Protein formulations and methods of making same

Abstract

The invention provides an aqueous formulation comprising water and a protein, and methods of making the same. The aqueous formulation of the invention may be a high protein formulation and/or may have low levels of conductity resulting from the low levels of ionic excipients. Also included in the invention are formulations comprising water and proteins having low osmolality.

What is claimed: 
     
         1 . An aqueous formulation comprising a protein and water, wherein the formulation has a characteristic selected from the group consisting of:
 (a) a conductivity of less than about 2.5 mS/cm, wherein the protein has a molecular weight (Mw) greater than about 47 kDa;   (b) an osmolality of no more than about 30 mOsmol/kg;   (c) a hydrodynamic diameter (Dh) which is at least about 50% less than the Dh of the protein in a buffered solution at a given concentration; and   (d) a hydrodynamic diameter (D h ) of less than about 4 nm.   
     
     
         2 . The formulation of  claim 1 , wherein the protein is an antibody, or an antigen-binding fragment thereof. 
     
     
         3 . The formulation of  claim 2 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb). 
     
     
         4 . The formulation of  claim 2 , wherein the antibody, or antigen-binding fragment thereof, is an anti-TNFα or an anti-IL-12 antibody. 
     
     
         5 . The formulation of  claim 2 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of adalimumab, alemtuzumab, CEA-Scan Arcitumomab (fab fragment), cetuximab, trastuzumab, imciromab pentetate), capromab pendetide, infliximab), abciximab, rituximab, basiliximab, palivizumab, nofetumomab, omalizumab, daclizumab, ibritumomab tiuxetan, muromonab-CD3, edrecolomab, gemtuzumab ozogamicin), golimumab, certolizumab pegol, eculizumab, ustekinumab, panitumumab, tositumomab and I131 tositumomab, and bevacizumab. 
     
     
         6 . The formulation of  claim 1 , wherein the protein is a therapeutic protein. 
     
     
         7 . The formulation of  claim 1 , wherein the concentration of protein is 50 to 200 mg/ml. 
     
     
         8 . The formulation of  claim 1 , further comprising a non-ionizable excipient. 
     
     
         9 . The formulation of  claim 8 , wherein the non-ionizable excipient is a sugar or a polysorbate. 
     
     
         10 . A method of treating a subject having a disorder, comprising administering to the subject the formulation of  claim 1 . 
     
     
         11 . A device comprising the formulation of  claim 1 . 
     
     
         12 . An article of manufacture comprising the device of  claim 11 . 
     
     
         13 . A method of preparing an aqueous formulation comprising a protein and water, the method comprising:
 a) providing the protein in a first solution; and   b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved to thereby prepare the aqueous formulation.   
     
     
         14 . A method of preparing an aqueous formulation of a protein, the method comprising:
 a) providing the protein in a first solution;   b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved to thereby prepare a diafiltered protein solution; and   c) concentrating the diafiltered protein solution to thereby prepare the aqueous formulation of the protein.   
     
     
         15 . The method of  claim 13 , wherein the protein is an antibody, or an antigen-binding fragment thereof. 
     
     
         16 . The method of  claim 15 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb). 
     
     
         17 . An aqueous formulation prepared according to the method of  claim 13 . 
     
     
         18 . The method of  claim 14 , wherein the protein is an antibody, or an antigen-binding fragment thereof. 
     
     
         19 . The method of  claim 18 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb). 
     
     
         20 . An aqueous formulation prepared according to the method of  claim 14 .