Antimicrobial oligomer

Abstract

The present invention relates to an antimicrobial oligomer and to an antimicrobial coating composition comprising said antimicrobial oligomer. The present invention also relates to a medical device comprising the antimicrobial coating composition and to a method for coating said coating composition on a medical device.

Description

[0001] 2024P00025WO (34824-WO-PCT)

[0002] ANTIMICROBIAL OLIGOMER

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to an antimicrobial oligomer and to an antimicrobial coating composition comprising said antimicrobial oligomer. The present invention also relates to a medical device comprising the antimicrobial coating composition and to a method for coating said composition on a medical device.

[0005] BACKGROUND

[0006] Since their discovery in the early 1900s, antimicrobial compounds have transformed the prevention and treatment of infectious diseases. Antimicrobial compounds are chemical compounds that are used to inhibit or kill microbial organisms. This is achieved by a variety of mechanisms dependent upon the mode of action, composition, degree of activity, and application of the antimicrobial compound.

[0007] Antimicrobial compounds are currently employed across a broad spectrum of commercial applications. Antimicrobial compounds are particularly useful in medical devices. Indeed, medical devices are to be inserted in the body to perform their function without causing infection.

[0008] It is common to coat medical devices for protection of the component materials or to impart a desired effect, such as to enhance lubricity or deliver drugs. Medical devices may also be coated to impart an anti-microbial effect.

[0009] However, antimicrobial compounds may be hazardous to human health or can adversely affect tissue healing around the medical device (for example, an implant) in certain circumstances or concentrations. To reduce or eliminate the uptake of antimicrobial compounds into the body, it is desirable to have non-leaching antimicrobial materials which remain effective over the life of usage without eluting into the body.

[0010] Moreover, if the antimicrobial material must be coated onto the medical device it may be difficult to maintain proper coating adhesion over the life of the medical device. Without proper adhesion, such coatings can delaminate and generate harmful particulates. The presence of particulates can cause a thrombogenic, or inflammatory response or even be occlusive. The problem of poor adhesion may be exacerbated when the medical device is a fabric or membrane that may have enhanced flexibility or porosity relative to other medical devices.

[0011] A further challenge is maintaining coating integrity while retaining sufficient flexibility of the medical device. For example, some medical devices must navigate a tortuous pathway to be delivered to their desired location in the body. In other instances, the device may rub against hard bone or stiff biological surfaces that may be more likely to inflict damage.2024P00025WO (34824-WO-PCT)

[0012] US2011 / 0124772 discloses polymers with non-leaching antimicrobial activity and their use as surface coatings or bulk resins for medical devices. Antimicrobial moieties are incorporated into a polymer chain end or to a polymer backbone at a side chain end. The antimicrobial moieties promote enrichment of the antimicrobial endgroups at the contacting surface of the polymeric body.

[0013] US2022 / 0265906 discloses medical articles formed from a polyurethane-based resin including an ionically-charged modifier to provide enhanced properties. The polyurethane-based resin is a reaction product of ingredients comprising: a diisocyanate; a diol chain extender; a polyglycol; and a cationic modifier incorporated into a backbone, as a side chain, or both of the polyurethane-based resin. Exemplary cationic modifier includes bis(2-hydroxyethyl)dimethylammonium chloride (BHDAC). The medical articles are alleged to have inherent antimicrobial and / or anti-fouling characteristics or can easily bond anionic active agents to provide desirable material properties.

[0014] It would therefore be beneficial to provide an antimicrobial coating for a medical device that would show a reduction in bacterial proliferation without elution or release of the antimicrobial agent, while showing good mechanical adhesion and suitable tensile properties for the intended application of the substrate medical device.

[0015] SUMMARY

[0016] The above-noted disadvantages may be overcome by employing an anti-microbial oligomer as more fully described below. Use of the antimicrobial oligomer herein described, whether employed as a coating or as an additive in a coating formulation or polymer molding process, may have advantages in antimicrobial efficacy, coating durability, ease of application into a desired base polymer or coating, non-leachability, coating or other surface durability, base material compatibility, and ease of manufacturing. It is surprising that an antimicrobial oligomer of such low molecular weight can achieve such low leachables and / or exhibit suitable coating integrity. The present invention further provides an antimicrobial oligomer designed to deliver effective reduction in bacterial growth while minimizing or eliminating the elution of antimicrobial agents into the body, thereby reducing potential health risks and negative effects on tissue healing. Instead, the antimicrobial oligomer utilizes contact killing through membrane disruption upon direct contact with bacterial cells. In addition, the coating compositions may demonstrate strong mechanical adhesion and integrity. This addresses common issues such as coating delamination, generation of particulates, and coating durability. The invention thus enables safer, more durable, and effective antimicrobial coatings for medical devices without compromising device performance or patient safety.2024P00025WO (34824-WO-PCT)

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a 1H-NMR spectrum of the antimicrobial oligomer of the present invention. Figure 2 is a photograph of no zone of inhibition with S. Aureus as inoculum.

[0019] DETAILED DESCRIPTION

[0020] Antimicrobial Oligomer

[0021] The present invention relates to an antimicrobial oligomer having the formula:

[0022] C-[B-A]m-B-C, wherein

[0023] A is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol having from two to fifty repeating units;

[0024] B is the residue of a diisocyanate;

[0025] C is the residue of a hydroxyl-functional quaternary ammonium salt; and

[0026] m is from 1 to 10.

[0027] By residue it is meant the portion of a molecule that is present in the antimicrobial oligomer due to a chemical reaction of the molecule with another molecule. For example, the reaction of a first hydroxyl-functional molecule and a second isocyanate functional molecule will result in the residue of the first molecule and the residue of the second molecule joined by a urethane bond.

[0028] A is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol having from two to fifty repeating units. In other words, A is the residue of OH-[(CH2)4O]n-H or OH-[CH(CH3)-(CH2)3-O-]n-H, wherein n is from 2 to 50. In an embodiment, the polytetrahydrofuran diol or polymethyl tetrahydrofuran diol has from 2 to 30, 2 to 25, 2 to 20, or 2 to 15 repeating units. In an embodiment, the polytetrahydrofuran diol or polymethyl tetrahydrofuran diol has from 4 to 30, 4 to 25, 4 to 20, or 4 to 15 repeating units. In an embodiment, the polymethyl tetrahydrofuran diol comprises poly(2-methyltetrahydrofuran) diol.

[0029] B is the residue of a diisocyanate. In an embodiment, the diisocyanate is an aliphatic diisocyanate, a cycloaliphatic diisocyanate, or an aromatic diisocyanate. The diisocyanate is preferably an aliphatic or cycloaliphatic diisocyanate, more preferably an aliphatic diisocyanate. In an embodiment, the diisocyanate comprises hexane diisocyanate (HDI), butane diisocyanate, cyclohexane-1,4-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate (HMDI), isophorone diisocyanate (IPDI); 4,4'-diphenylmethane diisocyanate (MDI), 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, 1,4-phenylene diisocyanate, a lysine diisocyanate, or a mixture thereof. In an embodiment, the diisocyanate comprises hexane diisocyanate (HDI), butane diisocyanate, ora mixture thereof.2024P00025WO (34824- WO-PCT)

[0030] In an embodiment, the diisocyanate comprises a carboxylic group, such as a lysine diisocyanate. In an embodiment, the antimicrobial oligomer comprises a lysine residue. In an embodiment, the lysine diisocyanate comprises lysine methyl ester diisocyanate or lysine butyl ester diisocyanate. At an elevated temperature, the ester may be boiled off, leaving the acid form. The elevated temperatures may be attendant to a coating process or chemical reaction. Such embodiments may have the benefit of enabling a chemical reaction, such as a cross-linking reaction, of the antimicrobial oligomer with other components of a coating composition or other composition into which the antimicrobial oligomer is added.

[0031] C is the residue of a hydroxyl-functional quaternary ammonium salt. The hydroxyl-functional quaternary ammonium salt is mono-functional. In an embodiment, a hydroxyl-functional quaternary ammonium salt is obtained by the reaction of a tertiary amine with an alcohol having chlorine functionality. Examples of suitable alcohols having chlorine functionality are 2-chloroethanol and 2-(2-chloroethoxy)ethanol. In an embodiment, the hydroxyl-functional quaternary ammonium salt comprises N-(2-(2-hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1 -ammonium chloride (HEDDA).

[0032] m is from 1 to 10, preferably from 1 to 5. In an embodiment, m is from 1 to 3. In an embodiment, m is at most 10, 9, 8, 7, 6, 5, 4, 3 or 2.

