Two dimensional polymer that generates nitric oxide

• US 20040033242A1
• Filed: 08/16/2002
• Published: 02/19/2004
• Est. Priority Date: 08/16/2002
• Status: Active Grant

• Current Assignee: The Michigan Biotechnology Institute
• Original Assignee: The Michigan Biotechnology Institute
• Inventors: McDonald, William F., Koren, Amy B.
• Granted Patent: US 6,951,902 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence

Abstract

A polymeric composition that generates nitric oxide and a process for rendering the surface of a substrate nonthrombogenic by applying a coating of the polymeric composition to the substrate are disclosed. The composition comprises: (1) a crosslinked chemical combination of (i) a polymer having amino group-containing side chains along a backbone forming the polymer, and (ii) a crosslinking agent containing functional groups capable of reacting with the amino groups; and (2) a plurality of nitric oxide generating functional groups associated with the crosslinked chemical combination. Once exposed to a physiological environment, the coating generates nitric oxide thereby inhibiting platelet aggregation. In one embodiment, the nitric oxide generating functional groups are provided by a nitrated compound (e.g., nitrocellulose) imbedded in the polymeric composition. In another embodiment, the nitric oxide generating functional groups comprise N₂O₂⁻ groups covalently bonded to amino groups on the polymer.

Claims

1. A polymeric composition capable of generating nitric oxide, the polymeric composition comprising:

a crosslinked chemical combination of (i) a polymer having side chains along a backbone forming the polymer, at least two of the side chains containing an amino group, and (ii) a crosslinking agent containing at least two functional groups capable of reacting with the amino groups; and

a plurality of nitric oxide generating functional groups associated with the crosslinked chemical combination.

2. The composition of claim 1 wherein:

the nitric oxide generating functional groups comprise nitrate groups.

3. The composition of claim 2 wherein:

the nitrate groups are provided by nitrocellulose imbedded within the crosslinked chemical combination.

4. The composition of claim 1 wherein:

the nitric oxide generating functional groups comprise N₂O₂⁻

groups covalently bonded to a plurality of the amino groups.

5. The composition of claim 1 wherein:

the polymer is a polyamide, and

the polymer is synthesized by (i) reacting a monomer selected from unsaturated carboxylic acids, esters of unsaturated carboxylic acids, anhydrides of unsaturated carboxylic acids, and mixtures thereof, and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, and (ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.

6. The composition of claim 5 wherein R and R₁ are alkyl and the second amine is a polyalkylene polyamine.

7. The composition of claim 5 wherein the monomer is selected from unsaturated dicarboxylic acids, esters of unsaturated dicarboxylic acids, anhydrides of unsaturated dicarboxylic acids, and mixtures thereof.

8. The composition of claim 5 wherein the monomer is selected from maleic anhydride, maleic acid esters, and mixtures thereof.

9. The composition of claim 5 wherein:

the nitric oxide generating functional groups comprise nitrate groups.

10. The composition of claim 5 wherein:

the nitrate groups are provided by nitrocellulose imbedded within the crosslinked chemical combination.

11. The composition of claim 5 wherein:

the nitric oxide generating functional groups comprise N₂O₂⁻

groups covalently bonded to a plurality of the amino groups.

12. The composition of claim 1 wherein:

the polymer is a polyamide, and

the polymer is synthesized by (i) reacting an α

,β

-unsaturated lactone and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, and (ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.

13. The composition of claim 12 wherein R and R₁ are alkyl and the second amine is a polyalkylene polyamine.

14. The composition of claim 12 wherein the lactone is 2(5H)-furanone.

15. The composition of claim 12 wherein:

the nitric oxide generating functional groups comprise nitrate groups.

16. The composition of claim 15 wherein:

the nitrate groups are provided by nitrocellulose imbedded within the crosslinked chemical combination.

17. The composition of claim 12 wherein:

the nitric oxide generating functional groups comprise N₂O₂⁻

groups covalently bonded to a plurality of the amino groups.

