Patent US5695741A successfully refreshed from Google Patents.
US5695741A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Stable microbubble precursors
Assignee: PHOTOGEN TECHNOLOGIES Inc
•
Filing: 1995-06-07
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Granted: 1997-12-09
•
Expires: 2015-06-07
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 David Anderson
- 👤 David P. Evitts
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 16:39
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: 80
Claim 1
Independent Claim
65 words
A microbubble precursor composition comprising a fluorocarbon gas osmotic agent dispersed in a plurality of spray dried microspheres having an average diameter of less than about 100 μm said spray dried microspheres comprising a surfactant in combination with a compound selected from the group consisting of starch, derivatized starch, dextran, and sugar esters having a component with a hydrophilic/lipophilic balance of less than about 8.
Claim 2
Dependent Claim
65 words
A microbubble precursor composition comprising a fluorocarbon gas osmotic agent dispersed in a plurality of spray dried microspheres having an average diameter of less than about 100 μm said spray dried microspheres comprising a surfactant in combination with a compound selected from the group consisting of starch, derivatized starch, dextran, and sugar esters having a component with a hydrophilic/lipophilic balance of less than about 8.
Claim 3
Dependent Claim
15 words
The composition of claim 1 wherein said microbubble precursor composition comprises a plurality of voids.
Claim 4
Dependent Claim
35 words
The composition of claim 1 wherein said fluorocarbon gas osmotic agent 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 5
Dependent Claim
30 words
The composition of claim 1 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 6
Dependent Claim
21 words
The composition of claim 4, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids and block copolymers.
Claim 7
Dependent Claim
20 words
The composition of claim 1, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.
Claim 8
Dependent Claim
12 words
The composition of claim 1, wherein said surfactant is a non-Newtonian surfactant.
Claim 9
Dependent Claim
10 words
The composition of claim 1 wherein said microspheres are proteinaceous.
Claim 10
Dependent Claim
13 words
The composition of claim 1, wherein said microspheres further comprise an additional carbohydrate.
Claim 11
Dependent Claim
12 words
The composition of claim 9, wherein said additional carbohydrate is a sugar.
Claim 12
Dependent Claim
102 words
A microbubble precursor composition comprising: a plurality of solid substantially liquid-soluble void-containing structures, said void-containing structures defining a plurality of voids having an average diameter less than about 100 μm; a gas comprising a gas osmotic agent having a water solubility of not more than about 0.5 mM at 25° C. and one atmosphere, said gas dispersed in said voids; and a surfactant associated with said void containing structures, wherein said void-containing structures, said gas and said surfactant are together adapted to form microbubbles upon addition of said microbubble precursor composition to a liquid in which said void-containing structures are substantially soluble.
Claim 13
Dependent Claim
102 words
A microbubble precursor composition comprising: a plurality of solid substantially liquid-soluble void-containing structures, said void-containing structures defining a plurality of voids having an average diameter less than about 100 μm; a gas comprising a gas osmotic agent having a water solubility of not more than about 0.5 mM at 25° C. and one atmosphere, said gas dispersed in said voids; and a surfactant associated with said void containing structures, wherein said void-containing structures, said gas and said surfactant are together adapted to form microbubbles upon addition of said microbubble precursor composition to a liquid in which said void-containing structures are substantially soluble.
Claim 14
Dependent Claim
13 words
The composition of claim 11 wherein said gas osmotic agent comprises a fluorocarbon.
Claim 15
Dependent Claim
32 words
The composition of claim 12 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 16
Dependent Claim
30 words
The composition of claim 11 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 17
Dependent Claim
20 words
The composition of claim 11, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.
Claim 18
Dependent Claim
12 words
The composition of claim 11, wherein said surfactant is a non-Newtonian surfactant.
Claim 19
Dependent Claim
23 words
The composition of claim 11 wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.
Claim 20
Dependent Claim
12 words
The composition of claim 11, wherein said void-containing structure comprises a powder.
Claim 21
Dependent Claim
14 words
The composition of claim 11, wherein said void-containing structures are formed of a carbohydrate.
Claim 22
Dependent Claim
24 words
The composition of claim 19 wherein said carbohydrate is selected from the group consisting of sugar crystals, spray dried sugar and dried lactose microspheres.
Claim 23
Dependent Claim
11 words
The composition of claim 11, wherein said void-containing structures are proteinaceous.
Claim 24
Dependent Claim
12 words
The composition of claim 11, wherein said void-containing structures comprise said surfactant.
