JP6426625B2 - Antithrombotic medical material and medical device using the medical material - Google Patents

Description

  The present invention relates to an antithrombotic medical device and a medical device using the medical material. More specifically, the present invention relates to a medical material containing a copolymer having a specific repeating unit, and a medical device using the medical material.

  In recent years, medical materials using various polymer materials have been studied, and are used for membranes for artificial kidneys, membranes for plasma separation, catheters, stents, membranes for artificial lungs, artificial blood vessels, adhesion preventive films, artificial skin etc. The use of is expected. In these cases, synthetic polymer materials, which are foreign substances for living bodies, are used in contact with body fluids such as living tissues and blood. Therefore, the medical material is required to be biocompatible. Although the biocompatibility required for medical materials varies depending on the purpose and method of use, medical materials used as materials in contact with blood include suppression of blood coagulation system, suppression of platelet adhesion and activation, activity of complement system It is required to have antithrombotic properties (antithrombotic).

  Usually, the provision of antithrombotic properties to a medical device is carried out by a method of coating a substrate constituting the medical device with an antithrombotic material, or a method of fixing the antithrombotic material to the surface of the substrate.

  For example, in JP-A-4-152952, a synthetic polymer that simultaneously satisfies biocompatibility such as suppression of adhesion and activation of platelets, suppression of activation of complement system, and affinity with in vivo tissue is provided on the surface. A membrane or medical device for artificial organ used in contact with the in vivo tissue or blood is disclosed.

  In medical devices that contact blood for a long time such as artificial blood vessels, artificial organs, etc., antithrombogenicity to prevent blood coagulation is very important. However, in a medical device having a step (step surface) on the surface in contact with blood, blood flow is stagnant at a portion (step portion) having the step surface, and thus thrombus tends to be formed around the step portion. For example, in a blood channel of a medical device, blood flow tends to be stagnant around a constriction portion such as a junction of a tube used for the medical device, and a thrombus is relatively easily formed.

  The invention disclosed in JP-A-4-152952 shows good results in terms of suppression of adhesion and activation of platelets. However, for example, under severe conditions in which a thrombus is relatively easily formed as described above, the antithrombotic properties may not be sufficient in the invention disclosed in JP-A-4-152952.

  Therefore, the present invention has been made in view of the above-mentioned circumstances, and an object thereof is to provide a medical material, in particular, having improved antithrombotic properties under severe conditions in which thrombus is easily formed.

As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by a medical material containing a copolymer having a specific repeating unit, and the present invention has been completed. It reached. The present invention uses the following contents as its main points.
(1) The following formula (1):

However, in the formula (1), R ¹¹ is a hydrogen atom or a methyl group; and a repeating unit (A) represented by the following formula (2):

However, in formula (2), R ²¹ is a hydrogen atom or a methyl group, R ²² is an alkylene group having 1 to 4 carbon atoms, and R ²³ is an alkyl group having 1 to 4 carbon atoms; A medical material comprising a copolymer having a repeating unit (B).
(2) The medical material according to (1), wherein the repeating unit (A) is 2.5 to 17.0% by mole in all constituent units of the copolymer.
(3) The medical material according to (1) or (2), wherein R ¹¹ is a hydrogen atom in the formula (1).
(4) The copolymer comprises 2.5 to 17.0 mol% of the repeating units (A), and 83.0 to 97.5 mol% of the repeating units (B) (the repeating units (A) And the total amount of the repeating units (B) is 100% by mole). The medical material according to any one of (1) to (3).
(5) A medical device having a substrate, and a coated layer containing the medical material according to any one of (1) to (4) on the surface of the substrate.

FIG. 1 shows a tube (step tube) connected at both ends with a connector used in the embodiment. In FIG. 1, a circled portion indicates a joint between the tube 1 and the tube 2. FIG. 2 is an enlarged view schematically showing a cross section in the long axis direction at the joint between the tube 1 and the tube 2 in FIG. FIG. 3 is an enlarged photograph of a joint immediately after an antithrombotic test on a stepped tube to which a medical material containing a polymer (2) manufactured in Example 2 is applied. FIG. 4 is an enlarged photograph of a joint immediately after an antithrombotic test on a stepped tube to which a medical material containing the comparative polymer (1) manufactured in Comparative Example 1 is applied. FIG. 5 is a photograph immediately after a blood circulation test for a blood circulation module to which the antithrombogenic material containing the polymer (3) produced in Example 3 is applied. FIG. 6 is a photograph immediately after a blood circulation test for a blood circulation module to which the antithrombogenic material containing the comparative polymer (1) produced in Comparative Example 1 is applied.

