US5487390A
Expired / Lapsed
US
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Gas-filled polymeric microbubbles for ultrasound imaging
Assignee: Penn State Research Foundation
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Filing: 1994-01-14
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Granted: 1996-01-30
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Expires: 2014-01-14
Abstract
Abstract Compositions, methods for preparing and methods of using air-filled polymeric microcapsules for ultrasound imaging are disclosed. Air-encapsulating microcapsules are formed by ionotropically gelling synthetic polyelectrolytes such as poly(carboxylatophenoxy)phosphazene, poly(acrylic acid), poly(methacrylic acid) and methacrylic acid copolymers (Eudragit's) by contact with multivalent ions such as calcium ions. In the preferred embodiment, the average size of the microcapsules is less than seven μm so that they are suitable for injection intravenously. The polymeric microcapsules are stable to imaging and display high echogenicity, both in vitro and in vivo. Due to their in vivo stability their potential application is extended beyond vascular imaging to liver and renal diseases, fallopian tube diseases, detecting and characterizing tumor masses and tissues, and measuring peripheral blood velocity. The microcapsules can optionally be linked with ligands that minimize tissue adhesion or that target the microcapsules to specific regions.
Inventors
- 👤 Smadar Cohen
- 👤 Alexander K. Andrianov
- 👤 Margaret Wheatley
- 👤 Harry R. Allcock
- 👤 Robert S. Langer
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-26 09:22
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/10; A61K9/127; A61K9/1271; A61K49/00; A61K49/22; A61K49/222; A61K49/223; A61K49/225; A61K49/226; A61K51/00; A61K51/12; A61K51/1258; A61K9/14; A61K9/16; A61K9/1605; A61K9/1629; A61K9/1641; A61K9/48; A61K9/50; A61K9/5005; A61K9/5021; A61K9/5031; B; B01; B01J; B01J13/00; B01J13/02; B01J13/06; B01J13/14; C; C08; C08G; C08G79/00; C08G79/02; C08G79/025; C12; C12N; C12N11/00; C12N11/02; C12N11/04; A61K2123/00; Y; Y10; Y10S; Y10S977/00; Y10S977/70; Y10S977/734; Y10S977/753; Y10S977/902; Y10S977/904; Y10S977/927; Y10S977/929; Y10T; Y10T428/00; Y10T428/29; Y10T428/2982; Y10T428/2984; Y10T428/2985; Y10T428/2987
Claims Analysis
Total Claims: 23
Claim 1
Independent Claim
66 words
A microcapsule having a diameter of 700 microns or less formed of biocompatible hydrogel formed by crosslinking with a multivalent ion of a polymer selected from the group consisting of poly(phosphazenes), poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid or methacrylic acid and polyvinyl ethers or poly(vinyl acetate), and sulfonated polystyrene, comprising a gas encapsulated therein in an amount effective for use as an imaging agent.
Claim 2
Dependent Claim
66 words
A microcapsule having a diameter of 700 microns or less formed of biocompatible hydrogel formed by crosslinking with a multivalent ion of a polymer selected from the group consisting of poly(phosphazenes), poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid or methacrylic acid and polyvinyl ethers or poly(vinyl acetate), and sulfonated polystyrene, comprising a gas encapsulated therein in an amount effective for use as an imaging agent.
Claim 3
Dependent Claim
17 words
The microcapsule of claim 1 wherein the diameter of the microcapsule is between one and ten microns.
Claim 4
Dependent Claim
48 words
The microcapsule of claim 1 wherein the hydrogel is prepared from an ionically crosslinkable synthetic polymer that is partially soluble in a gasified aqueous solution prior to crosslinking and has charged side groups which are crosslinked by reacting the side groups with multivalent ions of the opposite charge.
Claim 5
Dependent Claim
16 words
The microcapsule of claim 3 wherein the side groups are acidic and the ions are cations.
Claim 6
Dependent Claim
60 words
The microcapsule of claim 4 wherein the polymer is a polyelectrolyte selected from the group consisting of poly(phosphazenes), poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid or methacrylic acid and polyvinyl ethers or poly(vinyl acetate), sulfonated polystyrene, and the polymer is soluble in an aqueous solution selected from the group consisting of water, aqueous alcohol, and buffered aqueous salt solutions.
Claim 7
Dependent Claim
30 words
The microcapsules of claim 4 wherein the acidic side groups contain moieties selected from the group consisting of carboxylic acid, sulfonic acid, halogenated alcohol, phenolic OH, and acidic OH groups.
Claim 8
Dependent Claim
27 words
The microcapsules of claim 4 wherein the multivalent cation is selected from the group consisting of calcium, copper, aluminum, magnesium, strontium, barium, tin, zinc and organic cations.
Claim 9
Dependent Claim
16 words
The microcapsule of claim 3 wherein the side groups are basic and the ions are anions.
