Method for producing antithrombotic material

Abstract

The purpose of the present invention is to provide: a method for producing an antithrombotic material in which clouding is suppressed; a method for producing a medical device coated with an antithrombotic material produced by the method; and an antithrombotic material in which clouding is suppressed. This method for producing an antithrombotic material 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 also characterized in that a silicone (meth) acrylate having a weight-average molecular weight of 1450 or less is used as the silicone (meth) acrylate.

Description

Technical Field

[0001] This invention relates to a method for manufacturing an antithrombotic material that inhibits turbidity, a method for manufacturing a medical device coated with the antithrombotic material manufactured by this method, and an antithrombotic material that inhibits turbidity. Background Technology

[0002] In recent years, research on medical devices utilizing various polymer materials has been progressing, with anticipated applications in blood filters, artificial kidneys, plasma separators, catheters, artificial lungs, artificial blood vessels, anti-adhesion membranes, and artificial skin. In these cases, synthetic materials, which are foreign to the organism, come into contact with the organism's tissues and blood; therefore, biocompatibility is required for these medical devices.

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

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

[0005] Furthermore, as a material with prolonged contact with blood, the applicant of this application has developed an antithrombotic material comprising a (meth)acrylate copolymer, which is polymerized from specific (meth)acrylate monomers, has a specific weight-average molecular weight, is water-insoluble, and is a viscous liquid at room temperature (Patent Document 2). In addition, a catheter with excellent blood compatibility and biocompatibility, whose physical and scientific properties are not impaired even with long-term in vivo placement, has been developed, with at least a portion of its fluid contact portion coated with an antithrombotic material comprising a specific (meth)acrylate copolymer (Patent Document 3).

[0006] Furthermore, Patent Document 4 discloses a medical coating material with antithrombotic properties comprising copolymers having specific chain segments, and Patent Document 5 discloses a polymer containing phosphocholine-like groups having specific structural units and weight-average molecular weight and excellent biocompatibility.

[0007] Existing technical documents

[0008] Patent documents

[0009] Patent Document 1: Japanese Patent Application Publication No. 2008-289864

[0010] Patent Document 2: International Publication No. 2022 / 210759

[0011] Patent Document 3: Japanese Patent Application Publication No. 2009-261437

[0012] Patent Document 4: International Publication No. 2019 / 142710

[0013] Patent Document 5: Japanese Patent Application Publication No. 2002-356519 Summary of the Invention

[0014] The problem that the invention aims to solve

[0015] As mentioned above, various antithrombotic medical materials have been developed, and in particular, the antithrombotic material developed by the applicant of this application is soluble in alcohol solvents and can be easily used as a coating agent for medical devices that come into contact with blood.

[0016] However, the inventors have discovered that the antithrombotic material developed by the applicant in this application sometimes becomes cloudy. If the antithrombotic material becomes cloudy, the visibility of markings, values, text, etc., printed on the surface of medical devices may decrease, or it may become difficult to detect attached foreign matter. Furthermore, if coated on a transparent medical device, the transparency decreases. In addition, its solubility in solvents may also decrease.

[0017] Therefore, the object of the present invention is to provide: a method for manufacturing an antithrombotic material that inhibits turbidity, a method for manufacturing a medical device coated with the antithrombotic material manufactured by the method, and an antithrombotic material that inhibits turbidity.

[0018] Methods for solving problems

[0019] The inventors conducted repeated and in-depth research to solve the aforementioned problems. Their findings revealed that the turbidity of the antithrombotic material is caused by oligomers of silicone (meth)acrylate used as a raw material. By using an appropriate silicone (meth)acrylate as the raw material, the turbidity of the antithrombotic material can be suppressed, thus completing this invention.

[0020] The present invention is illustrated below.

[0021] [1] A method for manufacturing an antithrombotic material, characterized in that it includes a step of copolymerizing an alkyl methacrylate of formula (I), a silicone methacrylate of formula (II), and an alkoxy polyethylene glycol methacrylate of formula (III).

[0022] As the aforementioned silicone (meth)acrylate, a silicone (meth)acrylate with a weight-average molecular weight of 1450 or less is used.

[0023] [Chemical Formula 1]

[0024]

[0025] [In the formula,

[0026] R 1 Indicates a hydrogen atom or a methyl group.

[0027] R 2 Indicate C 6-20 Alkyl, C 6-12 Aromatic hydrocarbon groups, or C 6-12 Aromatic hydrocarbons - C 1-6 alkyl,

[0028] R 3 Indicates a hydrogen atom or a methyl group.

[0029] R 4 Indicate C 1-6 Alkyl,

[0030] R 5 Indicate C 1-6 alkyl,

[0031] R 6 Indicates a hydrogen atom or a methyl group.

[0032] R 7 Indicate C 1-6 alkyl,

[0033] m represents an integer greater than 1 and less than 50.

[0034] [n represents an integer greater than 2 and less than 10.]

[0035] [2] According to the method described in [1] above, wherein the weight-average molecular weight exceeds 1000.

[0036] [3] According to the method described in [1] or [2] above, the alkyl acrylate of the above-mentioned alkoxy polyethylene glycol (meth)acrylate is used at a rate of 1.5 times molar to 2 times molar to the above-mentioned alkoxy polyethylene glycol (meth)acrylate.

[0037] [4] The method described in any one of [1] to [3] above, wherein the silicone (meth) acrylate is used in an amount of 0.01 moles or more and 0.1 moles or less relative to the alkoxy polyethylene glycol (meth) acrylate.

[0038] [5] The method described in [2] above also includes a step of concentrating the reaction liquid of the copolymerization process under reduced pressure.

[0039] [6] A method for manufacturing a medical device that comes into contact with blood, characterized in that it comprises:

[0040] The process of copolymerizing the alkyl methacrylate of formula (I), the silicone methacrylate of formula (II), and the alkoxy polyethylene glycol methacrylate of formula (III) to obtain a copolymer; and

[0041] The process of coating the above copolymer or its solution onto the surface of a medical device.

[0042] As the silicone (meth) acrylate shown in formula (II) above, a silicone (meth) acrylate with a weight average molecular weight of 1450 or less is used.

[0043] [7] An antithrombotic material, characterized in that it comprises a copolymer of alkyl methacrylate as shown in formula (I), silicone methacrylate as shown in formula (II), and alkoxy polyethylene glycol methacrylate as shown in formula (III).

[0044] The turbidity of the above-mentioned antithrombotic materials is below 10.

[0045] [8] An antithrombotic material, characterized in that it contains a copolymer having an alkyl methacrylate structural unit as shown in formula (IV), a silicone (meth)acrylate structural unit as shown in formula (V), and an alkoxy polyethylene glycol (meth)acrylate structural unit as shown in formula (VI).

[0046] The turbidity of the above-mentioned antithrombotic materials is below 10.

[0047] [Chemical Formula 2]

[0048]

[0049] [In the formula, R] 1 ~R 7 The characters 'm' and 'n' have the same meaning as above.

