Details for Patent: 6,200,548

Title:	Gas or air filled polymeric microballoons
Abstract:	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 resilsient. These microballoons are used for ultrasonic echographic imaging of body organs.
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:	08/910,152
Claims:	1. Microballoons, each formed of a synthetic, nonproteinaceous, elastic deformable, resilient and interfacially depositable polymer membrane having a thickness of less than 500 nm and a porosity in the range of 50 nm to 2000 nm, said microballoons being filled with air or a gas and having a mean size in the range of about 0.5 to 1000 microns. 2. Microballoons, each defined by a 50 nm to 500 nm thick synthetic, nonproteinaceous, elastic deformable, resilient and interfacially depositable polymer membrane with a porosity in the range of 50 nm to 2000 nm and filled with air or a gas and having a mean size in the range of about 0.5 to 1000 microns. 3. Microballoons of an elastic, deformable, resilient and interfacially depositable synthetic nonproteinaceous, polymer membrane, each microballoon membrane having a wall thickness of less than 500 nm and porosity in the range of 50 nm to 2000 nm, the microballoons being filled with air or a gas and having a mean size in the range of about 0.5 to 1000 microns. 4. Non-coalescent dry microballoons, each microballoon being an interfacial synthetic nonproteinaceous, polymeric membrane having a wall thickness of 50 nm to 500 nm and porosity in the range of 50 nm to 2000 nm, said microballoons being filled with air or a gas and being instantly dispersible in an aqueous liquid carrier. 5. Non-coalescent microballoons of interfacial synthetic nonproteinaceous, polymeric membranes, each membrane having a wall thickness of 50 nm to 500 nm and porosity in the range of 50 nm to 2000 nm, said microballoons and being dispersed within an aqueous liquid carrier. 6. Microballoons of micronic or submicronic size, each microballoon comprising a polymer membrane filled with air or a gas said microballoons being suitable, when in the form of suspensions in a liquid carrier, for administration to human or animal patients for therapeutic or diagnostic applications including echography imaging, each membrane polymer being a synthetic nonproteinaceous, deformable, resilient and interfacially depositable polymer. 7. Air or gas filled microballoons, each microballoon comprising an elastic, interfacial synthetic nonproteinaceous, polymer membrane, said microballoons forming, with a physiologically acceptable aqueous liquid carrier, stable aqueous suspensions capable of being taken orally, rectally and urethrally, or injectable into living organisms for therapeutic or diagnostic purposes, the microballoons being non-coalescent, dry and instantly dispersible in a liquid carrier. 8. An injectable aqueous suspension of microballoons comprising microballoons according to claim 1, 2, 3, 4, 5, 6 or 7 in combination with a physiologically acceptable carrier, said suspension comprising 10.sup.6 -10.sup.10 microballoons/ml and being stable for a period exceeding 30 day. 9. The suspension of claim 8 wherein the microballoons are bounded by a membrane of interfacially precipitated DL-lactide polymer. 10. The microballoons of claim 1 or 6 having size mostly in the 0.5-10 .mu.m range suitable for injection into the blood-stream of living beings in which the membrane is of predetermined permeability to bioactive liquids for achieving a respectively corresponding rate of biodegradation. 11. The microballoons of claim 10 in which the polymer membrane has porosity ranging from a few nanometers to more than a thousand nanometers. 12. The microballoons of claim 10 in which the membrane has a thickness of 50-500 nm, and resists pressure variations produced by heart beat pulsations in the blood-stream. 13. The microballoons of claim 1, 6 or 7 in which the polymer of the membrane is a biodegradable polymer selected from polysaccharides, polyamino-acids, polylactides and polyglycolides and their copolymers, copolymers of lactides and lactones, polypeptides, poly-(ortho)esters, polydioxanone, poly-.beta.-aminoketones, polyphosphazenes, polyanhydrides and polyalkyl-(cyano)acrylates. 14. The microballoons of claim 1, 6 or 7 wherein the membrane polymer is selected from polyglutamic or polyaspartic acid derivatives and their copolymers with other amino acids. 15. The microballoons of claim 14 wherein the polyglutamic and polyaspartic acid derivatives are selected from esters and amides involving the carboxylated side function thereof, said side functions having formulae or or 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. 16. The microballoons of claim 1, 6 or 7 wherein the membrane polymer contains additives to control the degree of elasticity, and the size and density of the pores for permeability control. 17. The microballoons of claim 16 wherein said additives include plasticizers, amphipatic substances and hydrophobic compounds. 18. The microballoons of claim 17 wherein the plasticizers include isopropyl myristate, glyceryl monostearate and the like to control flexibility, the amphipatic substances include surfactants and phospholipids like the lecithins to control permeability by increasing porosity and the hydrophobic compounds include high molecular weight hydrocarbon like the paraffin-waxes to reduce porosity. 19. The microballoons of claim 17 wherein the additives include polymers of molecular weight in the range of 1,000 to 15,000 to control softness and resiliency of the microballoon membrane. 20. The microballoons of claim 19 wherein the low molecular weight polymer additives are selected from polylactides, polyglycolides, polyalkylene glycols like polyethylene glycol and polypropylene glycol, and polyols like polyglycerol. 21. The microballoons of claim 1, 6 or 7 having size of about 0.5 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 impervious to biological liquids. 22. The microballoons of claim 21 wherein the polymer is selected from polyolefins, polyacrylates, polyacrylonitrile, non-hydrolyzable polyesters, polyurethanes and polyureas.