Claims for Patent: 5,547,656

Summary for Patent: 5,547,656

Title:	Low density microspheres and their use as contrast agents for computed tomography, and in other applications
Abstract:	Substantially homogeneous aqueous suspensions of low density microspheres are presented as contrast media for imaging the gastrointestinal tract and other body cavities using computed tomography. In one embodiment, the low density microspheres are gas-filled. With computed tomography, the contrast media serve to change the relative density of certain areas within the gastrointestinal tract and other body cavities, and improve the overall diagnostic efficacy of this imaging method.
Inventor(s):	Unger; Evan C. (Tucson, AZ)
Assignee:	Imarx Pharmaceutical Corp. (Tucson, AZ)
Application Number:	08/449,090
Patent Claims:	1. A contrast medium for computed tomography imaging of the gastrointestinal region or other body cavities comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon. 2. A contrast medium according to claim 1 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, .epsilon.-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinyl pyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride, N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine, and methylenebis-(4-phenyl-isocyanate). 3. A contrast medium according to claim 2 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, .epsilon.-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates, and 2-methacryloyloxy-trimethylammonium chloride. 4. A contrast medium according to claim 1 wherein said microspheres comprise synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(.epsilon.-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), polyamide, polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile. 5. A contrast medium according to claim 1 wherein said microspheres comprise polyvinylidene-polyacrylonitrile copolymer. 6. A contrast medium according to claim 1 wherein the microspheres are prepared by a heat expansion process. 7. A contrast medium according to claim 1 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer. 8. A contrast medium according to claim 1 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having between 1 and about 9 carbon atoms and between about 4 and about 20 fluorine atoms. 9. A contrast medium according to claim 8 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having less than about 4 carbon atoms and less than about 10 fluorine atoms. 10. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C.sub.3 F.sub.8. 11. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C.sub.4 F.sub.10. 12. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C.sub.5 F.sub.12. 13. A contrast medium according to claim 8 wherein said perfluorocarbon gas is C.sub.6 F.sub.14. 14. A contrast medium according to claim 1 further comprising a thickening or suspending agent. 15. A contrast medium according to claim 14 wherein said thickening or suspending agent is selected from the group consisting of cellulose, carboxymethylcellulose, methylcellulose, and methylhydroxycellulose. 16. A contrast medium according to claim 15 wherein said thickening or suspending agent is methylcellulose. 17. A contrast medium according to claim 1 further comprising a compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants. 18. A contrast medium according to claim 17 wherein said compound selected from the group of antacids, antiflatulents, antifoaming agents, and surfactants, comprises a polymeric siloxane. 19. A contrast medium according to claim 18 wherein said polymeric siloxane is dimethylpolysiloxane. 20. A contrast medium according to claim 19 wherein said dimethylpolysiloxane is simethicone. 21. A contrast medium according to claim 1 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer, and said perfluorocarbon gas comprises C.sub.5 F.sub.12, and wherein said contrast medium further comprises methylcellulose and simethicone. 22. A contrast medium for diagnostic imaging comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon. 23. A contrast medium according to claim 22 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, .epsilon.-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinyl pyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride, N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine, and methylenebis-(4-phenyl-isocyanate). 24. A contrast medium according to claim 23 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, .epsilon.-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates, and 2-methacryloyloxy-trimethylammonium chloride. 25. A contrast medium according to claim 22 wherein said microspheres comprise synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(.epsilon.-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), polyamide, polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile. 26. A contrast medium according to claim 22 wherein said microspheres comprise a polyvinylidene-polyacrylonitrile copolymer. 27. A contrast medium according to claim 22 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer. 28. A contrast medium according to claim 22 wherein said microspheres are prepared by a heat expansion process. 29. A contrast medium according to claim 22 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having between 1 and about 9 carbon atoms and between about 4 and about 20 fluorine atoms. 30. A contrast medium according to claim 29 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having less than about 4 carbon atoms and less than about 10 fluorine atoms. 31. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C.sub.3 F.sub.8. 32. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C.sub.4 F.sub.10. 33. