JP2001061960A - Blood purifying film - Google Patents

Abstract

PROBLEM TO BE SOLVED: To reduce deterioration at radiation sterilization by determining a value of tearing strength after γ-ray sterilization at a specific dose to a specific ratio against the tearing strength before γ-ray sterilization and by determining the value of the tearing strength after γ-ray sterilization at higher specific ration to the specific ratio of the tearing strength before γ-ray sterilization. SOLUTION: A value of tearing strength of a blood purifying film after γ-ray sterilization of 25 kGy is more than 90% to the tearing strength of the blood purifying film before γ-ray sterilization, and the value of the tearing strength of the blood purifying film after γ-ray sterilization at 50 kGy is more than 60% against the tearing strength of the blood purifying film before γ-ray sterilization. For example, citric acid aqueous solution of 0.1% is filled in an artificial blood purifying container using reproduced cellulose hollow string film and tri-acetic acid cellulose hollow string film, and blood purifying container is put into a polyethylene bag to be wrapped under vacuum after tightly sealing an entire opening section with a resin plug to treat γsterilization at a dose of 25 kGy and 50 kGy.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a blood purification membrane used for artificial organs and the like.

[0002]

2. Description of the Related Art Conventionally, in the medical field, cellulosic polymers such as regenerated cellulose and cellulose acetate, polymethyl methacrylate,
A dialysis membrane and an ultrafiltration membrane using a material of a synthetic high molecular polymer such as polyacrylonitrile / polysulfone / polyvinyl alcohol-polyethylene copolymer are used. These materials need to satisfy the required characteristics of mechanical strength as well as excellent solute permeability to blood components as a blood purifier.

In recent years, various problems caused by the contact of medical materials with blood have been presented, and blood purification membranes are an important solution from the viewpoint that extracorporeal blood treatment requires a relatively long time. As a problem to be solved, for example, a problem of a transient decrease in white blood cells during hemodialysis and a problem of activation of complement components have been pointed out. The biocompatibility is an important indicator of the quality of a blood purification membrane.

[0004] In order to solve such a problem, a membrane made of regenerated cellulose is not a material having satisfactory biocompatibility since the complement in blood is activated by hydroxyl groups contained in the polymer molecule. . In this regard, modified cellulose and synthetic polymers have excellent properties.

[0005] On the other hand, since the blood purifier is intended for medical use, it is necessary to guarantee sterility. Usually, aseptic control is performed as much as possible from the manufacturing process, and finally used after sterilization.

As methods for sterilizing blood purifiers, methods generally used at present include formalin sterilization, ethylene oxide gas sterilization (hereinafter abbreviated as EOG sterilization), radiation sterilization, and high-pressure steam sterilization. In formalin sterilization,
Although a blood purifier is filled with a formalin aqueous solution at a certain concentration or more to obtain a sterilization effect, the toxicity of residual formalin during use poses a problem. For this reason, when used, it is required to distribute a large amount of sterile water for a long time to discharge formalin, and it is difficult to completely eliminate the residual. Performing these treatments at the time of manufacturing the blood purifier makes the manufacturing process extremely complicated and may reduce the safety. Therefore, the formalin sterilization method is currently used almost exclusively in temporary cases at medical sites, such as in hospitals, or as a regenerative sterilization method accompanying the reuse of a blood purifier.

[0007] In the EOG sterilization method, a blood purifier is placed in an ethylene oxide gas (EOG) atmosphere and sterilized by a killing action of EOG. However, EOG
In sterilization, a small amount of EOG remaining in the blood purifier may have an allergic effect on the human body, it is necessary to completely degas, and some people may not be able to use EOG sterilized equipment. is there. Also, of course, EOG
It cannot be used if the device is made of a material that is reactive to

High-pressure steam sterilization is usually performed at 115 ° C. to 130 ° C.
By treating for about several tens of minutes to about one hour in saturated steam. However, in the case of a blood purifier using a material having relatively low heat stability, high temperature in heat sterilization,
It is known that the structure of the semipermeable membrane is easily changed by the high-humidity treatment, and the permeation performance is significantly reduced.

