End-group zwitterionic polyurethane surface modifying additive

Abstract

A zwitterionic polyurethane additive, a base polymer comprising zwitterionic polyurethane additive, a medical device comprising an admixture of a base polymer and zwitterionic polyurethane additive, a method of reducing a thrombogenic and / or bacterial adhesion property of an admixture of a base polymer and zwitterionic polyurethane additive, are disclosed. The zwitterionic polyurethane additive is a reaction product of an isocyanate group terminated polyurethane prepolymer with tertiary amine alcohols, followed by reaction with at least one heterocycle selected from the group consisting of a sultone, a lactone, or a 2-alkoxy-2-oxo-1,3,2-dioxaphospholane.

Description

[0001] 202400001 Foreign Filing

[0002] 1

[0003] END-GROUP ZWITTERIONIC POLYURETHANE SURFACE MODIFYING ADDITIVE

[0004] Field of the Invention

[0005] The invention involves the development, composition and application of surface modifying additives for medical devices. The zwitterionic polyurethane additive is designed to be incorporated into the material composition of medical devices during manufacturing, and create a homogenous surface that would improve functionality, biocompatibilify, and blood compatibility of the modified surfaces.

[0006] Discussion of the Background

[0007] 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.

[0008] 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.

[0009] 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. Zwitterionic molecules have been demonstrated to reduce protein adsorption, platelet adhesion, thrombus adhesion and bacterial adhesion.

[0010] 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. 202400001 Foreign Filing

[0011] 2

[0012] 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.

[0013] 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- 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.

[0014] 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 (AgNO3, ZnSO4, CuSO4, Ce) crosslinking and (ii) diisocyanate, zwitterion (backbone), isosorbide (backbone), citric acid (end capping agent to allow for metal (AgNO3, 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.

[0015] 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.

[0016] 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.

[0017] While zwitterionic chemistries have been described in literature as generally improving biofouling resistance or hydrophilicity, they rely on creating a grafted matrix or coating of zwitterions to 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 202400001 Foreign Filing

[0018] 3 to a base polymer, can reduce thrombus attachments and / or bacterial adhesion when a polymer surface exposed to biological fluids.

[0019] SUMMARY OF THE INVENTION

[0020] 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 a reaction product of an isocyanate group terminated polyurethane prepolymer, with tertiary amine alcohols, followed by reaction 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, yielding a polyurethane oligomer with zwitterionic end-groups.

[0021] In a further aspect, the invention features a polymer comprising / consisting of a zwitterionic polyurethane additive and base polymer.

[0022] A further aspect of the invention is directed to a medical device comprising a zwitterionic polyurethane additive and base polymer, having a surface with reduced thrombus attachment and / or reduced bacterial adhesion properties.

[0023] A further aspect of the invention is directed to a method of reducing a thrombus attachment and / or reducing bacterial adhesion to a base polymer comprising adding a thrombus attachment and / or reduced bacterial adhesion reducing zwitterionic polyurethane additive to a base polymer.

[0024] 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.

[0025] The inventors have discovered new chemical entities of zwitterionic polyurethane additives which, in admixture with a base polymer, create a homogenous surfaces having reduced thrombus attachment and / or reduced bacterial adhesion properties.

[0026] BRIEF DESCRIPTION OF THE DRAWINGS

[0027] 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:

[0028] Fig. 1 : depicts a synthetic procedure for PUZE (zwitterionic polyurethane additive); 202400001 Foreign Filing

[0029] 4

[0030] Fig. 2: illustrates elemental sulfur and oxygen concentrations on polyurethane-PUZE admixture surfaces;

[0031] Fig. 3: illustrates water contact angle on polyurethane-PUZE admixture surfaces;

[0032] Fig. 4: illustrates thrombosis on polyurethane-PUZE admixture rod prototypes in in-vitro blood loop study; and

[0033] Fig. 5: illustrates bacterial adhesion on polyurethane-PUZE admixture rods after 2 hours of incubation in inoculated buffer.

