Antibacterial coating and use thereof on medical device

Abstract

The present invention relates to an antibacterial coating. The coating comprises at least one photocurable antibacterial polymer, at least one polyurethane, and a solvent. The photocurable antibacterial polymer is formed by polymerization of a component comprising a polymerizable photosensitive monomer and a polymerizable cationic guanidine salt monomer. The antibacterial coating of the present invention has good long-term antibacterial performance and excellent biosafety, has a small thickness, does not affect the structure of an original substrate, has good flexibility, and is especially suitable for a medical device.

Description

An antibacterial coating and its application in medical devices Technical Field

[0001] This invention relates to the field of polymer coating technology, specifically to an antibacterial coating and its application in medical devices. Background Technology

[0002] Healthcare-associated infections (HAIs) caused by bacterial adhesion during the use of medical devices remain a significant problem. The surfaces of medical devices easily become breeding grounds for pathogenic microorganisms, which, once formed into biofilms, are even more difficult to remove, leading to an increased risk of infection. This is especially true for long-term implantable or contact-with-body-fluid medical devices (such as cardiac stents, artificial joints, urinary catheters, ureteral stents, and intravenous catheters). Such infections not only affect the lifespan of the devices but can also seriously endanger patient lives. Therefore, developing antimicrobial coatings for medical devices that can effectively inhibit bacterial adhesion and reproduction, especially those with long-lasting antimicrobial properties, has become a research hotspot in this field.

[0003] Existing antibacterial coating technologies mainly include drug-release coatings, physical adsorption coatings, and composite antibacterial coatings. Their primary antibacterial mechanism typically relies on the release of antibacterial drugs (such as antibiotics, silver ions, or other active substances). However, this mechanism still has several problems. For example, while the initial antibacterial effect of the coating is good, the long-term antibacterial performance is difficult to guarantee due to the gradually decreasing release rate. Furthermore, long-term use of drug-release coatings may lead to bacterial resistance, not only reducing the antibacterial effect but also potentially exacerbating bacterial resistance, posing additional risks to patient treatment. Simultaneously, the release of high concentrations of antibacterial agents may have toxic effects on surrounding normal tissue cells, raising certain biosafety concerns.

[0004] Another prominent problem with existing technologies is the insufficient adhesion of many antibacterial coatings to the surfaces of medical devices, especially in vivo or high-humidity environments. These coatings are prone to peeling or decomposition, significantly reducing their antibacterial efficacy and application reliability. The substrates of existing medical devices are diverse, encompassing various materials such as metals, plastics, ceramics, glass, and rubber. Therefore, it is difficult for a single antibacterial coating to be universally compatible with all substrates. Ensuring the robust compatibility between antibacterial coatings and various polymeric substrates of medical devices, while guaranteeing that the coating does not affect the mechanical properties of the device surface, such as hardness, toughness, ductility, and flexural strength, remains a pressing issue. Furthermore, while some antibacterial coatings can achieve high performance (such as nanomaterial coatings), their production processes can be complex, involving multi-layer processing and intricate techniques, resulting in high costs. This limits their widespread clinical application.

[0005] CN117442787A discloses a lubricating antibacterial drug-loaded coating for medical catheters, its preparation method, and its application. Specifically, a ternary polymer containing a hydrophilic monomer, a guanidine-containing monomer, and a photosensitive monomer is synthesized, followed by drug loading via a Schiff base reaction to obtain a drug-loaded polymer. This drug-loaded polymer is then coated onto a polymer substrate to prepare a UV-curable lubricating antibacterial drug-loaded coating. However, its antibacterial mechanism still relies on the release of the antibacterial drug, and its suitable application is mainly with polymer substrates; it is not applicable to metallic or high-surface-energy substrates. Furthermore, its thickness is relatively thick, ranging from 20-30 μm. Summary of the Invention

[0006] The problem the invention aims to solve

[0007] To address the aforementioned problems in existing technologies, this invention combines a cationic guanidine salt antibacterial copolymer with hydrophilic polyurethane to form a coating composition, and then uses photocuring technology to prepare an antibacterial coating. This not only overcomes the problem of weak adhesion in existing antibacterial coatings but also provides long-term antibacterial performance and excellent biocompatibility, offering a novel technical solution for the development of antibacterial coating technology for medical devices. Furthermore, the antibacterial coating of this invention can be widely applied in various scenarios requiring antibacterial properties, such as in the civilian sector.

[0008] Solution for solving the problem

[0009] To address the aforementioned problems, this invention provides an antibacterial coating.

[0010] It includes: at least one photocurable antimicrobial polymer, at least one polyurethane, and a solvent, wherein the photocurable antimicrobial polymer is polymerized from a component comprising a polymerizable photosensitive monomer and a polymerizable cationic guanidine salt monomer.

[0011] Further, the mass ratio of the polyurethane to the photocurable antibacterial polymer is (2-20):1; preferably (5-10):1.

[0012] Furthermore, the polymerizable cationic guanidine salt monomer structure includes:

[0013] P-part: The polymer structural part containing a guanidine group, and,

[0014] Q part: It is a structural part that is bonded to the P part and contains unsaturated groups.

[0015] The P portion originates from the polymerization of guanidine compounds and diamine compounds.

[0016] Furthermore, the polymerizable cationic guanidine salt monomer has the structure shown in general formulas (I) to (VI) or its hydrochloride salt form:

[0017] Wherein, X is a linking group selected from alkyl or alkoxy structures containing C1-C6; A contains unsaturated bond groups; and n is selected from integers from 8 to 15.

[0018] Furthermore, A is preferably selected from at least one of an acrylate structure, an acrylamide structure, or a maleamide structure.

[0019] Furthermore, the polymerizable cationic guanidine salt monomer has the structure shown in general formula (VII) or general formula (VIII) or its hydrochloride salt form:

[0020] Where n is an integer selected from 8 to 15, and m is an integer selected from 2 to 6.

[0021] Furthermore, the polymerizable photosensitive monomer is selected from Norrish type I photosensitive monomers and / or Norrish type II photosensitive monomers; the molar concentration of the polymerizable photosensitive monomer in the photocurable antibacterial polymer is 1-5%.

