Method for producing anti‐thrombogenic material

Abstract

The purpose of the present invention is to provide: a method for producing an anti‐thrombogenic material in which white turbidness is reduced; a method for producing a medical instrument coated with the anti‐thrombogenic material produced by said method; and an anti‐thrombogenic material in which white turbidness is reduced. A method for producing an anti‐thrombogenic material according to the present invention is characterized by comprising a step for copolymerizing a specific alkyl (meth)acrylate, a silicone (meth)acrylate, and an alkoxy polyethylene glycol (meth)acrylate, and is characterized in that the silicone (meth)acrylate has a weight average molecular weight of 1450 or less.

Description

Method for producing antithrombotic material

[0001] The present invention relates to a method for producing an antithrombotic material with reduced turbidity, a method for producing a medical device coated with the antithrombotic material produced by said method, and an antithrombotic material with reduced turbidity.

[0002] In recent years, medical devices using various polymeric materials have been under study, and they are expected to be used in blood filters, artificial kidneys, plasma separators, catheters, artificial lungs, artificial blood vessels, adhesion prevention membranes, artificial skin, etc. In these cases, synthetic materials, which are foreign to the body, will be used in contact with tissues and blood in the body, so the medical devices must be biocompatible.

[0003] When using medical devices containing materials that come into contact with blood, the following three factors are important for biocompatibility: (a) inhibition of the blood coagulation system, (b) inhibition of platelet adhesion and activation, and (c) inhibition of complement system activation. In particular, when using devices that come into contact with blood for a relatively short period of time, such as extracorporeal circulation medical devices (e.g., artificial kidneys and plasma separation membranes), anticoagulants such as heparin and sodium citrate are generally used simultaneously, so the inhibition of platelet and complement system activation (b) and (c) above is particularly important.

[0004] The applicant of the present application has developed an antithrombotic material containing a (meth)acrylate copolymer which is obtained by polymerizing specific (meth)acrylate monomers and is water-insoluble and in the form of a viscous liquid at room temperature (Patent Document 1).

[0005] The applicant has also developed an antithrombotic material containing a (meth)acrylate copolymer that is polymerized from a specific (meth)acrylate monomer, has a specific weight-average molecular weight, is water-insoluble, and is a viscous liquid at room temperature, as a material that will be in contact with blood for a relatively long period of time (Patent Document 2).Furthermore, the applicant has developed a catheter that has excellent blood compatibility and biocompatibility, and whose physical and chemical properties are not impaired even when placed in the body for a long period of time, and in which at least a portion of the body fluid contact portion is coated with an antithrombotic material made of a specific (meth)acrylate copolymer (Patent Document 3).

[0006] Additionally, Patent Document 4 discloses an antithrombotic medical coating material containing a copolymer having a specific segment, and Patent Document 5 discloses a phosphorylcholine-like group-containing polymer having a specific structural unit and weight-average molecular weight and excellent biocompatibility.

[0007] Japanese Patent Application Laid-Open No. 2008-289864 International Publication No. 2022 / 210759 Pamphlet Japanese Patent Application Laid-Open No. 2009-261437 International Publication No. 2019 / 142710 Pamphlet Japanese Patent Application Laid-Open No. 2002-356519

[0008] As described above, various antithrombotic medical materials have been developed. In particular, the antithrombotic material developed by the present applicant can be dissolved in an alcohol solvent and easily used as a coating agent for medical devices that come into contact with blood. However, the present inventors have discovered that the antithrombotic material developed by the present applicant may become cloudy. Clouding of the antithrombotic material can reduce the visibility of symbols, numbers, letters, etc. printed on the surface of the medical device and make it difficult to detect attached foreign matter. Furthermore, coating a transparent medical device reduces transparency. Furthermore, solubility in the solvent may also be reduced. Therefore, the present invention aims to provide a method for producing an antithrombotic material with reduced clouding, a method for producing a medical device coated with the antithrombotic material produced by this method, and an antithrombotic material with reduced clouding.

[0009] The present inventors have conducted extensive research to solve the above problems. As a result, they have discovered that the cause of the clouding of antithrombotic materials is the oligomer of silicone (meth)acrylate used as a raw material, and that the clouding of antithrombotic materials can be suppressed by using an appropriate silicone (meth)acrylate as the raw material, thereby completing the present invention. The present invention is described below.

[0010] [1] A method for producing an antithrombotic material, comprising a step of copolymerizing an alkyl(meth)acrylate represented by the following formula (I), a silicone(meth)acrylate represented by the following formula (II), and an alkoxypolyethylene glycol(meth)acrylate represented by the following formula (III), wherein the silicone(meth)acrylate used has a weight-average molecular weight of 1,450 or less.

[0011]

[0012] [In the formula, R 1 represents a hydrogen atom or a methyl group, R 2 is C 6-20 Alkyl group, C 6-12 Aromatic hydrocarbon group, or C 6-12 Aromatic hydrocarbons - C 1-6 represents an alkyl group, R 3 represents a hydrogen atom or a methyl group, R 4 is C 1-6 represents an alkanediyl group, R 5 is C 1-6 represents an alkyl group, R 6 represents a hydrogen atom or a methyl group, R 7 is C 1-6 represents an alkyl group, m represents an integer of 1 or more and 50 or less, and n represents an integer of 2 or more and 10 or less.] [2] The method according to the above item [1], wherein the weight average molecular weight is greater than 1,000. [3] The method according to the above item [1] or [2], wherein the alkyl (meth)acrylate is used in an amount of 1.5 times by mole or more and 2 times by mole or less relative to the alkoxypolyethylene glycol (meth)acrylate. [4] The method according to any one of the above items [1] to [3], wherein the silicone (meth)acrylate is used in an amount of 0.01 times by mole or more and 0.1 times by mole or less relative to the alkoxypolyethylene glycol (meth)acrylate. [5] The method according to the above item [2], further comprising a step of concentrating the reaction solution of the copolymerization step under reduced pressure.

[0013] [6] A method for producing a medical device that comes into contact with blood, comprising the steps of copolymerizing an alkyl(meth)acrylate represented by formula (I), a silicone(meth)acrylate represented by formula (II), and an alkoxypolyethylene glycol(meth)acrylate represented by formula (III) to obtain a copolymer, and applying the copolymer or a solution thereof to the surface of the medical device, wherein the silicone(meth)acrylate represented by formula (II) has a weight average molecular weight of 1,450 or less.

[0014] [7] An antithrombotic material comprising a copolymer of an alkyl(meth)acrylate represented by the formula (I), a silicone(meth)acrylate represented by the formula (II), and an alkoxypolyethylene glycol(meth)acrylate represented by the formula (III), wherein the turbidity is 10 or less. [8] An antithrombotic material comprising a copolymer having an alkyl(meth)acrylate structural unit represented by the following formula (IV), a silicone(meth)acrylate structural unit represented by the following formula (V), and an alkoxypolyethylene glycol(meth)acrylate structural unit represented by the following formula (VI), wherein the turbidity is 10 or less.

[0015] [In the formula, R 1 ~R 7 , m and n have the same meanings as defined above.]

