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|Title:||Ultrasound imaging method using 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 D. (Lebanon, NJ), Evitts; David P. (La Jolla, CA)|
|Assignee:||Alliance Pharmaceutical Corp. (San Diego, CA)|
1. A method for imaging an object or body part or body cavity, comprising the steps of:
introducing into said object or body part or body cavity a microbubble preparation comprising a first gas, a second gas, a membrane forming material, and a liquid, wherein said first gas and said second gas are present in a molar ratio of about 1:100 to about 1,000:1, and wherein said 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 said vapor pressure of each of said first and second gases is greater than about 75 mm Hg at 37.degree. C., and the boiling point of at least one said second gas at atmospheric pressure is greater than about 37.degree. C., with the proviso that said first gas and said second gas are not water vapor, wherein said first and second gases are surrounded with said membrane forming material; and
imaging at least a portion of said object or body by ultrasound or magnetic resonance.
2. The method of claim 1, wherein said object or body is a vertebrate and said preparation is introduced into the vasculature or body cavity of said vertebrate.
3. The method of claim 1, wherein said membrane forming material is a surfactant.
4. The method of claim 3, wherein said surfactant is a phospholipid.
5. The method of claim 1, wherein said second gas is a fluorocarbon.
6. The method of claim 1, wherein said microbubble preparation is formed by:
providing a microbubble-forming composition comprising a surfactant and solid or semi-solid substantially liquidsoluble dry, hollow, particulate microspheres, said microspheres having a diameter less than about 100 .mu.m, said first and second gas in said microspheres;
combining said composition with a liquid in which said microspheres are soluble and said microspheres are dissolved in said liquid whereby the gases in said microspheres form microbubbles that are surrounded by said surfactant.
7. The method of claim 2, further comprising the step of preparing said microbubble preparation outside of said vertebrate prior to said introducing step.
8. The method of claim 7, further comprising the step of:
initially forming microbubbles having a first average diameter wherein the initial ratio of said first gas to said second gas in said microbubbles is at least about 1:1, wherein said microbubbles are adapted to shrink in blood in vivo as a result of loss of said first gas through said membrane to a second average diameter of less than about 75% of said first diameter and then remain stabilized at or about said second diameter for at least about 1 minute.
9. The method of claim 8, wherein said first diameter is at least about 5 .mu.m, and wherein the tension of the gas or gases dissolved in said blood is less than the pressure of the same gas or gases inside said microbubble.
10. The method of claim 8, wherein said first diameter is at least about 10 .mu.m and said second diameter is between about 1 .mu.m and 6 .mu.m.
11. The method of claim 8, wherein said second gas has an average molecular weight at least about 4 times that of said first gas.
12. The method of claim 8, wherein said second gas has a vapor pressure less than about 750 mm Hg at 37.degree. C.
13. The method of claim 8, wherein said molar ratio of said first gas to said second gas is from about 1:10 to about 500:1.
14. The method of claim 8, wherein said second gas comprises a fluorocarbon and said first gas is a nonfluorocarbon.
15. The method of claim 8, wherein said second gas comprises at least two fluorocarbons.
16. The method of claim 8, wherein said second gas comprises a perfluorocarbon.
17. The method of claim 8, wherein both said first gas and said second gas comprise fluorocarbons.
18. The method of claim 8, wherein said second gas is perfluorohexane.
19. The method of claim 8, 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.
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