JP4876704B2 - Blood purifier - Google Patents

Description

  The present invention has excellent blood compatibility, high safety and stability of performance, polysulfone-based hollow fiber membrane particularly suitable for blood purification and blood, blood compatibility, and high safety and stability of blood It relates to a purifier.

  In blood purification therapy for the treatment of renal failure, natural materials such as cellulose, cellulose diacetate, cellulose triacetate, synthetic polymers such as polysulfone, Blood purifiers such as hemodialyzers, hemofilters or hemodialyzers using a dialysis membrane using a polymer such as methyl methacrylate or polyacrylonitrile or an ultrafiltration membrane as a separating material are widely used. In particular, a blood purifier using a hollow fiber membrane as a separating material is highly important due to advantages such as a reduction in the amount of extracorporeal blood circulation, a high efficiency of removing substances in the blood, and productivity in the production of the blood purifier.

  Thus, a hollow fiber membrane for blood treatment must selectively permeate a specific substance according to the purpose. The performance is determined by the material of the hollow fiber membrane, the shape or distribution of the holes, the film thickness, and the like. By the way, in recent years, parathyroid hormone is considered to be related to β2-microglobulin (β2-MG, molecular weight 11800), pruritus, and hyperlipidemia, which are considered to be causative substances of dialysis amyloidosis, in relation to long-term complications of dialysis patients. (Molecular weight about 9500), the need for removal of toxic substances in the relatively medium high molecular weight region, such as erythroblast-inhibiting factor involved in anemia, substances with molecular weight of 20,000 to 40,000 that are considered to be related to joint pain and bone pain It came to be released. On the other hand, leakage of albumin (molecular weight 66000) necessary for the human body must be suppressed as much as possible. That is, a selective permselective membrane having a high molecular weight cut off of a molecular weight of 40,000 or less and a sharp molecular weight cut off with a good blocking rate of a substance having a molecular weight of 60,000 or more is desired. Specifically, the clearance of β2-MG is 50 mL / min. The amount of albumin leakage is preferably 4 g / 4 hr or less. More preferably, the clearance of β2-MG is 60 mL / min. The amount of albumin leakage is 3.5 g / 4 hr or less.

  In addition, nonspecific protein adsorption or denaturation or platelet adsorption or activation on the surface of the hollow fiber membrane is not caused.

  For this reason, blood purifiers such as hemodialyzers and hemodialysis filters used in hemodialysis therapy have excellent water removal and are designed to meet the above requirements for their fractional molecular weight characteristics. There is a need for a polymer hollow fiber membrane having performance.

  In addition, in order to suppress and reduce the activation of the blood system caused by blood coming into contact with the surface of the hollow fiber membrane and obtain excellent blood compatibility, membrane material selection and membrane structure design are actively studied.

  Among the above-mentioned membrane materials, polysulfone-based resins having high water permeability are attracting attention as the best match with the progress of dialysis technology. However, when a semi-permeable membrane is made of a single polysulfone resin, the polysulfone resin is hydrophobic, so it has poor affinity with blood and causes an airlock phenomenon. It is not possible.

As a method for solving the above problems, a method has been proposed in which a hydrophilic polymer is blended with a polysulfone resin to form a film, and the film is given hydrophilicity. For example, a method of blending a polyhydric alcohol such as polyethylene glycol is disclosed (see Patent Documents 1 and 2).
JP-A-61-232860 JP 58-114702 A

Moreover, the method of mix | blending polyvinylpyrrolidone is disclosed (for example, refer patent document 3, 4).
Japanese Patent Publication No. 5-54373 Japanese Examined Patent Publication No. 6-75667

  However, since such a material is a synthetic material, it is recognized as a foreign substance by a living body, and various biological reactions can occur. For example, when it comes into contact with blood, adhesion of platelets or activation of white blood cells may occur, resulting in poor blood compatibility.

As a method for maintaining the selective permeation performance and improving blood compatibility, a method is disclosed in which at least the blood contact surface of the hollow fiber membrane is an aggregate of polymer particles (for example, Patent Documents 5 to 7). reference).
JP-A-7-289866 JP 2002-45662 A JP 2003-10322 A

  On the other hand, in a blood purifier, a radiation irradiation treatment may be performed for the purpose of crosslinking or sterilizing polyvinyl pyrrolidone in a hollow fiber membrane filled in the blood purifier. However, when irradiated, modification may be caused to a part of the hydrophilic polymer in addition to the crosslinking reaction and sterilization effect. That is, it reacts with water or oxygen in the treatment atmosphere to generate an unstable functional group or partial structure in an oxidized state, or a new functional group is generated by hydrolysis. Even if the content of the hydrophilic polymer in the entire membrane is small, most of it is concentrated on the surface of the polysulfone-aggregated particles by phase separation, so these effects on blood are not negligible. As a result, the anti-thrombogenicity of the membrane may be reduced due to physicochemical changes in these modified parts. In addition, the denaturation continued during long-term storage after irradiation, and the antithrombogenicity could be lowered before actual use.

For example, as a method for solving the above problem, in a film irradiated with radiation, if the carboxyl group content and the peroxide content in the film are controlled within a certain range, the film has excellent antithrombogenicity and is stored for a long time. Has also disclosed a technique capable of maintaining an antithrombotic state (see Patent Document 8).
JP 2000-135421 A

  However, the blood purifier disclosed in the above-mentioned patent document is a method applied to a so-called wet type blood purifier irradiated with water in a state of water filling. The wet type blood purifier is naturally heavy due to water filling, and is inconvenient to transport and handle. In cold regions, the water filled in the blood purifier freezes in the severe cold season and the hollow fiber membrane ruptures. And problems such as damage. In addition, there are high cost factors such as preparation of a large amount of sterilized water. Moreover, in order to make the hollow fiber membrane both moist and easy for bacteria to propagate, it is conceivable that the bacteria will proliferate during a short period after packaging until sterilization. As a result, the blood purifier manufactured in this manner is not preferable because it takes a long time to obtain a completely sterilized state, which leads to higher cost or safety. This technique is irradiated with radiation in the presence of a radical scavenger, and has a problem that an operation for washing and removing the radical scavenger in advance is necessary when used for blood purification. Therefore, it is strongly desired to establish a so-called dry type blood purifier loaded with a dried polysulfone-based hollow fiber membrane, and a method capable of avoiding the above problems even when irradiated with radiation in the absence of a radical scavenger. ing.

  Further, when the blood purifier is used as an artificial dialyzer, it must be completely sterilized before use. For the sterilization treatment, formalin, ethylene oxide gas, high-pressure steam sterilization, γ-ray radiation or electron beam irradiation sterilization, etc. are used, each exhibiting a unique effect. Among these, sterilization by radiation or electron beam irradiation is adopted as a preferable sterilization method because the object to be processed can be processed in a packaged state and the sterilization effect is excellent.

However, it is known that hollow fiber membranes used in blood purifiers and adhesives used for fixing the hollow fiber membranes are deteriorated by radiation irradiation, and a method of sterilizing while preventing deterioration. Has been proposed. For example, a method for suppressing deterioration of the hollow fiber membrane by γ-ray irradiation by making the hollow fiber membrane in a wet state with a saturated moisture content or higher is disclosed. (See Patent Document 9). However, this method has the same problem as that of Patent Document 8.
Japanese Patent Publication No.55-23620

As a method of avoiding the above-mentioned wet state and suppressing deterioration due to radiation irradiation, a method of irradiating a hollow fiber membrane with a sterilizing protective agent such as glycerin or polyethylene glycol and irradiating with γ rays in a dry state is disclosed. (For example, refer to Patent Document 10). However, since this method contains a protective agent in the hollow fiber membrane, it is difficult to keep the water content of the hollow fiber membrane low, and the problem of deterioration of the protective agent due to γ-ray irradiation and the protective agent immediately before use are difficult. There was a problem that it took time and effort to clean and remove.
JP-A-8-168524

As a method for solving the above problems, in a dialyzer containing a semipermeable membrane, 100% or more of water is held with respect to the weight of the semipermeable membrane, and the inside of the dialyzer is made an inert gas atmosphere. A method of manufacturing a dialyzer that performs gamma irradiation is disclosed. (For example, refer to Patent Document 11). However, there is no mention of the characteristics that the hollow fiber membrane should have before irradiation with radiation and the influence on the priming property of the hollow fiber membrane due to the irradiation of radiation.
JP 2001-170167 A

Further, as a method for solving the above problems, a method of sterilizing by irradiating with radiation in a state where the moisture content of the hollow fiber membrane is 5% or less and the relative humidity near the hollow fiber membrane is 40% or less is disclosed. Yes. (For example, refer to Patent Document 12). In the method, the above-mentioned problems have been solved, and the ultraviolet absorbance at a wavelength of 220 to 350 nm measured in accordance with the dialysis membrane elution test of the dialysis artificial kidney device manufacturing approval standard satisfies the standard value of 0.1 or less. ing. However, in Patent Document 12, there is no mention of the influence of the oxygen concentration around the hollow fiber membrane at the time of sterilization, the change in the amount of eluate eluted over time after sterilization, and the like.
JP 2000-288085 A

Moreover, in the method of performing sterilization by γ-ray irradiation, a method is disclosed in which the insolubilized component of the membrane material is achieved to 10 wt% or less by performing γ-ray irradiation in a state where the moisture content of the hollow fiber membrane is 10 wt% or less. . (For example, refer to Patent Document 13). The patent document discloses that the amount of the hydrophilic polymer per 1 m ^{2 of the} liquid contact side area of the membrane extracted with a 40% ethanol aqueous solution can be 2.0 mg / m ² or less. However, in this patent document as well, the influence of oxygen concentration around the hollow fiber membrane when γ-irradiation is performed, the elution amount of the eluate after sterilization treatment over time or the effect on priming properties by sterilization treatment, etc. There is no mention about.
JP 2001-205057 A

Further, as a method for avoiding deterioration of the base material of the medical device due to oxygen, a method of sealing the medical device together with an oxygen scavenger with a packaging material made of an oxygen-impermeable material and performing radiation irradiation is known. Is also disclosed. (For example, refer to Patent Documents 14 to 16).
Japanese Patent Application Laid-Open No. 62-74364 JP-A-62-204754 WO98 / 58842 pamphlet

  As the deterioration in radiation irradiation using the oxygen scavenger described above, Patent Document 14 shows that odor is generated, Patent Document 15 shows that the strength of the base material and dialysis performance are reduced, and Patent Document 16 shows that the strength of the base material is reduced and aldehyde. Although the occurrence of sucrose has been described, there is no mention of the increase in the amount of extract described above. Moreover, although the oxygen concentration in the packaging bag at the time of radiation irradiation is described, nothing is mentioned about the importance of moisture in the hollow fiber membrane.

  Furthermore, as the material of the packaging bag used in the method of radiation sterilization in the above-mentioned system using an oxygen scavenger, the importance of gas, especially oxygen impermeability is described, but with respect to humidity permeability, Not mentioned.

Also disclosed is a method of radiation sterilizing a liquid processing device filled with a film protective agent in a wet or semi-wet shape in an inert gas atmosphere (see, for example, Patent Document 17). In this patent document, a method of using an oxygen scavenger as an achievement means for creating an inert gas atmosphere is disclosed. In addition, water is listed as a film protective agent. On the other hand, although the lower limit of the moisture content in the semi-wet state is not mentioned, the problem to be solved by the invention is that “glycerin, physiological saline or water oozes out and the inside wall of the liquid processor and the inside of the packaging bag There was a problem of adhering to the hand and adhering to the hand during the operation of the liquid treatment device, ”suggesting that the water content is higher than the saturated water content. Therefore, it can be considered that the technique has the same problem as that of Patent Document 9.
JP-A-8-280795

In order to maintain the sterilization effect for a long period of time, a method of sterilizing a dry-type hollow fiber membrane blood purifier by vacuum packaging and irradiating with γ rays has been disclosed (for example, see Patent Document 18). However, no consideration is given to the deterioration of the hollow fiber membrane during γ-ray irradiation or storage. In addition, no mention is made regarding the moisture content of the hollow fiber membrane.
JP 2001-149471 A

  Further, in the method of suppressing the elution of polyvinylpyrrolidone in the production of the polysulfone-based hollow fiber membrane used for blood purification treatment as described above, or the method of irradiating radiation such as γ rays for sterilization, the hollow fiber membrane at the time of the irradiation Some of the moisture content and irradiation atmosphere conditions are disclosed, but the properties of the hollow fiber membrane before irradiation with radiation and the effect on the priming property of the hollow fiber membrane by radiation irradiation are mentioned. Absent.

Further, a liquid separation membrane package and a storage method in which a liquid separation membrane used for various industrial water treatments or the like is packaged with a film having a specific composition in which air permeability is suppressed are disclosed (for example, patent documents). 19). The method relates to a package in a wet state in which a package is filled with deoxygenated water having a specific dissolved oxygen concentration, and a storage method.
JP 2004-195380 A

Moreover, in the drying of the hollow fiber membrane, a method of drying by irradiating microwaves is disclosed. However, in this patent document, the generation of hydrogen peroxide at the time of drying and the storage stability of the dried hollow fiber membrane are disclosed. Is not considered (for example, see Patent Documents 20 to 23).
JP 2003-175320 A JP 2003-175321 A JP 2003-175322 A JP 2004-305997 A

In order to improve the wettability of the hollow fiber membrane during priming in a dry type blood purifier, various studies have been made. In Patent Document 24, the ratio of the sieving coefficient of albumin immediately after priming with physiological saline or dialysate in a hemodialysis membrane made of a cellulose-based polymer and after standing for 24 hours is SCalb (24hr) / SCalb (0hr) ≧ 1. .2 is disclosed. In the technique disclosed in the patent document, there is a possibility that a blood purifier having stable performance and quality cannot be provided because the difference in performance between the priming process and the 24-hour performance is too large.
JP 2004-313359 A

Also disclosed is a porous polymer membrane made of a hydrophobic polymer and a hydrophilic polymer, which has the excellent mechanical strength of the hydrophobic polymer and has good wettability in the entire membrane. Yes. (See Patent Document 25). In the invention described in the patent document, the wettability of the film may be good because the periphery of the hydrophobic polymer skeleton is covered with a very thin hydrophilic polymer rich layer. As can be seen from the fact that it is high and the use of ventilation drying for drying, no consideration is given to degradation degradation of the hydrophilic polymer during long-term storage.
JP 2005-58906 A

Patent Document 26 discloses a blood purification process comprising a step of moistening a membrane with degassed water or an aqueous solution of a substance harmless to the human body, and a sterilization step of performing high-pressure steam sterilization while maintaining the wet state. A method for sterilizing a dialyzer is disclosed. The technique disclosed in the patent document is intended to simplify the priming operation itself, and does not include a technique related to the performance development or performance stabilization of the film after the priming process.
JP 7-148251 A

In Patent Document 27, in a blood purifier prepared using a polysulfone-based hollow fiber membrane containing polyvinyl pyrrolidone, elution of polyvinyl pyrrolidone from the hollow fiber membrane is 10 ppm or less, and the hollow fiber membrane is disposed in the longitudinal direction. A dry type that is divided into 10 parts and the hydrogen peroxide elution amount of the extract at each part is 5 ppm or less when the test defined by the dialysis-type artificial kidney device manufacturing approval standard is performed for each part. A hollow fiber membrane is disclosed. However, this patent document does not describe at all the water wettability of the hollow fiber membrane after the priming treatment and the performance manifestation related to the water wettability.
Japanese Patent No. 3636199

  The present invention has excellent permselectivity, high safety and stability of performance, particularly high water permeability used for the treatment of chronic renal failure, excellent water permeability after priming treatment, and long-term performance. The object is to provide a blood purifier with high storage stability.

