Medical device comprising coating for mitigating biofilm formation and / or growth

Abstract

The present invention relates to a medical device comprising a coating comprising: a polymer Z bound to the medical device and a moiety of formula A wherein X is an amino group covalently bound to Z or capable of ionically binding to a free carboxyl group wherein the moiety according to formula A is present in the coating in an amount of 0.5-30 nmol / cm2; and wherein polymer Z comprises free carboxyl groups in an amount of from 1 to 30 mol / cm2. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to medical devices for reducing biofilm formation and / or growth on a surface. More specifically, the present invention relates to medical devices comprising a coating that comprises 2-(pyridyldithio)ethylamine (PDEA) or a closely related compound covalently bound to a polymer or non-covalently bound to the coating. The amount of PDEA covalently or non-covalently bound in the coating may be low, but still allows for reduction of biofilm formation and / or growth when the medical device is exposed to microorganisms such as those in the human body. Background Art

[0002] A biofilm is an aggregate of microorganisms embedded in an extracellular polymeric substance matrix that readily adheres and grows on a surface such as a solid surface. The microorganisms can be different types of microorganisms such as bacteria, archaea, protozoa, fungi, and algae. It has been found that the structure of the biofilm provides a natural barrier and protective layer for the microorganisms, enabling them to thrive and making them more resistant to environmental stress compared to planktonic microorganisms that are not connected to each other. Thus, biofilm formation appears to be a survival strategy for microorganisms when exposed to external stresses such as UV irradiation, extreme temperatures and pH, chemicals, disinfectants, antimicrobial agents, etc. However, the protection that biofilms confer on microorganisms and their widespread presence pose problems for many industries including the healthcare industry, where biofilms are reported to be associated with 80% of chronic infections and 65% of other infections.

[0003] Biofilms are of particular concern due to their ability to tolerate or resist treatment with antimicrobial agents such as antibiotics, which makes infections associated with the presence of biofilms difficult or even impossible to treat. It has been reported that the difficulty in treating biofilm-related infections with antibiotics can be attributed to problems such as poor penetration of antibiotics into the biofilm, which may also be accompanied by poor diffusion within the biofilm, resulting in low antibiotic concentrations that allow bacteria to survive and develop resistance. In addition, bacteria change after being incorporated into the biofilm, such that they change from a planktonic to a sessile state, i.e., they change from free-living bacteria to bacteria that grow in an adherent manner, whereby their metabolic activity is reduced, making them less sensitive to antibiotics. Thus, for some antibiotics, the concentration required to kill bacteria embedded in the biofilm may be a thousand times the concentration required to kill planktonic bacteria.

[0004] Therefore, biofilm formation is an important cause of antibiotic resistance. Since antibiotics are one of the most important tools for treating bacterial infections and diseases, this means a reduced ability to adequately treat patients, leading to increased morbidity and mortality. Unfortunately, antimicrobial resistance has been increasing for many years and has been identified by the World Health Organization (WHO) as one of the top ten global health challenges.

[0005] The formation and growth of biofilms frequently occur on the surfaces of medical devices used in modern medicine. Biofilms can form on intermittent and indwelling medical devices, such as implants, catheters, etc. For example, catheter-associated urinary tract infections (so-called CAUTIs) are one of the most common healthcare-associated infections, affecting a large number of hospitalized patients who use catheters. Given the widespread use of medical devices, this poses a significant problem for the healthcare industry in terms of both human suffering and economic pressure. Therefore, measures to prevent biofilm formation and growth have attracted great interest and efforts.

[0006] Over the past many years, a large number of coating materials have been developed for modifying surfaces to minimize bacterial and biofilm adhesion. For example, antimicrobial agents are included in the coatings, such as small molecules, silver ions, and nanoparticles.

[0007] WO2006 / 101438 discloses an antimicrobial agent comprising a cysteine compound covalently bound to a substrate, in particular bound to the substrate through an S-S spacer molecule. It is described that this agent has excellent antimicrobial properties and can be used to coat the surfaces of various devices (such as medical devices, etc.) or substrates to reduce the accumulation and / or growth and / or proliferation and / or viability and / or biofilm formation of microorganisms. As stated in Example 16, the presence of the cysteine component is crucial for the antibacterial effect. Odeberg et al. (A novel cysteine-linked antibacterial surface coating significantly inhibits bacterial colonization of nasal silicone prongs in a phase one pre-clinical trial. Mater Sci Eng C Mater Biol Appl 2018 Dec 1;93:782-789) disclose a phase I first-in-human trial of nasal cannulas coated with a cysteine compound prepared by the method disclosed in WO2006 / 101438.

[0008] Although many coatings have been proven to be effective, there is still a need for improved coatings, such as coatings that prevent biofilm formation and / or growth over several days or longer upon exposure to microorganisms. One object of the present invention is to overcome or at least mitigate some of the problems associated with known coatings. In addition, one object of the present invention is to provide aspects and / or advantages not provided by the technologies known heretofore. Summary of the Invention

[0009] The present invention is based on the following unexpected finding: Coatings comprising a polymer containing free carboxyl groups and a certain concentration of moieties of formula A provide an anti-biofilm effect that has not been found heretofore.

[0010]

[0011] The new effect does not depend on inhibition of microbial growth on the coating, but rather prevents biofilm formation on the coated surface, which is particularly advantageous from a regulatory perspective (see Example 8). The preparation and characterization of the coating are shown in Examples 1 to 3. Example 4 shows that the coated surface is not cytotoxic. As shown in Examples 5 and reference Example 6, the amount of formula A according to the present invention is significantly lower than that of the prior art. Example 7 further shows the dose response of the anti-biofilm activity (compared to growth inhibition).

[0012] The present invention particularly relates to the following items. The subject matter disclosed in these items shall be considered to be disclosed in the same manner as the subject matter disclosed in the patent claims.

[0013] 1. A medical device comprising a coating, said coating comprising:

[0014] a polymer Z bound to the medical device

[0015] and moieties of formula A,

[0016]

[0017] wherein X is an amino group that is covalently bound to Z or can form an ionic bond with a free carboxyl group;

[0018] wherein the moieties according to formula A are present in the coating in an amount of 0.5 to 30 nmol / cm 2 ; and

[0019] wherein the polymer Z contains 1 to 30 μmol / cm 2 of free carboxyl groups.

[0020] 2. The medical device according to any one of the preceding items, wherein the coating comprises a structure of formula I:

[0021]

[0022] wherein the circle represents the surface of the medical device.

[0023] 3. The medical device according to any one of the preceding items, wherein the coating comprises moieties of formula A, wherein X is a primary amino group -NH2, a secondary amino group -NRH or a tertiary amino group -NR2, wherein each R is independently selected from C 1~4 alkyl.

[0024] 4. The medical device according to any one of the preceding items, wherein the coating comprises the following structure:

[0025] .

[0026] 5. The medical device according to any of the preceding items, wherein at least 20 mol % of the moieties according to formula A are linked to Z via a covalent bond.

[0027] 6. The medical device according to any of the preceding items, wherein at least 20 mol % of the moiety according to formula A is ionically bound to the coating.

[0028] 7. The medical device according to any one of the preceding items, wherein the moiety according to formula A is present in the coating at 0.5 to 15 nmol / cm 2 The amount exists.

[0029] 8. The medical device according to any one of the preceding items, wherein the polymer Z comprises 3 to 7 µmol / cm 2 of free carboxyl groups.

[0030] 9. The medical device according to any of the preceding items, wherein the coating comprises 2-(pyridyldithio)ethylamine (PDEA) covalently bonded to a polymer, wherein the polymer is covalently bonded to the medical device, wherein

[0031] The PDEA is present in an amount of 0.001 wt % to 1 wt % based on the total weight of the coating.

[0032] 10. The medical device according to item 9, wherein PDEA is present in an amount of 0.01 wt% to 1 wt% based on the total weight of the coating.

[0033] 11. The medical device according to any of the preceding items, wherein polymer Z is covalently bonded to the medical device.

[0034] 12. The medical device according to any of the preceding items, wherein the coating comprises a polymer selected from the group consisting of polyacrylic acid, polymethacrylic acid, poly-4-vinylbenzoic acid, polyitaconic acid, any combination thereof, and esters or amides thereof.

[0035] 13. The medical device according to any of the preceding items, wherein the polymer Z comprises an acrylate polymer or an acrylic polymer, such as polyacrylic acid or the like.

[0036] 14. The medical device according to any of the preceding items, wherein the polymer Z of the coating is grafted from the medical device.

[0037] 15. The medical device according to any one of the preceding items, wherein the coating contains water, thereby forming a hydrogel.

[0038] 16. The medical device according to any one of the preceding items, wherein the medical device is selected from the group consisting of a catheter, an implant, an endotracheal tube, a stent, a ventilator, a wound dressing, a face mask, a nasal cannula, a hearing aid, and a syringe.

[0039] 17. The medical device according to any one of the preceding items, wherein the medical device is selected from the group consisting of a central venous catheter, a ureteral stent, a wound dressing, a ventilator, a face mask, a nasal cannula, and an implant.

[0040] 18. The medical device according to any one of the preceding items, wherein the medical device is a catheter (such as a Foley catheter, etc.) or an endotracheal tube.

[0041] 19. The medical device according to any one of the preceding items, wherein the medical device comprises

[0042] a polymer, such as a thermoplastic and / or thermosetting polymer, etc., and / or

[0043] a metal.

