Method for producing medical device

Abstract

The present invention is a method for producing a medical device, wherein the method includes (1) a step in which an antithrombotic material, comprising a (meth)acrylate copolymer that contains an alkyl (meth)acrylate represented by general formula 1, a silicone (meth)acrylate represented by general formula 2, and a methoxy polyethylene glycol (meth)acrylate represented by general formula 3, is dissolved in a solvent to prepare a coating solution, (2) a step in which the coating solution is brought into contact with at least part of the surface of medical equipment made from a silicone base material, and (3) a step in which the coating solution is dried to solidify the antithrombotic material on at least part of the surface of the medical equipment, the Hansen solubility parameter (HSP) distance between the solvent and the silicone base material is 17 MPa0.5 or less, and the boiling point of the solvent is 90°C or less.

Description

Manufacturing method of medical devices

[0001] The present invention relates to a method for producing a medical device whose surface is coated with an antithrombogenic material. More specifically, the present invention relates to a method for producing a medical device in which at least a portion of a body fluid contact portion of a medical device made of a silicone-based substrate is coated with an antithrombogenic material containing a (meth)acrylate copolymer containing a hydrophobic (meth)acrylate and a hydrophilic (meth)acrylate using a specific solvent.

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

[0003] When medical devices are used as materials that come into contact with blood, the following three factors are important for biocompatibility: (a) inhibition of the blood coagulation system, (b) inhibition of platelet adhesion and activation, and (c) inhibition of activation of the complement system.

[0004] [Correction based on Rule 91 13.06.2024] For example, Patent Document 1 (WO2022 / 210759) discloses an antithrombotic material containing a (meth)acrylate copolymer consisting of alkyl (meth)acrylate, silicone (meth)acrylate, and methoxypolyethylene glycol (meth)acrylate, and discloses that solvents for coating a medical device with the antithrombotic material include methanol, ethanol, isopropyl alcohol, normal propyl alcohol, acetone, normal hexane, cyclohexane, tetrahydrofuran, 1,4-dioxane, cyclohexanone, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0005] Furthermore, Patent Document 2 (JP 2009-261437 A) discloses a catheter in which at least a part of a body fluid contact portion is coated with an antithrombotic material made of a (meth)acrylate copolymer obtained by copolymerizing a hydrophobic (meth)acrylate and a hydrophilic (meth)acrylate, and discloses a mixed solution of a water-soluble organic solvent and water as a coating suspension solvent used to coat the antithrombotic material.

[0006] Furthermore, Patent Document 3 (WO2019 / 142710) discloses a medical coating material that can form a continuous coating film on the surface of a silicone rubber substrate.

[0007] WO2022 / 210759 JP2009-261437A WO2019 / 142710

[0008] The types of materials (substrates) that constitute medical devices have become more diverse. For example, when attempting to fix or retain an antithrombotic material made of a synthetic polymer on the surface of a silicone-based substrate, a so-called "repellency phenomenon" occurs, making it impossible to form a uniform, continuous coating film.

[0009] [Amendment based on Rule 91 13.06.2024] The present invention has been made in consideration of the above circumstances, and aims to provide a method for producing a medical device having excellent antithrombotic properties.

[0010] The present inventors have conducted extensive research to solve the above problems and have found that a medical device with excellent antithrombogenicity can be obtained by coating at least a portion of the surface (body fluid contact portion) of a medical device made of a silicone-based substrate with an antithrombogenic material containing a (meth)acrylate copolymer containing a hydrophobic (meth)acrylate and a hydrophilic (meth)acrylate using a specific solvent, thereby completing the present invention. That is, the present invention has the following configuration.

[0011] [Correction based on Rule 91 13.06.2024] [1] A method for preparing a coating solution comprising: (1) dissolving an antithrombogenic material in a solvent, the antithrombogenic material including a (meth)acrylate copolymer containing an alkyl (meth)acrylate represented by the following general formula 1, a silicone (meth)acrylate represented by the following general formula 2, and a methoxypolyethylene glycol (meth)acrylate represented by the following general formula 3; (2) contacting the coating solution with the surface of a medical device made of a silicone-based substrate; and (3) drying the coating solution to immobilize the antithrombogenic material on the surface of the medical device, wherein the Hansen Solubility Parameter (HSP) distance between the solvent and the silicone-based substrate is 17 MPa. ０．５ and the boiling point of the solvent is 90°C or less. (In the formula, R １ is an alkyl group having 8 to 12 carbon atoms, R ２ represents a hydrogen atom or a methyl group.) (In the formula, R ３ is a hydrogen atom or a methyl group, R ４ is an alkylene group having 1 to 6 carbon atoms, R ５ represents an alkyl group having 1 to 6 carbon atoms, and n represents an integer of 1 to 30. (In the formula, R ６ represents a hydrogen atom or a methyl group, and n represents an integer of 2 to 4.) [2] The method for producing a medical device according to [1], wherein the concentration of the (meth)acrylate copolymer in the coating solution is 0.01% by mass or more and 10% by mass or less. [3] The method for producing a medical device according to [1] or [2], wherein the contact angle of water on the surface of the medical device is 45° to 100°. [4] The method for producing a medical device according to any of [1] to [3], wherein the silicone-based base material is a silicone resin and / or a silicone rubber. [5] The method for producing a medical device according to any of [1] to [4], wherein the medical device is a catheter.

[0012] According to the present invention, at least a portion of the body fluid contact portion of a silicone-based medical device, which is prone to the "repellent phenomenon," is coated with an antithrombotic material containing a (meth)acrylate copolymer containing a hydrophilic (meth)acrylate and a hydrophobic (meth)acrylate, thereby effectively suppressing the blood coagulation system, platelet adhesion and activation, and activation of the complement system, thereby providing a medical device with excellent antithrombotic properties.