[0050] [9] A composition containing a copolymer of alkyl methacrylate as shown in formula (I), silicone methacrylate as shown in formula (II) and alkoxy polyethylene glycol methacrylate as shown in formula (III), and having a turbidity of 10 or less, is used as an antithrombotic material.

[0051]

[10] Use of a composition having a copolymer having an alkyl methacrylate structural unit as shown in formula (IV), a silicone (meth)acrylate structural unit as shown in formula (V) and an alkoxy polyethylene glycol (meth)acrylate structural unit as shown in formula (VI) as an antithrombotic material.

[0052]

[11] A method for improving the antithrombotic properties of a medical device in contact with blood, characterized in that it comprises:

[0053] The process of copolymerizing the alkyl methacrylate of formula (I), the silicone methacrylate of formula (II), and the alkoxy polyethylene glycol methacrylate of formula (III) to obtain a copolymer; and

[0054] The process of coating the above copolymer or its solution onto the surface of the above medical device.

[0055] As the silicone (meth) acrylate shown in formula (II) above, a silicone (meth) acrylate with a weight average molecular weight of 1450 or less is used.

[0056]

[12] A method for improving the antithrombotic properties of a medical device in contact with blood, characterized in that it includes a step of coating a copolymer or a solution thereof having an alkyl methacrylate structural unit as shown in formula (IV), a silicone methacrylate structural unit as shown in formula (V), and an alkoxy polyethylene glycol methacrylate structural unit as shown in formula (VI) onto the surface of the medical device.

[0057] The turbidity of the above copolymer or its solution is below 10.

[0058] “C 1-6 "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group that has 1 or more but less than 6 carbon atoms, and is either straight-chain, branched, or cyclic. Examples include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, and cyclohexyl. As R 5 C is preferred. 2-6 Alkyl, more preferably C 3-5 Alkyl, most preferably n-butyl, as R 7 C is preferred. 1-4 Alkyl, more preferably C1-2 Alkyl group, with methyl group being the most preferred.

[0059] “C 6-20 "Alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon group with 6 or more but less than 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, etc. C4 is preferred. 8-12 Alkyl groups, more preferably branched C4 groups 8-12 alkyl.

[0060] “C 6-12 "Aromatic hydrocarbon group" refers to a monovalent aromatic hydrocarbon group with 6 or more but less than 12 carbon atoms. Examples include phenyl, naphthyl, indene, biphenyl, etc., with phenyl being the preferred choice.

[0061] “C 6-12 Aromatic hydrocarbons - C 1-6 "alkyl" refers to an alkyl group formed by C 6-12 C-substituted aromatic hydrocarbon groups 1-6 Alkyl groups. Examples include benzyl, phenethyl, phenylpropyl, naphthylmethyl, and biphenylmethyl, with benzyl being preferred.

[0062] “C 1-6 "Alkyl" refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon group with 1 or more but less than 6 carbon atoms. Examples include methylene, ethylene, methylmethylene, n-propylene, methylethylene, n-butylene, methylpropylene, dimethylethylene, n-pentylene, and n-hexylene. C4 is preferred. 1-4 Alkyl, more preferably C 3-4 Alkyl, with n-propanediyl being the most preferred.

[0063] As m, it is preferably 2 or more, more preferably 5 or more, even more preferably 8 or more, and preferably 25 or less or 20 or less, more preferably 15 or less, and even more preferably 12 or less.

[0064] The value of n is preferably 8 or less, more preferably 5 or less, and even more preferably 4 or 3.

[0065] Invention Effects

[0066] According to the method of the present invention, an antithrombotic material in which turbidity is suppressed can be manufactured. Because this antithrombotic material has a hydrophilic portion, platelet adhesion and protein adsorption are suppressed, exhibiting antithrombotic properties. Furthermore, because it also has a hydrophobic portion, complement activation is suppressed even upon contact with blood. Moreover, because it also has a hydrophobic portion, it exhibits affinity for the surface of similarly hydrophobic medical devices. Furthermore, because the antithrombotic material manufactured by the method of the present invention suppresses turbidity, it does not obstruct the visibility of the surface of medical devices, nor does it obstruct the transparency of transparent medical devices. Therefore, the present invention is industrially superior as a technology capable of manufacturing such an antithrombotic material, which imparts antithrombotic properties and allergy-inhibiting properties based on complement activation inhibition to medical devices. In addition, it provides durability against blood contact while maintaining these blood compatibility properties, and does not obstruct the visibility of the surface. Attached Figure Description

[0067] Figure 1 This 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 this monomer.

[0068] Figure 2 It is a raw material for opaque copolymers and transparent copolymers, namely polydimethylsiloxane methacrylate. 1 H NMR spectrum. Detailed Implementation

[0069] The following describes the manufacturing method of the antithrombotic material and the manufacturing method of the medical device in contact with blood according to the present invention, but the present invention is not limited to the specific examples below.

[0070] 1. Polymerization reaction process

[0071] In this process, the alkyl methacrylate shown in formula (I), the silicone methacrylate represented by formula (II) with a weight-average molecular weight of 1450 or less, and the alkoxy polyethylene glycol methacrylate shown in formula (III) are copolymerized. Hereinafter, the compound shown in formula (x) will sometimes be referred to simply as "compound (x)". For example, the alkyl methacrylate shown in formula (I) will sometimes be referred to simply as "alkyl methacrylate (I)".

[0072] Alkyl methacrylate (I) imparts hydrophobicity to the copolymer, improves the affinity between the surface of the medical device to be coated and the copolymer, and inhibits the peeling of the copolymer from the medical device.

[0073] As an alkyl ester (I) of (meth)acrylate, there are no particular limitations, and examples include: 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, palmitate (meth)acrylate, stearate (meth)acrylate, and other linear alkyl esters of (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 so on. Branched alkyl esters of methacrylates include 2-methyl octyl acrylate, 2-ethyl heptaacrylate, 2-methyl nonyl acrylate, 2-ethyl octyl acrylate, 2-methyl decyl acrylate, 2-ethyl nonyl acrylate, 2-methyl lauryl acrylate, 2-ethyl decyl acrylate, 2-methyl myristate acrylate, 2-ethyl lauryl acrylate, 2-methyl palmitate acrylate, and 2-ethyl myristate acrylate; cyclohexyl acrylate and other cyclic alkyl esters of methacrylates; phenyl acrylate and benzyl acrylate. From the viewpoint of cost and performance, 2-ethylhexyl acrylate and n-laurate acrylate are preferred. Furthermore, from the viewpoint of affinity to the surface of medical devices, branched alkyl esters of methacrylates are preferred.

[0074] Silicone (meth)acrylate (II) imparts hydrophobicity to copolymers, reducing their surface energy and inhibiting the immune response in the blood resulting from the recognition and activation of complement by foreign substances. It should be noted that hydrophobicity refers to the property of particularly repelling water within hydrophobicity, thereby inhibiting the adsorption and adhesion of proteins in the blood. Furthermore, it reduces the affinity for blood, which is primarily composed of water, resulting in the inhibition of complement activation.

