Zwitterionic backbone polyurethane surface modifying additive

Abstract

A zwitterionic polyurethane additive, a base polymer comprising a zwitterionic polyurethane additive, a medical device comprising an admixture of a base polymer and a zwitterionic polyurethane additive and a method of reducing a thrombus adhesion and / or bacterial adhesion on an admixture of a base polymer and a zwitterionic polyurethane additive are disclosed. The zwitterionic polyurethane additive is composed of non-zwitterionic diol, zwitterionic diol intermediate, isocyanate and mono- hydroxyl, a mono-amine or a mono- thiol terminated end groups. A wide range of diols, zwitterionic diol intermediates and isocyanates could be selected for the synthesis of zwitterionic polyurethane additive to achieve different properties.

Description

[0001] 202400064 Foreign Filing 1

[0002] ZWITTERIONIC BACKBONE POLYURETHANE SURFACE MODIFYING ADDITIVE

[0003] Field of the Invention

[0004] The invention involves the development, composition and application of surface modifying additives for medical devices. The current zwitterionic additive is designed to be incorporated into the material composition of medical devices during manufacturing, and create a homogenous surface that would improve functionality, biocompatibility and blood compatibility of the modified surfaces.

[0005] Discussion of the Background

[0006] Implantable medical devices are prone to protein / enzyme fouling, thrombus attachment and bacteria adhesion when exposed to bodily fluids (e.g., blood, urine, etc.). It is of great significance to develop surface-modifying additives that can modify the surface chemistry and / or properties of medical device components, thereby enhancing the functionalities and biocompatibility, including aspects such as reducing thrombogenicity, and reducing bacterial adhesion.

[0007] Polymers used to create medical devices or components which are in need of biocompatibility and anti-thrombogenic properties can be selected from the groups of polyurethanes, silicones, polyamides, polyesters, co-polyesters, polyethers, polyether-block-amide co-polymers, polypropylenes, polyethylenes, polyvinylchlorides, polysulfones, polyetherimides, polycarbonates, polyetheretherketones, ethyl vinyl acetates, polyolefins, styrenic block copolymers and vulcanized rubbers, among others. These polymers may also contain other additives such as radiopaque fillers, colorants, processing aids, antimicrobials, or antiseptics, among others.

[0008] Zwitterionic polymers and surface coating with zwitterionic molecules have been reported. A zwitterion is a molecule that contains an equal amount of positively and negatively charged functional groups. Such molecules have been demonstrated to reduce protein adsorption, platelet adhesion, thrombus adhesion and bacterial adhesion.

[0009] Ga et al., Tissue Engineering and Regenerative Medicine (2022), 19(1), 35-47 report that medical devices with combinatorial effects of zwitterionic functional group and anti-bacterial metal ions can effectively reduce thrombosis and bacterial infection of polymeric biomaterials. The authors used a series of zwitterionic polyurethane (zPU) additives to impart anti-thrombotic properties to a polyvinyl chloride (PVC) matrix.

[0010] Peng et al., Journal of Materials Chemistry B: Materials for Biology and Medicine (2023), 11 (33), 8020- 8032 report that antifouling coatings based on zwitterionic polymers have been widely applied for surface modification of interventional blood-contacting devices to combat thrombosis and infection.

[0011] US 2022 / 0265904 report medical articles formed from a polyurethane-based resin including an ionically-charged modifier provide enhanced properties. The polyurethane-based resin is a reaction product of ingredients comprising a diisocyanate, a diol chain extender, a polyglycol, and an ionically- 202400064 Foreign Filing 2 charged modifier incorporated into a backbone, as a side chain, or both, of the polyurethane-based resin. The ionically-charged modifier is a zwitterion comprising an anion and a cation.

[0012] WO 2018 / 174304 discloses the application of medical devices containing polyurethane zwitterionic polymers that impart antimicrobial, antifouling, and antithrombic properties for cardiovascular systems. The chemical structure of the target polymers may include (i) diisocyanate, zwitterion (backbone), citric acid (end capping agent to allow for metal (AgNOs, ZnSO4, CuSO4, Ce) crosslinking and (ii) diisocyanate, zwitterion (backbone), isosorbide (backbone), citric acid (end capping agent to allow for metal (AgNOs, ZnSO4, CuSO4, Ce) crosslinking. The zwitterionic polyurethane polymers at various concentrations were compounded with a high molecular weight base material polyvinyl chloride to produce films, a tube, a sheet, a stent, a catheter, an implant, a suture, a hydrogel, or a combination thereof.

[0013] WO 2017117472 disclose devices for detection of an analyte concentration (e.g., glucose) comprising a bio interface polymer which comprises polyurethane and / or polyurea segments and one or more zwitterionic repeating units, e.g. betaines.

[0014] CN 103724595 discloses amphoteric polymer modified polyurethane material and preparation method thereof. The prepared polyurethane material has high hydrophilicity, blood platelet adsorption resistance, low cytotoxicity, favorable properties for endothelial cell adhesion and proliferation, as well as good biocompatibility and blood compatibility.

[0015] While zwitterionic chemistries have been described in the literature as generally improving biofouling resistance or hydrophilicity, they rely on creating a grafted matrix or a coating of zwitterions on the surface to impart modification or functionality (e.g. Peng et al.). Other compounds that may be used as additives rely on zwitterionic charges in the main chain (e.g. US 2022 / 0265904) or require additional complexation with other functional chemistries such as metal ions (e.g. Ga et al.). Coatings and complexation require additional chemical reactions and / or coating steps, and have limitations in their design such as coating uniformity and durability. There remains a need for new designs of polymer additives which when added to a base polymer, can reduce thrombus attachments and bacterial adhesion in a polymer surface exposed to biological fluids.

