|Title:|| Stable microbubble suspensions comprising saturated phospholipios 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 stabiliser 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. (NL) |
|Filing Date:||Jun 26, 1997|
|Claims:||1. A method of ultrasonic imaging of an organ in a patient comprising: |
(a) injecting into the patient an aqueous suspension of gas filled microbubbles comprising at least 10.sup.7 microbubbles per milliliter and amphipatic compounds at least one of which is a saturated phospholipid stabilizer of the microbubbles, the concentration of the phospholipid in the suspension being below 0.01% by weight, and
(b) detecting contrast effect in the organ imaged.
2. The method of claim 1, wherein the concentration of microbubbles per milliliter is between 10.sup.8 and 10.sup.10.
3. The method of claim 1, wherein the concentration of phospholipids is below 0.01% but above 0.00013% wt.
4. The method of claim 1 wherein the liquid carrier further comprises water soluble poly- and oligo-saccharides, sugars and hydrophilic polymers.
5. The method of claim 4, wherein the hydrophilic polymer is polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, glycolic acid or maltol.
6. The method of claim 1, wherein the phospholipids are at least partially in lamellar or laminar form and are selected from the group consisting of phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol phosphatidylinositol, cardiolipin and sphingomyelin.
7. The method of claim 6, wherein the phospholipids further containing substances selected from phosphatidylglycerol, phosphatidic acid, dicetylphosphate, cholesterol, ergosterol, phytosterol, sitosterol, lanosterol, tocopherol, propylgallate, ascorbyl palmitate and butylated hydroxy-toluene.
8. The method of claim 1, wherein the phospholipids are in the form of powders obtained by freeze-drying or spray-drying.
9. The method of claim 1, wherein the suspension contains about 10.sup.8 and 10.sup.9 of microbubbles per milliliter with the microbubble size between 0.5-10 .mu.m showing little or no variation under storage.
10. The method 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.
11. The method of claim 1, wherein the microbubbles are filled with SF.sub.6.
12. The method of claim 1, wherein the microbubbles are filled with CF.sub.4.
13. The method of claim 1, wherein the microbubbles are filled with freons.
14. The method of claim 1, wherein the microbubbles are filled with air.
15. The method of claim 1, wherein the organ is the heart.
16. The method of claim 1, wherein the phospholipid molecules are present solely at the gas microbubble-liquid interface.