Claim 10
Dependent Claim
21 words
The microcapsules of claim 8 wherein the anions are selected from group consisting of dicarboxylic acids, sulfate ions and carbonate ions.
Claim 11
Dependent Claim
28 words
The microcapsules of claim 3 wherein the charged groups on the surface are further complexed with a multivalent polyion of the opposite charge to form a semi-permeable membrane.
Claim 12
Dependent Claim
19 words
The microcapsules of claim 10 wherein the hydrogel is liquefied within the semi-permeable membrane by removing the multivalent ions.
Claim 13
Independent Claim
105 words
A method for preparing synthetic polymeric crosslinked microcapsules encapsulating imaging contrast agents comprising the steps of: a) entrapping gas bubbles in an aqueous solution or dispersion of an ionically crosslinkable synthetic polymer selected from the group consisting of poly(phosphazenes), poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid or methacrylic acid and polyvinyl ethers or poly(vinyl acetate), and sulfonated polystyrene, that has charged side groups, and b) reacting the polymer with a multivalent ion of the opposite charge to form an ionically crosslinked hydrogel microparticle having a maximum diameter of 700 microns or less encapsulating an amount of gas effective for use as an imaging agent.
Claim 14
Independent Claim
105 words
A method for preparing synthetic polymeric crosslinked microcapsules encapsulating imaging contrast agents comprising the steps of: a) entrapping gas bubbles in an aqueous solution or dispersion of an ionically crosslinkable synthetic polymer selected from the group consisting of poly(phosphazenes), poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid or methacrylic acid and polyvinyl ethers or poly(vinyl acetate), and sulfonated polystyrene, that has charged side groups, and b) reacting the polymer with a multivalent ion of the opposite charge to form an ionically crosslinked hydrogel microparticle having a maximum diameter of 700 microns or less encapsulating an amount of gas effective for use as an imaging agent.
Claim 15
Dependent Claim
27 words
The method of claim 12 wherein the gas is entrapped in the polymer solution or dispersion by sonication of the polymer in the presence of the gas.
Claim 16
Dependent Claim
30 words
The method of claim 12 wherein the gas is mixed with the polymer solution or dispersion and atomized through an orifice forming droplets which are dispersed into the crosslinking solution.
Claim 17
Dependent Claim
48 words
The method of claim 12 wherein the polymer is a polyelectrolyte selected from the group consisting of polyphosphazenes, polyacrylic acids, polymethacrylic acids, copolymers of acrylic acid and polyvinyl acetate, polyvinyl ethers, polysulfonic acid derivatives, and polystyrene sulfonates and is soluble in an aqueous solution selected from the group.
Claim 18
Dependent Claim
27 words
The method of claim 15 wherein the multivalent ion is selected from the group consisting of calcium, copper, aluminum, magnesium, strontium, barium, tin, zinc and organic cations.
Claim 19
Dependent Claim
44 words
The method of claim 12 wherein the charged side groups are further complexed with a multivalent polyion of the opposite charge to form a semi-permeable membrane; and wherein the method further comprises liquefying the gel after forming the semi-permeable membrane to form a microcapsule.
Claim 20
Independent Claim
104 words
A method for ultrasonic imaging for use in medical procedures, comprising the steps of: a) administering microcapsules having a diameter of 700 microns or less formed of an ionically crosslinked biocompatible hydrogel formed from a polymer selected from the group consisting of poly(phosphazenes), poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid or methacrylic acid and polyvinyl ethers or poly(vinyl acetate), and sulfonated polystyrene, having a gas encapsulated therein in an amount effective for use as an imaging agent into a mammal to alter the acoustic properties of a predetermined area; and b) ultrasonically scanning a predetermined area to obtain an image of the area.
Claim 21
Independent Claim
104 words
A method for ultrasonic imaging for use in medical procedures, comprising the steps of: a) administering microcapsules having a diameter of 700 microns or less formed of an ionically crosslinked biocompatible hydrogel formed from a polymer selected from the group consisting of poly(phosphazenes), poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid or methacrylic acid and polyvinyl ethers or poly(vinyl acetate), and sulfonated polystyrene, having a gas encapsulated therein in an amount effective for use as an imaging agent into a mammal to alter the acoustic properties of a predetermined area; and b) ultrasonically scanning a predetermined area to obtain an image of the area.
Claim 22
Dependent Claim
17 words
The method of claim 19 wherein the diameter of the microcapsule is between one and ten microns.
Claim 23
Dependent Claim
48 words
The method of claim 18 wherein the hydrogel is prepared from an ionically crosslinkable synthetic polymer that is partially soluble in a gasified aqueous solution prior to crosslinking and has charged side groups which are crosslinked by reacting the side groups with multivalent ions of the opposite charge.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1999-01-29 | 1999-07-31 | 2000-01-30 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2003-01-29 | 2003-07-31 | 2004-01-30 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2007-01-29 | 2007-07-31 | 2008-01-30 | $7700.00 | Window Closed / Lapsed |