Radiopharmaceutical formulations

• US 20050074402A1
• Filed: 10/19/2001
• Published: 04/07/2005
• Est. Priority Date: 10/19/2000
• Status: Abandoned Application

• Current Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Original Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Inventors: Linder, Karen E., Marinelli, Edmund, Cagnolini, Aldo
• Application Number:
  US10/399,307
• Publication Number:
  US 20050074402A1
• Time in Patent Office: Days
• US Class Current: 424/1.650
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61K 51/1282 Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents

Abstract

A method is described for inhibiting the degradation of a diagnostic or radiotherapeutic radiopharmaceutical, especially radiolabeled compounds containing reducible moieties, by including oxidants either as a part of the composition for the preparation of such radiopharmaceuticals, or by adding an oxidant to such compositions immediately after the preparation of such radiopharmaceuticals.

Claims

1. A kit for preparing a radiopharmaceutical, the kit comprising a predetermined quantity of a complexing ligand and a predetermined quantity of an oxidant. wherein the radiopharmaceutical has a radiochemical purity of greater than 90% at about six hours after reconstitution.

2. The kit of claim 1, wherein the oxidant has the following structure:

3. The kit of claim 1, wherein the oxidant is benzoquinone.

4. The kit of claim 1, wherein the oxidant has the following structure:

5. The kit of claim 4, wherein the oxidant is coenzyme Q₀.

6. The kit of claim 1, wherein the ligand and the oxidant are in one vial.

7. The kit of claim 1, wherein the radiochemical purity is greater than about 92% at about six hours after reconstitution.

8. The kit of claim 1, wherein the radiochemical purity is greater than about 95% at about six hours after reconstitution.

9. The kit of claim 1, wherein the complexing ligand comprises a compound of Formula II:

10. The kit of claim 1, further comprising a reducing agent.

11. The kit of claim 10, wherein wherein the reducing agent is selected from stannous chloride, stannous pyrophosphate, stannous fluoride, stannous tartrate, stannous glucoheptonate, stannous DTPA, a borohydride salt, sodium dithionite, a Cu(I) salt, and a formamidine sulphinic acid.

12. The kit of claim 11, wherein the reducing agent is a stannous compound.

13. The kit of claim 12, wherein the stannous and the oxidant are present in a ratio from about 1:

0.39 to about 1;

25.

14. The kit of claim 1, wherein the radiopharmaceutical comprises a radionuclide selected from ^99mTc, ⁵¹Cr, ⁶⁷Cu, ⁹⁷Ru, ¹⁸⁸Re, ¹⁸⁶Re, and ¹⁹⁹Au.

15. The kit of claim 1, further comprising a transfer ligand, a bulking agent, a buffer, a stabilization aid, a solubilization aid or a bacteriostat.

16. The kit of claim 15, wherein the bulking agent is selected from maltose, sucrose, and hydroxypropyl-γ

-cyclodextrin.

17. A kit for the preparation of a radiopiharmaceutical, the kit comprising a lyophilized composition comprising a predetermined quantity of a complexing ligand and a predetermined quantity of an oxidant, wherein the oxidant has the following structure:

18. The kit of claim 17, wherein the radiopharmaceutical has a radiochemical purity of greater than 90% at about six hours after reconstitution.

19. The kit of claim 17, wherein the radiochemical purity is greater than about 95% at about six hours after reconstitution.

20. The kit of claim 17, wherein the oxidant is benzoquinone.

21. The kit of claim 17, wherein the ligand and oxidant are in one vial.

22. The kit of claim 17, wherein the oxidant has the following structure:

23. The kit of claim 22, wherein the oxidant is coenzyme Q₀.

24. The kit of claim 22, wherein the radiochemical purity is greater than about 92% at about six hours after reconstitution.

25. The kit of claim 22, further comprising a reducing agent.

26. The kit of claim 25, wherein the reducing agent is selected from stannous chloride, stannous pyrophosphate, stannous fluoride, stannous tartrate, stannous glucoheptonate, stannous DTPA, a borohydride salt, sodium dithionite, a Cu(I) salt, and a formamidine sulphinic acid.

27. The kit of claim 26, wherein the reducing agent is a stannous compound.

28. The kit of claim 27, wherein the stannous and the oxidant are present in a ratio from about 1:

0.39 to about 1;

25.

29. The kit of claim 22, wherein the radiopharmaceutical comprises a radionuclide selected from ^99mTc, ⁵¹Cr, ⁶⁷Cu, ⁹⁷Ru, ¹⁸⁸Re, ¹⁸⁶Re, and ¹⁹⁹Au.

30. The kit of claim 22, further comprising a transfer ligand, a bulking agent, a buffer, a stabilization aid, a solubilization aid or a bacteriostat.

31. The kit of claim 30, wherein the bulking agent is selected from maltose, sucrose, and hydroxypropyl-γ

-cyclodextrin.