[0044] 20. The medical device according to item 19, wherein

[0045] the polymer comprises one or more of the following: silicone, polyethylene, polypropylene, polyurethane, polyvinyl chloride, polycaprolactone, polycarbonate, a rubber such as latex rubber, polyetheretherketone (PEEK)

[0046] and / or

[0047] the metal comprises one or more of the following: steel (such as stainless steel, etc.), an alloy (such as a cobalt-based alloy or nitinol, etc.), titanium.

[0048] 21. The medical device according to any one of the preceding items, wherein the coating is present on at least a part of the inner surface and / or the outer surface of the medical device.

[0049] 22. The medical device according to any one of the preceding items, wherein the medical device has no or substantially no biofilm after 4 days or longer (such as 30 days, etc.) of clinical use.

[0050] 23. A coating for a medical device, wherein the coating is defined as in any one of the preceding items.

[0051] 24. Use of a coating for reducing biofilm formation and / or growth on the surface of a medical device, the coating comprising:

[0052] a polymer Z bound to the medical device

[0053] Part of Formula A

[0054]

[0055] wherein X is an amino group, which is covalently bonded to Z or can form an ionic bond with a free carboxyl group; and

[0056] wherein the polymer Z can form a hydrogel when contacted with an aqueous fluid.

[0057] 25. The use according to item 24, wherein the polymer Z is covalently bonded to the medical device.

[0058] 26. The use according to item 24 or 25, wherein Z contains a free carboxyl group.

[0059] 27. The use according to item 26, wherein Z contains from 1 to 30 µmol / cm 2 of free carboxyl groups.

[0060] 28. The use according to item 27, wherein Z contains from 3 to 20 µmol / cm 2 of free carboxyl groups.

[0061] 29. The use according to any one of items 24 to 28, wherein the coating comprises a structure of Formula I:

[0062]

[0063] wherein the circle represents the surface of the medical device.

[0064] 30. The medical device according to any one of items 24 to 29, wherein the coating comprises a part of Formula A, wherein X is a primary amino group -NH2, a secondary amino group -NRH or a tertiary amino group -NR2, wherein each R is independently selected from C 1~4 alkyl.

[0065] 31. The use according to any one of items 24 to 30, wherein the coating comprises the following structure:

[0066] .

[0067] 32. The use according to any one of items 24 to 31, wherein at least 20 mol% of the part according to Formula A is covalently bonded to Z.

[0068] 33. The use according to any one of items 24 to 32, wherein at least 20 mol% of the part according to Formula A is ionically bound to the coating.

[0069] 34. Use according to any one of items 24 to 33, wherein the moiety according to formula A is present in the coating in an amount of 0.5 to 30 nmol / cm 2 .

[0070] 35. Use according to item 34, wherein the moiety according to formula A is present in the coating in an amount of 0.5 to 15 nmol / cm 2 .

[0071] 36. Use according to any one of items 24 to 35, wherein the coating comprises a polymer selected from the group consisting of polyacrylic acid, polymethacrylic acid, poly-4-vinylbenzoic acid, itaconic acid, any combination of the foregoing substances, and esters or amides thereof.

[0072] 37. Use according to any one of items 24 to 36, wherein polymer Z comprises an acrylate polymer or an acrylic polymer, such as polyacrylic acid, etc.

[0073] 38. Use according to any one of items 24 to 37, wherein polymer Z of the coating is grafted from a medical device.

[0074] 39. Use according to any one of items 24 to 38, wherein the coating is defined as in any one of items 1 to 22.

[0075] 40. Use according to any one of items 24 to 39, wherein the alleviation does not involve bactericidal or bacteriostatic effects.

[0076] The present disclosure is divided into sections by title and subtitle solely to enhance readability and should not be construed as limiting in any way. In particular, such division does not exclude or limit in any way the mutual combination of features under different titles and subtitles. All references are incorporated herein by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 Shows the optical density (OD) of three catheter samples measured at a wavelength of 595 nm as described in Example 2. The OD is related to the EPS matrix and the number of embedded bacteria, indicating that the coating of the present invention results in almost complete inhibition of biofilm formation.

[0078] Figure 2 Shows the cumulative amount of 2-mercaptopyridine measured in Example 5, and the amount of PDEA in the coating measured therefrom.

[0079] Figure 3 Shows the cumulative amount of 2-mercaptopyridine measured in Reference Example 6, and the amount of PDEA in the coating measured therefrom.

[0080] Figure 4 isFigure 3 An enlarged view of the second and subsequent cycles as shown, using the first cycle as the baseline. This shows the amount of PDEA remaining in the previous generation product after coupling with the cysteine component (corresponding to the situation after 1 coupling cycle).

[0081] Figure 5 Shows the count of adherent bacteria present on the surface of the sample, expressed as log CFU / cm 2 It can be seen that at low concentrations, there is no effect on the number of bacteria.

[0082] Figure 6 Shows the count of bacteria in artificial urine medium (AUM), expressed as log CFU / ml. It can be seen that at low concentrations, there is no effect on the number of bacteria.

[0083] Figure 7 Shows the count of bacteria in artificial urine medium (AUM) and on the surface of the catheter, expressed as log CFU / ml. It can be seen that the coating has no effect on the count of bacteria in the solution, indicating that it has no bactericidal or bacteriostatic effect (CytaCoat refers to the coating of the present invention).

[0084] Figure 8 Shows the quantification of the biofilm on the surface of the catheter. The coating of the present invention (designated as "CytaCoat") almost completely prevented biofilm formation during the first week (right figure). When the bacteria from the first week come into contact with Control the catheter, they are still able to form biofilm during the second week (left figure), indicating that exposure to the surface of the present invention has not changed its properties.

[0085] Figure 9 Illustrates the experimental setup of Example 8. Detailed Description

[0086] Description

[0087] Medical device comprising a coating

[0088] In a first aspect, the present invention provides a medical device comprising a coating, the coating comprising:

[0089] Polymer Z bound (preferably covalently bound) to the medical device

[0090] and a moiety of formula A,

[0091]

[0092] wherein X is an amino group covalently bound to Z or capable of forming an ionic bond with a free carboxyl group;

[0093] Among them, the part according to formula A is present in the coating in an amount of about 0.5 to 30 nmol / cm 2 ; and

[0094] wherein polymer Z contains free carboxyl groups in an amount of about 1 to 30 μmol / cm 2 .

[0095] The present invention may also relate to a medical device comprising a coating, the coating comprising polymer Z bound (preferably covalently) to the medical device, and a disulfide compound of formula (I) as defined in WO2023 / 012305 (the full text of which is incorporated herein by reference) bound covalently or non-covalently to the polymer, wherein polymer Z preferably contains free carboxyl groups in an amount of about 1 to 30 μmol / cm 2 . The disulfide compounds disclosed in claims 10, 11 or 12 of WO2023 / 012305 are particularly preferred.

[0096] X can be a primary amino group -NH2, a secondary amino group -NRH or a tertiary amino group -NR2, wherein each R is independently selected from C 1~4 alkyl. Examples of C 1~4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In some embodiments, X is a primary amino group -NH2.

[0097] X can be covalently bound to the terminal functional group of Z and / or to the functional group on the polymer backbone. Examples of such functional groups include carboxyl groups. Alternatively, X can be ionically bound to the terminal free group or to the free group (such as a carboxyl group) on the polymer backbone. For example, when X is a primary amino group -NH2 and the polymer contains -COOH groups, these groups carry opposite charges (-NH3 + , -COO - ) in a wide pH range near neutrality, and can thus be ionically bound. Similarly, the secondary amino group NRH can be in its protonated form -NRH2 + and be ionically bound to -COO - , and the tertiary amino group -NR2 can be in its protonated form -NR2H + and be ionically bound to -COO - .

[0098] The coating can comprise the structure of formula I:

[0099]

[0100] where the circle represents the surface of the medical device. The coating can additionally or alternatively comprise a part of formula A, wherein X is an amino group as defined above. In some embodiments, the coating comprises the following structure:

[0101] .

[0102] At least about 1 mol% of the moiety according to formula A can be covalently bonded to Z, or bonded in increasing order of priority as follows: at least about 2 mol%, 5 mol%, 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, 90 mol%, or 100 mol%, such as 2-100 mol%, 5-100 mol%, 10-100 mol%, 30-100 mol%, 50-100 mol%, 80-100 mol%, 2-90 mol%, 5-90 mol%, 10-90 mol%, 20-90 mol%, 30-90 mol%, 50-90 mol%, 80-90 mol%, 2-70 mol%, 5-70 mol%, 10-70 mol%, 30-70 mol%, 50-70 mol%, 20-80 mol%, 30-90 mol%, 40-80 mol%, etc. At least 1 mol% of the moiety according to formula A can be ionically bonded to the coating, or bonded in increasing order of priority as follows: at least about 2 mol%, 5 mol%, 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, 90 mol%, or 100 mol%, such as 2-100 mol%, 5-100 mol%, 10-100 mol%, 30-100 mol%, 50-100 mol%, 80-100 mol%, 2-90 mol%, 5-90 mol%, 10-90 mol%, 20-90 mol%, 30-90 mol%, 50-90 mol%, 80-90 mol%, 2-70 mol%, 5-70 mol%, 10-70 mol%, 30-70 mol%, 50-70 mol%, 20-80 mol%, 30-90 mol%, 40-80 mol%, etc. It should be clear that both the covalently bonded moiety and the ionically bonded moiety can be present simultaneously.