[0034] DETAILED DESCRIPTION OF THE INVENTION

[0035] Compounds of the invention include formulations synthesized using zwitterionic building blocks (e.g. sulfobetaines, carboxy betaines and phosphobetaines) attached as end groups to 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 end-groups (PUZE).

[0036] The zwitterionic polyurethane additive is a reaction product of an isocyanate group terminated polyurethane prepolymer with tertiary amine alcohols, followed by reaction 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. A generic reaction scheme is depicted in Fig 1 .

[0037] Organotin compound or bismuth compounds are typically used as a catalyst for polyurethane synthesis. Non-limiting examples which can be used to synthesize PUZE are dibutyltin dilaurate or Bismuth carboxylate (e.g., K-Kat 348).

[0038] PUZE

[0039] A PUZE molecule is composed of diol, polyisocyanate and zwitterionic end groups. The (non zwitterionic) diol and polyisocyanate reacts to form isocyanate terminated prepolymer. A wide range of diols, di- or tri-isocyanates and zwitterionic end groups could be selected for the synthesis of PUZE to achieve different properties.

[0040] Possible non zwitterionic diols used in PUZE 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., 202400001 Foreign Filing

[0041] 5 hydrogenated polybutadiene, hydrogenated polyisoprene), or a combination of different types of diols mentioned above. The diol segment has a (theoretical) number average molecular weight of 500-3,500 Da.

[0042] The isocyanate building blocks may include linear diisocyanate, such as: hexamethylene diisocyanate (HDI), 4,4'-Methylene-bis(cyclohexyl isocyanate) (H12MDI), methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), and isophorone diisocyanate (I PDI); tri-isocyanates, as well as trifunctional isocyanurates (e.g., 3-lsocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate homopolymer, hexamethylene diisocyanate isocyanurate trimer, etc.) and biurets (e.g., hexamethylene diisocyanate homopolymer).

[0043] The zwitterionic end groups in PUZE can be attached by reaction of tertiary amine alcohol (e.g., 2-dimethylaminoethanol, 2-dimethylamino-1 -propanol, N,N-diethylethanolamine, 2-(diisopropylamino) ethanol, etc.) with the terminal isocyanate groups of the polyurethane prepolymer / copolymer followed by reaction with heterocycles^ such as sulfones (e.g., 1 ,3-propanesultone, 1 ,4-butane sulfone, etc.), lactones (e.g., p-propiolactone) or 2-alkoxy-2-oxo-1 ,3,2-dioxaphospholanes, to form sulfobetaines, carboxybetaines and phosphobetaines, respectively. Non-limiting 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.

[0044] The zwitterionic polyurethane additive may have a molecular weight 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. This molecular weight is particularly advantageous, as it facilitates the migration of the zwitterionic polyurethane additive to the surface of the base polymer upon mixing and / or compounding. Higher molecular weight zwitterionic polyurethane additive is not particularly advantageous for migration purposes, but it may still be suitable for coating medical devices.

[0045] Preferably the amount of zwitterionic end-groups in the product zwitterionic polyurethane additive may be from 1 - 50 wt. %, preferably from 5 - 35 wt. %, more preferably from 5 - 25 wt. %, and most preferably from 10 - 25 wt%, based on the weight of said zwitterionic polyurethane additive. 202400001 Foreign Filing

[0046] 6

[0047] The term “molecular weight,” as used herein, 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.

[0048] In a preferred aspect the invention provides a composition / admixture comprising / consisting of a base polymer and a compatible zwitterionic polyurethane additive. The zwitterionic polyurethane additive forms a homogenous surface on the base polymer. In another embodiment the zwitterionic polyurethane additive is present in a thrombus attachment reducing and / or bacterial adhesion reducing amount.

[0049] 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 in the base polymer and can include combinations of different zwitterionic formulations. The additives will migrate to all surfaces of the device during manufacturing to disperse homogeneously due to their surface-active properties, creating a unique surface chemistry.

[0050] Base polymers

[0051] 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 polyethylene 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.

[0052] The molecular weight of the base polymer is not particularly limited and is generally appropriate for the preparation of a medical device.

