Mixed gas microbubble compositions

• US 6,372,195 B1
• Filed: 01/17/1997
• Issued: 04/16/2002
• Est. Priority Date: 07/30/1993
• Status: Expired due to Fees

• Current Assignee: Targeson, Inc.
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Anderson, Charles David, Kinner, Rene Alta, Evitts, David P., Schutt, Ernest G., Weers, Jeffry G.
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/786,402
• Time in Patent Office: 1,915 Days
• Field of Search: 424/9.51, 424/9.52, 128/662.02, 600/458, 600/441
• 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 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° 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; kits for preparing microbubbles; and methods for using such microbubbles as ultrasound contrast agents.

Claims

1. An injectable ultrasound contrast medium comprising:

(a) biocompatible at body temperature gaseous substances which, when in suspension in an aqueous carrier liquid containing surfactants, additives, and stabilizers, provide contrast agents for ultrasound echocardiography, wherein;

(b) the medium is a mixture which contains a modifier gas A and the balance of the mixture is an osmotic agent gas B;

(c) the ratio of gas A to gas B is 200;

1 to 3;

2 by volume; and

(d) gas B has a water solubility of not more than about 0.5 mM at 25°

C. and one atmosphere and an average molecular weight at least about 4 times that of gas A.

3. The ultrasound contrast medium of claim 1 wherein gas B is a fluorocarbon biocompatible gas.

4. The ultrasound contrast medium of claim 3 wherein the fluorocarbon biocompatible gas is selected from the group consisting of CF₄, C₃F₈, C₄F₈, C₄F₁₀, C₅F₁₀, C₅F₁₂, and mixtures thereof.

5. The ultrasound contrast medium of claim 4 wherein the fluorocarbon gas is octafluorocyclobutane.

2. An injectable ultrasound contrast medium comprising:

(a) biocompatible at body temperature gaseous substances which, when in suspension in an aqueous carrier liquid containing surfactants, additives, and stabilizers, provide contrast agents for ultrasound echocardiography, wherein;

(b) the medium is a mixture which contains a modifier gas A and the balance of the mixture is an osmotic agent gas B;

(c) the ratio of gas A to gas B is 738;

22 to 3;

2 by volume; and

(d) gas B is selected from the group consisting of fluorocarbons, CCl₂F₂, CHClF₂, N(C₂F₅)₃, N(C₃F₇)₃, and mixtures thereof.

6. The ultrasound contrast medium of claim 2 wherein gas A is selected from the group consisting of air, oxygen, nitrogen, carbon dioxide, and mixtures thereof.

7. An injectable ultrasound contrast agent comprising:

(a) a suspension of gas filled microbubbles or microballoons in a physiologically acceptable aqueous carrier comprising surfactants, additives, and stabilizers, wherein;

(b) the gas is a gas mixture containing a biocompatible gas A and the balance of the mixture is a biocompatible gas B;

(c) the ratio of gas A to gas B is 200;

1 to 3;

2 by volume; and

(d) gas B has a water solubility of not more than about 0.5 mM at 25°

C. and one atmosphere and an average molecular weight at least about 4 times that of gas A.

9. The ultrasound contrast agent of claim 7 wherein gas B is a fluorocarbon biocompatible gas.

10. The ultrasound contrast agent of claim 9 wherein the fluorocarbon biocompatible gas is selected from the group consisting of CF₄, C₃F₈, C₄F₈, C₄F₁₀, C₅F₁₀, C₅F₁₂, and mixtures thereof.

11. The ultrasound contrast agent of claim 9 wherein gas A is selected from the group consisting of air, oxygen, nitrogen, carbon dioxide, and mixtures thereof.

12. The ultrasound contrast agent of claim 10 wherein the surfactants comprise at least one film forming surfactant and, optionally, stabilizers.

13. The ultrasound contrast agent of claim 12 wherein the film forming surfactant is a phospholipid.

14. The ultrasound contrast agent of claim 7 wherein the surfactant is polyethylene oxide sorbitan fatty acid ester or sorbitol.

8. An injectable ultrasound contrast agent comprising:

(a) a suspension of gas filled microbubbles or microballoons in a physiologically acceptable aqueous carrier comprising surfactants, additives, and stabilizers, wherein;

(b) the gas is a gas mixture containing a biocompatible gas A and the balance of the mixture is a biocompatible gas B;

(c) the ratio of gas A to gas B is 738;

22 to 3;

2 by volume; and

(d) gas B is selected from the group consisting of fluorocarbons, CCl₂F₂, CHClF₂, N(C₂F₅)₃, N(C₃F₇)₃, and mixtures thereof.

