Contrast agent comprising low density microspheres

• US 6,773,696 B2
• Filed: 10/25/2002
• Issued: 08/10/2004
• 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:
  US10/280,844
• Publication Number:
  US 20030053953A1
• Time in Patent Office: 655 Days
• Field of Search: 424/9.4, 424/9.5, 424/9.52, 424/489, 516/11, 516/77, 428/402, 425/501
• 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

Low density microspheres, methods for preparing same, and use of same as contrast agents are described. The microspheres have a void having a volume that comprises at least about 75% of the total volume of the microspheres, and which contains a gas or the vapor of a volatile liquid selected from the group consisting of aliphatic hydrocarbons, chlorofluorocarbons, tetraalkyl silanes and perfluorocarbons.

Claims

1. A contrast agent comprising an aqueous suspension of low density microspheres, said low density microspheres having a void containing a gas or the vapor of a volatile liquid selected from the group consisting of aliphatic hydrocarbons, chlorofluorocarbons, tetraalkyl silanes and perfluorocarbons, wherein said void has a volume that comprises at least about 75% of the volume of the microsphere and wherein said contrast agent is suitable for administration to a patient either orally, rectally, or by injection.

2. A contrast agent according to claim 1, wherein said microspheres comprise a biocompatible polymer.

3. A contrast agent according to claim 2 wherein said polymer comprises a synthetic polymer or copolymer 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, epichiorhydrin, 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).

4. A contrast agent according to claim 3 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, epichiorhydrin, 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.

5. A contrast agent according to claim 1 wherein said microspheres comprise biocompatible synthetic polymers or copolymers selected from the group consisting of polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polysiloxane, polydimethylsiloxane, polylactic acid, poly(ε

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

6. A contrast agent according to claim 1 wherein said microspheres are prepared by a heat expansion process.

7. A contrast agent according to claim 1 wherein said microspheres are gas-filled.

8. A contrast agent according to claim 7 wherein said gas in said gas-filled microspheres is selected from the group consisting of carbon dioxide, oxygen, nitrogen, xenon, argon, neon, and helium.

9. A contrast agent according to claim 1 wherein said microspheres are filled with the vapor of a perfluorocarbon.

10. A contrast agent according to claim 9 where said perfluorocarbon has between 1 and about 9 carbon atoms and between 4 and about 20 fluorine atoms.

11. A contrast agent according to claim 10 wherein said perfluorocarbon has between 1 and 4 carbon atoms and between 4 and 10 fluorine atoms.

12. A contrast agent according to claim 10 wherein said perfluorocarbon has between 4 and, about 9 carbon atoms and between 10 and about 20 fluorine atoms.

13. A contrast agent according to claim 10 wherein said perfluorocarbon is C₄F₁₀.

14. A contrast agent according to claim 1, further comprising a thickening or suspending agent.