Viscosity-reducing excipient compounds for protein formulations

Abstract

The invention encompasses formulations and methods for the production thereof that permit the delivery of concentrated protein solutions. The inventive methods can yield a lower viscosity liquid formulation or a higher concentration of therapeutic or nontherapeutic proteins in the liquid formulation, as compared to traditional protein solutions.

1 . A liquid formulation comprising a protein and an excipient compound selected from the group consisting of hindered amines, anionic aromatics, functionalized amino acids, oligopeptides, short-chain organic acids, and low molecular weight aliphatic polyacids, wherein the excipient compound is added in a viscosity-reducing amount. 
     
     
         2 . The liquid formulation of  claim 1 , wherein the protein is a PEGylated protein and the excipient compound is a low molecular weight aliphatic polyacid. 
     
     
         3 . The liquid formulation of  claim 1 , wherein the formulation is a pharmaceutical composition, and wherein the pharmaceutical composition comprises a therapeutic protein, and wherein the excipient compound is pharmaceutically acceptable excipient compound. 
     
     
         4 . The liquid formulation of  claim 1 , wherein the formulation is a non-therapeutic formulation, and wherein the non-therapeutic formulation comprises a non-therapeutic protein. 
     
     
         5 . The formulation of  claim 1 , wherein the viscosity-reducing amount reduces the viscosity of the formulation to a viscosity less than the viscosity of a control formulation. 
     
     
         6 . The formulation of  claim 5 , wherein the viscosity of the formulation is at least about 10% less than the viscosity of the control formulation. 
     
     
         7 . (canceled) 
     
     
         8 . The formulation of  claim 6 , wherein the viscosity of the formulation is at least about 50% less than the viscosity of the control formulation. 
     
     
         9 . (canceled) 
     
     
         10 . The formulation of  claim 8 , wherein the viscosity of the formulation is at least about 90% less than the viscosity of the control formulation. 
     
     
         11 . The formulation of  claim 5 , wherein the viscosity is less than about 100 cP. 
     
     
         12 . The formulation of  claim 5 , wherein the viscosity is less than about 50 cP. 
     
     
         13 . The formulation of  claim 5 , wherein the viscosity is less than about 20 cP. 
     
     
         14 . The formulation of  claim 5 , wherein the viscosity is less than about 10 cP. 
     
     
         15 . The formulation of  claim 1 , wherein the excipient compound has a molecular weight of <5000 Da. 
     
     
         16 . (canceled) 
     
     
         17 . The formulation of  claim 15 , wherein the excipient compound has a molecular weight of <500 Da. 
     
     
         18 . The formulation of  claim 1 , wherein the formulation contains at least about 25 mg/mL of the protein. 
     
     
         19 . (canceled) 
     
     
         20 . The formulation of  claim 18 , wherein the formulation contains at least about 200 mg/mL of the protein. 
     
     
         21 . (canceled) 
     
     
         22 . The formulation of  claim 1 , comprising between about 5 mg/mL to about 300 mg/mL of the excipient compound. 
     
     
         23 . (canceled) 
     
     
         24 . The formulation of  claim 22 , comprising between about 20 mg/mL to about 100 mg/mL. 
     
     
         25 . (canceled) 
     
     
         26 . The formulation of  claim 1 , wherein the formulation has an improved stability when compared to the control formulation. 
     
     
         27 . The formulation of  claim 1 , wherein the excipient compound is a hindered amine. 
     
     
         28 . The formulation of  claim 27 , wherein the hindered amine is selected from the group consisting of caffeine, theophylline, tyramine, imidazole, aspartame, saccharin, and acesulfame potassium. 
     
     
         29 . The formulation of  claim 28 , wherein the hindered amine is caffeine. 
     
     
         30 - 33 . (canceled) 
     
     
         34 . The formulation of claim  31 , wherein the hindered amine is present in the formulation in an amount that is less than a therapeutically effective amount. 
     
     
         35 . (canceled) 
     
     
         36 . The formulation of  claim 35 , wherein the second excipient compound is selected from the group consisting of caffeine, theophylline, tyramine, imidazole, aspartame, saccharin, and acesulfame potassium. 
     
     
         37 . (canceled) 
     
     
         38 . A method of treating a disease or disorder in a mammal in need thereof, comprising:
 administering to said mammal a liquid therapeutic formulation, wherein the liquid therapeutic formulation comprises a therapeutically effective amount of a therapeutic protein and wherein the liquid therapeutic formulation further comprises an pharmaceutically acceptable excipient compound selected from the group consisting of hindered amines, anionic aromatics, functionalized amino acids, oligopeptides, short-chain organic acids, and low molecular weight aliphatic polyacids; and   wherein the therapeutic formulation is effective for the treatment of the disorder.   
     
     
         39 . The method of  claim 38 , wherein the therapeutic protein is a PEGylated protein, and the excipient compound is a low molecular weight aliphatic polyacid. 
     
     
         40 . The method of  claim 38 , wherein the excipient compound is a hindered amine. 
     
     
         41 - 48 . (canceled) 
     
     
         49 . A method of improving stability of a liquid protein formulation, comprising:
 preparing a liquid protein formulation comprising a therapeutic protein and an excipient compound selected from the group selected from the group consisting of hindered amines, anionic aromatics, functionalized amino acids, oligopeptides, and short-chain organic acids, and low molecular weight aliphatic polyacids,   wherein the liquid protein formulation demonstrates improved stability compared to a control liquid protein formulation, wherein the control liquid protein formulation does not contain the excipient compound and is otherwise identical to the liquid protein formulation.   
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . A liquid formulation comprising a protein and an excipient compound selected from the group consisting of hindered amines, anionic aromatics, functionalized amino acids, oligopeptides, and short-chain organic acids, and low molecular weight aliphatic polyacids, wherein the excipient compound results in improved protein-protein interaction as measured by the protein diffusion interaction parameter kD, or the second virial coefficient B22. 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . A method of improving a protein-related process comprising:
 providing the liquid formulation of  claim 1 , and   employing it in a processing method.   
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . The method of  claim 55 , wherein the processing method is selected from the group consisting of filtration, pumping, mixing, centrifugation, membrane separation, lyophilization, and chromatography.