[0022] Further, the polyurethane is selected from hydrophilic polyurethane, and optionally, the polyurethane has polymerizable groups; the polymerizable photosensitive monomer is selected from water-soluble photosensitive monomer.

[0023] Furthermore, the hydrophilic polyurethane is selected from at least one of waterborne cationic polyurethane, waterborne anionic polyurethane, and waterborne nonionic polyurethane; the molecular weight of the hydrophilic polyurethane is 2000-30000.

[0024] The present invention also provides a medical device with an antibacterial coating, comprising:

[0025] The device body and an antibacterial coating formed on the surface of the body, the antibacterial coating being formed by photocuring of any of the above-described antibacterial coatings and covalently bonded to the surface.

[0026] Furthermore, the thickness of the antibacterial coating is 1μm ≤ thickness < 20μm.

[0027] The effects of the invention

[0028] 1. This invention uses guanidine salt copolymer as the antibacterial functional component, combined with polyurethane as a compounding component, and covalently bonds them to the substrate surface through photocuring. This innovative technical solution effectively solves the problem of insufficient coating adhesion in existing antibacterial coating technologies, while maintaining excellent antibacterial performance and biocompatibility, making it particularly suitable for the medical device field.

[0029] 2. The antibacterial coating of the present invention uses guanidine cationic groups, which can interact with negatively charged bacterial cells, destroy the structure of the bacterial cell membrane, inhibit the integrity of the cell membrane, and thus lead to the death of bacteria. It does not cause drug resistance problems, can be used for a long time, and is especially suitable for the medical device field.

[0030] 3. The guanidine substances in the antibacterial coating of the present invention form a macromolecular polymer of guanidine salt by copolymerization with photosensitive monomers. The macromolecular polymer can be firmly bound to the surface of the substrate through photosensitive group covalent bonds, and at the same time, a cross-linked structure is formed inside the coating. Unlike the traditional antibacterial drug release mechanism, there will be no problem of small molecule precipitation, which is safe for human body.

[0031] 4. The polyurethane in the antibacterial coating of the present invention, as a compound component, is adaptable to various substrates, avoiding complex surface treatment of the substrate. It not only enhances the mechanical properties and adhesion stability of the coating, but also, by controlling its content ratio in the coating composition, achieves coating firmness while efficiently maintaining the mechanical properties of the device's surface, such as hardness, toughness, ductility, and flexural strength.

[0032] 5. The hydrophilic polyurethane in the antibacterial coating of the present invention is used as a compound component, and the photosensitive monomer in the photocurable antibacterial polymer is selected from hydrophilic photosensitive monomers, which can form a water-soluble photocurable system. When used as a medical antibacterial coating for medical device applications, it can effectively reduce the use of organic solvents and reduce environmental pollution. At the same time, since water is used as a diluent, it is easier to adjust the viscosity of the prepolymer and will not cause skin irritation.

[0033] 6. The antibacterial coating of the present invention has a small coating thickness after curing, making it particularly suitable for precision and miniature medical devices. Attached Figure Description

[0034] Figures 1 and 2: Microscopic images after the coating staining and friction test. Detailed Implementation

[0035] To better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art will understand that the present invention can be practiced without certain specific details. In other instances, methods, means, apparatus, and steps well known to those skilled in the art have not been described in detail in order to highlight the spirit of the present invention.

[0036] Unless otherwise defined, the technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0037] In this specification, the range of values ​​referred to as "value A to value B" refers to the range including the endpoint values ​​A and B.

[0038] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0039] It should be understood that the singular form of the article “a” (corresponding to the English words “a”, “an”, and “the”) used in this application specification and appended claims includes plural objects, unless otherwise expressly stated in the text.

[0040] In this specification, references to "one or more specific / preferred embodiments / solutions," "another or more specific / preferred embodiments / solutions," "one or another embodiment / solution," "one or another technical solution," etc., refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to that embodiment, which are included in at least one embodiment described herein and may or may not exist in other embodiments. Furthermore, it should be understood that these elements can be combined in any suitable manner in various embodiments.

[0041] The term "comprising" and any variations thereof in the specification and claims of this invention are intended to cover a non-exclusive inclusion. For example, a process, method, system, product, or apparatus that comprises a series of steps or units is not limited to the steps or units listed, but may optionally include steps or units not listed, or may optionally include other steps or units inherent to such processes, methods, products, or apparatus.

[0042] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of the invention, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified. In the description of the present invention, "several" means at least one, such as one, two, etc., unless otherwise explicitly specified.

[0043] The materials used in this invention are not particularly limited in their source; they can be purchased from the market or prepared according to conventional methods known to those skilled in the art.

[0044] There are no particular restrictions on the purity or standards of any of the raw materials used in this invention. However, this invention preferably uses materials with conventional purity or medical purity levels suitable for the medical device field.

[0045] In this invention specification, the term "-substituent" in the structural formula indicates that the substituent can be located at any position within the group.

[0046] In this specification, the polymerizable photosensitive monomer is based on the applicant's prior Chinese patents (CN201810580272.1, CN201810507164.1, CN201810934611.1, CN201910107696.0, CN201910107797.8), the disclosure of which is incorporated herein by reference in its entirety.

[0047] In this invention, the solvent comprises one or more of water, low molecular weight alcohols (methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, propylene glycol, glycerol, etc.), N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetone, and phenol. Preferably, the solvent is a single or mixed solvent capable of dissolving the polymer of this invention to form a homogeneous solution. Preferably, the solvent is a mixture of water and isopropanol. Further, to promote rapid coating formation of the polymer, the isopropanol content in the solvent is suitably in the range of 15-70% of the total solvent weight, more preferably 20-60%, and even more preferably 30-50%. The mass fraction of the solvent in the coating composition ranges from 60% to 99.9%, preferably 90-99%.

[0048] The coating composition of this invention may also include additives as needed. These additives include one or more of the following: leveling agents, defoamers, film-forming aids, viscosity modifiers, pigments, antibacterial agents, colorants, surfactants, pH adjusters, buffer solutions, preservatives, etc., to optimize and adjust the coating base liquid.