The present invention relates to a blood purifier in which at least a blood contact surface is filled with a hollow fiber membrane made of an aggregate of polymer particles, the water permeability at 10 minutes after the priming treatment is the water permeability at 24 hours after the priming treatment. It is a blood purifier characterized by being 90% or more.
In this case, the average particle diameter of the polymer particles in a wet state is preferably 10 to 300 nm.
In this case, the ratio of the average particle diameter in the wet state to the average particle diameter in the dry state of the polymer particles is preferably 1.1 or more.
In this case, the hollow fiber membrane is preferably made of a polysulfone resin and polyvinyl pyrrolidone.
In this case, the water content of the hollow fiber membrane in the blood purifier is preferably 600% by mass or less.
In this case, the hollow fiber membrane in the blood purifier is adjusted to a moisture content of 5 to 600% by mass using degassed water, and then all the blood and dialysate entrances and exits of the blood purifier are sealed. It is preferable to irradiate with radiation by sealing with a packaging bag that blocks outside air and water vapor.
In this case, the deaerated water used for adjusting the moisture content of the hollow fiber membrane in the blood purifier is preferably deoxygenated water.
In this case, it is preferable that the deaerated water used for adjusting the moisture content of the hollow fiber membrane in the blood purifier is an inert gas saturated water.
In this case, the dissolved oxygen concentration of the deaerated water is preferably 0.5 ppm or less.
In this case, it is preferable that radiation is irradiated after at least 48 hours have passed since all the blood and dialysate entrances and exits of the blood purifier are sealed.
Further, in this case, after storing the blood purifier after irradiation for one year or more at room temperature, the hollow fiber membrane is taken out from the blood purifier, and the hollow fiber membrane is divided into 10 pieces in the longitudinal direction. It is preferable that the maximum value of UV (220 to 350 nm) absorbance in the extract of the hollow fiber membrane when the test defined by the dialysis-type artificial kidney device manufacturing approval standard is performed is 0.10 or less.

The hollow fiber membrane of the present invention has an optimized inner surface (blood contact side surface) structure and characteristics, and is excellent in selective permeability and blood compatibility.
Further, since the blood purifier of the present invention is a dry type, there are advantages such as being light, not freezing, and being difficult for germs to propagate. In addition, the blood purifier of the present invention is excellent in water permeability performance after the priming process, and has an advantage that the priming process can be performed in a short time. In addition, since the radical scavenger is not included, there is an advantage that when it is used for blood purification, an operation for washing and removing the radical scavenger in advance is unnecessary. Furthermore, in the present invention, an effect that cannot be achieved by the prior art is exhibited in that the deterioration of the hollow fiber membrane due to radiation irradiation is suppressed even when irradiated with radiation in the dry state and in the absence of a radical scavenger. Therefore, there is little production of hydrogen peroxide due to the deterioration reaction, and the blood purifier of the present invention has the advantage of excellent long-term storage stability. For example, the polysulfone-based hollow fiber membrane loaded in the blood purifier suppresses the generation of hydrogen peroxide even when irradiated with radiation, and the deterioration of polyvinylpyrrolidone and the like caused by the hydrogen peroxide is suppressed. Therefore, even if the blood purifier is stored for a long period of time, the maximum value of UV (220-350 nm) absorbance, which is the dialysis artificial kidney device manufacturing approval standard, can be maintained at 0.10 or less, and the blood purifier can be maintained for a long period of time. There is an advantage that safety when stored can be secured.

Hereinafter, the present invention will be described in detail.
The hollow fiber membrane used in the present invention is characterized in that it is composed of a polysulfone resin and polyvinylpyrrolidone. The polysulfone resin in the present invention is a general term for resins having a sulfone bond and is not particularly limited.
A polysulfone resin or a polyethersulfone resin having a repeating unit represented by is widely available as a polysulfone resin and is preferable because it is easily available.

  Polyvinyl pyrrolidone used in the present invention is a water-soluble polymer compound obtained by vinyl polymerization of N-vinyl pyrrolidone, “Kollidon” from BASF, “Prasdon” from ISP, and “Pittscall” from Daiichi Kogyo Seiyaku. Are commercially available under the trade name “,” and there are products of various molecular weights. In general, it is preferable to use a low molecular weight in terms of hydrophilicity imparting efficiency, while it is preferable to use a high molecular weight in terms of reducing the amount of elution, but depending on the required characteristics of the final hollow fiber membrane, Selected. Those having a single molecular weight may be used, or two or more products having different molecular weights may be mixed and used. Moreover, you may use what refine | purified a commercial product and sharpened molecular weight distribution, for example.

  In the present invention, it is preferable to produce a polysulfone-based hollow fiber membrane using polyvinylpyrrolidone having a hydrogen peroxide content of 300 ppm or less. By setting the hydrogen peroxide content in the polyvinylpyrrolidone used as a raw material to 300 ppm or less, the elution amount of hydrogen peroxide in the hollow fiber membrane after film formation can be easily suppressed to 5 ppm or less. This is preferable because the quality of the hollow fiber membrane can be stabilized. The hydrogen peroxide content in the polyvinylpyrrolidone used as a raw material is more preferably 250 ppm or less, further preferably 200 ppm or less, and further preferably 150 ppm or less.

  The hydrogen peroxide present in the polyvinyl pyrrolidone used as the raw material is considered to trigger the oxidative degradation of the polyvinyl pyrrolidone. As the oxidative degradation progresses, the hydrogen peroxide explosively increases. It is thought to promote oxidative degradation of pyrrolidone. Therefore, setting the hydrogen peroxide content to 300 ppm or less is the first means for suppressing the oxidative degradation of polyvinylpyrrolidone in the production process of the polysulfone-based hollow fiber membrane. It is also effective and recommended to take measures to suppress deterioration during transportation and storage of polyvinylpyrrolidone at the raw material stage. For example, it is preferable to use an aluminum foil laminated bag to shield the light and enclose with an inert gas such as nitrogen gas, or enclose and store an oxygen scavenger together. In addition, it is preferable that the measurement and preparation when the package is opened and subdivided be performed after inert gas replacement, and the above-mentioned measures are taken for the storage. In addition, in the manufacturing process of the hollow fiber membrane, it is also recommended as a preferred embodiment to take means such as replacing the inside of the supply tank in the raw material supply system with an inert gas. Moreover, it is not excluded to use polyvinylpyrrolidone in which the amount of hydrogen peroxide is reduced by a recrystallization method or an extraction method.

  The method for producing the hollow fiber membrane of the present invention is not limited at all, but, for example, a hollow fiber membrane type that can be produced by a method as disclosed in JP-A-2000-300663 is preferred. For example, 16 parts by mass of polyethersulfone (4800P, manufactured by Sumitomo Chemical Co., Ltd.) and 5 parts by mass of polyvinyl pyrrolidone (K-90, manufactured by BASF) disclosed in the patent document, 74 parts by mass of dimethylacetamide, 5 parts by mass of water Was dissolved and defoamed as a film-forming solution, and a 50% dimethylacetamide aqueous solution was used as a core solution, and this was simultaneously discharged from the outside and inside of the double-tube orifice, An example is a method in which a hollow fiber membrane is formed in a coagulation bath made of water at 75 ° C., and is washed after washing with water and dried at 60 ° C.

  The ratio of the polyvinyl pyrrolidone in the membrane to the polysulfone resin in the present invention may be within a range that can impart sufficient hydrophilicity to the hollow fiber membrane, and the polysulfone resin is 99 to 80% by mass and the polyvinyl pyrrolidone is 1 to 20% by mass. % Is preferable. When the ratio of polyvinyl pyrrolidone is too small relative to the polysulfone resin, the effect of imparting hydrophilicity to the film may be insufficient. Therefore, the ratio is more preferably 1.5% by mass or more, and 2.0% by mass or more. More preferably, 2.5 mass% or more is still more preferable. On the other hand, when the ratio is too large, the hydrophilicity-imparting effect is saturated, and the amount of polyvinylpyrrolidone and / or oxidatively deteriorated material eluted from the membrane increases, and the amount of polyvinylpyrrolidone eluted from the membrane described later exceeds 10 ppm. There is a case. Therefore, it is more preferably 18% by mass or less, further preferably 15% by mass or less, still more preferably 13% by mass or less, and particularly preferably 10% by mass or less.

  The membrane structure of the hollow fiber membrane has a sponge structure close to a uniform structure, and in recent years, a dense layer that performs substantially selective separation for the purpose of improving dialysis efficiency and a support layer that maintains membrane strength with a high porosity. There are some combinations.

  However, in any membrane, the factor that determines the permeation of the waste is mainly the sponge structure or the membrane structure of the dense layer, and is usually present in the portion in contact with the liquid to be treated. The state of the polymer that forms the membrane in the dry state can be controlled by the polymer concentration in the spinning dope, the solvent that promotes phase separation that forms the pore structure, the ratio of non-solvent, the temperature of the spinneret, etc. Some have a membrane structure such as a body and a network structure in which polymers are intertwined linearly. In the present invention, the polymer concentration in the spinning dope is set slightly higher than the spinnability limit so that the membrane forms a membrane structure like an aggregate of polymer particles. The polymer concentration in the spinning dope is preferably set to 17% by mass or more for polyethersulfone, for example.

  As for the relationship between the polymer particle size and the material permeation, the Kozenny-Carmann model is often used as a model for allowing water to permeate when gravel is deposited in the field of chemical engineering. According to this theoretical formula, the smaller the polymer particle diameter forming the film, the smaller the ability to remove low molecular weight proteins, and the larger the polymer particle diameter, the greater the amount of useful protein leakage. Therefore, by controlling the diameter of the polymer particles forming the membrane, the material permeation performance of the membrane itself can be controlled. Usually, the film surface structure in a dry state can be observed by observation with a differential scanning electron microscope.

  However, with a differential scanning electron microscope observed using an electron beam, it is impossible to observe the membrane structure in a wet state, and the relationship between the membrane structure and the substance permeability is determined by a model equation based on the water-soluble substance permeability characteristics. Even though it is possible to analogize the membrane structure, it is difficult to control the permeation performance starting from the membrane structure. Further, in a wet state as compared with a dry state, a phenomenon occurs in which the polymer particle diameter of the film swells due to water molecules entering the gaps between the polymer chains.

  The present inventors have made an evaluation by using an atomic force microscope that has been developed in recent years as a means for enabling measurement of polymer particle diameter in a wet state and has been widely developed as a measurement method and is expected in many fields. went. An atomic force microscope detects and amplifies the atomic force on the surface of a material and enables imaging. In the present invention, an atomic force microscope is used to observe the membrane structure in the dry state and the membrane structure in the wet state, and the obtained membrane structure information, the membrane structure change and material permeation characteristics during the wet state, and the spinning film formation By comparing the conditions, it was used to improve the structure and characteristics required for blood purification membranes.

  The polymer particle diameter in the wet state is preferably 10 to 300 nm as an average diameter. One of the characteristics of the present invention is that it has a particle structure, but each particle of the particle structure is considered to be composed of polymer particles in a polymer alloy state in which a polysulfone resin and polyvinylpyrrolidone are mixed and apparently compatible. Therefore, it is presumed that polyvinyl pyrrolidone is concentrated to a substantially uniform concentration on the surface of the aggregated particles formed by the aggregation of the single particles. Therefore, compared with the network structure which is another typical structure in the hollow fiber membrane, it is presumed that the hydrophilicity of the surface of the hollow fiber membrane on the blood contact side is high and the blood compatibility can be improved. On the other hand, if the average diameter is smaller than 10 nm, a dense membrane structure may be obtained and the desired separation characteristics may not be obtained. Therefore, the average diameter of the polymer particles in the wet state is more preferably 50 nm or more, further preferably 100 nm or more, and further preferably 150 nm or more. On the contrary, if the average diameter is larger than 300 nm, the unevenness of the inner surface becomes large, and turbulence or stagnation may occur in the blood flow, which may induce blood coagulation activation. Therefore, the average diameter of the polymer particles in a wet state is more preferably 280 nm or less, further preferably 260 nm or less, and further preferably 240 nm or less.

  The average polymer particle diameter in the wet state is preferably larger than the average polymer particle diameter in the dry state. This enables efficient fractionation when the flow path inside the membrane hole is filled with liquid as a medium. Therefore, the ratio of the average particle diameter in the wet state to the average particle diameter in the dry state of the polymer particles is preferably 1.1 times or more. By providing the properties, the balance of the selectivity of the protein, that is, unnecessary substances such as low molecular weight protein represented by β2-MG are efficiently removed, while useful proteins represented by albumin are removed as much as possible. Not to improve the characteristics. Improving the balance of protein selectivity by increasing the protein permeability at the start of treatment and reducing the albumin permeability by increasing the swelling of polymer particles as blood passes through the dialysis process. We can expect effect to let. That is, the protein selectivity improving effect utilizing the wet swellability of the polymer particles can be imparted. Accordingly, (wet polymer particle average diameter) / (dry polymer particle average diameter) is preferably 1.2 times or more, more preferably 1.3 times or more, and even more preferably 1.4 times or more.

  By having the above characteristics, high selective permeability and blood compatibility can be obtained.

The above polymer particle characteristics were evaluated by the following methods.
(1) Sample preparation The dried membrane used was dried for 24 hours or more by critical point drying. This was cut in the direction of the fiber axis on the sample stage, and used as a sample in such a manner that the inner surface of the hollow fiber membrane was exposed. As the wet membrane, water was passed through the inside and outside of the hollow fiber membrane, and this was immersed in water for at least 24 hours. This was cut in the fiber axis direction on a sample stage provided in water, and a sample was formed in such a way that the inner surface of the hollow fiber membrane was exposed.
(2) Measurement method The morphology of the inner surface of the hollow fiber membrane was observed with an atomic force microscope (AFM). AFM used was SPI3800N-SPA300 manufactured by Seiko Instruments. Wet observation was performed in pure water using an in-liquid observation kit, which is an option of this apparatus. A petri dish was used as the cell in which the sample was immersed during the observation. The observation mode was the DFM mode. The cantilever was a Si rectangular cantilever having a length of 450 μm, a width of 60 μm, and a thickness of 4 μm. The cantilever is commercially available as Si-DF3 from Seiko Instruments and has a spring constant of about 2 N / m. The cantilevers used were always new and had no contamination at the tip of the probe. The scanning speed of the probe was 0.25 to 1 Hz.
(3) Particle size measurement method It calculated using the analyzer attached to the said measuring apparatus. In order to measure the particle size by flattening the three-dimensional waviness of the sample, the AFM image after the measurement is subjected to three-dimensional tilt correction (TILT3) or the like. In some cases, flat processing or the like is also necessary. The particle size is determined by the line analysis process included in the software included with the device. The particles to be measured were randomly selected 120 particles, and particles that looked abnormally large and particles that looked abnormally small were excluded from the measurement. A specific measurement method will be described with reference to the drawings. FIG. 1 is a top view of particles whose particle size is determined by line analysis. FIG. 2 is a cross-sectional profile of the particles of FIG. Let the coordinates of each measurement point be (x, y, z). z is the height at the measurement point. The particle diameter is the distance between points AC, but AC must be a line segment through the vertex B of the particle. Also, the particles are not always perfect circles. It is assumed that the points A and C take the longest line segment among the line segments passing through the vertex B. The distance between ACs, that is, the particle diameter is expressed by the following formula.
D = ((x ₁ −x ₂ ) ² + (y ₁ −y ₂ ) ² ) ^1/2

  The same handling can be performed with a commercially available apparatus such as Nanoscope manufactured by Digital Instruments.

  As a result of intensive studies on the above results, it was found that the membrane structure in a wet state can be controlled by setting the polymer concentration, nozzle temperature, hollow forming agent composition, and drying conditions when forming a hollow fiber membrane. Specifically, the polymer concentration is preferably 16 to 23% by mass, and the nozzle temperature is preferably 30 to 80 ° C. In addition, if the polymer concentration is too low or the nozzle temperature is too high, the hollow forming agent concentration tends to form a network structure. Conversely, if the polymer concentration is too high or the nozzle temperature is too low, the spinnability is lowered. Membrane productivity may be reduced. When the hollow fiber membrane was dried, the control of the polymer particle diameter in a wet state was achieved by ventilating a gas having a humidity of 20 to 100% RH, and film formation suited to the purpose became possible. Therefore, the present inventors have found a method capable of controlling the polymer particle diameter in a wet state even when the dry state is the same, when they are immersed in an appropriate liquid. When the humidity is increased, the ratio of the particle size between the wet state and the dry state can be increased, and the permeation performance can be adjusted according to the purpose. Here, the ratio of the particle diameter between the wet state and the dry state (hereinafter referred to as the swelling ratio) was expressed as (average particle diameter in the wet state) / (average particle diameter in the dry state).

  Further, it is considered that the polyvinyl pyrrolidone on the outermost surface layer on the blood contact side having the above structure mainly contributes to the blood compatibility and performance stability. In the blood purification membrane of the present invention, the content of polyvinylpyrrolidone in the outermost surface layer on the blood contact side is preferably 5 to 50% by mass, more preferably 10 to 40% by mass, and further preferably 15 to 40% by mass. Even if the hydrophilic polymer content is lower or higher than this, excessive adsorption of blood components may be caused. If the polyvinyl pyrrolidone content is higher than this, a large amount of polyvinyl pyrrolidone may be eluted by contact with blood, which may be a problem from the viewpoint of safety.

