Manufacturing method of antithrombotic medical equipment

Abstract

The present invention addresses the problem of providing a method for coating an antithrombotic material, which is capable of suppressing dimensional changes such as swelling and contraction of a medical device when imparting antithrombotic properties to a polyurethane medical device such as a catheter. The present invention relates to a method for manufacturing an antithrombotic medical device. The present invention relates to a method for preparing a medical device, comprising a step for preparing an aliphatic hydrocarbon solution by dissolving an antithrombotic material containing a (meth) acrylate copolymer in an aliphatic hydrocarbon solvent, a step for applying the aliphatic hydrocarbon solution to the medical device, and a step for removing the aliphatic hydrocarbon solvent from the surface of the medical device, the medical device being made of a polyurethane.

Description

Technical Field

[0001] The present invention relates to a technology for coating at least a portion of a body fluid contact portion of a medical device such as a catheter with an antithrombotic material containing a (meth)acrylate copolymer. Background Art

[0002] Catheters are medical devices placed in the body for diagnostic and therapeutic purposes. Examples include central venous infusion catheters, intravenous catheters, epidural anesthesia catheters, cardiac output monitoring catheters, and nutritional catheters. These catheters are used to administer infusions such as saline, electrolytes, nutrients, and medications, blood transfusions, and anesthetics. They are also used to collect blood and measure blood composition, cardiac output, regional blood pressure, and blood gas analysis.

[0003] Intravascular catheters use materials such as silicone resins, vinyl chloride resins, nylon, polyolefins, and ethylene tetrafluoroethylene. However, these catheters can sometimes cause inflammatory reactions and generate reactive oxygen species and hydrolytic enzymes when placed in the body. Consequently, these materials are susceptible to biodegradation over time due to hydrolysis and reactive oxygen species in the body, making them often unsuitable for long-term placement in the body. When these catheters and other medical devices are used in contact with blood, three key factors for biocompatibility are (a) inhibition of the blood coagulation system, (b) inhibition of platelet adhesion and activation, and (c) inhibition of complement activation.

[0004] In order to improve biocompatibility, Patent Document 1 discloses an antithrombotic material comprising an alkyl (meth)acrylate, a silicone (meth)acrylate, and a methoxypolyethylene glycol (meth)acrylate. Furthermore, Patent Document 1 discloses a dispersion for treating medical materials in which the antithrombotic material is dispersed at a concentration of 0.001 to 10% by weight in a mixture of an organic solvent such as ethanol or isopropyl alcohol and water at a weight ratio of 3 to 30 / 97 to 70.

[0005] Patent Document 2 discloses a technique for coating the surface of a catheter with an antithrombotic material containing a (meth)acrylate copolymer using ethanol or a mixed solution of ethanol and water.

[0006] However, when coating the surface of catheters, particularly polyurethane resin catheters, with an antithrombotic material comprising a (meth)acrylate copolymer, the use of solvents such as ethanol can lead to shrinkage or swelling of the polyurethane resin, resulting in quality degradation such as dimensional variations between products.

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: Japanese Patent No. 4100452

[0010] Patent Document 2: Japanese Patent Application Laid-Open No. 2009-261437 Summary of the Invention

[0011] Problems to be solved by the invention

[0012] An object of the present invention is to provide a method for coating an antithrombotic material, which can suppress dimensional changes such as swelling and shrinkage of a polyurethane medical device such as a catheter when imparting antithrombotic properties to the medical device.

[0013] Means for solving problems

[0014] The present inventors have discovered that a medical device imbued with antithrombotic properties, obtained by applying a solution of an antithrombotic material dissolved in an aliphatic hydrocarbon solvent to a polyurethane medical device, exhibits minimal dimensional change due to solution application, leading to the completion of the present invention. Specifically, the present invention has the following configuration.

[0015] [1] A method for manufacturing an anti-thrombotic medical device, comprising:

[0016] a step of dissolving an antithrombotic material comprising a (meth)acrylate copolymer in an aliphatic hydrocarbon solvent to prepare an aliphatic hydrocarbon solution;

[0017] The process of applying the aliphatic hydrocarbon solution to a medical device; and

[0018] a step of removing the aliphatic hydrocarbon solvent from the surface of the medical device;

[0019] The above medical devices are made of polyurethane.

[0020] [2] The method according to [1], wherein the concentration of the (meth)acrylate copolymer in the aliphatic hydrocarbon solution is 0.01% by mass or more and 10% by mass or less.

[0021] [3] The method according to [1] or [2], wherein the temperature of the aliphatic hydrocarbon solution is 10° C. or higher and 45° C. or lower.

[0022] [4] The method according to any one of [1] to [3] above, wherein the aliphatic hydrocarbon solvent is removed by blowing air at a flow rate of 1 mL / min or more and 100 L / min or less toward the medical device.

[0023] [5] The method according to [4], wherein the air is blown toward the medical device for a period of not less than 1 second and not more than 180 seconds.

[0024] [6] The method according to any one of [1] to [5], wherein the (meth)acrylate copolymer comprises an alkyl (meth)acrylate unit represented by the following general formula (I), a silicone (meth)acrylate unit represented by the following general formula (II), and a methoxypolyethylene glycol (meth)acrylate unit represented by the following general formula (III).

[0025] [Chemical Formula 1]

[0026]

[0027] (Where R 1 Indicates C 6-20 Alkyl, R 2 represents a hydrogen atom or a methyl group)

[0028] [Chemical Formula 2]

[0029]

[0030] (Where R 3 represents a hydrogen atom or a methyl group, R 4 Indicates C 1-6 Alkylene, R 5 Indicates C 1-6 alkyl, m represents an integer of 1 to 30)

[0031] [Chemical Formula 3]

[0032]

[0033] (Where R 6 represents a hydrogen atom or a methyl group, and n represents an integer of 2 to 4)

[0034] [7] The method according to [6], wherein the molar ratio of the alkyl (meth)acrylate unit / the silicone (meth)acrylate unit / the methoxy polyethylene glycol (meth)acrylate unit in the (meth)acrylate copolymer is 80 to 20 / 10 to 0.01 / 10 to 79.99.

[0035] [8] The method according to any one of [1] to [7], wherein the weight average molecular weight of the (meth)acrylate copolymer is 50,000 or more and 1,500,000 or less.

