JPH0154061B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to an anti-blood coagulation polymer material and a method for producing the same. This article relates to blood coagulable polymer materials and their manufacturing methods. The polymeric material of the present invention does not cause coagulation of blood even when it comes into contact with blood, and has excellent mechanical strength, so it is useful as a medical material for artificial blood vessels, artificial organs, extracorporeal auxiliary circulation devices, and the like. [Prior Art] Various plastic materials have been used in the field of many medical devices, including artificial blood vessels and artificial organs, as well as various catheters, cannulae, tubes, blood storage containers, and syringes. There was a problem with the material causing blood clotting if it came into contact with blood. As a means to solve this problem, a method is known in which heparin, which has an anticoagulant effect, is blended or bonded to a polymeric material. However, when heparin is bonded to the surface of a polymeric material, some of its functional groups are consumed for bonding with the material, resulting in a decrease in the anticoagulant activity of heparin and poor production processability. When blending, it is not effective unless heparin is in contact with blood, and in that case, heparin is eluted into the blood, making it difficult to maintain anticoagulant effects for a long period of time. In order to solve these problems, the present inventors first developed an anti-blood coagulant polymer material whose main component is a cellulose polyion complex formed from a polyvalent cationic cellulose derivative and a polyvalent anionic cellulose derivative. (Japanese Unexamined Patent Publication No. 60-203265). [Problems to be Solved by the Invention] The polymeric material made of the cellulose polyion complex described above has the features of excellent anticoagulant action, no problem of elution of active ingredients, and easy production. ing. However, on the other hand, it has low mechanical strength and swells with moisture, so it cannot be used to manufacture medical devices by itself, and its use has been limited to applications such as coatings. Therefore, the present invention aims to solve the problems of mechanical strength and swelling properties of the above-mentioned polymeric material while maintaining its excellent anticoagulant activity. [Means for Solving the Problems] In order to achieve the above object, the present invention has the following configuration. That is, it is an anti-blood coagulant polymeric material whose main component is a polymeric polyion complex formed from a polyvalent cationic polymeric compound and a polyvalent anionic polymeric compound, wherein the polyvalent cationic or anionic polymeric compound is The anticoagulant polymeric material is characterized in that at least one of the above is substantially water-insoluble. A specific embodiment is an anti-blood coagulant polymer material in which the polyvalent cation polymer compound is an aminated product or a quaternary ammonium salt of a substantially water-insoluble polyhydroxy polymer compound. Furthermore, the anti-blood coagulation polymer material is a polyhydroxy polymer compound quaternary ammonium salt that is a cellulose quaternary ammonium salt. Further, it is an anti-blood coagulant polymer material in which the polyvalent anion polymer compound is carboxymethyl cellulose or cellulose sulfate. Furthermore, a method for producing an anti-blood coagulant polymer material, which comprises manufacturing a polymer polyion complex by immersing a substantially water-insoluble polyvalent cation polymer compound in a solution of a polyvalent anion polymer compound. It is. Furthermore, the anti-blood coagulant polymer material is characterized in that a substantially water-insoluble polyhydroxy polymer compound quaternary ammonium salt is immersed in an aqueous solution of carboxymethyl cellulose or cellulose sulfate to produce a polymer polyion complex. It's the manufacturing method. The polyvalent cationic or anionic polymer compound used in the present invention refers to a polyvalent cationic or anionic polymer compound having a large number of hydroxyl groups in the molecule,
It means a polymer compound having an amino group or a carboxyl group that is cationized or anionized by a method known per se. For example, the polyvalent cation polymer compound may be prepared by adding an aminating agent such as diethylaminoethyl chloride to the above-mentioned polymer compound.
Either react with aminoethyl sulfate or the like, or use a quaternary ammonium salt type cationizing agent such as glycidyl trimethyl ammonium halide, glycidyl triethylammonium halide, 3-chloro-
It is obtained by reacting 2-hydroxypropyltrimethylammonium halide, aryltrimethylammonium halide, etc. When using a quaternary ammonium salt having an epoxy group such as glycidyl triethylammonium chloride or glycidyl trimethyl ammonium chloride, the reaction is carried out in the presence of a Lewis acid, tertiary amine, sodium hydroxide, etc. However, from the viewpoint of operability and toxicity, it is preferable to use water. Preference is given to using sodium oxide. Shows poor solubility in polymer compounds as a solvent used in reactions,
A quaternary ammonium salt having an epoxy group is preferably dissolved and is substantially non-reactive, such as water, lower alcohol, dimethylformamide, etc. When using sodium hydroxide, its concentration is between 1×10 ^-6 and 1×10N, preferably 1×
10 ^-4 to 1×10 ^-1 N, and the reaction temperature is 200°C or less, preferably room temperature to 80°C. The reaction time depends on the reaction temperature, but is usually about 5 seconds to 50 hours. Cellulose itself is water-insoluble, but as is well known, cellulose becomes water-soluble as the degree of substitution with hydrophilic cations or anions increases.