[0016] [9] Use of a composition as an antithrombotic material, which contains a copolymer of an alkyl(meth)acrylate represented by the formula (I), a silicone(meth)acrylate represented by the formula (II), and an alkoxypolyethylene glycol(meth)acrylate represented by the formula (III), and has a turbidity of 10 or less.

[10] Use of a composition as an antithrombotic material, which contains a copolymer having an alkyl(meth)acrylate structural unit represented by the formula (IV), a silicone(meth)acrylate structural unit represented by the formula (V), and an alkoxypolyethylene glycol(meth)acrylate structural unit represented by the formula (VI), and has a turbidity of 10 or less.

[0017]

[11] A method for improving the antithrombogenicity of a medical device that comes into contact with blood, comprising the steps of copolymerizing an alkyl(meth)acrylate represented by formula (I), a silicone(meth)acrylate represented by formula (II), and an alkoxypolyethylene glycol(meth)acrylate represented by formula (III) to obtain a copolymer, and applying the copolymer or a solution thereof to the surface of the medical device, wherein the silicone(meth)acrylate represented by formula (II) has a weight average molecular weight of 1450 or less.

[12] A method for improving the antithrombogenicity of a medical device that comes into contact with blood, comprising the step of applying to the surface of the medical device a copolymer having an alkyl(meth)acrylate structural unit represented by formula (IV), a silicone(meth)acrylate structural unit represented by formula (V), and an alkoxypolyethylene glycol(meth)acrylate structural unit represented by formula (VI), or a solution thereof, wherein the turbidity of the copolymer or the solution thereof is 10 or less.

[0018] "C 1-6 The term "alkyl group" refers to a linear, branched, or cyclic monovalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, and cyclohexyl. R 5 Preferably, C 2-6 alkyl group, more preferably C 3-5 is an alkyl group, most preferably n-butyl; R 7 Preferably, C 1-4 alkyl group, more preferably C 1-2 It is an alkyl group, most preferably methyl.

[0019] "C 6-20The term "alkyl group" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 6 to 20 carbon atoms. Examples include n-hexyl, 2-methylpentyl, 2-ethylbutyl, cyclohexyl, n-heptyl, 2-methylhexyl, 2-ethylpentyl, n-octyl, 2-methylheptyl, 2-ethylheptyl, n-octyl, 2-methylheptyl, 2-ethylhexyl, n-nonyl, 2-methyloctyl, n-decyl, 2-methylnonyl, 2-ethyloctyl, n-lauryl, 2-methyldecyl, 2-ethylnonyl, n-myristyl, 2-methyllauryl, 2-ethyldecyl, n-palmityl, 2-methylmyristyl, 2-ethyllauryl, n-stearyl, 2-methylpalmityl, and 2-ethylmyristyl. Preferably, C 8-12 alkyl group, more preferably a branched C 8-12 It is an alkyl group.

[0020] "C 6-12 The term "aromatic hydrocarbon group" refers to a monovalent aromatic hydrocarbon group having 6 to 12 carbon atoms. Examples include phenyl, naphthyl, indenyl, and biphenyl, with phenyl being preferred.

[0021] "C 6-12 Aromatic hydrocarbons - C 1-6 The alkyl group is C 6-12 C substituted with an aromatic hydrocarbon group 1-6 It refers to an alkyl group, such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, naphthylethyl, and biphenylmethyl, with benzyl being preferred.

[0022] "C 1-6 The term "alkanediyl group" refers to a linear or branched divalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples include methylene, ethylene, methylmethylene, n-propylene, methylethylene, n-butylene, methylpropylene, dimethylethylene, n-pentylene, and n-hexylene. Preferably, C 1-4 An alkanediyl group is preferably C 3-4 It is an alkanediyl group, most preferably n-propanediyl.

[0023] m is preferably 2 or more, more preferably 5 or more, and even more preferably 8 or more, and is preferably 25 or less or 20 or less, more preferably 15 or less, and even more preferably 12 or less.

[0024] n is preferably 8 or less, more preferably 5 or less, and even more preferably 4 or 3.

[0025] The method of the present invention makes it possible to produce an antithrombogenic material with reduced opacity. The antithrombogenic material exhibits antithrombogenic properties due to the presence of hydrophilic portions, which inhibit platelet adhesion and protein adsorption. Furthermore, the antithrombogenic material also contains water-repellent portions, which inhibit complement activation even when in contact with blood. Furthermore, the antithrombogenic material also exhibits affinity for the surface of similarly hydrophobic medical devices due to its hydrophobic nature. Furthermore, the antithrombogenic material produced by the method of the present invention does not impair the visibility of the surface of medical devices, nor does it impair the transparency of transparent medical devices. Therefore, the present invention is industrially extremely advantageous as a technology for producing an antithrombogenic material that imparts antithrombogenic properties and allergic reaction suppression by inhibiting complement activation to medical devices, and also imparts durability to blood contact, thereby maintaining these blood compatibility properties, and does not impair the visibility of the surface.

[0026] Figure 1 is a graph showing the relationship between the weight average molecular weight of the raw material polydimethylsiloxane methacrylate and the turbidity of the copolymer of the monomer. Figure 2 is a graph showing the relationship between the weight average molecular weight of the raw material polydimethylsiloxane methacrylate of the cloudy copolymer and the transparent copolymer. 1 1 H NMR chart.

[0027] The method for producing an antithrombotic material and a method for producing a medical device that comes into contact with blood according to the present invention will be described below, but the present invention is not limited to the following specific examples.

[0028] 1. Polymerization Reaction Step In this step, an alkyl(meth)acrylate represented by formula (I), a silicone(meth)acrylate represented by formula (II) and having a weight-average molecular weight of 1,450 or less, and an alkoxypolyethylene glycol(meth)acrylate represented by formula (III) are copolymerized. Hereinafter, the compound represented by formula (x) may be abbreviated as "compound (x)." For example, the alkyl(meth)acrylate represented by formula (I) may be abbreviated as "alkyl(meth)acrylate (I)."

[0029] The alkyl (meth)acrylate (I) imparts hydrophobicity to the copolymer, improves the affinity between the surface of the medical device to be coated and the copolymer, and inhibits peeling of the copolymer from the medical device.

[0030] The alkyl (meth)acrylate (I) is not particularly limited, and examples thereof include linear alkyl (meth)acrylates such as n-hexyl (meth)acrylate, n-heptyl (meth)acrylate, n-octyl (meth)acrylate, n-nonyl (meth)acrylate, n-decyl (meth)acrylate, n-lauryl (meth)acrylate, myristyl (meth)acrylate, palmityl (meth)acrylate, and stearyl (meth)acrylate; 2-methylpentyl (meth)acrylate, 2-ethylbutyl (meth)acrylate, 2-methylhexyl (meth)acrylate, 2-ethylpentyl (meth)acrylate, 2-methylheptyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, and 2-methyl Examples of suitable alkyl (meth)acrylates include branched alkyl (meth)acrylates such as octyl (meth)acrylate, 2-ethylheptyl (meth)acrylate, 2-methylnonyl (meth)acrylate, 2-ethyloctyl (meth)acrylate, 2-methyldecyl (meth)acrylate, 2-ethylnonyl (meth)acrylate, 2-methyllauryl (meth)acrylate, 2-ethyldecyl (meth)acrylate, 2-methylmyristyl (meth)acrylate, 2-ethyllauryl (meth)acrylate, 2-methylpalmityl (meth)acrylate, and 2-ethylmyristyl (meth)acrylate; cyclic alkyl (meth)acrylates such as cyclohexyl (meth)acrylate; phenyl (meth)acrylate, benzyl (meth)acrylate, etc. From the standpoint of cost and performance, 2-ethylhexyl (meth)acrylate and n-lauryl (meth)acrylate are preferred. Furthermore, from the viewpoint of affinity with the surface of the medical device, branched alkyl (meth)acrylates are preferred.

