JPH02144070A - Easily slidable medical material - Google Patents

Abstract

PURPOSE:To obtain a medical material having both of excellent easy slidability and anti-thrombogenecity by fixing acidic polysaccharide to the hydrophilic copolymer, which is applied and fixed to a base material by a covalent bond, by an ionic bond or the covalent bond. CONSTITUTION:In a method for fixing acidic polysaccharide to a hydrophilic copolymer, an ionic bond or a covalent bond is adapted. In the ionic bond method, it is pref. to bond the tertiary group or quaternary ammonium salt thereof of the hydrophilic copolymer to the acidic polysaccharide by the ionic bond. In the covalent bond method, the amino group, hydroxyl group and carboxyl group being the functional groups of the hydrophylic copolymer are bonded to the amino group, hydroxyl group and carboxyl group contained in the acidic polysaccharide or the epoxy group or formyl group introduced by reaction of said polysaccharide. The amount of the acidic polysaccharide fixed to the hydrophilic copolymer is different according to objective easy slidability or anti-thrombogenecity and there is no special limit but said amount is pref. 0.1wt.% or more by wt. of the hydrophilic copolymer and especially pref. selected within a range of 1-50wt.%.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to medical materials that have excellent low friction properties when wetted, that is, have both slipperiness and antithrombotic properties, such as catheters, guide wires, It is a useful product that can be widely applied to canyures, etc.

[Prior art] In medical materials, especially catheters and guide wires,
Low friction (easiness of slipping) on the surface is an essential requirement. For example, if the catheter is not slippery, it may be painful to insert the catheter into the human body, and there is a risk of damaging tissue mucous membranes or causing inflammation.

As one of the conventional techniques for imparting slipperiness, a method of coating a base material with a hydrophilic polymer is known.

As a specific method for coating a hydrophilic polymer, fixation of polyvinylpyrrolidone using incyanate (Japanese Patent Application Laid-open No. 59-19582, U.S. Pat. No. 4,100,
309), a method using a hydrophilic polymer copolymerized with reactive functional groups and incyanate (Japanese Unexamined Patent Publication No. 59-81
341), fixation of polyethylene oxide using incyanate (Japanese Unexamined Patent Publication No. 193766/1982)
etc. are disclosed.

Antithrombotic properties are also an important requirement for medical materials. In other words, the decline in the functionality of medical materials and the occurrence of complications for living organisms due to the formation of blood clots are major problems.

As an antithrombotic material, hydrophilic heparinized material (Special Publication
4-18518>, segmented polyurethane, etc. are known.

“Problems to be Solved by the Invention” However, conventional slippery materials coated with hydrophilic polymers do not have antithrombotic properties, resulting in decreased functionality of medical materials and complications for living organisms due to thrombus formation. The scope of application has been limited due to concerns that this may occur.Conversely, conventional antithrombotic materials do not have sufficient slipperiness.

In this way, there has been no medical material that has both slipperiness and antithrombotic properties. That is, an object of the present invention is to provide a medical material that has both excellent slipperiness and antithrombotic properties not found in the prior art.

[Means for Solving the Problems] The present invention aims to achieve the above object and has the following configuration. That is, the present invention is a slippery medical material made by fixing an acidic polysaccharide by an ionic bond or a covalent bond to a hydrophilic copolymer coated and fixed to a base material by a covalent bond.

Various conventionally known methods can be applied to fixing the hydrophilic copolymer to the base material by covalent bonding in the present invention. For example, a method of coating a hydrophilic polymer on a base material made of a reactive polymer such as an incyanate group and reacting the same, or a method in which a reactive polymer containing an incyanate group or the like is coated on the surface of the base material in advance, and then an amine group, Preferred is a method in which a hydrophilic copolymer having a reactive functional group such as an amide group, a carboxyl group, a sulfonic acid group, or a hydroxyl group is coated and reacted. Further, one example of the polymer containing this incyanate group is polyincyanate. Specific examples thereof include adducts of polymethylene polyphenylisocyanate, toluene diisocyanate, 4,4-diphenylmethane diisocyanate-1 to 3,4-dichlorophenyl diisocyanate, and trimethylolpropane, polyol, and the like.

