JP2013094525A - Manufacturing method for hollow fiber membrane for blood purification excellent in biocompatibility - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a manufacturing method for hollow fiber membrane for blood purification capable of effectively producing antioxidant effect of vitamin added to spinning dope.SOLUTION: In the manufacturing method for the hollow fiber membrane for blood purification including a process in which after simultaneously discharging the spinning dope and core liquid from an outside annular part and a main hole of a double pipe nozzle, they are made to pass through the coagulability fluid, to be solidified and cleaned, the spinning dope is made to contain 0.05-1.2 mass% of lipid soluble vitamin, preferably vitamin E and also contain 0.004-0.045 mass% of citric acid.

Description

  The present invention relates to a method for producing a hollow fiber membrane for blood purification excellent in biocompatibility that can eliminate active oxygen produced during hemodialysis.

  In blood purification methods such as for renal failure treatment, natural materials such as cellulose, its derivatives cellulose diacetate, cellulose triacetate, synthetic polymers such as polysulfone, and polysulfone are used to remove uremic toxins and waste products in the blood. Blood purifiers such as hemodialyzers, hemofilters or hemodialyzers using dialysis membranes or ultrafiltration membranes using polymers such as ether sulfone, polymethyl methacrylate, and polyacrylonitrile as separation materials are widely used. ing. In particular, blood purifiers that use hollow fiber membranes as separators have the advantage of advantages such as reduced circulating blood volume related to extracorporeal circulation, high substance removal efficiency in blood, and productivity of blood purifier assembly. High utilization in the purification field.

  A blood purifier using a hollow fiber membrane usually causes blood to flow through the hollow part of the hollow fiber membrane, counterflowing dialysate to the outside, and urea and creatinine by mass transfer based on diffusion from blood to dialysate. The main aim is to remove low molecular weight substances such as However, with the increase in the number of long-term dialysis patients, dialysis complications have become a problem. In recent years, substances to be removed by dialysis are not only low molecular weight substances such as urea and creatinine, but also have a molecular weight of several thousand to a molecular weight of 1 to 20,000. Blood purification membranes are required to expand to high molecular weight substances and to remove these substances. In particular, β2 microglobulin having a molecular weight of 11700 has been found to be a causative substance of carpal tunnel syndrome and is a removal target. Membranes used for such high molecular weight substance removal treatment are called high performance membranes. In recent years, in Japan, a hollow fiber membrane having an asymmetric structure, in which a synthetic polymer is a main component of a base material, is often used as a high performance membrane in clinical practice.

  However, complications that may be caused by activation of white blood cells, platelets, and complements in blood due to blood contact with dialysis machines and dialysis treatment equipment that are not biological constituents occur. This contributes to a decrease in QOL (see Non-Patent Documents 1 and 2, for example). Furthermore, when hemodialysis is performed over a long period of time, active oxygen is produced when the blood cell component in the blood is activated, and accumulation of the oxidative stress has been confirmed to increase lipid peroxide. Complications such as arteriosclerotic disease of long-term dialysis patients that are thought to be increasing are increasing.

  In order to solve these problems, an artificial organ that coats the surface of dialysis membrane with vitamin E that exhibits physiological actions such as antioxidant action, membrane stabilization action, and platelet aggregation inhibitory action in vivo has been proposed and marketed. (For example, refer nonpatent literature 3, patent documents 1-4). However, when vitamin E is coated after the process of assembling the artificial organ, the use of a flammable organic solvent or a fluorocarbon solvent has been proposed, and the amount of solvent required to fill the dialyzer is large and there is an environmental risk. Depending on the type of solvent, there is a problem that it is a solvent that needs to be handled as a dangerous substance, or that it is an unusable solvent according to the Montreal Protocol concerning substances that destroy the ozone layer. Furthermore, in manufacturing, since vitamin E is coated after film formation / artificial organ assembly, production cost is high, and there is a concern that permeation of substances passing through the pores may be inhibited by the surface coating layer. There was a problem that vitamin E was covered with the protein adsorption layer on the surface layer and the effect was reduced.

