Details for Patent: 6,187,288

Title:	Stable microbubble suspensions as enhancement agents for ultrasonic echography
Abstract:	Disclosed are injectable suspensions of gas filled microbubbles in an aqueous carrier liquid usable as contrast agents in ultrasonic echography. The suspensions comprise amphipathic compounds of which at least one may be a laminarized phospholipid as a stabilizer of the microbubbles against collapse with time and pressure. The concentration of phospholipids in the carrier liquid is below 0.01% wt but is at least equal to or above that at which phospholipid molecules are present solely at the gas microbubble-liquid interface. Also disclosed is a method of preparation of the stable suspensions of air or gas filled microbubbles.
Inventor(s):	Schneider; Michel (Troinex, CH), Brochot; Jean (Feigeres, FR), Puginier; Jerome (Le Chable-Beaumont, FR), Yan; Feng (Geneva, CH)
Assignee:	Bracco International B.V. (Amsterdam, NL)
Filing Date:	Sep 11, 1998
Application Number:	09/151,651
Claims:	1. A stable suspension of gas-filled microbubbles in an aqueous carrier liquid, said gas-filled micobubbles being bounded by a gas/liquid interface comprising amphipathic compounds capable of stabilizing the microbubbles against collapse, the amphipathic compounds containing at least one saturated phospholipid whose concentration in the suspension is below 0.01% by weight but equal to or higher than the concentration at which the saturated phospholipid molecules are present solely at the gas/liquid interface, the suspension containing at least 10.sup.7 microbubbles per milliliter. 2. The stable suspension of claim 1, wherein the concentration of the phospholipid is between 0.001% and 0.009% by wt. 3. The stable suspension of claim 1, wherein the concentration of the phospholipid in the aqueous carrier is above 0.00013% wt. 4. The stable suspension of claim 1, wherein the liquid carrier further comprises at least one water soluble poly- and oligo-saccharides, sugars or hydrophilic polymers. 5. The stable suspension of claim 4, wherein the hydrophilic polymer is polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, glycolic acid or maltol. 6. The stable suspension of claim 1, wherein the phospholipid is at least partially in lamellar or laminar form. 7. The stable suspension of claim 1, wherein the phospholipid is selected from the group consisting of phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidyl-glycerol, phosphatidylinositol, cardiolipin and sphingomyelin. 8. The stable suspension of claim 6, wherein the amphipathic compounds further contain substances selected from phosphatidic acid, dicetylphosphate, cholesterol, ergosterol, phytosterol, sitosterol, lanosterol, tocopherol, propylgallate, ascorbylpalmitate and butylated hydroxy-toluene. 9. The stable suspension of claim 1, wherein the phospholipids are in the form of powders obtained by freeze-drying or spray-drying. 10. The stable suspension of claim 1, wherein the microbubble size is between 0.5-10 .mu.m. 11. The stable suspension of claim 1, wherein the suspension contains about 10.sup.8 to 10.sup.9 of microbubbles per milliliter showing little or no variation under storage. 12. The stable suspension of claim 1, wherein the suspension contains about 10.sup.9 to 10.sup.10 of microbubbles per milliliter showing little or no variation under storage. 13. The stable suspension of claim 1, wherein the liquid carrier further comprises up to 50% by weight non-laminar surfactants selected from fatty acids, esters and ethers of fatty acids and alcohols with polyols such as polyalkylene glycols, polyalkylenated sugars and other carbohydrates, and polyalkylenated glycerol. 14. The stable suspension of claim 1, wherein the saturated phospholipid forms a single monolayer around the gas microbubbles. 15. The stable suspension of claim 1, wherein the gas is physiologically acceptable fluorine containing gas. 16. The stable suspension of claim 1, wherein the microbubbles are filled with a freon. 17. The stable suspension of claim 1, wherein the microbubbles are filled with SF.sub.6. 18. The stable suspension of claim 1, wherein the microbubbles are filled with CF.sub.4. 19. The stable suspension of claim 1, wherein the microbubbles are filled with air. 20. The stable suspension of claim 1, wherein the microbubbles are filled with nitrogen. 21. The stable suspension of claim 1, wherein the microbubbles are filled with a noble gas.