  The present invention relates to a medical material containing a copolymer having a specific repeating unit, and a medical device using the medical material.

  Hereinafter, embodiments of the present invention will be described. The present invention is not limited to the following embodiments. Also, the dimensional proportions of the drawings are exaggerated for the convenience of the description, and may differ from the actual proportions.

  Further, in the present specification, “X to Y” indicating a range means “X or more and Y or less”, and “weight” and “mass”, “weight%” and “mass%” and “weight part” and “ Parts by mass are treated as synonyms. Moreover, unless otherwise indicated, measurement of operation, a physical property, etc. is measured on the conditions of room temperature (20-25 degreeC) / 40 to 50% of relative humidity.

  The medical material according to the present invention includes a copolymer having a repeating unit (A) represented by the following formula (1) and a repeating unit (B) represented by the following formula (2).

  Formula (1):

In formula (1), R ¹¹ is a hydrogen atom or a methyl group, preferably a hydrogen atom. When R ¹¹ is a hydrogen atom, a medical material having particularly excellent antithrombotic properties is provided.

  Formula (2):

In formula (2), R ²¹ is a hydrogen atom or a methyl group, preferably a hydrogen atom.

In Formula (2), R ²² is a cyclic, linear or branched alkylene group having 1 to 4 carbon atoms, and preferably a linear or branched alkylene group having 1 to 4 carbon atoms. Specifically, a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group etc. are mentioned. Among them, in consideration of the antithrombotic property improving effect, a linear or branched alkylene group having 1 to 3 carbon atoms is preferable, and a methylene group or an ethylene group is particularly preferable.

In Formula (2), R ²³ is a cyclic, linear or branched alkyl group having 1 to 4 carbon atoms, and preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Specifically, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, cyclopropyl group and the like can be mentioned. Among them, in consideration of the antithrombotic property improving effect, a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, a methyl group or an ethyl group is more preferable, and a methyl group is more preferable. Is particularly preferred.

[Copolymer]
The copolymer contained in the medical material according to the present invention comprises a monomer forming the repeating unit (A) (hereinafter also referred to as “monomer a”) and a monomer forming the repeating unit (B) (hereinafter referred to as “monomer b” (Also referred to as ")" can be obtained by the polymerization reaction.

  Examples of the monomer a include N-vinylacetamide (NVA), and / or N-isopropenylacetamide and the like, and preferably N-vinylacetamide (NVA). These monomers may be used alone or in combination of two or more. By using N-vinylacetamide (NVA), medical materials can be provided with high antithrombotic properties.

  As monomer b, methoxymethyl acrylate, methoxyethyl acrylate (MEA), methoxypropyl acrylate, methoxybutyl acrylate, ethoxymethyl acrylate, ethoxyethyl acrylate, ethoxypropyl acrylate, ethoxybutyl acrylate, acrylic acid Propoxymethyl, Propoxyethyl acrylate, Propoxypropyl acrylate, Propoxybutyl acrylate, Butoxy methyl acrylate, Butoxy ethyl acrylate, Butoxy propyl acrylate, Butoxy butyl acrylate, Methoxy methyl methacrylate, Methoxy ethyl methacrylate, Methacrylic acid Methoxypropyl, methoxybutyl methacrylate, ethoxymethyl methacrylate, ethoxyethyl methacrylate, ethoxypropyl methacrylate, meta Ethoxy butyl acrylic acid, methacrylic acid propoxymethyl, propoxyethyl methacrylate, propoxypropyl, methacrylic acid propoxy butyl, methacrylate butoxymethyl, butoxyethyl methacrylate, butoxy propyl, methacrylic acid butoxybutyl, and the like. Monomer b is preferably methoxymethyl acrylate, methoxyethyl acrylate (MEA), ethoxymethyl acrylate, ethoxyethyl acrylate, methoxymethyl methacrylate, methoxyethyl methacrylate, ethoxymethyl methacrylate, and ethoxyethyl methacrylate. It is more preferably methoxyethyl acrylate (MEA) from the viewpoint of being easy to obtain. These monomers may be used alone or in combination of two or more.

