JP4596171B2 - 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 purifiers and the like, and blood compatibility, blood with high safety and stability of performance 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, Modules such as hemodialyzers, hemofilters or hemodialyzers using dialysis membranes using polymers such as methyl methacrylate and polyacrylonitrile and ultrafiltration membranes as separation materials are widely used. In particular, modules using hollow fiber membranes as a separating material are highly important in the field of blood purifiers due to advantages such as reduction of extracorporeal blood volume, high efficiency of removing substances in blood, and productivity during module production. .

  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 polysulfone alone, the polysulfone resin is hydrophobic, so it has poor affinity with blood and causes an airlock phenomenon. Can not.

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. Specifically, a method of blending a polyhydric alcohol such as polyethylene glycol is disclosed (for example, 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 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.

Techniques for improving blood compatibility by controlling irregularities on the blood contact surface have been disclosed (see Patent Documents 5 and 6). In these techniques, the unevenness of the surface is defined from values measured by a white interference microscope. In Patent Document 1, it is said that the adhesion of platelets is preferably 10 ⁻⁶ cells / cm ² or less. A membrane having this characteristic is estimated to have a platelet retention rate (details will be described later) of approximately 100% in the present invention. However, in membranes with extremely high platelet retention, platelets activated by contact with the membrane are released into the blood, which triggers activation of the entire circulating blood in the body, resulting in biocompatibility. It may cause deterioration, which is not preferable.

In addition, as can be said in common with the technique of the above-mentioned patent document, a smooth blood contact surface may have a large contact area with blood cells, which may cause activation of blood cells. Control of the physical properties of the surface is considered to be effective as a technique for improving blood compatibility, but this approach alone has its own limitations as long as it uses materials that are essentially foreign to the living body. I must say that there is.
JP 2000-126286 A JP-A-11-309353

  On the other hand, in a blood purifier, radiation treatment may be performed for the purpose of crosslinking or sterilizing polyvinyl pyrrolidone in the 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, denaturation continued during long-term storage after irradiation, and the antithrombogenicity could be reduced before actual use.

For example, as a method for solving the above problems, 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 is excellent in antithrombogenicity and stored for a long time. However, a technique capable of maintaining an antithrombotic state is disclosed (see Patent Document 7).
JP 2000-135421 A

  However, the blood purifier of the technique disclosed in the above-mentioned patent document is a method applied to a so-called wet type blood purifier that is irradiated with radiation in a water-filled state. 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.

  In addition, when the blood purifier is used as a dialyzer for an artificial kidney, it is necessary to perform a complete sterilization process before use. For the sterilization treatment, formalin, ethylene oxide gas, high-pressure steam sterilization, γ-ray radiation or electron beam irradiation sterilization methods, and the like are used, each exhibiting a unique effect. Among these, the sterilization method by radiation or electron beam irradiation is adopted as a preferable sterilization method because it can process the object to be processed in a packaged state and has an excellent sterilization effect.

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. (For example, refer to Patent Document 8). However, this method has the same problem as that of Patent Document 7.
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 9). 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 10). 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 around the hollow fiber membrane is 40% or less is disclosed. . (For example, refer to Patent Document 11). 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 11, 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 with 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 12). This patent document discloses that the amount of the hydrophilic polymer per 1 m ² of the surface to be treated 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 13 to 15).
Japanese Patent Application Laid-Open No. 62-74364 JP-A-62-204754 WO98 / 58842 pamphlet

  As deterioration due to radiation irradiation using the oxygen scavenger described above, odor generation occurs in Patent Document 13, substrate strength and dialysis performance decrease in Patent Document 14, and substrate strength decrease and aldehyde in Patent Document 15. 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 for radiation sterilization of a liquid processing device in which a film protective agent is filled in a wet or semi-wet shape in an inert gas atmosphere (see, for example, Patent Document 16). 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 regarded as a technique having the same problem as that of Patent Document 8.
JP-A-8-280795

For the purpose of maintaining 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 17). 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. No (see, for example, Patent Document 18).
JP 2003-245526 A

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 separation 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 that is harmless to the human body, and a sterilization step of performing high-pressure steam sterilization while maintaining the wet state. Disclosed is a method for sterilizing a dialysis machine. 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 is a blood purifier that is realized at a high level of blood compatibility, performance retention at the time of blood contact, and safety, has excellent water permeability after priming treatment, and has high long-term storage stability. It is to provide.

The present invention relates to a blood purifier having a membrane area of 1.5 m ² (on the basis of hollow fiber membrane inner diameter) prepared using a polysulfone-based hollow fiber membrane containing polyvinylpyrrolidone , wherein the water content of the polysulfone-based hollow fiber membrane is determined. The concentration was adjusted to 0.8 to 600% by weight, and after measuring at least 48 hours after sealing all the blood and dialysate entrances and exits of the blood purifier, measurement was performed using the blood purifier by irradiation . The water permeability at 10 minutes after the priming treatment was 90% or more of the water permeability at 24 hours after the priming treatment, and heparinized human whole blood was perfused on the blood contact side of the blood purifier at a flow rate of 150 mL / min. In this case, the blood purifier is characterized in that the platelet retention after 60 minutes is 70% or more and 98% or less.
In this case, 1000 mL of the solution containing the cationic dye was filled on the blood contact side and dialysate side of the blood purifier, and the remaining cationic dye solution was perfused on the blood contact side of the blood purifier at a flow rate of 200 mL / min. In this case, the cationic dye adsorption rate after 5 minutes is preferably 40% or more and 70% or less.
In this case, heparin-added human whole blood is flowed at a flow rate of 150 mL / min on the blood contact side of a blood purifier having a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard) prepared using a polysulfone-based hollow fiber membrane. When the perfusion is performed, the platelet factor 4 concentration ratio (PF4 increase rate) before and after blood perfusion is preferably 5 times or less.
Also, in this case, the outside air in a state where the water content using degassed water have been sealed all doorways blood and dialysate blood purifier packed with adjusted polysulfone based hollow fiber membrane in 5 to 600 wt% It is preferable to irradiate with radiation by sealing with a packaging bag that blocks water vapor.
In this case, the deaerated water present in and around the polysulfone-based hollow fiber membrane is preferably deoxygenated water.
In this case, it is preferable that the deaerated water present in and around the polysulfone-based hollow fiber membrane is an inert gas saturated water.
In this case, the dissolved oxygen concentration of the deaerated water is preferably 0.5 ppm or less.
Also, in this case, the blood purifier after the irradiation after storage at room temperature for more than 1 year, taken out of the hollow fiber membrane from the blood purifier, by dividing the hollow fiber membranes 10 in the longitudinal direction, each 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 on the part is 0.10 or less.

The blood purifier of the present invention is adsorbed with a cationic dye, which is a measure of the charge state and hydrophilic-hydrophobic balance of the inner surface (blood contact side surface) of the polysulfone-based hollow fiber membrane filled in the blood purifier. The rate is optimized, and the platelet retention rate during blood perfusion is within a predetermined range, so that blood compatibility, performance retention when using blood contact, and safety are realized at a high level.
In addition, 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 bacteria 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, even in the dry state and in the absence of a radical scavenger, there is an effect that cannot be achieved by the prior art that the deterioration of the polysulfone-based hollow fiber membrane due to irradiation is suppressed even when irradiated with radiation. Since it is expressed, the production of hydrogen peroxide due to the deterioration reaction is small, 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 a dialysis-type 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 ensured.

Hereinafter, the present invention will be described in detail.
The hollow fiber membrane used in the present invention is characterized by being composed of a polysulfone resin containing 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, “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 the efficiency of imparting hydrophilicity, while it is preferable to use a high molecular weight in terms of reducing the amount of elution, but as appropriate depending on the required characteristics of the hollow fiber membrane of the final product. 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 hydrogen peroxide elution amount in the hollow fiber membrane bundle 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 presence of hydrogen peroxide in the polyvinyl pyrrolidone used as a raw material is considered to trigger the oxidative degradation of polyvinyl pyrrolidone, which increases explosively with the progress of oxidative degradation, and further oxidative degradation of polyvinyl pyrrolidone. It is thought that it promotes. Therefore, setting the hydrogen peroxide content to 300 ppm or less is the first means for suppressing the oxidative deterioration 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, a preferred embodiment is to shield the light using an aluminum foil laminate bag and enclose it 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. Also, 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. In addition, 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 production method of the polysulfone-based hollow fiber membrane of the present invention is not limited in any way, but a hollow fiber membrane type that can be produced by a method as disclosed in, for example, JP-A No. 2000-300663 is preferable. For example, 16 parts by mass of polyethersulfone (4800P, manufactured by Sumitomo Chemical Co., Ltd.) and 5 parts by mass of polyvinylpyrrolidone (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 composition ratio of the polyvinyl pyrrolidone in the membrane with respect 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%. It is preferable that it is mass%. When the proportion of polyvinyl pyrrolidone is too small with respect to the polysulfone-based resin, the hydrophilicity imparting effect of the film may be insufficient. Therefore, the proportion is more preferably 1.5% by mass or more, and 2.0% by mass or more. Is more preferable, and 2.5% by mass or more is even 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.

  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 polyvinyl pyrrolidone exceeds 10 ppm, side effects and complications during long-term dialysis due to the eluted polyvinyl pyrrolidone may occur. A method for satisfying the characteristics is optional without limitation. For example, it can be achieved by setting the composition ratio of polyvinylpyrrolidone to the polysulfone resin within the above range, optimizing the film forming conditions of the hollow fiber membrane, or the like. More preferably, the amount of polyvinylpyrrolidone eluted is 8 ppm or less, more preferably 6 ppm or less, and still more preferably 4 ppm or less. The elution amount of the polyvinylpyrrolidone 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. 100 ml of RO water is added to this, and the extract obtained by performing extraction at 70 ° C. for 1 hour is quantified.

  A measure for reducing the elution amount of the polyvinyl pyrrolidone is not limited and can be achieved, for example, by optimizing the composition ratio of polyvinyl pyrrolidone relative to the polysulfone resin and the film forming conditions of the hollow fiber membrane. In particular, optimization of the cleaning method is important.

The polysulfone-based hollow fiber membrane of the present invention is prepared by using heparinized human whole blood at 150 mL / min on the blood contact side of a blood purifier having a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard) prepared using the hollow fiber membrane. It is preferable that the platelet retention after 60 minutes is 70% or more and 98% or less when perfused at a flow rate of.

  As an index indicating blood compatibility, there is a method for evaluating adhesion of platelets when contacted with blood. Conventionally, in order to improve blood compatibility, studies have been made with the goal of reducing the amount of platelet adhesion (improving platelet retention). Activation is considered unavoidable in some sense, even if the degree of difference. In the case of a membrane with a very high platelet retention rate, the apparent blood compatibility is judged to be good, but if the view is changed, even the platelets activated by contact with foreign materials are in the blood. May have been released. From such a viewpoint, as a result of further intensive studies, it was found that the retention rate of platelets is actually preferably 70% to 98%, and the present invention has been achieved. If the platelet retention rate is less than this range, the amount of platelet adhesion increases, and blood clots may be easily formed or the blood purification function may be reduced. Therefore, the platelet retention rate is more preferably 75% or more, and further preferably 80% or more. In addition, if it is larger than this range, activated platelets are also released into the blood, so blood components such as blood cells and plasma circulating in the living body are stimulated, and the whole blood in the living body is activated Therefore, there is no denying the tendency to clot and in some cases the risk of embolization. Therefore, the platelet retention is more preferably 97% or less, still more preferably 96% or less, and even more preferably 95% or less.

