JP2000024104A - Membrane for blood treatment and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To additionally lessen the change in the properties of blood components and the stimulus to the blood components by suppressing the remaining of the chemical species subjected to an oxidation effect induced by being subjected to a radiation treatment into a blood treating membrane. SOLUTION: This blood treating membrane is a blood treating membrane having reducing power on at least the membrane surface of the blood treating membrane subjected to the radiation treatment and preferably the reducing power is <=20 in the (a*) value obtd. by an NR test. The process for preparing the blood treating membrane consists in subjecting the blood treating membrane to the radiation treatment in water of <=500 mV in oxidation reduction potential or the water subjected to saturation dissolution of oxygen at the time of subjecting the blood treating membrane to the radiation treatment. As a result, even the blood treating membrane sterilized by the radiation can have the reducing power and the influence on the blood may be made less.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a membrane for blood treatment used for hemodialysis or filtration therapy, adsorption therapy, and the like, and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, membranes for blood treatment used in hemodialysis, filtration therapy, adsorption therapy, etc., dispose waste or harmful substances accumulated in blood based on the principle of diffusion, filtration, adsorption and the like. And is used, for example, in the treatment of patients with complete loss of renal function. Examples of the material for the blood treatment membrane include a membrane made of regenerated cellulose and, for example, a membrane made of a synthetic polymer such as polyacrylonitrile, polysulfone, or polyethylene, and have a flat membrane or a hollow fiber membrane. In recent years, hollow fiber membranes that have a large contact area with the membrane and have a high processing capacity have become mainstream in recent years.

[0003] If these blood treatment membranes are flat membranes, a plurality of them are generally laminated and loaded into a plastic container. If they are hollow fiber membranes, hundreds to tens of thousands of them are bundled to form a cylindrical membrane. It is loaded into a plastic container, fixed with a potting material to produce a semi-finished product, and further sterilized to be used as a blood processing module. In addition, these blood processing modules require sterilization because they come into contact with blood. As a sterilization method, a drug, a gas, means of high-pressure steam and the like have been conventionally used.However, from the viewpoint that there is no residual drug or gas, and that the sterilization power is high,
Radiation treatment using gamma rays and electron beams has been performed.

[0004] On the other hand, when the radiation treatment is carried out, there is a concern that the film may be deteriorated by the influence of the radiation. Therefore, a method of irradiating radiation using an antioxidant (Japanese Patent Application Laid-Open No. 4-338223), and (Japanese Unexamined Patent Publication No. 7-1)
94949). JP-A-7-
194949 discloses that as a result of the deterioration, the pH of the enclosed water greatly changes to the acidic side, causing a problem during use, and also decomposing the membrane components to increase the elution amount.
Furthermore, when stored for a long period of time, the problem is that the deterioration of the film progresses and the film changes in terms of performance, and in order to solve them, a method of performing γ-ray treatment with a pH buffer solution or an alkaline aqueous solution is disclosed. .

[0005] However, although the blood treatment membrane prepared by the above-mentioned known method or the like can prevent acidification of the filling solution due to decomposition, it has a chemical action having an oxidizing action caused by the radiation treatment remaining in the membrane. Without suppressing the seeds,
When actually used, the contact between the membrane and the blood may alter the blood components or stimulate the blood components, causing the release of biologically active factors and possibly affecting the living body.

[0006]

DISCLOSURE OF THE INVENTION The present invention aims at reducing the influence of radiation-treated blood treatment membranes on blood by reducing the effect of radiation-treated chemical species having an oxidizing action on the blood treatment membrane. An object of the present invention is to suppress the residual and reduce the deterioration of blood components or the stimulation to blood components.

[0007]

Means for Solving the Problems As a result of intensive studies on the environment at the time of radiation treatment, the present inventors have surprisingly found that even a radiation-treated blood treatment membrane has a reducing ability. The present invention has been found to be possible and the effect on blood can be suppressed, and the present invention has been accomplished. That is, the present invention
A blood treatment membrane having the following configuration and a method for producing the same. (1) A blood processing membrane, wherein at least the surface of the radiation-treated blood processing membrane has a reducing ability. (2) The a ^* value obtained by the NR test is 20 as the reducing ability.
The blood processing membrane according to the above (1), which is the following membrane. (3) The blood processing membrane according to the above (1) or (2), wherein the blood processing membrane comprises polysulfone and a hydrophilic polymer. (4) A method for producing a blood processing membrane having reducing ability, which comprises subjecting the blood processing membrane to radiation treatment in water having an oxidation-reduction potential of -500 mV or less when the blood treatment membrane is subjected to radiation treatment. (5) A method for producing a blood processing membrane having a reducing ability, wherein the membrane is subjected to radiation treatment in water in which oxygen is saturated and dissolved when the blood treatment membrane is subjected to radiation treatment.

