JPS58173557A - Header for blood treating apparatus and production thereof - 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 The present invention relates to a header for blood processing equipment with excellent anti-coagulability and a method for manufacturing the same.

Blood processing using so-called heart-lung devices such as artificial kidney devices, artificial sweat assist devices, and heart-lung machines has been applied to many diseases, but in all cases, the problem is that the blood comes into contact with the blood. The part is biocompatible. especially,
A common problem with materials that come into contact with blood is that these materials have the property of coagulating blood. For example, when blood is processed with an artificial kidney device, heparin, a natural anticoagulant, is injected into the blood to prevent blood from coagulating even when it comes into contact with materials. Methods are used to prevent coagulation. Injecting heparin into the blood suppresses the coagulation function of the blood, and if for some reason the patient undergoing treatment develops, it will stop the bleeding as long as the effect of heparin lasts. becomes difficult. The idea is to eliminate the need to inject heparin into the blood, and to construct the device using only materials that do not harden by 1 m when blood comes into contact with it. Conventionally, many studies have been conducted to develop materials with excellent blood compatibility, and results are being achieved. Many of these studies focused on only a small part of the total equipment, such as dialysis membranes or transient membranes in the case of artificial kidney machines, and adsorbent coatings in the case of heart-lung machines. For example, as a method for imparting anti-coagulant properties to a blood processing membrane for an artificial kidney device, the authors of the present invention have previously proposed a patent application of Showa J≦-4! ≦Ko No. 17 was filed. The present inventors have further conducted extensive research into a method of imparting anticoagulant properties to areas other than the blood processing membrane, particularly to a portion of the header where blood clots are likely to occur due to expansion of blood flow. In the present invention, the header refers to a component that connects the blood circuit and the main body of the blood processing device, and in the case of a hollow fiber membrane artificial kidney device as an example, the header refers to the / part in the first cabinet.

Conventionally, when a part of the material of a header is used for translating, its mechanical strength has been considered important, and its anti-blood coagulation properties have not been given much attention. Therefore, the present inventors discovered a method of imparting anti-coagulant properties to the header while maintaining its mechanical strength without changing the leaf material of the header, and arrived at the present invention. The first object of the present invention is to provide an anticoagulated header for a blood processing device that has a heparinized polymer coating on the inner surface of the header in a portion that comes into contact with blood. To make a header for a blood processing device anticoagulant, Mi & Si applied a coating film made of a graft-polymerizable thermoplastic polymer substance, then smoothed the coating film by heat treatment, and then applied the polymer coating. The present invention provides a method in which a polymerizable monomer comprising at least one component of glycidyl methacrylate is graft-polymerized, and then an epoxy group of glycidyl methacrylate is bonded to heparin.

Various materials are used for headers for blood processing equipment. For example, header materials for artificial kidney containers include polycarbonate resin, acrylonitrile-styrene copolymer resin, polypropylene resin, and the like. As a method of forming a coating film on these materials, it is easy to think of methods such as immersing the parts in a coating solution, or casting the coating solution on the part to be coated. .

However, with these methods, unnecessary areas may be coated and contaminated, or the header may be eroded by the solvent of the coating solution due to long-term contact with the coating solution. This is a particularly serious problem for medical parts.

The coating film can be formed by various methods such as dipping and coating, but it is preferable to use a spoon to prevent erosion of the material by the solvent. In the spray method, the coating solution discharged from the nozzle is rapidly exposed to reduced pressure, causing the solvent to rapidly vaporize.
By the time the paint particles reach the header, most of the solvent has vaporized. Therefore, it is possible to prevent a large amount of solvent from coming into contact with the material. The solvent used in the spray method is not limited to 1aai as long as it can dissolve the polymeric/molecular substances that form the coating film, but considering the vaporization rate during spraying, it is preferable to use a low-boiling point solvent. Typical examples are shown in Table 1 in combination with coating S-forming polymer substances to be described later. However, the present invention is not limited to these representative examples. Any substance can be used as long as it can be converted into a substance that can be graft-polymerized by hydrolysis or the like and is soluble in a solvent, but typical examples are shown in Table 1. Examples of the former include cellulose acetate and ethyl heptamine, and examples of the latter include vinyl acetate polymer (hereinafter referred to as PVAc).
It is abbreviated as ), ethylene-vinyl acetate copolymer (hereinafter referred to as EV
Abbreviated as A. ) and styrene-butadiene copolymers.

Which substance to select from these polymeric substances must be determined by taking into consideration its affinity with the target material and the temperature during heat treatment.

