Hydrophilic coating for vascular medical products

Abstract

The present invention relates to the use of UV-sensitive copolymers and hydrophilic coatings containing copolymers for coating the surfaces of vascular medical products. The UV-sensitive copolymer comprises repeating units of (a) vinyl pyrrolidone and (b) perfluorophenyl azide wherein 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 invention further relates to a method for coating a surface of a vascular medical product, and to the coated vascular medical product obtained.

Description

[0001] 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 bound to the surface of vascular medical products by UV radiation. Further, the present invention relates to the use of coating compositions containing the specific copolymers, and methods for coating the surface of vascular medical products to provide coatings for vascular medical products.

[0002] It is generally known to use hydrophilic polymers to coat vascular medical products such as catheters, balloon components or pacemaker electrodes. Vascular medical devices require lubricating coatings to facilitate insertion into blood vessels and minimize damage thereto. Lubrication is achieved by hydrophilic coatings that absorb water and thereby become smooth. However, known systems are either expensive due to the chemicals used, or cannot reliably meet the requirements for vascular implantable medical products, in particular providing a permanent coating with a very low number of released particles on the surface and / or low friction to the 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 an improved coating for vascular medical products that overcomes the problems of the prior art. In particular, the coating should be hydrophilic and allow for easy or automated application. The coating should also be usable on surfaces that are difficult to coat, such as hydrophobic surfaces. Furthermore, the coating should result in low friction against abrasive objects, such as blood vessels, and release of very low numbers of particles.

[0004] This problem is solved by a method for coating the surface of a vascular medical product with a copolymer coating as claimed in claim 1 and by a vascular medical product as claimed in claim 12. Preferred embodiments are described in the dependent claims.

[0005] A method for coating a surface of a vascular medical product or at least one part thereof with a copolymer coating is described, wherein the copolymer coating is applied to a vascular medical product, and wherein the copolymer coating comprises or consists of at least one of the following copolymers having at least

[0006] a) repeating units of vinylpyrrolidone, and

[0007] b) at least one perfluorophenyl azide moiety,

[0008] And optionally the applied copolymer coating is dried and / or irradiated by UV radiation.

[0009] Thus, a method for coating the surface of a vascular medical product or at least one component thereof with a copolymer coating according to the following chemistry is described:

[0010]

[0011] wherein the at least one copolymer comprises

[0012] a) repeating units of vinylpyrrolidone, and

[0013] b) at least one perfluorophenyl azide moiety,

[0014] wherein the at least one perfluorophenyl azide moiety is inserted into a chemical CH bond at the surface of a vascular medical product (e.g., an interventional catheter) or at least one component thereof, preferably by irradiating the copolymer coating and the surface of the vascular medical product or at least one component thereof using UV irradiation.

[0015] The copolymer coating can be applied to the surface of the vascular medical product or at least one of its components by dipping, spraying, rolling, printing, painting, or by a doctor blade, a doctor roller, or a Langmuir-Blodgett film, followed by drying the applied composition and irradiating it with UV light. The surface of the vascular medical product or at least one of its components can be immersed in the coating composition and removed from the coating composition at a defined speed to obtain a defined coating thickness. The method can be performed in an automated manner.

[0016] The surface of the vascular medical product or at least one of its components 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 comprising polyamide and polyether blocks, preferably polyether block amides (e.g. Pebax or Vestamid).

[0017] Thus, a vascular medical product is obtained which is coated with a (hydrophilic) copolymer coating comprising at least one of the following copolymers or consisting of the following copolymers:

[0018]

[0019] Thus, a vascular medical product or at least one component thereof comprising a copolymer coating is described, wherein the copolymer coating is bonded to a surface of the vascular medical product and comprises or consists of at least one of the following copolymers:

[0020]

[0021] The (hydrophilic) copolymer coating described above, which absorbs water and thus becomes smooth, is able to achieve lubrication in the human or animal body (e.g. in blood vessels). The (hydrophilic) copolymer coating is mechanically resistant. The (hydrophilic) copolymer coating is chemically bonded to the surface of the vascular medical product or at least one of its components. Thus, no particles are released from the surface, so the (hydrophilic) copolymer coating produces a lower risk for thrombosis, embolism and arterial blockage. Compared with prior art products, the (hydrophilic) copolymer coating shows very good sliding properties and wear resistance.

