JPS6287163A - Method for manufacturing antithrombotic materials - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a method for manufacturing antithrombotic materials.

More specifically, the present invention relates to a method for producing an antithrombotic material using a graft polymerization method.

[Conventional technology]

Artificial blood vessels are one of the typical medical materials that require antithrombotic properties.
However, at present, sufficient antithrombotic properties have not been obtained, and they have only been put into practical use in a small number of areas. In other words, polyester knit fabrics or porous materials made of polytetrafluoroethylene have been used as artificial blood vessels for large-diameter arteries, but these materials do not have sufficient antithrombotic properties, so they cannot be used for small-diameter arteries or artificial blood vessels. In veins where the blood flow rate is low, blood clots form within a short period of time, resulting in occlusion, making it unusable.

Also, JP-A-46-42759, JP-A-50-1
No. 50793 and Japanese Unexamined Patent Publication No. 51-24651 disclose antithrombotic materials comprising hydrogels obtained by crosslinking hydrophilic polymers such as poly(2-hydroxyethyl) methacrylate and polyvinyl alcohol. However, it has problems in its use as an artificial blood vessel because it not only has insufficient antithrombotic properties but also low strength. Further, JP-A-49-125493 and JP-A-51-125978 disclose a method of graft polymerizing a monomer forming the above-mentioned hydrophilic polymer onto the surface of a base material. Although this method can improve the material strength by appropriately selecting the base material, it is only as effective as a hydrophilic polymer in terms of antithrombotic properties, so it cannot be applied to small-diameter arteries or veins. was difficult.

Furthermore, JP-A No. 48-66187 and JP-A No. 5
Publication No. 3-106778 and the like discloses a method of immobilizing a blood coagulation inhibitor such as heparin or urokinase on the surface of a material to impart antithrombotic properties. In this method, excellent antithrombotic properties can be obtained initially, but the blood coagulation inhibitory effect gradually decreases, so that stable antithrombotic properties cannot be obtained over a long period of time. Antithrombotic materials produced by this method have the disadvantage that they are extremely expensive because the blood coagulation inhibitor is expensive and sterilization is difficult, so they must be produced aseptically. there were.

Despite the many proposals that have been made in the past, there are currently no materials that can maintain antithrombotic properties so excellent that they can be applied to small-diameter arteries and veins as artificial blood vessels. I wasn't getting it.

As a result of various studies to improve antithrombotic properties, the present inventors have found that a water-soluble and substantially nonionic polymer is added to the surface of a base material made of a polymeric material in an extremely small amount (1 to 1). 10
It was discovered that the antithrombotic properties were dramatically improved by binding (0 μg/cnf) compared to when a large amount was bound, and a patent application was previously filed as Japanese Patent Application No. 87432/1983.

[Problem that the invention seeks to solve]

The invention related to the above patent application provides an excellent antithrombotic material, but according to the experience of the present inventors, the antithrombotic effect varies depending on the chain length of the bound polymer even if the amount of binding is the same. There may be gender differences. However, with the conventional graft polymerization method, it is difficult to control the chain length of the polymer so that it always falls within a certain range.

An object of the present invention is to provide a method that can control the chain length of a polymer within an optimal range and produce a product with extremely high antithrombotic properties. Another object of the present invention is to provide a method for stably producing a product having high antithrombotic properties.

[Means for solving problems]

The above-mentioned object is achieved by coexisting a redox reducing agent and/or a polymerization regulator during graft polymerization. That is, the present invention generates free radicals or peroxides on the surface of a substrate made of a polymeric material, and then applies a water-soluble monomer to the surface of the substrate in the presence of a redox reducing agent and/or a polymerization regulator. This is a method for producing an antithrombotic material, characterized by graft polymerizing the water-soluble monomer.

The optimum amount of the redox reducing agent and polymerization regulator varies depending on the type of compound used, but it is approximately 10-'
It is suitable to use it at a concentration in the range of mol/12 to 10 mol/1.

[For production]

According to the present invention, a material with better antithrombotic properties can be obtained than when no redox reducing agent and/or polymerization regulator is used, because the number of bonds of the graft polymer bonded to the base material increases. It is also presumed that this is because the chain length is limited to a certain range. That is, the redox reducing agent or polymerization regulator efficiently converts peroxide on the surface of the substrate into radicals and forms many starting points for graft polymerization on the surface of the substrate, thereby increasing the number of bonds in the graft polymer. Since these compounds also act as chain transfer agents, it is thought that elongation of the polymer chain is suppressed and the degree of polymerization is limited to a relatively low range.

In this way, it is thought that when a large number of polymers with relatively short chain lengths are bound together, the antithrombotic property is superior to when a small amount of polymers with long chain lengths are bound together even at the same binding weight.