The viscosity of the coating solution is λ~207 inch poise, abbreviated as e and p. ), preferably j~/Oc, p
.

It is. Therefore, it is preferable to determine the concentration of the thermoplastic polymer substance using the viscosity as an index. The coating solution prepared in this way is spray applied to the target material. At that time, contamination can be prevented by covering the area other than the area to be coated with a mold such as a PVC sheet. Further, the thickness of the coating film can be adjusted by adjusting the number of times of spraying. The coating surface thus formed has a rough surface, but is then smoothed by heat treatment. The heat treatment is performed at a temperature above the softening point of the coating material or at a temperature at which it softens with the solvent remaining, taking into consideration the heat resistance of the header material. To give a specific example of heat treatment, in the case of EVA, the vinyl acetate content is 4
If it is about 70% of IO, it is smoothed by heating at 90°C to 160°C, preferably 100″C to 720°C for about 1 hour.

In the present invention, "smooth" means that if the distance between the peaks and the height from the valley to the peak of surface irregularities observed with a scanning electron microscope is 10μ or less, preferably jμ or less, it is suitable for blood cell components. It means smooth.

The following graft polymerization treatment can be carried out with substances having graft-polymerizable hydroxyl groups such as ethyl cellulose, but EVA does not have such hydroxyl groups.

PVAe or the like is converted into a structure having a water group that can be graft-polymerized by hydrolysis or the like, and then subjected to a graft-polymerization treatment. As a method for introducing graft-polymerizable hydroxyl groups, known methods such as an alkali saponification sensitive layer can be mentioned. The conditions for alkali saponification sensitivity cannot be determined because they occur due to the softening of the coating film, but the simplest method is to determine the saponification state by observing changes in the absorption peak in an infrared absorption spectrum. Furthermore, in the case of a substance having a double bond such as a styrene-butadiene copolymer, a method of introducing a hydroxyl group into the double bond by applying peracetic acid may be used. The hydroxyl group introduction reaction is preferably carried out after the coating and heat treatment, but it is also possible to carry out the reaction before coating and then apply the coating.

Next, graph polymerization is performed to introduce graft chains.

As the polymerizable monomer to be graft-polymerized, at least glycidyl methacrylate (hereinafter abbreviated as GMA) is used.
It is preferable to use a hydrophilic polymerizable monomer having a higher solubility in water than GMA as a component. Examples of such polymerizable monomers include acrylamide, -monohydroxyethyl methacrylate, acrylic acid, N-vinylpyrrolidone, methyl acrylate-methallyl sodium sulfonate, and vinyl acetate. Among these, acrylamide, acrylic acid, and coffee chloride xyethyl methacrylate are particularly preferred. The charging ratio of hydrophilic polymerizable monomer and GMA is
Although it cannot be determined because it varies depending on the reactivity and reaction rate of GMA, considering it in relation to the amount of heparin fixed as described below,
For 7 parts by weight, the upper limit of the amount of hydrophilic polymerizable monomer is j
It is about OO parts by weight. For example, in the case of acrylamide, the preferable range is about 1 to 10 parts by weight based on 7 parts by weight of GMA. Moreover, the upper limit of these concentrations is limited by the solubility in the reaction medium.

The reaction concentration during graft polymerization is preferably at a low temperature, but in consideration of the reaction rate and ring opening of the epoxy group, it is in the range of 0°C to 70″C1, preferably 5°C to 410°C.

After introducing a graft chain having an epoxy group in this manner, unreacted monomers, initiators, etc. are washed away, and heparin can be fixed by immersing the product in a heparin solution. At this time, heparin is dissolved in water or a mixed solvent such as water/acetone or water/methanol and used as a solution. The mixing ratio of acetone and methanol is determined by the solubility of heparin. The higher the amount of heparin, the greater the amount of heparin, but considering solubility, solution viscosity, etc., it is 2 to 30% (W/■), preferably 10 to io% (W/V). The reaction concentration may be within a range in which the heparin solution does not freeze and the heparin activity is not impaired;
The range is 0°C, fFt' or jO°C to 70°C. The reaction time is preferably approximately one hour.

Next, an example of the odor body of the present invention is shown below! This will be explained based on the first page.

JI1 diagram shows a hollow fiber lll11 artificial kidney.

In the figure, l indicates a header. The thick line in the box shows the part where the header comes into contact with blood. The present invention provides a header for a hematology device having a smooth surface and a heparinized polymer coating on the thick line portion, and a method for manufacturing the header.

