|Title:|| Stable microbubble suspensions as enhancement agents for ultrasound 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. (NL) |
|Filing Date:||Mar 31, 1995|
|Claims:||1. A method of preparation of a suspension of air or gas filled microbubbles comprising a film forming surfactant, a hydrophilic stabilizer and an aqueous liquid carrier, said method comprising the steps of: |
dissolving the film forming surfactant and the hydrophilic stabilizer in an organic solvent;
freeze drying the solution to form a dry powder;
contacting the powder with air or another gas; and
admixing said powder with the aqueous carrier.
2. The method of claim 1, in which the hydrophilic stabilizer is polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, glycolic acid, malic acid or maltol.
3. The method of claim 1, in which the organic solvent is tertiary butanol, 2-methyl-2-butanol or C.sub.2 Cl.sub.4 F.sub.2.
4. The method of claim 1, in which the powder is contacted with SF.sub.6, CF.sub.4 or freons.
5. The method of claim 1, in which the suspension of air or gas filled microbubbles comprises at least 10.sup.7 microbubbles per milliliter and amphipathic compounds at least one of which is a phospholipid stabilizer of the microbubbles against collapse, the concentration of the phospholipid in the carrier liquid being below 0.01% and above 0.00013% wt.
6. The method of claim 5, in which the phospholipid is selected from phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, cardiolipin and sphingomycelin.
7. The method of claim 5, in which the amphipatic compound includes substances affecting the properties of phospholipids selected from the group consisting of dicetylphosphate, cholesterol, ergosterol, phytosterol, sitosterol, lanosterol, tocopherol, propylgallate, ascorbyl palmitate and butylated hydroxytoluene.
8. The method of claim 5, in which the concentration of microbubbles per milliliter is between 10.sup.8 and 10.sup.10 microbubbles per ml.
9. The method of claim 5, in which the microbubble size is between 0.5-10 .mu.m showing little or no variation under storage.
10. The method of claim 5, in which the microbubbles are filled with SF.sub.6, CF.sub.4, freons or air.