JP2006304826A - Blood purification device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood purification device which is a dry type blood purifier, prevents deterioration of a permselective hollow fiber membrane in a sterilizing treatment through radiation irradiation under the absence of radical scavengers, shows superior antithrombogenicity, superior permselectivity, and proper balance of separation characteristics, and is highly stable to retain its performance when used in contact with blood. <P>SOLUTION: The blood purification device is made of the permselective separating membrane which is made of a polysulfone-based polymer and polyvinyl pyrrolidone (PVP), has a skin layer with a thickness of 0.1-1.2 μm, has an outermost layer of the outer surface containing PVP of 25-50 mass% and is expressed by an inequality, (PVP content in the outermost layer of the outer surface)/(PVP content in the outer most layer of the inner surface)≥1.1. When bovine blood is poured into the blood purification device, the sieving coefficient [A] of albumin after 15 minutes is 0.01 or higher and 0.1 or lower, and a sieving coefficient [B], after 2 hours, is 0.005 or higher and 0.04 or lower. A carboxy group content in the permselective hollow fiber membrane is 100-800 nmol/g. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a blood purifier for the purpose of removing blood waste products by extracorporeal circulation.

  In blood purification therapy for the treatment of renal failure, for the purpose of removing urine toxins and waste products in the blood, cellulose is a natural material, and its derivatives are cellulose diacetate and cellulose triacetate. Blood purifiers such as hemodialyzers, hemofilters or hemodialyzers using a dialysis membrane using a polymer such as methyl methacrylate or polyacrylonitrile or an ultrafiltration membrane as a separating material are widely used. In particular, blood purifiers that use hollow fiber membranes as separation materials are used in the dialyzer field because of their advantages such as reducing the volume of extracorporeal blood circulation, increasing the efficiency of removing substances in the blood, and productivity during blood purifier production. Is highly important.

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

As a method for solving the above problems, a method for imparting hydrophilicity to a membrane by blending a polysulfone resin with a hydrophilic polymer to form a membrane has been proposed. For example, 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

In particular, the latter method using polyvinyl pyrrolidone is attracting attention from the viewpoint of safety and economy, and the above-described problems are solved by this method. However, in the hydrophilization technique by blending polyvinyl pyrrolidone, there arises a problem that polyvinyl pyrrolidone is eluted and mixed in purified blood during dialysis. When elution of the polyvinyl pyrrolidone increases, the accumulation of polyvinyl pyrrolidone, which is a foreign substance, in the human body during long-term dialysis may increase, causing side effects and complications. Therefore, the elution amount of polyvinylpyrrolidone is determined by the dialysis artificial kidney device manufacturing approval standard. In the dialysis artificial kidney device production approval standard, the amount of elution of polyvinylpyrrolidone and the like is quantified by UV absorbance. Techniques have been disclosed for determining the effect of elution control based on the dialysis-type artificial kidney device manufacturing approval criteria (see, for example, Patent Documents 5 to 7).
Japanese Patent No. 3314861 JP-A-6-165926 JP 2000-350926 A

  The above method solves the above problem. However, in the hydrophilization technology by blending polyvinylpyrrolidone, the content of polyvinylpyrrolidone present on the inner surface of the membrane (referred to as the inner surface) in contact with blood and the outer surface of the membrane on the opposite side (referred to as the outer surface) Therefore, the membrane performance of the selectively permeable hollow fiber membrane is greatly affected, and its optimization is important. For example, blood compatibility can be ensured by increasing the content of polyvinyl pyrrolidone on the inner surface of the membrane. However, if the surface content becomes too high, the amount of the polyvinyl pyrrolidone eluted into the blood increases, and the accumulation of the eluted polyvinyl pyrrolidone This is not preferable because it causes side effects and complications during long-term dialysis.

  On the other hand, if the content of polyvinylpyrrolidone present on the outer surface of the opposite surface is too high, there is a high possibility that highly hydrophilic endotoxin (endotoxin) contained in the dialysate will enter the blood, causing side effects such as fever. Cause problems, and when the membrane is dried, polyvinyl pyrrolidone present on the outer surface intervenes and the hollow fiber membranes stick together (adhere), causing new problems such as deterioration of blood purifier assembly. . Conversely, lowering the amount of polyvinylpyrrolidone present on the outer surface is preferable in terms of suppressing the invasion of endotoxin into the blood side, but the hydrophilicity of the outer surface is reduced, so it is assembled after assembly of the blood purifier. When the dried hollow fiber membrane is returned to the wet state, the familiarity with the physiological saline used for the wetness is reduced, so that the priming property, which is the expelling property of the air during the wet operation, is reduced. This is not preferable because it leads to problems.

  As a measure for solving the above problems, the content of polyvinyl pyrrolidone present in the dense layer on the inner surface of the selectively permeable hollow fiber membrane is within a specific range, and the content of polyvinyl pyrrolidone present in the dense layer on the inner surface is outside. A method of at least 1.1 times the content of polyvinylpyrrolidone present on the surface is disclosed (see Patent Document 5). That is, the above technique increases the content of polyvinyl pyrrolidone present on the inner surface of the dense layer to improve blood compatibility, and conversely lowers the content of polyvinyl pyrrolidone present on the outer surface and dries the membrane. This is a technology based on the idea of suppressing the occurrence of sticking between the generated hollow fiber membranes. In addition to the problem of sticking generation, this technology also improves the problem of endotoxin (endotoxin) contained in dialysate, which is one of the above-mentioned problems, entering the blood side. Since the content is too low, there remains a problem that leads to the generation of the problem that the priming property, which is another problem described above, is reduced.

Further, by specifying the content of polyvinyl pyrrolidone in the inner surface, outer surface and middle part of the polyvinyl pyrrolidone selectively permeable hollow fiber membrane near the surface determined by the infrared absorption method, one of the above-mentioned problems A method for improving the problem of endotoxin (endotoxin) contained in a dialysis fluid that enters the blood side is disclosed (for example, see Patent Document 8). Although one of the above problems is improved by the technique, for example, the problem that the priming property is lowered as in the above technique is not solved, and the selectively permeable hollow fiber membrane obtained by the technique is a membrane. Since the porosity of the outer surface is as high as 25% or more, there is a problem that the film strength is lowered, leading to problems such as blood leakage.
JP 2001-38170 A

Furthermore, by specifying the surface content of polyvinylpyrrolidone on the inner surface of the selectively permeable hollow fiber membrane, a method for improving blood compatibility and the amount of polyvinylpyrrolidone eluted into the blood is disclosed (for example, patents). Reference 9-9).
JP-A-6-296686 JP 11-309355 A JP 2000-157852 A

  None of the above-mentioned techniques has been mentioned at all regarding the content of polyvinylpyrrolidone on the outer surface of the opposite surface of the hollow fiber membrane, and all the problems due to the content of polyvinylpyrrolidone on the outer surface can be improved. Not in.

