JP2002143294A - Guide wire and method for manufacturing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a guide wire exhibiting an excellent lubricity keeping effect and thrombosis resistance. SOLUTION: The guide wire is constructed by chemically bonding a random copolymer on the surface of the guide wire on which maleic acid containing or a maleate derivative-containing polymer compound layer is formed by using a condensing agent. The random copolymer is a copolymer formed by copolymerizing allylamine or its salt (a1) with a monomer containing phosphorylcholine analogous group (a2) and has a number average molecular weight of 50,000-5.000,000 containing these constituent unit of 91.01-100 mol%, where the constituent unit based on a1 is 0.01-9 mol% and the constituent unit based on a2 is 91-99.99 mol%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

2. Description of the Related Art With the recent improvement of medical technology, guide wires having various performances have been invented. For example,
2. Description of the Related Art Guide wires for intravascular use, PTCA use, and the like, which have improved operability by imparting surface lubricity to an inner surface or an outer surface, are widely used. As a method for producing such a surface lubricating guidewire, for example, Japanese Patent Publication No. Sho 59-19582 discloses a method in which polyvinylpyrrolidone, which is a hydrophilic polymer, is covalently bonded to the surface of a medical material as a lubricating material. Japanese Patent Publication No. 33181/1989 discloses a method in which a maleic anhydride-based polymer, which is a hydrophilic polymer, is immobilized on the surface of a medical material by a covalent bond as a lubricating material. Further, Japanese Patent Application Laid-Open No. 6-7426 discloses a method of immobilizing a maleic anhydride polymer on the surface of a medical material by impregnation.

On the other hand, means for imparting antithrombotic properties to medical materials have been studied so far, and methods for imparting a function of dissolving thrombus to the surface of the material and a function of suppressing the activity of coagulation factors are known. . These are broadly divided into (a) biochemical methods and (b) material methods.

[0003] Regarding (a), JP-A-8-19599 and JP-A-8-24327 disclose examples in which a drug such as an antithrombotic drug such as heparin or an antiplatelet drug such as citric acid is contained in the surface hydrophilic layer. JP, JP-A-9-99057, JP-A-10-179
No. 722, and the like. Further, a catheter in which urokinase, which is a fibrinolytic activator, is immobilized via a maleic acid copolymer is commercially available from Unitika, for details, see JP-A-10-234847, JP-A-10-248918, It is disclosed in JP-A-10-248919, JP-A-10-248920, JP-A-10-248921 and the like. In these research examples, there are also research examples aiming at the surface lubrication property and the antithrombotic property at the same time, and it can be said that this is a remarkable result particularly in a medical instrument such as a guide wire, which emphasizes operability. As the hydrophilic material for imparting surface lubricity, a maleic acid-based polymer or the like containing carboxylic acid, carboxylic acid derivative, carboxylic anhydride, or the like is often used.

[0004] On the other hand, as for (b), although there is a research example of giving a negative charge to the surface or covering the surface with a hydrophilic polymer such as polyethylene glycol or 2-hydroxyethyl methacrylic acid, the adsorption of proteins or the like is considered. Cannot be suppressed in the long term, so that sufficient antithrombotic properties have not been developed.

[0005] On the other hand, some materials designed to imitate biological membrane components exhibit extremely excellent antithrombotic properties. For example, a polymer of 2- (meth) acryloyloxyethyl phosphorylcholine (hereinafter abbreviated as MPC) has a phosphorylcholine group (hereinafter abbreviated as a PC group) which is a phospholipid polar group in a molecule, and therefore has high biocompatibility. Has recently become apparent. Therefore, application development to medical polymer materials has been actively pursued.

[0006] For example, JP-A-10-151192 discloses an antithrombotic composition comprising a complex of a PC group-containing polymer and a mucopolysaccharide and a medical material. However, since this complex is not covalently bonded to the surface of the medical device, there may be problems such as the mechanical strength of the coating being weak or the bond in the complex being broken by the electrolyte in the body fluid. Therefore, it is not suitable for application to fields such as guide wires where the mechanical strength of the coating is required. When applied to these fields, it is desirable that the PC group-containing polymer be firmly immobilized by covalent bonds, and from the viewpoint of surface lubricity, it is desirable that the PC group-containing polymer be a high molecular weight material.

On the other hand, as a surface lubricating material widely used for a guide wire, a polymer containing a functional group such as a carboxylic acid, a carboxylic acid derivative, or a carboxylic anhydride, specifically, a maleic acid polymer can be mentioned. . Examples of a functional group that exhibits excellent reactivity with these functional groups include an amino group. Therefore, if a crosslinked coating is formed on the surface of a medical material using a copolymer consisting of an amino group-containing monomer and a PC group-containing monomer, a guide wire that maintains or improves the surface lubricity and also has antithrombotic properties can be easily prepared. Can be manufactured.

For example, Japanese Unexamined Patent Publication No. 7-502053 discloses a reactive comonomer such as a (meth) acrylic or styrene-based monomer and a monomer containing a phosphorylcholine-like group (hereinafter abbreviated as a PC group) (hereinafter abbreviated as a PC group). A coating agent for immobilizing a copolymer consisting of a monomer (abbreviated as a monomer) on a surface by covalent bond is disclosed. However, since amino group-containing (meth) acrylate monomers or amino group-containing styrene monomers are generally expensive, they are inexpensive for industrial use such as allyl-based monomers such as allylamine (hereinafter abbreviated as AAM). Is desirable.