[0049] The present invention specifically provides an antibacterial coating comprising at least one photocurable antibacterial polymer, at least one polyurethane, and a solvent, wherein the photocurable antibacterial polymer is polymerized from a component comprising a polymerizable photosensitive monomer and a polymerizable cationic guanidine salt monomer.

[0050] polymerization

[0051] The antibacterial polymer in this invention is prepared by free radical polymerization, including but not limited to ordinary free radical polymerization and living controlled free radical polymerization. Preferably, the photocurable antibacterial polymer is prepared by ordinary free radical polymerization. The photocurable antibacterial polymer is prepared in a certain medium, including but not limited to solution polymerization, emulsion polymerization, reverse emulsion polymerization, suspension polymerization, and bulk polymerization. From the perspective of ease of operation, it is preferred that the photocurable antibacterial polymer is completed by solution polymerization. From the perspective of environmental protection, it is more preferably that the photocurable antibacterial polymer is copolymerized in an aqueous solution. In one embodiment of this invention, a polymerizable photosensitive monomer and a polymerizable cationic guanidine salt monomer are dissolved in water, a free radical initiator is added to the system, oxygen is removed, and the reaction is carried out at a suitable temperature for free radical polymerization to obtain the antibacterial polymer of this invention.

[0052] Polymer monomer

[0053] <Polymerizable cationic guanidine salt monomers>

[0054] Polymerizable cationic guanidine salt monomers are monomers containing guanidine groups. These guanidine groups carry a positive charge, which can provide good antibacterial properties for coatings.

[0055] Guanidine antibacterial substances possess strong broad-spectrum antibacterial activity, inhibiting the growth of various bacteria, fungi, and viruses, particularly effective against Gram-negative bacteria (such as Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (such as Staphylococcus aureus). Guanidine antibacterial substances interact with negatively charged bacterial cells, disrupting the bacterial cell membrane structure and inhibiting its integrity, thus leading to bacterial death. Biguanide antibacterial substances can form multiple adsorption sites on various normally negatively charged bacteria and viruses, tightly encapsulating harmful microorganisms like a thin film. After encapsulating harmful microorganisms, phmblycine (Phmblycine monophosphate) can: ① denature or destroy the cell surface structure, inhibiting the division function of bacteria and viruses, rendering them infertile; ② the highly polymerized film blocks the respiratory channels of microorganisms, causing them to rapidly suffocate and die. Compared with quaternary ammonium salt antibacterial agents, guanidine salt antibacterial substances generally have a broader antibacterial spectrum, exhibiting good inhibitory effects against various Gram-positive bacteria, Gram-negative bacteria, and some fungi and viruses.

[0056] In some embodiments, the polymerizable cationic guanidine monomer of the present invention comprises:

[0057] Monomers containing guanidine groups, guanidine derivatives, biguanide groups, biguanide derivatives, polyaminopropyl biguanide groups, polyaminopropyl biguanide derivatives, poly(hexamethylene biguanide) groups, poly(hexamethylene biguanide) derivative groups, polyhexamethylene guanidine groups, polyhexamethylene guanidine derivatives, dichlorobenzyl biguanide hexyl groups, and dichlorobenzyl biguanide hexane derivative groups.

[0058] A subset of compounds having a guanidine group of the following general formula:

[0059] According to the present invention, R1, R2, R3 and R4 are independently selected from hydrogen, substituted or unsubstituted alkyl chains, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkoxy, amidine and amine.

[0060] A subset of compounds in which the biguanide group is a subunit of guanidine and has the following general formula:

[0061] According to the present invention, R1, R2, R3 and R4 are independently selected from hydrogen, substituted or unsubstituted alkyl chains, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkoxy, amidine and amine.

[0062] In some embodiments, the guanidine monomers include vinyl and methacrylic derivatives of the aforementioned guanidine or biguanidine groups.

[0063] In some embodiments, the polymerizable cationic guanidine salt monomer structure includes:

[0064] P portion: a polymer structural portion containing guanidine groups, and Q portion: a structural portion bonded to said P portion and containing unsaturated groups.

[0065] For the P part, it can be a polymer structure having multiple repeating units containing the aforementioned monoguanidine groups and biguanidine groups.

[0066] In some preferred embodiments, the P moiety is derived from the polymerization of a guanidine compound and a diamine compound. Examples include:

[0067] The P moiety is obtained by the condensation reaction of a salt of guanidine (iminomethyldiamine) with a diamine compound; or

[0068] The P moiety is obtained by the condensation reaction of cyanamide or dicyandiamide with a diamine compound.

[0069] For diamine compounds, compounds with two primary amino groups at the ends are preferred. Additionally, the diamine compound can be an alkylene diamine or a diamine having a polyalkylene ether unit in its structure.

[0070] For the Q part, it may have an unsaturated group derived from (meth)acryloyl or vinyl or maleic anhydride.

[0071] In some embodiments, the preferred polymerizable guanidine monomer is a compound containing a monoguanidine group, exemplary having the following structure or its corresponding hydrochloride salt form:

[0072] In some embodiments, the preferred polymerizable guanidine monomer is a compound containing a biguanide group, which is mainly obtained by reacting the biguanide group with a double-bonded monomer structure containing the desired linking group. Preferably, it can be obtained by reaction on the biguanide group (such as general formula I) or by reaction on the tertiary amine end group of the biguanide (such as general formula II).

[0073] Wherein, X is a linking group selected from alkyl or alkoxy structures comprising C1-C6, and optionally may further have an alkylimine structure; A contains an unsaturated bond group, preferably selected from at least one of (meth)acrylate, (meth)acrylamide, or maleimide structures.

[0074] Preferably, n is selected from an integer between 8 and 15.

[0075] For example, the polymerizable cationic guanidine salt monomer has the structure shown in general formula (VII) or general formula (VIII) or its hydrochloride salt form:

[0076] Where n is an integer selected from 8 to 15, and m is an integer selected from 2 to 6.

