Claims for Patent: 5,527,521

Summary for Patent: 5,527,521

Title:	Low density microspheres and suspensions 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:	08/456,738
Patent Claims:	1. A contrast medium for computed tomography imaging of the gastrointestinal region or other body cavities comprising an aqueous suspension of a biocompatible polymer, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with salad perfluorocarbon gas to form one or more gas-filled microspheres. 2. A contrast medium according to claim 1 wherein said biocompatible polymer comprises 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-phenylisocyanate). 3. A contrast medium according to claim 2 wherein said biocompatible polymer comprises 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 biocompatible polymer comprises 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 biocompatible polymer comprises a polyvinylidene-polyacrylonitrile copolymer. 6. A contrast medium according to claim 1 wherein said biocompatible polymer comprises a polyoxypropylene-polyoxyethylene copolymer. 7. 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. 8. A contrast medium according to claim 7 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. 9. A contrast medium according to claim 7 wherein said perfluorocarbon gas is C.sub.3 F.sub.8. 10. A contrast medium according to claim 7 wherein said perfluorocarbon gas is C.sub.4 F.sub.10. 11. A contrast medium according to claim 7 wherein said perfluorocarbon gas is C.sub.5 F.sub.12. 12. A contrast medium according to claim 1 wherein said thickening or suspending agent is selected from the group consisting of alginates, xanthan gum, guar, pectin, tragacanth, bassorin, karaya, gum arabic, casein, gelatin, cellulose, carboxymethylcellulose, methylcellulose, methylhydroxycellulose, bentonire, colloidal silicic acid, carrageenin, polyethylene glycol, polypropylene glycol, and polyvinylpyrrolidone. 13. A contrast medium according to claim 12 wherein said thickening or suspending agent is selected from the group consisting of cellulose, carboxymethylcellulose, methylcellulose, methylhydroxycellulose. 14. A contrast medium according to claim 13 wherein said thickening or suspending agent is methylcellulose. 15. A contrast medium according to claim 1 further comprising a compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants. 16. A contrast medium according to claim 15 wherein said compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants, comprises a polymeric siloxane. 17. A contrast medium according to claim 16 wherein said polymeric siloxane is dimethylpolysiloxane. 18. A contrast medium according to claim 17 wherein said dimethylpolysiloxane is simethicone. 19. A contrast medium according to claim 1 wherein said biocompatible polymer is a polyoxypropylene-polyoxyethylene copolymer, said perfluorocarbon gas is C.sub.5 F.sub.12, and said thickening or suspending agent is methylcellulose, and further comprising simethicone. 20. A contrast medium for diagnostic imaging comprising an aqueous suspension of a biocompatible polymer, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres. 21. A contrast medium according to claim 20 wherein said biocompatible polymer comprises 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-phenylisocyanate). 22. A contrast medium according to claim 21 wherein said biocompatible polymer comprises 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. 23. A contrast medium according to claim 20 wherein said biocompatible polymer comprises 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. 24. A contrast medium according to claim 20 wherein said biocompatible polymer comprises a polyvinylidene-polyacrylonitrile copolymer. 25. A contrast medium according to claim 20 wherein said biocompatible polymer comprises a polyoxypropylene-polyoxyethylene copolymer. 26. A contrast medium according to claim 20 wherein said perftuorocarbon 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. 27. A contrast medium according to claim 26 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. 28. A contrast medium according to claim 26 wherein said perfluorocarbon gas is C.sub.3 F.sub.8. 29. A contrast medium according to claim 26 wherein said perfluorocarbon gas is C.sub.4 F.sub.10. 30. A contrast medium according to claim 26 wherein said perfluorocarbon gas is C.sub.5 F.sub.12. 31. A contrast medium according to claim 20 wherein said thickening or suspending agent is selected from the group consisting of alginates, xanthan gum, guar, pectin, tragacanth, bassorin, karaya, gum arabic, casein, gelatin, cellulose, carboxymethylcellulose, methylcellulose, methylhydroxycellulose, bentonite, colloidal silicic acid, carrageenin, polyethylene glycol, polypropylene glycol, and polyvinylpyrrolidone. 32. A contrast medium according to claim 31 wherein said thickening or suspending agent is selected from the group consisting of cellulose, carboxymethylcellulose, methylcellulose, and methylhydroxycellulose. 33. A contrast medium according to claim 32 wherein said thickening or suspending agent is methylcellulose. 34. A contrast medium according to claim 20 further comprising a compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants. 35. A contrast medium according to claim 34 wherein said compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants, comprises a polymeric siloxane. 