JPH084618B2 - Manufacturing method of antithrombogenic material - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an antithrombotic material. More specifically, it relates to a method for producing an antithrombotic material by a graft polymerization method.

[Conventional technology]

Artificial blood vessels are one of the typical medical materials required to have antithrombotic properties, but at present, it has not been obtained that they have sufficient antithrombotic properties, and they have been put to practical use in a very limited area. I'm just there. That is, a polyester knitted material or a porous material made of polytetrafluoroethylene is conventionally used as an artificial blood vessel for a large-diameter artery, but since the antithrombotic property of these materials is not sufficient, a small-diameter artery or A vein with a low blood flow rate could not be used because a thrombus was formed and occluded in a short time.

Further, in JP-A-46-42759, JP-A-50-150793 and JP-A-51-24651, hydrophilic polymers such as poly (2-hydroxyethyl) methacrylate and polyvinyl alcohol are disclosed. Although an antithrombotic material comprising a hydrogel obtained by crosslinking treatment is disclosed,
Not only is the antithrombogenicity insufficient, but the strength is also low,
There was a problem in using it as an artificial blood vessel. Further, in JP-A-49-125493 and JP-A-51-125978, a method of graft-polymerizing the above-mentioned hydrophilic polymer-forming monomer on the surface of the material is disclosed. In the method, the material strength can be improved by appropriately selecting the base material, but the antithrombotic effect is similar to that of the hydrophilic polymer. Therefore, it is not applicable to arteries or veins having a small diameter. It was difficult.

Further, JP-A-48-66187 and JP-A-53-106.
Japanese Patent No. 778 discloses a method of imparting antithrombotic properties by immobilizing a blood coagulation inhibitor such as heparin or urokinase on the surface of the material. With this method, an excellent antithrombotic property was initially obtained, but the anticoagulant effect was gradually reduced, so that it was not possible to obtain a stable antithrombotic property for a long period of time. And, the antithrombotic material produced by such a method has a drawback that it becomes extremely expensive because the blood coagulation-inhibiting substance is expensive and sterilization is difficult, so that it is extremely expensive. there were.

In spite of the many proposals that have been made in the past, materials that can maintain the excellent antithrombotic properties for a long period of time so far as to be applicable as artificial blood vessels to small diameter arteries and veins are currently available. It was not obtained.

As a result of various investigations for improving antithrombotic properties, the present inventors have found that a very small amount (1 to 10) of a water-soluble and substantially nonionic polymer is present on the surface of a base material made of a polymeric material.
It was found that the antithrombotic property is dramatically improved by binding 0 μg / cm ² ) compared with the case of binding in a large amount, and the patent application was previously filed as Japanese Patent Application No. 59-87432.

[Problems to be solved by the invention]

The invention according to the above patent application provides an excellent antithrombotic material, but according to the experience of the present inventors,
Even with the same amount of binding, there is a possibility that the antithrombogenicity may differ depending on the chain length of the bound polymer. However, it has been difficult to control the chain length of the polymer so as to always fall within a certain range by the conventional graft polymerization method. An object of the method of the present invention is to provide a product having an extremely high antithrombotic property, which is produced by controlling the chain length of a polymer within an optimum range. Another object of the method of the present invention is to provide a product having a high antithrombotic property which can be stably supplied.

[Means for solving problems]

The above-mentioned object is achieved by allowing a redox reducing agent and / or a polymerization modifier to coexist during the graft polymerization. That is, the product produced by the method of the present invention is an antithrombotic material obtained by graft-polymerizing a water-soluble monomer on the surface of a base material made of a polymer material, wherein the water-soluble monomer is redox-reduced. An antithrombogenic material characterized in that a free radical or peroxide is generated in the presence of an agent and / or a polymerization modifier to carry out graft polymerization, and a limited amount is bound to a substrate. .

The optimum range of the amount of redox reducing agent and polymerization modifier used depends on the type of compound used, but it is generally 10 ^-5 mo.
It is suitable to use at a concentration in the range of l / l to 10 mol / l.

[Work]

According to the present invention, a superior antithrombotic material can be obtained as compared with the case where a redox reducing agent and / or a polymerization modifier is not used, because the number of graft polymers bonded to the base material increases. At the same time, it is presumed that the chain length is limited to a certain range. That is, the redox reducing agent or the polymerization modifier efficiently converts the peroxide on the surface of the base material into radicals, and a large number of starting points for graft polymerization are formed on the surface of the base material, so that the number of bonds of the graft polymer increases. Since these compounds also act as a chain transfer agent, it is considered that the elongation of the polymer chain is suppressed and the degree of polymerization is limited to a relatively low range. As described above, it is considered that the case where a large number of polymers having a relatively short chain length are bound exhibits a better antithrombotic property than the case where a small amount of a polymer having a long chain length is bound even with the same binding weight.

