Laminate, medical instrument, and laminate manufacturing method

Abstract

The present invention addresses the problem of providing: a laminate and a medical instrument which have excellent antithrombogenicity; and a laminate manufacturing method. This laminate comprises in the following order: a substrate; a layer containing a polymer of a phenolic compound; and a layer containing an acrylic resin. This laminate manufacturing method may comprise the following steps (1)-(4). Step (1) is a step for forming, on a substrate, a layer containing a polymer of a phenolic compound in a state in which a solution containing the phenolic compound is brought into contact with the substrate. Step (2) is a step for washing the substrate with water and then drying the resultant. Step (3) is a step for bringing a solution containing an acrylic resin into contact with the dried substrate. Step (4) is a step for drying the substrate taken out of the solution containing the acrylic resin.

Description

Laminate, medical device, and method for manufacturing laminate

[0001] The present invention relates to a laminate, and more particularly to a laminate and medical device having excellent antithrombogenicity, and a method for producing the laminate.

[0002] For medical devices such as blood circuits, heart-lung machines, catheters, and drainage tubes, a technique of treating the surfaces of the medical devices with a biocompatible coating agent is often used to suppress the adhesion and formation of thrombi.

[0003] Biocompatible coating agents are primarily made from animal-derived materials or highly water-soluble materials, including betaine-structured MPC polymers (phosphorylcholine-like amphoteric polymers), PEG (polyethylene glycol), PVP (polyvinylpyrrolidone), polysaccharides such as heparin and chondroitin, and gelatin. In particular, the biocompatible coating agents described in Patent Documents 1 to 3 are known to exhibit excellent safety and durability as well as excellent thrombus formation inhibitory effects by using acrylic resins having side chains with substituents such as alkoxy ethers and polyethers. Another known acrylic resin that exhibits thrombus formation inhibitory effects, i.e., an acrylic resin that can impart antithrombogenic properties to medical devices, is the (meth)acrylate copolymer described in Patent Document 5.

[0004] Polyolefin resins, fluororesins, and silicone resins are used in medical devices such as blood circuits, heart-lung machines, catheters, and drainage tubes. However, these resin materials have poor wettability due to their low surface free energy, making them classified as poorly adhesive materials. Because it is difficult to apply a biocompatible coating agent to the surface of poorly adhesive materials, there is a need to improve the wettability of coating agents for poorly adhesive materials.

[0005] A common method for improving the wettability of coating agents on poorly adhesive materials is to expose the surface of the material to plasma for hydrophilic functional groups. However, plasma surface treatment methods have the drawback of increased costs due to the introduction of new equipment, and when the poorly adhesive material contains a silicone-based resin, the hydrophilic silanol groups derived from the polysiloxane are deactivated within a few hours.

[0006] Recently, surface treatment methods invented from the perspective of biomimetics have attracted attention. One example is a surface treatment method that mimics the adhesive protein of mussels. Mussel adhesive proteins are composed of polyphenols with a catechol group, the basic structure of L-3,4-dihydroxyphenylalanine. Dopamine and its compounds, which are biomimics of these proteins, are materials that simplify the chemical structure of the adhesive protein. Polydopamine, formed from dopamine, can adhere to various substrates and impart hydrophilicity or wettability to their surfaces. Non-Patent Document 1 reports that this method can also be applied to metals, ceramics, fluororesins, and polyolefin resins.

[0007] Furthermore, it is known that compounds having a catechol group can form Michael adducts with thiols, amines, and the like, Schiff bases with amines, and coordinate bonds with inorganic compounds and metals. By utilizing these reactions and using a coating agent containing thiols, amines, and metals, it is possible to coat poorly adhesive materials via chemical bonds with the catechol group. For example, in Non-Patent Document 2, a polydopamine thin film is formed on a poorly adhesive material, and then an amino group-containing mucin aqueous solution is coated to bond the catechol group to the mucin. Patent Document 4 discloses a method for fabricating a device in which a polydopamine-containing polymer film and a metal layer are laminated using the above reaction.

[0008] Patent No. 6462278 Patent No. 7128632 Patent No. 4793700 Special Publication No. 2023-520554 Publication Patent No. 5114660

[0009] Science, 2007, 318, 426. Adv. Healthcare Mater. 2021, 10, 2000831.

[0010] As described above, the use of a compound having a catechol group can be useful as a method for improving the wettability of a coating agent for substrates such as poorly adhesive materials. However, coating agents containing metals that can form chemical bonds with catechol groups raise concerns about the toxicity of the metal. Furthermore, coating agents containing amines that can form chemical bonds with catechol groups raise concerns about the hemolytic activity of the amine. Furthermore, Non-Patent Documents 1 and 2 do not suggest laminating a substrate, a layer containing a polymer of a compound having a catechol group, and a layer containing an acrylic resin, nor do they evaluate the antithrombotic properties of the laminate.

[0011] The present invention has been made in view of the problems of the prior art. That is, an object of the present invention is to provide a laminate and a medical device having excellent antithrombogenicity, as well as a method for producing the laminate.

[0012] As a result of extensive research, the present inventors have found that the above problems can be solved by the following means, and have arrived at the present invention.

[0013] That is, the present invention has the following configuration [1]: [1] A laminate comprising, in this order, a substrate, a layer containing a polymer of a phenol compound, and a layer containing an acrylic resin.

[0014] The present invention preferably has the following configurations [2] and thereafter. [2] The laminate according to [1], wherein the phenol compound is a compound having a catechol group. [3] The laminate according to [2], wherein the compound having a catechol group includes at least one of dopamine and hydroxytyrosol. [4] The laminate according to any one of [1] to [3], wherein the acrylic resin is a (meth)acrylate polymer containing one or more of a (meth)acrylate unit represented by the following general formula [1], a (meth)acrylate unit represented by the following general formula [2], and a (meth)acrylate unit represented by the following general formula [3]: (In formula [1], R １ is a hydrogen atom or a methyl group, R ２ represents an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 1 to 5 carbon atoms, and n represents an integer of 1 to 4. (In formula [2], R ３ is an alkyl group having 2 to 30 carbon atoms or an aralkyl group having 2 to 30 carbon atoms, R ４ represents a hydrogen atom or a methyl group.) (In formula [3], R ５ is a hydrogen atom or a methyl group, R ６ is an alkylene group having 1 to 6 carbon atoms, R ７represents an alkyl group having 1 to 6 carbon atoms, and m is in the range of 1 to 1,000.) [5] The laminate according to any one of [1] to [4], wherein the substrate comprises at least one selected from a silicone-based resin, a fluorine-based resin, and a polyolefin-based resin. [6] The laminate according to any one of [1] to [4], wherein the substrate comprises a silicone-based resin. [7] The laminate according to any one of [1] to [4], wherein the substrate comprises a fluorine-based resin. [8] The laminate according to any one of [1] to [4], wherein the substrate comprises a polyolefin-based resin. [9] The laminate according to any one of [1] to [8], wherein the polymer of the phenol compound comprises at least one of a structural unit represented by the formula [4-1] described below and a structural unit represented by the formula [5-1] described below.