[0033] In an embodiment, the antimicrobial oligomer is according to the following chemical formula:

[0034]

[0035] wherein

[0036] Ri is - [(CH2)4O]n- or -[CH(CH3)-(CH2)3-O-]n- wherein n is from 2 to 50;

[0037] R2is (C2-Ci6)alkylene, cycloalkylene, arylene, substituted arylene, aryl-containing divalent groups, or a lysine residue;

[0038] R3is - [(CH2)2O]q- wherein q is from 1 to 8;

[0039] R4is (Ci-C20) alkyl; and

[0040] m is from 1 to 10.

[0041] In an embodiment, n is from 2 to 30, 2 to 25, 2 to 20, or 2 to 15. In an embodiment, n is from 4 to 30, 4 to 25, 4 to 20, or 4 to 15 repeating units.

[0042] In an embodiment, R2is (C2-Ci6)alkyl, cycloalkylene, isophorone, or a lysine ester. According to an embodiment, R2is (C2-Ci6)alkyl or cycloalkylene. According to an embodiment, R2is (C2-Ca)alkyl. According to an embodiment, R2is hexane, butane,2024P00025WQ (34824-WO-PCT)

[0043] cyclohexane, dicyclohexane, or dicyclohexyl methane. In an embodiment, R2is isophorone. In an embodiment, R2is lysine methyl ester or lysine butyl ester.

[0044] According to a particular embodiment, R4is (Ci - C20) alkyl.

[0045] According to a particular embodiment, R4is (Ci-C-is) alkyl, (Ci-Cis) alkyl, (C1-C12) alkyl, (Ca-C2o) alkyl, or (Cio-Cis) alkyl.

[0046] According to a particular embodiment, Ri is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol, R2is hexane, R3 is the residue of diethyleneglycol, and R4 is (Ci-Ci2) alkyl.

[0047] According to an embodiment, the antimicrobial oligomer is an adduct of poly(tetrahydrofuran) diol reacted with hexane diisocyanate (HDI) and terminated with N-(2-(2-hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1 -ammonium chloride (HEDDA).

[0048] According to an embodiment, R1 is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol, R2is -CeHs CHs)-, R3 is the residue of diethyleneglycol, and R4is (C10-C18) alkyl.

[0049] m is from 1 to 10, preferably from 1 to 5. In an embodiment, m is from 1 to 3. In an embodiment, m is at most 10, 9, 8, 7, 6, 5, 4, 3 or 2.

[0050] According to an embodiment, the antimicrobial oligomer is an adduct of poly(tetrahydrofuran) diol reacted with two equivalents of hexane diisocyanate (HDI) and terminated with two equivalents of N-(2-(2-hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1-ammonium chloride (HEDDA).

[0051] According to an embodiment, the antimicrobial oligomer is an adduct of poly(tetrahydrofuran) diol reacted with a toluene diisocyanate (TDI) and terminated with N-(2-(2-hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1 -ammonium chloride (HEDDA).

[0052] According to an embodiment, the antimicrobial oligomer is an adduct of poly(tetrahydrofuran) diol reacted with a toluene diisocyanate (TDI) and terminated with N-(2-(2-hydroxyethoxy)ethyl)-N,N-dimethylhexadecan-1 -ammonium chloride

[0053] In an embodiment, the antimicrobial oligomer has a number average molecular weight (Mn) of from 600 to 6500 g / mol, preferably from 1000 to 5000 g / mol. In an embodiment, the antimicrobial oligomer has a number average molecular weight (Mn) of at least 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 g / mol. In an embodiment, the antimicrobial oligomer has a number average molecular weight (Mn) of at most 6500, 6000, 5800, 5600, 5400, 5200, 5000, 4800, 4600, 4400, 4200, 4000, 3800, 3600, 3400, 3200, 3000, 2800, 2600, or 2500 g / mol. Number average molecular weight is determined by triple detection as described in the Examples herein.2024P00025WO (34824-WO-PCT)

[0054] Antimicrobial coating composition

[0055] A second embodiment of the present invention is an antimicrobial coating composition comprising the antimicrobial oligomer as defined previously.

[0056] The coating composition of the present invention may optionally comprise at least one further component (or additive). Examples of further components include a hydrophilic polymerizable compound, a low molar mass osmolality-increasing component such as urea, glycerol or an ionic or ionizable compound like sodium chloride. Other examples include one or more customary additives like a surfactant; an adhesion promoter, an antioxidant; a radical stabilizer; a UV absorber; a light stabilizer; a heat polymerization inhibitor; a (silane) coupling agent; a coating surface improver; a leveling agent; a colorant, for example a pigment or a dye; a preservative; a plasticizer; a lubricant; a filler; a wettability improver; or a chain transfer agent. Most of such additive compounds are typically applied at relatively low concentrations, like 0.01-3 mass% based on total dry mass of the coating composition. In embodiments, the coating composition comprises a surfactant. A surfactant may for example improve spreading of the coating composition over the surface of a substrate and / or surface properties of the applied and cured coating. Generally, a surfactant is a surface-active agent comprised of a hydrophobic portion, usually a long alkyl chain, attached to a hydrophilic or water solubility enhancing functional group. Surfactants can be categorized according to charge present in the hydrophilic portion of the molecule (after dissociation in aqueous medium): ionic surfactants, for example anionic or cationic surfactants, and non-ionic surfactants. Examples of ionic surfactants include sodium dodecylsulfate (SDS), sodium cholate, bis(2-ethylhexyl)sulfosuccinate sodium salt, cetyltrimethylammoniumbromide (CTAB), lauryldimethylamine-oxide (LDAO), N- laurylsarcosine sodium salt and sodium deoxycholate (DOC). Examples of non-ionic surfactants include alkyl polyglucosides such as Triton™ BG-10 Surfactant and Triton CG- 110 Surfactant, branched secondary alcohol ethoxylates such as Tergitol™ TMN Series, ethylene oxide I propylene oxide copolymers, such as Tergitol L Series, and Tergitol XD, XH, and XJ Surfactants, nonylphenol ethoxylates such as Tergitol NP Series, octylphenol ethoxylates, such as Triton X Series, secondary alcohol ethoxylates, such as Tergitol 15-S Series and specialty alkoxylates, such as Triton CA Surfactant, Triton N-57 Surfactant, Triton X-207 Surfactant, Tween 80 (polyethylene glycol sorbitan monooleate; with about 80 ethylene oxide units) and Tween 20 (polyethylene glycol sorbitan monolaurate; with about 20 ethylene oxide units). If used, surfactant is typically applied at relatively low concentration, for example 0.1 - 2 mass% based on the total mass of the dry coating.

[0057] In an embodiment, the coating comprises a hydrophilic polymerizable compound. A hydrophilic polymerizable compound typically comprises a hydrophilic polymer backbone and polymerizable groups. In an embodiment, the polymerizable groups are endgroups and the hydrophilic polymerizable compound is telechelic. In an embodiment, the hydrophilic polymer2024P00025WO (34824-WO-PCT)

[0058] backbone comprises a residue of a hydrophilic polyfunctional compound, preferably chosen from polyethers, polyesters, polyurethanes, polyepoxides, polyamides, poly(meth)acrylamides, poly(meth)acrylics, polyoxazolines, polyoxazolidones, polyvinyl alcohols, polyethylene imines, polysaccharides, such as cellulose or starch, or any combination of the above. In an embodiment, the hydrophilic polymer backbone comprises polyethylene oxide or polyoxazoline. In an embodiment, the polymerizable groups comprise a (meth)acrylate or (meth)acrylamide.

[0059] According to an embodiment, the coating composition comprises at least one solvent wherein the antimicrobial oligomer can be homogeneously dissolved. Examples of suitable solvents are generally relatively polar organic liquids. In embodiments, the solvent is miscible to at least some extent with water. Examples of suitable solvents include C1-C6 alcohols, like methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol; acetone; methylethyl ketone; tetrahydrofuran; and mixtures thereof. The solvent may also contain water, provided such mixed solvent can dissolve at least the antimicrobial oligomer. In further embodiments, the solvent is at least one selected from methanol, ethanol, and isopropanol, including mixtures thereof or mixtures comprising some water, like 96% ethanol by weight (comprising about 4% of water). In an embodiment, the solvent comprises 70% or more of ethanol and 30% or more of water by weight, such as 75% ethanol and 25% water. In embodiments, the solvent or mixture of solvents has relatively high volatility, or a relatively low boiling point, for example of at most 150, 130, 120, 110 or 100 °C, such that the solvent can quickly evaporate from a layer of coating composition applied to a substrate; allowing relatively fast solidification of the liquid composition and fast curing of the coating to result in short cycle times and an efficient and economic coating process.