[0103] The moiety according to formula A can be present in the coating in an amount of about 0.5-15 nmol / cm 2 In certain embodiments, the moiety according to formula A can be present in an amount of about 0.5-12 nmol / cm 2 , about 0.5-10 nmol / cm 2 , about 0.5-9 nmol / cm 2, about 0.5 to 8 nmol / cm 2 , about 0.5 to 7 nmol / cm 2 , about 0.5 to 6 nmol / cm 2 , about 0.5 to 5 nmol / cm 2 , about 0.5 to 4 nmol / cm 2 , about 0.5 to 3 nmol / cm 2 , about 0.5 to 2 nmol / cm 2 , about 0.5 to 1 nmol / cm 2 , about 1 to 12 nmol / cm 2 , about 1 to 10 nmol / cm 2 , about 1 to 9 nmol / cm 2 , about 1 to 8 nmol / cm 2 , about 1 to 7 nmol / cm 2 , about 1 to 6 nmol / cm 2 , about 1 to 5 nmol / cm 2 , about 1 to 4 nmol / cm 2 , about 1 to 3 nmol / cm 2 , about 1 to 2 nmol / cm 2 or in an amount of 1 nmol / cm 2 is present.

[0104] Polymer Z may preferably contain free carboxyl groups in an amount of at least 3 μmol / cm 2 , such as about 3 to 20 μmol / cm 2 and the like. In certain embodiments, the surface concentration of the carboxylic acid groups can be about 1 to 20 mol / cm 2 , about 1 to 15 mol / cm 2 , about 1 to 10 mol / cm 2 , about 1 to 7 mol / cm 2 or 1 to 5 mol / cm 2 . A carboxylic acid group surface concentration of about 3 to 7 mol / cm 2 is most preferred.

[0105] In a set of alternative embodiments of the first aspect, the present invention provides a medical device comprising a coating, the coating comprising 2-(pyridyldithio)ethylamine (PDEA) covalently bound to a polymer, the polymer being covalently bound to the medical device, wherein PDEA is present in an amount of 0.001 wt% to 35 wt% based on the total weight of the coating.

[0106] Based on the total weight of the coating, PDEA can be present in an amount of from about 0.001 wt% to about 35 wt%, such as from about 0.001 wt% to about 30 wt%, from about 0.001 wt% to about 25 wt%, from about 0.001 wt% to about 20 wt%, from about 0.001 wt% to about 15 wt%, from about 0.001 wt% to about 10 wt%, from about 0.001 wt% to about 5 wt%, 0.001 wt% to about 3 wt%, 0.001 wt% to about 2 wt%, from about 0.001 wt% to about 1 wt%, 0.001 wt% to about 0.5 wt%, etc. For example, based on the total weight of the coating, PDEA can be present in an amount of from about 0.001 wt% to about 2 wt% or from about 0.001 wt% to about 1 wt%. In another example, based on the total weight of the coating, PDEA can be present in an amount of from about 0.5 wt% to about 2 wt%, such as from about 0.5 wt% to about 1.5 wt%, etc. In yet another example, based on the total weight of the coating, PDEA can be present in an amount of from about 0.001 wt% to about 1 wt%, 0.01 wt% to 1 wt%, 0.05 wt% to 1 wt%, 0.08 wt% to 1 wt% or 0.1 wt% to 1 wt%.

[0107] It should be understood that the compound 2-(pyridyldithio)ethylamine can be abbreviated as PDEA. Further, the chemical structure of 2-(pyridyldithio)ethylamine (PDEA) can be shown as follows. In this document, the chemical name of 2-(pyridyldithio)ethylamine can be used interchangeably with 2-(pyridin-2-yl)dithioamine, 2-(pyridin-2-yldithioalkyl)ethylamine, 2-(2-pyridyldithio)ethylamine, and / or PDEA.

[0108]

[0109] In certain contexts herein, the term "PDEA" can also be used more broadly to refer to chemical structures containing a moiety according to Formula A. It is known that PDEA reacts with thiol-containing nucleophiles (such as cysteine, etc.), whereby the disulfide bond of PDEA is broken when the sulfur attached to the pyridine ring of PDEA is replaced by the sulfur of the thiol group of the nucleophile. As a result, a compound containing -S-(CH2)2-NH2 and pyridine-2-thiol is formed from PDEA. This is shown in Scheme 1 below, where the nucleophile R-SH reacts with PDEA.

[0110]

[0111] In the same way, the reaction of a thiol-containing nucleophile with PDEA has been used in applications such as the following: where the amino group of PDEA is covalently bound to the carbonyl group of a polymer, which in turn is bound (such as covalently bound) to the surface of a substrate (such as a medical device, etc.). This is shown in Scheme 2, where the circle represents the surface (such as the surface of a medical device, etc.), Z represents the polymer, and the carbonyl group is part of the polymer.

[0112]

[0113] For example, WO 2006 / 101438 A1 describes such a reaction using cysteine or a cysteine analogue as a thiol-containing nucleophile, which produces a surface with excellent antimicrobial properties.

[0114] Biofilm prevention or mitigation

[0115] In the context of this article, the term biofilm refers to a complex three-dimensional structure formed by a community of microorganisms (bacteria, fungi, or protists) embedded in extracellular polymeric substances (EPS) produced by themselves on a surface (such as a medical device, etc.). The formation of biofilms protects the microorganisms and makes them difficult to eradicate, and may significantly affect the pathogenicity of the microorganisms. Biofilm formation is a multi-step process involving attachment, EPS production, and biofilm maturation.

[0116] In the context of biofilm formation or / and growth, the terms "prevention" and "mitigation" refer to any degree of reduction in biofilm formation, including a slight, significant, or substantial reduction in biofilm formation and complete prevention. Preferably, the degree of reduction is at least a slight reduction. The degree of reduction can be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100%. For example, the degree of reduction can be between about 10% and about 100%, such as between about 20% and about 100%, between about 40% and about 100%, between about 60% and about 100%, between about 80% and about 100%, between about 20% and about 40%, between about 20% and about 60%, between about 20% and about 80%, between about 20% and about 100%, between about 40% and about 60%, between about 40% and about 80%, between about 40% and about 100%, between about 60% and about 80%, between about 60% and about 100%, or between about 80% and about 100%, etc. "Anti-biofilm effect" refers to the mitigation of biofilm formation and / or growth.

[0117] The present invention is based on the following unexpected finding: the reduction of biofilm formation and / or growth on a surface (such as the surface of a medical device) can be achieved by covalently binding PDEA or other moieties according to Formula A to a polymer and then binding the polymer (such as by covalent binding, etc.) to the surface of the medical device. Alternatively, PDEA or other compounds containing moieties according to Formula A can be non-covalently (such as ionically) bound to the polymer.

[0118] Therefore, there is no need to react PDEA or moieties according to Formula A with additional compounds to achieve the reduction of biofilm formation and / or growth. The possible chemical structure of the thus-functionalized surface is shown in Formula I, where the circle and Z have the meanings described herein, and the carbonyl group is part of the indicated polymer.

[0119] 。

[0120] Specifically, it has been found that the amount of the moiety of Formula A can be low, such as provided in the amounts described herein, but still allows the reduction of biofilm formation and / or growth on the surface of the medical device. At lower amounts, the coating does not have antibacterial or bactericidal effects, but the anti-biofilm effect prevents fouling of the medical device.

[0121] Of course, using PDEA or other structures containing Formula A as the sole anti-biofilm agent and using it in lower amounts is a significant benefit because it simplifies the preparation and / or minimizes the use of chemicals. In addition, using lower amounts of the structure according to Formula A covalently or non-covalently bound to the polymer minimizes the toxicity risk. As shown herein, testing of the coating shows no cytotoxicity. Thus, the amount providing the therapeutic effect does not release or releases the minimum amount of PDEA (or other compounds containing structures according to Formula A). This in turn simplifies the regulatory process for medical devices with the coating.

[0122] It should be understood that biofilms contain microorganisms, such as bacteria. The bacteria can be Gram-positive and / or Gram-negative bacteria. For example, the bacteria may involve one or more of the following bacteria: Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus faecium, Enterococcus faecium, Streptococcus spp., Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii. In one example, the Gram-positive bacteria can be one or more of the following: Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus viridans, Enterococcus faecium, Enterococcus faecium, Streptococcus spp. In another example, the Gram-negative bacteria can be one or more of the following: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa. Additionally or alternatively, the biofilm can contain fungi, such as Candida albicans, etc.

[0123] It should be understood that the mitigation of biofilm formation and / or growth described herein may involve minimizing, reducing, and / or preventing biofilm formation and / or growth. Although not wishing to be bound by any particular theory, it is believed that some bacteria may still adhere to the surface but not assemble into a biofilm, making them susceptible to treatment with antimicrobial agents such as antibiotics, or simply allowing them to be washed off or flushed away. It is also known that microorganisms without biofilm / EPS are less likely to cause infection (i.e., less invasive as pathogens). The lack of biofilm also makes them more susceptible to the body's immune system or more receptive to drug treatment.

[0124] Coated polymer

[0125] The polymer (optionally covalently bound to the moiety of formula A) provides a coating for the surface. In the presence of water, the coating can form a hydrogel. Thus, a coating as described herein is provided that comprises or consists of a hydrogel. As used herein, a hydrogel is a cross-linked hydrophilic polymer that is insoluble in water.