Among the above-mentioned issues, regarding the issue of endotoxin (endotoxin) entering the blood side, endotoxin has a hydrophobic part in its molecule and utilizes the property of being easily adsorbed to hydrophobic materials. A method is disclosed (for example, see Patent Document 12). That is, it can be achieved by setting the ratio of polyvinyl pyrrolidone to the hydrophobic polymer on the outer surface of the hollow fiber membrane to 5 to 25%. Certainly, this method is a preferable method for suppressing the entry of endotoxin into the blood side, but in order to impart this property, it is necessary to remove polyvinylpyrrolidone present on the outer surface of the membrane by washing, This cleaning requires a lot of processing time and is economically disadvantageous. For example, in the embodiment of the above-mentioned patent, shower cleaning with hot water at 60 ° C. and cleaning with hot water at 110 ° C. are performed for 1 hour each.
JP 2000-254222 A

In addition, it is preferable to reduce the amount of polyvinylpyrrolidone present on the outer surface from the viewpoint of suppressing the invasion of endotoxin into the blood side, but since the hydrophilicity of the outer surface is reduced, assembly after the blood purifier is assembled. Therefore, when the dried hollow fiber membrane is returned to a wet state, the familiarity with the physiological saline used for wetting is reduced, so that the priming property, which is the ability to expel air during the wet operation, is reduced. This is not preferable because it leads to the occurrence of As a method for improving this point, for example, a method of blending a hydrophilic compound such as glycerin is disclosed (for example, see Patent Documents 13 and 14). However, in this method, the hydrophilic compound acts as a foreign substance during dialysis, and the hydrophilic compound is susceptible to deterioration such as photodegradation, leading to problems such as adversely affecting the storage stability of the blood purifier. In addition, there is also a problem of causing adhesive inhibition of the adhesive when the hollow fiber membrane is fixed to the blood purifier in the blood purifier assembly.
JP 2001-190934 A Japanese Patent No. 3193262

On the other hand, a membrane in which the open area ratio and the pore area of the outer surface of the membrane are specified values is disclosed (for example, see Patent Document 15).
JP 2000-140589 A

The polyvinyl pyrrolidone content on the inner surface also has a great influence on the separation selectivity of the selectively permeable hollow fiber membrane. That is, regarding the blood treatment method for patients with chronic renal failure, it is necessary to actively remove other low molecular weight proteins while minimizing leakage of albumin, which is an effective protein. For example, a technique relating to a polysulfone-based selective separation membrane having an albumin permeability of 0.5 to 0.0001% is disclosed (see Patent Document 16). Certainly, the technique of this patent document is an excellent technique in that the permeability of albumin is suppressed to an extremely low level, but the selectively permeable hollow fiber membrane obtained by this technique is, for example, α1-microglobulin. There is a problem in that the removal rate of the material is low. In recent years, dialysis complications associated with the increase in long-term dialysis patients have attracted attention, not only low molecular weight substances such as urea, uric acid, creatinine, but also from low molecular weight proteins with molecular weights of about 5,000 daltons to low molecular weight proteins with molecular weights of 10,000 daltons or more. The removal target is spreading. Although it is demanded that a uremic substance having a molecular weight of about 30,000 typified by α1-microglobulin existing in blood can be efficiently removed, the technique of Patent Document 16 is inferior in the selectivity of protein separation. I can't answer. On the other hand, a technique relating to a polysulfone-based selective separation membrane having an ovalbumin sieving coefficient of 0.2 or more is disclosed (see Patent Document 17). The permselective hollow fiber membrane obtained in this patent document is effective in that it can efficiently remove uremic substances. Moreover, although it describes that the selective permeability with the removal rate of a useful protein is good, the detail regarding this effect is not mentioned. Furthermore, there is no mention at all regarding the change in the characteristics over time in the performance of hemodialysis, that is, the stability over time, which is an important characteristic in practicality as a blood purifier. Therefore, development of a selectively permeable hollow fiber membrane in which the removal balance of both albumin and α1-microglobulin and the stability with time of these properties is improved is strongly desired.
JP-A-11-309356 JP-A-7-289863

  On the other hand, in a blood purifier, radiation irradiation treatment may be performed for the purpose of crosslinking or sterilizing polyvinyl pyrrolidone in a selectively permeable 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 processing 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.

As a method for solving the above problems, in a film irradiated with radiation, when the carboxyl group content and the peroxide content in the film are controlled within a certain range, the antithrombogenicity is excellent, and even when stored for a long period of time. A technique capable of maintaining an antithrombotic state is disclosed (see Patent Document 18).
JP 2000-135421 A

  However, the blood purifier disclosed in the above-mentioned patent document is a method applied to a so-called wet type blood purifier irradiated with water in a 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 way is not preferable because it leads to cost increase or safety problems until a completely sterilized state is obtained. 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, the establishment of a so-called dry-type blood purifier loaded with a dry permeable hollow fiber membrane and capable of avoiding the above-described problems even when irradiated with radiation in the absence of a radical scavenger is strongly desired. Has been.

  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 19). However, this method has the same problem as that of Patent Document 18.
Japanese Patent Publication No.55-23620

As a method for avoiding the above-mentioned wet state and suppressing deterioration due to radiation irradiation, a method is disclosed in which a sterilizing protective agent such as glycerin or polyethylene glycol is contained in the hollow fiber membrane and γ-ray irradiation is performed in a dry state ( For example, see Patent Document 20). 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 γ-ray irradiation is disclosed (see Patent Document 21). However, there is no mention of the characteristics that the hollow fiber membrane should have before irradiation with radiation and the influence on the priming property of the hollow fiber membrane due to the irradiation of radiation.
JP 2001-170167 A

Further, as a method for solving the above problems, a method of sterilizing by irradiating with radiation in a state where the moisture content of the hollow fiber membrane is 5% or less and the relative humidity near the hollow fiber membrane is 40% or less is disclosed. Yes. (For example, refer to Patent Document 13). 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, the Patent Document 22 makes no mention of the influence of the oxygen concentration around the hollow fiber membrane during sterilization, the change in the amount of eluate after sterilization, and the like.
JP 2000-288085 A

Moreover, in the method of performing sterilization by γ-ray irradiation, a method for achieving that the insolubilized component of the membrane material is 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 is disclosed. Has been. (For example, refer to Patent Document 23). The patent document discloses that the amount of the hydrophilic polymer per 1 m ^{2 of the} liquid contact side area of the membrane extracted with a 40% ethanol aqueous solution can be 2.0 mg / m ² or less. However, even in this patent document, there is no influence on the influence of the oxygen concentration around the hollow fiber membrane when γ-irradiation is performed, on the change in the amount of eluate after sterilization, or on the priming property of sterilization. Not mentioned.
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 patent documents 24-26).
Japanese Patent Application Laid-Open No. 62-74364 JP-A-62-204754 WO98 / 58842 publication

  Regarding deterioration due to radiation irradiation using the oxygen scavenger described above, in Patent Document 24, odor is generated, in Patent Document 25, the strength of the base material and dialysis performance are decreased, and in Patent Document 26, the strength of the base material is decreased and Although the occurrence of sucrose has been described, there is no mention of the increase in the amount of extract described above. Moreover, although 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 for the method of radiation sterilization in the system using the oxygen scavenger described above, the importance of gas, especially oxygen impermeability is described, but regarding moisture permeability, Not mentioned.

Also disclosed is a method of radiation sterilizing a liquid processing device filled with a film protective agent in a wet or semi-wet shape in an inert gas atmosphere (see, for example, Patent Document 27). 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 processing apparatus, ”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 19.
JP-A-8-280795

In order to maintain the sterilization effect for a long period of time, a method of sterilizing a dry-type hollow fiber membrane blood purifier by vacuum packaging and irradiating γ rays has been disclosed (see Patent Document 28). 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, it is disclosed that the amount of peroxide in the hollow fiber membrane is increased by irradiating the dried hollow fiber membrane with γ rays compared to the irradiation in the wet state. No mention is made of a method for suppressing the formation of peroxides during irradiation (see Patent Document 29).
JP 2000-135421 A

  Further, in the production of the selectively permeable hollow fiber membrane used for blood purification treatment as described above, in the method of suppressing the elution of polyvinylpyrrolidone or irradiating radiation such as γ rays for sterilization, Although some have been disclosed regarding the moisture content and irradiation atmosphere conditions of the yarn membrane, mention is made regarding the characteristics that the hollow fiber membrane should have before irradiation and the effect on the priming property of the hollow fiber membrane by irradiation. It has not been.

