Hydrophilic Coating for Vascular Medical Products

Abstract

The present invention relates to the use of a UV-sensitive copolymer and a hydrophilic coating comprising the copolymer for coating the surface of a vascular medical product. The UV-sensitive copolymer comprises repeating units of (a) vinyl pyrrolidone and (b) perfluorophenyl azide, the copolymer has a statistical distribution of repeating units (a) and (b), and has a molecular weight of 5,000 to 50,000 g / mol. The present invention further relates to a method for coating the surface of a vascular medical product, and to the resulting coated vascular medical product.

Description

Technical Field

[0001] Applicant: Biotronik Date: 23.05.2023 Reference Number: 21.152P-WO The present invention generally relates to hydrophilic coatings for the surface of vascular medical products. In particular, the present invention relates to the use of specific hydrophilic copolymers that can be covalently bonded to the surface of vascular medical products by UV irradiation. Furthermore, the present invention relates to the use of coating compositions containing specific copolymers and to a method for coating the surface of vascular medical products in order to provide a coating for vascular medical products.

Background Art

[0002] It is generally known to coat vascular medical products such as catheters, balloon parts, or pacemaker electrodes with hydrophilic polymers. Vascular medical devices require lubricious coatings to facilitate insertion into blood vessels and minimize damage to the blood vessels. Lubrication is achieved by hydrophilic coatings that absorb water and become slippery. However, known systems are either expensive due to the chemicals used or do not reliably meet the requirements for permanent coatings for implantable medical products, particularly a very low number of released particles and / or low friction against blood vessels. It is further known that hydrophobic surfaces such as polyolefins or polysiloxanes are difficult to coat with hydrophilic compounds.

[0003] Therefore, there is a need to provide improved coatings for vascular medical products that overcome the problems of the prior art. In particular, the coating should be hydrophilic, easy to perform, or capable of being automatically applied. The coating should be applicable to surfaces that are difficult to coat, such as hydrophobic surfaces. Furthermore, the coating should result in low friction against a friction partner, such as a blood vessel, and the release of a very small number of particles.

[0004] This problem is solved by a method for coating the surface of a vascular medical product with the copolymer coating according to claim 1, and by the vascular medical product according to claim 12. Preferred embodiments are described in the dependent claims. SUMMARY OF THE INVENTION

[0005] A method for coating the surface of a vascular medical product or at least a part thereof with a copolymer coating, wherein the copolymer coating is applied to the vascular medical product, and the copolymer coating comprises at least a) repeating units of vinyl pyrrolidone, and b) at least one perfluorophenyl azide moiety comprises or consists of at least one of the following copolymers, Optionally, the method is described wherein the applied copolymer coating is dried and / or irradiated by UV irradiation.

[0006] Thus, a method for coating the surface of a vascular medical product or at least a part thereof with a copolymer coating according to the following chemical process,

Chemical formula

[0007] The copolymer coating may be applied to the vascular medical product or at least a part of its surface by dip coating, spray coating, roller coating, printing, painting, or by means of a doctor blade, doctor roller, or Langmuir-Blodgett film, and then the applied composition is dried and irradiated with UV light. The vascular medical product or at least a part of its surface may be immersed in the coating composition and withdrawn from the coating composition at a specified rate to obtain a specified coating thickness. The method may be carried out in an automated manner.

[0008] The vascular medical product or at least a part of its surface may comprise a polymer selected from thermoplastic elastomers, polyamides, polyether block amides, thermoplastic polyurethanes (TPU), polyesters, polyester-based elastomers, polyolefins, vinyl polymers, polysiloxanes, and combinations thereof, preferably selected from thermoplastic elastomers, polyamides, polyether block amides, thermoplastic polyurethanes (TPU), thermoplastic elastomers (TPE), such as thermoplastic elastomers containing polyamide and polyether blocks, preferably polyether block amides (e.g., Pebax or Vestamid).

[0009] Accordingly, the resulting vascular medical product comprises at least one of the following copolymers or is coated with a (hydrophilic) copolymer coating consisting of the following copolymers.

Chemical formula

[0010] Accordingly, there is described a vascular medical product or at least a part thereof comprising a copolymer coating, wherein the copolymer coating is bonded to the surface of the vascular medical product and comprises at least one of the following copolymers or consists of the following copolymers.