[0126] It should be understood that the polymer of the coating can be bound (such as covalently bound) to the surface of the medical device. It is believed that this can keep the coating in place and increase its abrasion resistance. Advantageously, it has been found that the coated medical device of the present invention has abrasion resistance.

[0127] Functionalization of the surface of the medical device involves polymerizing the monomer before reacting it with PDEA or other compounds containing the structure of formula A. The monomer can contain one or more functional groups such as carboxyl, amino, halogen, etc.

[0128] The monomer can be selected from the group consisting of acrylic acid, methacrylic acid, 4-vinylbenzoic acid, itaconic acid, vinylpyrrolidone, any combination thereof, and their esters or amides. For example, the monomer can include acrylate or acrylic monomers (such as acrylic acid, etc.) or consist of acrylate or acrylic monomers (such as acrylic acid, etc.). Thus, the polymer of the coating can be or contain polyacrylic acid, polymethacrylic acid, poly-4-vinylbenzoic acid, polyitaconic acid, any combination thereof, and their esters or amides. The coating can also contain polyvinylpyrrolidone. Specifically, the polymer can contain an acrylate polymer or an acrylic polymer (such as polyacrylic acid, etc.). For example, the polymer can contain polyacrylic acid or consist of polyacrylic acid. It should be understood that for a polymer containing carboxylic acid groups, the surface concentration of the carboxylic acid can range from about 1 mol / cm 2 to about 30 mol / cm 2 such as about 5 mol / cm 2 to about 25 mol / cm 2 about 5 mol / cm 2 to about 20 mol / cm 2, about 5 mol / cm 2 to about 10 mol / cm 2 , about 6 mol / cm 2 to about 9 mol / cm 2 etc. For example, the surface concentration of the carboxylic acid can range from about 3 mol / cm 2 to about 8 mol / cm 2 , about 4 mol / cm 2 to about 7 mol / cm 2 , or about 5 mol / cm 2 to about 6 mol / cm 2 etc. In certain embodiments, the surface concentration of the carboxylic acid groups can be about 1 - 20 mol / cm 2 , about 1 - 15 mol / cm 2 , about 1 - 10 mol / cm 2 , about 1 - 7 mol / cm 2 or 1 - 5 mol / cm 2 . The most preferred surface concentration of the carboxylic acid groups is about 3 - 7 mol / cm 2 .

[0129] The polymer of the coating can be grafted from the medical device. In this way, the polymerization will start and propagate from the surface to which the resulting polymer will covalently bind. Additionally or alternatively, the polymer can be grafted onto the surface of the medical device, thereby covalently binding the pre - formed polymer to the surface.

[0130] Suitable medical devices

[0131] The medical devices described herein can be selected from the group consisting of catheters, implants, endotracheal tubes, stents, ventilators, wound dressings, face masks, nasal cannulas, hearing aids, and syringes. In another example, the medical device can be selected from the group consisting of central venous catheters, ureteral stents, wound dressings, ventilators, face masks, nasal cannulas, and implants. In yet another example, the medical device can be a catheter (such as a Foley catheter, etc.) or an endotracheal tube.

[0132] The medical devices described herein may comprise or consist of a polymer (such as a thermoplastic and / or thermosetting polymer, etc.). For example, the polymer may comprise one or more of the following or consist of one or more of the following: silicone, polyethylene, polypropylene (PP), polyurethane, polyvinyl chloride (PVC), polycaprolactone, polycarbonate, rubber such as latex rubber, polyetheretherketone (PEEK). In one example, the polymer may comprise one or more of the following: silicone, polyvinyl chloride (PVC), polypropylene (PP). In another example, the polymer may comprise silicone or consist of silicone. In another example, the polymer may comprise polyvinyl chloride (PVC) or consist of polyvinyl chloride (PVC). In another example, the polymer may comprise polypropylene (PP) or consist of polypropylene (PP).

[0133] Additionally or alternatively, the medical device may comprise or consist of a metal. For example, the metal may include one or more of the following: steel (such as stainless steel, etc.), alloy (such as cobalt-based alloy or nitinol, etc.) or titanium. As used herein, nitinol is an alloy comprising or consisting of nickel and titanium.

[0134] A coating of the medical device may be present on at least a portion of the inner surface and / or outer surface of the medical device.

[0135] For example, it has been found that the surface of the medical devices described herein may be free or substantially free of biofilm after 4 days or longer of clinical use. For example, the medical device may be free of biofilm after 7, 14, 21 or 30 days of clinical use.

[0136] Methods known in the art may be used to provide a coating on the medical device. For example, the methods described in WO 2006 / 101438 A1 may be used to prepare the coated medical devices described herein. However, it should be understood that the PDEA or other structures incorporating Formula A will preferably not react further. For example, the surface of the medical device may be functionalized by polymerizing monomers (such as the monomers described herein) from the surface of the device using radiation (such as electron beam radiation, gamma radiation, UV radiation or gas plasma, etc.) in the presence of a photoinitiator. Subsequently, the formed polymer may be further reacted with PDEA or other moieties of Formula A in the presence of a coupling agent (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysulfosuccinimide (Sulfo-NHS) or its salts, etc.). Alternatively, the carboxylic acid groups may be converted to acyl chlorides or acid anhydrides instead of using a coupling agent. As shown in Scheme 3, where the circle represents the surface (such as the surface of a medical device, etc.), Z represents the polymer, and the carboxylic acid group is part of the polymer.

[0137]

[0138] Coatings for medical devices

[0139] In a second aspect, there is provided a coating for a medical device, the coating being as defined in the first aspect. Specifically, there is provided a coating comprising a polymer of formula II:

[0140] .

[0141] In the compound of formula II, Z can be a polymer as described herein. For example, Z can be an acrylate polymer or an acrylic polymer such as polyacrylic acid and the like. In addition, the carbonyl group in the polymer of formula I can be part of the polymer Z. The polymer of formula II can bind (such as covalently bind) to a surface (such as the surface of a medical device, etc.). For example, the polymer of formula II can bind to the surface via a covalent bond from Z to the surface. The coating can further comprise water such that the coating is provided in the form of a hydrogel. The coating can be provided on the surface of the medical device described herein.

[0142] Use of the coating for preventing biofilm formation on the surface of a medical device

[0143] In a third aspect, the present invention provides the use of the coating for reducing biofilm formation and / or growth on the surface of a medical device.

[0144] The coating can comprise:

[0145] A polymer Z that binds (preferably covalently binds) to the medical device

[0146] And a moiety of formula A

[0147]

[0148] Wherein X is an amino group that covalently binds to Z or can form an ionic bond with a free carboxyl group; and

[0149] Wherein the polymer Z is capable of forming a hydrogel when contacted with an aqueous fluid (such as water, aqueous buffer, aqueous salt solution or body fluid, etc., where body fluid includes but is not limited to urine, plasma, blood, wound fluid, saliva and cerebrospinal fluid).

[0150] The polymer Z can comprise free carboxyl groups. Preferably, the polymer Z can comprise free carboxyl groups in an amount of about 1 to 30 µmol / cm 2 of free carboxyl groups. In certain embodiments, the surface concentration of the carboxylic acid groups can be at least about 3 mol / cm 2 、about 1 to 20 mol / cm 2 、about 3 to 20 mol / cm 2, about 1 to 15 mol / cm 2 , about 1 to 10 mol / cm 2 , about 1 to 7 mol / cm 2 or about 1 to 5 mol / cm 2 . The most preferred surface concentration of the carboxylic acid group is about 3 to 7 mol / cm 2 .

[0151] X can be a primary amino group -NH2, a secondary amino group -NRH or a tertiary amino group -NR2, where each R is independently selected from C 1~4 alkyl. Examples of C 1~4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In some embodiments, X is a primary amino group -NH2.

[0152] X can be covalently bound to the terminal functional group of Z and / or to the functional group on the polymer backbone. Examples of such functional groups include carboxyl groups. Alternatively, X can form an ionic bond with the terminal free carboxyl group or with the free carboxyl group on the polymer backbone, as discussed in the first aspect.

[0153] The coating can comprise a structure of formula I:

[0154]

[0155] where the circle represents the surface of the medical device. The coating can additionally or alternatively comprise a moiety of formula A, where X is an amino group. Thus, the coating can comprise the following structure:

[0156] .

[0157] At least about 1 mol% of the moiety according to Formula A can be covalently attached to Z, or attached in order of increasing preference: at least about 2 mol%, 5 mol%, 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, 90 mol% or 100 mol%, such as 2-100 mol%, 5-100 mol%, 10-100 mol%, 30-100 mol%, 50-100 mol%, 80-100 mol%, 2-90 mol%, 5-90 mol%, 10-90 mol%, 20-90 mol%, 30-90 mol%, 50-90 mol%, 80-90 mol%, 2-70 mol%, 5-70 mol%, 10-70 mol%, 30-70 mol%, 50-70 mol%, 20-80 mol%, 30-90 mol%, 40-80 mol%, etc. At least 1 mol% of the moiety according to Formula A can be non-covalently bound to the coating, or bound in order of increasing preference: at least about 2 mol%, 5 mol%, 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, 90 mol% or 100 mol%, such as 2-100 mol%, 5-100 mol%, 10-100 mol%, 30-100 mol%, 50-100 mol%, 80-100 mol%, 2-90 mol%, 5-90 mol%, 10-90 mol%, 20-90 mol%, 30-90 mol%, 50-90 mol%, 80-90 mol%, 2-70 mol%, 5-70 mol%, 10-70 mol%, 30-70 mol%, 50-70 mol%, 20-80 mol%, 30-90 mol%, 40-80 mol%, etc. Both the covalently bound moiety and the non-covalently bound moiety can be present simultaneously.