[0022] Water-soluble polyvinylpyrrolidone (PVP) has hydrophilic properties. Monofunctional and multifunctional perfluorophenyl azide (PFPA) copolymers can be used for crosslinking and chemical bonding to vascular medical products or their components, such as (invasive) catheter surfaces.

[0023] In one embodiment, the vascular medical product may comprise a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises or consists of the following copolymer:

[0024]

[0025] wherein R is H or CH3 and wherein n is an integer of 1 or 2 and m is an integer in the range of from 15 to 35, preferably wherein n is an integer of 1 and m is an integer in the range of from 20 to 30.

[0026] In another embodiment, the vascular medical product may comprise a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises or consists of the following copolymer:

[0027]

[0028] wherein R is H or CH3 and wherein n is 1 or 2, m is 15 to 25, and o is 5 to 15, preferably wherein n is 1, m is 20, and o is 10.

[0029] In a further embodiment, the vascular medical product may comprise a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises or consists of the following copolymer:

[0030]

[0031] wherein R is H or CH3 and wherein n is 1 or 2, m is 15 to 25, and o is 5 to 15, preferably wherein n is 1, m is 20, and o is 1 to 10.

[0032] The (hydrophilic) copolymer coating may be (covalently) bonded to the surface of the vascular medical product, preferably via carbon-nitrogen (CN) bonds.

[0033] Vascular medical products are medical products or parts thereof, which are intended to be implanted or introduced into blood vessels, particularly in the fields of electrophysiology, cardiac rhythm management, neural stimulation, vascular and intravascular intervention, cardiac and cardiac intervention. Vascular medical products can be selected from coronary or peripheral catheters or parts thereof, CRM devices or parts, balloon parts or pacemaker electrodes. The surface of the vascular medical product may contain a polymer 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 selected from polyamides, polyether block amides, thermoplastic polyurethanes (TPU), thermoplastic elastomers (TPE) such as thermoplastic elastomers comprising polyamides and polyether blocks, preferably polyether block amides (e.g. Pebax or Vestamid).

[0034] The (hydrophilic) copolymer coating can be applied to vascular medical products or parts thereof, such as (invasive) catheters (tubes), via a dip coating method.

[0035] Also disclosed is a vascular medical product comprising a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises or consists of the following segments:

[0036] - azide,

[0037] - an aromatic moiety bonded to the azide,

[0038] - an ester bonded to an aromatic moiety,

[0039] - at least one hydrophilic repeating unit bonded to an ester.

[0040] In one embodiment, the vascular medical product comprises a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises or consists of the following segments:

[0041] - azide,

[0042] - bound to the perfluorophenyl moiety of the azide,

[0043] - an ester bonded to a perfluorophenyl moiety,

[0044] - an acrylate or methacrylate or a repeating unit of an acrylate or methacrylate bonded to an ester,

[0045] - repeating units of vinylpyrrolidone bonded to repeating units of acrylate or methacrylate or acrylate or methacrylate, and optionally

[0046] - a repeating unit bonded to a vinylpyrrolidone repeating unit, and wherein the repeating unit is selected from 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl (meth)acrylate and N,N-dimethylacrylamide (DMA).

[0047] Due to its hydrophobic nature, phenyl azide can preferably be bound to a hydrophobic surface, such as the surface of a vascular medical product. The aromatic moiety, preferably a perfluorophenyl moiety, is configured to absorb UV radiation and activate the azide. Azide is a reactive group that splits dinitrogen (N2) upon activation, preferably UV radiation, to form a highly reactive nitrene intermediate that can be inserted into the CH bond of the surface of the vascular medical product. Thus, the azide or a copolymer comprising an azide group becomes covalently bound to the surface of the vascular medical product. (Poly) vinyl pyrrolidone provides hydrophilic properties.

[0048] Still further, the present invention at least partially satisfies this need by providing the use of a UV-sensitive copolymer for coating the surface of a vascular medical product, wherein the UV-sensitive copolymer comprises repeating units of at least (a) vinyl pyrrolidone and (b) perfluorophenyl azide, wherein 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 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.