32. A kit for the preparation of a radiopharmaceutical, the kit comprising a predetermined quantity of a complexing ligand of Formula II:

33. The kit of claim 32, wherein the radiopharmaceutical has a radiochemical purity of greater than 90% at about six hours after reconstitution.

34. The kit of claim 32, wherein the radiochemical purity is greater than about 92% at about six hours after reconstitution.

35. The kit of claim 32, wherein the radiochemical purity is greater than about 95% at about six hours after reconstitution.

36. The kit of claim 32, wherein the ligand and the coenzyme Q₀ are in one vial.

37. The kit of claim 32, further comprising a reducing agent.

38. The kit of claim 37, wherein wherein the reducinig agent is selected from stannous chloride, stannous pyrophosphate, stannous fluoride, stannous tartrate, stannous glucoheptonate, stannous DTPA, a borohydride salt, sodium dithionite, a Cu(I) salt, and a formamidine sulphinic acid.

39. The kit of claim 38, wherein the reducing agent is a stannous compound.

40. The kit of claim 39, wherein the stannous and the oxidant are present in a ratio from about 1:

0.39 to about 1;

25.

41. The kit of claim 32, wherein the radiopharmaceutical comprises a radionuclide selected from ^99mTc, ⁵¹Cr, ⁶⁷CU, ⁹⁷Ru, ¹⁸⁸Re, ¹⁸⁶Re, and ¹⁹⁹Au.

42. The kit of claim 32, further comprising a transfer ligand, a bulking agent, a buffer, a stabilization aid, a solubilization aid or a bacteriostat.

43. The kit of claim 42, wherein the bulking agent is selected from maltose, sucrose, and hydroxypropyl-γ

-cyclodextrin.

44. A pharmaceutical composition comprisinig a radiopharmaceutical and an oxidant, wherein the radiopharmaceutical has a radiochemical purity of greater than 90% at about six hours after reconstitution.

45. The composition of claim 44, wherein the oxidant has the following structure:

46. The composition of claim 45, wherein the oxidant is benzoquinone.

47. The composition of claim 45, wherein the oxidant has the following structure:

48. The composition of claim 47, wherein the oxidant is coenzyme Q₀.

49. The composition of claim 48, wherein the radiopharmnceutical comprises a compound of formula I:

50. The composition of claim 49, further comprising a transfer ligand, a bulking agent, a buffer, a stabilization aid, a solubilization aid or a bacteriostat.

51. The composition of claim 50, wherein the bulking agent is selected from maltose, sucrose, and hydroxypropyl-γ

-cyclodextrin.

52. The composition of claim 44, wherein the radiopharmaceutical comprises a radionuclide selected from ^99mTc, ⁵¹Cr, ⁶⁷CU, ⁹⁷Ru, ¹⁸⁸Re, ¹⁸⁶Re, and ¹⁹⁹Au.

53. The composition of claim 44, wherein the composition has a radiochemical purity of greater than about 92% at about six hours after reconstitution.

54. The composition of claim 44, wherein the composition has a radiochemical purity of greater than about 94% at about six hours after reconstitution.

55. The composition of claim 44, wherein the composition has a radiochemical purity of greater than about 96% at about six hours after reconstitution.

56. A method of making a radiopharmaceutical composition, comprising the steps of:

a) contacting a complexing ligand with a radionuclide to form a complex; and

b) contacting the complexing ligand with an oxidant,

wherein the radiopharmaceutical composition has a radiochemical purity of greater than about 90% at about six hours after reconstitution.

57. The method of claim 56, further comprising the step of contacting a reducing agent with a radionuclide source to generate the radionuclide.

58. The method of claim 56, further comprising the step of reducing a radionuclide source with a transfer ligand to generate the radionuclide.

59. The method of claim 56, wherein step b) is performed prior to step a).

60. The method of claim 56, wherein step b) is performed simultaneously with step a).

61. The method of claim 56, wherein the oxidant has the following structure:

62. The method of claim 61, wherein the oxidant is benzoquinone.

63. The method of claim 61, wherein the oxidant has the following structure:

64. The method of claim 63, wherein the oxidant is coenzyme Q₀.

65. The method of claim 56, wherein the complexing ligand comprises a compound of Formula II:

66. The method of claim 65, wherein the radiopharmaceutical comprises a compound of Formula I:

67. The method of claim 56, wherein the radionuclide is selected from ⁹⁹Tc, ⁵¹Cr, ⁶⁷Cu, ⁹⁷Ru, ¹⁸⁸Re, ¹⁸⁶Re, and ¹⁹⁰Au.

68. The method of claim 56, wherein the radiopharmaceutical composition has a radiochemical purity of greater than about 92% approximately six hours after the complex is formed.

69. The method of claim 56, wherein the radiopharmaceutical composition has a radiochemical purity of greater than about 94% approximately six hours after the complex is formed.

70. The method of claim 56, wherein the radiopharmaceutical composition has a radiochemical purity of greater than about 96% approximately six hours after the complex is formed.

71. A radiopharmaceutical made by the method of claim 56.