[0158] The moiety according to Formula A can be present in the coating in an amount of about 0.5 - 30 nmol / cm 2 In certain embodiments, the moiety according to Formula A can be present in an amount of about 0.5 - 15 nmol / cm 2 about 0.5 - 12 nmol / cm 2 about 0.5 - 10 nmol / cm 2 about 0.5 - 9 nmol / cm 2 about 0.5 - 8 nmol / cm2 , about 0.5 to 7 nmol / cm 2 , about 0.5 to 6 nmol / cm 2 , about 0.5 to 5 nmol / cm 2 , about 0.5 to 4 nmol / cm 2 , about 0.5 to 3 nmol / cm 2 , about 0.5 to 2 nmol / cm 2 , about 0.5 to 1 nmol / cm 2 , about 1 to 12 nmol / cm 2 , about 1 to 10 nmol / cm 2 , about 1 to 9 nmol / cm 2 , about 1 to 8 nmol / cm 2 , about 1 to 7 nmol / cm 2 , about 1 to 6 nmol / cm 2 , about 1 to 5 nmol / cm 2 , about 1 to 4 nmol / cm 2 , about 1 to 3 nmol / cm 2 , about 1 to 2 nmol / cm 2 or in an amount of 1 nmol / cm 2 is present.

[0159] The coating may comprise a polymer Z selected from the group consisting of polyacrylic acid, polymethacrylic acid, poly-4-vinylbenzoic acid, itaconic acid, any combination of the foregoing substances, and esters or amides thereof. The coating may further comprise polyvinylpyrrolidone. The polymer Z may comprise an acrylate polymer or an acrylic polymer such as polyacrylic acid, etc. The polymer Z of the coating may be from a medical device.

[0160] The coating may be as defined in the first or second aspect.

[0161] Preferably, the reduction of biofilm formation and / or growth does not involve bactericidal or bacteriostatic effects.

[0162] Embodiments of the numbered items

[0163] In certain embodiments, the present invention relates to the following items:

[0164] 1. A medical device comprising a coating, the coating comprising

[0165] 2-(pyridyldithio)ethylamine (PDEA) covalently bound to a polymer, the polymer being covalently bound to the medical device,

[0166] wherein

[0167] Based on the total weight of the coating, PDEA is present in an amount of 0.001 wt% to 35 wt%.

[0168] 2. The medical device according to item 1, wherein based on the total weight of the coating, PDEA is present in an amount of 0.001 wt% to 1 wt%.

[0169] 3. The medical device according to item 1 or 2, wherein the polymer is selected from the group consisting of polyacrylic acid, polymethacrylic acid, poly-4-vinylbenzoic acid, itaconic acid, polyvinylpyrrolidone, any combination of the foregoing substances, and their esters or amides.

[0170] 4. The medical device according to any one of the foregoing items, wherein the polymer comprises an acrylate polymer or an acrylic polymer, such as polyacrylic acid, etc.

[0171] 5. The medical device according to any one of the foregoing items, wherein the polymer of the coating is grafted from the medical device.

[0172] 6. The medical device according to any one of the foregoing items, wherein the coating contains water, thereby forming a hydrogel.

[0173] 7. The medical device according to any one of the foregoing items, wherein the medical device is selected from the group consisting of catheters, implants, endotracheal tubes, stents, ventilators, wound dressings, face masks, nasal cannulas, hearing aids, and syringes.

[0174] 8. The medical device according to any one of the foregoing items, wherein the medical device is selected from the group consisting of central venous catheters, ureteral stents, wound dressings, ventilators, face masks, nasal cannulas, and implants.

[0175] 9. The medical device according to any one of the foregoing items, wherein the medical device is a catheter (such as a Foley catheter, etc.) or an endotracheal tube.

[0176] 10. The medical device according to any one of the foregoing items, wherein the medical device comprises

[0177] a polymer, such as a thermoplastic and / or thermosetting polymer, etc., and / or

[0178] a metal.

[0179] 11. The medical device according to item 10, wherein

[0180] the polymer comprises one or more of the following: silicone, polyethylene, polypropylene, polyurethane, polyvinyl chloride, polycaprolactone, polycarbonate, a rubber such as latex rubber, polyetheretherketone (PEEK), and / or

[0181] The metal includes one or more of the following: steel (such as stainless steel, etc.), alloy (such as cobalt-based alloy or nitinol, etc.), titanium.

[0182] 12. The medical device according to any one of the preceding items, wherein the coating is present on at least a part of the inner surface and / or outer surface of the medical device.

[0183] 13. The medical device according to any one of the preceding items, wherein the medical device has no or substantially no biofilm after 4 days or longer (such as 30 days, etc.) of clinical use.

[0184] 14. The coating for a medical device as defined in any one of the preceding items.

[0185] 15. Use of the coating as defined in any one of the preceding items for reducing biofilm formation and / or growth on the surface of a medical device.

[0186] The term "comprising" shall be construed as including but not limited to.

[0187] The numerical values in the description and claims of this application should be understood to include the same numerical values when reduced to the same number of significant figures and numerical values with differences less than the experimental error of the conventional measurement techniques used in this application for measuring the value.

[0188] All ranges disclosed herein include the endpoints and can be combined independently (for example, the range "2 to 10" includes the endpoints 2 and 10, and all intermediate values).

[0189] The term "about" can be used to include any numerical value that can vary without changing the basic function of the value. When used with a range, "about" also discloses the range defined by the absolute values of the two endpoints. For example, "about 2 to about 4" also discloses the range "2 to 4". The term "about" can mean plus or minus 10% of the indicated number.

[0190] The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

[0191] Examples

[0192] In this document, the chemical structural formula of the name "2-(pyridin-2-yldisulfanyl)ethylamine" and the compound of formula I was generated using the ChemDraw Ultra version 12.0.2.1076 program. If the picture is inconsistent with the name, the picture shall prevail.

[0193] Abbreviation

[0194] AUM artificial urine medium

[0195] aq. aqueous solution

[0196] BP Benzophenone

[0197] cfu Colony - forming unit

[0198] cm 2 Square centimeter

[0199] DI Deionized

[0200] g Gram

[0201] NHS N - Hydroxysuccinimide; CAS No.: 6066 - 82 - 6T

[0202] EDC 1 - Ethyl - 3-(3 - dimethylaminopropyl)carbodiimide; CAS No.: 25952 - 53 - 8

[0203] EPS Extracellular polymeric substances

[0204] ISO International Organization for Standardization

[0205] L Liter

[0206] L - Cysteine CAS No.: 52 - 90 - 4

[0207] mg Milligram

[0208] μmol Micromole

[0209] min. Minute

[0210] ml Milliliter

[0211] M Mole

[0212] MQ MilliQ

[0213] nm Nanometer

[0214] nmol Nanomole

[0215] OD Optical density

[0216] PAA Polyacrylic acid; CAS No.: 9003 - 01 - 4

[0217] PBS Phosphate - buffered saline

[0218] PDEA 2-(Pyridyldithio)ethylamine; CAS No.: 106139 - 15 - 5

[0219] Sulfo - NHS N - Hydroxysulfosuccinimide

[0220] UV Ultraviolet

[0221] wt% Weight percentage

[0222] The AUM used in this article has the same composition as that described in Letters in Applied Microbiology 1997, 24, 203-206.

[0223] Example 1: Preparation of an anti-biofilm silicone Foley catheter

[0224] The following describes a coating process scheme for implementing an anti-biofilm coating on a catheter. It can be understood that this scheme can be applied to a single catheter.

[0225] PAA hydrogel

[0226] 1. Clean the catheter in ethanol for 1 minute.

[0227] 2. Dry the catheter at ambient temperature for 10 minutes.

[0228] 3. Immerse the catheter in an ethanol solution (5%) of photoinitiator BP, and then irradiate it with UV light for 30 seconds.

[0229] 4. Clean the catheter in ethanol for 30 seconds to remove excess BP.

[0230] 5. Prepare an aqueous monomer solution (10%) of acrylic acid: For every liter of acrylic acid solution: 900 ml of deionized water, 100 ml of acrylic acid, Mohr's salt (1.65 g), Cu(NO3)2 (1.65 g). Degas the solution by adding a stir bar to the flask, place the flask on a stirring plate and stir under vacuum until no more bubbles are visible. As used herein, Mohr's salt refers to ammonium ferrous sulfate.

[0231] 6. Immerse the catheter in the prepared aqueous monomer solution, and then irradiate it with UV light for about 4 minutes.

[0232] 7. During sonication, immerse the catheter in deionized water for 2 x 10 minutes.

[0233] 8. During sonication, immerse the catheter in ethanol for 60 minutes.

[0234] 9. Dry the catheter for 30 minutes.

[0235] Characterization of the hydrogel:

[0236] The surface concentration of grafted polyacrylic acid was determined by adding a known amount of NaOH (aq.) to the conduit segment in a test tube and then shaking the test tube for 4 to 24 hours. The remaining NaOH (aq.) was titrated with HCl (aq.), and the HCl consumed in the titration was used as the basis for calculating the number of carboxylic acid groups. Subsequently, the number of carboxylic acid groups was divided by the surface area of the conduit segment to obtain the surface concentration of the carboxylic acid groups of polyacrylic acid. The surface concentration of the carboxylic acid groups was found to reach 1 μmol / cm 2 to 30 μmol / cm 2 .