[10] The laminate according to any one of [1] to [9], wherein the compound having a catechol group consists of at least one of dopamine and hydroxytyrosol.

[11] The laminate according to any one of [1] to

[10] , wherein the structural units of the polymer of the phenolic compound are composed solely of structural units derived from the phenolic compound, i.e., the polymer of the phenolic compound is composed solely of structural units derived from the phenolic compound.

[12] The laminate according to any one of [1] to

[11] , wherein the content of the polymer of the phenolic compound in the layer containing the polymer of the phenolic compound is 90% by mass or more or 95% by mass or more.

[13] The laminate according to any one of [1] to

[12] , wherein the content of the polymer of the phenolic compound in the layer containing the polymer of the phenolic compound is 98% by mass or more.

[14] The laminate according to any one of [1] to

[13] , wherein the acrylic resin contains structural units derived from a (meth)acrylate represented by the general formula [1].

[15] The laminate according to any one of [1] to

[14] , wherein the acrylic resin contains at least one of structural units derived from methoxytetraethylene glycol (meth)acrylate and structural units derived from methoxytriethylene glycol (meth)acrylate.

[16] The laminate according to any one of [1] to

[15] , wherein the acrylic resin contains a structural unit derived from methoxytriethylene glycol (meth)acrylate.

[17] The laminate according to any one of [1] to

[16] , wherein the acrylic resin contains a structural unit derived from a (meth)acrylate represented by the general formula [2].

[18] The laminate according to any one of [1] to

[17] , wherein the acrylic resin contains at least one of a structural unit derived from 2-ethylhexyl (meth)acrylate and a structural unit derived from lauryl (meth)acrylate.

[19] The laminate according to any one of [1] to

[18] , wherein the acrylic resin contains a structural unit derived from 2-ethylhexyl (meth)acrylate.

[20] The laminate according to any one of [1] to

[19] , wherein the acrylic resin contains a structural unit derived from a (meth)acrylate represented by the general formula [3].

[21] In the general formula [3], R. ５

[22] In the general formula [3], R is a methyl group. ６

[23] The laminate according to any one of [1] to

[21] , wherein the alkylene group in the formula [3] is linear. ６

[24] The laminate according to any one of [1] to

[22] , wherein the number of carbon atoms in the alkylene group is 2 or more and 4 or less, or 3. ７The laminate according to any one of [1] to

[23] , wherein the number of carbon atoms in the alkyl group is 2 to 5, or 4.

[25] The laminate according to any one of [1] to

[24] , wherein in the general formula [3], m is 5 or more, or 10 or more.

[26] The laminate according to any one of [1] to

[25] , wherein in the general formula [3], m is 100 or less, or 50 or less.

[27] The laminate according to any one of [1] to

[26] , wherein in the general formula [3], m is 30 or less, or 20 or less.

[28] The laminate according to any one of [1] to

[27] , wherein the number average molecular weight of the acrylic resin is 2,000 or more, or 5,000 or more.

[29] The laminate according to any one of [1] to

[28] , wherein the number average molecular weight of the acrylic resin is 200,000 or less, or 100,000 or less.

[30] The laminate according to any one of [1] to

[29] , wherein the number average molecular weight of the acrylic resin is 50,000 or less, or 30,000 or less.

[31] The laminate according to any one of [1] to

[30] , wherein, when all monomer units of the acrylic resin are taken as 100 mol%, the total of the structural units derived from the (meth)acrylate represented by the general formula [1] and the structural units derived from the (meth)acrylate represented by the general formula [2] is 70 mol% or more, or 90 mol% or more.

[32] The laminate according to

[31] , wherein the total of the structural units derived from the (meth)acrylate represented by the general formula [1] and the structural units derived from the (meth)acrylate represented by the general formula [2] is 95 mol% or more.

[33] The laminate according to any one of [1] to

[32] , wherein, when all monomer units of the acrylic resin are taken as 100 mol%, the total of the structural units derived from the (meth)acrylate represented by the general formula [1], the structural units derived from the (meth)acrylate represented by the general formula [2], and the structural units derived from the (meth)acrylate represented by the general formula [3] is 90 mol% or more, or 95 mol% or more.

[34] The laminate according to

[33] , wherein the total of the structural units derived from the (meth)acrylate represented by the general formula [1], the structural units derived from the (meth)acrylate represented by the general formula [2], and the structural units derived from the (meth)acrylate represented by the general formula [3] is 98 mol% or more, or 100 mol%.

[35] The laminate according to any one of [1] to

[34] , wherein the content of the acrylic resin in the layer containing the acrylic resin is 90 mass% or more, or 95 mass% or more.

[36] The laminate according to any one of [1] to

[35] , wherein the content of the acrylic resin in the layer containing the acrylic resin is 98 mass% or more.

[37] The laminate according to any one of [1] to

[36] , wherein the layer containing the acrylic resin forms at least a part of the surface of the laminate.

[38] A medical device comprising the laminate according to any one of [1] to

[37] .

[39] The medical device according to

[38] , wherein the layer containing the acrylic resin forms at least a part of the surface of the medical device.

[40] A method for producing a laminate, comprising sequentially performing the following steps: (1) forming a layer containing a polymer of a phenolic compound on a substrate while the substrate is in contact with a solution containing a phenolic compound; (2) washing the substrate with water and then drying the substrate; (3) contacting the dried substrate with a solution containing an acrylic resin; and (4) drying the substrate after removing it from the solution containing the acrylic resin.

[41] The method for producing a laminate according to

[40] , wherein the laminate is a laminate according to any one of [1] to

[37] .

[42] The method for producing a laminate according to

[40] or

[41] , wherein in step (1), polymerization of the phenolic compound proceeds while the solution containing the phenolic compound is in contact with the substrate.

[0015] According to the present invention, it is possible to provide a laminate and a medical device having excellent antithrombogenicity, as well as a method for producing the laminate.

