IMMOBILISED BIOLOGICAL ENTITIES

• US 20100074938A1
• Filed: 09/15/2009
• Published: 03/25/2010
• Est. Priority Date: 09/15/2008
• Status: Active Grant

• Current Assignee: Carmeda AB
• Original Assignee: Carmeda AB
• Inventors: Lahmann, Martina, Leontein, Karin, Vestberg, Robert, Oscarson, Stefan
• Granted Patent: US 8,992,963 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 2400/04 Materials for stopping bleeding
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 33/0029 using an intermediate layer of polymer
• CPC Class Codes: A61L 33/0035 using a polymer with positively charged atoms in the polymeric backbone, e.g. ionenes
• CPC Class Codes: A61L 33/0076 Chemical modification of the substrate
• CPC Class Codes: A61L 33/068 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L33/062 takes precedence
• CPC Class Codes: A61L 33/08 Polysaccharides
• 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 entity capable of interacting with mammalian blood to prevent coagulation or thrombus formation, which entity is covalently attached to said surface through a link comprising a 1,2,3-triazole.

Claims

1. A medical device having a surface which comprises a coating layer, said coating layer being a biocompatible composition comprising an entity capable of interacting with mammalian blood to prevent coagulation or thrombus formation, which entity is covalently attached to said surface through a link comprising a 1,2,3-triazole.

2. A device according to claim 1, wherein the entity is a heparin moiety.

3. A device according to claim 1, wherein the entity is an end point attached heparin moiety.

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

5. A device according to claim 1, wherein the entity is a full length heparin.

6. A device according to claim 1, wherein the surface comprises two or more coating layers, only the outer coating layer being attached to the entity.

7. A device 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 covalently attached to the entity.

8. A device according to claim 1, comprising a multiplicity of links of the same type.

9. A device according to claim 1, comprising a multiplicity of entities of the same type.

10. A device according to claim 1, wherein more than one entity is attached to each link.

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

12. A device 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 device according to claim 11, wherein the polyamine is cross-linked.

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

15. A device according to claim 1, which device is a sterile medical device for implantation, or other placement, at an anatomical site.

16. A device according to claim 1, which device has an antithrombin III binding activity of at least 2 picomoles antithrombin III per square centimeter (pmol/cm²) of surface.

17. A device according to claim 16, wherein the medical device has an antithrombin III binding activity of at least 5 picomoles e.g. at least 10 picomoles antithrombin III per square centimeter (pmol/cm²) of surface.

27. A process for the production of a medical device according to claim 1 which process comprises the reaction of a corresponding entity carrying an alkyne group with a corresponding surface carrying an azido group, or the reaction of a corresponding entity carrying an azido group with a corresponding surface carrying an alkyne group.

28. A process for the production of a device according to claim 1 wherein the device 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 with a polyamine carrying a corresponding entity through a link comprising a 1,2,3-triazole, or the reaction of a corresponding surface having an outer layer of polysaccharide with a polyamine carrying an azide or alkyne group and reacting the resulting product with an entity carrying an alkyne or azido group respectively.

18. A non-thrombogenic medical device having a surface comprising a functionalized cationic polymer outer layer whereby an anti-coagulant entity is attached to the cationic polymer outer layer by means of a link comprising a 1,2,3-triazole.

24. A non thrombogenic medical device according to claim 18 wherein the cationic polymer is a polyamine.

25. A non thrombogenic medical device according to claim 18 wherein the entity is a heparin moiety which is end-point attached.

26. A non thrombogenic medical device according to claim 25 wherein the heparin moiety is a full length heparin moiety.

19. A process for preparing a non-thrombogenic medical device which comprises:

(a) treating a medical device to present a cationic polymer surface layer which has been functionalized to bear azido groups;

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

thereby to attach the anti-coagulant entity to the device through a link comprising a 1,2,3-triazole.

35. A process according to claim 19 wherein the cationic polymer is a polyamine.

36. A process according to claim 19 wherein the entity is a heparin moiety which is end-point attached.

20. A process for preparing a non-thrombogenic medical device which comprises:

(a) treating a medical device to present a cationic polymer surface layer which has been functionalized to bear alkyne groups;

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

thereby to attach the anti-coagulant entity to the device through a link comprising a 1,2,3-triazole.

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

38. A process according to claim 20 wherein the entity is a heparin moiety which is end-point attached.

21. A process for preparing a non-thrombogenic medical device which comprises:

(a) treating a medical device to present a cationic polymer surface layer;

(b) associating with said cationic polymer surface layer a functionalized cationic polymer bearing a plurality of negatively charged anti-coagulant entities such as a heparin moieties which are attached thereto via a link comprising a 1,2,3-triazole said functionalized cationic polymer bearing a plurality of negatively charged anti-coagulant entities having a net negative charge.

22. A process for preparing a non-thrombogenic medical device which comprises:

(a) treating a medical device to present an anionic polymer surface layer;

(b) associating with said anionic polymer surface layer a functionalized cationic polymer bearing a plurality of negatively charged anti-coagulant entities such as a heparin moieties which are attached thereto via a link comprising a 1,2,3-triazole said functionalized cationic polymer bearing a plurality of negatively charged anti-coagulant entities having a net positive charge.

23. A process according to claim 22 wherein the anionic polymer is dextran sulfate or a derivative thereof.

29. A medical device having a polyamine surface carrying an azide or an alkyne group.

30. A medical device according to claim 29 in which the azide or alkyne group is connected to an amino group of the polyamine surface via a link.

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)