[0237] PDEA coupling process

[0238] 1. Prepare an EDC / NHS solution; the ratio is 4:1. 0.1 M / 0.025 M.

[0239] 2. Immerse the conduit in the EDC / NHS solution for about 10 minutes.

[0240] 3. Immerse the conduit in deionized water for 3 x 15 seconds.

[0241] 4. Prepare a PDEA solution in a borate buffer solution: for every 1 liter of borate buffer solution: Mix 6.18 g of H3BO3 with 1 L of deionized water. Adjust the pH to 8.5 using 1 M NaOH. Add 21 mg of PDEA to each liter of borate buffer solution and mix in a glass flask.

[0242] 5. Immerse the conduit in the PDEA solution for 10 minutes.

[0243] 6. Immerse the conduit in deionized water for 3 x 60 seconds.

[0244] 7. Immerse the conduit in 1 M phosphate buffer solution (pH 7.4) for 6 hours.

[0245] 8. Immerse the conduit in deionized water for 3 x 1 minute.

[0246] 9. Dry the conduit at ambient temperature for at least 6 hours.

[0247] Principle of the amount of PDEA bound

[0248] In one example, the PDEA loading was estimated to be 0.3 wt% based on the total weight of the coating. The principle of this estimate is based on the fact that the ratio of EDC / NHS + PDEA to polyacrylic acid is 1:1000. In other words, one of the 1000 carboxylic acid groups of polyacrylic acid reacts with PDEA, providing a loading of 0.3 wt% based on the total weight of the coating, corresponding to approximately 6 nmol / cm 2 .

[0249] Example 2: Test for biofilm formation and / or growth

[0250] As described in Example 1, silicone Foley catheter segments were functionalized with polyacrylic acid and PDEA. Each catheter segment had a size of 2 cm (16F).

[0251] Three uncoated catheter segments were provided as control samples. The control samples were sterilized by ethylene oxide. The control samples were designated as Sample A.

[0252] Three coated catheter segments were not sterilized. These samples were designated as Sample B.

[0253] Three coated catheter segments were sterilized using ethylene oxide. These samples were designated as Sample C.

[0254] The catheter segments of Samples A, B, and C were treated with Klebsiella pneumoniae according to the following protocol.

[0255] Scheme

[0256] 1. On the first day of the test, 1 ml of freshly prepared AUM solution containing 10 9 cfu / ml of Klebsiella pneumoniae (AO15200) was added to a test tube.

[0257] 2. The samples were incubated at 37 °C for 7 days, and the AUM solution was changed daily, except on weekends.

[0258] 3. On the 8th day, the samples were fixed as follows: a) 1% glutaraldehyde / PBS, 5 minutes; b) 60% ethanol, 15 minutes; c) 80% ethanol, 15 minutes; d) dried.

[0259] 4. The samples were stained in 0.04% aqueous crystal violet solution for 5 minutes, then rinsed and dried in MQ water. In this way, any bacteria or biofilm present on the sample surface would be stained.

[0260] 5. The samples were transferred to scotch tape and photographed.

[0261] 6. The crystal violet in the scotch tape segments was dissolved in 2 ml of 95% ethanol, and the optical density was measured using a spectrophotometer at a wavelength of 595 nm for quantification.

[0262] According to the protocol, the photographs showed clear staining of the segments of Sample A. In contrast, the segments of Samples B and C were substantially unstained.

[0263] In addition, the results of the spectrophotometric measurements are shown in Table 1.

[0264]

[0265] The average optical density of the samples in Table 1 was calculated, as Figure 1 shown. As shown in Table 1 and Figure 1 shown, the fragments of samples B and C were significantly less stained than those of sample A.

[0266] Based on the photographs and spectrophotometric measurements, it was concluded that, as observed for samples B and C respectively, in the presence of the coating containing PDEA, biofilm formation and / or growth was significantly reduced.

[0267] Example 3: Abrasion Resistance Test

[0268] In this example, the abrasion resistance of the coated catheter prepared as described in Example 1 was tested. Four different test methods were employed on the coated catheter or the coated tubing portion of the catheter (e.g., 6 cm in length), namely (1) dry pinch test, (2) wet pinch test, (3) gel pinch test, and (4) bending test. The test method protocols are described below.

[0269] Dry clamping test

[0270] It was carried out on the coated catheter or the coated tubing portion of the catheter (e.g., 6 cm in length).

[0271] 1. Hold the coated catheter (or the coated catheter portion), and gently pinch the coated catheter between the index finger and thumb with a hand wearing dry gloves. Gently rub the surface of the coated catheter longitudinally 10 times within a 4 cm area.

[0272] 2. Perform the staining test described herein on the abraded coated catheter (or the coated catheter portion), and compare it with the coated control (without dry abrasion) to visually evaluate any coating damage and resistance to minor abrasion.

[0273] Wet clamping test

[0274] It was carried out on the coated catheter or the coated tubing portion of the catheter (e.g., 6 cm in length).

[0275] 1. Hold the coated catheter (or the coated catheter portion), and gently pinch the coated catheter between the index finger and thumb with a hand wearing wet gloves. Gently rub the surface of the coated catheter longitudinally 10 times within a 4 cm area.

[0276] 2. Perform the staining test described herein on the abraded coated catheter (or the coated catheter portion), and compare it with the coated control (without wet abrasion) to visually evaluate any coating damage and resistance to minor abrasion.

[0277] Gel clamping test

[0278] Performed on a coated catheter or a coated tubing section of a catheter (e.g., 6 cm in length).

[0279] 1. Apply a large amount between the thumb and index finger of the hand wearing the dry glove Lidocaine gel (or the like).

[0280] 2. Hold the coated catheter (or coated catheter section), and gently pinch the coated catheter between the index finger and thumb with the hand wearing the glove coated with lidocaine gel (or the like). Gently rub the surface of the coated catheter longitudinally 10 times within a 4 cm area.

[0281] 3. After abrasion, the catheter or catheter fragment should be rinsed with deionized water to remove the excess gel on the surface.

[0282] 4. Perform the staining test described herein on the abraded coated catheter (or coated catheter section), and compare it with the coated control (no gel abrasion) to visually evaluate any coating damage and resistance to slight abrasion.

[0283] Bending test

[0284] Performed on a coated catheter or a coated tubing section of a catheter (e.g., 6 cm in length).

[0285] 1. Hold the coated catheter (or coated catheter section), and gently bend and twist the coated catheter 10 times with the hand wearing the dry glove.

[0286] 2. Perform the staining test described herein on the abraded coated catheter (or coated catheter section), and compare it with the coated control (no bending and twisting) to visually evaluate any coating damage and resistance to bending and twisting.

[0287] Staining test

[0288] The staining test described herein is performed by immersing the catheter or catheter tubing section in an aqueous solution containing crystal violet for 60 seconds. Thereafter, the catheter or catheter tubing section is removed from the aqueous solution and immersed in deionized water for 60 seconds, and then removed from the solution. Then, the color consistency, i.e., color uniformity, is visually evaluated. The coated area will be dyed purple / dark blue, while the uncoated area will not absorb the dye and thus will not be colored. The coating quality is also visually evaluated to check for any cracking, peeling, and / or delamination of the coating.

[0289] Each test method is repeated twice.

[0290] The results are shown in Table 2.

[0291]

[0292] As shown in Table 2, the coating did not wear during the test. The conclusion is that the coated medical devices described herein (such as the catheters described herein) are wear-resistant. Therefore, the coatings of the medical devices described herein are resistant to wear, such as wear during use.

[0293] Example 4: Cytotoxicity test

[0294] According to ISO standard ISO 10993-5:2009, the MTT cytotoxicity test was performed on the catheter fragments produced according to Example 1. MTT is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide salt. In this test, the yellow water-soluble MTT is metabolically reduced to blue-violet insoluble formazan in living cells. The number of living cells is related to the color intensity measured photometrically after dissolving the formazan in ethanol. No cytotoxicity was observed when the catheter fragments were subjected to the MTT test.

[0295] Example 5: Determination of the content of PDEA in the coating

[0296] To estimate the amount of PDEA bound in the coated catheter prepared in Example 1, L-cysteine was added to the coated sample in solution. When L-cysteine reacts with PDEA, 2-mercaptopyridine is released, which can be measured by ultraviolet spectrophotometry (342 nm), as shown in Scheme A below.

[0297]

[0298] Once the above reaction is complete, i.e., all PDEA has reacted with L-cysteine, the amount of 2-mercaptopyridine released represents the amount of PDEA present in the coating. Even if the PDEA is non-covalently (e.g., ionically) bound, the reaction will occur similarly (the scheme is not shown).

[0299] To ensure complete reaction, fresh L-cysteine solution was gradually added every 10 minutes until no additional 2-mercaptopyridine was detected, and the reaction was considered complete:

[0300] 1. Prepare a coated sample from a FR-16 size coated catheter. Two 5 cm catheter fragments were cut in half to obtain four samples, each with a total coated area of 13.5 cm 2 .

[0301] 2. Prepare 100 ml of L-cysteine solution (0.072 M).

[0302] 3. Add 5 ml of L-cysteine solution to the sample to initiate the reaction.

[0303] 4. After 10 minutes, remove the L-cysteine solution and measure 2-mercaptopyridine at 342 nm UV.

