Patent EP0458745B1 successfully refreshed from Google Patents.
EP0458745B1
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EP
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Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography
Assignee: Bracco International BV
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Filing: 1991-05-14
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Granted: 1994-09-28
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Expires: 2011-05-14
Abstract
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.
Inventors
- 👤 Daniel Bichon
- 👤 Philippe Bussat
- 👤 Michel Schneider
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 14:33
CPC Classifications
A; A61; A61K; A61K49/00; A61K49/22; A61K49/222; A61K49/223; A61B; A61B8/00
Claims Analysis
Total Claims: 33
Claim 1
Independent Claim
59 words
Microballoons of micronic or submicronic size 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, characterised in that the membrane polymer is synthetic, deformable, resilient and interfacially depositable polymer.
Claim 2
Dependent Claim
59 words
Microballoons of micronic or submicronic size 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, characterised in that the membrane polymer is synthetic, deformable, resilient and interfacially depositable polymer.
Claim 3
Dependent Claim
55 words
Air or gas filled microballoons comprising an elastic, interfacial synthetic 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 said liquid carrier.
Claim 4
Dependent Claim
55 words
Air or gas filled microballoons comprising an elastic, interfacial synthetic 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 said liquid carrier.
Claim 5
Dependent Claim
42 words
The microballoons of claim 1, having size mostly in the 0.5 - 10 /1.m range suitable for injection into the blood-stream of living beings in which the membrane is either impervious or permeable to bioactive liquids for increasing the rate of biodegradation.
Claim 6
Dependent Claim
28 words
The microballoons of claim 3, in which the polymer membrane is porous and has porosity ranging from a few nanometers to several thousands of nanometers, preferably 50-2,000 nm.
Claim 7
Dependent Claim
29 words
The microballoons of claim 3, in which the membrane is elastic, has a thickness of 50-500 nm, and resists pressure variations produced by heart beat pulsations in the blood-stream.
Claim 8
Dependent Claim
42 words
The microballoons of claims 1 or 2, 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- ,8-aminoketones, polyphosphazenes, polyanhydrides and polyalkyl-(cyano)acrylates.
Claim 9
Dependent Claim
25 words
The microballoons of claims 1 or 2, wherein the membrane polymer is selected from polyglutamic or polyaspartic acid derivatives and their copolymers with other amino-acids.
Claim 10
Dependent Claim
102 words
The microballoons of claim 7, 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 1 and R 2 are H or lower alkyls, or R and R 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 aminoacid residue.
Claim 11
Dependent Claim
30 words
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.
Claim 12
Dependent Claim
15 words
The microballoons of claim 9, wherein said additives include plasticizers. amphipatic substances and hydrophobic compounds.
Claim 13
Dependent Claim
51 words
The microballoons of claim 10, 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.
Claim 14
Dependent Claim
29 words
The microballoons of claim 10, 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.
Claim 15
Dependent Claim
29 words
The microballoons of claim 12, wherein the low molecular weight polymer additives are selected from polylactides, polyglycolides, polyalkylene glycols like polyethylene glycol and polypropylene glycol, and polyols like polyglycerol.
Claim 16
Dependent Claim
37 words
The microballoons of claims 1 or 2, having size up to about 1000 /1.m suitable for oral, rectal and urethral applications, wherein the membrane polymer is not biodegradable in the digestive tract and impervious to biological liquids.
Claim 17
Dependent Claim
19 words
The microballoons of claim 14, wherein the polymer is selected from polyolefins, polyacrylates, polyacrylonitrile, non-hydrolyzable polyesters, polyurethanes and polyureas.
Claim 18
Dependent Claim
39 words
An injectable aqueous suspension of microballoons according to claims 1 - 15, characterized in that the microballoons are present in a concentration of about 10 6 to 10 10 microballoons/ml, said suspension being stable for at least thirty days.
Claim 19
Dependent Claim
27 words
The injectable aqueous suspension of claim 16, wherein the microballoons are bounded by a membrane of interfacially precipitated DL-lactide polymer defined by the commercial name of Resomer.
Claim 20
Independent Claim
190 words
A method for making air or gas filled microballoons usable as suspensions in a carrier liquid for oral, rectal and urethral applications, or for injections into living organisms, this method characterized by the steps of: (1) 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; (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 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 or gas, whereby dry, free flowing, readily dispersible microballoons are obtained.
Claim 21
Independent Claim
190 words
A method for making air or gas filled microballoons usable as suspensions in a carrier liquid for oral, rectal and urethral applications, or for injections into living organisms, this method characterized by the steps of: (1) 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; (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 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 or gas, whereby dry, free flowing, readily dispersible microballoons are obtained.
Claim 22
Dependent Claim
35 words
The method of claim 18, 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).
Claim 23
Dependent Claim
38 words
The method of claim 18, wherein evaporation of said hydrophobic phase in step (4) is performed at a temperature where the partial vapour pressure of said hydrophobic phase is of the same order as that of water vapour.
Claim 24
Dependent Claim
17 words
The method of claim 18 wherein said evaporation of step (4) is carried out under freeze-drying conditions.
Claim 25
Dependent Claim
19 words
The method of claim 21, wherein freeze-drying is effected at temperatures of from -40 °C to 0 ° C.
Claim 26
Independent Claim
43 words
The method of claims 18 or 20, wherein the hydrophobic phase is selected from organic compounds having a vapour pressure of about 133.3 Nt/m 2 (1 Torr) at a temperature comprised in the interval of about -40 ° C to 0 ° C.
Claim 27
Independent Claim
38 words
The method of claims 18 or 19, 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.
Claim 28
Dependent Claim
45 words
The method of claim 19, wherein additives to 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.
Claim 29
Dependent Claim
37 words
The method of claim 25, wherein the said additives include hydrophobic solids like fats, waxes and high molecular weight hydrocarbons, the presence of which in the membrane polymer of the microballoons will reduce permeability toward aqueous liquids.
Claim 30
Dependent Claim
37 words
The method of claim 25, wherein the said additives include amphipatic compounds like the phospholipids, or low molecular weight polymers, the presence of which in the membrane polymer will increase permeability of the microballoons to aqueous liquids.
Claim 31
Dependent Claim
53 words
The method of claim 19, 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 emulsiflcation, will aid in reducing the size of droplets and induce inter- facial precipitation of the polymer before step (4) is carried out.
Claim 32
Dependent Claim
15 words
Use of microballoons of claims 1-15 for ultrasonic echography imaging of human or animal body.
Claim 33
Dependent Claim
12 words
Use of microballoons of claims 1-15 for ultrasonic echography imaging of liver.
References Cited (Backward Citations)
No citation records indexed.
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