Claims
- 1. A stabilized liquid pharmaceutical composition comprising:
a polypeptide or variant thereof as a therapeutically active component, wherein said polypeptide or variant thereof exhibits aggregate formation during storage in a liquid formulation; an amount of an amino acid base sufficient to decrease aggregate formation of said polypeptide or variant thereof during storage of said composition, wherein said amino acid base comprises at least one amino acid selected from the group consisting of arginine, lysine, aspartic acid, and glutamic acid; and a buffering agent, wherein said buffering agent is selected from the group consisting of an acid substantially free of its salt form, an acid in its salt form, and a mixture of an acid and its salt form.
- 2. The composition of claim 1, wherein said polypeptide is selected from the group consisting of interleukin-2 (IL-2), tissue factor pathway inhibitor (TFPI), and β-interferon (IFN-β).
- 3. The composition of claim 1, wherein said composition has an osmolarity of about 240 mmol/kg to about 360 mmol/kg.
- 4. The composition of claim 1, wherein said composition has a pH within a range of about pH 4.0 to about pH 9.0.
- 5. The composition of claim 1, wherein said acid is selected from the group consisting of acetic acid, succinic acid, citric acid, phosphoric acid, and glutamic acid.
- 6. The composition of claim 5, wherein said acid is succinic acid.
- 7. The composition of claim 6, wherein said amino acid base is arginine in its free base form present at a concentration of about 100 mM to about 400 mM and wherein said succinic acid is present in said composition within a concentration range of about 80 mM to about 190 mM.
- 8. The composition of claim 7, wherein said polypeptide is interleukin-2 (IL-2) or variant thereof and said arginine in its free base form is present at a concentration of about 150 mM to about 350 mM.
- 9. The composition of claim 8, wherein said arginine in its free base form is present at a concentration of about 230 mM and wherein said succinic acid is present at a concentration of about 128 mM.
- 10. The composition of claim 9, wherein said IL-2 is recombinant human IL-2 (rhIL-2) or variant thereof.
- 11. The composition of claim 9, wherein said composition has a pH of about 5.0 to about 6.5 and an osmolarity of about 250 mmol/kg to about 330 mmol/kg.
- 12. The composition of claim 7, wherein said polypeptide is tissue factor pathway inhibitor (TFPI) or variant thereof and said arginine in its free base form is present at a concentration of about 175 mM to about 325 mM.
- 13. The composition of claim 12, wherein said arginine in its free base form is present at a concentration of about 200 mM to about 300 mM and wherein said succinic acid is present at a concentration of about 120 mM to about 180 mM.
- 14. The composition of claim 13, wherein said TFPI is recombinant human TFPI or variant thereof.
- 15. The composition of claim 13, wherein said composition has a pH of about 5.0 to about 6.5 and an osmolarity of about 240 mmol/kg to about 360 mmol/kg.
- 16. The composition of claim 5, wherein said acid is citric acid.
- 17. The composition of claim 16, wherein said amino acid base is arginine in its free base form present at a concentration of about 175 mM to about 400 mM and wherein said citric acid is present in said composition within a concentration range of about 40 mM to about 200 mM.
- 18. The composition of claim 17, wherein said polypeptide is TFPI or variant thereof.
- 19. The composition of claim 18, wherein said TFPI is recombinant human TFPI (rhTFPI).
- 20. The composition of claim 18, wherein said arginine in its free base form is present at a concentration of about 250 mM to about 350 mM and said citric acid is present at a concentration of about 100 mM to about 150 mM.
- 21. The composition of claim 20, wherein said composition has a pH of about 5.0 to about 6.5 and an osmolarity of about 240 mmol/kg to about 360 mmol/kg.
- 22. The composition of claim 1, wherein said polypeptide or variant thereof comprises at least one methionine residue that undergoes oxidation during storage in a liquid formulation.
- 23. The composition of claim 22, further comprising methionine in an amount sufficient to inhibit oxidation of said at least one methionine residue in said polypeptide during storage of said composition.
- 24. The composition of claim 1 further comprising a nonionic surfactant in an amount sufficient to inhibit aggregation of said polypeptide or variant thereof in response to freeze-thawing or mechanical shearing during storage of said composition.
- 25. The composition of claim 24, wherein said nonionic surfactant is polysorbate 80.
- 26. A stabilized liquid pharmaceutical composition comprising interleukin-2 (IL-2) or variant thereof, arginine in its free base form, and succinic acid substantially free of its salt form, wherein said arginine in its free base form is present in said composition at a concentration of about 150 mM to about 350 mM and said succinic acid is present in said composition at a concentration of about 80 mM to about 190 mM.