Chemical formula

[0011] The above (hydrophilic) polymer coating that absorbs water and thereby becomes slippery enables lubrication in the body of a human or animal (e.g., intravascularly). The (hydrophilic) polymer coating has mechanical resistance. The (hydrophilic) polymer coating chemically binds to a vascular medical product or at least a part of its surface. Accordingly, the particles are not released from the surface, and thus the (hydrophilic) polymer coating reduces the risks of thrombosis, embolism, and arterial occlusion. The (hydrophilic) polymer coating exhibits very good slipperiness and abrasion resistance as compared with products of the prior art.

[0012] Water-soluble polyvinylpyrrolidone (PVP) is helpful for hydrophilicity. Monofunctional and polyfunctional perfluorophenyl azide (PFPA) copolymers can be used for crosslinking and chemical bonding to a vascular medical product or a part thereof, e.g., the surface of an (interventional) catheter.

[0013] In one embodiment, the vascular medical product may include a (hydrophilic) polymer coating, and the (hydrophilic) polymer coating includes or consists of the following polymers:

Chemical formula

[0014] In another embodiment, the vascular medical product may include a (hydrophilic) polymer coating, and the (hydrophilic) polymer coating includes or consists of the following polymers:

Chemical formula

[0015] In a further embodiment, the vascular medical product may include a (hydrophilic) copolymer coating, and the (hydrophilic) copolymer coating includes or consists of the following copolymers:

Chemical formula

[0016] The (hydrophilic) copolymer coating may preferably be (covalently) bonded to the surface of the vascular medical product via a carbon-nitrogen (C-N) bond.

[0017] The vascular medical product is a medical product or a part thereof intended to be implanted or introduced into a blood vessel, particularly in the fields of electrophysiology, cardiac rhythm management, nerve stimulation, vascular and endovascular interventions, and intracardiac and cardiac interventions. The vascular medical product may be selected from a coronary or peripheral catheter or a part thereof, a CRM device or part, a balloon part, or a pacemaker electrode. The surface of the vascular medical product may include or be made of a polymer selected from thermoplastic elastomers, polyamides, polyether block amides, thermoplastic polyurethanes (TPU), polyesters, polyester-based elastomers, polyolefins, vinyl polymers, polysiloxanes, and combinations thereof, preferably polyamides, polyether block amides, thermoplastic polyurethanes (TPU), thermoplastic elastomers (TPE), such as thermoplastic elastomers including polyamides and polyether blocks, preferably polyether block amides (e.g., Pebax or Vestamid).

[0018] (Hydrophilic) copolymer coatings may be applied to vascular medical products or parts thereof, such as (interventional) catheters (hoses), via a dip coating process.

[0019] Also disclosed is a vascular medical product comprising a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises the following segments: - azide, - an aromatic moiety bonded to the azide, - an ester bonded to the aromatic moiety, - at least one hydrophilic repeating unit bonded to the ester and consisting of or comprising.

[0020] In one embodiment, the vascular medical product comprises a (hydrophilic) copolymer coating, and the (hydrophilic) copolymer coating comprises the following segments: - azide, - a perfluorophenyl moiety bonded to the azide, an ester bonded to the perfluorophenyl moiety, - an acrylate or methacrylate or a repeating unit of acrylate or methacrylate bonded to the ester, - a repeating unit of vinylpyrrolidone bonded to the acrylate or methacrylate, or a repeating unit of acrylate or methacrylate, and optionally, - a repeating unit bonded to the vinylpyrrolidone repeating unit, the repeating unit being a repeating unit selected from 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl (meth) acrylate and N,N-dimethylacrylamide (DMA) and consisting of or comprising.

[0021] Due to its hydrophobicity, phenyl azide can preferably bind to hydrophobic surfaces, such as the hydrophobic surfaces of vascular medical products. The aromatic moiety, preferably the perfluorophenyl moiety, is configured to absorb UV irradiation and activate the azide. The azide is a reactive group that can form a highly reactive nitrene intermediate by separating dinitrogen (N 2 ) upon activation, preferably upon UV irradiation, and insert it into the C-H bond on the surface of the vascular medical product. Thus, the azide or the copolymer containing an azide group will covalently bond to the surface of the vascular medical product. (Poly)vinylpyrrolidone provides hydrophilic properties.