[0013] 1 is a schematic diagram for explaining the Hansen Solubility Parameter (HSP) distance. FIG. 2 is a schematic diagram for explaining the surface state of the medical device of the embodiment.

[0014] In the present invention, at least a portion of a body fluid-contacting portion of a medical device made of a silicone-based substrate is coated with an antithrombotic material containing a (meth)acrylate copolymer. The antithrombotic material containing a (meth)acrylate copolymer is applied to an artificial material containing a silicone-based substrate (material) to suppress a foreign body reaction in the living body when the material comes into contact with body fluids such as blood. This purpose is achieved by having the antithrombotic material present on at least a portion of the body fluid-contacting portion. Furthermore, coating only the body fluid-contacting portion with the (meth)acrylate copolymer also increases cost benefits, such as minimizing costs.

[0015] In the present invention, the (meth)acrylate copolymer contains a hydrophobic (meth)acrylate and a hydrophilic (meth)acrylate, and therefore is durable against elution in blood. Here, "durable against elution in blood" means that when the (meth)acrylate copolymer is immersed in an alcohol immersion treatment solution at room temperature for 16 hours, a certain amount of the (meth)acrylate copolymer remains, thereby exhibiting antithrombogenicity. If a predetermined amount of the (meth)acrylate copolymer remains after immersion in an alcohol immersion treatment solution at room temperature for 16 hours, it can be determined that the copolymer has (maintains) sufficient antithrombogenicity even when in contact with blood at 37°C for 30 days.

[0016] In the present invention, the hydrophobic (meth)acrylate includes an alkyl (meth)acrylate represented by the following general formula 1. In the following general formula 1, R １ is an alkyl group having 8 to 12 carbon atoms, and R ２is a hydrogen atom or a methyl group. Specific examples of such alkyl(meth)acrylates include normal hexyl(meth)acrylate, cyclohexyl(meth)acrylate, phenyl(meth)acrylate, benzyl(meth)acrylate, heptyl(meth)acrylate, octyl(meth)acrylate, 2-ethylhexyl(meth)acrylate, nonyl(meth)acrylate, decyl(meth)acrylate, lauryl(meth)acrylate, myristyl(meth)acrylate, palmityl(meth)acrylate, and stearyl(meth)acrylate. From the viewpoints of cost and performance, however, 2-ethylhexyl(meth)acrylate and lauryl(meth)acrylate are preferred. (In the formula, R １ is an alkyl group having 8 to 12 carbon atoms, R ２ represents a hydrogen atom or a methyl group.)

[0017] In the present invention, the hydrophobic (meth)acrylate includes a silicone (meth)acrylate represented by the following general formula 2. In the following general formula 2, R ３ is a hydrogen atom or a methyl group, and R ４ is an alkylene group having 1 to 6 carbon atoms, and R ５ is an alkyl group having 1 to 6 carbon atoms. The silicone (meth)acrylate of the present invention has 1 to 30 repeating dimethylsiloxane units. If the repeating units are too large, the viscosity of the resulting (meth)acrylate copolymer may become too high, making it difficult to handle. If the repeating units are too small, the viscosity may become too low, and the copolymer may easily disappear from the coating surface of the medical device. From this perspective, the number of repeating dimethylsiloxane units is preferably 1 to 20. (In the formula, R ３ is a hydrogen atom or a methyl group, R ４ is an alkylene group having 1 to 6 carbon atoms, R ５ represents an alkyl group having 1 to 6 carbon atoms, and n represents an integer of 1 to 30.

[0018] In the present invention, the hydrophilic (meth)acrylate includes a methoxypolyethylene glycol (meth)acrylate represented by the following general formula 3. In the following general formula 3, R６ is a hydrogen atom or a methyl group. Furthermore, the methoxypolyethylene glycol (meth)acrylate of the present invention has 2 to 10 repeating ethylene oxide units. Specific examples 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. If the repeating units are too large and hydrophilicity increases too much, the resulting (meth)acrylate copolymer will be more likely to leach into blood, potentially leading to easy detachment from medical devices. From this perspective, the number of repeating ethylene oxide units is preferably 2 to 5. Furthermore, methoxytetraethylene glycol (meth)acrylate having 4 repeating units of ethylene oxide and methoxytriethylene glycol (meth)acrylate having 3 repeating units of ethylene oxide are more preferred, and methoxytriethylene glycol (meth)acrylate having 3 repeating units of ethylene oxide is even more preferred. (In the formula, R ６ is a hydrogen atom or a methyl group, and n is an integer from 2 to 10.