[0077] <polymerizable photosensitive monomer>

[0078] In this invention, the polymerizable photosensitive monomer is selected from Norrish type I photosensitive monomers and / or Norrish type II photosensitive monomers. Under UV or visible light irradiation, the photosensitive monomer can generate active free radicals, which can abstract hydrogen atoms or other unstable atoms from the polymer, thereby achieving polymerization and curing crosslinking. The unit containing the photosensitive structure does not contain functional groups that would significantly interfere with the cationic polymerization process and is capable of absorbing light in the wavelength range of approximately 100 to approximately 600 nanometers (nm).

[0079] The unsaturated bonds in the molecular structure of photosensitive monomers allow photosensitive units to be incorporated into the polymer backbone as repeating units via free radical polymerization. Units containing unsaturated bonds can be selected from those with (meth)acrylate groups. The presence of polymerizable groups overcomes the toxicity and high mobility issues of conventional small-molecule photoinitiators, enabling the photoinitiator to be anchored in the polymer network. Furthermore, copolymerization with other monomers can improve material properties while suppressing undesirable volatilization caused by residual small-molecule photoinitiators.

[0080] This invention discovers that the molar fraction of polymerizable photosensitive monomers in antibacterial polymers, i.e., copolymers, affects the lubricity and antibacterial properties of the resulting coating. If the molar fraction is too high, the content of the polymerizable cationic guanidine salt monomer is relatively reduced, resulting in a slight decrease in the antibacterial properties of the obtained antibacterial coating. Furthermore, an excessively high molar fraction of photosensitive monomers leads to excessive cross-linking of the coating in the later stages, increasing both the coating hardness and friction. Conversely, an excessively low molar fraction of photosensitive monomers affects the curing efficiency, leading to incomplete curing of the coating, and the friction of the coating increases rapidly with increasing cycle count. In this invention, the molar fraction of the polymerizable photosensitive monomer in the copolymer is 0.08–12%, preferably 0.1–10%, more preferably 0.5–8%, and even more preferably 1–5%, for example, 1%, 2%, 3%, 4%, and 5%. Using this specific molar composition yields the lowest friction, with friction hardly increasing with increasing cycle count, and no increase in friction even after more than 30 cycles.

[0081] In a preferred embodiment of the present invention, the molecular structure of the photosensitive monomer preferably contains a quaternary ammonium salt ion structure in addition to the photoinitiating unit (i.e., the unit of the photosensitive structure) and unsaturated bonds. This gives the photosensitive monomer both water solubility and polymerizability, resulting in good compatibility with waterborne resins and its own polymerization onto the resin's macromolecular chain, effectively overcoming the defect of small molecules easily migrating to the surface of the product. The presence of the quaternary ammonium salt can greatly improve water solubility and also provide a certain degree of antibacterial properties. The unit containing the quaternary ammonium salt structure includes a quaternary ammonium salt group, and may also contain several alkylene groups.

[0082] For example, the water-soluble photosensitizer has the following structure:

[0083] Wherein: R1 = CH3 or H; R2 and R3 are independently selected from straight-chain alkyl groups with 1 to 20 carbon atoms or branched alkyl groups with 3 to 20 carbon atoms; X is a halogen; n = 1-10; m = 1-4; f = 1-3; preferably, R2 and R3 are the same, X is bromine, n = 1, m = 1, f = 1; more preferably, R2 and R3 are both methyl or ethyl, X is bromine, n = 1, m = 1, f = 1. The selection of groups and molecular chain length in the general formula is mainly based on the requirements of product viscosity, initiation rate, and migration.

[0084] <Antibacterial Polymers>

[0085] In this invention, to reduce migration, the photocurable antimicrobial polymer preferably has a number-average molecular weight of at least 2000, preferably a relatively high molecular weight photocurable polymer, but preferably below 1.5 million for ease of coating application. This invention also finds that the molecular weight of the photocurable antimicrobial polymer, when combined with the polyurethane, affects the overall uniformity and lubricity of the coating. To obtain a coating with good uniformity and good lubricity even after multiple cycles, the number-average molecular weight of the photocurable antimicrobial polymer is preferably 0.5 to 1,000,000, more preferably 200,000 to 800,000, more preferably 500,000 to 600,000, and most preferably 100,000 to 500,000.

[0086] polyurethane

[0087] In this invention, polyurethane specifically refers to polyurethane with good biocompatibility, mechanical properties, flexibility, anti-infective properties, and resistance to chemicals and hydrolysis.

[0088] It can be selected from thermoplastic polyurethane (TPU), polyether polyurethane, polyester polyurethane, etc. In this invention, a biocompatible polyurethane is selected and compounded with a cationic guanidine salt copolymer to form an antibacterial coating. As part of the coating composition, polyurethane can significantly improve the adhesion and firmness between the coating and the tube body by enhancing the interfacial affinity with the polyurethane substrate of the tube, hydrogen bonding, and improving wettability.

[0089] In some preferred embodiments of the present invention, the polyurethane may further have polymerizable groups, such polymerizable groups being derived, for example, from acryloyl groups.

[0090] In a preferred embodiment of the invention, the polyurethane is selected from hydrophilic polyurethanes, such as aqueous cationic polyurethanes, aqueous anionic polyurethanes, and aqueous nonionic polyurethanes.

[0091] Regarding hydrophilicity, in some specific implementations, it can be introduced into the polyurethane structure through hydrophilic diols or hydrophilic chain extenders (chain extenders with carboxyl or sulfonic acid groups), so that the final polyurethane structure has a hydrophilic polyether structure, a hydrophilic group-modified polyester structure, etc.

[0092] Furthermore, the unsaturated groups can be introduced into the final polyurethane by reacting (meth)acrylates with active hydrogen with the remaining NCO groups in the polyurethane.

[0093] In some preferred embodiments of the present invention, the hydrophilic polyurethane may be selected from one or more of polyether polyurethane acrylate, polyurethane acrylate having a carboxyl group, and polyurethane acrylate having a sulfonic acid group.

