Ultrasonic imaging system utilizing a long-persistence contrast agent

• US 20040033199A1
• Filed: 08/19/2003
• Published: 02/19/2004
• Est. Priority Date: 07/30/1993
• Status: Active Grant

• Current Assignee: Targeson, Inc.
• Original Assignee: Charles David Anderson, David P. Evitts, Ernest G. Schutt
• Inventors: Schutt, Ernest G., Anderson, Charles David, Evitts, David P.
• Granted Patent: US 6,939,531 B2
• Time in Patent Office: Days
• US Class Current: 424/9.52
• 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 method of forming stabilized microbubbles for in vivo use, comprising the steps of:

providing 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 second gas is a gas at 37°

C. and 760 mm Hg with the proviso that said first gas and said second gas are not water vapor; and

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

2. The method of claim 1, wherein the membrane forming material comprises at least one surfactant.

3. The method of claim 1, wherein the membrane forming material comprises a protein.

4. The method of claim 1 wherein the first gas is a gas osmotic agent.

5. The method of claim 1 wherein the second gas is a modifier gas.

6. The method of claim 4 wherein the first gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

7. The method of claim 1 wherein the second gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide and mixtures thereof.

8. The method of claim 1 wherein the liquid is water.

9. The method of claim 1 wherein the microbubbles are osmotically stabilized after being injected in vivo.

10. The method of claim 3 wherein the protein is albumin.

11. The method of claim 1 wherein the gas is perfluorohexane and the modifier gas is nitrogen.

12. The method of claim 1 wherein the molar ratio of said first gas to said second gas is 1:

100 to 100;

1.

13. The method of claim 1 wherein the stabilized microbubble is used for diagnostic imaging.

14. A composition comprising stabilized microbubbles for in vivo use, 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 second gas is a gas at 37°

C. and 760 mm Hg with the proviso that said first gas and said second gas are not water vapor; and

said first gas and said second gas are surrounded with said membrane forming material to form stabilized microbubbles in said liquid.

15. The composition of claim 14 wherein the membrane forming material comprises at least one surfactant.

16. The method of claim 14 wherein the first gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.

17. The composition of claim 14 wherein the second gas is selected from the group consisting of nitrogen, oxygen, carbon dioxide, air and mixtures thereof.

18. The composition of claim 14 wherein the membrane forming material is albumin.

19. The composition of claim 14 wherein the gas is perfluorohexane and the modifier gas is nitrogen.

20. The composition of claim 14 wherein the gas is perfluoropropane and the modifier gas is air.