[0019] Representative 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-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-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-methoxydiethylene glycol (meth)acrylate copolymer, 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 acrylate copolymer, silicone (meth)acrylate-lauryl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-lauryl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-nonyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-nonyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-nonyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-decyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-decyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymer, silicone (meth)acrylate-n-decyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer Polymers, silicone (meth)acrylate-stearyl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-stearyl (meth)acrylate-methoxytriethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-stearyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymers, silicone (meth)acrylate-lauryl (meth)acrylate-methoxydiethylene glycol (meth)acrylate copolymers,Examples of the copolymer include, but are not limited to, 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, and silicone (meth)acrylate-myristyl (meth)acrylate-methoxytetraethylene glycol (meth)acrylate copolymer. These (meth)acrylate copolymers are (meth)acrylate copolymers composed of alkyl (meth)acrylate units represented by the above general formula 1, silicone (meth)acrylate units represented by the above general formula 2, and methoxypolyethylene glycol (meth)acrylate units represented by the above general formula 3 in a molar ratio of 80 to 20 / 10 to 0.01 / 79.99 to 10. If the amount of hydrophobic (meth)acrylate is too small, the resulting (meth)acrylate copolymer will be more likely to dissolve in blood, etc. If the amount of hydrophobic (meth)acrylate is too large, the blood compatibility of the hydrophilic (meth)acrylate may not be fully exhibited. Therefore, the molar ratio of the alkyl (meth)acrylate units represented by the general formula 1 above, the silicone (meth)acrylate units represented by the general formula 2 above, and the methoxypolyethylene glycol (meth)acrylate units represented by the general formula 3 above is more preferably 80 to 50 / 5 to 0.01 / 49.99 to 15, even more preferably 77 to 55 / 5 to 0.01 / 44.99 to 18, and even more preferably 73 to 57 / 5 to 0.01 / 42.99 to 22.

[0020] While the molecular weight of a copolymer can be expressed by number-average molecular weight or weight-average molecular weight, the weight-average molecular weight is used as the indicator in the present invention because it has a greater effect on stability, adhesion, etc. If the weight-average molecular weight is too low, not only may the resulting (meth)acrylate copolymer be easily eluted into blood, but the strength and stability of the coating film may be lost. Furthermore, a higher weight-average molecular weight increases the viscosity of the coating solution when it is prepared, which has the secondary effect of improving adhesion to silicone-based substrates. From this perspective, the weight-average molecular weight of the (meth)acrylate copolymer is preferably 50,000 or more. Furthermore, to improve workability when coating medical devices with the (meth)acrylate copolymer, the weight-average molecular weight of the (meth)acrylate copolymer is preferably 1,500,000 or less. The weight-average molecular weight of the (meth)acrylate copolymer is more preferably 1,000,000 or less, and even more preferably 500,000 or less. Setting the weight-average molecular weight of the (meth)acrylate copolymer to 50,000 or more and 1,500,000 or less is also a very important technical requirement for achieving specific technical objectives related to the purification of the (meth)acrylate copolymer, handling of the treatment solution, adaptability to medical devices, stability of the coating film, etc. Methods for measuring the weight-average molecular weight include end-group determination method, osmometry, vapor pressure osmometry, vapor pressure depression method, freezing point depression method, boiling point elevation method, gel permeation chromatography (GPC) method, etc., but in the present invention, it is preferable to employ the commonly used method of gel permeation chromatography (GPC) method from the viewpoint of ease of operation.

[0021] In the present invention, the reduced viscosity (ηsp / C) of the (meth)acrylate copolymer is preferably 0.140 dL / g or more and 3.000 dL / g or less. By using a (meth)acrylate copolymer (antithrombogenic material) within this viscosity range, when it is coated onto a medical device made of a silicone-based substrate, such as an artificial heart-lung circuit or a catheter, excellent adhesion between the (meth)acrylate copolymer and the medical device is achieved, enabling the antithrombogenicity to be maintained over long-term use. The reduced viscosity range is more preferably 0.140 dL / g or more and 1.500 dL / g or less, and even more preferably 0.140 dL / g or more and 0.500 dL / g or less.

[0022] Here, as can be seen from its basic skeleton, the silicone contained in silicone (meth)acrylate has excellent heat resistance, cold resistance, etc., and a low glass transition temperature (Tg), thereby offering the advantage of stable properties over a wide temperature range. Silicone also has the advantage of being resistant to acids and alkalis and highly chemically stable due to its large bond energy. Furthermore, silicone 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 recently been recognized as a material highly safe for living organisms, having been adopted as a contact lens material. Therefore, it is believed that the silicone (meth)acrylate content in an antithrombogenic material is not too high and therefore a composition such as a silicone (meth)acrylate-methoxypolyethylene glycol (meth)acrylate copolymer may also be considered as an antithrombogenic material. However, due to the relatively high raw material cost of silicone (meth)acrylate, using silicone (meth)acrylate alone as a hydrophobic (meth)acrylate may be disadvantageous in terms of cost-effectiveness. Therefore, taking into consideration performance, quality, cost, etc. comprehensively, the content of silicone (meth)acrylate in the hydrophobic (meth)acrylate contained in the (meth)acrylate copolymer is preferably 50% by mass or less, more preferably 40% by mass or less, and even more preferably 35% by mass or less. On the other hand, if the content of silicone (meth)acrylate in the hydrophobic (meth)acrylate contained in the (meth)acrylate copolymer is too low, hydrolysis may proceed during storage, resulting in a decrease in long-term stability as an antithrombotic material. Therefore, the content of silicone (meth)acrylate in the hydrophobic (meth)acrylate contained in the (meth)acrylate copolymer 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.

[0023] The (meth)acrylate copolymer of the present invention may be a (meth)acrylate copolymer in which the monomer of the above general formula 1 and the monomer of the above general formula 2 or 3 are arranged alternately, but when analyzed from the total amount, it may also be a (meth)acrylate copolymer consisting of segments or blocks of hydrophobic monomers and segments or blocks of hydrophilic monomers. It is conceivable that the segments or blocks of hydrophobic monomers may function to fix the segments or blocks of hydrophilic monomers, and may have a complex structure such as a so-called microphase separation structure or a mosaic pattern structure. Regardless of the structure that can be conceived, the molecular weight of each monomer, the type and characteristics of the hydrophilic monomer, etc. may have some influence, but by making the amount of hydrophobic monomer slightly larger than the amount of hydrophilic monomer, it is possible to suppress the elution of the segments or blocks of the hydrophilic monomers of the (meth)acrylate copolymer. Furthermore, slightly increasing the amount of hydrophobic segments is thought to also serve the function of increasing affinity with hydrophobic medical devices, and it can be assumed that they will play an advantageous role in adhering to medical devices as a coating. Although the behavior related to the presence or absence of segments and the state of their affinity cannot currently be accurately verified based on technical grounds, (meth)acrylate copolymers are thought to be polymeric materials with biocompatible affinity. The (meth)acrylate copolymer of the present invention preferably comprises units consisting of hydrophobic (meth)acrylate and units consisting of hydrophilic (meth)acrylate in a molar ratio of 90:10 to 20.01:79.99.

