US5558853A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Phase shift colloids as ultrasound contrast agents
Assignee: GE Healthcare Ltd
•
Filing: 1994-01-19
•
Granted: 1996-09-24
•
Expires: 2014-01-19
Abstract
Abstract Agents for enhancing the contrast in a diagnostic ultrasound procedure comprise colloidal dispersions of the liquid-in-liquid type, i.e., emulsions or microemulsions, in which the dispersed liquid phase is a liquid having a boiling point below the temperature of the animal to be imaged and which therefore undergoes a phase change from a dispersed liquid to a highly echogenic dispersed gaseous foam or kugelschaum following administration to the animal. The liquid state of the dispersed phase allows one to manufacture extremely stable, pharmaceutically acceptable emulsions with particle sizes typically below 1000 nm. The gaseous state at body temperature yields highly echogenic microbubbles, typically below 10,000 nm in diameter, which are effective as ultrasound contrast agents. Intravenous, intraarterial, oral, intraperitoneal, and intrauterine dosage forms, methods of administration, and imaging techniques are described.
Inventors
- 👤 Steven C. Quay
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 12:29
CPC Classifications
A; A61; A61K; A61K49/00; A61K49/22; A61K49/222; A61K49/226; A61K49/223
Claims Analysis
Total Claims: 55
Claim 1
Independent Claim
44 words
An ultrasound contrast agent including a biocompatible colloidal dispersion, said dispersion comprising a liquid dispersed phase, an amphiphilic material and an aqueous continuous phase, said dispersed phase comprising a water immiscible fluorine-containing chemical in liquid form having a boiling point below about 40° C.
Claim 2
Dependent Claim
44 words
An ultrasound contrast agent including a biocompatible colloidal dispersion, said dispersion comprising a liquid dispersed phase, an amphiphilic material and an aqueous continuous phase, said dispersed phase comprising a water immiscible fluorine-containing chemical in liquid form having a boiling point below about 40° C.
Claim 3
Dependent Claim
18 words
The colloidal dispersion of claim 1 wherein said fluorine-containing chemical has a molecular weight of less than 300.
Claim 4
Dependent Claim
21 words
The colloidal dispersion of claim 1 wherein said chemical is selected from the group consisting of decafluorobutane, dodecafluoropentane, dodecafluoroneopentane and perfluorocyclopentane.
Claim 5
Dependent Claim
20 words
The colloidal dispersion of claim 1 wherein said amphiphilic material has a relative HLB matched to said dispersed phase liquid.
Claim 6
Dependent Claim
14 words
The colloidal dispersion of claim 1 wherein said amphiphilic material comprises a biocompatible protein.
Claim 7
Dependent Claim
15 words
The colloidal dispersion of claim 1 wherein said amphiphilic material comprises at least one surfactant.
Claim 8
Dependent Claim
25 words
The colloidal dispersion of claim 5 wherein said protein is selected from the group consisting of albumin, fibrinogen, fibrin, serum globulins, hemoglobin, myoglobin, and immunoglobulins.
Claim 9
Dependent Claim
17 words
The colloidal dispersion of claim 1 wherein said amphiphilic material comprises a polyoxypropylene-polyoxyethylene glycol nonionic block copolymer.
Claim 10
Dependent Claim
14 words
The colloidal dispersion of claim 4 wherein said amphiphilic material comprises a fluorine-containing surfactant.
Claim 11
Dependent Claim
25 words
The colloidal dispersion of claim 4 wherein said amphiphilic material is selected from the group of surfactants consisting of anionic, cationic, nonionic, or zwitterionic molecules.
Claim 12
Dependent Claim
75 words
The colloidal dispersion of claim 4 wherein said amphiphilic material comprises at least one surfactant selected from the group of surfactants which contain, as hydrophilic groups, one or more of the following chemical groups: sulfonate, sulfate, carboxylate, phosphate, ammonium, quaternary ammonium, betaines, sulfobetaines, polyoxyethylene, polyols, alcohols, ethers, polypeptide, or polyglycidyl; and as hydrophobic groups, one or more of the following chemical groups: fatty acids, paraffins, olefins, alkyl benzenes, alcohols, alkylphenols, polyoxypropylenes, polypeptides, fluorocarbons, and silicones.