[0031] The silicone (meth)acrylate (II) imparts water repellency to the copolymer, reducing its surface energy and suppressing the immune response in the blood resulting from the recognition and activation of complement by foreign substances. Note that water repellency refers to the hydrophobic property of repelling water in particular, which inhibits the adsorption and adhesion of blood proteins and reduces the affinity with blood, which is primarily composed of water, thereby suppressing complement activation.

[0032] The dimethylsiloxane repeating unit m of the silicone (meth)acrylate (II) is preferably 1 or more and 50 or less. If m is 50 or less, the viscosity of the resulting copolymer and its solution can be prevented from becoming too high, resulting in high handleability. On the other hand, if m is 1 or more, the viscosity of the resulting copolymer and its solution can be prevented from becoming too low, resulting in failure to adhere to the surface of the medical device to be coated. m is preferably 2 or more, more preferably 5 or more, and is preferably 40 or less or 30 or less, and more preferably 20 or less or 15 or less.

[0033] In the present invention, a silicone (meth)acrylate (II) having a weight-average molecular weight of 1,450 or less is used. According to the inventors' experimental findings, a weight-average molecular weight of 1,450 or less can sufficiently suppress cloudiness of the resulting copolymer and its solution; specifically, the turbidity of the copolymer and its solution can be reduced to 10 or less. The weight-average molecular weight is preferably 1,400 or less, more preferably 1,300 or less, and even more preferably 1,200 or less. On the other hand, if the weight-average molecular weight is too small, the polymerization reaction solution tends to foam, and when concentrated under reduced pressure, the polymerization reaction solution may overflow from the reaction vessel, making vacuum concentration impossible. Therefore, the weight-average molecular weight is preferably greater than 1,000, more preferably 1,050 or more, and even more preferably 1,100 or more.

[0034] Generally, the average molecular weight of a polymer is determined by the number average molecular weight and the weight average molecular weight. i and the number of molecules with that molecular weight, N i The product of this and the number of molecules N i The weight average molecular weight is the sum of the numbers divided by 1, and refers to the simple average of the molecular weight of one polymer chain contained in a polymer aggregate, and corresponds to the mass per mole (g / mol). i 2 ×N i M i ×N iThe weight-average molecular weight is the sum of the numbers divided by 1 / 2, i.e., it corresponds to the sum of the amounts obtained by multiplying the molecular weight of each polymer by its weight fraction, and since the weight-average molecular weight increases when the proportion of large molecular weight polymers, which contribute more to physical properties than the number-average molecular weight, is large, it can be said that there is a high correlation with the physical properties of the polymer aggregate. Methods for measuring the weight-average molecular weight include end-group determination, osmometry, vapor pressure osmometry, vapor pressure depression method, freezing point depression method, boiling point elevation method, gel permeation chromatography (GPC), etc., but in the present invention, the commonly used method of gel permeation chromatography (GPC) is adopted in terms of ease of operation.

[0035] As can be seen from its basic skeleton, silicone has excellent heat and cold resistance and a low glass transition temperature (Tg), thereby offering the advantage of stable properties over a wide temperature range. It also has the advantage of being resistant to acids and alkalis and highly chemically stable due to its large bond energy. Furthermore, it has excellent copolymerizability with (meth)acrylate monomers and can be preferably used as a raw material for the (meth)acrylate copolymer of the present invention. Silicone (meth)acrylates have been recognized as materials with high biological safety, such as being used in contact lenses in recent years. Therefore, it is believed that the content of silicone (meth)acrylate (II) in the antithrombotic material is not too high and will not cause any problems. However, since the raw material price of silicone (meth)acrylate (II) is currently relatively high, taking into consideration performance, quality, cost, and the like, it is sufficient for the silicone (meth)acrylate (II) to be present in an amount of 50% by mass or less relative to the total of alkyl (meth)acrylate (I) and silicone (meth)acrylate (II). The proportion is preferably 40% by mass or less, and more preferably 35% by mass or less. On the other hand, from the viewpoint of long-term stability of the copolymer, the proportion of the silicone (meth)acrylate (II) relative to the total of the alkyl (meth)acrylate (I) and the silicone (meth)acrylate (II) is preferably 0.1% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1.0% by mass or more.

[0036] The alkoxypolyethylene glycol (meth)acrylate (III) imparts hydrophilicity to the copolymer, inhibits the adhesion of platelets in the blood and their subsequent activation, and inhibits the adsorption of proteins.

[0037] In the alkoxypolyethylene glycol (meth)acrylate (III), the repeating unit n of ethylene oxide is preferably 2 or more and 10 or less. When n is 2 or more, the copolymer can be sufficiently hydrophilic, and when n is 10 or less, the copolymer can be sufficiently prevented from eluting into blood or being detached from medical devices. n is more preferably 5 or less, and even more preferably 3 or 4.

[0038] Specific examples of the alkoxypolyethylene glycol (meth)acrylate (III) 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.

[0039] The amounts of alkoxypolyethylene glycol (meth)acrylate (III) and alkyl (meth)acrylate (I) used may be adjusted as appropriate. For example, the molar ratio of alkyl (meth)acrylate (I) to 1 mole of alkoxypolyethylene glycol (meth)acrylate (III) can be set to 0.5 or more and 2.5 or less. When this molar ratio is within this range, the balance between the hydrophilic and hydrophobic portions of the antithrombotic material is improved, suppressing the adsorption of platelets and blood proteins to the surface of the medical device in the blood while ensuring affinity between the surface of the medical device and the antithrombotic material. This makes it possible to suppress the elution of the antithrombotic material into the blood and uneven coating. The ratio is preferably 1 or more, more preferably 1.2 or more or 1.4 or more, even more preferably 1.5 or more, and preferably 2.2 or less, more preferably 2 or less.

[0040] The amounts of alkoxypolyethylene glycol (meth)acrylate (III) and silicone (meth)acrylate (II) used may be adjusted as appropriate. For example, the molar ratio of silicone (meth)acrylate (II) to 1 mole of alkoxypolyethylene glycol (meth)acrylate (III) may be 0.001 or more and 1 or less. When this molar ratio is within the above range, it is possible to suppress the adsorption of platelets and blood proteins to the surface of the medical device in the blood, while also suppressing complement activation by the antithrombotic material, thereby making it possible to suppress excessive immune responses. This ratio is preferably 0.005 or more, more preferably 0.01 or more, and preferably 0.5 or less, more preferably 0.1 or less.

[0041] In this step, alkyl (meth)acrylate (I), silicone (meth)acrylate (II), and alkoxy polyethylene glycol (meth)acrylate (III) are copolymerized in a solvent. The copolymerization reaction itself for producing the antithrombotic material of the present invention is not particularly limited, and known methods such as radical polymerization, ionic polymerization, photopolymerization, and polymerization using a macromer can be used, but radical polymerization using a radical initiator is preferred.

