US5605673A
Expired / Lapsed
US
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Stabilized microbubble compositions for ultrasound
Assignee: PHOTOGEN TECHNOLOGIES Inc
•
Filing: 1994-08-01
•
Granted: 1997-02-25
•
Expires: 2014-08-01
Abstract
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 DEG C., where x is the vapor pressure of the second gas at 37 DEG C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37 DEG 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.
Inventors
- 👤 Ernest G. Schutt
- 👤 Charles D. Anderson
- 👤 David P. Evitts
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 13:17
CPC Classifications
A; A61; A61K; A61K49/00; A61K49/22; A61K49/222; A61K49/227; A61K49/223; G; G02; G02B; G02B6/00; G02B6/0001; G02B6/0005; G02B6/0006
Claims Analysis
Total Claims: 87
Claim 1
Independent Claim
113 words
A method for forming microbubbles, comprising the steps of: providing a first gas, a second component, a membrane forming material, and a liquid, wherein said first gas and said second component are present in a molar ratio of about 1:100 to about 1,000:1, and wherein said second component comprises vapor of a compound that is liquid at 37° C. and 760 mm Hg but which has a vapor pressure of at least 75 mm Hg at 37° C. with the proviso that said first gas and said second component are not water vapor; and surrounding said first gas and said second component with said membrane forming material to form microbubbles in said liquid.
Claim 2
Independent Claim
113 words
A method for forming microbubbles, comprising the steps of: providing a first gas, a second component, a membrane forming material, and a liquid, wherein said first gas and said second component are present in a molar ratio of about 1:100 to about 1,000:1, and wherein said second component comprises vapor of a compound that is liquid at 37° C. and 760 mm Hg but which has a vapor pressure of at least 75 mm Hg at 37° C. with the proviso that said first gas and said second component are not water vapor; and surrounding said first gas and said second component with said membrane forming material to form microbubbles in said liquid.
Claim 3
Dependent Claim
13 words
The method of claim 1, wherein said membrane forming material is a surfactant.
Claim 4
Dependent Claim
14 words
The method of claim 2, wherein said membrane forming material comprises a non-Newtonian surfactant.
Claim 5
Dependent Claim
95 words
The method of claim 1, further comprising the steps of: initially forming microbubbles having a first average diameter wherein the initial ratio of said first gas to said second component in said microbubbles is at least about 1:1; contacting said microbubbles having a first average diameter with a liquid medium; shrinking said microbubbles in said medium as a result of loss of said first gas through said membrane; and then stabilizing said microbubbles at a second average diameter of less than about 75% of said first diameter for a period of at least one minute.
Claim 6
Dependent Claim
55 words
The method of claim 4, wherein said microbubbles are stabilized at said second diameter by: providing a gas osmotic pressure differential across said membrane such that the tension of a gas or gases dissolved in said medium is equal to or greater than the partial pressure of the same gas or gases inside said microbubbles.
Claim 7
Dependent Claim
15 words
The method of claim 5, wherein said first diameter is at least about 5 μm.
Claim 8
Independent Claim
88 words
A method for forming microbubbles, comprising the steps of: providing solid or semi-solid substantially liquid-soluble void-containing structures, said void-containing structures defining a plurality of voids having a diameter less than about 100 μm; providing a halogenated gas in said voids; providing a surfactant; providing said void-containing structures, said halogenated gas, and said surfactant in admixture with a liquid in which said void-containing structures are soluble; and dissolving said void-containing structures in said liquid whereby the halogenated gas in said enclosures forms microbubbles that are surrounded by said surfactant.
Claim 9
Independent Claim
88 words
A method for forming microbubbles, comprising the steps of: providing solid or semi-solid substantially liquid-soluble void-containing structures, said void-containing structures defining a plurality of voids having a diameter less than about 100 μm; providing a halogenated gas in said voids; providing a surfactant; providing said void-containing structures, said halogenated gas, and said surfactant in admixture with a liquid in which said void-containing structures are soluble; and dissolving said void-containing structures in said liquid whereby the halogenated gas in said enclosures forms microbubbles that are surrounded by said surfactant.
Claim 10
Dependent Claim
11 words
The method of claim 7, wherein said void-containing structures are microspheres.
Claim 11
Dependent Claim
30 words
The method of claim 7, wherein said microbubbles contain a first gas and a second halogenated gas respectively present in a molar ratio of from about 1:100 to about 1000:1.
Claim 12
Dependent Claim
50 words
A method for imaging an object or body part or body cavity, comprising the steps of: introducing into said object or body or body part or body cavity a microbubble preparation according to claim 1; and then imaging at least a portion of said body by ultrasound or magnetic resonance.
Claim 13
Dependent Claim
25 words
The method of claim 10, wherein said body is a vertebrate and said preparation is introduced into the vasculature or body cavity of said vertebrate.
Claim 14
Dependent Claim
16 words
The method of claim 10, wherein said preparation is a preparation as defined in claim 2.
Claim 15
Dependent Claim
16 words
The method of claim 10, wherein said preparation is a preparation as defined in claim 7.
Claim 16
Dependent Claim
16 words
The method of claim 10, wherein said preparation is a preparation as defined in claim 8.