JP-A-7-184989 and JP-A-7-184990
Japanese Patent Application Publication No. JP-A-2005-17764 discloses a method in which an MPC copolymer having an epoxy group and an MPC copolymer having a hydroxyl group, an amino group, or a carboxyl group are used and immobilized on a substrate surface such as a guide wire by chemical bonding. Is disclosed. The amino group-containing MPC copolymer is disclosed as follows. That is, 6 g of MPC (20 mmol, 35 mol% in the monomer composition), 4.95 g of BMA (35 mmol, 60 mol% in the monomer composition), 0.18 g of AAM (3.2 mmol, in the monomer composition) 5 mol%) and 0.04 g of 2,2'-azobisisobutyronitrile (hereinafter abbreviated as AIBN) are dissolved in 28 mL of ethanol, and this reaction solution is immersed in a 60 ° C warm bath for 24 hours. To carry out a polymerization reaction. As a result, the number average molecular weight is 4500
0, the copolymer having an amino group content of 4.2 mol%
It is stated that it was obtained at 96%. However, as a result of additional tests by the present inventors, unlike the description, the content of amino groups contained in the copolymer was 0.001 mol%. This level of amino group content is not sufficient for the immobilization reaction, and even if immobilization is possible,
The coating may become brittle. From the viewpoint of surface lubricity, it is desirable that the molecular weight be large. That is, at present, in a PC group-containing polymer using AAM as a comonomer,
No high molecular weight product containing an amino group in an amount sufficient for the immobilization reaction and having a molecular weight of 50,000 or more has been obtained.

As described above, AAM is generally difficult to undergo radical polymerization and generally only produces a polymer having a low degree of polymerization in a low yield, and a polymer having a high molecular weight cannot be obtained.
There is a problem. Similarly, when copolymerizing AAM with another vinyl monomer having good polymerizability, there are also problems that a high molecular weight polymer cannot be obtained and the yield is low. One of the reasons for this is described as the occurrence of a self-terminating reaction due to the reaction between an allyl hydrogen atom and a radical. This reaction is usually called allyl-type destructive chain transfer and has been described in many documents and books. (For example, C.
E. SchildneCht, "Allylcompounds and their polymer
s ", Wiley Interscience, 19-30 (1973), RCLai
ble, Chemi. Rev., 58 (5), pp. 807-843 (1958), and Takayuki Otsu, "Revised Polymer Synthesis Chemistry", Chemistry Doujin,
(See pages 92-95 (Hatsusaka, 1968).) However, regarding the radical polymerization of AAM salts, it has been reported that a high molecular weight product was obtained in high yield by performing polymerization in a system containing water using an azo polymerization initiator (S. Harada). , S.Ha
segawa, Macromol.Chem., Rapid Commun., 5, 27-31 (1
984)).

On the other hand, various studies have been made on the blood compatibility of charged polymers. For example, it has been shown that blood compatibility is poor on surfaces with an excess of positive charges (Akaike et al., Polymers, 36, p.
217 (1979)). Therefore, it can be said that it is desirable to minimize the content of a monomer having a positive charge in a polymer aimed at blood compatibility. Also, in the reactive group-containing PC copolymer, if the content of the reactive group is too large, the number of reaction points at the time of immobilization increases, the water content of the generated PC copolymer layer decreases, and the lubricity increases. Therefore, it is unsuitable when using a material requiring lubricity such as a catheter.

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide AAM or a salt thereof and a PC monomer on the surface of a guide wire on which a reactive group-containing polymer compound layer containing maleic acid or a maleic acid derivative is formed. Produced by radical polymerization, the content of the structural unit based on AAM or a salt thereof is 0.01 to 9 mol%, and the content of the structural unit based on the PC monomer is 91 mol% to 99.99 mol%. Is contained in the copolymer in an amount of 90 to 100% by weight, and the number average molecular weight is 50,
It is an object of the present invention to provide a method for producing a guide wire obtained by chemically bonding 000 to 5,000,000 random copolymers by a reaction using a condensing agent.

[0013]

Means for Solving the Problems The present inventors diligently studied in view of the above problems, and prepared a monomer composition containing AAM or a salt of AAM and a PC monomer at a specific composition or at a specific temperature. As a result of the radical polymerization, a high molecular weight copolymer having a specific amino group and phosphorylcholine-like group ratio was obtained. As a result of study by immobilizing the copolymer described on the left on the surface of the guide wire, the present inventors have found that they have excellent lubricity maintaining effects and antithrombotic properties, and have completed the present invention. That is, the present invention includes the following (1) to (4).

(1) A copolymer obtained by polymerizing AAM or a salt of AAM (a1) and a PC monomer (a2), wherein the structural unit based on a1 is 0.01 to 9 mol%, and The constituent units are 91 to 99.99 mol% and the constituent units are 91.9 mol% in the polymer.
Number average molecular weight 50,000-5,000,000 containing 01-100 mol%
A guide wire obtained by chemically bonding a random copolymer of the above to the surface of the guide wire on which a reactive group-containing polymer compound layer containing maleic acid or a maleic acid derivative is formed, using a condensing agent.

