WO2015029625A1

WO2015029625A1 - Medical instrument and method for manufacturing same

Info

Publication number: WO2015029625A1
Application number: PCT/JP2014/068820
Authority: WO
Inventors: 彩子徳江; 弘昌小濱; さやか篠田; 智哉大岩
Original assignee: テルモ株式会社
Priority date: 2013-09-02
Filing date: 2014-07-15
Publication date: 2015-03-05
Also published as: JPWO2015029625A1; JP6335179B2

Abstract

Provided are a medical instrument having excellent lubricity in harsh conditions, and a method for manufacturing the medical instrument. A medical instrument in which a resin coating layer including a maleic-acid-based polymer substance is provided on a surface of a base material, the medical instrument being inserted in the body, the resin coating layer being formed by covalent bonding of the maleic-acid-based polymer substance with reactive functional groups present on at least a surface of the base material constituting the medical instrument, the maleic-acid-based polymer substance including constituent units derived from maleic acid, the constituent units derived from maleic acid comprising constituent unit (a) and constituent unit (b), and the mole ratio of constituent unit (a) to constituent unit (b) being 100:2 to 100:50. In the formulas, X₁-X₃ each independently represent hydrogen, an alkali metal, or an alkaline earth metal, and R represents a C1-24 straight-chain or branched alkyl group.

Description

Medical device and manufacturing method thereof

The present invention relates to a medical device and a manufacturing method thereof. In particular, the present invention relates to a medical device excellent in lubricity under severe conditions and a method for producing the same.

Medical devices such as airways, trachea, gastrointestinal tract, urethra, and blood vessels, and catheters, guidewires, and stylets that are inserted into tissues must be securely inserted to the target site without damaging the tissue. In addition, it is required to exhibit excellent lubricity to avoid damaging the mucous membrane and causing inflammation while indwelling in the tissue. .

In order to satisfy such requirements, a resin coating layer having lubricity is formed by covalently bonding a water-soluble polymer such as a maleic anhydride-based polymer substance to the base material surface of a medical device to be inserted into a living body. It is known to form (see, for example, JP-A-60-259269). In JP-A-60-259269, a coating layer of a water-soluble polymer such as a maleic anhydride-based polymer substance is formed on a substrate through an underlayer, and then preferably treated with water to Exhibits lubricity.

The medical device described in JP-A-60-259269 can exhibit sufficient lubricity in a normal air atmosphere, but the lubricity is excessively lowered under severe conditions such as high temperature, low temperature and high humidity. There was a problem to do. In recent years, there is a possibility that the medical device is exposed to the severe conditions as described above, particularly in a high humidity environment, depending on the transportation process when exporting the medical device or depending on the environment of the country where the medical device is used. For this reason, there is a strong demand for maintaining and improving lubricity under severe conditions such as high temperature, low temperature, and high humidity.

Therefore, the present invention has been made in view of the above circumstances, and an object thereof is to provide a medical device having excellent lubricity under severe conditions and a method for producing the same.

As a result of intensive studies to solve the above problems, the present inventors have found that a coating layer containing a maleic polymer material in which the proportion of carboxylic acid ester is adjusted to a predetermined range is formed on the base material of a medical device. The present invention was completed by finding that the above-mentioned problems can be solved by forming the film.

That is, the object is a medical device to be inserted into a living body in which a resin coating layer containing a maleic polymer material is provided on the surface of a substrate, wherein the resin coating layer is formed of the maleic polymer. It is formed by covalently bonding a substance to a reactive functional group present on at least the surface of a base material constituting the medical device, and the maleic polymer material includes a maleic acid-derived structural unit, The structural unit derived from an acid comprises the following structural unit (a) and the following structural unit (b), wherein the molar ratio of the structural unit (a) to the structural unit (b) is 100: 2 to 100: 50. Can be achieved with tools.

In the formula, X ₁ to X ₃ each independently represent hydrogen, an alkali metal, or an alkaline earth metal, and R represents a linear or branched alkyl group having 1 to 24 carbon atoms.

Further, the above object is to provide a solution containing a linear or branched alcohol having 1 to 24 carbon atoms and water, wherein the alcohol: water content ratio is 100: 0.1 to 150, and a maleic anhydride system. A step of obtaining a maleic polymer material containing a maleic acid-derived structural unit by reacting with a polymer material, and treating a substrate constituting a medical device with a solution containing a compound having a reactive functional group Forming a base layer having a reactive functional group on at least the surface of the base material; treating the base material on which the base layer is formed with the maleic polymer material; A step of covalently bonding a group and the maleic polymer material to form a resin coating layer containing the maleic polymer material on the underlayer, according to the method for producing a medical device of the present invention. Can also be achieved.

It is a schematic diagram of a surface lubricity maintenance evaluation test apparatus (friction measuring machine). In FIG. 1, 1 is water, 2 is a petri dish, 3 is a medical device (sample), 4 is a cylindrical butyl rubber terminal, 5 is a load, 6 is a moving table, and 10 is a friction measuring machine. It is a graph which shows the evaluation result of surface lubricity.

The present invention is a medical device to be inserted into a living body provided with a resin coating layer containing a maleic polymer material on the surface of a substrate,
The resin coating layer is formed by covalently bonding the maleic polymer material to a reactive functional group present on at least the surface of the base material constituting the medical device,
The maleic polymer material includes a structural unit derived from maleic acid, and the structural unit derived from maleic acid comprises the following structural unit (a) and the following structural unit (b), and the structural unit (a): Provided is a medical device wherein the molar ratio of the structural unit (b) is from 100: 2 to 100: 50.

In the formula, X ₁ to X ₃ each independently represents hydrogen, an alkali metal, or an alkaline earth metal, and R represents a linear or branched alkyl group having 1 to 24 carbon atoms.

In Examples 8 to 12 of JP-A-60-259269, a half ethyl ester (degree of esterification 40 to 50%) of methyl vinyl ether maleic anhydride copolymer (GANTREZ AN169) was used as a surface coating layer. It is described. A half ethyl ester of a methyl vinyl ether maleic anhydride polymer is produced by opening a maleic anhydride ring with an alcohol (for example, paragraph “0021” of JP-A-2008-279100). Therefore, the degree of esterification of the methyl vinyl ether maleic anhydride copolymer (GANTREZ AN169) of 50% refers to a state in which the anhydrous ring has completely opened and esterification with alcohol has completely proceeded. The derived structural unit consists only of the structural unit (a) (structural unit (b) = 0). Further, the degree of esterification of methyl vinyl ether maleic anhydride copolymer (GANTREZ AN169) described in JP-A-60-259269 refers to a state in which the esterification reaction with alcohol has not completely proceeded, It refers to the state where some maleic anhydride remains. In other words, a copolymer having a degree of esterification of 40% of methyl vinyl ether maleic anhydride copolymer (GANTREZ AN169) described in JP-A-60-259269 is a structural unit derived from maleic acid (a ) And the following structural unit (c) derived from maleic anhydride:

Refers to the form in which the structure remains (structural unit (a): structural unit (c) = 40: 20 (molar ratio), structural unit (b) = 0).

On the other hand, the maleic polymer material of the present invention does not contain the above structural unit (c) in order to completely open the maleic anhydride ring in the maleic anhydride copolymer.

In the maleic acid polymer material of the present invention, when a maleic anhydride copolymer is reacted with alcohol and water, hydrolysis reaction with water occurs together with esterification reaction with alcohol. Therefore, the maleic polymer material of the present invention includes a structural unit (a) formed by esterification reaction of maleic anhydride with alcohol and a structural unit (b) formed by hydrolysis of maleic anhydride. ) Will be included.