Claim 13
Dependent Claim
32 words
The colloidal dispersion of claim 4 wherein said amphiphilic material is present at a concentration such that the interfacial tension between water and the liquid dispersed phase is less than 26 dynes/cm.
Claim 14
Dependent Claim
22 words
The colloidal dispersion of claim 4 wherein said amphiphilic material is present at a concentration greater than 0.001% by weight per volume.
Claim 15
Dependent Claim
13 words
The colloidal dispersion of claim 1 wherein said dispersion further comprises a viscogen.
Claim 16
Dependent Claim
25 words
The colloidal dispersion of claim 14 wherein said viscogen is selected from the group consisting of glucose, iohexol, iopamidol, iopentol, sorbitol, sucrose, and polyethylene glycol.
Claim 17
Dependent Claim
23 words
The colloidal dispersion of claim 14 wherein the viscogen is present at a concentration sufficient to produce a viscosity greater than 1.1 cP.
Claim 18
Dependent Claim
23 words
The colloidal dispersion of claim 14 wherein the viscogen is present at a concentration of between 0.001 and 75% by weight per volume.
Claim 19
Dependent Claim
21 words
The colloidal dispersion of claim 1 wherein said liquid dispersed phase comprises particles having an average diameter less than 1000 nm.
Claim 20
Dependent Claim
23 words
The colloidal dispersion of claim 1 wherein the concentration of said liquid dispersed phase is between 0.00001 to 166% by weight per volume.
Claim 21
Dependent Claim
42 words
The colloidal dispersion of claim 1 wherein the aqueous medium comprises an additive selected from the group of acidifying agents, alkalizing agents, antimicrobial preservatives, antioxidants, buffering agents, chelating agents, complexing agents, solubilizing agents, humectants, solvents, suspending agents, viscosity-increasing agents and tonicity agents.
Claim 22
Dependent Claim
27 words
The colloidal dispersion of claim 20 wherein said additive is present at a concentration such that the osmolarity of said aqueous medium is at least 250 mOsm.
Claim 23
Dependent Claim
23 words
The colloidal dispersion of claim 1 wherein said liquid comprises a chemical selected from the group of chemicals containing 4 to 17 atoms.
Claim 24
Dependent Claim
24 words
The colloidal dispersion of claim 1 wherein said liquid comprises a chemical selected from the group of fluorine containing chemicals having five carbons atoms.
Claim 25
Dependent Claim
95 words
An ultrasound contrast agent including a biocompatible colloidal dispersion for imaging an animal having a body temperature T comprising a dispersed phase, an amphiphile and an aqueous continuous phase, said dispersed phase including a fluorine-containing chemical with a sufficiently high vapor pressure that a portion of said chemical is a gas at the temperature T, wherein said dispersed phase is present in an amount such that said portion of said chemical which forms a gas is adequate to provide ultrasound contrast enhancement due to the liquid-gas interface when said agent is administered to said animal.
Claim 26
Dependent Claim
95 words
An ultrasound contrast agent including a biocompatible colloidal dispersion for imaging an animal having a body temperature T comprising a dispersed phase, an amphiphile and an aqueous continuous phase, said dispersed phase including a fluorine-containing chemical with a sufficiently high vapor pressure that a portion of said chemical is a gas at the temperature T, wherein said dispersed phase is present in an amount such that said portion of said chemical which forms a gas is adequate to provide ultrasound contrast enhancement due to the liquid-gas interface when said agent is administered to said animal.
Claim 27
Independent Claim
72 words
A method of preparing a storage stable colloidal dispersion comprising the steps of (a) mixing at least one amphiphilic material with water to form an aqueous continuous phase; (b) adding an amount of a fluorine-containing chemical which has a boiling point less than 37° C. to said continuous phase; and (c) condensing said fluorine-containing chemical to form a liquid dispersed phase of particles with an average diameter of less than 5000 nm.
Claim 28
Independent Claim
72 words
A method of preparing a storage stable colloidal dispersion comprising the steps of (a) mixing at least one amphiphilic material with water to form an aqueous continuous phase; (b) adding an amount of a fluorine-containing chemical which has a boiling point less than 37° C. to said continuous phase; and (c) condensing said fluorine-containing chemical to form a liquid dispersed phase of particles with an average diameter of less than 5000 nm.
