Liquid insulin formulations and methods relating thereto
Liquid formulations of insulin that contain physically and chemically stable insulin but do not contain preservatives or stabilizers are provided. The formulations also lack surfactants. The formulations are useful for various modes of delivery including pulmonary delivery.
1. An insulin formulation, comprising:
insulin at a concentration of 1-13 mM;
a salt at a concentration of 50-150 mM;
a pH buffering agent at a concentration of 3-24 mM;
zinc at a ratio of 1.9-2.7 zinc ions per insulin hexamer; and
a pH in the range of 7.2 to 8.0,
wherein the formulation does not contain preservatives or stabilizers.
2. The formulation of claim 1 , wherein the insulin is human insulin.
3. The formulation of claim 1 , wherein the formulation comprises 30 mg/mL insulin.
4. The formulation of claim 1 , wherein the formulation comprises 10-30 mg/mL insulin.
5. The formulation of claim 1 , wherein the insulin concentration is about 30 mg/mL and the pH is about 7.55.
6. The formulation of claim 1 , wherein the salt comprises a chloride salt.
7. The formulation of claim 1 , wherein the salt comprises NaCl.
8. The formulation of claim 1 , wherein the pH buffering agent comprises citrate.
9. The formulation of claim 1 , wherein the tonicity (ionic strength) of the formulation is 100-300 mOsm.
10. The formulation of claim 1 , wherein the formulation is administrable by inhalation or injection.
11. The formulation of claim 1 , wherein the formulation is administrable by an inhalation device.
12. The formulation of claim 1 , wherein the formulation is aerosolizable.
13. The formulation of claim 1 , wherein the formulation does not contain surfactants.
14. The formulation of claim 1 , wherein the formulation is chemically and physically stable for 24 months at 2-8° C.
15. The formulation of claim 1 , wherein the formulation comprises a potency of 90-110% of the initial insulin concentration of the formulation at 24 months at 2-8° C.
16. The formulation of claim 1 , wherein the formulation comprises ≤1.7% of high molecular weight polymers of insulin at 24 months at 2-8° C.
17. The formulation of claim 1 , wherein the formulation comprises ≤6.0% of insulin related substances for 24 months at 2-8° C.
18. The formulation of claim 1 , wherein the formulation comprises ≤5.0% of B3 insulin products for 24 months at 2-8° C.
19. The formulation of claim 1 , wherein the formulation comprises ≤5.0% of A21 insulin products for 24 months at 2-8° C.
20. The formulation of claim 1 , wherein the formulation comprises little to no precipitated matter for 24 months at 2-8° C.
21. The formulation of claim 1 , wherein the formulation comprises 10 mg/mL insulin.
22. The formulation of claim 1 , wherein the formulation comprises 40 mg/mL insulin.
23. The formulation of claim 1 , wherein the formulation comprises 45 mg/mL insulin.
24. The formulation of claim 1 , wherein the formulation comprises 6-35 mg/mL insulin.
25. The formulation of claim 1 , wherein the formulation comprises insulin at a concentration of 280 U/mL.
26. The formulation of claim 1 , wherein the formulation comprises insulin at a concentration of 840 U/mL.
27. The formulation of claim 1 , wherein the formulation comprises insulin at a concentration of 280 U/mL 840 U/mL.
28. The formulation of claim 1 , wherein the formulation comprises a pH of 7.4.
29. The formulation of claim 1 , wherein the formulation comprises a pH of 7.5.
30. The formulation of claim 1 , wherein the formulation comprises a pH of 7.55.
31. The formulation of claim 1 , wherein the formulation comprises a pH of 7.6.
32. The formulation of claim 1 , wherein the formulation comprises a pH of 7.65.
33. The formulation of claim 1 , wherein the formulation comprises a pH of 7.7.
34. The formulation of claim 1 , wherein the formulation comprises a pH of 7.75.
35. The formulation of claim 1 , wherein the formulation comprises a pH of 7.8.
36. The formulation of claim 1 , wherein the formulation comprises a salt at a concentration of 65-75 mM.
37. The formulation of claim 1 , wherein the formulation comprises zinc at a ratio of 1.9 zinc ions per insulin hexamer.
38. The formulation of claim 1 , wherein the formulation comprises zinc at a ratio of 2.0 zinc ions per insulin hexamer.
39. The formulation of claim 1 , wherein the formulation comprises zinc at a ratio of 2.1 zinc ions per insulin hexamer.
40. The formulation of claim 1 , wherein the formulation comprises zinc at a ratio of 2.2 zinc ions per insulin hexamer.
41. A unit dose of the pharmaceutically acceptable formulation of claim 1 .
42. A method of treating a subject with diabetes mellitus, comprising administering to a subject having diabetes mellitus a therapeutically effective amount of the formulation according to claim 1 , wherein the formulation is administered to the subject via inhalation or injection.