阅读说明：本技术 生物活性涂层 (Bioactive coating ) 是由 S.奥尼斯 F.伯罗斯 K.卡普尔 A.罗德斯 A.K.卢思拉 于 2014-04-28 设计创作，主要内容包括：本发明涉及抗微生物和抗血栓形成聚合物或聚合物共混物、化合物、涂层和包含其的材料以及由其制备或涂有其的制品,以及制备其的方法,其表现出改进的抗微生物性质和减少的血小板粘附。实施方案包括具有连接到单个聚合物骨架的抗微生物和抗血栓形成基团的聚合物、与抗血栓形成聚合物共混的抗微生物聚合物,以及涂有该抗微生物和抗血栓形成聚合物或聚合物共混物的医用装置。(The present invention relates to antimicrobial and antithrombotic polymers or polymer blends, compounds, coatings and materials comprising the same and articles made therefrom or coated therewith, and methods of making the same, which exhibit improved antimicrobial properties and reduced platelet adhesion. Embodiments include polymers having antimicrobial and antithrombotic groups attached to a single polymer backbone, antimicrobial polymers blended with antithrombotic polymers, and medical devices coated with the antimicrobial and antithrombotic polymers or polymer blends.)

1. An antimicrobial polymer which is a copolymer of (a) and (b):

(a) an antimicrobial monomer consisting of a polymerizable group attached to a guanidine or biguanide antimicrobial agent via a polyoxyethylene linking group; and

(b) one or more comonomers selected from the group consisting of acrylates, methacrylates, (meth) acrylic acid, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate, n-butyl methacrylate, t-butyl methacrylate, n-hexyl methacrylate, 2-methoxyethyl methacrylate, and monomers comprising poly (ethylene glycol).

2. The antimicrobial polymer of claim 1, wherein the polymerizable group is a methacrylate group or an acrylate group.

3. The antimicrobial polymer of claim 1 or claim 2, wherein the antimicrobial agent is a poly (hexamethylene biguanide) (PHMB) group, a poly (hexamethylene guanidine) (PHMG) group, or a chlorhexidine group.

4. The antimicrobial polymer of claim 1, wherein the antimicrobial monomer has the molecular structure:

wherein n is 1 to 30, m is 1 to 10, p is 1 to 10,000, and X is methyl or hydrogen.

5. The antimicrobial polymer of claim 4, wherein n is 5 to 15.

6. The antimicrobial polymer of claim 4 or claim 5 wherein m is 3 to 6.

7. The antimicrobial polymer of claim 4 or claim 5 wherein m is 6.

8. The antimicrobial polymer of any one of claims 4 to 7, wherein p is 5 to 50.

9. The antimicrobial polymer of any one of claims 4 to 8, wherein X is methyl.

10. The antimicrobial polymer of claim 1, wherein the antimicrobial monomer is poly (ethylene glycol) methacrylate poly (hexamethylene guanidine) (PEGMA-PHMG) or poly (ethylene glycol) methacrylate poly (hexamethylene biguanide) (PEGMA-PHMB).

11. The antimicrobial polymer of any one of the preceding claims, wherein the one or more comonomers comprise a poly (ethylene glycol) (meth) acrylate monomer, including a methoxy poly (ethylene glycol) (meth) acrylate monomer.

12. The antimicrobial polymer of any one of claims 1 to 10, wherein the one or more comonomers comprise methacrylic acid and/or benzoylphenyl methacrylate and/or butyl methacrylate.

13. The antimicrobial polymer of claim 1 which is a copolymer of (a) and (b):

(a) poly (ethylene glycol) methacrylate poly (hexamethylene guanidine) (PEGMA-PHMG) or poly (ethylene glycol) methacrylate poly (hexamethylene biguanide) (PEGMA-PHMB) and

(b) methoxy poly (ethylene glycol) (meth) acrylate, butyl methacrylate, and methacrylic acid and/or 4-benzoylphenyl methacrylate.