(2) The following equation [1]

Embedded image (However, Z represents -NH ₂ or a salt thereof)
A structural unit based on AM or a salt thereof, and the following formula [2]

Embedded image (However, R ¹ , R ² , and R ³ may be the same or different and represent a hydrocarbon group having 1 to 4 carbon atoms. R ⁴ represents a hydrogen atom or a methyl group. Further, R ⁵ represents a carbon atom. A divalent hydrocarbon group represented by the following formulas 1 to 10, h represents a number of 0 to 10. j represents a number of 2 to 4.) Is a copolymer having a structural unit of the formula [1]
0.01 to 9 mol%, the structural unit of the formula [2] is 91 to 99.99 mol%
A random copolymer having a number average molecular weight of 50,000 to 5,000,000 containing 91.01 to 100 mol% of the constituent units is chemically bonded to the surface of the guide wire on which the maleic acid or maleic acid derivative-containing polymer compound layer is formed. Guide wire.

(3) The guide wire according to (1) or (2), wherein R ¹ , R ² , R ³ and R ⁴ are methyl groups.

(4) The above-mentioned (1), wherein the reactive group-containing polymer compound layer contains maleic acid or a maleic acid derivative.
Or the guidewire according to (2).

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION AAM used in the present invention may be a free form or a salt. Specific examples of AAM salts include, for example, allylamine hydrochloride (hereinafter abbreviated as AAM.HCl), allylamine sulfate, allylamine nitrite, allylamine phosphate, and the like. Among them, AAM.HCl is preferred from the viewpoint of availability and the like.

Specific examples of the monomer containing a PC analogous group used in the present invention include, for example, 2- (meth) acryloyloxyethyl-2 ′-(trimethylammonio) ethyl phosphate (of which 2-methacryloyloxy Ethyl-2 '-(trimethylammonio) ethylphosphate (= also referred to as 2-methacryloyloxyethylphosphorylcholine (hereinafter abbreviated as MPC)), 3- (meth) acryloyloxypropyl-2'-(trimethylammonio) ethyl Phosphate, 4- (meth) acryloyloxybutyl-2 '-(trimethylammonio) ethyl phosphate, 5- (meth) acryloyloxypentyl-2'-(trimethylammonio) ethyl phosphate, 6- (meth) acryloyloxyhexyl -2 '-(trimethylammonio) ethyl phosphate, 2- (meth) acryloyloxy Chill -2 '- (triethyl ammonio) ethyl phosphate, 2- (meth)
Acryloyloxyethyl-2 '-(tripropylammonio) ethyl phosphate, 2- (meth) acryloyloxyethyl-2'-(tributylammonio) ethylphosphate, 2- (meth) acryloyloxypropyl-2 '-(trimethyl Ammonio) ethyl phosphate, 2- (meta)
Acryloyloxybutyl-2 '-(trimethylammonio) ethyl phosphate, 2- (meth) acryloyloxypentyl-2'-(trimethylammonio) ethyl phosphate, 2- (meth) acryloyloxyhexyl-2'-
(Trimethylammonio) ethyl phosphate, 2- (meth) acryloyloxyethyl-3 ′-(trimethylammonio) propyl phosphate, 3- (meth) acryloyloxypropyl-3 ′-(trimethylammonio) propyl phosphate, 4- (Meth) acryloyloxybutyl-
3 '-(trimethylammonio) propyl phosphate, 5
-(Meth) acryloyloxypentyl-3 '-(trimethylammonio) propyl phosphate, 6- (meth) acryloyloxyhexyl-3'-(trimethylammonio)
Propyl phosphate, 2- (meth) acryloyloxyethyl-4 '-(trimethylammonio) butyl phosphate, 3- (meth) acryloyloxypropyl-4'-(trimethylammonio) butyl phosphate, 4- (meth) acryloyloxy Butyl-4 '-(trimethylammonio)
Butyl phosphate, 5- (meth) acryloyloxypentyl-4 ′-(trimethylammonio) butyl phosphate, 6- (meth) acryloyloxyhexyl-4 ′-(trimethylammonio) butyl phosphate and the like can be mentioned. Here, “(meth) acryl” means “acryl” and / or “methacryl”. These monomers may be used alone or as a mixture of two or more. Particularly, from the viewpoint of availability and the like, MPC is preferably mentioned.

The copolymer of AAM or a salt thereof and a PC monomer of the present invention is abbreviated as AA-PC copolymer. The content ratio of the structural unit based on AAM in the AA-PC copolymer is 0.01 mol% to 9 mol%.
Mol%, preferably 0.1 mol% to 5 mol%. Also,
The content of the structural unit based on the PC monomer is from 91 mol% to 99.99 mol%, preferably from 95 mol% to 99.9 mol%, based on the constituent components of the copolymer. If the amount is less than 0.01 mol%, the number of reactive functional groups in the copolymer which reacts with, for example, an epoxy group is not sufficient, as described above, which is not preferable.

