JPH07328111A - Sterilization method of blood purifier - Google Patents

Abstract

PURPOSE:To provide a radioactive sterilization method which achieves a reduction in the aging of a semi-permeable membrane of a blood purifier comprising a cellulose based semi-permeable membrane. CONSTITUTION:In this method, a blood purifier comprising a cellulose based semipermeable membrane is filled and sealed with an aqueous solution of polyvalent carbonic acid and radioactive sterilization is performed with the semipermeable membrane immersed in the polyvalent carbonic acid. This enables the radioactive sterilization with little deterioration of the semipermeable membrane in the blood purifier.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for sterilizing a blood purifier having a semipermeable membrane used for artificial organs and the like. More specifically, the present invention relates to a method for sterilizing a blood purifier for providing a semipermeable membrane in which deterioration of materials due to radiation sterilization treatment is reduced.

[0002]

Conventionally, in the medical field, cellulose-based polymers such as regenerated cellulose and cellulose acetate, polymethylmethacrylate
BACKGROUND ART A dialysis membrane and an ultrafiltration membrane using a material of a synthetic polymer such as polyacrylonitrile / polysulfone / polyvinyl alcohol / polyethylene copolymer are used. It is necessary that these materials satisfy the required properties of mechanical strength as well as excellent solute permeability for blood components as a blood purifier.

Further, in recent years, various problems caused by contact of medical materials with blood have been presented, and in blood purification membranes, extracorporeal blood treatment for blood requires a relatively long period of time, which is an important solution. As problems to be solved, for example, transient reduction of white blood cells during hemodialysis, activation of complement components, etc. have been pointed out, and they are important indicators of goodness and badness of blood purification membrane as biocompatibility.

With respect to such a problem, a membrane made of regenerated cellulose cannot be said to be a satisfactory material in terms of biocompatibility since the complement in blood is activated by the hydroxyl group contained in the polymer molecule. . In this regard, modified cellulose and synthetic polymers have excellent properties.

On the other hand, since the blood purifier is intended for medical use, it is necessary to guarantee sterility. Usually, it is aseptically controlled as much as possible from the manufacturing process, and finally subjected to sterilization treatment before use.

As a sterilizing method for blood purifiers, methods generally used at present are formalin sterilization, ethylene oxide gas sterilization (hereinafter abbreviated as EOG sterilization), radiation sterilization, high pressure steam sterilization and the like. With formalin sterilization,
Although a blood purifier is filled with an aqueous solution of formalin at a certain concentration or higher to obtain a sterilizing effect, the toxicity of residual formalin during use poses a problem. For this reason, when used, it is required to circulate a large amount of sterile water for a long time to discharge formalin, and it is difficult to completely eliminate the residue. In addition, performing these treatments at the time of manufacturing the blood purifier makes the manufacturing process extremely complicated and may rather reduce the safety. Therefore, the formalin sterilization method is currently used almost exclusively in the case of medical treatment such as in a hospital or as a regenerated sterilization method accompanying reuse of the blood purifier.

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

High-pressure steam sterilization is usually 115 ° C to 130 ° C.
It can be achieved by treating the saturated steam for several tens of minutes to one hour. However, in the case of a blood purifier using a material having relatively low heat stability, high temperature during heat sterilization,
It is known that the high-humidity treatment tends to change the structure of the semipermeable membrane, resulting in a significant decrease in permeation performance.

Radiation sterilization is different from the one based on the killing effect on bacteria due to the action of substances such as formalin and EOG, and the sterilization treatment can be performed in a completely sealed system without special injection and discharge operations to the blood purifier. It is used as a possible method. The equipment is large, but the sterilization assurance power is easy and reliable from the viewpoint of the sterilization principle, and far exceeds other methods. On the other hand, there is concern about deterioration of the membrane material and case member of the blood purifier 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 the sterilization method can sufficiently demonstrate the assurance of sterilization ability. I can say.

When sterilized by radiation (γ ray), the number of contaminating bacteria before sterilization and the resistance of bacteria to γ ray irradiation D
The value determines the irradiation dose. Based on this evaluation, the current dose is generally 25 kGy. In blood purifiers, the number of contaminating bacteria before sterilization has been reduced by improving the manufacturing process, and the sterilization dose is being reduced. However,
Even with the current minimum dose of 20 kGy, the fact is that the deterioration of the blood purification membrane has not been completely neglected, and the point of further reducing the number of contaminating bacteria is almost at the limit. For these reasons, there is a demand for the development of a radiation sterilization method that can suppress material deterioration without reducing the irradiation dose.