[0049] Vascular medical products may refer to medical products or components thereof that can be or (will be) inserted or introduced into a blood vessel, for example but not limited to the fields of electrophysiology, cardiac rhythm management, neurostimulation, vascular or intravascular interventions, and cardiac interventions.

[0050] 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 comprising polyamide 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) with alcohol-terminated polyethers (polytetramethylene glycol (PTMG) or PEG).

[0051] Herein, the term "(meth)acrylate" is used to mean "acrylate" or "methacrylate" as conventionally used in the art.

[0052] Herein, the term "smooth" in the context of a surface of a vascular medical product has the meaning that the vascular medical product can be inserted into the body without causing injury and / or pain or discomfort to the patient.

[0053] Further examples of the present disclosure are provided below:

[0054] Embodiment 1. A vascular medical product comprising a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer coating comprises or consists of a copolymer having the following segments:

[0055] - azide,

[0056] - an aromatic moiety bonded to the azide,

[0057] - an ester bonded to an aromatic moiety,

[0058] - at least one hydrophilic repeating unit bonded to an ester.

[0059] Embodiment 2. A vascular medical product according to embodiment 1, comprising a (hydrophilic) copolymer coating, wherein the (hydrophilic) copolymer comprises the following segments:

[0060] - azide,

[0061] - an aromatic moiety bonded to the azide,

[0062] - an ester bonded to an aromatic moiety,

[0063] - an acrylate or methacrylate or a repeating unit of an acrylate or methacrylate bonded to an ester,

[0064] - repeating units of vinylpyrrolidone bonded to repeating units of acrylate or methacrylate or acrylate or methacrylate, and optionally

[0065] - a repeating unit bonded to a vinylpyrrolidone repeating unit, and wherein the repeating unit is selected from 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl (meth)acrylate and N,N-dimethylacrylamide (DMA).

[0066] Embodiment 3. A vascular medical product comprising a (hydrophilic) coating, wherein the (hydrophilic) coating comprises at least one copolymer having at least

[0067] a) repeating units of vinylpyrrolidone, and

[0068] b) at least one perfluorophenyl azide moiety.

[0069] Embodiment 4. The vascular medical product of embodiment 3, wherein the repeating unit of vinyl pyrrolidone comprises more monomer units than the repeating unit of the perfluorophenyl azide moiety.

[0070] Embodiment 5. The vascular medical product of embodiment 3 or 4, wherein the copolymer comprises 1 to 50 mol% of repeating units a) and 0.1 to 5 mol% of repeating units b).

[0071] Embodiment 6. The vascular medical product according to one of embodiments 3 to 5, wherein the copolymer has a statistical distribution of repeating units a) and b).

[0072] Embodiment 7. A vascular medical product according to any one of embodiments 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).

[0073] Embodiment 8. The vascular medical product according to embodiment 7, wherein the copolymer comprises 1 to 20 mol % of repeating units c), preferably in a statistical distribution.

[0074] Embodiment 9. The vascular medical product of any one of the preceding embodiments, wherein the copolymer has a molecular weight of 5,000 to 50,000 g / mol.

[0075] Embodiment 10. The vascular medical product according to any one of the embodiments, wherein the (hydrophilic) copolymer coating is (covalently) bound to the surface of the vascular medical product, preferably via carbon-nitrogen (CN) bonds.

[0076] Embodiment 11. A vascular medical product according to any one of the embodiments, wherein the vascular medical product is a medical product or a component thereof, which is intended to be implanted or introduced into a blood vessel, particularly in the fields of electrophysiology, cardiac rhythm management, neurostimulation, vascular and intravascular interventions, interventions in and at the heart.

[0077] Embodiment 12. A vascular medical product according to any one of the embodiments, wherein the vascular medical product is selected from a coronary or peripheral catheter or component thereof, a CRM device or component, a balloon component or a pacemaker electrode.

[0078] Embodiment 13. A vascular medical product according to any one of the embodiments, wherein the surface of the vascular medical product comprises or is made of a polymer, and the polymer is 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 polyamides, polyether block amides, thermoplastic polyurethanes (TPU), thermoplastic elastomers (TPE) such as thermoplastic elastomers containing polyamide and polyether blocks, preferably polyether block amides (for example, Pebax or Vestamid).

