Patent EP0467031A2 successfully refreshed from Google Patents.
EP0467031A2
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EP
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Medical-grade lipid-coated microbubbles, paramagnetic labelling thereof and their therapeutic use
Assignee: Cavitation-Control Technology Inc
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Filing: 1991-05-13
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Granted: —
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Expires: 2011-05-13
Abstract
Abstract This invention relates to a large scale method for the production of medical grade lipid-coated microbubbles, to the paramagnetic labeling of such microbubbles and to therapeutic applications for the microbubbles. More particularly, the invention relates to a method of the production of medical grade, concentrated suspensions of stable, paramagnetically derivatized or underivatized microbubbles useful for ultrasonic and magnetic resonance imaging and also relates to therapeutic interventions such as selective tumor destruction. <IMAGE>
Inventors
- 👤 Joseph S. D'arrigo
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-24 23:23
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/48; A61K9/50; A61K9/5005; A61K9/5015; A61K41/00; A61K41/0047; A61K49/00; A61K49/06; A61K49/18; A61K49/1806; A61K49/1815; A61K49/22; A61K49/222; A61K49/223; Y; Y10; Y10T; Y10T436/00; Y10T436/24
Claims Analysis
Total Claims: 23
Claim 1
Independent Claim
239 words
A method of preparing medical-grade lipid-coated microbubbles comprising the steps of: A. forming at least a substantially saturated saline solution of a surfactant mixture comprising: (a) a member selected from the group consisting of glycerol monoesters of saturated carboxylic acids containing from about 10 to about 18 carbon atoms and aliphatic alcohols containing from about 10 to about 18 carbon atoms; (b) a sterol-aromatic acid ester; (c) a member selected from the group consisting of sterols, terpenes, bile acids and alkali metal salts of bile acids; (d) a member selected from the group consisting of sterol esters of aliphatic acids containing from one to about 18 carbon atoms; sterol esters of sugar acids; esters of sugar acids and aliphatic alcohols containing from about 10 to about 18 carbon atoms, esters of sugars and aliphatic acids containing from about 10 to about 18 carbon atoms; sugar acids; saponins; and sapogenins; and (e) a member selected from the group consisting of glycerol, glycerol di or triesters of aliphatic acids containing from about 10 to about 18 carbon atoms and aliphatic alcohols containing from about 10 to about 18 carbon atoms; B. shaking said solution mechanically for from about 2 to about 10 seconds in a gaseous atmosphere at room temperature, thereby forming a concentrated gas-in-liquid emulsion; and C. passing the thus obtained solution through a sterile polysulfone membrane filter having an average pore diameter of about .40 to about 6.0 /1.m.
Claim 2
Independent Claim
239 words
A method of preparing medical-grade lipid-coated microbubbles comprising the steps of: A. forming at least a substantially saturated saline solution of a surfactant mixture comprising: (a) a member selected from the group consisting of glycerol monoesters of saturated carboxylic acids containing from about 10 to about 18 carbon atoms and aliphatic alcohols containing from about 10 to about 18 carbon atoms; (b) a sterol-aromatic acid ester; (c) a member selected from the group consisting of sterols, terpenes, bile acids and alkali metal salts of bile acids; (d) a member selected from the group consisting of sterol esters of aliphatic acids containing from one to about 18 carbon atoms; sterol esters of sugar acids; esters of sugar acids and aliphatic alcohols containing from about 10 to about 18 carbon atoms, esters of sugars and aliphatic acids containing from about 10 to about 18 carbon atoms; sugar acids; saponins; and sapogenins; and (e) a member selected from the group consisting of glycerol, glycerol di or triesters of aliphatic acids containing from about 10 to about 18 carbon atoms and aliphatic alcohols containing from about 10 to about 18 carbon atoms; B. shaking said solution mechanically for from about 2 to about 10 seconds in a gaseous atmosphere at room temperature, thereby forming a concentrated gas-in-liquid emulsion; and C. passing the thus obtained solution through a sterile polysulfone membrane filter having an average pore diameter of about .40 to about 6.0 /1.m.
Claim 3
Dependent Claim
31 words
A method according to claim 1, wherein the sterile polysulfone membrane filter has an average pore diameter of about 0.40 to about 0.60 µm or more preferably of about 0.45 /1.m.
Claim 4
Dependent Claim
26 words
A method according to claim 1 or 2, wherein the components are present in the surfactant mixture in a weight ratio a:b:c:d:e of about 2-4:0.5-1.5: 0.5-1.5:0.5-1.5:0-1.5.
Claim 5
Dependent Claim
29 words
A method according to claim 3, wherein the surfactant mixture consists essentially of glycerol monolaurate, cholesterol benzoate, cholesterol, cholesterol acetate and glycerol tripalmitate in a weight ratio of 2-4:1:1:1:1.
Claim 6
Independent Claim
34 words
A method according to any of the claims 1 to 4, further comprising the step of dissolving a paramagnetic compound in the saline, in an amount of about 75 mg to about 200 mg.