  In the copolymer contained in the medical material according to the present invention, the ratio of the repeating unit (A) and the repeating unit (B) in all the structural units can be set arbitrarily, but the total structural units (100 mol%) of the copolymer Among them, for example, 1.0 to 40.0 mol% of the repeating unit (A) is contained, preferably 2.5 to 17.0 mol% of the repeating unit (A), and more preferably 3.0 to 15. 5 mol%. When the repeating unit (A) is 2.5 mol% or more in all the structural units of the copolymer, a medical material having high antithrombogenicity is provided even under severe conditions in which thrombus is easily formed . When the repeating unit (A) is 17.0 mol% or less, the medical device can be appropriately coated with the medical material, and the medical material applied to the medical device may be exfoliated from the substrate and mixed in blood. It can be prevented. The repeating unit (B) is contained, for example, in an amount of 60.0 to 99.0 mol%, preferably 83.0 to 97.5 mol%, and more preferably 84.5 to 57.5 mol%, based on the total constituent units of the copolymer. 97.0 mol% is included.

  The copolymer contained in the medical material according to the present invention is excellent in antithrombotic properties. Although not limiting the technical scope of the present invention, this mechanism is considered as follows. That is, the copolymer including the constituent unit (A) is more hydrophilic than the polymer formed only by the constituent unit (B), and a medical material containing the copolymer having such appropriate hydrophilicity It is considered that the application of the present invention to a medical device may improve the biocompatibility and suppress the formation of thrombus even when used under conditions where thrombus is likely to be formed.

  Therefore, according to the present invention, a medical material exhibiting excellent antithrombotic properties is provided, even when used under severe conditions in which thrombus is likely to be formed.

  In another embodiment, the medical material of the present invention may optionally be a copolymer of monomer a, monomer b, and other monomers copolymerizable therewith (hereinafter, also simply referred to as "other monomers"). Included in Examples of other monomers copolymerizable with the monomer a and the monomer b include acrylamide, N, N-dimethyl acrylamide, N, N-diethyl acrylamide, aminomethyl acrylate, aminoethyl acrylate, aminoisopropyl acrylate, diaminomethyl acrylate, and the like. Diaminoethyl acrylate, diaminobutyl acrylate, methacrylamide, N, N-dimethyl methacrylamide, N, N-diethyl methacrylamide, aminomethyl methacrylate, aminoethyl methacrylate, diaminomethyl methacrylate, diaminoethyl methacrylate, methyl acrylate, ethyl acrylate, isopropyl Acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethy Methacrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, carboxymethyl betaine methacrylate, ethylene, and propylene and the like.

  The proportion of repeating units derived from other monomers in the total constituent units of the copolymer is, for example, more than 0 mol% and 39.0 mol% or less, preferably more than 0 mol%, 14.5 It is less than mol%.

  The ratio of repeating units (A), repeating units (B), or repeating units derived from other monomers in the copolymer can be optionally adjusted by changing the ratio of monomers used in polymerization.

  In one embodiment of the invention, the copolymer is composed of recurring units (A) and recurring units (B). That is, in one embodiment of the present invention, the copolymer comprises 2.5 to 17.0 mol% of the repeating units (A), and 83.0 to 97.5 mol% of the repeating units (B) ( The total amount of the repeating unit (A) and the repeating unit (B) is 100 mol%.

  In another embodiment of the present invention, the copolymer comprises 3.0 to 15.5 mol% of said recurring units (A), and 84.5 to 97.0 mol% of said recurring units (B) (described above The total amount of the repeating unit (A) and the repeating unit (B) is 100 mol%.

  The end of the copolymer is not particularly limited and is appropriately determined by the type of the raw material used, but is usually a hydrogen atom. The structure of the copolymer is also not particularly limited, and may be any of a random copolymer, an alternating copolymer, a periodic copolymer, and a block copolymer.

  The weight average molecular weight of the copolymer is preferably 10,000 to 1,000,000. When it is contained in the said range, it is preferable from a soluble point. The weight average molecular weight of the copolymer is more preferably 50,000 to 500,000 in terms of the ease of coating of the coating layer. In the present invention, “weight average molecular weight” is a value measured by gel permeation chromatography (GPC) using polystyrene as a standard substance.

  The method for producing the copolymer contained in the medical material according to the present invention is not particularly limited. For example, known polymerization methods such as radical polymerization, anionic polymerization and cationic polymerization can be employed, and preferably radical polymerization which is easy to manufacture is used. As a method for producing a copolymer contained in the medical material according to the present invention, plasma polymerization by radiation or ultraviolet light may be employed to form a coat layer containing the copolymer on the surface of the substrate.

  The polymerization method of the monomer is usually one or two or more kinds of monomer a corresponding to the above repeating unit (A) (for example, N-vinylacetamide (NVA)) and the above monomer b corresponding to the above repeating unit (B) A method is employed in which one or two or more species of (for example, methoxyethyl acrylate (MEA)) and, if necessary, other monomers are copolymerized by stirring and heating with a polymerization initiator in a polymerization solvent .