14. A polymeric coating comprising the antimicrobial polymer of any of the preceding claims.

15. A medical device coated with the antimicrobial polymer of any one of claims 1-13.

16. The medical device according to claim 15, which is selected from the group consisting of a contact lens or intraocular lens, a catheter for vascular access (arteries and/or veins), an abdominal lumen tube, a drainage bag and/or connector, a catheter, a blood bag, an osmotic or other membrane, a surgical glove, a surgical instrument, a vascular graft, a stent, a contact lens cassette, a bottle, a diagnostic device, an oxygen generator, a heart valve and/or pump, a vascular prosthesis, a heart stent, a vein stent, an arterial stent, a kidney stent, a ureteral stent, a valve, a heart valve leaflet, a shunt, a heart device, a pacemaker, a percutaneous catheter, a dialysis port or a chemotherapy port.

17. A process for making the antimicrobial polymer of any one of claims 1 to 13, comprising the steps of mixing an antimicrobial monomer with one or more comonomers, degassing the mixture, heating the mixture to a reaction temperature, and adding a polymerization initiator.

18. The process of claim 17, wherein the reaction temperature is between about 60 ℃ to about 80 ℃.

19. A method for reducing the susceptibility of a substrate to platelet adhesion comprising the step of coating said substrate with an antimicrobial polymer according to any one of claims 1 to 13.

20. The method of claim 19, wherein the substrate is a medical device.

21. Use of an antimicrobial polymer according to any one of claims 1 to 13 for reducing platelet adhesion to a substrate.

22. The use of claim 21, wherein the substrate is a medical device.

23. An antithrombotic polymer which is a copolymer of (a) and (b):

(a) an antithrombotic monomer selected from the group consisting of poly (ethylene glycol) heparin methacrylate, benzalkonium-heparin methacrylate complex, and benzalkonium-heparin poly (ethylene glycol) methacrylate complex; and

(b) (i) methoxy poly (ethylene) glycol (meth) acrylate; (ii) (ii) butyl methacrylate and (iii) methacrylic acid and/or 4-benzoylphenyl methacrylate.

24. The anti-thrombotic polymer according to claim 23 comprising comonomers of methoxy (polyethylene glycol) methacrylate of MW 2000 and methoxy (polyethylene glycol) methacrylate of MW 350.

25. A process for the manufacture of an antithrombotic polymer according to claim 23 or claim 24, comprising the steps of mixing an antithrombotic monomer with a comonomer, degassing the mixture, heating the mixture to the reaction temperature, and adding a polymerization initiator.

26. The process of claim 25, wherein the reaction temperature is between about 60 ℃ to about 80 ℃.

27. A polymer coating comprising the anti-thrombotic polymer according to claim 23 or claim 24.

28. A coating formulation comprising the anti-thrombotic polymer according to claim 23 or claim 24 blended with a solvent and a cross-linking agent.

29. The coating formulation of claim 28, wherein the solvent is an organic solvent.

30. The coating formulation of claim 29, wherein the organic solvent comprises tetrahydrofuran and/or isopropanol.

31. A method of coating a substrate with an anti-thrombogenic polymer according to claim 23 or claim 24, comprising the steps of providing a coating formulation according to claim 28, claim 29 or claim 30, dip-coating the substrate by dipping into the coating formulation, drying the dip-coated substrate, and curing the dip-coated substrate.

32. The method of claim 31, wherein the substrate is a medical device.

33. A medical device coated with an anti-thrombotic polymer according to claim 23 or claim 24.

34. The medical device of claim 33, which is selected from a contact lens or intraocular lens, a catheter for vascular access (arteries and/or veins), an abdominal lumen tube, a drainage bag and/or connector, a catheter, a blood bag, an osmotic or other membrane, a surgical glove, a surgical instrument, a vascular graft, a stent, a contact lens cassette, a bottle, a diagnostic device, an oxygen generator, a heart valve and/or pump, a vascular prosthesis, a heart stent, a vein stent, an arterial stent, a kidney stent, a ureteral stent, a valve, a heart valve leaflet, a shunt, a heart device, a pacemaker, a percutaneous catheter, a dialysis port, or a chemotherapy port.

35. A method for reducing the susceptibility of a substrate to platelet adhesion comprising the step of coating said substrate with an antithrombotic polymer of claim 23 or claim 24.