Next, the hydrophilic copolymer used in the present invention will be explained in detail. This copolymer is characterized by being a hydrophilic polymer that reacts with reactive groups such as isocyanate groups and has functional groups capable of ionic or covalent bonding with acidic polysaccharides. The definition of hydrophilicity is to dissolve or swell in water. Such polymers include (A)! Aqueous components: (meth)acrylamide, methoxypolyethylene glycol mono(meth)acrylate, N-vinyl-2-pyrrolidone, maleic anhydride, 2
-vinylpyridine, 4-vinylpyridine, N-1,2,
4-triazolylethylene, methyl vinyl ether, 2
- at least one selected from hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, glyceryl (meth)acrylate, (meth)acrylic acid and its salts, vinyl sulfonate and its salts, (B ) Components that react with incyanate: (meth)acrylamide, 2-aminoethyl-4-vinylphenethylamine, (meth)acrylic acid, vinyl sulfonate, sulfonated styrene, 2-hydroxyethyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, at least one selected from glyceryl (meth)acrylate, (C) component that reacts with acidic polysaccharide: (meth)acrylic acid, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, Glyceryl (meth)
Acrylate, 2-vinylpyridine, 4-vinylpyridine, dialkylaminoalkyl (meth)acrylate,
It can be obtained by copolymerizing a combination of three essential components: dialkylaminoalkylstyrene and at least one selected from 2-aminoethyl-4-vinylphenethylamine (the essential components may overlap). do not have). In addition to these essential components, (D) hydrophobic component: at least one selected from ethylene, propylene, styrene, alkyl (meth)acrylate, vinyl chloride, vinylidene chloride, vinyl acetate, and (meth)acrylonitrile. can be copolymerized to improve durability.

The composition ratio of these four components is A:B:C:D=50-99
．． 8:0.1~49.9:0.1~49.9:O~49
A range of 8° is preferred.

Further, the molecular weight is preferably 10 to 5 million, and particularly preferably 100,000 or more.

Acidic polysaccharides used in this material include mucopolysaccharides such as hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin, and heparan sulfate, as well as dextran sulfate,
chitosan sulfate, cellulose sulfate, amylopectin sulfate,
Examples include highly hydrophilic polysaccharides such as pectin sulfate, alginic acid, and alginic acid sulfate. Among these, heparin or its derivatives (heparinoids) are particularly preferred as they have excellent antithrombotic properties. 'Ionic bonding or covalent bonding is used to immobilize these acidic polysaccharides onto the hydrophilic copolymer. As for the ionic bonding method, it is preferable to ionicly bond the tertiary amino group or its quaternary ammonium salt (quaternized product) in the hydrophilic copolymer to the acidic polysaccharide. On the other hand, as a covalent bond method,
The functional groups such as amino groups, hydroxyl groups, and carboxyl groups in the hydrophilic copolymer are combined with the amine groups, hydroxyl groups, and carboxyl groups contained in the acidic polysaccharide, as well as the epoxy groups and polmyl groups introduced by reaction. . Various catalysts such as condensing agents can be used in these reactions. Furthermore, it is also preferable to introduce a spacer upon bonding. Examples of the spacer include alkylene dihydric sulfonic acid, aminoalkyl carboxylic acid, alkylene diamine, alkylene diol, polyethylene glycol, diamino polyethylene oxide, and bisepoxy polyethylene glycol.

The slipperiness can be greatly improved by fixing acidic polysaccharides to hydrophilic copolymers, and the effect is particularly great when the acidic polysaccharides are based on ionic bonds.

Further, the amount of acidic polysaccharide fixed to the hydrophilic copolymer is not particularly limited depending on the desired slipperiness and antithrombotic properties, but is preferably 0.1 wt% or more based on the hydrophilic copolymer. In particular, it is preferably selected within the range of 1 to 50 wt%.

Next, a method for manufacturing the slippery medical material of the present invention will be explained.

Various base materials for medical materials are selected depending on the purpose of use, and various plastics, various inorganic materials, metal materials, etc. are preferably used. Specifically, polyvinyl chloride,
Examples include polyethylene, polypropylene, polystyrene, polyurethane, polyurea, polymethyl methacrylate, nylon, polyester, polyacrylonitrile, metal wire coated with these, stainless steel, elastic metals, ceramics, and wood.

Various methods can be used to form each coating layer, but a preferred method is to first coat the surface of the substrate with a solution prepared by dissolving a predetermined amount of polyisocyanate in a suitable good solvent by dip coating or spin coating. Next, a hydrophilic copolymer is coated in a similar manner, and reacted and immobilized by heating or the like.

When fixing acidic polysaccharides, there are different methods for ionic bonding and covalent bonding. , ionic bonds are present in the immobilized hydrophilic copolymer3
This can be achieved by using a quaternary amine group as it is or by treating it with an alkyl halide or the like to form a quaternary ammonium salt, and then reacting it with an acidic polysaccharide.