〔Example〕

In the antithrombotic material according to the present invention, free radicals or peroxides are first generated on the surface of a base material made of a polymeric material. As a method of generating free radicals or peroxides, (1) a method of irradiating high-energy radiation such as an electron beam or gamma ray, (2) a method of irradiating ultraviolet rays, (3) low temperature plasma discharge treatment, (4) glow discharge Treatment, (5) ozone treatment, and (6) a method of adding a radical polymerization initiator such as benzoyl peroxide. Further, as the base material, most of known polymer materials can be used, and polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyvinylidene chloride, polystyrene, polyacrylonitrile. , Polymethylmethacrylate, styrene-butadiene block copolymer, acrylonitrile-butadiene-styrene block copolymer, polybutadiene, polyisoprene, polytetrafluoroethylene, polyethylene terephthalate, polyethylene isophthalate, polybutylene terephthalate, polyether-ester Examples of block copolymers, polycarbonate, polyamide, polyurethane, polysulfone, polyether sulfone, silicone, cellulose and cellulose acetate Rukoto can. The form of the substrate may be any form such as non-porous, porous, woven or knitted, and the shape is tubular, cylindrical,
Any shape such as a sheet shape, a plate shape, a block shape, and a fiber shape can be used according to the purpose of use. Further, these may be made of a single material or may be a composite structure made of a plurality of materials.

The antithrombotic material according to the present invention performs graft polymerization by allowing a water-soluble monomer to act on a base material on which free radicals or peroxides are generated. As the water-soluble monomer used, acrylamide, dimethylacrylamide, Examples thereof include methacrylamide, vinylpyrrolidone, and polyalkylene glycol esters of acrylic acid or methacrylic acid. These may be used alone or in combination of two or more. Further, the water-soluble monomer can be used as it is,
It is preferably used in the form of an aqueous solution.

The redox reducing agent used in the antithrombotic material according to the present invention is a reducing substance that causes a redox reaction together with an oxidizing substance such as a peroxide, and is a divalent compound such as ferrous chloride, ferrous sulfate or Mohr salt. Examples thereof include iron salts, acidic sodium sulfite, rongalite, ascorbic acid or its salts, and tartaric acid. Further, the polymerization modifier is a compound having an action of suppressing the polymerization rate or the degree of polymerization, and examples thereof include mercaptans such as thioglycolic acid, allyl alcohol, isopropyl alcohol and methanol captan, propyl mercaptan and butyl mercaptan. it can.

Graft polymerization serves as a starting point for free radicals or pen oxides formed on the surface of the substrate, and the reaction is immediately initiated when the graft polymerization is brought into contact with the water-soluble monomer. The reaction proceeds even at room temperature, but may be heated or cooled depending on the case.

Hereinafter, the present invention will be described more specifically with reference to specific examples. In the following examples, the protein adsorption property was used as an index of antithrombotic property. That is, since it is said that the better the antithrombotic property, the less the adsorption of glycoprotein such as IgG, the antithrombotic property was evaluated by measuring the adsorbed amount of IgG.

Example 1 In the antithrombogenic material of this example, needle electrodes were set at both ends of a polyurethane tube, and glow discharge was applied for 5 seconds under an applied voltage of 50 V and 50 ml / min of air flow to treat the tube surface. Next, this tube was immersed in a 1.5 mol / l aqueous solution of dimethylactylamide containing various concentrations of Mohr's salt, and graft polymerization was carried out at 30 ° C. for 20 hours in a nitrogen atmosphere. This antithrombotic material evaluation was performed by fluorescently labeling bovine gamma globulin (IgG) with fluorescein isothiocyanate (FITC) and mixing it with non-fluorescent labeled IgG to prepare an aqueous solution with a total protein concentration of 2 mg / ml. A tube made of the antithrombotic material of this example was immersed in the solution to adsorb proteins at 37 ° C for 3 hours. After that, the tube surface is gently washed with a buffer solution to remove non-adsorbed proteins, and the adsorbed proteins are hydrolyzed using an autoclave under the conditions of 3 atm for 1 hour, and the fluorescence intensity of FITC is measured at an excitation wavelength of 490 nm and fluorescence. It was measured at a wavelength of 520 nm. The amount of adsorbed IgG was calculated from the measurement result and a calibration curve prepared separately. The results are shown in Table 1.

