|Title:|| Method of making polymeric gas or air filled microballoons for ultrasonic echography|
|Abstract:||Method of making 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 deformable and resilient for use in ultrasonic contrast compositions are described.|
|Inventor(s):|| Bichon; Daniel (Montpellier, FR), Bussat; Philippe (Collonges S/Saleve, FR), Schneider; Michel (Troinex, CH) |
|Assignee:|| Bracco International B.V. (NL) |
|Filing Date:||Aug 10, 1994|
|Claims:||1. A method of making air or gas filled microballoons suitable for administration to human or animal patients for ultrasonic echography, said method comprising the successive steps of: |
(a) emulsifying a hydrophobic organic phase into a water phase so as to obtain droplets of said hydrophobic phase as an oil-in-water emulsion in said water phase;
(b) adding to said emulsion a solution of at least one polymer in a volatile solvent insoluble in the water phase, so that said polymer forms a layer around said droplets;
(c) evaporating said volatile solvent so that the polymer deposits 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; and
(d) removing said encapsulated hydrophobic phase by evaporation by subjecting said suspension to reduced pressure;
wherein said hydrophobic phase is selected so that in step (d) it evaporates substantially simultaneously with said water phase and is replaced by air or gas, whereby dry, free flowing, readily dispersible microballoons having an elastic polymeric membrane 50 to 500 nm thick and having a mean size in the range of 0.5 to 1000 microns are produced.
2. A method as in claim 1 wherein evaporation of said hydrophobic phase in step (d) is performed at a temperature where the partial vapor pressure of said hydrophobic phase is of the same order as that of water vapor.
3. A method as in claim 1 wherein said hydrophobic phase is evaporated by freeze-drying.
4. A method as in claim 3 wherein said freeze-drying is effected at temperatures of from -40.degree. C. to 0.degree. C.
5. A method of making air or gas filled microballoons for ultrasonic echography by:
(a) dissolving an interfacial wall forming polymer in a hydrophobic organic phase;
(b) emulsifying said polymer containing hydrophobic organic phase into a water phase so as to obtain droplets of said hydrophobic base as an oil-in-water emulsion in the water phase;
(e) removing said hydrophobic phase by evaporation under reduced pressure;
(d) forming the interfacial wall polymer membrane around the droplets by said evaporation, said hydrophobic phase being selected such that it evaporates substantially simultaneously with said water phase and is replaced by air or gas; and
(e) producing dry, free-flowing, readily dispersible, resilient air or gas-filled microballoons having an elastic 50-500 nm thick polymeric membrane and a mean size in the range from 0.5 to 1,000 microns.
6. A method as in claim 1 or 5 wherein the hydrophobic phase is an organic compound having a vapor pressure of about 133.3 Nt/m.sup.2 (1 Torr) at a temperature in the range of about -40.degree. C. to 0.degree. C.
7. A method as in claim 1 or 5 wherein the aqueous phase comprises, dissolved, from about 1% to 20% by weight of a hydrophilic stabilizer selected from the group consisting of sugars, polyvinyl alcohol, polyvinyl pyrolidone, gelatin, starch dextran, polydextrose and albumin.
8. A method as in claim 5 wherein the polymer solution comprises a plasticizer and an additive added to the hydrophobic phase, wherein the plasticizer is selected from the group consisting of isopropyl myristate and glyceryl monostearate and the additive is selected from the group consisting of surfactants, phospholipids and paraffin waxes.
9. A method as in claim 8 wherein the additives are selected from the group consisting of polylactides, polyglycolides, polyalkylene glycols and polyols.
10. A method as in claim 1 or 5 wherein the polymer membrane is porous and has porosity ranging from 0.5 to 2000 nanometers.
11. A method as in claim 1 or 5 wherein the membrane is biodegradable and the polymer selected from the group consisting of polysaccharides, polyamino-acids, polylactides and polyglycolides and their copolymers, copolymers of factides and lactones, polypeptides, poly-(ortho)esters, polydioxanone, poly-.beta.-aminoketones, polyphosphazenes, polyanhydrides and polyalkyl(cyano)acrylates.
12. A method as in claim 1 or 5 wherein the membrane polymer is selected from the group consisting of polyglutamic acid esters or amides or polyaspartic acid esters and amides and their copolymers with amino acids.
13. A method as in claim 12 wherein the polyglutamic and polyaspartic acid esters and amides have side functions having formulae
wherein R is an alkyl or aryl substituent; R.sup.1 and R.sup.2 are H or lower alkyls, or R and R.sup.1 are connected together by a substituted or unsubstituted linking member to form a 5- or 6-membered ring; n is 1 or 2; p is 1, 2 or 3; m is an integer from 1 to 5 and X is a side chain of an amino acid residue.
14. A method as in claim 1 or 5 wherein the membrane polymer is non-biodegradable and is selected from the group consisting of polyolefins, polyacrylates, polyacrylonitrile, non-hydrolyzable polyesters, polyurethanes and polyureas.
15. A method of making injectable aqueous suspension of microballoons by suspending microballoons prepared according to claim 1 or 5 in a physiologically acceptable carrier comprising 10.sup.6 -10.sup.10 microballoons/ml.
16. A method as in claim 15 wherein the microballoons are bounded by a membrane of interfacially precipitated DL-lactide polymer.