[0024] In the present invention, the antithrombotic material containing a (meth)acrylate copolymer may contain other substances such as an antibacterial substance. The antibacterial substance is preferably contained in an amount of 0.01% by mass or more and 10% by mass or less relative to the mass of the (meth)acrylate copolymer. If the content of the antibacterial substance is too low, the antibacterial properties of the antibacterial substance may not be fully exhibited. Furthermore, if the content of the antibacterial substance is too high, the medical device may have a poor appearance after surface treatment such as coating, or the elution of the antibacterial substance into the patient's body may increase, causing local inflammation due to the eluted antibacterial substance. While the antibacterial substance may be present on the entire surface of the medical device, it is preferable to have it present only near the insertion site where the skin is inserted in order to suppress local inflammation.

[0025] The (meth)acrylate copolymer of the present invention may be any of a random copolymer, a block copolymer, and a graft copolymer. The copolymerization reaction for producing the (meth)acrylate copolymer of the present invention is not particularly limited, and known methods such as radical polymerization, ionic polymerization, photopolymerization, and polymerization using a macromer can be used.

[0026] In the present invention, a production method using radical polymerization is shown below as an example of how to produce a (meth)acrylate copolymer. For example, a monomer, solvent, and polymerization initiator are added to a stirrable reaction apparatus equipped with a reflux tower, and polymerization is initiated by heating after nitrogen substitution. The polymerization is allowed to proceed by maintaining that temperature for a certain period of time. A chain transfer agent can also be used during this polymerization to control the molecular weight. After polymerization is complete, the solvent is removed from the solution to obtain a crude (meth)acrylate copolymer. The crude (meth)acrylate copolymer is then stirred in a poor solvent for purification. The purification process is repeated one to several times to increase the purity of the (meth)acrylate copolymer. The (meth)acrylate copolymer obtained in this manner is then dried.

[0027] The solvent used in the copolymerization may be alcohols such as methanol, ethanol, isopropyl alcohol, or organic solvents such as ethyl acetate, toluene, benzene, or methyl ethyl ketone, or water. However, in the present invention, ethyl acetate, methanol, ethanol, or the like is preferred from the viewpoints of the solubility of each monomer and the resulting (meth)acrylate copolymer, ease of availability, etc. Furthermore, a mixture of multiple types of the above solvents may also be used. The mass ratio of the solvent to the monomer charged is preferably 20 to 90 / 60 to 10. If the charge ratio is within the above range, the polymerization reaction rate can be maximized.

[0028] As the polymerization initiator, peroxide-based or azo-based radical initiators commonly used in radical polymerization are used. Examples of peroxide-based radical initiators include inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide, and organic peroxides such as benzoyl peroxide, t-butyl hydroperoxide, and cumene peroxide. Examples of azo-based radical initiators include 2,2'-azobisisobutyronitrile, 2,2'-azobis(2-aminodipropane) dihydrochloride, dimethyl 2,2'-azobisbutyrate, and dimethyl 2,2'-azobis(2-methylpropionate). Redox-based polymerization initiators, which combine a peroxide-based polymerization initiator with a reducing agent, can also be used. These polymerization initiators are preferably added in an amount of 0.01% by mass or more and 1.0% by mass or less relative to the monomer. By adding the polymerization initiator in the above range, a (meth)acrylate copolymer having an appropriate weight-average molecular weight can be obtained with a good monomer reaction rate.

[0029] The temperature during polymerization varies depending on the type of solvent and the type of polymerization initiator, but is preferably set to around the 10-hour half-life temperature of the polymerization initiator. Specifically, when the above-mentioned polymerization initiator is used, the temperature is preferably 20°C or higher and 90°C or lower. As a chain transfer agent used to control the molecular weight during polymerization, high-boiling thiol compounds such as dodecyl mercaptan, thiomalic acid, and thioglycolic acid, isopropyl alcohol, phosphorous acid, hypophosphorous acid, etc. can be used.

[0030] In the present invention, the (meth)acrylate copolymer is produced by copolymerizing a hydrophilic monomer and a hydrophobic monomer, and therefore possesses both hydrophilic and hydrophobic properties. Therefore, the solution after copolymerization contains a mixture of unreacted hydrophilic monomers (methoxypolyethylene glycol (meth)acrylate), hydrophobic monomers (silicone (meth)acrylate, and optionally alkyl (meth)acrylate), and the (meth)acrylate copolymer. To isolate the water-insoluble (meth)acrylate copolymer from this mixture, for example, purification can be carried out by dropping a solution containing the (meth)acrylate copolymer into a solvent that dissolves the hydrophilic monomer, and then purifying the (meth)acrylate copolymer using a solvent that dissolves the hydrophobic monomer. Alternatively, the (meth)acrylate copolymer can be efficiently recovered by using a reprecipitation poor solvent, which is a mixture of alcohol and water in a specific ratio. Furthermore, a purification method can also be employed in which a poor solvent is added to a water-insoluble (meth)acrylate copolymer made of a mixture of alcohol and water in a specific ratio in a solution after the polymerization reaction is completed, and the mixture is stirred at a constant temperature to separate the (meth)acrylate copolymer, and then the precipitate is recovered by decantation, and a washing liquid is added and the same method is repeated.

