Method for producing Anti-thrombogenic material

Abstract

To provide: a method for producing an anti-thrombogenic material in which white turbidity is reduced; a method for producing a medical instrument coated with the anti-thrombogenic material produced by the method; and an anti-thrombogenic material in which white turbidity is reduced.SOLUTION: A method for producing an anti-thrombogenic material according to the present invention comprises a step of copolymerizing a specific alkyl (meth)acrylate, a silicone (meth)acrylate, and an alkoxy polyethylene glycol (meth)acrylate, wherein the silicone (meth)acrylate used here has a weight average molecular weight of 1450 or less.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] In recent years, studies on medical devices using various polymer materials have been advanced, and their use in blood filters, artificial kidneys, plasma separation, catheters, artificial lungs, artificial blood vessels, adhesion prevention membranes, artificial skin, etc. is expected. In this case, since a synthetic material that is a foreign substance to the living body is used in contact with living tissue or blood in the body, it is required that the medical device has biocompatibility.

[0003] When using a medical device as a material in contact with blood, three factors: (a) suppression of the blood coagulation system, (b) suppression of platelet adhesion / activation, and (c) suppression of complement system activation are important items as biocompatibility. Among them, when used as a material with a relatively short contact time with blood, such as a medical device for extracorporeal circulation (for example, an artificial kidney, a plasma separation membrane), generally, anticoagulants such as heparin and sodium citrate are used simultaneously, and thus, in particular, suppression of activation of platelets and the complement system in (b) and (c) is important.

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

[0005] In addition, the applicant of the present application has developed an antithrombotic material containing a (meth)acrylate copolymer obtained by polymerizing a specific (meth)acrylate monomer, having a specific weight average molecular weight, being water-insoluble, and being a viscous liquid at room temperature, as a material having a relatively long contact time with blood (Patent Document 2). Furthermore, the applicant has developed a catheter that is excellent in blood compatibility and biocompatibility and whose physical properties and scientific properties are not impaired even during long-term in-vivo indwelling, and in which at least a part of the body fluid contact portion is coated with an antithrombotic material composed of a specific (meth)acrylate copolymer (Patent Document 3).

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

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0008] As described above, various antithrombotic medical materials have been developed. In particular, the antithrombotic material developed by the applicant of the present application can be easily used as a coating agent for medical devices that are dissolved in an alcohol solvent and come into contact with blood. However, the inventors of the present invention have found that the antithrombotic material developed by the applicant of the present application may become cloudy. When the antithrombotic material becomes cloudy, the visibility of symbols, numerical values, characters, etc. printed on the surface of the medical device may decrease, and it may be difficult to detect adhered foreign substances. In addition, when a transparent medical device is coated, the transparency decreases. Furthermore, there is also a possibility that the solubility in the solvent decreases. Therefore, an object of the present invention is to provide a method for producing an antithrombotic material with suppressed cloudiness, a method for producing a medical device coated with the antithrombotic material produced by the method, and an antithrombotic material with suppressed cloudiness.

Means for Solving the Problems

[0009] The inventors of the present invention have conducted intensive research to solve the above problems. As a result, it has been found that the cause of the cloudiness of the antithrombotic material is the oligomer of silicone (meth) acrylate used as a raw material, and that the cloudiness of the antithrombotic material can be suppressed by using an appropriate silicone (meth) acrylate as the raw material, thus completing the present invention. The present invention is shown 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 having a weight average molecular weight of 1450 or less is used.

[0011]

Chemical Formula

[0012] [In the formula, R 1 represents a hydrogen atom or a methyl group, R 2 is C 6-20An alkyl group, C 6-12 an aromatic hydrocarbon group, or C 6-12 an aromatic hydrocarbon-C 1-6 alkyl group, where R 3 represents a hydrogen atom or a methyl group, and R 4 represents a C 1-6 alkanediyl group, and R 5 represents a C 1-6 alkyl group, and R 6 represents a hydrogen atom or a methyl group, and R 7 represents a C 1-6 alkyl group, and 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 [1] above, wherein the weight average molecular weight is more than 1000. [3] The method according to [1] or [2] above, wherein 1.5 times mole or more and 2 times mole or less of the alkyl (meth) acrylate with respect to the alkoxypolyethylene glycol (meth) acrylate is used. [4] The method according to any one of [1] to [3] above, wherein 0.01 times mole or more and 0.1 times mole or less of the silicone (meth) acrylate with respect to the alkoxypolyethylene glycol (meth) acrylate is used. [5] The method according to [2] above, further comprising a step of concentrating the reaction solution of the copolymerization step under reduced pressure.

[0013] [6] A method for manufacturing a medical device that comes into contact with blood, comprising: a step of copolymerizing the alkyl (meth) acrylate represented by the formula (I), the silicone (meth) acrylate represented by the formula (II), and the alkoxypolyethylene glycol (meth) acrylate represented by the formula (III) to obtain a copolymer, and a step of applying the copolymer or a solution thereof to the surface of a medical device, A method characterized by using a silicone (meth) acrylate represented by the formula (II) having a weight average molecular weight of 1450 or less.

[0014] [7] containing a copolymer of the alkyl (meth) acrylate represented by the formula (I), the silicone (meth) acrylate represented by the formula (II), and the alkoxypolyethylene glycol (meth) acrylate represented by the formula (III), An antithrombotic material characterized by having a turbidity of 10 or less.

[0015] "C 1-6 The "alkyl group" refers to a linear, branched or cyclic monovalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, etc. R 5 is preferably a C 2-6 alkyl group, more preferably a C 3-5 alkyl group, most preferably n-butyl, and R 7 is preferably a C 1-4 alkyl group, more preferably a C 1-2 alkyl group, most preferably methyl.

[0016] "C 6-20"Alkyl group" refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 6 to 20 carbon atoms. For example, 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, 2-ethylheptyl, 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. Preferably, it is a C 8-12 alkyl group, more preferably a branched C 8-12 alkyl group.