In the maleic polymer material of the present invention, the molar ratio of the structural unit (a) to the structural unit (b) is 100: 2 to 100: 50. When the molar ratio of the structural unit (b) to the structural unit (a) is less than 2 mol%, the number of carboxylic acid (salt) groups is reduced in the substance, and therefore, under severe conditions such as high temperature and high humidity. The lubricity of is reduced. Moreover, when the molar ratio of the structural unit (b) to the structural unit (a) 100 mol% exceeds 50 mol%, the lubricity of the medical device in a normal air atmosphere is deteriorated in addition to severe conditions.

Here, the mechanism that produces the effects as described above is unknown, but is estimated as follows. Note that the present invention is not limited to the following estimation. That is, when a maleic polymer material comes into contact with body fluids or blood, the carboxylate (alkali metal salt of carboxyl group) present in the material swells and gels in the body fluids or blood and exhibits lubricity. . Therefore, for example, in Example 1 of Japanese Patent Publication No. 7-83761, a catheter tube coated with a half ethyl ester of a methyl vinyl ether maleic anhydride copolymer is immersed in a NaHCO ₃ solution for alkali treatment. Is going.

For this reason, the maleic polymer material constituting the coating layer has a higher amount of carboxylate (alkali metal salt of carboxyl group) of the maleic polymer material, so that the swelling property (wetting property) is increased. ) Is high. However, under the severe conditions described above (especially in high humidity conditions), the metal salt of carboxyl group (—COOX) is converted to carboxyl group (—COOH), and the maleic polymer material in the coating layer As a result, the ratio of the carboxylate becomes low, and the swelling property (wetting property) at the time of wetting is lowered. For this reason, according to the present invention, by adjusting the degree of esterification so that a certain amount of carboxylate is present, the carboxyl group can be removed under the above-mentioned severe conditions (especially high humidity conditions). Even after a part of the metal salt is converted to a carboxyl group (-COOX → -COOH), a sufficient amount of carboxylate (alkali metal salt of the carboxyl group) remains in the maleic polymer material. Therefore, even after the coating layer according to the present invention is subjected to severe conditions such as high temperature, low temperature, and high humidity, a sufficient amount of carboxylate (carboxyl group alkali metal salt) It swells with blood and gels, and maintains excellent lubricity without reducing lubricity when wet.

On the other hand, when the molar ratio of the structural unit (b) to the structural unit (a) 100 mol% exceeds 50 mol%, the polymer substance is dissolved during the alkali treatment, the swelling does not proceed well, and the lubricity decreases. To do.

Therefore, the medical device of the present invention has excellent lubricity, and can suppress / prevent degradation of lubricity even when transported or affected by the harsh environment of the country where it is used, Maintains and exhibits excellent lubricity.

Hereinafter, embodiments of the present invention will be described. In the present specification, “X to Y” indicating a range means “X or more and Y or less”, “weight” and “mass”, “weight%” and “mass%”, “part by weight” and “weight part”. “Part by mass” is treated as a synonym. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.

(Medical equipment)
The medical device of the present invention is a medical device to be inserted into a living body in which a resin coating layer containing a maleic polymer material is formed on the surface of a base material (part) to be inserted into the living body. The medical device may be used for any application, but it is preferable that the medical device is used in contact with body fluid or blood in consideration of the effect of imparting lubricity due to contact with body fluid or blood. Specifically, catheters inserted or placed in blood vessels such as indwelling needles, IVH catheters, thermodilution catheters, angiographic catheters, vasodilator catheters (eg, PCTA catheters), dilators or introducers. Or guidewires and stylets for these catheters; catheters inserted or placed in the digestive organs orally or nasally, such as gastrointestinal catheters, nutritional catheters, tube feeding (ED) tubes; oxygen Catheter, oxygen cannula, endotracheal tube and cuff, tracheostomy tube and cuff, intratracheal suction catheter and other catheters that are inserted or placed in the trachea or intratracheally; urethral catheter, lead Urine catheter, urethral balloon catheter Catheters inserted or placed in the urethra or ureter such as catheters and balloons; catheters inserted or placed in various body cavities, organs, tissues such as suction catheter, drainage catheter, rectal catheter; artificial trachea, artificial bronchus ; Medical devices for extracorporeal circulation treatment (artificial lung, artificial heart, artificial kidney, etc.) and their circuits; low during insertion, sliding or indwelling on the outer surface of various intravascular insertion endoscopes Examples include medical devices that require frictional resistance. Among these, in terms of the high demand for lubricity imparting effect due to contact with body fluids and blood, the body fluid / blood contact surface of catheters, guide wires, and indwelling needles used in biological lumens such as blood vessels and ureters It is preferable to provide a coating layer according to the present invention.

(Resin coating layer)
The resin coating layer (coating layer) according to the present invention exhibits surface lubricity in aqueous liquids such as body fluids, blood, and physiological saline, so that medical devices such as catheters and guide wires can be easily placed in living body lumens. Operability can be improved, such as being insertable. Further, the resin coating layer (coating layer) according to the present invention can reduce the damage of the tissue mucous membrane during the above operation.

The resin coating layer is formed by covalently bonding a maleic polymer material with a reactive functional group present on at least the surface of the base material constituting the medical device. In addition, in medical devices such as catheters, guide wires, and indwelling needles that are used, it is not always necessary that all surfaces (the entire surface) of these medical devices (base materials) have lubricity, and at least body fluid and blood It is only necessary that the coating layer be formed only on the surface portion (in some cases or in all cases) in contact. For this reason, this invention includes the case where a part of surface of the base material which comprises a medical device, or the inside of a base material has lubricity. Further, the maleic polymer material can exhibit high wet lubricity and durability.

The maleic polymer material used for the resin coating layer includes a maleic acid-derived structural unit, and the maleic acid-derived structural unit includes the following structural unit (a) and the following structural unit (b).

In the formula, X ₁ to X ₃ each independently represent hydrogen, an alkali metal, or an alkaline earth metal. Here, examples of the alkali metal include lithium, sodium, potassium, rubidium, and cesium. Examples of the alkaline earth metal include magnesium, calcium, strontium, and barium. Preferably, X ₁ to X ₃ are sodium, potassium, magnesium and calcium, more preferably sodium and calcium, and particularly preferably sodium. When X ₁ to X ₃ is sodium, when the maleic polymer substance comes into contact with body fluid or blood, the sodium salt of the carboxyl group in the maleic polymer substance swells and gels in the body fluid or blood, In particular, excellent lubricity can be exhibited. When X is an alkaline earth metal, adjacent carboxyl groups / esters are linked via X ₁ to X ₃ (—C (═O) —O—X—O—C (═O) -)).

From the viewpoint of improving the lubricity, it is preferable that at least one of X ₁ to X ₃ is an alkali metal.

The form in which at least one of X ₁ to X ₃ is an alkali metal or an alkaline earth metal can be obtained by subjecting a substrate having an underlayer and a resin coating layer to an alkali treatment.

In the above formula, R is a linear or branched alkyl group having 1 to 24 carbon atoms. Here, examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, tert-pentyl group, neopentyl group, Hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 2-ethylhexyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, Examples include an eicosyl group, a heneicosyl group, and a docosyl group. Among these, considering the high swelling property (lubricity) when wet and the maintenance of the effect (durability), R is preferably a linear or branched alkyl group having 1 to 8 carbon atoms, A linear or branched alkyl group having 1 to 3 carbon atoms is more preferred.

The maleic polymer material of the present invention contains a structural unit derived from maleic acid. Here, the maleic acid-derived structural unit means a maleic anhydride-derived structural unit (the above-mentioned structural unit (c)) and a maleate-derived structural unit (structural unit (b)) obtained by ring-opening this. And a maleic ester-derived structural unit (structural unit (a)). Among these, the maleic polymer material of the present invention is composed of the structural unit (a) and the structural unit (b) as the structural unit derived from maleic acid, and does not include the structural unit (c). As will be described later, the maleic acid polymer material of the present invention causes hydrolysis and esterification of the maleic anhydride copolymer in the presence of alcohol and water. Therefore, as a structural unit derived from maleic acid, The structural unit (a) and the structural unit (b) are included.