〔Example〕

To carry out the present invention, free radicals or peroxides are first generated on the surface of a substrate made of a polymeric material.

Methods for generating free radicals or peroxides include (1) irradiation with high-energy radiation such as electron beams and gamma rays, (2) irradiation with ultraviolet rays, and (3) irradiation with ultraviolet rays.
) 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. In addition, most of the known polymeric materials can be used as the base material, including polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyvinylidene chloride, polystyrene, and polyacrylonitrile. , polylessyl methacrylate, styrene-
Butadiene block copolymer, acrylonitrile-butadiene-styrene block copolymer, polybutadiene, polyisoprene, polytetrafluoroethylene, polyethylene terephthalate, polyethylene isophthalate, polybutylene terethalate, polyether ester block copolymer , polycarbonate, polyamide, polyurethane, polysulfone, polyethersulfone, silicone, cellulose, and cellulose acetate. The form of the base material may be non-porous, porous, woven, knitted, etc.
Regarding the shape, there are tube-like, cylindrical, sheet-like, plate-like,
It can be used in any shape, such as block or fiber, depending on the purpose of use. Furthermore, these may be made of a single material, or may be a composite structure made of a plurality of materials.

In the present invention, graft polymerization is performed by allowing a water-soluble monomer to act on a base material in which free radicals or peroxides have been generated. Examples of the water-soluble monomers used include acrylamide, dimethylacrylamide, methacrylamide,
Examples include vinylpyrrolidone and polyalkylene glycol esters of acrylic acid or methacrylic acid. These may be used alone or in combination of two or more. Moreover, although the water-soluble monomer can be used as it is, it is preferable to use it in the form of an aqueous solution.

The redox reducing agent used in the present invention is a reducing substance that causes a redox reaction with an oxidizing substance such as peroxide, and includes divalent iron salts such as ferrous chloride, ferrous sulfate, Mohr's salt, acidic Examples include sodium sulfite, Rongalite, ascorbic acid or a salt thereof, and tartaric acid. In addition, a polymerization regulator is a compound that has the effect of suppressing the polymerization rate or degree of polymerization, such as thioglycolic acid,
Examples include various alcohols such as allyl alcohol, isopropyl alcohol and methanol, and mercaptans such as ethyl mercaptan, propyl mercaptan and butyl mercaptan.

In graft polymerization, free radicals or peroxides generated on the surface of a substrate act as an initiator, and the reaction is initiated immediately upon contact with a water-soluble monomer. The reaction proceeds at room temperature, but may be heated or cooled depending on the case.

Hereinafter, the present invention will be explained in more detail with reference to specific examples. In the following examples, protein adsorption properties were used as an index of antithrombotic properties.

In other words, it is said that the better the antithrombotic properties, the less adsorption of glycoproteins such as IgG.
The antithrombotic properties were evaluated by measuring the amount of adsorption.

Example 1 Needle-shaped electrodes were set at both ends of a polyurethane tube,
5 under applied voltage 50V, 50m Il/min air flow
The tube surface was treated by flashing and discharging for seconds. Next, this tube was immersed in a 1.5 mol/Il aqueous solution of dimethylacrylamide containing various concentrations of Mohr's salt, and graft polymerization was performed at 30° C. for 20 hours in a nitrogen atmosphere. Next, bovine gamma globulin (IgG) was fluorescently labeled with fluorescein isothiocyanate (FITC), and non-fluorescently labeled IgG was mixed with this to prepare an aqueous solution with a total protein concentration of 2 μ/m 1, and the grafts were added to this solution. The polymerized tube was immersed to adsorb proteins at 37°C for 3 hours.

After that, the surface of the tube was gently washed with a buffer solution to remove unadsorbed proteins, and then the tube was placed in an autoclave for 3
Hydrolyze the adsorbed protein under atmospheric pressure for 1 hour,
The fluorescence intensity of FITC was set to an excitation wavelength of 490 nm and a fluorescence wavelength of 5.
Measured at 20ra+. The amount of IgG adsorbed was calculated from the measurement results and a separately prepared calibration curve. Table 1 shows the results.
Shown below.

Table 1 Relationship between Mohr's salt concentration and IgG adsorption amount As is clear from Table 1, when Mohr's salt is used, IgG adsorption is extremely small, indicating that it has excellent antithrombotic properties.

Further, if the concentration of Mohr's salt is 10-' mol/1 or more, there is almost no change in antithrombotic properties.