[0304] 5. Repeat steps (3) and (4) until no 2-mercaptopyridine can be detected.

[0305] Figure 2 Show the cumulative amount of 2-mercaptopyridine measured, and the PDEA that has reacted as measured in this way.

[0306] A total of 12 consecutive 10-minute coupling reactions were carried out. The total amount of PDEA present in the coating was determined to be 2.22 nmol / cm 2 . Roughly, within the first 10 minutes, half of the total PDEA (1 nmol / cm 2 ) reacted with L-cysteine, and no additional 2-mercaptopyridine was detected after 10 rounds of coupling.

[0307] Reference Example 6: Determination of the Amount of PDEA in the Coating of the Previous Generation Product

[0308] The previous coating specification applies to the type of silicone nasal cannula used in the first human study (Odeberg et al., see above). The purpose of this experiment was to measure the amounts of PDEA and cysteine ligand present in the previous generation coating.

[0309] The main component of the previous coating was polyacrylic acid. In the previous coating, free radical electron beam (EB) induced polymerization was used instead of UV induced polymerization in the above examples.

[0310] The amount of PAA in the previous coating was about 4 - 15 µmol / cm 2 .

[0311] Couple PDEA to the surface in a similar manner to Example 1, except for using higher concentrations of EDC / NHS and PDEA.

[0312] After PDEA coupling, couple the cysteine ligand according to Protocol B:

[0313]

[0314] Determine the amount of unreacted PDEA remaining using a method similar to Example 5 (except that 18 consecutive coupling reactions were carried out).

[0315] For the PDEA coupling intermediate, the cumulative amount of 2-mercaptopyridine measured and the PDEA that has reacted as measured thereby are as Figure 3 shown.

[0316] The 10-minute data points represent the manufacturing process. Thus, due to the relatively high amount of PDEA and the relatively short L-cysteine reaction time (10 minutes), not all of the PDEA was consumed during the previous coating process. Therefore, the previous coating contained both covalently bound PDEA and cysteine ligands.

[0317] From Figure 3 it can be seen that the total amount of coupled PDEA ligands during the manufacturing process was approximately 257 nmol / cm 2 .

[0318] After the first 10 minutes of cysteine coupling, the cumulative amount of 2-mercaptopyridine (representing unreacted PDEA) measured is as Figure 4 shown. Based on the results, the amount of remaining PDEA ligands after completion of the manufacturing process was estimated to be at least approximately 65 nmol / cm 2 .

[0319] In summary, the previous coating contained approximately 74% (191 nmol / cm 2 ) of cysteine ligands and 26% of PDEA (66 nmol / cm 2 ).

[0320] Compared to the coating of Example 1, the previous coating contained at least 25 times more bound PDEA than 2.2 nmol / cm 2 , i.e., > 65 nmol / cm 2 .

[0321] Example 7: Dose Response with Different Amounts of PDEA

[0322] The purpose of this experiment was to determine the dose-response curve for different levels of bound PDEA in the coating. The PDEA limit for coating inhibition of bacterial growth was of particular interest because of the change in its mode of action: from a biofilm prevention coating that was independent of bacterial growth inhibition (the present invention) to the previous "bacterial growth inhibition" coating specification.

[0323] Silicone-coated catheters of size Fr14 were PAA-grafted, and the samples were cut into 2.5 cm segments. The amount of PAA was titrated to be ~6.5 µmol / cm 2 (see Example 1).

[0324] Coupling was carried out using the same EDC / NHS concentration as in Example 1 but with different PDEA concentrations. The amount of bound PDEA was determined by measuring 2-mercaptopyridine released after the reaction of the sample with L-cysteine by UV (342 nm) (see the method description in Example 5). The results are shown in the following table:

[0325]

[0326] Antibacterial test - Ahearn test

[0327] Bacterial strain: Escherichia coli CFT073

[0328] Initial inoculum: 15 x 10 5 CFU / ml

[0329] Culture medium: Artificial Urine Medium (AUM)

[0330] Each test sample was repeated three times

[0331] The Ahearn test procedure was used to determine the colony forming units of bacteria on the surface and in AUM after 3 hours of incubation with the bacteria.

[0332] 1. Incubate the test sample (2.5 cm, Fr14, total surface area 5.8 cm 2 ) overnight in phosphate buffer at room temperature with slow rotation.

[0333] 2. Place the test specimen in a 2 ml tube.

[0334] 3. Place 2 ml of AUM containing Escherichia coli (15 x 10 5 CFU / ml) into the tube.

[0335] 4. Incubate these at 37 ± 2 °C for 3 hours.

[0336] 5. Take samples for dilution.

[0337] 6. Wash the samples with 2 x 2 ml PBS to remove loosely adherent bacteria: discard the bacterial suspension.

[0338] 7. After washing, place the samples in new 2 ml microcentrifuge tubes.

[0339] 8. To recover the adherent bacteria: add 1 ml of PBS containing 0.05% Tween-20 to each tube, vortex the tubes for 30 seconds, then sonicate for 5 minutes (in a Bransonic ultrasonic bath at a frequency of 40 kHz and an output power of 100 W under ambient conditions), and vortex again for 30 seconds.

[0340] 9. Prepare serial dilutions in PBS, spread with glass beads and count on LA plates. Plate dilutions 0, -10, -100.

[0341] The results are as Figure 5 (adherent bacteria) and Figure 6(Bacteria in the culture medium) as shown. The dose-response relationship indicates that starting from a range above 30 nmol / cm 2 both the bacteria on the catheter surface and in the artificial urine medium (AUM) were significantly inhibited. In contrast, lower binding amounts of PDEA had no inhibitory effect on bacterial growth. Conversely, compared to the control, the number of adherent bacteria on both the 6 nmol / cm 2 sample and the 13 nmol / cm 2 sample was actually slightly higher.

[0342] The half-maximal inhibitory concentration (IC50) value of the bound PDEA was estimated and shown to be 39 nmol / cm 2 on the surface and 30 nmol / cm 2 in the AUM (by interpolation).

[0343] The log reduction of the bound PDEA at 77 nmol / cm 2 was 1.55 log CFU / cm 2 and 2.77 log CFU / ml, which was consistent with the previously filed patent application (WO 2006 / 101438 A1) and the estimated amount of bound PDEA in the prior art coatings (more than 65 nmol / cm 2 ).

[0344] In summary, the "no bacterial growth inhibition" range of the bound PDEA was defined as less than 30 nmol / cm 2 .

[0345] Example 8: The coating of the present invention has no metabolic or pharmacological effects

[0346] The purpose of this experiment was to demonstrate that the coating of the present invention (referred to herein as CytaCoat) has no metabolic or pharmacological effects on bacteria. The tests included the following Gram-positive and Gram-negative bacteria.

[0347] Klebsiella pneumoniae AO15200 (clinical isolate)

[0348] Staphylococcus epidermidis Se19 (clinical isolate)

[0349] Uncoated and coated samples of silicone size Fr20 catheters were used in the tests:

[0350] Untreated catheter, 2 cm segment ("control")

[0351] CytaCoat catheter sample, 2 cm segment ("Cytacoat").

[0352] The "CytaCoat" material was manufactured as described in the previous examples, so the coating contains approximately 2.2 nmol / cm 2 of PDEA.

[0353] The experimental setup is as Figure 9 shown.

[0354] Week 1:

[0355] 1. Six catheter control samples and six CytaCoat catheter samples were used in the experiment.

[0356] 2. On the first day of testing, 1 ml of freshly prepared artificial urine (AUM) solution containing 10 9 cfu / ml of Klebsiella pneumoniae or Staphylococcus epidermidis cells was added to the tubes.

[0357] 3. The samples were incubated at 37 °C for 7 days, with AUM replaced daily, except on weekends.

[0358] 4. When replacing the AUM, the samples were washed twice with 1.5 ml of PBS in new microcentrifuge tubes and transferred to 1.5 ml of fresh AUM in new microcentrifuge tubes.

[0359] 5. On the 8th day, three samples were taken for crystal violet biofilm quantification. They were fixed as follows: a) 1% glutaraldehyde / PBS, 5 minutes; b) 60% ethanol, 15 minutes; c) 80% ethanol, 15 minutes; d) dried.

[0360] 6. These samples were stained in 0.04% aqueous crystal violet solution for 5 minutes, then rinsed and dried in Milli Q water. The biofilm was removed with a clean cotton swab, and the crystal violet was extracted with 1.5 ml of 95% EtOH for 3 hours, and the OD595nm was measured ( Figure 8 ).

[0361] 7. Aliquots were taken from the tubes containing the other three samples for serial dilution and colony counting to evaluate the colony-forming units in the liquid culture ( Figure 7 ).

[0362] 8. Those samples were washed twice with 1.5 ml of PBS in new microcentrifuge tubes and transferred to 1.5 ml of fresh AUM in new microcentrifuge tubes. The biofilm in these samples was removed and disrupted by treating with a handheld ultrasonic homogenizer cell disruptor cell sonicator for 30 seconds. Aliquots were taken for serial dilution and colony counting to evaluate the colony-forming units on the catheter ( Figure 7 ).

[0363] 9. Transfer the biofilm bacteria from the resulting AUM into fresh Eppendorf tubes, all of which contain control catheter segments, and continue the experiment for another week (see Week 2).

[0364] Week 2:

[0365] 10. Incubate the samples from the previous week's experiment at 37 °C for 7 days, changing the AUM daily except on weekends.