In addition, it can be confirmed by infrared spectroscopy that the structural unit (c), which is a structural unit derived from maleic anhydride, does not remain in the maleic polymer material.

In the maleic polymer material of the present invention, the molar ratio of the structural unit (a) to the structural unit (b) is 100: 2 to 100: 50. When the molar ratio of the structural unit (b) to the structural unit (a) is less than 2 mol%, the lubricity under severe conditions such as high temperature and high humidity is lowered. Moreover, when the molar ratio of the structural unit (b) to the structural unit (a) 100 mol% exceeds 50 mol%, the lubricity of the medical device in a normal air atmosphere is deteriorated in addition to severe conditions. The molar ratio of the structural unit (a) to the structural unit (b) is preferably 100: 2 to 50, more preferably 100: 2 to 43.

Further, other monomers copolymerizable with the structural unit derived from maleic acid are effective according to the present invention (for example, lubricity when wet under normal conditions, lubricity when wet under severe conditions, There is no particular limitation as long as it does not hinder the lubricity maintenance property. Specific examples include monomers having an alkyl vinyl ether, acrylamide and derivatives thereof, vinyl pyrrolidone, acrylic acid and methacrylic acid and derivatives thereof, diene compounds, sugars, and phospholipids in the side chain. More specifically, methyl vinyl ether, ethyl vinyl ether, propyl vinyl ether, acrylic acid, methacrylic acid, N-methylacrylamide, N, N-dimethylacrylamide, acrylamide, acryloylmorpholine, N, N-dimethylaminoethyl acrylate, vinylpyrrolidone, Examples thereof include 2-methacryloyloxyethylphosphorylcholine, 2-methacryloyloxyethyl-D-glycoside, 2-methacryloyloxyethyl-D-mannoside, vinyl methyl ether, hydroxyethyl methacrylate and the like. Of these, alkyl vinyl ether is preferable, and methyl vinyl ether and ethyl vinyl ether are particularly preferable in consideration of wet lubricity, wet lubricity under severe conditions, and lubricity maintenance. That is, the maleic polymer material is preferably an alkyl vinyl ether-maleic acid ester copolymer, a maleic acid-derived structural unit (structural units (a) and (b)) and the following formula (d):

Particularly preferred is an alkyl vinyl ether-maleic acid ester copolymer composed of structural units derived from alkyl vinyl ether. In the above formula (d), the substituent R ′ in the constituent unit derived from alkyl vinyl ether is a linear or branched alkyl group having 1 to 24 carbon atoms. Here, the “alkyl group” has the same definition as the alkyl group relating to the substituent R in the structural unit (a), and thus the description thereof is omitted here. Of these, R ′ is preferably a linear or branched alkyl group having 1 to 8 carbon atoms, and more preferably a linear or branched alkyl group having 1 to 3 carbon atoms. In the case where the maleic polymer is a copolymer, each structural unit may be in a block shape or a random shape.

In addition, when the maleic polymer is a copolymer, the composition of each structural unit (monomer forming each structural unit) is not particularly limited, and a desired effect (for example, lubrication when wet) In consideration of the property, lubricity when wet under severe conditions, and maintenance of lubrication). Specifically, the maleic polymer is derived from 20 to 80 mol% of maleic acid-derived structural units (structural units (a) and (b)), and 80 to 20 mol% of other monomers. The structural unit is preferably composed of 30 to 70 mol% of a maleic acid-derived structural unit and more preferably 70 to 30 mol% of a structural unit derived from another monomer. Here, the total amount of structural units derived from maleic acid and structural units derived from other monomers is 100 mol%. In particular, the maleic polymer material is composed of 40 to 60 mol% of an alkyl vinyl ether-derived structural unit and 60 to 40 mol% of a maleic acid-derived structural unit (a total of a structural unit derived from an alkyl vinyl ether and a structural unit derived from maleic acid. An alkyl vinyl ether-maleic acid ester copolymer composed of 100 mol%) is preferred.

The maleic polymer material may have an insolubilized form as long as it has a degree of freedom in the molecular chain and can take a water-containing form. The form is not particularly limited as long as it has a degree of freedom in the molecular chain and can take a water-containing form. Specifically, amidated products, anhydrides, halides, etherified products, hydrolysates, acetalized products, formalized products, alkylated products obtained by condensation, addition, substitution, oxidation, reduction reaction, etc. Rolled product, quaternized product, diazotized product, hydrazide product, sulfonated product, nitrated product, ion complex; diazonium group, azide group, isocyanate group, acid chloride group, acid anhydride group, imino carbonate group, amino group, carboxyl group And a cross-linked product with a substance having two or more reactive functional groups such as an epoxy group, a hydroxyl group and an aldehyde group. When such a maleic polymer material is brought into contact with a body fluid or blood, it can remarkably reduce the frictional resistance with a living body lumen or tissue, and can be suitably used as a lubricant. Derivatives obtained by condensation or addition reaction or substitution reaction of these maleic acid-based polymer substances, and those partially crosslinked are also effective as lubricants.

Further, the molecular weight of the maleic polymer material is not particularly limited, and the desired effect (for example, lubricity when wet, lubricity when wet under harsh conditions, maintenance of lubrication) is taken into consideration. Are appropriately selected. Specifically, the weight average molecular weight of the maleic polymer material is preferably 10,000 to 7 million, more preferably 100,000 to 5 million. In the present specification, the molecular weight (weight average molecular weight) of the maleic polymer is measured by gel permeation chromatography (GPC) using polystyrene as a standard substance and tetrahydrofuran (THF) as a mobile phase. . The molecular weight of the maleic acid polymer substance can also be calculated from the type of repeating unit and the number of repeating units.

(Reactive functional group)
The maleic polymer material forms a coating layer on the substrate by covalently bonding at least a reactive functional group present on the substrate surface. This coating layer can exhibit continuous lubricity without dissolving in an aqueous liquid such as body fluid or blood. The reactive functional group may be present at least on the surface of the substrate. Thereby, it can couple | bond easily with the maleic acid type polymer substance in a coating layer. For this reason, a reactive functional group may exist in the inside of a base material in addition to the base material surface.

Here, the reactive functional group is not particularly limited as long as it reacts with a maleic polymer substance to form a covalent bond. Specific examples include a diazonium group, an azide group, an isocyanate group, an acid chloride group, an acid anhydride group, an imino carbonate group, an amino group, a carboxyl group, an epoxy group, a hydroxyl group, and an aldehyde group. Of these, the reactive functional group is preferably an isocyanate group, an amino group, an aldehyde group or an epoxy group. The reactive functional groups may be used alone or in combination of two or more.

The form of introduction of the reactive functional group is not particularly limited. Specifically, (i) a form using a base material (reactive functional group-containing base material) having at least a reactive functional group on the surface; (ii) a base material previously introduced with at least a reactive functional group on the surface Any form may be used, such as a form to be used; and (iii) a form in which another layer (underlayer) having a reactive functional group is formed on a substrate. Among these, considering the degree of freedom in selecting a base material, the form (iii) is preferable. In the form (iii), the base material constituting the medical device with a solution containing a compound having a reactive functional group is used. It is more preferable to form a base layer having a reactive functional group on at least the surface of the substrate by treatment.

