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|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 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 (Meyrin/Geneva, CH)|
|Assignee:||Bracco International B.V. (Amsterdam, NL)|
|Filing Date:||Oct 12, 1993|
|Claims:||1. A method of making a suspension of air or gas filled microbubbles, said method comprising the steps of: |
selecting at least one film forming surfactant;
converting said surfactant into a powder;
contacting said powder with air or another gas;
admixing said powder surfactant with an aqueous liquid carrier to form a suspension of air or gas filled microbubbles;
introducing said suspension into a container;
forming a layer of said microbubbles in an upper part of said container;
separating said layer of microbubbles; and
washing said separated microbubbles with an aqueous solution saturated with the microbubble gas.
2. The method of claim 1, in which prior to converting said surfactant into a powder, said surfactant is at least partially lamellarized.
3. The method of claim 2, in which prior to contacting said powder with air or another gas, said at least partially lamellarized surfactant is admixed with said aqueous liquid carrier.
4. The method of claim 2, in which the liquid carrier further comprises a stabilizer compound selected from the group consisting of hydrosoluble proteins, polypeptides, sugars, poly-and oligo-saccharides and hydrophilic polymers.
5. The method of claim 2, in which said conversion of said surfactant into a powder is effected by coating said surfactant onto particles of soluble or insoluble materials, leaving the coated particles for a period of time under air or a gas and admixing the coated particles with an aqueous liquid carrier.
6. The method of claim 2, in which said conversion of said surfactant into a powder is effected by sonicating or homogenizing under high pressure an aqueous solution of film forming lipids, said sonication or homogenization leading, at least in part, to the formation of liposomes.
7. The method of claim 6, in which prior to contacting said at least partially lamellarized surfactant with air or another gas, said liposome containing solution is freeze-dried.
8. The method of claim 6, in which said aqueous solution of film forming liquids also comprises viscosity enhancers or stabilizers selected from the group consisting of hydrophilic polymers and carbohydrates in weight ratio relative to said lipids of between 10:1 and 1000:1.
9. A method of making an injectable suspension of gas-filled microbubbles in an aqueous carrier liquid, said method comprising the steps off
suspending laminarized phospholipids in an aqueous carrier liquid, said phospholipids having been in contact with said gas prior to or after suspending, under conditions such that a concentration of microbubbles is sufficient to provide an echographic response is formed in said suspension;
allowing a portion of said phospholipids to form a stabilization layer around said bubbles; and
thereafter depleting the aqueous carrier liquid of excess phospholipids not involved in microbubbles stabilization.
10. The method of claim 9, wherein other additives are present in said suspension of laminarized phospholipids.
11. The method of claim 9, wherein said suspension comprises at least 10.sup.7 microbubbles per milliliter and said stabilizers stabilize the microbubbles against collapse.
12. The method of claims 9, wherein the concentration of said phospholipids in aqueous carrier liquid is below 0.1% by weight while being equal to or above that of which the phospholipids molecules are present solely at the gas microbubble-liquid interface.