Methods of imaging using osmotically stabilized microbubble preparations
DC
First Claim
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1. A method of imaging an object, a body part or a body cavity comprising the steps of:
- introducing into said object, body part or body cavity a microbubble preparation comprising an aqueous medium having dispersed therein a plurality of osmotically stabilized microbubbles, said microbubbles comprising a generally spherical microbubble membrane containing at least one modifier gas and at least one gas osmotic agent, wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;
100 to about 1,000;
1, wherein said ratio is effective to stabilize said microbubble preparation, with the proviso that said modifier gas is not water vapor, wherein said gas osmotic agent is selected from the group consisting of perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutane, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, perfluorotriethylamine and combinations thereof; and
imaging at least a portion of said object, body part or body cavity by ultrasound or magnetic resonance.
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Abstract
A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760−x) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° C.; also disclosed are methods for preparing microbubble compositions, including compositions that rapidly shrink from a first average diameter to a second average diameter less than about 75% of the first average diameter and are stabilized at the second average diameter; methods and kits for preparing microbubbles; and methods for using such microbubbles as contrast agents.
58 Citations
146 Claims
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1. A method of imaging an object, a body part or a body cavity comprising the steps of:
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introducing into said object, body part or body cavity a microbubble preparation comprising an aqueous medium having dispersed therein a plurality of osmotically stabilized microbubbles, said microbubbles comprising a generally spherical microbubble membrane containing at least one modifier gas and at least one gas osmotic agent, wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;
100 to about 1,000;
1, wherein said ratio is effective to stabilize said microbubble preparation, with the proviso that said modifier gas is not water vapor, wherein said gas osmotic agent is selected from the group consisting of perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutane, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, perfluorotriethylamine and combinations thereof; and
imaging at least a portion of said object, body part or body cavity by ultrasound or magnetic resonance. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 122, 123)
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53. A method of imaging an object, a body part or a body cavity comprising the steps of:
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introducing into said object, body part or body cavity a microbubble preparation comprising an aqueous medium having dispersed therein a plurality of osmotically stabilized microbubbles, said microbubbles comprising a generally spherical microbubble membrane containing at least one modifier gas and at least one gas osmotic agent, wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;
100 to about 1,000;
1, wherein said ratio is effective to stabilize said microbubble preparation and wherein said gas osmotic agent comprises the vapor of a compound which is a liquid at 37°
C. and 760 Torr, andimaging at least a portion of said object, body part or body cavity by ultrasound or magnetic resonance. - View Dependent Claims (54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 141, 142, 143, 144, 145, 146)
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70. A method of imaging an object, a body part or a body cavity comprising the steps of:
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providing a container having therein microbubble precursor components comprising an aqueous medium, a surfactant, at least one modifier gas that is relatively soluble in the aqueous medium, and at least one gas osmotic agent that is relatively insoluble in the aqueous medium, wherein said modifier gas and said gas osmotic agent are present in a molar ratio from about 1;
100 to about 1.000;
1, wherein said ratio is effective to stabilize a resulting microbubble, with the proviso that said modifier gas is not water vapor, and wherein said microbubble precursor components are adapted to form microbubbles upon the application of energy thereto;
applying energy to said microbubble precursor components to form a microbubble preparation comprising a plurality of microbubbles dispersed in said aqueous medium that are osmotically stabilized when introduced into a physiological liquid, in that the gas osmotic agent is present in an amount that dilutes the modifier gas sufficiently that gases ordinarily dissolved in the physiological liquid in vivo seek to diffuse into the bubble with an osmotic pressure sufficient to counteract the Laplace pressure of the microbubble, said microbubbles comprising a generally spherical microbubble membrane containing said gas osmotic agent and said modifier gas;
introducing at least a portion of said microbubble preparation into said object, body part or body cavity; and
imaging at least a portion of said object, body part or body cavity by ultrasound or magnetic resonance. - View Dependent Claims (71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 127, 129, 130, 131, 132, 133, 134, 137, 138, 139, 140)
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92. A method of imaging an object, a body part or a body cavity comprising the steps of:
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introducing into said object, body part or body cavity a microbubble preparation, comprising an aqueous medium having dispersed therein a plurality of microbubbles, said microbubbles comprising a generally spherical microbubble membrane comprising proteinaceous material containing at least one relatively water-soluble modifier gas and at least one relatively water-insoluble gas osmotic agent in a molar ratio from about 1;
100 to about 1.000;
1 such that the microbubbles are osmotically stabilized when introduced into a physiological liquid, with the proviso that said modifier gas is not water vapor, and whereby said gas osmotic agent dilutes the modifier gas sufficiently that gases ordinarily dissolved in the physiological liquid in vivo seek to diffuse into the bubble with an osmotic pressure sufficient to counteract the Laplace pressure of the microbubble; and
imaging at least a portion of said object, body part or body cavity by ultrasound or magnetic resonance. - View Dependent Claims (93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 128, 135, 136)
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124. The method of claim 124, in which the molar ratio of said modifier gas and said gas osmotic agent is greater than 1:
- 1.
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125. The method of claim 125, wherein the modifier gas is a non-fluorocarbon and the gas osmotic agent is a fluorocarbon.
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126. The method of claim 126, wherein said plurality of osmotically stabilized microbubbles have a diameter from about 1 to 10 μ
- m.
Specification
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Litigation Data
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Current AssigneeTargeson, Inc.
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Original AssigneeAlliance Pharmaceuticals Corp.
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InventorsSchutt, Ernest G., Anderson, Charles David, Evitts, David P.
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Primary Examiner(s)Hartley, Michael G.
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Application NumberUS08/841,846Time in Patent Office1,590 DaysField of Search424/9.52, 424/9.51, 600/458US Class Current424/9.51CPC Class CodesA61K 49/223 Microbubbles, hollow micros...A61K 49/227 Liposomes, lipoprotein vesi...G02B 6/0006 Coupling light into the fib...