In the above form (i), a substrate formed of polyurethane, polyamide or the like is suitably used as the reactive functional group-containing substrate. In the form (ii), a method of performing ionized gas plasma irradiation on the substrate surface can be suitably used. Here, the ionized gas plasma irradiation may be performed under any conditions, but it is preferable to irradiate ionized gas plasma containing oxygen or nitrogen. For example, by irradiating the substrate surface with ionized gas plasma containing oxygen, the substrate surface is modified and activated, and functional groups such as carboxyl groups, hydroxyl groups, and peroxides are introduced into the substrate surface. . In the above method, the content of oxygen in the ionized gas is not particularly limited as long as it has an effect as described above. Also, by irradiating the substrate surface with ionized gas plasma containing nitrogen, the substrate surface is modified and activated, and functional groups such as carboxyl groups, hydroxyl groups, peroxides, amino groups, etc. are formed on the substrate surface. be introduced. Also in the above method, the content of nitrogen in the ionized gas is not particularly limited as long as it has the above-described effects.

The form (iii) can be applied particularly suitably when a substrate that does not contain a reactive functional group is used as a base material that constitutes the outer wall and inner wall of various medical devices. That is, it is treated with a compound having a reactive functional group, the reactive functional group is present on the substrate, and a maleic polymer material is covalently bonded thereon.

The compound having the reactive functional group is not particularly limited as long as it has the reactive functional group. For example, as a compound having an isocyanate group as a reactive functional group, ethylene diisocyanate, hexamethylene diisocyanate, xylene diisocyanate, toluene diisocyanate, tolylene diisocyanate, 4,4′-diphenylmethane diisocyanate (MDI), naphthalene diisocyanate, diphenylmethane diisocyanate, phenylene Examples thereof include polyisocyanates such as diisocyanate, cyclohexylene diisocyanate, tolphenylmethane triisocyanate, and toluene isocyanate, and adducts (adducts) or prepolymers of these polyisocyanates and polyols (for example, trimethylolpropane).

Examples of the compound having an amino group as a reactive functional group include ethylenediamine, trimethylenediamine, 1,2-diaminopropane, tetramethylenediamine, 1,3-diaminobutane, 2,3-diaminobutane, pentamethylenediamine, 2, 4-diaminopentane, hexamethylenediamine, octamethylenediamine, nonamethylenediamine, decamethylenediamine, undecamethylenediamine, dedocamethylenediamine, tridecamethylenediamine, octadecamethylenediacin, N, N-dimethylethylenediamine, N , N-diethyltrimethylenediamine, N, N-dimethyltrimethylenediamine, N, N-dibutyltrimethylenediamine, N, N, N′-triethylethylenediamine, N-methyltrimethylenediamine, NN— Methyl-p-phenylenediamine, N, N-dimethylhexamethylenediamine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, heptaethyleneoctamine, nonaethylenedecamine, 1,3-bis (2'-aminoethylamino) Propane, bis (3-daminopropal) amine, 1,3-bis (3′-acinopropylamino) propane, 1,2,3-triaminopropane, tris (2-aminoethyl) amine, tetra (aminomethyl) methane , Methyliminobispropylamine, methyliminobisethylamine, ethyliminobisethylamine, N-aminopropyl-2-morpholine, N-aminopropyl-2-pipecoline, N- (2-hydroxyethyl) trimethylenediamine, xylylenediamine , Feni Diamine, piperazine, N-methylpiperazine, N- (2-aminoethyl) ethanolamine, N-aminoethylpiperazine, N, N, N'N'-tetramethylethylenediamine, N, N, N'N'-tetramethyl Low molecular weight polyamines such as tetramethylenediamine, poly (alkylene polyamines) synthesized from amines and alkylene dihalides or epichlorohydrins [Encyclopedia of Polymer Science and Technology, Volume 10 , P. 616], an alkyleneimine polymer obtained by ring-opening polymerization of alkyleneimine such as ethyleneimine and propyleneimine [Ensauclopidia of polymer Science and Technology, Volume 1, p. 734], and polyamines such as high molecular weight polyamines such as polyvinylamine and polylysine.

Examples of the compound having an aldehyde group as a reactive functional group include glutaraldehyde, terephthalaldehyde, isophthalaldehyde, dialdehyde, starch, galoxal, malonaldehyde, succinic acid aldehyde, adipaldehyde, pimelindialdehyde, suberindialdehyde, malein. Examples include aldehydes and polyaldehydes such as 2-pentene-1,5-dialdehyde.

Examples of the compound having an epoxy group as a reactive functional group include ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene diglycidyl ether, hexanediol diglycidyl ether, trimethylol propane triglycidyl ether. And polyepoxides.

Of these, the reaction with the maleic polymer substance (ie, lubricity when wet under normal conditions, lubricity when wet under severe conditions, lubricity maintenance) is considered. As the compound having a functional functional group, 4,4′-diphenylmethane diisocyanate (MDI), an adduct of tolylene diisocyanate and trimethylolpropane, an adduct of hexamethylene diisocyanate and trimethylolpropane, a trimer thereof, or diethylenetriamine is preferable. The compound having a reactive functional group may be used alone or in the form of a mixture of two or more.

(Base material)
The base material used in the present embodiment may be composed of any material, and the material is not particularly limited, and can be appropriately selected depending on the type of medical device provided with a coating layer on the surface. Specifically, examples of the material constituting (forming) the base material include metal materials, polymer materials, glass materials, and ceramic materials. Here, the entire base material (all) is composed (formed) of any of the above materials, or other than the surface of the base material core portion configured (formed) of any of the above materials. Any of the above materials may be coated (coated) by an appropriate method to form (form) a substrate surface layer. As an example of the latter case, a metal material is coated on the surface of a base material core portion formed of a resin material or the like by a suitable method (a conventionally known method such as plating, metal vapor deposition, sputtering, etc.) A material made of a material surface layer; a polymer material that is more flexible than a reinforcing material such as a metal material is suitable for the surface of the base material core portion formed of a hard reinforcing material such as a metal material or a ceramic material. Coating (coating) by a method (dipping (dipping), spraying (spraying), coating / printing, etc., conventionally known methods) or a composite material of a reinforcing material for a base material core and a polymer material for a surface layer of a base material (appropriate And the like formed by a reaction treatment) to form a substrate surface layer. Therefore, the base material core portion may be a multilayer structure in which different materials are laminated in multiple layers, or a structure (composite) in which members formed of different materials for each part of the medical device are connected. . Further, another middle layer may be formed between the base material core portion and the base material surface layer. Further, the substrate surface layer may be a multilayer structure in which different materials are laminated in multiple layers, or a structure (composite) in which members formed of different materials are connected to each part of the medical device. .

Among the materials constituting (forming) the base material, the metal material is not particularly limited, and metal materials generally used for medical devices such as catheters, guide wires, and indwelling needles are used. . Specifically, various stainless steels (SUS) such as SUS304, SUS316, SUS316L, SUS420J2, and SUS630, gold, platinum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, or nickel-titanium (Ni-Ti) ) Alloys, nickel-cobalt (Ni—Co) alloys, cobalt-chromium (Co—Cr) alloys, various alloys such as zinc-tungsten (Zn—W) alloys, and the like. These may be used individually by 1 type and may use 2 or more types together. What is necessary is just to select suitably the metal material optimal as base materials, such as a catheter, a guide wire, an indwelling needle which is a use application, for the said metal material.

Of the materials constituting (forming) the base material, the polymer material is not particularly limited, and is generally used for medical devices such as catheters, guide wires, and indwelling needles. Is used. Specifically, a polyolefin resin such as a polyamide resin, a linear low density polyethylene (LLDPE), a low density polyethylene (LDPE), a high density polyethylene (HDPE), or a polypropylene resin, a modified polyolefin resin, an epoxy resin, Urethane resin (polyurethane), diallyl phthalate resin (allyl resin), polycarbonate resin, fluorine resin, amino resin (urea resin, melamine resin, benzoguanamine resin), polyester resin, styrene resin, polyacetal resin, vinyl acetate resin, phenol resin, chloride Vinyl resin (polyvinyl chloride), silicone resin (silicon resin), polyether resin, polyimide resin, polystyrene, polyacrylic ester, polymethacrylic ester, polyacrylonitrile , Polyacrylamide, polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polymaleic anhydride, polyethylene imine. These may be used individually by 1 type and may use 2 or more types together. What is necessary is just to select suitably the polymeric material optimal as base materials, such as a catheter, a guide wire, and an indwelling needle which are use uses as the said polymeric material.