  In the present invention, it is preferable that elution of polyvinylpyrrolidone from the hollow fiber membrane is 10 ppm or less and elution of hydrogen peroxide is 5 ppm or less.

  When the elution amount of polyvinylpyrrolidone exceeds 10 ppm, side effects and complications during long-term dialysis may occur due to the eluted polyvinylpyrrolidone. A method for satisfying the characteristics is optional without limitation. For example, it can be achieved by setting the ratio of polyvinyl pyrrolidone to the polysulfone-based resin within the above range or optimizing the film forming conditions of the hollow fiber membrane. More preferably, the elution amount of polyvinylpyrrolidone is 8 ppm or less, more preferably 6 ppm or less, and still more preferably 4 ppm or less. The elution amount of the polyvinyl pyrrolidone is determined by quantification using an extract extracted by a method according to the elution test method of the dialysis-type artificial kidney device manufacturing approval standard. That is, the hollow fiber membrane is arbitrarily taken out from the dry hollow fiber membrane, and 1.0 g is weighed. The extract obtained by adding 100 ml of RO water to this and performing extraction at 70 ° C. for 1 hour is quantified.

  The method for reducing the elution amount of the polyvinyl pyrrolidone is optional without limitation, and can be achieved, for example, by optimizing the ratio of polyvinyl pyrrolidone to the polysulfone resin in the hollow fiber membrane and the film forming conditions of the hollow fiber membrane. In particular, optimization of the cleaning method is important.

  In the present invention, the elution amount of hydrogen peroxide from the polysulfone-based hollow fiber membrane is preferably 5 ppm or less. 4 ppm or less is more preferable, and 3 ppm or less is more preferable. When the elution amount of the hydrogen peroxide exceeds 5 ppm, as described above, the storage stability deteriorates due to the oxidative degradation of the polyvinyl pyrrolidone by the hydrogen peroxide. For example, the elution of the polyvinyl pyrrolidone when stored for a long period of time. The amount may increase. In terms of storage stability, the increase in the amount of polyvinylpyrrolidone eluted is the most prominent phenomenon. In addition, deterioration of the polysulfone-based polymer causes the hollow fiber membrane to become brittle, or polyurethane-based adhesive used for module assembly. This may accelerate the deterioration of the agent and increase the elution amount of deteriorated products such as urethane oligomers, possibly leading to a decrease in safety. The increase in the amount of eluate caused by deterioration caused by the oxidizing action of hydrogen peroxide during long-term storage can be evaluated by measuring UV (220-350 nm) absorbance set by the dialysis-type artificial kidney device manufacturing approval standard.

  The elution amount of hydrogen peroxide was also quantified using an extract extracted by a method according to the dissolution test method of the dialysis artificial kidney device manufacturing approval standard.

  In the present invention, it is a preferred embodiment that the amount of elution of hydrogen peroxide when measured for each of the hollow fiber membranes in the longitudinal direction of the hollow fiber membrane is 5 ppm or less at all sites. As described above, even when hydrogen peroxide is present in a specific part of the hollow fiber membrane, the degradation reaction of the hollow fiber membrane material starts from that point and propagates throughout the hollow fiber membrane. It is necessary to ensure that the amount of the hollow fiber membrane used in the length direction is constant or less over the entire region. That is, the oxidative degradation of polyvinyl pyrrolidone initiated by hydrogen peroxide at a specific site spreads throughout the hollow fiber membrane, and the amount of hydrogen peroxide further increases due to the degradation. The degraded polyvinyl pyrrolidone has a molecular weight. Since it falls, it becomes easy to elute from a hollow fiber membrane. This deterioration reaction proceeds in a chain. Accordingly, when the hollow fiber membrane is stored for a long period of time, the elution amount of hydrogen peroxide and polyvinylpyrrolidone increases, which may lead to a decrease in safety when used for a blood purifier.

  As a method for controlling the elution amount of hydrogen peroxide within the above regulated range, for example, it is effective to make the amount of hydrogen peroxide in polyvinylpyrrolidone used as a raw material 300 ppm or less. Since hydrogen is also generated during the manufacturing process of the hollow fiber membrane, it is necessary to strictly control the manufacturing conditions of the hollow fiber membrane. In particular, optimization of drying conditions is important because the production of the spinning solution during the production of the hollow fiber membrane greatly contributes to the production. In particular, the optimization of the drying conditions is an effective means for reducing the fluctuation in the elution amount in the longitudinal direction of the hollow fiber membrane.

  Regarding the dissolving step of the spinning solution, for example, when stirring and dissolving a spinning solution comprising a polysulfone resin, polyvinyl pyrrolidone, and a solvent, if hydrogen peroxide is contained in the polyvinyl pyrrolidone, oxygen present in the dissolving tank is present. It has been found that hydrogen peroxide increases explosively due to the effects of heat and heating during dissolution. Therefore, when charging the raw material into the dissolution tank, it is preferable to input the raw material into the dissolution tank that has been previously replaced with an inert gas. As the inert gas, nitrogen, argon or the like is preferably used. Moreover, although a solvent, and a non-solvent may be added depending on the case, it is also a preferable embodiment that oxygen dissolved in these solvent and non-solvent is replaced with an inert gas.

  In addition, as another method for suppressing the generation of hydrogen peroxide, it is an important requirement to dissolve the film forming solution in a short time. For this purpose, it is usually sufficient to increase the dissolution temperature and / or increase the stirring speed. However, when it does so, degradation and decomposition of polyvinyl pyrrolidone will proceed due to the influence of temperature, stirring linear velocity and shearing force. In fact, according to the study by the inventors, the molecular weight of polyvinylpyrrolidone in the film-forming solution moves in the direction of decomposition (shifts to the low molecular side) as the dissolution temperature increases, or the low molecular side. The appearance of a shoulder that appears to be a decomposition product was observed. From the above, increasing the temperature for the purpose of improving the dissolution rate of the raw material accelerates the degradation and decomposition of polyvinylpyrrolidone, and eventually blends the degradation product of polyvinylpyrrolidone into the hollow fiber membrane. When the obtained hollow fiber membrane is used for blood purification, the degradation product is eluted in the blood, and it has not been excellent in terms of product quality safety. Then, it tried to mix a raw material at low temperature in order to suppress decomposition | disassembly of polyvinylpyrrolidone. Even if it is low-temperature dissolution, it is usually preferable to have a temperature of 5 ° C. or higher and 70 ° C. or lower because it requires a running cost under extreme conditions that are below freezing. 60 degrees C or less is more preferable. However, simply lowering the melting temperature causes degradation of polyvinylpyrrolidone due to the longer melting time, lowering the operability and increasing the size of the equipment, which causes problems in industrial implementation. In particular, when polyvinyl pyrrolidone is dissolved at a low temperature, the polyvinyl pyrrolidone becomes a powdered powder, which makes it difficult to dissolve further, or has a problem that it takes a long time for uniform dissolution.

  As a result of examining the dissolution conditions for dissolving at low temperature without taking time, it was found that it is preferable to knead the components constituting the spinning solution prior to dissolution, and the present invention was reached. In the kneading, components such as polysulfone polymer, polyvinyl pyrrolidone and a solvent may be kneaded together, or polyvinyl pyrrolidone and polysulfone resin may be kneaded separately. As mentioned above, polyvinylpyrrolidone is accelerated by contact with oxygen and leads to the generation of hydrogen peroxide. Therefore, consideration must be given to suppressing contact with oxygen, such as in an atmosphere substituted with an inert gas, even during kneading. It is preferable to carry out in a separate line. A method of supplying only the polyvinyl pyrrolidone and the solvent and supplying the polysulfone resin directly to the dissolution tank without pre-kneading is also included in the scope of the present invention.

  The kneading may be performed by providing a kneading line separately from the dissolving tank, and the kneaded product may be supplied to the dissolving tank, or both the kneading and dissolving may be performed in a dissolving tank having a kneading function. The type and form of the kneading apparatus in the former separate apparatus are not limited. Either a batch system or a continuous system may be used. A static method such as a static mixer may be used, or a dynamic method such as a kneader or a stirring kneader may be used. The latter is preferred from the efficiency of kneading. The kneading method in the latter case is not limited, and any type such as a pin type, a screw type, and a stirrer type may be used. Screw type is preferred. What is necessary is just to select suitably the shape and rotation speed of a screw from the balance of kneading | mixing efficiency and heat_generation | fever. On the other hand, the type of dissolution tank when using a dissolution tank having a kneading function is not limited. For example, there is a kneading and dissolving machine of a type that expresses a kneading effect by so-called planetary motion in which two frame-type blades rotate and revolve. Recommended. For example, a planetary mixer or a trimix manufactured by Inoue Seisakusho Co., Ltd. corresponds to this method.

  The ratio of the resin component such as polyvinyl pyrrolidone or polysulfone resin and the solvent during kneading is not limited. A resin / solvent mass ratio of 0.1 to 3 is preferred. 0.5-2 are more preferable.

  As described above, the technical point of the present invention is to suppress the degradation of polyvinyl pyrrolidone and perform efficient dissolution. Therefore, a system in which at least polyvinylpyrrolidone is present is a preferred embodiment in which the system is kneaded and dissolved at a low temperature of 70 ° C. or lower in a nitrogen atmosphere. When the polyvinyl pyrrolidone and the polysulfone resin are kneaded in separate lines, this requirement may be applied to the polysulfone resin kneading line. The efficiency of kneading and dissolution and heat generation are two contradictory phenomena. Selection of an apparatus and conditions that avoid the trade-off as much as possible is an important element of the present invention. In this sense, the cooling method in the kneading mechanism is important and needs attention.

Subsequently, the material kneaded by the above method is dissolved. Although the dissolution method is not limited, for example, a dissolution method using a stirring type dissolution apparatus can be applied. In order to dissolve at a low temperature for a short time (within 3 hours), the Froude number (Fr = n ² d / g) is 0.7 to 1.3 and the stirring Reynolds number (Re = nd ² ρ / μ) is It is preferable that they are 50 or more and 250 or less. Where n is the blade rotation speed (rps), ρ is the density (Kg / m ³ ), μ is the viscosity (Pa · s), g is the gravitational acceleration (= 9.8 m / s ² ), and d is the stirring blade diameter. (M). If the Froude number is too large, the inertial force becomes strong, so that the raw material scattered in the tank adheres to the walls and ceiling, and the desired film-forming solution composition may not be obtained. Therefore, the fluid number is more preferably 1.25 or less, further preferably 1.2 or less, and further preferably 1.15 or less. On the other hand, if the fluid number is too small, the inertial force is weakened, so that the dispersibility of the raw material is lowered, and in particular, polyvinylpyrrolidone becomes a spatter, which makes it difficult to dissolve further or requires a long time for uniform dissolution. Sometimes. Therefore, the fluid number is more preferably 0.75 or more, and further preferably 0.8 or more.

  Since the film-forming solution in the present invention is a so-called low-viscosity fluid, if the stirring Reynolds number is too large, the defoaming time may be prolonged due to entrapment of bubbles in the film-forming solution during stirring, or insufficient defoaming may occur. Problems can arise. Therefore, the stirring Reynolds number is more preferably 240 or less, further preferably 230 or less, and still more preferably 220 or less. On the other hand, when the stirring Reynolds number is too small, the stirring force becomes small, so that dissolution may be easily made nonuniform. Therefore, the stirring Reynolds number is more preferably 35 or more, further preferably 40 or more, still more preferably 55 or more, and particularly preferably 60 or more. Furthermore, when a hollow fiber membrane is formed with such a spinning solution, the operability is deteriorated due to a decrease in spinnability due to bubbles, and in terms of quality, the portion becomes defective due to the entrapment of bubbles in the hollow fiber membrane, and the airtightness of the membrane is reduced. It has been found that this causes problems such as decreased sex and burst pressure. Defoaming of the spinning solution is an effective countermeasure, but it may involve a change in the composition of the spinning solution due to viscosity control of the spinning solution or evaporation of the solvent.

Furthermore, since polyvinylpyrrolidone tends to undergo oxidative degradation due to the influence of oxygen in the air, it is preferable to dissolve the spinning solution in an inert gas enclosure. Nitrogen, argon, etc. are raised as the inert gas, but nitrogen is preferably used. At this time, the residual oxygen concentration in the dissolution tank is preferably 3% or less. If the nitrogen filling pressure is increased, the melting time can be shortened. However, in order to increase the pressure, the equipment cost is increased, and from the viewpoint of work safety, atmospheric pressure and 2 kgf / cm ² or less are preferable.

  In addition, as the shape of the stirring blade used for dissolving the low-viscosity film forming solution used in the present invention, a radial turbine blade such as a disk turbine type, a paddle type, a curved blade fan turbine type, an arrow blade turbine type, or a propeller type An axial-flow type wing such as an inclined paddle type or a fiddler type is included, but is not limited thereto.

  By using the low-temperature dissolution method as described above, it is possible to obtain a highly safe hollow fiber membrane in which the degradation degradation of polyvinylpyrrolidone is suppressed. In addition, it is preferable to use a spinning solution having a residence time of 24 hours or less after dissolution of the raw material for film formation. This is because thermal energy was accumulated while the film forming solution was kept warm, and a tendency to cause deterioration of the raw material was recognized.

  As a method of controlling the elution amount of hydrogen peroxide within the above regulated range, it is important to suppress the deterioration of the hollow fiber membrane component, particularly polyvinyl pyrrolidone, even in the drying step. It is important to achieve uniform drying in the length direction of the hollow fiber membrane. When the hollow fiber membrane is dried by ventilating air from a certain direction, the drying proceeds sequentially from the air inlet portion of the hollow fiber membrane toward the outlet portion. The drying ends with a delay. That is, the difference in drying speed causes a difference in the mobility of polyvinyl pyrrolidone to the membrane surface of the hollow fiber membrane, the surface concentration of polyvinyl pyrrolidone changes, and the generation of hydrogen peroxide by the oxidative degradation of the polyvinyl pyrrolidone that has migrated to the surface Is estimated to be improved. In addition, it is presumed that a factor that changes the amount of hydrogen peroxide produced due to the difference in the degree of degradation of polyvinylpyrrolidone generated by non-uniform drying in the hollow fiber membrane is also considered. Therefore, the present inventors aim to make the drying speed of the hollow fiber membrane uniform and to dry it uniformly, and the direction of the air during drying is set to 180 at regular intervals (for example, every hour or every 30 minutes). As a result of studying the drying treatment of the hollow fiber membrane bundle while reversing the degree, the hollow fiber membrane bundle of the present invention could be obtained. In addition, in order to suppress the contribution of deterioration, the temperature in the dryer and the temperature of the drying air are reduced as much as possible to reduce the oxidation reaction rate due to heat during drying, and the atmosphere during drying is reduced to nitrogen gas or other such conditions. It is more preferable to use an active gas.

  In the present invention, as described above, in order to control the polymer particle diameter in a wet state, it is preferable to ventilate a gas whose humidity is adjusted to 20 to 100% RH. Therefore, it is preferable to use the air conditioned in this range. Of course, the humidity should be lower than the drying rate. Therefore, 20 to 80% RH is more preferable, and 20 to 60% RH is more preferable. The humidity control suppresses the deterioration of polyvinyl pyrrolidone and leads to a synergistic effect that hydrogen peroxide is reduced.

  The air volume and wind speed in the dryer may be adjusted according to the amount of hollow fiber membranes and the total amount of water, but the air volume is usually about 0.01 to 5 L / sec (per hollow fiber membrane bundle). . It is preferable to use an inert gas as the ventilation medium. The drying temperature may be 20 to 80 ° C. However, if the temperature is increased, damage to the hollow fiber membrane is increased, and drying tends to become partially unbalanced. Is preferable. For example, in a state where the moisture content is high, such as a moisture content of 200 to 1000% by mass, drying is possible at a relatively high temperature of 60 to 80 ° C., but the drying proceeds, for example, the moisture content is about 1 to 50% by mass. As the temperature decreases, the drying is preferably performed at a relatively low temperature ranging from room temperature to a maximum of about 60 ° C. Ideally, the moisture content of the center portion and the outer peripheral portion of the hollow fiber membrane bundle, as well as the center portion and the outer peripheral portion of the hollow fiber membrane bundle in which the drying is performed, is ideally unchanged. Actually, there is a slight difference in the moisture content of the center portion and the outer peripheral portion of the hollow fiber membrane and the hollow fiber membrane bundle. Therefore, the “moisture content” of the hollow fiber membrane bundle here refers to the water content at several points such as the center, middle, and outer periphery of the hollow fiber membrane bundle, based on the calculation. It is the average moisture content which calculated | required the average value of the moisture content. Of course, when not so much accuracy is expected, the total amount of water in the hollow fiber membrane bundle can be used as a basis for calculation, but there is an adverse effect that the accuracy is lowered. And since it is a preferable embodiment for producing a good quality product that the difference in moisture content of the hollow fiber membrane bundle such as the central part, the intermediate part and the outer peripheral part is small, it is technical to the drying method for producing it. It is necessary to give special consideration. For example, when an inert gas such as nitrogen gas or argon gas is used as the ventilation medium, since the drying is performed in a substantially oxygen-free state, the degradation and decomposition of the hydrophilic polymer hardly occur, and the drying temperature is increased. It is possible.

