Fibrinogen-coated microspheres

{
  "publication_number": "US6264988B1",
  "country": "US",
  "kind": "B1",
  "title": "Fibrinogen-coated microspheres",
  "abstract": "The invention provides compositions comprising microspheres of fibrinogen-coated cross-linked albumin microspheres having a size range of primarily from about 100 to about 5000 nanometers diameter, wherein the composition is substantially free microspheres and microsphere aggregates having a diameter of more than 10 micrometers. At least a portion of the fibrinogen on the surface of the microspheres is covalently attached. The particles of the invention are useful for reducing bleeding time when administered to a human or other animal.",
  "claims": [
    "1. A suspension of fibrinogen-coated cross-linked protein microspheres useful for reducing bleeding time in an animal with a platelet deficiency or dysfunction, said suspension comprising microspheres of cross-linked protein, said microspheres being monodisperse in said suspension, having internal structure with fenestrations on the surface leading to internal matrices, and having a size range of primarily from abotut 100 to about 5000 nanometers diameter, said microspheres further comprising on their surface fibrinogen, wherein at least a portion of said fibrinogen is covalently bound to the protein, and wherein said suspension is substantially free of microspheres and microsphere aggregates having a diameter of more than 7 micrometers.",
    "2. The suspension of claim 1, wherein said microspheres comprise human serum albumin cross-linked by treatment with glutaraldehyde.",
    "3. The suspension of claim 2, wherein the fibrinogen is recombinant or naturally occuring.",
    "4. The suspension of claim 2, wherein said microspheres have a sponge-like internal structure with fenestrations on the surface leading to internal matrices.",
    "5. The suspension of claim 4, wherein at least about 50% of the microspheres by number are between about 100 and about 500 nanometers in diameter, and at least about 10% are between about and 500 nm and about 1700 nm in diameter.",
    "6. The suspension of claim 4, wherein at least about 90% of said microspheres are between about 100 and about 500 nanometers in diameter.",
    "7. The suspension of claim 4, wherein said suspension comprises fewer than about 3×10 6 microspheres greater than 7 μm in diameter per 10 9 microspheres.",
    "8. The suspension of claim 2 further comprising an excipient.",
    "9. A dry composition produced by lyophilizing the suspension of claim 8 and characterized by having a reconstitution time of less than about 10 minutes.",
    "10. The suspension of claim 5, wherein said microspheres comprise at least about 4×10 12 molecules of fibrinogen per 10 9 microspheres.",
    "11. A method of making fibrinogen-coated microspheres useful for reducing bleeding time in an animal with a platelet deficiency or disfunction, comprising the steps of: adding a desolvating agent to an aqueous mixture of a protein and a surfactant, whereupon a turbid mixture comprising substantially monodisperse protein microspheres results; adding a first crosslinking agent to the turbid mixture; removing large microspheres and microsphere aggregates from the mixture; adding a second cross-linking agent, which may be the same as the first cross-linking agent; and adding fibrinogen.",
    "12. The method of claim 11, wherein the protein is human serum albumin, the desolvating agent is ethanol, the surfactant is sodium tetradecyl sulfate, the first cross-linking agent is glutaraldehyde, the second cross-linking agent is glutaraldehyde, and said large microspheres and microsphere aggregates are removed by filtration or centrifugation.",
    "13. A suspension of microspheres made according to claim 11.",
    "14. A method of making fibrinogen-coated microspheres useful for reducing bleeding time in an animal with a platelet deficiency or disfunction, comprising the steps of: adding a desolvating agent to an aqueous mixture of a protein and a surfactant, whereupon a turbid mixture comprising substantially monodisperse protein microspheres results; adding a crosslinking agent to the turbid mixture; adding fibrinogen to the mixture whereupon the particles are coated with the fibrinogen; and removing large particles and aggregates from the mixture.",
    "15. The method of claim 14, wherein the protein is human serum albumin, the desolvating agent is ethanol, the surfactant is sodium tetradecyl sulfate, the cross-linking agent is glutaraldehyde, and said large microspheres and microsphere aggregates are removed by centrifugation.",
    "16. A suspension of microspheres made according to claim 14.",
    "17. A method of reducing bleeding time in an animal comprising administering a therapeutically effective amount of the suspension of claim 1.",
    "18. A method of reducing blecding time in an animal comprising administering a therapeutically effective amount of the suspension of claim 13.",
    "19. The method of claim 18, wherein the animal is a human.",
    "20. The method of claim 18, wherein said administering comprises administering at least two doses of said suspension, wherein the second dose is administered within about 24 hours after administering the first dose.",
    "21. An aggregate-free suspension of microspheres capable of reducing bleeding time in an animal, when administered according to the method of claim 20."
  ],
  "cpc": [
    "A61K 38/363",
    "A61K 9/1676",
    "A61P 7/04"
  ],
  "assignees": [
    "HEMOSPHERE INC"
  ],
  "filing_date": "1998-06-04",
  "publication_date": "2001-07-24",
  "grant_date": "2001-07-24",
  "priority_date": "1997-06-05",
  "application_number": "US-9055798-A",
  "family_id": "21955872",
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}