The degree of substitution varies depending on the concentration of the reactant, reaction temperature, reaction time, alkali concentration, etc., but is usually controlled by the alkali concentration. For example, when cellulose and a cationizing agent are reacted at approximately 80°C for a predetermined time (5 hours), the alkali concentration increases.
Under conditions of 2.5N or less, polycationized cellulose (water-insoluble) with a degree of substitution of about 0.5 or less can be obtained. Under conditions where the alkali concentration is higher than 10N, the degree of substitution is approximately
Polycationized cellulose higher than 0.5 (water soluble)
is obtained. Examples of polyvalent cation polymer compounds include (β
-hydroxy-γ-trimethylammoniopropyl) cellulose chloride, (β-hydroxy-
Examples include cellulose derivatives such as γ-trimethylammoniopropyl) hydroxyethylcellulose chloride, aminoethylcellulose, diethylaminoethylcellulose, and cationized derivatives such as fibroin, collagen, chitin, chitosan, and polyethylene vinyl alcohol copolymers. Examples of polyvalent anionic polymer compounds include water-soluble ones such as cellulose ethers or cellulose esters such as sodium carboxymethylcellulose, sodium cellulose oxypropinate, sodium cellulose sulfate, and cellulose phosphate; Examples include polymethacrylic acid and copolymers thereof, polyacrylic acid and copolymers thereof, polyglutamic acid, etc., and these polyvalent anionic polymer compounds can be added to the above-mentioned polymer compounds according to methods known per se. It is produced by introducing an anion group into. The polymeric polyion complexes of the present invention are produced by methods known per se. That is, by dissolving polyvalent cation- and polyvalent anion polymer compounds in a common solvent such as formic acid, trifluoroacetic acid, dimethylformamide, dimethyl sulfoxide, etc., and mixing both solutions, a polyion complex is prepared. can be generated. Alternatively, a polyion complex can be produced by dissolving one polymer compound and immersing the other polymer compound in a solution of one polymer compound using a solvent such as water that does not dissolve the other polymer compound. can. The polyion complex thus obtained is molded into a film, tube or other desired shape according to a conventional method. Next, the present invention will be explained in more detail with reference to Examples and Test Examples. Example 1 Preparation of the polymeric compound of the present invention (1) Regenerated cellulose was immersed in an aqueous solution (approximately 0.1N) adjusted to pH 13 using sodium hydroxide,
Glycidyltrimethylammonium chloride is added in an amount equivalent to the hydroxyl group of cellulose, and the mixture is reacted for 5 hours using a shaker set at 80°C. After the reaction is completed, the product is thoroughly washed with distilled water to obtain water-insoluble (β-hydroxy-γ-trimethylammoniopropyl)cellulose chloride (degree of substitution 0.05). (2) Prepare a 1w/v% carboxymethyl cellulose (CMC) aqueous solution with a degree of substitution of 1.94 or 2.74 and a 1w/v% cellulose sulfate aqueous solution with a degree of substitution of 1.25, respectively, and adjust the pH to 8 with a 1/10N aqueous sodium hydroxide solution. Then, the polycationized cellulose obtained in 1) above is soaked for 24 hours.
After soaking, the product is thoroughly washed with distilled water to obtain the desired water-insoluble cellulose polyion complex. Preparation of control material Dissolve heparin sodium (151 IU/mg) in physiological saline to prepare a solution with a solution concentration of 0.2% (302 IU/ml). The polycationized cellulose prepared in 1) above is immersed in this solution for 24 hours to bind heparin. After treatment, thoroughly wash with physiological saline and use as a control material. Test Example 1 A sheet of the above-mentioned present invention material and control material (1
Platelet dilatation ability test was conducted on 1 cm) using the following method. 4.5 ml of venous blood from a healthy individual was collected using a plastic syringe containing 0.5 ml of 3.8% sodium citrate, and transferred to a plastic test tube.