  The air volume and the drying temperature are determined by the total amount of water contained in the hollow fiber membrane. When the moisture content is high, the air volume is set to a relatively high value of, for example, 0.1 to 5 L / sec (per hollow fiber membrane bundle), and the temperature is set to a relatively high value of 50 to 80 ° C. When drying progresses and the moisture content of the hollow fiber membrane decreases, the air volume is gradually adjusted to, for example, 0.1 L / sec (one hollow fiber membrane bundle) or less. One of the ideas of drying is to adopt a drying method that interlocks and gradually approaches room temperature. The small difference in the moisture content of the hollow fiber membrane bundle such as the central part, the intermediate part, and the outer peripheral part means that the drying of each part proceeds simultaneously and uniformly. For this reason, when the hollow fiber membrane bundle is air-dried, the air blowing direction is alternately reversed. This means that the air blowing direction with respect to the hollow fiber membrane bundle in the air dryer is alternately changed from the direction changed by 180 degrees. It is. Of course, the device may be devised so that the reversal of the blowing direction causes the hollow fiber membrane bundle itself to alternately rotate 180 degrees with respect to the ventilation direction. Further, there is a method in which a hollow fiber membrane bundle for drying is fixed and the blower is devised to blow air from the direction in which the ventilation direction is alternately changed by about 180 degrees, but the blower means is not particularly limited. In particular, in the case of a circulation type air dryer, an apparatus that alternately inverts the hollow fiber membrane bundle itself by 180 degrees functions not only in design but also in operation. The drying method of the present invention including inversion, which is common at first glance, is suitable for drying general-purpose materials in quality control in which local degradation of polyvinylpyrrolidone is suppressed, particularly in special materials such as hollow fiber membrane bundles. It was an unseen and unexpected result.

The alternate inversion time of ventilation in the drying is of a character that varies depending on factors such as the total moisture content of the hollow fiber membrane bundle for drying and the wind speed, air volume, drying temperature, degree of dehumidification of the air, etc. It is preferable to frequently reverse the blowing direction. The wind direction reversal time that is practically set industrially affects the moisture content after the start of drying, for example, at a high temperature of about 60 to 80 ° C., for example, at 65 ° C. for 1 to 4 hours, at 25 to 60 ° C., for example, When a total drying time of 24 hours is set at about 30 ° C. for 1 to 20 hours, the wind direction can be mechanically reversed at intervals of about 30 to 60 minutes. In the initial drying stage in which the moisture content of the hollow fiber membrane is high, the membrane is dried at a high temperature of, for example, about 60 to 80 ° C. under conditions of relatively large airflow of about 0.1 to 5 L / sec (one hollow fiber membrane bundle). In this case, since the portion that is directly exposed to the wind is relatively quickly dried, the reversal of the wind direction is repeated for about 1 to 5 hours at intervals of about 10 to 120 minutes. In particular, in the first stage, it is preferable to reverse the wind direction at intervals of 10 to 40 minutes. When the difference in moisture content at the center and outer periphery of the hollow fiber membrane bundle decreases and stabilizes, the drying temperature gradually approaches the room temperature of about 30 ° C., and the inversion time is reversed at intervals of about 30 to 90 minutes. Repeat the reversal of the wind direction for a relatively long 1 to 24 hours. The switching of the air volume and temperature at that time can be arbitrarily determined in consideration of the moisture content of the hollow fiber membrane. If it shows quantitatively, if the moisture content of the center part and outer peripheral part of a hollow fiber membrane bundle will be about 50-100 mass% or less, it can change suitably, observing the condition of drying. Since it is drying, it can be performed by mechanically setting the wind direction inversion time at fixed time intervals. On the other hand, there are factors that rely on situational judgment and empirical rules, such as deciding the wind direction inversion time and total drying time while observing the degree of progress of drying. In addition, the moisture content as used in the field of this invention measures the mass (g) of a hollow fiber membrane, and after that, vacuum-drying is performed for 12 hours under reduced pressure (-750 mmHg or less), and the mass (g) after drying is measured. . The difference between before and after drying is determined as a weight loss (g) in% based on the mass (g) after drying. The water content is determined by the following formula.
(Weight loss / mass after drying) × 100 = moisture content (mass%)

  Moreover, it is one of the effective means to dry by irradiating a microwave. Therefore, you may perform combining the said ventilation drying method and microwave irradiation drying method. For example, it is a preferable embodiment that the moisture content is 20 to 60% by mass by an efficient microwave irradiation drying method and the final finishing is performed by the above-described ventilation drying method. The microwave irradiation drying method is preferably performed under reduced pressure.

  As a method for controlling the elution amount of hydrogen peroxide within the above regulated range, it is also important to reduce contact with oxygen even in the drying step. For example, drying in an atmosphere substituted with an inert gas can be mentioned, but it is disadvantageous in terms of economy. As an economical drying method, a method of drying by irradiating microwaves under reduced pressure is effective and recommended. In performing so-called drying by removing a liquid from an object to be dried, it is well known that each of them is irradiated with reduced pressure and microwave. However, performing decompression and irradiating microwaves at the same time is a combination that is generally difficult to use in combination with microwave characteristics. The inventors of the present application adopt a combination with this difficulty in order to achieve improvement in safety and productivity by preventing oxidative degradation of polyvinylpyrrolidone and reducing the amount of eluate from the hollow fiber membrane, and drying conditions. It was found that the problem can be solved by a method that is economically advantageous by optimizing the above.

  As a drying condition of the drying method, it is preferable to irradiate microwaves with an output of 0.1 to 100 kW under a reduced pressure of 20 kPa or less. Moreover, it is a preferable embodiment that the frequency of the microwave is 1,000 to 5,000 MHz, and the highest temperature reached by the hollow fiber membrane during the drying process is 90 ° C. or less. If a means of decompression is also provided, drying of moisture will be promoted by itself, so there is an advantage that the microwave irradiation output can be reduced and the irradiation time can be shortened, but the temperature rise can also be made relatively low. Overall, there is little influence on the performance degradation of the hollow fiber membrane. Furthermore, drying accompanied by means of reduced pressure has the advantage that the drying temperature can be relatively lowered, and has a significant point that deterioration and decomposition of the hydrophilic polymer can be remarkably suppressed. An appropriate drying temperature is sufficient from 20 to 80 ° C. More preferably, it is 20-60 degreeC, More preferably, it is 20-50 degreeC, More preferably, it is 30-45 degreeC.

  The fact that the pressure is reduced means that the low pressure acts uniformly on the center portion and the outer peripheral portion of the hollow fiber membrane bundle, the moisture evaporation is promoted uniformly, and the hollow fiber membrane is uniformly dried. Therefore, the failure of the hollow fiber membrane bundle due to non-uniform drying is corrected. In addition, heating by microwaves also acts almost equally on the entire center and outer periphery of the hollow fiber membrane bundle, so it functions synergistically in uniform heating, and is unique in drying the hollow fiber membrane bundle. It will be of significance. The degree of vacuum may be set as appropriate depending on the output of the microwave, the moisture content of the hollow fiber membranes, and the number of hollow fiber membranes. In order to prevent the temperature of the hollow fiber membranes during drying, the degree of vacuum is more preferably 20 kPa or less. Is carried out at 15 kPa or less, more preferably 10 kPa or less. If it is 20 kPa or more, not only the water evaporation efficiency is lowered, but also the temperature of the polymer constituting the hollow fiber membrane may be increased and deteriorated. Moreover, although the one where a pressure reduction degree is higher is preferable in the meaning which raises temperature rise suppression and drying efficiency, since the cost concerning maintaining the sealing degree of an apparatus becomes high, 0.1 kPa or more is preferable. More preferably, it is 0.25 kPa or more, and further preferably 0.4 kPa or more.

In consideration of shortening the drying time, a higher microwave output is preferable.For example, in hollow fiber membrane bundles containing polyvinylpyrrolidone, degradation or decomposition of polyvinylpyrrolidone occurs due to overdrying or overheating, or wettability during use. It is preferable not to increase the output much because there is a problem such as a decrease. Further, the hollow fiber membrane bundle can be dried even with an output of less than 0.1 kW, but there is a possibility that a problem of reduction in throughput due to an increase in drying time may occur. The optimum value of the combination of the degree of decompression and the microwave output varies depending on the water content of the hollow fiber membrane bundle and the number of processed hollow fiber membrane bundles, and it is preferable to obtain a set value as appropriate through trial and error.
For example, as a temporary guide for carrying out the drying conditions of the present invention, when 20 hollow fiber membrane bundles having a moisture content of 50 g per hollow fiber membrane bundle are dried, the total moisture content is 50 g × 20 fibers = 1,000 g. At this time, it is appropriate that the microwave output is 1.5 kW and the decompression degree is 5 kPa.

  A more preferable microwave output is 0.1 to 80 kW, and a more preferable microwave output is 0.1 to 60 kW. The output of the microwave is determined by, for example, the total number of hollow fiber membrane bundles and the total amount of moisture. However, when the microwave is suddenly irradiated, drying is completed in a short time, but the hollow fiber membrane is partially denatured. May cause deformation such as curling. When drying using microwaves, for example, when using something like a water retention agent in the hollow fiber membrane, high power and extreme drying using microwaves will disappear due to scattering of the water retention agent It becomes the cause of. In particular, when accompanied by conditions of reduced pressure, considering the influence on the hollow fiber membrane, conventionally, it was not intended to irradiate microwaves under reduced pressure. Irradiation of microwaves under reduced pressure of the present invention means that the evaporation of aqueous liquid becomes active in a relatively low temperature state, so that degradation of polyvinylpyrrolidone due to high output microwave and high temperature, deformation of hollow fiber membrane, etc. This has a double effect of preventing damage to the hollow fiber membrane.

  Although the present invention enables one-stage drying in which the microwave output is constant, i.e., drying by microwaves under reduced pressure, as another embodiment, the microwave output is sequentially changed according to the progress of drying. So-called multi-stage drying, which lowers in stages, is included as a preferred embodiment. Therefore, the significance of multi-stage drying will be described as follows. When drying with microwaves at a relatively low temperature of about 30 to 90 ° C. under reduced pressure, multi-stage drying in which the output of the microwaves is sequentially reduced in accordance with the progress of drying of the hollow fiber membrane bundle. The method is excellent. The degree of pressure reduction, temperature, microwave output, and irradiation time may be determined in consideration of the total amount of hollow fiber membranes to be dried, appropriate industrially acceptable drying time, and the like. Multistage drying can be performed in any number of stages, for example, 2 to 6 stages, but it is appropriate to use 2 to 3 stages of drying that is industrially appropriate in consideration of productivity. Depending on the total amount of water contained in the hollow fiber membrane bundle, when relatively large, multistage drying is performed at a temperature of 90 ° C. or lower, for example, at a reduced pressure of about 5 to 20 kPa, and the first stage is 30 to 100 kW. The range can be determined in consideration of the microwave irradiation time such that the second stage is in the range of 10 to 30 kW and the third stage is in the range of 0.1 to 10 kW. When the output of the microwave is large, such as 90 kW in the high part and 0.1 kW in the low part, the number of stages for reducing the output may be increased to 4 to 8 stages, for example. In the case of the present invention, since technical consideration is given to the microwave irradiation called decompression, there is an advantage that the microwave output can be relatively lowered. For example, the first stage is about 10 to 100 minutes by 10 to 20 kW microwave, the second stage is about 3 to 10 kW and about 5 to 80 minutes, and the third stage is about 0.1 to 3 kW and about 1 to 60 minutes. Dry in stages. It is preferable that the microwave output and irradiation time of each stage are lowered in conjunction with the reduction in the total amount of moisture contained in the hollow fiber membrane. This drying method is a very gentle drying method for hollow fiber membrane bundles, and cannot be expected in the prior arts of the above-mentioned Patent Documents 20 to 23, and therefore the effect of the present invention is made significant.

  To explain another aspect, when the so-called moisture content of the hollow fiber membrane bundle is relatively small, that is, a so-called moisture content of 400% by mass or less, irradiation with a low output microwave of 12 kW or less may be excellent. For example, when the amount of water in the total amount of the hollow fiber membrane bundle is about 1 to 7 kg, the output is 12 kW or less under a reduced pressure of about 3 to 10 kPa at a temperature of 80 ° C. or less, preferably 60 ° C. or less. For example, irradiation with a microwave of about 1 to 5 kW for 10 to 240 minutes, irradiation with a microwave of less than 0.5 to 1 kW for about 1 to 240 minutes, and irradiation with a microwave of less than 0.1 to 0.5 kW for about 3 to 240 minutes If the irradiation output and the irradiation time of the microphone mouth wave are adjusted according to the degree of drying, drying is performed uniformly. The degree of vacuum is set to 0.1 to 20 kPa for each stage, but the first stage having a relatively high moisture content of the hollow fiber membrane is increased to 0.1 to 5 kPa, for example, and the microwave output is increased. The degree of pressure reduction at each stage, in which the microwave is irradiated at a pressure slightly higher than the first stage of 0.1 to 5 kW under a reduced pressure of 5 to 20 kPa in the second stage and the third stage. It is possible to arbitrarily set the appropriate adjustment in accordance with the change in consideration of the transition of the total moisture content and the moisture content of the hollow fiber membrane bundle. In each stage, the operation of changing the degree of reduced pressure further increases the significance of irradiating microwaves under reduced pressure according to the present invention. Of course, it is necessary to always consider the uniform irradiation and exhaust of the microwave in the microwave irradiation apparatus.

The microwave irradiation frequency is preferably 1,000 to 5,000 MHz in consideration of the suppression of irradiation spots on the hollow fiber membrane bundle and the effect of extruding water in the pores from the pores. More preferably, it is 1,500-4,000 MHz, More preferably, it is 2,000-3,000 MHz.
In drying by microwave irradiation, it is important to uniformly heat and dry the hollow fiber membrane bundle. In the above-described microwave drying, nonuniform heating due to the reflected wave that occurs accompanying the generation of the microwave occurs, so it is important to take measures to reduce the nonuniform heating due to the reflected wave. The method is not limited and is arbitrary. For example, a method of providing a reflector in an oven disclosed in Japanese Patent Application Laid-Open No. 2000-340356 to reflect reflected waves and uniformize heating is a preferred embodiment. One.

  Furthermore, it is preferable that the hollow fiber membrane does not dry out. When it is completely dried, the deterioration of polyvinyl pyrrolidone increases and the production of hydrogen peroxide may be greatly increased. In addition, wettability may be reduced during re-wetting during use, and polyvinyl pyrrolidone may be difficult to absorb water, and may be easily eluted from the hollow fiber membrane. The moisture content of the hollow fiber membrane after drying is preferably 1% by mass or more and less than the saturated moisture content. 1.5 mass% or more is more preferable. If the water content of the hollow fiber membrane is too high, bacteria may proliferate during storage of the hollow fiber membrane, the hollow fiber membrane may crush due to its own weight, or an adhesive failure may occur during assembly of the module. Therefore, the moisture content of the hollow fiber membrane is preferably 10% by mass or less, more preferably 7% by mass or less.

  The maximum temperature reached by the hollow fiber membrane during drying can be measured by applying an irreversible thermolabel to the side of the film that protects the bundle of hollow fiber membranes, drying, and taking out and confirming the display after drying. At this time, the maximum reached temperature of the hollow fiber membrane bundle during drying is preferably 90 ° C. or lower, more preferably 80 ° C. or lower. More preferably, it is 70 degrees C or less. If the maximum temperature reached exceeds 90 ° C., the film structure is likely to change, which may cause performance degradation or oxidative degradation. In particular, in a hollow fiber membrane containing a hydrophilic polymer, it is necessary to prevent the temperature rise as much as possible because the hydrophilic polymer is easily decomposed by heat.

  In addition, as described above, a method of removing hydrogen peroxide mixed from the raw material polyvinylpyrrolidone or generated in the manufacturing process of the hollow fiber membrane bundle by washing is also effective as a method for controlling the above-described characteristic values within a regulated range. is there.

