Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients

• US 5,804,162 A
• Filed: 06/07/1995
• Issued: 09/08/1998
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Photogen Technologies Inc., Targeson, Inc.
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Kabalnov, Alexey, Schutt, Ernest George, Weers, Jeffry Greg
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US08/479,621
• Time in Patent Office: 1,189 Days
• Field of Search: 424/9.3, 424/9.32, 424/9.5, 424/9.51, 424/400, 424/450, 424/9.2, 424/9.52, 252/302, 252/350, 128/662.02
• US Class Current: 424/9.51
• 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

Long lasting gas emulsions for ultrasound and magnetic resonance imaging contrast enhancement utilize low Ostwald coefficient fluoromono- and fluoropolyether compounds. Gas emulsion preparations are disclosed containing air mixed with perfluorodiglyme (CF₃ (OCF₂ CF₂)₂ OCF₃), perfluoromonoglyme (CF₃ OCF₂ CF₂ OCF₃), perfluorodiethylether, C₂ F₅ OC₂ F₅, perfluoroethylmethylether, CF₃ OC₂ F₅, and perfluorodimethylether, CF₃ OCF₃.

Claims

1. A gas emulsion for ultrasound contrast enhancement comprising a plurality of microbubbles in a liquid medium, said microbubbles comprising a gas or vapor selected from the group consisting of fluoromonoethers, fluoropolyethers, and mixtures thereof.

2. The composition of claim 1 wherein the gas or vapor is selected from the group consisting of perfluorodiethylether, perfluorodimethylether, perfluoromethylethylether, perfluoromonoglyme and perfluorodiglyme.

3. The composition of claim 1, wherein the microbubbles additionally comprises air or nitrogen.

4. The composition of claim 3, wherein the microbubbles additionally comprises air or nitrogen.

5. The gas emulsion of claim 1 wherein the microbubbles are surrounded by a surfactant layer.

6. The gas emulsion of claim 5, wherein the surfactant 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 wherein the second surfactant is more water soluble than the first surfactant.

7. The gas emulsion of claim 6, 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.

8. The gas emulsion of claim 6, wherein said second surfactant is selected from the group consisting of phospholipids, phosphocholine, lysophospholipid and combinations thereof wherein each acyl chain comprises no more than 14 carbon atoms.

9. The gas emulsion of claim 6, wherein said first surfactant comprises a phoshatidylcholine with one or more acyl chains, at least one chain comprising 12 to 18 carbon atoms, and said second surfactant comprises a phosphatidylcholine with one or more acyl chains, at least one chain comprising 6 to 12 carbon atoms.

19. 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.

20. The gas emulsion of claim 1 wherein said gas or vapor comprises a perfluoroether.

21. The gas emulsion of claim 20 wherein said perfluoroether is a perfluoropolyether.

22. The gas emulsion of claim 20 wherein said perfluoroether is a perfluoromonoether.

23. The gas emulsion of claim 1 wherein said gas or vapor comprises a polyether.

24. The gas emulsion of claim 1 wherein said gas or vapor comprises a monoether.

25. The gas emulsion of claim 1 wherein said gas or vapor is selected from the group consisting of CH₃ CH₂ OCF₂ CHF₂, CH₃ CH₂ OCF₂ CF₃, CHF₂ CH₂ OCF₂ CHF₂, CF₃ CH₂ OCF₂ CH₂ F, CF₃ CH₂ OCH₂ CF₃, CF₃ CH₂ OCF₂ CHF₂, CHF₂ CH₂ OCF₂ CF₃, CF₃ CH₂ OCF₂ CF₃, CH₃ OCH₂ CF₂ CHF₂, CH₃ OCH₂ CF₂ CF₃, CH₃ OCF₂ CF₂ CHF₂, CH₃ OCF₂ CHFCF₃, CH₃ OCF₂ CF₂ CF₃, CHF₂ OCH₂ CF₂ CHF₂, CHF₂ OCH₂ CF₂ CF₃, CF₃ OCH₂ CF₂ CHF₂, CF₃ OCH₂ CF₂ CF₃, CH₃ OCH(CF₃)₂, CH₃ OCF(CF₃)₂, CHF₂ OCH(CF₃)₂, CH₃ OCH₂ CHF₂, CH₃ OCF₂ CH₂ F, CH₃ OCH₂ CF₃, CH₃ OCF₂ CHF₂, CHF₂ OCH₂ CHF₂, CHF₂ OCF₂ CH₂ F, CHF₂ OCH₂ CF₃, CHF₂ OCHFCF₃, CF₃ OCH₂ CHF₂, CH₃ OCF₂ CF₃, CF₃ OCH₂ CF₃, CF₃ OCHFCF₃ and mixtures thereof.