[0060] The coating composition can contain a widely varying amount of solvent, which allows making a solution having a viscosity that is adjustable to use with different coating techniques. In other embodiments, the coating composition contains such amount of solvent that the solution has a relatively low viscosity, to enable applying thin coating layers via for example a dip-coating process on thin, elongated articles like catheters and guidewires. In embodiments, the coating composition contains 40-99.5 mass% of solvent based on the total composition.

[0061] In other embodiments, the coating composition contains at least 50, 60, 70, 80, 85, 90 mass% of solvent, and at most 99.0, 98.5, 98, 97.5, 97.0, 96.5, 96.0, 95.5 or 95.0 mass% of solvent.

[0062] Use of Antimicrobial Oligomer as an Additive with Thermoplastic Polymer

[0063] In addition to imparting antimicrobial function to an article utilizing the antimicrobial oligomer as a component of an antimicrobial coating composition, it may be possible to2024P00025WO (34824-WO-PCT)

[0064] achieve antimicrobial efficacy when employing the antimicrobial oligomer as an additive to a polymer composition. In such an embodiment, a polymer composition comprises the antimicrobial oligomer and a thermoplastic polymer.

[0065] In an embodiment, a polymer composition may be prepared by a method comprising the steps of:

[0066] a) providing an antimicrobial oligomer according to the invention,

[0067] b) mixing the antimicrobial oligomer of step a) and a thermoplastic polymer comprising a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, or a mixture thereof, at a temperature of from 130 to 190 °C,

[0068] c) shaping the mixture obtained in step b), and

[0069] d) cooling the mixture.

[0070] In an embodiment, the step of mixing is performed at a temperature of from 140 to 180 °C

[0071] The thermoplastic polymer may be a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, and mixtures thereof. In an embodiment, the thermoplastic polymer comprises a blend of two or more thermoplastic polymers. The thermoplastic polymer may be added in a powder or pellet form. In an embodiment, the thermoplastic polymer has a melting temperature of from 130 to 190 °C, preferably from 140 to 180 °C.

[0072] The polymer composition may comprise one or more customary additives that are allowed for the targeted application. Examples of additives include stabilizers, antioxidants, processing aids, lubricants, surfactants, antistatic agents, colorants, radiopacifiers and fillers. The additives may be present in the typically effective amounts as known in the art, such as 0.01-30 mass%, preferably 0.01-5 mass% based on the amount of the polymer composition, preferably 0.01-1 mass%. In another embodiment, the polymer composition consists of the thermoplastic polymer and the antimicrobial oligomer, and is substantially free of additives.

[0073] The mixing is preferably performed during an extrusion process. According to an embodiment, this is done using a single screw or twin-screw extruder which can either corotate or counter- rotate. However, it can also be done by kneading, melt-blending (solution blending.2024P00025WO (34824-WO-PCT)

[0074] The step of shaping may be performed by forming the polymer composition into a form that can be processed into another article using known techniques. For example, shaping the polymer composition into a pellet or a powder. In a subsequent step, the pellets may be formed into a medical device via, for example, injection molding. The shaping may be formed by extruding the polymer composition through a die and cutting the extrudate at a desired length.

[0075] Method for imparting an antimicrobial surface to a medical device

[0076] Another embodiment of the invention is a method for forming an antimicrobial surface on a medical device, the method comprising the steps of:

[0077] (i) Providing an antimicrobial oligomer as disclosed previously or an antimicrobial coating composition as disclosed previously,

[0078] (ii) Coating said antimicrobial oligomer or antimicrobial coating composition on at least one surface of a medical device.

[0079] In this method, the coating composition may be applied to a surface using known techniques in the art, like dip-coating, spray coating, wash coating, vapor deposition, or by using a brush or roller; for example dependent on the type of article. For elongated and relatively thin articles like guidewires and catheters, dip-coating may be the preferred application technique. It is an advantage of present coating composition that, in most cases, it can be applied directly to the said surfaces, which are preferably cleaned but need no chemical pretreatment of primer coating. Therefore, the process typically does not comprise a step of chemically pretreating or applying a primer composition to the surface to be coated before applying the coating composition of the invention.

[0080] According to a particular embodiment, the coating is carried out by spray coating or dip coating with optional in situ thermal, photo irradiation or plasma treatment. In an embodiment, a coating of the antimicrobial oligomer is formed on a surface by simultaneous plasma discharge and nebulized droplet spray of the antimicrobial oligomer in a solvent. In an embodiment, the surface is plasma treated with either oxygen or acetylene ammonia plasma prior to dip coating or spray coating.

[0081] The thickness of the layer of coating composition applied, may be controlled by altering coating parameters like the soaking time, pull-up speed, or viscosity of the coating formulation and the number of coating steps. Typically, the thickness of a dry coating on a surface of an article ranges from 0.1-300 microns, preferably at least 0.2, 0.3, 0.4, 0.5 microns, and preferably at most 200, 100, 50, 40, 30, 20 or 5 or 2 microns.2024P00025WG (34824-WO-PCT)

[0082] According to a particular embodiment, the method comprises a further step (iii) of photo curing comprising exposing the medical device to a suitable radiation source, like UV lamps, during a time sufficient to substantially react the polymerizable compounds in the coating. The skilled person will be able select suitable conditions like intensity and wavelength of radiation and exposing time, depending on type of photo-initiator and based on general knowledge and some experiments. Generally, exposing or curing time will be from about 5, 10, 20, and up to about 50, 100, 250 or 500 seconds, depending on the type and energy of the radiation source that is used.

[0083] In an embodiment, a coating may be formed by the following steps:

[0084] a. plasma treating a surface of a medical device,

[0085] b. dip coating or spray coating a coating composition on the surface of the medical device, the coating composition comprising the antimicrobial oligomer and a solvent,

[0086] c. evaporating the solvent.

[0087] In an embodiment, a coating may be formed by the following steps:

[0088] a) providing a coating composition comprising a solution of the antimicrobial oligomer according to the invention and a thermoplastic polymer comprising a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, or a mixture thereof in a solvent,

[0089] b) coating the solution onto a substrate, and

[0090] c) evaporating the solvent.

[0091] Medical device

[0092] Another embodiment of the invention is a medical device comprising a coating on a substrate, wherein the coating comprises the antimicrobial oligomer as defined previously. It should be understood that the coating is present on at least part of the substrate.

[0093] Preferably the coating is present homogeneously on the substrate. Typically, the coating is a single-layer coating and refers to a coating layer that has been applied on a substrate from one coating composition, in one or optionally more coating steps.

[0094] The substrate can be a polymeric or a metallic substrate. The polymeric substrate is preferably chosen in the group consisting of polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polyethylene, polylactide, polycaprolactone, silicones, and mixtures thereof. The metallic substrate is preferably chosen in the group consisting of stainless steel, titanium and titanium alloys, cobalt chromium alloys.2024P00025WO (34824-WO-PCT)

[0095] The substrate of the medical device that is coated with the coating of the invention may comprise any material from which medical devices (for example implants) are made of, including metals, ceramics and plastics. Examples of these materials include amorphous and / or (partially) crystalline carbon; complete carbon material; porous carbon; graphite; composite carbon materials; carbon fibers; ceramics such as calcium phosphates, zeolites, silicates, aluminum oxides, aluminosilicates, silicon carbide, and silicon nitride; clays, such as laponite; metal carbides; metal oxides; metal nitrides; metal carbonitrides; metal oxycarbides; metal oxynitridres and metal oxycarbonitrides of the transition metals (such as titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, rhenium, iron, cobalt, and nickel); metals and metal alloys of the noble metals gold, silver, ruthenium, rhodium, palladium, osmium, iridium, and platinum; metals and metal alloys of titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, rhenium, iron, cobalt, nickel and copper; steel, in particular stainless steel; shape memory alloys such as nitinol; nickel-titanium alloys; glass; stone; glass fibers; minerals; natural or synthetic bone substance; bone imitates based on alkaline earth metal carbonates such as calcium carbonate, magnesium carbonate, strontium carbonate and any desired combination of the above-mentioned materials.

[0096] The medical device may have a range of geometries, including films, sheets, rods, tubes, molded parts of regular or irregular shape, fibers, and fabrics; and can have a surface that is made from different materials and have different textures, like a porous, non- porous, smooth, rough, even or uneven surface.

