Medical device comprising glycosaminoglycan-antithrombin III/heparin cofactor II conjugates

• US 20030113314A1
• Filed: 10/10/2002
• Published: 06/19/2003
• Est. Priority Date: 11/30/1995
• Status: Abandoned Application

• Current Assignee: Hamilton Civic Hospitals Research Development Inc.
• Original Assignee: Hamilton Civic Hospitals Research Development Inc.
• Inventors: Berry, Leslie, Andrew, Maureen
• Application Number:
  US10/268,084
• Publication Number:
  US 20030113314A1
• Time in Patent Office: Days
• US Class Current: 424/94.64
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 33/0029 using an intermediate layer of polymer
• CPC Class Codes: A61L 33/0041 characterised by the choice of an antithrombatic agent other than heparin heparinoïd A61L33/08; polypeptides A61L33/12
• CPC Class Codes: C08L 5/10 Heparin; Derivatives thereof

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

1. A substantially pure covalent conjugate comprising heparin directly linked to antithrombin III by a covalent linkage wherein said species comprises at least one primary amino group, via a linkage between a primary amino group of the antithrombin III and a terminal aldose residue of the heparin, 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 use of a compound as described in claim 1 for the prophylactic and therapeutic treatment of ailments relating to high coagulation activity of blood in a mammal.

4. 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.

5. A prosthetic or medical device comprising the material of claim 4.

6. The material of claim 4, wherein the glycosaminoglycan is heparin, the species is antithrombin III, and the covalent conjugate is ATH.

7. The material of claim 6, wherein the ATH is covalently attached to the polymer.

8. The material of claim 7, 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.

9. The device of claim 5 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.

10. The device of claim 9, wherein the device is endovascular tubing.

11. The device of claim 10, wherein the polymer is polyurethane-polycarbonate.

12. The device of claim 9, 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.

13. The device of claim 12, wherein the polymer is polycarbonate-polyurethane

14. A method of reducing the thrombogenicity of a material comprising

coating the material with ATH.

15. The method of claim 14, wherein the ATH is covalently bound to the material.

16. The method of claim 15, wherein the material is a synthetic 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, polyester-polyurethane, polyurethane, polycarbonate-polyurethane, polyamide (Nylon) and polystyrene.

17. The method of claim 16, wherein the material is used in a medical or prosthetic device.

18. The method of claim 17, wherein the device is endovascular tubing.

19. The device of claim 18, wherein the polymer is polyurethane-polycarbonate.