JP6600560B2 - Method for producing antithrombogenic coating material - Google Patents

Description

  The present invention relates to a method for producing an antithrombogenic coating material.

  In recent years, medical materials using various polymer materials have been studied, such as artificial kidney membranes, plasma separation membranes, catheters, stents, artificial lung membranes, artificial blood vessels, adhesion prevention membranes, artificial skins, etc. Is expected to be used. In these, a synthetic polymer material that is a foreign substance for a living body is used in contact with a body fluid such as a living tissue or blood. Therefore, medical materials are required to have biocompatibility. The biocompatibility required for medical materials varies depending on the purpose and method of use, but medical materials used as materials that come into contact with blood include suppression of blood coagulation system, suppression of platelet adhesion and activation, and activity of the complement system. The characteristic (antithrombogenicity) of suppression of crystallization is required.

  Usually, antithrombogenicity is imparted to medical devices by coating the base material constituting the medical device with an antithrombotic material (antithrombogenic coating material) or by fixing the antithrombotic material on the surface of the base material. By the method.

  For example, Patent Document 1 discloses that a living body having a synthetic polymer that simultaneously satisfies biocompatibility such as suppression of platelet adhesion / activation, inhibitory effect of complement system activation, and affinity with tissue in vivo. Artificial organ membranes and medical devices used in contact with tissue and blood are disclosed. Patent Document 1 discloses polymethoxyethyl acrylate (PMEA) and the like as a synthetic polymer that is an antithrombotic material.

Japanese Patent Laid-Open No. 4-152952

  Polymethoxyethyl acrylate (PMEA) is a hydrophilic polymer material having excellent antithrombogenicity and biocompatibility, and is used as an antithrombogenic component of the surface coating material of medical devices that come into contact with blood. Since PMEA is hydrophilic, when it is used for an antithrombogenic coating material, a higher molecular weight is preferable because the stability of the coat layer is increased.

  As a polymerization method for PMEA, a solution polymerization method using a radical polymerization initiator is generally used. The solution polymerization method has an advantage that it can be carried out at low cost without any residual catalyst or the like, but it has heretofore been difficult to obtain a polymer having a large molecular weight by the solution polymerization method using a radical polymerization initiator.

  Accordingly, the present invention has been made in view of the above circumstances, and the object thereof is an antithrombogenic coating material capable of obtaining a polymer having a large molecular weight by a solution polymerization method using a radical polymerization initiator. It is to provide a manufacturing method.

  As a result of intensive studies to solve the above problems, the present inventors have prepared a methanol solution containing a monomer such as methoxyethyl acrylate; and radical polymerization having a 10-hour half-life temperature of 60 ° C. or lower. It has been found that the above problems can be solved by a method for producing an antithrombogenic coating material comprising a step of adding an initiator to the methanol solution and polymerizing the monomer, and the present invention has been completed.

  ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of an antithrombogenic coating material which can obtain a polymer with a large molecular weight by solution polymerization using a radical polymerization initiator is provided.

It is the photograph which dyed phenol red the cast film | membrane of the antithrombogenic coating material containing the polymer obtained in Example 6. FIG. It is the photograph which dyed the phenol red dyeing | staining of the cast film | membrane of the antithrombogenic coating material containing the polymer obtained by the comparative example 2. FIG. An untreated polypropylene film (FIG. 3a), a film (FIG. 3b) on which a cast film of an antithrombogenic coating material containing the polymer obtained in Comparative Example 2 was formed, and the polymer obtained in Example 7 were used. It is a photograph which shows the protein adsorption test result about the film (FIG. 3c) which formed the cast film | membrane of the antithrombogenic coating material containing.

  The present invention includes a step of preparing a methanol solution containing a monomer such as methoxyethyl acrylate; and adding a radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or less to the methanol solution to prepare a polymerization reaction solution, It is related with the manufacturing method of the antithrombogenic coating material including the process of polymerizing the said monomer. The production method according to the present invention can increase the molecular weight of the obtained polymer while adopting a solution polymerization method using a radical polymerization initiator. When the molecular weight of the polymer contained in the antithrombogenic coating material is large, the stability of the coat layer is improved. Although it does not limit the technical scope of the present invention, this is because the larger the molecular weight of the polymer, the more likely the polymers are entangled with each other, and thus the coat layer formed on the substrate is more stable. It is thought that there is not.

  Embodiments of the present invention will be described below. In addition, this invention is not limited only to the following embodiment.

  Further, in this specification, “X to Y” indicating a range means “X or more and Y or less”, and unless otherwise specified, measurement of operation and physical properties is room temperature (20 to 25 ° C.) / Relative humidity 40 to 50. Measured under the condition of%.

  The production method according to the present invention includes a step of preparing a methanol solution containing a monomer represented by the following general formula (1) (methanol solution preparation step).

In general formula (1), R ¹ is a hydrogen atom or a methyl group, preferably a hydrogen atom.

In the general formula (1), R ^2, ring having 1 to 4 carbon atoms or an alkylene group having a straight or branched chain, is preferably a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms. Specific examples include a methylene group, an ethylene group, a trimethylene group, a propylene group, a cyclopropylene group, a tetramethylene group, and a cyclobutylene group. Among these, in view of the effect of improving antithrombogenicity, a linear or branched alkylene group having 1 to 3 carbon atoms is preferable, and a methylene group or ethylene group is particularly preferable.

In the general formula (1), R ³ is a cyclic 1 to 4 carbon atoms, an alkyl group of straight or branched chain, it is preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, and a cyclopropyl group. Among these, considering the effect of improving antithrombogenicity, it is preferably a linear or branched alkyl group having 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group, and a methyl group. It is particularly preferred.

  Specific examples of the monomer represented by the general formula (1) include methoxymethyl acrylate, methoxyethyl acrylate (MEA), methoxypropyl acrylate, methoxybutyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, and ethoxypropyl. Acrylate, ethoxybutyl acrylate, propoxymethyl acrylate, propoxyethyl acrylate, propoxypropyl acrylate, propoxybutyl acrylate, butoxymethyl acrylate, butoxyethyl acrylate, butoxypropyl acrylate, butoxybutyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, methoxypropyl methacrylate, Methoxybutyl methacrylate, ethoxymethyl methacrylate Acrylate, ethoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, propoxymethyl methacrylate, propoxyethyl methacrylate, propoxy methacrylate, propoxy butyl methacrylate, butoxymethyl methacrylate, butoxyethyl methacrylate, butoxyethyl methacrylate, and a butoxy butyl methacrylate. The monomer represented by the general formula (1) is preferably methoxymethyl acrylate, methoxyethyl acrylate (MEA), ethoxymethyl acrylate, ethoxyethyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl. From the viewpoint that it is a methacrylate and is easily available, methoxyethyl (meth) acrylate is more preferable. These monomers can be used alone or in combination of two or more.

