Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral pH
View Patent ↗The present invention provides, among other aspects, storage stabile aqueous formulations of immunoglobulins with histidine at a mildly acidic to neutral pH. The present invention also provides methods for stabilizing immunoglobulin compositions by formulating with histidine at a mildly acidic to neutral pH. Advantageously, the methods and formulations provided herein allow stabile aqueous compositions of immunoglobulins at mildly acidic to neutral pH useful for parenteral administration.
1. A storage stable, aqueous immunoglobulin composition comprising:
(a) an immunoglobulin
(b) from 225 mM to 275 mM histidine;
(c) from 0 mM to 10 mM of an alkali metal cation; and
(d) a pH from 5.5 to 7.0,
wherein the composition is stable for at least 6 months when stored at from 28° C. to 32° C., and wherein the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state remains below 2%, and wherein the composition does not contain a surfactant or sugar.
2. The composition of claim 1 , containing from 0 mM to 1 mM of an alkali metal cation.
3. The composition of claim 1 , wherein the composition contains from 10 mM to 400 mM chloride ions.
4. The composition of claim 3 , containing from 100 mM to 200 mM chloride ions.
5. The composition of claim 1 , wherein the pH of the composition is from 5.5 to 6.5.
6. The composition of claim 5 , wherein the pH of the composition is 6.1±0.2.
7. The composition of claim 1 , wherein the composition further comprises an antioxidant.
8. The composition of claim 1 , wherein the composition is stored under an inert gas.
9. The composition of claim 8 , wherein the inert gas is selected from the group consisting of nitrogen, argon, carbon dioxide, helium, krypton, and xenon.
10. The composition of claim 8 , wherein the inert gas is nitrogen.
11. The composition of claim 8 , wherein the inert gas is argon.
12. The composition of claim 1 , wherein the immunoglobulin is a polyclonal immunoglobulin.
13. The composition of claim 1 , wherein the immunoglobulin is a monoclonal immunoglobulin.
14. The composition of claim 1 , wherein the immunoglobulin is an IgG immunoglobulin.
15. The composition of claim 1 , wherein the immunoglobulin is enriched from pooled human plasma.
16. The composition of claim 1 , wherein the immunoglobulin is a recombinant immunoglobulin.
17. The composition of claim 1 , wherein the concentration of the immunoglobulin is 50±5 g/L.
18. The composition of claim 1 , wherein the concentration of the immunoglobulin is less than 50 g/L.
19. The composition of claim 1 , wherein the concentration of the immunoglobulin is at least 50 g/L.
20. The composition of claim 19 , wherein the concentration of the immunoglobulin is from 50 g/L to 150 g/L.
21. The composition of claim 20 , wherein the concentration of the immunoglobulin is 100±10 g/L.
22. The composition of claim 19 , wherein the concentration of the immunoglobulin is at least 100 g/L.
23. The composition of claim 22 , wherein the concentration of the immunoglobulin is 150±15 g/L.
24. The composition of claim 22 , wherein the concentration of the immunoglobulin is from 150 g/L to 250 g/L.
25. The composition of claim 24 , wherein the concentration of the immunoglobulin is 200±20 g/L.
26. The composition of claim 19 , wherein the concentration of the immunoglobulin is at least 200 g/L.
27. The composition of claim 1 , wherein the composition is stable for at least 1 month when stored at from 38° C. to 42° C.
28. The composition of claim 27 , wherein the composition is stable for at least 3 months when stored at from 38° C. to 42° C.
29. The composition of claim 28 , wherein the composition is stable for at least 6 months when stored at from 38° C. to 42° C.
30. The composition of claim 1 , wherein the composition is stable for at least 1 year when stored at from 28° C. to 32° C.
31. The composition of claim 30 , wherein the composition is stable for at least 2 years when stored at from 28° C. to 32° C.
32. The composition of claim 1 , wherein the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is from 0% to 2% and the percentage of immunoglobulin in the monomeric state is from 85% to 100%.
33. The composition of claim 1 , wherein a composition having the same components, but formulated at pH 4.8, is stable for less than 1 month when stored at from 38° C. to 42° C.
34. The composition of claim 1 , wherein a composition having the same components, but formulated at pH 4.8, is stable for less than 6 months when stored at from 28° C. to 32° C.