[0075] The repeating unit m of dimethylsiloxane in silicone (meth)acrylate (II) is preferably 1 or more and 50 or less. If m is 50 or less, it is possible to prevent the viscosity of the resulting copolymer and its solution from becoming too high, resulting in high operability. On the other hand, if m is 1 or more, it is possible to prevent the viscosity of the resulting copolymer and its solution from becoming too low and failing to adhere to the surface of the medical device to be coated. As m, it is preferably 2 or more, more preferably 5 or more, and further preferably 40 or less or 30 or less, more preferably 20 or less or 15 or less.

[0076] In this invention, a silicone (meth)acrylate (II) with a weight-average molecular weight of 1450 or less is used. According to the experimental observations of the inventors, if this weight-average molecular weight is 1450 or less, the turbidity of the obtained copolymer and its solution can be sufficiently suppressed; specifically, the turbidity of the copolymer and its solution can be reduced to 10 or less. Preferably, this weight-average molecular weight is 1400 or less, more preferably 1300 or less, and even more preferably 1200 or less. On the other hand, if the above-mentioned weight-average molecular weight is too low, the polymerization reaction solution tends to foam, and if vacuum concentration is performed, the polymerization reaction solution sometimes overflows from the reaction vessel, thus sometimes vacuum concentration cannot be performed. Therefore, the above-mentioned weight-average molecular weight is preferably greater than 1000, more preferably 1050 or more, and even more preferably 1100 or more.

[0077] As the average molecular weight of polymers, number-average molecular weight and weight-average molecular weight are commonly used. Number-average molecular weight is the molecular weight M. i The number N of molecules with that molecular weight i The product divided by the number of numerators N i The sum of the obtained numbers refers to the simple average of the molecular weights of a single polymer chain contained in the polymer aggregate, equivalent to the mass per mole (g / mol). In contrast, the weight-average molecular weight is M. i 2 ×N i Divide by M i ×N i The sum of the obtained numbers is equivalent to the sum of the amounts obtained by multiplying the molecular weight of each polymer by its weight ratio. Compared with the number average molecular weight, the greater the proportion of high molecular weight polymers that contribute significantly to physical properties, the greater the weight average molecular weight value. Therefore, it can be said that the weight average molecular weight has a high correlation with the physical properties of the polymer aggregate. As methods for determining the weight average molecular weight, there are terminal group quantification methods, osmotic pressure methods, vapor pressure permeation methods, vapor pressure depression methods, freezing point depression methods, boiling point elevation methods, gel permeation chromatography (GPC), etc. In this invention, from the perspective of ease of operation, the conventional method of gel permeation chromatography (GPC) is adopted.

[0078] Regarding silicone, its basic framework reveals excellent heat and cold resistance, as well as a low glass transition temperature (Tg), thus exhibiting stable properties across a wide temperature range. Furthermore, its high binding energy provides advantages such as acid and alkali resistance and high chemical stability. Additionally, its excellent copolymerization with (meth)acrylate monomers makes it a preferred raw material for the (meth)acrylate copolymer of this invention. Silicone (meth)acrylate has recently been recognized as a material with high biocompatibility, used in contact lenses. Therefore, an excessive amount of silicone (meth)acrylate (II) in antithrombotic materials is not considered a problem. However, the current situation is that the price of silicone (meth)acrylate (II) raw materials is relatively high. Therefore, considering performance, quality, and cost, it is sufficient that the ratio of silicone (meth)acrylate (II) to the total of (meth)acrylate (I) and silicone (meth)acrylate (II) is 50% by mass or less. Preferably, this ratio is 40% by mass or less, and more preferably 35% by mass or less. On the other hand, from the viewpoint of the long-term stability of the copolymer, the ratio of silicone (meth)acrylate (II) to the total of (meth)acrylate (I) and 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.

[0079] Alkoxy polyethylene glycol (meth)acrylate (III) imparts hydrophilicity to copolymers, inhibiting platelet adhesion and subsequent activation in the blood, or inhibiting protein adsorption.

[0080] In alkoxy polyethylene glycol (meth)acrylate (III), the repeating unit n of ethylene oxide is preferably 2 or more and 10 or less. If n is 2 or more, the copolymer can be sufficiently endowed with hydrophilicity, and if it is 10 or less, the dissolution of the copolymer into the blood and its detachment from the medical device can be sufficiently suppressed. As n, it is more preferably 5 or less, and even more preferably 3 or 4.

[0081] As alkoxy polyethylene glycol (meth) acrylate (III), examples include: methoxy diethylene glycol (meth) acrylate, methoxy triethylene glycol (meth) acrylate, methoxy tetraethylene glycol (meth) acrylate, methoxy pentaethylene glycol (meth) acrylate, methoxy hexaethylene glycol (meth) acrylate, methoxy heptaethylene glycol (meth) acrylate, methoxy octaethylene glycol (meth) acrylate, methoxy nonaethylene glycol (meth) acrylate, methoxy decaethylene glycol (meth) acrylate, etc.

[0082] The amounts of alkoxy polyethylene glycol (meth)acrylate (III) and alkyl (meth)acrylate (I) used can be adjusted appropriately. For example, the molar ratio of alkyl (meth)acrylate (I) to 1 mole of alkoxy polyethylene glycol (meth)acrylate (III) can be 0.5 or more and 2.5 or less. If this molar ratio is within the above range, the balance between the hydrophilic and hydrophobic portions in the antithrombotic material becomes good, inhibiting the adsorption of platelets and proteins in the blood to the surface of the medical device, and also ensuring the affinity between the surface of the medical device and the antithrombotic material, thus inhibiting the dissolution of the antithrombotic material into the blood and uneven coating. As this ratio, 1 or more is preferred, 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.

[0083] The amounts of alkoxy polyethylene glycol (meth)acrylate (III) and silicone (meth)acrylate (II) used can be adjusted appropriately. For example, the molar ratio of silicone (meth)acrylate (II) to 1 mole of alkoxy polyethylene glycol (meth)acrylate (III) can be 0.001 or more and 1 or less. If this molar ratio is within the above range, the adsorption of platelets and proteins in the blood to the surface of the medical device can be inhibited, and the activation of complement caused by the antithrombotic material can also be inhibited, thereby suppressing excessive immune responses. As this ratio, it is preferably 0.005 or more, more preferably 0.01 or more, and preferably 0.5 or less, more preferably 0.1 or less.

[0084] In this process, alkyl methacrylate (I), silicone methacrylate (II), and alkoxy polyethylene glycol methacrylate (III) are copolymerized in a solvent. The copolymerization reaction used to manufacture the antithrombotic material of this invention is not particularly limited, and known methods such as free radical polymerization, ionic polymerization, photopolymerization, and polymerization using macromonomers can be used; free radical polymerization using a free radical initiator is preferred.

[0085] Solvents used in copolymerization include, for example, 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 perspective of the solubility of the monomer and the resulting copolymer, and the ease of obtaining them, ethyl acetate, methanol, and ethanol are preferred. Alternatively, a mixture of several of the above solvents can be used.