Radiation sterilization is different from that based on the killing effect on bacteria by the action of substances such as formalin and EOG, and sterilization can be performed in a completely sealed system without performing special injection and discharge operations on the blood purifier. It is used as a possible method. Although the equipment is large, sterilization assurance is easy and reliable in terms of sterilization principles, and far exceeds other methods. On the other hand, there is a concern that the membrane material and the case member of the blood purifier may be deteriorated due to high energy of radiation. However, if the characteristics are grasped and the manufacturing conditions are selected, deterioration can be minimized, the safety as a medical device can be sufficiently secured, and it can be said that this is a sterilization method that can fully express the sterility assurance power. .

In the case of sterilization by radiation (γ-ray), the number of contaminating bacteria before sterilization and D which indicates the resistance of the bacteria to γ-ray irradiation.
The value determines the irradiation dose. Based on this evaluation, the current dose is generally 25 kGy. In the blood purifier, the number of contaminating bacteria before sterilization is reduced by improving the manufacturing process, and the sterilization dose is being reduced. However,
Even at the current minimum dose of 20 kGy, the deterioration of the blood purification membrane has not yet been completely negligible, and the point of further reducing the number of contaminating bacteria is almost at its limit. For these reasons, there is a demand for the development of a radiation sterilization method capable of suppressing deterioration of the material without reducing the irradiation dose.

[0011]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a blood purification membrane with reduced deterioration when subjected to radiation sterilization.

[0012]

Means for Solving the Problems The inventors of the present invention have made intensive studies to provide a blood purification membrane which has solved the above-mentioned problems, and as a result, have reached the present invention. That is, according to the present invention, the rupture strength of the blood purification membrane after γ-ray sterilization at 25 kGy is 90% or more of the rupture strength of the blood purification membrane before γ-ray sterilization, and
The value of the breaking strength of the blood purification membrane after γ-ray sterilization in Gy is γ
This is a blood purification membrane that is 60% or more of the breaking strength of the blood purification membrane before the line sterilization.

The semipermeable membrane referred to in the present invention has solute permeability to an aqueous solution. In other words, it is a membrane that does not allow blood cell components to permeate blood but has a function of permeating other solute components. Materials constituting the membrane are regenerated cellulose, cellulose and cellulose derivatives such as cellulose acetate, chitin, natural polysaccharides such as chitosan or derivatives thereof, polyacrylonitrile, polysulfone,
Examples thereof include synthetic polymers such as polyethersulfone, polyamide, acrylic and methacrylic polymers, and composites thereof, and a cellulose-based semipermeable membrane, particularly a cellulose acetate semipermeable membrane, is preferred. Also, as the film shape,
Either a flat plate shape or a hollow fiber shape does not hinder the effects of the present invention.

The blood purification membrane of the present invention is preferably prepared by filling and sealing an aqueous solution of a polyvalent carboxylic acid in a blood purifier, and performing radiation sterilization with the semipermeable membrane immersed in the aqueous solution of a polyvalent carboxylic acid. Is obtained. The polyvalent carboxylic acid to be filled in the blood purifier includes citric acid, oxalic acid, iminodiacetic acid, aminodiacetic acid and salts thereof, but citric acid should be used from the viewpoint of safety as a medical material. Is desirable.

Deterioration of membrane materials and equipment members during radiation sterilization is due to photochemical reaction of material molecules due to radiation energy, and the resulting radicals cause a chain reaction to cause decomposition of the polymer. Since the sterilization effect of radiation also causes the destruction of bacteria by a similar reaction mechanism, killing bacteria necessarily involves destruction of the material. In addition, these reactions do not necessarily occur only during irradiation with radiation, and even after the irradiation is completed, deterioration may progress with time due to the autoxidation mechanism.

