the formulation is from 4 to 6. 
     
     
         16 . The aqueous pharmaceutical formulation of  claim 8 , 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. 
     
     
         17 . An aqueous pharmaceutical formulation comprising:
 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 comprising the LCDR3 domain of adalimumab, a CDR2 domain comprising the LCDR2 domain of adalimumab, and a CDR1 domain comprising the LCDR1 domain of adalimumab, and a heavy chain variable region (HCVR) having a CDR3 domain comprising the HCDR3 domain of adalimumab, a CDR2 domain comprising the HCDR2 domain of adalimumab, and a CDR1 domain comprising the HCDR1 domain of adalimumab, wherein the concentration of the antibody is 20 to 200 mg/ml, or 
 (b) epratuzumab; and 
 water; 
   wherein the formulation does not comprise a buffering agent.   
     
     
         18 . The aqueous pharmaceutical formulation of  claim 17 , wherein the antibody has a LCVR consisting of a LCVR of adalimumab, and a HCVR consisting of a HCVR of adalimumab. 
     
     
         19 . The aqueous pharmaceutical formulation of  claim 17 , wherein the antibody is adalimumab 
     
     
         20 . The aqueous pharmaceutical formulation of  claim 19 , wherein the formulation further comprises a non-ionizable excipient. 
     
     
         21 . The aqueous pharmaceutical formulation of  claim 19 , wherein the formulation further comprises a polyol. 
     
     
         22 . The aqueous pharmaceutical formulation of  claim 21 , wherein the polyol is selected from the group consisting of mannitol, sorbitol, and sucrose. 
     
     
         23 . The aqueous pharmaceutical formulation of  claim 19 , wherein the formulation further comprises a surfactant. 
     
     
         24 . The aqueous pharmaceutical formulation of  claim 23 , wherein the surfactant is selected from the group consisting of polysorbate 80 and polysorbate 20. 
     
     
         25 . The aqueous pharmaceutical formulation of  claim 19 , wherein the pH of the formulation is from 4 to 8. 
     
     
         26 . The aqueous pharmaceutical formulation of  claim 19 , wherein the pH of the formulation is from 4 to 6. 
     
     
         27 . The aqueous pharmaceutical formulation of  claim 19 , wherein the pH of the formulation is from 5 to 6. 
     
     
         28 . The aqueous pharmaceutical formulation of  claim 18 , wherein the pH of the formulation is from 4 to 6. 
     
     
         29 . The aqueous pharmaceutical formulation of  claim 17 , wherein the pH of the formulation is from 4 to 6. 
     
     
         30 . The aqueous pharmaceutical formulation of  claim 19 , wherein the pH of the formulation is 5. 
     
     
         31 . The aqueous pharmaceutical formulation of  claim 19 , 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.