[0036] [9] The method according to any one of [1] to [8], wherein the reduced viscosity of the (meth)acrylate copolymer is 0.18 dl / g or more and 0.50 dl / g or less.

[0037]

[10] The method according to any one of [1] to [9], wherein the medical device is coated with the (meth)acrylate copolymer at a concentration of 0.005 mg / cm 2 Above and 0.06mg / cm 2 the following.

[0038]

[11] A medical device, characterized in that it is made of polyurethane and:

[0039] It is coated with (meth)acrylate copolymer at 0.005 mg / cm 2 Above and 0.06mg / cm 2 the following.

[0040] Effects of the Invention

[0041] According to the present invention, not only can at least a portion of a body fluid contact portion of a polyurethane medical device be uniformly coated with an antithrombotic material, but swelling and shrinkage caused by coating with an organic solvent can also be suppressed. Consequently, a polyurethane medical device with excellent antithrombotic properties can be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is a schematic diagram for explaining the effect of a coating solvent on a tube used for a polyurethane medical device.

[0043] Figure 2 This is a schematic diagram showing an example of the results of measuring the effect of the coating solvent on the tube thickness.

[0044] Figure 3 This is a schematic diagram showing an example of the results of measuring the effect of the coating solvent on the inner diameter of the tube.

[0045] Figure 4 This is a schematic diagram showing an example of the results of measuring the effect of the coating solvent on the outer diameter of the tube.

[0046] Figure 5 These are photographs showing the results of a blood compatibility test using the tubes of Examples. DETAILED DESCRIPTION

[0047] The method for producing an antithrombotic medical device of the present invention comprises: dissolving an antithrombotic material comprising a (meth)acrylate copolymer in an aliphatic hydrocarbon solvent to prepare an aliphatic hydrocarbon solution; applying the aliphatic hydrocarbon solution to a medical device; and removing the aliphatic hydrocarbon solvent from the surface of the medical device. The medical device is made of polyurethane. The present invention is described below, but is not limited to the specific examples below.

[0048] 1. Solution preparation process

[0049] In this step, an antithrombotic material containing a (meth)acrylate copolymer is dissolved in an aliphatic hydrocarbon solvent to prepare an aliphatic hydrocarbon solution.

[0050] In the present invention, the (meth)acrylate copolymer comprises hydrophobic (meth)acrylate units and hydrophilic (meth)acrylate units and exhibits durability against blood contact. Here, "durability against blood contact" means that when the (meth)acrylate copolymer is immersed in an alcohol immersion treatment solution at room temperature for 16 hours, the (meth)acrylate copolymer remains insoluble to a certain extent and exhibits antithrombotic properties. If the (meth)acrylate copolymer remains at 0.1 μg / cm after immersion in an alcohol immersion treatment solution at room temperature for 16 hours, 2 Based on the above, it can be concluded that the material exhibits sufficient antithrombotic properties even after 30 days of contact with blood at 37°C. For alcohol immersion treatment solutions, a mixed solvent with a methanol / ethanol mass ratio of 80 / 20 is preferred due to its higher dissolution capacity compared to blood. Furthermore, the (meth)acrylate copolymer of the present invention is preferably in a viscous liquid state at room temperature. A liquid state and viscous state at room temperature have the advantage of suppressing dissolution into blood even when applied to medical devices and used.

[0051] In the present invention, the hydrophobic (meth)acrylate unit may contain other hydrophobic (meth)acrylate units in addition to the silicone (meth)acrylate unit (II). The other hydrophobic (meth)acrylate unit is not particularly limited, but as an example, an alkyl (meth)acrylate unit represented by the following general formula (I) is preferably added. In the following general formula (I), R 1 The number of carbon atoms in R is preferably 6 or more and 20 or less, more preferably 8 or more and 12 or less. 1 , n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-lauryl, n-tetradecyl, n-hexadecyl, n-octadecyl, and n-eicosyl may be mentioned, and from the viewpoint of cost and performance, 2-ethylhexyl and n-lauryl are preferred.

[0052] [Chemical Formula 4]

[0053]

[0054] (R 1 Indicates C 6-20 Alkyl, R 2 represents a hydrogen atom or a methyl group)

[0055] In the present invention, the hydrophobic (meth)acrylate unit preferably comprises a silicone (meth)acrylate unit represented by the following general formula (II). The silicone (meth)acrylate unit preferably comprises a dimethylsiloxane repeating number m of 1 to 30. When the repeating unit m is within this range, the copolymer exhibits a moderate viscosity, allowing for more reliable retention on the surface of medical devices and excellent handling properties. The repeating unit m is preferably 1 to 20.

[0056] [Chemical Formula 5]

[0057]

[0058] (Where R 3 represents a hydrogen atom or a methyl group, R 4 Indicates C 1-6 Alkylene, R 5 Indicates C 1-6 alkyl, m represents an integer of 1 to 30)

[0059] In the present invention, the hydrophilic (meth)acrylate unit preferably comprises a methoxypolyethylene glycol (meth)acrylate unit represented by the following general formula (III). In the following general formula (III), the repeating number n of ethylene oxide is preferably 2 or greater and 10 or less. A repeating number n of ethylene oxide of 2 or greater can more reliably inhibit platelet adhesion and plasma protein adsorption, while a repeating number n of 10 or less can more reliably inhibit the dissolution of the copolymer into the blood. Specific ethylene oxide structures include diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol, and decaethylene glycol. The repeating number n of ethylene oxide is more preferably 2 or greater and 5 or less. As for the ethylene oxide structure, a tetraethylene glycol (meth)acrylate structure having a repetition number of 4 and a triethylene glycol (meth)acrylate structure having a repetition number of 3 are more preferred, and a triethylene glycol (meth)acrylate structure having a repetition number of 3 is particularly preferred.

[0060] [Chemical Formula 6]

[0061]

[0062] (Where R 6 represents a hydrogen atom or a methyl group, and n represents an integer of 2 to 4)

[0063] Examples of the water-insoluble (meth)acrylate copolymer of 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-n-hexyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-hexyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-hexyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, and silicone (meth)acrylate-n-hexyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer. Acrylates-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-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.

