USRE49522EActiveUtility

Bioactive coatings

66
Assignee: BIOINTERACTIONS LTDPriority: Apr 26, 2013Filed: Feb 11, 2021Granted: May 9, 2023
Est. expiryApr 26, 2033(~6.8 yrs left)· nominal 20-yr term from priority
Inventors:Simon J. OnisFanny BurrowsKrishan KapoorAlan RhodesAjay Luthra
A61L 2400/10A61L 2300/42A61L 2300/236A61L 2300/208A61L 2300/206A61L 33/064A61L 33/0029A61L 33/0011A61L 31/10A61L 29/085A61L 27/34A61L 31/16A61L 27/54A61L 2300/404A61L 29/16A61K 31/728A61K 31/727A61K 31/131A61L 2300/45A61L 2300/44A61K 47/32A61L 29/049A61L 29/041A61K 31/14A61K 9/0012A61L 27/16A61L 31/041A61L 27/26A61L 31/048
66
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Cited by
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58
Claims

Abstract

Antimicrobial and antithrombogenic polymer or polymeric blend, compounds, coatings, and materials containing the same, as well as articles made with, or coated with the same, and methods of making the same exhibiting improved antimicrobial properties and reduced platelet adhesion. Embodiments include polymers with antimicrobial and antithrombogenic groups bound to a single polymer backbone, an antimicrobial polymer blended with an antithrombogenic polymer, and medical devices coated with the antimicrobial and antithrombogenic polymer or polymeric blend.

Claims

exact text as granted — not AI-modified
The invention claimed is: 
     
       1. A compound comprising
 a random polymer of:
 (i) a heparin-poly(ethylene glycol) methacrylate monomer having a single heparin, 
 (ii) methoxy(polyethylene glycol) methacrylate monomer, 
 (iii) butyl methacrylate monomer and/or methacrylic acid monomer and/or benzoylphenyl methacrylate monomer; and 
 (iv) poly(hexanide)-poly(ethylene glycol) methacrylate monomer and/or poly(hexanide) methacrylate monomer, 
 with the polymer being free of crosslinks. 
   
     
     
       2. The compound of  claim 1  wherein the heparin is a heparin derivative, a heparin sulfate, a heparan sulfate, a heparin salt, or a heparin amine. 
     
     
       3. The compound of  claim 1  wherein a ratio of a number of the heparin to a number of the hexanide groups on the polymer is between about 1:3 and about 1:25. 
     
     
       4. The compound of  claim 3  wherein the ratio is between about 1:6 and about 1:20. 
     
     
       5. The compound of  claim 1  wherein a concentration of the heparin compared to the polymer is between about 1% and about 20% w/w. 
     
     
       6. The compound of  claim 5  wherein the concentration of the heparin compared to the polymer is between about 1.5% and about 8% w/w. 
     
     
       7. The compound of  claim 1  wherein a concentration of the poly(hexanide) group compared to the compound is between about 2% and about 10% w/w. 
     
     
       8. The compound of  claim 7  wherein the concentration of the poly(hexanide) group compared to the com pound is between about 6% and about 8% w/w. 
     
     
       9. The compound of  claim 1  further comprising a lubricant group and/or an anti-fouling group covalently bound to the polymer. 
     
     
       10. The compound of  claim 1  wherein a number of CH 2 CH 2 O repeats in the heparin-poly(ethylene glycol) methacrylate monomer, methoxy(polyethylene glycol) methacrylate monomer, and the poly(hexanide)-poly(ethylene glycol) methacrylate monomer is independently selected to be from 1 to 50. 
     
     
       11. A polymeric coating comprising the compound of  claim 1  blended with a lubricant and/or an anti-fouling compound. 
     
     
       12. The polymeric coating of  claim 11  wherein the lubricant comprises an N-vinyl pyrrolidone group and/or a glycerol methacrylate group. 
     
     
       13. The polymeric coating of  claim 11  wherein the anti-fouling compound is methacryloyloxyethyl phosphorylcholine, 2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl 2-methoxyethyl phosphate, 2-((2-(methacryloyloxy)ethyl)dimethylammonio)propyl 2-methoxyethyl phosphate, or combinations thereof. 
     
     
       14. A medical device comprising a coating that comprises the compound of  claim 1 . 
     
     
       15. The medical device of  claim 14  wherein the polymeric coating further comprises a lubricant agent and/or an anti-fouling functional agent. 
     
     
       16. The medical device of  claim 15  wherein the lubricant agent is covalently bound to the polymer. 
     
     
       17. The medical device of  claim 15  wherein the lubricant agent comprises an N-vinyl pyrrolidone group and/or a glycerol methacrylate group. 
     