The shape of the base material is not particularly limited, and is appropriately selected depending on the use mode such as a sheet shape, a linear shape (wire), and a tubular shape.

(Method for manufacturing medical devices)
The medical device of this invention should just be provided with the coating layer for providing lubricity to the base-material surface, and the manufacturing method in particular is not restrict | limited. Specifically, the medical device of the present invention introduces a reactive functional group to the surface of the substrate, and then treats the reactive functional group with the maleic polymer material by treating with the maleic polymer material of the present invention. Are preferably bonded to form a coating layer. Here, as described above, the reactive functional group is preferably introduced to the surface of the base material by forming another layer (underlayer) having the reactive functional group on the base material. The base material constituting the medical device is treated with a solution containing a compound having a functional group to form an underlayer having a reactive functional group on at least the surface of the base material, thereby being introduced onto the base material surface. It is more preferable. Further, the coating layer containing the maleic polymer material is obtained by treating the substrate having the underlayer with the maleic polymer material to covalently bond the reactive functional group and the maleic polymer material. It is preferable to form on the underlayer. Furthermore, it is preferable that the coating layer formed as described above is subjected to alkali treatment.

Therefore, the method for producing a medical device of the present invention contains a linear or branched alcohol having 1 to 24 carbon atoms and water, and the alcohol: water content ratio is 100: 0.1 to 150. And a maleic anhydride polymer material to obtain a maleic polymer material containing a maleic acid-derived structural unit [step (1)],
Treating the substrate constituting the medical device with a solution containing a compound having a reactive functional group to form an underlayer having the reactive functional group on at least the surface of the substrate [step (2)]; ,
The base material on which the base layer is formed is treated with the maleic polymer material, and the reactive functional group and the maleic polymer material are covalently bonded to form a maleic acid-based material on the base layer. It is preferable to have a step [step (3)] of forming a resin coating layer containing a polymer substance to obtain a base material having a base layer and a resin coating layer. Furthermore, it is preferable to have the step [process (4)] which carries out the alkali treatment of the base material which has a base layer and a resin coating layer.

Hereinafter, a preferable method for producing the medical device of the present invention will be described in detail. In addition, this invention is not limited to the following form.

1. Process (1)
In this step, the maleic anhydride polymer material contains a linear or branched alcohol having 1 to 24 carbon atoms and water, and the alcohol: water content ratio is 100: 0.1 to 150 (Hereinafter, also simply referred to as a mixed solution), the esterification reaction and the hydrolysis reaction of the maleic anhydride-derived structural unit (c) in the maleic anhydride-based polymer substance are allowed to proceed simultaneously. The unit (c) is the structural unit (a) and (b).

Here, the maleic anhydride-based polymer substance only needs to contain a maleic anhydride-derived structural unit (c) as part of the maleic acid-derived structural unit in the polymer. As the structural unit that the maleic anhydride-based polymer substance can contain, in addition to the above-mentioned structural unit, there are structural units derived from other monomers described in the section of the maleic acid-based polymer substance. A commercially available product may be used as the maleic anhydride polymer substance. A. F. For example, GANTREZ AN series from Corporation.

The content mass ratio of alcohol: water is preferably 100: 0.1 to 150, and more preferably 100: 0.8 to 80. By using a solution in which the content ratio of alcohol: water is within the above range, maleic anhydride is completely ring-opened and esterification with alcohol easily proceeds, and the structural unit (a) and the structural unit Since it becomes easy to control content mass ratio with (b) in the range of the maleic acid type polymer substance of the present invention, it is preferred. As the linear or branched alcohol having 1 to 24 carbon atoms, an alcohol corresponding to R in the structural unit (a) to be esterified may be used.

The mass ratio between the maleic anhydride-based polymer substance used in the reaction and the mixed solution may be appropriately set so that the reaction proceeds. Usually, the maleic anhydride-based polymer substance: mixed in the mass ratio. Solution = 100: 50 to about 5000.

The esterification reaction and hydrolysis reaction for obtaining a maleic acid polymer substance can be obtained by heating and refluxing the maleic anhydride polymer substance using a mixed solution of alcohol and water. The reflux conditions are appropriately selected depending on the solvent (alcohol) to be used, but it is preferable to reflux for 5 to 120 hours in order to sufficiently proceed the reaction. The temperature at the reflux is appropriately set depending on the type of alcohol and water used and the mass ratio, but is preferably about 50 to 100 ° C.

2. Step (2)
In this step, the base material constituting the medical device is treated with a solution (coating solution) containing a compound having a reactive functional group to form a base layer in which the reactive functional group exists on at least the surface of the base material. .

Although the processing method of the base material (base material) which comprises the medical device by the solution containing the compound which has a reactive functional group is not restrict | limited, The method of apply | coating the solution containing the compound which has a reactive functional group to a base material is mentioned. Can be used. Here, dip coating (dipping method), spraying, spin coating, dripping, doctor blade, brush coating, roll coater, air knife coating, curtain coating, wire bar coating, gravure coating, mixed solution impregnation sponge coating A conventionally well-known method can be applied. In addition, the concentration of the compound having a reactive functional group in the coating solution is particularly limited as long as the compound having the reactive functional group is present in an amount capable of covalently bonding with a sufficient amount of the maleic polymer material in the next step (3). Not. Considering the reactivity with a sufficient amount of maleic polymer material in the next step (3), the coating amount with the maleic polymer material, etc., the concentration of the compound having a reactive functional group in the coating solution is: The content is preferably 0.5 to 10% by weight, and more preferably 2 to 5% by weight.

The solvent for preparing the coating solution is not particularly limited as long as it can dissolve a compound having a reactive functional group, and can be appropriately selected depending on the type of the compound having a reactive functional group to be used. Specifically, ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, ester solvents such as butyl acetate, ethyl acetate, carbitol acetate, butyl carbitol acetate, methyl cellosolve, ethyl cellosolve, butyl ether, tetrahydrofuran, etc. Ether solvents, alkane solvents such as butane and hexane, aromatic solvents such as benzene, toluene and xylene, halogen solvents such as dichloroethane, chloroform and methylene chloride, alcohols such as methanol, ethanol, isopropanol and ethylene glycol A solvent etc. are mentioned. The said solvent may be used individually by 1 type, and may be used together 2 or more types. The above solvent is used when the base material is made of a polymer material (resin) or when a layer made of a polymer material (base material surface layer) is formed in advance on the surface of the base material as described in detail below. Can dissolve or swell them to improve the adhesion strength of the coating layer and maintain lubricity (under normal conditions and harsh conditions) for a longer period of time.

The coating solution may contain an additive other than the compound having a reactive functional group. Here, the other additive is not particularly limited, and examples thereof include a polymer material and a drug. Here, as the polymer material, the polymer material exemplified by the material constituting (forming) the base material can be exemplified similarly. Of these, polyvinyl chloride, polyurethane, polyamide resin, and polyester resin are preferable in consideration of ease of formation of the underlayer. The drug can be appropriately selected depending on the indwelling site of the medical device, the disease to be applied, and the like. Here, the concentration of the other additive in the coating solution is not particularly limited, but it is preferably 0.5 to 15% by weight in view of ease of formation of the underlayer, and 2 to 10% by weight. More preferably.

