|Title:|| Resilient deformable microballoons for echographic imaging|
|Abstract:||Air or gas filled microballoons bounded by an interfacially deposited polymer membrane which can be dispersed in aqueous carrier liquids to be injected into living organisms or administered orally, rectally and urethrally for therapeutic or diagnostic purposes (echography). The properties of the polymeric membrane of the microballoons (elasticity, permeability, biodegradability) can be controlled at will depending on the selected polymer, the interfacial deposition conditions, and the polymer additives.|
|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:||Sep 12, 1997|
|Claims:||1. Microballoons having a mean size in the range of a fraction of micron to 1000 microns bounded by a soft and elastic 50-500 nm thick polymer membrane filled with a freon, the membrane being temporarily deformable under pressure variations, the polymer membrane being synthetic, resilient and formed from an interfacially depositable polymer. |
2. Freon-filled microballoons comprising a soft and elastic interfacial 50-500 nm thick polymeric membrane, the membrane being temporarily deformable under pressure variations the microballoons being non-coalescent, dry and instantly dispersible in an aqueous carrier liquid.
3. The microballoons of claim 1 or 2, wherein the polymer membrane is porous and has porosity ranging from 50-2,000 nm.
4. The microballoons of claim 1 or 2 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 lactides and lactones, polypeptides, poly-(ortho)esters, polydioxanone, poly-b-aminoketones, polyphosphazenes, polyanhydrides and polyalkyl(cyano)acrylates.
5. The microballoons of claim 1 or 2 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.
6. The microballoons of claim 5, 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.
7. The microballoons of claims 1 or 2, wherein the membrane polymer contains additives to control the degree of elasticity, and the size and density of the pores for permeability control.
8. The microballoons of claim 7, wherein said additives include plasticizers, amphipatic substances and hydrophobic compounds.
9. The microballoons of claim 8, wherein the plasticizers include isopropyl myristate, glyceryl monostearate, the amphipatic substances include surfactants and phospholipids and the hydrophobic compounds include the paraffin-waxes.
10. The microballoons of claim 7, wherein the additives include polymers with molecular weight in the range of 1000 to 15,000 to control softness and resiliency of the microballoon membrane.
11. The microballoons of claim 10, wherein the polymer additives are selected from the group consisting of polylactides, polyglycolides, polyalkylene glycols, polyethylene glycol and polypropylene glycol, and polyols like polyglycerol.
12. The microballoons of claim 10, wherein the polymer additives are selected from the group consisting of polyethylene glycol, polypropylene glycol and polyglycerol.
13. The microballoons of claim 1 or 2, having size up to about 1000 .mu.m suitable for oral, rectal and urethral applications, wherein the membrane polymer is not biodegradable in the digestive tract and is impervious to biological liquids.
14. The microballoons of claim 13, wherein the polymer is selected from the group consisting of polyolefins, polyacrylates, polyacrylonitrile, non-hydrolyzable polyesters, polyurethanes and polyureas.
15. The microballoons according to claim 1 or 2, wherein the microballoons are present in an aqueous suspension in a concentration of about 10.sup.6 to 10.sup.10 microballoons/ml, said suspension being stable for at least thirty days.
16. A method of making a contrast agent for ultrasonic echography, said contrast agent comprising microballoons, the method comprising:
making microballoons comprising a polymer membrane wall and at least on physiologically acceptable fluorinated gas that is a freon in a dry state, and dispersing said microballoons in a physiologically acceptable aqueous carrier.
17. Dry microballoons which, upon dispersion in an aqueous medium, form an aqueous dispersion comprising microballoons, said microballoons comprising a polymer membrane wall and at least one physiologically acceptable gas that is a freon, wherein said microballoons, upon dispersion in an aqueous medium form an aqueous dispersion of said microballoons.