  “(Meth) acrylate” means “acrylate” and / or “methacrylate”.

  In the method according to the present invention, in addition to the monomer represented by the general formula (1), another monomer copolymerizable with the monomer represented by the general formula (1) (hereinafter referred to as “monomer”) Or simply referred to as “other monomer”). Examples of other monomers copolymerizable with the monomer represented by the general formula (1) include acrylamide, N, N-dimethylacrylamide, N, N-diethylacrylamide, aminomethyl acrylate, aminoethyl acrylate, Aminoisopropyl acrylate, diaminomethyl acrylate, diaminoethyl acrylate, diaminobutyl acrylate, methacrylamide, N, N-dimethylmethacrylamide, N, N-diethylmethacrylamide, aminomethyl methacrylate, aminoethyl methacrylate, diaminomethyl methacrylate, diaminoethyl methacrylate , Methyl acrylate, ethyl acrylate, isopropyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl Methacrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, ethylene, and propylene and the like.

  When using another monomer in a methanol solution preparation process, the ratio of the other monomer with respect to the whole monomer is 10 to 50 weight%, for example, Preferably it is 15 to 30 weight%.

  In one Embodiment of this invention, the monomer used in a methanol solution preparation process is a monomer shown by General formula (1).

  In the present invention, methanol is used as the main component of the polymerization solvent. If a solvent other than methanol is used as the main component of the polymerization solvent, it will be difficult to increase the molecular weight of the polymer. Without limiting the technical scope of the present invention, this is believed to be due to the mobility of the growing radicals during polymerization.

  However, as long as the “methanol solution” in the present invention contains methanol as a main component of the polymerization solvent, it is not hindered to contain a solvent other than methanol as long as the objective effect of the present invention is not impaired. The above “as the main component” means that 95% by weight or more, preferably 99% by weight or more (upper limit of 100% by weight) of the total solvent used in the methanol solution is methanol. Examples of polymerization solvents other than methanol contained in the “methanol solution” include water; ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, tert-butanol, ethylene glycol, diethylene glycol, propylene glycol, Examples include, but are not limited to, alcohols such as dipropylene glycol; one or more selected from organic solvents such as chloroform, tetrahydrofuran, acetone, dioxane, and benzene. When a solvent other than methanol is contained in the “methanol solution”, the content of the solvent other than methanol (in the case of including plural types, the total amount) is, for example, 5 parts by weight or less with respect to 100 parts by weight of methanol. The amount is preferably 1 part by weight or less.

  In a preferred embodiment, the polymerization solvent contained in the “methanol solution” consists only of methanol.

  The content of the monomer represented by the general formula (1) contained in the methanol solution is preferably 10% by weight or more based on the whole methanol solution from the viewpoint of the molecular weight obtained, and is 20% by weight. More preferably, it is more preferably 25% by weight or more, and particularly preferably 30% by weight or more. The higher the monomer content in the methanol solution, the higher the molecular weight of the polymer obtained. Therefore, the upper limit of the monomer content represented by the general formula (1) in the methanol solution is not particularly limited. For example, it is 70% by weight or less, preferably 60% by weight or less. When the methanol solution contains other monomers, the total monomer content in the methanol solution (the total amount of the monomer represented by the general formula (1) and other monomers) is, for example, the saturation concentration It is as follows. When preparing the methanol solution, stirring may be performed as necessary.

  In the methanol solution preparation step, the methanol solution to which the monomer has been added may be degassed before the addition of the polymerization initiator. The deaeration process may be performed by bubbling the methanol solution for about 0.5 to 5 hours with an inert gas such as nitrogen gas or argon gas. In the degassing treatment, the methanol solution may be adjusted to a temperature of about 30 ° C. to 80 ° C., preferably the polymerization temperature in the polymerization step described below.

  The method according to the present invention comprises a polymerization reaction solution prepared by adding a radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or less to the methanol solution (“radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or less). A polymerization reaction solution prepared by adding the above to the methanol solution is also simply referred to as “polymerization reaction solution”), and a step of polymerizing the monomer (polymerization step) is included.

  In the polymerization step, a radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or lower is used. 10 hour half-life temperatures such as 2,2′-azobisisobutyronitrile (AIBN, T10 = 65 ° C.) and dimethyl 2,2′-azobis (2-methylpropionate) (T10 = 66 ° C.) When a radical polymerization initiator exceeding 60 ° C is used, it is necessary to perform the polymerization at a high temperature exceeding 60 ° C. For this reason, when the monomer concentration is low, chain transfer reaction to the solvent, monomer, and polymer easily occurs in radical polymerization, and it becomes difficult to obtain a high molecular weight polymer. On the other hand, when the monomer concentration is high, the polymerization is carried out at a high temperature, the polymerization rate is increased, and the growth radicals are difficult to diffuse, so that the polymer itself gels and becomes insoluble.

  In this specification, “10-hour half-life temperature (T10)” means that in a radical inert solvent such as benzene, the concentration decreases to half of the initial value (for example, 0.01 mol / L) in 10 hours. This is the temperature required for

  The radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or lower is not particularly limited. For example, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (T10 = 30 ° C.), 2,2′-azobis (2,4-dimethylvaleronitrile) (T10 = 51 ° C.), 2,2′-azobis [2- (2-imidazolin-2-yl) propane] dihydrochloride (T10 = 44 ° C.), 2,2′-azobis [2- (2-imidazolin-2-yl) propane] disulfate dihydrate (T10 = 46 ° C.), 2,2′-azobis (2-methylpropionamidine) ) Dihydrochloride (T10 = 56 ° C.), 2,2′-azobis [N- (2-carboxyethyl) -2-methylpropionamidine)] hydrate (T10 = 57 ° C.) 3-hydroxy-1,1-dimethylbutylperoxyneodecanoate (T10 = 37 ° C.), α-cumylperoxyneodecanoate (T10 = 38 ° C.), 1,1,3,3-tetrabutylper Oxyneodecanoate (T10 = 44 ° C), t-butylperoxyneodecanoate (T10 = 48 ° C), t-butylperoxyneoheptanoate (T10 = 53 ° C), t-butylperoxypi Valate (T10 = 58 ° C.), t-amyl peroxyneodecanoate (T10 = 46 ° C.), t-amyl peroxypivalate (T10 = 55 ° C.), di (2-ethylhexyl) peroxydicarbonate (T10 = 49 ° C), di (secondary butyl) peroxydicarbonate (T10 = 51 ° C), and the like.