In addition, a package and a storage method for a liquid separation membrane module in which a liquid separation membrane module used for various industrial water treatments and the like is packaged with a film having a specific composition in which air permeability is suppressed are disclosed (Patent Documents). 30). 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

  The present invention has no problem in the above-described conventional technology, that is, in a dry type blood purifier, even if sterilization treatment is performed by radiation irradiation in the absence of a radical scavenger, the selectively permeable hollow by radiation irradiation is performed. An object of the present invention is to provide a blood purifier that suppresses the degradation of the yarn membrane, has excellent antithrombogenicity, has a good balance of separation characteristics, and has high performance retention stability when blood contact is used.

In order to solve the above-mentioned problems, the present invention has finally been completed as a result of intensive studies. That is, according to the present invention, the skin layer thickness of the selectively permeable hollow fiber membrane mainly composed of a polysulfone polymer and polyvinyl pyrrolidone is 0.1 to 1.2 μm, and the content of polyvinyl pyrrolidone on the outermost surface layer is 25 to 50 mass. % And (purity of polyvinyl pyrrolidone on the outermost surface layer) / (content of polyvinyl pyrrolidone on the innermost surface layer) ≧ 1.1 Blood purification produced using a selectively permeable hollow fiber membrane When a 37 ° C. bovine blood to which hematocrit 30%, total protein concentration 6-7 g / dl, and sodium citrate was added was flowed at 200 ml / min at a filtration flow rate of 20 ml / min, the sieving coefficient of albumin after 15 minutes [A] is 0.01 or more and 0.1 or less, and the sieving coefficient [B] of albumin after 2 hours is 0.005 or more and less than 0.04, and the selectively permeable hollow fiber membrane Carboxyl group content of the blood purifier is 100~800nmol / g.
In this case, the sieving coefficient [B] of albumin after 2 hours is preferably smaller than the sieving coefficient [A] of albumin after 15 minutes.
In this case, the relationship between the sieving coefficient [A] of albumin after 15 minutes and the sieving coefficient [B] of albumin after 2 hours preferably satisfies the following formula.
[B] / [A] = 0.1 to 0.4
In this case, the peroxide content in the selectively permeable hollow fiber membrane is preferably 200 nmol / g or less.
In this case, the thickness of the selectively permeable hollow fiber membrane is preferably 25 to 50 μm.
In this case, it is preferable that the porosity of the outer surface of the selectively permeable hollow fiber membrane is 20 to 35%.
In this case, the moisture content of the selectively permeable hollow fiber membrane is preferably 600% by mass or less.
Further, in this case, the permselective hollow fiber membrane bundle before irradiation is divided into 10 in the longitudinal direction by the length unit for filling the blood purifier, and each is determined according to the dialysis artificial kidney device manufacturing approval standard. When the test is carried out, it is preferable that the hydrogen peroxide concentration in all the extract solutions is 5 ppm or less.

  Since the blood purifier of the present invention is excellent in selective permeability and is of a dry type, it has advantages such as being light, not freezing, and difficult to propagate various bacteria. In addition, since the polysulfone-based selectively permeable hollow fiber membrane loaded in the blood purifier of the present invention does not contain a radical scavenger, the radical scavenger is washed and removed in advance when used for blood purification. There is an advantage that the operation to perform is unnecessary. Furthermore, in the present invention, even in the dry state and in the absence of a radical scavenger, even if irradiated with radiation, the degradation of the selectively permeable hollow fiber membrane due to irradiation is suppressed, an effect that cannot be achieved with the prior art. Therefore, the production of the carboxyl group and peroxide caused by the deterioration reaction is small, and the blood purifier of the present invention has the advantage of excellent antithrombotic properties.

で示される繰り返し単位をもつポリスルホン樹脂やポリエーテルスルホン樹脂がポリスルホン系樹脂として広く市販されており、入手も容易なため好ましい。 Hereinafter, the present invention will be described in detail.
The selectively permeable hollow fiber membrane (hereinafter sometimes simply referred to as a hollow fiber membrane) used in the blood purifier of the present invention is characterized in that it is 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.

  The polyvinyl pyrrolidone used in the present invention is a water-soluble polymer compound obtained by vinyl polymerization of N-vinyl pyrrolidone. It is marketed under the trade name “Cole”, and there are products of various molecular weights. In general, it is preferable to use a low molecular weight in terms of hydrophilicity imparting efficiency, while it is preferable to use a high molecular weight from the viewpoint of lowering the elution amount. 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. As the molecular weight of polyvinylpyrrolidone, those having a mass average molecular weight of 10,000 to 1,500,000 can be used. Specifically, for example, those having a molecular weight of 9,000 (K17) commercially available from BASF, and the same shall apply hereinafter, 45,000 (K30), 450,000 (K60), 900,000 (K80), 1,200 000 (K90) is preferable, and in order to obtain the intended use, characteristics, and structure, each may be used alone, or two or more may be used in combination as appropriate.

  The selectively permeable hollow fiber membrane of the present invention is preferably produced using polyvinylpyrrolidone having a hydrogen peroxide content of 300 ppm or less. 250 ppm or less is more preferable, 200 ppm or less is more preferable, and 150 ppm or less is more preferable. Setting the hydrogen peroxide content in the polyvinyl pyrrolidone used as a raw material to 300 ppm or less is the first factor that stabilizes the hydrogen peroxide elution amount in the selectively permeable hollow fiber membrane to 5 ppm or less. This is preferable because the quality of the hollow fiber membrane can be stabilized.

It is presumed that hydrogen peroxide contained in the polyvinyl pyrrolidone used as the raw material is generated in the process of oxidative degradation of polyvinyl pyrrolidone. Therefore, to reduce the hydrogen peroxide content to 300 ppm or less, it is effective to take measures to suppress the oxidative degradation of polyvinylpyrrolidone in the production process of polyvinylpyrrolidone. It is also effective and recommended to take measures to suppress deterioration during transportation and storage of polyvinylpyrrolidone. For example, it is preferable to use an aluminum foil laminated bag to shield the light and enclose it with an inert gas such as nitrogen gas, or to enclose and store an oxygen scavenger together. In addition, when the package is opened and divided into small portions, it is preferable that the measurement and preparation be performed after replacing with an inert gas, and that the above-mentioned measures be taken for the storage. Also, in the manufacturing process of the hollow fiber membrane, it is also recommended as a preferred embodiment to take a means such as replacing the supply tank in the raw material supply system with an inert gas. In addition, it is not excluded to take a method of reducing the amount of hydrogen peroxide by a recrystallization method or an extraction method. Moreover, when dissolving this polyvinylpyrrolidone in a solvent, it is preferable to melt | dissolve at the temperature of 70 degrees C or less.
It is also a preferred embodiment that the dissolution is performed in a state where the inert gas is substituted.

  Thus, in the present invention, it is preferable to use the above-mentioned polyvinyl pyrrolidone, but other hydrophilic polymers such as polyglycol may be used in combination within the scope of the present invention.