[0079] Embodiment 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

[0080] a) repeating units of vinylpyrrolidone, and

[0081] b) at least one perfluorophenyl azide moiety, and optionally

[0082] c) repeating units selected from 2-hydroxyethyl methacrylate, N,N-dimethyl (meth)acrylate and N,N-dimethyl acrylamide.

[0083] 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 the following repeating units

[0084] (a) vinyl pyrrolidone, and

[0085] (b) perfluorophenyl azide,

[0086] wherein the repeating unit of vinyl pyrrolidone comprises more monomer units than the repeating unit of perfluorophenyl azide;

[0087] 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.

[0088] Embodiment 16. The use according to embodiment 14 or 15, wherein the copolymer comprises 1 to 50 mol% of repeating units (a) and 0.1 to 5 mol% of repeating units (b).

[0089] Embodiment 17. The use according to embodiment 14, wherein the copolymer comprises 1 to 20 mol % of repeating units (c), preferably in a statistical distribution.

[0090] Example 18. Use of a (UV-sensitive, hydrophilic) copolymer for coating the surface of a vascular medical product, wherein the copolymer comprises the following repeating units:

[0091]

[0092] wherein n is an integer of 1 or 2, m is an integer in the range of from 15 to 30 and wherein R is H or CH3.

[0093] Example 19. Use of a (UV-sensitive, hydrophilic) copolymer for coating the surface of a vascular medical product, wherein the copolymer comprises the following repeating units:

[0094]

[0095] wherein n is 1, m is 20, o is 10 and wherein R is H or CH3;

[0096] or

[0097]

[0098] wherein n is 1, m is 20, and o is 10 and wherein R is H or CH3.

[0099] Embodiment 20. Use of a coating composition for coating the surface of a vascular medical product, wherein the coating composition comprises:

[0100] a) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of less than 1,000,000 g / mol,

[0101] b) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of more than 1,000,000 g / mol,

[0102] c) 0.1 to 5 wt% of a copolymer as defined in any one of the preceding embodiments, and

[0103] d) 0 to 1% by weight of a polyfunctional UV-sensitive lower molecular phenyl azide compound having a UV absorption in the range of 200 to 300 nm,

[0104] Therein, components (a) to (d) are dissolved in 50 to 90% by volume of alcohol, preferably ethanol and / or 2-propanol, and 10 to 50% by volume of water.

[0105] Embodiment 21. The use according to embodiment 20, wherein the phenyl azide d) is a triazide, a polyethylene glycol-based bisazide, a diol bisazide and / or an ionic bisazide.

[0106] Subsequently, embodiments of the present invention will be described in detail with reference to the accompanying drawings. It will be noted that the embodiments are not intended to limit the present invention, but are merely illustrative examples. The accompanying drawings show:

[0107] Figure 1 The procedure for adding perfluorophenyl (meth)acrylate to a polymerization vessel via a syringe pump is shown;

[0108] Figure 2 shows the molecular weight distribution of exemplary copolymers by GPC;

[0109] Figure 3 The exemplary copolymers are shown 19 F-NMR spectroscopy;

[0110] Figure 4 The exemplary copolymers are shown 1 H-NMR spectroscopy;

[0111] Figure 5 For another exemplary copolymer 1 H-NMR, 19 F-NMR and FT-IR spectra and molecular weight distribution; and

[0112] Figure 6 The binding of the copolymer to the surface is shown schematically.

[0113] The copolymer used according to the present invention comprises at least repeating units of vinylpyrrolidone (VP) and repeating units of perfluorophenyl azide (PFPA), preferably perfluorobenzoyl (meth) acrylate azide. The repeating units of vinylpyrrolidone contain more monomer units than the repeating units of perfluorophenyl azide contain monomer (PFPA) units. Preferably, the repeating units of vinylpyrrolidone (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, most preferably 1 PFPA unit. Exemplary copolymers contain the following repeating units:

[0114]

[0115] wherein n is an integer of 1, 2 or 3, preferably 1 or 2, and wherein m is an integer in the range from 15 to 35 and wherein R is H or CH3.