[0017] "C 6-12 "Aromatic hydrocarbon group" refers to a monovalent aromatic hydrocarbon group having 6 to 12 carbon atoms. For example, phenyl, naphthyl, indenyl, biphenyl, etc., and preferably phenyl.

[0018] "C 6-12 aromatic hydrocarbon-C 1-6 alkyl group" is a C 6-12 alkyl group substituted with an aromatic hydrocarbon group. For example, benzyl, phenethyl, phenylpropyl, naphthylmethyl, naphthylethyl, biphenylmethyl can be mentioned, and benzyl is preferred. 1-6

[0019] "C 1-6 "Alkane diyl group" refers to a linear or branched divalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. For example, methylene, ethylene, methylmethylene, n-propylene, methylethylene, n-butylene, methylpropylene, dimethylethylene, n-pentylene, n-hexylene, etc. Preferably, it is a C 1-4 alkane diyl group, more preferably a C 3-4It is an alkanediyl group, most preferably n-propanediyl.

[0020] As m, 2 or more is preferable, 5 or more is more preferable, 8 or more is even more preferable, and 25 or less or 20 or less is preferable, 15 or less is more preferable, 12 or less is even more preferable.

[0021] As n, 8 or less is preferable, 5 or less is more preferable, 4 or 3 is even more preferable.

Advantages of the Invention

[0022] According to the method of the present invention, an antithrombotic material with suppressed turbidity can be produced. Since the antithrombotic material has a hydrophilic part, adhesion of platelets and adsorption of proteins are suppressed, and it exhibits antithrombotic properties. Also, since it has a water-repellent part, activation of complement is suppressed even when in contact with blood, and since it further has a hydrophobic part, it also shows affinity for the surface of medical devices that are also hydrophobic. Moreover, since the antithrombotic material produced by the method of the present invention has suppressed turbidity, it does not inhibit the visibility of the medical device surface and does not inhibit the transparency of transparent medical devices. Therefore, the present invention can impart antithrombotic properties and suppression of allergic reactions due to suppression of complement activation to medical devices, and also impart durability against blood contact to maintain these blood compatibilities, and is an extremely excellent technology in the industry for producing an antithrombotic material that does not inhibit the visibility of its surface, etc.

Brief Description of the Drawings

[0023]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0024] Hereinafter, a method for manufacturing an antithrombotic material and a method for manufacturing a medical device that comes into contact with blood according to the present invention will be described, but the present invention is not limited to the following specific examples and the like.

[0025] 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 1450 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)".

[0026] 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 suppresses the peeling of the copolymer from the medical device.

[0027] The alkyl (meth)acrylate (I) is not particularly limited. For example, linear alkyl (meth)acrylates such as normal hexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, lauryl (meth)acrylate, myristyl (meth)acrylate, palmityl (meth)acrylate, stearyl (meth)acrylate; branched alkyl (meth)acrylates such as 2-methylpentyl (meth)acrylate, 2-ethylbutyl (meth)acrylate, 2-methylhexyl (meth)acrylate, 2-ethylpentyl (meth)acrylate, 2-methylheptyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, 2-methyloctyl (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, 2-ethylmyristyl (meth)acrylate; cyclic alkyl (meth)acrylates such as cyclohexyl (meth)acrylate; phenyl (meth)acrylate, benzyl (meth)acrylate, etc. are mentioned. From the viewpoints of cost and performance, 2-ethylhexyl (meth)acrylate and lauryl (meth)acrylate are preferred. Also, from the viewpoint of affinity with the surface of medical devices, branched alkyl (meth)acrylates are preferred.

[0028] The silicone (meth)acrylate (II) imparts water repellency to the copolymer, reduces its surface energy, and suppresses the immune reaction in the blood resulting from the foreign body recognition and activation of the complement. The water repellency refers to the property of particularly repelling water among hydrophobic properties, which suppresses the adsorption and adhesion of blood proteins, and also reduces the affinity with blood mainly composed of water, and as a result, suppresses the activation of the complement.

[0029] As the dimethylsiloxane repeating unit m of the silicone (meth) acrylate (II), it is preferably 1 or more and 50 or less. If m is 50 or less, it is possible to prevent the viscosities of the resulting copolymer and its solution from becoming too high, and the handleability is high. On the other hand, if m is 1 or more, it is possible to prevent the viscosities of the resulting copolymer and its solution from becoming too low and not adhering to the surface of the medical device to be coated. As m, 2 or more is preferable, 5 or more is more preferable, 40 or less or 30 or less is preferable, and 20 or less or 15 or less is more preferable.

[0030] In the present invention, as the silicone (meth) acrylate (II), one having a weight average molecular weight of 1450 or less is used. According to the experimental findings of the present inventors, if the weight average molecular weight is 1450 or less, the cloudiness of the resulting copolymer and its solution can be sufficiently suppressed. Specifically, the turbidity of the copolymer and its solution can be made 10 or less. As the weight average molecular weight, 1400 or less is preferable, 1300 or less is more preferable, and 1200 or less is even more preferable. 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, so it may not be possible to concentrate under reduced pressure. Therefore, as the weight average molecular weight, more than 1000 is preferable, 1050 or more is more preferable, and 1100 or more is even more preferable.

[0031] As the average molecular weight of a polymer, generally, the number average molecular weight and the weight average molecular weight are used. The number average molecular weight is the sum of the products of the molecular weight M i and the number N i of the molecules having that molecular weight, divided by the number of molecules N i , and represents the simple average of the molecular weights of a single polymer chain contained in the polymer aggregate, corresponding to the mass per mole (g / mol). In contrast, the weight average molecular weight is M i 2 ×N i divided by M i ×N iIt is the sum of the numbers divided by [the number], that is, it corresponds to the sum of the amounts obtained by multiplying the molecular weight of each polymer by its weight fraction. Compared with the number-average molecular weight, if the proportion of high-molecular-weight polymers with a large contribution to physical properties is large, the value of the weight-average molecular weight will be large. Therefore, it can be said that there is a high correlation with the physical properties of the polymer aggregate. As methods for measuring the weight-average molecular weight, there are end-group determination method, osmotic pressure method, vapor pressure osmometry, vapor pressure lowering method, freezing point depression method, boiling point elevation method, gel permeation chromatography (GPC) method, etc. In the present invention, the conventional method of gel permeation chromatography (GPC) method is adopted in terms of ease of operation.