[0053] In further embodiments, the base polymer is a thermoplastic. 202400001 Foreign Filing

[0054] 7

[0055] 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 radioopaque 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.

[0056] The migration of the zwitterionic surface modifying 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.

[0057] The combination of zwitterionic polyurethane additive and base polymer (admixture) preferably has a thrombus accumulation less than 50%, more preferably less than 40%, even more preferably less than 30%, even more preferably less than 10%, even more preferably less than 5%, and most preferably less than 1% in comparison to that of the base polymer (admixture) without the zwitterionic polyurethane additive.

[0058] The combination of zwitterionic polyurethane additive and base polymer (admixture) preferably has a bacterial adhesion less than 50%, more preferably less than 40%, even more preferably less than 30%, even more preferably less than 10%, even more preferably less than 5%, and most preferably less than 1% in comparison to that of the base polymer (admixture) without the zwitterionic polyurethane additive.

[0059] Efficacy of the zwitterionic polyurethane additives to reduce thrombogenicity and bacterial adhesion can be evaluated by in-vitro blood loop test and static bacterial incubation / adhesion test respectively.

[0060] The surface modification of the base polymer upon admixing and / or compounding of the zwitterionic polyurethane additive was confirmed using X-ray photoelectron spectroscopy (XPS).

[0061] Devices

[0062] 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 202400001 Foreign Filing

[0063] 8 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.

[0064] 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.

[0065] ITEM

[0066] 1 . A zwitterionic polyurethane additive comprising / consisting a reaction product of: an isocyanate group terminated polyurethane prepolymer with a tertiary amine alcohol, followed by reaction 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, wherein said zwitterionic polyurethane has a molecular weight of from 1 ,000 to < 10,000 Da.

[0067] 2. The zwitterionic polyurethane additive according to item 1 , wherein the isocyanate group terminated polyurethane prepolymer comprises a reaction product of at least one polyisocyanate 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.

[0068] 3. The zwitterionic polyurethane additive according to any one of the items 1 to 2, wherein isocyanate group terminated polyurethane prepolymer comprises a reaction product of at least one diol selected from the group consisting of a polyether diol, a polyester diol, a polycarbonate diol, a polysiloxane diol and a hydrogenated diol. 202400001 Foreign Filing

[0069] 9

[0070] 4. The zwitterionic polyurethane additive according to any one of the items 1 to 3, wherein said tertiary amine alcohol is at least one selected from the group consisting of 2-dimethylaminoethanol, 2- dimethylamino-1 -propanol, N,N-diethylethanolamine and 2-(diisopropylamino) ethanol.

[0071] 5. The zwitterionic polyurethane additive according to any one of the items 1 to 4, wherein said heterocycle is at least one sultone selected from the group consisting of 1 ,3-propanesultone and 1 ,4-butane sultone.

[0072] 6. An admixture comprising / consisting of a base polymer and the zwitterionic polyurethane additive according to any one of the items 1 to 5.

[0073] 7. The admixture according to item 6, 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 polyethylene 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.

[0074] 8. The admixture according to any one of the preceding items 6 to 7, comprising 0.05-15% w / w of the said zwitterionic polyurethane additive relative to the base polymer.

[0075] 9. The admixture according to any one of the preceding items 6 to 8, wherein said admixture has a thrombus accumulation less than 50% in comparison to that of the said admixture without said zwitterionic polyurethane additive.

[0076] 10. The admixture according to any one of the preceding items 6 to 9, wherein said admixture has a bacterial adhesion less than 50% in comparison to that of the said admixture without said zwitterionic polyurethane additive.

[0077] 11 . A medical device comprising / consisting of the admixture according to any one of the preceding items 6 to 10. 202400001 Foreign Filing

[0078] 10

[0079] 12. The medical device according to item 11 , 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.

[0080] 13. A method of reducing thrombus adhesion and / or bacterial adhesion to an admixture comprising the step of adding the zwitterionic polyurethane additive according to any one of the preceding items 1 to 6 to a base polymer.

