Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same

• US 5,334,381 A
• Filed: 06/30/1993
• Issued: 08/02/1994
• 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
• Inventors: Unger, Evan C.
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): TILL, MARY C
• Application Number:
  US08/085,608
• Time in Patent Office: 398 Days
• Field of Search: 424/450, 424/9
• 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 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
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

Liposomes suitable as ultrasound contrast agents which contain media of various types including gases, gaseous precursors activated by pH, temperature or pressure, as well as other solid or liquid contrast enhancing agents, are described. Methods of using the same as ultrasound contrast agents are also disclosed. The present invention also comprises novel methods for synthesizing liposomes having encapsulated therein gases.

Claims

1. A method for synthesizing a liposome having encapsulated therein a gas comprising contacting liposomes in an aqueous medium with gas under elevated pressures.

2. A method according to claim 1 wherein said pressure is between about 50 and about 120 psi.

3. A method according to claim 1 further comprising contacting said liposomes with gas under decreased temperature.

4. A method according to claim 3 wherein said decreased temperature is between about 1°

and about 4°

C.

5. A method according to claim 1 wherein said gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide, xenon, argon, neon and helium.

6. A method according to claim 1 wherein said liposomes comprise egg phosphatidylcholine.

7. A method according to claim 5 wherein said gas is nitrogen.

8. A method according to claim 5 wherein said gas is oxygen.

9. A method according to claim 5 wherein said gas is carbon dioxide.

10. A method according to claim 5 wherein said gas is xenon.

11. A method according to claim 5 wherein said gas is argon.

12. A method according to claim 5 wherein said gas is neon.

13. A method according to claim 5 wherein said gas is helium.

14. A method according to claim 1 wherein said method further comprises contacting said liposomes with gas under decreased temperature, wherein said pressure is between about 50 and about 120 psi, and wherein said gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide, xenon, argon, neon and helium.

15. The method according to claim 14 wherein said decreased temperature is between about 1°

and about 4°

C.

16. A method according to claim 15 wherein said gas is nitrogen.

17. A method according to claim 15 wherein said gas is oxygen.

18. A method according to claim 15 wherein said gas is carbon dioxide

19. A method according to claim 15 wherein said gas is xenon.

20. A method according to claim 15 wherein said gas is argon.

21. A method according to claim 15 wherein said gas is neon.

22. A method according to claim 15 wherein said gas is helium.

23. A method according to claim 15 wherein said liposomes comprise egg phosphatidylcholine.

24. A method according to claim 23 wherein said gas is nitrogen.

25. A method according to claim 23 wherein said gas is oxygen.

26. A method according to claim 23 wherein said gas is carbon dioxide.

27. A method according to claim 23 wherein said gas is xenon.

28. A method according to claim 23 wherein said gas is argon.

29. A method according to claim 23 wherein said gas is neon.

30. A method according to claim 23 wherein said gas is helium.