Ultrasonic imaging system utilizing a long-persistence contrast agent

• US 6,280,704 B1
• Filed: 12/08/1997
• 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: Schutt, Ernest G., Anderson, Charles David, Evitts, David P.
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/986,879
• Time in Patent Office: 1,359 Days
• Field of Search: 424/9.52, 424/9.51, 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
• CPC Class Codes: G02B 6/0006 Coupling light into the fibre in general G02B6/4298

Abstract

A microbubble preparation formed of a plurality of microbubbles comprising a first gas and second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ration of from about 1:100 to abut 1000:1, and wherein the first gas has a vapor pressure of at least about (760−X) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° 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.

Claims

1. A system for providing a 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 wherein said preparation comprises an aqueous medium having dispersed therein a plurality of osmotically stabilized microbubbles, said microbubbles comprising a generally spherical microbubble membrane containing at least one modifier gas and at least one gas osmotic agent, wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;

100 to about 1000;

1 wherein said ratio is effective to stabilize said microbubble preparation, and wherein said gas osmotic agent is selected from the group consisting of perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutane, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, perfluorotriethylamine and combinations thereof.

2. The system of claim 1 wherein said modifier gas is a fluorocarbon gas.

3. The system of claim 2 wherein said fluorocarbon modifier gas is selected from the group comprising perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane and perfluorocyclopentane.

4. The system of claim 1 wherein said modifier gas is a nonfluorocarbon gas.

5. The system of claim 4 wherein said nonfluorocarbon modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

6. The system of claim 4 wherein said nonfluorocarbon modifier gas is air.

7. The system of claim 1, wherein said gas osmotic agent has a water solubility of not more than about 0.5 mM at 25°

C. and one atmosphere.

8. The system of claim 1 wherein the microbubble membrane comprises a surfactant.

9. The system of claim 8 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.

10. The system of claim 8 wherein said surfactant is a non-Newtonian surfactant.

11. The system of claim 8 wherein said surfactant is selected from the group consisting of polyoxypropylene polyoxyethylene copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, dodecyl poly(ethyleneoxy)ethanol nonylphenoxy poly(ethyleneoxy)ethanol hydroxy ethyl starch, hydroxy ethyl starch fatty acid esters, dextrans, dextran fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins, phospholipids, polyoxyethylene fatty acids esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycol oxystearate, glycerol polyethylene glycol ricinoleate, ethoxylated soybean sterols, ethoxylated castor oil, cholesterol oleic acid, sodium oleate and combinations thereof.

12. The system of claim 1 wherein the microbubble membrane comprises a liposome.

13. The system of claim 1 wherein the microbubble membrane comprises a proteinaceous material.

14. The system of claim 13 wherein said proteinaceous material is albumin.

15. The system of claim 7 wherein said gas osmotic agent is perfluoropentane.

16. The system of claim 15 wherein said nonfluorocarbon modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

17. The system of claim 15 wherein said nonfluorocarbon modifier gas is air.

18. The system of claim 15 wherein the microbubble membrane comprises a surfactant.

19. The system of claim 18 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.

20. The system of claim 18 wherein said surfactant is a fluorinated surfactant.

21. The system of claim 15 wherein the microbubble membrane comprises a proteinaceous material.

22. The system of claim 21 wherein said proteinaceous material is albumin.

23. The system of claim 1 wherein said gas osmotic agent is perfluoropentane and said modifier gas is nitrogen.

24. The system of claim 23 wherein the mnicrobubble membrane comprises a surfactant.

25. The system of claim 24 wherein said perfluoropentane is at least partially in a liquid state.

26. The system of claim 25 wherein the kit comprises a liquid-in-liquid emulsion, said emulsion comprising water and liquid perfluoropentane whereby said stabilized microbubble preparation may be formed by altering pressure on the emulsion.

27. The system of claim 24 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.

28. The system of claim 24 wherein said surfactant is a fluorinated surfactant.

29. The system of claim 24 wherein said surfactant is selected from the group consisting of polyoxypropylene polyoxyethylene copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, dodecyl poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, hydroxy ethyl starch, hydroxy ethyl starch fatty acid esters, dextrans, dextran fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins, phospholipids, polyoxyethylene fatty acids esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycol oxystearate, glycerol polyethylene glycol ricinoleate, ethoxylated soybean sterols, ethoxylated castor oil, cholesterol oleic acid, sodium oleate and conbinations thereof.