[0016] The results of ATR-FTIR (attenuated total reflectance) spectroscopy for the sample prepared in Example 1 (specifically, a sample having a silicone substrate and a layer containing polydopamine) are shown (see spectrum of polydopamine coating). The results of the sample prepared in Comparative Example 1 are also shown (see spectrum of silicone substrate (untreated)). The results of the laminated sample prepared in Example 1 are also shown (see spectrum of polydopamine / acrylic resin coating). Figure 1 shows examples of micrographs of the laminated samples prepared in Example 1 and Comparative Example 1.

[0017] A laminate according to an embodiment of the present invention will be described below. In the following, the notation "to" indicating a numerical range means "less than" or "exceeding" unless otherwise specified. In other words, "A to B" means "A or more and B or less."

[0018] "(Meth)acrylate" is a term that generically refers to both acrylate and methacrylate. Hereinafter, the "general formula" may be simply referred to as the "formula."

[0019] [Laminate] The laminate of the present invention comprises, in this order, a substrate, a layer containing a polymer of a phenolic compound, and a layer containing an acrylic resin. The laminate is useful as a medical device, particularly a medical device having a portion that comes into contact with blood or body fluids, or as a component of a medical device. Specific application forms include medical devices such as catheters, infusion tubes, artificial hearts and lungs, blood circuits, and drainage tubes. Examples of catheters include intravascular catheters.

[0020] In the laminate of the present invention, the layer containing a polymer of a phenol compound is present between the substrate and the layer containing an acrylic resin, and the layer containing an acrylic resin is adhered to the substrate via the layer containing a polymer of a phenol compound.

[0021] The layer containing a polymer of a phenolic compound may be formed on at least a portion of the surface of the substrate. The layer containing a polymer of a phenolic compound may be formed on a portion of the surface of the substrate, or may be formed on the entire surface of the substrate. The layer containing an acrylic resin may be formed on at least a portion of the surface of the layer containing a polymer of a phenolic compound. The layer containing an acrylic resin may be formed on a portion of the surface of the layer containing a polymer of a phenolic compound, or may be formed on the entire surface of the layer containing a polymer of a phenolic compound.

[0022] At least a portion of the surface of the laminate of the present invention is formed by a layer containing an acrylic resin, that is, the layer containing an acrylic resin forms at least a part of the surface of the laminate.

[0023] The laminate of the present invention can have excellent antithrombogenicity. This will be explained below. As described above, the laminate of the present invention includes a layer containing a polymer of a phenolic compound between a substrate and a layer containing an acrylic resin. The layer containing a polymer of a phenolic compound can bond the substrate and the layer containing an acrylic resin. This is thought to be because the polymer of a phenolic compound can contain oxygen atoms derived from the phenolic compound, thereby enhancing the wettability of the substrate when the substrate is formed of, for example, a poorly adhesive material. Furthermore, because the polymer of a phenolic compound can contain a benzene ring, van der Waals forces can act to a certain extent between the polymer of the phenolic compound and molecules contained in the substrate, which is thought to contribute to this (i.e., the layer containing a polymer of a phenolic compound can bond the substrate and the layer containing an acrylic resin). Because the polymer of a phenolic compound can contain a benzene ring, van der Waals forces can act to a certain extent between the polymer of the phenolic compound and the acrylic resin, which is thought to contribute to this (i.e., the layer containing a polymer of a phenolic compound can bond the substrate and the layer containing an acrylic resin). Since the layer containing the polymer of a phenol compound can bond the substrate and the layer containing the acrylic resin, the laminate of the present invention can exhibit the thrombus formation inhibitory effect of the acrylic resin, and therefore the laminate of the present invention can have excellent antithrombogenicity.

[0024] [Substrate] The material of the substrate of the present invention is preferably a material suitable for medical devices, particularly medical devices having parts that come into contact with blood or body fluids. From the viewpoint of chemical resistance and flexibility, specific examples include silicone-based resins, fluorine-based resins, and polyolefin-based resins. The material constituting the substrate of the present invention may be one or more types, but preferably contains at least one selected from silicone-based resins, fluorine-based resins, and polyolefin-based resins. Examples of silicone-based resins include organopolysiloxanes such as dimethylpolysiloxane, methylphenylpolysiloxane, and diphenylpolysiloxane, and copolymers of organopolysiloxanes with acrylic, epoxy, polyester, polyamide, etc., but are not limited to these. Examples of fluorine-based resins include, but are not limited to, fluoropolymers such as polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene copolymer (ETFE), ethylene chlorotrifluoroethylene copolymer (ECTFE), fluorinated ethylene propylene copolymer (FEP), perfluoroalkoxyalkane (PFA), polyvinyl fluoride (PVF), polyvinylidene fluoride (PVDF). Examples of polyolefin-based resins include, but are not limited to, polyethylene, polypropylene, high-density polyethylene (HDPE), low-density polyethylene (LDPE), polybutadiene, ethylene propylene copolymer, etc. The shape of the substrate of the present invention can be appropriately set according to the use of the laminate, and is not particularly limited.

[0025] [Phenol Compound] In the present invention, examples of the phenolic compound include aromatic compounds having one hydroxy group, such as phenol, cresol, ethylphenol, carvacrol, trimethylphenol, thymol, and tyrosine; aromatic compounds having two hydroxy groups, such as catechol, L-dopa, dopamine, hydroxytyrosol, resorcinol, and hydroquinone; aromatic compounds having three or more hydroxy groups, such as pyrogallol, gallic acid, and benzenetriol; and polyphenols such as catechin, lignins, tannins, and tyrosine-containing proteins, such as fibroin. In the present invention, one phenolic compound may be selected and used alone, or two or more phenolic compounds may be used in combination. Among the phenolic compounds, aromatic compounds having two hydroxy groups are preferred, compounds having a catechol group are more preferred, and dopamine and hydroxytyrosol are even more preferred.

[0026] [Phenol Compound Polymer] The phenol compound polymer of the present invention is a polymer obtained by reacting the above-mentioned phenol compound by oxidative condensation, oxidative coupling, etc. The phenol compound used to form the above-mentioned phenol compound polymer may be in the form of a salt such as a hydrochloride, as long as the oxidative condensation, oxidative coupling, etc. is possible.

[0027] The phenolic compound used to form the phenolic compound polymer may contain an initiator, a reactant, a catalyst, and a buffer to promote polymerization, as appropriate. Examples of catalysts include transition metals such as copper chloride, vanadium tetrachloride, manganese dioxide, and iron oxide; oxidases such as peroxidase, catalase, and tyrosinase; and hydrogen peroxide. Examples of buffers include HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), TRIS (trishydroxymethylaminomethane), and AMPD (2-amino-2-hydroxymethyl-1,3-propanediol). The concentration of the buffer is not particularly limited as long as it is within a range that allows the formation of a phenolic compound polymer, but is preferably in the range of 1 mM to 100 mM, and more preferably in the range of 10 mM to 50 mM.

