Stabilized gas emulsions containing phospholipid for ultrasound contrast enhancement

• US 6,193,952 B1
• Filed: 02/09/1998
• Issued: 02/27/2001
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Targeson, Inc.
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Kabalnov, Alexey, Schutt, Ernest G., Weers, Jeffry G.
• Primary Examiner(s): Dudash, Diana
• Assistant Examiner(s): SHARAREH, SHAHNAM J
• Application Number:
  US08/973,281
• Time in Patent Office: 1,114 Days
• Field of Search: 424/9.52, 424/9.51, 424/9.5, 424/9.3, 424/455, 424/450, 264/4.1, 514/937
• US Class Current: 424/9.52
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/226 Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels

Abstract

A gas emulsion for ultrasound contrast enhancement comprising a plurality of gas bubbles in a liquid medium, the gas bubbles comprising at least one fluoroether selected from the group consisting of CF₃OCF₂OCF₃, CF₃(OCF₂)₂OCF₃, CF₃(OCF₂)₃OCF₃, and CF₃(OCF₂)₄OCF₃.

Claims

1. A gas emulsion for ultrasound contrast enhancement comprising a plurality of microbubbles in a liquid medium, said gas bubbles comprising a first gas or vapor fluoroether selected from the group consisting of CF₃OCF₂OCF₃, CF₃(OCF₂)₂OCF₃, CF₃(OCF₂)₃OCF₃, and CF₃(OCF₂)₄OCF₃.

2. The gas emulsion of claim 1 wherein said gas bubbles further comprise a second fluoroether.

3. The gas emulsion of claim 2, wherein said second fluoroether is selected from the group consisting of a perfluorodiethylether, a perfluorodimethylether, a perfluorodiglyme, a perfluoromethylethylether, and a perfluoromonoglyme.

4. The gas emulsion of claim 1, wherein said microbubbles additionally comprise air or nitrogen.

5. The gas emulsion of claim 1, wherein said microbubbies are surrounded by a surfactant layer.

6. The gas emulsion of claim 5 wherein the surfactant layer comprises a surfactant selected from the group consisting of nonionic surfctants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

7. The gas emulsion of claim 5 wherein said surfactant layer comprises a non-Newtonian viscoelastic surfactant.

8. The gas emulsion of claim 5 wherein said surfactant layer comprises a compound selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.

9. The gas emulsion of claim 5, wherein the surfactant layer comprises at least a first and a second surfactant, the first surfactant consisting 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% wIw of total surfactant, and wherein the second surfactant is more water soluble than the first surfactant.

10. The gas emulsion of claim 9, wherein said second surfactant is selected from the group consisting of fatty acids, salts of a fatty acids, a sugar esters of fatty acids, polyoxypropylene-polyoxyethylene copolymers, nonionic alkylglucosides, polysorbate, and combinations thereof.

11. The gas emulsion of claim 1 wherein said microbubbles are free bubbles of gas.

12. The gas emulsion of claim 1 whxein said microbubbles further comprise microspheres.

13. The gas emulsion of claim 12 wherein said microspheres comprise a protein.

14. The gas emulsion of claim 1 wherein said microbubbles further comprise a liposome.

15. The gas emulsion of claim 1 wherein said microbubbles are formed through the solubilization of void containing structures.

16. The gas emulsion of claim 1 wherein said microbubbles are formed by altering the pressure on an emulsified liquid comprising an aqueous phase and said fluoroether.

17. The gas emulsion of claim 1 wherein said microbubbles are formed through sonication.

35. A method for ultrasonically imaging an object or body comprising the steps of:

introducing the contrast medium of claim 1 into said object or body; and

,

imaging at least a portion of said object or body.

36. The method of claim 35 wherein said imaging step comprises ultrasonic harmonic imaging.

37. A method for magnetic resonance imaging an object or body comprising the steps of:

introducing the contrast medium of claim 1 into said object or body; and

,

imaging at least a portion of said object or body.

18. A method for forming a gas emulsion comprising the steps of:

providing a container having therein a structural material defining a plurality of voids, a surfactant and a gas or gas mixture comprising a fluoroether dispersed in said voids;

adding an aqueous liquid to said container; and

,

admixing said structural material, said surfactant and said aqueous liquid, thereby forming a gas emulsion in said container, said gas emulsion comprising bubbles of said gas or gas mixture surrounded by a layer of the surfactant.

19. The method of claim 18 wherein said structural material is substantially water soluble.

20. The method of claim 18 wherein said fluoroether is selected from the group consisting of CH₃CH₂OCF₂CHF₂,CH₃CH₂OCF₂CF₃,CHF₂CH₂OCF₂CHF₂, CF₃CH₂OCF₂CH₂F,CF₃CH₂OCH₂CF₃, CF₃CH₂OCF₂CHF₂, CHF₂CH₂OCF₂CF₃, CF₃CH₂OCF₂CF₃, CH₃OCH₂CF₂CHF₂, CH₃OCH₂CF₂CF₃, CH₃OCF₂CF₂CHF₂, CD₃OCF₂CHFCF₃, CH₃OCF₂CF₂CF₃, CHF₂OCH₂CF₂CHF₂, CHF₂OCH₂CF₂CF₃, CF₃OCH₂CF₂CHF₂, CF₃OCH₂CF₂CF₃, CH₃OCH(CF₃)₂, CH₃OCF(CF₃)₂, CHF₂OCH(CF₃)₂, CH₃OCH₂CHF₂, CH₃OCF₂CH₂F, CH₃OCH₂CF₃, CH₃OCF₂CHF₂, CHF₂OCH₂CHF₂, CHF₂OCF₂CH₂F, CHF₂OCH₂CF₃, CHF₂OCHFCF₃, CF₃OCH₂CHF₂, CH₃OCF₂CF₃, CF₃OCH₂CF₃, CF₃OCHFCF₃, CF₃OCF₂OCF₃, CF₃(OCF₂)₂OCF₃, CF₃(OCF₂)₃OCF₃, CF₃(OCF₂)₄OCF₃ and mixtures thereof.