36. A contrast medium according to claim 35 wherein said polymeric siloxane is dimethylpolysiloxane. 37. A contrast medium according to claim 36 wherein said dimethylpolysiloxane is simethicone. 38. A contrast medium according to claim 20 wherein said biocompatible polymer is a polyoxypropylene-polyoxyethylene copolymer, said perfluorocarbon gas is C.sub.5 F.sub.12, and said thickening or suspending agent is methylcellulose, and further comprising simethicone. 39. An aqueous suspension comprising a biocompatible poller, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres. 40. An aqueous suspension according to claim 39 wherein said biocompatible polymer comprises 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-phenylisocyanate). 41. Ant aqueous suspension according to claim 40 wherein said biocompatible polymer comprises 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. 42. An aqueous suspension according to claim 34 wherein said biocompatible polymer comprises 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. 43. A contrast medium according to claim 39 wherein said biocompatible polymer comprises a polyvinylidene-polyacrylonitrile copolymer. 44. An aqueous suspension according to claim 39 wherein said biocompatible polymer comprises a polyoxypropylene-polyoxyethylene copolymer. 45. An aqueous suspension according to claim 39 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. 46. An aqueous suspension according to claim 45 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. 47. An aqueous suspension according to claim 45 wherein said perfluorocarbon gas is C.sub.3 F.sub.8. 48. An aqueous suspension according to claim 45 wherein said perfluorocarbon gas is C.sub.4 F.sub.10. 49. An aqueous suspension according to claim 45 wherein said perfluorocarbon gas is C.sub.5 F.sub.12. 50. An aqueous suspension according to claim 39 wherein said thickening or suspending agent is selected from the group consisting of alginates, xanthan gum, guar, pectin, tragacanth, bassorin, karaya, gum arabic, casein, gelatin, cellulose, carboxymethylcellulose, methylcellulose, methylhydroxycellulose, bentonire, colloidal silicic acid, carrageenin, polyethylene glycol, polypropylene glycol, and polyvinylpyrrolidone. 51. An aqueous suspension according to claim 50 wherein said thickening or suspending agent is selected from the group consisting of cellulose, carboxymethylcellulose, methylcellulose, and methylhydroxycellulose. 52. An aqueous suspension according to claim 51 wherein said thickening or suspending agent is methylcellulose. 53. An aqueous suspension according to claim 39 further comprising a compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants. 54. An aqueous suspension according to claim 53 wherein said compound selected from the group antacids, antiflatulents, antifoaming agents, and surfactants, comprises a polymeric siloxane. 55. An aqueous suspension according to claim 54 wherein said polymeric siloxane is dimethylpolysiloxane. 56. An aqueous suspension according to claim 55 wherein said dimethylpolysiloxane is simethicone. 57. An aqueous suspension according to claim 39 wherein said biocompatible polymer is a polyoxypropylene-polyoxyethylene copolymer, said perfluorocarbon gas is C.sub.5 F.sub.12, and said thickening or suspending agent is methylcellulose, and further comprising simethicone. 58. A kit for computed tomography imaging of the gastrointestinal region or other body cavities of a patient comprising a biocompatible polymer, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres. 59. A kit for diagnostic imaging of a patient comprising a biocompatible poller, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres. 60. 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 an aqueous suspension of a biocompatible polymer, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres, and (b) scanning the patient using computed tomography imaging to obtain visible images of the gastrointestinal region or other body cavities. 61. A method of providing-an image of a region of a patient comprising (a) administering to the patient a contrast medium comprising an aqueous suspension of a biocompatible polymer, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres, and (b) scanning the patient using diagnostic imaging to obtain visible images of the region of a patient. 62. 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 an aqueous suspension of a biocompatible polymer, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres, and (b) scanning the patient using computed tomography imaging to obtain visible images of any diseased tissue in the patient. 63. A method for diagnosing the presence of diseased tissue in a patient comprising (a) administering to the patient a contrast medium comprising an aqueous suspension of a biocompatible polymer, a perfluorocarbon gas, and a thickening or suspending agent, wherein in said suspension said biocompatible polymer associates with said perfluorocarbon gas to form one or more gas-filled microspheres, and (b) scanning the patient using diagnostic imaging to obtain visible images of any diseased tissue in the patient.