[0064] The molar ratio of the alkyl (meth)acrylate units (I) / silicone (meth)acrylate units (II) / methoxypolyethylene glycol (meth)acrylate units (III) in the (meth)acrylate copolymer is not particularly limited. For example, the ratio can be 80 to 20 / 10 to 0.01 / 10 to 79.99, with the total of the units being 100. If the total amount of the hydrophobic (meth)acrylate units, i.e., the alkyl (meth)acrylate units (I) and the silicone (meth)acrylate units (II), is 20.01 mol% or more relative to the total amount, the copolymer can be considered to be poorly soluble in blood, etc., while if it is 90 mol% or less, it can be considered to have sufficient blood compatibility. The molar ratio is preferably 80 to 50 / 5 to 0.01 / 15 to 49.99, more preferably 77 to 55 / 5 to 0.01 / 18 to 44.99, and still more preferably 73 to 57 / 5 to 0.01 / 22 to 42.99.

[0065] In the present invention, the copolymer does not necessarily contain silicone (meth)acrylate units as the hydrophobic (meth)acrylate units. However, silicone, as can be seen from its basic skeleton, has excellent heat and cold resistance and a low glass transition temperature (Tg), thus offering the advantage of exhibiting stable properties across a wide temperature range. Furthermore, due to its high bond energy, it offers the advantages of acid and alkali resistance and high chemical stability. Furthermore, silicone (meth)acrylate monomers exhibit excellent copolymerizability with other (meth)acrylate monomers and are therefore suitable as raw materials for the (meth)acrylate copolymers of the present invention. Silicone (meth)acrylates have recently been recognized as highly safe materials for use in contact lens materials, among others. Therefore, excessive silicone (meth)acrylate content in antithrombotic materials is not considered a problem, and silicone (meth)acrylate-methoxypolyethylene glycol (meth)acrylate copolymers are also suitable. However, the current situation is that the raw material price of silicone (meth)acrylate is sometimes high, making the use of silicone (meth)acrylate alone as the hydrophobic (meth)acrylate disadvantageous in terms of cost-effectiveness. Taking into account performance, quality, and cost, the proportion of silicone (meth)acrylate units in the hydrophobic (meth)acrylate units can be set to, for example, 50% by mass or less. This proportion is preferably 40% by mass or less, and more preferably 35% by mass or less. Alternatively, silicone (meth)acrylate can be mixed with the aforementioned alkyl (meth)acrylates. On the other hand, the proportion of silicone (meth)acrylate units in the hydrophobic (meth)acrylate units is preferably 0.1% by mass or greater. A proportion of 0.1% by mass or greater reduces hydrolysis during storage of the copolymer, resulting in superior long-term stability as an antithrombotic material. This proportion is more preferably 0.5% by mass or greater, and even more preferably 1.0% by mass or greater.

[0066] The (meth)acrylate copolymer may also be a copolymer formed by alternating hydrophobic monomers and hydrophilic monomers. When analyzed in terms of the total amount, it may also be a copolymer containing segments or blocks formed by hydrophobic monomers and segments or blocks formed by hydrophilic monomers. It can be generally conceived that complex structures such as a so-called microphase separation structure or a mosaic pattern (Japanese: モザイク模様) can be adopted, in which the segments or blocks formed by hydrophobic monomers play a function of fixing the segments or blocks formed by hydrophilic monomers. In short, the molecular weight of the copolymer, the types and properties of hydrophilic monomers, etc. also have somewhat of an influence. However, if the amount of hydrophobic monomers is increased, the dissolution of the segments or blocks formed by the hydrophilic monomers of the copolymer can be suppressed. In addition, it is considered that when the hydrophobic segments or blocks are slightly increased, it also plays a function of improving the affinity with hydrophobic medical devices, and it can also be conceived that it is beneficial for the fixation of the coating film to the medical device. Although the behavior related to the presence or absence of segments or blocks and their affinity state cannot be accurately verified based on technical grounds at present, this copolymer is a polymer material with good biocompatibility.

[0067] The homopolymer of methoxypolyethylene glycol (meth)acrylate has excellent blood compatibility due to its high hydrophilicity. However, since it is water-soluble, there is a problem of slow dissolution in the case of long-term contact with blood or the like. The inventors of the present invention have conducted in-depth research on materials that not only have excellent blood compatibility but also can withstand long-term use, and as a result, have found that a copolymer obtained by imparting appropriate hydrophobicity to prevent dissolution into blood or the like and softness to prevent physical film peeling of the coating film can solve this problem.

[0068] The copolymer contained in the coating liquid is substantially composed of two monomer components that play the so-called interface functions of different sides, that is, a part formed by hydrophilic monomers, segments or blocks having functions such as antithrombotic and dissolution prevention for blood, and hydrophobic monomers, segments or blocks having functions such as affinity and fixation for medical devices. On the other hand, it has also been observed that the monomers, segments or blocks constituting the copolymer are complementary to each other within the molecular structure, and bonds or structures have also been formed for stable molecules such as dissolution and dispersion.

[0069] Indicators for expressing the molecular weight of a copolymer include number-average molecular weight and weight-average molecular weight. Since weight-average molecular weight has a greater impact on stability and adhesion, weight-average molecular weight is selected as the indicator in the present invention. The weight-average molecular weight of the copolymer is preferably 50,000 or more and 1,500,000 or less. A weight-average molecular weight of 50,000 or more not only reliably suppresses dissolution into the blood but also more reliably ensures the strength and stability of the coating. Furthermore, due to the increased viscosity of the coating solution, adhesion to the surface of medical devices is improved. A weight-average molecular weight of 60,000 or more is preferred. Furthermore, a weight-average molecular weight of 1,500,000 or less improves the operability of the (meth)acrylate copolymer when applied to medical devices, etc. A weight-average molecular weight of 1,000,000 or less is more preferred, and 500,000 or less is even more preferred. Here, weight-average molecular weight refers to the value obtained by dividing the sum of the molecular weights of all molecules by the sum of the molecular weights, and is one of the indicators of the properties of a polymer.

[0070] Setting the weight-average molecular weight of the (meth)acrylate copolymer to 50,000 to 1,500,000 is a crucial technical requirement for achieving specific technical challenges related to the purification of the copolymer, handling of the coating solution, compatibility with medical devices, and coating film stability.

[0071] Methods for measuring the weight-average molecular weight include terminal group quantitative method, osmotic pressure method, vapor pressure osmotic method, vapor pressure depression method, freezing point depression method, boiling point elevation method, gel permeation chromatography (GPC) method, and the like. In the present invention, a conventional method such as gel permeation chromatography (GPC) is employed due to ease of handling.