The treatment conditions of the substrate with the coating solution are not particularly limited as long as the reactive functional group can be introduced onto the desired surface of the substrate. Specifically, the substrate is preferably applied with a coating solution at 0 to 50 ° C. for 1 second to 48 hours.

In particular, when a metal material, a glass material, a ceramic material, or the like is used as a base material, a layer made of a polymer material (base material surface layer) may be formed on the base material surface in advance before forming the base layer. preferable. Thereby, a base material and a base layer can be stuck more firmly, and the adhesion strength of a coating layer can be improved. Here, the type of the polymer material is not particularly limited, and can be appropriately selected depending on the type of the base material. Specifically, examples of the polymer material include the polymer materials exemplified as the material constituting (forming) the base material. Of these, polyvinyl chloride, polyurethane, polyamide resin, and polyester resin are preferable in consideration of the lubricity sustaining effect and adhesion to the underlayer. Here, when the layer made of the polymer material is previously formed on the surface of the substrate, the thickness of the layer made of the polymer material is not particularly limited, but considering the lubricity sustaining effect, the adhesion with the underlayer, etc. The thickness is preferably 1 to 70 μm, more preferably 5 to 50 μm.

After applying the base material with the coating solution as described above, the coating film is dried to form a base layer on the base material. Here, the drying conditions are not particularly limited as long as the underlayer can be formed. For example, the drying temperature is preferably about room temperature (25 ° C.) to about 80 ° C. The drying time is preferably about 5 minutes to 48 hours.

3. Process (3)
In this step, the base material (base material / underlayer) having the underlayer obtained in the above step (2) is treated with a maleic acid-based polymer material, and a reactive functional group and a maleic acid-based polymer material are treated. And a resin coating layer containing a maleic acid polymer material is formed on the underlayer.

Here, the method of treating the substrate / underlayer with the maleic polymer material is not particularly limited, but a method of applying a solution containing the maleic polymer material (coating layer forming solution) to the substrate can be used. . Here, dip coating (dipping method), spraying, spin coating, dripping, doctor blade, brush coating, roll coater, air knife coating, curtain coating, wire bar coating, gravure coating, mixed solution impregnation sponge coating A conventionally well-known method can be applied. In addition, the concentration of the maleic polymer material in the coating layer forming solution is not particularly limited as long as the coating layer can be formed with a sufficient amount of the maleic polymer material. Considering the amount of coating with the maleic polymer material, the concentration of the maleic polymer material in the coating layer forming solution is preferably 0.1 to 15% by weight, preferably 0.5 to 10% by weight. It is more preferable that With such a concentration, the medical device (coating layer) can exhibit excellent lubricity when wet under normal conditions, lubricity when wet under severe conditions, and lubricity maintenance.

The solvent for preparing the coating layer forming solution is not particularly limited as long as it can dissolve the maleic polymer material, and can be appropriately selected depending on the type of the maleic polymer material to be used. Specifically, the same solvent as that described in the above step (2) can be used. Of these, methyl ethyl ketone, tetrahydrofuran (THF), acetone and the like are preferable. These solvents have little or no reaction with the reactive functional groups present in the substrate / underlayer, and have appropriate solubility and swelling with respect to the substrate / underlayer. In addition, the said solvent may be used individually by 1 type, and may be used together 2 or more types.

The coating layer forming solution may contain an additive other than the maleic polymer material. Here, the other additive is not particularly limited, and examples thereof include a polymer material and a drug. Here, as the polymer material, the polymer material exemplified by the material constituting (forming) the base material can be exemplified similarly. The drug can be appropriately selected depending on the indwelling site of the medical device, the disease to be applied, and the like. Here, the concentration of the other additive in the coating layer forming solution is not particularly limited, but is preferably 0.5 to 15% by weight in view of the ease of forming the coating layer and the like, and is preferably 2 to 10% by weight. % Is more preferable.

The treatment conditions of the base material / underlayer with the coating layer forming solution are not particularly limited as long as a suitable amount of a coating layer of maleic polymer material can be formed on the base material / underlayer. Specifically, the substrate / undercoat layer is preferably applied with a coating layer forming solution at 0 ° C. to 80 ° C. for 1 second to 48 hours, more preferably at 10 to 30 ° C. for 1 second to 1 hour. .

After applying the substrate / underlayer with the coating layer forming solution as described above, the coating film is dried to form the coating layer on the substrate / underlayer. Here, the drying conditions are not particularly limited as long as the coating layer can be formed. For example, the drying temperature is preferably about room temperature (25 ° C.) to about 80 ° C. The drying temperature is preferably about 5 minutes to 48 hours.

4). Step (4)
In this step, the base material having the base layer and the resin coating layer obtained in the above step (3) is subjected to alkali treatment. At least a part of the carboxyl group (—COOH) and the ester moiety (—COOR) in the maleic polymer material in the coating layer obtained by the esterification reaction and hydrolysis reaction in the above step (1) by alkali treatment Is converted to the carboxylate (—COOX). When the maleic polymer material comes into contact with body fluid or blood by the alkali treatment, the carboxylate in the maleic polymer material swells and gels with the body fluid or blood, and exhibits excellent lubricity.

In the above alkali treatment, the alkali used for preparing the alkaline solution is not particularly limited, and is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, water. Examples include lithium oxide, sodium, and ammonia. Of these, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, and calcium hydroxide are preferable, and sodium hydrogen carbonate, sodium hydroxide, and sodium carbonate are particularly preferable.

Further, the solvent for dissolving the alkali is not particularly limited, but alcohols such as water, methanol, ethanol, isopropanol and ethylene glycol, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, chloroform and the like Examples include halides, alkanes such as butane and hexane, ethers such as tetrahydrofuran and butyl ether, aromatics such as benzene and toluene, and amides such as N, N-dimethylformamide (DMF). The said solvent may be used individually by 1 type, and may be used together 2 or more types.

The alkali solution may contain other components in addition to the alkali. Here, examples of other components include sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, ice, and sucrose. Sodium chloride is preferred. The preferred concentration of the other components is not particularly limited, but is such an amount that the concentration in the alkaline solution is preferably 0.01 to 10% by weight.

The pH of the alkaline solution is not particularly limited, but is preferably 7 to 14. The maleic polymer material before alkali treatment that has undergone hydrolysis and esterification reaction has many maleic acid-derived carboxyl groups in the maleic acid-derived structural unit, so that many carboxylates can be formed under mild alkaline conditions. Will have. For this reason, it has favorable lubricity even if it does not perform the alkali treatment under the strong alkali condition in which an ester part becomes a carboxylate by alkali treatment. For this reason, the pH of the alkaline solution is more preferably 7 or more and less than 10.

In addition, the conditions for immersing the base material having the base layer and the resin coating layer in the alkaline solution are not particularly limited, but if one condition is indicated, the immersion temperature is preferably 25 to 70 ° C., 30 It is more preferably from ˜65 ° C., particularly preferably from 40 to 60 ° C. The immersion time of the base material having the base layer and the resin coating layer in the alkaline solution is preferably from 0.1 to 20 hours, more preferably from 0.5 to 14 hours.

After the alkali treatment, if necessary, a washing step may be performed. By the washing step, the conversion from the carboxyl group (—COOH) and the ester moiety (—COOR) to the carboxylate (—COOX) by the alkali treatment can be easily completed. Here, the cleaning conditions are not particularly limited. For example, the cleaning liquid (solvent) that can be used in the cleaning step includes water, alcohols such as methanol, ethanol, isopropanol, and ethylene glycol, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate, halides such as chloroform, Examples include alkanes such as butane and hexane, ethers such as tetrahydrofuran and butyl ether, aromatics such as benzene and toluene, and amides such as N, N-dimethylformamide (DMF). The said solvent may be used individually by 1 type, and may be used together 2 or more types. The temperature of the cleaning liquid is preferably 0 to 70 ° C., more preferably 20 to 65 ° C. The washing time is 0.1 to 120 minutes, more preferably 0.5 to 120 minutes.