[0016] SUMMARY OF THE INVENTION

[0017] The present invention provides for zwitterionic polyurethane oligomers (zwitterionic polyurethane additive), which when added to a base polymer and processed into a medical device component can reduce thrombus attachments and / or bacterial adhesion when brought into contact with a biological fluid. The zwitterionic polyurethane additive is composed of non-zwitterionic diol, zwitterionic diol intermediate, isocyanate and mono hydroxyl or mono amino or mono thiol terminated end groups. A wide range of diols, zwitterionic diols intermediates and isocyanates could be selected for the synthesis of the additive to achieve different properties. 202400064 Foreign Filing 3

[0018] In a further aspect, the invention features a polymer comprising a zwitterionic polyurethane additive and base polymer.

[0019] A further aspect of the invention is directed to a medical device comprising / consisting of a zwitterionic polyurethane additive and a base polymer, having a surface with reduced thrombus attachment and / or reduced bacterial adhesion properties.

[0020] A further aspect of the invention is directed to a method of reducing thrombus attachment and / or reducing bacterial adhesion to a base polymer comprising adding a thrombus attachment and / or bacterial adhesion reducing zwitterionic polyurethane additive to a base polymer.

[0021] These and other aspects of the invention are provided for by an article, having a surface comprising a zwitterionic polyurethane additive admixed with a base polymer.

[0022] The inventors have discovered new chemical entities of a zwitterionic polyurethane additive which, in admixture with a base polymer, create a homogenous surfaces having reduced thrombus attachment and / or reduced bacterial adhesion properties.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same become better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:

[0025] Fig. 1 : depicts a synthetic procedure for PUZB (zwitterionic polyurethane additive);

[0026] Fig. 2: illustrates elemental sulfur and oxygen concentrations on polyurethane-PUZB admixture surfaces;

[0027] Fig. 3: illustrates water contact angle on polyurethane-PUZB admixture surfaces;

[0028] Fig. 4: illustrates thrombosis on polyurethane-PUZB admixture rod prototypes in in-vitro blood loop study; and

[0029] Fig. 5: illustrates bacterial adhesion on polyurethane-PUZB admixture rods after 2 hours of incubation in inoculated buffer.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] Compounds of the invention include formulations synthesized using zwitterionic building blocks (e.g. sulfobetaines, carboxy betaines and phosphobetaines) incorporated into the backbone of polyurethane oligomers. Other building blocks in the zwitterionic additives can include hydrophilic monomers (e.g. PEO units), hydrophobic polyethers or siloxane segments. Specific additives of the invention include: polyurethane chemistry with zwitterionic units in the backbone (PUZB).

[0032] PUZB additives can be synthesized by reacting an isocyanate with a zwitterionic diol intermediate and a non-zwitterionic diol to form an isocyanate group terminated polyurethane pre-polymer. The prepolymer is then reacted (end-capped) with molecules or oligomers such as mono-alcohols, mono-amines 202400064 Foreign Filing 4 or mono-thiols to form the PUZB additive (zwitterionic polyurethane additive). The zwitterionic diol intermediate is prepared by reacting at least one tertiary amine diol with at least one heterocycle, preferably selected from sulfones, lactones, 2-alkoxy-2-oxo-1 ,3,2-dioxaphospholanes, or a combination thereof. A generic reaction scheme is depicted in Fig. 1 .

[0033] Organotin compound or bismuth compounds are typically used as a catalyst for polyurethane synthesis. Non-limiting examples which can be used to synthesize PUZB are dibutyltin dilaurate or Bismuth carboxylate (e.g., K-Kat 348).

[0034] PUZB

[0035] A PUZB is composed of non-zwitterionic diol, zwitterionic diol intermediate, isocyanate and mono hydroxyl or mono amino or mono thiol terminated end groups. A wide range of diols, zwitterionic diol intermediates and isocyanate could be selected for the synthesis of PUZB to achieve different properties.

[0036] Possible non-zwitterionic diols used in PUZB may include polyether diols (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG), polytetramethylene oxide (PTMO), poloxamer diols, bisphenol A ethoxylate, etc.); polyester diols (e.g., poly(diethylene glycol) adipate, polycaprolactone diol, polylactide diol, etc.); polycarbonate diols (e.g., poly(hexamethylene carbonate) diol, polyethylene carbonate diol, etc.); polysiloxane diols (e.g., hydroxyl terminated polydimethylsiloxane, hydroxyalkyl terminated poly(propyleneoxy)-polydimethylsiloxane block copolymer); hydrogenated diols (e.g., hydrogenated polybutadiene, hydrogenated polyisoprene), or a combination of different types of diols mentioned above. The diol segment has a (theoretical) molecular weight of 500-3,500 Da.

[0037] Many zwitterionic diol intermediates may be used. One example of a zwitterionic diol intermediate used in PUZB may be a diol synthesized starting by ring-opening alkylations using tertiary amine diols (e.g., N-methyldiethanolamine, N-ethyldiethanolamine, etc.) with heterocycles, such as sulfones (e.g., 1 ,3-propanesultone, 1 ,4-butane sulfone, etc.), lactones (e.g., p-propiolactone) and 2-alkoxy-2-oxo-1 ,3,2- dioxaphospholanes, to form sulfobetaines, carboxybetaines and phosphobetaines, respectively. Nonlimiting examples of the reactants forming zwitterionic groups are: bis-1 ,4-((2-hydroxypropoxy)-2- propoxy)-butane sulfonate sodium salt (SULFADIOLO-7Q); 2, 3-dihydroxypropane-1 -sulfonate sodium salt; N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonate sodium salt; 2,2-bis(hydroxymethyl)propionic acid; 2,2-bis(hydroxymethyl)butyric acid (BHMBA); or combination thereof.

[0038] In one embodiment, the amount of zwitterionic intermediate in the product polyurethane (zwitterionic polyurethane additive) may be from 0.5-50 wt. %, preferably from 1-20 wt. %, more preferably from 1-15 wt. %, more preferably from 5-12 wt. %, based on a weight of said polyurethane (zwitterionic polyurethane additive).

