Methods of preparing gaseous precursor-filled microspheres

Abstract

Methods of and apparatus for preparing gas-filled microspheres are described. Gas-filled microspheres prepared by these methods are particularly useful, for example, in ultrasonic imaging applications and in therapeutic drug delivery systems.

1 - 15 . (canceled)  
     
     
         16 . Gas-filled lipid microspheres that comprise a lipid monolayer encapsulating a perfluorocarbon gas, said lipid comprising dipalmatoylphosphatidic acid, at least one phosphatidylcholine selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine, and at least one phosphatidylethanolamine selected from the group consisting of dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine-PEG 5,000, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine, wherein said gas-filled microspheres are prepared by a process that comprises shaking an aqueous suspension comprising said lipids in the presence of said perfluorocarbon gas at a temperature below the gel state to liquid crystalline transition temperature of said lipids, said shaking performed with sufficient intensity and duration to produce said gas-filled lipid microspheres.  
     
     
         17 . The gas-filled lipid microspheres of  claim 16  wherein said perfluorocarbon gas is selected from the group consisting of perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, and perfluorocyclobutane.  
     
     
         18 . The gas-filled lipid microspheres of  claim 17  wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, and perfluorocyclobutane.  
     
     
         19 . The gas-filled lipid microspheres of  claim 18  wherein said perfluorocarbon gas is perfluoropropane.  
     
     
         20 . The gas-filled lipid microspheres of  claim 16  wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine.  
     
     
         21 . The gas-filled lipid microspheres of  claim 16  wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG 5,000.  
     
     
         22 . The gas-filled lipid microspheres of  claim 16  wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine and said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG 5,000.  
     
     
         23 . The gas-filled lipid microspheres of  claim 22  wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, and perfluorocyclobutane.  
     
     
         24 . The gas-filled lipid microspheres of  claim 23  wherein said perfluorocarbon gas is perfluoropropane.  
     
     
         25 . The gas-filled lipid microspheres of  claim 24  wherein said microspheres comprise dipalmitoylphosphatidylcholine, dipalmatoylphosphatidic acid and dipalmitoylphosphatidylethanolamine-PEG 5,000 in a mole percent ratio of 82%:10%:8%.  
     
     
         26 . A method of ultrasound imaging comprising: 
 (i) shaking an aqueous solution comprising dipalmatoylphosphatidic acid, at least one phosphatidylcholine selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoylphosphatidylcholine, and at least one phosphatidylethanolamine selected from the group consisting of dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine-PEG 5,000, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine, in the presence of a perfluorocarbon gas at a temperature below the gel state to liquid crystalline transition temperature of said lipids, and with sufficient intensity and duration to produce gas-filled lipid microspheres that comprise a lipid monolayer encapsulating a perfluorocarbon gas;    (ii) administering said gas-filled microspheres to a patient; and    (iii) scanning the patient using ultrasonic imaging.    
     
     
         27 . The method of  claim 26  wherein the aqueous solution is provided in a vessel, said shaking produces a gas-filled lipid microsphere-containing foam above said aqueous solution, and said method further comprises the step of extracting said foam from said vessel for administration to said patient.  
     
     
         28 . The method of  claim 27  wherein said extraction is by syringe.  
     
     
         29 . The gas-filled lipid microspheres of  claim 26  wherein said perfluorocarbon gas is selected from the group consisting of perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, and perfluorocyclobutane.  
     
     
         30 . The gas-filled lipid microspheres of  claim 29  wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, and perfluorocyclobutane.  
     
     
         31 . The gas-filled lipid microspheres of  claim 30  wherein said perfluorocarbon gas is perfluoropropane.  
     
     
         32 . The gas-filled lipid microspheres of  claim 26  wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine.  
     
     
         33 . The gas-filled lipid microspheres of  claim 26  wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG 5,000.  
     
     
         34 . The gas-filled lipid microspheres of  claim 26  wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine and said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG 5,000.  
     
     
         35 . The gas-filled lipid microspheres of  claim 34  wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, and perfluorocyclobutane.  
     
     
         36 . The gas-filled lipid microspheres of  claim 35  wherein said perfluorocarbon gas is perfluoropropane.  
     
     
         37 . The gas-filled lipid microspheres of  claim 36  wherein said microspheres comprise dipalmitoylphosphatidylcholine, dipalmatoylphosphatidic acid and dipalmitoylphosphatidylethanolamine-PEG 5,000 in a mole percent ratio of 82%:10%:8%.