36. The method of claim 35, wherein the substrate is a medical device.

37. Use of an anti-thrombogenic polymer according to claim 23 or claim 24 or a polymer coating according to claim 27 for reducing the adhesion of platelets to a substrate.

38. The use of claim 37, wherein the substrate is a medical device.

39. The use of claim 37 or claim 38, wherein the substrate is coated with an anti-thrombogenic polymer or polymer coating.

40. The anti-thrombogenic polymer of claim 23 or claim 24 or the polymer coating of claim 27, for use in a method of reducing platelet adhesion to a medical device.

41. An anti-thrombotic polymer according to claim 23 or claim 24 or a polymer coating according to claim 27 for use in a method of preventing clot formation.

Technical Field

The technical field relates to antimicrobial and antithrombotic polymers; compounds, coatings and materials containing the same; articles made therefrom or coated therewith; and a method for preparing the same.

Background

In recent years, antimicrobial materials have been widely used as coatings for various surfaces, particularly those used for medical applications. These coatings reduce the likelihood of infection-based complications. Anti-fouling materials have also been used to coat these surfaces and reduce the likelihood of complications associated with the equipment.

Summary of The Invention

The polymeric materials described herein can be coated on a variety of articles and can enhance antimicrobial properties and reduce platelet adhesion. These polymeric materials can be used to prepare or coat various medical devices. Embodiments of the invention include polymers comprising antimicrobial and antithrombotic moieties attached to the same polymer backbone or polymer blends comprising a polymer having an antimicrobial moiety and a polymer having an antithrombotic moiety.

The object of the invention is to provide a polymer comprising both an antimicrobial component and an antithrombotic component, which polymer is suitable for use as a medicament for the treatment of diseases, especially of tumorsIt was surprisingly found that the individual components are not mutually exclusive in their functionality, whereby an enhanced antimicrobial activity is obtained. It has also been found that the polymers and polymer blends described herein unexpectedly have superior antimicrobial activity, particularly against gram-negative bacteria (e.g., pseudomonas aeruginosa), as compared to polymers currently in use Pseudomonas aeruginosa))。

It may be found that non-thrombogenic components generally have properties that do not enhance protein/platelet binding or activate platelets, that is, they may be considered negative phenomena for preventing clot formation; however, antithrombotic components, such as heparin and other polysaccharides (including glycosaminoglycans), may be considered positive phenomena, playing a particular role in preventing clot formation.

More specifically, the present invention provides compounds, polymer coatings, medical devices, methods of making the polymers, and polymer blends as set forth in both the appended claims and other aspects further described in the specification.

A compound comprising a polymer, an antithrombotic agent, and an antimicrobial agent, wherein the antithrombotic agent and the antimicrobial agent are covalently attached to the polymer.

The compound of claim 1, wherein the antimicrobial agent comprises a guanidine group or a quaternary ammonium salt.

The compound of claim 1 or claim 2, wherein the polymer comprises polymerized vinyl groups, allyl groups, methacrylate groups, acrylate groups, or a combination thereof.

The compound of any of the above claims, wherein the polymer comprises a copolymer.

The compound of any of the above claims, wherein either or both of the antithrombotic agent and the antimicrobial agent are pendant groups.

The compound of claim 5, wherein the antithrombotic agent and the antimicrobial agent are each covalently attached to a polymer having a linking group, and wherein the linking group comprises a polyoxyethylene group, an amine group, an ether group, or a combination thereof.

The compound of any of the above claims, wherein the anti-thrombotic agent comprises a polysaccharide, an aminodextran, warfarin, hirudin, a heparin group, a hyaluronic acid group, or a combination thereof.

The compound of claim 7, wherein the anti-thrombotic agent comprises heparin groups.

The compound of claim 8, wherein the heparin group is heparin derivative, heparinamine, heparin salt, heparin sulfate, heparan sulfate, heparin methacrylate quaternary ammonium salt complex, heparin methacrylate or poly (ethylene glycol) heparin methacrylate.

The compound of claim 2, wherein the guanidine group comprises a guanidine derivative (guanidine derivative), a biguanide group, a biguanide derivative, a polyaminopropyl biguanide group, a poly (hexamethylene biguanide) derivative group, a chlorhexidine group, or a chlorhexidine derivative group.