18. The composition of claim 1 wherein the crosslinking agent is selected from the group consisting of aliphatic aldehyde compounds having 2 or more —

CHO groups, aromatic aldehyde compounds having 2 or more —

CHO groups, and mixtures thereof.

19. The composition of claim 1 wherein the crosslinking agent is selected from the group consisting of silanes having 2 or more alkoxy groups, and mixtures thereof.

20. The composition of claim 1 wherein the crosslinking agent is selected from the group consisting of phosphines having the general formula (A)₃P, wherein A is hydroxyalkyl, and mixtures thereof.

21. The composition of claim 20 wherein the crosslinking agent is tris(hydroxymethyl)phosphine.

22. An article having a nonthrombogenic surface, the article comprising:

a substrate;

the composition of claim 1 disposed on at least a portion of the substrate.

23. An article having a nonthrombogenic surface, the article comprising:

a substrate;

the composition of claim 4 disposed on at least a portion of the substrate.

24. An article having a nonthrombogenic surface, the article comprising:

a substrate;

the composition of claim 5 disposed on at least a portion of the substrate.

25. An article having a nonthrombogenic surface, the article comprising:

a substrate;

the composition of claim 12 disposed on at least a portion of the substrate.

26. A process for rendering the surface of a substrate nonthrombogenic, the process comprising:

(a) providing a polymer having side chains along a backbone forming the polymer, at least two of the side chains containing an amino group;

(b) contacting the polymer with nitric oxide and mixing the polymer with a crosslinking agent to produce a polymer solution, the crosslinking agent containing at least two crosslinking functional groups capable of reacting with the amino groups; and

(c) coating at least a portion of the substrate with the polymer solution to produce a crosslinked polymer coating having nitric oxide generating functional groups on the substrate.

27. The process of claim 26 wherein:

the crosslinking agent is selected from the group consisting of polyaldehydes, phosphines having the general formula (A)₃P, wherein A is hydroxyalkyl, silanes having 2 or more alkoxy groups, and mixtures thereof.

28. The process of claim 26 wherein the substrate comprises a polymeric material selected from polyolefins, polyacrylics, polyvinyl chloride, polyamides, polyurethanes, polyurethaneureas, silicone urethane copolymers, polyvinylpyrrolidone, polyvinyl alcohols, cellulosic materials, polystyrene, polyesters, fluorinated polymers, silicone polymers, natural rubber, polycarbonates, and mixtures thereof.

29. The process of claim 26 wherein:

the nitric oxide generating functional groups comprise N₂O₂⁻

groups covalently bonded to a plurality of the amino groups.

30. The process of claim 26 wherein:

the polymer is a polyamide, and

step (a) comprises;

(i) reacting a monomer selected from unsaturated carboxylic acids, esters of unsaturated carboxylic acids, anhydrides of unsaturated carboxylic acids, and mixtures thereof, and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof; and

(ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.

31. The process of claim 30 wherein the monomer is selected from maleic anhydride, maleic acid esters, and mixtures thereof.

32. The process of claim 26 wherein:

the polymer is a polyamide, and

step (a) comprises;

(i) reacting an α

,β

-unsaturated lactone and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof; and

(ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.

33. A process for rendering the surface of a substrate nonthrombogenic, the process comprising:

(a) providing a polymer having side chains along a backbone forming the polymer, at least two of the side chains containing an amino group;

(b) mixing the polymer with a crosslinking agent and a nitrate group containing compound to produce a polymer solution, the crosslinking agent containing at least two crosslinking functional groups capable of reacting with the amino groups; and

(c) coating at least a portion of the substrate with the polymer solution to produce a crosslinked polymer coating on the substrate.

34. The process of claim 33 wherein:

the crosslinking agent is selected from the group consisting of polyaldehydes, phosphines having the general formula (A)₃P, wherein A is hydroxyalkyl, silanes having 2 or more alkoxy groups, and mixtures thereof.