[0097] According to an embodiment, the medical device is selected from the group consisting of urinary catheters, percutaneous catheters, central venous catheters, vascular access devices, intravenous delivery sites, drug delivery catheters, drains, gastric feeding tubes, tracheotomy tubes, contact lens, orthopedic implants, neuro-stimulation leads, polymeric woven or braided cerclage cable, metal implant, pacemaker leads, and blood bags.

[0098] In an embodiment, the medical device comprises a polymer cable. A polymer cable is a cable comprised of one or more polymers. In an embodiment, the polymer cable comprises polyethylene. In an embodiment, the polymer cable comprises polymer fibers. A fiber is a long continuous filament. In an embodiment, the polymer cable consists of polymer fibers. In an embodiment, the polymer cable comprises a braid of a plurality of strands of individual polymer cables or fibers. In an embodiment, the polymer cable comprises a braid that comprises a hollow tubular braid, a solid circular braid, a spiroid braid, a flat braid, a core-sheath (sometimes called kern-mantle or core-shell ) braid, or a braid-on-braid. A braid-on-braid is a core-shell construction in which a braided core is covered by another braided construction. In2024P00025WO (34824-WO-PCT)

[0099] an embodiment, the polymer cable comprises a yarn. Ayarn is a continuous strand of multiple, usually twisted, fibers. In an embodiment, the polymer cable comprises a braided, knitted, or woven cable, wherein the polymer cable comprises polymer fibers. In an embodiment, the polymer cable comprises a monofilament or a multifilament yarn. The yarn may in addition comprise other components or additives that provide some extra functional effect, such as antimicrobial or anti-inflammatory action, knotting performance, or visual contrast. In an embodiment, the polymer cable comprises a radiopaque agent.

[0100] In another embodiment, the polymer composition is formed into a medical device by thermoforming (extrusion, molding, etc.) the polymer composition into a medical device, wherein the polymer composition comprises the antimicrobial oligomer and a thermoplastic polymer comprising a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, or a mixture thereof, at a temperature of from 130 to 190 °C, preferably 140 to 180 °C.

[0101] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following exemplary embodiments and claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as” or “like”) provided herein, is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to practicing the invention.

[0102] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. While certain optional features are described as embodiments of the invention, the description is meant to encompass and specifically disclose all combinations of these embodiments unless specifically indicated otherwise or physically impossible.2024P00025WO (34824-WO-PCT)

[0103] The experiments and examples below further elucidate embodiments of the invention, but of course, should not be construed as in any way limiting the scope of the claims.

[0104] EXAMPLES

[0105] Example 1

[0106] Synthesis of C 12 Quat end group (DEG-QAC-C^I

[0107] Synthesis of N-(2-(2-Hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1-ammonium chloride - HEDDA (3)

[0108] ol

[0109]

[0110] 2-(2-Chloroethoxy)ethanol 2 (106 g, 0.85 mol) was added dropwise to a solution of N,N-dimethyl- dodecyl-diamine 1 (140 g, 0.66 mol) in 1-butanol (140 mL) at 70 °C. After stirring overnight at reflux (oil bath 120 °C) the mixture was concentrated in vacuo at 60 °C. The crude product was obtained as a brownish oil which was dissolved in 2L of warm acetone. Upon cooling and standing overnight at 4 °C off-white crystals were formed and collected by filtration. Re-crystallization of this product from acetone / THF (8 / 3, v / v) yielded 169 g (79%) of the pure product as white crystals.

[0111] 1H NMR: (399 MHz, CDCI3) 0 4.79 (t, 1H, OH), 4.06 (dd, 2H, OCH2CH2N), 3.88 (dd, 2H, OCH2CH2N),

[0112] 3.75, (m, 2H, NCH2CH2OH) 3.70 (m, 2H, CH2OH), 3.59 (m, 2H, CH2CH2CH2N), 3.43 (s, 6H, CH3N), 1.73 (m, 2H, (m, 2H, CH2CH2CH2N), 1.45-1.18 (m, 18H, CH2CH2CH2, 0.88 (t, 3H, CH2CH2CH3).

[0113] 13C NMR: (100 MHz, CDCI3) 672.95 (HOCH2CH2O), 65.84

[0114] (CH2CH2CH2N), 64.78 (OCH2CH2N), 63.43 (OCH2CH2N), 60.97 (HOCH2CH2O), 51.73 (N(CH3)2), 31.81 (CH2CH2CH3), 29.51 (CH2CH2CH2), 29.41 (CH2CH2CH2), 29.332024P00025WC (34824-WO-PCT)

[0115] (CH2CH2CH2), 29.24 (CH2CH2CH2), 29.19 (CH2CH2CH2), 26.22 (CH2CH2CH2N), 22.84 (CH2CH2CH2N), 22.59 (CH2CH2CH3), 14.04 (CH3).

[0116] FT-IR (ATR): v (cm-1): 3318, 3015, 2949, 2914, 2851 , 1472, 1420, 1371 , 1225, 1123, 1103, 1084, 1063, 1036, 966, 876, 866, 718.

[0117] ESI-MS: m / z Calc, for C18H40NO2+ 302.31 ; Obs. [M+H]+ 302.33.

[0118] Melting point: 84-85 °C.

[0119] Example 2

[0120] Synthesis and characterization of guat telechelic oligomer (UOSME-HDI-C12)

[0121] 198.4 g of dried PTMO diol (polytetramethylene oxide diol or polytetrahydrofuran diol) (moisture content <50 ppm) and charged in a 1 liter reactor and heated to 70 °C followed by the addition of 56.98 grams of HDI (hexamethylene diisocyanate). After 10 minutes 40 PPM of DBTDL (dibutyl tin dilaureate) was added. After two hours FTIR analysis indicates full conversion end functionalization of PTMO. 94.78g HEDDA (N-(2-(2-Hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1 -ammonium chloride) was then added along with the further 20 ppm of DBTDL. The reactor temp was then raised to 90 degrees centigrade 90 °C and held for one hour. In situ FTIR indicated full conversion and then functionalization with the quaternary ammonium chloride. The material was discharged as a viscous liquid to yield 327 grams (93% yield). 1 H NMR can be seen in Figure 1. The formula of the prepared oligomer is described below.

[0122]

[0123] 2024P00025WC (34824-WO-PCT)

[0124] Mn is measured with size exclusion chromatography (SEC / GPC) coupled to refractive index (Rl), multi-angle or low-angle light scattering (LS), and differential viscometry detectors (triple detection) as follows.

[0125] The SEC analysis was performed using Viscotek GPC Max (System ID: LT-7) equipped with Viscotek Triple Detector Array 305, refractive index (Rl), differential viscometer (DV) and right-angle light-scattering (RALS) detector.

[0126]

[0127] The sample was accurately weighed and dissolved in HFIP with target concentration of 1.5 mg polymer / mL HFIP. The samples are then gently shaken for 4 hours to dissolve properly. Once dissolved, the samples are filtered with a 0.22 pm PTFE filter and measured with the LT-SEC equipment. Each solution was measured twice.

[0128] This LT-SEC system is equipped with triple detection calibration. The masscalibration is done once for the instrument using PMMA narrow standards.

[0129] Calibration used Easical PMMA standards ranging from 535 Da to 1.5 MDa.

[0130] Example 3

[0131] Coating formulations

[0132] A coating formulation of 10 % antimicrobial oligomer in isopropanol was prepared. Antioxidants and adhesion promoters could be used in sub 1% amounts based on solids.

[0133] Example 4

[0134] Plasma spray coating applications

[0135] Coatings were applied onto woven flat radiopaque cables and round non-radiopaque cables as follows. The woven flat radiopaque cable is 4 mm wide and comprises radiopaque Ulteeva Purity™ fibers from dsm-firmenich. The round cable comprises non radiopaque USP2 grade yarns formed from Ulteeva Purity™ 110 dtex fibers.2024P00025WO (34824-WO-PCT)

[0136] Coating formulations were low temperature plasma spray coated as described by O’Neill et. al. Deposition of Cell Culture Coatings Using a Cold Plasma Deposition Method Appl. Sci. 2020, 70(19), 6670.