  Furthermore, in the manufacturing process of artificial organs, a sterilization process such as radiation sterilization is ultimately required.However, when radiation sterilization is performed in a wet state where the membrane coexists with moisture, water is decomposed during radiation sterilization. , Radicals are produced. Utilizing this phenomenon, a method of generating radicals in a wet state and accelerating the crosslinking of the added hydrophilic polymer has been applied to an artificial organ (see, for example, Non-Patent Document 4). Since the produced radical reacts immediately with the contact substance, naturally, it is assumed that vitamin E is immediately oxidized when vitamin E comes into contact with the produced radical. When vitamin E is oxidized, it changes to a compound having a quinone structure (tocopheryl quinone), etc., but this structure does not exhibit the expected antioxidant property, and the biological data from the minimum dose (TDLo: Toxic Dose Lowest) data. Since there is a concern that the risk given to vitamin B may be higher than that of vitamin E, it is important to maintain the activity of vitamin E from the viewpoint of antioxidant efficiency and safety.

In order to prevent radical generation during radiation sterilization, a method has been proposed in which radical sterilization is performed in a dry state to control the amount of radical production and improve stability during storage (for example, Patent Document 5). No consideration is given to vitamin E status. In addition to these sterilization methods, it is generally known that heavy metals accelerate the chain reaction in the process of radical chain reaction, and radical chain reaction while suppressing the amount of radical production in the manufacturing and storage process. It is important to control.

  On the other hand, a method of adding vitamin E to a spinning dope has been proposed in order to solve the problems of cost increase and antioxidant efficiency due to the additional coating process of vitamin E (see, for example, Patent Document 6). This method is excellent in that it can easily achieve cost reduction, but there is a concern about oxidation of vitamin E due to heat load and metal impurities in the manufacturing process. This document does not mention the state of vitamin E, and has not yet proposed an antioxidant film that sufficiently exhibits the antioxidant function of vitamin E by suppressing the oxidation of vitamin E in the production process.

Japanese Patent No. 3193919 Japanese Patent Laid-Open No. 11-178919 Japanese Patent No. 3357262 Japanese Patent No. 4038583 Japanese Patent No. 3928910 JP 09-66225 A

Artificial organ Vol.18, No.5, 539-1546 (1989) Kidney and dialysis, 15-19, separate volume 1998 Dialysis Journal 43 (3), 275-279 (2010) Kidney and dialysis, 26-31 (2009)

  The present invention has been made to solve the problems of the prior art, and its purpose is that the fat-soluble vitamin added to the spinning dope is distributed throughout the membrane, and the oxidation of the fat-soluble vitamin during production and storage is performed. It is in providing the manufacturing method of the hollow fiber membrane for blood purification which can exhibit the antioxidant effect | action effectively by suppressing, and the hollow fiber membrane obtained by it, and the dialyzer using the same.

  As a result of intensive studies on the method for inhibiting oxidation of fat-soluble vitamins added to the spinning dope to achieve the above object, the present inventors have added citric acid in a specific range to the spinning dope so that citric acid can be produced. As a result of stabilizing metal ions and preventing radical chain reaction due to metal ions, it was found that oxidation of fat-soluble vitamins can be suppressed, and the present invention has been completed.

That is, the present invention has the following configurations (1) to (6).
(1) A hollow fiber membrane for blood purification comprising the steps of simultaneously discharging a spinning solution and a core solution from an outer annular portion and a center hole of a double-tube nozzle, and then allowing the solution to pass through a coagulating liquid to coagulate and wash. In the production method, the spinning solution contains 0.05 to 1.2% by mass of a fat-soluble vitamin, and further 0.004 to 0.045% by mass of citric acid. Manufacturing method.
(2) The method for producing a hollow fiber membrane for blood purification according to (1), wherein the fat-soluble vitamin is vitamin E.
(3) The blood purification hollow according to (1) or (2), wherein the vitamin E is α-tocopherol, acetic acid-α-tocopherol, succinic acid-α-tocopherol, or calcium tocopherol succinate Yarn membrane manufacturing method.
(4) A hollow fiber membrane for blood purification obtained by the production method according to any one of (1) to (3), wherein the fat-soluble vitamin content in the membrane is 0.05 to 1.2% by mass A hollow fiber membrane for blood purification, wherein the peak area ratio of oxide / non-oxide in the fat-soluble vitamin based on measurement by high performance liquid chromatography is 30% or less.
(5) A hollow fiber membrane type dialyzer comprising the blood purification hollow fiber membrane according to (4).
(6) The hollow fiber membrane dialyzer according to (5), wherein the space inside the hollow fiber membrane dialyzer is sterilized with radiation and / or electron beam in a dry state.