[0008] The NR test referred to in the present invention is a test performed to ascertain the reducing ability of a membrane, using neutral red which is a redox indicator, and measuring the change in color tone of the reagent before and after the contact of the membrane with the reagent. This is to evaluate the reducing ability of the membrane. Since neutral red is red in an oxidized state and colorless in a reduced state, the oxidation-reduction state of the reagent can be estimated visually, and further, according to JISZ8729.
By digitizing the color tone using the L ^* , a ^*, and b ^* color systems, the oxidation-reduction state of the reagent can be quantitatively evaluated.

[0009] That is, L ^*, the a ^* and b ^* color system, the red neutral red oxidation state is represented by a ^* value, a ^* if neutral red value is high oxidation state, more if low By indicating that the film is in a reduced state, and by measuring the color tone of the neutral red after being brought into contact with the film, it is possible to know whether the film has the ability to reduce neutral red (reducing ability). Therefore, it is considered that the lower the a ^* value indicating the reducing ability of the membrane is, the higher the reducing ability is and the less oxidative effect on blood is, and the a ^* value is preferably 20 or less by a contact experiment with blood. The value of a ^* representing red is not less than 0, and the lower limit is naturally 0 or more since neutral red is only colorless even when sufficiently reduced.

[0010] The material of the blood treatment membrane used here is not particularly limited, and any known material treated with radiation, for example, using a regenerated cellulose-based membrane or polysulfone as a base material to obtain hydrophilicity. And a polysulfone-based membrane having a hydrophilic polymer such as polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol, or cellulose acetate, polymethyl methacrylate and the like. Among them, a hollow fiber membrane obtained by adding polyvinylpyrrolidone to polysulfone is mentioned as a preferred specific example of the present invention. The shape of the membrane may be any shape such as a hollow fiber or a flat membrane.

As a result of intensive studies on a manufacturing method for providing the above-mentioned blood processing membrane, the following method was found. That is, a method in which water having an oxidation-reduction potential of -500 mV or less is sealed in a membrane or a module, and then treated with radiation.
Alternatively, this is a method in which water in which oxygen is dissolved and dissolved is sealed in a membrane or a module, and thereafter, treatment is performed with radiation. Water having a predetermined oxidation-reduction potential used in the first method is, for example,
It is created by performing electrolysis in an electrolyzed water tank in which two electrodes are arranged via an ion-permeable diaphragm. A known apparatus such as a strongly electrolyzed water generator can be used as a generator, and the generated water can be used. Is generally called strong electrolytic alkaline water. The oxidation-reduction potential generated between the obtained strongly electrolyzed alkaline water and the platinum electrode ranges from -300 mV to -900 mV.
It has very different physical characteristics from alkaline ionized water that is generally used for drinking.

The strong electrolyzed alkaline water thus prepared is
For example, in the case of hollow fiber membranes, hundreds to tens of thousands are bundled, loaded into a cylindrical plastic container, filled into a fixed semi-finished product, plugged, and irradiated with radiation such as γ-rays. And Filling with strong electrolytic alkaline water, after putting the membrane in a container such as a test tube, filling with strong electrolytic alkaline water and performing radiation treatment, may be assembled into a module, but in this case, it is not limited to radiation treatment However, it is necessary to sterilize again, so it is preferable to assemble in a module, fill with the strong electrolytic alkaline water, and sterilize by radiation treatment.

Although the reason why the above-mentioned strongly electrolytic alkaline water achieves the object of the present invention is not necessarily clear, when the radiation treatment is performed, for example, hydroxyl radicals and peroxide radicals are present in water existing in or around the film. The strongly electrolyzed alkaline water is considered to function as a liquid that eliminates these radicals generated by radiation or denatures them into radicals with weaker oxidative power. Therefore, it is preferable that the oxidation-reduction potential of the strongly electrolyzed alkaline water to be enclosed is low, but the lower limit is substantially defined by the properties of water or the capacity of the electrolyzed water generator, and the lower limit is about -900 mV, and is not more than -500 mV. In water having an oxidation-reduction potential of, the object of the present invention can be achieved.
More preferably, water of 800 mV or less is used.