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C.sub.5 F.sub.12. 34. A contrast medium according to claim 29 wherein said perfluorocarbon gas is C.sub.6 F.sub.14. 35. A contrast medium according to claim 22 further comprising a thickening or suspending agent. 36. A contrast medium according to claim 35 wherein said thickening or suspending agent is selected from the group consisting of cellulose, carboxymethylcellulose, methylcellulose, and methylhydroxycellulose. 37. A contrast medium according to claim 36 wherein said thickening or suspending agent is methylcellulose. 38. A contrast medium according to claim 22 further comprising a compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants. 39. A contrast medium according to claim 38 wherein said compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants, comprises a polymeric siloxane. 40. A contrast medium according to claim 39 wherein said polymeric siloxane is dimethylpolysiloxane. 41. A contrast medium according to claim 40 wherein said dimethylpolysiloxane is simethicone. 42. A contrast medium according to claim 22 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer, and said perfluorocarbon gas comprises C.sub.5 F.sub.12, and wherein said contrast medium further comprises methylcellulose and simethicone. 43. A substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon. 44. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, .epsilon.-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2-sulfoxyethyl methacrylate, vinyl pyridine, aminoethyl methacrylates, 2-methacryloyloxy-trimethylammonium chloride, N,N'-methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'-(p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine, and methylenebis-(4-phenyl-isocyanate). 45. An aqueous suspension of microspheres according to claim 44 wherein said microspheres comprise synthetic polymers or copolymers prepared from the group of monomers consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, .epsilon.-caprolactone, acrolein, cyanoacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkyl-methacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2-pyrrolidone, 2,4-pentadiene-1-ol, vinyl acetate, acrylonitrile, styrene, p-amino-styrene, p-amino-benzyl-styrene, sodium styrene sulfonate, sodium 2- sulfoxyethylmethacrylate, vinyl pyridine, aminoethyl methacrylates, and 2-methacryloyloxy-trimethylammonium chloride. 46. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(.epsilon.-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), polyamide, polyvinylidene-polyacrylonitrile, polyvinylidene-polyacrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile. 47. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise a polyvinylidene-polyacrylonitrile copolymer. 48. An aqueous suspension of microspheres according to claim 43 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer. 49. An aqueous suspension of microspheres according to claim 43 wherein said microspheres are prepared by a heat expansion process. 50. An aqueous suspension of microspheres according to claim 43 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having between 1 and about 9 carbon atoms and between about 4 and about 20 fluorine atoms. 51. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is selected from the group consisting of perfluorocarbons having less than about 4 carbon atoms and less than about 10 fluorine atoms. 52. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C.sub.3 F.sub.8. 53. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C.sub.4 F.sub.10. 54. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C.sub.5 F.sub.12. 55. An aqueous suspension of microspheres according to claim 50 wherein said perfluorocarbon gas is C.sub.6 F.sub.14. 56. An aqueous suspension according to claim 43 wherein said microspheres comprise a polyoxypropylene-polyoxyethylene copolymer, and said perfluorocarbon gas comprises C.sub.5 F.sub.12, and wherein said aqueous suspension further comprises methylcellulose and simethicone. 57. A kit for computed tomography imaging of the gastrointestinal region or other body cavities of a patient comprising low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, in combination with a thickening or suspending agent. 58. A kit for diagnostic imaging of a patient comprising low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, in combination with a thickening or suspending agent. 59. A method of providing an image of the gastrointestinal region and other body cavities of a patient comprising (a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and (b) scanning the patient using computed tomography imaging to obtain visible images of the gastrointestinal region or other body cavities. 60. A method of providing an image of a region of a patient comprising (a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and (b) scanning the patient using diagnostic imaging to obtain visible images of the region of a patient. 61. A method for diagnosing the presence of diseased tissue in the gastrointestinal region or other body cavities of a patient comprising (a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and (b) scanning the patient using computed tomography imaging to obtain visible images of any diseased tissue in the patient. 62. A method for diagnosing the presence of diseased tissue in a patient comprising (a) administering to the patient a contrast medium comprising a substantially homogeneous aqueous suspension of low density gas-filled microspheres having an internal void volume of at least about 75% of the total volume of the microsphere, wherein said gas comprises a perfluorocarbon, and (b) scanning the patient using diagnostic imaging to obtain visible images of any diseased tissue in the patient.