The polymer containing a structural unit based on AAM or a salt thereof and a PC monomer may contain 0 to 8.99 mol% of a structural unit based on another monomer.

The number average molecular weight of the AA-PC copolymer produced is 50,000 to 5,000,000, preferably 100,000 to 1,
000,000. Number average molecular weight of AA-PC copolymer is 50,000
If it is less than, for example, when it is used as a surface treatment agent, physical properties such as abrasion resistance of the surface layer deteriorate, which is not preferable. If the number average molecular weight of the AA-PC copolymer exceeds 5,000,000, it is difficult to produce.

The terminal structure is a group generated by a termination reaction at the time of radical polymerization. Specifically, for example, a terminal group derived from a polymerization initiator represented by the following formulas [3] to [5] and a group represented by the formula [6] and terminal groups derived from the AAM monomer represented by [7].

[0024]

Embedded image

[0025]

Embedded image

[0026]

Embedded image

[0027]

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[0028]

Embedded image

Further, a polymerization terminal derived from a chain transfer agent or a solvent may be used.

The biocompatible polymer is prepared by subjecting the monomer composition to a polymerization system, if necessary, using known methods such as solution polymerization, bulk polymerization, emulsion polymerization, and suspension polymerization. For example, the polymerization temperature is replaced by an inert gas such as nitrogen, carbon dioxide, helium, or under the atmosphere of the above-mentioned inert gas.
It can be prepared by a method of radical polymerization under the polymerization conditions of 5 to 80 ° C. and a polymerization time of 10 minutes to 48 hours. Upon polymerization, the following radical polymerization initiator can be used.

As the radical polymerization initiator, for example, 2,2
2-Azobis (2-amidinopropyl) dihydrochloride, 2,2-azobis (2- (5-methyl-2-imidazolin-2-yl) propane) dihydrochloride, 4,4-azobis (4-cyanocyanic acid) , 2,2-
Azobisisobutylamide dihydrate, 2,2-azobis (2,
4-dimethylvaleronitrile), 2,2-azobisisobutyronitrile (AIBN), dimethyl-2,2'-azobisisobutyrate, 1-((1-cyano 1-methylethyl) azo) formamide, 2 , 2'-Azobis (2-methyl-N-phenylpropionamidine) dihydrochloride, 2,2'-azobis (2-methyl-N- (2-hydroxyethyl) -propionamide), 2,2'-azobis (2-methylpropionamide)
Examples include azo-based radical polymerization initiators such as dihydrate, 4,4'-azobis (4-cyanopentanoic acid), and 2,2'-azobis (2- (hydroxymethyl) propionitrile). Still further, benzoyl peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, t-butylperoxypivalate, t-
Butyl peroxydiisobutyrate, lauroyl peroxide, t-butyl peroxy neodecanoate, succinic peroxide (= succinyl peroxide), glutar peroxide, succinyl peroxyglutarate, t-butyl peroxymalate, t-butyl peroxypivalate , Di-2-ethoxyethyl peroxycarbonate, 3-
Organic peroxides such as hydroxy-1,1-dimethylbutyl peroxybivalate are exemplified. Still further, there may be mentioned persulfates such as ammonium persulfate, potassium persulfate and sodium persulfate. These radical polymerization initiators may be used alone or in a mixture. The amount of the polymerization initiator is usually 0.001 to 10 parts by weight based on 100 parts by weight of the monomer composition.
Parts by weight, preferably 0.01 to 5.0 parts by weight.

The solvent used for producing the AA-PC copolymer may be any solvent that dissolves the monomer that is a constituent unit of the copolymer and does not react with the solvent. Particularly, water or water may be used.
If the content is 50% by weight or more, a mixed solvent may be used.

As the solvent used for the mixed solvent, for example,
Alcohol solvents such as methanol, ethanol, and isopropanol; ketone solvents such as acetone, methyl ethyl ketone and diethyl ketone; ester solvents such as ethyl acetate; straight or cyclic ether solvents such as ethyl cellosolve and tetrahydrofuran; acetonitrile; Examples include a nitrogen-containing solvent such as nitromethane. Preferably, the solvent includes water or a mixed solvent of a water-alcohol system.

The polymer can be purified by a general purification method such as a reprecipitation method, a dialysis method and an ultrafiltration method.

The random copolymer of the present invention may be copolymerized with another monomer as the third component, if necessary, as long as the effects of the present invention are not impaired. The other monomer is not particularly limited as long as it is copolymerizable, and examples thereof include (meth) acrylic acid or a salt thereof; methyl (meth) acrylate, ethyl (meth) acrylate, and propyl (meth) acrylate. , (Meth) butyl acrylate, (meth)
Alkyl (meth) acrylates such as hexyl acrylate; 2-hydroxyethyl (meth) acrylate,
Hydroxypropyl (meth) acrylate, polyethylene glycol mono (meth) acrylate, polypropylene glycol mono (meth) acrylate, polyethylene glycol polypropylene glycol block or random copolymer mono (meth) acrylate, glycerol α-mono (meth) acrylate, Allyl alcohol, 2-allyl phenol, glycerol α-monoallyl ether, ethylene glycol monoallyl ether, N-
Hydroxy group-containing (meth) acrylic esters such as (hydroxymethyl) acrylamide and amides. The amount of these copolymerizable monomers to be added is 8.99 mol% or less, more preferably 5 mol% or less in the polymer.

