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WO1992005749A1 - Conjugues solubles d'un inhibiteur de la thrombogenese - Google Patents

Conjugues solubles d'un inhibiteur de la thrombogenese Download PDF

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Publication number
WO1992005749A1
WO1992005749A1 PCT/US1991/005353 US9105353W WO9205749A1 WO 1992005749 A1 WO1992005749 A1 WO 1992005749A1 US 9105353 W US9105353 W US 9105353W WO 9205749 A1 WO9205749 A1 WO 9205749A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
carrier
thrombogenesis
reagent
agent
Prior art date
Application number
PCT/US1991/005353
Other languages
English (en)
Inventor
Ralph K. Ito
Frank W. Logerfo
Original Assignee
New England Deaconess Hospital Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New England Deaconess Hospital Corporation filed Critical New England Deaconess Hospital Corporation
Publication of WO1992005749A1 publication Critical patent/WO1992005749A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6425—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell

Definitions

  • Materials having varying degrees of thromboresistance have been utilized in vascular prostheses with limited success. These materials include corroding (self-cleaning) metals, synthetic polymers such as polydimethyl siloxane. Teflon, acrylates and methacrylates such as polyethylene terphthalate, electrets, anionic copolymers, and hydrogels (for a review see Salzman et al. (1987) in Hemostasis and Thrombosis, Basic Principles and Clinical Practice (Colman et al., eds.) J. B. Lippincott Co., Phila. PA, pp. 1335-1347).
  • the synthetic material may be contacted with a solution which removes impurities therein and/or thereon prior to the activation step described above.
  • FIGURE 6 is a graphic representation of the activities of grafts including immobilized thrombomodulin or BSA;
  • Thrombogenesis inhibitors useful for these purposes include molecules which interfere with, or inhibit thrombogenesis. These include, but are not limited to, ATPase, ADPase, 5'-nucleotidase, streptokinase, urokinase, tissue plasminogen activator, thrombomodulin, anticoagulants, and platelet inhibit ' (e.g., prostacycline and aspirin) Active fragments of these thrombogenesis inhibitors may be provided by enzymatic digestion using any number of know proteolytic enzymes (e.g. trypsin, chymotrypsin) whose exact locus of cleavage along an amino acid sequence is well known in the art.
  • proteolytic enzymes e.g. trypsin, chymotrypsin
  • SPDP derivatization linkage of certain groups on the thrombogenesis inhibitor to SPDP may destroy some inhibitor activity because at least some of these groups may be required for such activity.
  • SPDP becomes somewhat selective for epsilon amino groups. The result of these conditions favor a 1:1 (mole:mole) conjugation ratio of inhibitor to SPDP covalently bound without destroying biological activity.
  • the activated material is placed into 100.0 ml of 10 mM water-soluble carbodiimide (EDC) in deionized water, pH 4.6-5.0, for 1 hour at RT with constant stirring.
  • EDC water-soluble carbodiimide

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)

Abstract

On décrit un agent pharmacologique biocompatible soluble servant à inhiber la génération de la thrombine et la formation d'un thrombus, ainsi que des méthodes servant à produire ledit agent. L'agent ou le conjugué pharmaceutique comprend un véhicule biocompatible soluble et un inhibiteur de thrombogenèse immobilisé sur ledit véhicule par un constituant du véhicule qui lie l'inhibiteur. L'inhibiteur de thrombogenèse est un inhibiteur autre que l'hirudine, ou un analogue actif ou un fragment actif de cet inhibiteur. L'inhibiteur peut être lié au constituant du véhicule au moyen d'un réactif de liaison transversale bifonctionnel.
PCT/US1991/005353 1990-10-04 1991-07-29 Conjugues solubles d'un inhibiteur de la thrombogenese WO1992005749A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US59258090A 1990-10-04 1990-10-04
US592,580 1990-10-04

Publications (1)

Publication Number Publication Date
WO1992005749A1 true WO1992005749A1 (fr) 1992-04-16

Family

ID=24371262

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1991/005353 WO1992005749A1 (fr) 1990-10-04 1991-07-29 Conjugues solubles d'un inhibiteur de la thrombogenese

Country Status (2)

Country Link
AU (1) AU8492991A (fr)
WO (1) WO1992005749A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0538459A4 (en) * 1991-05-09 1993-06-16 The Board Of Regents Of The University Of Washington Phospholipid-targeted thrombolytic agents
WO1997010509A1 (fr) * 1995-09-13 1997-03-20 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., Berlin Inhibiteurs d'enzymes metaboliques activables lies a des complexes, utilises comme marqueurs moleculaires pour le diagnostic et le controle therapeutique
US5632986A (en) * 1991-05-09 1997-05-27 The University Of Washington Phospholipid-targeted thrombolytic agents
EP1136082A1 (fr) * 2000-03-24 2001-09-26 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Administration locale de médicaments

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1979000638A1 (fr) * 1978-02-17 1979-09-06 Thin Conductive Coating Oester Methode de production de surfaces permettant d'eviter la formation de thrombus
US4273873A (en) * 1977-10-25 1981-06-16 Unitika Ltd. Preparation of antithrombogenic polymeric materials
US5002582A (en) * 1982-09-29 1991-03-26 Bio-Metric Systems, Inc. Preparation of polymeric surfaces via covalently attaching polymers

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273873A (en) * 1977-10-25 1981-06-16 Unitika Ltd. Preparation of antithrombogenic polymeric materials
WO1979000638A1 (fr) * 1978-02-17 1979-09-06 Thin Conductive Coating Oester Methode de production de surfaces permettant d'eviter la formation de thrombus
US5002582A (en) * 1982-09-29 1991-03-26 Bio-Metric Systems, Inc. Preparation of polymeric surfaces via covalently attaching polymers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. LAB. CLIN. MED., Volume 91, January 1978 (LINDON), "Interaction of human platelets with heparinized agarose gel", pages 47-59. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0538459A4 (en) * 1991-05-09 1993-06-16 The Board Of Regents Of The University Of Washington Phospholipid-targeted thrombolytic agents
US5632986A (en) * 1991-05-09 1997-05-27 The University Of Washington Phospholipid-targeted thrombolytic agents
WO1997010509A1 (fr) * 1995-09-13 1997-03-20 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., Berlin Inhibiteurs d'enzymes metaboliques activables lies a des complexes, utilises comme marqueurs moleculaires pour le diagnostic et le controle therapeutique
US6051390A (en) * 1995-09-13 2000-04-18 Max-Planck-Gesellschaft zur Forderung der Wissenschaften E.V., Berlin Complex-bound inhibitors of metabolic enzymes capable of being activated, useful as molecular markers for diagnostic and therapy monitoring purposes
EP1136082A1 (fr) * 2000-03-24 2001-09-26 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Administration locale de médicaments
WO2001070274A3 (fr) * 2000-03-24 2002-03-07 Tno Administration locale de medicaments

Also Published As

Publication number Publication date
AU8492991A (en) 1992-04-28

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