Stable sustained-release therapeutic composition in aprotic polar solvent and method for producing the same

Abstract

This formulation platform provides the stability and solubility offered by aprotic polar solvent systems, while also offering the flexibility and enhanced physiological management provided by sustained-release therapeutic formulations. [Solution] The present invention relates to the use of aprotic polar solvents and ionization stabilizers for preparing a storage-stable sustained-release therapeutic formulation by dissolving a therapeutic agent (active ingredient) in an aprotic polar solvent system, the formulation which can then be administered to patients with or susceptible to various physical conditions or disorders, particularly hypoglycemia. In a particular embodiment, a formulation comprising one or more therapeutic agents comprises at least one therapeutic agent dissolved in an aprotic polar solvent, such as DMSO, which comprises at least one ionization-stabilizing excipient (appropriately an inorganic acid) and at least one sustained-release modifier (appropriately a divalent cation-donating compound, e.g., a zinc salt and / or polymer).

Claims

1. (a) at least one therapeutic agent, (b) at least one ionization-stabilizing excipient, (c) at least one sustained-release modifier, (d) aprotic polar solvents and A sustained-release therapeutic formulation, which includes, The formulation has storage stability at 25°C for at least 6 months, and when administered to a patient, it provides a therapeutic level of the therapeutic agent in the patient's blood for a longer period compared to an immediate-release formulation containing the same therapeutic agent. A sustained-release therapeutic agent.

2. The formulation according to claim 1, wherein the therapeutic agent is a peptide.

3. The formulation according to claim 2, wherein the peptide is a glucagon peptide, a glucagon analog, a glucagon mimetic, or a salt thereof.

4. The formulation according to claim 1, wherein the ionization stabilizing excipient is an inorganic acid.

5. The formulation according to claim 4, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

6. The formulation according to claim 1, wherein the sustained-release regulator is a divalent cation donating compound.

7. The formulation according to claim 6, wherein the divalent cation donating compound is a zinc-containing compound.

8. The formulation according to claim 7, wherein the zinc-containing compound is a zinc salt.

9. The formulation according to claim 8, wherein the zinc salt is selected from the group consisting of zinc acetate, zinc chloride, and zinc sulfate.

10. The formulation according to claim 8, wherein the zinc salt is zinc sulfate.

11. The formulation according to claim 1, wherein the aprotic polar solvent is DMSO.

12. The formulation according to claim 1, wherein the therapeutic agent is glucagon, the ionization stabilizing excipient is an inorganic acid, the sustained release modifier is a zinc salt, and the aprotic solvent is DMSO.

13. A method for treating or preventing hypoglycemia by introducing an effective amount of the formulation described in claim 1 to a subject in need.

14. The method according to claim 13, wherein the formulation is introduced to a subject by parenteral administration.

15. The method according to claim 14, wherein parenteral administration is performed by injection or infusion.

16. The method according to claim 15, wherein the injection is subcutaneous, intradermal, or intramuscular.

17. The method according to claim 15, wherein the injection is intravenous.

18. The method according to claim 15, wherein the injection is achieved by pump injection.

19. The method according to claim 18, wherein the pump injection includes continuous pump injection, bolus pump injection, or a combination thereof.

20. A method for producing a storage-stable sustained-release therapeutic formulation, comprising the step of mixing at least one ionization-stabilizing excipient, at least one sustained-release modifier, a non-protic polar solvent, and at least one therapeutic agent, thereby forming a storage-stable therapeutic formulation that, when administered to a patient, provides the presence of therapeutic levels of the therapeutic agent in the patient's blood for a longer period of time compared to an immediate-release formulation containing the same therapeutic agent.

21. The method according to claim 20, wherein the therapeutic agent is a peptide.

22. The method according to claim 21, wherein the peptide is a glucagon peptide, a glucagon analog, a glucagon mimetic, or a salt thereof.

23. The method according to claim 20, wherein the ionization stabilizing excipient is an inorganic acid.

24. The method according to claim 23, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

25. The method according to claim 20, wherein the sustained-release regulator is a divalent cation donating compound.

26. The method according to claim 25, wherein the divalent cation donating compound is a zinc-containing compound.

27. The method according to claim 26, wherein the zinc-containing compound is a zinc salt.

28. The method according to claim 27, wherein the zinc salt is selected from the group consisting of zinc acetate, zinc chloride, and zinc sulfate.

29. The method according to claim 27, wherein the zinc salt is zinc sulfate.

30. The method according to claim 20, wherein the aprotic polar solvent is DMSO.

31. The method according to claim 20, wherein the therapeutic agent is glucagon, the ionization stabilizing excipient is an inorganic acid, the sustained release modifier is a zinc salt, and the aprotic solvent is DMSO.

32. A method for diagnosing a disease or physical disability in a human patient, comprising introducing an effective amount of the formulation according to claim 1 to a patient who is suffering from or susceptible to a disease or disability, as an accessory to a diagnostic test, and performing a diagnostic test on the patient.

33. The method according to claim 32, wherein the therapeutic agent is a peptide.

34. The method according to claim 33, wherein the peptide is a glucagon peptide, a glucagon analog, a glucagon mimetic, or a salt thereof.

35. The method according to claim 32, wherein the ionization stabilizing excipient is an inorganic acid.

36. The method according to claim 32, wherein the sustained-release regulator is a divalent cation donating compound.

37. The method according to claim 36, wherein the divalent cation donating compound is a zinc-containing compound.

38. The method according to claim 32, wherein the zinc-containing compound is a zinc salt.

39. The method according to claim 38, wherein the zinc salt is selected from the group consisting of zinc acetate, zinc chloride, and zinc sulfate.

40. The method according to claim 38, wherein the zinc salt is zinc sulfate.

41. The method according to claim 32, wherein the aprotic polar solvent is DMSO.

42. The method according to claim 32, wherein the therapeutic agent is glucagon, the ionization stabilizing excipient is an inorganic acid, the sustained release modifier is a zinc salt, and the aprotic solvent is DMSO.

43. The method according to claim 32, wherein the patient has or is susceptible to Alzheimer's disease.

44. The method according to claim 32, wherein the patient has or is susceptible to growth hormone deficiency.

45. The method according to claim 32, wherein the patient has or is prone to gastrointestinal disorders.

46. The method according to claim 32, wherein the diagnostic test is a radiographic examination of the patient's gastrointestinal tract.

47. The method according to claim 32, wherein the preparation is introduced into the patient intravenously, intramuscularly, or intradermally.

48. The formulation according to claim 1, further comprising at least one polymer suitable for use in the preparation of a sustained-release formulation of a peptide.

49. The formulation according to claim 48, wherein the polymer is PLGA.

50. The formulation according to claim 49, wherein PLGA is ester-terminated PLGA or acid-terminated PLGA.

51. The formulation according to claim 48, which provides complete release of the peptide from the formulation into the bloodstream of an animal administered the formulation within a period of 7 to 14 days.

Images