Details for Patent: 5,556,610

Title:	Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method
Abstract:	The invention relates to injectable media for ultrasonic echography in the form of microbubbles or microballoons comprising at least two biocompatible substances A and B (gaseous at the body temperature) forming a mixture which when in suspension with usual surfactants, additives and stabilisers provides useful ultrasound contrast agents. At least one of the components (B) in the mixture is a gas whose molecular weight is greater than 80 daltons and whose solubility in water is below 0.0283 ml per ml of water at standard conditions. The presence of the first component (B) in the contrast medium may vary between 0.15 and 41 volume percent. The other component (A) of the ultrasound contrast media is a gas or a mixture of gases whose molecular weight is below 80 daltons. The second component is present in a proportion of between 59-99.5% by vol., and is preferably chosen from oxygen, air, nitrogen, carbon dioxide or mixtures thereof. Gas mixtures described are found to be very effective as ultrasound contrast media. The invention also comprises a method of making the ultrasound contrast medium, the contrast agent and the ultrasound agent kit.
Inventor(s):	Yan; Feng (Carouge, CH), Schneider; Michel (Troinex, CH), Brochot; Jean (Feigeres, FR)
Assignee:	Bracco Research S.A. (CH)
Filing Date:	Nov 30, 1994
Application Number:	08/352,108
Claims:	1. An injectable ultrasound contrast medium comprising biocompatible at body temperature gaseous substances which when in suspension in an aqueous carrier liquid containing usual surfactants, additives and stabilisers provide contrast agents for ultrasound echography, wherein the medium is a mixture of gases (A) and (B) in which, at least one of the gases (B), present in an amount of between 0.5-41% by vol., has a molecular weight greater than 80 daltons and its solubility in water is below 0.0283 ml of gas per ml of water measured under standard conditions, the balance of the mixture being gas A. 2. The ultrasound contrast medium of claim 1, wherein gas (B) is a fluorine-containing biocompatible gas. 3. The ultrasound contrast medium of claim 2, wherein the fluorine-containing gas is selected from the group consisting of SF.sub.6, CF.sub.4, C.sub.2 F.sub.6, C.sub.2 F.sub.8, C.sub.3 F.sub.6, C.sub.3 F.sub.8, C.sub.4 F.sub.6, C.sub.4 F.sub.8, C.sub.4 F.sub.10, C.sub.5 F.sub.10, C.sub.5 F.sub.12 and mixtures thereof. 4. The ultrasound contrast medium of claim 3, wherein the fluorine-containing gas is sulfur hexafluoride or octafluoro cyclobutane. 5. The ultrasound contrast medium of claim 1, wherein gas A is selected from the group consisting of air, oxygen, nitrogen, carbon dioxide and mixtures thereof. 6. An injectable ultrasound contrast agent comprising of a suspension of gas filled microbubbles or microballoons in a physiologically acceptable aqueous carrier comprising usual surfactants, additives and stabilisers, wherein the gas is a gas mixture of at least two biocompatible gases A and B in which at least one gas (B) present in an amount of between 0.5-41% by vol. has a molecular weight greater than 80 daltons and solubility in water below 0.0283 ml per ml of water at standard conditions, the balance of the mixture being gas A. 7. The ultrasound contrast agent of claim 6, wherein gas (B) is a fluorine-containing biocompatible gas. 8. The ultrasound contrast agent of claim 7, wherein the fluorine-containing gas is selected from the group consisting of SF.sub.6, CF.sub.4, C.sub.2 F.sub.6, C.sub.2 F.sub.8, C.sub.3 F.sub.6, C.sub.3 F.sub.8, C.sub.4 F.sub.6, C.sub.4 F.sub.8, C.sub.4 F.sub.10, C.sub.5 F.sub.10, C.sub.5 F.sub.12 and mixtures thereof. 9. The ultrasound contrast agent of claim 6, wherein gas A is selected from the group consisting of air, oxygen, nitrogen, carbon dioxide or mixtures thereof. 10. The ultrasound contrast agent of claim 6, wherein the surfactants comprise at least one film forming surfactant present in laminar and/or lamellar form and, optionally, hydrophilic stabilizers. 