[0028] In the present invention, the polymer of a phenolic compound may be a polymer containing, in addition to the phenolic compound, a structural unit derived from another comonomer, as long as the polymer exhibits the antithrombotic effect of the present invention. From the viewpoint of further improving the antithrombotic effect, the polymer of the phenolic compound is preferably a polymer containing only structural units derived from the phenolic compound, without containing structural units derived from other comonomers.

[0029] The phenolic compound of the present invention undergoes oxidative polymerization in the presence of an oxidase and hydrogen peroxide. A specific example of polymerization using hydroxytyrosol is shown in the following formula [4], but is not limited thereto.

[0030] When dopamine is used as the phenolic compound of the present invention, oxidative polymerization proceeds in an alkaline aqueous solution at room temperature (20° C. to 25° C.) without the need for an initiator, reactant, or catalyst to promote polymerization. An example of polymerization using dopamine is shown in the following formula [5], but is not limited thereto.

[0031] In the present invention, the solvent used to form the polymer of the phenol compound is not particularly limited as long as it is a solvent in which the phenol compound is soluble. From the viewpoint of reducing the environmental load, however, a water-soluble solvent is preferred, and water is more preferred.

[0032] In the present invention, the solvent used for forming the polymer of the phenol compound preferably has a pH of 5.0 to 12.0, more preferably 8.0 to 9.0, and even more preferably 8.0 to 8.5. When the solvent has a pH of 5.0 to 12.0, the polymerization of the phenol compound proceeds.

[0033] In the present invention, the amount of the phenol compound contained in the solvent used to form the polymer of the phenol compound is preferably in the range of 0.01% by mass to 1.0% by mass, more preferably in the range of 0.05% by mass to 0.5% by mass, and even more preferably in the range of 0.05% by mass to 0.2% by mass.

[0034] The polymer of the phenol compound preferably contains a structural unit represented by the following formula [4-1]. When the polymer of the phenol compound contains this structural unit, the polymer of the phenol compound can further enhance the wettability of the substrate, for example, when the substrate is formed of a poorly adhesive material.

[0035] It is also preferable that the polymer of the phenol compound contains a structural unit represented by the following formula [5-1]. When the polymer of the phenol compound contains this structural unit, the polymer of the phenol compound can further enhance the wettability of the substrate, for example, when the substrate is formed of a poorly adhesive material.

[0036] The layer containing the polymer of a phenol compound of the present invention may contain, in addition to the polymer of a phenol compound, a preservative, a surfactant, an antibacterial agent, etc. as appropriate.

[0037] The layer containing the polymer of a phenol compound of the present invention can be laminated with the substrate by interaction due to hydrogen bonding or van der Waals forces.

[0038] In the present invention, the method for laminating a layer containing a polymer of a phenolic compound on a substrate is not particularly limited. For example, a method can be used in which a solution containing a phenolic compound is brought into contact with the substrate, and a layer containing a polymer of a phenolic compound is formed on the substrate. In this method, polymerization of the phenolic compound can proceed while the solution containing the phenolic compound is in contact with the substrate. The substrate on which the layer containing a polymer of the phenolic compound has been formed is removed from the solution containing the phenolic compound as needed, washed with water as needed, and dried as needed. A more specific method for contacting the solution containing the phenolic compound with the substrate is preferably a method in which the substrate is immersed in a solvent and the phenolic compound is added to the solvent. In this method, the substrate after immersion may be removed and then washed with water or dried as appropriate.

[0039] There are no limitations on the time and temperature for immersing the substrate, as long as the temperature and time are such that the oxidative polymerization or coupling polymerization of the phenol compound proceeds.

[0040] As described above, the layer containing a polymer of a phenol compound may be laminated on the entire surface of the substrate, or may be laminated on a part of the surface of the substrate.

[0041] In the present invention, the thickness of the layer containing a polymer of a phenolic compound can be determined by measuring the total light transmittance using a spectroscopic haze meter. The total light transmittance of the substrate alone (blank) and the total light transmittance of a substrate (sample) on which only a layer containing a phenolic compound is laminated are measured, and the thickness can be evaluated from the difference in total light transmittance between the blank and the sample. This difference can be calculated using the following formula: Difference in Total Light Transmittance Between Blank and Sample = Total Light Transmittance of Blank - Total Light Transmittance of Sample. The difference in total light transmittance between the blank and the sample is preferably in the range of 0.1% to 10%, more preferably in the range of 1% to 8%, and even more preferably in the range of 1% to 5%. When the difference in total light transmittance is 0.1% or more, the effect of improving the wettability of the substrate by the polymer of a phenolic compound can be further enhanced, for example, when the substrate is formed of a poorly adhesive material. When the difference in total light transmittance is 10% or more, the transparency as a medical device is reduced, and the device may not be suitable for use.

[0042] In the present invention, when dopamine is used as the phenolic compound, the polymer of the phenolic compound laminated on the substrate can be identified by ATR-FTIR (attenuated total reflection spectroscopy). In the ATR-FTIR spectrum, the substrate on which the layer containing the polymer of the phenolic compound is laminated has a peak intensity of 3400 to 3500 cm －１ Since absorption peaks due to N--H stretching and / or O--H stretching are observed, it is possible to confirm the presence or absence of a layer containing a polymer of a phenol compound on the substrate.

[0043] In the present invention, when hydroxytyrosol is used as the phenolic compound, the polymer of the phenolic compound laminated on the substrate can be identified by the ATR-FTIR method (attenuated total reflection spectroscopy). In the ATR-FTIR spectrum, the substrate on which the layer containing the polymer of the phenolic compound is laminated has a peak intensity of 3400 to 3500 cm －１Since an absorption peak due to O--H stretching is observed, it is possible to confirm the presence or absence of a layer containing a polymer of a phenol compound on the substrate.

[0044] The content of the phenolic compound polymer in the layer containing the phenolic compound polymer is preferably 90% by mass or more, more preferably 95% by mass or more, and even more preferably 98% by mass or more. When the layer contains 90% by mass or more, for example, when the substrate is made of a poorly adhesive material, the layer containing the phenolic compound polymer can further enhance the effect of improving the wettability of the substrate.

