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Details for Patent: 6,139,818

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Details for Patent: 6,139,818

Title: Method of making ultrasonic contrast agent
Abstract:Methods of making Ultrasonic contrast agents useful for echographic imaging body organs comprising a suspension of gas or air filled microballoons having a mean size in the range of 0.5 to 1000 microns bounded by a 50 to 500 nm thick biodegradable, interfacially deposited, synthetic polymer membrane which is both deformable and resilient are as described.
Inventor(s): Bichon; Daniel (Montpellier, FR), Bussat; Philippe (Collonges S/Saleve, FR), Schneider; Michel (Troinex, CH)
Assignee: Bracco International B.V. (Amsterdam, NL)
Filing Date:Aug 13, 1997
Application Number:08/910,149
Claims:1. A method of making ultrasonic contrast agent useful in ultrasonic imaging of human or animal patients comprising a suspension of gas filled microballoons, with a mean size in the range from a fraction of micron to 1,000 microns, in an aqueous carrier liquid, the method comprising the steps of:

(1) emulsifying a hydrophobic organic phase into a water phase so as to obtain droplets of said hydrophobic phase and an oil-in-water emulsion in said water phase;

(2) adding to said emulsion a solution of at least one polymer in a volatile solvent insoluble in the water phase, so that a layer of said polymer will form around said droplets;

(3) evaporating said volatile solvent so that the polymer will deposit by interfacial precipitation around the droplets which then form beads with a core of said hydrophobic phase encapsulated by a membrane of said polymer, said beads being in suspension in said water phase;

(4) subjecting said suspension to reduced pressure under conditions such that said encapsulated hydrophobic phase is removed by evaporation;

wherein said hydrophobic phase is selected so that it evaporates substantially simultaneously with the water phase and is replaced by a gas other than air, whereby dry, free flowing, readily dispersible microballoons with an envelope thickness ranging from 50-500 nm are obtained, and

(5) suspending the dry, free flowing, gas microballoons in an aqueous carrier liquid.

2. The method of claim 1, wherein said polymer is dissolved in said hydrophobic phase, so that steps (2) and (3) can be omitted and the polymer membrane will form by interfacial precipitation during step (4).

3. The method of claim 2, wherein the hydrophobic phase subjected to emulsification in said water phase also contains a water-soluble solvent which, upon being diluted into said water phase during emulsification, will aid in reducing the size of droplets and induce interfacial precipitation of the polymer before step (4) is carried out.

4. The method of claim 1, wherein evaporation of said hydrophobic phase in step (4) is performed at a temperature where the partial vapor pressure of said hydrophobic phase is of the same order as that of water vapor.

5. The method of claim 1, wherein said evaporation of step (4) is carried out under freeze-drying conditions.

6. The method of claim 5, wherein freeze-drying is effected at temperatures of from -40.degree. C., to 0.degree..

7. The method of claim 1, wherein the hydrophobic phase is selected from organic compounds having a vapor pressure of about 1 Torr at a temperature comprised in the interval of about -40.degree. C. to 0.degree. C.

8. The method of claim 1, wherein the aqueous phase comprises, dissolved, from about 1 to 20% by weight of stabilizers comprising hydrophilic compound selected from sugars, PVA, PVP, gelatin, starch, dextran, polydextrose, albumin and the like.

9. The method of claim 2, wherein additives of control the degree of permeability of the microballoons membrane are added to the hydrophobic phase, the rate of biodegradability of the polymer after injecting the microballoons into living organisms being a function of said degree of permeability.

10. The method of claim 9, wherein said additives include hydrophobic fats, waxes and high molecular weight hydrocarbons, the presence of which in the membrane polymer of the microballoons will reduce permeability toward aqueous liquids.

11. The method of claim 10, wherein said additives include amphipatic compounds the presence of which in the membrane polymer will increase permeability of the microballoons to aqueous liquids.

12. The method of claim 1, wherein the injectable aqueous suspension of microballoons contains 10.sup.6 -10.sup.10 vesicles/ml bounded by a membrane of an interfacially precipitated DL-lactide polymer.

13. The method of claim 1, wherein the gas in the microballoons is a fluorine containing gas.

14. The method of claim 13, wherein the fluorine containing gas is a freon.

15. The method of claim 11, wherein the amphipatic compound is a phospholipid or a low molecular weight polymer.

16. A method of making ultrasonic contrast agent useful in ultrasonic imaging of human or animal patients comprising a suspension of air filled microballoons, with a mean size in the range from a fraction of micron to 1,000 microns, in an aqueous carrier liquid, the method comprising the steps of:

(1) emulsifying a hydrophobic cyclohexane phase into a water phase so as to obtain droplets of said hydrophobic phase as an oil-in-water emulsion in said water phase;

(2) adding to said emulsion a solution comprising a polylactic-glycolic copolymer in tetrahydrofuran, so that a layer of said co-polymer will form around said droplets;

(3) evaporating said tetrahydrofuran so that the co-polymer will deposit by interfacial precipitation around the droplets which then form beads with a core of said hydrophobic phase encapsulated by a membrane of said co-polymer, said beads being in suspension in said water phase;

(4) subjecting said suspension to reduced pressure under conditions such that said encapsulated hydrophobic phase be removed by evaporation; wherein said hydrophobic phase is selected so that it evaporates substantially simultaneously with the water phase and is replaced by air whereby dry free flowing, readily dispersible microballoons with an envelope thickness ranging from 50-500 nm are obtained, and

(5) suspending the dry, free flowing, air or gas microballoons in an aqueous carrier liquid.
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