Microbubble compositions, method of making same, and method using same
Inventors
Unger, Evan C. • Hendon, Patrick W.
Assignees
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Publication Number
US-10279053-B2
Publication Date
2019-05-07
Expiration Date
Abstract
A method of forming a plurality of microbubbles, wherein the method disposes in a sealed container comprising a first volume at ambient pressure, a second volume of a mixture comprising one or more microbubble stabilizing materials. The first volume is greater than said second volume. The method further comprises sealing said container, introducing a gas into said sealed container, and shaking the container to form said plurality of microbubbles.
Core Innovation
The document discloses microbubbles for medical ultrasound imaging formed in a sealed container or sealed system. The microbubbles include a gas core, with perfluoropentane, perfluorobutane, and perfluorohexane described, and have a diameter less than about 1.25 microns.
Microbubble stabilizing materials are used during formation, including lipid components such as dipalmitoylphosphatidylcholine and PEG-containing lipids. The container is sealed with a septum and a headspace environment is used so that a perfluorocarbon gas is volatilized or introduced to support formation of smaller microbubbles with narrow size distribution.
The document contrasts different perfluorocarbon handling approaches and presents comparative results showing higher microbubble production and improved stability when using a headspace perfluoropentane approach. It also describes resistance to higher acoustic pressures and reports in vitro sonothrombolysis outcomes using targeted microbubble preparations.
Claims Coverage
The provided claims include two independent method claims, each covering formation of a plurality of microbubbles with diameter less than about 1.25 microns. The inventive coverage is organized around the sealed-container formation approach, the selection and handling of perfluorocarbon gas to generate the microbubble gas core, and the inclusion of specific lipid-based stabilizing materials in the microbubble-forming mixture.
Sealed-container microbubble formation with evacuated headspace and perfluoropentane volatilization
Disposing a dipalmitoylphosphatidylcholine-containing mixture in a container with a first volume at ambient pressure greater than a second volume; sealing with a septum; evacuating a headspace of the sealed container; cooling the sealed container; introducing liquid perfluoropentane; evacuating the headspace until the liquid perfluoropentane is volatilized; and shaking the container to form a plurality of microbubbles with diameter less than about 1.25 microns.
External formation of first gas from a low-boiling perfluorocarbon and injection of second gas
Disposing a dipalmitoylphosphatidylcholine-containing mixture in a container with a first volume at ambient pressure greater than a second volume; forming a first gas by volatizing, external to the container, a liquid perfluorocarbon having a boiling point less than about 57°C at 760 mm pressure; injecting the first gas into the container; sealing the container with a septum; injecting a second gas selected from air, nitrogen and oxygen; and shaking the container to form a plurality of microbubbles with diameter less than about 1.25 microns.
Both independent claims require formation of microbubbles smaller than about 1.25 microns and differ in how the perfluorocarbon gas component is generated and introduced. One claim relies on evacuating and then volatilizing perfluoropentane within a sealed container before shaking, while the other claim generates a perfluorocarbon-derived first gas external to the container, injects an additional second gas selected from air, nitrogen, or oxygen, and then shakes to form the microbubbles.
Stated Advantages
Higher bubble production and improved stability when using a headspace perfluoropentane approach.
Improved stability and resistance to higher acoustic pressures.
Smaller average microbubble diameters described as about 1 microns and less than about 1.25 microns.
Documented Applications
Medical ultrasound imaging, including echocardiography, using the disclosed microbubble contrast agent compositions.
In vitro sonothrombolysis outcomes using targeted microbubble preparations for fibrin binding peptide-mediated clot lysis.
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