[0081] 14. Use of zwitterionic polyurethane additive according to any one of items 1 to 5 for manufacture of medical device(s).

[0082] 15. Use of an admixture according to any one of items 6 to 10 for manufacture of medical device(s)

[0083] 16. A process for preparing zwitterionic polyurethane additive according to any one of items 1 to 6 comprising the steps of: i. reacting an isocyanate group terminated polyurethane prepolymer with a tertiary amine alcohols to obtain an intermediate, ii. Reacting the intermediate obtained in step i. 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 to obtain zwitterionic polyurethane additive.

[0084] 17. The process according to claim 16, wherein the tertiary amine alcohol is selected from 2- dimethylaminoethanol, 2-dimethylamino-1 -propanol, N,N-diethylethanolamine, 2-(diisopropylamino) ethanol, or a combination thereof.

[0085] 18. A process for preparing zwitterionic polyurethane additive according to any one of items 1 to 5 comprising the steps of: i. reacting an isocyanate group terminated polyurethane prepolymer with a tertiary amine alcohol to obtain an intermediate, 202400001 Foreign Filing

[0086] 11 ii. reacting the intermediate obtained in step i. 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 to obtain zwitterionic polyurethane additive. 19. A composition comprising the zwitterionic polyurethane additive according to any one of the itemsl to 5.

[0087] 20. The zwitterionic polyurethane additive according to any one of items 1-5 or a composition according to item 19 for reducing thrombus adhesion and / or bacterial adhesion.

[0088] 202400001 Foreign Filing

[0089] 12

[0090] General synthesis description of PUZE (zwitterionic surface-modifying macromolecules)

[0091] PUZE (zwitterionic polyurethane additive) SMMs can be synthesized in two steps. In the 1ststep, a diol such as polyethylene glycol (PEG), poloxamers and their derivatives, or hydroxyl terminated PDMS is reacted with diisocyanate (e.g., HMDI, TDI, TMDI, etc.) at 65 °C for 4 h in an organic solvent (e.g., THF, DMAC, etc.) under nitrogen flow to yield the pre-polymer. The pre-polymer is then end-capped with a dimethylamino-containing end-capping agent (e.g., 2-dimethylaminoethanol (DMEA), 3-dimethylamino- 1 -propanol, 2-[2-(dimethylamino)ethoxy] ethanol, etc.) at 45°C for over 18 h under nitrogen flow to yield the intermediate polymer. The intermediate polymer is purified by repeatedly dissolving in THF and precipitating in hexane for two times, followed by dissolving the polymer in THF and removing the solvent by rotary evaporation. In the 2ndstep, the intermediate polymer is reacted with 1 ,3-propanesultone (1 ,3- PS) in an organic solvent (e.g., THF) at 55 °C for over 18 h under nitrogen flow to yield PUZE SMM. The polymer (zwitterionic polyurethane additive) is purified by repeatedly dissolving in THF and precipitating in hexane for two 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.

[0092] 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.

[0093] EXAMPLES

[0094] Example 1 : Synthesis description of PUZE (zwitterionic surface-modifying macromolecules) - Compound 1

[0095] Glassware used for synthesis was dried in an oven at 110 °C overnight. In the 1ststep, to a 3- necked 250 mL oven dried round bottom flask equipped with a stir bar was added 30.0 g (29.4 mmol) of HDP-diol (MW=1 ,020 g / mol). The sealed flask with diol was degassed at 60 °C for 2 h under gentle stirring and then purged with nitrogen. 15 mL of anhydrous THF was then added to the HDP-diol using a syringe under stirring to fully dissolve the diol. 30 mg (1000 ppm of diol) of BHT was then added to the diol solution. All the materials were kept under gentle stirring and nitrogen flow. Another oven dried 25 mL flask was charged with 11.57 g (44.1 mmol) of HMDI. The sealed flask with HMDI was degassed at room temperature for 1 h and then purged with nitrogen. 5.8 mL of anhydrous THF was added to the HMDI using a syringe to fully dissolve the HMDI. The HDMI solution was then transferred to the HDP-diol solution using a syringe and the temperature was lowered to 50 °C. While waiting for the temperature, a DBTDL solution was prepared by dissolving 17 mg (0.15 wt% of HMDI) of DBTDL in 1 mL of anhydrous THF. When the temperature reached 50 °C, 0.5 mL of the DBTDL solution was injected to the HDP 202400001 Foreign Filing