Claim 29
Dependent Claim
52 words
An ultrasound contrast agent comprising: a liquid-in-liquid colloidal dispersion having an aqueous continuous phase, an amphiphile and a water immiscible dispersed phase; wherein said dispersed phase comprises a chemical fluorine-containing having a boiling point, under standard pressure conditions, below the body temperature of an organism to which said agent will be administered.
Claim 30
Dependent Claim
52 words
An ultrasound contrast agent comprising: a liquid-in-liquid colloidal dispersion having an aqueous continuous phase, an amphiphile and a water immiscible dispersed phase; wherein said dispersed phase comprises a chemical fluorine-containing having a boiling point, under standard pressure conditions, below the body temperature of an organism to which said agent will be administered.
Claim 31
Dependent Claim
12 words
The agent according to claim 26 wherein said chemical is a perfluorocarbon.
Claim 32
Dependent Claim
20 words
The agent according to claim 27 wherein said chemical is selected from the group consisting of perfluoropropane, perfluorobutane and perfluoropentane.
Claim 33
Dependent Claim
11 words
The agent according to claim 28 wherein said chemical is perfluoropentane.
Claim 34
Dependent Claim
45 words
An ultrasound contrast agent comprising: a liquid-in-liquid colloidal dispersion including an amphiphile selected from the group consisting of anionic, cationic and non-ionic surfactants, wherein said dispersed phase comprises a chemical fluorine-containing at least a portion of which percolates or vaporizes following administration to an organism.
Claim 35
Dependent Claim
45 words
An ultrasound contrast agent comprising: a liquid-in-liquid colloidal dispersion including an amphiphile selected from the group consisting of anionic, cationic and non-ionic surfactants, wherein said dispersed phase comprises a chemical fluorine-containing at least a portion of which percolates or vaporizes following administration to an organism.
Claim 36
Dependent Claim
18 words
The agent according to claim 30 wherein said chemical has a boiling point between -20° and 37° C.
Claim 37
Dependent Claim
12 words
The agent according to claim 30 wherein said chemical is a perfluorocarbon.
Claim 38
Dependent Claim
21 words
The agent according to claim 32 wherein said chemical is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane and perfluorohexane.
Claim 39
Dependent Claim
11 words
The agent according to claim 33 wherein said chemical is perfluoropentane.
Claim 40
Dependent Claim
43 words
A biocompatible ultrasound contrast agent comprising a colloidal dispersion of a finely divided water immiscible liquid distributed evenly throughout an aqueous continuous phase, said finely divided liquid comprising a chemical fluorine-containing which has a boiling point, under standard pressure conditions, below 40° C.
Claim 41
Dependent Claim
43 words
A biocompatible ultrasound contrast agent comprising a colloidal dispersion of a finely divided water immiscible liquid distributed evenly throughout an aqueous continuous phase, said finely divided liquid comprising a chemical fluorine-containing which has a boiling point, under standard pressure conditions, below 40° C.
Claim 42
Dependent Claim
11 words
The agent according to claim 35 further comprising a biocompatible protein.
Claim 43
Dependent Claim
25 words
The agent according to claim 36 wherein said protein is in the form of a microsphere, and said dispersed phase is contained within said microsphere.
Claim 44
Dependent Claim
11 words
The agent according to claim 36 wherein said protein is albumin.
Claim 45
Dependent Claim
18 words
The agent according to claim 35 wherein said chemical has a boiling point between -20° and 37° C.
Claim 46
Dependent Claim
20 words
The agent according to claim 35 wherein said dispersed phase is present at a concentration of 0.05 to 5.0% w/v.
Claim 47
Dependent Claim
12 words
The agent according to claim 35 wherein said chemical is a perfluorocarbon.
Claim 48
Dependent Claim
20 words
The agent according to claim 41 wherein said chemical is selected from the group consisting of perfluoropropane, perfluorobutane and perfluoropentane.
Claim 49
Dependent Claim
11 words
The agent according to claim 42 wherein said chemical is perfluoropentane.
