Methods of preparing gaseous precursor-filled microspheres

• US 20030003055A1
• Filed: 08/06/2002
• Published: 01/02/2003
• Est. Priority Date: 12/22/1989
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Ramaswami, VaradaRajan, Yellowhair, David, Matsunaga, Terry, Fritz, Thomas A., Unger, Evan C., Wu, Guanli
• Application Number:
  US10/213,600
• Publication Number:
  US 20030003055A1
• Time in Patent Office: Days
• 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 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Methods of and apparatus for preparing gas-filled microspheres are described. Gas-filled microspheres 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 microspheres comprising shaking an aqueous solution comprising a phospholipid and a polymer, in the presence of a gas, at a temperature below the gel state to liquid crystalline transition temperature of the lipid.

2. The method according to claim 1, further comprising the step of sizing said gas-filled microspheres.

3. The method according to claim 2, wherein the size of said gas-filled microspheres is controlled by extracting said microspheres through a filter.

4. The method according to claim 2, wherein the size of said gas-filled microspheres is controlled by the intensity of said shaking.

5. The method according to claim 1, further comprising the step of extracting said gas-filled microspheres into a syringe without further processing.

6. The method according to claim 1, wherein the step of shaking said aqueous solution comprises shaking said aqueous solution with sufficient intensity to create a gas-filled microspheres-containing foam in less than about 30 minutes.

7. The method according to claim 1, wherein said phospholipid is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoyl-phosphatidylethanolamine, 1-hexadecyl-2-palmitoylglycerophosphoethanolamine, and phosphatidic acids.

8. The method according to claim 7, wherein said phospholipid is selected from the group consisting of dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine.

9. The method according to claim 1 wherein said polymer is selected from the group consisting of poloxamers, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyethyleneglycol, polypropylene glycol, polyvinylpyrrolidone, polyvinylalcohol, dextran, starch, and phosphorylated and sulfonated polysaccharides.

10. The method according to claim 1, wherein said gas comprises sulfur hexafluoride.

11. The method according to claim 1, wherein said gas comprises a perfluorocarbon.

12. The method according to claim 11, wherein said gas comprises perfluorohexane.

13. The method according to claim 12, wherein said phospholipid comprises dimyristoylphosphatidylcholine and said polymer comprises a poloxamer.

14. The method according to claim 10, wherein said phospholipid comprises distearoylphosphatidylcholine and said polymer comprises polyethylene glycol.

15. A contrast agent for ultrasound imaging comprising gas-filled microspheres prepared according to the method of any one of claims 1 to 14.