After the alkali treatment or washing step, if necessary, the base material having the base layer and the resin coating layer is dried. Here, the drying conditions are not particularly limited as long as the substrate, the base layer, and the resin coating layer after the alkali treatment or the cleaning step can be sufficiently dried. For example, the drying temperature is preferably about room temperature (25 ° C.) to about 80 ° C. The drying temperature is preferably about 5 minutes to 48 hours.

In the medical device obtained as described above, the maleic polymer substance is covalently bonded to the reactive functional group, and the coating layer is formed on the surface of the base material to be inserted into the living body. On the other hand, non-lubricating treatment may be performed on a portion of the medical device of the present invention that is not inserted into the living body. Here, the non-lubricating treatment is not particularly limited, but for example, a method using an isocyanate compound described in JP-A-4-144567 can be suitably used. The isocyanate compound is considered to be non-lubricated by grafting to a maleic polymer material or partially crosslinking it.

The effect of the present invention will be described using the following examples and comparative examples. In the examples, “part” or “%” may be used, but “part by weight” or “% by weight” is expressed unless otherwise specified. Unless otherwise specified, each operation is performed at room temperature (25 ° C.).

Example 1
12 g of methyl vinyl ether maleic anhydride copolymer (trade name: GANTREZ AN-169 GAF) was put into a mixed solution of 85 g of ethanol and 0.7 g of distilled water and refluxed at 78 ° C. for 24 hours. It was. After cooling the reflux liquid, it was put in hexane, and the deposited precipitate was collected, dried at 70 ° C. under reduced pressure for 3 days while being pulverized as needed, and a reaction product of methyl vinyl ether maleic anhydride copolymer (hereinafter referred to as methyl vinyl ether-maleic acid). (Yield 9 g). The degree of esterification of the methyl vinyl ether-maleic acid copolymer obtained (ratio of the ester moiety in the structural unit derived from maleic acid) was 49% as measured by NMR (structural unit (a): structural unit). (B) molar ratio = 100: 2). The hydrolysis and esterification reaction proceeded completely, and the structural units derived from maleic acid in the methyl vinyl ether-maleic acid copolymer were only the structural unit (a) and the structural unit (b).

The NMR measurement conditions are as follows.

NMR equipment: Unity Plus NMR Spectrometer manufactured by Varian
Resonance frequency: 399.897 MHz
Integration: 8 times Measurement solvent: Acetone-d6
Reference peak: 2.04 ppm (residual protons in Acetone-d6)
Sample concentration: 10 mg / 0.75 mL Acetone-d6
Furthermore, the integral value A (δ3.2 to 2.8 ppm) of two protons of (1) and (2) in the following structure and the integral value B (δ4.25 to 4.0 ppm) of two protons of (3) ), The degree of esterification = (B / 2 / A) × 100 (%) was calculated.

A Ni—Ti wire having an outer diameter of 0.25 mm was coated with a thermoplastic polyurethane resin to have an outer diameter of 0.3 mm. Next, this polyurethane resin-coated wire was added to a solution of polyvinyl chloride (PVC) and 4,4′-diphenylmethane diisocyanate (MDI) in tetrahydrofuran (THF) (each concentration = 5% by weight) at room temperature (25 ° C.). It was immersed for 2 seconds and dried at room temperature (25 ° C.) for 30 minutes.

Further, it was immersed in a 1% by weight THF solution of the methyl vinyl ether-maleic acid copolymer (degree of esterification 49%) obtained above for 1 second at room temperature (25 ° C.) and dried at about 60 ° C. for 12 hours. It was.

Next, it was immersed in warm water (pH 8.2) of about 60 ° C. in which 0.1% by weight of NaCl and 0.05% by weight of NaHCO ₃ were dissolved, and then washed with warm water of about 60 ° C. for 1 minute. It dried at (25 degreeC) and obtained the medical device (1).

Example 2
12 g of methyl vinyl ether maleic anhydride copolymer (trade name: manufactured by GANTREZ AN-169 GAF) was put into a mixed solution of 83 g of ethanol and 3.2 g of distilled water and refluxed for 24 hours. The reaction was conducted in the same manner as in Example 1 to obtain a reaction product of methyl vinyl ether maleic anhydride copolymer (yield 11 g). The degree of esterification of the methyl vinyl ether-maleic acid copolymer obtained (the degree of esterification in the structural unit derived from maleic acid) was measured by NMR to be 46% (structural unit (a): structural unit ( b) molar ratio = 100: 8.7). The hydrolysis and esterification reaction proceeded completely, and the structural units derived from maleic acid in the methyl vinyl ether-maleic acid copolymer were only the structural unit (a) and the structural unit (b).

A medical device (2) was obtained in the same manner as in Example 1 except that the obtained methyl vinyl ether-maleic acid copolymer was used.

Example 3
12 g of methyl vinyl ether maleic anhydride copolymer (trade name: manufactured by GANTREZ AN-169 GAFF) was put into a mixed solution of 80 g of ethanol and 6.3 g of distilled water and refluxed for 24 hours. The same treatment as in Example 1 was performed to obtain a reaction product of methyl vinyl ether maleic anhydride copolymer (yield 8 g). The degree of esterification (the degree of esterification in the maleic acid-derived structural unit) of the resulting methyl vinyl ether-maleic acid copolymer was measured by NMR to be 43% (structural unit (a): structural unit ( b) molar ratio = 100: 16.3). The hydrolysis and esterification reaction proceeded completely, and the structural units derived from maleic acid in the methyl vinyl ether-maleic acid copolymer were only the structural unit (a) and the structural unit (b).

A medical device (3) was obtained in the same manner as in Example 1 except that the obtained methyl vinyl ether-maleic acid copolymer was used.

Example 4
12 g of methyl vinyl ether maleic anhydride copolymer (trade name: GANTREZ AN-169 GAF) was put into a mixed solution of 53 g of ethanol and 41 g of distilled water and refluxed for 24 hours. After cooling the reflux liquid, it was put into diethyl ether, and the deposited precipitate was collected and dried at 70 ° C. under reduced pressure for 3 days while pulverizing as needed to obtain a reaction product of methyl vinyl ether maleic anhydride copolymer (yield 8 g). . The degree of esterification (the degree of esterification in the maleic acid-derived structural unit) of the resulting methyl vinyl ether-maleic acid copolymer was measured by NMR and found to be 35% (structural unit (a): structural unit ( b) molar ratio = 100: 42.9). The hydrolysis and esterification reaction proceeded completely, and the structural units derived from maleic acid in the methyl vinyl ether-maleic acid copolymer were only the structural unit (a) and the structural unit (b).

A medical device (4) was obtained in the same manner as in Example 1 except that the obtained methyl vinyl ether-maleic acid copolymer was used.

Comparative Example 1
A comparative medical device (1) was obtained in the same manner as in Example 1 except that a half ethyl ester of methyl vinyl ether maleic anhydride copolymer (degree of esterification of about 50%) was used.

Comparative Example 2
12 g of methyl vinyl ether maleic anhydride copolymer (trade name: manufactured by GANTREZ AN-169 GAF) was put into a mixed solution of 38 g of ethanol and 60 g of distilled water and refluxed for 24 hours. The same treatment as in Example 1 was performed to obtain a reaction product of methyl vinyl ether maleic anhydride copolymer (yield 8 g). The degree of esterification (the degree of esterification in the maleic acid-derived structural unit) of the resulting methyl vinyl ether-maleic acid copolymer was 30% as measured by NMR (structural unit (a): structural unit ( b) molar ratio = 100: 66.6). The hydrolysis and esterification reaction proceeded completely, and the structural units derived from maleic acid in the methyl vinyl ether-maleic acid copolymer were only the structural unit (a) and the structural unit (b).