[0086] The amount of solvent used can be adjusted appropriately; for example, it can be adjusted to be 0.3 times or more but less than 10 times the total amount of monomer. Preferably, this ratio is 0.5 times or more but less than 5 times the total amount of monomer.

[0087] As free radical initiators, peroxide-based and azo-based free radical initiators commonly used in free radical polymerization are employed. Examples of peroxide-based free radical initiators include inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide; and organic peroxides such as benzoyl peroxide, tert-butyl hydroperoxide, and cumene peroxide. Examples of azo-based free radical initiators include 2,2'-azobisisobutyronitrile, 2,2'-azobis(2-aminodipropane)dihydrochloride, dimethyl 2,2'-azobisbutyrate, and dimethyl 2,2'-azobis(2-methylpropionic acid). Alternatively, redox initiators formed by combining a reducing agent with a peroxide-based initiator can also be used.

[0088] The amount of free radical initiator used can be adjusted appropriately. For example, relative to the total amount of monomers, it can be adjusted to 0.01% by mass or more and 1% by mass or less. As this ratio, it is preferably 0.05% by mass or more, and even more preferably 0.5% by mass or less, and more preferably 0.3% by mass or less.

[0089] Specifically, for example, monomers, polymerization solvents, and free radical initiators are added to a stirred reaction apparatus equipped with a reflux tower. After nitrogen replacement of the gas phase, polymerization is initiated by heating, and the polymerization is carried out by maintaining this temperature for a certain period of time. It is also possible to control the molecular weight during polymerization using chain transfer agents. Chain transfer agents used to control the molecular weight during polymerization include, in addition to high-boiling-point thiols such as dodecyl mercaptan, thiomalic acid, and mercaptoacetic acid, isopropanol, phosphorous acid, and hypophosphite.

[0090] The polymerization temperature varies depending on the type of solvent, free radical initiator, etc., and is preferably adjusted to be near the 10-hour half-life temperature of the free radical initiator. Specifically, when using the aforementioned free radical initiator, the temperature can be adjusted to 20°C or higher and 90°C or lower. Preferably, this temperature is 30°C or higher, and more preferably 40°C or higher. The polymerization reaction time can also be adjusted appropriately, for example, by determining the reaction time until any monomer is consumed using chromatography or by conducting preliminary experiments; specifically, it can be set to 1 hour or higher and 10 hours or lower.

[0091] After the polymerization reaction, the solvent is removed to obtain crude (meth)acrylate copolymer. At this point, if a silicone (meth)acrylate (II) with a low weight-average molecular weight is used to suppress the turbidity of the antithrombotic material, the reaction solution will foam, potentially overflowing from the container during vacuum concentration, thus sometimes making vacuum concentration impossible. Therefore, by using silicone (meth)acrylate (II) with a weight-average molecular weight exceeding 1000, this foaming can be suppressed more reliably, allowing for good vacuum concentration.

[0092] After removing the solvent, the obtained crude (meth)acrylate copolymer is stirred in a poor solvent, and then purified by removing the poor solvent. This purification process is repeated once or several times to improve the purity of the (meth)acrylate copolymer. The resulting copolymer is then dried.

[0093] In this invention, the (meth)acrylate copolymer is formed by copolymerizing hydrophilic and hydrophobic monomers, thus possessing both hydrophilic and hydrophobic properties. Therefore, in the solution after the polymerization reaction, unreacted hydrophilic monomers (methoxy polyethylene glycol (meth)acrylate) and hydrophobic monomers (silicone (meth)acrylate and alkyl (meth)acrylate), along with the (meth)acrylate copolymer, are mixed. To separate the water-insoluble (meth)acrylate copolymer from these mixtures, for example, the copolymer solution can be added dropwise to a solvent that dissolves the hydrophilic monomers to remove the hydrophilic monomers, followed by purification using a solvent that dissolves the hydrophobic monomers. Furthermore, by using a reprecipitation solvent prepared by mixing alcohol and water in a specific ratio, the (meth)acrylate copolymer can be efficiently recovered. Alternatively, the following purification method can be used: In the solution where the polymerization reaction has been completed, a poor solvent is added to the water-insoluble (meth)acrylate copolymer containing a mixture of alcohol and water in a specific ratio, and the mixture is stirred at a certain temperature to separate the (meth)acrylate copolymer. The precipitate is then recovered by decantation, and a washing solution is added. The same method is repeated.

[0094] In this invention, as a poor solvent for purifying the copolymer, it is preferable to use a poor solvent that does not dissolve the copolymer but dissolves both the hydrophilic monomer and the hydrophobic monomer.

[0095] In this invention, the alcohol used in the redeposition process is preferably an alcohol with 1 or more but less than 10 carbon atoms, more preferably an alcohol with 1 or more but less than 7 carbon atoms, and even more preferably an alcohol with 1 or more but less than 4 carbon atoms. Specific examples of such alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methoxy-1-propanol, tert-butanol, etc. From the perspective of being able to perform low-temperature and short-time drying, methanol, ethanol, 1-propanol, and 2-propanol are more preferred.

[0096] The amount of inferior solvent used can be adjusted appropriately within the range where the copolymer is sufficiently purified. For example, the volume ratio relative to the crude (meth)acrylate copolymer is preferably 1 or more and 20 or less, more preferably 5 or less.

[0097] The preferred purification temperature for the crude (meth)acrylate copolymer of the present invention is 30°C or higher and 60°C or lower, more preferably 40°C or higher and 60°C or lower. If the purification temperature is within the above range, the viscosity of the crude (meth)acrylate copolymer decreases due to heating, making it easier to separate from inferior solvents and maximizing the recovery rate of the (meth)acrylate copolymer.

[0098] In this invention, the recovery rate of the purified (meth)acrylate copolymer is preferably 20% by mass or more and 90% by mass or less. A recovery rate of 20% by mass or more indicates high production efficiency, while a rate of 90% by mass or less sufficiently suppresses the incorporation of unreacted monomers. It should be noted that adjusting the recovery rate to the above range may result in a slight loss or abandonment of the copolymer, but this is unavoidable from the perspective of minimizing the incorporation of unreacted monomers. This is because, considering the unique case of copolymers with both hydrophilic and hydrophobic properties used in medical devices, this must be taken into account.

[0099] In this invention, the amount of residual monomer, i.e., the amount of unreacted monomer during polymerization, is important because it relates to safety. Reducing the amount of residual monomer in the antithrombotic material certainly meets the criteria indicated by the dissolution guidelines from medical devices, but by keeping the amount of residual monomer at a very low level, such as below 4,000 ppm, it unexpectedly improves the adhesion and retention of the antithrombotic material on the surface of medical devices. Furthermore, the recovery rate is expressed as the ratio of the amount of copolymer obtained to the amount of monomer input.