  According to the method of the present invention, the fat-soluble vitamin is contained in the spinning dope and further contains citric acid that protects it from oxidation in an appropriate amount. A hollow fiber membrane having antioxidation properties dispersed therein can be produced. In particular, by suppressing oxidation during the manufacturing process and sterilization process, a large amount of active fat-soluble vitamin can remain in the membrane, and the active oxygen produced during dialysis can be effectively eliminated by this active vitamin. Can do.

FIG. 1 schematically shows an example of the production method of the present invention.

  The method for producing a hollow fiber membrane for blood purification according to the present invention basically comprises a conventionally known method as schematically shown in FIG. 1, and includes an outer annular portion and a center hole of a double tube nozzle. The method includes a step of discharging a spinning stock solution and a core solution simultaneously, forming a film by passing through a coagulating liquid in a coagulation bath, and washing the film. A feature of the production method of the present invention is that, in particular, a spinning stock solution contains a specific range of amounts of fat-soluble vitamins and citric acid. By including fat-soluble vitamins in the spinning dope, fat-soluble vitamins having anti-oxidation action and the like can be uniformly dispersed in the membrane by a simple method, and by adding citric acid, oxidation of fat-soluble vitamins Can be effectively suppressed. Therefore, the hollow fiber membrane of the present invention and the dialyzer using the membrane can effectively eliminate the active oxygen produced in the dialysis process as compared with the conventional one, and various kinds of active oxygen are caused. Can alleviate the disease.

  The stock solution for spinning contains a polymer or a combination of a plurality of polymers, a solvent and a non-solvent, and further contains a fat-soluble vitamin and citric acid. The total polymer mass ratio in the spinning dope is not a problem as long as stable film formation and performance can be ensured, but it is preferably 15 to 20% by mass. If the mass ratio of the polymer is too low, not only will the spinnability be reduced, but the spinnability will be lowered, and there may be an undesirable effect on the retention of fat-soluble vitamins in the membrane. On the other hand, if the polymer mass ratio is too high, the structure of the hollow fiber membrane may become too dense to obtain the desired membrane performance.

  The polymer used as the material for the hollow fiber membrane is not limited to any of cellulose, vinyl, and aromatic polymers. However, in order to uniformly disperse fat-soluble vitamins, cellulose triacetate and cellulose with high hydrophobicity are used. Cellulose ester such as diacetate, cellulose mixed ester such as cellulose acetate propionate, cellulose acetate butyrate, aromatic polysulfone polymer, aromatic polyamide polymer, aromatic polyimide polymer, aromatic polyether polymer, aromatic Polyester polymers, aromatic polyketone polymers, aromatic polysulfate polymers and the like are preferable. Furthermore, cellulose esters and aromatic polysulfone polymers are particularly preferred from the viewpoints of hollow fiber processability, film-forming properties, and biocompatibility. The aromatic polysulfone polymer is not particularly limited as long as it is a polysulfone polymer having an aromatic functional group in the molecule, and examples thereof include aromatic polysulfone and aromatic polyethersulfone. .

  A hydrophilic polymer can be added to the polymer as necessary. Examples of the hydrophilic polymer include synthetic polymers composed of polyvinyl alcohol, polyethylene glycol, polypropylene glycol, polyvinyl pyrrolidone, polyethyleneimine, and copolymers thereof, and polysaccharides. Among these, polyvinylpyrrolidone is particularly preferable from the viewpoints of compatibility with the above hydrophobic property, film forming property, and the like.