[0137] Plasma deposition was carried out using a purpose-built deposition system comprising a G2000 High Voltage power supply (Redline, Baesweiler, Germany) connected to a custom build Teflon® deposition unit that encased two metal electrodes. The plasma was operated at an input voltage of 110 V and 20.44 kHz. A pneumatic nebulizer T2100 (Burgener Research, Ontario, Canada) was placed between the electrodes and this was connected to a syringe pump to provide a constant flow of antimicrobial oligomer solution at 100 L / min. The liquid was nebulized using argon flow with a pressure of 3.1 Bar. In addition, a separate helium flow of 6 L / m was provided to the metal electrodes to create the plasma discharge. The plasma discharge was combined with the nebulized droplet spray in an acrylic tube (19 mm inner diameter * 35 mm samples) over the target surface with a gap height of 2 mm. In order to coat the surface evenly the plasma head was mounted on a computer numerically controlled table and moved in a desired pattern. For coating of flat surfaces, a raster pattern was used (4.5 mm step size, and speed of 200mm / min) over the target surface with a gap height of 2 mm.

[0138] Example 5

[0139] Antimicrobial studies

[0140] Coated and uncoated cables were cut into 10 cm lengths packaged in pouches and ETC (ethylene oxide) sterilized. The samples were preincubated in 5% blood plasma for 1 hour before testing. The samples were tested for antimicrobial efficacy, bacterial viability, and bacterial zone of inhibition studies.

[0141] Evaluation of antibacterial efficacy

[0142] The test was performed according to the regulations of DIN EN ISO / IEC 17025 for testing and calibration laboratories. The test was performed in 24-well titer plate and all volumes were adjusted accordingly. After a challenge time of 18 hours, samples were removed and a 200 pL aliquot of each well was transferred into a 96-well microtiter plate.

[0143] The coated and uncoated cables were preincubated in 5% blood plasma for 1 hour prior to testing.

[0144] The test objects are incubated with cells of the indicated test strain. Loose cell material that does not adhere to the test surface is removed in defined wash steps. The antimicrobial2024P00025WO (34824- WO-PCT)

[0145] properties of the material are tested with challenge time of 18 hours () at 37 °C (except for C. Albicans where the test is conducted at 30 °C) by tracking the ability of the bacteria on its surface to proliferate. The test results apply to measurements taken during this period. If all bacteria on the surface of the material are prevented from multiplying, no daughter cells are produced and the sample is considered bactericidal. Materials can also be antimicrobial, which means that not all cells on the test surface are prevented from growing. Some cells are able to divide and release daughter cells into the surroundings, which are then optically registered in a so-called growth curve. If surviving daughter cells are grown under controlled conditions over 48 hrs (observation time), a higher turbidity and therefore a bigger signal is generated. At the same time only vital and proliferative cells are accounted for. In particular, antimicrobial samples will release daughter cells into the surrounding environment. Hence, microbial growth is first observed noticeably later. This right-shift towards longer times is indicative for the antimicrobial efficacy of the tested samples. The so-called onset optical density (OD) serves as a quantifiable parameter and is equivalent to the required number of hours required for the surviving daughter cells to grow to a predefined optical density (OD = 0.2).

[0146] Antimicrobial efficacy is always measured in comparison to a non-antimicrobial blank sample, such as a cable that is free of antimicrobial additives. The value determined for the blank sample is subtracted from that of the actual sample (net onset OD). Internal controls that are present on all microplate assays serve as permanent monitors of the measuring process.

[0147] For the test, a material is regarded antimicrobial only if it inhibits the formation of at least 99.9% of the daughter cells during the observation period in comparison to the blank sample. The following assessment criteria are used to determine the antimicrobial efficacy:

[0148] Antimicrobial Efficacy

[0149]

[0150]

[0151]

[0152] Results are given in Table 1 .

[0153] Tablet: Antimicrobial activity

[0154]

[0155] 2024P00025WO (34824-WO-PCT)

[0156] Evaluation of bacterial viability

[0157] The indicator dye resazurin is used for determining the metabolic capacity of cells. Viable cells retain the ability to reduce resazurin to resorufin, which is highly fluorescent. Non-viable cells rapidly lose their metabolic capacity, do not reduce the indicator dye and therefore do not generate a fluorescent signal. This property is used to detect cell viability by means of a visible color change as well as a fluorescence signal. The fluorescence signal of the samples is measured and evaluated in comparison to a reference sample.

[0158] Samples of cables were cut into 10 cm lengths packaged in pouches and ETO sterilized. The samples were preincubated in 5% blood plasma for 1 hour before testing.

[0159] The test was performed in 24-well titer plate and all volumes were adjusted accordingly. After the challenge time of 18 hours under the conditions in Table 2, samples were removed, loose cell material removed by washing, and the samples transferred in a new 24-well titer plate for the microbial viability test setup.

[0160] Table 2: Test conditions

[0161]

[0162] Microbial viability is determined by incubating in resazurin solution The evaluation of cell viability is performed at defined time points depending on the test germ. At each time point, the color change of the resazurin substrate is documented photographically and the fluorescence signal is determined. At the end of the incubation with resazurin, the reaction is stopped and the fluorescence signal is stabilized by the addition of 3% SDS.

[0163] The bacterial viability of each sample is calculated by comparing the fluorescence signal of the reference sample and that of the coated sample ([coated sample] / [uncoated sample]*100). The mean values of respective sample replicates were used for calculation.

[0164] It can be concluded from Table 3 that there are consistently less viable microorganisms on the antimicrobial coated samples compared to the uncoated reference.2024P00025WO (34824-WO-PCT)

[0165] Table 3: Fluorescence values

[0166]

[0167] Example 6

[0168] Evidence of no leaching antimicrobial

[0169] This test was performed to show that there was no elution of antibacterial compound from the coating thereby demonstrating a contact killing coating.

[0170] This investigation was performed on the basis of DIN 58940-3:1989-06 “Medical microbiology - Susceptibility testing of microbial pathogens to antimicrobial agents - Part 3: Agar diffusion test”

[0171] Samples that had been preincubated in blood plasma as given in Example 5 were used on this test.

[0172] For the test a freshly prepared bacterial solution of one test strain with a density of 2.5 x 106 CFU / ml is evenly spread on a culture media plate to allow densely growing colonies. The inoculum is then incubated for 20 minutes. The test samples are then put on the inoculated agar surface and slightly pressed onto the agar surface. Afterwards the agar plates with the samples were incubated for 18 ± 2 hrs at 37 °C (30 °C for C. Albicans). The agar plates are then documented photographically and any areas of inhibition are measured and evaluated. The test is performed in replicates.

[0173] Results show no inhibition zone around the coated fabrics indicating the antimicrobial coating components were not leaching from the coated braids. If the antimicrobial oligomer had leached from the coated fabric then a halo effect around the coated fabric would have been visible.

[0174] A representative picture of no zone of inhibition is given in Figure 2 with S. Aureus as inoculum.

[0175] Example 7

[0176] Evidence of wear resistance of the coating

[0177] Using a custom-built abrasion setup, coated braids prepared according to Example 4 are rubbed back and forth in longitudinal direction over a metal pin with a diameter of 5mm for a set number of cycles. The wrap angle of the braid around the pin is approximately 156 degrees. The amplitude of the displacement was set to 20 mm with a speed of 600 mm / min,2024P00025WO (34824-WO-PCT)

[0178] using a Zwick / Roell Z010 tensile testing machine. Tension is applied to the braid by means of a mass at the end, in this case 4550 grams was used resulting in a tension of approximately 45N.

[0179] Table 4: Parameters

[0180]

[0181] Measured and derived quantities:

[0182] The force is measured at the end of the braid (opposite from the attached mass), using a 1kN load cell. The maximum force measured was Fmax= 67 N. The contact pressure between the pin surface and the braid is approximately 18 MPa, calculated using the tension and the braid diameter under the assumption that the braid does not deform.

[0183] To check that the antimicrobial coating was still on the braids after wear tests the coatings were dipped in Bromophenol Blue 90 ppm in 0.1 M phosphate buffer followed by rinsing in water. Reference for this staining method is C. Burel Letters in Applied Microbiology, 72, 358 -265, which is used to stain and detect quaternary ammonium compounds.

[0184] The results show the resultant coated braids maintained the quaternary ammonium antimicrobial coating despite repeated abrasion. Upon initial staining with Bromphenol Blue, the coated braids possess a blue hue, indicating the presence of quaternary ammonium groups at the surface of the coating. A purple hue would have been observed had no quaternary ammonium groups been present. Further, the blue hue is maintained with no noticeable damage after repeated abrasion. This points to a robust coating that can withstand manipulation of the fiber during production of a medical device or during its use.2024P00025WC (34824-WO-PCT)

[0185] Example 8

[0186] Preparation of Hydrophilic Coating Formulation Containing Antimicrobial Oligomer

[0187] Radiation-curable hydrophilic coating formulations with different loadings of the antimicrobial oligomer (UOSME) were prepared. UOSME was added to commercially available ComfortCoat® hydrophilic top coat 43003 from dsm-firmenich to result in a concentration of 2, 5 and 10% UOSME by weight of solids. By solids it is meant the components of the formulation excluding the solvent.