30. The system of claim 1 wherein said gas osmotic agent is perfluorohexane.

31. The system of claim 30 wherein said nonfluorocarbon modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

32. The system of claim 30 wherein said nonfluorocarbon modifier gas is air.

33. The system of claim 30 wherein the microbubble menmbrane comprises a surfactant.

34. The system of claim 33 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.

35. The system of claim 33 wherein said surfactant is selected from the group consisting of polyoxypropylene polyoxyethylene copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, dodecyl poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol hydroxy ethyl starch, hydroxy ethyl starch fatty acid esters, dextrans, dextran fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins, phospholipids, polyoxyethylene fatty acids esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycol oxystearate, glycerol polyethylene glycol ricinoleate, ethoxylated soybean sterols, ethoxylated castor oil, cholesterol oleic acid, sodium oleate and combinations thereof.

36. The system of claim 33 wherein said surfactant comprises a mixture of a phospholipid and a polyoxyethylene-polyoxypropylene copolymer.

37. The system of claim 36 wherein said microbubble membrane further comprises a hydroxy ethyl starch.

38. The system of claim 30 wherein the microbubble membrane comprises a proteinaceous material.

39. The system of claim 38 wherein said proteinaceous material is albumin.

40. The system of claim 1 wherein said gas osmotic agent is perfluorohexane and said modifier gas is nitrogen.

41. The system of claim 40 wherein the inicrobubble membrane comprises a surfactant.

42. The system of claim 41 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 system of claim 41 wherein said surfactant is a non-Newtonian surfactant.

44. The system of claim 41 wherein said surfactant is selected from the group consisting of polyoxypropylene polyoxyethylene copolymers, sugar esters, fatty alcohols, aliphatic atine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, dodecyl poly(ethyleneoxy)ethanol nonylphenoxy poly(ethyleneoxy)ethanol, hydroxy ethyl starch, hydroxy ethyl starch fatty acid esters, dextrans, dextran fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins, phospholipids, polyoxyethylene fatty acids esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycol oxystearate, glycerol polyethylene glycol ricinoleate, ethoxylated soybean sterols, ethoxylated castor oil, cholesterol, oleic acid, sodium oleate and cornbinations thereof.

45. The system of claim 41 wherein said surfactant comprises at least one phospholipid.

46. The system of claim 41 wherein said surfactant comprises a mixture of a phospholipid and a polyoxyethylene-polyoxypropylene copolymer.

47. The system of claim 46 wherein said microbubble mernbrane further comprises a hydroxy ethyl starch.

75. The system of claim 1, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

100 and 1;

1.

76. The system of claim 1, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

10 and 1;

1.

77. The system of claim 1, in which the molar ratio of said modifier gas and said gas osmotic agent is greater than 1:

1.

78. The system of claim 77, wherein the modifier gas is a non-fluorocarbon and the gas osmotic agent is a fluorocarbon.

79. The system of claim 78, wherein said plurality of osmotically stabilized microbubbles have a diameter from about 1 to 10 μ

m.

80. The system of claim 79, wherein the diameter of said plurality of osmotically stabilized microbubbles is about 6 μ

m.

48. A system for providing a 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 wherein said preparation comprises an aqueous medium having dispersed therein a plurality of osmotically stabilized microbubbles, said microbubbles comprising a generally spherical microbubble membrane containing at least one modifier gas and at least one gas osmotic agent, wherein said gas osmotic agent comprises the vapor of a compound which is a liquid at 37°

C. and 760 Torr, and wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;

100 to about 1.000;

1. wherein said ratio is effective to stabilize said microbubble preparation.

49. The system of claim 48 wherein said gas osmotic agent is selected from the group consisting of perfluorohexane, perluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoronethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, perfluorotriethylamine and combinations thereof.

50. The system of claim 48 wherein said modifier gas is a fluorocarbon gas.

51. The system of claim 50 wherein said fluorocarbon modifier gas is selected from the group comprising perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane and perfluorocyclopentane.

52. The system of claim 48 wherein said modifier gas is a nonfluorocarbon gas.

53. The system of claim 52 wherein said nonfluorocarbon modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mnixtures thereof.

54. The system of claim 52 wherein said nonfluorocarbon modifier gas is air.

55. The system of claim 48 wherein the microbubble membrane comprises a surfactant.

56. The system of claim 55 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 system of claim 55 wherein said surfactant is selected from the group consisting of polyoxypropylene polyoxyethylene copolymers, sugar esters, fatty alcohols, aliphatic amnine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, dodecyl poly(ethyleneoxy)ethanol nonylphenoxy poly(ethyleneoxy)ethanol hydroxy ethyl starch, hydroxy ethyl starch fatty acid esters, dextrans, dextran fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins, phospholipids, polyoxyethylene fatty acids esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycol oxystearate, glycerol polyethylene glycol ricinoleate, ethoxylated soybean sterols, ethoxylated castor oil, cholesterol oleic acid, sodium oleate and combinations thereof.

