Low density microspheres and their use as contrast agents for computed tomography and in other applications

• US 6,528,039 B2
• Filed: 06/18/1997
• Issued: 03/04/2003
• Est. Priority Date: 04/05/1991
• Status: Expired due to Fees

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Unger, Evan C.
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/878,233
• Publication Number:
  US 20010024639A1
• Time in Patent Office: 2,085 Days
• Field of Search: 424/9.52, 424/9.4, 424/450, 424/489, 516/11, 516/77
• US Class Current: 424/9.4
• CPC Class Codes: A61K 49/0419 Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]
• CPC Class Codes: Y10T 428/31862 Melamine-aldehyde

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.

Claims

1. A low density gas-filled microsphere 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 microsphere 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, ε

-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 microsphere according to claim 2 wherein said microsphere 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, ε

-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 microsphere according to claim 1 wherein said microsphere comprise synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(ε

-capro-lactone), epoxy resin, poly(ethylene oxide), poly(ethylene glycol), polyamide, polyvinylidene-polyacrylonitrile, polyvinylidene-poly-acrylonitrile-polymethylmethacrylate, and polystyrene-polyacrylonitrile.

5. A microsphere according to claim 1 wherein said microsphere comprise a polyvinylidene-polyacrylonitrile copolymer.

6. A microsphere according to claim 1 wherein said microsphere comprises a polyoxypropylene-polyoxyethylene copolymer.

7. A microsphere according to claim 1 wherein said microsphere is prepared by a heat expansion process.

8. A microsphere 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 microsphere 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 microsphere according to claim 8 wherein said perfluorocarbon gas is C₄F₈.

11. A microsphere according to claim 1 wherein said microsphere comprises a polymer.

12. A microsphere according to claim 11 wherein said polymer is prepared from a polyfunctional crosslinking monomer.

13. A microsphere according to claim 2 wherein said polymer comprises an acrylate.

14. A microsphere according to claim 2 wherein said polymer comprises a methacrylate.

15. A microsphere according to claim 2 wherein said polymer comprises a cyanoacrylate.

16. A microsphere according to claim 1 which has an outside diameter of from about 5 to about 70 microns.