[0188] Example 9

[0189] Forming hydrophilic coatings on polymer rods

[0190] Nylon 12 rods with a diameter of 1 mm and Elasthane™ 55D rods with a diameter of 2.43 mm were dip coated with theAlmepp dip coater CCS-12.175 and photocured under Dymax® lamps 400 Watt UV Bulb (metal halide bulb). The lamps are positioned 28 cm from the coated samples. The cylindrical samples are rotated at 4 rpm during photocuring.

[0191] A primer coating (ComfortCoat® hydrophilic coating Primer 41002) is first applied prior to application of the hydrophilic coating composition from Example 8. The coating conditions are given below in Table 5.

[0192] Table 5: Coating Conditions

[0193]

[0194] After curing and drying, the samples were tested for lubricity and wear.

[0195] Example 10

[0196] Lubricity of Prepared Hydrophilic Coating Formulations

[0197] Tests to determine lubricity of samples prepared in accordance with Example 9 were performed with a Harland Friction Tester FTS 6000, with the two friction pads applied to the2024P00025WO (34824-WO-PCT)

[0198] sample with 300 g clamp force and the sample submerged in demi water at room temperature (about 20-22 °C). 25 test cycles were run, wherein in each cycle the sample was moved upward 12 cm at 10 mm / s while measuring friction force, the clamp was opened, and sample moved back to starting position. Pads were cleaned after 10, 15, 20, and 25 cycles. Lubricity is the average friction force of 25 cycles (averaged friction). Wear is calculated by subtracting the average friction of the last three cycles, minus the average friction of the first three cycles. Reported values are averaged for n samples. The results are shown in Table 6, below.

[0199] Table 6: Coating Lubricity and Wear

[0200]

[0201] Although lubricity of samples containing 10% UOSME decreases and wear increases, the coatings containing 10% UOSME still exhibit very good lubricity and wear properties.

[0202] Example 11

[0203] Antimicrobial studies On Prepared Hydrophilic Coating Formulations

[0204] Antimicrobial and bacterial viability studies were performed on samples prepared in accordance with Example 9. Antimicrobial activity is tested in accordance with the procedure of Example 5.2024P00025WC (34824-WO-PCT)

[0205] Table 7: Antimicrobial activity (net onset OD)

[0206]

[0207] While some antimicrobial activity is observed at 2% UOSME, very high antimicrobial activity is obtained with 5% and 10% UOSME coating solutions.

[0208] Example 12

[0209] Synthesis of UOSME-TDI-C12

[0210] Toluene-diisocyanate (10.6 g; 0.06 mol) and 500 ppm (39 mg) of Sn(Oct)2 (Tin(ll) 2-ethylhexanoate) were stirred in 80 mL of Chloroform for 30 minutes at room temperature under a nitrogen atmosphere. DEG-QAC-C12 (Example 1) (25 g; 0.06 mol) was added slowly over a period of 30 minutes. After stirring for 3 h, polyTHFIOOO (36.5 g; 0.04 mol) was slowly added dropwise over a period of 30 minutes. After stirring overnight at 60 °C in an oil bath, ATIR analysis indicates a full conversion. The mixture was concentrated in vacuo at 60 °C. The material was discharged as a solid at room temperature. 80.8 grams (109% yield).

[0211] Example 13

[0212] Synthesis of C16 Quat end group (DEG-QAC-C16)

[0213] N-(2-(2-hydroxyethoxy)ethyl)-N,N-hexadecan-1 -ammonium chloride is synthesized as follows. Chloroethoxyethanol (21.0 g; 0.17 mol) was added dropwise to a solution of N,N-dimethyl-hexadecan-1 -amine 1 (35 g; 0.15 mol) in 1 -butanol (45 mL) at 70 °C under a nitrogen atmosphere. After stirring overnight at 110 °C in an oil bath, the mixture was concentrated in vacuo at 60 °C. The crude product was obtained as a brownish oil, which was dissolved in a mixture of 700 mL of warm acetone and 50ml of warm butanol (60 °C) in a rotary evaporator. Upon cooling and standing overnight at 4 °C, off-white crystals were formed and collected by filtration. Re-crystallization of this product from a mixture of 330 mL2024P00025WQ (34824-WO-PCT)

[0214] acetone / THF (8 / 3, v / v) and 20 mL butanol yielded 29.6 g (24%) of the pure product as white crystals.

[0215] 1H NMR: (100 MHz, CDCI3) 6 4.82 (t, 1H, OH), 4.00 (m, 2H, OCH2CH2OH), 3.82 (m, 2H, OCH2CH2N), 3.69, (m, 2H, NCH2OH) 3.63 (m, 2H, NCH2CH2O), 3.54 (m, 2H, CH2CH2CH2N), 3.30 (s, 6H, N(CH3)), 1.69 (m, 2H, CH2CH2CH2N), 1.39-1.13 (m, 26H, CH2CH2CH2), 0.83 (t, 3H, CH2CH2CH3).

[0216] 13C NMR: (400 MHz, CDCI3) 0 72.99 (OCH2CH2OH, 1C), 65.87 (NCH2CH2O, 1C), 64.83 (NCH2CH2O, 1C), 63.45 (NCH2CH2, 1C), 61.01 (CH2OH, 1C), 51.78 ((N(CH3)2, 2C), 31.90 (NCH2CH2, 1C), 29.51 (CH2CH2CH2, 10H), 26.29 (CH2CH2CH2CH3, 1C), 22.90 (CH2CH2CH3, 2C), 14.12 (CH3, 1C).

[0217] Example 14

[0218] Synthesis of Synthesis of UOSME-TDI-C16

[0219] Toluene-diisocyanate (10.6 g; 0.06 mol) and 500 ppm (32 mg) of Sn(Oct)2(Tin(ll) 2-ethylhexanoate) were stirred in 90 mL of Chloroform for 30 minutes at room temperature under a nitrogen atmosphere. DEG-QAC-C16 (24.1 g; 0.06 mol) was added slowly over a period of 30 minutes. After stirring for 3h, polyTHF OO (30.1 g; 0.03 mol) was slowly added dropwise over a period of 30 minutes. After stirring overnight at 60 °C in an oil bath, ATIR analysis indicates a full conversion. The mixture was concentrated in vacuo at 60 °C. The material was discharged as a solid at room temperature 66.0 grams (102% yield).

[0220] 1H NMR: (100 MHz, DMSO-D6) 59.80-9.34 (m, 1H, NH), 8.99-8.56 (m, 1H, NH), 7.48 (m, 1H, CHCHCH 7.12 (m, 2H, CHCHCH), 7.00 (m, 2H, CHCHCH), 4.17 (m, 4H, OCH2CH2OCO), 4.01 (m, 3H, NCH2CH2O), 3.82 (m, 4H, OCH2CH2OCO), 3.65 (m, 4H, NCH2CH2O), 3.49 (m, 4H, NCH2CH2CH2), 3.39-3.07 (m, 85H, OCH2CH2CH2CH2O, moisture of DMSO-D6), 2.46 (s, 12H, N(CH3)), 2.08 (m, 6H, CH3CH), 1.71-1.28 (m, 56H, OCH2CH2CH2CH2O, CH2CH2CH2), 1.28-1.02 (m, 55H, CH2CH2CH2), 0.83 (m, 6H, CH2CH2CH3).

[0221] 13C NMR: (400 MHz, CDCI3) 6 153.76, 137.19, 135.86, 130.03, 124.33, 115.2469.86, 65.36, 64.62, 62.77, 51.08, 31.63, 29.08, 26.61 , 22.39, 17.05, 13.88.

[0222] AT-IR v (cm-1): 3010 (NH), 2927 (CH2 / CH3-stretching), 2857 (CH2 / CH3-stretching), 1719 (C=O), 1532 (N-H), 1216 (C-N), 1103 (C-O)

[0223] GPC: Mw: 14.4 kDA, Mn: 8.8 kDA, Mz: 6.1 kDa using GPC with PMMA as standard.2024P00025WG (34824-WO-PCT)

[0224] Example 15

[0225] Formation of Coatings containing UOSME-TDI-C12 and UOSME-TDI-C16 12.7 mm titanium (6AI4VAMS 4298 Grade 5) discs that were washed in hexane and ethanol were dip coated in dsm-firmenich ComfortCoat® Primer 41006 at 10 mm / s and UV cured for 15 min. The discs were then coated with 10 wt% of UOSME-TDI-C12 or UOSME-TDI-C16 in THF by dispensing dropwise on the top of the coated discs. The samples were then air dried at 40 °C with ventilation.