  The polymerization temperature is preferably 30 ° C. to 100 ° C. from the viewpoint of molecular weight control. The polymerization reaction is usually carried out for 30 minutes to 24 hours.

  The polymerization solvent is preferably an aqueous solvent such as water; alcohols such as methanol, ethanol, propanol and n-butanol; polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol and dipropylene glycol; Preferably, it is methanol, ethanol or propanol. These may be used alone or in combination of two or more.

  The monomer concentration (solid content concentration) in the polymerization solvent is usually 10 to 90% by weight, preferably 15 to 80% by weight, based on the entire reaction solution. The monomer concentration relative to the polymerization solvent is the monomer a and the monomer b, and other monomers copolymerizable therewith (hereinafter referred to as “monomer a and monomer b, and these optionally copolymerized with these. Possible other monomers "refer to the concentration of the total weight of the) also referred to as" polymerized monomers ".

  The polymerization solvent to which the polymerization monomer has been added may be subjected to a degassing treatment before the addition of the polymerization initiator. In the degassing treatment, for example, a polymerization solvent to which a polymerization monomer is added may be bubbled with an inert gas such as nitrogen gas or argon gas for about 0.5 to 5 hours. In the case of the degassing treatment, the polymerization solvent to which the polymerization monomer is added may be heated to about 30 ° C. to 100 ° C.

  For the production of the copolymer, conventionally known polymerization initiators can be used, and although not particularly limited, for example, 2,2′-azobisisobutyronitrile, 2,2′-azobis (4 Azo polymerization initiators such as -methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis (2,4-dimethylvaleronitrile), etc .; potassium persulfate (KPS), sodium persulfate, ammonium persulfate, etc. Redox polymerization initiators combining an oxidant such as persulfate, hydrogen peroxide, t-butyl peroxide, peroxide such as methyl ethyl ketone peroxide with a reducing agent such as sodium sulfite, sodium bisulfite or ascorbic acid Can be used.

  The blending amount of the polymerization initiator is, for example, an amount of 0.0001 to 1 mole with respect to all the monomers (1 mole) used for producing the copolymer.

  Furthermore, chain transfer agents, polymerization rate modifiers, surfactants, and other additives may be appropriately used in polymerization, as necessary.

  The atmosphere in which the polymerization reaction is performed is not particularly limited, and the polymerization reaction may be performed in an atmosphere of inert gas such as nitrogen gas or argon gas. In addition, during the polymerization reaction, the reaction solution may be stirred.

  The copolymer after polymerization can be purified by a general purification method such as reprecipitation method, dialysis method, ultrafiltration method and extraction method.

  Although the copolymer after purification can also be dried by any method such as lyophilization, vacuum drying, spray drying, or heat drying, lyophilization or vacuum from the viewpoint of having less influence on the physical properties of the polymer. Drying is preferred.

The proportion of repeating units derived from the repeating unit (A), repeating unit (B), or other monomers in the obtained copolymer may be confirmed by NMR method, infrared spectrum analysis or the like. For example, in the case of a copolymer composed of the repeating unit (A) and the repeating unit (B), the repeating unit (A) and the repeating unit (B) in the copolymer are represented by the integration ratio in ¹ H-NMR Can analyze the ratio of Moreover, in measurement of < ¹ > H-NMR, when a peak overlaps, it can calculate using < ¹³ > C-NMR.

  It is preferable that the unreacted polymerization monomer contained in the obtained copolymer is 0.01 weight% or less with respect to the whole copolymer. The lower limit of the amount of unreacted polymerization monomer is preferably, but not limited to, 0% by weight. The content of residual monomers can be measured by methods known to those skilled in the art, such as high performance liquid chromatography.

  The medical material in the present invention may be used in the form of the obtained copolymer, or may be used after being processed into a gel form, a solution form or the like. For example, it can also be used as a medical material in the form of a coating agent in which a copolymer is dissolved in a solvent.

  When used in the form of a coating agent, the solvent used is not particularly limited as long as it can dissolve the copolymer, for example, water; alcohol solvents such as methanol, ethanol, isopropanol and butanol; chloroform, tetrahydrofuran, acetone, Non-proton donating organic solvents such as dioxane and benzene can be exemplified. The above solvents may be used singly or in combination of two or more. As the mixed solvent, a water-alcohol solvent is preferable, and particularly, a water-methanol mixed solvent is preferable.

