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Claims for Patent: 5,695,741

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Claims for Patent: 5,695,741

Title: Stable microbubble precursors
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; methods and kits for preparing microbubbles; and methods for using such microbubbles as contrast agents.
Inventor(s): Schutt; Ernest G. (San Diego, CA), Anderson; Charles David (Lebanon, NJ), Evitts; David P. (La Jolla, CA)
Assignee: Alliance Pharmaceutical Corp. (San Diego, CA)
Application Number:08/486,531
Patent Claims: 1. A microbubble precursor composition comprising a fluorocarbon gas osmotic agent dispersed in a plurality of spray dried microspheres having an average diameter of less than about 100 .mu.m said spray dried microspheres comprising a surfactant in combination with a compound selected from the group consisting of starch, derivatized starch, dextran, and sugar esters having a component with a hydrophilic/lipophilic balance of less than about 8.

2. The composition of claim 1 wherein said microbubble precursor composition comprises a plurality of voids.

3. The composition of claim 1 wherein said fluorocarbon 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.

4. The composition of claim 1 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

5. The composition of claim 4, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids and block copolymers.

6. The composition of claim 1, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.

7. The composition of claim 1, wherein said surfactant is a non-Newtonian surfactant.

8. The composition of claim 1 wherein said microspheres are proteinaceous.

9. The composition of claim 1, wherein said microspheres further comprise an additional carbohydrate.

10. The composition of claim 9, wherein said additional carbohydrate is a sugar.

11. A microbubble precursor composition comprising:

a plurality of solid substantially liquid-soluble void-containing structures, said void-containing structures defining a plurality of voids having an average diameter less than about 100 .mu.m;

a gas comprising a gas osmotic agent having a water solubility of not more than about 0.5 mM at 25.degree. C. and one atmosphere, said gas dispersed in said voids; and

a surfactant associated with said void containing structures, wherein said void-containing structures, said gas and said surfactant are together adapted to form microbubbles upon addition of said microbubble precursor composition to a liquid in which said void-containing structures are substantially soluble.

12. The composition of claim 11 wherein said gas osmotic agent comprises a fluorocarbon.

13. The composition of claim 12 wherein said fluorocarbon is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

14. The composition of claim 11 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

15. The composition of claim 11, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.

16. The composition of claim 11, wherein said surfactant is a non-Newtonian surfactant.

17. The composition of claim 11 wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.

18. The composition of claim 11, wherein said void-containing structure comprises a powder.

19. The composition of claim 11, wherein said void-containing structures are formed of a carbohydrate.

20. The composition of claim 19 wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar and dried lactose microspheres.

21. The composition of claim 11, wherein said void-containing structures are proteinaceous.

22. The composition of claim 11, wherein said void-containing structures comprise said surfactant.

23. The composition of claim 22, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.

24. The composition of claim 11, wherein said plurality of void-containing structures comprise a plurality of spray-dried microspheres.

25. A method for imaging, comprising:

providing a microbubble precursor composition according to claim 11;

dissolving at least a portion of said microbubble precursor composition in a liquid whereby the gas comprising said gas osmotic agent forms microbubbles that are surrounded by said surfactant;

introducing said microbubbles into a vertebrate; and

imaging said microbubbles in said vertebrate.

26. The method of claim 25, wherein said surfactant is a phospholipid.

27. The method of claim 25 wherein said gas osmotic agent comprises a fluorocarbon.

28. The method of claim 27 wherein said fluorocarbon 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.

29. The method of claim 27, wherein said gas further comprises a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.

30. The method of claim 25 wherein said void containing structures comprise said surfactant.

31. The method of claim 25 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

32. The method of claim 25, wherein said surfactant in selected from the group consisting of block copolymers, sugar esters and fatty acids.

33. The method of claim 25, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.

34. The method of claim 25, wherein said surfactant is a non-Newtonian surfactant.

35. The method of claim 25 wherein said void containing structures comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.

36. The method of claim 25, wherein said void containing structures comprise a proteinaceous compound.

37. The method of claim 25, wherein said void containing structures comprise a carbohydrate.

38. The method of claim 25 wherein said imaging step comprises a technique selected from the group consisting of magnetic resonance imaging and ultrasound imaging.

