Kits & systems for ultrasonic imaging

• US 6,280,705 B1
• Filed: 01/26/1998
• Issued: 08/28/2001
• Est. Priority Date: 07/30/1993
• Status: Expired due to Fees

• Current Assignee: Targeson, Inc.
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Trevino, Leo A., Schutt, Ernest George, Weers, Jeffry G., Tarara, Thomas E., Kabalnov, Alexey, Klein, David H.
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US09/013,357
• Time in Patent Office: 1,310 Days
• Field of Search: 424/9.52, 424/9.51, 424/450, 600/458
• US Class Current: 424/9.51
• 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

A gas emulsion forming composition comprising a dry, hollow, particulate, approximately microspherical material permeated with a gas or gas mixture, which upon dissolution in aqueous liquid forms a gas emulsion comprising a plurality of bubbles surrounded by a layer of at least a first and a second surfactant, wherein the first surfactant consists essentially of a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, and wherein the second surfactant may or may not be a phospholipid and is more water soluble than the first surfactant; kits for preparing such microbubbles; and methods for using such microbubbles as contrast agents.

Claims

1. A system for providing an ultrasound image of at least a part of an object or body comprising:

an ultrasound imaging apparatus; and

a kit capable of producing a stabilized microbubble preparation comprising an aqueous medium, a plurality of dry microbubble precursors incorporating a gas osmotic agent, said microbubble precursors defined by a generally spherical shell comprising a first surfactant and a second surfactant, wherein said first surfactant comprises a phospholipid or mixture of phospholipids having at least one acyl chain of 10 or more carbon atoms, and said second surfactant is more water soluble than said first surfactant, so that upon reconstitution with said aqueous medium, said second surfactant facilitates shell dissolution, leaving said first surfactant surrounding said gas osmotic agent to form an osmotically stabilized microbubble.

2. The system of claim 1 wherein said gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

3. The system of claim 1 wherein said microbubbles further comprise a modifier gas selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof.

4. The system of claim 1 wherein said gas osmotic agent comprises perfluoropropane.

5. The system of claim 1 wherein said gas osmotic agent comprises perfluorobutane.

6. The system of claim 1 wherein said second surfactant is selected from the group consisting of a fatty acid, a salt of a fatty acid, a sugar ester of a fatty acid, a polyoxypropylene-polyoxyethylene copolymer, a nonionic alkylglucoside, a polysorbate, and combinations thereof.

7. The system of claim 1 wherein said second surfactant comprises a poloxamer.

8. The system of claim 7 wherein said first surfactant comprises a phospholipid selected from the group consisting of dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine.

9. The system of claim 8 wherein said gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

10. The system of claim 8 wherein said gas osmotic agent comprises perfluorohexane.

11. The system of claim 10 wherein said microbubbles further comprise a modifier gas selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof.

12. The system of claim 7 wherein said gas osmotic agent comprises perfluoropropane.

13. A kit for the formation of stabilized microbubble preparation comprising:

a container having dispersed therein a gas osmotic agent, and a plurality of dry microbubble precursors comprising a first surfactant comprising a phospholipid or mixture of phospholipids having at least one acyl chain of 10 or more carbon atoms and a second surfactant more water soluble that the first surfactant whereby a plurality of stabilized microbubbles are formed by reconstituting said microbubble precursors with an aqueous medium, whereby said second surfactant facilitates shell dissolution, resulting in said first surfactant surrounding said gas osmotic agent to form an osmotically stabilized microbubble in said container.

14. The kit of claim 13 wherein said gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

15. The kit of claim 13 wherein said container further comprise a modifier gas selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof.

16. The kit of claim 13 wherein said gas osmotic agent comprises perfluoropropane.

17. The kit of claim 13 wherein said gas osmotic agent comprises perfluorobutane.

18. The kit of claim 13 wherein said second surfactant is selected from the group consisting of a fatty acid, a salt of a fatty acid, a sugar ester of a fatty acid, a polyoxypropylene-polyoxyethylene copolymer, a nonionic alkylglucoside, a polysorbate, and combinations thereof.

19. The kit of claim 13 wherein said second surfactant comprises a poloxamer.

20. The kit of claim 19 wherein said first surfactant comprises a phospholipid selected from the group consisting of dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine.

21. The kit of claim 20 wherein said gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

22. The kit of claim 20 wherein said gas osmotic agent comprises perfluorohexane.

23. The kit of claim 22 wherein said container further comprises a modifier gas selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof.

24. The kit of claim 19 wherein said gas osmotic agent comprises perfluoropropane.

25. A kit for the formation of a stabilized microbubble preparation comprising:

a container having dispersed therein a gas osmotic agent and a powdered material incorporating a first surfactant comprising a phospholipid or mixture of phospholipids having at least one acyl chain of 10 or more carbon atoms and a second surfactant more water soluble than the first surfactant whereby a plurality of stabilized microbubbles incorporating the gas osmotic agent and defined by a surfactant layer comprising the first surfactant are formed by the reconstitution of said powdered material facilitated by diffusion of said second surfactant from said powdered material upon addition of said aqueous medium in said container.

26. The kit of claim 25 wherein said gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

27. The kit of claim 25 wherein said container further comprise a modifier gas selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof.

28. The kit of claim 25 wherein said gas osmotic agent comprises perfluoropropane.

29. The kit of claim 25 wherein said gas osmotic agent comprises perfluorobutane.

30. The kit of claim 25 wherein said second surfactant is selected from the group consisting of a fatty acid, a salt of a fatty acid, a sugar ester of a fatty acid, a polyoxypropylene-polyoxyethylene copolymer, a nonionic alkylglucoside, a polysorbate, and combinations thereof.

31. The kit of claim 25 wherein said powdered material comprises spray dried microspheres.

32. The kit of claim 31 wherein said powdered material comprises a hydrophilic monomer or polymer.

33. The kit of claim 32 wherein said second surfactant comprises a poloxamer.

34. The kit of claim 33 wherein said first surfactant comprises a phospholipid selected from the group consisting of dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine.

35. The kit of claim 34 wherein said gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

36. The kit of claim 34 wherein said gas osmotic agent comprises perfluorohexane.

37. The kit of claim 36 wherein said microbubbles further comprise a modifier gas selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof.

38. The kit of claim 37 wherein said modifier gas comprises nitrogen.

39. The kit of claim 25 wherein said powdered material comprises lyophilized phospholipid.

40. The kit of claim 39 wherein said gas osmotic agent comprises perfluorobutane.