[0032] As can be seen from its basic skeleton, silicone has excellent heat resistance and cold resistance and also has a low glass transition temperature (Tg), so it has the advantage of being able to exhibit stable properties in various temperature ranges. In addition, due to its large bond energy, it has acid and alkali resistance and has the advantage of high chemical stability. 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)acrylate has also been recognized in recent years as a material with high safety for living bodies, such as being adopted as a material for contact lenses. Therefore, it is considered that the content of silicone (meth)acrylate (II) in the antithrombotic material will not cause a problem even if it is too much. However, at present, since the raw material price of silicone (meth)acrylate (II) is relatively high, considering performance, quality, cost, etc. comprehensively, the proportion of silicone (meth)acrylate (II) to the total of alkyl (meth)acrylate (I) and silicone (meth)acrylate (II) can be said to be sufficient if it is contained at 50% by mass or less. As the proportion, 40% by mass or less is preferable, and 35% by mass or less is more preferable. On the other hand, from the viewpoint of the long-term stability of the copolymer, the proportion of silicone (meth)acrylate (II) to the total of alkyl (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.

[0033] Alkoxypolyethylene glycol (meth)acrylate (III) imparts hydrophilicity to the copolymer, suppresses the adhesion and subsequent activation of platelets in the blood, and suppresses protein adsorption.

[0034] In alkoxypolyethylene 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, sufficient hydrophilicity can be imparted to the copolymer, and if n is 10 or less, the elution of the copolymer into the blood and the detachment from the medical device can be sufficiently suppressed. More preferably, n is 5 or less, and even more preferably 3 or 4.

[0035] Specific examples of 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, methoxydecaethylene glycol (meth)acrylate, and the like.

[0036] The usage amounts of alkoxypolyethylene glycol (meth)acrylate (III) and alkyl (meth)acrylate (I) may be adjusted as appropriate. For example, the molar ratio of alkyl (meth)acrylate (I) to 1 mol of alkoxypolyethylene glycol (meth)acrylate (III) can be set to 0.5 or more and 2.5 or less. If the molar ratio is within the above range, the balance between the hydrophilic part and the hydrophobic part in the antithrombotic material will be good, suppressing the adsorption of platelets and blood proteins on the surface of the medical device in the blood, while ensuring the affinity between the surface of the medical device and the antithrombotic material, and it becomes possible to suppress the elution of the antithrombotic material into the blood and the non-uniformity of the coating. As the ratio, 1 or more is preferable, 1.2 or more or 1.4 or more is more preferable, 1.5 or more is even more preferable, and 2.2 or less is preferable, 2 or less is more preferable.

[0037] The usage amounts of alkoxypolyethylene glycol (meth)acrylate (III) and silicone (meth)acrylate (II) may also be adjusted as appropriate. For example, the molar ratio of silicone (meth)acrylate (II) to 1 mol of alkoxypolyethylene glycol (meth)acrylate (III) can be set to 0.001 or more and 1 or less. If the molar ratio is within the above range, while suppressing the adsorption of platelets and blood proteins on the surface of the medical device in the blood, it is also possible to suppress the activation of complement by the antithrombotic material, and thus it becomes possible to suppress an excessive immune reaction. As the ratio, 0.005 or more is preferable, 0.01 or more is more preferable, and 0.5 or less is preferable, 0.1 or less is more preferable.

[0038] In this step, alkyl (meth)acrylate (I), silicone (meth)acrylate (II), and alkoxypolyethylene glycol (meth)acrylate (III) are copolymerized in a solvent. There are no particular restrictions on the copolymerization reaction itself for producing the antithrombotic material of the present invention, and known methods such as radical polymerization, ionic polymerization, photopolymerization, and polymerization using macromers can be used, but radical polymerization using a radical initiator is preferable.

[0039] As solvents used during copolymerization, 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; water, etc. can be used. From the perspectives of the solubility of the monomers and the resulting copolymer and the ease of availability, it is preferable to use ethyl acetate, methanol, ethanol, etc. Also, a plurality of these solvents can be mixed and used.

[0040] The amount of the solvent used can be adjusted as appropriate. For example, it can be adjusted to be 0.3 times or more and 10 times or less by mass based on the total amount of the monomers. As this ratio, 0.5 times or more and 5 times or less by mass is preferable.

[0041] As radical initiators, generally peroxide-based or azo-based radical initiators used in radical polymerization are used. Examples of peroxide-based radical initiators include inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide; 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, dimethyl 2,2'-azobis(2-methylpropionate), etc. Also, redox initiators in which a reducing agent is combined with a peroxide-based initiator can be used.

[0042] The amount of the radical initiator used can be adjusted as appropriate. For example, it can be adjusted to be 0.01% or more and 1% or less by mass based on the total amount of the monomers. As this ratio, 0.05% or more is preferable, 0.5% or less is preferable, and 0.3% or less is more preferable.

[0043] Specifically, for example, in a stirrable reactor equipped with a reflux column, each monomer, polymerization solvent, and radical initiator are added. After replacing the gas phase with nitrogen, heating is carried out to initiate polymerization, and polymerization is allowed to proceed by maintaining that temperature for a certain period of time. It is also possible to control the molecular weight by using a chain transfer agent in combination during polymerization. Examples of the chain transfer agent used for controlling the molecular weight during polymerization include high-boiling thiol compounds such as dodecyl mercaptan, thiomalic acid, and thioglycolic acid, and isopropyl alcohol, phosphorous acid, hypophosphorous acid, etc. can also be used.