- 27. The composition of claim 26, wherein said arginine in its free base form is present in said composition at a concentration of about 230 mM and said succinic acid is present at a concentration of about 128 mM, wherein said composition has a pH of about 5.0 to about 6.5 and an osmolarity of about 250 mmol/kg to about 330 mmol/kg.
- 28. A stabilized liquid pharmaceutical composition comprising tissue factor pathway inhibitor (TFPI) or variant thereof, arginine in its free base form, and succinic acid substantially free of its salt form, wherein said arginine in its free base form is present in said composition at a concentration of about 175 mM to about 325 mM and said succinic acid is present in said composition at a concentration of about 80 mM to about 190 mM.
- 29. The composition of claim 28, wherein said arginine in its free base form is present in said composition at a concentration of about 200 mM to about 300 mM and said succinic acid is present at a concentration of about 120 mM to about 180 mM, wherein said composition has a pH of about 5.0 to about 6.5 and an osmolarity of about 240 mmol/kg to about 360 mmol/kg.
- 30. A stabilized liquid pharmaceutical composition comprising tissue factor pathway inhibitor (TFPI) or variant thereof, arginine in its free base form, and citric acid substantially free of its salt form, wherein said arginine in its free base form is present in said composition at a concentration of about 175 mM to about 400 mM and said citric acid is present in said composition at a concentration of about 40 mM to about 200 mM.
- 31. The composition of claim 30, wherein said arginine in its free base form is present in said composition at a concentration of about 250 mM to about 350 mM and said citric acid is present at a concentration of about 100 mM to about 150 MM, wherein said composition has a pH of about 5.0 to about 6.5 and an osmolarity of about 240 mmol/kg to about 360 mmol/kg.
- 32. A method for increasing stability of a polypeptide or variant thereof in a liquid pharmaceutical composition, where said polypeptide or variant thereof exhibits aggregate formation during storage in a liquid formulation, said method comprising incorporating into said composition an amino acid base in an amount sufficient to decrease said aggregate formation of said polypeptide or variant thereof and a buffering agent, wherein said buffering agent is selected from the group consisting of an acid substantially free of its salt form, an acid in its salt form, and a mixture of an acid and its salt form, and wherein said amino acid base comprises at least one amino acid selected from the group consisting of arginine, lysine, aspartic acid, and glutamic acid.
- 33. The method of claim 32, wherein said composition has an osmolarity of about 240 mmol/kg to about 360 mmol/kg.
- 34. The method of claim 32, wherein said composition has a pH within a range of about pH 4.0 to about pH 9.0.
- 35. The method of claim 32, wherein said acid is selected from the group consisting of acetic acid, succinic acid, citric acid, phosphoric acid, and glutamic acid.
- 36. The method of claim 35, wherein said acid is succinic acid.
- 37. A method for increasing storage stability of a pharmaceutical composition comprising a polypeptide or variant thereof, where said polypeptide or variant thereof exhibits aggregate formation during storage in a liquid formulation, said method comprising incorporating into said composition an amino acid base in an amount sufficient to decrease said aggregate formation of said polypeptide or variant thereof and a buffering agent, a buffering agent, wherein said buffering agent is selected from the group consisting of an acid substantially free of its salt form, an acid in its salt form, and a mixture of an acid and its salt form, and wherein said amino acid base comprises at least one amino acid selected from the group consisting of arginine, lysine, aspartic acid, and glutamic acid.
- 38. The method of claim 37, wherein said acid is succinic acid.
- 39. A dried form of the composition of claim 1, wherein said dried form is selected from the group consisting of a lyopholized form and a spray-dried form.
- 40. A formulation for the diagnosis, prevention, or treatment of diseases responsive to therapy with interleukin-2 (IL-2), tissue-factor pathway inhibitor (TFPI), or β-interferon (IFN-β), said formulation comprising the pharmaceutical composition of claim 1, wherein the polypeptide is selected from the group consisting of IL-2, TFPI, and IFN-β.
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser. No. 09/677,643, filed Oct. 3, 2000, which claims the benefit of U.S. Provisional Application Serial No. 60/157,696, filed Oct. 4, 1999, the contents of which are herein incorporated by reference in their entirety.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60157696 |
Oct 1999 |
US |
Continuations (1)
|
Number |
Date |
Country |
Parent |
09677643 |
Oct 2000 |
US |
Child |
10299039 |
Nov 2002 |
US |