[0039] Preferably, the molar ratio of zwitterionic diol intermediate to non-zwitterionic diol in the zwitterionic polyurethane additive is in the range of 1 :0.4 to 1 :20, more preferably 1 :1 to 1 :10, even more preferably 1 :1 to 1 :5, most preferably 1 :2 to 1 :5 and in particular 1 :3 to 1 :5. 202400064 Foreign Filing 5

[0040] The isocyanate building blocks could include linear diisocyanates, such as: hexamethylene diisocyanate (HDI), 4,4'-Methylene-bis(cyclohexyl isocyanate) (H12MDI), methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), and isophorone diisocyanate (I PDI) ; as well as trifunctional isocyanuates (e.g., 3-lsocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, Hexamethylene diisocyanate isocyanurate trimer, etc.) and biurets (e.g., hexamethylene diisocyanate homopolymer).

[0041] The end groups could be any mono-functionalized molecules or oligomers capable of reacting with the terminal isocyanate groups of a polyurethane pre-polymer, such as mono-alcohols, monoamines and mono-thiols. End groups with PEG units are preferred. Preferably the end groups with PEG units are selected from poly(ethylene glycol) methyl ether, poly(ethylene glycol) methyl ether amine, O-(2- Mercaptoethyl)-O'-methyl-hexa(ethylene glycol) or a mixture thereof. Preferably the mono-functionalized molecules or oligomers capable of reacting with the terminal isocyanate groups of a polyurethane prepolymer have an average molecular weight (Mn) less than 1000 Da, more preferably in the range of 50 Da to 1000 Da, even more preferably 200 Da to 1000 Da, most preferably 300 Da to 1000 Da, and in particular 300 Da to 900 Da.

[0042] The zwitterionic polyurethane additive may have a molecular weight (theoretical) of less than 10,000 Da, preferably 1 ,000 to < 10,000 Da, more preferably 2,000-8,000 Da, more preferably 3,000-6,000 Da. The molecular weight of the zwitterionic polyurethane additive may be adjusted depending on the properties of the base polymer.

[0043] The term “molecular weight,” as used throughout the specification, refers to a theoretical weight of an Avogadro number of molecules of identical composition. As preparation of a surface modifying macromolecule can involve generation of a distribution of compounds, the term “molecular weight” refers to an idealized structure determined by the stoichiometry of the reactive ingredients. Thus, the term “molecular weight,” as used herein, refers to a theoretical molecular weight.

[0044] In a preferred aspect the invention provides a composition comprising an admixture of a base polymer and a zwitterionic polyurethane additive. In the admixture the base polymer and the zwitterionic polyurethane additive form a homogenous mixture. In another embodiment the additive is present in an amount such that it leads to the reduction of thrombus attachment and / or bacterial adhesion.

[0045] The zwitterionic polyurethane additive is admixed with the base polymer or material composite used in the manufacture of a device. The concentration of the additive can be between 0.05-15% w / w, preferably 0.7- 12% w / w, more preferably 1 % to 10% w / w, even more preferably 2-6% w / w relative to the base polymer and can include combinations of different zwitterionic polyurethane additive formulations. The additives will migrate to all surfaces of the device during manufacturing due to their surface-active properties forming a homogenous surface with the zwitterionic polyurethane additive, creating a unique surface chemistry. 202400064 Foreign Filing 6

[0046] Base polymers

[0047] Examples of a typical base polymer of use in admixture with aforesaid zwitterionic polyurethane additive are a polyurethane (PU), a silicone, a polyamide (PA), a polyester, a co-polyester, a polyether, a polyether-block-amide co-polymer (PEBA), a polyetherimide, a polycarbonate, a polyetheretherketone (PEEK), an ethyl vinyl acetate (EVA), a polypropylene (PP), a polyethylene (PE), a polyvinylchloride (PVC), a polyvinyl alcohol (PVA), a polyvinylpyrrolidone (PVP), a polyacrylamide (PAAM), a polyethylene oxide (PEO), a poly(ethylene oxide)-b-poly (propylene oxide)-b-poly(ethylene oxide), a poly(hydroxyethylmethacrylate) (polyHEMA), polyethylene terephthalate (PET), a polybutylene terephthalate (PBT), a polymethylmethacrylate (PMMA), a polysulfone, a polyethersulfone, a polymethylpentene, a styrenic block copolymer, a vulcanized rubber, a polyolefin , a cyclic olefin polymer (COP), cyclic olefin copolymer (COC), a cellulosic polymer, or a copolymer or blend thereof.

[0048] The molecular weight of the base polymer is not particularly limited and is generally appropriate for the preparation of a medical device.

[0049] In further embodiments, the base polymer is a thermoplastic.

[0050] The base polymer may contain suitable additives known to those of ordinary skill in the art, such as fillers, colorants, pigments, stabilizers, antioxidants, plasticizers, reinforcing agents, impact modifiers, blowing agents, curing agents, flame retardants, antistatic agents, conductive agents, processing aids, antimicrobials, antiseptics, antibiotics or other functional additives. The additives may be organic or inorganic in nature. Example fillers include radiopaque fillers such as barium sulphate, bismuth subcarbonate, bismuth trioxide, or tungsten. Example plasticizers include bis (2- ethylhexyl)phthalate (DEHP), di(2-ethylhexyl) terephthalate (DEHT), or trioctyltrimellitate (TOTM) used to plasticize PVC resins. Example antimicrobial, antiseptic or antibiotic agents include triclosan, silver sulfadiazine, chlorohexidine, rifampin or clindamycin.

[0051] The migration of the zwitterionic polyurethane additives to the device surface can be confirmed using standard analytical methods such as X-ray Photoelectron Spectroscopy to measure surface chemistry. Visual inspection and microscopy techniques can be utilized to confirm no aggregation or phase separation of the additives on the surfaces of the device. The hydrophilicity of the modified surfaces can be determined by techniques such as water contact angle analysis.

[0052] The combination of zwitterionic polyurethane additive and base polymer preferably has a relative thrombus accumulation which is no more than 50%, more preferably no more than 40%, even more preferably no more than 30%, even more preferably no more than 10%, even more preferably no more than 5%, and most preferably no more than 1 % that of the base polymer without the additive.