  The amount of the copolymer contained in the coating agent can be arbitrarily set, and it can also be used as a solution in which the copolymer is dissolved to a saturated amount, for example, 0.01 to 60% by weight based on the entire coating agent , Preferably 0.1 to 50% by weight.

  The coating agent may be composed of the copolymer and the above-mentioned solvent, but may optionally contain other components such as a crosslinking agent, a thickener, a preservative, a pH adjuster and the like. By including the crosslinking agent, the copolymer can be more firmly immobilized on the substrate surface.

[Medical device]
In one embodiment of the present invention, a medical device using the above-mentioned medical material is provided. That is, one embodiment of the present invention provides a medical device having a substrate and a coat layer containing the above-mentioned medical material on the surface of the substrate.

  As the medical device according to the present invention, for example, an endoprosthesis-type endoprosthesis or treatment instrument, an extracorporeal circulation-type artificial organ, a catheter, a guide wire, etc. can be exemplified. Specifically, implanted medical devices such as artificial blood vessels, artificial trachea, stent artificial skin, artificial pericardium, etc. inserted or substituted into blood vessels or lumens; artificial heart systems, artificial lung systems, artificial heart-lung systems, artificial Artificial organ system such as kidney system, artificial liver system, immune modulation system; Indwelling needle, IVH catheter, catheter for medical fluid administration, thermodilution catheter, catheter for angiography, catheter for blood vessel dilation and dilator or introducer etc. Or catheters inserted or indwelled in blood vessels; or guide wires for these catheters, stylets, etc .; gastric tube catheters, feeding catheters, tube feeding tube (ED) tubes, urinary catheters, urinary catheters, balloon catheters , Including endotracheal suction catheters Catheters are inserted or indwelled in the living body tissues other than blood vessels, such as the suction catheter and drainage catheter; can be exemplified. In particular, it is suitably used as an artificial lung system in contact with a large amount of blood or as an artificial heart-lung system.

(Base material)
The medical device of the present invention has the above-mentioned medical material on the substrate surface. The material of the substrate is not particularly limited. For example, polyolefins such as polyethylene, polypropylene, ethylene-α-olefin copolymer and modified polyolefins; polyamides; polyimides; polyurethanes; polyethylene terephthalates (PET), polybutylene terephthalates (PBT) ), Polyesters such as polycyclohexane terephthalate, polyethylene-2,6-naphthalate; polyvinyl chloride; polyvinylidene chloride (PVDC); polycarbonate; polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene copolymer (ETFE), etc. And various polymer materials such as fluorocarbon resin, metals such as SUS, ceramics, carbon, and composite materials thereof.

  The shape of the substrate is appropriately selected in accordance with the application of the medical device and the like, and may be, for example, a tube, sheet, rod or the like. The form of the substrate is not limited to a molded body using the above-described materials alone, and may be used as a blended molded article, an alloyed molded article, a multilayered molded article, and the like. The substrate may be a single layer or may be laminated. Under the present circumstances, when a base material is laminated | stacked, the base material of each layer may be same or different. However, when it is desired to swell the substrate with a solvent to immobilize the copolymer firmly, at least as a material to be present on the surface of the substrate, the above-mentioned polymer material can be favorably swollen by the solvent, which is preferable.

  In the present invention, the “substrate surface” is a substrate surface facing body fluid such as living tissue and blood. By forming a coating layer having a copolymer on the substrate surface, the antithrombotic property of the substrate surface is improved. In the medical device according to the present invention, a coat layer having a copolymer may be formed on the surface of the base material facing body fluid such as a living tissue or blood, but the coat layer may also be formed on other faces. Does not interfere with

  In order to enhance the stability of the coating layer on the substrate surface, the substrate may be surface-treated before forming the coating layer on the substrate surface. As a method of surface treatment of the substrate, for example, a method of irradiating active energy ray (electron beam, ultraviolet ray, X-ray, etc.), a method of utilizing plasma discharge such as arc discharge, corona discharge, glow discharge, high electric field Methods of application, methods of applying ultrasonic vibration through polar liquid (water etc.), methods of treatment with ozone gas, etc. may be mentioned.

(Coat layer)
In the medical device according to the present invention, a coat layer containing the above-mentioned medical material is formed on the surface of a substrate.

  The formation of the coat layer on the substrate surface is achieved by coating the substrate surface by applying a coating solution containing the above-mentioned medical material (for example, the above-mentioned coating agent), or, as described above, polymerization comprising a polymerization monomer A solvent may be applied to the substrate surface to carry out plasma polymerization. From the viewpoint of easiness of production, it is preferable to form a coat layer by covering the substrate surface with a coating solution containing the above-mentioned medical material. The term "coating" refers not only to the form in which the entire surface of the substrate is completely covered by the coat layer, but also to the form in which a part of the surface of the substrate is covered by the coat layer, ie, the substrate surface It also includes a form in which a coating layer is attached to a part of.

