Ultrasound contrast agents and methods of making and using them

• US 20030175211A1
• Filed: 03/12/2003
• Published: 09/18/2003
• Est. Priority Date: 05/03/1991
• Status: Active Grant

• Current Assignee: Bracco International B.V. (Bracco SPA)
• Original Assignee: Bracco International B.V. (Bracco SPA)
• Inventors: Yan, Feng, Schneider, Michel, Bussat, Philippe, Grenier, Pascal, Bichon, Daniel, Puginier, Jerome, Garcel, Nadine, Hybl, Eva, Barrau, Marie-Bernadette
• Granted Patent: US 7,083,778 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

Abstract

Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain surfactants and, optionally, hydrophilic stabilizers. The surfactants can be in the form of liposomes. The suspensions are obtained by exposing the surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003. Contrast agents with particular mixtures of gases are also disclosed that have advantageous properties.

Claims

1. An ultrasound contrast agent comprising an aqueous solution and phospholipid stabilized microbubbles, the phospholipid comprising saturated phospholipid, and the phospholipid stabilized microbubbles containing gas comprising a halogenated hydrocarbon.

2. The ultrasound contrast agent of claim 1 wherein the saturated phospholipid comprises at least dipalmitoylphosphatidylcholine and dipalmitoylphosphatidic acid.

3. The ultrasound contrast agent of claim 1 wherein the halogenated hydrocarbon is a freon.

4. The ultrasound contrast agent of claim 1 wherein the halogenated hydrocarbon is C₃F₈.

5. The ultrasound contrast agent of claim 1 wherein the gas further comprises nitrogen.

6. The ultrasound contrast agent of claim 1 wherein the gas further comprises air.

10. A method of preparing the ultrasound contrast agent of claim 1 comprising,

forming the stabilized microbubbles in aqueous solution in the presence of the gas.

14. A method of ultrasound imaging using the ultrasound contrast agent of claim 1 comprising,

administering the ultrasound contrast agent to a subject, and

imaging the subject.

7. An ultrasound contrast agent comprising an aqueous solution and phospholipid stabilized microbubbles, the phospholipid comprising at least dipalmitoylphosphatidylcholine and dipalmitoylphosphatidic acid, and the microbubbles containing gas comprising C₃F₈.

11. A method of preparing the ultrasound contrast agent of claim 7 comprising,

forming the stabilized microbubbles in aqueous solution in the presence of the gas.

15. A method of ultrasound imaging using the ultrasound contrast agent of claim 7 comprising,

administering the ultrasound contrast agent to a subject, and

imaging the subject.

8. An ultrasound contrast agent comprising an aqueous solution and phospholipid stabilized microbubbles, the phospholipid comprising at least dipalmitoylphosphatidylcholine and dipalmitoylphosphatidic acid, and the microbubbles containing gas comprising C₃F₈ and nitrogen.

12. A method of preparing the ultrasound contrast agent of claim 8 comprising,

forming the stabilized microbubbles in aqueous solution in the presence of the gas.

16. A method of ultrasound imaging using the ultrasound contrast agent of claim 8 comprising,

administering the ultrasound contrast agent to a subject, and

imaging the subject.

9. An ultrasound contrast agent comprising an aqueous solution and phospholipid stabilized microbubbles, the phospholipid comprising at least dipalmitoylphosphatidylcholine and dipalmitoylphosphatidic acid, and the microbubbles containing gas comprising C₃F₈ and air.

13. A method of preparing the ultrasound contrast agent of claim 9 comprising,

forming the stabilized microbubbles in aqueous solution in the presence of the gas.

17. A method of ultrasound imaging using the ultrasound contrast agent of claim 9 comprising,

administering the ultrasound contrast agent to a subject, and

imaging the subject.