[0116] Polyvinyl pyrrolidone repeating unit imparts hydrophilicity and smoothness to the coating obtained by using copolymer. Perfluorophenyl azide unit can covalently bind or attach copolymer to surface, especially to polymer or siloxane material via azide group (which can be activated by UV radiation). The reaction mechanism activated by azide is known from Siegmann, K., Inauen, J., Villamaina, D. and Winkler, M. article "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. article "Spectroscopy on photografted polyethylene surfaces using aperfluorophenyl azide: Evidence for covalent attachment" Surface and Interface Analysis, 50 (2) 205-211 (2018). The mechanism is shown below, where R represents the corresponding residue of the perfluorophenyl azide unit:

[0117]

[0118] Upon UV activation, preferably at a wavelength between 200 and 350 nm, more preferably between 240 and 320 nm, the azide groups are converted to cleaved molecular nitrogen and highly reactive nitrenes which undergo very fast non-specific insertion reactions into CX bonds (e.g., CH bonds) of the substrate. Due to the presence of multiple PFPA repeating groups and thus multiple azide groups in the copolymer, the copolymer can be covalently bound and thereby permanently attached to the substrate at these multiple locations.

[0119] 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.

[0120] In a preferred embodiment, the copolymer comprises further hydrophilic repeating units, for example, repeating units (c) derived from 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl (meth)acrylate and N,N-dimethylacrylamide (DMA). The additional repeating units further improve the hydrophilicity and slippery properties of the coating obtained by using the copolymer.

[0121] Exemplary copolymers may comprise the following repeating units:

[0122]

[0123] wherein, for example, n is 1, m is 15 to 25, preferably 20, and o is 5 to 15, preferably 10; and wherein R is H or CH3.

[0124] Another exemplary copolymer may comprise the following repeating units:

[0125]

[0126] wherein, for example, n is 1, m is 15 to 25, preferably 20, and o is 5 to 15, preferably 10, and wherein R is H or CH3.

[0127] In a preferred embodiment, the copolymer used according to the 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 exemplary copolymers comprising further repeating units (c) as described above, the copolymer comprises 1 to 20 mol % of repeating units (c). In a further preferred embodiment, the repeating units (a), (b) and (c) are statistically distributed.

[0128] The copolymer used according to the invention can be prepared by a process comprising at least the following steps:

[0129] (a) Esterification of perfluorobenzoyl chloride with 2-hydroxyethyl (meth)acrylate;

[0130] (b) reacting the product obtained in step (a) with sodium azide to obtain 4-azidoperfluorophenylacrylate; and

[0131] (c) copolymerizing the 4-azidoperfluorophenylazide acrylate of step (b) with vinyl pyrrolidone using a free radical initiator.

[0132] The esterification step (a) can be carried out as described in the following reaction scheme:

[0133]

[0134] As shown, perfluorobenzoyl chloride is reacted with 2-hydroxyethyl (meth)acrylate in triethylamine, where R represents H or methyl. In an exemplary embodiment, the reaction is carried out in dichloromethane at about 0°C and for about 12 hours. Exemplary yields are 98% for R=H and 95% for R=methyl. The obtained compounds can be identified by, for example, FT-IR, 1 H and 19 The samples were characterized by F-NMR spectroscopy.

[0135] The compounds preferably obtained after step (a) are shown below (left: methacrylate; right: acrylate):

[0136]

[0137] Acrylamide or vinyl ether can also be used instead of 2-hydroxyethyl (meth)acrylate to obtain the following compounds (left: acrylamide; right: vinyl ether):

[0138]

[0139] After step (a), the product is reacted with an azide, preferably sodium azide. The reaction can be carried out under suitable conditions, for example at room temperature and for 24 hours. In step (b), an azide group is introduced by replacing the F atom of the perfluorobenzene ring.

[0140] In step (c), the product obtained in step (b) is polymerized with vinyl pyrrolidone, wherein vinyl pyrrolidone is used in excess of azide perfluorophenyl acrylate. A free radical polymerization initiator such as AIBN or dibenzoyl peroxide (BPO) is used to initiate the copolymerization. The copolymerization is carried out in a manner known in the art.

[0141] An exemplary process with steps (a) to (c) is shown in the scheme below (esterification, azide substitution, polymerization):

[0142]

[0143] wherein n is an integer of 1, 2 or 3, preferably 1 or 2, most preferably 1 and represents the number of perfluorophenyl azide units, specifically perfluorobenzoyl (meth)acrylate azide units, and m is an integer in the range of from 15 to 35, preferably 20 to 30, representing the number of vinylpyrrolidone units, and wherein R is H or CH3.