[0053] The combination of zwitterionic polyurethane additive and base polymer preferably has a bacterial adhesion level which is no more than 50%, more preferably no more than 40%, even more preferably no more than 30%, even more preferably no more than 10%, even more preferably no more than 5%, and most 202400064 Foreign Filing 7 preferably no more than 1 % in comparison to that of the base polymer without the zwitterionic polyurethane additive.

[0054] Efficacy of the zwitterionic additives to reduce thrombogenicity and bacterial adhesion level can be evaluated by in-vitro blood loop test and static bacterial incubation / adhesion test, respectively.

[0055] Devices

[0056] Medical devices requiring improved biocompatibility and functionality include catheters, shunts, surgical cannula, guidewires, stents, grafts, stent-grafts, endoprostheses, angioplasty balloons, insertion sheaths, introducers, stylets, implantable biosensors, contraceptive devices, breast implants, scaffolds, tympanostomy tubes, ophthalmic devices, contact lenses, lOLs, corneal implants, endotracheal tubes, tracheostomy tubes, endoscopes, syringes, medical blood or fluid transfer tubing, 3D-printed implants, orthopedic implants, prosthetic implants, implantable pacemaker and defibrillator leads, LVAD drivelines, structural heart implants, wound retractors, vena cava filters, device valves and manifolds, vascular closure devices, embolic protection devices, blood filters, dialyzers, oxygenators, and other devices that come into contact with body fluids. Catheters specifically can include vascular catheters, drainage catheters, neurovascular catheters, infusion catheters, interventional catheters, parenteral feeding catheters, stroke therapy catheters, urological catheters, peritoneal dialysis catheter, support catheter, diagnostic catheters, atherectomy catheters, electrophysiology catheters, microcatheters, angioplasty catheters, mechanical thrombectomy catheter, aspiration catheter, imaging catheter, and delivery catheters, among others.

[0057] The device manufacturing processes relating to this invention can include melt processes such as extrusion or molding, or solution processes such as film casting, solution spinning, electrospinning, dip coating, spray coating, and 3D printing, among others, and techniques known to those of ordinary skill in the art without undue experimentation.

[0058] ITEM

[0059] 1 . A zwitterionic polyurethane additive comprising / consisting of a reaction product of: a non zwitterionic diol, a zwitterionic diol intermediate, an isocyanate, and at least one selected from mono hydroxyl terminated end groups, mono amino terminated end groups, mono thiol terminated end groups, or a combination thereof, wherein said zwitterionic polyurethane has a molecular weight of from 1 ,000 to 10,000 Da.

[0060] 2. The zwitterionic polyurethane additive according to item 1 , wherein said isocyanate is selected from the group consisting of hexamethylene diisocyanate, 4,4'-Methylene-bis(cyclohexyl isocyanate), methylene diphenyl diisocyanate, toluene diisocyanate, isophorone diisocyanate, a tri-isocyanate, a trifunctional isocyanurate and a biuret. 202400064 Foreign Filing 8

[0061] 3. The zwitterionic polyurethane additive according to item 1 or item 2, wherein said zwitterionic polyurethane additive is a reaction product of said zwitterionic diol intermediate, said isocyanate and at least one non zwitterionic diol selected from the group of a polyether diol, a polyester diol, a polycarbonate diol, a polysiloxane diol and a hydrogenated diol, or copolymer thereof.

[0062] 4. The zwitterionic polyurethane additive according to any one of the items 1 to 3, wherein said zwitterionic diol intermediate is a reaction product of a tertiary amine diol with at least one heterocycle selected from the group of a sultone, a lactone, a 2-alkoxy-2-oxo-1 ,3,2-dioxaphospholane, or a combination thereof.

[0063] 5. The zwitterionic polyurethane additive according to any one of the items 1 to 4, wherein said sultone is selected from the group consisting of 1 ,3-propanesultone and 1 ,4-butane sultone.

[0064] 6. The zwitterionic polyurethane additive according to any one of the items 1 to 5, wherein said rection product of said zwitterionic intermediate and said isocyanate is further reacted with at least one of a mono- alcohol, a mono-amine or a mono- thiol.

[0065] 7. An admixture comprising / consisting of the zwitterionic polyurethane additive according to any one of the items 1 to 6 and a base polymer

[0066] 8. The admixture according to item 7, wherein said base polymer is at least one polymer selected from the group consisting of a polyurethane, a silicone, a polyamide, a polyester, a co-polyester, a polyether, a polyether-block-amide co-polymer, a polyetherimide, a polycarbonate, a polyetheretherketone, an ethyl vinyl acetate, a polypropylene, a polyethylene, a polyvinylchloride, a polyvinyl alcohol, a polyvinylpyrrolidone, a polyacrylamide, a polyethylene oxide, a poly(ethylene oxide)-b- poly(propylene oxide)-b-poly(ethylene oxide), a poly(hydroxyethylmethacrylate), a polyethylene terephthalate, a polybutylene terephthalate, a polymethylmethacrylate, a polysulfone, a polyethersulfone, a polymethylpentene, a styrenic block copolymer, a vulcanized rubber, a polyolefin , a cyclic olefin polymer, cyclic olefin copolymer, a cellulosic polymer, a copolymer thereof and a blend thereof.

[0067] 9. The admixture according to any one of the items 7 to 8 comprising 0.05-15% w / w of said zwitterionic polyurethane additive relative to the base polymer, preferably 2-6% w / w of said zwitterionic polyurethane additive relative to the base polymer. 202400064 Foreign Filing 9

[0068] 10. The admixture according to any one of the items 7 to 9, wherein said admixture has a relative thrombus accumulation which is less than 50% in comparison to that of said admixture without said zwitterionic polyurethane additive.

[0069] 11. The admixture according to any one of the items 7 to 10, wherein said admixture has a relative level of bacterial adhesion which is less than 50% in comparison to that of said admixture without said zwitterionic polyurethane additive.

[0070] 12. A medical device comprising / consisting of the admixture of any one of the items 7 to 11 .