[0022] Furthermore, the present invention at least partially meets this need by providing the use of a UV-sensitive copolymer for coating the surface of a vascular medical product, the UV-sensitive copolymer comprising at least (a) repeating units of vinylpyrrolidone and (b) perfluorophenyl azide, the copolymer having a statistical distribution of the repeating units (a) and (b) and having a molecular weight of 5,000 to 50,000 g / mol. The present invention further relates to the use of a coating composition for coating the surface of a vascular medical product, wherein the coating composition contains the copolymer, a method for coating the surface of a vascular medical product, and the resulting coated vascular medical product.

[0023] Vascular medical products can be related to, for example, but not limited to, medical products or parts thereof that can be inserted or introduced into blood vessels, or are (intended to be) inserted or introduced, in the fields of electrophysiology, cardiac rhythm management, nerve stimulation, vascular or endovascular intervention, and cardiac intervention.

[0024] The surface of the vascular medical product comprises a polymer selected from thermoplastic elastomers (TPE), polyamides, polyether block amides, thermoplastic polyurethanes (TPU), polyesters, polyester-based elastomers, polyolefins, vinyl polymers, polysiloxanes, and combinations thereof. The surface of the vascular medical product preferably comprises a polymer selected from thermoplastic elastomers, polyamides, polyether block amides, thermoplastic polyurethanes (TPU), thermoplastic elastomers (TPE), such as thermoplastic elastomers containing polyamides and polyether blocks, preferably polyether block amides (e.g., Pebax or Vestamid). Polyether block amides are block copolymers obtained by polycondensation of carboxylic acid polyamides (PA6, PA11, or PA12) and alcohol-terminated polyethers (polytetramethylene glycol (PTMG) or PEG).

[0025] As used herein, the term “(meth)acrylate” is used to denote “acrylate” or “methacrylate” as commonly used in the art.

[0026] As used herein, the term “slip-friendly” in the context of the surface of a vascular medical product means that the vascular medical product can be inserted into the body without causing damage and / or without causing pain or discomfort to the patient.

[0027] Further examples of the present disclosure are provided below.

[0028] Example 1. A vascular medical product comprising a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises a copolymer having the following segments: - azide, - an aromatic moiety bonded to the azide, - an ester bonded to the aromatic moiety, - at least one hydrophilic repeating unit bonded to the ester and comprising or consisting of a copolymer having the segments.

[0029] Example 2. A vascular medical product as described in Example 1, comprising a (hydrophilic) polymer coating, wherein the (hydrophilic) polymer comprises the following segments: - azide, - an aromatic moiety bonded to the azide, - an ester bonded to the aromatic moiety, - acrylate or methacrylate bonded to the ester, or a repeating unit of acrylate or methacrylate, - a repeating unit of vinylpyrrolidone bonded to the acrylate or methacrylate, or a repeating unit of acrylate or methacrylate, and optionally, - a repeating unit bonded to the vinylpyrrolidone repeating unit, wherein the repeating unit is a repeating unit selected from 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl (meth) acrylate, and N,N-dimethylacrylamide (DMA). The vascular medical product according to Example 1.

[0030] Example 3. A vascular medical product comprising a (hydrophilic) coating, wherein the (hydrophilic) coating comprises at least a) a repeating unit of vinylpyrrolidone, and b) at least one copolymer having at least one perfluorophenyl azide moiety The vascular medical product according to Example 3.

[0031] Example 4. The vascular medical product according to Example 3, wherein the repeating unit of vinylpyrrolidone comprises more monomer units than the repeating unit of the perfluorophenyl azide moiety.

[0032] Example 5. The vascular medical product according to Example 3 or 4, wherein the copolymer comprises 1 to 50 mol% of repeating unit a) and 0.1 to 5 mol% of repeating unit b).

[0033] Example 6. The vascular medical product according to any one of Examples 3 to 5, wherein the copolymer has a statistical distribution of repeating units a) and b).

[0034] Example 7. The vascular medical product according to any one of Examples 3 to 6, wherein the copolymer further comprises at least one repeating unit c) selected from 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl(meth)acrylate, and N,N-dimethylacrylamide (DMA).

[0035] Example 8. The vascular medical product according to Example 7, wherein the copolymer preferably contains 1 to 20 mol% of repeating unit c) in a statistical distribution.

[0036] Example 9. The vascular medical product according to any one of the preceding examples, wherein the copolymer has a molecular weight of 5,000 to 50,000 g / mol.