[0044] The temperature during polymerization varies depending on the types of the solvent, radical initiator, etc. For example, it is preferably adjusted to around the 10-hour half-life temperature of the radical initiator. Specifically, when using the radical initiator, it can be adjusted to 20°C or higher and 90°C or lower. As the temperature, 30°C or higher is preferable, and 40°C or higher is more preferable. The polymerization reaction time can also be adjusted as appropriate. For example, it can be until any monomer is consumed by chromatography or the like, or determined by preliminary experiments. Specifically, it can be 1 hour or more and 10 hours or less.

[0045] After the polymerization reaction, the solvent is removed to obtain a crude (meth)acrylate copolymer. At this time, if a silicone (meth)acrylate (II) with an excessively small weight average molecular weight is used for the purpose of suppressing the turbidity of the antithrombotic material, the reaction solution may foam and overflow from the container during concentration under reduced pressure, so it may not be possible to concentrate under reduced pressure. Therefore, by using a silicone (meth)acrylate (II) with a weight average molecular weight exceeding 1000, such foaming can be more reliably suppressed, and concentration under reduced pressure can be carried out well.

[0046] Following the removal of the solvent, the obtained crude (meth)acrylate copolymer is stirred in a poor solvent and then the poor solvent is removed for purification. The purification treatment is repeated 1 to several times to increase the purity of the (meth)acrylate copolymer. The copolymer thus obtained is dried.

[0047] In the present invention, since the (meth)acrylate copolymer is formed by copolymerizing hydrophilic and hydrophobic monomers, it has both hydrophilic and hydrophobic properties. Therefore, in the solution after the polymerization reaction, there are mixed hydrophilic monomers (methoxypolyethylene glycol (meth)acrylate) and hydrophobic monomers (silicone (meth)acrylate and alkyl (meth)acrylate), which are unreacted monomers, and the (meth)acrylate copolymer. In order to isolate the water-insoluble (meth)acrylate copolymer from these mixtures, for example, the copolymer solution is 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. Further, the (meth)acrylate copolymer can be efficiently recovered by using a reprecipitation poor solvent obtained by mixing alcohol and water at a specific ratio. Furthermore, after adding a poor solvent to the water-insoluble (meth)acrylate copolymer composed of a mixed solution of a specific ratio of alcohol and water in the solution in which the polymerization reaction is completed and stirring at a constant temperature, the (meth)acrylate copolymer is separated, and then the precipitate is recovered by decantation, and a purification method can be adopted by repeating the same method by adding a washing solution.

[0048] In the present invention, as the poor solvent used 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.

[0049] In the present invention, as the alcohol used for the reprecipitation treatment, it is preferable to use an alcohol having 1 to 10 carbon atoms, more preferably an alcohol having 1 to 7 carbon atoms, and still 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, tertiary butanol, etc. However, since drying can be performed at low temperature and in a short time, methanol, ethanol, 1-propanol, and 2-propanol are more preferable.

[0050] The amount of the poor solvent may be appropriately adjusted within the range where the copolymer can be sufficiently purified. For example, the volume ratio to the crude (meth)acrylate copolymer is preferably 1 or more and 20 or less, more preferably 5 or less.

[0051] The temperature during the purification of the crude (meth)acrylate copolymer of the present invention is preferably 30°C or higher and 60°C or lower, more preferably 40°C or higher and 60°C or lower. If the temperature during purification is within the above range, the viscosity of the crude (meth)acrylate copolymer will decrease due to heating, making it easier to separate from the poor solvent, and the recovery rate of the (meth)acrylate copolymer can be maximally increased.

[0052] 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, it can be said that the production efficiency is relatively high. If it is 90% by mass or less, the mixing of unreacted monomers can be sufficiently suppressed. Note that adjusting the recovery rate within the above range also means that the copolymer will be slightly lost or discarded, but this is inevitable considering that it is necessary to prevent the mixing of unreacted monomers as much as possible. This is because, due to the specific situation that the copolymer has both hydrophilic and hydrophobic properties applicable to medical devices, such considerations must be taken for granted.

[0053] In the present invention, the amount of residual monomer, that is, the amount of unreacted monomer in the polymerization, is important because it is related to safety. By reducing the amount of residual monomer in the antithrombotic material, it is natural to meet the standards shown in the guidelines regarding elution from medical devices. However, by setting the amount of residual monomer to a very low level of 4,000 ppm or less, it has led to an unexpected effect of enhancing the adhesion and retention of the antithrombotic material on the surface of medical devices. Also, the ratio of the obtained copolymer amount to the monomer input amount is represented as the recovery rate.

[0054] By performing the purification process as described above once, or if necessary, two or more times and eight or fewer times, it becomes 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. When the contents of unreacted monomers, oligomers, and polymerization residues contained in the copolymer are high, it is conceivable that they elute into the blood and become causative substances for symptoms such as shock in patients. Although most of these causative substances can be removed by the purification process, considering the safety of patients, it is more preferable to reduce their content to 3,000 ppm or less, even more preferably 2,000 ppm or less, and particularly preferably 1,000 ppm or less.

[0055] In order to use the purified copolymer for imparting antithrombogenicity to medical devices, it is necessary to remove the solvent by drying. As the drying method, for example, it can be carried out under reduced pressure of 1 Torr or less at 60 °C, and if sufficient drying cannot be obtained, subsequent vacuum drying may be performed.

