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Claims for Patent: 5,605,673

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Claims for Patent: 5,605,673

Title: Stabilized microbubble compositions for ultrasound
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 D. (Lebanon, CA), Evitts; David P. (La Jolla, CA)
Assignee: Alliance Pharmaceutical Corp. (San Diego, CA)
Application Number:08/284,083
Patent Claims: 1. A method for forming microbubbles, comprising the steps of:

providing a first gas, a second component, a membrane forming material, and a liquid, wherein said first gas and said second component are present in a molar ratio of about 1:100 to about 1,000:1, and wherein said second component comprises vapor of a compound that is 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. with the proviso that said first gas and said second component are not water vapor; and

surrounding said first gas and said second component with said membrane forming material to form microbubbles in said liquid.

2. The method of claim 1, wherein said membrane forming material is a surfactant.

3. The method of claim 2, wherein said membrane forming material comprises a non-Newtonian surfactant.

4. The method of claim 1, further comprising the steps of:

initially forming microbubbles having a first average diameter wherein the initial ratio of said first gas to said second component in said microbubbles is at least about 1:1;

contacting said microbubbles having a first average diameter with a liquid medium;

shrinking said microbubbles in said medium as a result of loss of said first gas through said membrane; and then

stabilizing said microbubbles at a second average diameter of less than about 75% of said first diameter for a period of at least one minute.

5. The method of claim 4, wherein said microbubbles are stabilized at said second diameter by:

providing a gas osmotic pressure differential across said membrane such that the tension of a gas or gases dissolved in said medium is equal to or greater than the partial pressure of the same gas or gases inside said microbubbles.

6. The method of claim 5, wherein said first diameter is at least about 5 .mu.m.

7. A method for forming microbubbles, comprising the steps of:

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

providing a halogenated gas in said voids;

providing a surfactant;

providing said void-containing structures, said halogenated gas, and said surfactant in admixture with a liquid in which said void-containing structures are soluble; and

dissolving said void-containing structures in said liquid whereby the halogenated gas in said enclosures forms microbubbles that are surrounded by said surfactant.

8. The method of claim 7, wherein said void-containing structures are microspheres.

9. The method of claim 7, wherein said microbubbles contain a first gas and a second halogenated gas respectively present in a molar ratio of from about 1:100 to about 1000:1.

10. A method for imaging an object or body part or body cavity, comprising the steps of:

introducing into said object or body or body part or body cavity a microbubble preparation according to claim 1; and then

imaging at least a portion of said body by ultrasound or magnetic resonance.

11. The method of claim 10, wherein said body is a vertebrate and said preparation is introduced into the vasculature or body cavity of said vertebrate.

12. The method of claim 10, wherein said preparation is a preparation as defined in claim 2.

13. The method of claim 10, wherein said preparation is a preparation as defined in claim 7.

14. The method of claim 10, wherein said preparation is a preparation as defined in claim 8.

15. The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 1.

16. The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 4.

17. The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 5.

18. The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 7.

19. A method for producing microbubbles having increased in-vial stability, comprising the steps of:

spray drying a liquid formulation containing a biocompatible film-forming material to form a microsphere powder therefrom;

combining the microspheres with a gas osmotic agent and storing the microspheres in a container with the gas osmotic agent; and then

mixing an aqueous phase with the powder, wherein said powder substantially dissolves in the aqueous phase to form microbubbles.

20. The method of claim 19, wherein said film forming material comprises a starch or derivatized starch.

21. The method of claim 20, wherein said film forming material comprises a starch or derivatized starch having a molecular weight of greater than about 500,000 or a dextrose equivalency value less than about 12.

22. The method of claim 20, wherein said starch is hydroxyethyl starch.

23. The method of claim 19, wherein said film-forming material comprises a non-Newtonian surfactant.

24. The method of claim 19, wherein said gas osmotic agent comprises a fluorocarbon.

25. The method of claim 19, wherein said film forming material comprises a sugar ester.

26. The method of claim 25, wherein said sugar ester has a component with a hydrophilic-lipophilic balance less than about eight.

27. The method of claim 26, wherein said sugar ester component is sucrose tristearate.

28. A method for forming microbubbles, comprising the steps of:

providing a gas osmotic agent-permeated surfactant-containing powder; and

combining said powder with an aqueous phase.