In the strong electrolytic alkaline water, a water-soluble substance such as sodium pyrosulfite, acetone sodium bisulfite or the like may be dissolved if the oxidation-reduction potential of the strong electrolytic alkaline water does not deviate from the above range. I can't tell. In addition, as raw water for preparing strong electrolyzed alkaline water, drinking water specified by the Water Supply Law or pure water treated with an ion exchange membrane can be used. On the other hand, the method of encapsulating the water in which the second oxygen is dissolved and then treating it with radiation is to introduce oxygen gas from a cylinder while cooling in order to increase the oxygen solubility, and to disperse the oxygen-saturated water into the above-mentioned strong water. Filling is performed instead of electrolytic alkaline water, and radiation treatment is performed.

[0015] The module filled with water saturated with oxygen dissolves the radical species having strong oxidizing power generated in the film or water by the radiation, as in the case of the strongly electrolytic alkaline water, in which the dissolved oxygen eliminates or increases the oxidizing power. It is considered that the oxidized species having a strong oxidizing power is suppressed from remaining in the film because the radical is denatured into a weak radical, and the resulting film becomes a blood treatment film having a reducing ability. However, the method of enclosing oxygen-saturated water,
It is difficult to manufacture stably from the viewpoint of the control of dissolved oxygen, and the obtained membrane is filled with strong electrolytic alkaline water. It is better to do. The radiation treatment method of the present invention can be carried out using α-rays, β-rays, γ-rays, electron beams, or the like.
Gamma rays or electron beams are generally used. In the present invention, there is no particular limitation on the type of radiation and the irradiation dose.

[0016]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples, but the present invention is not limited to these examples. The NR test and the blood stimulation test in Examples and Comparative Examples were performed according to the following methods. In any of the tests, the blood treatment membrane used for the test drains the liquid filled in the module in advance, and further performs a washing operation with a physiological saline in the same manner as actually used in dialysis or the like. After disassembly, the membrane was taken out.

(NR test) 5 g of the membrane taken out from the module was precisely weighed and immersed in 50 ml of a separately prepared neutral red aqueous solution (50 mg / L) for 1 hour. After that, remove the membrane from the liquid, remove the remaining liquid with filter paper, etc.,
The a ^* value was measured. The a ^* value measurement was quantified using a colorimeter (CR-300 manufactured by Minolta). (Blood stimulation test) Membrane (5g) taken out of module
Was cut into pieces and contacted with fresh human blood (37 ° C., 50 ml) for 10 minutes to quantify the blood concentration of prostaglandin E ₂ (hereinafter, PGE ₂ ) released into the blood upon leukocyte stimulation. PGE ₂ was measured using a PGE ₂ EIA kit (Funakoshi). Since PGE ₂ has a certain concentration in blood even before contact with a foreign substance, the difference in concentration between before and after contact and the difference before and after contact The concentration ratio (increase rate) was calculated.

[0018]

Example 1 A hollow fiber membrane made of polysulfone and polyvinylpyrrolidone was assembled into a module having an effective membrane area of 1.5 m ² , and prior to irradiation with a radiation, a strong electrolytic alkaline water generator (manufactured by Toa Medical Electronics Co., Ltd.) SL-
2500), the oxidation-reduction potential is -820 m
V strong electrolyzed alkaline water was sealed, and γ-rays were irradiated at 25 kGy. The blood treatment membrane subjected to the test was drained in advance of the liquid filled in the module, and further washed with physiological saline in the same manner as actually used in dialysis and the like, and then disassembled. The membrane was removed and subjected to an NR test and a blood irritation test. The results are shown in Table 1.

[0019]

Example 2 The same operation as in Example 1 was carried out except that a strongly electrolyzed alkaline water having an oxidation-reduction potential of -740 mV was sealed, and the results of NR test and blood stimulation test were shown in Table 1. .

Example 3 The same operation as in Example 1 was carried out except that a strongly electrolyzed alkaline water having an oxidation-reduction potential of -510 mV was enclosed, and the results of an NR test and a blood stimulation test were shown in Table 1. .