Centrifuge at 800 rpm for 5 minutes. The platelet-rich plasma (PRP) obtained was diluted with a diluent (3.8% sodium citrate: physiological saline = 1:9) to reduce the platelet count to 60,000/
Adjust to mm ³ and make a platelet suspension. Drop the above platelet suspension onto the sample sheet and leave it in contact for 30 minutes at room temperature. After contact, each sample was lightly washed with the above diluted solution, fixed with 2.5% glutaraldehyde,
Dry with ethanol. The amount of platelets immobilized on the sample and changes in morphology were observed using a scanning electron microscope. The results are shown in Table 1. Morphological changes were classified into the following three types. Type: From the normal disc shape to a spherical shape, 3
What formed the pseudopodium of the book. Type: Four or more pseudopods are extended, and the cytoplasm is expanded to half the length of the pseudopods. Type: From those with a thin cell expanded to more than half the length of the pseudopod, to those with a completely expanded cell.

Table 1 It is clear from Table 1 that the material of the present invention has less platelet deformation and fewer platelets attached than the heparin-treated control material or the untreated material. These results indicate that the material of the present invention does not activate platelets and is less likely to cause blood coagulation. Example 2 Cellulose triacetate was coated on the surface of a refined polyester surgical thread (manufactured by Nichiko Kogyo Co., Ltd., International Standard No. 1-0) using a solvent evaporation method from a methylene chloride solution. The coated cellulose triacetate is regenerated into cellulose by deacetylation treatment in a 15% ammonia aqueous solution. The above-mentioned cellulose-coated polyester surgical thread and glycidyltrimethylammonium chloride are added in equimolar amounts to the hydroxyl groups of cellulose into an aqueous solution adjusted to pH 13 using sodium hydroxide, and further reacted at 80° C. for 5 hours with shaking. After the reaction is completed, the fibers are sufficiently washed with distilled water to obtain cationized cellulose coated fibers. Carboxymethyl cellulose 1w/v% aqueous solution with degree of substitution 1.94 and degree of substitution
A 1w/v% aqueous solution of cellulose sulfate of 2.5% was prepared, and the pH was adjusted to 8 with sodium hydroxide.
Cationized cellulose coated fibers are immersed in these aqueous solutions for 24 hours to obtain the desired water-insoluble polyion complex fibers. Test Example 2 The polyion complex fiber of the present invention obtained in Example 2 was inserted into the peripheral vein of a dog, and after one day had passed, it was converted to heparin, blood was removed, the vein was incised, and the fiber was washed with physiological saline. The surface condition was observed and evaluated with the naked eye. The results are shown in Table 2.

Table 2 It is clear from Table 2 that cellulose-coated polyester fibers form thrombi, whereas the polyion complex-coated material of the invention does not. [Effects of the Invention] The present invention provides an anti-blood coagulation polymeric material containing a polymeric polyion complex formed from a polyvalent cationic polymeric compound and a polyvalent anionic polymeric compound as a main component. Alternatively, at least one of the anionic polymer compounds is made of a water-insoluble anticoagulant polymer material, and is useful as a material for medical devices that come into contact with blood, such as artificial blood vessels, artificial organs, catheters, blood collection tubes, and blood storage containers. The polymeric material of the present invention has excellent anticoagulant activity. Furthermore, in the polymer material of the present invention, at least one of the polyvalent cation and anion polymer compounds is water-insoluble, so the polyion complex does not swell with water and has excellent mechanical strength. There is. Therefore, the various medical devices described above can be manufactured using the polymeric material of the present invention itself.

Claims (1)

[Scope of Claims] 1. An anti-blood coagulant polymeric material whose main component is a polymeric polyion complex formed from a polyvalent cationic polymer compound and a polyvalent anionic polymeric compound, wherein the polyvalent cation - or an anionic polymeric compound, wherein at least one of the anionic polymeric compounds is substantially water-insoluble. 2. The anti-blood coagulant polymer material according to claim 1, wherein the polyvalent cation polymer compound is an aminated product or a quaternary ammonium salt of a substantially water-insoluble polyhydroxy polymer compound. 3. The anti-blood coagulant polymer material according to claim 2, wherein the polyhydroxy polymer compound quaternary ammonium salt is a cellulose quaternary ammonium salt. 4. The anti-blood coagulant polymer material according to claim 1, wherein the polyvalent anion polymer compound is carboxymethyl cellulose or cellulose sulfate. 5. A method for producing an anti-blood coagulant polymer material, which comprises manufacturing a polymeric polyion complex by immersing a substantially water-insoluble polyvalent cationic polymeric compound in a solution of a polyvalent anionic polymeric compound. 6. Claim 5, characterized in that the polymer polyion complex is produced by immersing a substantially water-insoluble polyhydroxy polymer compound quaternary ammonium salt in an aqueous solution of carboxymethyl cellulose or cellulose sulfate. A method for producing the anticoagulant polymeric material described.