[0045] [Acrylic Resin] The acrylic resin of the present invention preferably contains a (meth)acrylate unit represented by the following general formula [1]. That is, the acrylic resin preferably contains a structural unit derived from a (meth)acrylate represented by the following general formula [1]. In the following general formula [1], R ２It is preferable to use one having 1 to 5 carbon atoms, and more preferably 1 to 2. In the following general formula [1], it is preferable to use one having 1 to 4 ethylene oxide units, and more preferably 2 to 4. Specific examples include methoxyethyl (meth)acrylate, ethoxyethyl (meth)acrylate, methoxydiethylene glycol (meth)acrylate, methoxytriethylene glycol (meth)acrylate, and methoxytetraethylene glycol (meth)acrylate. Examples include methoxydiethylene glycol (meth)acrylate, methoxytriethylene glycol (meth)acrylate, methoxytetraethylene glycol (meth)acrylate, methoxypentaethylene glycol (meth)acrylate, methoxyhexaethylene glycol (meth)acrylate, methoxyheptaethylene glycol (meth)acrylate, methoxyoctaethylene glycol (meth)acrylate, methoxynonaethylene glycol (meth)acrylate, and methoxydecaethylene glycol (meth)acrylate. If the repeating unit becomes too large and hydrophilicity increases too much, there is a possibility that the acrylic resin will leach out more into blood. Therefore, more preferred are methoxytetraethylene glycol (meth)acrylate, which has 4 repeating ethylene oxide units, and methoxytriethylene glycol (meth)acrylate, which has 3 repeating ethylene oxide units. Especially preferred is methoxytriethylene glycol (meth)acrylate, which has 3 repeating ethylene oxide units. (In formula [1], R １ is a hydrogen atom or a methyl group, R ２ represents an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 1 to 5 carbon atoms, and n represents an integer of 1 to 4.

[0046] From the viewpoint of imparting antithrombotic properties, the acrylic resin of the present invention is preferably a (meth)acrylate polymer containing a (meth)acrylate unit represented by the following general formula [2]. In other words, the acrylic resin preferably contains a structural unit derived from a (meth)acrylate represented by the following general formula [2]. R ３Preferably, the carbon number of R is 2 to 30, more preferably 4 to 24, and even more preferably 6 to 18. Specific examples include normal hexyl (meth)acrylate, cyclohexyl (meth)acrylate, phenyl (meth)acrylate, benzyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, lauryl (meth)acrylate, myristyl (meth)acrylate, palmityl (meth)acrylate, and stearyl (meth)acrylate. ３ If the number of carbon atoms in R is too small, the hydrophobicity is insufficient, and the compound may not dissolve uniformly in the solvent, resulting in cloudiness. ３ If the number of carbon atoms is too large, the hydrophilicity may decrease, and the antithrombotic properties may decrease. In view of these, 2-ethylhexyl (meth)acrylate and lauryl (meth)acrylate are particularly preferred. (In formula [2], R ３ is an alkyl group having 2 to 30 carbon atoms or an aralkyl group having 2 to 30 carbon atoms, R ４ represents a hydrogen atom or a methyl group.)

[0047] The acrylic resin of the present invention is preferably a (meth)acrylate polymer containing a (meth)acrylate unit represented by the following general formula [3]. That is, the acrylic resin preferably contains a structural unit derived from a (meth)acrylate represented by the following general formula [3]. It is preferable to use a silicone (meth)acrylate containing 1 to 1,000 dimethylsiloxane repeating units. If the repeating units are too large, the viscosity of the resulting (meth)acrylate polymer may become too high, making it difficult to handle. On the other hand, if the repeating units are too small, the viscosity may become too low, causing it to easily disappear from the coating surface of a medical device or the like. Therefore, the number of dimethylsiloxane repeating units is more preferably 1 to 500, more preferably 5 to 100, even more preferably 10 to 50, and particularly preferably 10 to 30. It is particularly preferable that the number of dimethylsiloxane repeating units is 20 or less. (In formula [3], R ５ is a hydrogen atom or a methyl group, R６ is an alkylene group having 1 to 6 carbon atoms, R ７ represents an alkyl group having 1 to 6 carbon atoms, and m is in the range of 1 to 1000.

[0048] R ５ is a hydrogen atom or a methyl group. ５ is preferably a methyl group.

[0049] R ６ may be a linear alkylene group having 1 to 6 carbon atoms, or a branched alkylene group having 1 to 6 carbon atoms. ６ Examples of R include a methylene group, an ethylene group, and an n-propylene group. ６ may have 2 or more and 4 or less carbon atoms, or may have 3 carbon atoms.

[0050] R ７ R may be a linear alkyl group having 1 to 6 carbon atoms, or a branched alkyl group having 1 to 6 carbon atoms. ７ Examples of R include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. ７ may have 2 or more and 5 or less carbon atoms, or may have 4 carbon atoms.

[0051] The number-average molecular weight (Mn) of the acrylic resin of the present invention is preferably 2,000 to 200,000. If the number-average molecular weight (Mn) of the acrylic resin is less than 2,000, not only may the acrylic resin be easily eluted into blood, but the strength and stability of the coating film may be lost. If the number-average molecular weight (Mn) of the acrylic resin exceeds 200,000, workability during coating may be reduced. That is, the number-average molecular weight (Mn) of the acrylic resin is preferably 2,000 to 200,000, more preferably 5,000 to 100,000, even more preferably 5,000 to 50,000, and particularly preferably 5,000 to 30,000. Methods for measuring the number average molecular weight (Mn) include end group determination, osmometry, vapor pressure osmometry, vapor pressure depression, freezing point depression, boiling point elevation, and gel permeation chromatography (GPC). In the present invention, gel permeation chromatography (GPC) is used because of its ease of operation.

[0052] In the acrylic resin of the present invention, the (meth)acrylate unit represented by the general formula [1], the (meth)acrylate unit represented by the general formula [2], and the (meth)acrylate unit represented by the general formula [3] are preferably copolymerized in a molar ratio of Formula 1:(Formula 2+Formula 3)=100-5:0-95, more preferably 70-5:30-95, even more preferably 45-5:55-95, and particularly preferably 40-15:60-85. When the ratios are within this range, the laminate can achieve both antithrombogenicity and transparency.

[0053] As described above, the acrylic resin preferably contains a structural unit derived from a (meth)acrylate represented by general formula [1]. That is, the acrylic resin preferably contains a structural unit represented by the following general formula [1-1]. This is because, when the acrylic resin contains this structural unit, the acrylic resin can exhibit a thrombus formation inhibitory effect. (In formula [1-1], R １ is a hydrogen atom or a methyl group, R ２represents an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 1 to 5 carbon atoms, and n represents an integer of 1 to 4.