The maleic acid derivative-containing polymer compound on the surface of the guide wire used in the present invention is generally used as a copolymer because maleic acid or a maleic acid derivative is unlikely to be homopolymerized. Specifically, carboxylic acid anhydride-containing copolymers such as maleic anhydride-vinyl methyl ether copolymer, maleic acid-vinyl methyl ether copolymer, maleic acid methyl ester-vinyl methyl ether copolymer, Examples include carboxylic acid ester-containing copolymers such as maleic acid ethyl ester-vinyl methyl ether copolymer, maleic acid propyl ester-vinyl methyl ether copolymer, and maleic acid butyl ester-vinyl methyl ether copolymer. The carboxylic acid ester may be a half ester or a diester, but in the case of a diester, partial hydrolysis is performed,
It is necessary to form free carboxylic acids. Therefore,
Preferably, it is a half ester of maleic acid.

As the guide wire, for example, a guide wire obtained by coating stainless steel with polyurethane and treating the surface with the above-mentioned polymer compound containing a maleic acid derivative can be used.

[0038]

The guide wire of the present invention is a guide wire having excellent lubricity maintaining effect and antithrombotic properties, because a specific copolymer is chemically bonded thereto.

[0039]

Next, the present invention will be described in more detail with reference to examples. Next, the measuring method used was shown. 1. Measurement of molecular weight Measurement of number average molecular weight of copolymer The number average molecular weight of the copolymer is a value of the number average molecular weight measured by gel permeation chromatography (GPC) using polyethylene glycol as a standard sample. That is, the obtained aqueous copolymer solution was diluted with distilled water to a concentration of 0.5% by weight, and this solution was diluted with distilled water.
The solution was filtered through a 0.45 μm membrane filter to obtain a test solution. The measurement conditions for GPC analysis are as follows. <Measurement conditions for GPC analysis> Column: G3000PWXL x 2 (manufactured by Tosoh Corporation), elution solvent: 20
mM phosphate buffer, standard substance; polyethylene glycol (manufactured by Polymer Laboratory), detection; parallax refractometer,
Calculation of weight average molecular weight (Mw), number average molecular weight measurement (Mn), molecular weight distribution (Mw / Mn); Molecular weight calculation program with built-in integrator (GPC program for SC-8020, manufactured by Tosoh Corporation), flow rate: 0.5 mL / min, sample Solution usage: 10 μL, column temperature: 45 ° C.

2. Measurement of Composition Ratio in Copolymer The method for measuring the composition ratio in the copolymer was determined by measuring the amino group content in the polymer. That is, the amino group content in the polymer was measured using trinitrobenzene sulfonic acid. Quantification was performed by a labeling reaction using trinitrobenzenesulfonic acid (hereinafter abbreviated as TNBS).
AA · HCl aqueous solutions of various concentrations were prepared for the calibration curve, and the linearity was confirmed. In addition, AAM-H
A Cl aqueous solution (50 ppm) was prepared, and as a sample solution, a filter aqueous solution containing 1% (w / w) of a polymer was prepared. As a reaction solution, a labeling reaction was performed according to the following procedure in which a borate buffer solution (3.81 g of borax dissolved in 100 mL of warm water), an aqueous TNBS solution (0.10%), and an aqueous sodium sulfite solution (0.13%) were prepared. 1. Collect 0.5 mL of sample solution into a test tube. 2. Add 2.0 mL of borate buffer solution. 3. Add 0.5 mL of sodium sulfite aqueous solution. 4. Add 0.5 mL of TNBS aqueous solution. 5. Incubate for 60 minutes in a thermostat at 37 ° C. As a measuring device, UV-visible absorption spectrometer U-best manufactured by JASCO
35 was used. The measurement was performed using a disposable cell made of PMMA having an optical path length of 10 mm for the spectroscopic cell, and the absorbance at a wavelength of 420 nm was obtained. The linearity of absorption at 420 nm was confirmed using AAM / HCl as a monomer component as a standard, and the composition of AAM / HCl in the AA-PC polymer was quantified using AAM / HCl 50 ppm as a standard sample as follows. And the composition ratio was calculated. AAM ・ HCl 5
Absorbance at 420 nm of 0 ppm: s. 420% 1% solution of polymer
Absorbance at nm: t. The amount of amino groups in 1% of polymer = 10000 ppm (in terms of AAM · HCl): When x is x, x = 50 × t / s, and when the AAM · HCl unit in 1 mol of polymer is amol, the MPC unit is 1- a mol. When the molecular weight of AAM / HCl is MA and the molecular weight of MPC is MM, the amount of amino groups in the polymer is a × 100mo
l%, aMA / ((1-a) MM + aMA) = x / 10000,
Thus, a = x × MM / ((10000 + x) MA + x × MM).