21. The method of claim 18 wherein the fluoroether is selected from the group consisting of perfluorodiethylethers, perfluorodimethylethers, perfluoromethylethylethers, perfluoromonoglymes and perfluoipdiglymes.

22. The method of claim 18 wherein said structural material comprises said surfactant.

23. The method of claim 18 wherein the surfactant is selected from the group consisting of phospholipids, phosphocholines, lysophospholipids, nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

24. The method of claim 18 wherein said material is selected from the group comprising void-containing structures and soluble void-forming structures.

25. The method of claim 18 wherein said structural material is selected from the group consisting of sugars, spray dried microspheres, lyophilized powders, lyophilized cake, powdered and granulated sugars, protein microspheres, and dried porous hyaluronic acid.

26. a microbubble precursor composition comprising:

a structural material defining a plurality of voids;

a gas or gas mixture comprising a fluoroether dispersed in said voids; and

a surfactant, wherein said material, said gas or gas mixture and said surfactant are together adapted to form microbubbles upon addition of a liquid to said container.

27. The composition of claim 26 wherein said structural material is substantially water soluble.

28. The composition of claim 26 wherein said fluoroether is selected from the group consisting of CH₃CH₂OCF₂CHF₂, CH₃CH₂OCF₂CF₃, CHF₂CH₂OCF₂CHF₂, CF₃CH₂OCF₂CH₂F, CF₃CH₂OCH₂CF₃, CF₃CH₂OCF₂CHF₂, CHF₂CH₂OCF₂CF₃, CF₃CH₂OCF₂CF₃, CH₃OCH₂CF₂CHF₂, CH₃OCH₂CF₂CF₃, CH₃OCF₂CF₂CHF₂, CH₃OCF₂CHFCF₃, CH₃OCF₂CF₂CF₃, CHF₂OCH₂CF₂CHF₂, CHF₂OCH₂CF₂CF₃, CF₃OCH₂CF₂CHF₂, CF₃OCH₂CF₂CF₃, CH₃OCH(CF₃)₂, CH₃OCF(CF₃)₂, CHF₂OCH(CF₃)₂, CH₃OCH₂CHF₂, CH₃OCF₂CH₂F, CH₃OCH₂CF₃, CH₃OCF₂CHF₂, CHF₂OCH₂CHF₂, CHF₂OCF₂CH₂F, CHF₂OCH₂CF₃, CHF₂OCHFCF₃, CF₃OCH₂CHF₂, CH₃OCF₂CF₃, CF₃OCH₂CF₃, CF₃OCHFCF₃, CF₃OCF₂OCF₃, CF₃(OCF₂)₂OCF₃, CF₃(OCF₂)₃OCF₃, CF₃(OCF₂)₄OCF₃ and mixtures thereof.

29. The composition of claim 26 wherein the fluoroether is selected from the group consisting of perfluorodiethylethers, perfluorodimethylethers, perfluoromethylethylethers, perfluoromonoglymes and perfluorodigles.

30. The composition of claim 26 wherein said structural material comprises said surfactant.

31. The composition of claim 26 wherein the surfactant is selected from the group consisting of phospholipids, phosphocholines, lysophospholipids, nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

32. The composition of claim 26 herein said structural material is selected from the group of void-containing structures and water soluble-forming structures.

33. The composition of claim 26 wherein said structural material is selected from the group consisting of spray dried microspheres, granulated and powdered sugars, lyophilized powders, lyophilized cakes, protein microspheres and dried porous hyaluronic acid.

34. The composition of claim 33 wherein said structural material comprises spray dried microspheres and said spray dried microspheres comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.

38. A microbubble composition for use in imaging comprising a plurality of microbubbles in a biocompatible liquid medium wherein said microbubbles comprise at least one fluoroether gas osmotic agent selected from the group consisting of CF₃OCF₂OCF₃, CF₃(OCF₂)₂OCF₃, CF₃(OCF₂)₃ and CF₃(OCF₂)₄OCF₃ and at least one modifier gas.

39. The microbubble composition of claim 38 wherein said fluoroether gas osmotic agent comprises a mixture of said fluoroethers.

40. The microbubble composition of claim 38 wherein said microbubbles futher comprise microspheres.

41. The microbubble composition of claim 40 wherein said microspheres comprise a protein.

42. The microbubble composition of claim 38 wherein said microbubbles further comprise a liposome.

43. The microbubble composition of claim 38 wherein said microbobles are formed through the solubilization of void containing structures.

44. The microbubble composition of claim 38 wherein said microbubbles are formed by altering the pressure on an emulsified liquid comprising an aqueous phase and said fluoroether gas osmotic agent.

45. The microbubble composition of claim 38 wherein said microbubbles are formed through sonication.

46. The microbubble composition of claim 38 wherein said microbubbles further comprise a surfactant layer.

47. The microbubble composition of claim 46 wherein said surfactant layer comprises a compound selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

48. The microbubble composition of claim 46 wherein said surfactant layer comprises a non-Newtonian surfactant.

49. The microbubble composition of claim 46 wherein said surfactant layer comprises a compound selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.

50. The microbubble composition of claim 38 wherein said modifier gas comprises oxygen.

51. The microbubble composition of claim 38 wherein said modifier gas comprises nitrogen.