CA2237159A1 - Glycosaminoglycan-antithrombin iii/heparin cofactor ii conjugates - Google Patents

Glycosaminoglycan-antithrombin iii/heparin cofactor ii conjugates

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Publication number
CA2237159A1
CA2237159A1 CA002237159A CA2237159A CA2237159A1 CA 2237159 A1 CA2237159 A1 CA 2237159A1 CA 002237159 A CA002237159 A CA 002237159A CA 2237159 A CA2237159 A CA 2237159A CA 2237159 A1 CA2237159 A1 CA 2237159A1
Authority
CA
Canada
Prior art keywords
glycosaminoglycan
conjugate
polyurethane
amino group
group
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
CA002237159A
Other languages
French (fr)
Other versions
CA2237159C (en
Inventor
Leslie Berry
Maureen Andrew
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McMaster University
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to US08/768,035 priority Critical patent/US6491965B1/en
Publication of CA2237159A1 publication Critical patent/CA2237159A1/en
Application granted granted Critical
Publication of CA2237159C publication Critical patent/CA2237159C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0041—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate characterised by the choice of an antithrombatic agent other than heparin
    • 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
    • A61K47/56—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0029—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using an intermediate layer of polymer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

Novel conjugates of glycosaminoglycans, particularly heparin and dermatan sulfate, and amine containing species and therapeutic uses thereof are described. In particular, mild methods of conjugating heparins to proteins, such as antithrombin III and heparin cofactor II, which provide covalent conjugates which retain maximal biological activity are described. Uses of these conjugates to prevent thrombogenesis, in particular in lung airways, such as found in infant and adult respiratory distress syndrome and on surfaces in contact with blood are also described.

Claims (41)

1. A covalent conjugate comprising a glycosaminoglycan linked to a species by a covalent linkage wherein said species comprises at least one primary amino group, wherein said species is directly covalently linked via said amino group to a terminal aldose residue of said glycosaminoglycan, and pharmaceutically acceptable salts thereof.
2. The conjugate of Claim 1 wherein said covalent linkage is selected from the group consisting of:
(a) a -HC=N- group formed between said amino group and the C1 carbonyl group of said terminal aldose residue; and (b) a -CH2-NH- group between said amino group and the C1 carbonyl group of said terminal aldose residue.
3. The compound of Claim 1 wherein said glycosaminoglycan is heparin, dermatan sulfate, heparan sulfate, chondroitin-6-sulfate, chondroitin-4-sulfate, chondroitin, keratan sulfate, hyaluronic acid, or a fragment thereof.
4. The conjugate of Claim 1 wherein said species is a protein.
5. The conjugate of Claim 4, wherein said protein is a serine protease inhibitor.
6. The conjugate of Claim 5, wherein said protease inhibitor is selected from the group consisting of antithrombin III and heparin cofactor II.
7. The conjugate of Claim 6 wherein said glycosaminoglycan is heparin, dermatan sulfate, heparan sulfate, chondroitin-6-sulfate, chondroitin-4-sulfate, chondroitin, keratan sulfate, hyaluronic acid, or a fragment thereof.
8. The conjugate of claim 7 wherein the glycosaminoglycon is heparin, and the species is antithrombin III.
9. The conjugate of claim 8 wherein the heparin comprises a single pentasaccharide.
10. A covalent conjugate comprising a glycosaminoglycan and a molecule comprising at least one amino group, wherein said amino group is directly covalently linked to said glycosaminoglycan, wherein said conjugate is made by the process comprising:
(a) incubating said glycosaminoglycan with said compound under conditions which allow imine formation between said amino group and a terminal aldose residue of said glycosaminoglycan;
(b) optionally reducing said imine to an amine; and (c) isolating said conjugate; and pharmaceutically acceptable salts thereof.
11. The conjugate of claim 10, wherein said glycosaminoglycan is heparin, dermatan sulfate or a fragment thereof of either, and said molecule is antithrombin III or heparin cofactor II.
12. A process for conjugating a molecule comprising at least one primary amino group to a glycosaminoglycan, said process comprising:
(a) incubating said glycosaminoglycan with said molecule under conditions which allow formation of an imine between said amino group and a terminal aldose residue of said glycosaminoglycan;
(b) optionally reducing said imine to an amine; and (c) isolating said conjugate.
13. A process for conjugating a molecule comprising at least one primary amino group to a glycosaminoglycan, said process comprising:
(a) incubating said glycosaminoglycan with said molecule under conditions which allow formation of an imine between said amino group and a terminal aldose residue of said glycosaminoglycan and subsequent rearrangement of said imine to a .alpha.-carbonyl amine; and (b) isolating said conjugate.
14. The process of claim 12 or 13, wherein said molecule is a protein.
15. The process of claim 12 or 13, wherein said glycosaminoglycan is heparin, dermatan sulfate or a fragment thereof of either, and said molecule is a protein.
16. The process of claim 15, wherein said protein is antithrombin III or heparin cofactor II.
17. A pharmaceutical preparation, containing a conjugate as in claim 3 as active ingredient in association with a pharmaceutically acceptable carrier.
18. A pharmaceutical preparation as described in claim 17, in the form of an aqueous solution for injection or in the form of an ointment or in the form of an aerosol.
19. The use of a compound as described in claim 3 for the prophylactic and therapeutic treatment of ailments relating to high coagulation activity of blood in a mammal.
20. The use as described in claim 19, wherein said mammal is man.
21. The use of a compound as described in claim 3, for the prevention and treatment of thrombosis.
22. The use of a compound of claim 3 for the treatment of infant or adult respiratory distress syndrome.
23. The use as in claim 22, wherein the compound of claim 3 is delivered directly to the airways of the lung.
24. The use as in claim 23, wherein a lung surfactant, an anti-inflammatory steroid, an anti-asthmatic drug, or a bronchodilator is concurrently administered.
25. The use of a compound of claim 3 for the prevention of fibrin deposition in the lung alveoli.
26. A material for use in a medical or prosthetic device, said material comprising a polymer in contact with a covalent conjugate, said covalent conjugate comprising a glycosaminoglycan linked to a species by a covalent linkage, wherein the species comprises at least one primary amino group, and wherein the species is directly covalently linked via said amino group to a terminal aldose residue of the glycosaminoglycan.
27. A prosthetic or medical device comprising the material of claim 1.
28. The material of claim 26, wherein the glycosaminoglycan is heparin, the species is antithrombin III, and the covalent conjugate is ATH.
29. The material of claim 28, wherein the ATH is covalently attached to the polymer.
30. The material of claim 29, wherein the polymer is a synthetic polymer selected from the group consisting of poly 2-hydroxyethyl methoacrylate, poly acrylamide, poly ether polyurethane urea (PEUU), polyethylene, polypropylene, polytetrafluoroethylene, poly(vinylchloride), polydimethylsiloxane, an ethylene-acrylic acid copolymer, Dacron, polyester-polyurethane, polyurethane, polycarbonate-polyurethane, polyamide (Nylon) and polystyrene.
31. The device of claim 27 selected from the group consisting of endovascular tubing, a central venous line, a cardiac catheter, a cardiopulmonary bypass circuit, a dialysis circuit, and an in vivo prosthesis.
32. The device of claim 31, wherein the device is endovascular tubing.
33. The device of claim 32, wherein the polymer is polyurethane-polycarbonate.
34. The device of claim 31, wherein the polymer is selected from the group consisting of poly 2-hydroxyethyl methoacrylate, poly acrylamide, poly ether polyurethane urea (PEUU), polyethylene, polypropylene, polytetrafluoroethylene, poly(vinylchloride), polydimethylsiloxane, an ethylene-acrylic acid copolymer, Dacron, and polyester-polyurethane, polyurethane, polycarbonate-polyurethane, polyamide (Nylon) and polystyrene.
35. The device of claim 34, wherein the polymer is polycarbonate-polyurethane.
36. A method of reducing the thrombogenicity of a material comprising coating the material with ATH.
37. The method of claim 36, wherein the ATH is covalently bound to the material.
38. The method of claim 37, wherein the material is a synthetic polymer is selected from the group consisting of poly 2-hydroxyethyl methoacrylate, poly acrylamide, poly ether polyurethane urea (PEW), polyethylene, polypropylene, polytetrafluoroethylene, poly(vinylchloride), polydimethylsiloxane, an ethylene-acrylic acid copolymer, Dacron, polyester-polyurethane, polyurethane, polycarbonate-polyurethane, polyamide (Nylon) and polystyrene.
39. The method of claim 38, wherein the material is used in a medical or prosthetic device.
40. The method of claim 39, wherein the device is endovascular tubing.
41. The device of claim 40, wherein the polymer is polyurethane-polycarbonate.
CA2237159A 1995-11-30 1996-11-29 Glycosaminoglycan-antithrombin iii/heparin cofactor ii conjugates Expired - Lifetime CA2237159C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/768,035 US6491965B1 (en) 1995-11-30 1996-12-17 Medical device comprising glycosaminoglycan-antithrombin III/heparin cofactor II conjugates

