Methods of preparing gas-filled liposomes

• US 5,469,854 A
• Filed: 06/11/1993
• Issued: 11/28/1995
• Est. Priority Date: 12/22/1989
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Ramaswami, VaradaRajan, Yellowhair, David, Matsunaga, Terry, Fritz, Thomas A., Unger, Evan C., Wu, Guanli
• Primary Examiner(s): Jaworski, Francis
• Application Number:
  US08/076,239
• Time in Patent Office: 900 Days
• Field of Search: 128/662.02, 264/4.1, 264/4.3, 264/4.5, 424/9
• US Class Current: 600/458
• 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 47/6925 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 49/22 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: A61M 5/3145 Filters incorporated in syringes
• CPC Class Codes: Y10S 977/795 Composed of biological material
• CPC Class Codes: Y10S 977/801 Drug
• CPC Class Codes: Y10S 977/905 Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/907 Liposome
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent
• CPC Class Codes: Y10S 977/929 Ultrasound contrast agent
• CPC Class Codes: Y10S 977/962 for carrying or transporting

Abstract

Methods of and apparatus for preparing gas-filled liposomes are described. Gas-filled liposomes prepared by these methods are particularly useful, for example, in ultrasonic imaging applications and in therapeutic drug delivery systems.

Claims

1. A method for preparing gas-filled lipid microspheres comprising shaking an aqueous solution comprising a lipid in the presence of a gas at a temperature below the gel state to liquid crystalline state phase transition temperature of the lipid.

2. A method as in claim 1 wherein the shaking step comprises vortexing.

3. A method as in claim 1 further comprising filtering and heat sterilizing said aqueous lipid solution.

4. A method as in claim 1 further comprising extruding the microspheres through at least one filter of a selected pore size.

5. A method as in claim 4 wherein the pore size is about 10 μ

m or smaller.

6. A method as in claim 1 further comprising hydrating a dried lipid to form an aqueous solution comprising a lipid.

7. The method of claim 1 wherein said microsphere comprises a lipid selected from the group consisting of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, and a phosphatidic acid, and said microsphere further comprising polyethylene glycol.

8. The method of claim 1 wherein said lipid comprises at least one dipalmitoyl lipid.

9. The method of claim 1 wherein said lipid comprises dipalmitoylphosphatidylethanolamine and polyethylene glycol.

10. The method of claim 1 wherein said lipid comprises dipalmitoylphosphatidylcholine, phosphatidic acid, dipalmitoylphosphatidylethanolamine, and polyethylene glycol.

11. The method of claim 1 wherein said microsphere comprises a gas selected from the group consisting of a fluorine gas and a nitrogen gas.

12. The method of claim 1 wherein said microsphere comprises a gas which is a fluorine gas.

13. The method of claim 1 wherein said microsphere comprises a gas which is nitrogen.

14. The method of claim 1 wherein said microsphere comprises a gas selected from the group consisting of a fluorine gas and a nitrogen gas and a lipid selected from the group consisting of dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, and a phosphatidic acid, and said microsphere further comprising polyethylene glycol.

15. The method of claim 1 wherein said microsphere comprises a gas selected from the group consisting of a fluorine gas and a nitrogen gas and a lipid comprising dipalmitoylphosphatidylcholine, phosphatidic acid, dipalmitoylphosphatidylethanolamine, and polyethylene glycol.

16. The method of claim 1 wherein said microsphere comprises a gas which is a fluorine gas and a lipid comprising dipalmitoylphosphatidylethanolamine and polyethylene glycol.

17. The method of claim 1 wherein said microsphere comprises 90% gas.

18. The method of claim 1 wherein said microsphere comprises a gas which is a fluorine gas and a lipid comprising dipalmitoylphosphatidylethanolamine and polyethylene glycol, said microsphere comprising 90% gas.

19. The method of claim 1 performed at a pressure above ambient pressure.