Gas filled liposomes and their use as ultrasonic contrast agents

• US 5,228,446 A
• Filed: 06/18/1991
• Issued: 07/20/1993
• Est. Priority Date: 12/22/1989
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Evan C. Unger, Guanli Wu
• Inventors: Unger, Evan C., Wu, Guanli
• Primary Examiner(s): JAWORSKI, FRANCIS J
• Application Number:
  US07/717,084
• Time in Patent Office: 763 Days
• Field of Search: 128/662.02, 128/654, 424/9, 424/450, 264/4.1, 264/4.3, 264/4.6, 436/829, 514/78
• US Class Current: 424/9.51
• 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 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/1815 compo-inhalant, e.g. breath tests
• 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

Abstract

Contrast agents for ultrasonic imaging comprising gas filled liposomes prepared using vacuum drying gas instillation methods, and gas filled liposomes substantially devoid of liquid in the interior thereof, are described. Methods of and apparatus for preparing such liposomes and methods for employing such liposomes in ultrasonic imaging applications are also disclosed. Also described are diagnostic kits for ultrasonic imaging which include the subject contrast agents.

Claims

1. A contrast agent for ultrasonic imaging comprising a gas filled liposome prepared by a vacuum drying gas instillation method.

2. A contrast agent of claim 1 wherein said liposomes are comprised of lipid materials selected from the group consisting of fatty acids, lysolipids, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidic acid, sphingomyelin, cholesterol, cholesterol hemisuccinate, tocopherol hemisuccinate, phosphatidylethanolamine, phosphatidylinositol, lysolipids, sphingomyelin, glycosphingolipids, glucolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids, and polymerized lipids.

3. A contrast agent of claim 2 wherein said liposomes are comprised of dipalmitoylphosphatidylcholine.

4. A contrast agent of claim 1 wherein said liposomes are filled with a gas selected from the group consisting of air, nitrogen, carbon dioxide, oxygen, argon, xenon, helium, and neon.

5. A contrast agent of claim 4 wherein said liposomes are filled with nitrogen gas.

6. A contrast agent of claim 1 wherein said liposomes are stored suspended in an aqueous medium.

7. A contrast agent of claim 1 wherein said liposomes are stored dry.

8. A contrast agent of claim 1 wherein said liposomes have a stability of greater than about three weeks.

9. A contrast agent of claim 1 wherein said liposomes have a reflectivity of greater than about 2 dB.

10. A contrast agent of claim 9 wherein said liposomes have a reflectivity of between about 2 dB and about 20 dB.

11. A contrast agent for ultrasonic imaging comprising a gas filled liposome substantially devoid of liquid in the interior thereof.

12. A contrast agent of claim 11 wherein said liposomes are comprised of lipid materials selected from the group consisting of fatty acids, lysolipids, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidic acid, sphingomyelin, cholesterol, cholesterol hemisuccinate, tocopherol hemisuccinate, phosphatidylethanolamine, phosphatidylinositol, lysolipids, sphingomyelin, glycosphingolipids, glucolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids, and polymerized lipids.

13. A contrast agent of claim 12 wherein said liposomes are comprised of dipalmitoylphosphatidylcholine.

14. A contrast agent of claim 11 wherein said liposomes are filled with a gas selected from the group consisting of air, nitrogen, carbon dioxide, oxygen, argon, xenon, helium, and neon.

15. A contrast agent of claim 14 wherein said liposomes are filled with nitrogen gas.

16. A contrast agent of claim 11 wherein said liposomes are stored suspended in an aqueous medium.

17. A contrast agent of claim 11 wherein said liposomes are stored dry.

18. A contrast agent of claim 11 wherein said liposomes have a shelf life stability of greater than about three weeks.

19. A contrast agent of claim 11 wherein said liposomes have a reflectivity of greater than about 2 dB.

20. A contrast agent of claim 19 wherein said liposomes have a reflectivity of between about 2 dB and about 20 dB.

21. A kit for ultrasonic imaging comprising gas filled liposomes prepared by a vacuum drying gas instillation method.

22. A kit in accordance with claim 21 further comprising conventional ultrasonic imaging components.

23. A kit for ultrasonic imaging comprising gas filled liposomes, substantially devoid of liquid in the interior thereof.

24. A kit in accordance with claim 23 further comprising conventional ultrasonic imaging components.