  The total solvent ratio in the spinning dope is preferably 50 to 70% by mass, and the total non-solvent ratio is preferably 10 to 30% by mass. In order to stabilize the dissolution of the fat-soluble vitamin, the total solvent ratio in the spinning dope is preferably 50% by mass or more. As the solvent, a so-called aprotic polar solvent capable of solubilizing polymers and fat-soluble vitamins, N, N-dimethylformamide, N, N-dimethylacetamide, γ-butyrolactone, N-methylpyrrolidone, etc. may be used alone or in combination. Are preferably used. Non-solvents include inorganic salts and alcohols, but glycols such as glycerin, ethylene glycol, triethylene glycol, and polyethylene glycol are preferably used alone or in combination.

  In the production method of the present invention, it is an unprecedented feature that the spinning dope contains fat-soluble vitamins and citric acid. The content of the fat-soluble vitamin in the spinning dope is 0.05 to 1.2% by mass, preferably 0.1 to 1.0% by mass. If the content of the fat-soluble vitamin is less than the above range, the effect of the fat-soluble vitamin is not sufficient, and if it exceeds the above range, the production is possible, but it is disadvantageous from the viewpoint of cost effectiveness due to the increase in raw material cost. Examples of the fat-soluble vitamin include vitamin A, vitamin D, vitamin E, vitamin K and the like, but vitamin E is preferred from the viewpoint of heat resistance and antioxidant function. Vitamin E includes α-tocopherol and vitamin E derivatives acetic acid-α-tocopherol, succinic acid-α-tocopherol, and calcium tocopherol succinate. These vitamin E derivatives can also be expected to have the same effect because they are deesterified by blood components when they are brought into contact with blood and converted to α-tocopherol.

  In the manufacturing process, it is inevitable that heavy metals such as iron and chromium are mixed in from raw materials and manufacturing machines, and these heavy metals take multiple oxidation numbers, causing fat-soluble vitamins and oxidation-reduction reactions, resulting in fat-soluble vitamins. Is known to be altered. Therefore, by adding citric acid to the spinning dope, heavy metal impurities and citric acid from raw materials and production machine bases react, and by stabilizing heavy metals, it is possible to suppress the reaction between fat-soluble vitamins and heavy metals. It becomes. Furthermore, heavy metals are known to amplify the amount of peroxide as represented by the Fenton reaction. By stabilizing heavy metals in advance, fats caused by peroxides in the sterilization process and storage process after sterilization can be obtained. It becomes possible to prevent oxidation of soluble vitamins. The content of citric acid in the spinning dope is 0.004 to 0.045% by mass, preferably 0.005 to 0.04% by mass. If the citric acid content is less than the above range, an effect can be seen in suppressing yarn breakage, but it is not preferable because the reaction between metal impurities and fat-soluble vitamins cannot be completely suppressed. It is necessary to add 7 to 60 times the molar amount of metal impurities contained in the spinning dope. On the other hand, when the above range is exceeded, acidification with excess citric acid proceeds to induce oxidation of fat-soluble vitamins and further promote corrosion of the production machine base, which is not preferable.

  The spinning dope prepared as described above is heated, filtered through a polymer, fat-soluble vitamin and citric acid uniformly dissolved, and then extruded from the outer annular portion (slit) of the double tube nozzle. Thus, the core liquid (inner liquid) is simultaneously projected from the center hole of the double tube nozzle. As the core liquid, a liquid that does not dissolve the hydrophobic polymer is preferably used. For example, liquid paraffin or an inert liquid is preferably used. The spinning dope extruded from the nozzle travels through the dry section and then passes through a coagulating liquid (coagulation bath) to coagulate and phase separate to form a membrane structure in which fat-soluble vitamins are distributed throughout the membrane. . It is estimated that most of the citric acid added to the spinning dope elutes in the coagulating liquid (coagulation bath) when it passes through the coagulating liquid (coagulation bath). There is no problem. As the coagulable liquid, water, or a solvent used in water and the stock solution for spinning and a non-solvent mixed aqueous solution can be used. If necessary, additives such as antioxidants and lubricants can be added.