[0037] Example 10. The vascular medical product according to any one of the examples, wherein the (hydrophilic) copolymer coating is preferably (covalently) bonded to the surface of the vascular medical product via a carbon-nitrogen (C-N) bond.

[0038] Example 11. The vascular medical product according to any one of the examples, which is a medical product or a part thereof intended to be implanted or introduced into a blood vessel, particularly in the fields of electrophysiology, cardiac rhythm management, nerve stimulation, vascular and endovascular interventions, and intracardiac and cardiac interventions.

[0039] Example 12. The vascular medical product according to any one of the examples, which is selected from a coronary or peripheral catheter or a part thereof, a CRM device or a part thereof, a balloon part, or a pacemaker electrode.

[0040] Example 13. The surface of the vascular medical product comprises or is made from a polymer selected from thermoplastic elastomers, polyamides, polyether block amides, thermoplastic polyurethanes (TPU), polyesters, polyester-based elastomers, polyolefins, vinyl polymers, polysiloxanes, and combinations thereof, preferably polyamides, polyether block amides, thermoplastic polyurethanes (TPU), thermoplastic elastomers (TPE), such as a thermoplastic elastomer comprising a polyamide and a polyether block, preferably a polyether block amide (e.g., Pebax or Vestamid), and is a vascular medical product according to any one of the examples.

[0041] Example 14. Use of a copolymer coating for coating the surface of a vascular medical product, wherein the copolymer coating comprises or consists of a copolymer having at least a) repeating units of vinyl pyrrolidone, and b) at least one perfluorophenyl azide moiety, and optionally c) repeating units selected from 2-hydroxyethyl methacrylate, N,N-dimethyl(meth)acrylate, and N,N-dimethylacrylamide and is a use.

[0042] Example 15. Use of a (UV-sensitive, hydrophilic) copolymer for coating the surface of a vascular medical product, wherein the (UV-sensitive, hydrophilic) copolymer comprises at least (a) vinyl pyrrolidone, and (b) perfluorophenyl azide in repeating units, the repeating units of vinyl pyrrolidone contain more monomer units than the repeating units of perfluorophenyl azide, the copolymer has a statistical distribution of repeating units (a) and (b) and has a molecular weight of 5,000 to 50,000 g / mol, and is a use.

[0043] Use according to Example 14 or 15, wherein the copolymer comprises 1 to 50 mol% of repeating unit (a) and 0.1 to 5 mol% of repeating unit (b).

[0044] Use according to Example 14, wherein the copolymer preferably comprises 1 to 20 mol% of repeating unit (c) in a statistical distribution.

[0045] Use of a (UV-sensitive, hydrophilic) copolymer for coating the surface of a vascular medical product, wherein the copolymer comprises the following repeating units:

Chemical formula

[0046] Use of a (UV-sensitive, hydrophilic) copolymer for coating the surface of a vascular medical product, wherein the copolymer comprises the following repeating units:

Chemical formula

Chemical formula

[0047] Use of a coating composition for coating the surface of a vascular medical product, wherein the coating composition comprises a) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of less than 1,000,000 g / mol, b) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of more than 1,000,000 g / mol, c) 0.1 to 5% by weight of a copolymer as defined in any one of the examples of the preceding claims, and d) 0 to 1% by weight of a polyfunctional UV-sensitive low molecular weight phenyl azide compound having a UV absorption in the range of 200 to 300 nm comprising, components (a) to (d) being dissolved in 50 to 90% by volume of alcohol, preferably ethanol and / or 2-propanol, and 10 to 50% by volume of water, use.

[0048] Example 21. The use according to Example 20, wherein the phenyl azide compound d) is a triazide, a polyethylene glycol-based bisazide, a diol bisazide, and / or an ionic bisazide.

[0049] Subsequently, embodiments of the present invention will be described in detail with reference to the drawings. It should be noted that the embodiments are not limiting to the present invention and merely represent exemplary examples.