  Among these, a radical polymerization initiator having a 10-hour half-life temperature of 50 ° C. or less is preferable, and a 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile having a particularly low 10-hour half-life temperature of 40 ° C. or less is preferable. ), 3-hydroxy-1,1-dimethylbutylperoxyneodecanoate, α-cumylperoxyneodecanoate, and the like are more preferable.

  Commercially available products may be used as such radical polymerization initiators, for example, V-70 (T10 = 30 ° C.), V-65 (T10 = 51 ° C.), VA-044 (T10 = 44 ° C.), VA- 046B (T10 = 46 ° C.), VA-50 (T10 = 56 ° C.), VA-057 (T10 = 57 ° C.) (above, manufactured by Wako Pure Chemical Industries, Ltd.), AZO series ADVN (T10 = 52 ° C.) (Otsuka Manufactured by Chemical Co., Ltd., Lupelox (registered trademark) 610 (T10 = 37 ° C.), Lupelox (registered trademark) 188 (T10 = 38 ° C.), Lupelox (registered trademark) 844 (T10 = 44 ° C.), Luperox (registered trademark) 10 (T10 = 48 ° C.), Lupelox (registered trademark) 701 (T10 = 53 ° C.), Lupelox (registered trademark) 11 (T10 = 58 ° C.), Lupelox (registered trademark) 5 6 (T10 = 46 ° C.), Lupelox (registered trademark) 554 (T10 = 55 ° C.), Lupelox (registered trademark) 223 (T10 = 49 ° C.), Lupelox (registered trademark) 225 (T10 = 51 ° C.) (above, Arkema Examples include Yoshitomi Corporation).

  The blending amount of the radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or less is preferably 0 with respect to, for example, 100 parts by weight of the monomer (the whole when plural kinds of monomers are used). 0.005 to 2 parts by weight, and more preferably 0.1 to 0.5 parts by weight. When the blending amount of the radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or less is 0.005 parts by weight or more with respect to 100 parts by weight of the monomer, a high-molecular weight body is obtained with good reproducibility. In addition, there is an advantage that the molecular weight is prevented by being 2 parts by weight or less.

  The radical polymerization initiator may be added to methanol at an arbitrary concentration, and then added to a methanol solution containing the monomer as an initiator methanol solution. In this case, the content of the radical polymerization initiator in the initiator methanol solution is not particularly limited, but is, for example, 0.01 to 10% by weight.

  The initiator methanol liquid is not prevented from containing a solvent other than methanol as long as the objective effect of the present invention is not impaired. For example, the initiator methanol solution may contain, for example, 5 parts by weight or less (for example, 1 part by weight or less) of the solvent other than methanol with respect to 100 parts by weight of methanol.

  The content of the monomer represented by the general formula (1) contained in the polymerization reaction solution in the polymerization step is the above-mentioned single unit contained in the polymerization reaction solution with respect to the entire polymerization reaction solution from the viewpoint of the molecular weight obtained. The content of the monomer is preferably 10% by weight or more. The content of the monomer contained in the polymerization reaction solution is more preferably 20% by weight or more, further preferably 25% by weight or more, and more preferably 30% by weight or more based on the entire polymerization reaction solution. It is particularly preferred. The higher the monomer content in the polymerization reaction solution, the higher the molecular weight of the resulting polymer. Therefore, the upper limit of the monomer content represented by the general formula (1) in the polymerization reaction solution is not particularly limited. For example, it is 70% by weight or less, preferably 60% by weight or less. In one Embodiment of this invention, the content of the monomer shown by General formula (1) contained in a polymerization reaction liquid is 20 weight% or more and a saturated concentration or less. Further, when the polymerization reaction liquid contains other monomers, the total monomer content in the polymerization reaction liquid (the monomer represented by the general formula (1) and the total amount of other monomers) is, for example, Below the saturation concentration. You may stir as needed at the time of polymerization reaction liquid preparation.

  From the viewpoints of increasing the molecular weight of the polymer and preventing gelation in the polymerization step, the polymerization temperature is preferably low, but if it is too low, the progress of the reaction is slowed, leading to a reduction in production efficiency. Polymerization temperature is 30-60 degreeC, for example, Preferably it is 40-55 degreeC.

  The polymerization time is, for example, 1 to 24 hours, preferably 3 to 12 hours at the above polymerization temperature.

  Furthermore, if necessary, a polymerization rate adjusting agent, a surfactant, and other additives may be appropriately used in the polymerization.

  The atmosphere in which the polymerization reaction is performed is not particularly limited, and can be performed in an air atmosphere or an inert gas atmosphere such as nitrogen gas or argon gas. Further, during the polymerization reaction, the reaction solution may be stirred.

  The polymer after polymerization can be purified by a general purification method such as a reprecipitation method, a dialysis method, an ultrafiltration method, or an extraction method.

  The polymer after purification can be dried by any method such as freeze drying, reduced pressure drying, spray drying, or heat drying. However, from the viewpoint of little influence on the physical properties of the polymer, freeze drying or reduced pressure drying is performed. Is preferred.

  According to the solution polymerization method using the above radical polymerization initiator, a polymer having a large molecular weight can be obtained. The weight average molecular weight of the polymer obtained by polymerization of the monomer is preferably 200,000 or more, more preferably more than 300,000, and still more preferably 400,000 or more, from the viewpoint of the stability of the coat layer. . The upper limit of the molecular weight of the polymer is not particularly limited, but is, for example, 1 million or less, preferably less than 1 million, and more preferably 800,000 or less from the viewpoint that the polymer itself does not gel and become insoluble. In one preferred embodiment, the weight average molecular weight of the polymer obtained by polymerization of the monomer is more than 300,000 and not more than 1 million.

  In the present invention, “weight average molecular weight” is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance. Specifically, the polymer is dissolved in THF (tetrahydrofuran) to 1 mg / ml. A Shodex GPC column LF-804 (manufactured by Showa Denko KK) is attached to a GPC system LC-20 manufactured by Shimadzu Corporation, and THF is passed as a mobile phase to measure standard polystyrene and GPC of the polymer. After creating a calibration curve with standard polystyrene, the weight average molecular weight of the polymer is calculated.

  The antithrombogenic coating material obtained by the production method according to the present invention may be in the form of the polymer obtained by the above process. The production method according to the present invention further includes a step of adding other additives such as a gelling agent, a thickening agent, a plasticizer, and a solvent to the above polymer to process it into a gel or solution form. But it ’s okay. Optionally, a step of adding other components such as a crosslinking agent, thickener, preservative, pH adjuster, etc. to the polymer to form a composition may be included. When the antithrombogenic coating material contains a crosslinking agent, the polymer can be more firmly fixed to the substrate surface.