[0100] By performing the purification process as described above once, or, if necessary, two to eight times, water-insoluble (meth)acrylate copolymers with an unreacted monomer content of 4,000 ppm or less can be recovered with a high recovery rate of 30% by mass or more. When the copolymer contains a high amount of unreacted monomers, oligomers, and polymerization residues, it is considered that these substances dissolve into the bloodstream and become contributing factors to shock symptoms in patients. While most of these contributing factors can be removed through purification, it is more preferable for the content to be 3,000 ppm or less, more preferably 2,000 ppm or less, and particularly preferably 1,000 ppm or less, considering patient safety.

[0101] To use the purified copolymer to impart antithrombotic properties to medical devices, the solvent needs to be removed by drying. Drying methods include, for example, performing drying at 60°C and a reduced pressure below 1 Torr; if insufficient drying is achieved, depressurized drying can be continued.

[0102] In this invention, the copolymer obtained by copolymerizing alkyl methacrylate (I), silicone methacrylate (II), and alkoxy polyethylene glycol (methacrylate) (III), i.e., the copolymer having alkyl methacrylate structural units (IV), silicone methacrylate structural units (V), and alkoxy polyethylene glycol (methacrylate) structural units (VI), is preferably a liquid that is durable for blood contact and viscous at room temperature. Here, durability for blood contact means that when the methacrylate copolymer is immersed in the following alcohol impregnation treatment solution for 16 hours at room temperature, a certain amount of the methacrylate copolymer remains, exhibiting antithrombotic properties. When a specified amount of methacrylate copolymer remains after immersion in the alcohol impregnation treatment solution at room temperature for 16 hours, it can be determined that it also has sufficient antithrombotic properties even after 30 days of contact with blood at 37°C. Furthermore, since it is liquid but viscous at room temperature, it also has the advantage of inhibiting dissolution into the blood when coated on medical devices, etc.

[0103] Furthermore, the copolymer produced by the method of the present invention exhibits suppressed turbidity and excellent transparency. Specifically, the turbidity of the copolymer and the antithrombotic material of the present invention is suppressed to 10 or less. In this disclosure, "turbidity" refers to the turbidity measured according to the methods specified in JIS K0101:2017 Industrial Water Test Method and the 18th Revision of the Japanese Pharmacopoeia. Specifically, a standard curve is prepared by measuring the absorbance at 660 nm of a turbidity standard solution. Additionally, the absorbance at 660 nm of the copolymer and the antithrombotic material of the present invention is measured, and the turbidity of the copolymer and the antithrombotic material of the present invention is determined based on the measured values ​​using the standard curve. Preferably, the turbidity is 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.

[0104] As a method to confirm the durability of the antithrombotic material of the present invention against dissolution in blood, an alcohol impregnation treatment at room temperature can be cited. As the alcohol, a mixture of methanol and ethanol is preferred. For example, a solvent prepared by mixing methanol and ethanol at a mass ratio of 80 / 20 has a slightly stronger dissolving power than blood; therefore, by impregnating the antithrombotic material in the above-mentioned mixed solvent for 16 hours, the persistence of the antithrombotic effect can be evaluated.

[0105] In this invention, the (meth)acrylate copolymer has the property of being insoluble in methanol but soluble in ethanol. As an alcohol impregnation treatment solution for confirming the durability (persistence of antithrombotic properties) after 30 days of contact with blood at 37°C, when methanol and ethanol are mixed at a specified ratio, the durability after 30 days of contact with blood at 37°C can be confirmed even in a short time such as 16 hours. The preferred mass ratio of methanol to ethanol in the alcohol impregnation treatment solution is methanol:ethanol = 90-60:10-40, more preferably 90-70:10-30. It should be noted that in tests using the evaluation sheets described later, if the adhesion of blood clots is low, i.e., the number of blood clots on the evaluation sheets confirmed after solvent impregnation is less than 1 out of 10 sheets, and the (meth)acrylate copolymer residue is 0.1 μg / cm³, then the test is considered successful. 2 Based on the above, it can be determined that it has sufficient durability.

[0106] In this invention, one method for evaluating the blood compatibility of copolymers is the blood coagulation test. Specifically, this method utilizes the reaction in which fibrin in plasma gels due to calcium ions, forming a fibrin gel. By confirming the presence or absence of blood clots after immersion in water in calcium-added plasma that comes into contact with the sample, the blood compatibility of the polymer can be determined. For example, half of a polycarbonate sheet is immersed in an ethanol solution of the copolymer, and the resulting evaluation sheet is dried and then subjected to a test blood solution. If fewer than 4 out of 10 evaluation sheets show blood clot adhesion, the blood compatibility can be considered good.

[0107] If we specifically list representative substances belonging to the (meth)acrylate copolymers of the present invention, examples 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-(meth)hexyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)hexyl acrylate-(meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, and silicone (meth)acrylate-(meth)hexyl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer. , silicone (meth)acrylate-cyclohexyl methacrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-cyclohexyl methacrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-cyclohexyl methacrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl methacrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl methacrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-phenyl methacrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate 2-Ethylene methacrylate-(meth)acrylate-(octyl)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(octyl)acrylate-(meth)acrylate-(triethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(octyl)acrylate-(meth)acrylate-(tetraethylene glycol (meth)acrylate) copolymer, silicone (meth)acrylate-(2-ethylhexyl)acrylate-(meth)acrylate-(triethylene glycol (meth)acrylate) copolymer, silicone (meth)acrylate-(2-ethylhexyl)acrylate-(meth)acrylate-(tetraethylene glycol (meth)acrylate) copolymer Polymers, silicone (meth)acrylate-lauryl methacrylate-methoxydiethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-lauryl methacrylate-methoxytriethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-lauryl methacrylate-methoxytetraethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-nonyl methacrylate-nonyl methacrylate-methoxydiethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-nonyl methacrylate-nonyl methacrylate-methoxytetraethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-nonyl methacrylate-nonyl methacrylate-methoxytetraethylene glycol (meth)acrylate copolymers,Silicone (meth)acrylate-(meth)decyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)decyl acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)decyl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)stearyl acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)stearyl acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)stearyl acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone Ketone (meth)acrylate-(meth)acrylate lauryl ester-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate lauryl ester-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate lauryl ester-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate myristyl ester-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate myristyl ester-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-(meth)acrylate myristyl ester-methoxytetraethylene glycol (meth)acrylate copolymer. The copolymers of the present invention are not limited to those described herein, but also include (meth)acrylate copolymers with a molar ratio of (meth)acrylate alkyl acrylate (I): silicone (meth)acrylate (II): methoxy polyethylene glycol (meth)acrylate (III) = 80-20: 10-0.01: 10-79.99. By using the (meth)acrylate alkyl acrylate (I) unit and the silicone (meth)acrylate (II) unit as hydrophobic (meth)acrylates, the dissolution of the copolymer into the blood is inhibited, improving blood durability and affinity to medical device surfaces. Furthermore, by using the alkoxy polyethylene glycol (meth)acrylate (III) unit as a hydrophilic (meth)acrylate, the adhesion of platelets and proteins is inhibited. Therefore, the preferred molar ratio is 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. It should be noted that the proportion of each acrylate structural unit in the copolymer of the present invention can be determined by analyzing the copolymer using nuclear magnetic resonance (NMR) or mass spectrometry, through the intensity ratio of the peaks characteristic of each acrylate.