26. The gas emulsion of claim 1 wherein said microbubbles further comprise microspheres.

27. The gas emulsion of claim 26 wherein said microspheres comprise a protein.

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

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

30. The gas emulsion of claim 29 wherein said void containing structures comprise microspheres.

31. The gas emulsion of claim 30 wherein said microspheres comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.

32. The gas emulsion of claim 1 wherein said microbubbles are formed by altering the pressure on an emulsified liquid comprising an aqueous phase and a compound selected from the group consisting of fluoromonoethers, fluoropolyethers and mixtures thereof.

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

34. The gas emulsion of claim 1 wherein said liquid medium comprises a viscosity enhancing agent.

35. The gas emulsion of claim 5 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.

36. The gas emulsion of claim 5, wherein said surfactant is a non-Newtonian surfactant.

37. 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.

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

introducing the contrast medium of claim 5 into said object or body; and

, imaging at least a portion of said object or body.

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

introducing the contrast medium of claim 29 into said object or body; and

,

imaging at least a portion of said object or body.

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

introducing the contrast medium of claim 37 into said object or body; and

,

imaging at least a portion of said object or body.

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

introducing the contrast medium of claim 79 into said object or body; and

,

imaging at least a portion of said object or body.

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

providing a container having therein a dry, hollow, particulate, approximately microspherical material comprising a surfactant, a hydrophilic monomer or polymer or combination thereof, and a gas or gas mixture comprising a compound with Ostwald coefficient of less than about 100×

10^-6 at 37 degrees C.;

adding an aqueous liquid to said container; and

,

substantially dissolving said microspherical material in 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.

11. The method of claim 10 wherein the gas comprises a fluoromono- or fluoropolyether vapor.

12. The method of claim 11 wherein the gas is selected from the group consisting of perfluorodiethylether vapor, perfluorodimethylether vapor, perfluoromethylethylether vapor, perfluoromonoglyme vapor and perfluorodiglyme vapor.

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

providing a container having therein a dry, hollow, particulate, approximately microspherical material comprising a surfactant, a hydrophilic monomer or polymer or combination thereof, and a gas or gas mixture comprising a fluoromono- or fluoropolyether;

adding an aqueous liquid to said container; and

,

substantially dissolving said microspherical material in 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.

14. The method of claim 13 wherein the gas is selected from the group consisting of perfluorodiethylether vapor, perfluorodimethylether vapor, perfluoromethylethylether vapor, perfluoromonoglyme vapor and perfluorodiglyme vapor.

15. A gas emulsion forming composition comprising:

a spray dried dispersion of a hydrophilic monomer or polymer or combination thereof, and a surfactant; and

,

a gas or gas mixture comprising a compound with Ostwald coefficient of less than about 500×

10^-6 at 37 degrees C. in said container impregnated into said spray dried dispersion.

16. The composition of claim 15, wherein said surfactant comprises a phospholipid, a mixture of phospholipids, a phosphocholine, or a lysophospholipid.

17. A gas emulsion forming composition comprising:

a spray dried dispersion of a hydrophilic monomer or polymer or combination thereof, and a surfactant; and

,

a gas or gas mixture comprising a fluoromono- or fluoropolyether in said container impregnated into said spray dried dispersion.

18. The composition of claim 17, wherein said surfactant comprises a phospholipid, a mixture of phospholipids, a phosphocholine, or a lysophospholipid.

38. A microbubble composition for use in imaging comprising a plurality of microbubbles in a biocompatible liquid medium, said microbubbles comprising a perfluoroether in a gaseous or vaporous state.

39. The microbubble composition of claim 38 wherein said perfluoroether is a perfluoropolyether.

40. The microbubble composition of claim 38 wherein said perfluoroether is a perfluoromonoether.

41. The microbubble composition of claim 38 wherein said perfluoroether is selected from the group consisting of perfluorodiethylether, perfluorodimethylether, perfluoromethylethylether, perfluoromonoglyme, perfluorodiglyme and mixtures thereof.

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

43. The microbubble composition of claim 42 wherein said microspheres comprise a protein.

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

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

46. The microbubble composition of claim 45 wherein said void containing structures comprise microspheres.

47. The microbubble composition of claim 46 wherein said microspheres comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.

48. 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 perfluoroether.

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

50. The microbubble composition of claim 38 wherein said liquid medium comprises a viscosity enhancing agent.

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

52. The microbubble composition of claim 51 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.

53. The microbubble composition of claim 51, wherein said surfactant layer comprises a non-Newtonian surfactant.

54. The microbubble composition of claim 51 wherein said surfactant layer comprises a compound selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.