The organic polymer material has many molecular structures such as ether, ester, ketone, alcohol, and amide in its structure, and can be said to be a material that is easily susceptible to radical attack. Therefore, the resistance to radiation is not always good, and has a surface that is susceptible to oxidative degradation. Usually, in the field of resin processing, in order to prevent such oxidative deterioration, antioxidants such as phenol-based, phosphorus-based, and piperazine-based materials are included in the material. It is not preferable to add these components from the viewpoint of safety for medical use. The present invention can be positioned as a sterilization method for overcoming the weakness of the semipermeable membrane material to radiation and maintaining the characteristics of a conventionally excellent blood purification membrane. The deterioration of the semipermeable membrane is remarkably manifested as a change in the permeability of the membrane, a decrease in the strength and elongation as a material, and an increase in eluted substances. Therefore, the state of deterioration can be evaluated based on the degree of these changes.

It is known that all of these oxidation reactions are catalyzed by a trace amount of heavy metals (eg, iron, copper, cobalt, etc.), and the reactions proceed dramatically. Therefore, it is clear that if these trace components remain in the blood purification membrane device, it leads to accelerated deterioration of the semipermeable membrane. However, these heavy metals are added or mixed in the production of the raw material polymer, in the purification process, or in the process of forming into a membrane,
Even if a considerable amount of removal operation is performed, it is inevitable that a small amount will remain. In reality, reduction to the order of ppb or less is almost impossible from the standpoint of industrial production.

In the present invention, it is recommended that the inside of the blood purifier be filled with an aqueous solution of a polycarboxylic acid, and that the radiation be applied while the semipermeable membrane is immersed in the aqueous solution. The polyvalent carboxylic acid can reduce the catalytic activity of oxidation due to the chelating effect on the water-eluting heavy metal remaining in the semipermeable membrane and suppress the deterioration of the semipermeable membrane. Heavy metals are generally insoluble in water, that is, they do not have a catalytic activity for oxidation when they are not ionized. However, the polymer around the heavy metals undergoes an oxidation reaction by oxygen, heat, light, or the like, and is ionized to become a catalyst. Therefore, there is a risk that the heavy metal is ionized by the radical reaction of the polymer by γ-rays, and the deterioration of the semipermeable membrane accelerates.
In addition, the ionized heavy metal is solubilized when there is water around and is eluted into bulk water. Therefore, in the present invention, a strong effect on inactivating these eluted metals is expected. Further, these polyvalent carboxylic acid aqueous solutions are replaced with physiological saline or the like at the time of use, are washed away, and are substantially harmless to living bodies even if some amount remains.

The polycarboxylic acid concentration in the aqueous solution is 0.0
1-5.0% is preferable, and more preferably 0.05-
1.0%. A concentration of 5.0% or more is not preferred because the pH of the aqueous solution decreases due to the polyvalent carboxylic acid itself and the residual amount increases when the replacement washing treatment with physiological saline is incomplete.

The method of filling the blood purifier with the aqueous solution of a polycarboxylic acid can be achieved by injecting the aqueous solution from the blood outflow port or the purification fluid outflow port of the purifier and sealing the blood purifier. The amount of the aqueous solution to be filled is sufficient to substantially uniformly wet the semipermeable membrane.However, if oxygen such as air is present inside, the oxidation is promoted and connected. Care should be taken to avoid contamination. Further, a polyurethane material of a potting portion which is a member other than the semipermeable membrane constituting the blood purifier,
It goes without saying that a material that is less degraded by radiation must be selected for the container material.

According to the method described above, it becomes possible to sterilize a blood purifier made of a semipermeable membrane, particularly a cellulosic semipermeable membrane, by radiation without deteriorating the membrane performance and the like. In the following, description will be made with reference to examples, but before that, a method for adjusting and evaluating a sample performed in the examples will be described. First, a method for producing a cellulosic semipermeable membrane used in the present invention will be described. As a means for preparing a blood purification membrane from a cellulose polymer, a dope stock solution is prepared by dissolving a cellulose polymer in a solvent, or a solvent comprising a mixture of a solvent and a poor solvent, and discharging the solution from a nozzle to coagulate. A method of forming a film by phase separation in a bath may be used. According to this method, it is possible to narrow the pore size distribution of the pores of the membrane and obtain a sharp blood component fractionation characteristic. Various solute separation characteristics can be imparted to the membrane by selecting appropriate doping conditions and coagulation conditions. In this example, as the cellulosic polymer,
A hollow fiber type semipermeable membrane was prepared using cellulose triacetate. In addition, a commercially available regenerated cellulose artificial kidney dialyzer was also evaluated.