Claim 25
Dependent Claim
23 words
The composition of claim 22, wherein said surfactant is selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.
Claim 26
Dependent Claim
17 words
The composition of claim 11, wherein said plurality of void-containing structures comprise a plurality of spray-dried microspheres.
Claim 27
Dependent Claim
56 words
A method for imaging, comprising: providing a microbubble precursor composition according to claim 11; dissolving at least a portion of said microbubble precursor composition in a liquid whereby the gas comprising said gas osmotic agent forms microbubbles that are surrounded by said surfactant; introducing said microbubbles into a vertebrate; and imaging said microbubbles in said vertebrate.
Claim 28
Dependent Claim
11 words
The method of claim 25, wherein said surfactant is a phospholipid.
Claim 29
Dependent Claim
13 words
The method of claim 25 wherein said gas osmotic agent comprises a fluorocarbon.
Claim 30
Dependent Claim
35 words
The method of claim 27 wherein said fluorocarbon gas osmotic agent 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 31
Dependent Claim
24 words
The method of claim 27, wherein said gas further comprises a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.
Claim 32
Dependent Claim
13 words
The method of claim 25 wherein said void containing structures comprise said surfactant.
Claim 33
Dependent Claim
30 words
The method of claim 25 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 34
Dependent Claim
22 words
The method of claim 25, wherein said surfactant in selected from the group consisting of block copolymers, sugar esters and fatty acids.
Claim 35
Dependent Claim
20 words
The method of claim 25, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.
Claim 36
Dependent Claim
12 words
The method of claim 25, wherein said surfactant is a non-Newtonian surfactant.
Claim 37
Dependent Claim
25 words
The method of claim 25 wherein said void containing structures comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.
Claim 38
Dependent Claim
14 words
The method of claim 25, wherein said void containing structures comprise a proteinaceous compound.
Claim 39
Dependent Claim
13 words
The method of claim 25, wherein said void containing structures comprise a carbohydrate.
Claim 40
Dependent Claim
24 words
The method of claim 25 wherein said imaging step comprises a technique selected from the group consisting of magnetic resonance imaging and ultrasound imaging.
Claim 41
Dependent Claim
18 words
The method of claim 25 wherein said plurality of void containing structures comprise a plurality of spray-dried microspheres.
Claim 42
Dependent Claim
97 words
A stable microbubble precursor for use in preparing stabilized microbubbles in a liquid, said composition comprising: a plurality of solid substantially liquid-soluble void containing structures comprising at least one surfactant, said void containing structures defining a plurality of voids having an average diameter less than about 100 μm; and a gas mixture comprising a fluorocarbon gas osmotic agent and a modifier gas dispersed in said plurality of voids wherein said void containing structures and said gas mixture are together adapted to form microbubbles upon addition of a liquid in which said void containing structures are substantially soluble.
Claim 43
Dependent Claim
97 words
A stable microbubble precursor for use in preparing stabilized microbubbles in a liquid, said composition comprising: a plurality of solid substantially liquid-soluble void containing structures comprising at least one surfactant, said void containing structures defining a plurality of voids having an average diameter less than about 100 μm; and a gas mixture comprising a fluorocarbon gas osmotic agent and a modifier gas dispersed in said plurality of voids wherein said void containing structures and said gas mixture are together adapted to form microbubbles upon addition of a liquid in which said void containing structures are substantially soluble.
Claim 44
Dependent Claim
35 words
The composition of claim 46 wherein said fluorocarbon gas osmotic agent is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcycopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohoxane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine.
Claim 45
Dependent Claim
30 words
The composition of claim 40 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 46
Dependent Claim
23 words
The composition of claim 42, wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters and fatty acids.
Claim 47
Dependent Claim
20 words
The composition of claim 42, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.
Claim 48
Dependent Claim
12 words
The composition of claim 40, wherein said surfactant is a non-Newtonian surfactant.
Claim 49
Dependent Claim
24 words
The composition of claim 40, wherein said modifier gas comprises a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.
Claim 50
Dependent Claim
26 words
The composition of claim 46 wherein the molar ratio of said nonfluorocarbon gas to said fluorocarbon gas osmotic agent is from about 1:10 to about 1000:1.
Claim 51
Dependent Claim
23 words
The composition of claim 40 wherein said void containing structures comprise a compound selected from the group consisting of starches and derivatized starches.
Claim 52
Dependent Claim
14 words
The composition of claim 40, wherein said void containing structures comprise a proteinaceous compound.