[0031] In the present invention, the poor solvent used to purify the (meth)acrylate copolymer is preferably a poor solvent that does not dissolve the (meth)acrylate copolymer but can dissolve both the hydrophilic monomer and the hydrophobic monomer.

[0032] In the present invention, the alcohol used in the reprecipitation treatment is preferably an alcohol having 1 to 10 carbon atoms. Specific examples of such alcohols include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methoxy-1-propanol, and tertiary butanol. However, methanol, ethanol, 1-propanol, and 2-propanol are more preferred because they allow drying at low temperatures and in a short time.

[0033] In the present invention, the amount of residual monomer (the amount of unreacted monomer in the polymerization) in the (meth)acrylate copolymer is important because it affects safety. Naturally, reducing the amount of residual monomer in the antithrombotic material will meet the standards set forth in the guidelines regarding the elution of residual monomer from medical devices. However, an unexpected effect is that reducing the amount of residual monomer to an extremely low level of 4,000 ppm or less leads to improved adhesion and retention of the (meth)acrylate copolymer on the surface of the medical device. Considering patient safety, the amount of residual monomer in the (meth)acrylate copolymer is preferably 3,000 ppm or less, more preferably 2,000 ppm or less, and even more preferably 1,000 ppm or less.

[0034] In the present invention, the volume ratio of the crude (meth)acrylate copolymer to the poor solvent is preferably 1: 1 to 1: 20. When the volume ratio is within the above range, the purification efficiency and recovery rate can be maximized.

[0035] In the present invention, the temperature during purification of the crude (meth)acrylate copolymer is preferably 30° C. or higher and 60° C. or lower. When the temperature during purification is within the above range, the viscosity of the crude (meth)acrylate copolymer decreases by heating, facilitating separation from the poor solvent, and the recovery rate of the (meth)acrylate copolymer can be maximized.

[0036] In the present invention, the recovery rate of the (meth)acrylate copolymer after the purification treatment is preferably 20 to 90%. This is because if the recovery rate of the (meth)acrylate copolymer after the purification treatment exceeds 90%, there is a risk of unreacted monomers being contained in the recovered material, and if it is below 20%, production efficiency decreases. Although limiting this recovery rate to 20 to 90% means that some of the (meth)acrylate copolymer is lost or discarded, this is a consideration from the perspective of preventing contamination with unreacted monomers as much as possible. This is due to the unique circumstances of obtaining a (meth)acrylate copolymer that combines hydrophilic and hydrophobic properties for use in medical devices.

[0037] In order to use the purified (meth)acrylate copolymer to impart antithrombotic properties to a medical device, it is necessary to remove the solvent by drying. The drying method can be, for example, at 60°C under a reduced pressure of 1 Torr or less. If sufficient drying is not achieved, subsequent drying under reduced pressure can be performed.

[0038] The resulting (meth)acrylate copolymer is water-insoluble and can be preferably used as a surface treatment agent for medical devices, etc. Specifically, the antithrombogenic material can be obtained by dissolving the resulting (meth)acrylate copolymer in a solvent such as an organic solvent, applying the resulting solution (suspension) to at least a portion of the surface of a medical device made of a silicone-based substrate, and then removing the solvent. Methods for immobilizing (supporting) the antithrombogenic material on the surface of a medical device include known methods such as coating, graft polymerization using radiation, electron beams, ultraviolet rays, etc., and chemical reactions with functional groups on the substrate. Among these, coating is practically preferred due to its easy manufacturing process. The coating method is not particularly limited, and examples include application, spraying, and dipping. For example, application can be performed by simple procedures such as contacting a substrate such as a medical device with a coating solution prepared by dissolving the antithrombogenic material in a suitable organic solvent, removing excess solution, and then air-drying. It is also preferable to heat and dry the coated substrate. This allows the adhesion between the substrate and the antithrombotic material of the present invention to be further increased, resulting in more firmly fixed structure.

[0039] In the present invention, when coating a medical device with an antithrombotic material by a coating method, the concentration of the (meth)acrylate copolymer in the coating solution is preferably 0.01% by mass or more and 10% by mass or less. If the concentration of the (meth)acrylate copolymer in the coating solution is too low, it may be impossible to uniformly coat the body fluid-contacting portion of the medical device in a single coating process, or the amount of coating may be too small to exhibit the desired antithrombotic properties. On the other hand, if the concentration of the (meth)acrylate copolymer in the coating solution is too high, it may lead to increased costs in manufacturing the medical device. The concentration of the (meth)acrylate copolymer in the coating solution is more preferably 0.05% by mass or more and 7% by mass or less, and even more preferably 0.1% by mass or more and 5% by mass or less. The coating process may be performed multiple times.

[0040] Conventionally, ethanol or the like has been used as a solvent when coating a medical device with an antithrombogenic material. However, for example, when a solution of the antithrombogenic material in ethanol or the like is brought into contact with a medical device made of a silicone-based substrate, the silicone-based substrate repels the ethanol, making it impossible to uniformly coat the antithrombogenic material. The present inventors investigated the cause of this and found that, because the solubility parameters of ethanol and the silicone-based substrate are far apart, the coating solution containing ethanol is poorly wetted by the silicone-based substrate and is repelled, making it impossible to uniformly coat the silicone-based substrate with the antithrombogenic material. Generally, the shorter the distance between the solubility parameter of the silicone-based substrate (medical device) and the solubility parameter of the coating solvent, the better the wettability.

