NON-FOULING, ANTI-MICROBIAL, ANTI-THROMBOGENIC GRAFT-FROM COMPOSITIONS

• US 20100152708A1
• Filed: 12/07/2009
• Published: 06/17/2010
• Est. Priority Date: 12/05/2008
• Status: Active Grant

• Current Assignee: Arrow International Incorporated (Teleflex Incorporated)
• Original Assignee: Semprus BioSciences Corp. (Teleflex Incorporated)
• Inventors: O'Shaughnessy, William Shannan, Li, Jun, Zhang, Zheng, Bouchard, Michael, Hencke, Michael, Huval, Chad, Squier, Trevor, Loose, Christopher R.
• Granted Patent: US 9,895,470 B2
• Time in Patent Office: Days
• US Class Current: 604/523
• CPC Class Codes: A61L 27/14 Macromolecular materials
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 29/14 Materials characterised by their function or physical properties , e.g. lubricating compositions
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 33/06 Use of macromolecular materials grafting of a monomer onto the substrate A61L33/0088
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: C08F 220/387 and containing nitrogen and oxygen
• CPC Class Codes: C08F 220/56 Acrylamide; Methacrylamide
• CPC Class Codes: C08F 265/04 on to polymers of esters
• CPC Class Codes: C08F 283/00 Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
• CPC Class Codes: C08F 283/006 on to polymers provided for in C08G18/00 C08F283/004 takes precedence
• CPC Class Codes: C08F 291/18 on to irradiated or oxidised macromolecules epoxidised C08F291/10
• CPC Class Codes: C08F 4/40 Redox systems
• CPC Class Codes: C08L 25/08 Copolymers of styrene C08L29/08, C08L35/06, C08L55/02 take precedence
• CPC Class Codes: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 75/04 Polyurethanes
• CPC Class Codes: C09D 151/003 grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds C09D151/04, C09D151/06 take precedence
• CPC Class Codes: C09D 151/06 : grafted on to homopolymers or copolymers of aliphatic hydrocarbons containing only one carbon-to-carbon double bond
• CPC Class Codes: C09D 151/08 : grafted on to macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: C09D 151/085 : on to polysiloxanes
• CPC Class Codes: C09D 5/1637 : Macromolecular compounds
• CPC Class Codes: C09D 5/1693 : as part of a multilayer system
• CPC Class Codes: Y10T 428/31507 : Of polycarbonate
• CPC Class Codes: Y10T 428/31511 : Of epoxy ether
• CPC Class Codes: Y10T 428/31529 : Next to metal
• CPC Class Codes: Y10T 428/31663 : As siloxane, silicone or silane
• CPC Class Codes: Y10T 428/31678 : Of metal
• CPC Class Codes: Y10T 428/31681 : Next to polyester, polyamide or polyimide [e.g., alkyd, glue, or nylon, etc.]
• CPC Class Codes: Y10T 428/31692 : Next to addition polymer from unsaturated monomers
• CPC Class Codes: Y10T 442/2525 : Coating or impregnation functions biologically [e.g., insect repellent, antiseptic, insecticide, bactericide, etc.]

Abstract

Substrates, optionally coated with an undercoating layer, having grafted there from one or more non-fouling materials are described herein. The non-fouling, polymeric material can be grafted from a variety of substrate materials, particularly polymeric substrates and/or polymeric undercoating layers. The graft-from techniques described herein can result in higher surface densities of the non-fouling material relative to graft-to formulations. Graft-from methods can be used to produce covalently tethered polymers. The compositions described herein are highly resistant protein absorption, particularly in complex media and retain a high degree of non-fouling activity over long periods of time. The compositions described herein may also demonstrate antimicrobial and/or anti-thrombogenic activity. The non-fouling material can be grafted from the substrate, or optionally from an undercoating layer on the substrate, preferably without significantly affecting the mechanical and/or physical properties of the substrate material.

Claims

1. A composition comprising a substrate, optionally comprising an undercoating layer immobilized on the substrate, having covalently bound to the substrate or the undercoating layer a non-fouling polymeric material, wherein the polymeric material is grafted from within the substrate or the undercoating layer.

3. The composition of claim 1 or 2, wherein the substrate is selected from the group consisting of metallic materials, ceramics, polymers, woven materials, non-woven materials, silicon, and combinations thereof.

4. The composition of claim 3, wherein the metallic material is selected from the group consisting of titanium and alloys thereof, stainless steel, tantalum, palladium, zirconium, niobium, molybdenum, nickel-chrome, cobalt or alloys thereof, and combinations thereof.