[0096] 13 diol / HDMI mixture through a syringe to initiate the polymerization. After the addition of the Tin catalyst, the temperature of the oil bath was raised to 65 °C. The reaction was allowed to proceed at 65 °C for 4 h under nitrogen flow to yield the pre-polymer. During the pre-polymerization another oven dried 25 mL flask was charged with 2.75 g (30.9 mmol) of DMEA. The sealed flask with DMEA was degassed at room temperature for 30 min (with a controlled vacuum of 250 Torr) and then purged with nitrogen. 1 .4 mL of anhydrous THF was then added to DMEA to fully dissolve DMEA. After 4 h pre-polymerization, the temperature of the oil bath was lowered to 45 °C. Once the temperature reached 45 °C, the DMEA solution was added to the pre-polymer solution through a syringe, followed by the addition of the remaining 0.5 mL of DBTDL solution. The end-capping reaction was allowed to proceed at 45 °C over 18 h under gentle stirring and nitrogen flow to yield the intermediate polymer.

[0097] The intermediate polymer was purified by precipitating the polymer in 300 mL of hexane under vigorous stirring. After 45 minutes of stirring at room temperature, the mixture was allowed to settle, followed by decanting the supernatant. The polymer was re-dissolved in 30 mL of IPA, followed by precipitating in another 300 mL of hexane. The dissolving-precipitating process was repeated for once more to remove as much impurities as possible. After the purification, the intermediate polymer was dissolved in 40 mL of THF and was transferred to a round bottom flask. The solvent was removed through rotary evaporation.

[0098] In the 2ndstep, the intermediate polymer was dissolved in 160 mL of anhydrous THF in a 3- necked round bottom flask. A hot 25 mL round bottom flask was charged with 3.77 g (30.9 mmol) of the melted 1 ,3-PS. The sealed flask with 1 ,3-PS was degassed at 45 °C for 30 min and then purged with nitrogen. 4 mL of anhydrous THF was then added to the 1 ,3-PS to fully dissolve it. The 1 ,3-PS solution was then slowly added to the intermediate polymer solution under gentle stirring and nitrogen flow through a syringe. After the addition of 1 ,3-PS solution, the reaction was allowed to proceed at 55 °C for over 18 h under stirring and nitrogen flow to yield the final product (zwitterionic polyurethane additive).

[0099] The final product (zwitterionic polyurethane additive) was purified by diluting the reaction mixture with 20 mL of IPA and allowing the solution to stir until uniform. The polymer was precipitated in 400 mL of hexane under mechanical stirring. After 45 min of stirring at room temperature, the mixture was allowed to settle, followed by decanting the supernatant. The polymer (zwitterionic polyurethane additive) was redissolved in 80 mL of THF, followed by precipitating in another 400 mL of hexane under mechanical stirring. The dissolving-precipitating process was repeated one more time to remove as much impurities as possible. After the purification, the final polymer (zwitterionic polyurethane additive) was dissolved in 100 mL of THF and was transferred to a round bottom flask. The solvent was removed through rotary 202400001 Foreign Filing

[0100] 14 evaporation. The final polymer (zwitterionic polyurethane additive) was further dried at 60 °C or at room temperature over several days under vacuum in a vacuum oven.

[0101] Example 2: Preparation and surface characterization of zwitterionic additive-modified polyurethane prototypes

[0102] 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.

[0103] X-ray photoelectron spectroscopy (XPS) was used to confirm surface modification on the PUZE- 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 end-group of the PUZE Compound 1 contains sulfur and is 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.

[0104] 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 were more hydrophilic than unmodified surfaces.