[0042] Examples of the solvent used in the copolymerization include alcohol solvents such as methanol, ethanol, and 2-propanol; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene and benzene; ketone solvents such as methyl ethyl ketone; and water. From the viewpoints of the solubility of the monomers and the resulting copolymer and ease of availability, it is preferable to use ethyl acetate, methanol, ethanol, etc. A mixture of two or more of the above solvents can also be used.

[0043] The amount of the solvent used may be adjusted as appropriate, for example, to 0.3 to 10 times by mass relative to the total amount of the monomers, and the ratio is preferably 0.5 to 5 times by mass.

[0044] As the radical initiator, peroxide-based or azo-based radical initiators generally used in radical polymerization are used. Examples of peroxide-based radical initiators include inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide; and organic peroxides such as benzoyl peroxide, t-butyl hydroperoxide, and cumene peroxide. Examples of azo-based radical initiators include 2,2'-azobisisobutyronitrile, 2,2'-azobis(2-aminodipropane) dihydrochloride, dimethyl 2,2'-azobisbutyrate, and dimethyl 2,2'-azobis(2-methylpropionate). In addition, redox initiators in which a peroxide-based initiator is combined with a reducing agent can also be used.

[0045] The amount of the radical initiator used may be adjusted appropriately, for example, to 0.01% by mass or more and 1% by mass or less relative to the total amount of the monomers, preferably 0.05% by mass or more, and more preferably 0.5% by mass or less, and more preferably 0.3% by mass or less.

[0046] Specifically, for example, each monomer, polymerization solvent, and radical initiator are added to a stirrable reaction apparatus equipped with a reflux tower, the gas phase is purged with nitrogen, and then the polymerization is initiated by heating. The polymerization is allowed to proceed by maintaining that temperature for a certain period of time. A chain transfer agent can also be used during polymerization to control the molecular weight. Examples of chain transfer agents used to control the molecular weight during polymerization include high-boiling thiol compounds such as dodecyl mercaptan, thiomalic acid, and thioglycolic acid, as well as isopropyl alcohol, phosphorous acid, and hypophosphorous acid.

[0047] The temperature during polymerization varies depending on the types of solvent, radical initiator, etc., but is preferably adjusted to, for example, around the 10-hour half-life temperature of the radical initiator. Specifically, when the radical initiator is used, it can be adjusted to 20°C or higher and 90°C or lower. The temperature is preferably 30°C or higher, and more preferably 40°C or higher. The polymerization reaction time can also be adjusted appropriately, but can also be determined, for example, until one of the monomers is consumed by chromatography or the like, or by a preliminary experiment, and specifically can be set to 1 hour or higher and 10 hours or lower.

[0048] After the polymerization reaction, the solvent is removed to obtain a crude (meth)acrylate copolymer. If a silicone (meth)acrylate (II) with an excessively small weight-average molecular weight is used to prevent the antithrombotic material from becoming cloudy, the reaction solution may foam and overflow from the container during vacuum concentration, making vacuum concentration impossible. Therefore, by using a silicone (meth)acrylate (II) with a weight-average molecular weight of more than 1,000, such foaming can be more reliably prevented, enabling successful vacuum concentration.

[0049] Following removal of the solvent, the resulting crude (meth)acrylate copolymer is purified by stirring it in a poor solvent and then removing the poor solvent. This purification process is repeated one to several times to increase the purity of the (meth)acrylate copolymer. The copolymer thus obtained is then dried.

[0050] In the present invention, the (meth)acrylate copolymer is produced by copolymerizing hydrophilic and hydrophobic monomers, and therefore possesses both hydrophilic and hydrophobic properties. Therefore, the solution after the polymerization reaction contains a mixture of unreacted hydrophilic monomers (methoxypolyethylene glycol (meth)acrylate), hydrophobic monomers (silicone (meth)acrylate and alkyl (meth)acrylate), and the (meth)acrylate copolymer. To isolate the water-insoluble (meth)acrylate copolymer from this mixture, for example, the copolymer solution can be dropped into a solvent that dissolves the hydrophilic monomer to remove the hydrophilic monomer, and then the copolymer can be purified using a solvent that dissolves the hydrophobic monomer. Alternatively, the (meth)acrylate copolymer can be efficiently recovered by using a reprecipitation poor solvent, which is a mixture of alcohol and water in a specific ratio. Furthermore, a purification method can also be employed in which a poor solvent is added to a water-insoluble (meth)acrylate copolymer made of a mixture of alcohol and water in a specific ratio in a solution after the polymerization reaction is completed, and the mixture is stirred at a constant temperature to separate the (meth)acrylate copolymer, and then the precipitate is recovered by decantation, and a washing liquid is added and the same method is repeated.

[0051] In the present invention, the poor solvent used to purify the copolymer is preferably a poor solvent that does not dissolve the copolymer but dissolves both the hydrophilic monomer and the hydrophobic monomer.

[0052] In the present invention, the alcohol used in the reprecipitation treatment is preferably an alcohol having 1 to 10 carbon atoms, more preferably an alcohol having 1 to 7 carbon atoms, and even more preferably an alcohol having 1 to 4 carbon atoms. Specific examples of such alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methoxy-1-propanol, and tertiary butanol. However, methanol, ethanol, 1-propanol, and 2-propanol are more preferred because they can be dried at low temperature in a short time.

[0053] The amount of the poor solvent used may be adjusted as appropriate within the range in which the copolymer is sufficiently purified. For example, the volume ratio of the poor solvent to the crude (meth)acrylate copolymer is preferably 1 or more and 20 or less, more preferably 5 or less.

[0054] The temperature during purification of the crude (meth)acrylate copolymer of the present invention is preferably 30° C. or higher and 60° C. or lower, and more preferably 40° C. or higher and 60° C. or lower. When the temperature during purification is within the above range, the viscosity of the crude (meth)acrylate copolymer decreases by heating, facilitating separation from the poor solvent, and the recovery rate of the (meth)acrylate copolymer can be maximized.

[0055] In the present invention, the recovery rate of the (meth)acrylate copolymer after the purification treatment is preferably 20% by mass or more and 90% by mass or less. If the recovery rate is 20% by mass or more, the production efficiency can be said to be relatively high, and if it is 90% by mass or less, the incorporation of unreacted monomers can be sufficiently suppressed. Note that adjusting the recovery rate within the above range may result in some loss or abandonment of the copolymer, but this is unavoidable in terms of preventing the incorporation of unreacted monomers as much as possible. This is because, given the unique circumstances of the copolymer having both hydrophilic and hydrophobic properties that are applied to medical devices, such consideration must naturally be taken into account.

[0056] In the present invention, the amount of residual monomer, i.e., the amount of monomer that remains unreacted in the polymerization, is important because it affects safety. Naturally, reducing the amount of residual monomer in the antithrombotic material will meet the standards set forth in the guidelines for elution from medical devices. However, an unexpected effect was that reducing the amount of residual monomer to an extremely low level of 4,000 ppm or less led to improved adhesion and retention of the antithrombotic material on the surface of the medical device. Furthermore, the ratio of the amount of copolymer obtained to the amount of monomer input is expressed as the recovery rate.