[0054] As described above, the acrylic resin preferably contains a structural unit derived from a (meth)acrylate represented by general formula [2]. That is, the acrylic resin preferably contains a structural unit represented by the following general formula [2-1]. This is because, when the acrylic resin contains this structural unit, the acrylic resin can exhibit a thrombus formation inhibitory effect. (In formula [2-1], R ３ is an alkyl group having 2 to 30 carbon atoms or an aralkyl group having 2 to 30 carbon atoms, R ４ represents a hydrogen atom or a methyl group.)

[0055] The acrylic resin preferably contains at least one of a structural unit derived from a (meth)acrylate represented by general formula [1] and a structural unit derived from a (meth)acrylate represented by general formula [2]. When the total monomer units of the acrylic resin are taken as 100 mol%, the total of the structural units derived from a (meth)acrylate represented by general formula [1] and the structural units derived from a (meth)acrylate represented by general formula [2] is preferably 70 mol% or more, more preferably 90 mol% or more, and even more preferably 95 mol% or more.

[0056] As described above, the acrylic resin preferably contains a structural unit derived from a (meth)acrylate represented by general formula [3]. That is, the acrylic resin preferably further contains a structural unit represented by the following general formula [3-1]: (In formula [3-1], R ５ is a hydrogen atom or a methyl group, R ６ is an alkylene group having 1 to 6 carbon atoms, R ７ represents an alkyl group having 1 to 6 carbon atoms, and m is in the range of 1 to 1000.

[0057] The acrylic resin preferably contains a structural unit derived from a (meth)acrylate represented by general formula [1], a structural unit derived from a (meth)acrylate represented by general formula [2], and a structural unit derived from a (meth)acrylate represented by general formula [3].

[0058] When all monomer units of the acrylic resin are taken as 100 mol%, the total of the structural units derived from the (meth)acrylate represented by general formula [1], the structural units derived from the (meth)acrylate represented by general formula [2], and the structural units derived from the (meth)acrylate represented by general formula [3] is preferably 90 mol% or more, more preferably 95 mol% or more, and even more preferably 98 mol% or more, and may even be 100 mol%.

[0059] Specific examples of acrylic resins include copolymers of polydimethylsiloxane methacrylate (PDMSMA), 2-ethylhexyl acrylate (EHA), and methoxytriethylene glycol acrylate (MTEGA) (see, for example, Production Example 1 below), copolymers of 2-ethylhexyl acrylate (EHA) and methoxytriethylene glycol acrylate (MTEGA) (see, for example, Production Example 2 below), and homopolymers of 2-methoxyethyl acrylate (MEA) (see, for example, Production Example 3 below).

[0060] (Production Example 2) Production of Acrylic Resin 15.1 g of methoxytriethylene glycol acrylate (MTEGA) (Shin-Nakamura Chemical Co., Ltd.) and 29.7 g of 2-ethylhexyl acrylate (EHA) (Tokyo Chemical Industry Co., Ltd.) were added with 0.0447 g of azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.), and the mixture was polymerized in 178.9 g of ethyl acetate (Tokyo Chemical Industry Co., Ltd.) at 80°C for 20 hours. After the polymerization reaction was completed, 10 mL of the reaction solution was added dropwise to 50 mL of ethanol under stirring to dissolve the solution, and the polymer was isolated by adding water dropwise. The supernatant was removed by decantation. This purification process was repeated twice, and the precipitate was dried under reduced pressure at 60°C overnight to obtain a copolymer. This produced an acrylic resin with a number average molecular weight of 12,000 and a copolymer composition ratio of MTEGA / EHA = 73.51 / 26.53.

[0061] (Production Example 3) Production of Acrylic Resin 44.8 g of 2-methoxyethyl acrylate (MEA) (Tokyo Chemical Industry Co., Ltd.) was added with 0.052 g of azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.), and the mixture was subjected to a polymerization reaction in 200.2 g of ethyl acetate (Tokyo Chemical Industry Co., Ltd.) at 80°C for 20 hours. After the polymerization reaction was completed, 10 mL of the reaction solution was added dropwise to 50 mL of ethanol under stirring to dissolve the solution, and the polymer was isolated by adding water dropwise. The supernatant was removed by decantation. This purification process was repeated twice, and the precipitate was then dried under reduced pressure at 60°C overnight to obtain a copolymer. This produced an acrylic resin with a number average molecular weight of 18,000.

[0062] The solvent for dissolving the acrylic resin of the present invention is not particularly limited as long as it dissolves the acrylic resin, but tetrahydrofuran, ethyl acetate, methanol, and ethanol are preferred.

[0063] The layer containing an acrylic resin of the present invention may contain a preservative, a surfactant, an antibacterial agent, and the like in addition to the acrylic resin.

[0064] The acrylic resin content in the acrylic resin-containing layer is preferably 90% by mass or more, more preferably 95% by mass or more, and even more preferably 98% by mass or more. When the content is 90% by mass or more, the acrylic resin-containing layer can exhibit a greater effect of inhibiting thrombus formation.

[0065] The content of the acrylic resin in the solvent for dissolving the acrylic resin is preferably 0.5% by mass to 5.0% by mass, more preferably 1.0% by mass to 4.0% by mass, and even more preferably 1.0% by mass to 3.0% by mass. That is, the content of the acrylic resin in the solution containing the acrylic resin is preferably 0.5% by mass to 5.0% by mass, more preferably 1.0% by mass to 4.0% by mass, and even more preferably 1.0% by mass to 3.0% by mass.

[0066] In the present invention, methods for laminating a layer containing an acrylic resin on a layer containing a polymer of a phenolic compound include spraying, dipping, immersion, coating, layer-by-layer, etc., but immersion and dipping are preferred from the viewpoint of simple methods. In the operation for laminating a layer containing an acrylic resin on a layer containing a polymer of a phenolic compound, for example, a substrate on which a layer containing a polymer of a phenolic compound has been formed (specifically, a substrate on which a layer containing a polymer of a phenolic compound has been formed, washed with water as necessary, and dried as necessary) can be brought into contact with a solution containing an acrylic resin, and then the substrate can be removed from the solution containing the acrylic resin and dried. The time and temperature for laminating a layer containing an acrylic resin on a layer containing a polymer of a phenolic compound are not limited as long as the time and temperature are such that the two layers are sufficiently adhered to each other.

[0067] The layer containing an acrylic resin may be laminated over the entire surface of the substrate or over a portion of the substrate, so long as the laminate of the present invention has antithrombogenicity.

[0068] The present invention will be specifically explained below by showing examples, but the present invention is not limited to these examples.