[0071] 13. The medical device according to item 12, selected from the group consisting of a catheter, a shunt, a surgical cannula, a guidewire, a stent, a graft, a stent-graft, an endoprosthesis, an angioplasty balloon, an insertion sheath, an introducer, a stylet, an implantable biosensor, a contraceptive device, a breast implant, a scaffold, a tympanostomy tube, an ophthalmic device, a contact lens, an intraocular lens, a corneal implant, an endotracheal tube, a tracheostomy tube, an endoscope, a syringe, medical blood or fluid transfer tubing, a 3D-printed implant, an orthopedic implant, a prosthetic implant, an implantable pacemaker and defibrillator lead, a LVAD driveline, a structural heart implant, a wound retractor, a vena cava filter, a device valve and manifold, a vascular closure device, an embolic protection device, a blood filter, a dialyzer, an oxygenator, and any other device that comes into contact with body fluids.

[0072] 14. A method of reducing a thrombus adhesion and / or bacterial adhesion on an admixture comprising the step of adding the zwitterionic polyurethane additive of item 1 to 6 to a base polymer.

[0073] 15. Use of zwitterionic polyurethane additive according to any one of items 1 to 6 for manufacture of medical device(s).

[0074] 16. Use of an admixture according to any one of items 7 to 11 for manufacture of medical device(s)

[0075] 17. A process for preparing zwitterionic polyurethane additive according to any one of items 1 to 6 comprising the steps of: i. reacting at least one tertiary amine diol with at least one heterocycle to obtain a zwitterionic diol intermediate, ii. reacting at least one isocyanate with at least one non-zwitterionic diol and one zwitterionic diol intermediate to obtain a prepolymer. 202400064 Foreign Filing 10 iii. reacting the prepolymer of step ii. with one of a mono- alcohol, a mono-amine or a monothiol to obtain the zwitterionic polyurethane additive.

[0076] 18. The process according to item17 wherein the tertiary amine diol is selected from the group of N- methyldiethanolamine, N-ethyldiethanolamine, or a mixture thereof.

[0077] 19. The process according to any one of items 17 -18, wherein the heterocycle is selected from a sultone, a lactone, a 2-alkoxy-2-oxo-1 ,3,2-dioxaphospholane, or a combination thereof.

[0078] 20. The process according to any one of items 17 -19, wherein the isocyanate is selected form hexamethylene diisocyanate, 4,4'-Methylene-bis(cyclohexyl isocyanate), methylene diphenyl diisocyanate, toluene diisocyanate, isophorone diisocyanate, a tri-isocyanate, a trifunctional isocyanurate, a biuret, or a combination thereof.

[0079] 21 . The process according to any one of items 17 -20 wherein the non zwitterionic diol is selected form a polyether diol, a polyester diol, a polycarbonate diol, a polysiloxane diol and a hydrogenated diol, or copolymer thereof

[0080] 22. The zwitterionic polyurethane additive obtained according to any one of the items 17-21 .

[0081] 23. A composition comprising the zwitterionic polyurethane additive according to any one of the items 1 to 6 or a zwitterionic polyurethane additive according to item 22.

[0082] 24. The zwitterionic polyurethane additive according to any one of the items 1 to 6 or a zwitterionic polyurethane additive according to item 22 or a composition according to item 23 for use in reducing thrombus accumulation.

[0083] 25. The zwitterionic polyurethane additive according to any one of the items 1 to 6 or a zwitterionic polyurethane additive according to item 22 or a composition according to item 23 for use in reducing bacterial adhesion.

[0084] 26. The process according to any one of items 16 to 21 , wherein the amount of zwitterionic diol intermediate in the zwitterionic polyurethane additive is in the range of 0.5-50 wt. %, preferably from 1-20 wt. %, more preferably from 1-15 wt. %, more preferably from 5-12 wt. %, based on weight of said zwitterionic polyurethane additive. 202400064 Foreign Filing 11

[0085] 27. The process according to any one of items 16 to 21 , wherein the molar ratio of zwitterionic diol intermediate to non-zwitterionic diol in the zwitterionic polyurethane additive is in the range of 1 :0.4 to 1 :20, more preferably 1 :1 to 1 :10, even more preferably 1 :1 to 1 :5, most preferably 1 :3 to 1 :5.

[0086] 28. The zwitterionic polyurethane additive according to any one of items 1 to 6, wherein the amount of zwitterionic diol intermediate in the zwitterionic polyurethane additive is in the range of 0.5-50 wt. %, preferably from 1-20 wt. %, more preferably from 1-15 wt. %, more preferably from 5-12 wt. %, based on weight of said zwitterionic polyurethane additive.

[0087] 29. The zwitterionic polyurethane additive according to any one of items 1 to 6, wherein the molar ratio of zwitterionic diol intermediate to non-zwitterionic diol in the zwitterionic polyurethane additive is in the range of 1 :0.4 to 1 :20, more preferably 1 :1 to 1 :10, even more preferably 1 :1 to 1 :5, most preferably 1 :3 to 1 :5.

[0088] General synthesis description of PUZB (zwitterionic surface-modifying macromolecules)

[0089] For PUZB SMMs, a mixture of two types of diols (diol A such as polyethylene glycol (PEG), poloxamers and their derivatives, or hydroxyl terminated PDMS and diol B, the zwitterionic intermediate such as sulfobetaine-diol (SB-diol) or carboxybetaine-diol (CB-diol)) at different ratios is reacted with isocyanate (e.g., HMDI, TDI, TMDI, etc.) at 65 °C for 4 h in an organic solvent (e.g., DMSO, DMF, DMAC, etc.) under gentle stirring and nitrogen flow to yield the pre-polymer. The pre-polymer is then end-capped with poly(ethylene glycol) methyl ether or its derivatives at 45 °C for over 18 h under gentle stirring and nitrogen flow to yield the final polymer. The final polymer is extracted and purified by liquid-liquid extraction using tert-butyl methyl ether (MTBE) for three times, followed by dissolving the polymer in THF and removing the solvent by rotary evaporation. The final product is further dried at 60 °C under vacuum in a vacuum oven.

