|Title:||Stable microbubbles suspensions injectable into living organisms|
|Abstract:||Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase.|
|Inventor(s):||Schneider; Michel (Troinex, CH), Bichon; Daniel (Montpellier, FR), Bussat; Philippe (Collonges S/Saleve, FR), Puginier; Jerome (Le Chable-Beaumont, FR), Hybl-Sutherland; Eva (Wiesbaden, DE)|
|Assignee:||Bracco International B.V. (NL)|
|Filing Date:||Feb 11, 1998|
|Claims:||1. A method for the preparation of an aqueous suspension of gas-filled microbubbles stabilized by film forming surfactants including phospholipids, the method comprising the steps of: |
(a) selecting at least one saturated phosphilipid and converting it into lamellar form,
(b) admixing said phospholipid in lamellar form with an aqueous liquid carrier to obtain a dispersion of said phospholipid in said liquid,
(c) contacting the dispersion with a pressurized air or an adsorbable or entrappable gas for a time sufficient for that air or gas to become bound by said phospholipid, and
(d) releasing said air or gas pressure whereby a stable suspension of air or gas microbubbles in said liquid is formed.
2. The method of claim 1, wherein the liquid carrier contains dissolved hydrophilic stabilizer compounds.
3. The method of claim 1, wherein admixing is brought about by gentle mixing of the components whereby the air or gas bound to the lamellar phospholipid develops into a suspension of stable air or gas microbubbles.
4. The method of claim 1, wherein the lamellar phospholipid forms a mono- or pluri molecular layers thereby stabilizing the air or gas microbubbles.
5. The method of claim 2, wherein the hydrophilic stabilizer is a hydrosoluble protein.
6. The method of claim 5, wherein the hydrophilic stabilizer is a polypeptide.
7. The method of claim 2, wherein the hydrophilic stabilizer is a polyol.
8. The method of claim 7, wherein the hydrophilic stabilizer is a poly- or oligo-saccharide.
9. The method of claim 2, wherein the hydrophilic stabilizer is a hydrophilic polymer.
10. The method of claim 1, wherein the conversion step (a) is effected by coating the phospholipid onto particles of soluble or insoluble materials; step (b) is effected by admixing the coated particles with an aqueous liquid carrier.
11. The method of claim 1, wherein the conversion of step (a) is effected by sonicating or homogenizing under high pressure an aqueous solution of film forming lipids, this operation leading, at least partly, to the formation of liposomes.
12. The method of claim 11, wherein the water solution further contains film forming lipids and viscosity enhancers or stabilizers selected from hydrophilic polymers and carbohydrates in weight ratio relative to the lipids comprised between 1:5 and 100:1.