  In the present invention, the properties such as the amount of polyvinyl pyrrolidone eluted and the endotoxin, which is an endotoxin, are prevented from entering the blood side, and the hollow fiber membranes are prevented from sticking to each other when the hollow fiber membranes are dried. In order to balance, the content of polyvinyl pyrrolidone on the outer surface of the hollow fiber membrane is preferably in a specific range. As a method for satisfying this requirement, it can be achieved, for example, by setting the ratio of polyvinyl pyrrolidone to the polysulfone-based resin within the above-mentioned range, or optimizing the film forming conditions of the hollow fiber membrane. It is also an effective method to wash the formed hollow fiber membrane. Film formation conditions include optimization of the humidity at the air gap at the nozzle outlet, stretching conditions, coagulation bath temperature, composition ratio of solvent to non-solvent in the coagulation liquid, and introduction of a cleaning process is also effective. It is.

  As a hollow formation agent, 0-60 mass% dimethylacetamide (DMAc) aqueous solution is preferable. More preferably, it is 15-60 mass%, More preferably, it is 25-60 mass%, More preferably, it is 30-58 mass%. If the hollow forming agent concentration is too low, the dense layer on the blood contact surface becomes thick, which may reduce the solute permeability. On the other hand, if the concentration of the hollow forming agent is too high, the formation of the dense layer tends to be incomplete and the fractionation characteristics may be lowered.

  The external coagulation liquid is preferably a 0 to 50% by weight DMAc aqueous solution. If the concentration of the external coagulation solution is too high, the outer surface open area ratio and the outer surface average pore area will become too large, which may increase the backflow of endotoxin to the blood side and decrease the burst pressure when using hemodialysis. There is. Therefore, the external coagulation liquid concentration is more preferably 40% by mass or less, further preferably 30% by mass or less, and still more preferably 25% by mass or less. If the concentration of the external coagulation liquid is too low, it is necessary to use a large amount of water to dilute the solvent brought in from the spinning solution, and the cost for waste liquid treatment increases. Therefore, the lower limit of the external coagulation liquid concentration is more preferably 5% by mass or more, further preferably 10% by mass or more, and still more preferably 15% by mass or more.

  In the production of the hollow fiber membrane of the present invention, it is preferable that stretching is not substantially applied before the hollow fiber membrane structure is completely fixed. The fact that the film is not substantially stretched means that the roller speed during the spinning process is controlled so that the spinning solution discharged from the nozzle is not loosened or excessively tensioned. The discharge linear speed / coagulation bath first roller speed ratio (draft ratio) is preferably in the range of 0.7 to 1.8. If the ratio is less than 0.7, the running hollow fiber membrane may be loosened, leading to a decrease in productivity. Therefore, the draft ratio is more preferably 0.8 or more, further preferably 0.9 or more, and More preferably 95 or more. If it exceeds 1.8, the membrane structure may be destroyed, for example, the dense layer of the hollow fiber membrane is torn. Therefore, the draft ratio is more preferably 1.7 or less, still more preferably 1.6 or less, still more preferably 1.5 or less, and particularly preferably 1.4 or less. By adjusting the draft ratio to this range, deformation and destruction of the pores can be prevented, clogging of blood protein into the membrane pores can be prevented, and performance stability over time and sharp fractionation characteristics can be expressed. Is possible.

In the present invention, as described above, in the process of producing a hollow fiber membrane as a means for reducing the elution amount of hydrogen peroxide or making the content of polyvinylpyrrolidone on the outer surface of the hollow fiber membrane a specific range, It is important to introduce a washing step before the drying step. For example, a hollow fiber membrane that has passed through a water-washing bath is wound into a basket in a wet state to form a bundle of 3,000 to 20,000. Next, the obtained hollow fiber membrane is washed to remove excess solvent, polyvinylpyrrolidone. As a method for cleaning the hollow fiber membrane, in the present invention, it is preferable to treat the hollow fiber membrane by immersing it in hot water at 70 to 130 ° C., or at room temperature to 50 ° C. and 10 to 40 vol% ethanol or isopropanol aqueous solution.
(1) In the case of hot water washing, the hollow fiber membrane is immersed in excess RO water and treated at 70 to 90 ° C. for 15 to 60 minutes, and then the hollow fiber membrane is taken out and subjected to centrifugal dehydration. This operation is repeated several times while updating the RO water to perform the cleaning process.
(2) A method of treating a hollow fiber membrane immersed in excess RO water in a pressurized container at 121 ° C. for about 2 hours can also be employed.
(3) When using an ethanol or isopropanol aqueous solution, it is preferable to repeat the same operation as in (1).
(4) It is also a preferable washing method that the hollow fiber membranes are arranged radially in a centrifugal washer and centrifugally washed for 30 minutes to 5 hours while spraying washing water at 40 ° C. to 90 ° C. from the rotation center in a shower shape.
Two or more cleaning methods may be combined. In any method, when the processing temperature is too low, it is necessary to increase the number of times of cleaning, which may lead to an increase in cost. On the other hand, if the treatment temperature is too high, the decomposition of polyvinylpyrrolidone is accelerated, and conversely, the cleaning efficiency may be reduced. By performing the above-described washing, the content of the outer surface polyvinyl pyrrolidone is optimized, and it is possible to suppress sticking and reduce the amount of eluate, as well as to reduce the hydrogen peroxide elution amount.

  Sterilization is essential for blood purifiers. As a sterilization treatment method, radiation sterilization by irradiating γ rays or electron beams is preferable because of its reliability and simplicity. However, since irradiation generates hydrogen peroxide due to degradation of polyvinylpyrrolidone and the generation thereof is promoted by hydrogen peroxide present at the time of irradiation, the above-described suppression treatment is necessary, and 10 in the longitudinal direction is required. It is a preferred embodiment that the polysulfone-based hollow fiber membrane, which is divided into individual pieces and has a hydrogen peroxide elution of 3 ppm or less at all sites when measured for each, is irradiated with radiation. Thus, the polysulfone-based hollow fiber membrane, which is the first requirement of the present invention, is divided into 10 pieces in the longitudinal direction, and the elution of hydrogen peroxide when measured for each is 5 ppm or less at all sites. Achievable. Therefore, in the present invention, even after sterilization by γ-ray or electron beam irradiation, the polysulfone-based hollow fiber membrane is divided into 10 pieces in the longitudinal direction, and elution of hydrogen peroxide when measured for each of all sites Is preferably maintained at 5 ppm or less.

  In the present invention, the blood purifier is preferably filled with a hollow fiber membrane having the above characteristics. The blood purifier preferably has a shape in which the hollow fiber membrane obtained by the above method is loaded into a blood purifier container and both ends thereof are fixed with resin. An example is shown in FIG.

  The blood purifier 1 has a hollow housing 2 loaded with a hollow fiber membrane bundle 3, and both ends of the hollow fiber membrane bundle 3 are fixed to both ends of the housing 2 with an adhesive or the like. Is covered with caps 5a and 5b. A dialysate inlet 6a for introducing dialysate into the housing 2 is provided near one end of the side of the housing 2, and a dialysate outlet 6b for discharging dialysate is provided near the other end. Each is formed to protrude. One cap 5a is formed with a blood introduction port 7a for introducing blood into the housing 2, and the other cap 5b is formed with a blood discharge port 7b for discharging blood.

  The blood enters the space formed by the cap 5a and one end face of the hollow fiber membrane bundle 3 from the blood introduction port 7a as shown by the arrow A, passes through the hollow portion of the hollow fiber membrane bundle 3, It enters into the space formed by the other end face of the hollow fiber membrane bundle 3 and the cap 5b, and is discharged from the blood outlet 7b as shown by the arrow B. On the other hand, the dialysate enters the housing 2 through the dialysate introduction port 6a as shown by the arrow C, flows outside the hollow fiber membranes of the hollow fiber membrane bundle 3, and as shown by the arrow D, the dialysate discharge port. It is discharged from 6b. At this time, the flow of blood to be dialyzed and the flow of dialysate are opposite so-called opposite flows. During this time, waste in the blood flowing in the hollow fiber membrane is dialyzed into the outer dialysate through the hollow fiber membrane.

  Examples of the material for the housing and the cap include polycarbonate, polyester, and polypropylene. Examples of the adhesive material used for fixing both ends include polyurethane resin, epoxy resin, and silicone resin.

  The method of injecting the adhesive used for fixing both ends into the fixing portion is not limited, but a centrifugal bonding method in which the injection is performed using the centrifugal force generated by rotating the blood purifier to be injected is recommended. The method of the centrifugal bonding method is not limited. For example, sealing jigs are attached to both ends of the housing loaded with the dried hollow fiber membrane bundle and set in a centrifugal bonding machine. A predetermined amount of uncured adhesive resin is injected from the dialysate inlets 6a and 6b at a temperature near room temperature while rotating the centrifugal adhesive machine at a predetermined rotational speed, and then the temperature of the centrifugal adhesive machine is injected. The curing temperature is raised and the curing is terminated, or at least the resin is precured until the fluidity of the resin is lost, and the centrifugal bonding machine is stopped. In the latter case, heating is performed in a stationary state, post-curing is performed, and curing is terminated. This centrifugal bonding method may be a two-layer centrifugal bonding method in which the hollow fiber membrane at the bonding interface is reinforced by covering the inside of the bonding portion of the hollow fiber membrane bundle with a flexible resin layer.

In the case of the centrifugal bonding method, it is important that the adhesive is uniformly injected into the entire space in the hollow fiber membrane bundle. If this injection becomes non-uniform and a part where the injection amount of the adhesive is insufficient is produced, it leads to poor adhesion. In particular, if there is a portion where the hollow fiber membranes are fixed, penetration of the adhesive is inhibited. Therefore, in order to unravel the adhering portion, for example, so-called yarn trimming treatment in which air is blown from the nozzle onto the end surface of the hollow fiber membrane bundle is performed. Certainly, the present warping treatment is effective for unraveling the fixed hollow fiber membrane, but this treatment is not preferable because the hollow fiber membrane at the end face part is deformed and the inclined hollow fiber membrane is generated.
The hollow fiber membrane bundle of the present invention is characterized in that the uniformity of the injection of the adhesive is ensured without performing the yarn setting treatment because partial adhesion during drying is suppressed. However, since it is important to ensure the uniformity of the injection of the adhesive, it is preferable to implement the following measures. For example, it is preferable to select a low viscosity brand as the adhesive. The viscosity after 2 minutes of mixing the two liquids is preferably 2000 mPa · s or less. 1600 mPa · s or less is more preferable. Moreover, it is preferable to lower the filling density of the hollow fiber membrane restrained by the hollow package when inserting the dried hollow fiber membrane bundle into the housing used for assembling the blood purifier.

  The number and length of the hollow fiber membranes to be filled are appropriately set according to market requirements and hollow fiber membrane characteristics. The length and diameter of the housing are set so as to match the size of the hollow fiber membrane bundle to be filled.

  Sterilization is essential for blood purifiers. As a sterilization treatment method, radiation sterilization by irradiating γ rays or electron beams is preferable because of its reliability and simplicity. However, polyvinyl pyrrolidone is deteriorated by irradiation, hydrogen peroxide is generated, and generation thereof is accelerated by hydrogen peroxide present at the time of irradiation. Therefore, it is preferable to have the above-described characteristics even after the irradiation. In order to impart this characteristic even after the radiation irradiation treatment, it is important to use a polysulfone-based hollow fiber membrane having the above characteristics before irradiation, but it is only one of the necessary requirements. After satisfying this requirement, it is necessary to take measures to suppress the deterioration reaction caused by irradiation.

  In the present invention, the water content in the hollow fiber membrane is preferably 600% by mass or less. Moreover, it is preferable that a radical scavenger is not included in the blood purifier during radiation irradiation. When the water content exceeds 600% by mass, the weight of the blood purifier increases, so that handling is reduced, transportation costs increase, bacteria are easily generated, freezing in a cold region, and other problems occur. There are things to do. Moreover, since polyvinylpyrrolidone is too cross-linked, the blood coagulation reaction may be activated when used for blood purification. On the other hand, when the water content is less than 0.8% by mass, deterioration of polyvinyl pyrrolidone by irradiation is promoted, and it is determined by increased production of hydrogen peroxide, carboxyl groups, peroxides, etc. May cause an increase in UV (220 to 350 nm) absorbance, a long-term storage stability, blood compatibility, and stability of the hollow fiber membrane extract when the test is performed. Therefore, 1.0-300 mass% is more preferable, and 1.5-200 mass% is further more preferable.

  It is difficult to suppress the deterioration reaction due to irradiation in the dry state and in the absence of a radical scavenger, which is the object of the present invention, and conventionally, this is unavoidably performed by a wet method and in the presence of a radical scavenger. It was. As a result of intensive studies on solving the problem, the present inventors have promoted the deterioration reaction by oxygen gas adsorbed on the localized portion of polyvinyl pyrrolidone in the hollow fiber membrane and adsorbed on the localized portion of polyvinyl pyrrolidone. The present invention was completed by finding a method for suppressing the degradation reaction of polyvinyl pyrrolidone based on the presumed mechanism of being suppressed by the generated water. Although it is a well-known phenomenon that the deterioration reaction is affected by oxygen, the present inventors have found for the first time that the deterioration reaction is suppressed by a trace amount of water adsorbed on the localized portion of polyvinylpyrrolidone. Phenomenon. Preferred embodiments are described below.

  The present inventors have disclosed a blood purifier in which the moisture content of a hollow fiber membrane is adjusted to 5% by mass or more using degassed water when irradiating in a dry state using the hollow fiber membrane having the characteristics described above. The present inventors have found that the degradation reaction of polyvinyl pyrrolidone can be suppressed even in the absence of a radical scavenger.

  That is, the outside air and the dialysate in the blood purifier filled with a hollow fiber membrane containing polyvinyl pyrrolidone whose water content is adjusted to 5 to 600% by mass using deaerated water are sealed. It is preferable to apply radiation by sealing with a packaging bag that blocks water vapor.

  In the present invention, the deaerated water used for adjusting the moisture content of the hollow fiber membrane is preferably deoxygenated water. Further, it is more preferably inert gas saturated water.

  The deoxygenated water is water having a dissolved oxygen content of 0.5 ppm or less. The dissolved oxygen content is more preferably 0.2 ppm or less, and further preferably 0.1 ppm or less.

Usually, about 20 L of air per 1 m ³ is dissolved in water, and oxygen gas of 8 mg / L water is dissolved in normal tap water. The method for preparing the deoxygenated water is not limited as long as the amount of dissolved oxygen is satisfied. Those prepared by a generally known degassing method can be applied. Examples thereof include a heat degassing method, a vacuum degassing method, a nitrogen gas bubbling method, a membrane degassing method, a reducing agent addition method, and a reducing method. The membrane deaeration method is particularly preferable because the amount of dissolved oxygen can be reduced to the ppb level. The membrane degassing method may be prepared by either a non-porous membrane method or a porous membrane method.

  In order to provide the highest quality blood purifier that can obtain a high level of sterilization effect and has no deterioration in quality or variation in quality even if stored for a long time, the present inventors As a result of pursuing the cause and countermeasures, it was found that the amount of water contained in the blood purifier and the technical considerations for dissolved oxygen in the water had a subtle effect. In particular, in the sterilization process of blood purifiers before shipment, it is possible to provide the highest quality blood purifiers to the medical field by giving technical consideration to the generation of active oxygen by irradiation. This is based on the knowledge of the present inventors. Reducing dissolved oxygen in the water that causes active oxygen generation can be achieved by simple water treatment, but in the process of including it in the blood purifier, the entry route such as diffusion and permeation of oxygen in the atmosphere However, using water pre-saturated with an inert gas has the advantage of effectively suppressing oxygen ingress and simplifying water handling. .

  The amount of dissolved oxygen is recommended to be lower, for example 0.001 ppm or less, but there are technical difficulties, and this operation may be reflected in the price of the blood purifier. There is. Usually, if consideration is given to reducing the dissolved oxygen to about 0.001 to 0.5 ppm, it is a temporary measure that the maximum elution amount of hydrogen peroxide can be suppressed to 5 ppm or less in the radiation sterilization treatment. Here, the dissolved oxygen in water can be measured using, for example, a dissolved oxygen meter OM-51-L1 manufactured by HORIBA Ltd.

  It is preferable to use the deoxygenated water that has been subjected to reverse osmosis treatment (RO treatment).

  If only deoxygenated water is used, oxygen contained in the surrounding air is dissolved again, and the re-dissolved oxygen gas is adsorbed on the localized portion of polyvinylpyrrolidone. It is difficult to completely suppress the deterioration reaction. By using an inert gas saturated water such as nitrogen, this problem can be solved. That is, by containing an inert gas in a saturated state, even when irradiation is performed in an environment containing oxygen in the surroundings, re-dissolution of oxygen gas into water is suppressed, and the concentration of oxygen contained in water is low. Will be maintained.