[0069] (Measurement of number average molecular weight) 3 mL of mobile phase for GPC measurement was added to 15 mg of acrylic resin to dissolve the acrylic resin, and the mixture was filtered with 0.45 μm hydrophilic PTFE (Millex-LH; Nihon Millipore). GPC measurement was performed using a 510 high-pressure pump, a 717plus automatic injection device (Nihon Waters), and a RI-101 (Showa Denko) measuring device. The column was PLgel 5 μMIXED-D (600 × 7.5 mm) (Polymer Laboratories). The column temperature was performed at room temperature, and the mobile phase was tetrahydrofuran (THF) with 0.03 wt% dibutylhydroxytoluene (BHT). Detection was performed using RI (Refractive Index), and 50 μL was injected. Molecular weight calibration was performed using monodisperse PMMA (Easi Cal: Polymer Laboratories).

[0070] (Measurement of Copolymerization Composition Ratio) 50 mg of an acrylic resin was added to an NMR test tube (specification: N-5, manufactured by Nippon Precision Chemicals Co., Ltd.) using a Pasteur pipette, and then 0.7 mL of deuterated chloroform (manufactured by Wako Pure Chemical Industries, Ltd.) was added and thoroughly mixed, and the tube was then covered with a sample cap (specification: NC-5, manufactured by Nippon Precision Chemicals Co., Ltd.). The copolymerization composition ratio was calculated by carrying out 1H NMR measurement at room temperature using a GEMINI-200 manufactured by VARIAN.

[0071] (Evaluation of antithrombotic properties) 200 μL of blood solution (a mixture of citrated rabbit blood and 80 mM calcium chloride aqueous solution at a volume ratio of 12:1) was dropped onto each of the left and right halves of a laminated sample (2 cm × 4 cm) and kept warm at 37° C. for 30 minutes. The sample was then immersed in physiological saline and the presence or absence of detachment of the blood paste was determined. The test was repeated five times, and if all of the blood was detached, it was determined to have antithrombotic properties, and if no detachment occurred, it was determined to have no antithrombotic properties.

[0072] (Measurement of Total Light Transmittance) The total light transmittance was measured in accordance with JIS K 7361-1:1997 using a haze meter (NDH5000, manufactured by Nippon Denshoku Industries Co., Ltd.) on a sample (5 cm x 5 cm).

[0073] (Production Example 1) Production of Acrylic Resin 17.8 g of methoxytriethylene glycol acrylate (MTEGA) (Shin-Nakamura Chemical Co., Ltd.), 4.8 g of silicone methacrylate (SiSM) (Gelest, product name: MCR-M11), and 27.5 g of 2-ethylhexyl acrylate (EHA) (Tokyo Chemical Industry Co., Ltd.) were added with 0.052 g of azobisisobutyronitrile (AIBN) (Wako Pure Chemical Industries, Ltd.), and the mixture was polymerized in 200.2 g of ethyl acetate (Tokyo Chemical Industry Co., Ltd.) at 80°C for 20 hours. After completion of the polymerization reaction, 10 mL of the reaction solution was added dropwise to 50 mL of ethanol with stirring to dissolve the solution, and the polymer was isolated by adding water dropwise. The supernatant was removed by decantation. This purification process was repeated twice, and the precipitate was then dried under reduced pressure at 60°C overnight to obtain a copolymer. The number average molecular weight of the produced acrylic resin was 23,000, and the copolymer composition ratio was MTEGA / (EHA+SiSM)=35.53 / 64.47.

[0074] Example 1: Preparation of a sample having a silicone substrate and a layer containing polydopamine A 10 mM Tris-HCl (pH 8.5) aqueous solution manufactured by Nacalai Tesque was prepared, and a substrate (a medical silicone substrate measuring 10 cm x 20 cm x 5 mm) was immersed in the solution and degassed using ultrasonic waves. Dopamine hydrochloride manufactured by Tokyo Chemical Industry Co., Ltd. was added to the aqueous solution in which the substrate was immersed so that the concentration was 0.2 mass %, and the solution was allowed to stand for 2 hours at room temperature (20 to 25°C). The substrate was removed, and the surface of the substrate was washed with water and air-dried at room temperature (20 to 25°C) for 1 hour. A sample was obtained by the above procedure. Measurement of the sample (i.e., a substrate having a layer containing polydopamine laminated thereon) by the ATR-FTIR method (attenuated total reflection measurement method) revealed a peak intensity of 3400 to 3500 cm as shown in Figure 1. －１ Absorption peaks due to N-H and O-H stretching were observed (see the polydopamine coating in Figure 1). This confirmed the formation and adhesion of polydopamine to the substrate surface. Furthermore, the total light transmittance of the sample (i.e., the silicone substrate with polydopamine attached) was measured using a haze meter manufactured by Murakami Color Research Laboratory and found to be 77.07%. This was a difference of 4.8% compared to the total light transmittance of the silicone substrate (Comparative Example 1), which was 81.89%.

[0075] Example 2: Preparation of a sample having a silicone substrate and a layer containing polydopamine. This was carried out as in Example 1, except that the concentration of dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.) added was changed from 0.2% by mass to 0.1% by mass. The total light transmittance of the sample was measured and found to be 79.07%, a difference of 2.8% compared to the total light transmittance of the silicone substrate (Comparative Example 1), which was 81.89%.

[0076] Example 3: Preparation of a sample having a silicone substrate and a layer containing polydopamine. This was carried out as in Example 1, except that the concentration of dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.) added was changed from 0.2% by mass to 0.05% by mass. The total light transmittance of the sample was measured to be 80.28%, a difference of 1.6% compared to the total light transmittance of the silicone substrate (Comparative Example 1), which was 81.89%.

[0077] Example 4: Preparation of a sample having a PTFE substrate and a layer containing polydopamine The same procedure as in Example 1 was carried out, except that a PTFE substrate was used instead of the silicone substrate.

[0078] Example 5 Preparation of a Sample Having an HDPE Substrate and a Layer Containing Polydopamine The same procedure as in Example 1 was carried out, except that an HDPE substrate was used instead of the silicone substrate.

[0079] Example 6: Preparation of a sample having a silicone substrate and a layer containing a hydroxytyrosol polymer The procedure of Example 1 was repeated, except that hydroxytyrosol (0.2% by mass, manufactured by Tokyo Chemical Industry Co., Ltd.), peroxidase (0.2% by mass, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and hydrogen peroxide (0.2% by mass) were used instead of dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.).

[0080] (Example 7) Preparation of a sample having a PTFE substrate and a layer containing a hydroxytyrosol polymer The same procedure as in Example 1 was repeated, except that a PTFE substrate was used instead of the silicone substrate, and hydroxytyrosol (0.2% by mass, manufactured by Tokyo Chemical Industry Co., Ltd.), peroxidase (0.2% by mass, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and hydrogen peroxide (0.2% by mass) were used instead of dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.).

