|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 BV (NL) |
|Filing Date:||Sep 30, 1994|
|Claims:||1. A composition suitable for injection into the bloodstream and body cavities of living beings, said composition comprising a suspension of stabilized air or gas microbubbles in a physiologically acceptable aqueous carrier phase having from 0.01 to about 20% by weight of one or more dissolved or dispersed surfactants, at least one of said surfactants being a film-forming surfactant present in a composition at least partially in lamellar or laminar form, in which the surfactant comprises, bound thereto, bioactive species designed for specific targeting purposes. |
2. The composition of claim 1, comprising a liposome solution containing air or gas microbubbles developed therein.
3. The composition of claim 1, wherein the surfactant comprises, bound thereto, bioactive species designed for immobilizing the bubbles in specifically defined sites in the circuitry system, or in organs, or in tissues.
4. A method of imaging organs in a living body, said method comprising the steps of:
administering to said body a suspension prepared from a formulation which, upon dissolution in water, forms an aqueous suspension of microbubbles for ultrasonic echography and contains one or more film-forming surfactants in laminar form and hydrosoluble stabilizers; and
subjecting said body to ultrasonic echography.
5. A method according to claim 4, wherein said suspension is administered by injection.
6. A method according to claim 5, wherein 0.1 to 2 ml of the suspension contains 10.sup.8 -10.sup.9 microbubbles/ml, the microbubbles being in the size range from 1-5 .mu.m, is injected into a peripheral vein thereby providing opacification of the left heart under echographic measurements.
7. A method of transporting in the bloodstream or body cavities of a host bubbles of a foreign gas active therapeutically or diagnostically, said method comprising the step of adminisitering to said host a suspension of a formulation as defined in claim 4.
8. A method according to claim 7, wherein said composition is administered by injection.
9. A mixable combination suitable for generating a suspension of microbubbles for use in ultrasonic imaging, said combination comprising:
(a) a dry blend comprising one or more film-forming surfactants in at least partially lamellar or laminar form and capable of generating a suspension of microbubbles when brought into contact with an aqueous carrier phase; and
(b) an aqueous carrier phase mixable with said dry blend,
said dry blend and said aqueous carrier phase being mixable with each other to produce said suspension of microbubbles.
10. A combination according to claim 9, wherein said surfactants are phospholipids.
11. The combination according to claim 10, wherein said phospholipids are lecithins.
12. The combination of claim 10, wherein said phospholipids are selected from the group consisting of phosphatidic acid, phosphatidyl-choline, phosphatidyl-ethanolamine, phosphatidyl-serine, phosphatidyl-glycerol, phosphatidyl-inositol, cardiolipin and sphyngomyelin.
13. The combination according to claim 9, wherein said surfactants are in association with other substances affecting properties of liposomes, said other substances being selected from the group consisting of dicetyl-phosphate, cholesterol, ergosterol, phytosterol, sitosterol, lanosterol, tocopterol, propyl gallate, ascorbyl palmitate and butylated hydroxytoluene.
14. The combination according to claim 9, wherein said surfactants are in association with dissolved viscosity enhancers or stabilizers selected from the group consisting of linear and cross-linked poly- and oligo-saccharides, sugars, hydrophilic polymers and iodinated compounds in a weight ratio to said surfactants of between about 1:5 to 100:1.
15. The combination according to claim 14, wherein said viscosity enhancer is Iopamidol.
16. The combination according to claim 9, in which the surfactants comprise up to 50% by weight of non-laminar surfactants selected from the group consisting of fatty acids, esters and ethers of fatty acids and alcohols with polyols.
17. The combination according to claim 16, wherein said polyols are selected from the group consisting of polyalkylene glycols, polyalkylenated sugars and other carbohydrates, and polyalkylenated glycerol.
18. The combination according to claim 9, wherein said surfactants in laminar form are in the form of fine layers deposited on the surface of soluble or insoluble solid particulate material.
19. The combination according to claim 18, in which said insoluble solid particulate material is glass or polymer beads.
20. The combination according to claim 18, in which said soluble particulate material is made of hydrosoluble carbohydrates, polysaccharides, synthetic polymers, albumin, gelatin or Iopamidol.
21. The combination according to claim 9, which comprises freeze-dried liposomes.