In the present invention, the water permeability at 10 minutes after the priming treatment of a blood purifier having a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard) prepared using a polysulfone-based hollow fiber membrane is 24 hours after the priming treatment. 90% or more of the water permeability (hereinafter simply abbreviated as “permeability ratio”), and when heparinized human whole blood was perfused on the blood contact side of the blood purifier at a flow rate of 150 mL / min, 60 minutes A blood purifier having a subsequent platelet retention of 70% or more and 98% or less.
Looking at the technical meaning of 90% of the water permeability ratio, the water permeability at 10 minutes after the priming process of the blood purifier is 24 hours after the priming process. This means that the blood purifier is in a stable and stable state. It is a condition to operate. The fact that the blood purifier of the present invention achieves 90% or more of the water permeability ratio at the time of 10 minutes after the priming process means that it functions in a very short time. The blood purifier is subjected to a priming process using a dialysate or physiological saline before use, but the time until the blood purifier is actually used after the priming process varies depending on each dialysis center. In some cases, blood purification is performed immediately after the priming process, but the priming process may be performed on the previous day.
The present invention can be regarded as expressing a highly optimal dialysis state immediately after the start of dialysis, regardless of the elapsed time after the priming process at each dialysis center. In such advanced dialysis state, there is a tendency to reduce the amount of platelet adhesion, and not only greatly improves the platelet retention rate, but also can keep the activation of blood in the living body relatively low. It can be said.

  When looking closely at such a state based on FIG. 5, the blood purifier of the present invention can perform dialysis with the highest function of the blood purifier, which can be said to be a constant state, at 10 minutes after the priming process. Therefore, not only is it possible to discharge more waste products out of the body within a limited dialysis time, but it also reduces the amount of platelet adhesion, The activation of blood can be kept relatively low. However, in FIG. 5, when the water permeability ratio is as low as 60% or 80%, it means that there are many hydrophobic parts in the hollow fiber membrane in the blood purifier, and the adhesion amount of platelets is reduced. In terms of decreasing and keeping the activation of blood in the living body relatively low, a disadvantageous state is conceivable as compared with the performance with a water permeability ratio of 90% or more.

Therefore, the present invention further reduces the adhesion amount of platelets in a state in which the advanced performance of the blood purifier can be exhibited, that is, in an appropriate condition where the water permeability ratio is 90% or more, and platelet retention. This is a pursuit of what conditions can greatly increase the rate. In that case, it is actually found that the retention rate of platelets is preferably 70% to 98%.
In a blood purifier having only a function of a water permeability ratio of about 60%, it is not easy to keep the activation of blood in a living body relatively low even if the retention rate of platelets is 70% to 98%. .

FIG. 6 shows the relationship between the water permeability ratio and the platelet retention rate of the blood purifier of the present invention.
The area (A) in FIG. 6 shows the amount of platelet adhesion that is the lowest adhesion and is a measure for improving blood compatibility when the adhesion of platelets when contacted with blood, which is an indicator of blood compatibility, is evaluated. This is the most suitable range when it is evaluated with the goal of reducing (increasing platelet retention).
Further, in the region (B) of FIG. 6, since the water permeability ratio is 60% or 80%, so-called 90% or less, the platelet retention rate is a high value such as 80 to 100%. It is predicted that it will be very difficult to raise the activation of blood in the living body to a relatively low level. The area (c) in FIG. 6 is that the platelet retention rate is 70% or less, and there is no expectation for such performance, and it is evaluated that the performance is good as a blood purifier. I can't.
Thus, in the blood purifier, by setting the dialysis rate ratio and the platelet retention rate within a specific range, the blood is less likely to be activated even when it comes into contact with a foreign substance, and appropriate blood compatibility is achieved. It is based on the knowledge of the present inventors that the conditions regarding the range in which the property can be satisfied are set.

The platelet retention in the present invention indicates a value calculated from the number of platelets in blood before and after blood perfusion by the following method.
(1) Heparin calcium is put in advance in a blood collection bag so that the concentration becomes 5 U / mL, and blood of healthy adults is collected from the vein inside the elbow into this blood collection bag. Prior to blood perfusion, blood is sampled for analysis of blood components.
(2) The blood side and dialysate side of a hollow fiber membrane module having a membrane area of 1.5 m ² are primed with physiological saline, and the heparinized human whole blood is perfused to the blood side of this module at a flow rate of 150 mL / min. . At this time, a circuit is constructed so that the blood flowing out of the blood collection bag passes through the blood side of the module and returns to the blood collection bag.
(3) After blood perfusion for 60 minutes in an environment of 37 ° C., blood sampling is performed, and blood components are analyzed.
(4) From the number of platelets in the blood before and after perfusion, the platelet retention rate is calculated by the following formula.
(Platelet retention) [%] = 100 × [{number of platelets in blood after perfusion) × (hematocrit of blood before perfusion)} / (hematocrit of blood after perfusion)] ÷ (in blood before perfusion) Platelet count)

  As an index of blood compatibility, there is an increase rate of platelet factor 4 (hereinafter abbreviated as PF4) when blood is brought into contact with a blood purification membrane and perfused. When blood comes into contact with a foreign substance, adhesion and activation of blood cells are caused, and at the same time, the coagulation system is activated and finally a thrombus is generated. The degree of platelet activation in this step is the PF4 concentration, and the low ratio of PF4 concentration before and after blood perfusion (PF4 increase rate) means that platelet activation is unlikely to occur, and blood compatibility It means that it is excellent. The rate of increase in PF4 in the blood purification membrane of the present invention is preferably 5 times or less, more preferably 3 times or less, and even more preferably 2 times or less. The lower limit is 1.0 times.

  Furthermore, a C characteristic value is known as an index of blood compatibility performance retention. The C characteristic value is a percentage of the value of water permeability measured using blood 15 minutes after the start of blood perfusion with respect to the value 15 minutes after the start of blood perfusion. Means that the performance decreases with time. From the viewpoint of performance retention, the C characteristic value in the hollow fiber blood purification membrane of the present invention is preferably 70% or more, more preferably 75% or more, and further preferably 80% or more. In normal hemodialysis, a treatment time of about 3 to 5 hours is common, and when the C characteristic value is less than this, the performance retention is low, so a sufficient therapeutic effect may not be obtained. . In addition, since water permeability decreases with time due to adsorption of blood components during blood perfusion, a high C characteristic value can be regarded as low adsorption of blood components, and a value indicating blood compatibility. You can also think about it.

  The present inventors have found that the above-mentioned platelet retention rate is correlated with the adsorption rate of the cationic dye in the hollow fiber membrane.

  Examples of important indexes for considering blood compatibility on the surface of the material include a charged state, a hydrophilic-hydrophobic balance, and a nonspecific adsorption ability. The hollow fiber membrane of the present invention preferably has a cationic dye adsorption rate of 40% to 70%, but the cationic dye adsorption rate herein refers to the charge state, hydrophilic-hydrophobic balance, non-specificity. It can be considered as an index indicating a typical adsorption capacity. When the adsorption rate of the cationic dye is in the range of 40% to 70%, it is considered that the membrane surface properties are optimized and a membrane excellent in biocompatibility can be obtained. If the adsorption rate of the cationic dye is smaller than this range, the negative charge becomes too small, and the electrostatic interaction with the negatively charged platelets on the surface increases and the platelets tend to stick. Sometimes. Accordingly, the adsorption rate of the cationic dye is more preferably 43% or more, and further preferably 46% or more. On the other hand, if it is larger than this range, hydrophobic interaction and non-specific adsorption increase, and various blood components are likely to be adsorbed, so that the blood purification function may deteriorate over time. Therefore, the adsorption rate of the cationic dye is more preferably 68% or less, further preferably 65% or less, and further preferably 63% or less.

The cationic dye adsorption rate in the present invention is a value calculated from the concentration of the cationic dye in the solution before and after perfusion of the cationic dye solution by the following method.
(1) A cationic dye solution is prepared by dissolving a cationic dye in water to a concentration of 0.5 ppm.
(2) Sampling the cationic dye solution before contacting the membrane.
(3) Measure 1000 mL of the cationic dye solution and fill the blood side and dialysate side of the hollow fiber membrane module having a membrane area of 1.5 m ² .
(4) After filling the module, the remaining cationic dye solution is pooled and perfused at a flow rate of 200 mL / min to the blood side of the module. At this time, a circuit is constructed so that the solution flowing out of the solution pool passes through the blood side of the module and returns to the pool.
(5) After perfusion for 5 minutes, the cationic dye solution filled in the module and the pooled cationic dye solution are combined and sampled.
(6) A calibration curve is created from the absorbance (Absλmax) of the maximum absorption wavelength (λmax) of the ultraviolet absorption spectrum of the cationic dye solution, and the concentration of the cationic dye in the cationic dye solution before and after contact with the membrane is measured.
(7) The cationic dye adsorption rate is calculated from the following formula.
(Cationic dye adsorption rate) [%] = 100 × (cationic dye concentration in solution after perfusion) / cationic dye concentration in solution before perfusion)

  In the present invention, the cationic dye is not particularly limited, such as methylene blue, crystal violet, toluidine blue, and azul, but methylene blue is preferable because it is relatively inexpensive and easily available and has low toxicity.

  It is considered that polyvinyl pyrrolidone on the outermost surface of the blood contact surface 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 of the blood contact surface is preferably 5 to 50% by weight, more preferably 10 to 40% by weight, and further preferably 15 to 40% by weight. Even if the polyvinylpyrrolidone content is lower or higher than this, excessive adsorption of blood components may be caused. If the polyvinylpyrrolidone content is higher than this, a large amount of polyvinylpyrrolidone may be eluted by contact with blood, which may be a problem from the viewpoint of safety.

  It can be considered that polyvinylpyrrolidone whose structure is partially modified by treatment such as crosslinking exhibits a slightly different behavior from the characteristics inherent to the polyvinylpyrrolidone. In order to ensure the performance retention at the time of blood contact use, it is preferable that the polyvinylpyrrolidone contained in the hollow fiber membrane of the present invention is not substantially insolubilized, and specifically, the content of insoluble components is in the entire membrane. It is preferably less than 2% by weight. The content of the insoluble component is 10 g of a membrane, and a solution dissolved in 100 ml of dimethylformamide is applied at 1500 rpm for 10 minutes with a centrifuge, and then the supernatant is removed. 100 ml of dimethylformamide is again added to the remaining insoluble matter, and the mixture is stirred and then centrifuged under the same conditions to remove the supernatant. Again, 100 ml of dimethylformamide is added and stirred, the same centrifugation operation is performed, and then the supernatant is removed. The remaining solid is evaporated to dryness, and the content of insoluble matter is determined from the amount.

  Blood compatibility is also closely related to physical characteristics such as fine surface shape. In the blood purification membrane of the present invention, the blood contact surface of the membrane preferably has a network structure. The network structure mentioned here means that the film is not composed of a fine particulate structure of material as a constituent component but is composed of a fibrillar minute structure. Since the surface composed of the microparticle aggregate is in contact with the blood cells at points, the stimulation to the blood cells is large, which may lead to activation. Further, as described above, a smooth blood contact surface has a large contact area with blood cells, which may cause blood cell activation. Compared to these surface structures, the mesh structure is in contact with blood cells with lines, so that stimulation to the blood cells and the contact area are suitable, and it is considered that blood compatibility is excellent.

  As specific means for obtaining a blood purification membrane excellent in blood compatibility intended by the present invention, the following methods are exemplified. A blood purification membrane having excellent blood compatibility can be obtained by appropriately combining these techniques.

1. Optimization of reduced viscosity of polysulfone resin The reduced viscosity of the polysulfone resin used is preferably 0.15 to 0.6. Although the detailed mechanism is unknown, coagulation in the coagulation bath is moderately controlled by using such a reduced viscosity polysulfone resin, and the content of polyvinylpyrrolidone on the blood contact surface is within the above-mentioned preferred range. It is thought that it is suitable for. A more preferable range of the reduced viscosity is 0.2 to 0.6, more preferably 0.3 to 0.6, and still more preferably 0.35 to 0.58. Polysulfone resins having such reduced viscosity include polyethersulfone manufactured by Sumitomo Chemical Co., Sumika Excel (registered trademark) 3600P (reduced viscosity 0.36), 4800P (0.48), 5200P (0. 52) or the like is preferably used.