11. The ultrasound contrast agent of claim 10, wherein the film forming surfactant is a phospholipid. 12. The ultrasound contrast agent of claim 11, wherein the phospholipid is selected from the group consisting of phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, cardiolipin, sphingomyelin and mixtures thereof. 13. The ultrasound contrast agent of claim 11, wherein in addition to the phospholipid the aqueous carrier comprises copolymers of polyoxyethylene and polyoxypropylene, and glycerol. 14. The ultrasound contrast agent of claim 6, wherein the surfactants are soy bean oil, a polyethylene oxide sorbitan ester, or sorbitol. 15. A dry formulation comprising surfactants, additives and stabilisers stored under a mixture of substances which at the body temperature are biocompatible gases, at least one of which is a fluorine-containing gas whose molecular weight is greater than 80 daltons, and whose solubility in water is below 0.0283 ml per ml of water at standard conditions, the fluorine-containing gas being present in the mixture in an amount between 0.5-41% by vol., the balance 59-99.5% by vol. being air, oxygen, nitrogen, carbon dioxide or mixtures thereof. 16. A two component kit comprising, as the first component, a dry formulation of surfactants, additives and stabilisers stored under a mixture of substances which at body temperature are gases and, 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, in which at least one of the gases in the mixture is a fluorine-containing biocompatible gas whose molecular weight is greater than 80 daltons and whose solubility in water is below 0.0283 ml of gas per ml of water at standard conditions, wherein the gas is fluorine-containing biocompatible gas and is present in the mixture in an amount of between 0.5-41% by vol., the balance being air, oxygen, nitrogen, carbon dioxide or mixtures thereof. 17. The two component kit of claim 16, wherein the fluorine-containing gas is selected from the group consisting of SF.sub.6, CF.sub.4, C.sub.2 F.sub.6, C.sub.2 F.sub.8, C.sub.3 F.sub.6, C.sub.3 F.sub.8, C.sub.4 F.sub.6, C.sub.4 F.sub.8, C.sub.4 F.sub.10, C.sub.5 F.sub.10, C.sub.5 F.sub.12 and mixtures thereof. 18. 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 of a suspension of gas filled microbubbles or microballoons in a physiologically acceptable aqueous carrier comprising surfactants, additives and stabilizers, wherein the gas is a gas mixture of at least two biocompatible gases A and B in which at least one gas (B) present in an amount of between 0.5-41% by vol. has a molecular weight greater than 80 daltons and solubility in water below 0.0283 ml per ml of water at standard conditions, the balance of the mixture being gas A; and (2) subjecting said body to ultrasound therapy. 19. The method of claim 18, wherein gas (B) is a fluorine-containing biocompatible gas. 20. The method of claim 19, wherein the fluorine-containing gas is selected from the group consisting of SF.sub.6, CF.sub.4, C.sub.2 F.sub.6, C.sub.2 F.sub.8, C.sub.3 F.sub.6, C.sub.3 F.sub.8, C.sub.4 F.sub.6, C.sub.4 F.sub.8, C.sub.4 F.sub.10, C.sub.5 F.sub.10, C.sub.5 F.sub.12 and mixtures thereof. 21. The method of claim 18 wherein gas A is selected from the group consisting of air, oxygen, nitrogen, carbon dioxide and mixtures thereof. 22. The method of claim 18, wherein the surfactants comprise at least one film forming surfactant present in laminar or lamellar form and, optionally, hydrophilic stabilizers. 23. The method of claim 22, wherein the film forming surfactant is a phospholipid. 24. The method of claim 23, wherein the phospholipid is selected from the group consisting of phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, cardiolipin, sphingomyelin and mixtures thereof. 25. The method of claim 23, wherein in addition to the phospholipid the aqueous carrier comprises copolymers of polyoxyethylene and polyoxypropylene, and glycerol. 26. The method of claim 18, wherein the surfactants are soy bean oil, a polyethylene oxide sorbitan ester, or sorbitol.