  When used in the form of a composition, the medium used is not particularly limited as long as it can dissolve, suspend or disperse the polymer. For example, water, toluene, xylene, diethyl ether, chloroform, ethyl acetate, methylene chloride, Examples include tetrahydrofuran, acetone, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propanol, n-butanol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol and the like. You may use the said medium individually by 1 type or in mixture of 2 or more types. Among these, it is preferable that the solvent to be used is methanol from a soluble viewpoint of a polymer.

  The amount of the polymer contained in the composition can be arbitrarily set, and can be used as a solution in which the polymer is dissolved up to a saturated amount, but is, for example, 0.1 to 50% by weight with respect to the entire coating material.

  The unreacted monomer contained in the antithrombogenic coating material is preferably 0.01% by weight or less based on the whole polymer. The lower the number of unreacted monomers, the better, so the lower limit is not particularly limited, but it is, for example, 0% by weight. The content of the residual monomer can be measured by a method known to those skilled in the art, such as high performance liquid chromatography.

  In one embodiment of the present invention, a polyalkoxyalkyl (meth) acrylate (hereinafter referred to as “the following general formula (2)” comprising the structural unit (A) represented by the following general formula (2) and having a weight average molecular weight of 200,000 or more. The “polyalkoxyalkyl (meth) acrylate” containing the structural unit (A) represented by 2) and having a weight average molecular weight of 200,000 or more is also simply referred to as “polymer according to the present invention”). An antithrombogenic coating material dissolved in a methanol / methanol mixture is provided. That is, this embodiment includes a polyalkoxyalkyl (meth) acrylate having a structural unit (A) represented by the following general formula (2) and having a weight average molecular weight of 200,000 or more, and methanol or a water / methanol mixture. And a composition for imparting antithrombogenicity. When the molecular weight of the polyalkoxyalkyl (meth) acrylate contained in the coat layer is large, the stability of the coat layer becomes excellent as described above.

In the general formula (2), R ¹ is a hydrogen atom or a methyl group, R ² is an alkylene group having 1 to 4 carbon atoms, and R ³ is an alkyl group having 1 to 4 carbon atoms. For R ¹ , R ² , and R ³ in general formula (2), the descriptions for R ¹ , R ² , and R ³ described above for general formula (1) are applied.

  The antithrombogenic coating material containing the high molecular weight hydrophilic material as described above can be obtained through the methanol solution preparation step and the polymerization step. More specifically, in the above polymerization step, the weight average molecular weight is 200,000 or more by setting the content of the monomer represented by the general formula (1) contained in the polymerization reaction solution to 20% by weight or more. A polyalkoxyalkyl (meth) acrylate can be obtained.

  The weight average molecular weight of the polyalkoxyalkyl (meth) acrylate is more preferably more than 300,000, and still more preferably 400,000 or more, from the viewpoint of the stability of the coat layer. The upper limit of the weight average molecular weight of the polymer is not particularly limited, but is 1 million or less, more preferably less than 1 million, and more preferably 800,000 or less from the viewpoint that the polymer itself gels and does not insolubilize. . In addition, the value measured by the gel permeation chromatography (Gel Permeation Chromatography, GPC) which uses said polystyrene as a standard substance shall be employ | adopted for the "weight average molecular weight" of polyalkoxyalkyl (meth) acrylate.

  Depending on the state of the water absorbed by the polymer material, free water (freezing at 0 ° C and weakly interacting with the polymer material or antifreeze water), intermediate water (from 0 ° C during the temperature rising process) Water that freezes at low temperatures and has an intermediate interaction with polymer materials or antifreeze water), or antifreeze water (water that does not freeze even at -100 ° C due to strong interaction with polymer materials) The In a polymer material having a hydration structure with a large proportion of intermediate water, the contact between the hydration structure of a biological component such as blood and antifreeze water can be suppressed, so that the hydration structure of the biological component is stably maintained. For this reason, such a polymer material is more excellent in biocompatibility. The polyalkoxyalkyl (meth) acrylate is preferably such that the proportion of intermediate water calculated by the following mathematical formula (1) exceeds 32% when it is equilibrated with water. That is, in one preferred embodiment of the present invention, the proportion of intermediate water calculated by the following mathematical formula (1) for the polyalkoxyalkyl (meth) acrylate that has been equilibrated with water (hereinafter, the following formula (1 The ratio of intermediate water calculated in step) is also simply referred to as “intermediate water ratio.”) An antithrombogenic coating material is provided in which the ratio exceeds 32%.

  In the above formula 1, a and x represent the intermediate water content (% by weight) and the equilibrium water content (% by weight) in the polyalkoxyalkyl (meth) acrylate that has been subjected to equilibrium water content, respectively. In the present specification, “equilibrium water content” refers to a state in which the water content of polyalkoxyalkyl (meth) acrylate has substantially reached equilibrium in ultrapure water at 25 ° C. More specifically, This refers to a state where water is added until the weight change per hour is within ± 1% by weight.

The intermediate water ratio can be obtained by the following method. That is, about 0.1 g of polyalkoxyalkyl (meth) acrylate was weighed and immersed in an excess amount (at least 100 times the weight of polyalkoxyalkyl (meth) acrylate) in ultrapure water at 25 ° C. for 1 week. , Equilibrate water. At this time, it is confirmed that the weight change per hour is within ± 1% by weight. An appropriate amount of a sample containing water in an equilibrium state is collected, excess moisture on the surface of the sample is taken up with a low dusting wiper, and then placed on a glass petri dish that has been previously weighed, and the weight is measured within 3 minutes (W _aq (g )). Separately, the equilibrated water-containing sample is vacuum-dried at 120 ° C. for 1 hour, allowed to cool in a desiccator for 30 minutes, and then weighed (W _dry (g)). From the measured weight, the equilibrium water content (x, wt%) is determined based on the following formula 2.

  The equilibrium water-containing sample is analyzed by differential scanning calorimetry (hereinafter “DSC”) under the following conditions to measure the low-temperature crystallization and melting behavior of water. Then, the water adsorbed on the polymer material is classified into free water, intermediate water, and antifreeze water. From the equilibrium water content, low temperature crystallization heat (−ΔHcc) of −40 ° C. and heat of fusion (ΔHm) of 0 ° C., Calculate the proportion of each hydrated structure present in the sample. Specifically, the intermediate water content (a,% by weight), and the free water content (% by weight) and the antifreeze water content (% by weight) are obtained as necessary.

(DSC measurement conditions)
Temperature range: -90 ° C (10 minutes hold) → 50 ° C
Temperature increase rate: 2.5 ° C / min
Measurement atmosphere: Nitrogen 50 ml / min
Measuring container: Aluminum hermetic pan equipment: DSC Q100 TA instruments manufactured.