2. Optimization of discharge speed of hollow forming agent and dope immediately after nozzle discharge When manufacturing hollow fiber membranes, the dope is discharged from the double tube type nozzle together with the hollow forming agent, and then into the coagulation bath through the idle part. It has already been mentioned that it is common to guide and solidify. At this time, when the hollow forming agent discharge linear velocity immediately after being discharged from the nozzle and the dope discharge linear velocity are in the relationship of hollow forming agent discharge linear velocity> dope discharge linear velocity, the interface between the hollow fiber membrane inner surface and the hollow forming agent It is preferable because shear stress works, friction occurs, and appropriate charge is imparted. Preferred conditions will be described later.

3. Friction with non-conductor during film formation In the film-forming step, the hollow fiber membrane is charged with static electricity by bringing the traveling hollow fiber membrane into contact with the non-conductor, thereby imparting the desirable characteristics intended by the present invention. Useful for. Specifically, the contact between the hollow fiber membrane and the non-conductor during travel is preferably performed using a non-conductor at the hollow fiber membrane contact portion of the film forming machine base. Examples of the hollow fiber membrane contact portion referred to here include a guide and a roller. Examples of the non-conductor that can be used include ebonite, Teflon (registered trademark), ceramic, or a metal material coated with these.

4). Spraying mist-like water Since mist-like water is weakly charged, spraying mist-like water on the formed blood purification membrane causes the membrane to be electrostatically charged. Useful for granting. The above operation can be positioned as a cleaning operation simultaneously with the realization of preferable characteristics by applying static electricity. Specifically, for example, in the hollow fiber membrane spinning process, water is sprayed on the running hollow fiber membrane to wash it, and then it is wound through a drying step, and the hollow fiber membrane obtained through the spinning step is used. Examples of the method include a method of spraying water as a yarn bundle to perform washing.

5). Avoiding over-drying of hollow fiber membranes In addition, the degradation rate of polyvinyl pyrrolidone present in the outermost layer on the inner surface of the hollow fiber membrane is also an important factor in the adsorption rate of the cationic dye. The deterioration reaction of the outermost layer polyvinyl pyrrolidone proceeds at an accelerated rate in the drying process of the hollow fiber membrane when it becomes overdried. For example, when the hollow fiber membrane is overdried in a state where the content of polyvinyl pyrrolidone in the outermost layer is high, the degradation reaction of polyvinyl pyrrolidone proceeds. When the outermost polyvinyl pyrrolidone is high, it should be inherently hydrophilic and methylene blue adsorption suppressed and blood compatibility should be good, but if the outermost polyvinyl pyrrolidone deteriorates, the adsorption rate of the cationic dye Has been found empirically to increase and decrease blood compatibility. The reason is not clear, but it is presumed that the adsorption rate of the cationic dye increases by opening the pyrrolidone ring in polyvinylpyrrolidone, generating a carboxyl group, and changing the negative charge balance on the inner surface. .

  The deterioration reaction due to overdrying is greatly affected by the moisture content at the end of drying of the hollow fiber membrane. When the water content is less than 1% by mass, the deterioration reaction is accelerated. Therefore, drying is preferably stopped when the moisture content is 1% by mass or more.

  The above-described suppression of overdrying of the hollow fiber membrane is largely due to the fact that the UV absorbance of the extract from the hollow fiber membrane described later is controlled within a preferable range regulated by the present invention, and also has a large influence on partial sticking suppression. The effect is great because of the heavy effect.

6). Avoidance of cross-linking of polyvinyl pyrrolidone Since polyvinyl pyrrolidone is cross-linked, it can be considered that the behavior of polyvinyl pyrrolidone is slightly different from the original characteristics. Therefore, in order to ensure performance retention when using blood contact, the present invention As described above, it is preferable that the polyvinylpyrrolidone contained in the hollow fiber membrane is not substantially insolubilized. Specifically, the following techniques are exemplified as means for avoiding the crosslinking of polyvinylpyrrolidone.

  For sterilization of blood purification membranes, irradiation with high energy rays such as γ rays is used. Polyvinyl pyrrolidone is known to be cross-linked by γ ray irradiation. The γ-ray to be irradiated is preferably 20 to 60 kGy. If the γ dose is too small, the sterilization effect may be insufficient. In addition, when the γ dose is excessive, the film material may be deteriorated. In order to control the content of the insoluble component due to γ-ray crosslinking within the range intended by the present invention, the moisture content of the membrane is preferably 0.8 to 5.0% by mass, more preferably 1. It is preferably a substantially dry film of 0 to 4.0% by mass, particularly preferably 1.5 to 3.5% by mass. In consideration of the requirement to avoid the above-described overdrying of the hollow fiber membrane, the lower limit of the moisture content is more preferably 1% by mass. If the moisture content of the membrane is within this range, it is possible to obtain both the effects of suppressing the deterioration / decomposition of polyvinyl pyrrolidone during γ-ray irradiation and suppressing crosslinking. In addition, impregnation with 30 to 80% by mass of glycerin is also a preferable mode for suppressing cross-linking during γ-ray irradiation. The substantially dry membrane here is not immersed in water or an aqueous solvent, and when the membrane is taken out, no dripping of water or aqueous solvent is seen, and when the membrane surface is wiped with filter paper or the like This means that the film cannot be visually confirmed on the wiping material (filter paper or the like).

  In the hollow fiber membrane for a blood purifier, the characteristics on the outer surface side as well as the characteristics on the inner surface side are important.

  In this invention, it is preferable that content in the outer surface outermost layer of the hollow fiber membrane of the above-mentioned polyvinyl pyrrolidone is 25-50 mass%. When the content of polyvinyl pyrrolidone on the outermost surface layer is less than 25% by mass, the content of polyvinyl pyrrolidone on the entire membrane, particularly the inner surface of the membrane becomes too low, and blood compatibility and permeation performance may be deteriorated. In the case of a dry film, the priming property may be lowered. When the hemodialyzer is used for blood purification therapy, it is necessary to perform wetting and defoaming by allowing physiological saline or the like to flow inside and outside the hollow fiber membrane of the hemodialyzer. In this priming operation, the roundness of the hollow fiber membrane, edge crushing, deformation, hydrophilicity of the membrane material, etc. are thought to affect the priming properties, but the hollow fiber membrane made of polysulfone resin and polyvinylpyrrolidone In the case of a dry membrane blood purifier, the hydrophilic / hydrophobic balance of the hollow fiber membrane greatly affects the priming property. Therefore, the content of polyvinyl pyrrolidone on the outer surface is more preferably 27% by mass or more, further preferably 29% by mass or more, and further preferably 31% by mass or more. In addition, if the content of polyvinyl pyrrolidone on the outermost surface layer exceeds 50% by mass, the endotoxin (endotoxin) contained in the dialysate may enter the blood, leading to side effects such as fever. When the membrane is dried, polyvinyl pyrrolidone present on the outer surface of the membrane intervenes and the hollow fiber membranes stick to each other (adhere), which may cause problems such as deterioration in workability of the blood purifier assembly. Therefore, 47 mass% or less is more preferable, 43 mass% or less is further more preferable, and 41 mass% or less is further more preferable.

  As a method for bringing the content and pore diameter of the polyvinyl pyrrolidone in the innermost surface layer and outermost surface layer of the hollow fiber membrane described above into the above ranges, for example, the content of polyvinyl pyrrolidone relative to the polysulfone resin in the membrane-forming solution is 65:35 to 90:10, or by optimizing the film forming conditions of the hollow fiber membrane. It is also an effective method to wash the formed hollow fiber membrane. As film forming conditions, humidity adjustment of the air gap part at the nozzle outlet, stretching conditions, temperature of the coagulation bath, optimization of the composition ratio of the solvent and the non-solvent in the coagulation liquid, etc. Washing, alcohol washing, centrifugal washing and the like are effective. Among these methods, as the film forming conditions, optimization of the humidity of the air gap and the composition ratio of the solvent and the non-solvent in the external coagulating liquid is particularly effective as the cleaning method.

  The air gap portion is preferably surrounded by a member for blocking outside air, and the humidity inside the air gap is preferably adjusted by the composition of the film forming solution, the nozzle temperature, the air gap length, the temperature of the external coagulation bath, and the composition. For example, a film-forming solution consisting of polyethersulfone / polyvinylpyrrolidone / dimethylacetamide / RO water = 10-25 / 0.5-12.5 / 52.5-89.5 / 0-10.0 is formed at 30-60 ° C. When the air gap is discharged from the nozzle and passed through an air gap of 50 to 1000 mm and led to an external coagulation bath having a concentration of 0 to 70 mass% and a temperature of 50 to 80 ° C., the absolute humidity of the air gap portion is 0.01 to 0.3 kg. / Kg dry air. By adjusting the humidity of the air gap portion to such a range, it becomes possible to control the outer surface open area ratio, the outer surface average pore area, and the outer surface polyvinylpyrrolidone content to an appropriate range.

  The air gap length is more preferably 100 to 900 mm, further preferably 200 to 800 mm. If the air gap length is too long, fusing due to yarn breakage and yarn swinging tends to occur, and spinning stability may decrease. On the other hand, if the air gap length is too short, the progress of phase separation becomes insufficient, and a uniform pore diameter may not be obtained.

When spinning a hollow fiber membrane, the dope is discharged from a double tube type nozzle together with a hollow forming agent, and is guided to a coagulation bath through a free running portion to be solidified. When the hollow forming agent discharge linear velocity immediately after being discharged from the nozzle and the dope discharge linear velocity are in the relationship of hollow forming agent discharge linear velocity> dope discharge linear velocity, shear stress is generated at the interface between the hollow fiber inner surface and the hollow forming agent. Works, friction is generated, and moderate charge is imparted. The hollow forming agent discharge linear velocity is more preferably 3 to 10 times the dope discharge linear velocity. If it is less than 3 times, the stress at the interface between the hollow fiber inner surface and the hollow forming agent is small, and there is a possibility that the charge cannot be controlled appropriately. If it exceeds 10 times, the pressure loss of the spinneret becomes large and uneven discharge may occur, resulting in non-uniform film shape. The dope discharge speed is preferably 10,000 cm / min or less. When the dope discharge speed is higher than this, there is a possibility that the pressure loss of the spinneret becomes large and discharge unevenness occurs, spinning becomes unstable, and the film structure becomes non-uniform.
The discharge linear velocity and the linear velocity ratio can be calculated by the following equation.
(Discharge linear velocity immediately after discharge) (cm / min) = Discharge amount (ml / min) / (Discharge hole area) (cm ² )
(Linear velocity ratio) = (Discharge linear velocity of hollow forming agent) / (Discharge linear velocity of dope)

  As the internal coagulation liquid, a 0 to 80% by mass dimethylacetamide (DMAc) aqueous solution is preferable. More preferably, it is 20-70 mass%, More preferably, it is 25-60 mass%, More preferably, it is 35-50 mass%. By controlling the concentration of the internal coagulation liquid within this range, it is possible to obtain a pore diameter that achieves both solute permeability and polyvinylpyrrolidone and endotoxin cutting properties. Although the detailed reason is not known, the use of a mixed solution of dimethylacetamide and water causes a change in the mobility of the polysulfone resin and polyvinylpyrrolidone, and the hydrophilicity / hydrophobicity of the blood contact side surface of the hollow fiber membrane after film formation The ratio is thought to be reasonably balanced. If the concentration of the internal coagulation solution is too low, the dense layer on the blood contact surface becomes thick, which may reduce the solute permeability. If the concentration of the internal coagulation solution is too high, the formation of a dense layer tends to be incomplete, and polyvinylpyrrolidone and endotoxin (fragment) contained in the membrane are likely to elute to the blood side, resulting in poor biocompatibility (blood). Sometimes.