  The method for producing the selectively permeable hollow fiber membrane of the present invention is not limited in any way, but for example, a method for producing a hollow fiber membrane type as disclosed in JP 2000-300663 A is preferred. 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, A hollow fiber membrane is introduced into a water coagulation bath at 75 ° C., washed, washed, and bundled up to 10,000 bundles, loaded into a cylindrical polypropylene film, cut into a length of 27 cm, and a wet hollow fiber membrane is formed. The drying of the wet hollow fiber membrane produced and obtained by passing air at 60 ° C. in the longitudinal direction of the hollow fiber membrane bundle for 20 hours from one direction can be exemplified.

  As described above, the permselective hollow fiber membrane of the present invention can be produced by a dry and wet membrane formation method using a membrane-forming solution obtained by dissolving the polysulfone-based polymer and polyvinyl pyrrolidone as constituent components in a solvent. As such a solvent, an amide-based polar solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or the like, which can dissolve both components, or a sulfoxide-based polar solvent such as dimethylsulfoxide is used. Moreover, if it is 10 mass% or less, you may use together the nonsolvent with respect to polysulfone type polymers, such as water and alcohol. This makes it possible to control the phase separation of polyvinylpyrrolidone relative to the polysulfone polymer.

  The blood purifier of the present invention is a blood purifier prepared by loading a selectively permeable hollow fiber membrane having the above composition, and hematocrit 30%, total protein concentration 6-7 g / dl, and sodium citrate is added at 37 ° C. Of bovine blood at a flow rate of 200 ml / min and a filtration flow rate of 20 ml / min, the sieving coefficient [A] of albumin after 15 minutes is 0.01 to 0.1 and the sieving coefficient of albumin after 2 hours [ B] is preferably 0.005 or more and less than 0.04 (Requirement 1). The sieving coefficient of albumin after 15 minutes is preferably from 0.01 to 0.09, more preferably from 0.01 to 0.08. On the other hand, the sieving coefficient [B] of albumin after 2 hours is more preferably 0.005 or more and 0.035 or less, and further preferably 0.005 or more and 0.03 or less. If the sieving coefficient of albumin after 15 minutes and 2 hours is too large, the permeability of albumin, which is a useful protein, is increased, which may increase the burden on the patient. On the other hand, when the sieving coefficients of albumin after 15 minutes and 2 hours are too small, it is preferable in terms of low albumin permeability, but uremic substances such as α1 microglobulin may not be efficiently removed.

  Albumin is a protein useful for the living body, and it is considered that the amount of albumin leakage per one hemodialysis treatment (water removal amount 3 L) is 3 g or less in clinical practice. Excessive albumin leakage can cause disorders such as hypoalbuminemia in patients with low dietary intake. Therefore, the amount of albumin leakage per hemodialysis is more preferably 2.5 g or less, further preferably 2.0 g or less, and further preferably 1.5 g or less. Conversely, the presence of toxins that bind to albumin is also known in the living body, and even if the amount of albumin leakage is too small, various disorders may be caused. Therefore, the amount of albumin leakage per dialysis treatment is preferably 0.05 g or more, more preferably 0.1 g or more, and further preferably 0.15 g or more.

  In the present invention, the sieving coefficient [B] of albumin after 2 hours is more preferably smaller than the sieving coefficient [A] of albumin after 15 minutes (Requirement 2). By satisfying this requirement, the effects of the present invention can be remarkably exhibited. Further, the relationship between the sieving coefficient [A] of albumin after 15 minutes and the sieving coefficient [B] of albumin after 2 hours preferably satisfies [B] / [A] = 0.1 to 0.4. (Requirement 3). [B] / [A] = 0.15 to 0.38 is more preferable. When [B] / [A] is too large, the permeability of albumin, which is a useful protein, increases, and the burden on the patient may increase. On the other hand, when [B] / [A] is too small, uremic substances such as α1 microglobulin may not be efficiently removed.

In the present invention, the clearance of α1 microglobulin (molecular weight 33,000) is preferably 10 ml / min (1.0 m ² ) or more (Requirement 4). If the clearance of α1 microglobulin is too small, the removal amount of a substance having a molecular weight of about 30,000 is small, so that the effect of preventing dialysis complications and the improvement of clinical symptoms such as itch and pain may not be obtained. Therefore, the clearance of α1 microglobulin is preferably 12 ml / min (1.0 m ² ) or more, more preferably 15 ml / min (1.0 m ² ) or more, and even more preferably 17 ml / min (1.0 m ² ) or more. 20 ml / min (1.0 m ² ) or more is particularly preferable. In addition, it is preferable that the clearance is large in order to enhance the removal property of α1 microglobulin. However, if the clearance is too large, it becomes difficult to suppress the leakage of albumin, which is a useful protein, so the clearance of α1 microglobulin is 100 ml / ml. Min (1.0 m ² ) or less is preferable, 80 ml / min (1.0 m ² ) or less is more preferable, and 60 ml / min (1.0 m ² ) or less is more preferable.

  In the present invention, the measurement of the protein concentration in the filtrate immediately after the start of blood filtration is 15 minutes later for the following reason. In the present invention, as apparent from the object of the invention, the pore diameter of the membrane immediately after blood filtration must be greater than a certain value, and therefore the protein concentration in the filtrate is accurately measured as early as possible after the start of blood filtration. It is desirable to do. However, the membrane is preliminarily primed with physiological saline before coming into contact with blood, and the filtrate side in the membrane and blood purifier is filled with physiological saline. For this reason, even if blood is flowed and filtration is started, the filtrate obtained first is diluted with physiological saline, and it is difficult to obtain an accurate protein concentration in the filtrate. When the filtrate flow rate is about 15 ml / min, the shortest time in which the influence of dilution with physiological saline can be ignored is 15 minutes after the start of filtration.

  In the present invention, the protein concentration in the filtrate after 120 minutes is preferably 0.005 or more and less than 0.04. If the protein concentration in the filtrate after 120 minutes is 0.005 or more, the removal of the molecular weight substance having a molecular weight of about 30,000 is efficiently performed over the entire treatment time. If it is less than 0.005, the substance removal performance at the beginning of treatment is high, but the removal effect may not be sustained over the entire treatment time. Moreover, if the protein concentration in the filtrate after 120 minutes is too high, protein leakage increases throughout the treatment time, and hypoproteinemia tends to occur.

The causative agent of itchiness and irritation is estimated to have a molecular weight of about 30,000, but has not yet been identified. Also, if the molecular weight is the same but the molecular shape is different, the removal characteristics when filtered through a membrane cannot be defined unconditionally. In our study, when the protein concentration in the filtrate after 15 minutes is 0.01 or more, the clearance of α1 microglobulin (molecular weight 33,000) is found to be 10 ml / min (1.0 m ² ) or more. Yes. We introduced α1 microglobulin (molecular weight 33,000) clearance as a standard for objectively judging clinical effects in the laboratory, and when this clearance is 10 ml / min (1.0 m ² ) or more, I thought I could eliminate the irritation.