5. The composition of claim 3, wherein the ceramic is selected from the group consisting of oxides, carbides, or nitrides of the transition metal elements or metalloid elements.

6. The composition of claim 3, wherein the polymer is selected from the group consisting of polystyrene and substituted polystyrenes, poly(urethane)s, polyacrylates and polymethacrylates, polyacrylamides and polymethacrylamides, polyesters, polysiloxanes, polyethers, poly(orthoester), poly(carbonates), poly(hydroxyalkanoate)s, polyfluorocarbons, PEEK, Teflon, silicones, epoxy resins, polyamides and copolymers thereof, nylon, polyalkenes, phenolic resins, PTFE, natural and synthetic elastomers, adhesives and sealants, polyolefins, polysulfones, polyacrylonitrile, polysaccharides, and combinations thereof.

7. The composition of claim 6, wherein the polymer is polyurethane or a polycarbonate-based polyurethane.

8. The composition of claim 1 or 2, wherein the substrate is not gold or glass.

9. The composition of claim 1 or 2, wherein the surface of the substrate comprises an undercoating layer to form a surface having a uniform chemical composition.

10. The composition of claim 9, wherein the undercoating layer is a polyurethane.

11. The composition of claim 1 or 2, wherein the substrate is a peroxide treated substrate.

12. The antimicrobial polymeric composition of claim 1, wherein the substrate is substantially thiol free.

13. The composition of claim 1 or 2, wherein the non-fouling polymeric material is a zwitterionic polymer.

14. The composition of claim 13, wherein the zwitterionic polymer is a homopolymer or copolymer comprising one more monomers having the following formula:

15. The composition of claim 14, wherein ZI is selected from the group consisting of:

16. The composition of claim 14, wherein x is from about 10 to about 500, from about 20 to about 250, or from about 30 to about 100.

17. The composition of claim 15, wherein the zwitterionic polymer is a homopolymer of sulfobetaine methacrylate (SBMA) or sulfobetaine acrylamide.

18. The composition of claim 15, wherein the zwitterionic polymer is a copolymer comprising sulfobetaine methacrylate (SBMA) or sulfobetaine acrylamide.

19. The composition of claim 13, wherein the zwitterionic polymer has the following structure:

20. The composition of claim 13, wherein the polymer comprises one or more monomers selected from the group consisting of:

21. The composition of claim 19, wherein the negatively charged group is selected from the group consisting of carboxylate group, —

SO₃⁻

, —

OSO₃⁻

, —

PO₃⁻

, and —

OPO₃⁻

.

22. The composition of claim 19, wherein the positively charged group is a quaternized nitrogen or cationic phosphorous containing group.

23. The composition of claim 19, wherein x, m, and n are from about 10 to about 500, from about 20 to about 250, or from about 30 to about 100.

24. The composition of claim 1 or 2, wherein the non-fouling material is a non-zwitterionic polymer selected from the group consisting of polyethers, polysaccharides, polyvinylpyrrolidone, hydroxyethyl-methacrylate, acrylanitrile-acrylamide copolymers, heparin, mixed charge polymers, and polymers containing hydrogen bond accepting groups.

25. The composition of claim 1 or 2, wherein the polymeric material is formed by UV-initiated free radical polymerization.

26. The composition of claim 1 or 2, wherein the polymeric material is formed by redox-initiated free radical polymerization.

27. The composition of claim 26, wherein the non-fouling material is polymerized by radicals present in the substrate and/or undercoating layer.

28. The composition of claim 26, wherein the radicals are formed from a redox pair comprising a peroxide and a metal salt.

29. The composition of claim 28, wherein the peroxide is imbibed in the substrate.

30. The composition of claim 28, wherein the peroxide is dicumyl peroxide and the metal salt is Fe(II) gluconate.

31. The composition of claim 1, wherein the non-fouling polymeric material is end-tethered to the substrate to form a brush structure.

32. The composition of claim 1 or 2, wherein the non-fouling polymeric material is grafted from the substrate or undercoating layer through a tether.

33. The composition of claim 1 or 2, wherein the non-fouling polymeric material, the substrate, the undercoating layer, or combinations thereof has immobilized thereon one or more bioactive agents.

34. The composition of claim 33, wherein the one or more bioactive agents are immobilized covalently or non-covalently on the non-fouling material, substrate, undercoating layer, or combinations thereof.