Brief Description of the Drawings

[0050]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

[0051] The copolymers used in accordance with the present invention comprise at least repeating units of vinyl pyrrolidone (VP) and repeating units of perfluorophenyl azide (PFPA), preferably perfluorobenzoyl (meth) acrylate azide. The repeating units of vinyl pyrrolidone contain more monomer units than the repeating units of perfluorophenyl azide contain monomer units (PFPA). Preferably, the repeating units of vinyl pyrrolidone (VP) contain 15 to 35 VP units, more preferably 20 to 30 VP units. Preferably, the repeating units of PFPA contain 1 to 3 PFPA units, more preferably 1 or 2 PFPA units, and most preferably 1 PFPA unit. Exemplary copolymers include the following repeating units: [Chemical formula] (wherein n is an integer of 1, 2 or 3, preferably 1 or 2, m is an integer in the range of 15 to 35, and R is H or CH 3 3.)

[0052] The repeating unit of polyvinylpyrrolidone imparts hydrophilic and slippery properties to the coating obtained by using the copolymer. The perfluorophenyl azide unit enables the copolymer to be covalently bonded or attached to the surface, particularly to polymer or siloxane materials, via an azide group that can be activated by UV radiation. The reaction mechanism of activation by the azide group is known from the papers of Siegmann, K., Inauen, J., Villamaina, D. and Winkler, M., "Photografting of perfluoroalkanes onto polyethylene surfaces via azide / nitrene chemistry" Applied Surface Science, 396 672-680 (2017), and Siegmann, K., Inauen, J., Sterchi, R. and Winkler, M., "Spectroscopy on photografted polyethylene surfaces using a perfluorophenyl azide: Evidence for covalent attachment.." Surface and Interface Analysis, 50(2) 205-211 (2018). The mechanism in which R represents the corresponding residue of the perfluorophenyl azide unit is shown below: [Chemical formula]

[0053] When UV activation is carried out at a wavelength preferably of 200 to 350 nm, more preferably 240 to 320 nm, the azide group is converted into a separating nitrogen molecule and a highly reactive nitrene, which undergoes a very fast non-specific insertion reaction into the C-X bond of the substrate, such as a C-H bond. Since there are several PFPA repeating groups, and thus several azide groups, in the copolymer, the copolymer can form covalent bonds and thus permanently adhere to the substrate at some of these positions.

[0054] The copolymer has a statistical distribution of VP repeating units (a) and PFPA repeating units (b) and has a molecular weight of 5,000 to 50,000 g / mol, preferably 10,000 to 45,000 g / mol.

[0055] In a preferred embodiment, the copolymer further comprises repeating units (c) derived from additional hydrophilic repeating units such as 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl(meth)acrylate, and N,N-dimethylacrylamide (DMA). The additional repeating units further improve the hydrophilic and slip performance of the coating obtained by using the copolymer.

[0056] Exemplary copolymers can include the following repeating units:

Chemical formula

[0057] Another exemplary copolymer can include the following repeating units:

Chemical formula

[0058] In a preferred embodiment, the copolymer used according to the present invention comprises 1 to 50 mol% of vinylpyrrolidone repeating units (a), preferably 5 to 45 mol% of vinylpyrrolidone repeating units (a), and 0.1 to 5 mol% of PFPA repeating units (b), preferably 1 to 5 mol% of PFPA repeating units (b). In an exemplary copolymer containing further repeating units (c) as described above, the copolymer comprises 1 to 20 mol% of repeating units (c). In a more preferred embodiment, the repeating units (a), (b) and (c) are statistically distributed.

[0059] The copolymer used according to the present invention comprises at least the following steps: (a) esterifying perfluorobenzoyl chloride with 2-hydroxyethyl (meth)acrylate; (b) reacting the product obtained in step (a) with sodium azide to obtain 4-azidopentafluorophenyl acrylate; and (c) copolymerizing 4-azidopentafluorophenyl acrylate of step (b) with vinylpyrrolidone using a radical initiator It can be prepared by a method comprising.

[0060] The esterification step (a) may be carried out as described in the following reaction scheme: [Chemical formula]

[0061] As shown, perfluorobenzoyl chloride is reacted with 2-hydroxyethyl (meth)acrylate where R represents H or methyl in triethylamine. In an exemplary embodiment, the reaction is carried out in dichloromethane at about 0 °C for about 12 hours. Exemplary yields are 98% for R = H and 95% for R = methyl. The resulting compound can be characterized, for example, by FT-IR, 1 H and 19 19F-NMR spectroscopy.