Various methods can be applied to the covalent bond, and there are no particular limitations. For example, a primary amine group (or carboxyl group) present in a hydrophilic copolymer and a carboxyl group (or primary amino When reacting with (group), this can be achieved by using a condensing agent such as carbodiimide or Woodward's reagent. In addition, when introducing a spacer, the spacer is introduced into a hydrophilic copolymer or acidic polysaccharide in advance, and one of the spacers is bonded to the reactive end of the spacer, or the spacer is reacted and bonded all at once via the spacer. achieved.

Since the slippery medical material of the present invention has both excellent slipperiness and antithrombotic properties, it can be widely applied to medical materials such as various catheters, guide wires, cannulae, and endoscopes.

[Example] The present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 16.0 g of N-vinyl-2-pyrrolidone and N.

2.0 g of N-dimethylamine ethyl acrylate and 2.0 g of 2-hydroxyethyl acrylate were dissolved in azobisdimethylvaleronitrile (V-6) in ethyl alcohol.
A hydrophilic copolymer having a molecular weight of 500,000 was obtained by polymerization using 5> as an initiator.

Stainless steel wire coated with polyurethane, length 70cm,
A guide wire with a diameter of 2 mm was made of polyisocyanate (
Manufactured by Nippon Polyurethane Industries, product name: CL, TDI
3% methyl ethyl ketone (ME
K) After being immersed in the solution for 1 minute, it was dried at 50°C for 1 hour.

Next, this guide wire was immersed in a 4% chloroform solution of the previously synthesized hydrophilic copolymer for 5 seconds, then pulled out, and allowed to react at dry temperature and 80° C. for 5 hours. After the reaction, the guide wire was thoroughly washed with hot water to remove unbound hydrophilic copolymer.

Furthermore, this guide wire was immersed in methyl alcohol containing 5% ethyl bromide at 35°C for 2 hours to quaternize the tertiary amine groups in the vinylpyrrolidone polymer.
% heparin aqueous solution at 50° C. for 24 hours to perform immobilization by ionic bonding. Next, unbound heparin and residual salts were removed by washing with ion-exchanged water, and the product was vacuum-dried at room temperature for two days and nights.

The content of heparin in the coating polymer layer was determined by quantifying sulfur atoms using an X-ray microanalyzer, and found to be 20.5 wt%. Furthermore, the heparin elution rate in plasma was 0.01 U/Ci/stone.

The slipperiness was quantified using the following procedure and method.

(1) Lay the guide wire over the glass slide.

(2) Immerse the guide wire in physiological saline.

(3) Place a 100 g weight whose bottom surface is coated with polyurethane on the guide wire.

(4) Fix one end of the slide glass in the long axis direction and gradually lift the other end, and the inclination angle when the weight starts to slide (
θ).

(5) From the obtained inclination angle (θ), the formula μ-tanθ
Calculate the friction coefficient μ using

As a result of evaluation using the above method, the static friction coefficient μ−〇,
026, and showed excellent slipperiness.

In addition, the guide wire before coating is μ = 0°36
It did not show any slipperiness.

The antithrombotic properties were evaluated by using a guide wire (approximately 15 kg) and indwelling the guide wire in the vena cava for two weeks, and then observing the state of thrombus adhesion on the surface of the guide wire.

As a result, no thrombus was observed on the surface of the slippery guide wire of this example, both macroscopically and by electron microscopy.
It showed excellent hyperthrombotic properties. On the other hand, significant thrombus adhesion was observed on the guidewire before coating.

As described above, it has been revealed that the present slippery guidewire has both excellent slipperiness and antithrombotic properties.

Example 2 18.0 g of methacrylamide and 2.0 g of N,N-dimethylaminoethyl methacrylate were polymerized in tetrahydrofuran using AIBN (azobisisobutyronitrile) as an initiator, resulting in a hydrophilic copolymer with a molecular weight of approximately 300,000. Obtained union.

A guide wire coated with polyisocyanate in the same manner as in Example 1 was immersed in 5% acetone of this hydrophilic copolymer for 5 seconds, pulled up, dried, and reacted at 80° C. for 5 hours. After the reaction, the guide wire was thoroughly washed with hot water to remove unbound hydrophilic copolymer. Quaternization and heparinization were carried out in the same manner as in Example 1°. Moreover, the hevelin content in the coating polymer layer was 11.7 wt%.

When the slipperiness and antithrombotic properties were evaluated in the same manner as in Example 1, the coefficient of static friction μ was excellent, 0.035, and no thrombus adhesion was observed.