  The external coagulation liquid is preferably 10 to 80 ° C. and 0 to 40% by mass of N-methyl-2-pyrrolidone (NMP) or DMAc aqueous solution. If the temperature and concentration of the external coagulation liquid are too high, the dialysate side surface pore ratio and the dialysate side surface average pore area will be too large, increasing the backflow of endotoxin (fragment) to the blood side when using dialysis. there is a possibility. Further, when the temperature and concentration of the external coagulation liquid are too low, it is necessary to use a large amount of water to dilute the solvent brought in from the film forming solution, and the cost for waste liquid treatment increases. Therefore, the temperature and concentration of the external coagulation liquid are more preferably 20 to 80 ° C. and 0 to 35% by mass, further preferably 30 to 80 ° C. and 0 to 30% by mass, and still more preferably 40 to 80 ° C. and 5 to 30%. They are 50 mass%, Most preferably, it is 50-80 degreeC and 10-30 mass%.

  In the production of the hollow fiber membrane of the present invention, it is preferable that stretching is not substantially applied after the hollow fiber membrane structure is completely fixed. “Substantially no stretching” means that the hollow fiber membrane drawn from the external coagulation liquid is run with only a tension that does not cause slack in the hollow fiber membrane that runs in the subsequent process, and is finally wound on a bag. Means that. If a hollow fiber membrane with a completely fixed membrane structure is stretched, pore deformation, crushing, tearing, and orientation may occur, increasing the elution of polyvinylpyrrolidone, and endotoxin may easily leach into the blood side. is there. Due to the friction with the contact member and the liquid resistance during the film forming process, the hollow fiber membrane that is running is stretched, so that it is difficult to form the film at the same speed of all the rollers. The tension that does not cause slackness specifically means that the roller speed during the spinning process is controlled so that slack or excessive tension does not occur in the film forming solution discharged from the nozzle. The drawing ratio here is the speed ratio between the rollers. A preferable range of the stretch ratio between the rollers is 0.01 to 1.5%. A more preferable range is 0.05 to 1%, and a further preferable range is 0.1 to 0.7%.

  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 slack, which may lead to a decrease in productivity. Therefore, the draft ratio is more preferably 0.8 or more, and even more preferably 0.9 or more. 0.95 or more is even more preferable. When the draft ratio 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 order to have an appropriate negative charge, it is preferable to reduce static electricity on the film surface. Static electricity on the film surface is generated mainly by drying and friction. Examples of the method for preventing the hollow fiber membrane from drying include not drying completely in the drying step and glycerin treatment. 10-70 mass% is preferable and, as for the density | concentration of the glycerol aqueous solution used for glycerol treatment, 15-65 mass% is more preferable. As another means, it is effective to neutralize air during drying. Neutralization treatment is performed by neutralizing the static electricity of the membrane by using a static elimination device that generates plus and minus and giving ions of the opposite polarity to the electrode resistance of the hollow fiber membrane according to the charge amount of the membrane. . As a method of supplying ions of opposite polarity according to the amount of charge, the hollow fiber membrane can be directly neutralized using a method using a static eliminator incorporating the Ion Current Control method. The Ion Current Control method senses the charged state of a charged object by sensing the ionic current caused by the potential difference between the charged object and the earth electrode of the static eliminator, and supplies ions of opposite polarity according to the amount of charge. Thus, the time (pulse width) for applying a high voltage to the positive and negative electrode needles is controlled. As a method of preventing friction that causes static electricity, it is also effective to optimize the materials of the rollers and guides of the spinning machine. As materials for rollers and guides, there are Teflon (registered trademark), bakelite, stainless steel, plastic, and the like. Stainless steel that minimizes friction with the hollow fiber membrane is suitable. Further, in order to minimize the friction with the hollow fiber, it is preferable that the contact portion has a smooth curve. It is also preferable to attach a ground. By controlling the process so that static electricity and friction do not occur in this way, the negative charge inherent to the polysulfone resin can be appropriately controlled.

  In the present invention, the amount of hydrogen peroxide eluted 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, the degradation of the polysulfone polymer causes the hollow fiber membrane to become brittle, or the polyurethane 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 due to deterioration caused by the oxidizing action of hydrogen peroxide during long-term storage can be evaluated by measuring UV (220-350 nm) absorbance determined by the dialysis 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, the polysulfone-based hollow fiber membrane described above is divided into 10 pieces in the longitudinal direction, and the amount of hydrogen peroxide eluted when measured for each is preferably 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 to the entire hollow fiber membrane, so it is used as a module. The abundance in the length direction of the hollow fiber membrane needs to be secured below a certain amount 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 of controlling the elution amount of hydrogen peroxide within the above regulated range, for example, as described above, it is effective to make the amount of hydrogen peroxide in polyvinylpyrrolidone used as a raw material 300 ppm or less, Since the hydrogen peroxide is also produced during the manufacturing process of the hollow fiber membrane described above, it is necessary to strictly control the manufacturing conditions of the hollow fiber membrane. In particular, optimization of the 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 the spinning solution comprising a polysulfone resin, polyvinyl pyrrolidone, and a solvent is stirred and dissolved, if polyvinyl pyrrolidone contains hydrogen peroxide, oxygen present in the dissolving tank 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, 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 promotes the degradation and degradation 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 that the temperature is 5 ° C. or higher and 70 ° C. or lower because the running cost is also required when the temperature is 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. The kneading may be performed by kneading components such as polysulfone polymer, polyvinyl pyrrolidone and a solvent at once, or kneading polyvinyl pyrrolidone and polysulfone polymer 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 restraining 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 polymer directly to the dissolution tank without pre-kneading is also included in the scope of the present invention.

  The kneading is carried out by providing a kneading line separately from the dissolving tank, and the kneaded product may be supplied to the dissolving tank, or both kneading and dissolving may be carried out 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, planetaryum mixers and trimixes manufactured by Inoue Seisakusho fall under this method.

  The ratio of the resin component such as polyvinyl pyrrolidone or polysulfone polymer 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 or more and 1.3 or less, and the stirring Reynolds number (Re = nd ² ρ / μ) is It is preferable that they are 50 or more and 250 or less. Here, 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, a long defoaming time or insufficient defoaming occurs due to entrapment of bubbles in the film-forming solution during stirring. Problems may occur. 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 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 sealing pressure is increased, the melting time can be shortened. However, in order to increase the pressure, the equipment cost increases, and from the viewpoint of work safety, it is preferably from atmospheric pressure to 2 kgf / cm ² .

  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 and 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 for controlling the elution amount of hydrogen peroxide within the above regulated range, it is 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 of the hollow fiber membrane during the drying treatment 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 suppressed low 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 in particular, there is a significant point that deterioration degradation of polyvinylpyrrolidone can be remarkably suppressed. An appropriate drying temperature of 20 to 80 ° C. is sufficient. 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 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 that it functions synergistically in uniform heating, and is unique in drying the hollow fiber membranes. It will be meaningful. The degree of vacuum may be set as appropriate depending on the output of the microwave, the total moisture content of the hollow fiber membranes, and the number of hollow fiber membrane bundles. In order to prevent the temperature of the hollow fiber membranes during drying, the degree of vacuum is 20 kPa or less. More preferably, it is 15 kPa or less, More preferably, it is 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 suppresses a temperature rise and raises 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 membranes containing polyvinylpyrrolidone, polyvinylpyrrolidone deteriorates or decomposes due to overdrying or overheating, and wettability decreases during use. Therefore, it is preferable not to increase the output so much. In addition, it is possible to dry the hollow fiber membrane even with an output of less than 0.1 kW, but there is a possibility that a problem of a decrease 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 moisture content of the hollow fiber membrane and the number of processed hollow fiber membranes, 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 water content, but 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, in view of 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 microwave of 10 to 20 kW, 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 membranes and cannot be expected in the prior arts of the above-mentioned Patent Documents 8 to 10, and therefore makes the effects of the present invention 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, about 1 to 5 kW of microwave for 10 to 240 minutes, less than 0.5 to 1 kW of microwave for about 1 to 240 minutes, more preferably about 3 to 240 minutes, less than 0.1 to 0.5 kW Drying is performed uniformly by adjusting the irradiation power and irradiation time of the microphone mouth wave according to the degree of drying, which is irradiation with microwaves for about 1 to 240 minutes. 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 in 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 drying of the hollow fiber membrane bundle is performed by irradiating with microwaves under reduced pressure, and using a drying method that alternately reverses the direction of ventilation also makes the process complicated in drying, but an effective drying method It is. The microwave irradiation method and the alternating ventilation reverse method also have merits and demerits, and these can be used in combination when high quality is required. In the first stage, when the average alternating water content proceeds to about 20 to 60% by mass by adopting a ventilation alternating reversal method, it can be dried by irradiating microwaves under reduced pressure in the next stage. In this case, after drying by irradiating microwaves, a ventilation drying method in which the ventilation direction is alternately reversed can be used in combination. These can be determined in consideration of the quality of the hollow fiber membrane produced by drying, particularly the quality of the polysulfone-based hollow fiber membrane bundle having no partial fixation in the length direction of the hollow fiber membrane. These drying methods can be performed simultaneously, but are not practical because of disadvantages such as the complexity and complexity of the apparatus and the price increase. However, using an effective heating method such as far infrared rays is not excluded from the scope of the drying method of the present invention.

  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 exceeds 90 ° C., the film structure is likely to change, which may cause performance degradation or deterioration of oxidation. In particular, in a hollow fiber membrane bundle containing polyvinylpyrrolidone, it is necessary to prevent the temperature rise as much as possible because polyvinylpyrrolidone is easily decomposed by heat. Temperature rise can be prevented by optimizing the degree of decompression and microwave output and irradiating intermittently. Moreover, although the one where a drying temperature is lower is preferable, 30 degreeC or more is preferable from the surface of the maintenance cost of pressure reduction degree, and the shortening of drying time.

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 optional. For example, the method disclosed in JP 2000-340356 A is a method in which a reflector is provided in an oven to reflect microwaves and uniform heating. One.

  After the water content of the hollow fiber membrane bundle is reduced to 10 to 20% by mass, the hollow fiber membrane bundle is preferably dried by irradiation with far infrared rays. Although it is preferable to irradiate microwaves or to perform drying by heating (ventilation) in the sense that the material to be dried is dried more quickly, in the case of a separation membrane containing polyvinylpyrrolidone, polyvinylpyrrolidone progresses in drying, that is, in the hollow fiber membrane. As the water content decreases, there is a problem that it is susceptible to degradation by heat. Therefore, in the final stage of drying (low moisture content), it is a preferred embodiment to dry mildly with lower energy. Further, far-infrared rays are a kind of electromagnetic wave and are preferable because they penetrate into the material to be dried as in the case of microwaves, and thus have a characteristic that the material to be dried can be uniformly dried even at low energy.

  The irradiation wavelength of far infrared rays is preferably 1 to 30 μm. Since water and organic matter have a high absorption rate of far infrared rays having a wavelength of 3 to 12 μm, it is difficult to raise the temperature of the object to be dried even if the wavelength of the far infrared rays is too short or too long. Such costs may increase. Therefore, the wavelength of the far infrared ray to be irradiated is more preferably 1.5 to 26 μm, further preferably 2 to 22 μm, and further preferably 2.5 to 18 μm.

As a radiation medium for irradiating far infrared rays, a stainless steel medium having a metal oxide film on its surface is preferably used. For example, an austenitic stainless steel powder as described in JP-A-10-5265 is coated with a metal oxide such as Al ₂ O ₃ , Fe ₂ O ₃ , TiO ₂ , CaO, MgO, K ₂ O and Na ₂ O. It is a more preferable embodiment to use a far-infrared radiator coated with, because far-infrared rays can be extracted efficiently at low cost.