  The method for preparing the inert gas saturated water is not particularly limited, and a method of bubbling an inert gas such as nitrogen can be suitably used. As known in the art, the inert gas bubbling method is known as a method for removing dissolved oxygen from water, but dissolved oxygen is eventually removed by introduction of inert gas. It is also preferable to dissolve the active gas. Specifically, oxygen is removed by bubbling an inert gas in water from which oxygen has been removed in advance by a heat degassing method, a vacuum degassing method, a membrane degassing method, a reducing agent addition method, or the like, and the inert gas is dissolved. Is done efficiently. Here, the dissolved oxygen amount of the inert gas saturated water is preferably 0.5 ppm or less, more preferably 0.2 ppm or less, and further preferably 0.1 ppm or less. In addition, it is preferable to use the water used here that was subjected to reverse osmosis membrane (RO) treatment.

  By using the above deaerated water, the deterioration of the hollow fiber membrane due to irradiation, particularly the degradation reaction of polyvinylpyrrolidone, is more effectively suppressed than when non-deaerated water is used. Increase in UV (220-350 nm) absorbance, antithrombogenicity, long-term storage stability, and priming treatment in the extract of hollow fiber membranes when testing is conducted according to the increase or dialysis-type artificial kidney device manufacturing approval criteria The effect of suppressing an undesirable deterioration reaction that causes a decrease in performance and the like is increased.

  In the present invention, the oxygen concentration in the atmosphere in the blood purifier before sterilization is 4.0% by volume or less in order to more effectively express the effect of suppressing the deterioration reaction caused by irradiation with radiation from the degassed water. Preferably there is. 3.0% by volume or less is more preferable, and 2.0% by volume or less is more preferable. When the oxygen concentration exceeds 4.0% by volume, the hollow fiber membrane, particularly polyvinyl pyrrolidone, may be deteriorated when irradiated with radiation or an electron beam even if the above-described requirements are satisfied. Moreover, when the oxygen concentration in the atmosphere in the blood purifier before sterilization is too low, deterioration of the hollow fiber membrane constituent material and the potting material is suppressed, but the sterilization effect by radiation irradiation may not be sufficiently exhibited. Therefore, the oxygen concentration in the atmosphere in the blood purifier before sterilization is preferably 0.1% by volume or more, more preferably 0.2% by volume or more, and further preferably 0.3% by volume or more.

  In the above method, the mechanism by which the degradation reaction of polyvinylpyrrolidone during irradiation is suppressed is presumed as follows. The polyvinyl pyrrolidone in the hollow fiber membrane is localized in the hollow fiber membrane without being uniformly dispersed, and the water present inside and on the surface of the hollow fiber membrane is selectively around the highly hydrophilic polyvinyl pyrrolidone. It is presumed that it is localized by being adsorbed on the surface. It is presumed that the presence of water around the polyvinyl pyrrolidone blocks the attack of oxygen activated by radiation irradiation on the polyvinyl pyrrolidone and suppresses the degradation reaction. Therefore, it is guessed that the effect is expressed more notably by deaeration water conversion. In addition, in the present invention, a hollow fiber membrane is used in which the amount of hydrogen peroxide that is activated by radiation and causes a deterioration reaction is suppressed in the same manner as oxygen, so that the deterioration reaction is also suppressed. It is presumed that the effect of the present invention is manifested by heavy effects.

  The oxygen concentration in the atmosphere in the blood purifier after sterilization is preferably 2.0% by volume or less. If the oxygen concentration in the atmosphere in the blood purifier after sterilization is too high, the components of the hollow fiber membrane will undergo oxidative degradation when the blood purifier is stored for a long period of time, and degraded degradation products will elute into the blood when hemodialysis is used. There is a risk of doing. Therefore, the oxygen concentration in the blood purifier after sterilization is more preferably 1.8% by volume or less, and further preferably 1.5% by volume or less. The oxygen concentration in the atmosphere in the blood purifier after sterilization is preferably 0.01% by volume or more. If the oxygen concentration in the atmosphere in the blood purifier after sterilization is too low, there is a possibility that oxygen in the system has already been consumed during the sterilization process, and a sufficient sterilization effect may not be obtained. Therefore, the oxygen concentration in the atmosphere in the blood purifier after sterilization is more preferably 0.02% by volume or more, and further preferably 0.03% by volume or more.

  The method for adjusting the oxygen concentration in the blood purifier is not limited, but it is preferable to fill the blood purifier with an inert gas. As described above, a blood purifier is assembled using the hollow fiber membrane dried by the above-described method, and deoxygenated water or inert gas saturated water is injected and filled into the blood purifier, and the blood purifier is present in the blood purifier. In addition, the oxygen in the hollow fiber membrane and the surroundings of the hollow fiber membrane are filled with deoxygenated water or inert gas saturated water, and then the deoxygenated water is injected and filled into the blood purifier. A method of simultaneously performing crystallization and oxygen concentration reduction is preferred. The inert gas is preferably nitrogen gas from the viewpoint of economy. In order to suppress a decrease in blood compatibility and sterilization effect, in the case where a small amount of oxygen coexists, it is preferable to replace with an inert gas having an adjusted oxygen concentration.

  In the above method, after adjusting the water content of the hollow fiber membrane and the oxygen concentration in the blood purifier, it is preferable to seal all the blood and dialysate inlet / outlet of the blood purifier. By this method, the volatilization of moisture from the hollow fiber membrane filled in the blood purifier is suppressed, and the invasion of oxygen gas contained in the outside air into the blood purifier is suppressed, so that the effect of the present invention is achieved. Is remarkably expressed. Further, it is possible to prevent invasion of various germs into the blood purifier. Moreover, since the volatilization of moisture from the hollow fiber membrane is suppressed for a long period of time, shrinkage due to the hollow fiber membrane being dried over time and deterioration of the membrane characteristics are suppressed. Therefore, the effect that the generation | occurrence | production of a defect, the fall of a film | membrane characteristic, etc. at the time of storing a blood purifier for a long term is suppressed appears. For example, when the shrinkage of the hollow fiber membrane occurs, peeling of the interface between the hollow fiber membrane and the adhesive at the fixing portion to the blood purifier due to the adhesive of the hollow fiber membrane occurs, leading to the occurrence of liquid leakage at the portion. Further, in the case of a hollow fiber membrane provided with crimps, the crimping of the dialysis fluid may increase due to relaxation of the crimps due to drying of the hollow fiber membranes.

  In the present invention, it is preferable that the blood purifier hermetically sealed by the above method is sealed with the aforementioned packaging bag and irradiated with radiation. By sealing with the packaging bag, contamination of the outer surface of the blood purifier, adhesion of germs and the like are prevented. In the method, the atmospheric gas in the packaging bag is not particularly limited. Air may be used, but an inert gas atmosphere such as nitrogen gas is more preferable because it suppresses the growth of various bacteria (aerobic bacteria) mixed after sterilization and the effect of the above-mentioned sealing plug is complemented. Furthermore, in the present invention, it is preferable to irradiate with radiation and electron beams after sealing tightly as will be described later. Therefore, there is an advantage that oxygen gas can be prevented from entering the blood purifier from outside air during this period. is there. In addition, for example, even when there is a poor sealing of the blood purifier, oxygen gas can be prevented from entering the blood purifier.

  The above-described method can be adopted as a method for sterilization more easily and at low cost when the moisture content of the hollow fiber membrane is 5% by mass or more. On the other hand, when using a hollow fiber membrane that does not require much consideration for sterilization treatment, such as manufactured in a clean room that meets at least class 100,000 standards, the moisture content of the hollow fiber membrane should be less than 5% by mass. In addition, a method of optimizing the oxygen concentration and humidity of the atmosphere surrounding the hollow fiber membrane during the radiation irradiation treatment can be employed. Of course, even when the moisture content of the hollow fiber membrane is 5% by mass or more, there is no problem even if the method is additionally used. The first requirement in the method is a requirement relating to the oxygen concentration of the atmosphere surrounding the hollow fiber membrane during sterilization. Radiation irradiation is preferably performed in a state where the oxygen concentration is 3.6% by volume or less. It is more preferably 1% by volume or less, and further preferably 0.1% by volume or less. If it exceeds 3.6% by volume, hydrogen peroxide production due to deterioration of polyvinylpyrrolidone may increase and the above characteristics may not be satisfied.

  The method for making the inside of the packaging bag an inert gas atmosphere is not limited, but a method of forming a substantial deoxygenated state by absorbing oxygen in the packaging bag using an oxygen scavenger is preferable.

  The oxygen scavenger in the method is not limited as long as it has a oxygen scavenging function. For example, sulfite, bisulfite, dithionite, hydroquinone, catechol, resorcin, pyrogallol, gallic acid, longalit, ascorbic acid and / or its salts, sorbose, glucose, lignin, dibutylhydroxytoluene, dibutylhydroxyanisole, Examples of the oxygen scavenger include a ferrous salt, metal powder such as iron powder, and the like, which can be selected as appropriate. In addition, oxygen scavengers for metal powders are used as an oxidation catalyst, if necessary, such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium bromide, odor. One or two kinds of metal halides such as potassium iodide, magnesium bromide, calcium bromide, iron bromide, nickel bromide, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, iron iodide, etc. The above may be added. Moreover, adding a deodorant, a deodorant, and another functional filler is not restrict | limited at all. Further, the shape of the oxygen scavenger is not particularly limited, and may be any of powder, granule, lump, sheet, etc., or a sheet in which various oxygen absorbent compositions are dispersed in a thermoplastic resin or A film-like oxygen scavenger may be used.

The packaging bag used in the present invention preferably has, for example, a function of forming a space that is deoxygenated by the oxygen scavenger and maintaining the deoxygenated state for a long period of time. Therefore, it is necessary to be made of a material having a low oxygen gas permeability. The oxygen permeability is preferably 10 cm ³ / m ² · 24 h · MPa (20 ° C., 90% RH) or less. 8 cm ³ / m ² · 24 h · MPa (20 ° C., 90% RH) or less is more preferable, 6 cm ³ / m ² · 24 h · MPa (20 ° C., 90% RH) or less is more preferable, and 4 cm ³ / m ² · MP ² or less. 24 h · MPa (20 ° C., 90% RH) or less is even more preferable.
If the oxygen permeability exceeds 10 cm ³ / m ² · 24 h · MPa (20 ° C, 90% RH), oxygen gas will pass through the packaging bag from the outside even if it is sealed with the packaging bag. This is not preferable because the oxygen concentration increases and the substantial deoxygenation state cannot be maintained.

As described above, in the present invention, the hollow fiber membrane filled in the blood purifier needs to maintain a specific moisture content. Therefore, it is preferable that the packaging bag in the present invention is made of a material having a low water vapor permeability so as to suppress the invasion of water vapor into the blood purifier and, conversely, the release of water vapor from the blood purifier. The water vapor permeability is preferably 50 g / m ² · 24 h · MPa (40 ° C., 90% RH) or less. 40 g / m ² · 24 h · MPa (40 ° C., 90% RH) or less is more preferable, 30 g / m ² · 24 h · MPa (40 ° C., 90% RH) or less is further preferable, and 20 g / m ² · 24 h · MPa (40 ° C., 90% RH) or less is more preferable. When it exceeds 50 g / m ² · 24 h · MPa (40 ° C., 90% RH), even if sealed with a packaging bag, water vapor passes through the packaging bag, so that the drying of the hollow fiber membrane proceeds. In some cases, the preferred water content cannot be maintained. For example, it is possible to suppress the progress of the drying of the hollow fiber membrane even when the blood purifier is poorly sealed.

  The material and configuration of the packaging bag used in the present invention are arbitrary without limitation as long as they have the characteristics described above. In a preferred embodiment, the material is made of an impermeable material for both oxygen gas and water vapor such as aluminum foil, aluminum vapor deposited film, inorganic oxide vapor deposited film such as silica and / or alumina, and vinylidene chloride polymer composite film. is there. Further, the sealing method in the packaging bag is not limited and is arbitrary, and examples thereof include a heat sealing method, an impulse sealing method, a fusing sealing method, a frame sealing method, an ultrasonic sealing method, and a high frequency sealing method. A composite material composed of a composite of the film material and the above-described impermeable material is preferred. In particular, both the impervious and heat-sealable functions, in which the outer layer is made of a polyester film, the intermediate layer is made of an aluminum foil, and the inner layer is made of a polyethylene film. It is preferable to apply a laminated sheet having the same.

In the present invention, in the above-mentioned method, it is preferable that at least 48 hours elapse after packaging to irradiate the radiation. More preferably 72 hours or more. However, if the time until irradiation with radiation after packaging is too long, miscellaneous bacteria may grow, and it is preferable to perform the irradiation within 10 days after packaging. More preferably, it is within 7 days, and more preferably within 5 days. There is no particular need for temperature control between packaging and radiation, for example, room temperature. If the irradiation treatment is performed in a state of less than 48 hours, the expression of water permeability after the priming treatment may be deteriorated. The factor of performance development after priming is difficult because it is difficult to identify the cause because many technical factors are complicated due to the situation of a delicate hollow fiber membrane obtained by cutting long fibers into a certain length. However, effects such as the content of polyvinyl pyrrolidone in the innermost and outermost surface layers of the hollow fiber membrane, the amount of polyvinyl pyrrolidone eluted from the hollow fiber membrane, the water content, and the dissolved oxygen concentration of deaerated water cannot be ignored.
However, the following can be predicted by examining the expression of performance after priming from the viewpoint of the elapsed time until sterilization, in addition to empirical rules and technical viewpoints at the production site. As shown in FIG. 4, if the elapsed time until the sterilization treatment is relatively short, such as 10 hours, 20 hours, and 30 hours, there is a variation in performance after priming, and a uniform and stable product cannot be produced. The potential is great. On the other hand, if it irradiates after about 48 hours, for example, 60 hours and 120 hours, it will be converged on the area | region with little dispersion | variation in the performance expression after priming. If it does so, when it supplies to a medical field, the rise of performance will be good and there is no doubt that it is very useful in handling also in shortening of dialysis time.

  When the performance expression after priming is set to 90% and the behavior is examined with respect to the amount of hydrogen peroxide eluted from the hollow fiber membrane, the amount of hydrogen peroxide eluted of a hollow fiber membrane of 5 ppm or less, for example, is examined. In some cases, when sterilization is performed in about 48 hours or less, there is little variation, especially around 90%. On the other hand, when the elution amount of hydrogen peroxide is, for example, 10 ppm or more, there is a tendency that the behavior varies greatly in the region of 48 hours or less shown in FIG. However, if the elapsed time until sterilization is 48 hours or more, the amount of hydrogen peroxide eluted from the polysulfone hollow fiber membrane will be affected to some extent, but the ideal performance after priming will converge to an area of 90% or more. It is possible to do. Such a material behavior seems to show the same tendency even when, for example, the content of polyvinylpyrrolidone in the outermost surface layer of the polysulfone-based hollow fiber membrane is analyzed from 25 to 50% by mass.

  Further, the tendency as shown in FIG. 4 may show some difference in behavior even under the condition that the water content of the polysulfone-based hollow fiber membrane is 600% by mass or less. However, when deaerated water is used, and the inert gas Even when saturated water is used, the performance expression after priming with a blood purifier set in a state where the dissolved oxygen concentration is 0.5 ppm or less and 0.001 ppm or more and sterilization treatment If the critical behavior at an elapsed time of 48 hours is analyzed, the same tendency is expected. If analyzed from such a technical point of view, the technical matters such as performance performance after priming of the present invention and the elapsed time until sterilization greatly enhance the usability, quality control, and medical field benefits of the hollow fiber membrane. Is. Of course, it is not fixed and fixed for 48 hours, but arbitrarily determined in consideration of factors such as quality, productivity, material, and structure.

  The complex material and structure of the hollow fiber membrane cannot be determined for a single reason, but the dissolved oxygen present in and around the hollow fiber membrane should be 5 ppm or less, and the oxygen concentration should be 0.001 ppm or more. When the inside of the blood purifier is adjusted to a lower specification, the dissolved oxygen concentration and the moisture content in the hollow fiber membrane become uniform over time due to diffusion, permeation, movement, etc. The quality related to oxygen and hydrophilic polymer is in an equilibrium state, and if it is sterilized after such a state, it becomes a blood purifier containing a hollow fiber membrane of uniform quality. is there. Rather, it can also be said to be a kind of material fixation of a hollow fiber membrane having a complicated material and structure. Such a tendency has already been described in detail in the present specification.