[0090] Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

[0091] EXAMPLES

[0092] Example 1 : Synthesis description of PUZB (zwitterionic surface-modifying macromolecules) - Compound 1

[0093] Glassware used for the synthesis was dried in an oven at 110 °C overnight. To a hot 3-necked

[0094] 500 mL oven dried round bottom flask with a stir bar was added melted 1 ,3 propanesultone 7.33 g ( 60 202400064 Foreign Filing 12 mmol) and 100 mL of DCM. The mixture was allowed to stir until completely dissolved. In a separate three neck 250 mL round bottom flask with a stir bar charge n-methyldiethanolamine 7.15 g (60 mmol) and 90 mL of DCM. Stir the mixture until the reagent dissolves. Seal the reactor and use a septa on one neck of the round bottom flask. Insert a syringe needle that will submerge in the solution and degas the system with nitrogen for 20 minutes. Allow for a slow flow of nitrogen, which will prevent the DCM from evaporating. After degassing, charge the n-methyldiethanolamine in DCM solution to a 250 mL addition funnel. Connect the addition funnel to the 500 mL round bottom flask and charge the solution methyldiethanolamine in DCM solution at ~ 2.1 mL / min. Use a syringe with 10 mL of DCM to rinse the walls of the addition funnel and charge it to the round bottom flask. Remove the addition funnel and insert a Vigreux condenser. Heat the reaction to 40 °C and allow it to proceed overnight.

[0095] The reaction mixture was concentrated using rotary evaporation to yield a white precipitate (SB Diol). The white solids (SB Diol) were washed with 300 mL of diethyl ether for 1 hour and filtered using a Buchner funnel setup equipped with a Whatman filter paper #1 . The purification was repeated once more by washing the white solids with 300 mL of diethyl ether, filtering and drying under vacuum at room temperature overnight.

[0096] In the second step, glassware used for the synthesis was dried in an oven at 110 °C overnight. To a 3-necked 250 mL oven dried round bottom flask with a stir bar was added 15.0 g (14.7 mmol) of HDP diol and 0.887 g (3.7 mmol) of SB-diol. 30 mL of anhydrous DMSO was transferred to the flask through a syringe. The flask with the mixture was degassed at 80 °C under gentle stirring for 2 h until all the solid was dissolved and then purged with nitrogen. Another oven dried 25 mL round bottom flask was charged with 7.23 g (27.6 mmol) of HMDL The sealed flask with HMDI was degassed at room temperature for 1 h and then purged with nitrogen. 7.2 mL of anhydrous DMSO was transferred to the flask to fully dissolve the HMDI. The temperature of the oil bath was lowered to 50 °C. 15 mg (1000 ppm of diol) of BHT was added to the flask with the diol solution. A slow addition of the HMDI solution was added to the diol solution over ~ one hour using an addition funnel. 11 mg (0.15 wt% of HMDI) of DBTDL was dissolved in 1 mL of THF. 0.5 mL of the DBTDL solution was injected to the mixture when the temperature reached 50 °C to initiate the polymerization. After the addition of DBTDL solution, the temperature of the oil bath was increased to 65 °C. The reaction was allowed to proceed at 65 °C under gentle stirring and nitrogen flow for 4 h to yield the pre-polymer. Another oven dried 25 mL round bottom flask was charged with 10.11 g (18.38 mmol) of poly(ethylene glycol) methyl ether (MW= 550 g / mol). The flask with poly(ethylene glycol) methyl ether was degassed at room temperature for 30 min and then purged with nitrogen. 10 mL of anhydrous DMSO was added to fully dissolve the poly(ethylene glycol) methyl ether. After 4 h of pre-polymerization, the temperature of the oil bath was lowered to 45 °C. The poly(ethylene glycol) methyl ether solution was transferred to the pre-polymer solution through a syringe. 0.5 mL of the DBTDL solution was injected to the mixture to initiate the end-capping reaction. The endcapping reaction was allowed to proceed at 45 °C under gentle stirring and nitrogen flow for overnight. 202400064 Foreign Filing 13

[0097] The polymer (zwitterionic polyurethane additive) was extracted and purified through liquid-liquid extraction using tert-butyl methyl ether (MTBE). The reaction mixture was transferred to a 1000 mL separatory funnel, and then 400 mL of MTBE was added to the separatory funnel. The polymer (zwitterionic polyurethane additive) was extracted and washed by vigorous shaking. The mixture was settled in the separatory funnel for 20 min. The bottom layer (polymer layer) was drained in a clean beaker and the upper MTBE layer was discarded. The extraction process was repeated for three times using 400 mL of MTBE to remove as much impurities as possible. After the final extraction, the bottom polymer (zwitterionic polyurethane additive) layer was kept in the separatory funnel and only the MTBE layer was discarded from the top. 50 mL of THF was added to the separatory funnel to fully dissolve the polymer (zwitterionic polyurethane additive) through vigorous shaking. After the polymer was dissolved, the polymer (zwitterionic polyurethane additive) solution was drained in a clean 250 mL round bottom flask. The solvent was removed through rotary evaporation and the polymer (zwitterionic polyurethane additive) was further dried at 60 °C under vacuum in a vacuum oven for 3 days or at room temperature over ~ 5 days. nd surface characterization of zwitterionic additive-modified

[0098] Polyurethane with tradename Carbothane PC 3585A (CB 85A) rods containing 4 wt% Compound 1 (zwitterionic polyurethane additive) of the invention were prepared using a laboratory micro compounder. The resin was first dried in a vacuum oven at 65° C for 5 hours, and then blended with Compound 1 (zwitterionic polyurethane additive) using a 15 mL twin-screw micro compounder operated in batch mode, with a cycle time of 3 min (after resin load) and melt temperature of -220 °C. The blend was extruded into rods approximately -3 mm in diameter. Unmodified Control prototypes were prepared using the same method but without the additive.