[0094] Hydrophilic polyurethane can form a hydration film on its surface, which not only reduces direct contact with tissues, thus lowering the risk of immune responses and inflammation, but also effectively reduces the likelihood of thrombosis. This is especially important for medical devices such as catheters and vascular stents that are in prolonged contact with body fluids. Furthermore, the hydrophilic surface has a low coefficient of friction, making the device smoother when in contact with human tissue, reducing discomfort and tissue damage during insertion, thereby improving comfort and safety. In addition, hydrophilic polyurethane can inhibit bacterial adhesion to a certain extent, reducing the risk of infection, and can work synergistically with antibacterial polymers. This is crucial for medical devices implanted in the body for extended periods. The introduction of hydrophilic polyurethane in this invention, when compounded with an antibacterial polymer containing water-soluble photosensitive monomers, forms a water-soluble photocurable system. When used as a medical antibacterial coating for medical device applications, it effectively reduces the use of organic solvents, thus reducing environmental pollution. The hydrophilic polyurethane system of this invention can reduce the use of organic solvents by at least 50%, for example, by 55%; 60%; or 65%. Furthermore, since water is used as a diluent, the viscosity of the prepolymer is easier to adjust, and it does not cause skin irritation. It also further improves the aqueous dispersibility and stability of the coating, preventing cracking or peeling during the drying process.

[0095] In this invention, the molecular weight of the hydrophilic polyurethane is preferably 2000-30000, for example, it can be 3000, 4000, 5000, 8000, 10000, 12000, 15000, 18000, 20000, 25000, etc.

[0096] In a preferred embodiment of the present invention, the polyurethane is further selected from photocurable polyurethane. The photocurable polyurethane is compounded with a photocurable antibacterial polymer. Since both contain photosensitive groups, their cross-linking is further enhanced under light irradiation, which is more beneficial to the adhesion between the coating and the substrate, as well as within the coating itself.

[0097] Antibacterial coatings

[0098] In this invention, the mass ratio of the polyurethane to the photocurable antibacterial polymer is (2-20):1; preferably (5-10):1. Exemplary ratios include 20:1, 18:1, 15:1, 10:1, 8:1, 5:1, 2:1, etc. If the polyurethane ratio is too low, the coating's film-forming properties and adhesion will be poor. If the polyurethane ratio is too high, the coating's antibacterial performance will decrease, and the thickness will increase accordingly.

[0099] Solvent

[0100] The solvent used in this invention is suitable for any solvent that allows the antibacterial coating to be applied to the surface. Preferably, the solvent is one or a mixture of solvents capable of dissolving the aforementioned photocurable antibacterial polymer and polyurethane to form a homogeneous solution. Examples of solvents include one or more of water, low molecular weight alcohols (methanol, ethanol, isopropanol, butanol, pentanol, ethylene glycol, propylene glycol, glycerol, etc.), ethyl acetate, n-hexane, dichloromethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetone, diethyl ether, toluene, benzene, xylene, cyclohexane, and phenol. A mixture of water and isopropanol is preferred as a solvent suitable for dissolving and mixing formulations uniformly, and is low in cost and non-polluting. Preferably, the volume ratio of water to isopropanol is 1:10-10:1, which is suitable for dissolving and mixing formulations uniformly. More preferably, the volume ratio of water to isopropanol is 1:5-5:1, such as 1:3, 1:3, 1:2, 1:1, 1:0.8, 1:0.6, 1:0.4, etc.

[0101] In one embodiment of the invention, conventional non-aqueous polyurethane is used as the compound with the antibacterial polymer. Typically, a higher proportion of organic solvent is required; otherwise, it is difficult to dissolve and form a homogeneous solution during implementation.

[0102] In a preferred embodiment of the invention, a coating composition can be made by compounding waterborne polyurethane with an antibacterial polymer formed from a water-soluble photosensitive monomer. In this case, the organic solvent portion of the applicable solvent can be significantly reduced. This is extremely important for the medical industry.

[0103] In addition, lubricating additives, such as surfactants, waxes, lubricants, soaps, and detergents, can be added to the coating composition as needed. These lubricating additives do not increase the osmotic pressure concentration of the coating too much, but can increase lubricity during wetting and reduce adhesion; their low solubility in water helps them remain in the coating. Other additives may include supporting polymers, polyelectrolytes, wetting agents, leveling agents, defoamers, film-forming aids, thickeners, pigments, antibacterial agents, colorants, surfactants, etc. In specific embodiments of the present invention, the coating composition achieves good lubricity and adhesion without the addition of additional optional components other than the photocurable polymer, solvent, and optionally hydrophilic polymer.

[0104] Formation of antibacterial coating on instrument surface

[0105] In this invention, the antibacterial coating described herein is applied to a substrate, such as the surface of a medical device, using one or more methods including brushing, dipping, spraying, pouring, and scraping. The coating is then cured by light and covalently bonded to the surface of the medical device. This method can provide medical devices with excellent antibacterial properties, such as antibacterial central venous catheters, antibacterial urinary catheters, and antibacterial ureteral stents, thereby reducing the occurrence of infections within the body. In specific embodiments of this invention, the antibacterial coating exhibits significant antibacterial effects, long-lasting antibacterial efficacy, and coating adhesion.

[0106] It is important to clarify that medical device coatings need to possess extremely high durability, biocompatibility, and antibacterial properties because they not only need to be in prolonged contact with human tissue but also need to maintain stable function in complex biological environments. The antibacterial coating of this invention performs exceptionally well in medical devices, meaning it provides effective antibacterial protection and is not easily detached or decomposed during use. This gives it a certain degree of long-term stability and highly efficient antibacterial activity, characteristics that also facilitate its application in other civilian antibacterial fields.

[0107] Preferably, the coating composition of the present invention is applied by scraping or dipping; most preferably, the coating composition of the present invention is applied to the surface of a medical device by dipping to obtain a coating of relatively uniform thickness. The light source used in the curing process of the present invention includes any one of UV light source, visible light source, and infrared light source; preferably, the light source is a UV light source and a visible light source; more preferably, it is a UV light source. Preferably, the ultraviolet light intensity during curing is 5–25 mW / cm². 2 The curing time of the coating composition is 2 to 7 minutes, preferably 3 to 5 minutes. The thickness of the hydrophilic coating can be controlled by changing the soaking time, the traction rate, or the viscosity of the coating composition and the number of coating steps. In this invention, the thickness of the antibacterial coating on the surface of medical devices (e.g., central venous catheters) is ≥1 μm and <20 μm, most preferably in the range of 2 to 10 μm. When the coating thickness is less than 1 μm, the coating cannot achieve good water absorption and retention, resulting in poor water absorption and swelling effect, and failing to achieve good water absorption and lubrication effect and the desired antibacterial ability; however, when the coating thickness is greater than 20 μm, the coating curing is incomplete, which easily leads to poor coating gelation, resulting in reduced overall coating firmness. The cured polymer is easily released during use, causing residue and pollution, thus reducing the durability and safety of the coating.