Example 2 A polyurethane tube was treated with glow discharge in the same manner as in Example 1, and this tube was treated with dimethylacrylamide for 1 hour.
．． 5mol/1. Mohr's salt was immersed in an aqueous solution containing 10-'' mat/i and graft polymerization was carried out at 30°C for 1 to 20 hours.Then, the amount of IgG adsorption was measured in the same manner as in Example 1.The results are shown in Table 2. show.

Table 2 Relationship between polymerization time and IgG adsorption amount As is clear from Table 2, if the polymerization time is 3 hours or more, the antithrombotic properties become almost constant.

Example 3 A polyurethane tube was treated with glow discharge in the same manner as in Example 1, and this tube was treated with dimethylacrylamide for 1 hour.
．． 5 mol/II, allyl alcohol 2~
Graft polymerization was carried out at 60° C. for 5 hours by immersion in three types of aqueous solutions containing 10% by weight. Next, the amount of IgG adsorption was measured in the same manner as in Example 1.

The results are shown in Table 3.

Example 4 A polyurethane tube was treated with glow discharge in the same manner as in Example 1, and this tube was treated with dimethylacrylamide for 1 hour.
．． 5+wol/it, 0.25-24 at 60℃ by immersion in an aqueous solution containing 5% by weight of allyl alcohol.
Time graft polymerization was carried out. Next, the amount of IgG adsorption was measured in the same manner as in Example 1. The results are shown in Table 4.

Table 4 Relationship between polymerization time and IgG adsorption amount Example 5 A polyurethane tube was treated with glow discharge in the same manner as in Example 1, and this tube was treated with 10% by weight of acrylamide.
, Mohr's salt was immersed in an aqueous solution containing 10-'' mol/l, and graft polymerization was carried out at 30°C for 3 hours.Then, the adsorption amount of IgG was measured in the same manner as in Example 1, and it was found to be 0.26 μg/l. In contrast, the amount of IgG adsorption when Mohr's salt was not used was 0.41 μg/cA.

Example 6 A polyurethane tube was treated with glow discharge in the same manner as in Example 1, and this tube was treated with dimethylacrylamide for 1 hour.
', 5 mol/l, ascorbic acid 0.2
4 by immersing it in three types of aqueous solutions containing ~1.0% by weight.
Graft polymerization was carried out at 0°C for 20 hours. Next, the amount of IgG adsorption was measured in the same manner as in Example 1. Table 5 shows the results.
Shown below.

Example 7 A polyurethane tube was treated with glow discharge in the same manner as in Example 1, and this tube was treated with dimethylacrylamide for 1 hour.
．． 5 mol/l, thioglycolic acid 0.2-1.
It was immersed in three types of aqueous solutions containing 0% by weight at 40℃ for 2 hours.
Graft polymerization was carried out for 0 hours. Next, the amount of IgG adsorption was measured in the same manner as in Example 1. The results are shown in Table 6.

Example 8 A polyethylene tube was treated with glow discharge in the same manner as in Example 1, and this tube was treated with dimethylacrylamide for 1 hour.
．． Graft polymerization was carried out at 60° C. for 0.25 to 24 hours by immersing the sample in an aqueous solution containing 5 mol/l and 5% by weight of allyl alcohol. Then, in the same manner as in Example 1, I
The adsorption amount of gG was measured. The results are shown in Table 7.

Table 7 Relationship between polymerization time and rgG adsorption amount [Effects of the invention] As is clear from the above results, according to the method of the present invention, a material having extremely excellent antithrombotic properties can be easily produced. Moreover, since the effects of the redox reducing agent and the polymerization regulator are stable over a wide range, products of constant quality can always be produced.

In addition, by using a redox reducing agent or a polymerization regulator, the formation of homopolymers during graft polymerization is suppressed, and the amount of homopolymers that adhere to the surface of the obtained antithrombotic material is small and the degree of polymerization is low. Since it is low, the operation to remove it is also easy.

Claims (5)

[Claims] (1) Free radicals or peroxides are generated on the surface of a base material made of a polymeric material, and then a water-soluble monomer is applied to the surface of the base material in the presence of a redox reducing agent and/or a polymerization regulator. A method for producing an antithrombotic material, which comprises graft polymerizing a water-soluble monomer. (2) The production method according to claim 1, wherein the redox reducing agent is a divalent iron salt. (3) Claim 2 in which the divalent iron salt is Mohr's salt
Manufacturing method described in section. (4) The production method according to claim 1, wherein the redox reducing agent is one or more compounds selected from the group consisting of acidic sodium sulfite, Rongalite, ascorbic acid or its salt, and tartaric acid. (5) The polymerization regulator is one or more compounds selected from the group consisting of thioglycolic acid, allyl alcohol, isopropyl alcohol, methanol, ethyl mercaptan, propyl mercaptan, and butyl mercaptan. The manufacturing method described in item 1.