39. The method of claim 25 wherein said plurality of void containing structures comprise a plurality of spray-dried microspheres.

40. A stable microbubble precursor for use in preparing stabilized microbubbles in a liquid, said composition comprising:

a plurality of solid substantially liquid-soluble void containing structures comprising at least one surfactant, said void containing structures defining a plurality of voids having an average diameter less than about 100 .mu.m; and

a gas mixture comprising a fluorocarbon gas osmotic agent and a modifier gas dispersed in said plurality of voids wherein said void containing structures and said gas mixture are together adapted to form microbubbles upon addition of a liquid in which said void containing structures are substantially soluble.

41. The composition of claim 46 wherein said fluorocarbon gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcycopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohoxane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

42. The composition of claim 40 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

43. The composition of claim 42, wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters and fatty acids.

44. The composition of claim 42, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.

45. The composition of claim 40, wherein said surfactant is a non-Newtonian surfactant.

46. The composition of claim 40, wherein said modifier gas comprises a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.

47. The composition of claim 46 wherein the molar ratio of said nonfluorocarbon gas to said fluorocarbon gas osmotic agent is from about 1:10 to about 1000:1.

48. The composition of claim 40 wherein said void containing structures comprise a compound selected from the group consisting of starches and derivatized starches.

49. The composition of claim 40, wherein said void containing structures comprise a proteinaceous compound.

50. The composition of claim 40, wherein said void containing structures comprise a carbohydrate.

51. A method for imaging, comprising:

providing a stable microbubble precursor according to claim 40;

combining said microbubble precursor with a liquid to provide a plurality of microbubbles;

introducing said microbubbles into a vertebrate; and

imaging said microbubbles in said vertebrate.

52. The method of claim 51, wherein the fluorocarbon gas osmotic agent has a water solubility of not more than about 0.5 mM at 25.degree. C. and one atmosphere.

53. The method of claim 51 wherein said fluorocarbon 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.

54. The method of claim 53 wherein said fluorocarbon gas osmotic agent is perfluorohexane.

55. The method of claim 51 wherein said modifier gas is a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.

56. The method of claim 51 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

57. The method of claim 51, wherein said surfactant is selected from the group consisting of block copolymers, sugar esters and fatty acids.

58. The method of claim 51, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.

59. The method of claim 51, wherein said surfactant is a non-Newtonian surfactant.

60. The method of claim 51, wherein the surfactant is a phospholipid.

61. The method of claim 51, wherein said void containing structures comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.

62. The method of claim 51, wherein said void containing structures comprise a proteinaceous compound.

63. The method of claim 51, wherein said void containing structures comprise a carbohydrate.

64. The method of claim 51, wherein said plurality of void containing structures comprise a plurality of spray-dried microspheres.

65. The method of claim 51, wherein said imaging step comprises a technique selected from the group consisting of magnetic resonance imaging and ultrasound imaging.

66. A method of forming a stable microbubble precursor for use in preparing stabilized microbubbles in a liquid, said method comprising the steps of:

spray-drying a liquid formulation to produce a plurality of solid substantially liquid-soluble microspheres defining a plurality of voids having an average diameter less than about 100 .mu.m; and

permeating said microspheres with a gas comprising a fluorocarbon gas osmotic agent wherein said microspheres and said gas are together adapted to form microbubbles upon addition of a liquid in which said microspheres are substantially soluble.

67. The method of claim 66 wherein said liquid formulation comprises at least one surfactant.

68. The method of claim 67 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

69. The method of claim 68, wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters and fatty acids.

70. The method of claim 66, wherein said surfactant is a non-Newtonian surfactant.

71. The method of claim 66 wherein said fluorocarbon 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.

72. The method of claim 66, wherein said gas further comprises a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.

73. The method of claim 66 further comprising the step of storing said spray-dried composition in a container.

74. The composition of claim 24 wherein said spray-dried microspheres comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.

75. The composition of claim 24 wherein said spray-dried microspheres comprise said surfactant.

76. The composition of claim 75 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, fatty acids and sugar esters.
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