Details for Patent: 5,578,292

Title:	Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
Abstract:	One can impart outstanding resistance against collapse under pressure to gas-filled microvesicle 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.
Inventor(s):	Schneider; Michel (Troinex, CH), Yan; Feng (Geneva, CH), Grenier, deceased; Pascal (late of Ambilly, FR), Puginier; Jerome (Le Chable-Beaumont, FR), Barrau; Marie-Bernadette (Geneva, CH)
Assignee:	Bracco International B.V. (Amsterdam, NL)
Filing Date:	Jan 30, 1995
Application Number:	08/380,588
Claims:	1. A contrast agent for ultrasonic echography comprising, as a suspension in an aqueous liquid carrier phase, microvesicles filled with a gas or a gas mixture, wherein the gas mixture comprises at least one physiologically acceptable halogenated gas whose ratio of solubility in water, expressed in liters of gas by liter of water under standard conditions, to square root of the molecular weight, in daltons, is below 0.0027. 2. The contrast agent of claim 1, wherein the halogenated gas is selected from the group consisting of SF.sub.6, SeF.sub.6 and a freon. 3. The contrast agent of claim 2, wherein the freon is selected from the group consisting of CF.sub.4, CBrF.sub.3, C.sub.4 F.sub.8, CClF.sub.3, CCl.sub.2 F.sub.2, C.sub.2 F.sub.6, C.sub.2 ClF.sub.5, CBrClF.sub.2, C.sub.2 Cl.sub.2 F.sub.4, CBr.sub.2 F.sub.2 and C.sub.4 F.sub.10. 4. The contrast agent of claim 1 wherein the gas mixture contains a gas selected from the group consisting of nitrogen, carbon dioxide and air. 5. The contrast agent of claim 4, wherein the microvesicles are microbubbles bounded by an evanescent gas/liquid interfacial closed surface made from dissolved lameliar or laminar phospholipids. 6. The contrast agent of claim 5 wherein at least part of the phospholipids are in the form of liposomes. 7. The contrast agent of claim 6, wherein the liquid carrier phase further contains stabilizers. 8. The contrast agent of claim 5, wherein at least one of the phospholipids is a diacylphosphatidyl compound wherein the acyl group is a C.sub.16 fatty acid residue or a higher homologue thereof. 9. The contrast agent of claim 4, whereto the microvesicles are microballoons bounded by a material envelope made of an organic polymeric membrane. 10. The contrast agent of claim 9, wherein the polymers of the membrane are selected from polylactic or polyglycolic acid and their copolymers, reticulated serum albumin, reticulated haemoglobin, polystyrene, and esters of polyglutamic and polyaspaaic acids. 11. The contrast agent of claim 10, wherein the microvesicles are filled with SF.sub.6. 12. The contrast agent of claim 1, wherein the halogenated gas is selected from the group consisting of SeF.sub.6, CF.sub.4, CBrF.sub.3, C.sub.4 F.sub.8, CClF.sub.3, CCl.sub.2 F.sub.2, C.sub.2 F.sub.6, C.sub.2 ClF.sub.5, CBrClF.sub.2, C.sub.2 Cl.sub.2 F.sub.4, CBr.sub.2 F.sub.2 and C.sub.4 F.sub.10. 13. Contrast agent precursors consisting of a dry powder comprising lyophilized liposomes and stabilizers, the powder being dispersible in an aqueous liquid carrier to form echogenic suspensions of gas-filled microvesicles of claim 1, wherein said powder is stored under an atmosphere of a gas mixture comprising at least one physiologically acceptable halogenated gas whose ratio of solubility in water, expressed in liters of gas by liter of water under standard conditions, to square root of the molecular weight, in daltons, is below 0.0027. 14. The contrast agent precursors of claim 13, wherein the liposomes comprise phospholipids whose fatty acid residues have 16 or more carbon atms. 15. The contrast agent precursors of claim 13, wherein the halogenated gas is selected from the group consisting of SF.sub.6, SeF.sub.6 and a freon. 16. The contrast agent precursors of claim 15, wherein the freon is selected from the group consisting of CF.sub.4, CBrF.sub.3, C.sub.4 F.sub.8, CClF.sub.3, CCl.sub.2 F.sub.2, C.sub.2 F.sub.6, C.sub.2 ClF.sub.5, CBrClF.sub.2, C.sub.2 Cl.sub.2 F.sub.4, CBr.sub.2 F.sub.2 and C.sub.4 F.sub.10. 17. The contrast agent precursors of claim 13, wherein the mixture contains a gas selected frown the group consisting of nitrogen, carbon dioxide and air. 18. Contrast agent precursors consisting of a dry powder comprising lyophilized liposomes and stabilizers, the powder being dispersible in an aqueous liquid carrier to form echogenic suspensions of gas-filled microvesicles of claim 1, wherein said powder is stored under an atmosphere of a halogenated gas selected from the group consisting of SF.sub.6, SeF.sub.6, CF.sub.4, CBrF.sub.3, C.sub.4 F.sub.8, CClF.sub.3, CCl.sub.2 F.sub.2, C.sub.2 F.sub.6, C.sub.2 ClF.sub.5, CBrClF.sub.2, C.sub.2 Cl.sub.2 F.sub.4, CBr.sub.2 F.sub.2 and C.sub.4 F.sub.10. 19. A contrast agent for ultrasonic echography comprising, as a suspension in an aqueous liquid carrier phase, microvesicles filled with a gas or a gas mixture, wherein the gas or gas mixture in the microvesicles suspended in the aqueous carrier is such that under standard conditions and at a rate of pressure increase to the suspension of about 100 Torr/min the pressure difference .DELTA.P between pressures at which the microvesicles counts are about 75% and 25% of the original microvesicle count is at least 25 Torr. 20. The contrast agent of claim 19 wherein the gas is selected from the group consisting of SeF.sub.6, CF.sub.4, CBrF.sub.3, C.sub.4 F.sub.8, CClF.sub.3, CCl.sub.2 F.sub.2, C.sub.2 F.sub.6, C.sub.2 ClF.sub.5, CBrClF.sub.2, C.sub.2 Cl.sub.2 F.sub.4, CBr.sub.2 F.sub.2 and C.sub.4 F.sub.10.