Method for Preparing Hollow Fiber A spin dope comprising 10-30% by weight of a cellulosic polymer, N-methylpyrrolidone (NMP) as a solvent, and ethylene glycol / triethylene glycol as a poor solvent is prepared. The mixture was discharged together with the core liquid from the double tube nozzle to form a hollow fiber, and was coagulated in a coagulation bath comprising the same mixed components as the solvent and poor solvent for the dope to produce a hollow fiber membrane. The hollow fiber was spun while controlling the inner diameter to 200 μm and the film thickness to 15 μm.

Manufacturing method of blood purifier About 1 hour of the hollow fiber was placed in a polycarbonate case.
0000 pieces were inserted, and both ends were fixed with a urethane resin composed of diisocyanate and castor oil-based diol, cut open, and fitted with a cap having an inflow port. A polyhydric carboxylic acid aqueous solution of a predetermined concentration was filled into the mounting from the purifying fluid outflow / inlet port of the blood purifier, and all openings were closed with resin stoppers. Thereafter, the whole blood purifier was placed in a polyethylene bag, vacuum-packaged, and irradiated with a predetermined dose of γ-rays. The irradiation dose is 25 kGy, 5 which is enough to guarantee sterilization.
Performed at 0 kGy.

Evaluation of Degraded State of Cellulose-based Semipermeable Membrane After the sealed liquid was removed from the apparatus by gravity, only the hollow fiber was taken out and the yarn quality (yield, breaking strength, elongation) in a wet state was measured. Was served. In addition, other eluate tests were carried out in accordance with the dialysis-type artificial kidney approval standard (issued by Japan Medical Plastics Association and Japan Artificial Organs Association).

[0025]

The present invention will be described below with reference to examples. An artificial blood purifier using a regenerated cellulose hollow fiber membrane and a cellulose triacetate hollow fiber membrane is filled with an aqueous 0.1% citric acid solution, and all openings are sealed with a resin stopper. Then, the blood purifier is made of a polyethylene bag. , Vacuum-packed, 25kGy and 50
Gamma sterilization with a dose of kGy was performed. As a comparative example, the same test was performed without filling and only filling with deoxygenated water. The results are shown in Tables 1 and 2. In the citric acid aqueous solution system, as shown in the table, a decrease in pH, an increase in ultraviolet absorbance, a decrease in thread quality, and the like in the eluate test are slightly suppressed. Therefore, it is shown that the deterioration of the semipermeable membrane, which is the object of the present invention, is reduced. Also, the water permeability of the semipermeable membrane is
For regenerated cellulose, 6 ml / hr · mmHg · m ² ,
For cellulose triacetate, 30 ml / hr · mmHg · m
^Two were used, but no significant change in water permeability was observed even after gamma irradiation.

[0026]

[Table 1] ΔpH is represented by the difference between the blank value and the sample value. UV
Is represented by the maximum value in the ultraviolet absorbance of 360 nm to 220 nm. The percentages in parentheses indicate the ratio of the breaking strength of the blood purification membrane after γ-ray sterilization to the rupture strength of the blood purification membrane before γ-ray sterilization.

[0027]

[Table 2] ΔpH is represented by the difference between the blank value and the sample value. UV
Is represented by the maximum value in the ultraviolet absorbance of 360 nm to 220 nm. The percentages in parentheses indicate the ratio of the breaking strength of the blood purification membrane after γ-ray sterilization to the rupture strength of the blood purification membrane before γ-ray sterilization.

[0028]

As is clear from the above description, according to the present invention, it is possible to provide a blood purification membrane with reduced deterioration when subjected to radiation sterilization.

Claims (1)

[Claims] 1. The rupture strength of a blood purification membrane after γ-ray sterilization at 25 kGy is 90% or more of the rupture strength of the blood purification membrane before γ-ray sterilization, and the γ-ray at 50 kGy. A blood purification membrane wherein the value of the rupture strength of the blood purification membrane after sterilization is 60% or more of the value of the rupture strength of the blood purification membrane before γ-ray sterilization.