     
       18. The medical device of  claim 15  wherein the anti-fouling agent is covalently bound to the polymer. 
     
     
       19. The medical device of  claim 15  wherein the anti-fouling agent is methacryloyloxyethyl phosphorylcholine, 2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl 2-methoxyethyl phosphate, 2-((2-(methacryloyloxy)ethyl)dimethylammonio)propyl 2-methoxyethyl phosphate, or combinations thereof. 
     
     
       20. The medical device of  claim 14  further comprising an artificial blood vessel, a cardiac stent, a venous stent, an arterial stent, a kidney stent, a ureter stent, a valve, a cardiac valve leaflet, a shunt, a cardiac device, a pacemaker, a transcutaneous catheter, a dialysis port, or a port for chemotherapy. 
     
     
       21. A method for making a polymer, the method comprising:
 polymerizing a mixture of:
 (i) heparin-poly(ethylene glycol) methacrylate monomer having a single heparin, 
 (ii) methoxy(polyethylene glycol) methacrylate monomer, 
 (iii) butylmethacrylate monomer and/or methacrylic acid monomer and/or benzovlphenyl methacrylate monomer; and 
 (iv) poly(hexanide)-poly(ethylene glycol) methacrylate monomer and/or poly(hexanide) methacrylate monomer, 
   with the polymer being made without crosslinks.   
     
     
       22. The method of  claim 21  further comprising adding a free radical initiator to the mixture. 
     
     
       23. The method of  claim 21  wherein the polymerizing step is performed between about 60° C. and about 80° C. 
     
     
       24. The method of  claim 21  wherein the polymerizing step is terminated after no more than about 90 minutes. 
     
     
       25. The method of  claim 21  wherein the polymerizing step is terminated after at least 20 minutes has passed. 
     
     
       26. The method of  claim 21  wherein the ratio of a number of the heparin to a number of the hexanide groups on the polymer is between about 1:3 and about 1:25. 
     
     
       27. The method of  claim 26  wherein the ratio is between about 1:6 and about 1:20. 
     
     
       28. An anti-thrombogenic polymer which is a copolymer of:
 (a) an anti-thrombogenic monomer selected from heparin methacrylate, heparin poly(ethylene glycol) methacrylate, benzalkonium-heparin methacrylate complex and benzalkonium-heparin poly(ethylene glycol) methacrylate complex; and   (b) co-monomers of: (i) methoxy poly(ethylene glycol) methacrylate; (ii) butyl methacrylate and (iii) methacrylic acid and/or 4-benzoylphenyl methacrylate;   (c) wherein said polymer does not comprise an antimicrobial agent covalently bound to the polymer.    
     
     
       29. The anti-thrombogenic polymer of claim 28, wherein said anti-thrombogenic monomer is heparin poly(ethylene glycol) methacrylate.  
     
     
       30. The anti-thrombogenic polymer of claim 29, comprising co-monomers of methoxy(polyethylene glycol) methacrylate.  
     
     
       31. A method for making an anti-thrombogenic polymer as claimed in claim 28, comprising the steps of mixing the anti-thrombogenic monomer with the co-monomers, degassing the mixture, heating the mixture to a reaction temperature, and adding a polymerisation initiator.  
     
     
       32. The method of claim 31, wherein the reaction temperature is between about 60° C. and about 80° C.  
     
     
       33. A polymeric coating comprising the anti-thrombogenic polymer of claim 28.   
     
     
       34. A coating formulation comprising the anti-thrombogenic polymer of claim 28 blended with a solvent and a crosslinker.  
     
     
       35. The coating formulation of claim 34, wherein the solvent is an organic solvent.  
     
     
       36. The coating formulation of claim 35, wherein the organic solvent comprises tetrahydrofuran and/or isopropanol.  
     
     
       37. A method of coating a substrate with an anti-thrombogenic polymer, said method comprising the steps of providing a coating formulation according to claim 34, dip-coating the substrate by dipping the substrate in the coating formulation, drying the dip-coated substrate, and curing the dip-coated substrate.  
     
     
       38. A method of coating a substrate with an anti-thrombogenic polymer comprising the steps of providing a composition comprising the anti-thrombogenic polymer of claim 28 dissolved in a solvent, and applying the composition to the substrate by spray-coating.  
     
     
       39. The method of claim 38, wherein the spray-coating is thermal spray-coating, electrostatic spray-coating, or ultrasonic spray-coating.  
     