[0057] By performing the above-mentioned purification treatment once, or if necessary, twice or more, up to eight times, it is possible to recover a water-insoluble (meth)acrylate copolymer having an unreacted monomer content of 4,000 ppm or less at a high recovery rate of 30% by mass or more. If the copolymer contains a large amount of unreacted monomer, oligomer, or polymerization residue, it is thought that these will leach into the blood and become substances that cause shock symptoms in patients. Although most of these causative substances can be removed by the purification treatment, considering patient safety, it is more preferable to keep the content at 3,000 ppm or less, even more preferably 2,000 ppm or less, and particularly preferably 1,000 ppm or less.

[0058] In order to use the purified copolymer to impart antithrombotic properties to a medical device, it is necessary to remove the solvent by drying. The drying method can be, for example, at 60°C under reduced pressure of 1 Torr or less, and if sufficient drying is not achieved, subsequent reduced pressure drying can be performed.

[0059] In the present invention, the copolymer obtained by copolymerizing alkyl (meth)acrylate (I), silicone (meth)acrylate (II), and alkoxy polyethylene glycol (meth)acrylate (III), i.e., the copolymer having alkyl (meth)acrylate structural units (IV), silicone (meth)acrylate structural units (V), and alkoxy polyethylene glycol (meth)acrylate structural units (VI), is preferably durable to blood contact and a viscous liquid at room temperature. Here, "durable to blood contact" means that when the (meth)acrylate copolymer is immersed in the following alcohol immersion treatment solution at room temperature for 16 hours, a certain amount of the (meth)acrylate copolymer remains, thereby exhibiting antithrombotic properties. If a predetermined amount of the (meth)acrylate copolymer remains after immersion in the alcohol immersion treatment solution at room temperature for 16 hours, it can be determined that the copolymer has sufficient antithrombotic properties even when contacted with blood at 37°C for 30 days. Furthermore, because the copolymer is liquid at room temperature but viscous, it has the advantage of suppressing elution into blood when used as a coating on medical devices, etc.

[0060] Furthermore, the copolymer produced by the method of the present invention exhibits reduced cloudiness and excellent transparency. Specifically, the turbidity of the copolymer and antithrombogenic material according to the present invention is suppressed to 10 or less. In this disclosure, "turbidity" refers to the turbidity measured according to the method specified in JIS K0101:2017 Industrial Water Testing Methods and the 18th Edition of the Japanese Pharmacopoeia. Specifically, the absorbance at 660 nm of a turbidity standard solution is measured to create a calibration curve, and the absorbance at 660 nm of the copolymer and antithrombogenic material according to the present invention is also measured, and the turbidity of the copolymer and antithrombogenic material according to the present invention can be determined from the measured values ​​using the calibration curve. The turbidity is preferably 8 or less or 6 or less, more preferably 5 or less, 4 or less, or 3 or less, and even more preferably 2 or less, 1.5 or less, or 1 or less.

[0061] One method for confirming the durability of the antithrombogenic material of the present invention against elution in blood is to immerse it in alcohol at room temperature. A mixed solvent of methanol and ethanol is preferably used as the alcohol. For example, a solvent obtained by mixing methanol and ethanol in an 80 / 20 (mass ratio) mixture has a slightly stronger elution force than blood. Therefore, the durability of the antithrombogenicity can be evaluated by immersing the antithrombogenic material in the mixed solvent for 16 hours.

[0062] In the present invention, the (meth)acrylate copolymer has the property of being insoluble in methanol but soluble in ethanol. When methanol and ethanol are mixed in a predetermined ratio to form an alcohol immersion treatment solution for confirming durability after 30 days of blood contact at 37°C (sustained antithrombogenicity), durability after 30 days of blood contact at 37°C can be confirmed even in as short a time as 16 hours. The mass ratio of methanol to ethanol in the alcohol immersion treatment solution is preferably methanol:ethanol = 90-60:10-40, more preferably 90-70:10-30. In addition, in a test using evaluation sheets described below, blood clot adhesion was low, i.e., the number of evaluation sheets on which blood clot adhesion was confirmed after solvent immersion was one or less out of ten evaluation sheets, and the (meth)acrylate copolymer was 0.1 μg / cm 2 If the above condition remains, it can be determined that the product has sufficient durability.

[0063] In the present invention, one method for evaluating the hemocompatibility of a copolymer is a blood coagulation test. Specifically, this test utilizes the reaction in which fibrin in plasma gels with calcium ions, forming a fibrin gel. The hemocompatibility of a polymer can be confirmed by checking whether or not blood clots form after immersion in water in calcium ion-added plasma that has come into contact with a sample. For example, half of a polycarbonate sheet is immersed in an ethanol solution of the copolymer and dried to obtain an evaluation sheet. A test blood solution is then added to the resulting evaluation sheet. If blood clots form on four or fewer of the ten evaluation sheets, the polymer's hemocompatibility can be determined to be good.

[0064] Specific examples of representative (meth)acrylate copolymers according to the present invention include silicone (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-normal hexyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-normal hexyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-normal hexyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-cyclohexyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, and silicone (meth)acrylate-cyclohexyl (meth)acrylate. tri-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-cyclohexyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-octyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-octyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-octyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer,Silicone (meth)acrylate-2-ethylhexyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-2-ethylhexyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-2-ethylhexyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-lauryl (meth)acrylate-methoxydiethylene glycol (meth)acrylate acrylate copolymer, silicone (meth)acrylate-lauryl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-lauryl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-nonyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-nonyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-nonyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-decyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-decyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-decyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer Polymers, silicone (meth)acrylate-stearyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-stearyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-stearyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-lauryl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymers,Examples of the copolymer include a silicone (meth)acrylate-lauryl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, a silicone (meth)acrylate-lauryl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, a silicone (meth)acrylate-myristyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, a silicone (meth)acrylate-myristyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, and a silicone (meth)acrylate-myristyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer. The copolymer according to the present invention is not limited thereto, but further includes a (meth)acrylate copolymer having an alkyl (meth)acrylate (I):silicone (meth)acrylate (II):methoxypolyethylene glycol (meth)acrylate (III) ratio of 80 to 20:10 to 0.01:10 to 79.99 (molar ratio). The alkyl (meth)acrylate (I) unit and silicone (meth)acrylate (II) unit, which are hydrophobic (meth)acrylates, inhibit the copolymer from eluting into blood, enhance its durability against blood, and increase its affinity for medical device surfaces. Furthermore, the alkoxypolyethylene glycol (meth)acrylate (III) unit, which is a hydrophilic (meth)acrylate, inhibits the adhesion of platelets and proteins. Therefore, the molar ratio is preferably 80-50:5-0.01:15-49.99, more preferably 77-55:5-0.01:18-44.99, and even more preferably 73-57:5-0.01:22-42.99. The ratio of each acrylate structural unit in the copolymer of the present invention can be determined, for example, by analyzing the copolymer by nuclear magnetic resonance (NMR) or mass spectrometry and determining the intensity ratio of peaks specific to each acrylate.