[0108] instrument body

[0109] In this invention, there are no particular limitations on the shape and material of the medical device body; it can be any tube or stent material used in the art. The material used to prepare the tube body in this invention is selected from natural or synthetic polymers, metals, etc. Typically, it can be any one of latex, polyvinyl chloride (PVC), silicone rubber, polyurethane, nylon, PVC, Pebax, nickel-titanium alloy, etc. The medical device includes Class I, Class II, or Class III interventional polymer medical devices made of different materials, specifically such as urinary catheters, central venous catheters, ureteral stents, drainage tubes, etc.

[0110] Example Section

[0111] Referring to the above implementation content, in order to make the technical solution of this application more specific, clear and easy to understand, examples of the technical solution of this application are now given. However, it should be noted that the following examples are used to illustrate the present invention. Those skilled in the art can understand that the examples are merely exemplary and not exhaustive.

[0112] Preparation Example 1:

[0113] <Synthetic photocurable cationic guanidine salt antibacterial copolymer 1>

[0114] 15 g (6 mmol) of polymerizable guanidine monomer of general formula (VII), 0.15 g (0.3 mmol) of aryl ketone acrylate (Norrish type I photosensitive monomer), and 0.5% azobisisobutyronitrile (AIBN) by mass fraction were weighed and added to a 100 mL round-bottom flask. 50 mL of anhydrous ethanol was added, and the mixture was mechanically stirred to dissolve. The solution was deoxygenated by purging with N2 for 30 min. The reaction flask was then placed in a 65 °C oil bath and heated to initiate the reaction. After 6 h of reaction, the reaction solution was removed, cooled to room temperature, and precipitated in anhydrous diethyl ether. The precipitate was then dried in an oven at 35 °C in the dark for 36 h. The photocurable cationic guanidine salt copolymer was thus prepared, denoted as antibacterial copolymer 1.

[0115] Preparation Example 2:

[0116] <Synthetic photocurable cationic guanidine salt antibacterial copolymer 2>

[0117] 15 g (6 mmol) of polymerizable guanidine monomer of general formula (VIII), 0.38 g (0.5 mmol) of thioxanthone acrylate (Norrish type II photosensitive monomer), and 0.5% azobisisobutyronitrile (AIBN) by mass fraction of the total monomers were weighed and added to a 100 mL round-bottom flask. 50 mL of anhydrous ethanol was added, and the mixture was mechanically stirred to dissolve. The solution was deoxygenated by purging with N2 for 30 min. The reaction flask was then placed in a 65 °C oil bath and heated to initiate the reaction. After 6 h of reaction, the reaction solution was removed, cooled to room temperature, and precipitated in anhydrous diethyl ether. The precipitate was then dried in an oven at 35 °C in the dark for 36 h. The photocurable cationic guanidine salt copolymer was thus prepared, denoted as antibacterial copolymer 2.

[0118] Preparation Example 3:

[0119] <Synthetic photocurable cationic guanidine salt antibacterial copolymer 3>

[0120] Weigh 15 g (6 mmol) of polymerizable guanidine monomer of general formula (VII), 0.25 g (0.5 mmol) of water-soluble photosensitizing monomer as shown in the figure below, and 0.5% (w / w) of azobisisobutyronitrile (AIBN) into a 100 mL round-bottom flask. Add 50 mL of anhydrous ethanol and stir mechanically to dissolve. Purge the solution with N2 for 30 min to remove oxygen. Place the reaction flask in a 65 °C oil bath and heat to begin the reaction. After 6 h of reaction, remove the reaction solution and cool to room temperature. Precipitate the solution in anhydrous diethyl ether and dry the precipitate in an oven at 35 °C in the dark for 36 h. The photocurable cationic guanidine salt copolymer is thus prepared and is designated as antibacterial copolymer 3.

[0121] Example 1:

[0122] <Preparation and curing of antibacterial coating compositions 1-6>

[0123] Weigh 2g of the above-mentioned antibacterial copolymer 1 and polyethylene glycol-based waterborne polyurethane acrylate and dissolve them in 95g of a mixed solvent of deionized water / isopropanol (1:9 v / v) according to the ratio shown in Table 1 below. Stir for 18 hours in the dark to obtain a colorless and clear coating solution. Wipe the surface of the central venous catheter clean with lint-free paper soaked in 75% ethanol and let it dry. Immerse the catheter in a container filled with the above coating solution, let it stand for 1 minute, and then pull the catheter up at a speed of 0.5cm / s. Irradiate the catheter with the coating solution with a UV lamp for 5 minutes for curing treatment. The UV light intensity is 10mW / cm. 2 The guide tube rotates at 4 rpm. The cured samples are then air-dried and labeled as tubes 1#-6#.

[0124] Table 1. Ratio of polyurethane to antibacterial copolymer

[0125] Example 2:

[0126] <Preparation and curing of antibacterial coating composition 7>

[0127] Weigh 2g of the above-mentioned antibacterial copolymer 2 and 20g of polyethylene glycol-based waterborne polyurethane acrylate, and dissolve them in 95g of a mixed solvent of deionized water / isopropanol (1:9 v / v). Stir for 18 hours in the dark to dissolve, obtaining a colorless and clear coating solution. Wipe the surface of the central venous catheter clean with lint-free paper soaked in 75% ethanol and let it dry. Immerse the catheter in a container filled with the above coating solution, let it stand for 1 minute, and then pull the catheter up at a speed of 0.5cm / s. Irradiate the coated catheter with a UV lamp for 5 minutes for curing treatment, with a UV light intensity of 10mW / cm².2 The guide tube rotates at 4 rpm. The cured sample is then air-dried and designated as tube #7.

