Gas-filled lipid spheres for use in diagnostic and therapeutic applications

• US 6,146,657 A
• Filed: 11/01/1996
• Issued: 11/14/2000
• Est. Priority Date: 12/22/1989
• Status: Expired due to Fees

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Yellowhair, David, Matsunaga, Terry, Unger, Evan C.
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/741,598
• Time in Patent Office: 1,474 Days
• Field of Search: 424/9.52, 424/9.5, 424/9.51, 424/450, 424/9.32, 424/9.321, 424/489, 424/502, 228/662.02, 600/441, 600/458, 264/4.1, 428/402.2
• US Class Current: 424/450
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 41/0052 Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
• CPC Class Codes: A61K 49/1815 compo-inhalant, e.g. breath tests
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/1278 Post-loading, e.g. by ion or pH gradient
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Abstract

A container comprising an aqueous lipid suspension and a gaseous phase substantially separate from the aqueous stabilizing phase, useful in diagnostic imaging such as ultrasound and magnetic resonance imaging and in therapeutic applications, is disclosed.

Claims

1. A gas filled liposome comprising a substantially insoluble gas in combination with a soluble gas, wherein said liposome comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimystoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine, said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine and N-succinyl-dioleoyl-phosphatidylethanolamine, and said phosphatidic acid is dipalmatoylphosphatidic acid.

2. A gas-filled liposome of claim 1 wherein said substantially insoluble gas is a perfluorocarbon gas or sulfur hexafluoride.

3. A gas-filled liposome of claim 1 wherein said soluble gas is selected from the group consisting of air, oxygen, nitrogen, and carbon dioxide.

4. A gas-filled liposome of claim 1 wherein said substantially insoluble gas is a perfluorocarbon gas or sulfur hexafluoride, and said soluble gas is selected from the group consisting of air, oxygen, nitrogen, and carbon dioxide.

5. A gas-filled liposome of claim 1 wherein said liposome is comprised of a lipid monolayer.

6. A gas-filled liposome of claim 1 wherein said liposome is comprised of a lipid bilayer.

7. A gas-filled liposome of claim 2 wherein said substantially insoluble gas is a perfluorocarbon.

8. A gas-filled liposome of claim 7 wherein said perfluorocarbon is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, and perfluorohexane.

9. A gas-filled liposome of claim 8 wherein said substantially insoluble gas is perfluoropropane.

10. A gas-filled liposome of claim 9 wherein said soluble gas is nitrogen.

11. A gas-filled liposome of claim 8 wherein said substantially insoluble gas is perfluoropentane.

12. A gas-filled liposome of claim 11 wherein said soluble gas is nitrogen.

13. A gas-filled liposome of claim 8 wherein said substantially insoluble gas is perfluorohexane.

14. A gas-filled liposome of claim 13 wherein said soluble gas is nitrogen.

15. A gas-filled liposome of claim 2 wherein said substantially insoluble gas is sulfur hexafluoride.

16. A gas-filled liposome of claim 1 wherein said substantially insoluble gas or said soluble gas comprises a paramagnetic gas.

17. A gas-filled liposome of claim 16 wherein said paramagnetic gas is selected from the group consisting of oxygen, oxygen¹⁷ (¹⁷ O₂), neon, xenon, and rubidium enriched hyperpolarized xenon.

18. A gas-filled liposome of claim 1 wherein said liposome further comprises a targeting ligand.

19. A gas-filled liposome of claim 18 wherein said targeting ligand is polyethyleneglycol or polyvinylpyrrolidone.

20. A gas-filled liposome of claim 1 wherein said phosphatidylethanolamine is present in an amount of from about 2.5 mole percent to about 8.0 mole percent based on the total moles of said liposome.

21. A gas-filled liposome of claim 1 wherein said phosphatidylcholine, said phosphatidylethanolamine, and said phosphatidic acid are in a mole percent ratio of about 82%:

8%;

10%.

22. A gas-filled liposome of claim 1 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine, said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine, and said phosphatidic acid is dipalmitoylphosphatidic acid.

23. A gas-filled liposome of claim 22 wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG5000.

24. A gas-filled liposome of claim 23 wherein said dipalmitoylphosphatidylethanolamine-PEG5000 is present in an amount of from about 2.5 mole percent to about 8 mole percent based on the total moles of said liposome.