Claim 17
Dependent Claim
25 words
The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 1.
Claim 18
Dependent Claim
25 words
The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 4.
Claim 19
Dependent Claim
25 words
The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 5.
Claim 20
Dependent Claim
25 words
The method of claim 10, further comprising the step of preparing said microbubble preparation prior to said introduction according to the method of claim 7.
Claim 21
Independent Claim
70 words
A method for producing microbubbles having increased in-vial stability, comprising the steps of: spray drying a liquid formulation containing a biocompatible film-forming material to form a microsphere powder therefrom; combining the microspheres with a gas osmotic agent and storing the microspheres in a container with the gas osmotic agent; and then mixing an aqueous phase with the powder, wherein said powder substantially dissolves in the aqueous phase to form microbubbles.
Claim 22
Independent Claim
70 words
A method for producing microbubbles having increased in-vial stability, comprising the steps of: spray drying a liquid formulation containing a biocompatible film-forming material to form a microsphere powder therefrom; combining the microspheres with a gas osmotic agent and storing the microspheres in a container with the gas osmotic agent; and then mixing an aqueous phase with the powder, wherein said powder substantially dissolves in the aqueous phase to form microbubbles.
Claim 23
Dependent Claim
16 words
The method of claim 19, wherein said film forming material comprises a starch or derivatized starch.
Claim 24
Dependent Claim
34 words
The method of claim 20, wherein said film forming material comprises a starch or derivatized starch having a molecular weight of greater than about 500,000 or a dextrose equivalency value less than about 12.
Claim 25
Dependent Claim
11 words
The method of claim 20, wherein said starch is hydroxyethyl starch.
Claim 26
Dependent Claim
13 words
The method of claim 19, wherein said film-forming material comprises a non-Newtonian surfactant.
Claim 27
Dependent Claim
13 words
The method of claim 19, wherein said gas osmotic agent comprises a fluorocarbon.
Claim 28
Dependent Claim
14 words
The method of claim 19, wherein said film forming material comprises a sugar ester.
Claim 29
Dependent Claim
20 words
The method of claim 25, wherein said sugar ester has a component with a hydrophilic-lipophilic balance less than about eight.
Claim 30
Dependent Claim
13 words
The method of claim 26, wherein said sugar ester component is sucrose tristearate.
Claim 31
Independent Claim
24 words
A method for forming microbubbles, comprising the steps of: providing a gas osmotic agent-permeated surfactant-containing powder; and combining said powder with an aqueous phase.
Claim 32
Independent Claim
24 words
A method for forming microbubbles, comprising the steps of: providing a gas osmotic agent-permeated surfactant-containing powder; and combining said powder with an aqueous phase.
Claim 33
Independent Claim
59 words
A method for forming microbubbles, comprising the steps of: providing a spray dried formulation comprising a starch, derivatized starch or dextrin; providing a gas osmotic agent in combination with said spray dried formulation that permeates said formulation; and combining said formulation with an aqueous phase to form microbubbles having a half-life in vivo of at least about 20 seconds.
Claim 34
Independent Claim
59 words
A method for forming microbubbles, comprising the steps of: providing a spray dried formulation comprising a starch, derivatized starch or dextrin; providing a gas osmotic agent in combination with said spray dried formulation that permeates said formulation; and combining said formulation with an aqueous phase to form microbubbles having a half-life in vivo of at least about 20 seconds.
Claim 35
Dependent Claim
25 words
The method of claim 29, wherein said spray dried formulation has been spray dried in combination with an inflating agent to form spray dried microspheres.
Claim 36
Dependent Claim
24 words
The method of claim 30, wherein said inflating agent is selected from the group consisting of: methylene chloride, Freon® 113, perfluorohexane and carbon dioxide.
Claim 37
Dependent Claim
15 words
The method of claim 29, wherein said spray dried formulation further comprises a sugar polyester.
Claim 38
Dependent Claim
14 words
The method of claim 1 wherein said second component comprises a gas osmotic agent.
Claim 39
Dependent Claim
13 words
The method of claim 33 wherein said gas osmotic agent comprises a fluorocarbon.
Claim 40
Dependent Claim
32 words
The method of claim 34 wherein said fluorocarbon is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.
Claim 41
Dependent Claim
11 words
The method of claim 1 wherein said second component comprises perfluorohexane.
Claim 42
Dependent Claim
30 words
The method of claim 2 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
Claim 43
Dependent Claim
67 words
The method of claim 1 wherein said membrane forming material is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.
Claim 44
Dependent Claim
12 words
The method of claim 1, wherein said film-forming material comprises a protein.
Claim 45
Dependent Claim
12 words
The method of claim 1, wherein said film-forming material comprises a carbohydrate.
Claim 46
Dependent Claim
24 words
The method of claim 1 wherein said film-forming material comprises a compound selected from the group consisting of starches, derivatized starches and sugar esters.
Claim 47
Dependent Claim
12 words
The method of claim 7 wherein said halogenated gas comprises a fluorocarbon.
Claim 48
Dependent Claim
32 words
The method of claim 42 wherein said fluorocarbon is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.