  In the blood treatment of patients with chronic renal failure, it is important to minimize leakage of albumin, which is a useful protein, but when this is suppressed, the removal rate of α1 microglobulin and the like is greatly reduced. . In order to have the appropriate balance, the performance of the selectively permeable hollow fiber membrane was examined. A hematocrit 30 was applied to a blood purifier prepared by loading a selectively permeable hollow fiber membrane comprising a polysulfone polymer and polyvinylpyrrolidone. %, Total protein concentration 6-7 g / dl, 37 ° C. bovine blood added with sodium citrate at 200 ml / min, filtration flow rate 20 ml / min, the sieving coefficient [A] of albumin after 15 minutes is 0 It is optimal to use a selectively permeable hollow fiber membrane having a characteristic that the sieving coefficient [B] of albumin after 2 hours is within the range of 0.005 or more and less than 0.04 after 0.01 hours or more and 0.1 or less It was found that this is a necessary condition. In order to manufacture a separation membrane with such optimal conditions, it is important to control various materials, their specifications, manufacturing processes, drying conditions, etc. One method is to analyze the relationship between albumin sieving coefficients.

  The content of polyvinyl pyrrolidone on the innermost surface layer of the hollow fiber membrane [C] and the content of polyvinyl pyrrolidone on the outermost surface layer of the outer surface [D], which are one of the most typical features of the separation membrane of the present invention FIG. 2 shows the relationship between [D] / [C], albumin sieving coefficient [A] after 15 minutes, and albumin sieving coefficient [B] after 2 hours. According to this, when [D] / [C] specified in claim 1 of the present invention is 1.1 times or more, with respect to albumin sieving coefficient [A], in Examples 1 to 3, a predetermined value is used. A stable permselective hollow fiber membrane having a balance between albumin and α1 microglobulin that is properly within the range of 0.01 to 0.1 and 0.005 to less than 0.04 is obtained. Of course, the molecular weight of polyvinylpyrrolidone and the content in the film are considered to affect the albumin sieving coefficient, but [D] / [C] is more than 1.1 in the range verified in this example. It can be easily understood that this is one of the factors having a great influence in that the albumin sieving coefficient falls within a predetermined range.

  Similarly, when the relationship between [B] / [A], which is the ratio of albumin sieving coefficient, and [D] / [C], which is the polyvinylpyrrolidone content ratio, is examined (see FIG. 3), , [D] / [C] is more than 1.1, [B] / [A] fits within the range of 0.1 to 0.4. Is far off.

  In the present invention, the method for imparting the selectivity balance of protein separation described above to the selectively permeable hollow fiber membrane is not limited, but the selectively permeable hollow fiber membrane in the present invention has a skin layer on the inner surface, and the outer surface. It is preferable to have a so-called asymmetric structure in which the hole diameter increases toward the bottom. Furthermore, the thickness of the skin layer is preferably 0.1 to 1.2 μm (Requirement 6). A thinner skin layer, which is a substantial separation active layer, is preferable because the solute movement resistance is small, preferably 1.1 μm or less, and more preferably 1.0 μm or less. However, if the thickness of the skin layer is too thin, potential pore structure defects are likely to be manifested, and leakage of albumin, a useful protein, cannot be suppressed, or it becomes difficult to ensure pressure resistance, etc. Problems may occur. Therefore, the skin layer thickness is preferably 0.2 μm or more, more preferably 0.3 μm or more, and further preferably 0.4 μm or more.

  In the above production method, the film-forming solution is composed of a polysulfone polymer, polyvinyl pyrrolidone, and a solvent, the ratio of polyvinyl pyrrolidone to the polysulfone polymer is 10 to 18% by mass, and the internal liquid is 30 amide solvents. It is also a preferred embodiment that the aqueous solution contains ˜60% by mass, the liquid temperature of the internal liquid is lower by 30 to 60 ° C. than the liquid temperature of the film forming solution, and the liquid temperature is discharged at 0 to 40 ° C. As a polyvinylpyrrolidone ratio, 12.0-17.5 mass% is more preferable, and 13.0-17.5 mass% is further more preferable. The amount of the amide solvent in the internal liquid is more preferably from 32 to 58 mass%, further preferably from 34 to 56 mass%, still more preferably from 35 to 54 mass%. The difference between the liquid temperature of the internal solution and the liquid temperature of the film forming solution is more preferably 30 to 60 ° C, further preferably 30 to 55 ° C, and further more preferably 35 to 50 ° C. The liquid temperature of the internal liquid is more preferably 0 to 35 ° C, further preferably 5 to 30 ° C, and further preferably 10 to 30 ° C. By selecting these conditions, the skin layer thickness of the selectively permeable hollow fiber membrane, the inner surface properties such as the polyvinylpyrrolidone content on the inner surface, the average pore size and the pore size distribution are optimized and the protein selectivity is improved. The required properties of the selectively permeable hollow fiber membrane can be achieved.

  In addition, by setting the temperature of the internal liquid within the above range, it is possible to suppress the dissolved gas that has dissolved into bubbles when the internal liquid is discharged from the nozzle. That is, by suppressing the bubble formation of the dissolved gas in the internal liquid, there is also a secondary effect of suppressing yarn breakage immediately below the nozzle and generation of a knob.

  Although there is no limitation on the method of providing a temperature difference between the liquid temperature of the internal liquid and the liquid temperature of the film forming solution, a tube-in-orifice type nozzle is provided with a heat exchanger in the piping from the internal liquid tank to the nozzle and in the nozzle block. In a preferred embodiment, an internal liquid heat medium circulating block capable of adjusting the liquid temperature separately from the temperature of the solution is used.

  Further, as an achievement means for imparting the selectivity balance of the protein, it is mentioned that polyvinylpyrrolidone is substantially non-crosslinked (requirement 8). In the present invention, one of the means for accomplishing this is to provide a balance of the above-mentioned protein selectivity by the swelling effect of the polyvinyl pyrrolidone present in the selectively permeable hollow fiber membrane by the passage of blood. That is, at the start of treatment, the permeability of the protein is increased and the permeability of albumin is reduced by the swelling of polyvinylpyrrolidone in the selectively permeable hollow fiber membrane with the passage of blood due to the progress of dialysis. This utilizes the effect of improving the selectivity of protein separation. When polyvinylpyrrolidone is cross-linked, the molecular mobility of polyvinylpyrrolidone and the swelling property with blood are lowered, so that the function of action is lowered and the selectivity of protein separation may be lowered.

  In the present invention, the content of insolubles is preferably 30% by mass or less based on the total polyvinyl pyrrolidone present in the selectively permeable hollow fiber membrane. 25 mass% or less is more preferable, 20 mass% or less is more preferable, 15 mass% or less is further more preferable, 10 mass% or less is especially preferable, and less than 5 mass% is the most preferable. The content of the insoluble matter is a measure of the degree of crosslinking of polyvinyl pyrrolidone, and when the content of the insoluble content exceeds 30% by mass, the crosslinking of the polyvinyl pyrrolidone present in the selectively permeable hollow fiber membrane proceeds. In other words, the above-mentioned function and function may be reduced, leading to a decrease in protein selectivity and a decrease in blood compatibility of the selectively permeable hollow fiber membrane. However, since the selectively permeable hollow fiber membrane of the present invention preferably maintains the moisture content after drying at 1 to 10% by mass, a certain degree of cross-linking reaction occurs due to the influence of moisture slightly present during irradiation sterilization. In addition, by making it slightly cross-linked (insolubilized), it is possible to exert a secondary effect of not adversely affecting residual blood during blood flow and reducing the amount of eluate. Therefore, the content of insoluble matter is preferably 0.1% by mass or more, more preferably 0.2% by mass or more, further preferably 0.3% by mass or more, and further preferably 0.5% by mass or more.

