Thermally stabilized contrast agent

• US 6,562,320 B1
• Filed: 06/26/2000
• Issued: 05/13/2003
• Est. Priority Date: 02/19/1996
• Status: Expired due to Term

• Current Assignee: GE Healthcare As (GE Healthcare Technologies, Inc.)
• Original Assignee: Amersham Health AS (GE Healthcare Technologies, Inc.)
• Inventors: Gulliksen, Per Helge, Braenden, Jorunn Undheim, Swaerd-Nordmo, Marit, Fahlvik, Anne Kjersti
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US09/604,276
• Time in Patent Office: 1,051 Days
• Field of Search: 424/9.52, 424/9.51, 424/9.5, 516/11, 516/77, 600/441, 600/458
• US Class Current: 424/9.52
• 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

Abstract

This invention relates to a freeze-dried vesicle containing ultrasound contrast agent containing a freeze-drying stabilizer and thermally stable at temperatures in excess of 20° C.

Claims

1. A freeze-dried vesicle-containing ultrasound contrast agent containing at least one bulking agent selected from the group consisting of glycerol, propylene glycol, dextran and polyethylene glycol and at least one freeze-drying stabilizer selected from the group consisting of sucrose, maltose.H₂O, trehalose, raffinose and stachyose, wherein the weight ratio of said stabilizer to the vesicles in said agent is at least 10:

1, and said agent has a Tg value in excess of 20°

C, a Tg′

value of −

37°

C or above, and is thermally stable at temperatures in excess of 20°

C.

2. A contrast agent as claimed in claim 1 wherein said stabilizer comprises sucrose.

3. A contrast agent as claimed in claim 1 wherein the weight ratio of said stabilizer to the vesicles in said agent is at least 20:

1.

4. A contrast agent as claimed in claim 1 wherein the vesicles contain a halocarbon gas or gas precursor or a sulphur fluoride gas.

5. A contrast agent as claimed in claim 4 wherein said halocarbon gas or gas precursor is a perfluoroalkane.

6. A contrast agent as claimed in claim 5 wherein said perfluoroalkane is selected from the group consisting of perfluorobutane and perfluoropentane.

7. A contrast agent as claimed in claim 4 wherein said sulphur fluoride gas is selected from the group consisting of sulphur hexafluoride, disulphur decafluoride and trifluoromethylsulphur pentafluoride.

8. A contrast agent as claimed in claim 1 wherein the vesicles have membranes which comprise a phospholipid.

9. A process for the preparation of a freeze-dried vesicle-containing ultrasound contrast agent as claimed in claim 1, said process comprising freeze-drying an aqueous dispersion comprising a vesicular ultrasound contrast agent, at least one bulking agent selected from the group consisting of glycerol, propylene glycol, dextran and polyethylene glycol and at least one freeze-drying stabilizer selected from the group consisting of sucrose, maltose.H₂O, trehalose, raffinose and stachyose, wherein said stabilizer is present in said dispersion in a weight ratio relative to the vesicles therein of at least 10:

1.

10. A process as claimed in claim 9 wherein said aqueous dispersion contains from 1 to 50% by weight of said stabilizer.

11. A process as claimed in claim 9 wherein said vesicular contrast agent contains a halocarbon gas or gas precursor or a sulphur fluoride gas.

12. A process as claimed in claim 11 wherein said halocarbon gas or gas precursor is selected from the group consisting of perfluorobutane and perfluoropentane.

13. A process as claimed in claim 11 wherein said sulphur fluoride gas is selected from the group consisting of sulphur hexafluoride, disulphur decafluoride and trifluoromethylsulphur pentafluoride.

14. A process as claimed in claim 9 wherein said aqueous dispersion contains 3 to 10% by weight of said bulking agent.

15. A process for the storage or transportation of a freeze-dried vesicle-containing ultrasound contrast agent as defined in claim 1 wherein said storage or transport takes place without use of cooling.

16. A process for the preparation of an injectable vesicle-containing ultrasound contrast agent which comprises dispersing a freeze-dried vesicle-containing ultrasound contrast agent as defined in claim 1 in a physiologically tolerable injectable aqueous carrier medium.

17. A method of diagnosis of a mammal involving diagnostic ultrasound imaging, which method comprises administering a vesicle-containing ultrasound contrast agent containing at least one bulking agent selected from the group consisting of glycerol, propylene glycol, dextran and polyethylene glycol and at least one freeze-drying stabilizer selected from the group consisting-of sucrose, maltose.H₂O, trehalose, raffinose and stachyose, wherein the weight ratio of said stabilizer to the vesicles in said agent is at least 10:

1, and said agent has a Tg value in excess of 20°

C, a Tg′

value of −

37°

C or above, and is thermally stable at temperatures in excess of 20°

C., and performing ultrasound imaging.