Hereinafter, the present invention will be further illustrated by examples.
! I will clarify. In addition, the grafting rate, the amount of heparin fixed, the method of measuring anticoagulability, and the evaluation by extracorporeal circulation in the examples were carried out according to the following methods: [Gelabut ratio] [Amount of heparin fixed] Dodgison-Pries
) was quantified by nephelometric method and converted into heparin amount.

[Anti-11n liquid coagulability] Evaluation was made by Lindformtes (modified method) shown below.

After washing the tested sample with water, - It was immersed day and night in a ratio of 7 parts by weight to 100 parts by weight of saline, and then thoroughly washed with physiological saline.

The sample was placed on a thick glass plate and a hole of lj3φ was drilled in the center. Hold it down with a simple silicone gasket, then set a glass plate with holes of the same size so that the holes are evenly distributed with the silicone gasket holes, and press it down from above to tighten. Next, the first aSI from the dog's irritating pulse.
After flushing out the I7, just replace the syringe! -t
For each 1 sample, drop ajd and spread it evenly on the film.
After 0 minutes had elapsed, the container was tilted once every other part, and the time required for the cage to solidify and stop moving was measured. The dog JiI was subjected to electrolysis using this method, and the average value was taken as the Lindholm blood coagulation time.

[Evaluation by extracorporeal circulation]

Extracorporeal circulation experiments were conducted using adult dogs under anesthesia. A blood indwelling needle was punctured in the carotid artery to force blood out of the body, which was then introduced into a dialyzer using a blood pump, and then returned to the avulsion vein. Heparin is / j 01U/”f
Intermittent injections were made every 30 minutes at the timing of -be. In addition, blood was flowed at a rate of 00117/min and the test was carried out for several hours.

After completion of extracorporeal circulation, the dialyzer was washed with physiological saline under certain conditions. After that, fixation treatment was carried out using a glutaraldehyde solution, and dehydration treatment was carried out using an ethanol series. It was then dried under vacuum. Only the header was removed from the dialyzer, and observation with the naked eye and scanning electron microscope was performed to observe the state of adhesion of blood components and the state of precipitation of ipurin.

Example 1 ELVA in the header for a polycarbonate resin artificial kidney
A Schiff's stomach hexane solution (viscosity 7 e, p, ) of
Heat treated for hours. Furthermore, on the surface of the ll1Ik film, a spray gun was used to apply a solution (viscosity: C, T) of Soare Stars DI@Cgv, manufactured by Nippon Gosei Kagaku, to a thickness of JOμ. , and further heat-treated for 1 hour at 110° C., which is a temperature higher than the softening point. The header was immersed in a 1 gL aqueous solution of caustic soda≦0 ethanol, and saponification was carried out at 0° C. for λ hours.

11. Distilled water in JL Santsuro 7 Lasco. GM MuJf and acrylamide≦Of were dissolved and the header #OII, which had been thoroughly washed with water, was immersed. After replacing with nitrogen, add cocerium ammonium nitrate and nitric acid to each kQJ%/1avaOL.
The mixture was added at a temperature of 1/2 and reacted at 20°C for 1 hour.

After the reaction, the header was washed with water to remove unreacted monomers, initiators, etc., and then immersed in a J O% (W/V) heparin aqueous solution and allowed to react at 40° C. for one hour.

After the reaction, the header was washed in pure water all day and night. moreover,
It was immersed in 25% saline for several days. Thereafter, it was washed by immersing it in physiological saline overnight, and then washed with pure water. After that, it was dried, and a part of it was immersed in sixehexane to peel off the coating. As a result of analyzing the amount of hebalin added to the coating film, the following values were obtained.

Heparin circulation amount 3. KOX/0-” (j/cd
ml 1 side) In addition, eluate tests [based on artificial kidney equipment standards (II)] and biological tests [pyrogenic substance test, acute toxicity test, hemolytic test] were conducted on the header after heparinization. All passed the standards.Furthermore, as a result of observing the paint film surface of the header using an electronic dust mirror with an industrial inspection cover, it was found that:
The surface was extremely smooth, with only 1 micron temperature unevenness observed. Comparative Example 1 Implemented on a header for an artificial kidney made of polycarbonate 11. A coating film surface (ii) was formed, and a coating film of Soarex D eel was further formed thereon. However, no heat treatment was performed after the coating was applied. The header was processed in the same manner as in Example to create a heparinized header. As a result of heparin analysis, the amount of heparin fixed was as follows.

Fixed amount of heparin, 2j X/0-” (fA
(I) In addition, a leachate test and a biological test were conducted, and both passed the standards. Further, as a result of observing the coating surface using a scanning electron microscope, irregularities and pores ranging from several tons to several tens of tons were observed, and the surface was extremely moderate.