[0072] In the present invention, the reduced viscosity (ηsp / c) of the (meth)acrylate copolymer is preferably 0.18 dl / g to 3.00 dl / g. Using a copolymer as an antithrombotic material within this viscosity range allows for excellent adhesion to medical devices such as cardiopulmonary circuits and catheters when applied, enabling sustained antithrombotic properties during long-term use. A more preferred reduced viscosity range is 0.18 dl / g to 1.50 dl / g, and even more preferably 0.18 dl / g to 0.50 dl / g.

[0073] In the present invention, the (meth)acrylate copolymer is preferably soluble in an aliphatic hydrocarbon solvent. Solubility in an aliphatic hydrocarbon solvent having 5 to 8 carbon atoms is more preferred because drying after coating is facilitated. Soluble herein means that when 1 g of the (meth)acrylate copolymer is immersed in 10 mL of the aliphatic hydrocarbon solvent at 25°C, at least 90% by mass of the (meth)acrylate copolymer dissolves within 16 hours at room temperature.

[0074] In the present invention, the (meth)acrylate copolymer may be any of a random copolymer, a block copolymer, and a graft copolymer. The copolymerization reaction used to produce the (meth)acrylate copolymer is not particularly limited, and known methods such as free radical polymerization, ionic polymerization, photopolymerization, and polymerization using macromonomers may be used.

[0075] Free radical polymerization can be initiated by, for example, dissolving the (meth)acrylate monomers in a solvent and then adding a free radical polymerization initiator. The ratio of the structural units in the (meth)acrylate copolymer corresponds to the ratio of the (meth)acrylate monomers used. In other words, the ratio of the structural units in the (meth)acrylate copolymer can be adjusted based on the ratio of the structural units in the target compound. Examples of solvents include: alcohol solvents such as methanol, ethanol, and 2-propanol; water; aromatic hydrocarbon solvents such as toluene and xylene; aliphatic hydrocarbon solvents such as n-hexane and n-heptane; ester solvents such as ethyl acetate and butyl acetate; ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; and mixed solvents thereof.

[0076] Examples of the alkyl (meth)acrylate (1) used to constitute the alkyl (meth)acrylate unit (I) include n-hexyl (meth)acrylate, cyclohexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate, and lauryl (meth)acrylate. From the viewpoint of cost and performance, 2-ethylhexyl (meth)acrylate and lauryl (meth)acrylate are particularly preferred.

[0077] [Chemical Formula 7]

[0078]

[0079] (Where R 1 Indicates C 6-20 Alkyl, R 2 represents a hydrogen atom or a methyl group)

[0080] The silicone (meth)acrylate (2) used to constitute the silicone (meth)acrylate unit (II) is preferably a silicone (meth)acrylate having a dimethylsiloxane repeating unit m of 1 or more and 30 or less. When the repeating unit m is within the above range, the viscosity of the copolymer becomes moderate, allowing for more reliable retention on the surface of the medical device and excellent handling properties. The repeating unit m is preferably 1 or more and 20 or less.

[0081] [Chemical Formula 8]

[0082]

[0083] (Where R 3 represents a hydrogen atom or a methyl group, R 4 Indicates C 1-6 Alkylene, R 5 Indicates C 1-6 alkyl, m represents an integer of 1 to 30)

[0084] The number of ethylene oxide units n in the methoxypolyethylene glycol (meth)acrylate (3) constituting the methoxypolyethylene glycol (meth)acrylate unit (III) is preferably 2 or more and 10 or less. If the number of ethylene oxide repeats n is 2 or more, platelet adhesion and plasma protein adsorption can be more reliably inhibited, and if it is 10 or less, the dissolution of the copolymer into the blood can be more reliably inhibited. The number of ethylene oxide repeats n is more preferably 2 or more and 5 or less. Examples of the methoxypolyethylene glycol (meth)acrylate (3) include methoxydiethylene glycol (meth)acrylate, methoxytriethylene glycol (meth)acrylate, methoxytetraethylene glycol (meth)acrylate, methoxypentaethylene glycol (meth)acrylate, methoxyhexaethylene glycol (meth)acrylate, methoxyheptaethylene glycol (meth)acrylate, methoxyoctaethylene glycol (meth)acrylate, methoxynonaethylene glycol (meth)acrylate, and methoxydecaethylene glycol (meth)acrylate. As methoxypolyethylene glycol (meth)acrylate (3), tetraethylene glycol (meth)acrylate having a repeating number of 4 and triethylene glycol (meth)acrylate having a repeating number of 3 are more preferable, and triethylene glycol (meth)acrylate having a repeating number of 3 is particularly preferable.

[0085] [Chemical Formula 9]

[0086]

[0087] (Where R 6 represents a hydrogen atom or a methyl group, and n represents an integer of 2 to 4)

[0088] Taking into account performance, quality, cost, etc., the proportion of silicone (meth)acrylate units (II) in the copolymer is preferably 50% by mass or less. It is more preferably 40% by mass or less, and even more preferably 35% by mass or less. In addition, silicone (meth)acrylate (2) can also be mixed with the above-mentioned other alkyl (meth)acrylates (1). The proportion of silicone (meth)acrylate (2) in the hydrophobic (meth)acrylate is preferably 0.1% by mass or more. If this proportion is 0.1% by mass or more, the hydrolysis of the copolymer can be more reliably suppressed, and the long-term stability as an antithrombotic material can be more reliably maintained. With respect to this proportion, it is more preferably 0.5% by mass or more, and even more preferably 1.0% by mass or more. The upper limit of this proportion is also not particularly limited, and for example, it can be set to 50% by mass or less. With respect to this proportion, it is preferably 40% by mass or less or 30% by mass or less, and more preferably 20% by mass or less or 10% by mass or less.

[0089] In the present invention, the antithrombotic material comprising a (meth)acrylate copolymer may also contain substances such as antimicrobial substances. These antimicrobial substances can be broadly divided into water-soluble and poorly water-soluble ones. Representative examples of water-soluble antimicrobial substances include benzalkonium chloride, penicillin G potassium, and streptomycin sulfate. Representative examples of poorly water-soluble antimicrobial substances include silver sulfadiazine and chlorhexidine. These substances may be used alone or in combination.

