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 - 33 . (canceled) 
     
     
         34 . A process for preparing 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 that of approximately 4.0 mM sodium acetate buffet 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 further, exclusive Of the buffer capacity of said protein, 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,   said process comprising removing residual buffer using a counter ion.   
     
     
         35 . A process for preparing a composition according to  claim 34 , comprising removing residual buffer using any one or more of the following in the presence of a counter ion: size exclusion chromatography, dialysis, and/or tangential flow filtration. 
     
     
         36 . A process for preparing a composition according to  claim 35 , comprising removing residual buffer using ion exchange chromatography. 
     
     
         37 . A process for preparing 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 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 further, exclusive of the buffer capacity of said protein, 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 5M to 4.0 or pH 5.0 to 5.5 under the same conditions,   said process comprising removing residual buffer by diafiltration against a bufferless solution having a pH below the desired pH.   
     
     
         38 . A process for preparing a composition according to  claim 37 , wherein following diafiltration the, pH is adjusted to a desired pH by addition of dilute acid and/or dilute base. 
     
     
         39 - 65 . (canceled) 
     
     
         66 . A process for preparing a composition according to  claim 34 , wherein exclusive of the buffer capacity of said protein, the buffer capacity per unit volume of the composition is less than 0.5 mEq/liter-pH unit. 
     
     
         67 . A process for preparing a composition according to  claim 34 , wherein the protein provides at least 80% of the buffer capacity of the composition. 
     
     
         68 . A process for preparing a composition according to  claim 67 , wherein the concentration of the protein is between approximately 20 and 400 mg/ml. 
     
     
         69 . A process for preparing a composition according to  claim 68 , wherein the pH maintained by the buffering action of the protein is between approximately 3.5 and 8.0. 
     
     
         70 . A process for preparing a composition according to  claim 69 , wherein the pH maintained by the buffering-action of the protein is between approximately 4 and 6. 
     
     
         71 . A process for preparing a composition according to  claim 69 , said composition further comprising one or more pharmaceutically acceptable salts, wherein the total salt concentration is less than 150 mM. 
     
     
         72 . A process for preparing a composition according to  claim 71 , said composition further comprising one or more pharmaceutically acceptable salts, wherein the total salt concentration is less than 100 mM.