[0041] In the present invention, the Hansen solubility parameter (HSP) distance between the solvent that dissolves (suspends) the antithrombotic material and the silicone-based substrate (medical device) (the distance between the HSP coordinates of the coating solvent and the HSP coordinates of the silicone-based substrate in the Hansen space) is 17 MPa. ０．５ is preferably 15 MPa or less ０．５ More preferably, it is 10 MPa or less. ０．５ The following is the result.

[0042] According to the study by the inventors, the above HSP distance is 17 MPa. ０．５ If the content is below this level, it is possible to increase the affinity between the coating solvent and the silicone-based substrate, and the surface of the silicone-based substrate can be uniformly coated with the antithrombotic material without causing swelling or deterioration of the silicone-based substrate.

[0043] The Hansen Solubility Parameter (HSP) is an index of affinity that indicates how easily a substance gets along with another substance. Affinity is expressed as a multidimensional vector, and substances with similar vectors are considered to have high affinity with each other.

[0044] This vector is expressed as [dispersion term (dD), polar term (dP), hydrogen bond term (dH)]. The dispersion term (dD) is the van der Waals force (energy due to dispersion forces between molecules). The polar term (dP) is the force of the dipole moment (energy due to dipole interactions between molecules). The hydrogen bond term (dH) is the hydrogen bond force (energy due to hydrogen bonds between molecules) that water, alcohol, etc. possess. The unit of each vector (parameter) is "MPa" ０．５ "

[0045] As shown in Figure 1, the three parameters dD, dP, and dH can be considered as coordinates in a three-dimensional space (Hansen space). When the coordinates of the HSPs of two substances are placed in Hansen space, the closer the distance between the two points (HSP distance), the more easily they will fit together (higher affinity). The HSP vector (coordinates) of the solvent is [dD1, dP1, dH1], and the HSP vector (coordinates) of the silicone-based base material of the medical device is [dD2, dP2, dH2]. In this case, the HSP distance (the distance between the HSP coordinates of the solvent and the HSP coordinates of the silicone-based base material of the medical device in Hansen space) is calculated using the following formula: HSP distance = {4(dD1 - dD2) ２ +(dP1-dP2) ２ +(dH1-dH2) ２} ０．５

[0046] [Correction based on Rule 91, 13.06.2024] In the present invention, the solvent used to coat at least a portion of the body fluid-contacting portion of a medical device made of a silicone-based substrate with an antithrombotic material is one that has a relatively short HSP distance with silicone and a low boiling point, such as isopropyl alcohol, n-propyl alcohol, n-hexane, cyclohexane, tetrahydrofuran, 1,4-dioxane, cyclohexanone, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, with isopropyl alcohol, n-hexane, cyclohexane, and tetrahydrofuran being preferred, and cyclohexane being more preferred. Table 1 shows the HSP distance with silicone and the boiling points of various solvents.

[0047] [Amendment under Rule 91 13.06.2024]

[0048] When a medical device treated with an antithrombotic material comes into contact with blood, the highly hydrophilic methoxypolyethylene glycol (meth)acrylate protrudes from the surface and exerts its antithrombotic properties, while the hydrophobic (meth)acrylate remains in the vicinity of the silicone-based base material, preventing direct contact between the blood and the medical device.

[0049] Medical devices in which at least a portion of a body fluid contact portion is coated with an antithrombotic material can exhibit excellent antithrombotic properties. Examples of medical devices made of silicone-based substrates that can be used for such medical devices include blood filters, blood storage containers, blood circuits, indwelling needles, catheters, guidewires, stents, artificial lungs, dialysis machines, adhesion inhibitors, wound dressings, adhesives for biological tissue, and repair materials for biological tissue regeneration. Examples of silicone-based substrates include silicone resins and / or silicone rubbers.

[0050] In the present invention, when cyclohexane is used as a solvent, many polymer droplets with a relatively small area (small particles) adhere to the surface of the silicone-based substrate. If more polymer droplets adhere, when blood of a certain size adheres to the surface, it adheres to the polymer droplets, which is thought to lead to the exertion of antithrombotic properties on the surface (see Figure 2). In the present invention, the number of polymer droplets with an average diameter of 30 μm or more is 8 / mm ２ It is preferable that the number of particles is 15 or more per mm. ２ More preferably, 80 pieces / mm ２ On the other hand, if the number of polymer droplets is too large, adjacent droplets may bond together, making it impossible to obtain a uniform antithrombogenic surface. From this viewpoint, the number of polymer droplets with an average diameter of 30 μm or more is set to 300 / mm ２ Preferably, 250 pieces / mm or less ２ More preferably, 200 or less pieces / mm ２ The following is more preferable: By setting the content within the above range, it becomes possible to impart antithrombogenicity while reducing the amount (cost) of the antithrombogenic material used.

[0051] In the present invention, the contact angle of water on the surface of a medical device coated with an antithrombotic material is preferably 100° or less, more preferably 90° or less, and even more preferably 80° or less. The contact angle is preferably 45° or more, more preferably 50° or more, and even more preferably 55° or more. Since the antithrombotic material used in the present invention has an excellent balance between hydrophilicity and hydrophobicity (water repellency), it can be said that excellent antithrombotic properties can be exhibited when the contact angle of water on the surface of the medical device is within the above range.

