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

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.

What is claimed is:  
     
         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 —CH 2 —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.