  On the other hand, in the case of drying by far-infrared irradiation performed after the completion of microwave drying, unlike the case of microwave drying, the discharge phenomenon does not occur even if irradiation is performed under reduced pressure. It can be carried out. From the point of drying efficiency, 5 kPa or less is preferable, 4 kPa or less is more preferable, 3 kPa or less is more preferable, and 2 kPa or less is more preferable. The irradiation energy of the far-infrared irradiation is preferably controlled so as to be 80 ° C. or lower at a temperature detected by a thermocouple provided at the center of the oven. It is more preferable to control at 70 ° C. or lower. This far-infrared radiation is highly absorbed by water and converted to energy, has excellent thermal efficiency, and has the safety that temperature control according to the transition of drying can be made appropriate. Have advantages. This is significant in terms of dry finishing in order to maintain the surface effects including the drying method by far-infrared irradiation, the color of the hollow fiber membrane, surface roughness, bending, cracking, smoothness and soft feel.

A specific embodiment of a preferable drying method in the present invention includes: (1) a drying step of simultaneously irradiating the hollow fiber membrane bundle with microwave irradiation and far-infrared irradiation; (2) a drying step of performing microwave irradiation; It includes embodiments of a plurality of drying processes called drying processes that perform infrared irradiation. The proper drying method of the present invention employs a drying process in which (A) a hollow fiber membrane bundle is simultaneously subjected to (1) microwave irradiation and far-infrared irradiation, and the moisture content of the hollow fiber membrane bundle is lowered to a constant value. In general, a drying method that employs a drying step of (3) far-infrared irradiation is common. Another aspect of the drying method is that (B) a hollow fiber membrane bundle adopts (2) a drying step in which microwave irradiation is performed, and the moisture content of the hollow fiber membrane bundle is lowered to a constant value, (3) It is a drying method that employs a drying process that performs far-infrared irradiation. Of course, it is an essential requirement for each drying step to adopt appropriate temperature control, pressure control when performing under reduced pressure, and ventilation exhaust when necessary.
Theoretically, (1) Drying step and (2) Drying step are used together, (3) Drying step and (1) Drying step are used together, (2) Drying step and (3) Drying step are used together Although it is on-site operation of the drying apparatus for carrying out the drying method of the present invention, and the like, it is feasible, but compared to the drying methods of (A) and (B), the practical result is I have not examined it enough.

  Thus, far-infrared irradiation may be started after the end of microwave irradiation, or may be performed at the time of microwave irradiation, and microwave drying and far-infrared drying may be performed simultaneously. By performing microwave and far-infrared irradiation simultaneously, evaporation of water that has been excited by microwave irradiation and moved to the surface of the hollow fiber membrane is accelerated by irradiation with far-infrared radiation, leading to improved drying efficiency. Further, this efficient evaporation of surface moisture suppresses the concentration fluctuation of the surface of the hollow fiber membrane of polyvinylpyrrolidone induced by the surface moisture, which is preferable because it leads to suppression of partial sticking. As described above, microwave drying is preferably performed under reduced pressure. Therefore, microwave drying and far-infrared drying are simultaneously performed under reduced pressure, and microwave irradiation is performed when the moisture content is reached. A method of stopping, continuing far-infrared irradiation while maintaining a reduced pressure state, and continuing further drying is preferable. At this time, after the microwave irradiation is completed, the degree of decompression of the system may be lowered and conditioning may be performed, and then the degree of decompression may be raised again to start far-infrared irradiation. Therefore, in the present invention, it is preferable to perform drying using a microwave dryer in which a far-infrared heater is attached in the heating oven and an exhaust system capable of reducing the pressure (vacuum) in the heating oven is attached. It is an aspect.

  When drying under conditions of reduced pressure and temperature by microwave drying and far-infrared drying, generally, for example, when high-power microwaves are added in a short period of time under reduced pressure and high temperature, the moisture content decreases. However, the uneven distribution of moisture and polyvinyl pyrrolidone are also related to microwave heating, which induces a phenomenon such as bumping. There is a risk that it will not be possible to guarantee a structure that can cope with this. The present invention appropriately adjusts the output of microwaves and far-infrared rays, and also adjusts the environment of temperature and pressure, thereby promoting the overall drying of the inside and outside of the hollow fiber membrane bundle by microwaves in particular. Thus, the drying of the whole including the surface of the bundle of hollow fiber membranes by far infrared rays is promoted, and the microwave drying and the far infrared drying increase a synergistic drying effect.

  In the present invention, it is a preferred embodiment that an inert gas such as nitrogen gas is used when the inside of the drying system is returned to normal pressure after drying. Immediately after the drying, the temperature of the hollow fiber membrane is high, so when returning the inside of the drying chamber to normal pressure, when a gas containing oxygen such as air is fed, in the case of a hollow fiber membrane containing polyvinylpyrrolidone, polyvinylpyrrolidone is Oxidative degradation may occur due to the influence of oxygen and heat. Therefore, when the inside of the drying chamber is returned to normal pressure after the drying is completed, the oxidative deterioration of the polyvinyl pyrrolidone in the hollow fiber membrane is suppressed by feeding the inert gas.

  For the drying of the hollow fiber membrane bundle, the use of microwaves and far infrared rays for unlimited time does not have a good influence on the quality. This is because the influence of thermal deterioration of the polysulfone resin constituting the hollow fiber membrane or of polyvinylpyrrolidone and environmental deterioration such as oxygen, water, and steam can be considered. Therefore, from the viewpoint of industrial production, it is necessary to consider an appropriate time that is naturally allowed for the drying time. From the viewpoint of protecting the quality of the hollow fiber membrane subjected to relatively harsh drying conditions such as microwaves and far infrared rays, from the viewpoint of further industrial productivity, the present inventors have performed from the start to the end of drying. The drying time is preferably within 3 hours. More preferably within 2.5 hours, still more preferably within 2 hours.

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 thus 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 easily proliferate during storage, and the hollow fiber membrane may crush due to its own weight, or an adhesive failure may occur during assembly of the module. The water content of the hollow fiber membrane is preferably 10% by mass or less, more preferably 7% by mass or less. 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%)

  Further, as described above, a method of removing hydrogen peroxide mixed from the raw material polyvinyl pyrrolidone or generated in the manufacturing process of the hollow fiber membrane by washing is also effective as a method of controlling the above-described characteristic value within a regulated range. .

  In the present invention, the properties such as the amount of polyvinylpyrrolidone eluted and the endotoxin, which is an endotoxin, are prevented from penetrating into the blood side, and the hollow fiber membranes are prevented from sticking together when the hollow fiber membranes are dried. In order to balance, it is preferable to set the proportion of polyvinyl pyrrolidone present on the outer surface of the hollow fiber membrane within a specific range. As a method for satisfying this requirement, it can be achieved, for example, by setting the composition ratio of polyvinyl pyrrolidone to the polysulfone-based resin within the above 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.

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 existing ratio 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, it is possible to optimize the abundance ratio of the outer surface polyvinyl pyrrolidone, thereby suppressing sticking and reducing the amount of eluate, and also leading to a reduction in the hydrogen peroxide elution amount.

  After the polysulfone-based hollow fiber membrane obtained by the above method is stored in a dry state for 3 months or longer, UV (220 in the extract of the hollow fiber membrane when the test defined by the dialysis artificial kidney device manufacturing approval criteria is performed. The absorbance is preferably 0.10 or less at all sites. In the evaluation, the dried sample was stored in a dry box (atmosphere: air) conditioned at a humidity of 50% RH for 3 months at room temperature, and then UV (220-350 nm) absorbance was measured by the method described above. . In consideration of storing the hollow fiber membrane in a dry state in the manufacturing process of the hollow fiber membrane, transportation, storage of stock, etc., it is preferable to give the above characteristics.

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

  In the blood purifier 1, a polysulfone-based hollow fiber membrane bundle 3 is loaded into a cylindrical housing 2, and both ends of the hollow fiber membrane bundle 3 are fixed 4 to both ends of the housing 2 with an adhesive or the like. Both ends are 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.

  Then, as shown by an arrow A, blood enters the space formed by the cap 5a and one end face of the polysulfone-based hollow fiber membrane bundle 3 from the blood introduction port 7a, and the hollow of the polysulfone-based hollow fiber membrane bundle 3 is formed. It passes through the yarn, enters the space formed by the other end face of the polysulfone-based hollow fiber bundle 3 and the cap 5b, and is discharged from the blood outlet 7b as shown by an arrow B. On the other hand, the dialysate enters the housing 2 through the dialysate inlet 6a as indicated by an arrow C, flows outside the hollow fiber of the polysulfone-based hollow fiber membrane bundle 3, and is discharged as indicated by an arrow D. It is discharged from the outlet 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 polysulfone-based 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 in which the dried polysulfone-based hollow fiber membrane bundle is loaded, 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 until the resin is no longer fluid, 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 inside of the bonding portion of the polysulfone-based hollow fiber membrane bundle is covered with a flexible resin layer to reinforce the polysulfone-based hollow fiber membrane at the bonding interface.

  In the case of the centrifugal bonding method, it is important that the adhesive is uniformly injected into the entire space in the polysulfone-based hollow fiber membrane bundle. If this injection becomes non-uniform and a portion 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 polysulfone-based hollow fiber membranes are fixed, penetration of the adhesive is inhibited. Therefore, in order to unravel the adhering portion, for example, so-called yarn shaping treatment is performed in which air is blown from a nozzle onto the end surface of the polysulfone-based hollow fiber membrane bundle. Certainly, the present warping treatment is effective in unraveling the fixed hollow fiber membrane, but this treatment is not preferable because the polysulfone-based hollow fiber membrane at the end face portion is deformed and the inclined hollow fiber membrane is generated.

  The polysulfone-based 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 fixation 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 packing density of the polysulfone-based hollow fiber membrane bundle restrained by the hollow package when the dry polysulfone-based hollow fiber membrane bundle is inserted into the housing used for assembling the blood purifier.

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

  Sterilization is essential for blood purifiers. As the 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 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 polysulfone-based 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 polysulfone-based hollow fiber membrane, and 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 that it is suppressed by water adsorbed on the 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 used the polysulfone-based hollow fiber membrane having the above-mentioned characteristics to perform blood purification in which the moisture content of the hollow fiber membrane is adjusted to 5% by mass or more using degassed water. The vessel found that the degradation reaction of polyvinylpyrrolidone can be suppressed even in the absence of a radical scavenger.

  That is, all the blood and dialysate entrances and exits of a blood purifier filled with a polysulfone-based hollow fiber membrane bundle containing polyvinylpyrrolidone whose water content is adjusted to 5 to 600% by mass using deaerated water are sealed. It is preferable to irradiate with radiation by sealing with a packaging bag that blocks outside air and water vapor.

  In the present invention, the deaerated water present in and around the polysulfone-based 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 is dissolved in 1 m ^{3 of} water, and oxygen gas of 8 mg / l of 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 production 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. This problem can be solved by using an inert gas saturated water such as nitrogen. That is, by containing an inert gas in a saturated state, even when irradiation is performed in an environment where oxygen is included in the surroundings, dissolution of oxygen gas in water is suppressed, and there is a state where the concentration of oxygen contained in water is low. Will be kept.

  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. 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. The water used here is preferably RO-treated water.

  By using the above deaerated water, the deterioration of the hollow fiber membrane due to irradiation, particularly the degradation reaction of polyvinyl pyrrolidone, is more effectively suppressed than when non-deaerated water is used, and the generation of hydrogen peroxide as described above is suppressed. Increase in UV (220-350 nm) absorbance, antithrombogenicity, long-term storage stability and priming treatment in the extract of the hollow fiber membrane when the test specified by the increase and dialysis-type artificial kidney device manufacturing approval standards is performed 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. It is preferable that 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.

