Claims for Patent: 5,798,091

Summary for Patent: 5,798,091

Title:	Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
Abstract:	A gas emulsion forming composition comprising a dry, hollow, particulate, approximately microspherical material permeated with a gas or gas mixture, which upon dissolution in aqueous liquid forms a gas emulsion comprising a plurality of bubbles surrounded by a layer of at least a first and a second surfactant, wherein the first surfactant consists essentially of a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, and wherein the second surfactant may or may not be a phospholipid and is more water soluble than the first surfactant; kits for preparing such microbubbles; and methods for using such microbubbles as contrast agents.
Inventor(s):	Trevino; Leo A. (San Diego, CA), Schutt; Ernest George (San Diego, CA), Klein; David H. (Carlsbad, CA), Tarara; Thomas E. (San Diego, CA), Weers; Jeffry G. (San Diego, CA), Kabalnov; Alexey (San Diego, CA)
Assignee:	Alliance Pharmaceutical Corp. (San Diego, CA)
Application Number:	08/395,680
Patent Claims:	1. A method for forming a gas emulsion comprising the steps of: providing a container having therein a substantially non-lamellar approximately microspherical material comprising at least a first and a second surfactant, a hydrophilic monomer or polymer or combination thereof, and a gas or gas mixture, said first surfactant comprising a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, said second surfactant being more water soluble than said first surfactant; adding an aqueous liquid to said container; substantially dissolving said microspherical material in said aqueous liquid, thereby forming a gas emulsion in said container, said gas emulsion comprising bubbles of said gas or gas mixture surrounded by a layer of said first and said second surfactants said gas emulsion substantially free of lamellar surfactant structures. 2. The method of claim 1, wherein said second surfactant is selected from the group consisting of a fatty acid, a salt of a fatty acid, a sugar ester of a fatty acid, a polyoxypropylene-polyoxyethylene copolymer, a nonionic alkylglucoside, a polysorbate, and combinations thereof. 3. The method of claim 1, wherein said second surfactant is selected from the group consisting of a phospholipid, a mixture of phospholipids, a phosphocholine, a lysophospholipid and combinations thereof wherein each acyl chain comprises no more than 14 carbon atoms. 4. The method of claim 1, wherein said first surfactant is a phosphatidylcholine with one or more acyl chains, at least one chain comprising 12 to 18 carbon atoms, and said second surfactant is a phosphatidylcholine with one or more acyl chains, at least one chain comprising 6 to 12 carbon atoms. 5. The method of claim 1, wherein said hydrophilic monomer or polymer or combination thereof is selected from the group consisting of starches, derivatized starches and combinations thereof. 6. The method of claim 1, wherein said gas or gas mixture comprises a gas osmotic agent and a modifier gas. 7. The method of claim 6, wherein said gas osmotic agent has a vapor pressure of less than 760 mm Hg at 37 degrees C. 8. The method of claim 6 wherein said modifier gas comprises a compound selected from the group consisting of nitrogen oxygen, carbon dioxide and combinations thereof. 9. The method of claim 6 wherein said 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. 10. The method of claim 9 wherein said modifier gas is air. 11. The method of claim 9 wherein said gas osmotic agent is perfluorohexane. 12. The method of claim 11 wherein said modifier gas is nitrogen. 13. A method for imaging an object or body comprising the steps of: introducing a gas emulsion made according to the method of claim 1 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 14. A method for imaging an object or body comprising the steps of: introducing a gas emulsion made according to the method of claim 6 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 15. A method for imaging an object or body comprising the steps of: introducing a gas emulsion made according to the method of claim 9 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 16. A method for imaging an object or body comprising the steps of: introducing a gas emulsion made according to the method of claim 12 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 17. A gas emulsion ultrasound contrast medium, comprising: an aqueous continuous phase substantially free of lamellar surfactant structures comprising a plurality of bubbles of a gas or gas mixture comprising a fluorocarbon or mixture of fluorocarbons having at least four carbon atoms surrounded by a surfactant layer comprising at least a first and a second surfactant, said first surfactant consisting essentially of a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, and wherein said second surfactant is more water soluble than said first surfactant. 