  As the radiation used in the present invention, α rays, β rays, γ rays, neutron rays, X rays, electron rays, ultraviolet rays, and ion beams are used. From the viewpoint of sterilization efficiency and ease of handling, γ rays or electron rays are used. Preferably used. The irradiation dose of radiation is not particularly limited as long as it can be sterilized and crosslinked, but generally 10 to 30 kGy is preferable.

  In the blood purifier of the present invention, the water permeability at 10 minutes after the priming treatment is preferably 90% or more of the water permeability at 24 hours after the priming treatment. 92% or more is more preferable, and 94% or more is more preferable. As a result, the hydrophilicity necessary for the performance of the membrane can be sufficiently obtained by the priming treatment, and the reliability of the blood purifier is improved. If the water permeability ratio is less than 90%, the hydrophilicity of the membrane by the priming treatment is insufficient, not only the original membrane performance is not expressed, but also the hydrophobicity that is not familiar with water There is a risk of clogging and adhesion of platelets due to protein adsorption to the hydrophobic part during blood circulation. A water permeability ratio of 90% or more indicates that a state in which substantially necessary membrane performance is developed is in progress, and is in an appropriate state in which familiarity with water is rapidly progressing. Is shown.

  The blood purifier is subjected to a so-called priming process in which filling, washing, expelling air bubbles, and the like are performed with physiological saline or dialysate in use. The polysulfone-based hollow fiber membrane may not necessarily have sufficient compatibility with water, and it may take time for the priming process to take time or until the performance is fully expressed. There is a problem of being. In particular, in the case of a dry type blood purifier such as the present invention, the time for the performance of the hollow fiber membrane such as water permeability during the priming process to reach a predetermined level may vary, and the predetermined level is reached in a short time. The development of a hollow fiber membrane exhibiting the above membrane performance is desired, and the present invention responds to this demand.

  In the blood purifier of the present invention, after the blood purifier is stored at room temperature for 1 year or more after irradiation, the hollow fiber membrane is taken out from the blood purifier and divided into approximately equal 10 parts for each of them. It is preferable that the maximum value of UV (220 to 350 nm) absorbance in the hollow fiber membrane extract when the test defined by the manufacturing approval standard is performed is 0.10 or less at all sites. More preferably, the characteristics are maintained even after two years or more. Since the warranty period of the blood purifier is set to 3 years, it is particularly preferable that the characteristics are maintained for at least 3 years. It has been empirically confirmed that if the maximum value of UV (220 to 350 nm) absorbance is maintained at 0.06 or less after 1 year, it can be maintained for 3 years.

  Hereinafter, the effectiveness of the present invention 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 the following examples is as follows.

1. Measurement of water permeability The blood outlet circuit of the dialyzer (the outlet side from the pressure measurement point) is sealed with forceps and is subjected to total filtration. Purified water kept at 37 ° C is put into a pressurized tank, and the pressure is controlled by a regulator. The pure water is sent to a dialyzer kept warm in a 37 ° C constant temperature bath, and the amount of filtrate flowing out from the dialysate side is measured with a graduated cylinder. To do. The transmembrane pressure difference (TMP) is TMP = (Pi + Po) / 2
And Here, Pi is the dialyzer inlet side pressure, and Po is the dialyzer outlet side pressure. The TMP is changed at four points, the filtration flow rate is measured, and the water permeability (mL / hr / mmHg) is calculated from the slope of the relationship. At this time, the correlation coefficient between TMP and the filtration flow rate must be 0.999 or more. In order to reduce the pressure loss error due to the circuit, TMP is measured in the range of 100 mmHg or less. The water permeability of the hollow fiber membrane is calculated from the membrane area and the water permeability of the dialyzer.
UFR (H) = UFR (D) / A
Here, UFR (H) is the water permeability of the hollow fiber membrane (mL / m ² / hr / mmHg), UFR (D) is the water permeability of the dialyzer (mL / hr / mmHg), and A is the membrane area of the dialyzer (mL m ² ).

2. Calculation of membrane area The membrane area of the dialyzer is obtained as a reference for the inner diameter of the hollow fiber membrane.
A = n × π × d × L
Here, n is the number of hollow fiber membranes in the dialyzer, π is the circumference, d is the inner diameter (m) of the hollow fiber membrane, and L is the effective length (m) of the hollow fiber membrane in the dialyzer.

3. Elution amount of polyvinylpyrrolidone Extracted by the method defined in the dialysis-type artificial kidney device manufacturing approval standard, and polyvinylpyrrolidone in the extract was quantified by a colorimetric method.
In the case of a dry hollow fiber membrane, 100 ml of pure water is added to 1 g of the hollow fiber membrane and extracted at 70 ° C. for 1 hour. The obtained extract (2.5 ml), 0.2 molar aqueous citric acid solution (1.25 ml) and 0.006 normal iodine aqueous solution (0.5 ml) were mixed well and allowed to stand at room temperature for 10 minutes, and the absorbance at 470 nm was measured. Quantification was performed with a calibration curve obtained by measuring according to the above method using a standard polyvinylpyrrolidone.
In the case of a wet hollow fiber membrane, physiological saline was passed through the dialysate side channel of the module at 500 mL / min for 5 minutes, and then passed through the blood side channel at 200 mL / min. Thereafter, the solution was passed from the blood side to the dialysate side at a rate of 200 mL / min for 3 minutes and then freeze-dried to obtain a dry membrane, and the above quantification was performed using the dry membrane.

4. UV (220-350 nm) absorbance The absorbance in the wavelength range of 200 to 350 nm was measured using a spectrophotometer (U-3000 manufactured by Hitachi, Ltd.) for the extract extracted by the method defined in the dialysis artificial kidney device manufacturing approval standard. Measurement was made to determine the maximum absorbance in this wavelength range.
In this measurement, the hollow fiber membrane was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of a hollow fiber membrane in a dry state was weighed from each part and measured for all samples.
In the case of a wet hollow fiber membrane, the measurement was performed using a dry membrane obtained by processing in the same manner as the measurement of the polyvinylpyrrolidone elution amount.

5. Quantitative determination of hydrogen peroxide TiCl ₄ mixed in an equimolar ratio with an ammonium chloride buffer solution (PH 8.6) 0.2 ml in 2.6 ml of the extract extracted by the method defined in the dialysis artificial kidney device manufacturing approval standard. A mixture of a hydrogen chloride solution of 4- (2-pyridylazo) resorcinol with an aqueous Na salt solution was added, and 0.2 ml of a coloring reagent prepared to 0.4 mM was further added. After cooling, the absorbance at 508 nm was measured. A quantitative value was obtained using a calibration curve obtained by measuring in the same manner using a sample.
In this measurement, the hollow fiber membrane was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of a hollow fiber membrane in a dry state was weighed from each part and measured for all samples.
In the case of a wet hollow fiber membrane, the measurement was performed using a dry membrane obtained by processing in the same manner as the measurement of the polyvinylpyrrolidone elution amount. Moreover, when quantifying about the hollow fiber membrane of a wet state, it measured about the dry membrane obtained by drying with the freeze-dry method.

6. Measurement of polymer particle diameter The measurement was carried out by the following method.
(1) Sample preparation The dried membrane used was dried for 24 hours or more by critical point drying. The sample was cut in the fiber axis direction on the sample table to expose the inner surface of the hollow fiber membrane. As the wet membrane, water was passed through the inside and outside of the hollow fiber membrane, and this was immersed in water for at least 24 hours. This was split in the fiber axis direction on a sample stage provided in water, and a sample was formed in such a manner that the inner surface of the hollow fiber membrane was exposed.
(2) Measurement method The morphology of the inner surface of the hollow fiber membrane was observed with an atomic force microscope (AFM). AFM used was SPI3800N-SPA300 manufactured by Seiko Instruments. Wet observation was performed in pure water using an in-liquid observation kit, which is an option of this apparatus. A petri dish was used as the cell in which the sample was immersed during the observation. The observation mode was the DFM mode. The cantilever was a Si rectangular cantilever having a length of 450 μm, a width of 60 μm, and a thickness of 4 μm. The cantilever is commercially available as Si-DF3 from Seiko Instruments and has a spring constant of about 2 N / m. The cantilevers used were always new and had no contamination at the tip of the probe. The scanning speed of the probe was 0.25 to 1 Hz.
(3) Particle size measurement method It calculated using the analyzer attached to the said measuring apparatus. In order to measure the particle size by flattening the three-dimensional waviness of the sample, the AFM image after the measurement is subjected to three-dimensional tilt correction (TILT3) or the like. In some cases, flat processing or the like is also necessary. The particle size is determined by the line analysis process included in the software included with the device. The particles to be measured were randomly selected 120 particles, and particles that looked abnormally large and particles that looked abnormally small were excluded from the measurement. A specific measurement method will be described with reference to the drawings. FIG. 1 is a top view of particles whose particle size is determined by line analysis. FIG. 2 is a cross-sectional profile of the particles of FIG. Let the coordinates of each measurement point be (x, y, z). z is the height at the measurement point. The particle diameter is the distance between points A and C, but AC must be a line segment passing through the vertex B of the particle. Also, the particles are not always perfect circles. It is assumed that the points A and C take the longest line segment among the line segments passing through the vertex B. The distance between ACs, that is, the particle diameter is expressed by the following formula.
D = ((x ₁ −x ₂ ) ² + (y ₁ −y ₂ ) ² ) ^1/2

7, β2MG clearance ACD-added bovine plasma adjusted to a total protein concentration of 7.0 ± 0.5g / dL and kept at 37 ° C in a blood purifier with a membrane area of 1.5m ² (inside of hollow fiber membrane inner diameter) and blood flow rate of 200mL The commercial dialysate is flowed at 500 mL / min and the filtration flow rate is 15 mL / min. The blood purifier outlet plasma is a recycling circuit that returns to the beaker containing the original plasma, along with ACD-added physiological saline for the filtration flow rate. To the bovine plasma, human β2MG is added to a concentration of 0.05 to 0.1 mg / L. Measure the β2MG concentration in the blood inlet / outlet and dialysate outlet for 20 min at 5 min intervals from the start of dialysis. The clearance is calculated using the following formula.
CL (β2MG) = 200 × [(200 × CBi) − (185 × CBo)] / (200 × CBi)
Here, CBi: blood inlet concentration, CBo: blood outlet concentration.
Also, when% MBE calculated by the following formula exceeds ± 50%, it is not adopted as data.
% MBE = 100 × (MB-MD) / MD
Here, MB: (200 × CBi) − (185 × CBo), MD: 515 × CDo.

8. Albumin leakage amount 37 ° C. bovine blood to which citrate was added to suppress coagulation was used. Dilute with bovine plasma and adjust hematocrit to 30%. The blood was fed to a blood purifier at 200 mL / min, and the blood was filtered at a rate of 20 mL / min. At this time, the filtrate is returned to blood to be a circulatory system. In order to prevent hemolysis, the blood purifier is sufficiently replaced with physiological saline in advance. It was confirmed that a predetermined filtration flow rate was obtained 5 minutes after the start of circulation, and about 1 cc of the filtrate was sampled every 15 minutes from 15 minutes after the start. In addition, blood at the inlet side and outlet side of the blood purifier was sampled at 15 minutes, 60 minutes, and 120 minutes after the start, and plasma was obtained by centrifugation, which was used as a test solution. The collected sample is subjected to bromcresol green (BCG method) using A / GB B-Test Wako (manufactured by Wako Pure Chemical Industries), and the albumin concentration in the filtrate and blood / plasma is calculated. Based on the concentration, the sieving coefficient of albumin was obtained by the following equation.
SCalb = 2 × Cf / (Ci + Co)
Here, Cf is the albumin concentration in the filtrate, Ci is the albumin concentration in blood and plasma at the blood purifier inlet, and Co is the albumin concentration in blood and plasma at the blood purifier outlet. By substituting the data at 15 minutes and 120 minutes into this equation, the sieving coefficient of albumin at 15 minutes and 120 minutes can be obtained.
Moreover, the amount of albumin leak in terms of 3L water removal can be determined as follows. Sampling is performed at 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, and 120 minutes. Similarly, the albumin concentration in the filtrate is calculated by the BCG method of A / GB-Test Wako. Using these data, albumin leak (TAL [mg / dL]) on the vertical axis, ln (time [min]) (lnT) on the horizontal axis, and spreadsheet software (ex. Microsoft EXCEL-XP) To draw a fitting curve by linear approximation and obtain constants a and b in the relational expression TAL = a × lnT + b (correlation coefficient is preferably 0.95 or higher, more preferably 0.97 or higher, and 0.99 or higher. More preferred). The average albumin leak concentration [mg / dL] is calculated by integrating from T = 0 to T = 240 using this equation TAL = a × lnT + b and dividing this by 240 [min]. By multiplying the calculated average albumin leak concentration by 30 dL, the amount of albumin leak in terms of 3 L water removal in the present application can be obtained.

Example 1
In a kneading and dissolving machine, 1 part by mass of polyethersulfone (Sumika Excel (registered trademark) 4800P manufactured by Sumika Chemtex Co., Ltd.), 0.144 part by mass of polyvinylpyrrolidone (Collidon (registered trademark) K90 manufactured by BASF) and dimethylacetamide (DMAc) 1 part by mass was charged and kneaded by stirring for 2 hours. Subsequently, a mixed solution of 3.02 parts by mass of DMAc and RO water 0.16 parts by mass was added. Stirring was continued for an additional hour by increasing the number of revolutions of the stirrer and dissolved uniformly. At this time, kneading and dissolution were performed in a nitrogen atmosphere. The temperature during kneading and dissolution was cooled so as not to exceed 40 ° C. Subsequently, the inside of the system was depressurized to −500 mmHg using a vacuum pump, and the film forming solution was defoamed. After the defoaming was completed, the inside of the system was again purged with nitrogen and maintained in a weakly pressurized state. The polyvinyl pyrrolidone having a hydrogen peroxide content of 130 ppm was used. The obtained film-forming solution was passed through a two-stage sintered filter in order, and then discharged from a tube-in orifice nozzle heated to 75 ° C. together with a 53% by mass DMAc aqueous solution previously degassed as a hollow forming agent. After passing through a 400 mm dry part cut off from the outside air, it was coagulated in a 20 mass% DMAc aqueous solution at 60 ° C., and it was rolled up in a wet state. A film was wound around a bundle of about 10,000 hollow fiber membranes, cut to a length of 27 cm, and washed in hot water at 80 ° C. for 30 minutes × 4 times. This was dried at 60 ° C. for 3 hours in a ventilator having a passage in the longitudinal direction, and then dried at 50 ° C. for 20 hours. From the start of drying to the end of drying, drying was carried out by reversing the direction of ventilation by 180 degrees every hour. Air used for ventilation was conditioned to 35% RH. As a result, a dried hollow fiber membrane was obtained. The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 28 μm, a water content of 3.0% by mass, and the ratio of the hydrophilic polymer to the hydrophobic polymer was 3.1% by mass. The amount of PVP elution was 3 ppm, which was a satisfactory level.

  The obtained polysulfone-based hollow fiber membrane is equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of the dried polysulfone-based hollow fiber membrane is weighed from each part, and is determined as a dialysis-type artificial kidney device manufacturing approval standard. An extract was obtained by the test, and the amount of hydrogen peroxide eluted and UV (220-350 nm) absorbance in the extract were measured. Both measured values were stable at a low level in all sites, and the maximum value of each measured value was 2 ppm and 0.03.

Insert the polysulfone-based hollow fiber membrane prepared by the above method into a polycarbonate container, adhesively fix both ends with urethane resin, cut the resin end, open the hollow, and attach the cap with the inlet A blood purifier having a polysulfone-based hollow fiber membrane having an effective length of 215 mm and a membrane area of 1.5 m ² was produced. On the other hand, nitrogen was bubbled into deoxygenated water having a dissolved oxygen concentration of 0.05 ppm by passing RO water through a hollow fiber membrane deaeration module to prepare nitrogen-saturated water. After this nitrogen-saturated water was filled into the blood side of the blood purifier at 200 ml / min for 5 minutes, the blood side was stopped and the filled water was expelled with nitrogen gas at 60 ° C. at a pressure of 0.1 MPa. By continuing, the moisture content of the hollow fiber membrane was adjusted to 30% by mass. All the blood and dialysate inlets and outlets of the blood purifier dried under these conditions are plugged with caps made of ethylene-propylene synthetic rubber, the outer layer is a biaxially stretched polyamide film with a thickness of 25 μm, and the inner layer is unstretched with a thickness of 50 μm. It sealed in the packaging bag which consists of a laminated body of a polyethylene film. After being stored in a sealed state at room temperature for 72 hours, 25 kGy of γ rays were irradiated.