  In the case of forming a coating layer by coating the substrate surface with a coating solution containing a medical material, the method of preparing the above-mentioned coating agent is appropriately referred to as a method of preparing a coating solution containing a medical material.

  The method of applying the coating liquid containing the medical material to the substrate surface may be a known method, and is not particularly limited. For example, dip coating, spraying, spin coating, dropping, doctor blade, brush Coating, roll coater, air knife coat, curtain coat, wire bar coat, gravure coat and the like can be mentioned.

  The thickness of the coating solution may be appropriately adjusted depending on the application of the medical device, and is not particularly limited, and is, for example, 0.1 μm to 1 mm.

  The coated layer is formed on the surface of the substrate by drying the surface of the substrate to which the coating solution containing the copolymer is applied. The drying step may be appropriately set in consideration of the glass transition temperature of the base material and the like, and is 15 to 50 ° C., for example. The atmosphere in the drying step is not particularly limited, and may be performed in the air or in an inert gas atmosphere such as nitrogen gas or argon gas.

  The effects of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples.

[Example 1: Copolymer of NVA and MEA (repeating unit (A): 1.5 mol%)]
Dissolve 5 g (38.4 mmol) of methoxyethyl acrylate (MEA) and 0.055 g (0.6 mmol) of N-vinylacetamide (NVA) in 25.5 g of methanol, place in a four-necked flask, and N ₂ at 50 ° C. Bubbling was performed for 1 hour.

  Thereafter, methanol in which a solution of 0.006 g of 2,2'-azobis (4-methoxy-2,4-dimethyl valeronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in 1 mL of methanol is dissolved in a polymerization monomer The solution was added and polymerized at 50 ° C. for 5 hours. The polymerization solution was added dropwise to diethyl ether, and the precipitated copolymer was recovered. The weight average molecular weight of the recovered copolymer was 195,000.

[Example 2: Copolymer of NVA and MEA (repeating unit (A): 3.3 mol%)]
5 g (38.4 mmol) of MEA and 0.11 g (1.3 mmol) of NVA were dissolved in 25.5 g of methanol, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour.

  Thereafter, methanol in which a solution of 0.006 g of 2,2'-azobis (4-methoxy-2,4-dimethyl valeronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in 1 mL of methanol is dissolved in a polymerization monomer The solution was added and polymerized at 50 ° C. for 5 hours. The polymerization solution was added dropwise to diethyl ether, and the precipitated copolymer was recovered. The weight average molecular weight of the recovered copolymer was 192,000.

[Example 3: Copolymer of NVA and MEA (repeating unit (A): 6.3 mol%)]
5 g (38.4 mmol) of MEA and 0.22 g (2.6 mmol) of NVA were dissolved in 25.5 g of methanol, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour.

  Thereafter, methanol in which a solution of 0.006 g of 2,2'-azobis (4-methoxy-2,4-dimethyl valeronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in 1 mL of methanol is dissolved in a polymerization monomer The solution was added and polymerized at 50 ° C. for 5 hours. The polymerization solution was added dropwise to diethyl ether, and the precipitated copolymer was recovered. The weight average molecular weight of the recovered copolymer was 188,000.

[Example 4: Copolymer of NVA and MEA (repeating unit (A): 15.0 mol%)]
5 g (38.4 mmol) of MEA and 0.58 g (6.8 mmol) of NVA were dissolved in 25.5 g of methanol, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour.

  Thereafter, methanol in which a solution of 0.006 g of 2,2'-azobis (4-methoxy-2,4-dimethyl valeronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in 1 mL of methanol is dissolved in a polymerization monomer The solution was added and polymerized at 50 ° C. for 5 hours. The polymerization solution was added dropwise to diethyl ether, and the precipitated copolymer was recovered. The weight average molecular weight of the recovered copolymer was 167,000.

[Example 5: Copolymer of NVA and MEA (repeating unit (A): 19.7 mol%)]
5 g (38.4 mmol) of MEA and 0.80 g (9.4 mmol) of NVA were dissolved in 25.5 g of methanol, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour.

  Thereafter, methanol in which a solution of 0.006 g of 2,2'-azobis (4-methoxy-2,4-dimethyl valeronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in 1 mL of methanol is dissolved in a polymerization monomer The solution was added and polymerized at 50 ° C. for 5 hours. The polymerization solution was added dropwise to diethyl ether, and the precipitated copolymer was recovered. The weight average molecular weight of the recovered copolymer was 148,000.