The compound of any of the above claims, wherein the ratio of the number of antithrombotic agent moieties to the number of antimicrobial agent moieties on the polymer is about 1:3 to about 1: 25.

The compound of claim 11 wherein the ratio is about 1:6 to about 1: 20.

The compound of any of the above claims, wherein the weight proportion of the antithrombotic agent relative to the polymer is about 1% to about 20% w/w.

The compound of claim 13, wherein the weight ratio of the anti-thrombotic agent to the polymer is from about 1.5% to about 8% w/w.

The compound of any of the above claims, wherein the weight proportion of the antimicrobial agent relative to the compound is from about 2% to about 10% w/w.

The compound of claim 15, wherein the weight ratio of the antimicrobial agent to the compound is from about 6% to about 8% w/w.

The compound of any one of the above claims, further comprising a lubricant group and/or an anti-fouling group covalently attached to the polymer.

A polymeric coating comprising a compound of any of the above claims blended with a lubricant and/or an anti-fouling compound.

The polymeric coating of claim 18, wherein the lubricant comprises N-vinyl pyrrolidone groups and/or glycerol methacrylate groups.

The polymeric coating of claims 18 or 19, wherein the anti-fouling compound comprises one or more of the following: methacryloyloxyethyl phosphorylcholine, 2- ((2- (methacryloyloxy) ethyl) dimethylammonio) ethyl phosphate 2-methoxyethyl, 2- ((2- (methacryloyloxy) ethyl) dimethylammonio) propyl phosphate 2-methoxyethyl, or combinations thereof.

A medical device having a coating comprising a compound according to any of claims 1 to 17 or a coating according to any of claims 18 to 20.

The medical device of claim 21, further comprising a vascular prosthesis, a cardiac stent, a venous stent, an arterial stent, a renal stent, a ureteral stent, a valve, a heart valve leaflet, a shunt, a cardiac device, a pacemaker, a percutaneous catheter, a dialysis port, or a chemotherapy port.

A method of making a polymer, the method comprising polymerizing a mixture of an antimicrobial agent and an antithrombotic agent, wherein the antimicrobial agent comprises a first backbone precursor having a covalently linked antimicrobial compound and a first polymerizable group, and the antithrombotic agent comprises a second backbone precursor having a covalently linked antithrombotic compound and a second polymerizable group.

The method of claim 23, further comprising adding a free radical initiator to the mixture.

The process of claims 23 or 24 wherein said polymerizing step is conducted at a temperature of from about 60 ℃ to about 80 ℃.

The method of any of claims 23-25, wherein the polymerizing step ends after no more than 90 minutes.

The method of any of claims 23-26, wherein the polymerizing step ends after about 20 minutes to 40 minutes.

The method of any of claims 23-27, wherein the first polymerizable group and/or the second polymerizable group comprises a polymerizable vinyl group, an allyl group, a methacrylate group, an acrylate group, or a combination thereof.

The method of any of claims 23-28, wherein the anti-thrombotic compound comprises a polysaccharide, an aminodextran, warfarin, hirudin, a heparin group, a hyaluronic acid group, or a combination thereof.

The method of claim 29, wherein the anti-thrombotic compound comprises heparin groups.

The method of claim 30, wherein the heparin group is heparin derivative, heparinamine, heparin salt, heparin sulfate, heparan sulfate, heparin methacrylate quaternary ammonium salt complex, heparin methacrylate, or poly (ethylene glycol) heparin methacrylate.

The method of any of claims 23-31, wherein the antimicrobial compound comprises a guanidine group, guanidine derivative, biguanide group, biguanide derivative, polyaminopropyl biguanide group, polyaminopropyl biguanide derivative, poly (hexamethylene biguanide) group, poly (hexamethylene biguanide) derivative group, polyhexamethylene guanidine derivative, chlorhexidine group, chlorhexidine hexane derivative group, or a quaternary ammonium salt.

The method of any of claims 23-32, wherein the ratio of the number of antithrombotic agent moieties to the number of antimicrobial agent moieties on the polymer is about 1:3 to about 1: 25.

The method of claim 33, wherein the ratio is about 1:6 to about 1: 20.

