IMMOBILISED BIOLOGICAL ENTITIES

• US 20110223229A1
• Filed: 03/11/2011
• Published: 09/15/2011
• Est. Priority Date: 03/12/2010
• Status: Active Grant

• Current Assignee: Carmeda AB
• Original Assignee: Carmeda AB
• Inventors: VESTBERG, Robert
• Granted Patent: US 8,501,212 B2
• Time in Patent Office: Days
• US Class Current: 424/422
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6957 the form being a device or a kit, e.g. stents or microdevices
• CPC Class Codes: A61L 33/0029 using an intermediate layer of polymer
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

There is described inter alia a medical device having a surface which comprises a coating layer, said coating layer being a biocompatible composition comprising an anti-coagulant entity capable of interacting with mammalian blood to prevent coagulation or thrombus formation, which anti-coagulant entity is covalently attached to said surface through a linker comprising a thioether.

Claims

1. A solid object having a surface which comprises an outer coating layer, said outer coating layer being a biocompatible composition comprising a polymer and an anti-coagulant entity capable of interacting with mammalian blood to prevent coagulation or thrombus formation, which anti-coagulant entity is covalently attached to said polymer through a linker comprising a thioether.

2. A solid object according to claim 1, wherein the anti-coagulant entity is a heparin moiety.

3. A solid object according to claim 1, wherein the anti-coagulant entity is an end point attached heparin moiety.

4. A solid object according to claim 3, wherein the end point attached heparin moiety is connected through its reducing end.

5. A solid object according to claim 1, wherein the anti-coagulant entity is a full length heparin.

6. A solid object according to claim 1, wherein the surface comprises two or more coating layers, only the outer coating layer being attached to the anti-coagulant entity.

7. A solid object according to claim 1, wherein the surface comprises one or more coating bilayers of cationic polymer and anionic polymer, the innermost layer being a layer of cationic polymer and the outermost layer being a layer of cationic polymer to which the anti-coagulant entity is covalently attached via a linker comprising a thioether.

8. A solid object according to claim 1, comprising a multiplicity of linkers of the same type.

9. A solid object according to claim 1, comprising a multiplicity of anti-coagulant entities of the same type.

10. A solid object according to claim 1, wherein more than one anti-coagulant entity is attached to a linker.

11. A solid object according to claim 1, wherein the coating comprises a polyamine as cationic polymer.

12. A solid object according to claim 11, wherein the coating comprises a layer of a high average molecular weight polyamine and a layer of an anionic polysaccharide as anionic polymer.

13. A solid object according to claim 11, wherein the polyamine is cross-linked.

14. A solid object according to claim 1, which solid object comprises a metal or a synthetic or naturally occurring organic or inorganic polymer.

15. A solid object according to claim 1 which is a medical device.

16. A solid object according to claim 15, which is a sterile medical device for implantation, or other placement, at an anatomical site.

17. A solid object according to claim 1, which object has an antithrombin Ill binding activity of at least 1 picomole antithrombin III per square centimeter (pmol/cm²) of surface.

18. A solid object according to claim 17, wherein the object has an antithrombin III binding activity of at least 5 picomoles e.g. at least 10 picomoles antithrombin Ill per square centimeter (pmol/cm²) of surface.

19. A process for the production of a solid object having a surface which comprises an outer coating layer, said outer coating layer being a biocompatible composition comprising a polymer and an anti-coagulant entity capable of interacting with mammalian blood to prevent coagulation or thrombus formation, which anti-coagulant entity is covalently attached to said polymer through a linker comprising a thioether;

which process comprises the reaction of a corresponding anti-coagulant entity carrying an alkene or alkyne group with a corresponding surface carrying a thiol group, or the reaction of a corresponding anti-coagulant entity carrying a thiol group with a corresponding surface carrying an alkene or alkyne group.

20. A process according to claim 19 comprising:

(a) treating a solid object to present a surface comprising a cationic polymer outer coating layer which has been functionalized to bear thiol groups;

(b) reacting said cationic polymer outer coating layer which has been functionalized to bear thiol groups with an anti-coagulant entity which is functionalized to bear an alkene or alkyne group;

thereby to attach the anti-coagulant entity to the cationic polymer through a linker comprising a thioether.

21. A process according to claim 19 comprising:

(a) treating a solid object to present a cationic polymer outer coating layer which has been functionalized to bear alkene or alkyne groups;

(b) reacting said cationic polymer outer coating layer which has been functionalized to bear alkyne groups with an anti-coagulant entity which is functionalized to bear a thiol group;

thereby to attach the anti-coagulant entity to the cationic polymer through a linker comprising a thioether.

22. A process according to claim 19 comprising:

(a) treating a solid object to present a cationic polymer surface layer;

(b) associating with said cationic polymer surface layer a functionalized catonic polymer bearing a multiplicity of negatively charged anti-coagulant entities such as heparin moieties which are attached thereto via a linker comprising a thioether, said cationic polymer bearing a multiplicity of negatively charged anti-coagulant entities and said functionalized cationic polymer having a net negative charge.

23. A process according to claim 19 comprising:

(a) treating a solid object to present an anionic polymer surface layer;

(b) associating with said anionic polymer surface layer a functionalized cationic polymer bearing a multiplicity of negatively charged anti-coagulant entities such as a heparin moieties which are attached thereto via a linker comprising a thioether, said functionalized cationic polymer bearing a multiplicity of negatively charged anti-coagulant entities and having a net positive charge.

24. A process according to claim 23, wherein the anionic polymer is dextran sulfate or a derivative thereof.

25. A process according to claim 20, wherein the cationic polymer is a polyamine.

26. A process according to claim 19, wherein the solid object is a medical device.

27. A process according to claim 19, wherein the solid object has a surface which comprises one or more layers of polysaccharide and polyamine, which process comprises the reaction of a corresponding surface having an outer layer of polysaccharide which has a net negative charge with a polyamine, carrying a corresponding anti-coagulant entity through a linker comprising a thioether, having a net positive charge.

28. A process according to claim 19, wherein the solid object has a surface which comprises one or more layers of polysaccharide and polyamine, which process comprises the reaction of a corresponding surface having an outer layer of polysaccharide which has a net negative charge with a polyamine carrying an thiol or an alkene or alkyne group which has a net positive charge and reacting the resulting product with an anti-coagulant entity carrying an alkene or alkyne or a thiol group respectively.

29. A process according to claim 19, wherein the solid object has a surface which comprises one or more layers of polysaccharide and polyamine, which process comprises the reaction of a corresponding surface having an outer layer of polyamine having a net positive charge with a polyamine carrying a multiplicity of corresponding anti-coagulant entities through a linker comprising a thioether such that said polyamine has a net negative charge.

30. A heparin moiety capable of interacting with mammalian blood to prevent coagulation or thrombus formation which anti-coagulant entity carries an alkene or thiol group, which alkene or thiol group is attached to a linker, wherein the linker is end-point attached to the heparin moiety.