     
       40. The method of claim 37, wherein the substrate is a surface of a medical device.  
     
     
       41. The method of claim 38, wherein the substrate is a surface of a medical device.  
     
     
       42. A medical device which is coated, in whole or in part, with the anti-thrombogenic polymer of claim 28.   
     
     
       43. A medical device as claimed in claim 42, which device comprises one or more surfaces that are, in normal use of the device, exposed to biological environments, wherein the biological environments comprise blood, tissues or fluids.  
     
     
       44. The medical device of claim 42, which is selected from a contact lens or intraocular lens, a catheter for vascular access (arterial and/or venous), abdominal cavity tubing, a drainage bag and/or a connector, a catheter, a blood bag, a dialysis or other membrane, surgical gloves, a surgical instrument, a vascular graft, a stent, a contact lens case, a bottle, diagnostic apparatus, an oxygenator, a heart valve and/or pump, artificial blood vessels, a cardiac stent, a venous stent, an arterial stent, a kidney stent, a ureter stent, a valve, a cardiac valve leaflet, a shunt, a cardiac device, a pacemaker, a transcutaneous catheter, a dialysis port or a port for chemotherapy.  
     
     
       45. A method for reducing the susceptibility of a substrate to platelet adhesion, comprising the step of coating the substrate with an anti-thrombogenic polymer as claimed in claim 28.   
     
     
       46. The method of claim 45, wherein the substrate is a surface of a medical device; wherein the surface of the medical device is exposed, in use, to blood.  
     
     
       47. A method for reducing the likelihood of clot formation at the surface of a substrate when the substrate is brought into contact with blood, comprising the step of coating the substrate with an anti-thrombogenic polymer as claimed in claim 28.   
     
     
       48. The method of claim 47, wherein the substrate is a surface of a medical device; wherein the surface of the medical device is, in normal use of the device, contacted with blood.  
     
     
       49. A coating formulation comprising the anti-thrombogenic polymer of claim 28, blended with an anti-microbial polymer.  
     
     
       50. The coating formulation of claim 49, wherein the anti-microbial polymer is a copolymer of:
 (a) an anti-microbial monomer selected from: poly(hexanide) methacrylate (PHMB-MA); poly(ethylene glycol) methacrylate-poly(hexanide); chlorhexidine methacrylate; and chlorhexidine digluconate; and   (b) co-monomers of: (i) methoxy poly(ethylene glycol) methacrylate; (ii) butyl methacrylate and (iii) methacrylic acid and/or 4-benzoylphenyl methacrylate.    
     
     
       51. The coating formulation of claim 50, wherein the anti-microbial monomer is poly(hexanide) methacrylate or poly(ethylene glycol) methacrylate-poly(hexanide).  
     
     
       52. The coating formulation of claim 49, wherein the anti-microbial polymer is a copolymer of:
 (a) an anti-microbial monomer consisting of a polymerizable group that is connected to a guanide or biguanide antimicrobial agent by a polyethylene oxide attachment group; and   (b) one or more co-monomers selected from acrylates, methacrylates, (meth)acrylic acid, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate, n-butyl methacrylate, tert-butyl methacrylate, n-hexyl methacrylate, 2-methoxyethyl methacrylate, and monomers comprising poly(ethylene glycol).    
     
     
       53. The coating formulation of claim 49, wherein the anti-microbial polymer is free of anti-thrombogenic agents.  
     
     
       54. The coating formulation of claim 49, further comprising a solvent and a crosslinker.  
     
     
       55. A method of coating a substrate with an anti-thrombogenic polymer, said method comprising the steps of providing a coating formulation according to claim 54, dip-coating the substrate by dipping the substrate in the coating formulation, drying the dip-coated substrate, and curing the dip-coated substrate.  
     
     
       56. A medical device which is coated, in whole or in part, with the coating formulation of claim 49.   
     
     
       57. A medical device as claimed in claim 56, which device comprises one or more surfaces that are, in normal use of the device, exposed to biological environments, wherein the biological environments comprise blood, tissues or fluids.  
     
     
       58. The medical device of claim 56, which is selected from a contact lens or intraocular lens, a catheter for vascular access (arterial and/or venous), abdominal cavity tubing, a drainage bag and/or a connector, a catheter, a blood bag, a dialysis or other membrane, surgical gloves, a surgical instrument, a vascular graft, a stent, a contact lens case, a bottle, diagnostic apparatus, an oxygenator, a heart valve and/or pump, artificial blood vessels, a cardiac stent, a venous stent, an arterial stent, a kidney stent, a ureter stent, a valve, a cardiac valve leaflet, a shunt, a cardiac device, a pacemaker, a transcutaneous catheter, a dialysis port or a port for chemotherapy.

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