[Comparative Example 1: (Mono) polymer of MEA (repeating unit (A): 0 mol%)]
5 g (38.4 mmol) of MEA was dissolved in 25.5 g of methanol, placed in a four-necked flask, and N ₂ bubbling was performed at 50 ° C. for 1 hour.

  Thereafter, methanol in which a solution of 0.006 g of 2,2'-azobis (4-methoxy-2,4-dimethyl valeronitrile) (V-70, manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in 1 mL of methanol is dissolved in a polymerization monomer The solution was added and polymerized at 50 ° C. for 5 hours. The polymerization solution was dropped into diethyl ether, and the precipitated polymer was recovered. The weight average molecular weight of the recovered polymer was 130,000.

  The copolymer or the polymer obtained in Examples or Comparative Examples was purified by a reprecipitation method. Thereafter, these copolymers or polymers were dried by vacuum drying and subjected to the following test.

Test Example 1 Solubility test of polymer (copolymer or polymer)]
0.1 g of each of the copolymer or the polymer obtained in Examples or Comparative Examples was weighed out and placed in separate glass test tubes.

  5 g of physiological saline was added to the above test tube and stirred to check the solubility of the polymer. When observed visually, the polymer was considered insoluble in water if it maintained its form when placed in a glass test tube. When the insoluble component was absent or slightly turbid but dispersed, it was regarded as being dissolved in water.

  The results in Table 1 indicate that, even in the case of a copolymer containing a highly hydrophilic repeating unit (A), 17.0 mol% or less of the repeating unit (A) in all the structural units of the copolymer. It shows that it does not dissolve in saline.

  From this result, if the repeating unit (A) is 17.0 mol% or less in the total constituent units of the copolymer, the medical device can be appropriately coated with the medical material, and the medical material is peeled off from the substrate It can be seen that it is possible to prevent the contamination of blood more effectively.

[Test Example 2 Antithrombotic test]
(Preparation of coating agent)
A 0.5% by weight methanol solution was prepared for each of the copolymer or the polymer obtained in Examples or Comparative Examples, and used as a coating agent.

(Preparation of medical tools)
The ends 1 cm of the soft vinyl chloride tube (tube 2) with a total length of 5 cm x inner diameter 6 mm x outer diameter 9 mm were inserted into both ends of a 30 cm long x 8 mm inner diameter soft vinyl chloride tube (tube 1) to make a step tube .

  FIG. 1 shows the manufactured step tube. The circled portion in FIG. 1 indicates the joint between the tube 1 and the tube 2.

  FIG. 2 is an enlarged view schematically showing a joint between the tube 1 and the tube 2 in FIG. Since the inner diameter of the tube 2 is smaller than the inner diameter of the tube 1, the step surface 3 is formed. When blood is passed through the step tube, a thrombus is very likely to be formed on the step surface 3.

  Using the produced step tube as a substrate, the above-mentioned coating agent was passed through the step tube, and the coating agent was applied to the surface of the substrate. Thereafter, the step tube was dried at room temperature (25 ° C.) to form a coated layer containing a medical material on the substrate surface (step tube inner surface).

(Antithrombotic test)
In order to evaluate the antithrombotic property of the medical material under severe conditions in which thrombus is likely to be formed, the following test system was constructed using the above-mentioned step tube having a coated layer formed thereon.

  That is, the lumen of the above-mentioned step tube in which the coating layer was formed was filled with 6 ml of a solution (diluted blood) obtained by diluting human fresh blood twice with physiological saline. Both ends of the step tube were connected by connectors, fixed to a cylindrical rotating device, and rotated at 40 rpm for 2 hours. Thereafter, the circulating blood was removed from the stepped tube, and the state of thrombus adhesion to the junction (a stepped surface) of the tube 1 and the tube 2 was visually observed. Here, fresh blood refers to blood collected from a healthy human donor by whole blood transfusion for 30 minutes or less. In addition, no anticoagulant was added to fresh blood.

  3 shows the copolymer produced in Example 2, and FIG. 4 shows the joint immediately after the antithrombotic test for the step tube to which the medical material containing the polymer produced in Comparative Example 1 is applied. It is an enlarged picture. No thrombus formation was observed in the step tube to which the copolymer according to the present invention was applied (FIG. 3). On the other hand, in the step tube to which the polymer of Comparative Example 1 was applied, thrombus 4 was observed at the junction (FIG. 4).

