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Claims for Patent: 5,639,443

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Claims for Patent: 5,639,443

Title: Stabilized microbubble compositions
Abstract:A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760-x) mm Hg at 37.degree. C., where x is the vapor pressure of the second gas at 37.degree. C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37.degree. C.; also disclosed are methods for preparing microbubble compositions, including compositions that rapidly shrink from a first average diameter to a second average diameter less than about 75% of the first average diameter and are stabilized at the second average diameter; kits for preparing microbubbles; and methods for using such microbubbles as ultrasound contrast agents.
Inventor(s): Schutt; Ernest G. (San Diego, CA), Evitts; David P. (La Jolla, CA), Kinner; Rene Alta (San Diego, CA), Anderson; Charles David (Lebanon, NJ), Weers; Jeffry G. (San Diego, CA)
Assignee: Alliance Pharmaceutical Corp. (San Diego, CA)
Application Number:08/405,447
Patent Claims: 1. A microbubble preparation, comprising:

an aqueous medium containing a plurality of microbubbles, said microbubbles comprising:

a generally spherical microbubble membrane;

a first gas and a second component contained within said membrane, wherein said second component comprises the vapor of a compound that is a liquid at 37.degree. C. and 760 mm Hg but which has a vapor pressure of at least 75 mm Hg at 37.degree. C., wherein the first gas and the second component are respectively present in a molar ratio of about 1:100 to about 1000:1, with the proviso that said first gas and said second component are not water vapor.

2. The preparation of claim 1, wherein said second component comprises a fluorocarbon and said first gas is a nonfluorocarbon.

3. The preparation of claim 2, wherein said first gas comprises nitrogen, oxygen, carbon dioxide, or a mixture thereof.

4. The preparation of claim 2, wherein:

said microbubbles are in a liquid medium and have a first average diameter;

the ratio of said first gas to said second component in said microbubbles is at least 1:1; and

said microbubbles are adapted to shrink in said medium as a result of loss of said first gas through said membrane to a second average diameter of less than about 75% of said first diameter and then remain stabilized at or about said second diameter for at least about 1 minute as a result of a gas osmotic pressure differential across said membrane.

5. The preparation of claim 4, wherein said liquid medium contains gas or gases dissolved therein with a gas tension of at least about 700 mm Hg, wherein said first diameter is at least about 5 .mu.m, and wherein the tension of the gas or gases dissolved in said medium is less than the pressure of the same gas or gases inside said microbubbles.

6. The preparation of claim 4, wherein said first diameter is at least about 10 .mu.m and said second diameter is between about 1 .mu.m and 6 .mu.m.

7. The preparation of claim 1, wherein said second component has an average molecular weight at least about 4 times that of said first gas.

8. The preparation of claim 1, wherein said molar ratio of said first gas to said second component is from about 1:10 to about 500:1.

9. The preparation of claim 1, wherein said second component comprises a fluorocarbon and said first gas is a nonfluorocarbon.

10. The preparation of claim 9, wherein said second component comprises at least two fluorocarbons.

11. The preparation of claim 9, wherein said second component comprises a perfluorocarbon.

12. The preparation of claim 1, wherein both said first gas and said second component comprise fluorocarbons.

13. The preparation of claim 1, wherein said second component has a water solubility of not more than about 0.5 mM at 25.degree. C. and one atmosphere, and wherein said first gas has a water solubility at least about 10 times greater than that of said second component.

14. The preparation of claim 1, wherein the permeability of the membrane to said first gas is at least about 5 times greater than the permeability of said membrane to said second component.

15. The preparation of claim 1, further comprising:

a liquid in said container in admixture with said microbubbles, wherein said container further comprises means for transmission of sufficient ultrasonic energy to said liquid to permit formation of said microbubbles by sonication.

16. The preparation of claim 15, wherein said means for transmission comprises a flexible polymer material having a thickness less than about 0.5 mm.