Example 4 Pure water treated with an ion-exchange membrane was cooled to 5 ° C., and oxygen-saturated water produced by passing oxygen gas introduced from an oxygen cylinder at 100 ml per minute for 2 hours was sealed.
After performing the same operation as in Example 1, the results of NR test and blood stimulation test are shown in Table 1.

[0020]

[Comparative Example 1] The same operation as in Example 1 was carried out except that a strongly electrolyzed alkaline water having an oxidation-reduction potential of -450 mV was enclosed, and then an NR test and a blood stimulation test were performed. 1 is shown.

Comparative Example 2 The same operation as in Example 1 was performed, except that alkaline ionized water having an oxidation-reduction potential of -180 mV was sealed, and then an NR test and a blood stimulation test were performed. It was shown to.

[0021]

[Comparative Examples 3 and 4] At the time of making the module shown in Example 1, the sealing solution was converted to a solution having a redox potential of +98 mV obtained by dissolving sodium hydrogen carbonate (0.1 w / v%) in pure water treated with an ion exchange membrane. Table 1 shows the results of the NR test and the blood irritation test performed on the membrane that was prepared in a different manner, irradiated with 25 kGy of γ-rays, and taken out after the same washing operation as in Example 1 as Comparative Example 3. Further, the same as Comparative Example 3 was carried out except that sodium hydrogen carbonate was replaced with sodium hydroxide (0.1 w /
v%), and a film taken out after the same washing operation as in Example 1 from a module filled with a solution having an oxidation-reduction potential of +146 mV and irradiated with 25 kGy of γ-ray was taken as Comparative Example 4.
Table 1 shows the results of the NR test and the blood stimulation test.

[0022]

[Comparative Example 5] When the module shown in Example 1 was prepared, the filling liquid was changed to pure water treated with an ion exchange membrane, and γ was prepared.
After irradiation with 25 kGy of the line, the NR test and the blood stimulation test were performed on the membrane taken out after the same washing operation as in Example 1. The results are shown in Table 1 as Comparative Example 5.

REFERENCE EXAMPLE In the same manner as in Comparative Example 5, a NR test and a blood irritation test were performed using a membrane taken out from a module filled with pure water and not irradiated with gamma rays after the same washing operation as in Example 1 as a reference example. The results are shown in Table 1. A * by irradiation
The values increased, and PGE ₂ increased significantly.

[0023]

[Table 1]

In Examples 1, 2 and 3 according to the present invention in which alkaline ionized water having an oxidation-reduction potential of -500 mV or less was encapsulated, the a ^* value did not increase despite the radiation treatment, and the blood PGE was not increased. _{2 The} concentration hardly increased. However, in Comparative Example 1 in which alkaline ionized water having an oxidation-reduction potential of -450 mV was enclosed, the a ^* value exceeded 20, the blood PGE ₂ concentration increased, and the blood was stimulated more. Further, in Comparative Example 2, the redox potential was −180 mV in alkaline ionized water, and in Comparative Examples 3 and 4 where the redox potential of the solution was a positive value, the a ^* value was a comparative example using pure water. Blood PGE ₂ concentration rises as in 5,
There was much irritation to the blood.

[0025]

According to the present invention, even a blood treatment membrane sterilized by radiation can have a reducing ability, and the influence on blood can be further reduced.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C077 AA01 AA05 BB01 BB02 BB03 GG05 LL02 LL05 LL23 PP15 4D006 GA13 HA01 MA01 MA03 MB09 MB20 MC40X MC62 MC62X

Claims (5)

[Claims] 1. A blood processing membrane, wherein at least the surface of the radiation-treated blood processing membrane has a reducing ability. 2. The method of claim 1, wherein the reducing ability is obtained by an NR test ^.
2. The blood processing membrane according to claim 1, wherein the value is 20 or less. 3. The blood processing membrane according to claim 1, wherein the blood processing membrane is made of polysulfone and a hydrophilic polymer. 4. A method for producing a blood processing membrane having reducing ability, which comprises irradiating the blood processing membrane with water having an oxidation-reduction potential of -500 mV or less when the blood processing membrane is subjected to radiation treatment. 5. A method for producing a blood processing membrane having a reducing ability, wherein the blood processing membrane is subjected to radiation treatment in water in which oxygen is saturated and dissolved when the blood treatment membrane is subjected to radiation treatment.