[0052] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0053] (Production of Antithrombotic Material) 694.5 g of 2-ethylhexyl acrylate (EHA) (Toa Gosei Co., Ltd.) as the alkyl(meth)acrylate represented by general formula 1 and 694.5 g of silicone methacrylate (PDMSMA) (Gelest Co., Ltd., product name: MCR-M11) as the silicone(meth)acrylate represented by general formula 2 (where R ３ is CH ３ and R ４ is C ３ H ６ and R ５ is C ４ H ９where n is 11. 71.8 g of methoxypolyethylene glycol (meth)acrylate represented by general formula 3, and 471.8 g of methoxytriethylene glycol acrylate (MTEGA) (Shin-Nakamura Chemical Co., Ltd.) were prepared. 1.2325 g of azobisisobutyronitrile (AIBN) (Fujifilm Wako Pure Chemical Industries, Ltd.), a polymerization initiator, was added to these, and a polymerization reaction was carried out in 1628.3 g of ethanol (Kishida Chemical Co., Ltd.) at 85°C for 3 hours. After the polymerization reaction was completed, the mixture was dried at 85°C for 2 hours under normal pressure. It was then dried under reduced pressure at 60°C for 1 hour to obtain a concentrate. The resulting concentrate was divided into two equal parts, Concentrate A and Concentrate B. Next, 3162.7 g of methanol (Kishida Chemical Co., Ltd.) and 305.3 g of water were added to 612.1 g of Concentrate A 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 this precipitate and stirred for 30 minutes. After standing for 1.5 hours, the supernatant was removed by decantation. This process was repeated three times to obtain Precipitate A. The amounts of methanol used were 3161.7 g, 3161.4 g, and 3163.9 g, respectively. Similarly, 3162.3 g of methanol and 303.1 g of water were added to 614.4 g of concentrate B and stirred for 30 minutes. After stirring, the mixture was allowed to stand for 1.5 hours, and the supernatant was removed by decantation. This process was repeated three times in the same manner to obtain Precipitate B. The amounts of methanol used were 3165.5 g, 3167.5 g, and 3165.4 g, respectively. The resulting precipitates A and B were combined and dried under reduced pressure at 40°C for 1.5 hours to obtain (meth)acrylate copolymer 1. The molar ratio (mol %) of alkyl (meth)acrylate units, silicone (meth)acrylate units, and methoxypolyethylene glycol (meth)acrylate units in the resulting (meth)acrylate copolymer 1 was 67.4:1.7:30.9. The resulting (meth)acrylate copolymer 1 had a weight-average molecular weight of 68,300, a reduced viscosity of 0.214 dl / g, and a residual monomer content of 40 ppm. Furthermore, the HSP distance between the (meth)acrylate copolymer 1 and silicone was 6.71 MPa. ０．５It was confirmed that there was no problem with the compatibility (affinity) between (meth)acrylate copolymer 1 and silicone.

[0054] (Production of Coating Liquid) Treatment liquids 1 to 6 were obtained by adding a solvent to (meth)acrylate copolymer 1 and mixing thoroughly (see Table 2).

[0055]

[0056] Example 1 A silicone tube made of silicone rubber as a base material, having an inner diameter of 4 mm, an outer diameter of 6 mm, and a length of 10 cm, was immersed in treatment liquid 1 for 10 seconds, and treatment liquid 1 was brought into contact with the inner surface of the tube. The silicone tube was removed from treatment liquid 1, and air was applied to the inner cavity at a flow rate of 10 mL / min for 30 seconds to dry it. It was then dried at room temperature for 16 hours. Note that silicone tubes made of the same base material were also used in the following Examples 2-4 and Comparative Examples 1-3.

[0057] Example 2 A silicone tube having an inner diameter of 4 mm, an outer diameter of 6 mm, and a length of 10 cm was immersed in treatment liquid 2 for 10 seconds, bringing the treatment liquid 2 into contact with the inner surface of the tube. The silicone tube was removed from treatment liquid 2, and air was blown onto the inner cavity at a flow rate of 10 mL / min for 30 seconds to dry it. It was then dried at room temperature for 16 hours.

[0058] Example 3 A silicone tube having an inner diameter of 4 mm, an outer diameter of 6 mm, and a length of 10 cm was immersed in treatment liquid 3 for 10 seconds, bringing the treatment liquid 3 into contact with the inner surface of the tube. The silicone tube was removed from treatment liquid 3, and air was blown onto the inner cavity at a flow rate of 10 mL / min for 30 seconds to dry it. It was then dried at room temperature for 16 hours.

[0059] Example 4 A silicone tube having an inner diameter of 4 mm, an outer diameter of 6 mm, and a length of 10 cm was immersed in treatment liquid 4 for 10 seconds, bringing the treatment liquid 4 into contact with the inner surface of the tube. The silicone tube was removed from treatment liquid 4, and air was blown onto the inner cavity at a flow rate of 10 mL / min for 30 seconds to dry it. It was then dried at room temperature for 16 hours.

[0060] Comparative Example 1 A silicone tube having an inner diameter of 4 mm, an outer diameter of 6 mm, and a length of 10 cm was immersed in treatment liquid 5 for 10 seconds, and the treatment liquid 5 was brought into contact with the inner surface of the tube. The silicone tube was removed from treatment liquid 5, and air was blown onto the inner cavity at a flow rate of 10 mL / min for 30 seconds to dry it. It was then dried at room temperature for 16 hours.

[0061] Comparative Example 2 A silicone tube having an inner diameter of 4 mm, an outer diameter of 6 mm, and a length of 10 cm was immersed in treatment liquid 5 for 10 seconds to bring the inner surface of the tube into contact with treatment liquid 5. The silicone tube was removed from treatment liquid 5 and dried at room temperature for 16 hours.