(Calculation method of weight and proportion of each hydrated structure)
Define "equilibrium moisture content (wt%) = antifreeze water (wt%) + intermediate water (wt%) + free water (wt%)". calculate.

  Intermediate water: Divide −ΔHcc (mJ) by the heat of solidification of water 334 J / g to obtain the weight (mg) of intermediate water. Further, the weight of the intermediate water is divided by the amount of the sample to be measured to obtain the intermediate water content (a, weight%).

  Free water: ΔHm (mJ) is divided by the heat of fusion of water 334 J / g to obtain the total weight (mg) of intermediate water and free water. Subtract the weight of intermediate water from the total weight to obtain the weight (mg) of free water. Moreover, the free water content (% by weight) is obtained by dividing the weight of free water by the amount of sample to be measured.

  Antifreeze water: Multiply the measured sample amount (mg) by the equilibrium water content (x, wt%) to obtain the equilibrium water content (mg). Subtract the weight of intermediate water and the weight of free water from the equilibrium water content to determine the weight (mg) of antifreeze water. Further, the weight of the antifreeze water is divided by the amount of the sample to be measured to obtain the antifreeze water content (% by weight).

  By using a polyalkoxyalkyl (meth) acrylate having a high intermediate water ratio as described above as a coating material, protein adsorption and thrombus adhesion to the coating layer can be further suppressed. The intermediate water ratio of the polyalkoxyalkyl (meth) acrylate is more preferably 35% or more, and further preferably 37% or more. The upper limit of the intermediate water ratio is not particularly limited (upper limit 100%).

  The intermediate water ratio of the polyalkoxyalkyl (meth) acrylate can be controlled, for example, by appropriately adjusting the weight average molecular weight. For example, the intermediate water fraction can be increased by increasing the weight average molecular weight. More specifically, in the case of polymethoxyethyl acrylate (PMEA), the intermediate water ratio exceeding 32% can be controlled by setting the weight average molecular weight to more than 90,000.

  The structural unit (A) represented by the general formula (2) is derived from the monomer represented by the general formula (1). The polymer according to the present invention may include a structural unit derived from the above-mentioned other monomer that can be copolymerized with the monomer represented by the general formula (1).

  The polymer according to the present invention may have 50 to 100 mol% of the structural unit (A) in all the structural units (100 mol%), preferably 70 to 100 mol%, more preferably the structure. Consists of units (A) (100 mol%). By setting the proportion of the structural unit (A) within the above range, the adhesion and antithrombotic properties of the coat layer can be improved.

  The proportion of the structural unit (A) in the polymer according to the present invention and the structural unit derived from another monomer can be arbitrarily adjusted by changing the proportion of the monomer used in the polymerization.

  The terminal of the polymer according to the present invention is not particularly limited and is appropriately defined depending on the type of raw material used, but is usually a hydrogen atom. When the polymer according to the present invention is a copolymer, the structure of the copolymer is not particularly limited, and may be any of a random copolymer, an alternating copolymer, a periodic copolymer, and a block copolymer. .

What is necessary is just to confirm the ratio of the structural unit (A) in the obtained copolymer, and the structural unit derived from another monomer by NMR method, infrared spectrum analysis, etc. For example, in the case of a copolymer composed of a structural unit (A) and a structural unit derived from another monomer, the structural unit (A) and the other in the copolymer are determined by an integration ratio in ¹ H-NMR measurement. The ratio with the structural unit derived from the monomer of can be analyzed. Moreover, when a peak overlaps in the measurement of ¹ H-NMR, it can be calculated using ¹³ C-NMR.

  The antithrombogenic coating material according to this embodiment is obtained by dissolving the polymer according to the present invention in methanol or a water / methanol mixture. As the medium for dissolving the polymer according to the present invention, methanol or a water / methanol mixture is used from the viewpoint of solubility of the polymer. When other media are used, it becomes difficult to dissolve the polymer according to the present invention at a desired concentration. When a water / methanol mixture is used as the medium, the volume ratio of water and methanol is not particularly limited as long as the polymer according to the present invention can be dissolved at a desired concentration, but the water: methanol volume ratio (v / v) For example, 0.1: 99.9 to 99: 1 (v / v), preferably 80:20 to 99: 1 (v / v), more preferably 85:15 to 97: 3 (v / V).

  The amount of the polymer according to the present invention contained in the antithrombogenic coating material according to the present embodiment can be arbitrarily set, and includes, for example, 0.01 to 50% by weight of the polymer according to the present invention with respect to the entire coating material. , Preferably 0.1 to 50% by weight, more preferably 0.2 to 10% by weight.

  A method for dissolving the polymer according to the present invention in methanol or a water / methanol mixed solution is not particularly limited, and a conventionally known method can be adopted. For example, it can be performed by a stirrer, a homogenizer, ultrasonic treatment, or the like. it can.

[Medical equipment]
The antithrombogenic coating material obtained by the production method according to the present invention and the antithrombogenic coating material dissolved in methanol or water / methanol mixture according to the present invention are suitably used for medical devices. That is, in one embodiment of the present invention, the base material and the surface of the base material are dissolved in the antithrombogenic coating material obtained by the production method according to the present invention or the methanol or water / methanol mixture according to the present invention. And a coating layer made of a coating film of the antithrombogenic coating material.

  Examples of medical devices include implantable artificial organs and therapeutic instruments, extracorporeal circulation type artificial organs, catheters, guide wires, and the like. Specifically, implantable medical devices such as artificial blood vessels, artificial trachea, stent artificial skin, and artificial pericardium that are inserted or replaced into blood vessels and lumens; artificial heart systems, artificial lung systems, artificial cardiopulmonary systems, artificial Artificial organ systems such as kidney system, artificial liver system, immunoregulatory system; indwelling needle, IVH catheter, drug solution administration catheter, thermodilution catheter, angiographic catheter, vasodilator catheter and dilator or introducer, etc. Catheters inserted or placed in blood vessels; or guide wires and stylets for these catheters; gastric catheters, nutrition catheters, tube feeding (ED) tubes, urethral catheters, urinary catheters, balloon catheters , Each intratracheal suction catheter Catheters are inserted or indwelled in the living body tissues other than blood vessels, such as the suction catheter and drainage catheter; can be exemplified. In particular, the above-mentioned antithrombogenic coating material is suitably used for an artificial lung system that contacts a large amount of blood or an artificial cardiopulmonary system. For example, when forming a coating layer made of a coating of an antithrombotic coating material on a hollow fiber membrane of a hollow fiber membrane external blood perfusion type artificial lung, the thickness of the hollow fiber membrane (film thickness, inner surface of the hollow fiber membrane and The thickness between the outer surface and the outer surface is, for example, 20 μm to 100 μm.