  The content of the insoluble matter can be simply determined by the presence or absence of insoluble matter in a solution obtained by immersing and dissolving the selectively permeable hollow fiber membrane in dimethylformamide. That is, 10 g of the selectively permeable hollow fiber membrane is dissolved in 100 ml of dimethylformamide and visually observed to determine that no insoluble matter can be seen as non-crosslinked.

  In this invention, it is preferable that the film thickness of a selectively permeable hollow fiber membrane is 25-50 micrometers (requirement 7). If the film thickness is too thin, the pressure resistance may decrease. In addition, the permselective hollow fiber membrane may become weak and the assembly of the blood purifier may be deteriorated. Therefore, the film thickness is more preferably 26 μm or more, and further preferably 27 μm or more. On the other hand, when the film thickness is too thick, it leads to a decrease in the clear run of α1 microglobulin and an increase in the elution amount of polyvinylpyrrolidone. In addition, for example, in the case of a hollow fiber membrane, there is a risk of losing the merit that the blood purifier is compact, for example, in the case of a hollow fiber membrane. Therefore, the film thickness is more preferably 45 μm or less, further preferably 40 μm or less, and further preferably 35 μm or less.

  In the present invention, the content of polyvinyl pyrrolidone in the outermost layer on the inner surface of the selectively permeable hollow fiber membrane is preferably 20 to 40% by mass (Requirement 9). If it is less than 20% by mass, the hydrophilicity of the inner surface of the hollow fiber membrane is low and the blood compatibility is deteriorated, blood coagulation tends to occur on the surface of the hollow fiber membrane, and the hollow fiber membrane is blocked by the coagulated thrombus. The separation performance of the membrane may decrease, and the residual blood after use for hemodialysis may increase. The content of polyvinyl pyrrolidone in the outermost layer on the inner surface of the hollow fiber membrane is more preferably 21% by mass or more, further preferably 22% by mass or more, and further preferably 23% by mass or more. On the other hand, when the amount exceeds 40% by mass, the amount of polyvinylpyrrolidone eluted in the blood increases, and side effects and complications due to long-term dialysis due to the eluted polyvinylpyrrolidone may occur. The content of polyvinyl pyrrolidone in the outermost layer on the inner surface of the hollow fiber membrane is more preferably 38% by mass or less, and further preferably 36% by mass or less.

Blood compatibility is also affected by the amount of plasma protein adsorbed. That is, plasma protein, which is a hydrophilic protein, is adsorbed to the inner surface (blood contact side surface) of the selectively permeable hollow fiber membrane, thereby increasing the hydrophilicity of the surface and improving blood compatibility. In the present invention, the adsorption amount of α1 microglobulin (molecular weight: 33,000) in plasma protein is 2.0 to 2.0 as an index of clinical symptoms (itch / pain) improving effect and blood compatibility of the selectively permeable hollow fiber membrane. It is preferably 20 mg / m ² (Requirement 5). In addition, α1 microglobulin has a property of easily binding to immunoglobulin (molecular weight of 100,000 or more) in blood (plasma). Since α1 microglobulin bound to immunoglobulin becomes larger than the pores of the selectively permeable hollow fiber membrane, there is a problem that it cannot be sufficiently removed only by the sieving effect. Therefore, in order to enhance the effect of improving clinical symptoms, it is another aspect of the present invention that the removal amount is increased by the effect of adsorption to the selectively permeable hollow fiber membrane. If the amount of α1 microglobulin adsorbed is too small, the blood compatibility may be deteriorated and the effect of improving clinical symptoms may be insufficient. Therefore, the adsorption amount is more preferably 2.5 mg / m ² or more, more preferably 3.0 mg / m ² or more, and even more preferably 3.5 mg / m ² . On the other hand, when the amount of adsorption is too large, it leads to a decrease in effective pore diameter, and as a result, the removability of medium molecular weight substances to low molecular weight proteins may decrease. Therefore, the amount of adsorption is more preferably 19 mg / m ² or less, more preferably 18 mg / m ² or less, 17 mg / m ² even more preferably more.

In order to bring the adsorption amount of α1 microglobulin into the above range, the optimization of the content of the outermost surface polyvinylpyrrolidone on the inner surface greatly contributes. In addition, it is affected by the form of the surface layer on the inner surface. The method for imparting these characteristics is not limited, but can be achieved by combining the manufacturing conditions described above and below, for example. In particular, it is greatly affected by the liquid temperature of the internal liquid. Therefore, it is important that the liquid temperature of the above-described internal liquid is lower by 30 to 60 ° C. than the liquid temperature of the film forming solution and the liquid temperature is 0 to 40 ° C. This optimizes the polyvinyl pyrrolidone content of the innermost outermost layer. Furthermore, by increasing the draft ratio at the time of film formation under the above conditions, streak-like micro irregularities that are continuous in the longitudinal direction of the hollow fiber membrane are formed on the surface layer of the inner surface. This micro unevenness increases the surface area of the inner surface and optimizes the amount of adsorption. In addition, the amount of α1 microglobulin adsorbed is affected by the degree of orientation of polyvinylpyrrolidone on the inner surface of the hollow fiber membrane. The higher the degree of orientation, the greater the amount of adsorption. Therefore, as shown in FIG. 1, it is a preferred embodiment that the shear stress of the film forming solution in the tube-in-orifice nozzle during film forming is in the range of 1 × 10 ⁴ to 1 × 10 ⁸ s ⁻¹ . If the shear stress is too small, the degree of orientation of the polyvinyl pyrrolidone on the inner surface of the hollow fiber membrane becomes small, which may reduce the amount of α1 microglobulin adsorbed. Therefore, the shear stress in the nozzle is more preferably 5 × 10 ⁴ s ⁻¹ or more, further preferably 1 × 10 ⁵ s ⁻¹ or more, and even more preferably 5 × 10 ⁵ s ⁻¹ or more. When the shear stress is too large, crystallization of polyvinyl pyrrolidone on the inner surface of the hollow fiber membrane proceeds, and the solute permeability may be reduced. Therefore, the shear stress is more preferably 5 × 10 ⁷ s ⁻¹ or less, further preferably 1 × 10 ⁷ s ⁻¹ or less, and further preferably 5 × 10 ⁶ s ⁻¹ or less. Similarly, it is an important requirement to define the time during which the film-forming stock solution is subjected to shear stress. The shear stress time is preferably 1 × 10 ^{−5 to} 0.1 sec. More preferably, it is 5 * 10 ^{< -4} > -5 * 10 ^<-2 > sec, More preferably, it is 1 * 10 ^{< -4} > ^-1 * 10 ^<-2 > sec. As a specific nozzle shape for achieving these requirements, it is preferable that the maximum outer diameter of the film-forming stock solution discharge hole is 100 to 700 μm and the land length is 0.1 to 5 mm. The maximum outer diameter is more preferably 150 to 600 μm, further preferably 180 to 550 μm, and still more preferably 200 to 500 μm. By using such a nozzle, it becomes possible for the film-forming stock solution that has been sheared in the nozzle to be appropriately oriented after ejection from the nozzle and to form micro unevenness on the blood contact surface.

  The amount of α1 microglobulin adsorbed is also affected by the charged state of the inner surface of the hollow fiber membrane. In the present invention, it is effective to use RO water as the water used for producing the hollow fiber membrane. For example, in the washing process of the hollow fiber membrane, by using RO water, the chargeable substance adhering to the membrane can be efficiently removed. In addition, since the ionic substance is not contained in the RO water, ions are not adsorbed on the membrane. The RO water used preferably has a specific resistance of 0.3 to 2 MΩcm, more preferably 0.4 to 1.9 MΩcm.

