Methods of coating a device using anti-thrombin heparin
First Claim
1. A method for reducing the thrombogenicity of a material by coating the material with a covalent conjugate comprising heparin linked to antithrombin III wherein the antithrombin III is directly covalently linked via its amino group to a terminal aldose residue of the heparin and the covalent linkage comprises an imine (>
- C═
N—
) formed between the amino group and C1 of the terminal aldose or the amine reduction product thereof (>
C═
H—
NH—
), or a pharmaceutically acceptable salt thereof.
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Accused Products
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.
121 Citations
5 Claims
-
1. A method for reducing the thrombogenicity of a material by coating the material with a covalent conjugate comprising heparin linked to antithrombin III wherein the antithrombin III is directly covalently linked via its amino group to a terminal aldose residue of the heparin and the covalent linkage comprises an imine (>
- C═
N—
) formed between the amino group and C1 of the terminal aldose or the amine reduction product thereof (>
C═
H—
NH—
), or a pharmaceutically acceptable salt thereof.
- C═
-
2. A method for reducing the thrombogenicity of a material by coating the material with a conjugate composition comprising glycosaminoglycans to a substantial degree covalently linked to an amino-group containing species by —
- CO—
CH2—
NH—
said —
COCH2—
portion being derived from said glycosaminoglycans and said —
NH—
portion being derived from an amino group of said species, wherein the glycosaminoglycan is heparin or a fragment thereof, and the species is antithrombin III.
- CO—
-
3. A method for coating a medical device or prosthetic device comprising applying covalent conjugates to the device to form a coating on the device wherein the covalent conjugate comprises heparin linked to antithrombin III wherein the antithrombin III is directly covalently linked via its amino group to a terminal aldose residue of the heparin and the covalent linkage comprises an imine (>
- C═
N—
) formed between the amino group and C1 of the terminal aldose or the amine reduction product thereof (>
CH—
NH—
), or a pharmaceutically acceptable salt thereof.
- C═
-
4. A method of forming a coating on a surface of a medical or prosthetic device comprising applying a product on the surface that is prepared by (a) incubating heparin with antithrombin III under conditions which allow imine formation between the terminal aldose residue of the heparin and an amine of the antithrombin III and (b) allowing Amadori rearrangement to an α
- -carbonyl amine.
-
5. A method of imparting antithrombotic properties to a surface comprising modifying the surface with covalent conjugates wherein the covalent conjugates comprise heparin linked to antithrombin III wherein the antithrombin III is directly covalently linked via its amino group to a terminal aldose residue of the heparin and the covalent linkage comprises an imine (>
- C═
N—
) formed between the amino group and C1 of the terminal aldose or the amine reduction product thereof (>
CH—
NH—
), or a pharmaceutically acceptable salt thereof.
- C═
Specification