  Table 1 shows the characteristics of the blood purifier obtained by the above method and the characteristics of the polysulfone-based hollow fiber membrane in the blood purifier. The polysulfone-based hollow fiber membrane obtained in this example had a low hydrogen peroxide elution amount and a low UV (220-350 nm) absorbance and maintained high quality even after γ-irradiation. Other characteristics were also good. Moreover, the amount of polyvinyl pyrrolidone eluted from the blood purifier was low, the water permeability after priming treatment and the long-term storage stability were good, and the blood purifier was highly practical.

(Comparative Example 1)
In Example 1, Comparative Example 1 was carried out in the same manner as in Example 1 except that 7% RH dehumidified air was used as air used for ventilation drying, and the second stage drying temperature was changed to 40 ° C. A polysulfone-based hollow fiber membrane and a blood purifier were obtained. The results are shown in Table 2.
The polysulfone-based hollow fiber membrane obtained in this comparative example was poor in permselectivity. This is considered to be caused by the fact that the swelling ratio of the polymer particles was lowered because dehumidified air was used to dry the hollow fiber membrane.

(Comparative Example 2)
In Example 1, polyvinyl pyrrolidone having a hydrogen peroxide content of 500 ppm is used as a raw material, the kneading and dissolution temperature is 85 ° C., nitrogen gas replacement in the raw material supply system and dissolution tank is stopped, and the hollow fiber membrane is dried at normal pressure A hollow fiber membrane was obtained in the same manner as in Example 1 except that drying was performed by irradiating with microwaves. The microwave irradiation output was 2 kW until the moisture content in the hollow fiber membrane reached 65% by mass, and thereafter 0.8 kW, and dried until the moisture content became 0.5% by mass. Further, from the start of drying to the end of drying, dehumidified air (7% RH) was ventilated from the lower part of the yarn bundle to the upper part at a wind speed of 8 m / sec. The maximum temperature reached by the hollow fiber membrane during the drying was 65 ° C. Also in this comparative example, since it was dried using dehumidified air, the swelling ratio of the polymer particles was low and the selective permeability was poor. In addition, the amount of hydrogen peroxide eluted from the hollow fiber membrane obtained in this comparative example was high, and the amount of hydrogen peroxide eluted was varied greatly depending on the sampling location, and the quality was low. Also in this comparative example, since it was dried using dehumidified air, the swelling ratio of the polymer particles was low and the selective permeability was poor.

  Using the hollow fiber membrane obtained by the above method, a blood purifier was assembled in the same manner as in Example 1 except that water that was not subjected to deoxygenation treatment and inert gas replacement treatment was used, and stored for 50 hours. Sterilization was performed.

  As described above, the blood purifier obtained in this comparative example is inferior in selective permeability and increased in elution amount of hydrogen peroxide by γ-irradiation and inferior in long-term storage stability. It was quality. Further, the water permeability after the priming treatment was inferior due to deterioration due to the γ-ray irradiation. These results are shown in Table 2.

(Comparative Example 3)
In Comparative Example 2, the blood purifier was assembled and sterilized in the same manner as in Comparative Example 2, except that the inert gas was not exchanged in the blood purifier and the packaging bag, and the storage period until sterilization was 120 hours. went. The characteristics of the obtained hollow fiber membrane and blood purifier are shown in Table 2. In this comparative example, in addition to the problems of Comparative Example 2, the oxygen gas present in the atmosphere in the module is dissolved in the hollow fiber membrane-containing water, so that the effect of suppressing deterioration of polyvinylpyrrolidone due to γ-ray irradiation is reduced. The elution amount of hydrogen peroxide increased by γ-ray irradiation, and the UV (220-350 nm) absorbance deteriorated. Therefore, long-term storage stability was further deteriorated. Moreover, the water permeability after the priming treatment was inferior, and the blood purifier was of low quality.

(Example 2)
1 part by weight of polyethersulfone (Sumika Chemtex, Sumika Excel (registered trademark) 4800P), 0.21 part by weight of polyvinylpyrrolidone (BASF Koridone (registered trademark) K-90), 1.5 parts by weight of DMAc Kneading with a screw type kneader. The obtained kneaded material was put into a stirring type dissolution tank charged with 2.57 parts by mass of DMAc and 0.28 parts by mass of water, and stirred for 3 hours to dissolve. The kneading and dissolution were cooled so that the internal temperature did not rise above 30 ° C. Subsequently, the inside of the system was depressurized using a vacuum pump to defoam the film forming solution. The polyvinyl pyrrolidone having a hydrogen peroxide content of 100 ppm was used, and the supply tank in the raw material supply system and the dissolution tank were replaced with nitrogen gas. The obtained film-forming solution was passed through a two-stage filter, and then discharged from a tube-in orifice nozzle heated to 70 ° C. at the same time as a 50% by mass DMAc aqueous solution previously degassed as a hollow forming agent. And then solidified in water at 60 ° C. The hollow fiber membrane pulled up from the coagulation bath was passed through a 85 ° C. water-washing tank for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound around a basket. A polyethylene film was wound around a bundle of about 10,000 hollow fiber membranes, and then immersed and washed in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes × 2 times.

  The obtained wet hollow fiber membrane bundle was introduced into a microwave irradiation type dryer and dried under the following conditions. After heating the hollow fiber membrane bundle for 30 minutes under a reduced pressure of 7 kPa at an output of 1.5 kW, the microwave irradiation was stopped and simultaneously the pressure was increased to 1.5 kPa and maintained for 3 minutes. Subsequently, the degree of vacuum was returned to 7 kPa, and the hollow fiber membrane bundle was heated for 10 minutes at an output of 0.5 kW by irradiating microwaves. At this time, the maximum temperature reached on the surface of the hollow fiber membrane bundle was 65 ° C. The moisture content of the hollow fiber membrane bundle before drying is 315% by mass, the moisture content of the hollow fiber membrane bundle after the first stage is 29% by mass, and the moisture content of the hollow fiber membrane bundle after the second stage is 16% by mass. Met. Subsequently, drying was performed by an alternate ventilation direction switching method using humidity-controlled air similar to Example 1, and a dry hollow fiber membrane having a moisture content of 3.3% by mass was obtained. The obtained hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 27 μm.

  The obtained hollow fiber membrane was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of the dry hollow fiber membrane was weighed from each site, and tested according to the dialysis type artificial kidney device manufacturing approval standard. An extract was obtained, and the amount of hydrogen peroxide eluted and UV (220-350 nm) absorbance in the extract were measured. Both measured values were stable at a low level in all sites, and the maximum value of each measured value was 2 ppm and 0.04.

Using the hollow fiber membrane thus obtained, a blood purifier was assembled in the same manner as in Example 1. The blood purifier was prepared in the same manner as in Example 1 except that the moisture content of the hollow fiber membrane was adjusted to 280% by mass and the storage time until sterilization was 216 hours. Irradiation was performed.
The hollow fiber membrane and blood purifier obtained in this example were of high quality similar to those obtained in Example 1. The results are shown in Table 1.

(Example 3)
In the same manner as in Example 2, 18% by mass of polysulfone (P-3500 manufactured by Amoco), 9% by mass of polyvinylpyrrolidone (Collidon (registered trademark) K-60 manufactured by BASF), 68% by mass of dimethylacetamide (DMAc), A film forming solution consisting of 5% by mass of water was prepared. As the polyvinyl pyrrolidone, one having a hydrogen peroxide content of 100 ppm was used. The obtained film-forming solution was passed through a two-stage filter, and then discharged from a tube-in orifice nozzle heated to 40 ° C. at the same time as a 55 mass% DMAc aqueous solution previously subjected to vacuum degassing treatment as a hollow forming agent. After passing through a 600 mm air gap portion that was blocked from outside air, it was solidified in water at 50 ° C. The draft ratio was 1.1. The hollow fiber membrane pulled up from the coagulation bath was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up. A bundle of about 10,000 hollow fiber membranes was immersed in pure water and washed in an autoclave at 121 ° C. for 1 hour. Subsequently, it was dried in the same manner as in Example 1. The moisture content of the hollow fiber membrane after drying was 1.6% by mass. The resulting hollow fiber membrane had an inner diameter of 201 μm and a film thickness of 43 μm.

  The obtained hollow fiber membrane was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of the dry hollow fiber membrane was weighed from each site, and tested according to the dialysis type artificial kidney device manufacturing approval standard. An extract was obtained, and the amount of hydrogen peroxide eluted and UV (220-350 nm) absorbance in the extract were measured. Both measured values were stable at a low level in all sites, and the maximum value of each measured value was 3 ppm and 0.04.

  Using the hollow fiber membrane thus obtained, the water used for adjusting the moisture content of the hollow fiber membrane is degassed water, and the standing time from packaging to γ-ray irradiation is changed to 120 minutes. A blood purifier was obtained in the same manner as in Example 1. Sealed blood purifier and oxygen scavenger (Tamotsu (registered trademark) manufactured by Oji Tac Co., Ltd.) is sealed with a packaging bag to remove oxygen from the packaging bag. Measures were taken to prevent oxygen gas from entering inside. The hollow fiber membrane and blood purifier obtained in this example were of high quality similar to those obtained in Example 1. The results are shown in Table 1.

Example 4
In the same manner as in Example 2, 17% by mass of polysulfone (Amoco P-1700), 5% by mass of polyvinylpyrrolidone (BASF Kollidon (registered trademark) K-60), 73% by mass of dimethylacetamide (DMAc), A film forming solution consisting of 5% by mass of water was prepared. As the polyvinyl pyrrolidone, one having a hydrogen peroxide content of 120 ppm was used. The obtained membrane-forming solution is passed through a filter, and then discharged from a tube-in orifice nozzle heated to 40 ° C. simultaneously with a 35 mass% DMAc aqueous solution subjected to vacuum degassing treatment as a hollow forming agent, and blocked from the outside air by a spinning tube. After passing through the 600 mm air gap portion, it was solidified in water at 50 ° C. The hollow fiber membrane pulled up from the coagulation bath was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up. About 10,000 bundles of the hollow fiber membranes were immersed in pure water, washed in an autoclave at 121 ° C. for 1 hour, and dried in the same manner as in Example 1. The water content was 1.4% by mass. The maximum temperature reached by the hollow fiber membrane during the drying treatment was 56 ° C. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 43 μm.

  The obtained hollow fiber membrane was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of the dry hollow fiber membrane was weighed from each site, and tested according to the dialysis type artificial kidney device manufacturing approval standard. An extract was obtained, and the amount of hydrogen peroxide eluted and UV (220-350 nm) absorbance in the extract were measured. Both measured values were stable at a low level in all sites, and the maximum value of each measured value was 2 ppm and 0.03.

  A blood purifier was assembled in the same manner as in Example 1 except that the water content of the hollow fiber membrane was changed to 360% by mass using the hollow fiber membrane thus obtained. A sterilized blood purifier was obtained in the same manner as in Example 1 except that it was changed to γ rays after time and changed to irradiate the electron beam using an electron beam irradiator having an acceleration voltage of 5000 kV. The hollow fiber membrane and blood purifier obtained in this example were of high quality, similar to those obtained in Example 3. The results are shown in Table 1.

(Comparative Example 4)
In the same manner as in Example 2, a film forming solution comprising 13% by mass of polysulfone, 5% by mass of polyvinylpyrrolidone, 77% by mass of dimethylacetamide, and 5% by mass of water was prepared. The polyvinyl pyrrolidone having a hydrogen peroxide content of 500 ppm was used. A hollow fiber membrane was obtained by discharging from a tube-in orifice nozzle heated to 85 ° C. simultaneously with a 65 mass% DMAc aqueous solution subjected to vacuum deaeration treatment as a hollow forming agent. A blood purifier was prepared using the obtained hollow fiber membrane, and the sterilization treatment was performed in the same manner as in Comparative Example 3 except that the blood purifier was not sealed and the storage period until sterilization was 216 hours. . The results are shown in Table 2. In this comparative example, the cross-sectional structure of the hollow fiber membrane was a network structure. In addition, the water present in the hollow fiber membrane is not saturated with nitrogen, and the blood and dialysate inlet / outlet were not plugged. It is considered that the surroundings were filled with air, and the deterioration of the hollow fiber membrane material was further increased as compared with Comparative Example 3.

(Reference Examples 1 and 2)
In the method of Example 1, the hollow fiber membranes were the same as in Example 1 except that after packaging, the samples were left to stand at room temperature for 24 hours and 40 hours, respectively, so that γ-ray irradiation was performed under the same conditions as in Example 1. And got a blood purifier. These characteristics are shown in Table 3. In this comparative example, since the time from sealing to γ-ray treatment is short, the blood purifier obtained in Example 1 was inferior in water permeability after priming. Therefore, the blood purifier of this comparative example has a low practicality. Moreover, it was shown that the elapsed time from packaging to γ-ray irradiation has an influence on the expression of water permeability after priming.

  Since the blood purifier of the present invention is of a dry type, it has advantages such as being light, not freezing, and difficult to propagate various germs. In addition, the blood purifier of the present invention is excellent in water permeability performance after the priming process, and has an advantage that the priming process can be performed in a short time. In addition, since the radical scavenger is not included, there is an advantage that when it is used for blood purification, an operation for washing and removing the radical scavenger in advance is unnecessary. Furthermore, in the present invention, an effect that cannot be achieved by the prior art is exhibited in that the deterioration of the hollow fiber membrane due to radiation irradiation is suppressed even when irradiated with radiation in the dry state and in the absence of a radical scavenger. Therefore, there is little production of hydrogen peroxide due to the deterioration reaction, and the blood purifier of the present invention has the advantage of excellent long-term storage stability. For example, the hollow fiber membrane loaded in the blood purifier suppresses the generation of hydrogen peroxide even when irradiated with radiation, and the deterioration of polyvinylpyrrolidone and the like caused by the hydrogen peroxide is suppressed. Therefore, even if the blood purifier is stored for a long time, the maximum value of UV (220-350 nm) absorbance, which is the dialysis-type artificial kidney device manufacturing approval standard, can be maintained at 0.10 or less, and the blood purifier can be stored for a long time. There is an advantage that safety can be ensured. Therefore, it is important to contribute to the industry.

It is a conceptual diagram at the time of determining a particle size by line analysis. It is a figure which shows the cross-sectional profile of the particle | grains of FIG. It is sectional drawing of a blood purifier. It is a schematic diagram showing the general tendency of the performance expression property after a priming process, and the elapsed time before a sterilization process.

Explanation of symbols

1: Blood purifier 2: Housing 3: Hollow fiber membrane bundle 4: Adhesive resin 5: Cap 6a: Dialysate inlet 6b: Dialysate outlet 7a: Blood inlet 7b: Blood outlet

Claims (6)

It consists of a polysulfone resin and polyvinylpyrrolidone, at least the blood contact side surface is an aggregate of polymer particles, the average particle diameter in the wet state of the polymer particles is 10 to 300 nm, and the average particle diameter in the dry state of the polymer particles the ratio of mean particle diameter is not less than 1.1, the blood purifier of the hollow fiber membrane water content of Ru der less 600 weight% is filled and sealed with packaging bag, aged at least 48 hours in a wet state for by irradiating the radiation from the 90% water permeability of at least 10 minutes time point after the priming process is the water permeability at 24 hours after post-priming, blood albumin leakage amount is 1.8~2.6g / 4hr Purifier. After adjusting the hollow fiber membrane in the blood purifier to a water content of 5 to 600 mass% using degassed water, the outside air and water vapor are shut off with all blood and dialysate inlets and outlets plugged. The blood purifier according to claim 1 , wherein the blood purifier is sealed with a packaging bag and irradiated with radiation. The blood purifier according to claim 2 , wherein the deaerated water used for adjusting the water content of the hollow fiber membrane in the blood purifier is deoxygenated water. The blood purifier according to claim 2 , wherein the deaerated water used for adjusting the moisture content of the hollow fiber membrane in the blood purifier is an inert gas saturated water. The blood purifier according to any one of claims 2 to 4 , wherein the dissolved oxygen concentration of deaerated water is 0.5 ppm or less. After storing the blood purifier after irradiation for one year or more at room temperature, the hollow fiber membrane is taken out from the blood purifier, and the hollow fiber membrane is divided into 10 pieces in the longitudinal direction. The blood purifier according to any one of claims 1 to 5 , wherein the maximum value of UV (220 to 350 nm) absorbance in the hollow fiber membrane extract when a test defined by the manufacturing approval standard is performed is 0.10 or less.