[0366] 11. On Day 15, take 2 samples for the crystal violet biofilm quantification procedure. Fix them as follows: a) 1% glutaraldehyde / PBS, 5 minutes; b) 60% ethanol, 15 minutes; c) 80% ethanol, 15 minutes; d) dry.

[0367] 12. Stain these samples in 0.04% aqueous crystal violet solution for 5 minutes, then rinse and dry in Milli Q water. Remove the biofilm with a clean cotton swab, extract the crystal violet with 1.5 ml of 95% EtOH for 3 hours, and measure OD595nm( Figure 8 )).

[0368] 13. Select 1 control sample and CytaCoat for microscopic visualization. Stain the sample segments with Ebba Biotech Red (680 nm) / Concanavalin A - Alexa probe as follows:

[0369] a) The working solution of the dye is prepared as follows: 1 μl of Ebba Biolight Red (630 nm) and 1 μl of Concanavalin A, Alexa FluorTM 594 Conjugate (50 μg / ml).

[0370] b) Place the sample segments in 1 ml of the staining solution and incubate in the dark at room temperature for 30 minutes.

[0371] c) After staining, briefly rinse the sample segments with water and additionally wash in 1 ml of water in the dark.

[0372] d) After staining, observe the sample segments under a fluorescence microscope.

[0373] Discussion

[0374] After the first week, both Klebsiella pneumoniae and Staphylococcus epidermidis phospholipids formed EPS / biofilms in the control, while there was little detectable biofilm on the CytaCoat catheter samples. After the second week, when the pre-exposed bacteria from the first week were transferred to the control catheters, they formed even more EPS / biofilms compared to week 1. Biofilm formation on the control surface in week 2 was independent of whether the bacteria were exposed to the CytaCoat catheter or the control catheter during week 1.

[0375] Conclusion

[0376] The CytaCoat surface does not impede the growth of Klebsiella pneumoniae AO15200 or Staphylococcus epidermidis Se19, while preventing normal biofilm formation. Additionally, the nature of the bacteria grown on the CytaCoat surface is unchanged and they retain the ability to form biofilms when transferred to the control silicone catheter surface.

[0377] The results suggest that the CytaCoat coating creates a local anti-biofilm environment and has no metabolic or pharmacological adjuvant effects on bacteria.

[0378] References

[0379] 1. WO 2006 / 101438 A1

[0380] 2. Letters in Applied Microbiology 1997, 24, 203 - 206

[0381] 3. Jacob Odeberg, Anders Wirsén, Åke Norberg, Jakob Frie, Gordana Printz, Hugo Lagercrantz, Gudmundur H Gudmundsson, Birgitta Agerberth, Baldvin Jonsson; A novel cysteine-linked antibacterial surface coating significantly inhibits bacterial colonization of nasal silicone prongs in a phase one pre-clinical trial. Mater Sci Eng C Mater Biol Appl 2018 Dec 1;93:782 - 789.

Claims

1. A medical device comprising a coating, the coating comprising: Polymer Z bound to the medical device And a moiety of formula A: , wherein X is an amino group, which is covalently bound to Z or can form an ionic bond with a free carboxyl group; wherein, The moiety according to formula A is present in the coating in an amount of 0.5 to 30 nmol / cm 2 ; and wherein the content of polymer Z is 1 to 30 µmol / cm 2 of free carboxyl groups.

2. The medical device according to any one of the preceding claims, wherein the coating comprises a structure of formula I: , wherein the circle represents the surface of the medical device.

3. The medical device according to any one of the preceding claims, wherein the coating comprises a moiety of formula A, wherein X is a primary amino group -NH2, a secondary amino group -NRH or a tertiary amino group -NR2, wherein each R is independently selected from C 1~4 alkyl.

4. The medical device according to any one of the preceding claims, wherein the coating comprises the following structure: .

5. The medical device according to any one of the preceding claims, wherein at least 20 mol% of the moiety according to formula A is covalently linked to Z.

6. The medical device according to any one of the preceding claims, wherein at least 20 mol% of the moiety according to formula A is ionically bound to the coating.

7. The medical device according to any one of the preceding claims, wherein the moiety according to formula A is present in the coating in an amount of 0.5 - 15 nmol / cm 2 .

8. The medical device according to any one of the preceding claims, wherein the polymer Z contains free carboxyl groups in an amount of 3 - 7 µmol / cm 2 .

9. The medical device according to any one of the preceding claims, the coating comprises 2-(pyridyldithio)ethylamine (PDEA) covalently bound to a polymer, the polymer being covalently bound to the medical device, wherein based on the total weight of the coating, the PDEA is present in an amount of 0.001 wt% to 1 wt%.

10. The medical device according to claim 9, wherein based on the total weight of the coating, the PDEA is present in an amount of 0.01 wt% to 1 wt%.

11. The medical device according to any one of the preceding claims, wherein the polymer Z is covalently bonded to the medical device.

12. The medical device according to any one of the preceding claims, wherein the coating comprises a polymer selected from the group consisting of polyacrylic acid, polymethacrylic acid, poly-4-vinylbenzoic acid, itaconic acid, any combination of the foregoing substances, and esters or amides thereof.

13. The medical device according to any one of the preceding claims, wherein the polymer Z comprises an acrylate polymer or an acrylic polymer, such as polyacrylic acid.

14. The medical device according to any one of the preceding claims, wherein the polymer Z of the coating is grafted from the medical device.

15. The medical device according to any one of the preceding claims, wherein the coating contains water, thereby forming a hydrogel.

16. The medical device according to any one of the preceding claims, wherein the medical device is selected from the group consisting of a catheter, an implant, an endotracheal tube, a stent, a ventilator, a wound dressing, a face mask, a nasal cannula, a hearing aid, and a syringe.

17. The medical device according to any one of the preceding claims, wherein the medical device is selected from the group consisting of a central venous catheter, a ureteral stent, a wound dressing, a ventilator, a face mask, a nasal cannula, and an implant.

18. The medical device according to any one of the preceding claims, wherein the medical device is a catheter (such as a Foley catheter) or an endotracheal tube.

19. The medical device according to any one of the preceding claims, wherein the medical device comprises a polymer, such as a thermoplastic and / or thermosetting polymer, and / or a metal.

20. The medical device according to claim 19, wherein the polymer comprises one or more of the following: silicone, polyethylene, polypropylene, polyurethane, polyvinyl chloride, polycaprolactone, polycarbonate, rubber (such as latex rubber), polyetheretherketone (PEEK), and / or the metal comprises one or more of the following: steel (such as stainless steel), an alloy (such as a cobalt-based alloy or nitinol), titanium.

21. The medical device according to any one of the preceding claims, wherein the coating is present on at least a portion of the inner surface and / or the outer surface of the medical device.

22. The medical device according to any one of the preceding claims, wherein the medical device has no or substantially no biofilm after 4 days or more (such as 30 days) of clinical use.

23. A coating for a medical device, wherein the coating is defined as in any one of the preceding claims.

24. Use of a coating for reducing biofilm formation and / or growth on the surface of a medical device, the coating comprising: Polymer Z bound to the medical device and a moiety of formula A , wherein X is an amino group which is covalently bound to Z or can form an ionic bond with a free carboxyl group; and wherein the polymer Z is capable of forming a hydrogel upon contact with an aqueous fluid.

25. Use according to claim 24, wherein the polymer Z is covalently bound to the medical device.

26. Use according to claim 24 or 25, wherein Z comprises free carboxyl groups.

27. Use according to claim 26, wherein Z comprises free carboxyl groups in an amount of 1 to 30 µmol / cm 2 of the free carboxyl groups.

28. Use according to claim 27, wherein Z comprises free carboxyl groups in an amount of 3 to 20 µmol / cm 2 of the free carboxyl groups.

29. Use according to any one of claims 24 to 28, wherein the coating comprises a structure of formula I: , wherein the circle represents the surface of the medical device.

30. A medical device according to any one of claims 24 to 29, wherein the coating comprises a moiety of formula A, wherein X is a primary amino group -NH2, a secondary amino group -NRH or a tertiary amino group -NR2, wherein each R is independently selected from C 1~4 alkyl.

31. Use according to any one of claims 24 to 30, wherein the coating comprises the following structure: .

32. Use according to any one of claims 24 to 31, wherein at least 20 mol% of the moiety according to formula A is covalently linked to Z.

33. Use according to any one of claims 24 to 32, wherein at least 20 mol% of the moiety according to formula A is ionically bound to the coating.

34. Use according to any one of claims 24 to 33, wherein the moiety according to formula A is present in the coating in an amount of 0.5 to 30 nmol / cm 2 of the amount.

35. Use according to claim 34, wherein the moiety according to formula A is present in the coating in an amount of 0.5 to 15 nmol / cm 2 .

36. Use according to any one of claims 24 to 35, wherein the coating comprises a polymer selected from the group consisting of polyacrylic acid, polymethacrylic acid, poly-4-vinylbenzoic acid, itaconic acid, any combination of the foregoing substances, and esters or amides thereof.

37. Use according to any one of claims 24 to 36, wherein the polymer Z comprises an acrylate polymer or an acrylic polymer, such as polyacrylic acid.

38. Use according to any one of claims 24 to 37, wherein the polymer Z of the coating is grafted from the medical device.

39. Use according to any one of claims 24 to 38, wherein the coating is defined as in any one of claims 1 to 22.

40. Use according to any one of claims 24 to 39, wherein the alleviation does not involve bactericidal or bacteriostatic effects.

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