25. A gas-filled liposome of claim 24 wherein said dipalmitoylphosphatidylcholine, said dipalmitoylphosphatidylethanolamine-PEG5000, and said dipalmitoylphosphatidic acid are in a mole percent ratio of about 82%:

8%;

10%.

26. A gas-filled liposome of claim 5 further comprising polyethylene glycol.

27. A gas-filled liposome of claim 5 wherein said substantially insoluble gas is sulfur hexafluoride.

28. A gas-filled liposome of claim 5 wherein said substantially insoluble gas is perfluoropropane.

29. A gas-filled liposome of claim 28 wherein said soluble gas is nitrogen.

30. A gas-filled liposome of claim 5 wherein said substantially insoluble gas is perfluoropentane.

31. A gas-filled liposome of claim 30 wherein said soluble gas is nitrogen.

32. A gas-filled liposome of claim 5 wherein said substantially insoluble gas is perfluorohexane.

33. A gas-filled liposome of claim 32 wherein said soluble gas is nitrogen.

34. A gas-filled liposome of claim 6 further comprising polyethylene glycol.

35. A gas-filled liposome of claim 6 wherein said substantially insoluble gas is sulfur hexafluoride.

36. A gas-filled liposome of claim 6 wherein said substantially insoluble gas is perfluoropropane.

37. A gas-filled liposome of claim 36 wherein said soluble gas is nitrogen.

38. A gas-filled liposome of claim 6 wherein said substantially insoluble gas is perfluoropentane.

39. A gas-filled liposome of claim 38 wherein said soluble gas is nitrogen.

40. A gas-filled liposome of claim 6 wherein said substantially insoluble gas is perfluorohexane.

41. A gas-filled liposome of claim 40 wherein said soluble gas is nitrogen.

42. A gas-filled liposome of claim 1 wherein said liposome comprises a lipid multilayer.

43. A gas-filled liposome of claim 42 further comprising polyethylene glycol.

44. A gas-filled liposome of claim 42 wherein said substantially insoluble gas is sulfur hexafluoride.

45. A gas-filled liposome of claim 42 wherein said substantially insoluble gas is perfluoropropane.

46. A gas-filled liposome of claim 45 wherein said soluble gas is nitrogen.

47. A gas-filled liposome of claim 42 wherein said substantially insoluble gas is perfluoropentane.

48. A gas-filled liposome of claim 47 wherein said soluble gas is nitrogen.

49. A gas-filled liposome of claim 42 wherein said substantially insoluble gas is perfluorhexane.

50. A gas-filled liposome of claim 49 wherein said soluble gas is nitrogen.

51. A gas-filled liposome of claim 1 wherein said liposome is formed from a rehydrated lyophilized composition.

52. A gas-filled lipid sphere comprising a substantially insoluble gas in combination with a soluble gas, wherein said lipid comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidlicholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine, said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine, and said phosphatidic acid is dipalmatoylphosphatidic acid.

53. A gas-filled lipid sphere of claim 52 wherein said substantially insoluble gas is sulfur hexafluoride or a perfluorocarbon.

54. A gas-filled lipid sphere of claim 53 wherein said substantially insoluble gas is sulfur hexafluoride.

55. A gas-filled lipid sphere according to claim 52 wherein said substantially insoluble gas is a perfluorocarbon.

56. A gas-filled lipid sphere according to claim 55 wherein said perfluorocarbon is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, and perfluorohexane.

57. A gas-filled lipid sphere of claim 56 wherein said substantially insoluble gas is perfluoropropane.

58. A gas-filled lipid sphere of claim 57 wherein said soluble gas is nitrogen.

59. A gas-filled lipid sphere of claim 56 wherein said substantially insoluble gas is perfluoropentane.

60. A gas-filled lipid sphere of claim 59 wherein said soluble gas is nitrogen.

61. A gas-filled lipid sphere of claim 56 wherein said substantially insoluble gas is perfluorohexane.

62. A gas-filled lipid sphere of claim 61 wherein said soluble gas is nitrogen.

63. A gas-filled lipid sphere of claim 52 wherein said soluble gas is selected from the group consisting of air, oxygen, nitrogen, and carbon dioxide.

64. A gas-filled lipid sphere of claim 52 wherein said substantially insoluble gas is selected from the group consisting of sulfur hexafluoride and a perfluorocarbon, and said soluble gas is selected from the group consisting of air, oxygen, nitrogen, and carbon dioxide.

65. A gas-filled lipid sphere of claim 52 wherein said substantially insoluble gas or said soluble gas comprises a paramagnetic gas.