[0090] In the present invention, the antimicrobial substance is preferably 0.01% by mass or more and 70% by mass or less relative to the mass of the antithrombotic composition. If the ratio is 0.01% by mass or more, the antimicrobial property of the antimicrobial substance can be more reliably exerted. If it is 70% by mass or less, the poor appearance of the medical device after surface treatment such as coating can be more reliably suppressed. In addition, the dissolution of the antimicrobial substance into the body and the local inflammation caused by the dissolved antimicrobial substance can be more reliably suppressed. In terms of this ratio, it is more preferably 0.05% by mass or more and 50% by mass or less, further preferably 0.1% by mass or more and 30% by mass or less, and particularly preferably 0.1% by mass or more and 10% by mass or less. The antimicrobial substance can be present on the entire surface of the medical device, but in terms of suppressing local inflammation, it is preferably present only near the puncture site that penetrates the skin.

[0091] In the present invention, the (meth)acrylate copolymer obtained by copolymerizing an alkyl (meth)acrylate (1) and / or a silicone (meth)acrylate (2) with a methoxypolyethylene glycol (meth)acrylate (3) has an appropriate balance between hydrophilicity and hydrophobicity and is therefore suitable for use as a blood-compatible material. In particular, a (meth)acrylate copolymer containing a silicone (meth)acrylate unit (II) within a specific range can inhibit the adsorption and adhesion of blood proteins and the like and is therefore suitable for use as a treatment material for medical devices and the like. The above-mentioned (meth)acrylate copolymers may be used alone or in combination of two or more.

[0092] In the present invention, it is believed that when a medical device treated with an antithrombotic material comes into contact with blood, the highly hydrophilic methoxypolyethylene glycol (meth)acrylate units (III) protrude from the surface and exert antithrombotic properties, while the hydrophobic (meth)acrylate units (I) and (II) remain near the substrate, thereby preventing direct contact between the blood and the medical device.

[0093] The aliphatic hydrocarbon solvent for the aliphatic hydrocarbon solution of the (meth)acrylate copolymer should be selected to moderately dissolve the (meth)acrylate copolymer while minimizing damage to the medical device substrate. Examples of such aliphatic hydrocarbon solvents include: chain aliphatic hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and n-octane; cyclic aliphatic hydrocarbon solvents such as cyclopentane, methylcyclopentane, cyclohexane, and methylcyclohexane; and mixtures of two or more thereof. Cyclohexane is particularly preferred among aliphatic hydrocarbon solvents. According to experimental findings by the present inventors, aliphatic hydrocarbon solvents can maintain the dimensions of polyurethane medical devices without causing them to swell or shrink.

[0094] The reason why the dimensional change of polyurethane medical devices is reduced when an aliphatic hydrocarbon solvent is used as a solvent is not clear, but it is considered as follows. Figure 1 In FIG, cyclohexane is representatively shown as the aliphatic hydrocarbon solvent, ethanol is shown as the conventional solvent, and a tube is shown as the medical device.

[0095] like Figure 1As shown, when a polyurethane medical device tube is immersed in ethanol, the ethanol, which has a solubility parameter similar to that of the polyurethane, is absorbed more quickly and in greater quantities by the thicker wall portions of the tube. Consequently, the tube's inner diameter, outer diameter, and thickness tend to increase. The molecular orientation of the polyurethane resin after absorbing the ethanol decouples, and even after the ethanol is removed, the tube becomes a tube with a uniform molecular orientation. A uniform molecular orientation reduces the apparent volume, so it is believed that the drying process specifically reduces the thickness. On the other hand, when a polyurethane medical device is immersed in an aliphatic hydrocarbon solvent such as cyclohexane, which has a solubility parameter significantly different from that of the polyurethane resin, the polyurethane medical device absorbs the aliphatic hydrocarbon solvent much more slowly, resulting in less change in the inner diameter, outer diameter, and thickness of the polyurethane medical device.

[0096] On the other hand, (meth)acrylate copolymers have high solubility in aliphatic hydrocarbon solvents. Therefore, using an aliphatic hydrocarbon solvent as the solvent for a (meth)acrylate copolymer solution can form a uniform antithrombotic coating on the surface of a polyurethane medical device. Therefore, when an antithrombotic material containing a (meth)acrylate copolymer is applied to a polyurethane medical device, using an aliphatic hydrocarbon solvent as the solvent can suppress deformation of the polyurethane medical device, such as swelling and shrinkage, while uniformly coating the surface of the medical device with the antithrombotic material.

[0097] The concentration of the (meth)acrylate copolymer in the aliphatic hydrocarbon solution used to coat the surface of a polyurethane medical device with the (meth)acrylate copolymer can be appropriately adjusted, for example, to a value between 0.01% and 10% by mass. If this concentration is 1.0% or more by mass, the performance of the (meth)acrylate copolymer applied to the surface of the medical device can be more reliably exerted. If this concentration is 0.01% or more by mass, the concentration of the coating solution is moderate, and it can be said that workability is high. If it is 10% or less by mass, the performance of the (meth)acrylate copolymer applied to the surface of the medical device can be more reliably exerted. With regard to this concentration, it is preferably 0.1% or more by mass, more preferably 1.0% or more by mass, more preferably 1.5% or more by mass, and even more preferably 2.0% or more by mass. In addition, it is preferably 8.0% or less by mass, or 5.0% or less by mass, and more preferably 3.0% or less by mass, or 2.5% or less by mass.

[0098] 2. Coating process

[0099] In this step, the aliphatic hydrocarbon solution prepared in the above step 1 is applied to the medical device.

[0100] In the present invention, the (meth)acrylate copolymer is water-insoluble and can be preferably used as the main component of a surface treatment agent for medical devices, etc. Specifically, a solution obtained by dissolving an antithrombotic material containing a (meth)acrylate copolymer in an aliphatic hydrocarbon solvent is applied to the surface of a substrate of a medical device, etc., followed by removal of the aliphatic hydrocarbon solvent. Methods for loading the antithrombotic material onto the substrate surface include known methods such as coating, graft polymerization using radiation, electron beams, or ultraviolet light, and chemical reactions with functional groups on the substrate. Coating is practically preferred due to its ease of production. The coating method is not particularly limited, and methods such as coating, spraying, and dipping can be used. For example, coating can be performed by applying a coating solution containing the antithrombotic material dissolved in an aliphatic hydrocarbon solvent to the substrate, removing excess solvent, and then air-drying. It is also preferred to heat and dry the coated substrate. This can further enhance the adhesion between the substrate and the antithrombotic material, thereby achieving more secure fixation.