[0108] 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, dissolution into the 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, the workability when coating medical devices is sufficiently high. More preferably, it is 1,000,000 or less, and even more preferably 500,000 or less.

[0109] The specific viscosity (ηsp / c) of the (meth)acrylate copolymer of the present invention is preferably 0.18 dl / g or more and 3.00 dl / g or less. By using an antithrombotic material in such a viscosity range, the copolymer exhibits excellent adhesion to medical devices such as artificial heart-lung circuits and catheters, enabling sustained antithrombotic properties over long-term use. The specific viscosity range is more preferably 0.18 dl / g or more, further preferably 1.50 dl / g or less, and even more preferably 0.50 dl / g or less.

[0110] The antithrombotic material of the present invention can be any of random copolymers, block copolymers, and graft copolymers. The (meth)acrylate copolymer of the present invention can also be a copolymer composed of alternating monomers; if analyzed based on the total amount, it can also be a copolymer containing segments or blocks formed by hydrophobic monomers and segments or blocks formed by hydrophilic monomers. It is conceivable that the segments or blocks formed by hydrophobic monomers can also adopt complex structures such as so-called microphase separation structures or mosaic patterns that function to fix the segments or blocks formed by hydrophilic monomers. In short, the molecular weight of the copolymer and the type and characteristics of the hydrophilic monomers will have an impact, but if the amount of hydrophobic monomers is slightly higher, the dissolution of the segments or blocks formed by hydrophilic monomers in the copolymer can be suppressed. In addition, it is believed that having a slightly higher number of hydrophobic segments can also improve the affinity with hydrophobic medical devices. It is also expected that the copolymer can act as a coating to help fix the medical devices. However, the behavior related to the presence or absence of segments and the affinity of the segments cannot be accurately verified based on technical evidence at present. Nevertheless, the copolymer is a polymer material with a gentle affinity for biological organisms.

[0111] Homopolymers of alkoxy polyethylene glycol (meth)acrylate (III) exhibit excellent blood compatibility due to their high hydrophilicity; however, because they are water-soluble, they suffer from slow dissolution upon prolonged contact with blood or similar substances. The inventors conducted in-depth research on materials that not only possess excellent blood compatibility but also withstand long-term use. They discovered that copolymers obtained by imparting moderate hydrophobicity to prevent dissolution into blood or similar substances and flexibility to prevent physical peeling of the coated film can solve this problem.

[0112] Thus, the copolymer of the present invention is essentially formed by two monomeric components that perform so-called interfacial functions on two different sides. The copolymer is formed by hydrophilic monomers, segments or blocks that have functions such as antithrombotic and antidissolution properties for blood, and hydrophobic monomers, segments or blocks that have functions such as affinity and fixation for medical devices. On the other hand, the monomers, segments or blocks that form the copolymer complement each other in the molecular structure and appear to be bonded or form structures with molecules that are stable for dissolution, dispersion, etc.

[0113] The (meth)acrylate copolymer of the present invention is preferably soluble in any one of alcohols having 1 to 6 carbon atoms. Solubility in alcohols having 1 to 3 carbon atoms facilitates drying after coating, and is therefore more preferred. Here, "soluble" means that when 1 g of the (meth)acrylate copolymer is immersed in 10 mL of the aforementioned alcohol at 25°C, at least 90% by mass of the (meth)acrylate copolymer dissolves within 16 hours at room temperature.

[0114] The antithrombotic material comprising (meth)acrylate copolymers of the present invention may contain substances such as antibacterial agents. The antibacterial agents are not particularly limited, but examples include: ampicillin, nafcillin, amoxicillin, oxacillin, azoxacillin, penicillin G, carbenicillin, penicillin V, dicloxacillin, feneccillin, flucloxacillin, piperacillin, mecillin, sulfamethoxazole, methicillin, ticarcillin, mezlocillin, cefaclor, cefotaxime, cefadroxil, cefoperazone, cefamandole, cefadroxil, ceftriaxone, ceftriaxone, ceftriaxone, ceftriaxone, ceftriaxone, cefadroxil ... Retard, Ceftriaxone, Cefoxitin, Cefuroxime, Cefetrazol, Latamoxef, Cephalexin, Amikacin, Neomycin, Dibekacin, Kanamycin, Gentamicin, Netilmicin, Tobramycin, Amphotericin B, Neomycin, Bacitracin, Nystatin, Clindamycin, Polymyxin, Colistin, Spiramycin, Erythromycin, Streptomycin, Spectinomycin, Lincomycin, Vancomycin, Chlortetracycline, Oxytetracycline, Demeclocycline, Rolicycline, Doxycycline, Tetracycline Antibiotics such as minocycline; antifungal agents such as amphotericin B, ketoconazole, clotrimazole, miconazole, econazole, natamycin, flucytosine, nystatin, and griseofulvin; parabens such as isobutylparaben, isopropylparaben, ethylparaben, butylparaben, and propylparaben; biguanide compounds such as chlorhexidine; benzyl chloride, benzalkonium chloride, lauryl sulfate, alkyl polyaminoethyl glycine, fatty acids, and bromine. Compounds with surface activity such as domomiphen; phenol derivatives such as thymol, phenol, hexachlorophenol, 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, methyl bromide, and silver sulfadiazine; antibacterial pigment compounds such as rivanol and methylrosaniline; and sulfonamides such as sulfamidone acetate, sulfadiazine, sulfadiazine, and sulfamethoxazole. These antibacterial substances can be sodium, potassium, magnesium, calcium, hydrochloride, sulfate, gluconate, and other salt compounds. Furthermore, two or more antibacterial substances can be used in combination.

[0115] The aforementioned antibacterial substances can be broadly categorized into water-soluble and poorly water-soluble substances. Representative examples of water-soluble antibacterial substances include benzalkonium chloride, povidone-iodine, potassium penicillin G, and streptomycin sulfate. Representative examples of poorly water-soluble antibacterial substances include silver sulfadiazine and chlorhexidine.

[0116] 2. Coating process

[0117] In this process, after coating the surface of the medical device with the copolymer or its solution of the present invention, it is dried as needed. The antithrombotic material of the present invention exhibits inhibition of platelet and protein adsorption, and inhibition of complement activity. In addition, it has blood resistance and affinity for hydrophobic surfaces. Therefore, by coating medical devices with the antithrombotic material of the present invention, these properties can also be imparted to the medical devices.

[0118] Methods for loading the antithrombotic material of the present invention onto the surface of a substrate such as a medical device include: coating, graft polymerization based on radiation, electron beam, or ultraviolet light, and methods utilizing chemical reactions with functional groups of the substrate. Among these, coating is preferred in practice due to its ease of manufacturing process. For example, by coating a solution obtained by dissolving the antithrombotic material of the present invention in an organic solvent onto the surface of a substrate such as a medical device, and then removing the solvent, the medical device can be coated. The coating method is not particularly limited; methods such as application, spraying, and dipping can be used. Furthermore, it is preferable to heat the coated substrate to dry it. This further improves the adhesion between the substrate and the antithrombotic material of the present invention, resulting in a more secure fixation.