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

introducing the contrast medium of claim 38 into said object or body; and

,

imaging at least a portion of said object or body.

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

introducing the contrast medium of claim 46 into said object or body; and

,

imaging at least a portion of said object or body.

55. 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 and at least one modifier gas.

56. The microbubble composition of claim 55 wherein said fluoroether gas osmotic agent comprises a perfluoroether.

57. The microbubble composition of claim 56 wherein said perfluoroether is a perfluoropolyether.

58. The microbubble composition of claim 56 wherein said perfluoroether is a perfluoromonoether.

59. The microbubble composition of claim 55 wherein said fluoroether gas osmotic agent comprises a monoether.

60. The microbubble composition of claim 55 wherein said fluoroether gas osmotic agent comprises a polyether.

61. The microbubble composition of claim 55 wherein said fluoroether gas osmotic agent is selected from the group consisting of CH₃ CH₂ OCF₂ CHF₂, CH₃ CH₂ OCF₂ CF₃, CHF₂ CH₂ OCF₂ CHF₂, CF₃ CH₂ OCF₂ CH₂ F, CF₃ CH₂ OCH₂ CF₃, CF₃ CH₂ OCF₂ CHF₂, CHF₂ CH₂ OCF₂ CF₃, CF₃ CH₂ OCF₂ CF₃, CH₃ OCH₂ CF₂ CHF₂, CH₃ OCH₂ CF₂ CF₃, CH₃ OCF₂ CF₂ CHF₂, CH₃ OCF₂ CHFCF₃, CH₃ OCF₂ CF₂ CF₃, CHF₂ OCH₂ CF₂ CHF₂, CHF₂ OCH₂ CF₂ CF₃, CF₃ OCH₂ CF₂ CHF₂, CF₃ OCH₂ CF₂ CF₃, CH₃ OCH(CF₃)₂, CH₃ OCF(CF₃)₂, CHF₂ OCH(CF₃)₂, CH₃ OCH₂ CHF₂, CH₃ OCF₂ CH₂ F, CH₃ OCH₂ CF₃, CH₃ OCF₂ CHF₂, CHF₂ OCH₂ CHF₂, CHF₂ OCF₂ CH₂ F, CHF₂ OCH₂ CF₃, CHF₂ OCHFCF₃, CF₃ OCH₂ CHF₂, CH₃ OCF₂ CF₃, CF₃ OCH₂ CF₃, CF₃ OCHFCF₃ and mixtures thereof.

62. The microbubble composition of claim 55 wherein said microbubbles further comprise microspheres.

63. The microbubble composition of claim 62 wherein said microspheres comprise a protein.

64. The microbubble composition of claim 55 wherein said microbubbles further comprise a liposome.

65. The microbubble composition of claim 55 wherein said microbubbles are formed through the solubilization of void containing structures.

66. The microbubble composition of claim 65 wherein said void containing structures comprise microspheres.

67. The microbubble composition of claim 66 wherein said microspheres comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.

68. The microbubble composition of claim 55 wherein said microbubbles are formed by altering the pressure on an emulsified liquid comprising an aqueous phase and said fluoroether gas osmotic agent.

69. The microbubble composition of claim 55 wherein said microbubbles are formed through sonication.

70. The microbubble composition of claim 55 wherein said liquid medium comprises a viscosity enhancing agent.

71. The microbubble composition of claim 55 wherein said microbubbles further comprise a surfactant layer.

72. The microbubble composition of claim 71 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 a nd combinations thereof.

73. The microbubble composition of claim 71, wherein said surfactant layer comprises a non-Newtonian surfactant.

74. The microbubble composition of claim 71 wherein said surfactant layer comprises a compound selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.

75. The microbubble composition of claim 55 wherein said modifier gas comprises oxygen.

76. The microbubble composition of claim 55 wherein said modifier gas comprises nitrogen.

82. A method for ultrasonically imaging an object or body comprising the steps of;

introducing the contrast medium of claim 55 into said object or body; and

,

imaging at least a portion of said object or body.

83. The composition of claim 56 wherein said modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

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

introducing the contrast medium of claim 67 into said object or body, and,

imaging at least a portion of said object or body.

86. The composition of claim 67 wherein said modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

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

introducing the contrast medium of claim 74 into said object or body;

and,

imaging at least a portion of said object or body.

88. The composition of claim 74 wherein said modifier gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

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

introducing the contrast medium of claim 76 into said object or body; and

,

imaging at least a portion of said object or body.