[0101] The method for applying the aliphatic hydrocarbon solution containing the antithrombotic material (meth)acrylate copolymer to the medical device is not particularly limited and conventional methods can be used. For example, the aliphatic hydrocarbon solution can be applied to or sprayed on the medical device, or immersed in the aliphatic hydrocarbon solution. The temperature of the aliphatic hydrocarbon solution during application to the medical device is not particularly limited and can be, for example, between 10°C and 45°C. This temperature is preferably above 15°C or above 25°C, and preferably above room temperature. Alternatively, the temperature can be adjusted to 20±10°C or 20±5°C.

[0102] The coating amount or spraying amount of the aliphatic hydrocarbon solution may be adjusted appropriately. For example, it may be adjusted so that the coating amount of the (meth)acrylate copolymer on the surface of the medical device becomes 0.005 mg / cm 2 Above and 0.06mg / cm 2 In addition, the immersion time of the medical device in the aliphatic hydrocarbon solution can also be appropriately adjusted, for example, it can be set to be more than 1 second and less than 60 seconds. As far as this time is concerned, it is preferably less than 30 seconds, more preferably less than 20 seconds or less than 15 seconds.

[0103] 3. Drying process

[0104] In this step, the aliphatic hydrocarbon solvent is removed from the aliphatic hydrocarbon solution applied to the surface of the medical device in the coating step 2. The method for removing the aliphatic hydrocarbon solvent is not particularly limited, and examples thereof include natural drying, heating, reduced pressure, air blowing, and combinations thereof. Air blowing is effective and therefore preferred.

[0105] The blowing conditions can be adjusted appropriately. For example, when the surface area of ​​medical equipment is less than 10cm 2 In the case of laboratory-level implementation, the flow rate of the blown air can be adjusted to 1 mL / min or more and 20 L / min or less. In addition, when the surface area of ​​the medical device is 10 cm 2 In the case of the above industrial practice level, the flow rate of the blown air can be adjusted to 10 L / min or more and 100 L / min or less. In addition, in the case between the above, the flow rate of the blown air can also be adjusted to 10 L / min or more and 50 L / min or less.

[0106] The time for blowing air to the medical device can also be adjusted appropriately, for example, it can be set to 1 second or longer and 180 seconds or shorter. This time is preferably 5 seconds or longer or 10 seconds or longer, more preferably 20 seconds or longer or 25 seconds or longer, and preferably 150 seconds or shorter or 120 seconds or shorter, more preferably 100 seconds or shorter or 50 seconds or shorter.

[0107] In natural drying, the aliphatic hydrocarbon solvent is evaporated by placing the medical device coated with the above solution under normal temperature and atmospheric pressure. The time required for natural drying can be appropriately adjusted within the range of sufficient removal of the aliphatic hydrocarbon solvent, for example, it can be set to more than 30 minutes and less than 24 hours. The conditions for heat drying can also be appropriately adjusted according to the aliphatic hydrocarbon solvent used, for example, it can be set to a temperature of more than 40°C and less than 120°C for more than 10 minutes and less than 10 hours. For reduced pressure drying, the pressure can be reduced for more than 10 minutes and less than 10 hours under the conditions of more than 10 Pa and less than 100 Pa. For example, if heat drying and reduced pressure drying are combined, the aliphatic hydrocarbon solvent can be effectively removed, but from the perspective of cost, air blowing is preferred.

[0108] Polyurethane medical devices coated with a (meth)acrylate copolymer using the method of the present invention exhibit high adhesion between the (meth)acrylate copolymer and the polyurethane medical device due to the hydrophobic (meth)acrylate units of the (meth)acrylate copolymer. Furthermore, the hydrophilic (meth)acrylate units inhibit activation of the blood coagulation system, platelet adhesion and activation, and complement system activation. Consequently, polyurethane medical devices coated with a (meth)acrylate copolymer using the method of the present invention exhibit excellent in vivo stability and biocompatibility.

[0109] Medical devices made of polyurethane are not particularly limited as long as they can come into contact with body fluids such as blood within a living body. Examples include catheters such as peripheral intravenous catheters, implantable intravenous ports, atraumatic needles, peripherally inserted central venous catheters, dialysis catheters, midline catheters, central venous catheters, cardiac catheters, and urethral catheters. Furthermore, these medical devices may include cardiac catheter tip chips, cardiac catheter bulbs, and pacemaker leads that come into contact with body fluids.

[0110] This application claims the benefit of priority based on Japanese Patent Application No. 2023-53423, filed on March 29, 2023. The entire contents of the specification of Japanese Patent Application No. 2023-53423, filed on March 29, 2023, are incorporated herein by reference.

[0111] Example

[0112] Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited to these Examples.

[0113] Example 1

[0114] (1) Production of (meth)acrylate copolymers

[0115] Azobisisobutyronitrile (AIBN) (Fujifilm Wako Pure Chemical Industries, Ltd.) (1.2325 g) was added to methoxytriethylene glycol acrylate (MTEGA) (manufactured by Shin-Nakamura Chemical Co., Ltd.) (471.8 g), silicone methacrylate (PDMSMA) ("MCR-M11" manufactured by Gelest, Inc., 78.0 g), 2-ethylhexyl acrylate (EHA) (manufactured by Toagosei Co., Ltd.) (694.5 g), and ethanol (manufactured by Kishida Chemical Co., Ltd.) (1628.3 g). A polymerization reaction was carried out at 85°C for 3 hours. After completion of the polymerization reaction, the mixture was dried at atmospheric pressure at 85°C for 2 hours. Subsequently, the mixture was dried under reduced pressure at 60°C for 1 hour to obtain a concentrate. The concentrate was then divided equally into concentrate A and concentrate B.

[0116] Methanol (manufactured by Kishida Chemical Co., Ltd.) (3162.7 g) and water (305.3 g) were added to concentrate A (612.1 g) and stirred for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. Methanol was added to the resulting precipitate, stirred for 30 minutes, allowed to stand for 1.5 hours, and the supernatant was removed by decantation. This procedure was repeated three times to obtain precipitate A. The amounts of methanol added were 3161.7 g, 3161.4 g, and 3163.9 g, respectively.