35. The process of claim 33 wherein the substrate comprises a polymeric material selected from polyolefins, polyacrylics, polyvinyl chloride, polyamides, polyurethanes, polyurethaneureas, silicone urethane copolymers, polyvinylpyrrolidone, polyvinyl alcohols, cellulosic materials, polystyrene, polyesters, fluorinated polymers, silicone polymers, natural rubber, polycarbonates, and mixtures thereof.

36. The process of claim 33 wherein:

the nitrate group containing compound is nitrocellulose.

37. The process of claim 33 wherein:

the polymer is a polyamide, and

step (a) comprises;

(i) reacting a monomer selected from unsaturated carboxylic acids, esters of unsaturated carboxylic acids, anhydrides of unsaturated carboxylic acids, and mixtures thereof, and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof; and

(ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.

38. The process of claim 37 wherein the monomer is selected from maleic anhydride, maleic acid esters, and mixtures thereof.

39. The process of claim 33 wherein:

the polymer is a polyamide, and

step (a) comprises;

(i) reacting an α

,β

-unsaturated lactone and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof; and

(ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.

40. A process for rendering the surface of a substrate nonthrombogenic, the process comprising:

(a) providing a polymer having side chains along a backbone forming the polymer, at least two of the side chains containing an amino group;

(b) mixing the polymer with a crosslinking agent to produce a polymer solution, the crosslinking agent containing at least two crosslinking functional groups capable of reacting with the amino groups;

(c) coating at least a portion of the substrate with the polymer solution to produce a crosslinked polymer coating on the substrate; and

(d) contacting the crosslinked polymer coating with nitric oxide to create nitric oxide generating functional groups on the crosslinked polymer coating.

41. The process of claim 40 wherein:

the crosslinking agent is selected from the group consisting of polyaldehydes, phosphines having the general formula (A)₃P, wherein A is hydroxyalkyl, silanes having 2 or more alkoxy groups, and mixtures thereof.

42. The process of claim 40 wherein the substrate comprises a polymeric material selected from polyolefins, polyacrylics, polyvinyl chloride, polyamides, polyurethanes, polyurethaneureas, silicone urethane copolymers, polyvinylpyrrolidone, polyvinyl alcohols, cellulosic materials, polystyrene, polyesters, fluorinated polymers, silicone polymers, natural rubber, polycarbonates, and mixtures thereof.

43. The process of claim 40 wherein:

the nitric oxide generating functional groups comprise N₂O₂⁻

groups covalently bonded to a plurality of the amino groups.

44. The process of claim 40 wherein:

the polymer is a polyamide, and

step (a) comprises;

(i) reacting a monomer selected from unsaturated carboxylic acids, esters of unsaturated carboxylic acids, anhydrides of unsaturated carboxylic acids, and mixtures thereof, and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof; and

(ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.

45. The process of claim 44 wherein the monomer is selected from maleic anhydride, maleic acid esters, and mixtures thereof.

46. The process of claim 40 wherein:

the polymer is a polyamide, and

step (a) comprises;

(i) reacting an α

,β

-unsaturated lactone and a first amine to form an intermediate reaction product, wherein the first amine is selected from RR₁NH, RNH₂, RR₁NH₂⁺, RNH₃⁺ and mixtures thereof, wherein R and R₁ can be the same or different and each contain between about I and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof; and

(ii) reacting the intermediate reaction product and a second amine to form the polyamide, wherein the second amine is selected from R₂R₃NH, R₂NH₂, R₂R₃NH₂⁺, R₂NH₃⁺ and mixtures thereof, wherein R₂ and R₃ can be the same or different and each contain between about 1 and 50 carbon atoms and are optionally substituted with heteroatoms oxygen, nitrogen, sulfur, and phosphorus and combinations thereof, wherein multiples of the R, R₁, R₂, and R₃ are in vertically aligned spaced relationship along a backbone formed by the polyamide.