17. The preparation of claim 1, wherein said membrane is a surfactant.

18. The preparation of claim 17, wherein said surfactant comprises a non-Newtonian viscoelastic surfactant.

19. The preparation of claim 17, wherein said surfactant is a carbohydrate.

20. The preparation of claim 19, wherein said carbohydrate is a polysaccharide.

21. The preparation of claim 17, wherein said surfactant is a fatty acid ester of a sugar.

22. The preparation of claim 17, wherein said surfactant is sucrose stearate.

23. The preparation of claim 17, wherein said surfactant is a phospholipid.

24. The preparation of claim 1, wherein said membrane is solid or semi-solid.

25. The preparation of claim 1, wherein said membrane is a proteinaceous material.

26. The preparation of claim 25, wherein said proteinaceous material is albumin.

27. The preparation of claim 2, wherein:

said microbubbles have a first average diameter;

the ratio of said first gas to said second component in said microbubbles is at least 1:1; and

said microbubbles are adapted to shrink in blood in vivo as a result of loss of said first gas through said membrane to a second average diameter of less than about 75% of said first diameter and then remain stabilized at or about said second diameter for at least about 1 minute as a result of a gas osmotic pressure differential across said membrane.

28. The preparation of claim 27, wherein said first diameter is at least about 5 .mu.m, and wherein the tension of the gas or gases dissolved in said blood is less than the pressure of the same gas or gases inside said microbubbles.

29. The preparation of claim 27, wherein said first diameter is at least about 10 .mu.m and said second diameter is between about 1 .mu.m and 6 .mu.m.

30. The preparation of claim 27, wherein said second component has an average molecular weight at least about 4 times that of said first gas.

31. The preparation of claim 27, wherein said molar ratio of said first gas to said second component is from about 1:10 to about 500:1.

32. The preparation of claim 27, wherein said second component comprises a fluorocarbon and said first gas is a nonfluorocarbon.

33. The preparation of claim 32, wherein said second component comprises at least two fluorocarbons.

34. The preparation of claim 32, wherein said second component comprises a perfluorocarbon.

35. The preparation of claim 27 wherein both said first gas and said second component comprise fluorocarbons.

36. The preparation of claim 1, wherein said microbubbles contain as said first gas, or as said second component, or respectively as said first gas and said second component, gaseous perfluorobutane and perfluorohexane in a ratio from about 1:10 to about 10:1.

37. The preparation of claim 1, wherein said microbubbles contain as said first gas, or as said second component, or respectively as said first gas and said second component, gaseous perfluorobutane and perfluoropentane in a ratio from about 1:10 to about 10:1.

38. The preparation of claim 4, wherein said medium is aqueous.

39. A kit for use in preparing microbubbles, comprising:

a sealed container;

a liquid in said container;

a surfactant in said container; and

a fluorocarbon gas in said container, wherein said liquid, said surfactant, and said fluorocarbon gas are together adapted to form microbubbles upon the application of energy to the sealed container.

40. The kit of claim 39, further comprising

means in said container for permitting transmission of sufficient external ultrasonic energy to said liquid to form microbubbles in said container.

41. The kit of claim 40, wherein said means for transmission comprises a flexible polymer membrane having a thickness less than about 0.5 mm.

42. The kit of claim 39, further comprising:

a nonfluorocarbon gas in said container, wherein the molar ratio of said nonfluorocarbon gas to said fluorocarbon gas is from about 1:10 to about 1000:1, with the proviso that said nonfluorocarbon gas is not water vapor.

43. A kit for use in preparing microbubbles, comprising:

a container;

dried liquid-soluble void-containing structures in said container, said void-containing structures defining voids having an average diameter less than about 100 .mu.m;

a liquid suitable for in vivo injection in which said void-containing structures are substantially soluble;

a gas in said voids, wherein said gas is the vapor of a non-aqueous material that is a liquid at 37.degree. C.; and

a surfactant, wherein said void-containing structures, said gas, and said surfactant are together adapted to form microbubbles upon addition to said container of said liquid.

44. The kit of claim 43, wherein said void-containing structures comprise at least in part said surfactant.

45. The kit of claim 43, wherein said surfactant is a non-Newtonian viscoelastic surfactant.

46. The kit of claim 43, wherein said surfactant is a fatty acid ester of a sugar.

47. The kit of claim 43, wherein said surfactant is a phospholipid.

48. The kit of claim 43, wherein said void-containing structures are proteinaceous.

49. The kit of claim 43, wherein said void-containing structures are formed of a carbohydrate.

50. The kit of claim 43, wherein said gas is a fluorocarbon.

51. The kit of claim 43, wherein said gas comprises perfluorohexane.

52. The kit of claim 43, wherein said void-containing structures comprise spray dried microspheres.
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