[0099] X-ray photoelectron spectroscopy (XPS) was used to confirm surface modification on the PUZB-containing prototypes. XPS can provide surface elemental composition information at penetration depth up to 10 nm. Low resolution survey spectra were obtained at 90° X-ray take-off angle over elliptical spot size of 200 pm (long axis) using a Thermo Scientific K-Alpha XPS machine. Two replicate samples were analyzed for each material. The zwitterionic building blocks in the PUZB additive contain sulfur and are also rich in oxygen. The concentrations of these two elements of interest are shown in Fig. 2. The increased concentration of these elements on the surface in the modified prototypes compared to unmodified Control indicates successful surface modification with the zwitterionic additive of the invention.

[0100] Static water contact angle measurement showed changes in surface hydrophilicity due to the surface modification. Contact angles were measured for nine (9) droplets on each material and the data is shown in Fig. 3. Surfaces containing Compound 1 (zwitterionic polyurethane additive) were more hydrophilic than unmodified surfaces. 202400064 Foreign Filing 14

[0101] Example 3: Reduction of thrombosis on zwitterionic additive-modified polyurethane prototypes

[0102] Polyurethane (CB 85A) rods, unmodified and modified with 4 wt% Compound 1 of the invention, were prepared using a laboratory micro compounder as described in Example 1 .

[0103] Thrombogenicity of the rods was evaluated using an in-vitro re-circulating blood flow model (Thrombodyne Inc, Salt Lake City, UT). Unmodified and additive-modified rods, 15 cm in length, were inserted into independent tubing circuits (ID = 6.4 mm) connected to a peristaltic pump. One liter (1 L) of fresh bovine blood with 2-5% of 99m-Technetium radiolabeled platelets and 0.75 U / mL heparin was circulated through each circuit at -200 mL / min. The same donor blood was used in each circuit. Blood flow was stopped at 30, 60, and 90 min and samples were inspected visually for thrombus formulation. The experiment was stopped when significant thrombus formation was observed on the unmodified Control rods, or until a maximum run time of 120 min was reached. At end of the experiment, samples were removed from the circuits, rinsed, photographed, and measured for radioactivity using a gamma counter. Four experiments with blood from 4 different animals were conducted in the study.

[0104] Radioactive counts correlate to platelet adhesion and thrombus formation. To compare thrombogenicity of the prototype materials, radioactivity of the modified rods in an experiment was normalized to the radioactivity of the unmodified Control. The relative thrombus formation was averaged across experiments and is shown in Fig. 4. The PUZB Compound 1 reduced thrombus formation on Carbothane 85A rods by 97%, showing potential of the zwitterionic additives to improve the biocompatibility of device surfaces.

[0105] Example 4: Reduction in bacterial adhesion on zwitterionic additive-modified polyurethane prototypes

[0106] Polyurethane (CB 85A) rods, unmodified and modified with 4 wt% Compound 1 were prepared using a laboratory micro compounder as described in Example 1.

[0107] Bacterial adhesion to the rod samples was evaluated using one gram +ve strain (S. epidermidis 35984) and one gram -ve strain (E coli 67) obtained from the Lawson Health Research Institute (London, Ontario, Canada). Bacterial strains were grown overnight in Tryptic Soy Broth (TSB) at 37°C with shaking. To prepare bacterial inoculum, the bacterial culture was centrifuged at 4,500 rpm for 10 min, washed with phosphate buffered saline (PBS), and re-suspended in PBS at a concentration of 108CFU / mL (colony forming units / mL).

[0108] Prototype rod samples were cut into 1 .5 cm segments, ethylene oxide sterilized, and placed in sterile microcentrifuge tubes. One milliliter (1 mL) of bacterial inoculum solution was added to the microcentrifuge tubes and the samples were incubated for 2 hours at 37°C with minimal agitation. After 2 hours, the samples were washed 3x with 750 pL PBS to remove loosely adhered bacteria and transferred to new microcentrifuge tubes with 1 mL of PBS. The samples were sonicated for 30 min, followed by 202400064 Foreign Filing 15 vortexing for 30 sec, to detach adhered bacteria. The sonicated solutions were serially diluted and drop plated in quadruplicate on TSB agar plates. The plates were incubated at 37 °C overnight, after which bacterial colonies were counted and bacterial adhesion was calculated in CFU / cm2.

[0109] Two duplicate experiments with n = 3 rod samples were conducted for each bacterial strain, and the data is shown in Fig. 5. Bacterial counts are presented in log format. Compound 1 reduced S. epidermidis and E. coli adhesion on polyurethane rods by 2.0 log (99%), showing the potential of zwitterionic additives of the invention to limit bacterial colonization of device surfaces.

[0110] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

202400064 Foreign Filing 16CLAIMS:1 . A zwitterionic polyurethane additive comprising a reaction product of: a non zwitterionic diol, a zwitterionic diol intermediate, an isocyanate, and at least one selected from mono-hydroxyl terminated end groups, mono-amine terminated end groups, mono-thiol terminated end groups, or a combination thereof, wherein said zwitterionic polyurethane has a theoretical molecular weight from 1 ,000 to 10,000 Da.

2. The zwitterionic polyurethane additive according to claim 1 , wherein the isocyanate is selected from the group consisting of hexamethylene diisocyanate, 4,4'-Methylene-bis(cyclohexyl isocyanate), methylene diphenyl diisocyanate, toluene diisocyanate, isophorone diisocyanate, a triisocyanate, a trifunctional isocyanurate, and a biuret.

3. The zwitterionic polyurethane additive according to claim 1 or claim 2, wherein the non zwitterionic diol is selected from a polyether diol, a polyester diol, a polycarbonate diol, a polysiloxane diol and a hydrogenated diol, or copolymer thereof.

4. The zwitterionic polyurethane additive according to any one of the claims 1 to 3, wherein the zwitterionic diol intermediate is a reaction product of at least one tertiary amine diol with at least one heterocycle selected from the group consisting of a sultone, a lactone, and a 2-alkoxy-2-oxo-1 ,3,2- dioxaphospholane.

5. The zwitterionic polyurethane additive according to any one of the claims 1 to 4, wherein the heterocycle is selected from the group consisting of 1 ,3-propanesultone, and 1 ,4-butane sultone.