18. The contrast medium of claim 17, wherein said second surfactant is selected from the group consisting of a fatty acid, a salt of a fatty acid, a sugar ester of a fatty acid, a polyoxypropylene-polyoxyethylene copolymer, a nonionic alkylglucoside, a polysorbate, and combinations thereof. 19. The contrast medium of claim 17, wherein said second surfactant is selected from the group consisting of a phospholipid, a mixture of phospholipids, a phosphocholine, a lysophospholipid and combinations thereof wherein each acyl chain comprises no more than 14 carbon atoms. 20. The contrast medium of claim 17, wherein said first surfactant is a phoshatidylcholine with one or more acyl chains, at least one chain comprising 12 to 18 carbon atoms, and said second surfactant is a phosphatidylcholine with one or more acyl chains, at least one chain comprising 6 to 12 carbon atoms. 21. The contrast medium of claim 17, wherein said gas or gas mixture comprises a gas osmotic agent and a modifier gas. 22. The contrast medium of claim 21, wherein said modifier gas comprises a compound selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof. 23. A method for imaging an object or body comprising the steps of: introducing an ultrasound contrast medium according to claim 17 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 24. A method for imaging an object or body comprising the steps of: introducing an ultrasound contrast medium according to claim 22 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 25. The contrast medium of claim 21 wherein said gas osmotic agent is selected from the group consisting of perfluoropropane, perfluroropropane, perfluorocyclobutane, perfluoromethylcyclobutane, perfluoropentane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclobutanes, perfluorohexane, perfluorocyclohexane, perfluoroheptane, perfluorocycloheptane, perfluoromethylcyclohexane, perfluorodimethylcyclopentane, perfluorotrimethylcyclobutane, and perfluorotriethylamine. 26. The contrast medium of claim 25 wherein said gas osmotic agent is perfluorohexane. 27. The contrast medium of claim 25 wherein said modifier gas is air. 28. A method for imaging an object or body comprising the steps of: introducing an ultrasound contrast medium according to claim 25 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 29. A method for imaging an object or body comprising the steps of: introducing an ultrasound contrast medium according to claim 26 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 30. The contrast agent of claim 26 wherein said modifier gas is nitrogen. 31. A method for imaging an object or body comprising the steps of: introducing an ultrasound contrast medium according to claim 30 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 32. A method of making an ultrasound contrast medium comprising substantially dissolving a substantially non-lamellar composition in an aqueous liquid thereby forming a gas emulsion substantially free of lamellar surfactant structures, said gas emulsion comprising bubbles containing said gas or gas mixture surrounded by a layer of said first and said second surfactants wherein said first surfactant is a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, and said second surfactant is more water soluble than said first surfactant. 33. A method of making an ultrasound contrast medium comprising substantially dissolving a composition associated with a gas mixture comprising perfluorohexane and a modifier gas selected from the group consisting of nitrogen, oxygen, carbon dioxide and combinations thereof in an aqueous liquid, thereby forming a gas emulsion in said container, said gas emulsion comprising bubbles containing said gas mixture surrounded by a layer of said first and said second surfactants wherein said first surfactant is a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, and said second surfactant is more water soluble than said first surfactant. 34. A method for imaging an object or body comprising the steps of: introducing an ultrasound contrast medium made according to the method of claim 33 into said object or body, and; ultrasonically imaging at least a portion of said object or body. 35. A gas emulsion ultrasound contrast medium, comprising: an aqueous continuous phase substantially free of lamellar surfactant structures comprising a plurality of bubbles of a gas or gas mixture comprising a fluorocarbon or mixture of fluorocarbons surrounded by a surfactant layer comprising dimyristoyl phosphatidylcholine and a second surfactant wherein said second surfactant is more water soluble than dimyristoyl phosphatidylcholine.