  As shown in Table 2, FIG. 3, and FIG. 4, the medical material according to the present invention exhibits high antithrombotic properties.

  In particular, when the repeating unit (A) in the copolymer is 2.5 mol% or more, it is understood that particularly high antithrombotic properties can be obtained. In Example 5, the solubility of the medical material was high, so the medical device could not be coated properly. Therefore, antithrombotic properties could not be evaluated.

[Test 3: Blood circulation test using simulated product form]
The antithrombotic properties of the base material coated with the polymer (3) obtained in Example 3 and the comparative polymer (1) obtained in Comparative Example 1 were evaluated according to the following method.

(Preparation of coating agent)
The polymer (3) and the comparative polymer (1) were each dissolved in a water-alcohol (methanol) mixed solution at a concentration of 0.2% by weight to form a coating agent.

(Preparation of medical tools)
The above coating agent is used as a simulated product form (blood circulation module: blood external perfusion type hollow fiber artificial lung according to Example 1 disclosed in JP-A-11-114056; As an artificial lung having the structure disclosed in the above; filled with polypropylene, polyurethane, polycarbonate, and SUS as a substrate constituting a blood circulation route from the blood import side and allowed to stand for 120 seconds and then removed. Blow dry at room temperature (25 ° C.) for 240 minutes.

(Evaluation)
The blood circulation module was incorporated into an extracorporeal circulation circuit by connecting it to a blood storage tank using a connection tube (made of soft vinyl chloride, about 100 cm in length × 8 mm in inside diameter). Subsequently, 200 ml of Ringer's lactate solution was charged into the above-mentioned extracorporeal circulation circuit, and then 200 ml of heparinized human fresh blood was added. The concentration of heparin in the circulating blood was 0.5 unit / ml. It circulated at room temperature (25 ° C.) and 500 ml / min for 6 hours. One hundred twenty minutes after the start of circulation, blood was sampled from each blood circulation circuit to measure the concentration of thrombin antithrombin complex (TAT), which is an activation indicator of the blood coagulation system. The TAT concentration used the measurement kit by EIA method. A high TAT concentration indicates that the coagulant is in an activated state, and it can be said that thrombosis is likely to occur.

  In the blood circulation module coated with the polymer (3) of Example 3, the TAT concentration was lower than that of the blood circulation module coated with the comparative polymer (1) of Comparative Example 1. That is, it was confirmed that the activation of the blood coagulation system was low and the antithrombotic properties were excellent.

  After circulating for an additional 6 hours, the blood circulation route was washed with phosphate buffered saline (PBS), and the site where blood stagnation was observed. In the blood circulation module coated with the polymer (3) of Example 3, almost no thrombus adhesion was observed. On the other hand, in the blood circulation module coated with the comparative polymer (1) of Comparative Example 1, adhesion of a thrombus (shown by symbol "4" in FIG. 6) was confirmed. It has been confirmed that the polymer (3) of Example 3 has excellent antithrombotic properties even in simulated products.

  From the above, it can be seen that the medical material according to the present invention has high antithrombotic properties even when used under severe conditions where thrombus is likely to be formed. The medical material according to the present invention is particularly useful in use conditions in which a step is provided on the surface in contact with blood, such as a medical device provided with a throttling portion such as a junction of a tube.

  Furthermore, the present application is based on Japanese Patent Application No. 2013-270970 filed on Dec. 27, 2013, the disclosure of which is incorporated by reference in its entirety.

1 tube 1,
2 tubes 2,
3 step surface,
4 Thrombus.

Claims (4)

Following formula (1):
Wherein, in the formula (1), R ¹¹ is a hydrogen atom or a methyl group;
And a repeating unit (A) represented by
Following formula (2):
However, in formula (2), R ²¹ is a hydrogen atom or a methyl group, R ²² is an alkylene group having 1 to 4 carbon atoms, and R ²³ is an alkyl group having 1 to 4 carbon atoms;
In looking containing a copolymer having a repeating unit (B) represented, in all the structural units of the copolymer, the repeating unit (A) is from 2.5 to 17.0 mol%, medical materials. The medical material according to claim 1, wherein in the formula (1), R ¹¹ is a hydrogen atom. The copolymer comprises 2.5 to 17.0 mol% of the repeating units (A), and 83.0 to 97.5 mol% of the repeating units (B) (the repeating units (A), and The medical material according to claim 1 or 2 , wherein the total amount of the repeating units (B) is 100 mol%. A substrate,
A medical device having a coated layer containing the medical material according to any one of claims 1 to 3 on the surface of the substrate.