  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 of 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 in 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. On the contrary, 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 it cannot be confirmed that a sufficient sterilization effect has been obtained. . Therefore, the oxygen concentration in the atmosphere in the blood purifier after sterilization is more preferably 0.1% by volume or more, and further preferably 0.5% 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 effectively 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 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. When a small amount of oxygen is present in order to suppress a decrease in blood compatibility and sterilization effect, replacement with an inert gas with an adjusted oxygen concentration is preferable.

  In the above method, it is preferable to seal all the blood and dialysate inlets and outlets of the blood purifier after adjusting the water content and oxygen concentration in the blood purifier. By this method, the volatilization of water 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 effectively expressed. Moreover, invasion of various germs into the blood purifier can be prevented. Moreover, since volatilization of moisture from the hollow fiber membrane is suppressed for a long period of time, shrinkage and deterioration of membrane characteristics due to drying of the hollow fiber membrane over time are suppressed. Therefore, the effect that the generation | occurrence | production of a defect, the fall of a 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 method in which crimping is applied to the hollow fiber membrane to suppress the dialysis fluid drift, the crimping of the dialysis fluid may increase due to the relaxation of the crimp due to drying of the hollow fiber membrane.

  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 germs (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 or electron beam after sealing tightly as will be described later, and there is also an advantage that oxygen gas can be prevented from entering into the blood purifier 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 water content in the polysulfone-based hollow fiber membrane is 5% by mass or more. On the other hand, in the case of using a polysulfone-based hollow fiber membrane that does not require much consideration for sterilization treatment, such as manufactured in a clean room corresponding to at least a class 100,000 standard, the moisture content of the hollow fiber membrane is 5%. A method of optimizing the oxygen concentration and humidity of the atmosphere surrounding the polysulfone-based hollow fiber membrane during the radiation irradiation treatment can be employed. Of course, 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 polysulfone-based hollow fiber membrane during sterilization. Radiation irradiation is preferably performed in a state where the oxygen concentration is 3.6% by volume or less. 1% by volume or less is more preferable, and 0.1% by volume or less is more preferable. 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.

  A 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. Therefore, it is not limited as long as it has a deoxygenation function. For example, the following is preferable.

  The oxygen scavenger 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, and the like, 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 a function of forming a space 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 more preferable, and 20 g / m ² · 24 h · MPa (40 ° C., 90% RH) or less is more preferable. If 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. There is a possibility that the preferable water content of the glass 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. In addition, 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 preferable. In particular, the outer layer with an aluminum foil that can substantially block oxygen gas and water vapor as a constituent layer is a polyester film, the intermediate layer is an aluminum foil, and the inner layer is a polyethylene film. It is preferable to apply a laminated sheet having the same.

  In the present invention, in the above method, it is preferable that the radiation is irradiated after at least 48 hours have passed after sealing. More preferably 72 hours or more. However, if the time until irradiation with radiation after sealing is too long, miscellaneous bacteria may grow. Therefore, it is preferable to perform the irradiation within 10 days after sealing. More preferably, it is within 7 days, and more preferably within 5 days. There is no limitation on the temperature at the time from sealing to irradiation with radiation, for example, room temperature. When the irradiation treatment is performed in a state of less than 48 hours, the water permeability performance after the priming treatment may be deteriorated. The factor of the performance development after priming is that, based on the situation of a delicate hollow fiber membrane bundle obtained by cutting long fibers into a certain length, many technical factors are complicated and it is not easy to identify the cause. Although difficult, the content of polyvinylpyrrolidone in the innermost and outermost surface layers of the hollow fiber membrane has a great influence, elution of polyvinylpyrrolidone from the hollow fiber membrane should be 10 ppm or less, and adjustment of water content using deaerated water The influence of 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 seen in FIG. 3, if the elapsed time until the sterilization treatment is relatively short, such as 10 hours, 20 hours, and 30 hours, there will be variations in performance after priming, and a uniform and stable product cannot be produced. The possibility is great. On the other hand, after about 48 hours have passed, for example, after 60 hours and 120 hours have passed, the irradiation will converge to a region where there is little variation in performance development 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 material behavior seems to show the same tendency even when the content of polyvinylpyrrolidone in the outermost surface layer of the polysulfone-based hollow fiber membrane is analyzed for 25 to 50% by mass.

  Further, the tendency as shown in FIG. 3 will 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. Even in the case of using saturated water, the performance expression after priming with a blood purifier set with a dissolved oxygen concentration of 0.5 ppm or less, 0.001 ppm or more, and 90% sterilization treatment. If the critical behavior at an elapsed time of 48 hours is analyzed, the same tendency is expected. If the behavior in the polysulfone-based hollow fiber membrane is analyzed from such a technical point of view, the technical matters such as the performance expression after priming of the present invention and the elapsed time until the sterilization treatment are the availability of the hollow fiber membrane, quality control, It greatly enhances the benefits of medical practice. Of course, it is not fixed and fixed for 48 hours, but is 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. However, the dissolved oxygen present in and around the polysulfone-based hollow fiber membrane is reduced to 5 ppm or less and 0.001 ppm or more. When the inside of the blood purifier is adjusted to a specification with a low concentration, the dissolved oxygen concentration and the water content in the polysulfone-based hollow fiber membrane will be uniform over time due to diffusion, permeation, migration, etc. If the quality related to water, dissolved oxygen, hydrophilic polymer, etc. is in an equilibrium state and sterilization is performed after such a state, a blood purifier containing a hollow fiber membrane of uniform quality That is why. 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.

  The reason why the expression of water permeability after priming changes depending on the elapsed time until irradiation treatment is unknown, but the trace amount of oxygen adsorbed on the surface of the hollow fiber membrane is localized. It is presumed that this is caused by the shift to air and water, which suppresses the degradation reaction that inhibits the affinity between the membrane surface and water caused by radiation irradiation.

  As the radiation used in the present invention, α rays, β rays, γ rays, neutron rays, X rays, electron rays, ultraviolet rays, ion beams 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 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 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, and each of them is a dialysis artificial kidney device. 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 carried out is 0.10 or less at all sites. It is more preferable that 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 over one 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 polyvinyl pyrrolidone Extracted by the method defined in the dialysis artificial kidney device production standard, and the polyvinyl pyrrolidone in the extract was quantified by a colorimetric method.
In the case of a dry hollow fiber membrane module, 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 the wet hollow fiber membrane module, 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 through for 3 minutes while filtering from the blood side to the dialysate side at 200 mL / min, 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 Absorbance in the wavelength range of 200-350 nm using a spectrophotometer (Hitachi, U-3000) extracted from the extract extracted by the method defined in the dialysis artificial kidney device manufacturing approval standard And the maximum absorbance in this wavelength range was determined.
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 module, the measurement was performed using a dry membrane obtained by processing in the same manner as the measurement of the amount of polyvinylpyrrolidone eluted.

5. Quantitative determination of hydrogen peroxide TiCl ₄ mixed in an equimolar ratio with an ammonium chloride buffer solution (PH8.6) 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, 0.2 ml of a coloring reagent prepared to 0.4 mM was further added, and the mixture was heated at 50 ° C. for 5 minutes, and then brought to room temperature. 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 module, the measurement was performed using a dry membrane obtained by processing in the same manner as the measurement of the amount of polyvinylpyrrolidone eluted. 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. Platelet retention rate A value calculated from the number of platelets in blood before and after blood perfusion by the following method.
(1) Heparin calcium is put in advance in a blood collection bag so that the concentration becomes 5 U / mL, and blood of healthy adults is collected from the vein inside the elbow into this blood collection bag. Prior to blood perfusion, blood is sampled for analysis of blood components.
(2) The blood side and dialysate side of a hollow fiber membrane module having a membrane area of 1.5 m ² are primed with physiological saline, and the heparinized human whole blood is perfused at a flow rate of 150 mL / min into the blood side of this module. . At this time, a circuit is constructed so that the blood flowing out of the blood collection bag passes through the blood side of the module and returns to the blood collection bag.
(3) After blood perfusion for 60 minutes in an environment of 37 ° C., blood sampling is performed, and blood components are analyzed.
(4) From the number of platelets in the blood before and after perfusion, the platelet retention rate is calculated by the following formula.
(Platelet retention rate) [%] = 100 × [{(platelet number in blood after perfusion) × (hematocrit of blood before perfusion)} / (hematocrit of blood after perfusion)] / (in blood before perfusion) Platelet count)

7. Adsorption rate of cationic dye The cationic dye adsorption rate is a value calculated from the concentration of the cationic dye in the solution before and after perfusion of the cationic dye solution by the following method. Methylene blue was used as the cationic dye.
(1) A methylene blue solution is prepared by dissolving methylene blue in water to a concentration of 0.5 ppm.
(2) Sampling the methylene blue solution before contact with the membrane.
(3) Measure 1000 mL of methylene blue solution and fill the blood side and dialysate side of the hollow fiber membrane module with a membrane area of 1.5 m ² .
(4) After filling the module, pool the excess methylene blue solution and perfuse the blood side of the module at a flow rate of 200 mL / min. At this time, a circuit is constructed so that the solution flowing out of the solution pool passes through the blood side of the module and returns to the pool.
(5) After perfusion for 5 minutes, the methylene blue solution filled in the module and the pooled methylene blue solution are combined and sampled.
(6) A calibration curve is created from the absorbance at the maximum absorption wavelength of 490 nm in the ultraviolet absorption spectrum of the methylene blue aqueous solution, and the concentration of the methylene blue solution before and after contact with the membrane is measured.
(7) The methylene blue adsorption rate is calculated from the following equation.
(Methylene blue adsorption rate) [%] = 100 × (methylene blue concentration of solution after perfusion) / methylene blue concentration of solution before perfusion)

8. Increasing rate of PF4 Using standard reagent for platelet factor 4 (PF4) measurement by EIA (sandwich method) manufactured by Roche Diagnostics, Japan standard product classification number issued by the company: 877422 (approval number: 16200EZY0045300, 2002) (Revised version) Measured according to the measurement method described.

9, C characteristic value Using a hollow fiber membrane module, hematocrit 35% by mass of bovine blood was perfused inside the hollow fiber membrane at a flow rate of 200 mL / min. At the same time, filtration was performed at a flow rate of 20 mL / min from the inside of the hollow fiber membrane toward the outside of the hollow fiber membrane. The water permeability in the bovine blood system (hereinafter abbreviated as MFR) was calculated from the transmembrane pressure and the amount of filtrate 15 minutes after the start of perfusion / filtration. With this value as (A), 120 minutes after the start of perfusion / filtration, the C characteristic value is calculated by the calculation of 100 (%) × (B) / (A) from the MFR value (B) obtained by the same operation. Calculated.

10. Endotoxin permeation Dialysate with an endotoxin concentration of 200 EU / L is fed from the inlet of the dialysate at a flow rate of 500 ml / min, and dialysate containing endotoxin from the outside to the inside of the hollow fiber membrane is filtered at a filtration rate of 15 ml / min. Time filtration was performed, the dialysate filtered from the outside of the hollow fiber membrane to the inside of the hollow fiber membrane was stored, and the endotoxin concentration of the stored solution was measured. Endotoxin concentration was analyzed using Limulus ESII Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.) according to the manual method (gelation overturning method).

11. Measurement of inner diameter and film thickness of hollow fiber membrane The hollow fiber membrane is cut with a sharp razor perpendicular to the length direction, and the cross section is observed with a microscope at a magnification of 200 times. The inner diameter value and the outer diameter value are measured at n = 5, and the average value is calculated.
Film thickness [μm] = {(outer diameter) − (inner diameter)} / 2

12. Storage stability of blood purifier After storing the blood purifier after γ-ray irradiation for one year at room temperature, UV (220-350 nm) absorbance was measured by the method described above. Stability was determined by the degree of increase in UV (220-350 nm) absorbance due to the storage. The degree of increase was obtained by equally dividing the hollow fiber membrane into 10 pieces in the longitudinal direction, measuring each sample, and determining the maximum value. Those whose maximum value did not exceed 0.10 were considered acceptable.