3. Lubricity Test Method <Pretreatment> Polyurethane-coated guide wire (diameter
0.8 mm, length 15.0 mm), immerse a maleic anhydride / methyl vinyl ether copolymer (manufactured by ISP, trade name “Gantrez”) in a 1.0% by weight methyl ethyl ketone solution for 10 seconds, and dry at 60 ° C. for 2 hours. A sample was obtained. An immobilization reaction was performed on the guide wire using a sample copolymer as follows. <Immobilization Reaction 1> A guide wire was immersed in 100 mL of an aqueous solution containing 2% by weight of an amino group-containing sample polymer, and left standing at room temperature for 2 hours. <Immobilization reaction 2> A guide wire was immersed in 100 mL of an aqueous solution containing 2% by weight of the amino group-containing sample polymer and 0.2 g of water-soluble carbodiimide, and left at room temperature for 2 hours. <Lubricity evaluation method> For evaluation of lubricity, a guide wire was immersed in a 1% by weight aqueous solution of calcium chloride, and the inner diameter was 1.0
The sample was repeatedly passed through a polyurethane tube having a length of 150 cm and a length of 150 cm. The contents of the evaluation are as follows. 5 points = very good, 4 points = good,
3 points = somewhat bad, 2 points = bad, 1 point = very bad.

4. <Thrombotic Test> The carotid artery and jugular vein of a Japanese white rabbit (male) weighing 2 kg were connected with a medical tube, and a test piece was placed inside to maintain blood flow for 30 minutes. Was. After the completion, washing with physiological saline was performed five times, the inside of the tube was filled with a 2.5% by weight glutaraldehyde aqueous solution, and the tube was left overnight to fix the thrombus. Thereafter, the test piece was taken out, and after gold deposition, surface observation was performed using a scanning electron microscope to evaluate the adhesion of platelets and the degree of thrombus formation. The contents of the evaluation are as follows. 5 points = no platelet adhesion and thrombus formation, 4 points = slight platelet adhesion but no thrombus formation, 3 points = high platelet adhesion but no thrombus formation , 2 points = platelet adhesion and thrombus formation observed, 1 point = platelet adhesion and significant thrombus formation observed.

. [0043] 5. <Structure confirmed> 5.1 ¹ Measurements of H-NMR method model; JEOL Ltd., JNM-EX270, measurement conditions: using a polymer powder 20 mg, deuterium oxide (D ₂ 0) 1.5 A sample solution dissolved in ml was used. 5.2. FT / IR Measurement Model: FT / IR-7300 manufactured by JASCO Corporation was used. Measurement conditions: A 5.0% by weight methanol solution of a sample was cast and used as a film.

Example 1-1 Synthesis of MPC / AAM.HCl Polymer 70 g (237 mmol, 90 mol%) of 2-methacryloyloxyethyl phosphorylcholine (hereinafter abbreviated as MPC), allylamine hydrochloride (AAM) 2.5 g (27 mmol, 10 mol%), 2,2′-azobis (2-amidinopropane) dihydrochloride (Wako Pure Chemical Industries, Ltd.) as a polymerization initiator
(Trade name: V-50) 0.37 g (1.4 mmol) was dissolved in 400 mL of water, and the inside of the reaction vessel was sufficiently replaced with nitrogen gas. The polymerization was carried out by immersing the reaction vessel in a 60 ° C. warm bath for 2 hours. After cooling, the reaction solution was dialyzed in water and purified. Thereafter, the entire amount of the solution was freeze-dried to obtain 60.9 g of a polymer as a solid. The yield based on the charged amount was 84%. As a result of measurement according to the above measurement method, the number average molecular weight of the polymer was 134,00
0, the content based on AAM.HCl was 0.2 mol%. The obtained polymer was measured according to the above-mentioned ¹ H-NMR measurement and IR measurement. The results are shown below. ¹ H-NMR measurement results; δ (ppm) 1.3; -C-CH ₃ , 2.2; -CH _2- , 3.3; -N (CH ₃ ) ₃ , 3.7; -O-
_{CH 2 CH 2 -N-, 4.0~4.4;} -O-CH 2 CH 2 -O-. FT / IR measurement results; (cm ^-1 ) 3400; -OH, 1720-C = O, 1480; -CH, 1235; -CC-, 129
0; -PO-, 970; -POC-. From the above results, the obtained polymer was a polymer having a ratio based on AAM · HCl of 0.2 mol%, a ratio based on MPC of 99.8 mol%, and a number average molecular weight of 134,000.

Examples 1-2, 1-3; Synthesis of MPC / AAM.HCl polymer Monomer composition with V-50 amount, solvent amount, reaction temperature and reaction time as described in Example 1-1 While keeping the total amount of the product at 264 mmol, polymerization was carried out while changing the charge ratio of MPC and AAM.HCl to 70:30 mol% (Example 1-2) and 50:50 mol% (Example 1-3). Was done. Table 1 shows the number average molecular weight, the content based on AAM.HCl, and the yield of the obtained polymer. In addition, ¹ H-NMR measurement results and IR measurement results were similarly confirmed.