15. A dry formulation comprising:

(a) surfactants, additives, and stabilizers stored under a mixture of substances which at body temperature are biocompatible gases, wherein;

(b) at least one of the biocompatible gases is a fluorine-containing gas having a water solubility of not more than about 0.5 mM at 25°

C. and one atmosphere and an average molecular weight at least about 4 times that of air, oxygen, nitrogen, carbon dioxide or mixtures thereof;

(c) the balance is air, oxygen, nitrogen, carbon dioxide, or mixtures thereof; and

(d) the ratio of said air, oxygen, nitrogen, carbon dioxide, or mixtures thereof to said fluorine-containing gas is 200;

1 to 3;

2 by volume.

16. A dry formulation comprising:

(a) surfactants, additives, and stabilizers stored under a mixture of substances which at body temperature are biocompatible gases, wherein;

(b) at least one of the biocompatible gases is a fluorocarbon gas;

(c) the balance is air, oxygen, nitrogen, carbon dioxide, or mixtures thereof; and

(d) the ratio of said air, oxygen, nitrogen, carbon dioxide, or mixtures thereof to said fluorine-containing gas is 738;

22 to 3;

2 by volume.

17. A two component kit comprising:

(a) as the first component, a dry formulation of surfactants, additives, and stabilizers stored under a mixture of substances which at body temperature are gases; and

,

(b) as the second component, a physiologically acceptable carrier liquid which, when admixed with the first component, provides, as a suspension of the two components, an ultrasound contrast agent, wherein;

(c) at least one of the gases in the mixture is a gas having a water solubility of not more than about 0.5 mM at 25°

C. and one atmosphere and an average molecular weight of at least about 4 times that of air, oxygen, nitrogen, carbon dioxide, or mixtures thereof;

(d) the balance is air, oxygen, nitrogen, carbon dioxide, or mixtures thereof; and

(e) the ratio of said air, oxygen, nitrogen, carbon dioxide, or mixtures thereof to said gas having a water solubility of not more than about 0.5 mM at 25°

C. and one atmosphere and an average molecular weight of at least about 4 times that of air, oxygen, nitrogen, carbon dioxide, or mixtures thereof is 200;

1 to 3;

2 by volume.

18. A two component kit comprising:

(a) as the first component, a dry formulation of surfactants, additives, and stabilizers stored under a mixture of substances which at body temperature are gases; and

,

(b) as the second component, a physiologically acceptable carrier liquid which, when admixed with the first component, provides, as a suspension of the two components, an ultrasound contrast agent wherein;

(c) at least one of the gases in the mixture is a fluorocarbon biocompatible gas;

(d) the balance is air, oxygen, nitrogen, carbon dioxide, or mixtures thereof; and

(e) the ratio of said air, oxygen, nitrogen, carbon dioxide, or mixtures thereof to said gas having a water solubility of not more than about 0.5 mM at 25 °

C. and one atmosphere and an average molecular weight of at least about 4 times that of air, oxygen, nitrogen, carbon dioxide, or mixtures thereof is 200;

1 to 3;

2 by volume.

19. The two component kit of claim 18 wherein the fluorocarbon biocompatible gas is selected from the group consisting of CF₄, C₃F₈, C₄F₈, C₄F₁₀, C₅F₁₀, C₅F₁₂, and mixtures thereof.

20. A method of imaging organs in a living body, said method comprising the steps of:

(1) administering to said body an ultrasound contrast agent comprising a suspension of gas filled microbubbles or microballoons in a physiologically acceptable aqueous carrier comprising surfactants, additives, and stabilizers, wherein;

(a) the gas is a gas mixture containing a biocompatible gas A and a biocompatible gas B;

(b) gas B has a water solubility of not more than about 0.5 mM at 25° and

one atmosphere and an average molecular weight at least about 4 times that of gas A, and

(c) the ratio of gas A to gas B is 200;

1 to 3;

2 by volume; and

(2) subjecting said body to ultrasound therapy.

26. The method of claim 20 wherein the surfactant is a polyethylene oxide sorbitan fatty acid ester or sorbitol.

21. A method of imaging organs in a living body, said method comprising the steps of:

(1) administering to said body an ultrasound contrast agent comprising a suspension of gas filled microbubbles or microballoons in a physiologically acceptable aqueous carrier comprising surfactants, additives, and stabilizers, wherein;

(a) the gas is a gas mixture containing a biocompatible gas A and a biocompatible gas B;

(b) gas B is a fluorocarbon; and

(c) the ratio of gas A to gas B is 738;

22 to 3;

2 by volume; and

(2) subjecting said body to ultrasound therapy.

22. The method of claim 21 wherein the flourocarbon biocompatible gas is selected from the group consisting of CF₄, C₃F₈, C₄F₈, C₄F₁₀, C₅F₁₀, C₅F₁₂, and mixtures thereof.

23. The method of claim 21 wherein gas A is selected from the group consisting of air, oxygen, nitrogen, carbon dioxide, and mixtures thereof.

24. The method of claim 21 wherein the surfactants comprise at least one film forming surfactant and, optionally, stabilizers.

25. The method of claim 24 wherein the film forming surfactant is a phospholipid.