66. A gas-filled lipid sphere of claim 65 wherein said paramagnetic gas is selected from the group consisting of oxygen, oxygen¹⁷ (¹⁷ O₂), neon, xenon, and rubidium enriched hyperpolarized xenon.

67. A gas-filled lipid sphere of claim 52 wherein said lipid sphere further comprises a targeting ligand.

68. A gas-filled lipid sphere of claim 67 wherein said targeting ligand is polyethyleneglycol or polyvinylpyrrolidone.

69. A gas-filled lipid sphere of claim 52 wherein said phosphatidylethanolamine is present in an amount of from about 2.5 mole percent to about 8.0 mole percent based on the total moles of said lipid sphere.

70. A gas-filled lipid sphere of claim 52 wherein said phosphatidylcholine, said phosphatidylethanolamine, and said phosphatidic acid are in a mole percent ratio of about 82%:

8%;

10%.

71. A gas-filled lipid sphere of claim 52 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine, said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine, and said phosphatidic acid is dipalmitoylphosophatidic acid.

72. A gas-filled lipid sphere of claim 71 wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG5000.

73. A gas-filled lipid sphere of claim 72 wherein said dipalmitoylphosphatidylethanolamine-PEG5000 is present in an amount from about 2.5 mole percent to about 8 mole percent based on the total moles of said lipid sphere.

74. A gas-filled lipid sphere of claim 73 wherein said dipalmitoylphosphatidylcholine, said dipalmitoylphosphatidylethanolamine-PEG5000, and said dipalmitoylphosophatidic acid are in a mole percent ratio of about 82%:

8%;

10%.

75. A gas-filled lipid sphere of claim 74 wherein said lipid comprises a lipid monolayer.

76. A gas-filled lipid sphere of claim 75 further comprising polyethyleneglycol.

77. A gas-filled lipid sphere of claim 75 wherein said substantially insoluble gas is sulfur hexafluoride.

78. A gas-filled lipid sphere of claim 75 wherein said substantially insoluble gas is perfluoropropane.

79. A gas-filled lipid sphere of claim 78 wherein said soluble gas is nitrogen.

80. A gas-filled lipid sphere of claim 75 wherein said substantially insoluble gas is perfluoropentane.

81. A gas-filled lipid sphere of claim 80 wherein said soluble gas is nitrogen.

82. A gas-filled lipid sphere of claim 75 wherein said substantially insoluble gas is perfluorohexane.

83. A gas-filled lipid sphere of claim 82 wherein said soluble gas is nitrogen.

84. A gas-filled lipid sphere of claim 52 wherein said lipid comprises a lipid bilayer.

85. A gas-filled lipid sphere of claim 84 further comprising polyethylene glycol.

86. A gas-filled lipid sphere of claim 84 wherein said substantially insoluble gas is sulfur hexafluoride.

87. A gas-filled lipid sphere of claim 84 wherein said substantially insoluble gas is perfluoropropane.

88. A gas-filled lipid sphere of claim 87 wherein said soluble gas is nitrogen.

89. A gas-filled lipid sphere of claim 84 wherein said substantially insoluble gas is perfluoropentane.

90. A gas-filled lipid sphere of claim 89 wherein said soluble gas is nitrogen.

91. A gas-filled lipid sphere of claim 84 wherein said substantially insoluble gas is perfluorohexane.

92. A gas-filled lipid sphere of claim 91 wherein said soluble gas is nitrogen.

93. A gas-filled lipid sphere of claim 52 wherein said lipid comprises a lipid multilayer.

94. A gas-filled lipid sphere of claim 93 further comprising polyethylene glycol.

95. A gas-filled lipid sphere of claim 93 wherein said substantially insoluble gas is sulfur hexafluoride.

96. A gas-filled lipid sphere of claim 93 wherein said substantially insoluble gas is perfluoropropane.

97. A gas-filled lipid sphere of claim 96 wherein said soluble gas is nitrogen.

98. A gas-filled lipid sphere of claim 93 wherein said substantially insoluble gas is perfluoropentane.

99. A gas-filled lipid sphere of claim 98 wherein said soluble gas is nitrogen.

100. A gas-filled lipid sphere of claim 93 wherein said substantially insoluble gas is perfluorohexane.

101. A gas-filled lipid sphere of claim 100 wherein said soluble gas is nitrogen.

102. A gas-filled lipid sphere of claim 52 wherein said lipid sphere is formed from a rehydrated lyophilized composition.