[0056] In the present invention, the copolymer obtained by copolymerizing alkyl (meth)acrylate (I), silicone (meth)acrylate (II), and alkoxypolyethylene glycol (meth)acrylate (III) preferably has durability against blood contact and is in a liquid state having viscosity at room temperature. Here, having durability against blood contact means that when the (meth)acrylate copolymer is immersed in the following alcohol immersion treatment liquid at room temperature for 16 hours, the (meth)acrylate copolymer remains at a certain level or more and exhibits antithrombogenicity. If a predetermined amount of the (meth)acrylate copolymer remains after immersion in the alcohol immersion treatment liquid at room temperature for 16 hours, it can be judged that it has sufficient antithrombogenicity even when contacted with blood at 37 °C for 30 days. Also, since it is liquid at room temperature but has viscosity, there is an advantage that elution into the blood is suppressed when used by coating medical devices and the like.

[0057] In addition, the copolymer produced by the method of the present invention is suppressed from becoming turbid and has excellent transparency. Specifically, the turbidity of the copolymer and the antithrombotic material according to the present invention is suppressed to 10 or less. In the present disclosure, "turbidity" refers to the turbidity measured according to the method defined in JIS K0101:2017 Industrial Water Test Method and the eighteenth revised Japanese Pharmacopoeia. Specifically, the absorbance at 660 nm of the turbidity standard solution is measured to create a calibration curve, and the absorbance at 660 nm of the copolymer and the antithrombotic material according to the present invention is measured, and the turbidity of the copolymer and the antithrombotic material according to the present invention is determined from the measured value using the calibration curve. As the turbidity, 8 or less or 6 or less is preferable, 5 or less, 4 or less, or 3 or less is more preferable, and 2 or less, 1.5 or less, or 1 or less is even more preferable.

[0058] As a method for confirming the durability of the antithrombotic material according to the present invention against blood elution, alcohol immersion treatment at room temperature can be mentioned. As the alcohol, it is preferable to use a mixed solvent of methanol and ethanol. For example, since a solvent obtained by mixing methanol and ethanol at 80 / 20 (mass ratio) is slightly stronger than the blood elution power, the durability of the antithrombotic property can be evaluated by immersing the antithrombotic material in the mixed solvent for 16 hours.

[0059] In the present invention, the (meth)acrylate copolymer has the property of not dissolving in methanol but dissolving in ethanol. When methanol and ethanol are mixed at a predetermined ratio as an alcohol immersion treatment solution for confirming the durability (persistence of antithrombotic property) 30 days after blood contact at 37°C, the durability 30 days after blood contact at 37°C can be confirmed even in a short time of 16 hours. The mass ratio of methanol to ethanol in the alcohol immersion treatment solution is preferably methanol:ethanol = 90 to 60:10 to 40, and more preferably 90 to 70:10 to 30. In the test using the evaluation sheet described later, if the adhesion of blood clots is small, that is, the number of blood clot adhesions after solvent immersion is 1 or less out of 10 evaluation sheets, and the (meth)acrylate copolymer remains at 0.1 μg / cm 2 If it remains above, it can be determined that there is sufficient durability.

[0060] In the present invention, as one of the methods for evaluating the blood compatibility of the copolymer, a blood coagulation test can be mentioned. Specifically, it utilizes the reaction in which fibrin in plasma gels with calcium ions to form a fibrin gel. In the calcium ion-added plasma that has come into contact with the sample, the blood compatibility of the polymer can be confirmed by checking the presence or absence of blood clot adhesion after immersion in water. For example, when one side of a polycarbonate sheet is immersed in an ethanol solution of the copolymer and dried to obtain an evaluation sheet, if the number of evaluation sheets with confirmed blood clot adhesion is 4 or less out of 10, it can be determined that the blood compatibility is good.

[0061] Specific examples of representative ones belonging to the (meth)acrylate copolymer 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, silicone (meth)acrylate-cyclohexyl (meth)acrylate-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 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, silicone (meth)acrylate-stearyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-stearyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-stearyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-lauryl (meth)acrylate-methoxydiethylene glycol (meth)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 - myristyl (meth) acrylate - methoxydiethylene glycol (meth) acrylate copolymer, silicone (meth) acrylate - myristyl (meth) acrylate - methoxytriethylene glycol (meth) acrylate copolymer, silicone (meth) acrylate - myristyl (meth) acrylate - methoxytetraethylene glycol (meth) acrylate copolymer can be mentioned. The copolymer according to the present invention is not limited thereto, and further, (meth) acrylate copolymer of alkyl (meth) acrylate (I): silicone (meth) acrylate (II): methoxypolyethylene glycol (meth) acrylate (III) = 80 - 20:10 - 0.01:10 - 79.99 (molar ratio) can be mentioned. The units of alkyl (meth) acrylate (I) and silicone (meth) acrylate (II), which are hydrophobic (meth) acrylates, suppress the elution of the copolymer into the blood, enhance the durability against blood, and also enhance the affinity to the surface of medical devices. Further, the units of alkoxypolyethylene glycol (meth) acrylate (III), which is a hydrophilic (meth) acrylate, suppress the adhesion of platelets and proteins. Therefore, as the molar ratio, 80 - 50:5 - 0.01:15 - 49.99 is preferable, 77 - 55:5 - 0.01:18 - 44.99 is more preferable, and 73 - 57:5 - 0.01:22 - 42.99 is even more preferable.

[0062] 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 the blood is sufficiently suppressed, and the strength and stability of the coating film can be more reliably ensured. Further, if the weight average molecular weight is 1,500,000 or less, the 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.

[0063] 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 in such a viscosity range, when coating medical devices such as cardiopulmonary bypass circuits and catheters, the copolymer has excellent adhesiveness to the medical device, and the antithrombotic property can be maintained during long-term 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.