[0062] Preferably, the compound obtained after step (a) is as shown below (left: methacrylate, right: acrylate):

Chemical formula

[0063] It is also possible to use acrylamide or vinyl ether instead of 2-hydroxyethyl (meth)acrylate to obtain the following compounds (left: acrylamide, right: vinyl ether):

Chemical formula

[0064] After step (a), the product is reacted with an azide, preferably sodium azide. The reaction can be carried out under appropriate conditions, for example, at room temperature for 24 hours. In step (b), an azide group is introduced by substituting the F atom of the perfluorophenyl ring.

[0065] In step (c), the product obtained in step (b) is polymerized with vinyl pyrrolidone, where vinyl pyrrolidone is used in excess over azidoperfluorophenyl acrylate. The copolymerization is initiated using a radical polymerization initiator, such as AIBN or dibenzoyl peroxide (BPO). The copolymerization is carried out by methods known in the art.

[0066] An exemplary method having steps (a) to (c) is shown in the following scheme (esterification, azide substitution, polymerization):

Chemical formula

[0067] The polymerization can be optimized by adding the azidoperfluorophenyl (meth) acrylate, for example, via a syringe pump and / or over a period of 4 to 8 hours. The addition of acrylate over a period of 4 to 8 hours promotes the formation of a copolymer having a statistical distribution of repeating units due to the different copolymerization parameters of the monomers used, such as their different reaction rates. In contrast, rapid addition of acrylate (less than 4 hours) and / or addition without using a syringe pump promotes the formation of block copolymers. As an example, for methacrylate, r = about 3.9, and for vinylpyrrolidone, r = 0.004. Figure 1 shows an exemplary procedure. According to Figure 1, the azidoperfluorophenyl (meth) acrylate is slowly added (via a syringe pump) into a polymerization vessel containing vinylpyrrolidone and an initiator (e.g., AIBN as shown) over a period of, for example, 4 to 8 hours.

[0068] For an exemplary copolymer of the present invention, Figure 2 shows the molecular weight distribution by GPC (gel permeation chromatography) in units of normalized intensity versus molar mass (g / mol). A unimodal distribution is obtained.

[0069] Figures 3 and 4 show 19 F-NMR and 1 H-NMR spectra. Figure 4 also shows how the ratio of the two repeating units to each other or the two parameters m and n can be determined from the H-NMR spectrum by H atoms at specific positions. 1

[0070] For another exemplary copolymer 1 ​H-NMR, 19 F-NMR and FT-IR spectra (transmittance vs. wavenumber (cm -1 )), and the molecular weight distribution are shown in Figure 5.

[0071] In an exemplary embodiment, the copolymerization is carried out using benzoyl peroxide (BPO) in N,N-dimethyl-p-toluidine (DMT) at room temperature. The appropriate reaction scheme is shown below:

Chem.

[0072] Alternatively, the copolymerization can be carried out using reversible addition-fragmentation chain transfer (RAFT) polymerization in the presence of BPO, DMT, and benzyl 1H-imidazole-1-carbodithioate (BICDT). The appropriate reaction is shown below:

Chem.

[0073] In the described preparation method using steps (a), (b), and (c), it is also possible to change the order of steps (b) and (c), i.e., the copolymerization is carried out before azide substitution. An exemplary reaction pathway is shown below (top: free radical polymerization, bottom: azide substitution):

Chem.

[0074] In a more preferred embodiment of the present invention, the copolymerization in step (c) is carried out in the presence of additional monomers such as 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl(meth)acrylate, and N,N-dimethylacrylamide (DMA). Exemplary repeating units are shown below:

Chem.

[0075] Exemplary copolymers include at least one of the following repeating units:

Chemical formula

Chemical formula

Chemical formula

[0076] The present invention further relates to the use of a coating composition for coating the surface of a vascular medical product, wherein the coating composition comprises a) 0.1 to 10 wt% of polyvinylpyrrolidone having a molecular weight of less than 1,000,000 g / mol, b) 0.1 to 10 wt% of polyvinylpyrrolidone having a molecular weight of more than 1,000,000 g / mol, c) 0.1 to 5 wt% of the copolymer of the present invention, and d) 0 to 1 wt% of a polyfunctional UV-sensitive low molecular weight phenyl azide compound having a UV absorption preferably in the range of 200 to 300 nm is provided.

[0077] Components a) to d) are dissolved in an aqueous alcohol, preferably an alcohol of 50 to 90% by volume and water of 10 to 50% by volume. The alcohol is preferably ethanol and / or 2-propanol.