The method of any of claims 23-34, further comprising:

reacting the lubricant group and/or the anti-fouling group with a third backbone precursor comprising a linking group and a third polymerizable group to form an additive, and

the additives are mixed with the mixture prior to polymerization.

A polymer blend comprising an antimicrobial polymer blended with an anti-thrombogenic polymer,

wherein the antimicrobial polymer comprises a first backbone, a first linking group covalently attached to the first backbone, and an antimicrobial group covalently attached to the first linking group, and

wherein the antithrombotic polymer comprises a second backbone, a second linking group covalently linked to the second backbone, and an antithrombotic group covalently linked to the second linking group.

The polymer blend of claim 36, wherein the first backbone and/or the second backbone comprises polymerized vinyl groups, allyl groups, methacrylate groups, acrylate groups, or a combination thereof.

The polymer blend of claims 36 or 37, wherein the antimicrobial group comprises a guanidine group or a quaternary ammonium salt.

The polymer blend of any of claims 36-38, wherein the anti-thrombogenic groups comprise polysaccharides, aminodextran, warfarin, hirudin, heparin groups, hyaluronic acid groups, or combinations thereof.

The polymer blend of claim 39, wherein the anti-thrombotic groups comprise heparin groups.

The polymer blend of claim 40, wherein the heparin group is heparin derivative, heparin amine, heparin salt, heparin sulfate, heparan sulfate, heparin methacrylate quaternary ammonium salt complex, heparin methacrylate, or poly (ethylene glycol) heparin methacrylate.

The polymer blend of claim 38, wherein the guanidine group comprises a guanidine derivative, a biguanide group, a biguanide derivative, a polyaminopropyl biguanide group, a poly (hexamethylene biguanide) derivative group, a polyhexamethylene guanidine derivative, a chlorhexidine group, or a chlorhexidine derivative group.

The polymer blend of any of claims 36-42, wherein the ratio of the number of antithrombotic agent groups to the number of antimicrobial agent groups on the polymer is about 1:3 to about 1: 25.

The polymer blend of claim 43, wherein the ratio is from about 1:6 to about 1: 20.

The polymer blend of any of claims 36-44, further comprising a lubricant group and/or an anti-fouling group.

The polymer blend of claim 45, wherein the lubricant groups and/or the anti-fouling groups are covalently attached to the antimicrobial polymer and/or to the anti-thrombogenic polymer.

In one aspect, the invention provides a compound comprising a polymer, an antithrombotic agent, and an antimicrobial agent, wherein the antithrombotic agent and antimicrobial agent are covalently attached to the polymer. In certain preferred aspects, the polymer may comprise polymerized vinyl groups, allyl groups, methacrylate groups, acrylate groups, or combinations thereof. The polymer may also include a copolymer.

Either or both of the antithrombotic agent and the antimicrobial agent can be pendant. The pendant group includes a group attached to a polymer backbone chain. Such attachment can be achieved by copolymerizing moieties (moieties) (suitable species such as monomers, oligomers, etc.) directly or in stages (e.g., initially forming a polymer from the appropriate species, which may itself be a copolymer, followed by attachment of pendant functional groups) to produce a longer chain polymer structure having pendant groups. In one compound according to the invention, the antithrombotic agent and the antimicrobial agent may each be covalently linked to a polymer having a linking group. In certain embodiments, the linking group comprises a polyoxyethylene group, an amine group, an ether group, or a combination thereof.

In certain compounds encompassed by the present invention, the antithrombotic agent can comprise a polysaccharide, an aminodextran, warfarin, hirudin, a heparin group, a hyaluronic acid group, or a combination thereof. In the case of a heparin group, the antithrombotic agent may suitably comprise a heparin derivative, heparin amine, heparin salt, heparin sulfate, heparan sulfate, heparin methacrylate quaternary ammonium complex, heparin methacrylate, or poly (ethylene glycol) heparin methacrylate.

In certain embodiments, the antimicrobial agent may include a guanidine group or a quaternary ammonium salt. Preferred guanidine groups may include guanidine derivatives (guanidine derivatives), biguanide groups, biguanide derivatives, polyaminopropyl biguanide groups, poly (hexamethylene biguanide) derivative groups, chlorhexidine groups or chlorhexidine derivative groups.