[0119] When the copolymer of the present invention is a liquid at room temperature and pressure, it can be directly used for coating. When the copolymer of the present invention is a solid at room temperature and pressure, or even when it is a liquid, its viscosity is high, a solution or suspension obtained by dissolving or suspending it in a solvent can be used. As the organic solvent used for the coating solution, an organic solvent that will not cause damage to the medical device as the substrate should be selected. Specifically, alcohol solvents such as methanol, ethanol, 2-propanol, and n-propanol are used; ketone solvents such as acetone and cyclohexanone are used; aliphatic hydrocarbon solvents such as n-hexane and cyclohexane are used; ether solvents such as tetrahydrofuran and 1,4-dioxane are used; and amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone are used. Among these, methanol, ethanol, and 2-propanol, which have low boiling points and are easy to dry after coating, are more preferred.

[0120] The concentration of the (meth)acrylate copolymer in the solution of the antithrombotic material of the present invention can be appropriately adjusted, for example, it can be set to 0.001% by mass or more and 10% by mass or less. If the concentration is 0.001% by mass or more, the antithrombotic material of the present invention can be used to fully coat medical devices, and if it is 10% by mass or less, the viscosity of the solution will not become too high, resulting in excellent workability. As this concentration, 0.01% by mass or more and 5% by mass or less is preferred.

[0121] One method for quantifying the coating amount of antithrombotic materials is NMR quantification. Specifically, the method involves extracting the substrate coated with the antithrombotic material with ethanol, drying the extract, and then performing NMR analysis. The coating amount is calculated based on the peak area. Durability can also be evaluated by comparing the coating amount before and after ethanol impregnation. Specifically, the residual amount of (meth)acrylate copolymer in the evaluation sheet after impregnation with 99.5% ethanol was 3.0 μg / cm³. 2 When the above conditions are met, it can be determined that the antithrombotic properties in the initial stage of blood contact are fully demonstrated.

[0122] Medical devices whose surfaces are coated with the antithrombotic material of the present invention 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, anti-adhesion materials, wound dressing materials, tissue adhesive materials, and tissue regeneration repair materials. Medical devices having an extracorporeal circulation circuit and a blood contact portion are particularly preferred.

[0123] As a substrate for medical devices, it includes all commonly used materials. Examples include: polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, poly-4-methylpentene-1, thermoplastic polyether polyurethane, thermosetting polyurethane, silicone rubbers such as polydimethylsiloxane with crosslinking portions, polymethyl methacrylate, polyvinylidene fluoride, polytetrafluoroethylene, polysulfone, polyethersulfone, polyacetal, polystyrene, ABS resin and mixtures of these resins, metals such as stainless steel, titanium, and aluminum. The antithrombotic material of the present invention, by balancing material composition, molecular weight, viscosity, etc., and by optimizing coating conditions, can achieve uniform and firm coating regardless of the material, shape, or surface properties to which the coating is applied.

[0124] In this invention, when medical devices are coated with the antithrombotic substance (copolymer) of this invention and a water-poorly soluble antibacterial substance, it is unclear whether this is because the copolymer is water-insoluble or because the water insolubility of the copolymer and the water-poor solubility of the antibacterial substance complement each other, but the dissolution of the antibacterial substance becomes extremely small and continuous, maintaining long-term antibacterial activity. On the other hand, when coated with a copolymer and a water-soluble antibacterial substance, the copolymer is water-insoluble, but the antibacterial substance is water-soluble. Therefore, the amount of dissolution is greater compared to the case where a water-poorly soluble antibacterial substance is used. Although a strong, momentary antibacterial effect can be observed, long-term antibacterial activity cannot be maintained. For example, in-dwelling vascular catheters, infusion tubes, artificial lungs, and other medical devices are used continuously for one to several days, and long-term continuous antibacterial activity is required in such applications. Furthermore, by incorporating both water-soluble and water-poorly soluble antibacterial substances into the copolymer, a multi-stage antibacterial effect can be achieved, where the water-soluble antibacterial substance initially exerts strong bactericidal activity, followed by long-term antibacterial activity from the water-poorly soluble antibacterial substance. If this multi-stage antibacterial effect is applied to indwelling vascular catheters, the water-soluble antibacterial substance dissolves early, exhibiting strong antibacterial activity, thereby killing resident skin bacteria introduced into the blood vessel during catheter insertion and reducing the risk of infection at insertion. Moreover, during catheter placement, the long-term antibacterial activity of the water-poorly soluble antibacterial substance can prevent bacterial adhesion to the catheter and the proliferation of bacteria invading from the insertion site, further reducing the risk of infection during placement.

[0125] In this invention, the proportion of the antibacterial substance relative to the mass of the antithrombotic material is preferably 0.01% by mass or more and 70% by mass or less. If this proportion is 0.01% by mass or more, the antibacterial activity of the antibacterial substance is more reliably exerted; if it is 70% by mass or less, it can more reliably suppress defects in the appearance of the medical device after surface treatment such as coating, dissolution of the antibacterial substance into the body, and the resulting local inflammation. This proportion is more preferably 0.05% by mass or more, even more preferably 0.1% by mass or more, and even more preferably 50% by mass or less or 30% by mass or less, and even more preferably 10% by mass or less. Furthermore, the antibacterial substance can be present throughout the entire surface of the medical device, but from the perspective of suppressing local inflammation, it is preferable that it is only present near the insertion point through the skin.

[0126] The (meth)acrylate copolymer of the present invention, obtained by copolymerizing (meth)acrylate (I), silicone (meth)acrylate (II), and alkoxy polyethylene glycol (meth)acrylate (III), has a moderate balance of hydrophilicity and hydrophobicity, making it suitable for use as a blood-compatible material. Furthermore, because it can inhibit the adsorption and adhesion of platelets, blood proteins, etc., it is suitable for use as a processing material in medical devices. Additionally, the (meth)acrylate copolymer of the present invention can be used alone or in combination of two or more types.

[0127] It can be assumed that when a medical device treated with this antithrombotic material comes into contact with blood, the highly hydrophilic alkoxy polyethylene glycol (meth)acrylate (III) may protrude to the surface to exert antithrombotic properties. In addition, the hydrophobic alkyl (meth)acrylate (I), silicone (meth)acrylate (II) and (meth)acrylate remain near the substrate, thereby preventing direct contact between blood and the medical device.

[0128] 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 description of Japanese Patent Application No. 2023-205501, filed on December 5, 2023, are incorporated herein by reference.

[0129] [Example]

[0130] The present invention will be described in more detail below with examples, but the present invention is of course not limited to the following examples. It can also be implemented by appropriate modifications within the scope of the above and following spirit, and all of these are included in the technical scope of the present invention.