[0078] The copolymer c) is the copolymer described above.

[0079] The phenyl azide compound d) is preferably a triazide, a polyethylene glycol-based bisazide, a diol bisazide, and / or an ionic bisazide. Exemplary polyfunctional phenyl azide compounds are shown below (in this order, triazide, PEG-bisazide, diol-bisazide, ionic bisazide):

Chemical formula

[0080] The present invention further provides a method for coating the surface of a vascular medical product. In this method, the coating composition of the present invention or the above-described coating composition is applied to the surface of the vascular medical product by a procedure known in the art. Suitable coating methods are dip coating, spray coating, roller coating, printing, or painting. The coating composition may also be applied by a doctor blade, a doctor roller, or a Langmuir-Blodgett film. The preferred method is dip coating. After application to the surface, the applied composition is dried. Thereafter, the composition is irradiated with UV light. The UV light preferably has a wavelength in the range of 200 to 350 nm, more preferably 240 to 320 nm. Suitable wavelengths are, for example, 254 nm or 265 nm by using an Hg lamp.

[0081] Figure 6 schematically shows the adhesion of the copolymer to the substrate. In Figure 6, the adhesion points 1 to the surface of the substrate 2 represent the perfluoro groups of the copolymer. The points shown as not adhering to the surface represent hydrophilic groups such as polyvinylpyrrolidone units. The covalent bonding of the copolymer to the surface (after UV irradiation) can be analyzed by FT-IR, for example, through the disappearance of the azide peak, which appears at 2134 cm -1 in the spectrum before UV irradiation.

[0082] In a preferred embodiment, the substrate is immersed in the coating composition and withdrawn from the coating composition at a defined rate to obtain a defined coating thickness. The film thickness of the coating can be determined by the Landau-Levich equation:

Equation

[0083] The substrate of the vascular medical product can include a polymer selected from polyamide, such as polyamide 11 or polyamide 12, polyether block amide, thermoplastic polyurethane (TPU), polyester, such as PET, or polyester-based elastomer, polyolefin, such as HDPE, LDPE, PP or olefin copolymer, vinyl polymer, such as polystyrene, polysiloxane, and combinations of one or more thereof.

[0084] In a preferred embodiment of the present invention, the vascular medical product is a medical product or a part thereof intended to be implanted or introduced into blood vessels, particularly in the fields of electrophysiology, cardiac rhythm management, nerve stimulation, vascular and endovascular interventions, and intracardiac and cardiac interventions. Particularly preferred vascular medical products are selected from coronary or peripheral catheters or parts thereof, CRM devices or parts, balloon parts, or pacemaker electrodes.

[0085] In another preferred embodiment, the coating method of the present invention is performed in an automated manner.

[0086] The present invention further provides a coated vascular medical product obtained by the coating according to the present invention or by the coating method described above.

[0087] The coating obtained by the present invention exhibits low friction against a friction partner, e.g., a blood vessel, and very few particle emissions. The particle emissions can be determined, for example, by a particle counter using a simulated use model according to ASTM F2394-07(2017), X.2.4. In an exemplary embodiment of a catheter having a hydrophilic coating particle, the desired value is less than 2000 particle emissions, where the limit for particles exceeding 10 μm is 6000 particles. The friction of the coating can be determined by the coefficient of friction COF.

Claims

1. A method for coating a vascular medical product or at least a part of its surface with a copolymer coating, wherein the copolymer coating is applied to the vascular medical product, the copolymer coating comprising at least a) repeating units of vinyl pyrrolidone, and b) at least one perfluorophenyl azide moiety and optionally being dried and / or irradiated by UV irradiation, wherein the applied copolymer coating is dried and / or irradiated by UV irradiation.

2. The method according to claim 1, wherein the copolymer coating is applied to the surface by dip coating, spray coating, roller coating, printing, painting or by means of a doctor blade, doctor roller or Langmuir - Blodgett film.

3. The method according to claim 2, wherein the copolymer coating is applied to the vascular medical product via a copolymer coating solution.

4. The method according to claim 3, wherein in the copolymer coating solution, the copolymer is dissolved in 50 - 90% by volume of alcohol, preferably ethanol and / or 2 - propanol, and 10 - 50% by volume of water.