[0064] The antithrombotic material of the present invention may be any of a random copolymer, a block copolymer, and a graft copolymer. The (meth)acrylate copolymer according to the present invention may be a copolymer in which each monomer is alternately arranged, but when analyzed from the total amount, it may also be a copolymer composed of a segment or block made of a hydrophobic monomer and a segment or block made of a hydrophilic monomer. It can be tentatively assumed that the segment or block made of a hydrophobic monomer may adopt a complex structure such as a so-called microphase separation structure or a structure like a mosaic pattern, which functions to fix the segment or block made of a hydrophilic monomer. Anyway, although the molecular weight of the copolymer, the type and properties of the hydrophilic monomer, etc. will also have some influence, if the amount of the hydrophobic monomer is slightly increased, the elution of the segment or block made of the hydrophilic monomer of the copolymer can be suppressed. Also, increasing the amount of this hydrophobic segment is thought to also function to increase the affinity with hydrophobic medical devices, and it can be assumed that it will play an advantageous role in fixing to medical devices as a coating. However, regarding the behavior regarding the presence or absence of the segment and its affinity state, at present, it cannot be accurately verified based on technical grounds, but the copolymer is a polymer material with excellent biocompatibility.

[0065] The homopolymer of alkoxypolyethylene glycol (meth)acrylate (III) has high hydrophilicity and thus excellent blood compatibility, but since it is water-soluble, there is a problem that it gradually elutes when in contact with blood or the like for a long time. As a result of intensive studies on a material that not only has excellent blood compatibility but also can withstand long-term use, the present inventors have found that a copolymer obtained by imparting appropriate hydrophobicity to prevent elution into blood or the like and flexibility to prevent physical film peeling of the coating film can solve this problem.

[0066] Thus, the copolymer according to the present invention is substantially composed of two types of monomer components that perform so-called interface functions on two different sides, namely, a hydrophilic monomer, segment, or block having functions such as antithrombogenicity and elution prevention with respect to blood, and a hydrophobic monomer, segment, or block having functions such as affinity and adhesiveness with respect to medical devices. On the other hand, the monomers, segments, or blocks constituting the copolymer seem to complement each other within the molecular structure and form stable molecular bonds or structures against elution, dispersion, and the like.

[0067] The (meth)acrylate copolymer according to the present invention is preferably soluble in any of the alcohols having 1 to 6 carbon atoms. It is more preferable to be soluble in an alcohol having 1 to 3 carbon atoms because drying after coating becomes easier. Here, being 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.

[0068] The antithrombotic material made of a (meth)acrylate copolymer according to the present invention may contain substances such as antibacterial substances.The antibacterial substance is not particularly limited. For example, antibiotics such as ampicillin, nafcillin, amoxicillin, oxacillin, azlocillin, penicillin G, carbenicillin, penicillin V, dicloxacillin, phenethicillin, floxacillin, piperacillin, mecillinam, sulbenicillin, methicillin, ticarcillin, mezlocillin, cefaclor, cephalothin, cefadroxil, cepapirin, cefamandole, cefradine, cefatrizine, cefroxadine, cefazolin, ceftazidime, ceforanide, ceftriaxone, cefoxitin, cefuroxime, cefacetrile, latamoxef, cephalexin, amikacin, neomycin, dibekacin, kanamycin, gentamicin, netilmicin, tobramycin, amphotericin B, novobiocin, bacitracin, nystatin, clindamycin, polymyxin, colistin, lovastatin, erythromycin, streptomycin, spectinomycin, lincomycin, vancomycin, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, doxycycline, tetracycline, minocycline, etc.; antifungal agents such as amphotericin B, ketoconazole, clotrimazole, miconazole, econazole, natamycin, flucytosine, nystatin, griseofulvin, etc.; paraoxybenzoic acid esters such as isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, etc.; biguanide compounds such as chlorhexidine, etc.; compounds with surface activity such as benzethonium, benzalkonium, lauryl sulfate, alkyl polyaminoethyl glycine, fatty acids, domiphen bromide, etc.; phenolic derivatives such as thymol, phenol, hexachlorophene, resorcinol, etc.; boric acid compounds such as boric acid, borax, etc.; iodine compounds such as iodine, iodoform, povidone iodine, etc.; metals such as gold, silver, copper, mercury, etc.; metal compounds such as thimerosal, methyl bromide, silver sulfadiazine, etc.; antibacterial dye compounds such as acrinol, methylrosaniline, etc.; sulfonamides such as mafenide acetate, sulfadiazine, sulfisomidine, sulfamethoxazole, etc.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 antibacterial substances may also be used in combination.

[0069] The antibacterial substances can be roughly classified into water-soluble and poorly water-soluble ones. Representative examples of water-soluble antibacterial substances include benzalkonium chloride, povidone iodine, penicillin G potassium, streptomycin sulfate, etc. Representative examples of poorly water-soluble antibacterial substances include silver sulfadiazine, chlorhexidine, etc.

[0070] 2. Coating process In this process, after applying the copolymer according to the present invention or its solution to the surface of a medical device, it is dried as necessary. Since the antithrombotic material according to the present invention exhibits an action of suppressing the adsorption of platelets and proteins and an action of suppressing the activity of maintaining the body, and also has resistance to blood and affinity for a hydrophobic surface, by coating a medical device with the antithrombotic material according to the present invention, it becomes possible to impart these properties to the medical device as well.

[0071] As a method for supporting the antithrombotic material of the present invention on the surface of a substrate such as a medical device, known methods such as a coating method, a method using graft polymerization by radiation, electron beam, or ultraviolet ray, and a method using a chemical reaction with a functional group of the substrate can be mentioned. Among them, the coating method is preferably practical because the manufacturing process is easy. For example, a medical device can be coated by applying a solution obtained by dissolving the antithrombotic material according to the present invention in an organic solvent to the surface of a substrate such as a medical device and then removing the solvent. The coating method is not particularly limited, and coating methods, spraying methods, dipping methods, etc. can be used. Also, it is preferable to heat the coated substrate to dry it. Thereby, the adhesiveness between the substrate and the antithrombotic material of the present invention can be further enhanced, and it can be fixed more firmly.

[0072] As the organic solvent for the coating solution, one that causes as little damage as possible to the medical device serving as the base material is selected. Specifically, 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; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone are used. Among these, methanol, ethanol, and 2-propanol, which have a low boiling point and are easy to dry after coating, are more preferable.