6. The zwitterionic polyurethane additive according to any one of the claims 1 to 5, wherein the amount of zwitterionic diol intermediate in the zwitterionic polyurethane additive is in the range of 0.5-50 wt. %, preferably from 1-20 wt. %, more preferably from 1-15 wt. %, more preferably from 5-12 wt. %, based on the weight of said zwitterionic polyurethane additive.

7. An admixture comprising a base polymer and the zwitterionic polyurethane additive according to any one of the claims 1 to 6.

8. The admixture according to claim 7, wherein the base polymer is selected from the group consisting of a polyurethane, a silicone, a polyamide, a polyester, a co-polyester, a polyether, a polyether- block-amide co-polymer, a polyetherimide, a polycarbonate, a polyetheretherketone, an ethyl vinyl acetate, a polypropylene, a polyethylene, a polyvinylchloride, a polyvinyl alcohol, a polyvinylpyrrolidone, a polyacrylamide, a polyethylene oxide, a poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene202400064 Foreign Filing 17 oxide), a poly(hydroxyethylmethacrylate), a polyethylene terephthalate, a polybutylene terephthalate, a polymethylmethacrylate, a polysulfone, a polyethersulfone, a polymethylpentene, a styrenic block copolymer, a vulcanized rubber, a polyolefin , a cyclic olefin polymer, cyclic olefin copolymer, a cellulosic polymer, a copolymer thereof, and a blend thereof.

9. The admixture according to any one of the claims 7 to 8 comprising 0.05-15% w / w of said zwitterionic polyurethane additive relative to the base polymer.

10. The admixture according to any one of the claims 7-9, wherein the admixture has a thrombus accumulation less than 50% in comparison to that of said base polymer without said zwitterionic polyurethane additive.11 . The admixture according to any one of the claims 7 -10, wherein the admixture has a bacterial adhesion less than 50% in comparison to that of said base polymer without said zwitterionic polyurethane additive.

12. A medical device comprising the admixture in any one of the claims 7 to 11 .

13. The medical device according to claim 12, selected from the group consisting of a catheter, a shunt, a surgical cannula, a guidewire, a stent, a graft, a stent-graft, an endoprosthesis, an angioplasty balloon, an insertion sheath, an introducer, a stylet, an implantable biosensor, a contraceptive device, a breast implant, a scaffold, a tympanostomy tube, an ophthalmic device, a contact lens, an intraocular lens, a corneal implant, an endotracheal tube, a tracheostomy tube, an endoscope, a syringe, medical blood or fluid transfer tubing, a 3D-printed implant, an orthopedic implant, a prosthetic implant, an implantable pacemaker and defibrillator lead, a LVAD driveline, a structural heart implant, a wound retractor, a vena cava filter, a device valve and manifold, a vascular closure device, an embolic protection device, a blood filter, a dialyzer, an oxygenator, and any other device that comes into contact with body fluids.

14. A method of reducing a thrombus adhesion and / or bacterial adhesion on an admixture comprising a step of adding the zwitterionic polyurethane additive of claim 1 to 6 to a base polymer.

15. Use of zwitterionic polyurethane additive according to any one claims 1 to 6 for manufacture of medical device(s).

16. Use of an admixture according to any one of claims 7 to 11 for manufacture of medical device(s)17. A process for preparing zwitterionic polyurethane additive according to any one of claims 1 to 6 comprising the steps of:202400064 Foreign Filing 18 i) reacting at least one tertiary amine diol with at least one heterocycle to obtain a zwitterionic diol intermediate, ii) reacting at least one isocyanate with at least one non-zwitterionic diol and one zwitterionic diol intermediate to obtain a prepolymer; and iii) reacting the prepolymer of step ii) with one of a mono- alcohol, a mono-amine or a monothiol to obtain the zwitterionic polyurethane additive.

18. The process according to claim 17 wherein the tertiary amine diol is selected from the group of N-methyldiethanolamine, N-ethyldiethanolamine, or a mixture thereof.

19. The process according to any one of claims 17 -18, wherein the heterocycle is selected from a sultone, a lactone, a 2-alkoxy-2-oxo-1 ,3,2-dioxaphospholane, or a combination thereof.

20. The process according to any one of claims 17 -19, wherein the isocyanate is selected form hexamethylene diisocyanate, 4,4'-Methylene-bis(cyclohexyl isocyanate), methylene diphenyl diisocyanate, toluene diisocyanate, isophorone diisocyanate, a tri-isocyanate, a trifunctional isocyanurate, a biuret, or a combination thereof.21 . The process according to any one of claims 17 -20 wherein the non zwitterionic diol is selected form a polyether diol, a polyester diol, a polycarbonate diol, a polysiloxane diol and a hydrogenated diol, or copolymer thereof.

22. The process according to any one of claims 17 -21 , wherein the amount of zwitterionic diol intermediate in the zwitterionic polyurethane additive is in the range of 0.5-50 wt. %, preferably from 1- 20 wt. %, more preferably from 1-15 wt. %, more preferably from 5-12 wt. %, based on a weight of said polyurethane.

23. The process according to any one of claims 17 -21 , wherein the molar ratio of zwitterionic diol intermediate to non-zwitterionic diol in the zwitterionic polyurethane additive is in the range of 1 :0.4 to1 :20, more preferably 1 :1 to 1 :10, even more preferably 1 :1 to 1 :5, most preferably 1 :3 to 1 :5.

24. The zwitterionic polyurethane additive obtained according to any one of the claims 17-23.

25. A composition comprising the zwitterionic polyurethane additive according to any one of claims 1 to 6 or a zwitterionic polyurethane additive according to claim 24.202400064 Foreign Filing 1926. The zwitterionic polyurethane additive according to any one of claims 1 to 6 or a zwitterionic polyurethane additive according to claim 24 or a composition according to claim 25 for use in reducing thrombus accumulation.

27. The zwitterionic polyurethane additive according to any one of claims 1 to 6 or a zwitterionic polyurethane additive according to claim 24 or a composition according to claim 25 for use in reducing bacterial adhesion.

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