[0105] Example 3: Reduction of thrombosis on zwitterionic additive-modified polyurethane prototypes

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

[0107] Thrombogenicity of the rods was evaluated using an in-vitro re-circulating blood flow model (Thrombodyne Inc, Salt Lake City, UT). Unmodified and zwitterionic polyurethane 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 202400001 Foreign Filing

[0108] 15 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.

[0109] 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 PUZE Compound 1 reduced thrombus formation on Carbothane 85A rods by 99%, showing potential of the zwitterionic additives to improve the biocompatibility of device surfaces.

[0110] Example 4: Reduction in bacterial adhesion on zwitterionic additive-modified polyurethane prototypes

[0111] Polyurethane (CB 85A) rods, unmodified and modified with 4 wt% Compound 1 were prepared using a laboratory micro compounder as described in Example 1 .

[0112] 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).

[0113] 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 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. 202400001 Foreign Filing

[0114] 16

[0115] 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 1.6 log (97%) and 1.9 log (99%) respectively, showing the potential of zwitterionic additives of the invention to limit bacterial colonization of device surfaces.

[0116] 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

202400001 Foreign Filing17CLAIMS:1 . A zwitterionic polyurethane additive comprising a reaction product of: an isocyanate group terminated polyurethane prepolymer with a tertiary amine alcohol, followed by reaction 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, wherein said zwitterionic polyurethane additive has a theoretical molecular weight of from 1 ,000 to 10,000 Da.

2. The zwitterionic polyurethane additive according to claim 1 , wherein the isocyanate group terminated polyurethane prepolymer comprises a reaction product of at least one polyisocyanate 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.

3. The zwitterionic polyurethane additive according to claim 1 , wherein isocyanate group terminated polyurethane prepolymer comprises a reaction product of at least one diol selected from the group consisting of a polyether diol, a polyester diol, a polycarbonate diol, a polysiloxane diol, and a hydrogenated diol.

4. The zwitterionic polyurethane additive according to claim 1 , wherein said tertiary amine alcohol is at least one selected from the group consisting of 2-dimethylaminoethanol, 2-dimethylamino-1- propanol, N,N-diethylethanolamine, and 2-(diisopropylamino) ethanol.

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

6. An admixture comprising a base polymer and 0.05-15% w / w of the zwitterionic polyurethane additive according to any one of the claims 1 to 5 relative to the base polymer.

7. The admixture according to claim 6, 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,202400001 Foreign Filing18 cyclic olefin copolymer, a cellulosic polymer, a copolymer thereof and a blend thereof.

8. The admixture according to any one of the claims 6-7 , comprising 2 - 6 % w / w of said zwitterionic polyurethane additive relative to the base polymer.

9. The admixture according to any one of the claims 6-8, wherein said admixture has a thrombus accumulation less than 50% in comparison to that of said admixture without said zwitterionic polyurethane additive.

10. The admixture according to any one of the claims 6-9, wherein said admixture has a level of bacterial adhesion less than 50% in comparison to that of said admixture without said zwitterionic polyurethane additive.

11. A medical device comprising / consisting of the admixture of any one of the claims 6 to 1012. The medical device according to claim 1 1 , 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.

13. A method of reducing thrombus adhesion and / or bacterial adhesion to an admixture comprising a step of adding the zwitterionic polyurethane additive according to any one of claims 1-5 to a base polymer.

14. Use of a zwitterionic polyurethane additive according to any one of the claims 1 to 5 for manufacture of medical device(s).

15. Use of an admixture according to any one of items 6 to 10 for manufacture of medical device(s).

16. A process for preparing zwitterionic polyurethane additive according to any one of claims 1 to 5 comprising the steps of: i. reacting an isocyanate group terminated polyurethane prepolymer with a tertiary amine alcohol to obtain an intermediate,202400001 Foreign Filing19 ii. reacting the intermediate obtained in step i. 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 to obtain zwitterionic polyurethane additive.

17. A composition comprising the zwitterionic polyurethane additive according to any one of the claims 1 to 5.

18. The zwitterionic polyurethane additive according to any one of claims 1-5 or a composition according to claim 17 for reducing thrombus adhesion and / or bacterial adhesion.

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