13. Moisture content of hollow fiber membrane The moisture content of the hollow fiber membrane was measured by measuring the mass (g) of the hollow fiber membrane before drying, and then vacuum drying under reduced pressure (-750 mmHg or less) for 12 hours, after drying The mass (g) of the hollow fiber membrane is measured. The mass difference between before and after drying is determined as a weight loss (g) in% based on the mass after drying (g). The moisture content is determined by the following formula.
(Weight loss / weight after drying) × 100 = water content (mass%)
Here, by setting the mass of the hollow fiber membrane within the range of 1 to 2 g, it can be in an absolutely dry state (a state in which there is no further mass change) after 2 hours.

14. Measurement of oxygen concentration in packaging bag and water Measurement of oxygen concentration in the packaging bag was performed by gas chromatography. A column packed with molecular sieve (Molecular sieve 13X-S mesh 60/80 manufactured by GL Science) was used, the carrier gas was analyzed using argon gas, the detector was analyzed using a heat conduction method, and the column temperature was 60 ° C. The gas in the packaging bag was collected by piercing the syringe needle directly into the unopened packaging bag.
The oxygen concentration in water was measured using a dissolved oxygen meter OM-51-L1 manufactured by HORIBA.

15. Performance expression after priming treatment Water permeability at the time of 10 minutes and 24 hours after the physiological saline was flowed from the blood side inlet port of the blood purifier (priming treatment) was evaluated by the above evaluation method. The ratio of the water permeability at 10 minutes with respect to the water permeability at the time elapsed was determined. After measuring the water permeability at 10 minutes, the blood purifier was filled with water and kept at room temperature for up to 24 hours.

Example 1
In a kneading and dissolving machine that expresses a kneading effect by so-called planetary motion in which two frame-type blades rotate and revolve, 1 part by mass of polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (registered trademark) 4800P), 0.144 parts by mass of polyvinylpyrrolidone (BASF Koridone (registered trademark) K90) and 1 part by mass of dimethylacetamide (DMAc) were charged, and the mixture was stirred for 2 hours and kneaded. Subsequently, a mixed solution of 3.02 parts by mass of DMAc and 0.16 parts by mass of RO water was added over 1 hour. 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. The stirring fluid number and stirring Reynolds number at the final dissolution were 1.0 and 100, respectively. The system was then depressurized to -500 mmHg using a vacuum pump, and the system was immediately sealed and allowed to stand for 15 minutes so that the solvent and the like were evaporated and the composition of the film forming solution did not change. This operation was repeated three times to degas the film forming solution. 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 sequentially passed through a two-stage sintered filter of 30 μm and 15 μm, and then degassed at −700 mmHg for 30 minutes in advance as a hollow forming agent from a tube-in orifice nozzle heated to 75 ° C. After passing through a 400 mm dry section, which was discharged together with a 53 mass% DMAc aqueous solution and cut off from the outside air by a spinning tube, it was coagulated in a 20 mass% DMAc aqueous solution at 60 ° C., and was rolled up in a wet state. The nozzle slit width of the tube-in-orifice nozzle used was an average of 60 μm, the maximum 61 μm, the minimum 59 μm, the ratio of the maximum and minimum slit widths was 1.03, and the draft ratio was 1.04. The linear velocities immediately after discharge were 17790 cm / min and 484 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.6. During the spinning process, all the rollers with which the hollow fiber membranes contacted were mirror-finished on the surface, and all the guides were textured on the surface. These guides and rollers were surface-treated with Teflon (registered trademark). In addition, mist-like water was sprayed on the hollow fiber membrane that was running just before winding. A polyethylene film whose surface on the hollow fiber bundle side was textured was wound around a bundle of about 10,000 hollow fiber membranes, and then cut into a length of 27 cm (hereinafter referred to as a bundle). Was washed 3 times for 30 minutes in water to remove excess polyvinylpyrrolidone, solvent, and endotoxin (fragment) contained in the polysulfone-based hollow fiber membrane. Some of these conditions are shown in Table 1.

  The obtained wet polysulfone-based hollow fiber membrane was introduced into a microwave irradiation type dryer having a structure in which a reflecting plate was installed in an oven and uniform heating was possible, 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 polysulfone-based hollow fiber membrane was heated with microwave irradiation for 10 minutes at an output of 0.5 kW, and then the microwave was cut to increase the degree of vacuum and maintain 0.7 kPa for 3 minutes. . Furthermore, the degree of vacuum was returned to 7 kPa, and microwave irradiation was performed at an output of 0.2 kW for 8 minutes to heat the polysulfone-based hollow fiber membrane bundle. After microwave cutting, the degree of vacuum was raised to 0.5 kPa and maintained for 5 minutes to condition the polysulfone-based hollow fiber membrane bundle and finish drying. The maximum temperature reached on the surface of the polysulfone-based hollow fiber membrane bundle at this time was 65 ° C. The moisture content of the polysulfone-based hollow fiber membrane before drying is 330 mass%, the moisture content of the polysulfone-based hollow fiber membrane after the first stage is 32 mass%, and the moisture content of the polysulfone-based hollow fiber membrane after the second stage is The water content of the 16% by mass polysulfone-based hollow fiber membrane after completion of the third stage was 1.5% by mass.

  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 portion, and is determined as a dialysis artificial kidney device manufacturing approval standard. The extracted liquid was obtained by the test and the hydrogen peroxide elution amount and UV (220-350 nm) absorbance in the extracted liquid 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.

The polysulfone-based hollow fiber membrane prepared by the above method is inserted into a polycarbonate blood purifier container, both ends are fixed with urethane resin, the resin end is cut, the hollow fiber membrane hollow portion is opened, and an inflow port is provided. A blood purifier having an effective length of 215 mm and a membrane area of 1.35 m ² of a polysulfone-based hollow fiber membrane was prepared by attaching a cap. 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 water content in the hollow fiber membrane was adjusted to 10% by mass. All the blood and dialysate inlets and outlets of the blood purifier dried under these conditions are sealed with a cap made of ethylene-propylene synthetic rubber, a biaxially stretched polyamide film having an outer layer thickness of 25 μm and an unstretched polyethylene having an inner layer thickness of 50 μm. It sealed in the packaging bag which consists of a laminated body of a film. After being stored in a sealed state at room temperature for 72 hours, 25 kGy of γ rays were irradiated.

  Table 3 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 small amount of hydrogen peroxide eluted after γ-irradiation and low UV (220-350 nm) absorbance, maintaining high quality. Other characteristics were also good. Moreover, the amount of polyvinylpyrrolidone 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 Examples 1 and 2)
In Example 1, the hollow forming agent discharge linear velocity was changed to 12100 and 53240 cm / min, respectively, the linear velocity ratio was 2.5 and 11.0, respectively, and the guide of the spinning process and the Teflon (registered trademark) processing of the roller surface were performed. Implemented except omitting and changing to omit the spraying of mist water during winding of the spinning process and slow current treatment during loading of the polysulfone-based hollow fiber membrane into the module housing. The polysulfone-based hollow fiber membrane and blood purifier of Comparative Examples 1 and 2 were obtained in the same manner as in Example 1. Table 2 shows some of the conditions of the production method.
The polysulfone-based hollow fiber membranes obtained in both comparative examples were inferior in blood compatibility. In the polysulfone-based hollow fiber membrane obtained in Comparative Example 1, the ratio of the linear velocity immediately after ejection is as low as 2.5 times, and friction at the interface between the dope and the hollow forming agent is not sufficient, so that the negative charge is controlled appropriately. It is thought that the contribution of not being able to do was significant. On the other hand, in the polysulfone-based hollow fiber membrane obtained in Comparative Example 2, the ratio of the linear velocity immediately after discharge is as high as 11.0 times, the friction at the interface between the dope and the hollow forming agent is excessive, and an appropriate negative charge is obtained. In addition to being unable to be controlled, stable spinning could not be performed, so a uniform hollow fiber membrane could not be obtained, and it was considered that the contribution of the deterioration of the inner surface state was significant.

(Comparative Example 3)
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 polysulfone-based hollow fiber membrane is dried. A polysulfone-based hollow fiber membrane was obtained in the same manner as in Example 1 except that drying was performed by irradiating microwaves under normal pressure. The microwave irradiation was 2 kW until the water content in the polysulfone-based hollow fiber membrane bundle reached 65% by mass, and thereafter 0.8 kW and dried until the water content became 0.5% by mass. Further, from the start of drying to the end of drying, dehumidified air (humidity of 10% or less) was passed from the lower part of the yarn bundle to the upper part at a wind speed of 8 m / sec from the lower part of each polysulfone-based hollow fiber membrane. The maximum temperature reached by the polysulfone-based hollow fiber membrane during the drying was 65 ° C. The hydrogen peroxide elution amount of the polysulfone-based hollow fiber membrane obtained in this comparative example was high, and the amount of hydrogen peroxide elution amount varied greatly depending on the sampling location, and the quality was low. Further, the UV (220-350 nm) absorbance level was high, and the fluctuation thereof was large, and partial fixation of the hollow fiber membrane was observed.

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

  Table 4 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 comparative example increased the elution amount of hydrogen peroxide by γ-ray irradiation, was inferior in long-term storage stability, and had a low quality as a blood purifier. Moreover, the water permeability development property after the priming treatment was inferior.

(Comparative Example 4)
In Comparative Example 3, the blood purifier was assembled and sterilized in the same manner as in Comparative Example 3, except that the inside of the module was not replaced with inert gas and the storage period until sterilization was 120 hours. Table 4 shows the characteristics of the obtained polysulfone-based hollow fiber membrane and blood purifier. In this comparative example, since the water present in the polysulfone-based hollow fiber membrane is not in a nitrogen saturated state, oxygen gas is dissolved in the water in the polysulfone-based hollow fiber membrane, and γ due to moisture in the polysulfone-based hollow fiber membrane Since the effect of suppressing the degradation of polyvinylpyrrolidone by irradiation with rays is reduced, the amount of hydrogen peroxide eluted by γ-irradiation increases and the UV (220-350 nm) absorbance deteriorates. Therefore, long-term storage stability is deteriorated. Moreover, the water permeability after the priming treatment was inferior, and the blood purifier was of low quality.

(Comparative Example 5)
In the method of Comparative Example 4, the blood purifier was assembled and sterilized in the same manner as in Comparative Example 4 except that the sealing plug was not changed and the storage period until sterilization was 216 hours. The results are shown in Table 5. In this comparative example, the water present in the polysulfone-based hollow fiber membrane is not saturated with nitrogen, and the blood and dialysate inlet / outlet are not sealed, so that air enters the blood purifier and γ rays Since the periphery of the polysulfone-based hollow fiber membrane was filled with air during irradiation, the deterioration of the polysulfone-based hollow fiber membrane was further increased as compared with Comparative Example 4.

(Comparative Example 6)
In the method of Example 1, the water content of the polysulfone-based hollow fiber membrane was not adjusted (inert gas saturated water replacement was not performed), and the storage time until sterilization was changed to 168 hours. Thus, a polysulfone-based hollow fiber membrane and a blood purifier were obtained. The results are shown in Table 5. Polyvinyl pyrrolidone in the polysulfone-based hollow fiber membrane loaded in the blood purifier obtained in this comparative example had a low water content in the polysulfone-based hollow fiber membrane, and thus polyvinyl pyrrolidone did not crosslink. Therefore, the amount of polyvinylpyrrolidone eluted was large and the quality was low. In addition, the effect of suppressing the degradation reaction of the hollow fiber membrane caused by nitrogen-saturated water in γ-irradiation is reduced, so that the degradation reaction of polyvinylpyrrolidone is increased, the amount of hydrogen peroxide eluted by γ-irradiation is increased, and UV (220-350 nm) Absorbance deteriorated. Of course, the storage stability was not good. Furthermore, the expression of water permeability after the priming treatment was inferior.