Example 3 Methoxypolyethylene glycol monomethacrylate having polyethylene oxide units with a degree of polymerization of 23 (manufactured by Shin Nakamura Chemical Co., Ltd., M-23G>18.0 g and acrylic acid 2.0 g)
g was polymerized using azobisdimethylvaleronitrile (V-65> as an initiator) to obtain a hydrophilic copolymer with a molecular weight of about 600,000.

A guide wire coated with polyisocyanate in the same manner as in Example 1 was immersed in a 4% tetrahydrofuran solution of this hydrophilic copolymer for 5 seconds, then pulled out, dried, and reacted at 80° C. for 5 hours. After the reaction, the guide wire was thoroughly washed with hot water to remove unbound hydrophilic copolymer.

The wire was immersed in a 1% aqueous solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride at 4°C for 24 hours. In addition to this, 5g of heparin
and 1-ethyl-3-(3-dimethylaminepropyl)-
Add 0.05 g of carbodiimide hydrochloride to 100 g of ion-exchanged water.
g and allowed to react at 4°C for 24 hours.

A carbodiimide-activated guide wire was immersed in a 5% aqueous solution of hexamethylene diamine at 25° C. for 2 hours to react, and then thoroughly washed with ion-exchanged water.

This guidewire was immersed in the previously prepared activated heparin solution at 25° C. for 2 hours to react, thereby fixing heparin by covalent bonding. The heparin content in the coating polymer layer was 8.3 wt%.

When the slipperiness and antithrombotic properties were evaluated in the same manner as in Example 1, they were excellent with a static friction coefficient μ of 0.026, and no thrombus adhesion was observed.

Comparative Example I A hydrophilic copolymer with a molecular weight of approximately 300,000 was obtained by polymerizing 18.0 g of N-vinyl-2-pyrrolidone and 2.0 g of 2-hydroxyethyl methacrylate in ethyl alcohol using AIBN as an initiator. Ta.

A guide wire coated with polyisocyanate in the same manner as in Example 1 was immersed in a 4% chloroform solution of this hydrophilic copolymer for 5 seconds, then pulled out, dried, and reacted at 80° C. for 5 hours. After the reaction, the guide wire was thoroughly washed with hot water to remove unbound hydrophilic copolymer.

Evaluation of slipperiness and antithrombotic property was performed in the same manner as in Example 1. The coefficient of static friction was μ=0.043, and the slipperiness was relatively excellent, but it was not as good as the examples.

Furthermore, in the evaluation of antithrombotic properties, considerable adhesion of blood clots was observed.

Comparative Example 2 0.03 diethylthiocarbamate group as photofunctional group
Polyvinyl chloride 20 with a degree of polymerization of 1100 containing 2 mol%
Methoxypolyethylene glycol monomethacrylate (manufactured by Shin Nakamura Chemical, M-23G>20 g) having polyethylene oxide units with a polymerization degree of 23 and 10 g of N,N-dimethylamine ethyl methacrylate were dissolved in 200 g of tetrahydrofuran, and an immersion type light inside the light source was prepared. Polymerization equipment (
Using a high-pressure mercury lamp in Ushio Inc.'s ULO-6QR, UV rays were irradiated at 30°C for 7 hours under an argon flow.
A graft copolymer in which the above two types of monomers were grafted onto polyvinyl chloride was obtained. The chemical composition of the copolymer determined by elemental analysis is 63 wt% polyvinyl chloride, 26 wt% methoxypolyethylene glycol monomethacrylate.
t%, N, N dimethylaminoethyl methacrylate 11
It was wt%.

The same polyurethane-coated guide wire as in Example 1 was immersed in a 5% dimethylformamide solution of this copolymer for 1 minute, then pulled out and dried at 50° C. for 1 hour. Subsequently, quaternization and heparinization were performed in the same manner as in Example 1. Moreover, the heparin content in the coating polymer layer was 12.3 wt%.

Evaluation of slipperiness and antithrombotic property was performed in the same manner as in Example 1. The coefficient of static friction was μ=0.27, indicating no slipperiness. However, in the evaluation of antithrombotic properties, no adhesion of thrombus was observed and the product was excellent.

Table 1 shows the evaluation results of slipperiness and antithrombotic properties of Examples 1 to 3 and Comparative Example 1.2.

had.

1) Better low friction than conventional slippery materials Table 1 Friction (easy slipping) have.

2) Excellent antithrombotic properties.

3) High safety.

Claims (1)

[Claims] (1) A slippery medical material made by fixing an acidic polysaccharide by ionic or covalent bonds to a hydrophilic copolymer coated and fixed to a base material by covalent bonds.