[0065] The weight-average molecular weight of the copolymer is not particularly limited, but is preferably 50,000 or more and 1,500,000 or less. If the weight-average molecular weight is 50,000 or more, elution into blood is sufficiently suppressed, and the strength and stability of the coating film can be more reliably ensured. Furthermore, if the weight-average molecular weight is 1,500,000 or less, workability when coating medical devices is sufficiently high. The weight-average molecular weight is more preferably 1,000,000 or less, and even more preferably 500,000 or less.

[0066] The reduced viscosity (ηsp / c) of the (meth)acrylate copolymer according to the present invention is preferably 0.18 dl / g or more and 3.00 dl / g or less. By using an antithrombotic material within this viscosity range, when it is applied to medical devices such as cardiopulmonary bypass circuits and catheters, the copolymer exhibits excellent adhesion to the medical device, enabling the antithrombotic properties to be maintained over long periods of use. The reduced viscosity range is more preferably 0.18 dl / g or more, and more preferably 1.50 dl / g or less, and even more preferably 0.50 dl / g or less.

[0067] The antithrombotic material of the present invention may be a random copolymer, a block copolymer, or a graft copolymer. The (meth)acrylate copolymer of the present invention may be a copolymer in which each monomer is arranged alternately, but when analyzed from the total amount, it may also be a copolymer consisting of segments or blocks of hydrophobic monomers and segments or blocks of hydrophilic monomers. It is conceivable that the segments or blocks of hydrophobic monomers may function to fix the segments or blocks of hydrophilic monomers, resulting in a complex structure such as a microphase-separated structure or a mosaic-like structure. In any case, although the molecular weight of the copolymer and the type and characteristics of the hydrophilic monomer may have some influence, slightly increasing the amount of hydrophobic monomer can suppress the elution of the segments or blocks of hydrophilic monomers from the copolymer. Furthermore, increasing the amount of hydrophobic segments is thought to increase the affinity with hydrophobic medical devices, and it can be assumed that they will play an advantageous role in adhering to medical devices as a coating. However, at present, it is not possible to accurately verify on a technical basis the behavior related to the presence or absence of segments and the state of their affinity. However, the copolymer is a polymeric material with a friendly affinity for living organisms.

[0068] Although a homopolymer of alkoxypolyethylene glycol (meth)acrylate (III) has excellent blood compatibility due to its high hydrophilicity, it has the problem of gradual elution when it is in contact with blood, etc. for a long period of time due to its water solubility. As a result of extensive research into a material that is not only excellent in blood compatibility but also durable for long-term use, the present inventors have found that a copolymer obtained by imparting appropriate hydrophobicity to prevent elution into blood, etc., and flexibility to prevent physical peeling of the coating film can solve the problem.

[0069] As described above, the copolymer of the present invention is essentially composed of two types of monomer components that fulfill two different interfacial functions: one is composed of hydrophilic monomers, segments, or blocks that have functions such as antithrombogenicity and anti-elution properties against blood, and the other is composed of hydrophobic monomers, segments, or blocks that have functions such as affinity and adhesion to medical devices. On the other hand, it also appears that the monomers, segments, or blocks that make up the copolymer complement each other within the molecular structure, forming bonds or structures that are stable against elution, dispersion, etc.

[0070] The (meth)acrylate copolymer according to the present invention is preferably soluble in any of alcohols having 1 to 6 carbon atoms. It is more preferable that the copolymer is soluble in an alcohol having 1 to 3 carbon atoms, since this facilitates drying after coating. Here, "soluble" means that when 1 g of the (meth)acrylate copolymer is immersed in 10 mL of the alcohol at 25°C, at least 90% by mass of the (meth)acrylate copolymer dissolves within 16 hours at room temperature.

[0071] The antithrombotic material made of the (meth)acrylate copolymer according to the present invention may contain substances such as antibacterial substances.The antibacterial substance is not particularly limited, and examples thereof include ampicillin, nafcillin, amoxicillin, oxacillin, azlocillin, penicillin G, carbenicillin, penicillin V, dicloxacillin, phenethicillin, floxacillin, piperacillin, mecillinam, sulbenicillin, methicillin, ticarcillin, mezlocillin, cefaclor, cephalothin, cefadroxil, cephapirin, cefamandole, cephradine, cefatrizine, cefsulodin, cefazolin, ceftazidime, ceforanide, ceftriaxone, and cephalosporin. Foxitin, cefuroxime, cephacetrile, latamoxef, cephalexin, amikacin, neomycin, dibekacin, kanamycin, gentamicin, netilmicin, tobramycin, amphotericin B, novobiocin, bacitracin, nystatin, clindamycin, polymyxin, colistin, rovamycin, erythromycin, streptomycin, spectinomycin, lincomycin, vancomycin, chlortetracycline, oxytetracycline, demeclocycline, rolitetracycline, doxicycline Antibiotics such as iclin, tetracycline, and minocycline; antifungal agents such as amphotericin B, ketoconazole, clotrimazole, miconazole, econazole, natamycin, flucytosine, nystatin, and griseofulvin; parahydroxybenzoic acid esters such as isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, and propyl parahydroxybenzoate; biguanide compounds such as chlorhexidine; benzethonium, benzalkonium, lauryl sulfate, alkyl polyamines, etc. Examples of suitable antibacterial agents include surface-active compounds such as monoethylglycine, fatty acids, and domiphen bromide; phenol derivatives such as thymol, phenol, hexachlorophene, and resorcinol; boric acid compounds such as boric acid and borax; iodine compounds such as iodine, iodoform, and povidone-iodine; metals such as gold, silver, copper, and mercury; metal compounds such as thimerosal, methylbromine, and silver sulfadiazine; antibacterial pigment compounds such as acrinol and methylrosalinin; and sulfa drugs such as mafenide acetate, sulfadiazine, sulfisomidine, and sulfamethoxazole.These antibacterial substances may be salt compounds such as sodium salts, potassium salts, magnesium salts, calcium salts, hydrochlorides, sulfates, gluconates, etc., and two or more types of antibacterial substances may be used in combination.

[0072] The antibacterial substances can be roughly divided into water-soluble and water-insoluble ones, and representative examples of water-soluble antibacterial substances include benzalkonium chloride, povidone-iodine, penicillin G potassium, streptomycin sulfate, etc. Representative examples of water-insoluble antibacterial substances include silver sulfazidine, chlorhexidine, etc.

[0073] 2. Coating Step In this step, the copolymer of the present invention or a solution thereof is applied to the surface of a medical device, and then dried as necessary. The antithrombogenic material of the present invention exhibits the effects of inhibiting the adsorption of platelets and proteins and inhibiting their hemostatic activity, and also has resistance to blood and affinity for hydrophobic surfaces. Therefore, by coating a medical device with the antithrombogenic material of the present invention, it is possible to impart these properties to the medical device.

[0074] Methods for supporting the antithrombotic material of the present invention on the surface of a substrate such as a medical device include known methods such as coating, graft polymerization using radiation, electron beams, or ultraviolet light, and chemical reactions with functional groups on the substrate. Among these, coating methods are preferred for practical use due to their simple manufacturing process. For example, a medical device can be coated by dissolving the antithrombotic material of the present invention in an organic solvent, applying a solution to the surface of the substrate, and then removing the solvent. The coating method is not particularly limited, and examples include painting, spraying, and dipping. It is also preferable to heat the coated substrate to dry it. This can further enhance the adhesion between the substrate and the antithrombotic material of the present invention, resulting in a more firmly fixed structure.