(Base material)
The material of the base material of the medical device is not particularly limited, and examples thereof include polyolefins such as polyethylene, polypropylene, and ethylene-α-olefin copolymers, and modified polyolefins; polyamides; polyimides; polyurethanes; polyethylene terephthalate (PET), polybutylenes. Polyesters such as terephthalate (PBT), polycyclohexane terephthalate, polyethylene-2,6-naphthalate; polyvinyl chloride; polyvinylidene chloride (PVDC); polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene copolymer (ETFE) Examples thereof include various polymer materials such as fluororesins, metals, ceramics, carbon, and composite materials thereof. The above polymer material may be subjected to a stretching treatment (for example, ePTFE).

  The shape of the base material is appropriately selected according to the use of the medical device, and can be, for example, a tube shape, a sheet shape, or a rod shape. The form of the substrate is not limited to a molded body using the above-mentioned material alone, and a blend molded product, an alloyed molded product, a multilayered molded product, and the like can also be used. The substrate may be a single layer or may be laminated. At this time, when the base material is laminated, the base material of each layer may be the same or different. However, when it is desired to firmly fix the polymer by swelling the substrate with a solvent, at least the material present on the surface of the substrate is preferable because the polymer material can be swollen well with the solvent.

  In the present invention, the “base material surface” is a base material surface for a body fluid such as a biological tissue or blood. By forming the coating layer having a polymer on the surface of the base material, the antithrombogenicity of the base material surface is improved. In the medical device, a coating layer having a polymer may be formed on the base material surface against body fluid such as biological tissue or blood, but this does not prevent the coating layer from being formed on other surfaces. .

  In order to enhance the stability of the coat layer to the substrate surface, the substrate may be surface-treated before forming the coat layer on the substrate surface. Examples of the surface treatment method of the substrate include a method of irradiating active energy rays (electron beam, ultraviolet ray, X-ray, etc.), a method using plasma discharge such as arc discharge, corona discharge, glow discharge, etc., and a high electric field. Examples thereof include a method of applying, a method of applying ultrasonic vibration via a polar liquid (water or the like), a method of treating with ozone gas, and the like.

(Coat layer)
In the medical device, a coating layer made of the antithrombogenic coating material is formed on the surface of the base material.

  The formation of the coating layer on the surface of the substrate covers the surface of the substrate by applying a coating solution containing the antithrombogenic coating material (for example, a methanol solution of the polymer according to the present invention). “Coating” is not only a form in which the entire surface of the substrate is completely covered with the coat layer, but also a form in which a part of the surface of the substrate is covered with the coat layer, that is, the surface of the substrate. A form in which a coat layer is attached to a part of the film is also included.

  The method for applying the coating solution containing the antithrombogenic coating material to the surface of the substrate can adopt a known method, and is not particularly limited. For example, dip coating, spraying, spin coating, dripping, Examples include doctor blades, brush coating, roll coaters, air knife coats, curtain coats, wire bar coats, and gravure coats.

  The thickness of the coating solution may be appropriately adjusted depending on the use of the medical device, and is not particularly limited, but is formed thinner than, for example, 0.1 μm.

  A coating layer is formed on the substrate surface by drying the substrate surface to which the coating solution containing the antithrombogenic coating material is applied. Although a drying process should just be set suitably in consideration of the glass transition temperature etc. of a base material, it is 0.5 to 10 hours at 20-80 degreeC, for example. The atmosphere in the drying step is not particularly limited, and can be performed in the air or in an inert gas atmosphere such as nitrogen gas or argon gas.

  The effects of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. Unless otherwise specified, the operation was performed at room temperature (25 ° C.).

[1. Production example]
(Example 1. Weight average molecular weight of polymer: 140,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 80 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Thereafter, 0.015 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 15% by weight). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 140,000.

(Example 2. Weight average molecular weight of polymer: 200,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 55 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Thereafter, 0.015 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 20% by weight). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 200,000.

(Example 3. Weight average molecular weight of polymer: 250,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 40 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Thereafter, 0.015 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 25% by weight). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 250,000.

(Example 4. Weight average molecular weight of polymer: 320,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 30 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Thereafter, 0.015 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 30% by weight). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 320,000.

(Example 5. Weight average molecular weight of polymer: 410,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 25 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Then, 0.015 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 3 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 35% by weight). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 410,000.

(Example 6. Weight average molecular weight of polymer: 420,000)
80 g (0.61 mol) of methoxyethyl acrylate (MEA) was dissolved in 115 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Thereafter, 0.08 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 40% by weight). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 420,000.

(Example 7. Weight average molecular weight of polymer: 800,000)
100 g (0.77 mol) of methoxyethyl acrylate (MEA) was dissolved in 95 g of methanol, put into a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a methanol solution (methanol solution preparation step). Thereafter, 0.1 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of methanol. The initiator solution dissolved in was added to a methanol solution in which MEA was dissolved to prepare a polymerization reaction solution (monomer content of the polymerization reaction solution: 50% by weight). While stirring the polymerization reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into ethanol, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 800,000.

(Comparative Example 1. Weight average molecular weight of polymer: 60,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 80 g of toluene, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour to prepare a toluene solution. Thereafter, 0.015 g of dimethyl 2,2′-azobis (2-methylpropionate) (V-601, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 66 ° C.) was dissolved in 5 g of toluene. The agent solution was added to a toluene solution in which MEA was dissolved to prepare a reaction solution (monomer content of the reaction solution: 15% by weight). While stirring the reaction solution, polymerization was performed at 80 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into normal hexane, and the precipitated polymer was recovered. The recovered polymer had a weight average molecular weight of 60,000.

(Comparative Example 2. Weight average molecular weight of polymer: 90,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 55 g of toluene, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour to prepare a toluene solution. Thereafter, 0.015 g of dimethyl 2,2′-azobis (2-methylpropionate) (V-601, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 66 ° C.) was dissolved in 5 g of toluene. The agent solution was added to a toluene solution in which MEA was dissolved to prepare a reaction solution (monomer content of the reaction solution: 20% by weight). While stirring the reaction solution, polymerization was performed at 80 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into normal hexane, and the precipitated polymer was recovered. The recovered polymer had a weight average molecular weight of 90,000.