58. The system of claim 48 wherein the microbubble membrane comprises a liposome.

59. The system of claim 48 wherein the microbubble membrane comprises a proteinaceous material.

60. The system of claim 59 wherein said proteinaceous material is albumin.

74. The system of claim 59 wherein said proteinaceous material is albumin.

81. The system of claim 48, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

100 and 1;

1.

82. The system of claim 48, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

10 and 1;

1.

83. The system of claim 48, in which the molar ratio of said modifier gas and said gas osmotic agent is greater than 1:

1.

84. The system of claim 83, wherein the modifier gas is a non-fluorocarbon and the gas osmotic agent is a fluorocarbon.

85. The system of claim 84, wherein said plurality of osmotically stabilized microbubbles have a diameter from about 1 to 10 μ

m.

86. The system of claim 84, wherein the diameter of said plurality of osmotically stabilized microbubbles is about 6 μ

m.

61. A system for providing a 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 wherein the preparation comprises an aqueous medium having dispersed therein a plurality of osmotically stabilized microbubbles, said microbubbles comprising a generally spherical microbubble membrane comprising proteinaceous material containing at least one modifier gas and at least one gas osmotic agent, wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;

100 to about 1,000;

1, wherein said ratio is effective to stabilize said microbubble preparation.

62. The system of claim 61, wherein said gas osmotic agent has a water solubility of not more than about 0.5 mM at 25°

C. and one atmosphere.

63. The system of claim 61 wherein said gas osmotic agent comprises a fluorocarbon.

64. The system of claim 63 wherein said fluorocarbon gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodinethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotriinthylcyclobutane, perfluorotriethylamine and combinations thereof.

65. The system of claim 61 wherein said modifier gas is a nonfluorocarbon gas.

66. The system of claim 65 wherein said nonfluorocarbon modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

67. The system of claim 61 wherein said modifier gas is a fluorocarbon gas.

68. The system of claim 67 wherein said fluorocarbon modifier gas is selected from the group conmrising perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane and perfluorocyclopentane.

69. The system of claim 61 wherein the microbubble membrane further comprises a surfactant.

70. The system of claim 69 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.

71. The system of claim 69 wherein said surfactant is a non-Newtonian surfactant.

72. The system of claim 69 wherein said surfactant is a fluorinated surfactant.

73. The system of claim 69 wherein said surfactant is selected from the group consisting of polyoxypropylene polyoxyethylene copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, dodecyl poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, hydroxy ethyl starch, hydroxy ethyl starch fatty acid esters, dextrans, dextran fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, phospholipids, polyoxyethylene fatty acids esters, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycol oxystearate, glycerol polyethylene glycol ricinoleate, ethoxylated soybean sterols, ethoxylated castor oil, cholesterol, oleic acid, sodium oleate and combinations thereof.

87. The system of claim 61, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

100 and 1;

1.

88. The system of claim 61, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

10 and 1;

1.

89. The system of claim 61, in which the molar ratio of said modifier gas and said gas osmotic agent is greater than 1:

1.

90. The system of claim 89, wherein the modifier gas is a non-fluorocarbon and the gas osmotic agent is a fluorocarbon.

91. The system of claim 90, wherein said plurality of osmotically stabilized microbubbles have a diameter from about 1 to 10 μ

m.

92. The system of claim 91, wherein the diameter of said plurality of osmotically stabilized microbubbles is about 6 μ

m.

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

an ultrasound imaging apparatus; and

a kit capable of producing a stabilized microbubble preparation wherein said preparation comprises an aqueous medium having dispersed therein a plurality of osmotically stabilized microbubbles, said microbubbles comprising a generally spherical microbubble membrane containing at least one modifier gas and at least one gas osmotic agent, wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;

100 to 1,000;

1, wherein said ratio is effective to stabilize said microbubble preparation, and wherein said modifier gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane and perfluorocyclopentane and combinations thereof.

94. The system of claim 93, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

100 and 1;

1.

95. The system of claim 93, wherein the molar ratio of said modifier gas and said gas osmotic agent is between about 1:

10 and 1;

1.

96. The system of claim 93, in which the molar ratio of said modifier gas and said gas osmotic agent is greater than 1:

1.

97. The system of claim 96, wherein the modifier gas is a non-fluorocarbon and the gas osmotic agent is a fluorocarbon.

98. The system of claim 97, wherein said plurality of osmotically stabilized microbubbles have a diameter from about 1 to 10 μ

m.

99. The system of claim 98, wherein the diameter of said plurality of osmotically stabilized microbubbles is about 6 μ

m.