  The hollow fiber membrane that has undergone the coagulation bath ishes away unnecessary components such as a solvent in the washing step. The cleaning liquid used at this time is preferably a solvent that does not dissolve fat-soluble vitamins, and water is used, for example. A reducing aqueous solution such as reducing water or a reducing substance such as ascorbic acid can be added to the cleaning liquid as necessary. The hollow fiber membrane which passed through the washing process is subjected to glycerin treatment as necessary. For example, in the case of a hollow fiber membrane made of a cellulose-based polymer, the membrane is wound through a drying step after passing through a bath of a glycerin aqueous solution. In this case, the glycerin concentration in the bath is preferably 60 to 90% by mass. If the glycerin concentration is too low, the hollow fiber membrane tends to shrink during drying, and storage stability may deteriorate. Furthermore, there is a growing concern about residual moisture, and water-derived radicals are produced in the sterilization process, which may promote the oxidation of fat-soluble vitamins. Also, if the glycerin concentration is too high, excess glycerin tends to adhere to the hollow fiber membrane, and the adhesiveness at the end of the hollow fiber membrane may deteriorate when assembled into a blood purifier. The temperature of the glycerin bath is preferably 50 ° C. or higher and 80 ° C. or lower. When the temperature of the glycerin bath is too low, the viscosity of the glycerin aqueous solution is high, and there is a possibility that the glycerin aqueous solution does not reach all the pores of the hollow fiber membrane. If the temperature of the glycerin bath is too high, the hollow fiber membrane may be denatured and altered by heat.

  About the film | membrane after washing | cleaning, the water | moisture content provided at the solvent used for washing | cleaning and a glycerol treatment process is removed at a drying process. The temperature in the drying step is preferably 40 ° C. or higher and 80 ° C. or lower. If the drying temperature is too low, removal of these solvents may be insufficient, and the adhesiveness at the end of the hollow fiber membrane may deteriorate when assembled into a blood purifier. Furthermore, residual moisture can generate radicals during the sterilization process and promote the oxidation of fat-soluble vitamins. Conversely, if the drying temperature is too high, the hollow fiber membrane and the fat-soluble vitamin may be denatured and altered by heat.

  A hollow fiber membrane containing a fat-soluble vitamin in which oxidation is suppressed can be produced by winding through these steps. Specifically, the hollow fiber membrane obtained by the production method of the present invention has a fat-soluble vitamin content in the membrane of 0.05 to 1.2% by mass, and the fat based on the measurement by high performance liquid chromatography. The peak area ratio of oxide / non-oxide in the soluble vitamin can be 30% or less. By limiting the amount to 30% or less, the ratio of vitamin oxide can be suppressed to several percent, and a film maintaining the efficacy of vitamins can be obtained. The hollow fiber membrane produced by these methods preferably has an inner diameter of 150 to 300 μm and a membrane thickness of 10 to 70 μm.

  The hollow fiber membrane obtained by the production method of the present invention can be used for blood purification of a dialyzer. When the membrane surface is coated with fat-soluble vitamins, it is estimated that the effects of vitamins are reduced by coating with proteins in the blood, but in the present invention, fat-soluble vitamins are distributed throughout the membrane. Thus, it can be expected that the active oxygen produced during blood purification is efficiently erased without the concerns described above. The modularization of such a hollow fiber membrane type dialyzer is, for example, by inserting a hollow fiber membrane bundle into a container of a dialyzer, injecting a potting agent such as polyurethane into both ends of the bundle and sealing both ends, and then adding an extra potting agent. It can be performed by cutting and removing to open the end face of the hollow fiber membrane and attaching a header.

  The hollow fiber membrane type dialyzer is preferably sealed in a packaging bag together with an oxygen scavenger and sterilized by irradiation with radiation and / or electron beams in a dry state inside the dialyzer. Examples of the radiation or electron beam include α-rays, β-rays, γ-rays, and electron beams, and γ-rays or electron beams are preferably used from the viewpoint of sterilization efficiency and ease of handling. The irradiation dose of radiation or electron beam is not particularly limited as long as it can be sterilized, but generally 10 to 30 kGy is preferable.