Example 2-1: 70 g of MPC, 1.5 g of AAM, 0.37 g (1.4 mmol) of V-50 as a polymerization initiator were dissolved in 400 mL of water, and the inside of the reaction vessel was sufficiently replaced with nitrogen gas. . AAM
Since the boiling point was about 55 ° C., polymerization was carried out by immersing this reaction vessel in a 40 ° C. warm bath for 6 hours. After cooling, the reaction solution was dialyzed in water for purification. Thereafter, the entire amount of the solution was freeze-dried to obtain a polymer as a solid. The number average molecular weight of the polymer is 324,000, AAM
The content based on HCl was 2.6 mol%, and the yield was 44%.

Examples 2-2, 2-3; V-5 same as described in Example 2-1
With the amount of the solvent, the amount of the solvent, the reaction temperature and the reaction time, while keeping the total amount of the monomer composition at 263 mmol, the charge ratio of MPC to AAM was 80:20 mol% (Example 2-2), 70:30 Mol% (Example 2
-3) and polymerization was carried out. Table 1 shows the number average molecular weight, amino group content, and yield of the obtained polymer.

Example 3 With the same monomer composition, V-50 amount, solvent amount, reaction temperature and reaction time as described in Example 1-1, ethanol was maintained while maintaining the total amount of the monomer composition at 264 mmol. Two
Polymerization was carried out in a solvent obtained by mixing 00 mL and 200 mL of water. Table 1 shows the number average molecular weight, the content based on AAM.HCl, and the yield of the obtained polymer.

Comparative Example 1 The reaction temperature was changed to 85 ° C.
Polymerization was carried out under the same conditions as in Example 1-2. The number average molecular weight of the obtained polymer was 48,200, the amino group content was 0.7 mol%, and the yield was 78%. Comparative Example 2 Polymerization was carried out under the same conditions as in Example 1-2 except that 400 mL of ethanol was used as a polymerization solvent. The amino group content of the obtained polymer was 2.5 mol%, and the yield was 12%.
%, The number average molecular weight was 8,000. Comparative Example 3 Polymerization was carried out under the same conditions as in Example 1-2, except that 0.32 g (1.4 mmol) of succinic peroxide (manufactured by NOF CORPORATION, trade name: Perloyl SA) was used as a polymerization initiator. . The number average molecular weight of the polymer was 72,600, the amino group content was 0.4 mol%, and the yield was 22%. Comparative Example 4 Aminoethyl methacrylate hydrochloride (AEM) 4.4 g
(27 mmol, 10 mol% in the monomer composition), MPC 70 g (23
7 mmol, 90 mol% in the monomer composition), V-50
0.37 g (1.4 mmol) was dissolved in 400 mL of water, and the inside of the reaction vessel was sufficiently replaced with nitrogen gas. This reaction vessel is 60
Polymerization was performed by immersion in a warm bath at 2 ° C. for 2 hours.
After cooling, the reaction solution was dialyzed in water for purification.
Thereafter, the entire amount of the solution was lyophilized and analyzed. The polymer obtained a molar ratio of AEM / MPC = 10.2 / 89.8 and a number average molecular weight of 153,000. The yield was 95%. Table 1 shows the above results.

Synthesis Reference Example 1 Polymerization was carried out according to the following procedure according to a copolymerization method using MPC, n-butyl methacrylate (hereinafter abbreviated as BMA) and AAM disclosed in JP-A-7-184989. Was. MPC 6 g (20 mmol, 35 in monomer composition)
Mol%), 4.95 g of BMA (35 mmol, 60 in monomer composition)
Mol%), AAM 0.18 g (3.2 mmol, 5 in monomer composition)
Mol%), 2,2'-azobisisobutyronitrile (hereinafter A
0.04 g) was dissolved in 28 mL of ethanol, and the inside of the reaction vessel was sufficiently replaced with argon gas. The polymerization reaction was performed by immersing this reaction vessel in a 60 ° C. warm bath for 24 hours. After cooling, the polymerization solution was poured into chloroform according to the method disclosed, but no precipitate was obtained, so precipitation was performed with ethyl ether instead of chloroform. After the copolymer precipitate was filtered off, it was dried under vacuum. The number average molecular weight of the obtained polymer was 44,300 and the yield was 96%. JP-A-7-184989 describes that the content of amino groups contained in the obtained copolymer (hereinafter, MPC-BMA-AAM copolymer) is 4.2 mol%. But,
As a result of quantification, unlike the description, the content of amino groups contained in the copolymer was only 0.001 mol%. As a result of measurement using a commercially available phosphorus determination kit, the MPC content in the copolymer was 36.8 mol%.
Met. Therefore, the BMA content is calculated to be 63.2 mol%.

Reference Examples 1 and 2, Comparative Reference Examples 1, 2, 3, and 4; Comparison of Lubricity and Antithrombotic Property AAM / HCl-MPC copolymer obtained in Example 1-2 (Reference Example 1)
And AAM / HCl-MPC copolymer obtained in Comparative Example 1 (Comparative Reference Example 1), polymer of MPC and aminoethyl methacrylate (AEM) (Comparative Reference Example 2), MPC-BMA-AAM copolymer Using (Comparative Reference Example 3), lubricity was evaluated in accordance with the pretreatment method, the fixing method (1), and the test method described above. Further, using the AAM · HCl-MPC copolymer obtained in Example 1-2, lubricity was evaluated according to the pretreatment method, the immobilization method (2), and the test method (Reference Example 2). ). In addition, a guide wire (diameter 0.8 mm, length 1) coated with polyurethane
5.0mm) pre-treated sample (Comparative Reference Example)
4) A sample not subjected to the pretreatment (Comparative Reference Example 5) was prepared, and the lubricity and antithrombotic properties were evaluated according to the test method. Table 2 shows the results of the lubricity test, and Table 3 shows the results of the antithrombotic test.