[0117] Similarly, methanol (3162.3 g) and water (303.1 g) were added to concentrate B (614.4 g) and stirred for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. Methanol was added to the resulting precipitate, stirred for 30 minutes, allowed to stand for 1.5 hours, and the supernatant was removed by decantation. This procedure was repeated three times to obtain precipitate B. The amounts of methanol added were 3165.5 g, 3167.5 g, and 3165.4 g, respectively.

[0118] The obtained precipitate A and precipitate B were collected together and dried under reduced pressure at 40° C. for 1.5 hours to obtain copolymer 1.

[0119] (2) Determination of weight average molecular weight

[0120] Copolymer 1 (15 mg) was weighed into a vial, and the mobile phase for GPC measurement (3.0 mL) was added. The mixture was allowed to stand overnight. The resulting solution was filtered using a 0.45 μm hydrophilic PTFE membrane cartridge ("Millex-LH" manufactured by Nihon Millipore). For GPC measurement, a "515 HPLC pump" and a "717plus automatic injection system" manufactured by Waters were used, along with a "2× PLgel 5μ MIXED-D, 7.5×300 mm" column manufactured by Agilent Technologies. The column temperature was set at 40°C, and the mobile phase was tetrahydrofuran for liquid chromatography (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) containing butylated hydroxytoluene as a stabilizer. Detection was performed using RI, and 20 μL of the sample was injected. Molecular weight was calibrated using monodisperse polystyrene ("EasiCal PS-1" manufactured by Agilent Technologies).

[0121] The weight average molecular weight of Copolymer 1 was 68,300.

[0122] (3) Determination of reduced viscosity

[0123] Copolymer 1 (1 g) was weighed into a glass bottle, and acetone (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (15 mL) was added. Shake the mixture by hand every 20 minutes. After 1 hour, visually check for dissolution and transfer the mixture to a 25 mL volumetric flask. After pre-washing, add acetone to adjust the volume to 25 mL. The resulting solution was filtered through a 5 μm diameter filter (manufactured by Merck) and used as the test solution. Using an Ubbelohde viscometer with a viscometer constant C = 0.003426 cSt / s, the falling time of the sample solution and acetone at 30°C was measured, and the reduced viscosity was calculated using the following formula.

[0124] Reduced viscosity (ηsp / c) = (A / B-1) / C = (A / B-1) / (S / 25×100) = (A / B-1) / (S×4)

[0125] A: Number of seconds for the sample solution to fall (seconds)

[0126] B: Acetone falling time (seconds)

[0127] S: test sample weight (g)

[0128] C: sample solution concentration (g / dL)

[0129] The reduced viscosity of Copolymer 1 was 0.214 dl / g.

[0130] (4) Manufacturing of coating liquid

[0131] Cyclohexane (78.4 g) was added to the copolymer 1 (1.6 g) and mixed thoroughly to obtain a coating liquid 1. The concentration of the copolymer 1 in the coating liquid 1 was 2.0% by mass.

[0132] (5) Anti-thrombotic treatment of polyurethane tubes

[0133] A polyurethane tube with an inner diameter of 2.3 mm, an outer diameter of 3.8 mm, a thickness of 0.7 mm, and a length of 21 mm was immersed in coating solution 1 for 10 seconds. The tube was then removed from the coating solution 1 and air was blown at a flow rate of 10 mL / min over both the outer and inner surfaces for 30 seconds each to remove excess cyclohexane. The tube was then dried at room temperature for 16 hours, yielding a polyurethane tube 1 coated with a (meth)acrylate copolymer serving as an antithrombotic material.

[0134] (6) Determination of surface adhesion rate of (meth)acrylate copolymers

[0135] Copolymer 1 (20 mg) was dissolved in deuterated chloroform (1 mL) and the mixture was heated at 30°C. 1 H-NMR measurement: Based on the obtained peak areas, A to D were calculated according to the following calculation formulas.

[0136] A: Peak integral of one methoxy group of MTEGA near 3.4 ppm / 3 (number of H atoms) × 218 g / mol (molecular weight of MTEGA)

[0137] B: Peak integration value of two methyl groups of EHA near 0.8 ppm / 6 (number of H) × 184 g / mol (molecular weight of EHA)

[0138] C: Peak integration value of two methylene groups of PDMSMA near 0.5 ppm / 4 (number of H) × 971 g / mol (molecular weight of PDMSMA)

[0139] D: Integrated value of the peak derived from PDMSMA near 0 ppm

[0140] Next, the coated polyurethane tube was immersed in ethanol (5 mL) for 30 minutes to obtain an extract. Nitrogen gas was blown into the obtained extract at 40°C to dry it until the ethanol smell disappeared. This operation was repeated three times. Dimethyl isophthalate (DMI) was added to the total amount of the obtained dry solid, dissolved in deuterated chloroform (0.6 mL), and then dried at 30°C. 1 H-NMR measurement: Based on the obtained peak areas, E and F were calculated according to the following calculation formula.

[0141] E: integrated value of the peak derived from the phenyl group of DMI near 7.5 ppm / 1 (number of H) × 194 g / mol (molecular weight of DMI)

[0142] F: integrated value of the peak derived from PDMSMA near 0 ppm

[0143] G: Surface area of ​​polyurethane tube (cm 2 )

[0144] The surface adhesion amount was calculated by the following calculation formula based on A to G described above.

[0145] Surface adhesion (mg / cm 2 ) = [F × {(A + B + C) / D}] × (DMI addition amount (mg) / E) / G

[0146]

[0147] The results shown in Table 1 show that the use of cyclohexane as the coating solvent enables the surface of the polyurethane tube to be uniformly coated with the antithrombotic material.

[0148] (7) Inner diameter measurement

[0149] A polyurethane tube was placed upright on the stage of an optical microscope ("Digital Microscope VHX-900" manufactured by KEYENCE; using a "VH-100R" or "VH-Z20R" lens). The inner and outer diameters of one end were measured using the optical microscope. The inner and outer diameters of five polyurethane tubes were measured at three randomly selected locations on one cross-section of the tube using the software's "Diameter Menu" (Japanese). The average value was calculated.