[0011]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for sterilizing radiation in a blood purifier having a semipermeable membrane, in which deterioration of the semipermeable membrane is reduced.

[0012]

Means for Solving the Problems The present invention has been achieved as a result of intensive research to provide a radiation sterilization method for a blood purifier using a semipermeable membrane that solves the above problems. That is, the present invention is a blood purifier using a semipermeable membrane, filled and sealed with an aqueous solution of a polyvalent carboxylic acid inside the blood purifier, and the semipermeable membrane is immersed in the aqueous solution of the polyvalent carboxylic acid for radiation. It is a method of sterilizing a blood purifier characterized by performing sterilization.

The semipermeable membrane referred to in the present invention has a solute permeability to an aqueous solution. That is, it is a membrane that does not allow blood cell components to permeate blood and has a function of permeating other solute components. Materials constituting the membrane are regenerated cellulose, cellulose and cellulose derivatives such as cellulose acetate, natural polysaccharides such as chitin and chitosan, or derivatives thereof, polyacrylonitrile, polysulfone,
Synthetic polymers such as polyether sulfone, polyamide, acrylic and methacrylic polymers, and composites thereof can be mentioned, but a cellulose semipermeable membrane, particularly a cellulose acetate semipermeable membrane is preferable. In addition, as the film shape,
Either flat plate shape or hollow fiber shape does not impair the effects of the present invention.

Examples of the polyvalent carboxylic acid to be filled in the blood purifier include citric acid, oxalic acid, iminodiacetic acid, aminodiacetic acid and salts thereof, but citric acid is a safe material for medical use. Is preferred.

Deterioration of the film material and the device member caused by radiation sterilization is caused by photochemical reaction of material molecules by radiation energy, and radicals generated thereby cause chain reaction and decomposition of the polymer. Since the sterilization effect by radiation causes the destruction of bacteria by a similar reaction mechanism, killing bacteria inevitably involves destruction of the material. Further, these reactions do not always occur only during irradiation of radiation, and deterioration may progress over time due to the autoxidation mechanism even after the irradiation is completed.

The organic polymer material has many molecular structures such as ethers, esters, ketones, alcohols and amides in its structure and can be said to be a material which is easily attacked by radicals. Therefore, it cannot be said that the resistance to radiation is good, and it has a surface that is prone to oxidative deterioration. In the field of resin processing, it is common practice to include phenolic, phosphorus, piperazine, and other antioxidants in materials to prevent these oxidative deteriorations. In terms of safety for medical use, it is not preferable to add these components. The present invention can be positioned as a sterilization method for overcoming the weakness of such a semipermeable membrane material against radiation and maintaining the excellent characteristics as a conventional blood purification membrane. Since the deterioration of the semipermeable membrane significantly appears as a change in membrane permeability, strength as a material, a decrease in elongation, and an increase in eluate, etc., the deterioration state can be evaluated by the degree of these changes.

It is known that all of these oxidation reactions are dramatically catalyzed by an extremely small amount of heavy metals (iron, copper, cobalt, etc.). Therefore, it is clear that if these trace components remain in the blood purification membrane device, the deterioration of the semipermeable membrane is promoted. However, in the production of the raw material polymer, the purification process, or the process of forming into a film, these heavy metals are added or mixed,
It is inevitable that a small amount remains even after a considerable removal operation. In reality, it is almost impossible to reduce the ppb order or less from the viewpoint of industrial production.

In the present invention, the inside of the blood purifier is filled with a polyvalent carboxylic acid aqueous solution, and the semi-permeable membrane is immersed in this aqueous solution and the radiation is applied. The polycarboxylic acid can reduce the catalytic ability of oxidation by a chelating effect on the water-eluting heavy metal remaining in the semipermeable membrane and suppress the deterioration of the semipermeable membrane. Heavy metals usually have no catalytic ability for oxidation in a water-insoluble state, that is, in a non-ionized state, but as a result of the oxidation reaction of the polymer around the heavy metal due to oxygen, heat, light, etc., the heavy metal becomes a catalyst. Therefore, γ
Due to the radical reaction of the polymer on the lines, there is a risk that the heavy metal will be ionized and the semipermeable membrane deterioration will accelerate. Also,
Ionized heavy metals are solubilized in the presence of water around them and are eluted into bulk water, so that the present invention is expected to have a strong effect on the inactivation of these eluted metals. In addition, these polyvalent carboxylic acid aqueous solutions are practically harmless to the living body even when they are replaced with physiological saline or the like at the time of use, washed off, and some amount remains.