Example copolycarbonate) 1181111 A hot acetone solution of Soarex D- (viscosity 7 e, >) in the header for artificial kidney
was applied with a spray gun to form ikM. Thereafter, heat treatment and heparinization treatment similar to those in Example 1 were performed to produce a heparinization header. Cut the wrinkled header into the /Ices corner and perform the Lindholm test (
Anticoagulant properties were evaluated by a modified method). As a result, the following results were obtained.

Blood coagulation time: 30 minutes for untreated samples; 720 minutes for samples prepared by an uninvented method; and the amount of heparin fixed was iJ x /(f5(r/i:j)).

Implementation HJ Soarex FH■ (EVA, vinyl acetate content 17%.

[manufactured by Nippon Gosei Kagaku ■] was dissolved in ethylene acetate and the solution viscosity was adjusted to 10e, p. The solution was applied to a polypropylene resin artificial kidney header using a spray gun. Thereafter, the surface was smoothed by heat treatment at 710°C for 1 hour, and then kerified by immersion at 30°C for 1 minute in a 1-N caustic soda solution containing 10% ethanol aqueous solution as a solvent. did. Implement the header/
A heparinized header was created by grafting and heparinization in the same manner as above.

In addition, the same treatment was performed on the header that had not been heat-treated after coating to create a heparinized header.

The heparin binding amount, Lindholm test (modified method) blood coagulation time, and electron microscope observation results for each header were as follows.
A coating film solution of , p was prepared, and a coating film was formed by spraying it onto a human kidney refill made of pyrene resin using a spray gun. Thereafter, it was smoothed by thermal heat treatment at llj''C for 1 hour. The heparinization was performed by the method shown in Example.

A dialyzer made of a cuproammonium rayon hollow fiber membrane was assembled using the Beck 1 Non-Ich header produced by the method of the above example. The membrane area was set at α for each dialyzer. Using the hollow fiber membrane artificial kidney thus assembled, the extracorporeal circulation test described above was conducted.

The results of visual and electron microscopic observations of the used hestuters! -3. Furthermore, as the smoothness in Table 3, the distance between the peaks and the peak height of the unevenness observed with a scanning electron microscope are shown.

(Margin below)

[Brief explanation of the drawing] ljl! /The figure shows a hollow fiber artificial kidney device as an example. / indicates a header. The thick line portion of λ indicates a portion of the header that comes into contact with blood. 3 indicates a blood inlet. @
The λ diagram shows only a part of the header shown in FIG. ≠ thick I
Section S indicates a portion of the header that comes into contact with blood. Patent applicant Asahi Medical Co., Ltd.

Claims (1)

[Scope of Claims] (1) A header for a blood processing device, which has a smooth surface and a heparinized polymer material coating on a portion of the inner surface of the header that comes into contact with blood. (2) The blood processing device according to claim 1, wherein the distance between the peaks and the height from the valley to the peak of the unevenness on the surface of the polymer coating film is IOμ or less. header. (8) A coating film of a thermoplastic polymeric material capable of grafting is formed on the inner surface of a header for a blood processing device, and then the coating film is smoothed by heating, and then glycidyl is added to the polymeric material. 1. A method for producing a header for a blood processing device, which comprises graft polymerizing a polymerizable monomer containing at least one component of methacrylate, and then bonding heparin to the glycidyl methacrylate group. (4) The method according to claim 1, wherein the thermoplastic polymer forming the coating film has a hydroxyl group capable of graft polymerization @ (5) The thermoplastic polymer forming the im group The method according to claim 11, wherein is ethyl cellulose or acetic acid cellulose. (6) The method according to claim tIIi, item 3, wherein the thermoplastic polymer substance that enhances the coating film is a compound that can be converted by a chemical method into a compound having a hydroxyl group that can be grafted. (7) The method according to claim 4, wherein the thermoplastic polymer substance that strengthens the coating film is an ethylene-vinyl acetate copolymer or a styrene-butadiene copolymer. (8) The method according to claim 1, wherein the heating temperature is higher than the glass transition point of the thermoplastic polymer material forming the coating film. (g) The method according to claim WMJIIJ, in which, together with glycidyl methacrylate, a polymerizable monomer that is more wood-philic than glycidyl methacrylate is used as the graft copolymer component. 10. The method according to claim 9, wherein the polymerizable monomer that is more wood-philic than -, glycidylmethatalyryl F is acrylamide, acrylic acid, or -hydroxyethyl methacrylate.