[0144] The polymerization can be optimized by adding azide perfluorophenyl (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 copolymers with 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 (less than 4 hours) and / or addition of acrylate without a syringe pump promotes the formation of block copolymers. For example, for methacrylate r = about 3.9, and for vinyl pyrrolidone r = 0.004. Figure 1 An exemplary procedure is shown. Figure 1 , perfluorophenyl azide (meth)acrylate is slowly added (via a syringe pump) (eg, over a period of 4 to 8 hours) to a polymerization vessel containing vinyl pyrrolidone and an initiator (eg, AIBN as shown).

[0145] For exemplary copolymers of the present invention, Figure 2 Molecular weight distribution by GPC (gel permeation chromatography) is shown in units of normalized intensity vs. molar mass (g / mol). A unimodal distribution was obtained.

[0146] Figure 3 and Figure 4 Shows 19 F-NMR and 1 H-NMR spectrum. Figure 4 It also shows how to 1 H-NMR spectroscopy determines the ratio of two repeating units to one another or the two parameters m and n due to H atoms at specific positions.

[0147] For another exemplary copolymer 1 H-NMR, 19 F-NMR and FT-IR spectra (transmission vs. wavenumber (cm -1 )) and molecular weight distribution are shown in Figure 5 middle.

[0148] In an exemplary embodiment, the copolymerization is carried out at room temperature in N,N-dimethyl-p-toluidine (DMT) using dibenzoyl peroxide (BPO). A suitable reaction scheme is shown below:

[0149]

[0150] Alternatively, copolymerization can be carried out using reversible addition fragmentation chain transfer (RAFT) polymerization in the presence of BPO, DMT and benzyl 1H-imidazole-1-dithiocarbamate (BICDT). A suitable reaction is shown below:

[0151]

[0152] Wherein R is H or CH3.

[0153] It is also possible to change the order of steps (a), (b) and (c), steps (b) and (c) in the described preparation method, that is, to carry out copolymerization before azide substitution. An exemplary reaction pathway is shown below (top: free radical polymerization; bottom: azide substitution):

[0154]

[0155] In a further preferred embodiment of the present invention, the copolymerization in step (c) is carried out in the presence of further monomers, such as 2-hydroxyethyl methacrylate (HEMA), N,N-dimethyl (meth)acrylate and N,N-dimethylacrylamide (DMA). Exemplary repeating units are shown below:

[0156]

[0157] wherein R is H or CH3. PHEMA stands for poly(2-hydroxyethyl methacrylate) (HEMA), and PDMA stands for poly(N,N-dimethylacrylamide).

[0158] Exemplary copolymers include at least one of the following repeating units:

[0159]

[0160] Where R is H or CH3 and where, for example, the molecular weight M n The molecular weight M of the copolymer is 33,000 g / mol, the m:n ratio is 20:1, and the PFPA content is preferably 5 mol%. n PHEMA-co-PFPA; m:n ratio is 20:1; PFPA content is 5 mol%. The solvent is preferably ethanol / water in a ratio of 1:1; and the concentration of the copolymer is 20 wt%.

[0161]

[0162] Where R is H or CH3 and where, for example, the molecular weight M n The copolymer is about 50,000 g / mol; the m:o:n ratio is 20:10:1 and preferably the PFPA content is 3 mol% and the PDMA content is 32 mol%. Preferably, the copolymer is PVP-co-PHEMA-co-PFPA, wherein the PFPA content is 3 mol%; and the PDMA content is 32 mol%.

[0163]

[0164] Among them, for example, the molecular weight M n The copolymer is preferably PDMA-co-PFPA with a PFPA content of 5 mol%. The solvent is preferably acetone / water in a ratio of 1:1; and the copolymer concentration is 20 wt%.

[0165]

[0166] Where R is H or CH3 and where, for example, the molecular weight M n 12,000 to 30,000 in g / mol; m:o:n ratio of 20:1:1 to 20:10:1, and preferably PFPA content of 3 mol% to 5 mol%, and preferably PDMA content of 5 mol% to 32 mol%. Preferably, the copolymer has a molecular weight M of 30,000 or 12,000 in g / mol. n PVP-co-PDMA-co-PFPA; m:o:n ratio is 20:1:1 or 20:10:1; and preferably the PFPA content is 5 mol% or 3 mol%; and the PDMA content is 5 mol% or 32 mol%. The solvent is preferably acetone / water in a ratio of 1:1; and the copolymer concentration is 20 wt%.