[0131] Example 1

[0132] (1) Copolymerization reaction

[0133] Polydimethylsiloxane methacrylates (PDMSMA) with different weight-average molecular weights were obtained. The weight-average molecular weights of each PDMSMA are shown in Table 1.

[0134] Polymerization was carried out at 85°C for 3 hours with 471.3 g of methoxytriethylene glycol acrylate (MTEGA) (manufactured by Shin-Nakamura Chemical Co., Ltd.), 78.0 g of PDMSMA, 693.3 g of 2-ethylhexyl acrylate (EHA) (manufactured by Toa Synthetic Co., Ltd.), 1.23 g of azobisisobutyronitrile (AIBN) (manufactured by Fujifilm and Koko Pure Chemical Co., Ltd.), and 1615.4 g of ethanol (manufactured by KISHIDA Chemical Co., Ltd.). After polymerization, the product was dried at 85°C under normal pressure for 2 hours, followed by drying under reduced pressure at 60°C for 40 minutes to obtain a concentrate. 6320.0 g of methanol (KISHIDA Chemical Co., Ltd.) and 600.0 g of water were added to 1234.8 g of the concentrate, and the mixture was stirred for 20 minutes. After stirring, the mixture was allowed 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, stirred for 20 minutes, and allowed to stand for 1.5 hours. The supernatant was removed by decantation. This operation was repeated three times to wash the precipitate. The washed precipitate was dried under reduced pressure at 40°C for 1 hour to obtain the copolymer.

[0135] (2) Turbidity evaluation

[0136] Turbidity test standard solution containing kaolin particles ("Turbidity Standard Solution (Turbidity: 100 degrees)" manufactured by Fujifilm and Koichi Chemical Co., Ltd.) was diluted with distilled water to prepare turbidity samples of 0-50 degrees (kaolin).

[0137] Using an absorbance meter ("UV-1700", manufactured by Shimadzu Corporation), the absorbance at 660 nm of turbidity samples was determined based on JIS K0101:2017 Test Methods for Industrial Water and the 18th Revision of the Japanese Pharmacopoeia. An absorbance-turbidity graph was plotted, yielding an approximate formula y = 382.38x + 0.1836, with a coefficient of determination R0. 2 The value is very high, at 0.9992, indicating that the measured absorbance is proportional to the turbidity.

[0138] Similarly, the absorbance at 660 nm of each copolymer (1 mL) obtained in Example 1 (1) was measured, and the turbidity was determined according to the above standard curve. The results are shown in Table 1.

[0139] [Table 1]

[0140]

[0141] As shown in Table 1, if the weight-average molecular weight of the raw material PDMSMA is large, the copolymer solution tends to be turbid. Although there are measurement errors in the low absorbance range, it at least confirms that if the weight-average molecular weight of the raw material PDMSMA is below 1376, the turbidity of the copolymer can be significantly reduced.

[0142] Plot a graph showing the relationship between the weight-average molecular weight of the raw material PDMSMA and the turbidity of the copolymer. Present the results in... Figure 1 It is known that in order to suppress the turbidity of the copolymer to below 10, PDMSMA with a weight-average molecular weight of below 1450 is required.

[0143] (3) Analysis

[0144] use 1 ¹H NMR was used to analyze the PDMSMA raw material of the turbid copolymer 2 and the PDMSMA raw material of the clear copolymer 4. The results are presented below. Figure 2 .

[0145] like Figure 2 The results show that, compared to the transparent PDMSMA raw material of copolymer 4, the peak near 4 ppm is broadened in the NMR spectrum of the turbid PDMSMA raw material of copolymer 2. This peak is the methyl peak of the dimethylsiloxane group; therefore, it is thought that the PDMSMA with high weight-average molecular weight readily polymerizes with each other, and the resulting oligomers precipitate from copolymer 2, which may be the cause of the turbidity.

[0146] Therefore, in order to suppress the turbidity of the copolymer, silicone monomers with a weight-average molecular weight below the specified value, specifically below 1450, should be used.

Claims

1. A method for manufacturing an antithrombotic material, characterized in that, The process includes copolymerizing alkyl methacrylates of formula (I), silicone methacrylates of formula (II), and alkoxy polyethylene glycol methacrylates of formula (III). As the silicone (meth)acrylate, a silicone (meth)acrylate with a weight average molecular weight of 1450 or less is used. In the formula, R 1 Indicates a hydrogen atom or a methyl group. R 2 C represents 6-20 Alkyl, C 6-12 Aromatic hydrocarbon groups, or C 6-12 Aromatic hydrocarbons - C 1-6 alkyl, R 3 Indicates a hydrogen atom or a methyl group. R 4 C represents 1-6 Alkyl, R 5 C represents 1-6 alkyl, R 6 Indicates a hydrogen atom or a methyl group. R 7 C represents 1-6 alkyl, m represents an integer greater than 1 and less than 50. n represents an integer greater than 2 and less than 10.

2. The method according to claim 1, wherein, The weight-average molecular weight exceeds 1000.

3. The method according to claim 1, wherein, The alkyl methacrylate is used in an amount of 1.5 to 2 times the molar ratio relative to 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 molar to 0.1 molar relative to the alkoxy polyethylene 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 manufacturing a medical device that comes into contact with blood, characterized in that, include: The process of copolymerizing an alkyl methacrylate of formula (I), a silicone methacrylate of formula (II), and an alkoxy polyethylene glycol methacrylate of formula (III) to obtain a copolymer; and The process of coating the copolymer or a solution thereof onto the surface of a medical device. As the silicone (meth)acrylate represented by formula (II), a silicone (meth)acrylate with a weight-average molecular weight of 1450 or less is used. In the formula, R 1 Indicates a hydrogen atom or a methyl group. R 2 C represents 6-20 Alkyl, C 6-12 Aromatic hydrocarbon groups, or C 6-12 Aromatic hydrocarbons - C 1-6 alkyl, R 3 Indicates a hydrogen atom or a methyl group. R 4 C represents 1-6 Alkyl, R 5 C represents 1-6 alkyl, R 6 Indicates a hydrogen atom or a methyl group. R 7 C represents 1-6 alkyl, m represents an integer greater than 1 and less than 50. n represents an integer greater than 2 and less than 10.

7. An antithrombotic material, characterized in that, A copolymer containing an alkyl methacrylate as shown in formula (I), a silicone methacrylate as shown in formula (II), and an alkoxy polyethylene glycol methacrylate as shown in formula (III), The turbidity of the antithrombotic material is below 10. In the formula, R 1 Indicates a hydrogen atom or a methyl group. R 2 C represents 6-20 Alkyl, C 6-12 Aromatic hydrocarbon groups, or C 6-12 Aromatic hydrocarbons - C 1-6 alkyl, R 3 Indicates a hydrogen atom or a methyl group. R 4 C represents 1-6 Alkyl, R 5 C represents 1-6 alkyl, R 6 Indicates a hydrogen atom or a methyl group. R 7 C represents 1-6 alkyl, m represents an integer greater than 1 and less than 50. n represents an integer greater than 2 and less than 10.

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