In the compounds, polymers, and methods of the invention, the ratio of the number of antithrombotic agent moieties to the number of antimicrobial agent moieties on the polymer (i.e., the molar ratio thereof) can generally be about 1:3 to about 1:25, or about 1:6 to about 1: 20.

The compounds of the present invention may also comprise lubricant groups and/or anti-fouling groups covalently attached to the polymer. The lubricating group and the anti-fouling or non-fouling group are groups that have a lubricant or anti-fouling or non-fouling effect, respectively, in the environment in which the invention is deployed in relation to time. Thus, a lubricious group includes a group or moiety that reduces the coefficient of friction of a compound or coating of the invention when compared to a corresponding compound or coating that does not contain such a group or moiety in the relevant environment. In a corresponding manner, the anti-fouling or non-fouling groups reduce or prevent biological and/or chemical substances from settling on and adhering to the surface. The invention also extends to a polymeric coating comprising a compound of the invention. Such polymeric coatings may comprise the compounds of the present invention blended with a lubricant and/or an anti-fouling or non-fouling compound.

In a preferred embodiment of the invention, the polymer coating may comprise a lubricant comprising N-vinylpyrrolidone groups and/or glycerol methacrylate groups. In a further preferred embodiment, the polymeric coating may comprise an anti-fouling compound comprising one or more of the following: methacryloyloxyethyl phosphorylcholine, 2- ((2- (methacryloyloxy) ethyl) dimethylammonio) ethyl phosphate 2-methoxyethyl, 2- ((2- (methacryloyloxy) ethyl) dimethylammonio) propyl phosphate 2-methoxyethyl, or combinations thereof.

The invention extends to medical devices employing such compounds or coatings, and in particular to medical devices having a coating according to the invention. Such medical devices may include, but are not limited to, vascular grafts, cardiac stents, venous stents, arterial stents, renal stents, ureteral stents, valves, heart valve leaflets, shunts, cardiac devices, pacemakers, percutaneous catheters, dialysis ports, or chemotherapy ports. The compounds and coatings are typically applied to surfaces of the devices that are exposed to a biological environment (e.g., bodily fluids, tissues, etc.) during use.

The invention also extends to a method of making a polymer, the method comprising polymerizing a mixture of an antimicrobial agent and an antithrombotic agent, wherein the antimicrobial agent comprises a first backbone precursor having a covalently linked antimicrobial compound and a first polymerizable group, and the antithrombotic agent comprises a second backbone precursor having a covalently linked antithrombotic compound and a second polymerizable group. Where appropriate, the process further comprises adding a free radical initiator to the mixture.

In certain preferred methods, the first polymerizable group and/or the second polymerizable group comprises a polymerizable vinyl group, an allyl group, a methacrylate group, an acrylate group, or a combination thereof.

In certain preferred methods, the antimicrobial compound comprises a guanidine group, guanidine derivative, biguanide group, biguanide derivative, polyaminopropyl biguanide group, polyaminopropyl biguanide derivative, poly (hexamethylene biguanide) group, poly (hexamethylene biguanide) derivative group, polyhexamethylene guanidine derivative, chlorhexidine group, chlorhexidine hexane derivative group, or a quaternary ammonium salt.

The invention also provides a polymer blend comprising an antimicrobial polymer blended with an antithrombotic polymer, wherein the antimicrobial polymer comprises a first backbone, a first linking group covalently attached to the first backbone, and an antimicrobial group covalently attached to the first linking group, and wherein the antithrombotic polymer comprises a second backbone, a second linking group covalently attached to the second backbone, and an antithrombotic group covalently attached to the second linking group.

The process of the invention may further comprise reacting the lubricant groups and/or the anti-fouling groups with a further backbone precursor, which may be a third backbone precursor, comprising a linking group and a third polymerisable group to form an additive, which is mixed with the mixture prior to polymerisation.

In the polymer blend, the first backbone and/or the second backbone may preferably comprise polymerized vinyl groups, allyl groups, methacrylate groups, acrylate groups, or combinations thereof.