[0128] Example 3:

[0129] <Preparation and curing of antibacterial coating composition>

[0130] Weigh 2g of the above-mentioned antibacterial copolymer 3 and 20g of carboxyl waterborne polyurethane acrylate (Covestro Neopac waterborne acrylic polyurethane resin), and dissolve them in 95g of a mixed solvent of deionized water / isopropanol (3:2 v / v). Stir for 18 hours in the dark to dissolve, obtaining a colorless and clear coating solution. Wipe the surface of the vascular stent (metallic material) clean with lint-free paper soaked in 75% ethanol and let it dry. Immerse the stent in a container filled with the above coating solution, let it stand for 1 minute, and then lift the stent at a speed of 0.5cm / s. Irradiate the stent with the coating solution with a UV lamp for 5 minutes for curing treatment, with a UV light intensity of 10mW / cm². 2 The support rotates at 4 rpm. The cured sample is then air-dried and designated as tube #8.

[0131] Example 4:

[0132] <Preparation and curing of antibacterial coating composition 9>

[0133] Weigh 2g of the above antibacterial copolymer 2 and 20g of non-aqueous polyurethane (Refober). HYR-2710 was dissolved in 95g of isopropanol (1:15 v / v) mixed solvent and stirred in the dark for 18 hours to obtain a colorless and clear coating solution. The surface of the vascular stent (metallic material) was wiped clean with lint-free paper soaked in 75% ethanol and then air-dried. The stent was immersed in a container filled with the above coating solution and allowed to stand for 1 minute. The stent was then lifted at a speed of 0.5 cm / s, and the coated stent was irradiated with a UV lamp for 5 minutes for curing treatment at a UV light intensity of 10 mW / cm². 2 The support rotates at 4 rpm. The cured sample is then air-dried and designated as tube #9.

[0134] Example 5

[0135] Same as Example 2, except that the polyethylene glycol-based waterborne polyurethane acrylate was replaced with DSM waterborne polyurethane (Neopac E-123), designated as tube #13.

[0136] Comparative Example 1:

[0137] Weigh 10g of the above antibacterial copolymer 3 and dissolve it in 95g of a deionized water / isopropanol (1:9 v / v) mixed solvent. Stir for 18 hours in the dark to obtain a colorless and clear coating solution. Wipe the surface of the central venous catheter clean with lint-free paper soaked in 75% ethanol and let it air dry. Immerse the catheter in a container filled with the above coating solution, let it stand for 1 minute, and then pull the catheter up at a speed of 0.5cm / s. Irradiate the coated catheter with a UV lamp for 5 minutes for curing treatment. The UV light intensity is 10mW / cm². 2 The guide tube rotates at 4 rpm. The cured sample is then air-dried and designated as tube #10.

[0138] Comparative Example 2

[0139] A ternary polymer containing a hydrophilic monomer, a guanidine-containing monomer, and a photosensitive monomer was prepared according to the preparation method disclosed in Example 1 of CN117442787A. Then, 10g of the above ternary polymer was weighed and dissolved in 95g of a deionized water / isopropanol (1:9 v / v) mixed solvent. The solution was stirred in the dark for 18 hours to obtain a colorless and clear coating. The surface of the central venous catheter was wiped clean with lint-free paper soaked in 75% ethanol and then air-dried. The catheter was immersed in a container filled with the above coating and allowed to stand for 1 minute. The catheter was then pulled up at a speed of 0.5 cm / s, and the coated catheter was irradiated with a UV lamp for 5 minutes for curing treatment at a UV light intensity of 10 mW / cm². 2 The guide tube rotates at 4 rpm. The cured sample is then air-dried and designated as tube #11.

[0140] Comparative Example 3

[0141] Similar to Comparative Example 2, except that the central venous catheter was replaced with a vascular stent (metallic material). This was designated as tube #12.

[0142] Comparative Example 4

[0143] Referring to Example 1 of CN117442787A, a photocurable drug-loaded polymer coating was prepared, designated as tube #14.

[0144] Performance testing

[0145] 1) Antibacterial performance test: Ethylene oxide-sterilized tubing was cut into 0.5×0.5cm samples and placed in sterile 48-well plates with the coated side facing up. 10 μL of bacterial suspension (containing *Escherichia coli* and *Staphylococcus aureus*) with a LOD600 of 0.01 was added, and the plates were covered and incubated at 37°C for 3 hours. 500 μL of liquid culture medium was added to soak the samples, which were then thoroughly shaken and soaked for 10 minutes. Bacteria were collected by sonication (150 W) for 1 minute (10 seconds of sonication followed by a 5-second interval). The samples were serially diluted 1:100 and 1:500 and then plated. After overnight incubation at 37°C, the plates were photographed, and the colony counts were recorded. The antibacterial effect was verified by comparing the samples with tubing without an antibacterial coating. The test results are shown in Table 2 below.

[0146] The test results show that for pipes #1-#6, the antibacterial performance initially increases and then decreases with increasing polyurethane content. This demonstrates that the antibacterial polymer and polyurethane content of this invention need to be controlled at a certain ratio. If the polyurethane content is too high, the amount of antibacterial substance carried is insufficient, and a large amount of antibacterial polymer is encapsulated within the polyurethane, resulting in too low an amount of antibacterial substance exposed on the surface. If the polyurethane content is too low, the coating adhesion to the pipe is insufficient, making it difficult for the antibacterial substance to firmly bond to the pipe surface. When the ratio of polyurethane to antibacterial polymer is controlled within the range of 10:1 to 5:1, the antibacterial performance remains at a high level.

[0147] Pipes #7-#9, using either waterborne or non-waterborne polyurethane, can guarantee highly efficient antibacterial effects. Furthermore, the coating composition of this invention is not only suitable for polymeric pipes but also for metal substrates, greatly expanding the application range of antibacterial coatings. The implementation process demonstrates that when using a combination of waterborne polyurethane and an antibacterial polymer synthesized from waterborne photosensitive monomers, the amount of organic solvent used can be reduced by more than 55%.