From the results of the lubricity test, when the copolymer having a number average molecular weight of 127,000 of the present invention was used for a guide wire from Reference Examples 1 and 2, the comparison was made regardless of whether a condensing agent was used or not. Comparative reference example 2 of reference example 1 with a number average molecular weight of 48,200 without treatment, comparative reference example 3 with a large number of amino groups using aminoethyl methacrylate, guide wire coated with polyurethane (with and without pretreatment; comparative reference examples respectively)
Excellent lubricity was shown in the first pass compared to cases 4 and 5). However, those using a condensing agent were excellent in durability. MPC disclosed in JP-A-7-184989,
The lubricity of a guide wire using a copolymer composed of n-butyl methacrylate and AAM was equivalent to that of a guide wire subjected to only the pretreatment (Comparative Reference Example 4).

From the results of the antithrombotic test, when the copolymer having a number average molecular weight of 127,000 according to the present invention was used for a guide wire from Reference Examples 1 and 2, regardless of whether a condensing agent was used or not, Comparative Reference Example 1 of 48,200 number average molecular weight, Comparative Reference Example 2 without treatment, Comparative Reference Example 3 with a large number of amino groups using aminoethyl methacrylate, guide wire coated with polyurethane (with and without pretreatment; Comparative Reference Examples, respectively)
It showed superior antithrombotic properties as compared to cases 4 and 5). The antithrombotic property of a guidewire using a copolymer comprising MPC, n-butyl methacrylate and AAM disclosed in JP-A-7-184989 is comparable to that of a guidewire subjected to only pretreatment (Comparative Reference Example 4). It was equivalent.

[0054]

[Table 1]

[0055]

[Table 2]

[0056]

[Table 3]

From the above results, it can be seen that the copolymer of the present invention can be produced according to Examples 1-1 to 1-3, 2-1 to 2-3 and 3. Further, it can be seen that the copolymer of the present invention exerts a great effect on lubricity and antithrombotic properties, and that the use of a condensing agent improves the sustainability.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) // (C08F 230/02 A61L 33/00 C 226: 02) A61M 25/00 450B (72) Inventor Yoshitoshi Takami Gifu No. 3, Takehaya-cho, Kawashima-cho, Hashima-gun, Japan Within the clinical supply of the corporation (72) Inventor Masahiko Tsugi 3 of Takehaya-cho, Kawashima-cho, Hashima-gun, Gifu Prefecture F-term (reference) in the clinical supply of the corporation 4C081 AC06 BA02 BB05 CA061 CA071 CC01 DA04 DB07 DC05 4C167 AA28 BB06 CC08 FF03 GG02 GG07 GG42 HH08 HH14 4J027 AC02 AC03 AC04 AC06 AC09 AJ02 AJ08 BA04 BA07 BA08 BA13 BA14 CB02 CB03 CB09 CC02 CD07 4J031 AA16 AA01 AA20 AA03 AB04 BA63P CA04 DA01 JA51

Claims (3)

[Claims] 1. A copolymer obtained by copolymerizing an allylamine or a salt thereof (a1) with a phosphorylcholine-like group-containing monomer (a2), wherein the structural unit based on a1 is 0.01 to 9 mol% and a2 A random copolymer having a number average molecular weight of 50,000 to 5,000,000 containing 91 to 99.99 mol% of these constituent units and forming a maleic acid or maleic acid derivative-containing polymer compound layer is formed. A guide wire chemically bonded to the surface of a guide wire using a condensing agent. 2. A compound represented by the following formula [1]: (Where Z represents —NH ₂ or a salt thereof) and a structural unit based on allylamine or a salt thereof, and the following formula [2] (However, R ¹ , R ² , and R ³ may be the same or different and represent a hydrocarbon group having 1 to 4 carbon atoms. R ⁴ represents a hydrogen atom or a methyl group. Further, R ⁵ represents a carbon atom. A divalent hydrocarbon group represented by the following formulas 1 to 10, h represents a number of 0 to 10. j represents a number of 2 to 4), and a structural unit based on a phosphorylcholine analog-containing monomer represented by the following formula: The copolymer is contained, and the structural unit of the formula [1] is 0.01 to 9 mol%, the structural unit of the formula [2] is 91 to 99.99 mol%, and the structural unit is 91.01 to 100.
A guide wire obtained by chemically bonding a random copolymer having a number average molecular weight of 50,000 to 5,000,000 containing mol% to a surface of a guide wire on which a maleic acid or a maleic acid derivative-containing polymer compound layer is formed using a condensing agent. 3. The guide wire according to claim ¹ , wherein R ¹ , R ² , R ³ and R ^{4 in the} formula [2] are methyl groups.