  The adsorbed amount of α1 microglobulin contributes not only to the improvement of blood compatibility but also to the removal of α1 microglobulin, and is also favorable for the prevention of dialysis complications and the improvement of clinical symptoms such as itching and pain. It seems to have an effect.

  In this invention, it is preferable that content of polyvinylpyrrolidone in the surface vicinity layer of the inner surface of a selectively permeable hollow fiber membrane is 5-20 mass% (requirement 10). 7-18 mass% is more preferable. As described above, the content of polyvinyl pyrrolidone in the outermost layer on the inner surface of the selectively permeable hollow fiber membrane is preferably higher than the blood compatibility point, but when the content increases, the amount of polyvinyl pyrrolidone eluted into the blood increases. It becomes a contradictory phenomenon of increasing. In the present invention, the content of polyvinyl pyrrolidone in the outermost layer of the selectively permeable hollow fiber membrane is set to the lowest level at which blood compatibility can be expressed. However, with the content of the outermost layer, the initial blood compatibility is satisfactory, but when dialysis is performed for a long time, the polyvinyl pyrrolidone present in the outermost layer gradually elutes into the blood, gradually with the progress of dialysis. The problem that blood compatibility falls will generate | occur | produce. The present invention has been completed by the technical idea of solving the problem by replenishing the polyvinyl pyrrolidone existing in the surface vicinity layer by moving it to the outermost layer. If the content of polyvinyl pyrrolidone in the inner surface layer of the hollow fiber membrane is too small, the supply of polyvinyl pyrrolidone to the outermost layer will not be performed, which may reduce the solute removal performance and the stability over time of blood compatibility. . Therefore, the content of polyvinyl pyrrolidone in the hollow fiber membrane inner surface vicinity layer is more preferably 6% by mass or more, and further preferably 7% by mass or more. On the other hand, if the content of polyvinylpyrrolidone in the inner layer near the inner surface of the hollow fiber membrane is too large, the amount of polyvinylpyrrolidone eluted in the blood increases, which may cause side effects and complications due to long-term dialysis. Therefore, the content of polyvinyl pyrrolidone in the hollow fiber membrane inner surface vicinity layer is more preferably 19% by mass or less, and further preferably 18% by mass or less.

  In the present invention, the content of polyvinylpyrrolidone in the outermost layer on the outer surface of the selectively permeable hollow fiber membrane is 25 to 50% by mass, and (content of polyvinylpyrrolidone in the outermost surface layer) / (the innermost surface) It is preferable that the content of polyvinylpyrrolidone in the surface layer) ≧ 1.1 (Requirement 11). If the content of polyvinyl pyrrolidone in the outermost surface layer of the outer surface is too small, the amount of blood protein adsorbed on the support layer portion of the hollow fiber membrane will increase, and blood compatibility and permeation performance may be lowered. In the case of a dry film, the priming property may be lowered. Therefore, the content of polyvinyl pyrrolidone in the outermost outermost layer is more preferably 27% by mass or more, further preferably 29% by mass or more, and further preferably 31% by mass or more. Conversely, if the content of polyvinylpyrrolidone on the outer surface is too high, the endotoxin (endotoxin) contained in the dialysate is likely to enter the blood side, leading to side effects such as fever, When it is dried, polyvinylpyrrolidone present on the outer surface intervenes, and the hollow fiber membranes adhere to each other, which may cause problems such as deterioration of blood purifier assembly. The content of polyvinyl pyrrolidone in the outermost outermost layer is more preferably 43% by mass or less, further preferably 41% by mass or less, and still more preferably 39% by mass or less.

The content of polyvinyl pyrrolidone affects the shrinkage rate of the hollow fiber membrane after film formation. That is, the shrinkage rate of the hollow fiber membrane increases as the polyvinylpyrrolidone content increases. For example, when the content of polyvinyl pyrrolidone in the outermost surface layer is higher than the content of polyvinyl pyrrolidone in the outermost surface layer, wrinkles occur on the inner surface side due to the difference in shrinkage between the inner surface side and the outer surface side. Or the hollow fiber membrane may break. If wrinkles enter the inner surface, for example, when used for hemodialysis, blood proteins and the like are likely to be deposited on the membrane surface when blood is flowed, so the permeation performance deteriorates over time. There is a possibility of connection. For these reasons, it is preferable to increase the content of polyvinylpyrrolidone on the outer surface side. Furthermore, the hollow fiber membrane of the present invention has a dense layer on the inner surface and a structure in which the pore diameter gradually increases toward the outer surface. That is, since the porosity on the outer surface side is higher than that on the inner surface side, the shrinkage rate on the outer surface side is larger. In consideration of the influence, the content of polyvinyl pyrrolidone in the outermost surface layer is preferably 1.1 times or more than the content of polyvinyl pyrrolidone in the outermost surface layer. More preferably, it is 1.2 times or more, and further preferably 1.3 times or more.
For the above reasons, it is preferable that the content of polyvinyl pyrrolidone on the outermost surface layer is higher. However, if the content exceeds 2.0 times, the content of polyvinyl pyrrolidone with respect to the polysulfone-based polymer becomes too high, resulting in insufficient strength or between the hollow fiber membranes. May cause problems such as adhering to the blood, reverse endotoxin flow during hemodialysis, and elution of polyvinylpyrrolidone. More preferably, it is 1.9 times or less, More preferably, it is 1.8 times or less, More preferably, it is 1.7 times or less.

  Regarding the innermost surface layer and the inner surface vicinity layer, the difference between the two layers in detail shows that it has a two-layer structure due to the difference in the content of the hydrophilic polymer. Since the pore diameter tends to increase from the layer (dense layer) toward the outer surface, a two-layer structure with a difference in density between the outermost layer and the surface vicinity may be formed. The thickness of each layer and its boundary line are arbitrarily changed depending on the production conditions of the selectively permeable hollow fiber membrane, and the structure of the layer also has some influence on the performance. Then, even if guessed from the manufacturing process of the hollow fiber membrane by solvent exchange, if the outermost layer and the surface vicinity layer are manufactured almost at the same time and both layers are manufactured adjacent to each other, two layers are formed once. Even if it can be recognized, the boundary is not something that can be drawn clearly, and if you look at the distribution curve of the content of hydrophilic polymer across two layers, it is often connected by a continuous line, in polyvinylpyrrolidone It would be technically impossible to assume that there are two discontinuous layers with different material behavior due to the fault in the distribution curve of the content of the hydrophilic polymer. The content of polyvinyl pyrrolidone is 20-40% by mass in the outermost layer and 5-20% by mass in the vicinity of the surface layer as the optimal range. In terms of the mechanism of diffusion movement, for example, a design in which the outermost layer is 40% by mass and the surface vicinity layer is 5% by mass may not function sufficiently. In short, it is also important to design by paying attention to the difference in the content of simple polyvinylpyrrolidone present in the two layers. As the appropriate difference value, that is, the ratio of the outermost layer polyvinyl pyrrolidone content to the surface vicinity layer polyvinyl pyrrolidone content is 1.1 times or more, specifically, the content of polyvinyl pyrrolidone in the two layers If the difference in the amount is about 1 to 35% by mass, optimally about 5 to 25% by mass, it means that the diffusion movement of the polyvinyl pyrrolidone from the surface vicinity layer to the outermost layer is smoothly performed. For example, when the outermost layer is 32% by mass, the surface vicinity layer is in the range of about 7 to 27% by mass, which satisfies the requirement of about 1.1 to 10 times.