The term "agent" as used herein in the claims and specification in the expressions "antithrombotic agent", "antimicrobial agent", "therapeutic agent", "lubricant", "anti-fouling functionality" and the like extends not only to the compounds themselves (including but not limited to monomers and polymers), but also to the corresponding active moieties of the compounds having the relevant properties, such as groups (radials) and groups (groups).

Brief Description of Drawings

FIG. 1 is a series of optical micrographs showing a polyurethane film in an uncoated state; coated with 90% polyhexamethylene biguanide polymer: 10% heparin polymer polyurethane; and 75% coated polyhexamethylene biguanide polymer: platelet adhesion on polyurethane of 25% heparin polymer.

Figure 2 illustrates the turbidity of a solution associated with a catheter containing a combination polymeric coating, an antimicrobial polymeric coating, or no coating.

Fig. 3 is a series of optical micrographs showing platelet adhesion on uncoated polyurethane and polyurethane coated with one of two polymers.

FIG. 4 shows a diagram of Pseudomonas aeruginosa when used Pseudomonas aeruginosa) On challenge, with a group containing no coating, an antimicrobial polymer coating, or heparinTurbidity of the solution associated with the coated catheter.

FIG. 5 shows enterococcus faecalis: ( Enterococcus faecalis) In a challenge, turbidity of the solution associated with a catheter that does not include a coating, includes an antimicrobial polymer coating, or includes a combination coating that includes heparin.

FIG. 6 shows a schematic representation of the results obtained when Escherichia coli (E.coli) is used Escherichia coli) In a challenge, turbidity of the solution associated with a catheter that does not include a coating, includes an antimicrobial polymer coating, or includes a combination coating that includes heparin.

FIG. 7 shows Staphylococcus aureus (S.aureus) Staphylococcus aureus) In a challenge, turbidity of the solution associated with a catheter that does not include a coating, includes an antimicrobial polymer coating, or includes a combination coating that includes heparin.

FIG. 8 shows Staphylococcus aureus (S.aureus) Staphylococcus aures) In a challenge, turbidity of the solution associated with a catheter that does not include a coating, includes an antimicrobial polymer coating, or includes a combination coating that includes heparin.

FIG. 9 shows the results when Pseudomonas aeruginosa is used (see Pseudomonas aeruginosa) In a challenge, turbidity of the solution associated with a catheter that does not include a coating, includes an antimicrobial polymer coating, or includes a combination coating that includes heparin.

Fig. 10 illustrates platelet adhesion of a surface coated with an antimicrobial polymer, a combination polymer, or a polymer blend.

Fig. 11 is an optical micrograph showing platelet adhesion of uncoated polyurethane.

Fig. 12 is an optical micrograph showing platelet adhesion of polyurethane coated with a combination polymer.

Figure 13 is a graph of surface heparin activity of the combination polymer over time.

Detailed description of the invention

A polymer is a molecule made up of repeats of smaller units sometimes referred to as monomers. Polymers are typically prepared by a specific chemical process that causes monomers to chemically react with each other to form molecular chains that can range in length from short to very long molecules. Polymers can be assembled into larger materials, for example, many polymers can be linked together to form a hydrogel. The polymer may or may not be crosslinked. Crosslinking is a covalent bond that links one polymer chain to another.