A comparative medical device (2) was obtained in the same manner as in Example 1 except that the obtained methyl vinyl ether-maleic acid copolymer was used.

Comparative Example 3
12 g of methyl vinyl ether maleic anhydride copolymer (trade name: GANTREZ AN-169 GAF) was put in a solution of 85 g of ethanol and refluxed for 3.5 hours. After cooling the reflux liquid, it was put into hexane, and the deposited precipitate was collected and dried at 70 ° C. under reduced pressure for 3 days while being pulverized as needed to obtain a reaction product of methyl vinyl ether maleic anhydride copolymer (yield 10 g). The degree of esterification (degree of esterification in the structural unit derived from maleic acid) of the resulting methyl vinyl ether-maleic acid copolymer was measured by NMR and found to be 40%. However, in this copolymer, hydrolysis and esterification reaction do not proceed completely, and the structural unit derived from maleic acid in the methyl vinyl ether-maleic acid copolymer is composed of structural unit (a), structural unit ( In addition to b), the structural unit (c) was included.

A comparative medical device (3) was obtained in the same manner as in Example 1 except that the obtained methyl vinyl ether-maleic acid copolymer was used.

For the medical devices (1) to (4) prepared in Examples 1 to 4 and the comparative medical devices (1) to (3) prepared in Comparative Examples 1 to 3, the following tests were conducted under normal circumstances. Swellability, swellability under severe conditions and surface lubricity were evaluated. The results are shown in Table 2 below.

(Evaluation of swellability under normal environment)
Each medical device is immersed in distilled water at 25 ° C. for 1 minute and sufficiently swollen, and then the film thickness (μm) is measured with a microscope. According to the measured film thickness, it classifies as follows. If the film thickness is 20 μm or more (“◯” in Table 2 below), it is determined that the medical device can exhibit sufficient lubricity.

(Evaluation of swellability under severe conditions)
Each medical device was subjected to a temperature and humidity cycle test under the conditions shown in Table 1 below. Each medical device after the temperature and humidity cycle test is immersed in distilled water at 25 ° C. for 1 minute and sufficiently swollen, and then the film thickness (μm) is measured with a microscope. According to the measured film thickness, classification is performed in the same manner as described above (evaluation of swellability in a normal environment). If the film thickness is 20 μm or more (“◯” in Table 2 below), it is determined that the medical device can exhibit sufficient lubricity.

From Table 2, the maleic acid-derived structural unit consists only of the structural unit (a) and the structural unit (b), and the molar ratio of the structural unit (a): the structural unit (b) is 100: 2 to 100. : Medical devices (1) to (4) of Examples 1 to 4 using a maleic polymer material in the range of 50 are used under normal conditions (room temperature) and harsh conditions (temperature and humidity cycle test). In both cases, it can be seen that in both cases, the film thickness when swollen is 20 μm or more and exhibits good lubricity. On the other hand, the comparative medical device (1) of Comparative Example 1 using a maleic acid-based polymer substance, which is a maleic anhydride half ester containing a maleic anhydride-derived structural unit (c), under normal circumstances. Although the film thickness at swelling of 20 μm or more shows good lubricity, it can be seen that under severe conditions (after the temperature and humidity cycle test), the film thickness at swelling is less than 20 μm, and the lubricity is inferior to the allowable range. Further, the comparative medical device (2), the structural unit (a), and the structural unit of Comparative Example 2 using a maleic polymer material having a molar ratio of the structural unit (a): the structural unit (b) exceeding 100: 50 In the comparative medical device (3) of Comparative Example 3 using the maleic polymer material containing (b) and the structural unit (c), the film thickness when swollen in a normal environment is less than 20 μm, and the lubricity is acceptable. It turns out that it is inferior to the range.

(Evaluation of surface lubricity)
For each medical device (hereinafter simply abbreviated as “sample”) subjected to the temperature and humidity cycle test, a friction measuring machine (manufactured by Trinity Lab, Handy Tribomaster TL201) 10 shown in FIG. 1 is used according to the following method. Thus, the lubricity of the surface lubricating layer was evaluated.

That is, each sample 3 after the temperature and humidity cycle test was fixed in the petri dish 2 and immersed in water 1 having a height that the entire sample 3 was immersed. This petri dish 2 was placed on the moving table 6 of the friction measuring machine 10 shown in FIG. A cylindrical butyl rubber terminal (φ = 7 mm) 4 was brought into contact with the sample 3 and a load 5 of 70 g was applied on the terminal 4. The moving table 6 was reciprocated horizontally five times at a speed of 10 m / sec and a moving distance of 25 mm, and the sliding resistance value (gf) at the fifth reciprocation was measured. The results are shown in FIG.

From FIG. 2, the structural unit derived from maleic acid consists only of the structural unit (a) and the structural unit (b), and the molar ratio of the structural unit (a) to the structural unit (b) is 100: 2 to 100. : The medical devices (1) to (4) of Examples 1 to 4 using a maleic acid polymer material in the range of 50 are derived from maleic anhydride under severe conditions (after temperature and humidity cycle test). Comparative medical device (1) of Comparative Example 1 using a maleic acid-based polymer substance which is a half ester of maleic anhydride containing the structural unit (c): The molar ratio of the structural unit (a) to the structural unit (b) Comparative medical device (2) of Comparative Example 2 using a maleic acid polymer material having a ratio of more than 100: 50 or a maleic acid polymer comprising the structural unit (a), the structural unit (b) and the structural unit (c) Comparative medical device of Comparative Example 3 using substance ( ) As compared to when it imparts excellent lubricity to the medical device surface, it is discussed.

This application is based on Japanese Patent Application No. 2013-181452 filed on September 2, 2013, the disclosure of which is incorporated by reference in its entirety.

Claims

A medical device inserted into a living body provided with a resin coating layer containing a maleic polymer material on the surface of a base material,
The resin coating layer is formed by covalently bonding the maleic polymer material to a reactive functional group present on at least the surface of the base material constituting the medical device,
The maleic polymer material includes a structural unit derived from maleic acid, and the structural unit derived from maleic acid comprises the following structural unit (a) and the following structural unit (b), and the structural unit (a): A medical device wherein the molar ratio of the structural unit (b) is 100: 2 to 100: 50.

In the formula, X 1 to X 3 each independently represents hydrogen, an alkali metal, or an alkaline earth metal, and R represents a linear or branched alkyl group having 1 to 24 carbon atoms.
The medical device according to claim 1, wherein at least one of the X 1 to X 3 is an alkali metal.
The medical device according to claim 1 or 2, wherein the reactive functional group is an isocyanate group, an amino group, an aldehyde group or an epoxy group.
The medical device according to any one of claims 1 to 3, wherein the maleic polymer material is an alkyl vinyl ether-maleic acid ester copolymer.
A solution containing a linear or branched alcohol having 1 to 24 carbon atoms and water, wherein the mass ratio of alcohol: water is 100: 0.1 to 150, and a maleic anhydride-based polymer substance. Reacting to obtain a maleic polymer material containing a maleic acid-derived constitutional unit;
Treating a substrate constituting the medical device with a solution containing a compound having a reactive functional group to form an underlayer having the reactive functional group on at least the surface of the substrate;
The base material on which the base layer is formed is treated with the maleic polymer material, and the reactive functional group and the maleic polymer material are covalently bonded to form a maleic acid-based material on the base layer. The method for producing a medical device according to any one of claims 1 to 4, further comprising the step of forming a resin coating layer containing a polymer substance.
Furthermore, the method of Claim 5 which has a step which carries out the alkali treatment of the base material which has the said foundation | substrate layer and resin coating layer.