[0075] When the copolymer according to the present invention is a liquid at room temperature and normal pressure, it may be used as is for coating. When the copolymer according to the present invention is a solid at room temperature and normal pressure, or a liquid with high viscosity, it may be dissolved or suspended in a solvent to obtain a solution or suspension. The organic solvent for the coating solution should be selected so as to minimize damage to the medical device substrate. Specific examples include alcohol solvents such as methanol, ethanol, 2-propanol, and n-propanol; ketone solvents such as acetone and cyclohexanone; aliphatic hydrocarbon solvents such as n-hexane and cyclohexane; ether solvents such as tetrahydrofuran and 1,4-dioxane; and amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. Among these, methanol, ethanol, and 2-propanol are more preferred because of their low boiling points and ease of drying after coating.

[0076] The concentration of the (meth)acrylate copolymer in the solution of the antithrombotic material according to the present invention may be adjusted as appropriate, but may be, for example, 0.001% by mass or more and 10% by mass or less. If the concentration is 0.001% by mass or more, the medical device can be sufficiently coated with the antithrombotic material according to the present invention, while if the concentration is 10% by mass or less, the viscosity of the solution does not become excessively high, resulting in excellent workability. The concentration is preferably 0.01% by mass or more and 5% by mass or less.

[0077] A method for quantifying the coating amount of the antithrombogenic material includes quantification by NMR. Specifically, a substrate coated with the antithrombogenic material is extracted with ethanol, the extract is dried, and then subjected to NMR measurement, and the coating amount is calculated from the area of ​​the corresponding peak. Durability can also be evaluated by comparing the coating amount before and after alcohol immersion treatment. Specifically, the remaining amount of the (meth)acrylate copolymer after immersing the evaluation sheet in 99.5% by mass ethanol was 3.0 μg / cm. 2 If the above conditions are met, it can be determined that the antithrombotic properties can be sufficiently exhibited in the early stages of blood contact.

[0078] Medical devices at least partially coated with the antithrombotic material of the present invention can exhibit excellent antithrombotic properties. Examples of such medical devices include blood filters, blood storage containers, blood circuits, indwelling needles, catheters, guidewires, stents, artificial lung devices, dialysis devices, adhesion inhibitors, wound dressings, adhesive materials for biological tissue, and repair materials for biological tissue regeneration. In particular, medical devices having an extracorporeal circulation circuit and a blood-contacting portion therein are preferred embodiments.

[0079] The substrate for medical devices includes all commonly used materials. Examples include polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, poly-4-methylpentene-1, thermoplastic polyether polyurethane, thermosetting polyurethane, silicone rubber such as cross-linked polydimethylsiloxane, polymethyl methacrylate, polyvinylidene fluoride, polytetrafluoroethylene, polysulfone, polyethersulfone, polyacetal, polystyrene, ABS resin, and mixtures of these resins, as well as metals such as stainless steel, titanium, and aluminum. The antithrombotic material of the present invention has a balanced material composition, molecular weight, viscosity, and the like, and the coating conditions are optimized, allowing for uniform and strong coating regardless of the material, shape, surface properties, etc., to be coated.

[0080] In the present invention, when a medical device or the like is coated with the antithrombotic substance (copolymer) of the present invention and a water-insoluble antibacterial substance, the elution of the antibacterial substance is extremely small and sustained, and long-term antibacterial properties can be maintained, although it is unclear whether this is due to the water-insolubility of the copolymer or the complementary function of the water-insolubility of the copolymer and the water-insolubility of the antibacterial substance. On the other hand, when the copolymer is coated with a water-soluble antibacterial substance, the elution amount is greater than when a water-insoluble antibacterial substance is used, because the copolymer is water-insoluble but the antibacterial substance is water-soluble. This allows for instantaneous strong antibacterial properties to be exhibited, but does not allow for long-term antibacterial properties to be maintained. For example, intravascular catheters, infusion tubes, oxygenators, etc. are medical devices that are used continuously for one to several days, and long-term antibacterial properties are required for such applications. Furthermore, by combining a water-soluble antibacterial substance with a water-soluble antibacterial substance, it is possible to impart multi-stage antibacterial properties, such as initially exhibiting strong bactericidal properties due to the water-soluble antibacterial substance, followed by long-term antibacterial properties due to the water-insoluble antibacterial substance. If this multistage antibacterial property is applied to an intravascular catheter, the water-soluble antibacterial substance will be eluted early and exhibit strong antibacterial properties, thereby sterilizing the normal skin bacteria that are brought into the blood vessels when the catheter is inserted, reducing the risk of infection during insertion. Furthermore, while the catheter is indwelling, the long-term antibacterial properties of the poorly water-soluble antibacterial substance can prevent bacteria from settling on the catheter and the proliferation of bacteria that have invaded through the insertion site, reducing the risk of infection during placement.

[0081] In the present invention, the proportion of the antibacterial substance is preferably 0.01% by mass or more and 70% by mass or less relative to the mass of the antithrombotic material. A proportion of 0.01% by mass or more ensures that the antibacterial properties of the antibacterial substance are more reliably exhibited, while a proportion of 70% by mass or less can more reliably suppress poor appearance of the medical device after surface treatment such as coating, elution of the antibacterial substance into the body, and resulting local inflammation. The proportion is more preferably 0.05% by mass or more, even more preferably 0.1% by mass or more, and more preferably 50% by mass or less or 30% by mass or less, and even more preferably 10% by mass or less. The antibacterial substance may be present over the entire surface of the medical device, but it is preferable to have it present only near the insertion site where the skin is inserted in order to suppress local inflammation.

[0082] The (meth)acrylate copolymer according to the present invention, obtained by copolymerizing an alkyl (meth)acrylate (I), a silicone (meth)acrylate (II), and an alkoxy polyethylene glycol (meth)acrylate (III), has an appropriate balance of hydrophilicity and hydrophobicity, and therefore can be suitably used as a blood-compatible material. Furthermore, since it can inhibit the adsorption and adhesion of platelets, blood proteins, and the like, it can be suitably used as a treatment material for medical devices. Furthermore, the (meth)acrylate copolymer according to the present invention can be used alone or in combination of two or more types.

[0083] When a medical device treated with this antithrombotic material comes into contact with blood, the highly hydrophilic alkoxypolyethylene glycol (meth)acrylate (III) probably protrudes from the surface and exerts antithrombotic properties, while the hydrophobic alkyl (meth)acrylate (I), silicone (meth)acrylate (II) and (meth)acrylate remain near the substrate, thereby preventing direct contact between the blood and the medical device.

[0084] This application claims the benefit of priority based on Japanese Patent Application No. 2023-205501, filed on December 5, 2023. The entire contents of the specification of Japanese Patent Application No. 2023-205501, filed on December 5, 2023, are incorporated herein by reference.

[0085] The present invention will be explained in more detail below with reference to examples. However, the present invention is not limited to the following examples, and it is of course possible to carry out the invention by making appropriate modifications within the scope of the above and below-described aims, and all such modifications are included in the technical scope of the present invention.