(Comparative Example 3. Weight average molecular weight of polymer: 120,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 40 g of toluene, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour to prepare a toluene solution. Thereafter, 0.015 g of dimethyl 2,2′-azobis (2-methylpropionate) (V-601, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 66 ° C.) was dissolved in 5 g of toluene. The agent solution was added to a toluene solution in which MEA was dissolved to prepare a reaction solution (monomer content of the reaction solution: 25% by weight). While stirring the reaction solution, polymerization was performed at 80 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into normal hexane, and the precipitated polymer was recovered. The recovered polymer had a weight average molecular weight of 120,000.

(Comparative Example 4.)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 30 g of toluene, put into a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour to prepare a toluene solution. Thereafter, 0.015 g of dimethyl 2,2′-azobis (2-methylpropionate) (V-601, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 66 ° C.) was dissolved in 5 g of toluene. The agent solution was added to a toluene solution in which MEA was dissolved to prepare a reaction solution (monomer content of the reaction solution: 30% by weight). Immediately after the addition of the radical polymerization initiator, an abrupt increase in temperature and viscosity was confirmed, and gelation of the reaction solution occurred.

(Comparative Example 5.)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 25 g of toluene, placed in a four-necked flask, and N ₂ bubbling was performed at 80 ° C. for 1 hour to prepare a toluene solution. Thereafter, 0.015 g of dimethyl 2,2′-azobis (2-methylpropionate) (V-601, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 66 ° C.) was dissolved in 3 g of toluene. The agent solution was added to a toluene solution in which MEA was dissolved to prepare a reaction solution (monomer content of the reaction solution: 35% by weight). Immediately after the addition of the radical polymerization initiator, an abrupt increase in temperature and viscosity was confirmed, and gelation of the reaction solution occurred.

(Comparative Example 6. Weight average molecular weight of polymer: 90,000)
15 g (0.115 mol) of methoxyethyl acrylate (MEA) was dissolved in 40 g of toluene, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour to prepare a toluene solution. Thereafter, 0.015 g of 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd., 10 hour half-life temperature: 30 ° C.) was added to 5 g of toluene. The initiator solution dissolved in was added to the toluene solution in which MEA was dissolved to prepare a reaction solution (monomer content of the reaction solution: 25% by weight). While stirring the reaction solution, polymerization was performed at 50 ° C. for 5 hours in a nitrogen gas atmosphere. The liquid after polymerization was dropped into hexane, and the precipitated polymer was collected. The recovered polymer had a weight average molecular weight of 90,000.

[2. Antithrombogenicity test]
(Formation of coat layer)
The polymers obtained in Examples 2, 3, 5 and Comparative Example 2 were each dissolved in methanol at a concentration of 1% by weight.

  ePTFE artificial blood vessels (inner diameter 5 mm, outer diameter 7 mm, total length 5 cm) were each immersed in the above methanol solution and allowed to stand for 5 minutes. The artificial blood vessel was taken out from the methanol solution and dried by heating in an oven set at 60 ° C. for 3 to 4 hours to form a coat layer.

(Anti-thrombogenicity test)
A polycarbonate connector was connected to both ends of a soft vinyl chloride tube (inner diameter 6 mm, total length 27 cm). Furthermore, one end of each artificial blood vessel in which the coat layer was formed as described above was connected to one of the connectors. The lumen of a soft vinyl chloride tube was filled with 4.5 ml of human blood (heparin concentration 0.2 unit / ml) whose anticoagulant property was enhanced with heparin. Thereafter, the connector not connected to the artificial blood vessel and the end portion of the artificial blood vessel not connected to the connector were connected to form a loop. The loop was fixed to a cylindrical rotating device, and blood was circulated in the loop lumen at 14 rotations / minute for 120 minutes at room temperature (25 ° C.). The artificial blood vessel was removed from the loop, the lumen of the artificial blood vessel was washed with physiological saline, and the thrombus formed on the surface of the lumen (blood contact surface) was fixed (25 ° C.) with a 1% by weight glutaraldehyde aqueous solution. After the fixing treatment, the artificial blood vessel was washed with water and dried, and the blood contact surface of the artificial blood vessel was observed with an electron microscope to confirm the degree of thrombus formation. The ratio of the area covered with the formed thrombus to the area of the entire observation screen by the electron microscope was calculated. The results are shown in Table 2.

  As shown in Table 2, thrombus formation was suppressed by using an antithrombotic coating material containing a high molecular weight polymer. This indicates that the coating layer formed by the coating film of the antithrombogenic coating material is stable.

[3. Blood circulation test]
For the base material coated with the polymer having a weight average molecular weight of 410,000 obtained in Example 5 (porous polypropylene fiber for gas exchange made of porous polypropylene, hollow fiber thickness of 25 μm), the following method was used. Thrombosis was evaluated.

  That is, the polymer was dissolved in a water / methanol mixed solution (water: methanol = 95: 5 (v / v)) at a concentration of 0.05% by weight to obtain a coating material (coating solution). This coating material was filled into a simulated product form (blood circulation module) from the blood import side and allowed to stand for 120 seconds. Thereafter, the coating material was removed from the blood circulation module and dried by blowing at room temperature (25 ° C.) for 240 minutes to form a coating layer. This blood circulation module was incorporated into an extracorporeal circuit and filled with diluted human fresh blood (heparin: 0.2 unit / ml) mixed with 90 ml of heparin (0.45 unit / ml) -added human fresh blood and 110 ml of physiological saline. . Diluted human fresh blood was circulated in the blood circulation module at room temperature (25 ° C.) and 500 ml / min. After 60 minutes from the start of circulation, blood was sampled from the blood circulation circuit, the number of platelets was measured, and the ratio of the number of platelets after circulation to the number of platelets (100%) before the start of circulation (platelet number maintenance rate) was determined. As a result, the platelet count maintenance rate was 91%.

  In the blood circulation module coated with the coating material containing the polymer of Example 5, platelets were maintained at a high maintenance rate. That is, it was confirmed that the platelet count was not decreased due to aggregation of platelets starting from the activation of the coagulation system and platelet system, adhesion to the base material, etc., and excellent antithrombotic properties.

[4. Cast film formation test]
The polymer synthesized in Example 6 (weight average molecular weight = 420,000) was dissolved in methanol so that the concentration of the polymer was 1% by weight (coating material (1)). Separately, the polymer synthesized in Comparative Example 2 (weight average molecular weight = 90,000) was dissolved in methanol so that the concentration of the polymer was 1% by weight (coating material (2)). About the coating material (1) and the coating material (2), the cast film was produced with the following method and the film-forming property was evaluated.

  A biaxially stretched polypropylene film having a thickness of 50 μm and a size of 10 cm × 10 cm was prepared. 0.1 g of the coating material was dropped on this polypropylene film and dried at room temperature (25 ° C.) for 5 hours to form a coat layer (cast film) on the polypropylene film. Subsequently, the coat layer (cast film) was dyed with a phenol red aqueous solution, and the form of the cast film was observed.