[0226] Example 16

[0227] Antimicrobial studies of Coatings from Example 15

[0228] All bacterial stocks were stored in 20% glycerol at -80 °C. Overnight axenic cultures were prepared of bacterial strains S. aureus (ATCC25923) on blood agar plates (Thermo Scientific, R01217) at 37 °C. From this axenic culture, 2-3 colonies were cultured (18-20 h, 37 °C, 200 rpm) in 5 ml_ Mueller Hinton broth (MHB; BD, 211443). The suspension was diluted to the target inoculum concentration using optical density (OD) measurements at 600 nm. The target inoculum was serially diluted, and 100 pL aliquots were plated in duplicate on blood agar plates to quantify the exact colony-forming units (CFU) / mL.

[0229] A biofilm proliferation assay was performed to investigate the antibacterial properties of the UOSME coatings on titanium discs as compared to uncoated discs. Bacterial adhesion was investigated. The test inoculum with a concentration of 106CFU / mL was prepared by diluting the bacterial culture in MHB. The test discs were aseptically placed in 24-well sterile polystyrene tissue culture plates. All discs were inoculated with 1 mL of the test inoculum and were incubated for 4 h at 37 °C in a humid environment. After 4 h, the discs were rinsed with PBS and incubated in 2 mL MHB in 12-well sterile culture plates for 24 h at 37 °C in a humid environment. After 24 h, the discs were rinsed with PBS and placed in 2 mL PBS, and the bacteria were detached from the discs following 5 min of sonication in a sonication bath. The viable bacteria retrieved from each sample were quantified by making a serial dilution of the sonicate and plating out 100 pL aliquots of the serial dilution on blood agar plates. After 24 h incubation of the blood agar plates at 37 °C, the CFUs were counted.

[0230] Results are given in Table 8.2024P00025WG (34824-WO-PCT)

[0231] Table 8: Bacterial Challenge

[0232]

[0233] Substantial reduction of bacteria is observed with both UOSME-TDI-12 and UOSME-TDI-16. An even greater reduction is exhibited by UOSME-TDI-16.

[0234] Example 17

[0235] Synthesis of UOSME-LDI-C16

[0236] Ethyl ester L-Lysine-diisocyanate (8.6 g; 0.04 mol) and 500 ppm (20 mg) of Sn(Oct)2(Tin(ll) 2-ethylhexanoate) were stirred in 60 mL of Chloroform for 30 minutes at room temperature under a nitrogen atmosphere. DEG-QAC-C16 (14.9 g; 0.04 mol) was added slowly over a period of 30 minutes. After stirring for 3h, polyTHF1000 (18.6 g; 0.02 mol) was slowly added dropwise over a period of 30 minutes. After stirring overnight at 60 °C in an oil bath, ATIR analysis indicates a full conversion. The mixture was concentrated in vacuo at 60 °C. The material was discharged as a solid at room temperature. 47.9 grams (113% crude yield). 1H NMR: (100 MHz, DMSO-D6) 57.63 (m, 1H, NH), 7.44 (m, 1H, NH), 7.18 (m, 1H, NH), 7.99 (m, 1H, NH), 4.14-3.95 (m, 8H, OCH2CH3, OCH2CH2OCO), 3.90-3.75, (m, 4H, HNCH), 3.66-3.43 (m, 8H, NCH2CH2CH2CHN), 3.42-3.12 (m, 68H, NCH2CH2O, NCH2CH2O, OCH2CH2O, OCH2CH2CH2CH2O), 3.06 (s, 12H, N(CH3)), 2.90 (m, 4H, NCH2CH2CH2), 1.74-1.38 (m, 60H, OCH2CH2CH2CH2O, CH2CH2CH2), 1.38-1.10 (m, 72H, CH2CH2CH2, OCH2CH3), 0.80 (m, 6H, CH2CH2CH3).

[0237] 13C NMR: (400 MHz, CDCI3) 5 172.61 , 156.16, 70.70, 65.54, 64.80, 63.24, 61.10, 52.05, 32.84, 30.02, 26.84, 22.91, 14.25.

[0238] AT-IR v (cm-1): 3007 (NH), 2929 (CH2 / CH3-stretching), 2861 (CH2 / CH3-stretching), 1717 (C=O), 1523 (N-H), 1222 (C-N), 1108 (C-O)

[0239] GPC: Mw: 18.7 kDA, Mn: 9.4 kDA, Mz: 6.3 kDa using GPC with PMMAas standard.

[0240] The higher molecular weights can be attributed to conducting the reaction in chloroform. It is expected that a commercial process will result in more controlled molecular weight.

[0241] Molecular weight measured with GPC will measure higher than with triple detection due to the structure and charge of the antimicrobial oligomer. It is expected that triple detection will measure molecular weight of the antimicrobial oligomer more accurately.2024P00025WO (34824- WO-PCT)

[0242]

[0243] Embodiments

[0244] 1) An antimicrobial oligomer having the formula C-[E3-A]m-B-C, wherein

[0245] (a) A is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol having from two to fifty repeating units;

[0246] (b) B is the residue of a diisocyanate;

[0247] (c) C is the residue of a hydroxyl-functional quaternary ammonium salt; and

[0248] (d) m is from 1 to 10.

[0249] 2) An antimicrobial oligomer according to the following chemical formula:

[0250]

[0251] wherein

[0252] Ri is - [(CH2)4O]n- or -[CH(CH3)-(CH2)3-O-]n- wherein n is from 2 to 50;

[0253] R2is (C2-Ci6)alkylene, cycloalkylene, arylene, substituted arylene, aryl-containing divalent groups, or a lysine residue;

[0254] R3 is - [(CH2)2O]q- wherein q is from 1 to 8;

[0255] R4 is (C1-C20) alkyl; and

[0256] m is from 1 to 10.

[0257] 3) The antimicrobial oligomer according to the previous exemplary embodiment, wherein the polytetrahydrofuran diol or polymethyl tetrahydrofuran diol has from 2 to 15 repeating units.

[0258] 4) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein A is the residue of HO-[(CH2)4O]n-H or HO-[CH(CH3)-(CH2)3-O-]n- H, wherein n is from 2 to 5.

[0259] 5) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein the number of repeating units of the polytetrahydrofuran diol or polymethyl tetrahydrofuran diol is from 2 to 30, 2 to 25, 2 to 20, or 2 to 15.

[0260] 6) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein the number of repeating units of the polytetrahydrofuran diol or polymethyl tetrahydrofuran diol is from 4 to 30, 4 to 25, 4 to 20, or 4 to 15.2024P00025WO (34824-WO-PCT)

[0261] 7) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein n is from 2 to 30, 2 to 25, 2 to 20, 2 to 15, 4 to 30, 4 to 25, 4 to 20, or 4 to 15.

[0262] 8) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein B is the residue of a an aliphatic diisocyanate, a cycloaliphatic diisocyanate, or an aromatic diisocyanate.

[0263] 9) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein B is the residue of an aliphatic or cycloaliphatic diisocyanate, preferably an aliphatic diisocyanate.

[0264] 10) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein B is the residue of a hexane diisocyanate (HDI), butane diisocyanate, cyclohexane-1 ,4-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate (HMDI), isophorone diisocyanate (I PDI); 4,4'-diphenylmethane diisocyanate (MDI), 2,4- toluene diisocyanate, 2,6-toluene diisocyanate, 1,4-phenylene diisocyanate, a lysine diisocyanate, or a mixture thereof.

[0265] 11 ) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein B is the residue of a toluene diisocyanate.

[0266] 12) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein B is the residue of hexane diisocyanate (HDI), butane diisocyanate, or a mixture thereof.

[0267] 13) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein B is the residue of an aliphatic diisocyanate.

[0268] 14) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein B is the residue of a lysine diisocyanate.

[0269] 15) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein B is the residue of a lysine ester diisocyanate.

[0270] 16) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R2 is (C2-Cis)alkyl, cycloalkylene, isophorone, or a lysine ester.2024P00025WO (34824-WO-PCT)

[0271] 17) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R2is hexane, butane, cyclohexane, dicyclohexane, or dicyclohexyl methane.

[0272] 18) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R2is -C6H4-CH2-C6H4-, -CeHs CHs)-, or -C6H4-.