  Hereinafter, the production method of the present invention and the effectiveness of the hollow fiber membrane obtained thereby will be described with reference to examples, but the present invention is not limited thereto. In addition, the evaluation method of the physical property in an Example is as follows.

1. Pretreatment for vitamin E analysis 20 mg of hollow fiber membrane was dissolved in a small amount of N-methylpyrrolidone (NMP), and reprecipitation was performed using ethanol as a poor solvent. The precipitated polymer was removed by centrifugation, and the supernatant was separated to make a certain amount of ethanol solution. This solution was used as a pretreatment liquid.

2. Determination of vitamin E The pretreatment solution was subjected to high performance liquid chromatography (HPLC) to detect vitamin E. For the quantification of vitamin E, the concentration was calculated using DL-α-tocopherol manufactured by Nacalai Tesque as a standard, and appropriately adjusted for dilution with an ethanol solution so as to obtain an appropriate concentration.
[HPLC conditions]
Device: Agilent 1100
Column: Imtakt Unison UK-C18
(Inner diameter 2mm, column length 100mm)
Mobile phase: A 0.1% formic acid, B isopropalol
0 min (40% B) -15 min (98% B) -25 min (98% B)
Flow rate: 0.2 ml / min
Column temperature: 45 ° C
Injection volume: 5 μl
Detection wavelength: 291 nm and 260 nm

3. Vitamin E oxide / non-oxide peak area ratio The pretreatment liquid is subjected to high performance liquid chromatography (HPLC) to detect non-oxidized vitamin E (α-tocopherol) and oxidized vitamin E (α-tocopherylquinone). Went. The maximum absorption wavelength and elution time were different for each, and the elution time was confirmed using a sample. Since the elution time varies depending on the apparatus and measurement conditions, confirmation was made at each measurement. Under the above measurement conditions, for non-oxidized vitamin E, a peak eluting at 291 nm detection wavelength at 14.3 minutes is detected, and for oxidized vitamin E, a peak eluting at 260 nm detection wavelength at 13 minutes is detected and calculated using the following formula: did.
Peak area ratio (%) = oxidized vitamin E (260 nm detection, 13 minutes) /
Non-oxidized vitamin E (291 nm detection, 14.3 minutes) × 100

Example 1
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.5% by mass, and citric acid 0.015% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 195 μm and a film thickness of 17 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Example 2)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.5% by mass, and citric acid 0.005% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 196 μm and a film thickness of 19 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Example 3)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.5% by mass, and citric acid 0.03% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 195 μm and a film thickness of 21 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

Example 4
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.5% by mass, and citric acid 0.04% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 194 μm and a film thickness of 18 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Example 5)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.5% by mass, and citric acid 0.015% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Then, after removing the core liquid and washing, the whole blood purifier is vacuum packed in a packaging bag consisting of a general-purpose iron powder-based oxygen scavenger, an outer layer made of polyester film, an intermediate layer made of aluminum foil, and an inner layer made of polyethylene film And was sterilized by irradiation with 25 kGy dose of γ-rays. After sterilization, the blood purifier was taken out, and after disassembly, the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 195 μm and a film thickness of 17 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Example 6)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 1.0% by mass, and citric acid 0.015% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 196 μm and a film thickness of 18 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Example 7)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.10% by mass, and citric acid 0.015% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 194 μm and a film thickness of 18 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Comparative Example 1)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.5% by mass, and citric acid 0.002% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 195 μm and a film thickness of 15 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Comparative Example 2)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries) at 15.2% by mass, α-tocopherol 0.5% by mass, and citric acid 0.05% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 195 μm and a film thickness of 15 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope, the vitamin E content of the hollow fiber membrane, and the oxide / non-oxide peak area ratio of vitamin E.