[0167] The present invention further provides a use of a coating composition for coating the surface of a vascular medical product, wherein the coating composition comprises:

[0168] a) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of less than 1,000,000 g / mol,

[0169] b) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of more than 1,000,000 g / mol,

[0170] c) 0.1 to 5% by weight of a copolymer according to the invention, and

[0171] d) 0 to 1% by weight of a polyfunctional UV-sensitive lower molecular phenyl azide compound having UV absorption, preferably in the range of 200 to 300 nm.

[0172] Components a) to d) are dissolved in aqueous alcohol, preferably in 50 to 90% by volume of alcohol and 10 to 50% by volume of water. The alcohol is preferably ethanol and / or 2-propanol.

[0173] Copolymers c) are the copolymers described above.

[0174] The phenyl azide compound d) is preferably a triazide, a polyethylene glycol-based bisazide, a diol bisazide and / or an ionic bisazide. Exemplary multifunctional phenyl azide compounds are shown below (in this order: triazide, PEG-bisazide, diol-bisazide, ionic bisazide):

[0175]

[0176]

[0177] The present invention further provides a method for coating the surface of a vascular medical product. In the method, the coating composition of the present invention or the coating composition as described above is applied to the surface of a vascular medical product by a procedure known in the art. Suitable application methods are dip coating, spray coating, roller coating, printing or painting. The coating composition can also be applied by a scraper, a scraper roller or a Langmuir-Blodgett film. A preferred method is dip coating. After it is applied to the surface, the applied composition is dried. Thereafter, the composition is irradiated by UV light. The UV light has a wavelength preferably in the range of from 200 to 350nm, more preferably in the range of from 240 to 320nm. Suitable wavelengths are, for example, 254nm or 265nm, for example, by using a Hg lamp.

[0178] Figure 6 The copolymer is schematically shown attached to a substrate. Figure 6 In FIG. 1 , the adhesion points 1 to the surface of the substrate 2 represent the perfluorinated groups of the copolymer. The points not attached to the surface as shown represent hydrophilic groups, such as polyvinyl pyrrolidone units. The covalent binding of the copolymer to the surface (after UV irradiation) can be analyzed, for example, by FT-IR via the disappearance of the azide peak, which is at 2134 cm in the spectrum before UV irradiation. -1 Appears everywhere.

[0179] In a preferred embodiment, the substrate is immersed in the coating composition and removed from the coating composition at a defined speed to obtain a defined coating thickness. The film thickness of the coating can be determined by the Landau-Levich equation:

[0180]

[0181] Where v is the velocity, η is the viscosity, ρ is the density, and γ is the surface tension. The film thickness may be, for example, 2 μm.

[0182] The substrate of the vascular medical product may include a polymer selected from the following: polyamides, such as polyamide 11 or polyamide 12; polyether block amides; thermoplastic polyurethanes (TPU); polyesters, such as PET or polyester-based elastomers; polyolefins, such as HDPE, LDPE, PP or olefin-based copolymers; vinyl polymers, such as polystyrene; polysiloxanes; and combinations of one or more thereof.

[0183] In a preferred embodiment of the invention, a vascular medical product is a medical product or a component thereof, which is intended to be implanted or introduced into a blood vessel, in particular in the fields of electrophysiology, cardiac rhythm management, neurostimulation, vascular and intravascular interventions, interventions in and at the heart. Particularly preferred vascular medical products are selected from coronary or peripheral catheters or components thereof, CRM devices or components, balloon components or pacemaker electrodes.

[0184] In another preferred embodiment, the coating method according to the invention is carried out in an automated manner.

[0185] The present invention further provides a coated vascular medical product obtained by means of the coating according to the present invention or the coating method described above.

[0186] The coating obtained by the present invention exhibits low friction against friction objects such as blood vessels and the release of very low numbers of particles. The release of particles can be determined by a particle counter using, for example, a simulated use model according to ASTM F2394-07 (2017), X.2.4. In an exemplary embodiment for a catheter with hydrophilic coated particles, the desired value is less than 2000 particles released, with a limit of 6000 particles for particles above 10 μm. The friction of the coating scan is determined by the coefficient of friction COF.