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

The method for filling the blood purifier with the aqueous solution of polycarboxylic acid can be achieved by injecting the aqueous solution from the blood outflow port or the purifying fluid outflow port of the purifier and sealing it. The amount of the aqueous solution to be filled is sufficient so that the semipermeable membrane is substantially evenly moistened, but the presence of oxygen such as air in the interior promotes oxidation, which leads to oxidation. Care should be taken to prevent contamination. In addition, the polyurethane material of the potting portion, which is a member other than the semipermeable membrane that constitutes the blood purifier,
It goes without saying that it is necessary to select a material that is less likely to be deteriorated by radiation as a container material.

According to the method described above, it becomes possible to sterilize a blood purifier composed of a semipermeable membrane, particularly a cellulosic semipermeable membrane, by radiation without causing deterioration of membrane performance and the like. Examples will be described below, but before that, a sample adjusting method and an evaluating method performed in the examples will be described. First, the method for producing a cellulosic semipermeable membrane used in the present invention will be described. As a means for producing a blood purification membrane from a cellulosic polymer, a dope stock solution is prepared by dissolving the cellulosic polymer in a solvent or a solvent consisting of a solvent and a poor solvent, and then coagulating the dope by discharging it from a nozzle. A method of forming a film by phase separation in a bath can be mentioned. With 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. Further, it is possible to give various solute separation characteristics to the membrane by selecting appropriate doping conditions and solidification conditions. In this example, as the cellulose-based 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.

Preparation Method of Hollow Fiber A cellulosic polymer is used in an amount of 10 to 30% by weight, N-methylpyrrolidone (NMP) is used as a solvent, and a spinning dope composed of ethylene glycol, triethylene glycol or the like is used as a poor solvent. A hollow fiber membrane was produced by discharging the mixture from the heavy tube nozzle together with the core liquid to make it hollow, and coagulating it in a coagulation bath consisting of the same mixed system components as the solvent of the dope and the poor solvent. The hollow fiber was spun while controlling the inner diameter to 200 μm and the film thickness to 15 μm.

Method for manufacturing blood purifier In a case made of polycarbonate, about 1 hollow fiber is used.
0000 pieces were inserted, both ends were fixed with a urethane resin composed of diisocyanate and castor oil-based diol, cut and opened, and a cap having an inlet was attached. From the purifying fluid outlet / inlet of this blood purifier, a polyvalent carboxylic acid aqueous solution having a predetermined concentration was filled into the inside of the attachment, and all openings were closed with a resin stopper. Then, the whole blood purifier was put in a polyethylene bag, vacuum-packaged, and irradiated with a predetermined dose of γ-rays. The irradiation dose is 25 kGy, 5 which is sufficient for sterilization assurance.
It was carried out at 0 kGy.

Evaluation of Deteriorated State of Cellulose-based Semipermeable Membrane After removing the enclosed liquid from the device by natural fall, only hollow fibers were taken out and the yarn quality (yield, breaking strength, elongation) in wet state was measured. I went to The other eluate tests were performed according to the dialysis type artificial kidney approval standard (published by the Japan Medical Plastics Association and the Japan Artificial Organs Association).

[0025]

EXAMPLES 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 was filled with a 0.1% citric acid aqueous solution, and the whole opening was sealed with a resin stopper, and then the blood purifier was made into a polyethylene bag. Put in a vacuum package, 25kGy and 50
Gamma sterilization was performed with a dose of kGy. As a comparative example, the same test was performed with no filling and with deoxygenated water only. The results are shown in Tables 1 and 2. In the citric acid aqueous solution system, as shown in the table, the pH drop, the ultraviolet absorbance increase, the thread quality drop, etc. in the eluate test are slightly suppressed. Therefore, it is shown that the reduction of the deterioration of the semipermeable membrane which is the object of the present invention is realized. In addition, 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
^{No. 2} was used, but no significant change in water permeability was observed even after γ-ray irradiation.

[0026]

[Table 1]

[0027]

[Table 2]

[0028]

As is apparent from the above description, according to the present invention, it is possible to provide a radiation sterilized blood purifier with reduced deterioration of semipermeable membrane.

Claims (1)

[Claims] 1. A blood purifier using a semipermeable membrane, wherein blood purification is filled and sealed with an aqueous solution of polyvalent carboxylic acid, and radiation sterilization is performed with the semipermeable membrane immersed in the polyvalent carboxylic acid aqueous solution. A method for sterilizing a blood purifier characterized by applying.