[0081] (Example 8) Preparation of a sample having an HDPE substrate and a layer containing a hydroxytyrosol polymer The procedure of Example 1 was repeated, except that an HDPE substrate was used instead of the silicone substrate, and hydroxytyrosol (0.2% by mass, manufactured by Tokyo Chemical Industry Co., Ltd.), peroxidase (0.2% by mass, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and hydrogen peroxide (0.2% by mass) were used instead of dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.).

[0082] (Comparative Example 1) Preparation of Silicone Base (Untreated) A sample was prepared as described in Example 1, except that dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.) was not added. This sample, i.e., the silicone base, was designated as Comparative Example 1.

[0083] (Comparative Example 2) Preparation of PTFE Substrate (Untreated) A sample was prepared using a PTFE substrate (10 cm × 20 cm × 5 mm, manufactured by Kawamura Sangyo Co., Ltd.) instead of the silicone substrate described in Example 1, but without adding dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.). This sample, i.e., the PTFE substrate, was designated Comparative Example 2.

[0084] (Comparative Example 3) Preparation of HDPE Substrate (Untreated) A sample was prepared using an HDPE substrate (manufactured by AS ONE, 10 cm × 20 cm × 5 mm) instead of the silicone substrate described in Example 1, but without adding dopamine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.). This sample, i.e., the HDPE substrate, was designated Comparative Example 3.

[0085] Test Example 1: Preparation and Evaluation of Laminated Samples (i.e., Samples Further Having a Layer Containing an Acrylic Resin) The acrylic resin prepared in Preparation Example 1 was dissolved in ethanol to a concentration of 3.0% by mass. The samples described in Examples 1 to 8 and Comparative Examples 1 to 3 were immersed in the ethanol solution containing the acrylic resin for 10 seconds at room temperature (20-25°C). The samples were removed from the solution and then dried at room temperature (20-25°C). The surfaces of the dried samples (i.e., laminated samples) were observed using an optical microscope (Keyence Digital Microscope, VHX-900, 100x magnification) to evaluate coating uniformity. Figure 2 shows micrographs of the samples prepared in Example 1 and Comparative Example 1 after immersion in an ethanol solution containing 3.0% by mass of acrylic resin and drying. Specifically, micrographs of the laminated samples prepared in Example 1 and Comparative Example 1 are shown in Figure 2. In Comparative Example 1, the wettability of the acrylic resin was poor and dried droplets were significantly observed, whereas in Example 1, the wettability was improved and it was confirmed that the acrylic resin was uniformly coated. The evaluation results of the laminated samples of Examples 1 to 8 and Comparative Examples 1 to 3 are shown in Table 1.

[0086] The evaluation criteria are as follows: ×: Dried droplets of acrylic resin were observed, and the coated surface was non-uniform. ○: Dried droplets of acrylic resin were not observed, and the coated surface was uniform.

[0087] Test Example 2: Antithrombogenicity Test Example 9 The acrylic resin prepared in Production Example 1 was dissolved in an ethanol solution to a concentration of 1.0% by mass. A sample (2 cm x 4 cm) prepared in Example 1 was immersed in the ethanol solution containing the acrylic resin at room temperature (20-25°C) for 10 seconds. The sample was removed from the solution and dried at room temperature (20-25°C). The dried sample (i.e., laminated sample) was used to evaluate the antithrombogenicity described above. Specifically, 200 μL of blood solution (a 12:1 volumetric mixture of citrated rabbit blood and 80 mM calcium chloride aqueous solution) was dropped onto each of the left and right halves of the laminated sample and incubated at 37°C for 30 minutes. The sample was then immersed in physiological saline, and the presence or absence of detachment of the blood paste was determined. Five tests were conducted; a case in which all the blood was detached was judged to have antithrombogenicity, and a case in which no blood was detached was judged to have no antithrombogenicity. As a result, this laminate sample (i.e., a laminate obtained by immersing a layer containing polydopamine laminated on the surface of a silicone substrate in an ethanol solution containing 1.0% by mass or more of an acrylic resin) was determined to have antithrombotic properties.

[0088] Example 10 The procedure was carried out in the same manner as in Example 9, except that the concentration of the acrylic resin added was changed from 1.0% by mass to 3.0% by mass. This example (i.e., Example 10) was also determined to have antithrombotic properties.

[0089] The evaluation criteria are as follows: ×: (n=5) The blood stain did not come off from any of the test samples. ○: (n=5) The blood stain came off from all of the test samples.

[0090] The laminate of the present invention has excellent antithrombotic properties and is therefore useful for medical devices such as blood circuits, heart-lung machines, catheters, and drain tubes.

Claims

1. A laminate comprising, in this order, a substrate, a layer containing a polymer of a phenolic compound, and a layer containing an acrylic resin.

2. The laminate according to claim 1, wherein the phenol compound is a compound having a catechol group.

3. The laminate according to claim 2, wherein the compound having a catechol group includes at least one of dopamine and hydroxytyrosol.

4. The laminate according to claim 1, wherein the acrylic resin is a (meth)acrylate polymer containing one or more of a (meth)acrylate unit represented by the following general formula [1], a (meth)acrylate unit represented by the following general formula [2], and a (meth)acrylate unit represented by the following general formula [3]: (In formula [1], R １ is a hydrogen atom or a methyl group, R ２ represents an alkyl group having 1 to 5 carbon atoms or an aralkyl group having 1 to 5 carbon atoms, and n represents an integer of 1 to 4. (In formula [2], R ３ is an alkyl group having 2 to 30 carbon atoms or an aralkyl group having 2 to 30 carbon atoms, R ４ represents a hydrogen atom or a methyl group.) (In formula [3], R ５ is a hydrogen atom or a methyl group, R ６ is an alkylene group having 1 to 6 carbon atoms, R ７ represents an alkyl group having 1 to 6 carbon atoms, and m is in the range of 1 to 1000.

5. The laminate according to claim 1, wherein the substrate comprises at least one selected from the group consisting of silicone-based resins, fluorine-based resins, and polyolefin-based resins.

6. A medical device comprising the laminate according to any one of claims 1 to 5.

7. A method for manufacturing a laminate, characterized by sequentially carrying out the following steps: (1) forming a layer containing a polymer of a phenolic compound on a substrate while the substrate is in contact with a solution containing the phenolic compound; (2) washing the substrate with water and then drying the substrate; (3) contacting the dried substrate with a solution containing an acrylic resin; and (4) drying the substrate removed from the solution containing the acrylic resin.

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