The antithrombotic and antimicrobial groups can be pendant groups independently selected and attached to the polymer backbone. The various pendant groups can be independently attached to the polymer backbone such that the polymer comprises the polymer backbone and the plurality of pendant groups. In addition, other pendant groups may be attached to the polymer, or the polymer may be free of pendant groups other than antithrombotic and/or antimicrobial groups. The polymer compositions generally have a molecular weight distribution that can be characterized in general by an average property. The weight of the polymer or polymer backbone can be, for example, from a minimum of 100 daltons, or a minimum of 1,000 daltons up to a maximum of, for example, 1,000,000 daltons or 10,000,000 daltons. Thus, an exemplary molecular weight range for the polymer or polymer backbone may be from 100 to 10,000,000 daltons, or from 1,000 to 1,000,000 daltons. A highly crosslinked polymer may not be easily characterized by molecular weight, but the polymer may be characterized by the polymer chains in the polymer and the degree of crosslinking. The amount of antithrombotic or antimicrobial groups which may be pendant groups can vary freely, for example from about 0.1% to about 99% w/w of the total compound comprising the pendant groups. In further embodiments, the concentration (i.e., weight proportion) of the antithrombotic side group relative to the total weight of the polymer can be at least 1%, or at least 1.5%, which can be no more than 8%, or no more than 20%. Thus, the concentration of antithrombotic groups ranges include, for example, about 1% to about 20%, or about 1.5% to about 8%. In further embodiments, the concentration (weight proportion) of antimicrobial side groups relative to the total weight of the polymer may be at least 2%, or at least 6%, and may not exceed 7%, 8%, or 10%. Thus, the concentration range of antimicrobial groups includes, for example, from about 2% to about 10%, or from about 6% to about 7% or 8%. Those of ordinary skill in the art will appreciate that other ranges are contemplated by and are within the scope of the present disclosure. The skilled person will immediately understand that all values and ranges within the explicitly stated limits are to be taken into account. To achieve these ranges, the monomer compound may be polymerized from a concentrated state, or may be mixed with various other monomers to be polymerized, for example. Alternatively, the polymer can be selected to act as a polymer backbone and lightly or heavily modified with anti-thrombogenic/antimicrobial side groups, as well as other side groups.

FIG. 1 shows uncoated polyurethane obtained at 400 times magnification (FIG. 1A), polyurethane coated with polymer (90% PHMB-polymer (where PHMB represents polyhexamethylene biguanide) and 10% heparin polymer) (FIG. 1B) and polyurethane coated with polymer (75% PHMB-polymer and 25% heparin polymer) (FIG. 1C) on exposure to 1 x 10 ⁵A series of three light micrographs (micrographs) of platelets adhering after platelets/μ l Platelet Rich Plasma (PRP). It is evident that the combined coatings each reduced platelet adhesion.

FIG. 2 shows a schematic representation of a coating with an antimicrobial polymer or a combination of polymers (antimicrobial polymer + heparin) and using Pseudomonas aeruginosa: ( Pseudomonas aeruginosa) Biofilm-mediated turbidity of challenging hemodialysis catheters. Specifically, FIG. 2 shows the turbidity of a solution associated with a substrate coated with a combination polymer (combination polymer 33, designated A, and combination polymer 46, designated B), an antimicrobial polymer (designated C), and an uncoated (D),

(A) double lumen 14Fr polyurethane dialysis catheter coated with a low heparin combination polymer

(B) Double lumen 14Fr polyurethane dialysis catheter coated with high heparin composite polymer

(C) Dual lumen 14Fr polyurethane dialysis catheter coated with an antimicrobial polymer

(D) An uncoated dual lumen 14Fr polyurethane dialysis catheter.

The substrate is treated with the bacteria source for the correct amount of time to allow the bacteria to adhere to the surface and then rinsed. The treated substrate is then placed in solution and the bacteria allowed to multiply. After a set period of time, the Optical Density (OD) of the solution was determined. A higher optical density indicates that there are more bacteria present in the solution and therefore on the substrate. As can be seen from FIG. 2, the combination polymer is directed against Pseudomonas aeruginosa: ( P. aeriginosa) Relative to uncoated substrate and coating onlyBoth substrates with antimicrobial polymers provide significant improvements in antimicrobial properties.

Fig. 3 shows the uncoated polyurethane (fig. 3A), the polyurethane coated with the combination polymer 33 (fig. 3B), and the polyurethane coated with the combination polymer 44 (fig. 3C) as tested in fig. 2 after exposure to 1 x 10 ⁵A series of three light micrographs (400x micrographs) of platelet adhesion after platelets/μ l PRP. The combination coating was found to reduce platelet adhesion.

Example 1 describes the synthesis of an antithrombotic monomer. Generally, a monomer comprising a polymerizable group (e.g., methacrylate) bearing a linking group (poly (ethylene glycol)) such as poly (ethylene glycol) methacrylate is activated and then mixed with the desired antithrombotic group, usually in an active form (e.g., a salt). The monomer is subsequently purified. An analogous method to that of example 1 was used to produce the antimicrobial monomers of examples 4-6, 39 and 43.