(Comparative Example 7)
In the method of Comparative Example 6, polyvinyl pyrrolidone and DMAc in the film forming solution were changed to 0.6 and 74.9% by mass, and only the oxygen scavenger was sealed without using a humidity control agent during sterilization. A hollow fiber membrane and a blood purifier of Comparative Example 7 were obtained in the same manner as Comparative Example 6 except that the change was made. Table 5 shows the evaluation results of the obtained polysulfone-based hollow fiber membrane and blood purifier.

  The polysulfone-based hollow fiber membrane obtained in this comparative example was poor in blood compatibility. Due to the low content of polyvinylpyrrolidone on the inner surface, the hydrophilic-hydrophobic balance is not suitable, the cationic dye adsorption rate is higher, the inner surface is in a state where substances are easily adsorbed, and results in poor blood compatibility. It is thought. In addition, the polysulfone-based hollow fiber membrane after drying obtained in this comparative example was stable at a low level of hydrogen peroxide elution at all sites, but was not packaged because a humectant was not used in the sterilization process. The storage humidity of the blood purifier was inferior because the space humidity in the bag was as low as 40% RH, the polyvinylpyrrolidone was deteriorated by γ-ray irradiation, and the hydrogen peroxide elution amount was increased.

  FIG. 2 is a schematic diagram showing the relationship between the cationic dye (methylene blue) adsorption rate and the platelet retention rate obtained from the results of the above Examples and Comparative Examples. From these figures, it can be understood that the limited range of the present invention is a critical range.

(Example 2)
Polyethersulfone (Sumika Chemtex, Sumika Excel (registered trademark) 4800P) 1 part by weight Polyvinylpyrrolidone (BASF Koridone (registered trademark) K-90) 0.21 part by weight, DMAc 1.5 parts by weight 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. Next, after the pressure in the system was reduced to −700 mmHg using a vacuum pump, the dissolution tank was immediately sealed and allowed to stand for 10 minutes so that the solvent and the like would volatilize and the film forming solution composition would not change. This operation was repeated three times to degas the film forming solution. As the polyvinyl pyrrolidone, one having a hydrogen peroxide content of 100 ppm was used, and the supply tank of the raw material supply system and the dissolution tank were replaced with nitrogen gas. Moreover, the fluid number and the stirring Reynolds number at the time of dissolution were 1.1 and 120, respectively. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and then degassed in advance at −700 mmHg for 2 hours as a hollow forming agent from a tube-in orifice nozzle heated to 70 ° C. 50 mass at 50 ° C. The solution was discharged at the same time as the% DMAc aqueous solution, passed through a 350 mm air gap portion cut off from the outside air by a spinning tube, and then coagulated in water at 60 ° C. The nozzle slit width of the tube-in-orifice nozzle used was an average of 45 μm, the maximum was 45.5 μm, the minimum was 44.5 μm, the ratio of the maximum and minimum slit widths was 1.02, and the draft ratio was 1.06. It was. The linear velocities immediately after discharge were 17790 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.6. The polysulfone-based hollow fiber membrane bundle 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. During the spinning process, all the rollers in contact with the polysulfone-based hollow fiber membrane were mirror-finished on the surface, and the guides were all finished on the surface. These guides and rollers were surface-treated with Teflon (registered trademark). Further, mist-like water was sprayed on the running polysulfone-based hollow fiber membrane immediately before winding. A polyethylene film similar to that in Example 1 was wound around about 10,000 bundles of the polysulfone-based hollow fiber membranes, and then washed by immersing in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes × 2 times.

  The obtained wet polysulfone-based hollow fiber membrane was dried in the same manner as in Example 1. The water content after drying was 2.8% by mass. The resulting polysulfone-based hollow fiber membrane had an inner diameter of 199.5 μm and a film thickness of 28.5 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 hydrogen peroxide elution amount 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 using the polysulfone-based hollow fiber membrane thus obtained. The blood purifier was prepared in the same manner as in Example 1 except that the water content of the polysulfone-based hollow fiber membrane was adjusted to 280% by mass and the storage time until sterilization was 216 hours. Then, γ-ray irradiation was performed.
The polysulfone-based 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 3.

(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 of 15 μm and 15 μm, and simultaneously with a 55 mass% DMAc aqueous solution at 60 ° C. that was degassed in advance as a hollow forming agent from a tube-in orifice nozzle heated to 40 ° C. After discharging and passing through a 600 mm air gap portion cut off from the outside air by a spinning tube, it was solidified in 50 ° C. water. The nozzle slit width of the tube-in-orifice nozzle used was an average of 60 μm, the maximum 61 μm, the minimum 59 μm, the ratio of the maximum and minimum slit widths was 1.03, and the draft ratio was 1.01. The linear velocities immediately after discharge were 17790 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.6. The polysulfone-based hollow fiber membrane pulled up from the coagulation bath was rolled up after passing through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone. A bundle of about 10,000 polysulfone-based 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 roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. These guides and rollers were surface-treated with Teflon (registered trademark). The polysulfone hollow fiber membrane obtained by spraying mist-like water on the running polysulfone hollow fiber membrane just before winding was 201.0 μm in diameter and 44.0 μm in thickness.

  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 portion, and is determined as a dialysis artificial kidney device manufacturing approval standard. The extracted liquid was obtained by the test and the hydrogen peroxide elution amount and UV (220-350 nm) absorbance in the extracted liquid 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.

  Example 1 except that the polysulfone-based hollow fiber membrane thus obtained was used as deaerated water for adjusting the moisture content of the hollow fiber membrane, and the moisture content was adjusted to 4.5% by mass. A blood purifier was assembled in the same manner. Further, the blood purifier was sealed with one general-purpose oxygen scavenger (TAMOTSU (registered trademark) manufactured by Oji Tac Co., Ltd.) in the same packaging bag as in Example 1, and allowed to stand at room temperature for 120 hours. The γ-ray irradiation was performed under the conditions of In this experimental example, the production of the polysulfone-based hollow fiber membrane and the assembly of the blood purifier were performed in a class 100,000 clean room. The polysulfone-based 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 3.

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 film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and simultaneously with a 35 mass% DMAc aqueous solution at 60 ° C. degassed as a hollow forming agent from a tube-in orifice nozzle heated to 40 ° C. After discharging and passing through a 600 mm air gap portion cut off from the outside air by a spinning tube, it was solidified in 50 ° C. water. The nozzle slit width of the tube-in-orifice nozzle used was an average of 60 μm, the maximum 61 μm, the minimum 59 μm, the ratio of the maximum and minimum slit widths was 1.03, and the draft ratio was 1.01. The linear velocities immediately after discharge were 17790 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.6. The polysulfone-based hollow fiber membrane pulled up from the coagulation bath was rolled up after passing through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone. During the spinning process, all the rollers in contact with the polysulfone-based hollow fiber membrane were mirror-finished on the surface, and the guides were all finished on the surface. These guides and rollers were surface-treated with Teflon (registered trademark). Further, mist-like water was sprayed on the running polysulfone-based hollow fiber membrane immediately before winding. About 10,000 bundles of the polysulfone-based 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 3.8% by mass.

  The maximum reached temperature of the polysulfone-based hollow fiber membrane during the drying treatment was 56 ° C. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. The hollow fiber membrane obtained had an inner diameter of 200.5 μm and a film thickness of 43.2 μm.

  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 portion, and is determined as a dialysis artificial kidney device manufacturing approval standard. The extracted liquid was obtained by the test and the hydrogen peroxide elution amount and UV (220-350 nm) absorbance in the extracted liquid 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 polysulfone-based hollow fiber membrane thus obtained, a blood purifier was assembled, sealed and packaged in the same manner as in Example 3 except that the moisture content of the hollow fiber membrane was 360% by mass. 50 hours later, a sterilized blood purifier was obtained in the same manner as in Example 1 except that it was changed to γ rays and changed to irradiate with an electron beam using an electron beam irradiator with an acceleration voltage of 5000 KV. The polysulfone-based 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 3.

(Reference Examples 1 and 2)
In the method of Example 1, a polysulfone-based hollow was prepared in the same manner as in Example 1 except that after sealing and after leaving for 24 hours and 40 hours at room temperature, γ-ray irradiation was performed under the same conditions as in Example 1. Yarn membrane and blood purifier were obtained. These characteristics are shown in Table 5. 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. In addition, it was shown that the elapsed time from the sealing to the γ-ray irradiation on the expression of water permeability after the priming treatment was affected.

The blood purifier of the present invention is adsorbed with a cationic dye, which is a measure of the charge state and hydrophilic-hydrophobic balance of the inner surface (blood contact side surface) of the polysulfone-based hollow fiber membrane filled in the blood purifier. The rate is optimized, and the platelet retention rate during blood perfusion is within a predetermined range, so that blood compatibility, performance retention when using blood contact, and safety are realized at a high level.
In addition, 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 bacteria 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, even in the dry state and in the absence of a radical scavenger, there is an effect that cannot be achieved by the prior art that the deterioration of the polysulfone-based hollow fiber membrane due to irradiation is suppressed even when irradiated with radiation. Since it is expressed, the production of hydrogen peroxide due to the deterioration reaction is small, 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 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. There is an advantage that safety can be secured when stored for a long time. Therefore, it is important to contribute to the industry.

It is sectional drawing of a blood purifier. It is a schematic diagram showing the relationship between cationic dye (methylene blue) adsorption rate and platelet retention. It is a schematic diagram which shows the relationship between the elapsed time after sealing the entrance / exit of a blood purifier after carrying out a gamma ray irradiation, and the water permeation performance expression property after a priming process. 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. It is a schematic diagram showing the general tendency of the elapsed time and permeable ratio after a priming process. It is a schematic diagram which shows the relationship between a water permeability ratio and platelet retention.

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 (8)

A blood purifier having a membrane area of 1.5 m ² (on the basis of hollow fiber membrane inner diameter) prepared using a polysulfone-based hollow fiber membrane containing polyvinylpyrrolidone , wherein the water content of the polysulfone-based hollow fiber membrane is 0.8 to At least 48 hours after sealing all the blood and dialysate inlets and outlets of the blood purifier after adjusting to 600% by weight, and after irradiation, irradiation was performed, and after the priming treatment measured using the blood purifier 10 The water permeability at the time of the minute was 90% or more of the water permeability at 24 hours after the priming treatment, and when the heparinized human whole blood was perfused at a flow rate of 150 mL / min on the blood contact side of the blood purifier, 60 minutes A blood purifier having a subsequent platelet retention of 70% or more and 98% or less.   When 1000 mL of a solution containing a cationic dye was filled on the blood contact side and dialysate side of the blood purifier, and the remaining cationic dye solution was perfused on the blood contact side of the blood purifier at a flow rate of 200 mL / min, 5 The blood purifier according to claim 1, wherein the adsorption rate of the cationic dye after 40 minutes is 40% or more and 70% or less.   When the heparinized human whole blood is perfused on the blood contact side of the blood purifier at a flow rate of 150 mL / min, the platelet factor 4 concentration ratio (PF4 increase rate) before and after blood perfusion is 5 times or less. The blood purifier according to claim 1 or 2, characterized in that A packaging bag that shuts off outside air and water vapor in a state where all blood and dialysate inlets and outlets of a blood purifier filled with a polysulfone-based hollow fiber membrane whose water content is adjusted to 5 to 600% by mass using deaerated water are sealed. blood purifier according to any one of claims 1-3, characterized in in that irradiating the sealed and radiation. The blood purifier according to claim 4 , wherein the deaerated water present in and around the polysulfone-based hollow fiber membrane is deoxygenated water. The blood purifier according to claim 4 or 5 , wherein the deaerated water existing in and around the polysulfone-based hollow fiber membrane is an inert gas saturated water. The blood purifier according to any one of claims 4 to 6 , wherein the dissolved oxygen concentration of the 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 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, or any one of claims 1 to 7 The blood purifier according to 1.