[0062] Comparative Example 3 A silicone tube having an inner diameter of 4 mm, an outer diameter of 6 mm, and a length of 10 cm was immersed in treatment liquid 6 for 10 seconds, and the treatment liquid 6 was brought into contact with the inner surface of the tube. The silicone tube was removed from treatment liquid 6, and air was blown onto the inner cavity at a flow rate of 10 mL / min for 30 seconds to dry it. It was then dried at room temperature for 16 hours.

[0063] (Calculation of the number of coated droplets) The tubes obtained in Examples 1-4 and Comparative Examples 1-3 were cut to a length of approximately 1 cm, and then cut into a trough shape so that the inner surface of the tube could be observed. The tube was placed on the stage of an optical microscope (KEYENCE Digital microscope VHX-900; lens VH-100R or VH-Z20R used) so that it was concave, and an image of the inner lumen surface was taken. Next, using image processing software (Wayne Rasband ImageJ), the number of coated droplets was calculated based on the inner lumen surface area of ​​2.25 mm. ２ The number of droplets present in the tube lumen surface area (1.5 mm square) was counted. ２ The number of droplets per unit area was calculated. Measurements were taken at three locations along the length of the tube, and the average of the droplet counts at the three locations was taken as the number of coated droplets. Droplets with a diameter of less than approximately 30 μm were excluded because they may be counted as noise. The results are shown in Table 3.

[0064] (Contact Angle Measurement) The tubes obtained in Examples 1-4 and Comparative Examples 1-3 were cut to a length of approximately 2 mm and then cut into a trough shape. The trough-shaped tube was placed on the stage of a simple contact angle meter (KRUSS DSA25S) so that it formed a concave shape, 0.5 μL of water was dropped, and the water contact angle was measured after 30 seconds. Dedicated software (KRUSS ADVANCE) was used to analyze the water contact angle. The water contact angle was calculated as the average value of five points. The results are shown in Table 3.

[0065] (Blood Coagulation Test) 800 μL of preserved rabbit blood (product number: 003-00053-01, Japan Bio-Ceram Co., Ltd.) was added to a 1.5 mL centrifuge tube. 66.6 μL of 80 mM calcium chloride solution was added and thoroughly stirred to prepare the test blood solution. The silicone rubber sheets obtained in Examples 1-4 and Comparative Examples 1-3 were placed on plastic petri dishes. The plastic petri dishes were placed in a water bath set to 37°C. 200 μL of the test blood solution was added to the untreated and treated portions of the silicone rubber sheet. The sheet was then incubated at 37°C for 25 minutes. After incubation, the silicone rubber sheet was submerged in 100 mL of physiological saline (Otsuka Pharmaceutical Co., Ltd.) and gently shaken. The number of blood clots adhering to the surface of the silicone rubber sheet was counted after it was removed from the physiological saline. If blood clots were found to adhere to 4 or fewer silicone rubber sheets out of 10, the antithrombogenicity (blood compatibility) was judged to be excellent, if 5 to 7 or fewer were found to adhere, it was judged to be fair, and if 8 or more were found to adhere, it was judged to be poor. The results are shown in Table 3.

[0066]

[0067] From the results shown in Table 3, the HSP distance with the silicone-based substrate is 17 MPa. ０．５ By using the following solvent (cyclohexane) to coat the antithrombogenic material, it is possible to uniformly disperse relatively small droplets (antithrombogenic material) on the treated surface, probably because the balance between wetting and repellency is optimized, and it is clear that excellent antithrombogenicity is exhibited.

[0068] In the medical device of the present invention, at least a portion of the body fluid contact area is coated with an antithrombotic material containing a (meth)acrylate copolymer containing a hydrophilic (meth)acrylate and a hydrophobic (meth)acrylate, and the blood coagulation system, platelet adhesion and activation, and activation of the complement system are effectively suppressed, making it possible to provide a medical device with excellent antithrombotic properties.

Claims

1. (1) preparing a coating solution by dissolving an antithrombotic material containing a (meth)acrylate copolymer containing an alkyl (meth)acrylate represented by the following general formula 1, a silicone (meth)acrylate represented by the following general formula 2, and a methoxypolyethylene glycol (meth)acrylate represented by the following general formula 3 in a solvent; (2) contacting the coating solution with at least a portion of the surface of a medical device made of a silicone-based substrate; (3) drying the coating solution to immobilize the antithrombogenic material on at least a portion of the surface of the medical device; Including, The Hansen Solubility Parameter (HSP) distance between the solvent and the silicone-based substrate is 17 MPa. ０．５ and the boiling point of the solvent is 90°C or less. 【Chemistry 1】 (In the formula, R １ is an alkyl group having 8 to 12 carbon atoms, R ２ represents a hydrogen atom or a methyl group.) 【Chemistry 2】 (In the formula, R ３ is a hydrogen atom or a methyl group, R ４ is an alkylene group having 1 to 6 carbon atoms, R ５ represents an alkyl group having 1 to 6 carbon atoms, and n represents an integer of 1 to 30. 【Transformation 3】 (In the formula, R ６ represents a hydrogen atom or a methyl group, and n represents an integer of 2 to 4.

2. 2. The method for producing a medical device according to claim 1, wherein the concentration of the (meth)acrylate copolymer in the coating solution is 0.01% by mass or more and 10% by mass or less.

3. 3. The method for manufacturing a medical device according to claim 1, wherein the contact angle of water on the surface of the medical device is 45° to 100°.

4. 3. The method for producing a medical device according to claim 1, wherein the silicone-based base material is a silicone resin and / or a silicone rubber.

5. 3. The method for manufacturing a medical device according to claim 1, wherein the medical device is a catheter.

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