[0073] The concentration of the (meth)acrylate copolymer in the solution of the antithrombotic material according to the present invention may be adjusted as appropriate. For example, it can be 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. If it is 10% by mass or less, the viscosity of the solution will not become excessively high and the workability is excellent. As the concentration, 0.01% by mass or more and 5% by mass or less is preferable.

[0074] As a method for quantifying the coating amount of the antithrombotic material, quantification by NMR can be mentioned. Specifically, it is a method in which a base material coated with the antithrombotic material is extracted with ethanol, the extract is dried, and then NMR measurement is performed, and the coating amount is calculated from the area of the corresponding peak. The durability can also be evaluated by comparing the coating amounts before and after the alcohol immersion treatment. Specifically, if the remaining amount of the (meth)acrylate copolymer after immersing the evaluation sheet in 99.5% by mass ethanol is 3.0 μg / cm 2 or more, it can be determined that the antithrombotic property at the initial stage of blood contact can be sufficiently exhibited.

[0075] A medical device with at least a part of its surface coated with the antithrombotic material of the present invention can exhibit excellent antithrombotic properties. Such medical devices include, for example, blood filters, blood storage containers, blood circuits, indwelling needles, catheters, guidewires, stents, artificial lung devices, dialysis devices, adhesion prevention materials, wound dressing materials, biological tissue adhesives, and repair materials for biological tissue regeneration. In particular, a medical device having an extracorporeal circulation circuit and a blood contact portion therein is a preferred embodiment.

[0076] The base materials of medical devices include all materials commonly used. For example, polyvinyl chloride, polycarbonate, polyethylene terephthalate, polyethylene, polypropylene, poly-4-methylpentene-1, thermoplastic polyether polyurethane, thermosetting polyurethane, silicone rubbers such as polydimethylsiloxane having crosslinked 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, etc. are mentioned. In addition to balancing the material composition, molecular weight, viscosity, etc., the antithrombotic material of the present invention can uniformly and firmly coat regardless of the material, shape, surface properties, etc. of the material to be coated because the coating conditions are optimized.

[0077] In the present invention, when a medical device or the like is coated with the antithrombotic substance (copolymer) according to the present invention and a poorly water-soluble antibacterial substance, the elution of the antibacterial substance becomes extremely small and continuous, and long-term antibacterial properties can be maintained, although it is unclear whether this is because the copolymer is water-insoluble or because the water-insolubility of the copolymer and the poor water-solubility of the antibacterial substance function complementarily. On the other hand, when the copolymer and a water-soluble antibacterial substance are coated, the copolymer is water-insoluble, but the antibacterial substance is water-soluble, so the elution amount is greater than that when a poorly water-soluble antibacterial substance is used, and although instantaneous strong antibacterial properties can be expressed, long-term antibacterial properties cannot be maintained. For example, intravascular catheters, infusion tubes, artificial lungs, etc. are medical devices that are used continuously for one to several days, and long-term antibacterial properties are required for such applications. In addition, by using a water-soluble antibacterial substance and a poorly water-soluble antibacterial substance in combination with the copolymer, it is also possible to impart multi-stage antibacterial properties, such as initially exerting strong bactericidal power by the water-soluble antibacterial substance and then exerting long-term antibacterial properties by the poorly water-soluble antibacterial substance. If this multi-stage antibacterial property is applied to an intravascular catheter, the water-soluble antibacterial substance will be eluted early and will exhibit strong antibacterial properties, thereby sterilizing the normal skin bacteria that may be brought into the blood vessel 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 will be able to prevent bacteria from settling on the catheter and the proliferation of bacteria that have invaded from the insertion site, reducing the risk of infection during placement.

[0078] In the present invention, the proportion of the antibacterial substance is preferably 0.01% by mass or more and 70% by mass or less with respect to the mass of the antithrombotic material. If the proportion is 0.01% by mass or more, the antibacterial property of the antibacterial substance is more surely exhibited. If it is 70% by mass or less, appearance defects of the medical device after surface treatment such as coating, elution of the antibacterial substance into the body, and local inflammation caused thereby can be more surely suppressed. As the proportion, more preferably 0.05% by mass or more, still more preferably 0.1% by mass or more, and more preferably 50% by mass or less or 30% by mass or less, still more preferably 10% by mass or less. Further, the antibacterial substance may be present throughout the entire surface of the medical device, but it is preferable to be present only in the vicinity of the insertion portion penetrating the skin in terms of suppressing local inflammation.

[0079] The (meth)acrylate copolymer obtained by copolymerizing the alkyl (meth)acrylate (I), silicone (meth)acrylate (II), and alkoxypolyethylene glycol (meth)acrylate (III) according to the present invention has appropriately balanced hydrophilicity and hydrophobicity, and thus can be suitably used as a blood-compatible material. Further, since adsorption and adhesion of platelets, blood proteins, etc. can be suppressed, it can be suitably used as a treatment material for medical devices. Further, the (meth)acrylate copolymer of the present invention can be used alone or in combination of two or more.

[0080] When the medical device treated with the present antithrombotic material comes into contact with blood, presumably, the highly hydrophilic alkoxypolyethylene glycol (meth)acrylate (III) protrudes to the surface and exhibits antithrombotic properties, and the hydrophobic alkyl (meth)acrylate (I), silicone (meth)acrylate (II), and (meth)acrylate are considered to prevent direct contact between the blood and the medical device by staying near the base material.

Examples

[0081] Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, and it is of course possible to appropriately modify and implement it within the scope that conforms to the gist of the foregoing and following descriptions, and all of them are included in the technical scope of the present invention.

