VISCOSITY-REDUCING EXCIPIENT COMPOUNDS FOR PROTEIN FORMULATIONS
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.