Claim 53
Dependent Claim
13 words
The composition of claim 40, wherein said void containing structures comprise a carbohydrate.
Claim 54
Dependent Claim
40 words
A method for imaging, comprising: providing a stable microbubble precursor according to claim 40; combining said microbubble precursor with a liquid to provide a plurality of microbubbles; introducing said microbubbles into a vertebrate; and imaging said microbubbles in said vertebrate.
Claim 55
Dependent Claim
28 words
The method of claim 51, wherein the fluorocarbon gas osmotic agent has a water solubility of not more than about 0.5 mM at 25° C. and one atmosphere.
Claim 56
Dependent Claim
35 words
The method of claim 51 wherein said fluorocarbon gas osmotic agent 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 57
Dependent Claim
13 words
The method of claim 53 wherein said fluorocarbon gas osmotic agent is perfluorohexane.
Claim 58
Dependent Claim
24 words
The method of claim 51 wherein said modifier gas is a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.
Claim 59
Dependent Claim
30 words
The method of claim 51 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 60
Dependent Claim
22 words
The method of claim 51, wherein said surfactant is selected from the group consisting of block copolymers, sugar esters and fatty acids.
Claim 61
Dependent Claim
20 words
The method of claim 51, wherein said surfactant has a component having a hydrophilic/lipophilic balance of less than about 8.
Claim 62
Dependent Claim
12 words
The method of claim 51, wherein said surfactant is a non-Newtonian surfactant.
Claim 63
Dependent Claim
11 words
The method of claim 51, wherein the surfactant is a phospholipid.
Claim 64
Dependent Claim
25 words
The method of claim 51, wherein said void containing structures comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.
Claim 65
Dependent Claim
14 words
The method of claim 51, wherein said void containing structures comprise a proteinaceous compound.
Claim 66
Dependent Claim
13 words
The method of claim 51, wherein said void containing structures comprise a carbohydrate.
Claim 67
Dependent Claim
18 words
The method of claim 51, wherein said plurality of void containing structures comprise a plurality of spray-dried microspheres.
Claim 68
Dependent Claim
24 words
The method of claim 51, wherein said imaging step comprises a technique selected from the group consisting of magnetic resonance imaging and ultrasound imaging.
Claim 69
Independent Claim
87 words
A method of forming a stable microbubble precursor for use in preparing stabilized microbubbles in a liquid, said method comprising the steps of: spray-drying a liquid formulation to produce a plurality of solid substantially liquid-soluble microspheres defining a plurality of voids having an average diameter less than about 100 μm; and permeating said microspheres with a gas comprising a fluorocarbon gas osmotic agent wherein said microspheres and said gas are together adapted to form microbubbles upon addition of a liquid in which said microspheres are substantially soluble.
Claim 70
Independent Claim
87 words
A method of forming a stable microbubble precursor for use in preparing stabilized microbubbles in a liquid, said method comprising the steps of: spray-drying a liquid formulation to produce a plurality of solid substantially liquid-soluble microspheres defining a plurality of voids having an average diameter less than about 100 μm; and permeating said microspheres with a gas comprising a fluorocarbon gas osmotic agent wherein said microspheres and said gas are together adapted to form microbubbles upon addition of a liquid in which said microspheres are substantially soluble.
Claim 71
Dependent Claim
14 words
The method of claim 66 wherein said liquid formulation comprises at least one surfactant.
Claim 72
Dependent Claim
30 words
The method of claim 67 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 73
Dependent Claim
23 words
The method of claim 68, wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, sugar esters and fatty acids.
Claim 74
Dependent Claim
12 words
The method of claim 66, wherein said surfactant is a non-Newtonian surfactant.
Claim 75
Dependent Claim
35 words
The method of claim 66 wherein said fluorocarbon gas osmotic agent 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 76
Dependent Claim
24 words
The method of claim 66, wherein said gas further comprises a nonfluorocarbon gas with the proviso that said nonfluorocarbon gas is not water vapor.
Claim 77
Dependent Claim
17 words
The method of claim 66 further comprising the step of storing said spray-dried composition in a container.
Claim 78
Dependent Claim
24 words
The composition of claim 24 wherein said spray-dried microspheres comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters.
Claim 79
Dependent Claim
12 words
The composition of claim 24 wherein said spray-dried microspheres comprise said surfactant.
Claim 80
Dependent Claim
23 words
The composition of claim 75 wherein said surfactant is selected from the group consisting of phospholipids, block copolymers, fatty acids and sugar esters.
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