35. The composition of claim 33, wherein the one or more bioactive agents are immobilized to the non-fouling material, the substrate, undercoating layer, or combinations thereof through a tether.

36. The composition of claim 1 or 2, wherein the composition reduces fouling by greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, after storage in phosphate buffered saline (PBS), media, serum, or in vivo at 37°

C. for a period of at least 1, 7, 14, 30, 90, 365, or 1000 days compared to uncoated substrate.

37. The composition of claim 1 or 2, wherein the composition is biocompatible.

38. The composition of claim 37, wherein the composition is substantially non-hemolytic and substantially non-cytotoxic.

39. The composition of claim 1 or 2, wherein the composition is antimicrobial.

40. The composition of claim 1 or 2, wherein the composition is anti-thrombogenic.

41. The composition of claim 1 or 2, wherein the composition retains at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of its original material properties such as surface contact angle, non-fouling, anti-thrombogenic, and/or antimicrobial activity in PBS, media, serum, or in vivo for a time of 1, 7, 14, 30, 90, 365, or 1000 days.

42. The composition of claim 1 or 2, wherein the composition is in the form of a medial device.

43. The composition of claim 42, wherein the medical device is selected from the group consisting of fibers;

surgical, medical or dental instruments;

blood oxygenators, ventilators, pumps, drug delivery devices, tubing, wiring, electrodes, contraceptive devices, feminine hygiene products, endoscopes, grafts, stents, stent grafts, pacemakers, implantable cardioverter-defibrillators, cardiac resynchronization therapy devices, cardiovascular device leads, ventricular assist devices and drivelines, heart valves, vena cava filters, endovascular coils, catheters, catheter connectors and valves, intravenous delivery lines and manifolds, shunts, wound drains, dialysis membranes, infusion ports, cochlear implants, endotracheal tubes, tracheostomy tubes, ventilator breathing tubes and circuits, guide wires, fluid collection bags, drug delivery bags and tubing, implantable sensors, ophthalmic devices, orthopedic devices, dental implants, periodontal implants, breast implants, penile implants, maxillofacial implants, cosmetic implants, valves, appliances, scaffolding, suturing material, needles, hernia repair meshes, tension-free vaginal tape and vaginal slings, prosthetic neurological devices, tissue regeneration or cell culture devices, or other medical devices used within or in contact with the body.

44. The composition of claim 43, wherein the device contains lumens, cavities, porous structures, or combinations thereof.

45. The composition of claim 44, wherein the device is a vascularly inserted catheter selected from the group consisting of a peripherally inserted central catheter (PICC), central venous catheter (CVC), and hemodialysis catheter

46. The composition of claim 1 or 2, wherein the tensile strength, modulus, device dimensions, or combinations thereof are within 20%, 10%, 5%, or 1% of the tensile strength, modulus, device dimensions, or combinations thereof of the uncoated substrate.

47. A method of making the composition of claim 1 or 2 comprising grafting from within, and/or from the surface of, the substrate, undercoating layer or both a non-fouling polymeric material.

48. The method of claim 47, wherein the non-fouling polymeric material is grafted from within, and/or from the surface of the substrate, undercoating layer, or both using one or more free radical initiators.

49. The method of claim 48, wherein the one or more initiators is an ultraviolet (UV) initiator.

50. The method of claim 48, wherein the one or more initiators is a redox initiator pair.

51. The method of claim 49, wherein the one or more free radical initiators are imbibed into the substrate, the undercoating layer, or combinations thereof.

52. The method of claim 50, wherein the redox initiator comprises a hydrophobic-hydrophilic redox initiator pair.

53. The method of claim 52, wherein the redox initiator system comprises a peroxide and a metal salt.

54. The method of claim 53, wherein the peroxide is dicumyl peroxide and the metal salt is Fe(II) gluconate.

56. The method of claim 47, wherein the substrate, undercoating layer, or combinations thereof are not treated with plasma or ozone to produce free radicals to initiate polymerization.

57. The method of claim 47, wherein the graft-from polymerization occurs in the presence of one or more oxygen scavengers.

2. A composition comprising a substrate, optionally comprising an undercoating layer immobilized on the substrate, having covalently bound to the substrate or the undercoating layer a non-fouling polymeric material, wherein the density of the non-fouling polymer material is from about 0.50 μ

g/cm² to about 5 mg/cm² or wherein the inter-polymer chain distance decreases the penetration of fouling molecules into the non-fouling polymeric material.

55. The method of 47, wherein the graft-from polymerization does not require line of sight.