Claim 7
Dependent Claim
67 words
A concentrated, storable imaging agent suitable for enhancement for ultrasonic imaging and magnetic resonance imaging, comprising: lipid-coated microbubbles associated with a paramagnetic complex, wherein the mean microbubble diameter is about 1.5 to about 4.5 µm and 100 % of the microbubbles are less than 6 µm in diameter, the imaging agent being preferably prepared by a method according to any one of the claims 1 to 5.
Claim 8
Dependent Claim
39 words
An imaging agent according to claim 6, wherein the paramagnetic complex is selected from the group consisting of gadolinium diethylenetriaminepentaacetic acid (Gd DTPA), manganese diethylenetriaminepentaacetic acid (Mn DTPA), gadolinium ethylenediaminetetraacetic acid (Gd EDTA) and manganese ethylenediaminetetraacetic acid (Mn EDTA).
Claim 9
Dependent Claim
27 words
An imaging agent according to claim 6 or 7, wherein the paramagnetic complex is covalently bound to a hydrophobic polymer, the complex being preferably gadolinium diethylenetriaminepentaacetic acid.
Claim 10
Independent Claim
79 words
A method for preparing an imaging agent suitable for enhancement of ultrasonic imaging and magnetic resonance imaging comprising the steps of: A. obtaining a hydrophobic polymer labeled with a paramagnetic complex; B. dissolving the labeled, hydrophobic polymer in a saline solution in an amount of about 10mM; C. adding a surfactant mixture according to any of the claims 1 to 5; and D. processing the solution obtained in step C. according to any of the claims 1 to 5.
Claim 11
Dependent Claim
26 words
A method according to claim 9, wherein the hydrophobic polymer is selected from the group consisting of homopolymers of valine, glycine and alanine and copolymers thereof.
Claim 12
Dependent Claim
26 words
A method according to claim 10, wherein the paramagnetic complex is selected from the group consisting of gadolinium DTPA, manganese DTPA, gadolinium EDTA and manganese EDTA.
Claim 13
Dependent Claim
13 words
A method according to claim 11, wherein the paramagnetic complex is gadolinium DTPA.
Claim 14
Independent Claim
81 words
A method of enhancing ultrasonic imaging of a tumor by increasing image contrast, comprising the steps of: A. providing a suspension of medical-grade, lipid-coated microbubbles; B. injecting the microbubble suspension into the tumor-bearing individual; C. allowing the microbubbles to pool in the tumor tissue; and D. employing high frequency diagnostic ultrasound in the area of the tumor; E. receiving reflections of ultrasound wave signals from the underlying area enhanced by reflections from the microbubbles and transforming the signal data into images.
Claim 15
Independent Claim
81 words
A method of enhancing ultrasonic imaging of a tumor by increasing image contrast, comprising the steps of: A. providing a suspension of medical-grade, lipid-coated microbubbles; B. injecting the microbubble suspension into the tumor-bearing individual; C. allowing the microbubbles to pool in the tumor tissue; and D. employing high frequency diagnostic ultrasound in the area of the tumor; E. receiving reflections of ultrasound wave signals from the underlying area enhanced by reflections from the microbubbles and transforming the signal data into images.
Claim 16
Dependent Claim
21 words
A method according to claim 13, wherein the lipid-coated microbubbles according to any one of claims 6 to 8 are used.
Claim 17
Dependent Claim
35 words
A method according to claim 13, wherein the lipid-coated microbubbles are formed from a substantially saturated saline solution of a surfactant mixture according to any one of claims 1 to 5 and 9 to 12.
Claim 18
Dependent Claim
26 words
Use of lipid-coated microbubbles for the manufacture of a therapeutic agent for destruction of tumors by ultrasound heating and/or cavitation of microbubbles at a tumor site.
Claim 19
Dependent Claim
26 words
Use of lipid-coated microbubbles for the manufacture of a therapeutic agent for destruction of tumors by ultrasound heating and/or cavitation of microbubbles at a tumor site.
Claim 20
Dependent Claim
42 words
Use of lipid-coated microbubbles according to claim 16, wherein the microbubbles are produced according to a method of any one of the claims 1 to 5 and 9 to 12 or selected according to any one of the claims 6 to 8.
Claim 21
Dependent Claim
29 words
Use of lipid-coated microbubbles according to claim 16 or 17, wherein the therapeutic agent is injectable to a tumor-bearing individual and the microbubbles are pooling in the tumor tissue.
Claim 22
Dependent Claim
44 words
Use of lipid-coated microbubbles according to any one of claims 16 to 18, wherein after detecting the tumor site the intensity of ultrasound on a specific tumor volume is increased, the sound waves creating by interaction with the microbubbles a localized heating and/or cavitation.
Claim 23
Dependent Claim
28 words
Use of lipid-coated microbubbles according to claim 19, wherein the microbubbles contain a therapeutic pharmaceutical agent and the microbubbles are caused to burst at the increased ultrasound intensity.
References Cited (Backward Citations)
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