Claims

1. A method for coating a surface of a vascular medical product or at least one component thereof with a copolymer coating, wherein the copolymer coating is applied to the vascular medical product, and wherein the copolymer coating comprises or consists of a copolymer having at least a) repeating units of vinylpyrrolidone, and b) at least one perfluorophenyl azide moiety, And optionally the applied copolymer coating is dried and / or irradiated by UV radiation.

2. The method of claim 1, wherein the copolymer coating is applied to the surface by dipping, spraying, rolling, printing, painting, or by doctor blade, doctor roller, or Langmuir-Blodgett film.

3. The method of 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 to 90% by volume of an alcohol, preferably ethanol and / or 2-propanol, and 10 to 50% by volume of water.

5. A method according to any of the preceding claims, wherein the surface of the vascular medical product comprises or is made of a polymer selected from the group consisting of polyamides, polyether block amides, thermoplastic polyurethanes (TPU), polyesters, polyester-based elastomers, thermoplastic elastomers, polyolefins, vinyl polymers, polysiloxanes, and combinations thereof.

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

7. The method according to any one of claims 1 to 5, wherein the copolymer coating comprises: i) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of less than 1,000,000 g / mol, ii) 0.1 to 10% by weight of polyvinylpyrrolidone having a molecular weight of more than 1,000,000 g / mol, iii) greater than 0% and up to 6% by weight of perfluorophenyl azide.

8. The process of claim 7 wherein greater than 0 wt% and up to 0.3 wt% is 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-dimethyl acrylamide.

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

11. The method according to any one of the preceding claims, wherein the copolymer has the following chemical structure: wherein R is H or CH3, wherein n is an integer of 1 or 2, and m is an integer in the range of from 15 to 35; preferably n is an integer of 1 and m is an integer in the range of from 20 to 30; or wherein n is 1 or 2, m is 15 to 25, and o is 5 to 15; preferably n is 1, m is 20, and o is 10; or wherein n is 1 or 2, m is 15 to 25, and o is 5 to 15; preferably n is 1, m is 20, and o is 1 to 10.

12. A vascular medical product or at least one component thereof, preferably obtained by the method according to any one of claims 1 to 11, comprising a copolymer coating, wherein the copolymer coating is bound to the surface of the vascular medical product and comprises or consists of at least one of the following copolymers:

13. The vascular medical product or at least one component thereof of claim 12, wherein the copolymer coating comprises or consists of at least one of the following copolymers: wherein R is H or CH3 and wherein n is an integer of 1 or 2, and m is an integer in the range of from 15 to 35; preferably n is an integer of 1 and m is an integer in the range of from 20 to 30; or wherein R is H or CH3 and wherein n is 1 or 2, m is 15 to 25, and o is 5 to 15; preferably n is 1, m is 20, and o is 10; or wherein R is H or CH3 and wherein n is 1 or 2, m is 15 to 25, and o is 5 to 15; preferably wherein n is 1, m is 20, and o is 1 to 10.

14. A vascular medical product or at least one component thereof according to claim 12 or 13, wherein the vascular medical product or at least one component thereof is intended to be implanted or introduced into a blood vessel, in particular an implant in the fields of electrophysiology, cardiac rhythm management, neurostimulation, vascular and intravascular interventions, interventions in and at the heart, preferably wherein the vascular medical product is selected from a coronary or peripheral catheter or a component thereof, a CRM device or a component, a balloon, a balloon component or a pacemaker electrode.

15. A vascular medical product or at least one component thereof according to one of claims 12 to 14, wherein the surface of the vascular medical product comprises or is made of a polymer selected from the group consisting of polyamides, polyether block amides, thermoplastic polyurethanes (TPU), polyesters, polyester-based elastomers, thermoplastic elastomers, polyolefins, vinyl polymers, polysiloxanes and combinations thereof.

16. Use of a copolymer coating for coating the surface of a vascular medical product or at least one component thereof, wherein the copolymer coating comprises or consists of a copolymer having at least a) repeating units of vinylpyrrolidone, 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-dimethyl acrylamide.

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