[0273] 19) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R4is (Ci-Ci2) alkyl.

[0274] 20) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R4is (C1-C16) alkyl.

[0275] 21) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R4is (C8-C20) alkyl.

[0276] 22) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R4is (Cio-Ci8) alkyl.

[0277] 23) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R1 is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol, R2is hexane, R3 is the residue of diethyleneglycol, and R4 is (Ci- 012) alkyl.

[0278] 24) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R1 is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol, R3 is the residue of diethyleneglycol, and / or R4 is (Ci-Cis) alkyl.

[0279] 25) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein R1 is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol, R2is -C6H3(CH3)-, R3 is the residue of diethyleneglycol, and R4is (C10-C18) alkyl.

[0280] 26) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein the antimicrobial oligomer that is an adduct of poly(tetrahydrofuran) diol reacted with hexane diisocyanate (HDI) and terminated with N- (2-(2-hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1 -ammonium chloride (HEDDA).2024P00025WQ (34824-WO-PCT)

[0281] 27) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein the antimicrobial oligomer that is an adduct of poly(tetrahydrofuran) diol reacted with a toluene diisocyanate (TDI) and terminated with N-(2-(2-hydroxyethoxy)ethyl)-N,N-dimethyldodecan-1 -ammonium chloride (HEDDA).

[0282] 28) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein the antimicrobial oligomer that is an adduct of poly(tetrahydrofuran) diol reacted with a toluene diisocyanate (TDI) and terminated with N-(2-(2-hydroxyethoxy)ethyl)-N,N-dimethylhexadecan-1 -ammonium chloride.

[0283] 29) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein the poly(tetrahydrofuran) diol has from 2 to 15 repeating units.

[0284] 30) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein the antimicrobial oligomer has a number average molecular weight (Mn) of from 600 to 6500 g / mol, preferably from 1000 to 5000 g / mol.

[0285] 31) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein the antimicrobial oligomer has a number average molecular weight (Mn) of at least 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 g / mol.

[0286] 32) The antimicrobial oligomer according to any one of the preceding exemplary embodiments, wherein the antimicrobial oligomer has a number average molecular weight (Mn) of at most 6500, 6000, 5800, 5600, 5400, 5200, 5000, 4800, 4600, 4400, 4200, 4000, 3800, 3600, 3400, 3200, 3000, 2800, 2600, or 2500.

[0287] 33) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein m is 1.

[0288] 34) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein m is from 1 to 5.

[0289] 35) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein m is from 1 to 3.

[0290] 36) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein m is at most 10, 9, 8, 7, 6, 5, 4, 3 or 2.2024P00025WO (34824-WO-PCT)

[0291] 37) The antimicrobial oligomer according to any one of the previous exemplary embodiments, wherein the antimicrobial oligomer is telechelic.

[0292] 38) A coating composition comprising the antimicrobial oligomer according to any one of the preceding exemplary embodiments, a hydrophilic compound, and a solvent.

[0293] 39) A coating composition comprising the antimicrobial oligomer according to any one of the preceding exemplary embodiments, a hydrophilic compound, a polymerizable compound, and a solvent.

[0294] 40) A composition comprising the antimicrobial oligomer according to any one of the preceding exemplary embodiments and a thermoplastic polymer, wherein the thermoplastic polymer comprises a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, or a mixture thereof.

[0295] 41) A method of forming an antimicrobial surface on a medical device comprising the steps of:

[0296] (a) optionally, plasma treating a surface of a medical device,

[0297] (b) dip coating or spray coating a coating composition on the surface of the medical device, the coating composition comprising the antimicrobial oligomer according to any one of the preceding exemplary embodiments and a solvent,

[0298] (c) evaporating the solvent and / or applying electromagnetic radiation.

[0299] 42) A method of forming an antimicrobial surface on a medical device comprising the steps of:

[0300] (a) providing a coating composition comprising a solution of the antimicrobial oligomer any one of the preceding exemplary embodiments and a thermoplastic polymer comprising a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, or a mixture thereof in a solvent,

[0301] (b) coating the solution onto a substrate, and

[0302] (c) curing the coating by evaporating the solvent.

[0303] 43) A medical device comprising a coating, the coating comprising the antimicrobial oligomer according to any one of the preceding exemplary embodiments.2024P00025WO (34824-WO-PCT)

[0304] 44) A medical device comprising the antimicrobial oligomer according to any one of the preceding exemplary embodiments.

[0305] 45) A medical device comprising a thermoplastic polymer and the antimicrobial oligomer according to any one of the preceding exemplary embodiments.

Claims

2024P00025WQ (34824- WO-PCT)CLAIMS1 . An antimicrobial oligomer having the formula C-[B-A]m-B-C, wherein(a) A is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol having from two to fifty repeating units;(b) B is the residue of a diisocyanate;(c) C is the residue of a hydroxyl-functional quaternary ammonium salt; and(d) m is from 1 to 10.

2. The antimicrobial oligomer according to claim 1 , wherein the polytetrahydrofuran diol or polymethyl tetrahydrofuran diol has from 2 to 15 repeating units.

3. The antimicrobial oligomer according to any one of the preceding claims, wherein B is the residue of an aliphatic diisocyanate.

4. The antimicrobial oligomer according to any one of the preceding claims, wherein B is the residue of a lysine diisocyanate.

5. An antimicrobial oligomer according to the following chemical formula:whereinRi is - [(CH2)4O]n- or -[CH(CH3)-(CH2)3-O-]n- wherein n is from 2 to 50;R2 is (C2-Ci6)alkylene, cycloalkylene, arylene, substituted arylene, aryl-containing divalent groups, or a lysine residue;R3 is - [(CH2)2O]q- wherein q is from 1 to 8;R4is (C1-C20) alkyl; andm is from 1 to 10.

6. The antimicrobial oligomer according to claim 5, wherein R2 is (C2-Ci6)alkylene, cycloalkylene, isophorone, or a lysine ester.

7. The antimicrobial oligomer according to claim 5, wherein R2is hexane, butane, cyclohexane, dicyclohexane, or dicyclohexyl methane.2024P00025WO (34824-WO-PCT)8. The antimicrobial oligomer according to claim 5, wherein R2is -C6H4-CH2-C6H4-, - C6H3(CH3)- or-C6H4-.

9. The antimicrobial oligomer according to any one of claims 5-8, wherein R4 is (C8-C20) alkyl.

10. The antimicrobial oligomer according to claim 5, wherein R1 is the residue of a polytetrahydrofuran diol or a polymethyl tetrahydrofuran diol, R3is the residue of diethyleneglycol, and R4 is (Ci-Cie) alkyl.

11. The antimicrobial oligomer according to claim 10, wherein the poly(tetrahydrofuran) diol has from 2 to 15 repeating units.

12. The antimicrobial oligomer according to any one of the preceding claims, wherein m is from 1 to 5.

13. The antimicrobial oligomer according to any one of the preceding claims, wherein m is 1.

14. The antimicrobial oligomer according to any one of the preceding claims, wherein the antimicrobial oligomer has a number average molecular weight (Mn) of from 1000 to 5000 g / mol.

15. A coating composition comprising the antimicrobial oligomer according to any one of claims 1-14, a hydrophilic polymerizable compound, and a solvent.

16. A composition comprising the antimicrobial oligomer according to any one of claims 1-14 and a thermoplastic polymer, wherein the thermoplastic polymer comprises a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, or a mixture thereof.

17. A method of forming an antimicrobial surface on a medical device comprising the steps of:(a) optionally, plasma treating a surface of a medical device,(b) dip coating or spray coating a coating composition on the surface of the medical device, the coating composition comprising the antimicrobial oligomer according to any one of claims 1-14 and a solvent,(c) evaporating the solvent and / or applying electromagnetic radiation.2024P00025WO (34824-WO-PCT)18. The method of claim 17, wherein the coating composition further comprises (i) a hydrophilic compound and a polymerizable compound, or (ii) a hydrophilic polymerizable compound.

19. A method of forming an antimicrobial surface on a medical device comprising the steps of:(a) providing a coating composition comprising a solution of the antimicrobial oligomer according to any one of claims 1-14 and a thermoplastic polymer comprising a polyurethane, polyamide, polyester, polycarbonate, polyurea, polyesteramide, polylactide, polycaprolactone, polyethylene, or a mixture thereof in a solvent, (b) coating the solution onto a substrate, and(c) curing the coating by evaporating the solvent.

20. A medical device comprising a coating, the coating comprising the antimicrobial oligomer according to any one of claims 1-14.

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