[0086] Example 1 (1) Copolymerization Reaction Polydimethylsiloxane methacrylate (PDMSMA) with various weight-average molecular weights was obtained. The weight-average molecular weight of each PDMSMA is shown in Table 1. 471.3 g of methoxytriethylene glycol acrylate (MTEGA) (Shin-Nakamura Chemical Co., Ltd.), 78.0 g of each PDMSMA, and 693.3 g of 2-ethylhexyl acrylate (EHA) (Toagosei Co., Ltd.) were added with 1.23 g of azobisisobutyronitrile (AIBN) (Fujifilm Wako Pure Chemical Industries, Ltd.), and the mixture was polymerized in 1615.4 g of ethanol (Kishida Chemical Co., Ltd.) at 85°C for 3 hours. After the polymerization reaction was completed, the mixture was dried at 85°C for 2 hours under normal pressure, and then dried under reduced pressure at 60°C for 40 minutes to obtain a concentrate. To 1234.8 g of the concentrate, 6320.0 g of methanol (Kishida Chemical Co., Ltd.) and 600.0 g of water were added and stirred for 20 minutes. After stirring, the mixture was left to stand for 1.5 hours, and the supernatant was removed by decantation to obtain a precipitate. 6320.0 g of methanol was added to the precipitate, and the mixture was stirred for 20 minutes. After leaving the mixture to stand for 1.5 hours, the supernatant was removed by decantation. This process was repeated three times to wash the precipitate. The washed precipitate was dried under reduced pressure at 40 ° C for 1 hour to obtain a copolymer.

[0087] (2) Turbidity Evaluation A turbidity standard solution for turbidity testing containing kaolin particles ("Turbidity Standard Solution (Turbidity: 100 degrees)" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was diluted with distilled water to prepare turbidity samples of 0 to 50 degrees (kaolin). Using an absorption spectrometer ("UV-1700" manufactured by Shimadzu Corporation), the absorbance of the turbidity samples at 660 nm was measured based on JIS K0101:2017 Industrial Water Testing Methods and the 18th Revised Japanese Pharmacopoeia. When the absorbance and turbidity were plotted, an approximate equation of y = 382.38x + 0.1836 was obtained, and its coefficient of determination R 2 The absorbance at 660 nm of each copolymer (1 mL) obtained in Example 1(1) was measured in the same manner, and the turbidity was calculated from the calibration curve. The results are shown in Table 1.

[0088]

[0089] As shown in Table 1, when the weight-average molecular weight of the raw material PDMSMA is high, the copolymer solution tends to become cloudy. Although there is measurement error in the low absorbance range, it was demonstrated that the turbidity of the copolymer can be significantly reduced at least if the weight-average molecular weight of the raw material PDMSMA is 1376 or less. The relationship between the weight-average molecular weight of the raw material PDMSMA and the turbidity of the copolymer was plotted. The results are shown in Figure 1. It was found that in order to suppress the turbidity of the copolymer to 10 or less, it was necessary to use PDMSMA with a weight-average molecular weight of 1450 or less.

[0090] (3) Analysis: The PDMSMA raw material for the cloudy copolymer 2 and the PDMSMA raw material for the transparent copolymer 4 were mixed. 1The PDMSMA was analyzed by H NMR. The results are shown in Figure 2. As can be seen from the results shown in Figure 2, the NMR chart of the PDMSMA, the raw material for the cloudy copolymer 2, had a broader peak near 4 ppm than the transparent PDMSMA for the transparent copolymer 4. This peak corresponds to the methyl group of the dimethylsiloxane group, and it is thought that PDMSMA with a high weight-average molecular weight likely polymerizes with itself, and the resulting oligomer precipitates from copolymer 2, possibly causing cloudiness. This indicates that in order to suppress cloudiness in the copolymer, a silicone monomer with a weight-average molecular weight of a predetermined value or less, specifically 1450 or less, should be used.

Claims

1. A method for producing an antithrombotic material, comprising a step of copolymerizing an alkyl (meth)acrylate represented by the following formula (I), a silicone (meth)acrylate represented by the following formula (II), and an alkoxy polyethylene glycol (meth)acrylate represented by the following formula (III), wherein the silicone (meth)acrylate used has a weight average molecular weight of 1,450 or less. [In the formula, R 1 represents a hydrogen atom or a methyl group; R 2 is C 6-20 Alkyl group, C 6-12 Aromatic hydrocarbon group, or C 6-12 Aromatic Hydrocarbons-C 1-6 represents an alkyl group, R 3 represents a hydrogen atom or a methyl group; R 4 is C 1-6 represents an alkanediyl group, R 5 is C 1-6 represents an alkyl group, R 6 represents a hydrogen atom or a methyl group; R 7 is C 1-6 represents an alkyl group, m represents an integer of 1 or more and 50 or less, and n represents an integer of 2 or more and 10 or less.

2. The method of claim 1, wherein said weight average molecular weight is greater than 1,000.

3. The method according to claim 1, wherein the alkyl (meth)acrylate is used in an amount of 1.5 to 2 times by mole based on the alkoxy polyethylene glycol (meth)acrylate.

4. The method according to claim 1, wherein the silicone (meth)acrylate is used in an amount of 0.01 to 0.1 times by mole relative to the alkoxypolyethylene glycol (meth)acrylate.

5. The method according to claim 2, further comprising a step of concentrating the reaction solution of the copolymerization step under reduced pressure.

6. A method for producing a medical device that comes into contact with blood, comprising the steps of: copolymerizing an alkyl (meth)acrylate represented by the following formula (I), a silicone (meth)acrylate represented by the following formula (II), and an alkoxy polyethylene glycol (meth)acrylate represented by the following formula (III) to obtain a copolymer; and applying the copolymer or a solution thereof to the surface of the medical device, wherein the silicone (meth)acrylate represented by formula (II) has a weight average molecular weight of 1,450 or less. [In the formula, R 1 represents a hydrogen atom or a methyl group; R 2 is C 6-20 Alkyl group, C 6-12 Aromatic hydrocarbon group, or C 6-12 Aromatic Hydrocarbons-C 1-6 represents an alkyl group, R 3 represents a hydrogen atom or a methyl group; R 4 is C 1-6 represents an alkanediyl group, R 5 is C 1-6 represents an alkyl group, R 6 represents a hydrogen atom or a methyl group; R 7 is C 1-6 represents an alkyl group, m represents an integer of 1 or more and 50 or less, and n represents an integer of 2 or more and 10 or less.

7. An antithrombotic material comprising a copolymer of an alkyl (meth)acrylate represented by the following formula (I), a silicone (meth)acrylate represented by the following formula (II), and an alkoxy polyethylene glycol (meth)acrylate represented by the following formula (III), and having a turbidity of 10 or less. [In the formula, R 1 represents a hydrogen atom or a methyl group; R 2 is C 6-20 Alkyl group, C 6-12 Aromatic hydrocarbon group, or C 6-12 Aromatic Hydrocarbons-C 1-6 represents an alkyl group, R 3 represents a hydrogen atom or a methyl group; R 4 is C 1-6 R represents an alkanediyl group; 5 is C 1-6 represents an alkyl group, R 6 represents a hydrogen atom or a methyl group; R 7 is C 1-6 represents an alkyl group, m represents an integer of 1 or more and 50 or less, and n represents an integer of 2 or more and 10 or less.

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