[0148] For tube #10, the antibacterial effect is slightly lower due to the lack of polyurethane in the coating composition. However, because it is a polymer-type substrate, the photosensitive portion of the antibacterial polymer can bond with the substrate, thus achieving an antibacterial performance of approximately 93%. As for tube #12, according to the prior art, it is a ternary polymer containing hydrophilic monomers, guanidine monomers, and photosensitive monomers, which cannot achieve coating bonding on metal-type substrates.

[0149] 2) Durability Test: The tubing was held in place with double clamps in deionized water. A certain pressure was applied through the clamps, and the tubing was repeatedly pulled up and down. The clamping force was 300g, the pulling speed was 10mm / s, and the test was repeated 5 times. After the test, the tubing was stained with alkaline fuchsin, and the coating morphology was observed under a microscope. The criteria for judging the coating durability were as follows: ≤3 2*2mm point breaks were considered excellent; ≤10 2*2mm point breaks were considered good; >10 2*2mm point breaks were considered poor. The test results are shown in Table 2 below. Meanwhile, the staining results after testing with tubes #7 and #10 are shown in Figures 1-2.

[0150] As shown in Table 2, for pipes #1-#6, the coating adhesion decreases as the polyurethane ratio decreases. Pipes #7-#9 have high coating adhesion, while pipe #10 has low coating adhesion.

[0151] 3) For Example 5, polyurethane was replaced with polyurethane based on Example 2. In terms of antibacterial data, there was almost no change compared with Example 2, but the coating firmness was slightly worse and was rated as "good".

[0152] As can be seen from Figures 1-2, after testing, the coating of the pipe in Comparative Example 1 peeled off / thinned, the dye color became lighter, and the surface appeared mottled, proving that the coating had low adhesion.

[0153] Table 2

[0154] 4) Flexibility test: The flexibility of the coating film is determined according to standard GB / T 1731-93. After the paint film is fully cured, the sample of the coating film is pressed tightly on the standard diameter shaft with both hands and bent around the shaft; the paint film is observed with a 4x magnifying glass after bending.

[0155] 5) Thickness Test: After curing, the sample tube was side-cut with a stainless steel scalpel to obtain the sample cross-section. The sample cross-section was then attached to the copper testing stage of a scanning electron microscope with the cross-section facing upwards. The sample was then vacuum-sputtered with gold before testing. The coating thickness in the SEM image was marked and measured using IPP (Image-ProPlus) (measurements were taken at 5 locations and the average value was taken).

[0156] The test results are detailed in Table 3 below.

[0157] Table 3. Test results of antibacterial coating performance

[0158] 6) Cytotoxicity test: According to the requirements of GB / T 16886, samples of catheters #7 and #14 were selected and immersed in sterile PBS buffer at 37℃ for 14 days to prepare extracts. Mouse fibroblasts L929 were selected and cytotoxicity was tested according to the MTT assay.

[0159] Test results showed that after 14 days of PBS immersion in tube #7, the L929 cell viability decreased by less than 3% using the direct contact method, indicating no cytotoxicity. The material was considered safe and showed no significant toxic reactions. In contrast, the extract from tube #14 in the control group showed a 42% decrease in L929 cell viability, indicating some cytotoxicity.

Claims

1. An antibacterial coating, characterized in that, include: The mixture comprises at least one photocurable antibacterial polymer, at least one polyurethane, and a solvent, wherein, The photocurable antibacterial polymer is polymerized from components including polymerizable photosensitive monomers and polymerizable cationic guanidine salt monomers.

2. The antibacterial coating according to claim 1, characterized in that, The mass ratio of the polyurethane to the photocurable antibacterial polymer is (2-20):1; preferably (5-10):

1.

3. The antibacterial coating according to claim 1 or 2, characterized in that, The polymerizable cationic guanidine salt monomer structure includes: P-part: The polymer structural part containing a guanidine group, and, Q part: It is a structural part that is bonded to the P part and contains unsaturated groups. The P portion originates from the polymerization of guanidine compounds and diamine compounds.

4. The antibacterial coating according to any one of claims 1 to 3, characterized in that, The polymerizable cationic guanidine salt monomer has the structure shown in general formulas (I) to (VI) or its hydrochloride salt form: Wherein, X is a linking group selected from alkyl or alkoxy structures containing C1-C6; and A contains an unsaturated bond group. Where n is an integer selected from 8 to 15.

5. The antibacterial coating according to claim 4, characterized in that, The A is selected from at least one of the following: (meth)acrylate structure, (meth)acrylamide structure, or maleimide structure.

6. The antibacterial coating according to any one of claims 1 to 5, characterized in that, The polymerizable cationic guanidine salt monomer has the structure shown in general formula (VII) or general formula (VIII) or its hydrochloride salt form: Where n is an integer selected from 8 to 15, and m is an integer selected from 2 to 6.

7. The antibacterial coating according to any one of claims 1-6, characterized in that, The polymerizable photosensitive monomer is selected from Norrish type I photosensitive monomers and / or Norrish type II photosensitive monomers; the molar concentration of the polymerizable photosensitive monomer in the photocurable antibacterial polymer is 1-5%.

8. The antibacterial coating according to any one of claims 1 to 7, characterized in that, The polyurethane is selected from hydrophilic polyurethane, and optionally, the polyurethane has polymerizable groups; the polymerizable photosensitive monomer is selected from water-soluble photosensitive monomers.

9. The antibacterial coating according to claim 8, characterized in that, The hydrophilic polyurethane is selected from at least one of waterborne cationic polyurethane, waterborne anionic polyurethane, and waterborne nonionic polyurethane; the molecular weight of the hydrophilic polyurethane is 2000-30000.

10. A medical device with an antibacterial coating, characterized in that, include: The device body and an antimicrobial coating formed on the surface of the body, the antimicrobial coating being formed by photocuring of the antimicrobial coating according to any one of claims 1-9 and covalently bonded to the surface.

11. The medical device with an antibacterial coating according to claim 10, characterized in that, The thickness of the antibacterial coating is 1μm ≤ thickness < 20μm.

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