As is clear from Table 1, when Mohm's salt is used as the redox reducing agent in the antithrombotic material of this example, the adsorption of IgG is extremely reduced and the antithrombotic property is excellent. Moreover, if the concentration of Mohr's salt is 10 ^-4 mol / l or more, it hardly changes to antithrombotic property.

Example 2 A polyurethane tube was subjected to glow discharge treatment in the same manner as in Example 1, and the tube was treated with dimethylacrylamide.
It was immersed in an aqueous solution containing 1.5 mol / l and Mohr's salt at 10 ^-2 mol / l, and graft polymerization was carried out at 30 ° C for 1 to 20 hours. Then, the amount of IgG adsorbed was measured in the same manner as in Example 1. Table 2 shows the results.

As is clear from Table 2, the antithrombotic property is almost constant when the polymerization time in the antithrombotic material of this example is 3 hours or more.

Example 3 A polyurethane tube was subjected to glow discharge treatment in the same manner as in Example 1, and the tube was treated with dimethylacrylamide 1.
It was immersed in three types of aqueous solutions containing 5 mol / l and 2 to 10% by weight of allyl alcohol, and graft polymerization was carried out at 60 ° C. for 5 hours. Then, the amount of IgG adsorbed was measured in the same manner as in Example 1. The results are shown in Table 3.

Example 4 A polyurethane tube was subjected to glow discharge treatment in the same manner as in Example 1, and the tube was treated with dimethylacrylamide.
It was immersed in an aqueous solution containing 1.5 mol / l and 5% by weight of allyl alcohol to carry out graft polymerization at 60 ° C. for 0.25 to 24 hours. Then, the amount of IgG adsorbed was measured in the same manner as in Example 1. The results are shown in Table 4.

Example 5 A polyurethane tube was subjected to glow discharge treatment in the same manner as in Example 1, and the tube was immersed in an aqueous solution containing 10% by weight of acrylamide and 10 ⁻² mol / l of Mohr's salt,
Graft polymerization was carried out at 0 ° C. for 3 hours. Then Example 1
When the amount of IgG adsorbed was measured in the same manner as above, 0.26 μg / c
It was m ² .

On the other hand, the amount of IgG adsorbed when Mohr's salt was not used was 0.41 μg / cm ² .

Example 6 A polyurethane tube was treated by glow discharge in the same manner as in Example 1, and the tube was treated with dimethylacrylamide.
1.5mol / l, 0.2-1.0wt% of ascorbic acid 3
Various kinds of aqueous solutions were dipped and graft polymerization was carried out at 40 ° C. for 20 hours. Then, the amount of IgG adsorbed was measured in the same manner as in Example 1. The results are shown in Table 5.

Example 7 A polyurethane tube was treated by glow discharge in the same manner as in Example 1, and the tube was treated with dimethylacrylamide.
It was immersed in three types of aqueous solutions containing 1.5 mol / l and thioglycolic acid in an amount of 0.2 to 1.0% by weight, and graft polymerization was carried out at 40 ° C. for 20 hours. Then, the amount of IgG adsorbed was measured in the same manner as in Example 1. The results are shown in Table 6.

Example 8 A polyethylene tube was subjected to glow discharge treatment in the same manner as in Example 1, and the tube was treated with dimethylacrylamide.
It was immersed in an aqueous solution containing 1.5 mol / l and 5% by weight of allyl alcohol to carry out graft polymerization at 60 ° C. for 0.25 to 24 hours. Then, the amount of IgG adsorbed was measured in the same manner as in Example 1. The results are shown in Table 7.

[Effects of the Invention] As is clear from the above results, the antithrombotic material according to the method of the present invention can easily produce and provide a material having an extremely excellent antithrombotic property. Moreover, since the effects of the redox reducing agent and the polymerization modifier are stable in a wide range, it is possible to always produce and provide a product having a constant quality.

Further, by using a redox reducing agent or a polymerization modifier, the production of a homopolymer during graft polymerization is suppressed, and the homopolymer attached to the surface of the obtained antithrombotic material has a small amount and a low degree of polymerization. Since it is low, the operation for removing it is also easy.

Claims (2)

[Claims] 1. A free radical or peroxide is generated on the surface of a base material made of a polymer material, and then selected from the group consisting of a divalent iron salt, ascorbic acid or its salt, or thioglycolic acid or allyl alcohol. A water-soluble monomer is allowed to act in the presence of one or more redox reducing agents and / or polymerization regulators to graft-copolymerize the water-soluble monomer on the surface of the substrate. A method for producing an antithrombotic material. 2. The method for producing an antithrombotic material according to claim 1, wherein the divalent iron salt is Mohr's salt in an aqueous solution having a concentration of 10 ⁻⁴ mol / l or more.