[0150] (8) Calculation of the rate of change of inner diameter, outer diameter and thickness

[0151] The change rates of the inner diameter, outer diameter, and thickness of the polyurethane tube were calculated using the following formula.

[0152] Change rate (%) = [(measured value after treatment - measured value before treatment) / measured value before treatment] × 100

[0153] Comparative Example 1

[0154] A polyurethane tube 2 was obtained by coating the polyurethane tube with the (meth)acrylate copolymer in the same manner as in Example 1 except that ethanol was used instead of cyclohexane.

[0155] Test Example 1: Effect of Solvent

[0156] In Example 1 and Comparative Example 1, the polyurethane tubes were coated by immersing them in the coating liquid for only 10 seconds. Therefore, the influence of the solvents was tested by immersing the polyurethane tubes in the solvents for a longer period of time.

[0157] Specifically, the tube 1 obtained above was immersed in cyclohexane for 23 hours and then dried by standing at about 20°C for 5 hours. The thickness, inner diameter, and outer diameter of the tube were measured before the immersion treatment, 15 seconds after the immersion treatment, 1 hour after the immersion treatment, 2 hours after the immersion treatment, 3 hours after the immersion treatment, 4 hours after the immersion treatment, and 1 hour after the drying treatment. The obtained measurement results are shown in Tables 2 and Figures 2-4 .

[0158]

[0159] For comparison, the inner diameter, outer diameter and thickness of the tube were measured in the same manner except that ethanol was used instead of cyclohexane. The obtained measurement results are shown in Table 3 and Figures 2-4 .

[0160]

[0161] According to Tables 2, 3 and Figures 2-4 The results shown confirmed that the Example using cyclohexane when coating the (meth)acrylate copolymer on the polyurethane tube suppressed swelling / contraction of the inner diameter, outer diameter, and thickness less than the Comparative Example using ethanol.

[0162] Test Example 2: Blood compatibility test

[0163] A polyurethane tube with an inner diameter of 0.82 mm, an outer diameter of 1.12 mm, and a length of 21 mm was immersed in coating solution 1 at room temperature for 10 seconds, then removed. Air was blown over the inner and outer surfaces of the tube at a flow rate of 10 mL / min for 30 seconds each to remove excess cyclohexane. The tube was then allowed to stand at room temperature for 16 hours to dry, thereby immobilizing the antithrombotic material on the tube surface.

[0164] The obtained tube was cut into a length of 1 cm and placed in a 15 mL centrifuge tube. In addition, rabbit blood was mixed with 80 mM calcium chloride physiological saline solution at a volume ratio of 12:1 to prepare test blood. The test blood (1 mL) was added to the centrifuge tube and incubated at 37°C for 25 minutes. Then, the tube was removed from the centrifuge tube, transferred to a centrifuge tube added with physiological saline (5 mL), and oscillated for 5 seconds using "VORTEX SI-0246" manufactured by Scientific Industries at an oscillation setting of 6. The tube was removed from the physiological saline and the state of blood clot adhesion on the outer surface and the inner cavity was visually confirmed. The above test was carried out using 5 tubes. The results are shown in Figure 5 .

[0165] like Figure 5 The results shown here show that no blood clots or thrombi were observed in any of the tubes. This indicates that the use of cyclohexane as a coating solvent enables the surface of the polyurethane tube to be coated with an antithrombotic material.

[0166] Industrial applicability

[0167] According to the present invention, not only can at least a portion of the body fluid contact portion of a polyurethane medical device be uniformly coated with an antithrombotic material, but the swelling / contraction of the medical device caused by the coating process can also be suppressed, thereby providing a high-quality polyurethane medical device that has been subjected to an antithrombotic treatment.

Claims

1. A method for manufacturing an antithrombotic medical device, characterized in that It includes: a step of dissolving an antithrombotic material comprising a (meth)acrylate copolymer in an aliphatic hydrocarbon solvent to prepare an aliphatic hydrocarbon solution; The process of applying the aliphatic hydrocarbon solution to a medical device; and a step of removing the aliphatic hydrocarbon solvent from the surface of the medical device, The medical device is made of polyurethane.

2. The method according to claim 1, wherein The concentration of the (meth)acrylate copolymer in the aliphatic hydrocarbon solution is 0.01% by mass or more and 10% by mass or less.

3. The method according to claim 1, wherein The temperature of the aliphatic hydrocarbon solution is 10° C. or higher and 45° C. or lower.

4. The method according to claim 1, wherein The aliphatic hydrocarbon solvent is removed by blowing air at a flow rate of 1 mL / min or more and 100 L / min or less toward the medical device.

5. The method according to claim 4, wherein The air is blown toward the medical device for 1 second or longer and 180 seconds or shorter.

6. The method according to claim 1, wherein The (meth)acrylate copolymer comprises an alkyl (meth)acrylate unit represented by the following general formula (I), a silicone (meth)acrylate unit represented by the following general formula (II), and a methoxypolyethylene glycol (meth)acrylate unit represented by the following general formula (III). In the general formula (I), R 1 Indicates C 6-20 Alkyl, R 2 represents a hydrogen atom or a methyl group, In the general formula (II), R 3 represents a hydrogen atom or a methyl group, R 4 Indicates C 1-6 Alkylene, R 5 Indicates C 1-6 alkyl, m represents an integer of 1 to 30, In the general formula (III), R 6 represents a hydrogen atom or a methyl group, and n represents an integer of 2 or more and 4 or less.

7. The method according to claim 6, wherein: The molar ratio of the alkyl (meth)acrylate unit / the silicone (meth)acrylate unit / the methoxy polyethylene glycol (meth)acrylate unit in the (meth)acrylate copolymer is 80 to 20 / 10 to 0.01 / 10 to 79.

99.

8. The method according to claim 1, wherein The (meth)acrylate copolymer has a weight average molecular weight of 50,000 to 1,500,000.

9. The method according to claim 1, wherein The (meth)acrylate copolymer has a reduced viscosity of 0.18 dl / g or more and 0.50 dl / g or less.

10. The method according to claim 1, wherein The medical device was coated with the (meth)acrylate copolymer at 0.005 mg / cm 2 Above and 0.06mg / cm 2 the following.

11. A medical device, characterized in that: It is made of polyurethane and, It is coated with (meth)acrylate copolymer 0.005mg / cm 2 Above and 0.06mg / cm 2 the following.

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