  The cast film produced with the coating material (1) maintained a circular shape, and the cast film was stable. On the other hand, the cast film produced with the coating material (2) did not maintain a beautiful film shape. In the coating material (1), it is considered that the entanglement of the molecular chains increases due to the high molecular weight of the polymer, and a tough cast film is formed.

[5. Analysis of hydration structure]
About 0.1 g of each of the polymers obtained in Example 3, Example 5, Example 7 and Comparative Example 2 was weighed and put into an excess amount (100 times the weight of the polymer) of ultrapure water. It was immersed for 1 week at 25 ° C. and allowed to equilibrate with water. It was confirmed that the weight change per hour was within ± 1% by weight. An appropriate amount of each water sample that had been equilibrated was collected, and excessive moisture on the surface of the sample was taken up with a low dusting wiper, and then placed on a glass petri dish that had been previously weighed, and the weight was measured within 3 minutes (W _aq ( g)). Separately, the equilibrated water-containing sample was vacuum-dried at 120 ° C. for 1 hour, allowed to cool in a desiccator for 30 minutes, and then weighed (W _dry (g)). From the measured weight, the equilibrium water content (x, wt%), intermediate water content (a, wt%), free water content (wt%), and antifreeze water content (wt%) by the above method. Asked.

[6. Protein adsorption test]
The polymers of Example 7 and Comparative Example 2 were each dissolved in methanol to a final concentration of 1% by weight, and coating material (3) (Mw = 800,000) and coating material (4) (Mw = 90,000) were obtained. Prepared. The above coating material (3) or coating material (4) was cast on a polypropylene biaxially stretched film (FOP50, manufactured by Nimura Chemical Co., Ltd., thickness 50 μm) and then allowed to stand at room temperature (25 ° C.) for 48 hours or longer. . Thereafter, a protein adsorption test was performed according to the following procedure. For comparison, a similar test was performed using a biaxially stretched polypropylene film that does not form a cast film.

  Each film was immersed in a TBS solution containing BSA (bovine serum albumin, manufactured by Sigma) at a concentration of 1% by weight and shaken at room temperature (25 ° C.) for 1 hour. Thereafter, the film was immersed in a TBS-T diluent and washed for 5 minutes. Washing was repeated 3 times. Next, the film was immersed in 5% by weight skim milk (manufactured by Wako Pure Chemical Industries) TBS solution and shaken at room temperature (25 ° C.) for 1 hour to perform blocking. The film was immersed in a TBS-T diluent and washed for 5 minutes. Washing was repeated 3 times. Subsequently, it was immersed in a diluted solution (antibody concentration 5 μg / ml) of a primary antibody (rabbit anti-bovine albumin antibody, manufactured by BETHYL) and shaken at room temperature (25 ° C.) for 2 hours. The film was immersed in a TBS-T diluent and washed for 5 minutes. Washing was repeated 3 times. It was immersed in a diluted solution (100-fold dilution of the stock solution) of a gold-labeled secondary antibody (goat anti-rabbit IgG antibody, manufactured by KPL) and shaken at room temperature (25 ° C.) for 2 hours. The film was placed in TBS-T diluent and washed for 5 minutes. Washing was repeated 3 times. Then, the sensitization process of the adsorbed gold | metal | money was performed in the silver enhanced circuit (made by Sigma). After platinum-depositing the sensitized surface, the surface was observed with a scanning electron microscope (device name: S-3400N, manufactured by Hitachi High-Technologies Corporation, magnification: 5000 times). The composition of TBS and TBS-T diluted solution is as follows.

  TBS: 24.2 g of Tris (trishydroxymethylaminomethane) and 80 g of NaCl were dissolved in pure water, and the pH was adjusted to 7.6 with HCl. Pure water was added to adjust the total volume to 1 L (0.2 M Tris).

  TBS-T dilution: Tween (registered trademark) was dissolved in the above TBS so as to have a final concentration of 0.05% by weight.

  The results are shown in FIG. As shown in FIG. 3, in the cast film (FIG. 3c) in which the coating layer is formed with the coating material (3), compared with the cast film (FIG. 3b) in which the coating layer is formed with the coating material (4), silver particles are almost all. It was not seen, and the amount of protein adsorption was very small. It was shown that the coating material containing polyalkoxyalkyl (meth) acrylate having a large proportion of intermediate water when equilibrated water content was excellent in coatability and very low in protein adsorption.

Claims (9)

Preparing a methanol solution containing a monomer represented by the following general formula (1); and adding a radical polymerization initiator having a 10-hour half-life temperature of 60 ° C. or less to the methanol solution to prepare a polymerization reaction solution, Polymerizing the monomer,
A method for producing an antithrombogenic coating material comprising:
However, in the general formula (1), ^{R 1} is a hydrogen atom or a methyl group, ^{R 2} is an alkylene group having 1 to 4 carbon atoms, ^{R 3} is an alkyl group having 1 to 4 carbon atoms.   The manufacturing method of Claim 1 whose content of the said monomer contained in the said polymerization reaction liquid is 10 weight% or more.   The manufacturing method of Claim 2 whose content of the said monomer contained in the said polymerization reaction liquid is 20 weight% or more and a saturated concentration or less.   The manufacturing method of any one of Claims 1-3 whose weight average molecular weights of the polymer obtained by superposition | polymerization of the said monomer are 200,000 or more.   The manufacturing method of Claim 4 whose weight average molecular weights of the polymer obtained by superposition | polymerization of the said monomer are 300,000 or more and 1 million or less.   The production method according to claim 1, wherein the monomer is methoxyethyl (meth) acrylate. An antithrombosis obtained by dissolving a polyalkoxyalkyl (meth) acrylate having a structural unit (A) represented by the following general formula (2) and having a weight average molecular weight of 200,000 or more in methanol or a water / methanol mixture. Coating material;
However, in the general formula (2), ^{R 1} is a hydrogen atom or a methyl group, ^{R 2} is an alkylene group having 1 to 4 carbon atoms, ^{R 3} is an alkyl group having 1 to 4 carbon atoms. The antithrombogenic coating material according to claim 7, wherein the proportion of intermediate water calculated by the following mathematical formula (1) for the polyalkoxyalkyl (meth) acrylate with equilibrium water content exceeds 32%;
In the above formula 1, a and x represent the intermediate water content (% by weight) and the equilibrium water content (% by weight) in the polyalkoxyalkyl (meth) acrylate that has been subjected to equilibrium water content, respectively.   The antithrombogenic coating material according to claim 7 or 8, wherein the polyalkoxyalkyl (meth) acrylate has a weight average molecular weight of less than 1 million.