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/564,976 US6562781B1 (en) 1995-11-30 1995-11-30 Glycosaminoglycan-antithrombin III/heparin cofactor II conjugates
US08/564,976 1995-11-30
PCT/CA1996/000799 WO1997019701A2 (en) 1995-11-30 1996-11-29 Glycosaminoglycan-antithrombin iii/heparin cofactor ii conjugates

Publications (2)

Publication Number Publication Date
CA2237159A1 true CA2237159A1 (en) 1997-06-05
CA2237159C CA2237159C (en) 2010-11-16

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ID=24256690

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2237159A Expired - Lifetime CA2237159C (en) 1995-11-30 1996-11-29 Glycosaminoglycan-antithrombin iii/heparin cofactor ii conjugates

Country Status (8)

Country Link
US (2) US6562781B1 (en)
EP (1) EP0863768B1 (en)
JP (1) JP4166275B2 (en)
AT (1) ATE350066T1 (en)
AU (1) AU7688396A (en)
CA (1) CA2237159C (en)
DE (1) DE69636813T2 (en)
WO (1) WO1997019701A2 (en)

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AU7688396A (en) 1997-06-19
JP2000501082A (en) 2000-02-02
EP0863768A2 (en) 1998-09-16
ATE350066T1 (en) 2007-01-15
WO1997019701A2 (en) 1997-06-05
JP4166275B2 (en) 2008-10-15
US6562781B1 (en) 2003-05-13
DE69636813D1 (en) 2007-02-15
US20030100487A1 (en) 2003-05-29
WO1997019701A3 (en) 1997-08-28
EP0863768B1 (en) 2007-01-03
CA2237159C (en) 2010-11-16
DE69636813T2 (en) 2007-10-04

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