(Comparative Example 3)
The spinning dope was N-methyl-2-pyrrolidone and cellulose triacetate (CTA) (Daicel Chemical Industries, Ltd.) 15.2% by mass, α-tocopherol 0.025% by mass, and citric acid 0.015% by mass. It was prepared by uniformly dissolving using a triethylene glycol mixed solvent. The solvent ratio in the mixed solvent was adjusted so that N-methyl-2-pyrrolidone was 70% by mass and triethylene glycol was 30% by mass. The obtained spinning dope was discharged from the outer annular portion of a heated double tube nozzle, and at the same time, liquid paraffin was discharged from the center hole as a core solution. After running the dry section, it was allowed to pass through a coagulable liquid to solidify and phase separate to form a membrane structure, and unnecessary components were removed in the washing step. Subsequently, after passing through a 75% by mass glycerin bath and drying in an atmosphere at 40 ° C., the hollow fiber was wound up. About 10,000 hollow fibers were inserted into a polycarbonate case, both ends were fixed with urethane resin, cut and opened, and caps having inflow ports were attached. Thereafter, the core liquid was removed and washed, the blood purifier was disassembled, and the hollow fiber was taken out. The obtained hollow fiber membrane had an inner diameter of 195 μm and a film thickness of 17 μm. Table 1 shows the vitamin content and citric acid content of the spinning dope and the vitamin E content of the hollow fiber membrane.

(Comparative Example 4)
Regarding a commercially available dialyzer coated with a fat-soluble vitamin (Asahi Vitablen, manufactured by Asahi Kasei Kuraray Medical Co., Ltd.), the filling water in the dialyzer was drained, the dialyzer was disassembled, and the hollow fiber was taken out. And after making it dry at room temperature, it evaluated similarly to the other Example. Table 1 shows the vitamin E content of the hollow fiber membrane and the oxide / non-oxide peak area ratio of vitamin E.

  As is clear from Table 1 above, the hollow fiber membranes of Examples 1 to 7 all have the peak area ratio of oxidant vitamin E suppressed, and the effect of suppressing vitamin oxidation during the production process is recognized. . On the other hand, in the hollow fiber membranes of Comparative Examples 1 and 2, the peak area ratio of oxidized vitamin E is high due to insufficient stabilization of heavy metal by citric acid or acidification by excessive addition, and oxidation of vitamin E proceeds. Yes. For Comparative Example 3, vitamin addition is insufficient and a sufficient effect cannot be expected. About the comparative example 4, it is sterilization in a wet state and vitamin oxidation has advanced by the radical produced at the time of sterilization.

  According to the present invention, a hollow fiber membrane blood purifier having excellent biocompatibility can be produced simply and at low cost. Furthermore, since the oxidation of fat-soluble vitamins during the radiation sterilization process is prevented, effective antioxidant performance and high safety can be expected.

Claims (6)

  In a method for producing a hollow fiber membrane for blood purification, comprising a step of simultaneously discharging a spinning solution and a core solution from an outer annular portion and a center hole of a double tube nozzle, and then allowing the solution to pass through a coagulable liquid to be coagulated and washed. A method for producing a hollow fiber membrane for blood purification, wherein 0.05 to 1.2% by mass of a fat-soluble vitamin and 0.004 to 0.045% by mass of citric acid are further contained in the spinning solution. .   The method for producing a hollow fiber for blood purification according to claim 1, wherein the fat-soluble vitamin is vitamin E.   The method for producing a hollow fiber membrane for blood purification according to claim 1 or 2, wherein the vitamin E is α-tocopherol, acetic acid-α-tocopherol, succinic acid-α-tocopherol, or tocopherol calcium succinate. .   A hollow fiber membrane for blood purification obtained by the production method according to claim 1, wherein the fat-soluble vitamin content in the membrane is 0.05 to 1.2% by mass, and a high-speed liquid A hollow fiber membrane for blood purification, wherein the peak area ratio of oxide / non-oxide in the fat-soluble vitamin based on chromatography is 30% or less.   A hollow fiber membrane dialyzer comprising the blood purification hollow fiber membrane according to claim 4.   6. The hollow fiber membrane dialyzer according to claim 5, wherein the space inside the hollow fiber membrane dialyzer is sterilized by radiation and / or electron beam in a dry state.