Claim 50
Dependent Claim
68 words
An ultrasound contrast agent comprising a non-aqueous liquid dispersed phase, an amphiphile and an aqueous continuous phase; said dispersed phase comprising a fluorine-containing chemical having a boiling point of between -20° and 37° C. and being present at a concentration 0.05 to 5% w/v; and said amphiphile being present at a concentration such that the interfacial tension between the dispersed and continuous phases is less than 26 dynes/cm.
Claim 51
Dependent Claim
68 words
An ultrasound contrast agent comprising a non-aqueous liquid dispersed phase, an amphiphile and an aqueous continuous phase; said dispersed phase comprising a fluorine-containing chemical having a boiling point of between -20° and 37° C. and being present at a concentration 0.05 to 5% w/v; and said amphiphile being present at a concentration such that the interfacial tension between the dispersed and continuous phases is less than 26 dynes/cm.
Claim 52
Dependent Claim
19 words
The agent according to claim 44 wherein said chemical has a boiling point of between 28° and 37° C.
Claim 53
Dependent Claim
12 words
The agent according to claim 44 wherein said chemical is a perfluorocarbon.
Claim 54
Dependent Claim
20 words
The agent according to claim 46 wherein said chemical is selected from the group consisting of perfluoropropane, perfluorobutane and perfluoropentane.
Claim 55
Dependent Claim
11 words
The agent according to claim 47 wherein said chemical is perfluoropentane.
References Cited (Backward Citations)
DE410470C
Cited
US3898843A
Cited
WO1980002365A1
Cited
US4276885A
Cited
US4265251A
Cited
US4681119A
Cited
US4657756A
Cited
US4442843A
Cited
JPS57177790A
Cited
US4533254A
Cited
EP0077752A2
Cited
US4466442A
Cited
AU9170982A
Cited
JPS5967229A
Cited
US4718433A
Cited
US4572203A
Cited
US5141738A
Cited
US4900540A
Cited
US4544545A
Cited
US4767610A
Cited
US4859363A
Cited
US4684479A
Cited
US4832941A
Cited
US5155215A
Cited
US4774958A
Cited
US4865836A
Cited
US4927623A
Cited
US4987154A
Cited
US5393513A
Cited
US5080885A
Cited
EP0231091A1
Cited
EP0245019A2
Cited
JPS6360943A
Cited
US4895876A
Cited
US5354549A
Cited
US5284645A
Cited
EP0307087A1
Cited
US4844882A
Cited
EP0324938A1
Cited
WO1989006978A1
Cited
EP0327490A1
Cited
WO1989010118A1
Cited
US5171755A
Cited
US4993415A
Cited
EP0357163A1
Cited
EP0359246A2
Cited
US4957656A
Cited
DE3834705A1
Cited
WO1990007491A1
Cited
US5114703A
Cited
US5344930A
Cited
US5260496A
Cited
US5078146A
Cited
JPH02196730A
Cited
US5088499A
Cited
WO1991009629A1
Cited
US5123414A
Cited
WO1991012823A1
Cited
US5271928A
Cited
WO1991015244A2
Cited
EP0454044A2
Cited
US5137928A
Cited
EP0458745A1
Cited
WO1991018612A1
Cited
EP0467031A2
Cited
WO1992002560A1
Cited
WO1992005806A1
Cited
WO1992008496A1
Cited
DE4100470A1
Cited
EP0494615A1
Cited
EP0502814A2
Cited
US5107842A
Cited
WO1992015284A1
Cited
WO1992017212A1
Cited
WO1992017213A1
Cited
US5205290A
Cited
US5281408A
Cited
WO1992018165A2
Cited
WO1992018169A1
Cited
US5147631A
Cited
WO1992021382A1
Cited
WO1992022247A1
Cited
WO1993000930A1
Cited
WO1993000933A1
Cited
WO1993001798A1
Cited
DE4127442A1
Cited
WO1993005819A1
Cited
WO1993006869A1
Cited
WO1993007905A2
Cited
EP0554213A1
Cited
WO1993017718A1
Cited
US5401493A
Cited
US5385147A
Cited
US5406950A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1999-09-24 | 2000-03-25 | 2000-09-24 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2003-09-24 | 2004-03-25 | 2004-09-24 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2007-09-24 | 2008-03-25 | 2008-09-24 | $7700.00 | Window Closed / Lapsed |