5. The method according to any one of the preceding claims, wherein the surface of the vascular medical product comprises or is made of a polymer selected from polyamide, polyether block amide, thermoplastic polyurethane (TPU), polyester, polyester - based elastomer, thermoplastic elastomer, polyolefin, vinyl polymer, polysiloxane, and combinations thereof.

6. The method according to any one of the preceding claims, wherein the copolymer comprises 1 - 50 mol% of repeating unit a) and 0.1 - 5 mol% of repeating unit b).

7. The copolymer coating comprising i) 0.1 - 10% by weight of polyvinyl pyrrolidone having a molecular weight of less than 1,000,000 g / mol, ii) 0.1 - 10% by weight of polyvinyl pyrrolidone having a molecular weight of more than 1,000,000 g / mol, iii) more than 0% by weight and up to 6% by weight of perfluorophenyl azide and being a method according to any one of claims 1 - 5.

8. The method according to claim 7, wherein more than 0% by weight and up to 0.3% by weight is the perfluorophenyl azide.

9. The method according to any one of the preceding claims, wherein the copolymer further comprises at least one repeating unit c) selected from 2-hydroxyethyl methacrylate, N,N-dimethyl(meth)acrylate, and N,N-dimethylacrylamide.

10. The method according to claim 9, wherein the copolymer preferably contains 1 to 20 mol% of the repeating unit c) in a statistical distribution.

11. The copolymer has the following chemical structure: 【Chemical 1】 (wherein, R is H or CH ３ ; n is an integer of 1 or 2; m is an integer in the range of 15 to 35, preferably n is an integer of 1 and m is an integer in the range of 20 to 30), or [Chemical 2] (wherein n is 1 or 2, m is 15 to 25, o is 5 to 15, preferably n is 1, m is 20, and o is 10), or 【Chemical Formula 3】 (wherein n is 1 or 2, m is 15 to 25, o is 5 to 15, preferably n is 1, m is 20, and o is 1 to 10) The method according to any one of the preceding claims.

12. A vascular medical product or at least a part thereof, comprising a copolymer coating, wherein the copolymer coating is bonded to the surface of the vascular medical product and contains at least one of the following copolymers or consists of one of the following copolymers, preferably obtained by the method according to any one of claims 1 to 11. 【Chemical Formula 4】

13. The vascular medical product or at least a part thereof according to claim 12, wherein the copolymer coating contains at least one of the following copolymers or consists of one of the following copolymers: 【Chemical Formula 5】 (wherein R is H or CH ３ ; n is an integer of 1 or 2; m is an integer in the range of 15 to 35, preferably n is an integer of 1 and m is an integer in the range of 20 to 30), or 【Chemical Formula 6】 (wherein, R is H or CH ３ ; n is 1 or 2; m is 15 to 25; o is 5 to 15; preferably, n is 1, m is 20, and o is 10), or 【Chemical Formula 7】 (wherein R is H or CH ３ wherein n is 1 or 2, m is 15 to 25, o is 5 to 15, preferably n is 1, m is 20, and o is 1 to 10).

14. The vascular medical product or at least a part thereof is intended to be implanted or introduced into a blood vessel, particularly an implant in the fields of electrophysiology, cardiac rhythm management, nerve stimulation, vascular and endovascular intervention, cardiac intervention, and intervention in the heart. Preferably, the vascular medical product is selected from a coronary or peripheral catheter or a part thereof, a CRM device or part, a balloon, a balloon part, or a pacemaker electrode. The vascular medical product or at least a part thereof according to claim 12 or 13.

15. The surface of the vascular medical product comprises or is made of a polymer selected from polyamide, polyether block amide, thermoplastic polyurethane (TPU), polyester, polyester-based elastomer, thermoplastic elastomer, polyolefin, vinyl polymer, polysiloxane, and combinations thereof, or at least a part of the vascular medical product according to one of claims 12 to 14. **Claim 16** Use of a copolymer coating for coating the surface of a vascular medical product or at least a part thereof, wherein the copolymer coating comprises at least a) repeating units of vinyl pyrrolidone, and b) at least one perfluorophenyl azide moiety, and optionally c) repeating units selected from 2-hydroxyethyl methacrylate, N,N-dimethyl(meth)acrylate, and N,N-dimethylacrylamide and comprising or consisting of a copolymer having the same.

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