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Claims for Patent: 5,720,938

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Claims for Patent: 5,720,938

Title: Systems for the formation of microbubbles
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:08/476,079
Patent Claims: 1. A system for forming stabilized microbubbles from a solid precursor, said system comprising:

a first chamber containing a plurality of solid or semi-solid substantially water soluble void-containing structures defining a plurality of voids having an average diameter less than about 100 .mu.m;

a fluorocarbon gas osmotic agent dispersed in said voids;

a second chamber containing an aqueous liquid;

a surfactant in said first chamber or said second chamber; and

a seal separating said first and second chambers, wherein said fluorocarbon gas osmotic agent, said void-containing structure, said aqueous liquid, and said surfactant are adapted to form microbubbles when combined together in said first or second chamber.

2. The system 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.

3. The system 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.

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

5. The system of claim 1, wherein said surfactant is a non-Newtonian surfactant.

6. The system of claim 1 wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, sugar esters and block copolymers.

7. The system of claim 1, further comprising a container in which said first and second chambers are provided, and wherein said seal and said aqueous liquid are interposed between said gaseous phase and tho exterior of said container.

8. The system of claim 7, wherein said container is glass.

9. The system of claim 7, wherein said container is a syringe.

10. The system of claim 9, wherein said syringe has a barrel in which said first and second chambers are located, and a plunger adjacent said second chamber but separated from said first chamber by said aqueous liquid and said seal.

11. The system of claim 1 wherein said seal comprises a membrane.

12. The system of claim 1 wherein said void-containing structures comprise a carbohydrate.

13. The system of claim 12 wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar, and dried lactose microspheres.

14. The system of Clam 1, wherein said void-containing structures comprise said surfactant.

15. The system of claim 14, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, sugar esters and block copolymers.

16. The system of claim 1, wherein said plurality of void-containing structures comprises a plurality of spray-dried microspheres.

17. The system of claim 16 wherein said spray-dried microspheres comprise a compound selected from the group consisting of starches and derivatized starches.

18. The system of claim 17 wherein said spray-dried microspheres comprise said surfactant.

19. The system of claim 18 wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, sugar esters and block copolymers.

20. A kit for use in preparing stabilized microbubbles directly in a liquid, said kit comprising:

a sealed container;

a liquid in said container;

a surfactant in said container;

a modifier gas in said container; and

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

21. The kit of claim 20 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.

22. The kit of claim 20, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than 8.

23. The kit of claim 20, wherein said surfactant is a non-Newtonian surfactant.

24. The kit of claim 20, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, sugar esters and block copolymers.

25. The kit of claim 20, further comprising means in said container for permitting transmission of sufficient external energy to said liquid to form microbubbles in said container.

26. The kit of claim 25, wherein said means for transmission comprises a flexible polymer membrane.

27. A kit for producing stabilized microbubbles from a solid microbubble precursor, comprising:

a container;

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

a gas mixture dispersed in said voids, said gas mixture comprising at least one fluorocarbon gas osmotic agent and at least one modifier gas; and

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

28. The kit 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 kit of claim 27 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.

30. The kit of claim 27, wherein said surfactant is a non-Newtonian surfactant.

31. The kit of claim 27, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, sugar esters and block copolymers.

32. The kit of claim 27, wherein the void-containing structures comprise said surfactant.

33. The kit of claim 32, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, sugar esters and block copolymers.

34. The kit of claim 27, wherein the void-containing structures comprise a plurality of spray-dried microspheres.

35. The kit of claim 34 wherein said spray-dried microspheres comprise a compound selected from the group consisting of starches and derivatized starches.

36. The kit of claim 34 wherein said spray-dried microspheres comprise said surfactant.

37. The kit of claim 36 wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.

38. The kit of claim 27, wherein said void-containing structures are proteinaceous.

39. The kit of claim 27, wherein said void-containing structures comprise a carbohydrate.

40. The kit of claim 39, wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar and dried lactose microspheres.

41. A kit for use in preparing stabilized microbubbles directly in a liquid, said kit comprising:

a sealed container;

a liquid in said container;

a surfactant in said container;

a fluorocarbon gas osmotic agent in said container; and

a nonfluorocarbon modifier gas in said container, wherein the molar ratio of said nonfluorocarbon modifier gas to said fluorocarbon gas osmotic agent is from about 1:10 to about 1000:1, with the proviso that said nonfluorocarbon modifier gas is not water vapor and wherein said liquid, said surfactant, said modifier gas and said fluorocarbon gas osmotic agent are together adapted to form microbubbles upon the application of energy thereto.

42. A kit for use in preparing stabilized microbubbles directly in a liquid, said kit comprising:

a sealed container;

a liquid in said container;

a surfactant in said container; and

a fluorocarbon gas osmotic agent comprising perfluoropentane in said container, wherein said liquid, said surfactant and said fluorocarbon gas osmotic agent are together adapted to form microbubbles upon the application of energy thereto.

43. The kit of claim 42 further comprising a nonfluorocarbon modifier gas comprising nitrogen.

44. The kit of claim 43 wherein said perfluoropentane is in a liquid state.

45. The kit of claim 44 wherein said container is a syringe, said kit adapted to form microbubbles upon reducing pressure in said syringe through the application of said energy thereto.

46. The kit of claim 41 wherein said nonfluorocarbon modifier gas is at least partially solubilized in said liquid in said container.
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