[0082] 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. To 471.3 g of methoxytriethylene glycol acrylate (MTEGA) (manufactured by Shin-Nakamura Chemical Co., Ltd.), 78.0 g of each PDMSMA, and 693.3 g of 2-ethylhexyl acrylate (EHA) (manufactured by Toagosei Co., Ltd.), 1.23 g of azobisisobutyronitrile (AIBN) (manufactured by Fujifilm Wako Pure Chemical Corporation) was added, and a polymerization reaction was carried out at 85 °C for 3 hours in 1615.4 g of ethanol (manufactured by Kishida Chemical Co., Ltd.). After the polymerization reaction was completed, drying was carried out at 85 °C for 2 hours under normal pressure, and then drying was carried out at 60 °C for 40 minutes under reduced pressure to obtain a concentrate. To 1234.8 g of the concentrate, 6320.0 g of methanol (manufactured by Kishida Chemical Co., Ltd.) and 600.0 g of water were added, and the mixture was stirred for 20 minutes. After the stirring was completed, 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 this precipitate, and the mixture was stirred for 20 minutes. After standing for 1.5 hours, the operation of removing the supernatant by decantation was repeated 3 times in the same manner to wash the precipitate. The washed precipitate was dried under reduced pressure at 40 °C for 1 hour to obtain a copolymer.

[0083] (2) Turbidity evaluation A turbidity standard solution for turbidity test containing kaolin particles (「Turbidity Standard Solution (Turbidity: 100 degrees)」 manufactured by Fujifilm Wako Pure Chemical Corporation) was diluted with distilled water to prepare a turbidity specimen of 0 to 50 degrees (kaolin). Using an absorptiometer (「UV-1700」 manufactured by Shimadzu Corporation), based on JIS K0101:2017 Industrial Water Test Method and the 18th Revised Japanese Pharmacopoeia, the absorbance at 660 nm of the turbidity specimen was measured. When the absorbance and turbidity were plotted, an approximate formula of y = 382.38x + 0.1836 was obtained, and its determination coefficient R2 It was as high as 0.9992, indicating that there is a proportional relationship between the measured absorbance and turbidity. The absorbance at 660 nm of each copolymer (1 mL) obtained in Example 1(1) was similarly measured, and the turbidity was determined from the calibration curve. The results are shown in Table 1.

[0084]

Table 1

[0085] As shown in the results in Table 1, when the weight-average molecular weight of the raw material PDMSMA is large, the solution of the copolymer tends to become turbid, and there is also a measurement error in the low absorbance range. However, it was demonstrated that at least when the weight-average molecular weight of the raw material PDMSMA is 1376 or less, the turbidity of the copolymer can be significantly reduced. 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 is necessary to use PDMSMA with a weight-average molecular weight of 1450 or less.

[0086] (3) Analysis The raw material PDMSMA of the turbid copolymer 2 and the raw material PDMSMA of the transparent copolymer 4 were 1 analyzed by 1H NMR. The results are shown in Figure 2. As shown in the results in Figure 2, in the NMR chart of the raw material PDMSMA of the turbid copolymer 2, the peak around 4 ppm was broad compared to the raw material PDMSMA of the transparent copolymer 4. Since such a peak is the peak of the methyl group of the dimethylsiloxane group, it is considered that PDMSMAs with a large weight-average molecular weight are likely to polymerize with each other, and the generated oligomers precipitate from the copolymer 2, possibly causing turbidity. Therefore, it was shown that in order to suppress the turbidity of 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 alkoxypolyethylene glycol (meth)acrylate represented by the following formula (III), wherein the silicone (meth)acrylate having a weight-average molecular weight of 1450 or less is used. 【Chemical Formula 1】 [In the formula, R 1 represents a hydrogen atom or a methyl group, R 2 is a C 6-20 alkyl group, a C 6-12 aromatic hydrocarbon group, or a C 6-12 aromatic hydrocarbon-C 1-6 alkyl group, R 3 represents a hydrogen atom or a methyl group, R 4 is a C 1-6 alkanediyl group, R 5 is a C 1-6 alkyl group, R 6 represents a hydrogen atom or a methyl group, R 7 is a C 1-6 alkyl group, m represents an integer of 1 or more and 50 or less, n represents an integer of 2 or more and 10 or less. ]

2. The method according to claim 1, wherein the weight-average molecular weight is more than 1000.

3. The method according to claim 1, wherein 1.5 times mole or more and 2 times mole or less of the alkyl (meth)acrylate is used with respect to the alkoxypolyethylene 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 the molar amount of 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 manufacturing a medical device that comes into contact with blood, 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) to obtain a copolymer, and A step of applying the copolymer or a solution thereof to the surface of a medical device, The method is characterized in that, as the silicone (meth) acrylate represented by the formula (II), one having a weight average molecular weight of 1450 or less is used. 【Chemical formula 2】 [In the formula, R 1 represents a hydrogen atom or a methyl group, R 2 is a C 6-20 alkyl group, a C 6-12 aromatic hydrocarbon group, or a C 6-12 aromatic hydrocarbon-C 1-6 alkyl group, R 3 represents a hydrogen atom or a methyl group, R 4 is a C 1-6 alkanediyl group, R 5 is a C 1-6 alkyl group, R 6 represents a hydrogen atom or a methyl group, R 7 is a C 1-6 alkyl group, m represents an integer of 1 or more and 50 or less, n represents an integer of 2 or more and 10 or less. ]

7. A copolymer containing 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), An antithrombotic material characterized by having a turbidity of 10 or less. 【Chemical Formula 3】 [In the formula, R 1 represents a hydrogen atom or a methyl group, R 2 is a C 6-20 alkyl group, a C 6-12 aromatic hydrocarbon group, or a C 6-12 aromatic hydrocarbon-C 1-6 alkyl group, R 3 represents a hydrogen atom or a methyl group, R 4 is a C 1-6 alkanediyl group, R 5 is a C 1-6 alkyl group, R 6 represents a hydrogen atom or a methyl group, R 7 is a C 1-6 alkyl group, m represents an integer of 1 or more and 50 or less, n represents an integer of 2 or more and 10 or less. ]

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