29. A method for forming microbubbles, comprising the steps of:

providing a spray dried formulation comprising a starch, derivatized starch or dextrin;

providing a gas osmotic agent in combination with said spray dried formulation that permeates said formulation; and

combining said formulation with an aqueous phase to form microbubbles having a half-life in vivo of at least about 20 seconds.

30. The method of claim 29, wherein said spray dried formulation has been spray dried in combination with an inflating agent to form spray dried microspheres.

31. The method of claim 30, wherein said inflating agent is selected from the group consisting of: methylene chloride, Freon.RTM. 113, perfluorohexane and carbon dioxide.

32. The method of claim 29, wherein said spray dried formulation further comprises a sugar polyester.

33. The method of claim 1 wherein said second component comprises a gas osmotic agent.

34. The method of claim 33 wherein said gas osmotic agent comprises a fluorocarbon.

35. The method of claim 34 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.

36. The method of claim 1 wherein said second component comprises perfluorohexane.

37. The method of claim 2 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.

38. The method of claim 1 wherein said membrane forming material is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.

39. The method of claim 1, wherein said film-forming material comprises a protein.

40. The method of claim 1, wherein said film-forming material comprises a carbohydrate.

41. The method of claim 1 wherein said film-forming material comprises a compound selected from the group consisting of starches, derivatized starches and sugar esters.

42. The method of claim 7 wherein said halogenated gas comprises a fluorocarbon.

43. The method of claim 42 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.

44. The method of claim 7 wherein said halogenated gas comprises perfluorohexane.

45. The method of claim 7, wherein said surfactant is a non-Newtonian surfactant.

46. The method of claim 7 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.

47. The method of claim 7 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.

48. The method of claim 7, wherein said void-containing structure comprises a powder.

49. The method of claim 7, wherein said void-containing structures comprise a carbohydrate.

50. The method of claim 7, wherein said void-containing structures comprise a compound selected from the group consisting of starch, derivatized starch, dextrin or combinations thereof.

51. The method of claim 7, wherein said void-containing structures comprise said surfactant.

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

53. The method of claim 7, wherein said void containing structure comprises a protein.

54. The method of claim 24 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.

55. The method of claim 19 wherein said gas osmotic agent comprises perfluorohexane.

56. The method of claim 19 wherein said film-forming material comprises a surfactant.

57. The method of claim 56 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.

58. The method of claim 56 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.

59. The method of claim 19, wherein said film-forming structures comprise a carbohydrate.

60. The method of claim 59 wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar and dried lactose microspheres.

61. The method of claim 19, wherein said film-forming material comprises a protein.

62. The method of claim 28 wherein said gas osmotic agent-permeated surfactant-containing powder comprises a surfactant selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.

63. The method of claim 62 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.

64. The method of claim 28 wherein said surfactant-containing powder comprises a non-Newtonian surfactant.

65. The method of claim 28 wherein said non-Newtonian surfactant comprises one or more phospholipids.

66. The method of claim 28 wherein said gas osmotic agent-permeated surfactant-containing powder comprises a fluorocarbon.

67. The method of claim 66 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.

68. The method of claim 28 wherein said gas osmotic agent comprises perfluorohexane.

69. The method of claim 28, wherein said gas osmotic agent-permeated surfactant-containing powder comprises a carbohydrate.

70. The method of claim 69 wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar and dried lactose microspheres.

71. The method of claim 28, wherein said gas osmotic agent-permeated surfactant-containing powder comprises a protein.

72. The method of claim 28, wherein said gas osmotic agent-permeated surfactant-containing powder comprises a compound selected from the group consisting of starch, derivatized starch, dextrin or combinations thereof.

73. The method of claim 72, wherein said compound comprises a starch or derivatized starch having a molecular weight of greater than about 500,000 or a dextrose equivalency value less than about 12.

74. The method of claim 72, wherein said starch is hydroxyethyl starch.

75. The method of claim 29 wherein said spray dried formulation comprises a surfactant.

76. The method of claim 75 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.

77. The method of claim 75 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.

78. The method of claim 75 wherein said surfactant comprises a non-Newtonian surfactant.

79. The method of claim 78 wherein said non-Newtonian surfactant comprises one or more phospholipids.

80. The method of claim 29 wherein said gas osmotic agent comprises a fluorocarbon.

81. The method of claim 80 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.

82. The method of claim 29 wherein said gas osmotic agent comprises perfluorohexane.
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