Claim 49
Dependent Claim
11 words
The method of claim 7 wherein said halogenated gas comprises perfluorohexane.
Claim 50
Dependent Claim
12 words
The method of claim 7, wherein said surfactant is a non-Newtonian surfactant.
Claim 51
Dependent Claim
30 words
The method of claim 7 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
Claim 52
Dependent Claim
65 words
The method of claim 7 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.
Claim 53
Dependent Claim
12 words
The method of claim 7, wherein said void-containing structure comprises a powder.
Claim 54
Dependent Claim
12 words
The method of claim 7, wherein said void-containing structures comprise a carbohydrate.
Claim 55
Dependent Claim
25 words
The method of claim 7, wherein said void-containing structures comprise a compound selected from the group consisting of starch, derivatized starch, dextrin or combinations thereof.
Claim 56
Dependent Claim
12 words
The method of claim 7, wherein said void-containing structures comprise said surfactant.
Claim 57
Dependent Claim
23 words
The method of claim 51, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.
Claim 58
Dependent Claim
13 words
The method of claim 7, wherein said void containing structure comprises a protein.
Claim 59
Dependent Claim
32 words
The method of claim 24 wherein said fluorocarbon is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.
Claim 60
Dependent Claim
12 words
The method of claim 19 wherein said gas osmotic agent comprises perfluorohexane.
Claim 61
Dependent Claim
12 words
The method of claim 19 wherein said film-forming material comprises a surfactant.
Claim 62
Dependent Claim
30 words
The method of claim 56 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
Claim 63
Dependent Claim
65 words
The method of claim 56 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.
Claim 64
Dependent Claim
12 words
The method of claim 19, wherein said film-forming structures comprise a carbohydrate.
Claim 65
Dependent Claim
24 words
The method of claim 59 wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar and dried lactose microspheres.
Claim 66
Dependent Claim
12 words
The method of claim 19, wherein said film-forming material comprises a protein.
Claim 67
Dependent Claim
36 words
The method of claim 28 wherein said gas osmotic agent-permeated surfactant-containing powder comprises a surfactant selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
Claim 68
Dependent Claim
65 words
The method of claim 62 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.
Claim 69
Dependent Claim
13 words
The method of claim 28 wherein said surfactant-containing powder comprises a non-Newtonian surfactant.
Claim 70
Dependent Claim
14 words
The method of claim 28 wherein said non-Newtonian surfactant comprises one or more phospholipids.
Claim 71
Dependent Claim
15 words
The method of claim 28 wherein said gas osmotic agent-permeated surfactant-containing powder comprises a fluorocarbon.
Claim 72
Dependent Claim
32 words
The method of claim 66 wherein said fluorocarbon is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.
Claim 73
Dependent Claim
12 words
The method of claim 28 wherein said gas osmotic agent comprises perfluorohexane.
Claim 74
Dependent Claim
15 words
The method of claim 28, wherein said gas osmotic agent-permeated surfactant-containing powder comprises a carbohydrate.
Claim 75
Dependent Claim
24 words
The method of claim 69 wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar and dried lactose microspheres.
Claim 76
Dependent Claim
15 words
The method of claim 28, wherein said gas osmotic agent-permeated surfactant-containing powder comprises a protein.
Claim 77
Dependent Claim
28 words
The method of claim 28, wherein said gas osmotic agent-permeated surfactant-containing powder comprises a compound selected from the group consisting of starch, derivatized starch, dextrin or combinations thereof.
Claim 78
Dependent Claim
32 words
The method of claim 72, wherein said compound comprises a starch or derivatized starch having a molecular weight of greater than about 500,000 or a dextrose equivalency value less than about 12.
Claim 79
Dependent Claim
11 words
The method of claim 72, wherein said starch is hydroxyethyl starch.
Claim 80
Dependent Claim
13 words
The method of claim 29 wherein said spray dried formulation comprises a surfactant.
Claim 81
Dependent Claim
30 words
The method of claim 75 wherein said surfactant is selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
Claim 82
Dependent Claim
65 words
The method of claim 75 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters, fatty alcohols, aliphatic amine oxides, hyaluronic acid aliphatic esters, hyaluronic acid aliphatic ester salts, poly(ethyleneoxy)ethanol, nonylphenoxy poly(ethyleneoxy)ethanol, derivatized starches, hydroxy ethyl starch fatty acid esters, commercial food vegetable starches, dextrans, dextrin fatty acid esters, sorbitol, sorbitol fatty acid esters, gelatin, serum albumins and combinations thereof.
Claim 83
Dependent Claim
12 words
The method of claim 75 wherein said surfactant comprises a non-Newtonian surfactant.
Claim 84
Dependent Claim
14 words
The method of claim 78 wherein said non-Newtonian surfactant comprises one or more phospholipids.
Claim 85
Dependent Claim
13 words
The method of claim 29 wherein said gas osmotic agent comprises a fluorocarbon.
Claim 86
Dependent Claim
32 words
The method of claim 80 wherein said fluorocarbon is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.
Claim 87
Dependent Claim
12 words
The method of claim 29 wherein said gas osmotic agent comprises perfluorohexane.
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