  In addition, the content of the selectively permeable hollow fiber membrane outermost layer of the polyvinylpyrrolidone was measured and calculated by the ESCA method as described later, and the outermost layer part (depth number from the surface layer) of the selectively permeable hollow fiber membrane. The absolute value of the content of Å to several tens of liters) is obtained. Normally, the ESCA method can measure the polyvinylpyrrolidone content up to about 10 nm (100 mm) deep from the surface. The content of polyvinylpyrrolidone in the surface vicinity layer is measured by surface infrared spectroscopy (ATR method). In the ATR method (surface vicinity layer), the depth is 1000 to 1500 nm (1 to 1.5 μm from the surface). It is possible to measure polyvinylpyrrolidone content up to a degree.

  The content of polyvinylpyrrolidone on the inner and outer surfaces may also be related to the molecular weight of polyvinylpyrrolidone. For example, when polyvinyl pyrrolidone having a molecular weight of about 450,000 is lower than when using polyvinyl pyrrolidone having a high molecular weight of about 1,200,000, the solubility and elution amount of polyvinyl pyrrolidone is large in coagulation, Is relatively high, such as 20 to 40% by mass of the outermost layer and 5 to 20% by mass of the surface vicinity layer with respect to 1 to 20% by mass of the polyvinylpyrrolidone to the polysulfone polymer. A pyrrolidone content tends to be produced.

  Examples of a method for achieving the above requirements 5, 9, 10 and 11 in the present invention include setting the composition ratio of polyvinyl pyrrolidone to the polysulfone polymer to be in the above-described range, or forming conditions of the selectively permeable hollow fiber membrane. This can be achieved by optimizing the above. Specifically, the dense layer formed on the inner surface side of the selectively permeable hollow fiber membrane preferably has a two-layer structure having a density difference between the outermost layer portion and the surface vicinity portion. That is, although the detailed reason is not known, the outermost layer portion of the inner surface of the hollow fiber membrane can be obtained by setting the composition ratio of the polysulfone polymer and polyvinylpyrrolidone in the membrane forming solution and the concentration and temperature of the internal solution within the range described later. There is a difference between the solidification rate and / or the phase separation rate in the vicinity of the surface, and the difference in solubility between the polysulfone polymer and the polyvinylpyrrolidone in the solvent / water may express the above requirements. For requirement 9, it is important to optimize the drying conditions. That is, when the wet hollow fiber membrane is dried, polyvinyl pyrrolidone dissolved in water moves from the inside of the hollow membrane to the surface side with the movement of water. Here, by using the drying conditions as described later, it is possible to give a certain speed to the movement of water and make the movement speed uniform throughout the hollow fiber membrane. It moves quickly to both surfaces. Since the evaporation of water from the membrane surface is greater from the outer surface side than from the inner surface side of the hollow fiber membrane, the amount of polyvinyl pyrrolidone that moves to the outer surface side is increased, and therefore the selectively permeable hollow fiber of the present invention is increased. It is assumed that requirement 9 which is a characteristic of the film can be achieved. In order to achieve requirement 9, the method and conditions for cleaning the hollow fiber membrane are also important, and optimization is desirable.

  In the present invention, the porosity of the outer surface of the selectively permeable hollow fiber membrane is preferably 25 to 35% (Requirement 12). 27-33% is more preferable. If the open area ratio is less than 25%, there is a possibility that sticking between the selectively permeable hollow fiber membranes is likely to occur. If the porosity is too large, the porosity of the selectively permeable hollow fiber membrane will increase, making it difficult to obtain the desired burst pressure and possibly preventing the leakage of albumin, which is a useful protein. .

  Although the method of making an open area ratio into the said range is not limited, For example, the method of implementing according to the method of patent document 6 is mentioned. However, when this method is used, there is a possibility that the film strength becomes low, leading to problems such as blood leakage. Therefore, since the preferred embodiment (requirement 13) in the present invention in which the burst pressure of the selectively permeable hollow fiber membrane is 0.5 MPa or more cannot be cleared, it is necessary to introduce a measure for solving this problem. The burst pressure of the selectively permeable hollow fiber membrane is an indicator of the pressure resistance performance of the selectively permeable hollow fiber membrane. Is the pressure when bursting without bursting the internal pressure. The higher the burst pressure, the less the hollow fiber membrane is cut and the occurrence of pinholes during use, so 0.5 MPa or more is preferred, 0.55 MPa or more is more preferred, and 0.6 MPa or more is even more preferred. If the burst pressure is less than 0.5 MPa, there may be a potential defect. The higher the burst pressure, the better. However, if the emphasis is on increasing the burst pressure and the film thickness is increased too much or the porosity is decreased too much, the desired film performance may not be obtained. Therefore, when finished as a hemodialysis membrane, the burst pressure is preferably less than 2.0 MPa. More preferably, it is less than 1.7 MPa, more preferably less than 1.5 MPa, still more preferably less than 1.3 MPa, and particularly preferably less than 1.0 MPa.

  The above characteristics have been found on the basis of the knowledge that the safety of hollow fiber membranes in long-term dialysis cannot be sufficiently proved by blood leak characteristics governed by conventionally known macro characteristics such as membrane strength. That is, as a result of examining the physical properties of the selectively permeable hollow fiber membranes used in blood purifiers, the hollow fiber membranes used for blood purification are usually defective in the hollow fiber membranes and blood purifiers at the final stage of production. In order to confirm this, a leak test is performed in which the inside or outside of the hollow fiber membrane is pressurized with air. When a leak is detected by the pressurized air, the blood purifier is discarded as a defective product or is repaired. The air pressure in this leak test is often several times the guaranteed pressure resistance of the blood purifier (usually 500 mmHg (0.067 MPa)). However, in the case of hollow fiber membranes with particularly high water permeability, the microscopic scratches, crushes, and tears of the hollow fiber membrane that cannot be detected by the normal pressure leak test are the manufacturing processes after the leak test (mainly sterilization and packaging). This may cause troubles such as cutting of hollow fiber membranes or pinholes during transportation process or clinical practice (unpacking, priming, etc.) and blood leakage during treatment. The present inventors have found out. As a result of intensive studies on the above events, potential yarn defects that lead to the breakage of hollow fiber membranes and pinholes during clinical use cannot be detected by pressure in normal pressurized air leak tests, and are higher. The present inventors have found that pressure is required and that it is effective to suppress the occurrence of the above-described potential defects to suppress the mixing of the uneven thickness yarn of the hollow fiber membrane.

  The present invention has been found based on the finding that conventionally known macro properties such as membrane strength cannot sufficiently guarantee the safety of a hollow fiber membrane. That is, in the hollow fiber membrane of the present invention, the film thickness and skin layer are made very thin in order to improve the permeability of a substance having a molecular weight of about 30,000 typified by α1 microglobulin. As a result, defects (pinholes, scratches, etc.) that the hollow fiber membranes potentially have may become apparent particularly during clinical use. In the present invention, in order to ensure safety, it is extremely important to eliminate the above-described potential defects in addition to macro characteristics.

  The hollow fiber membrane preferably has a carboxyl group content in the hollow fiber membrane of 100 to 800 nmol / g. The carboxyl group content is involved in antithrombogenicity, especially platelet activation, and the peroxide content is important for maintaining antithrombogenicity during long-term storage, and these contents are irradiated It is disclosed in Patent Document 18 that the increase is increased. Accordingly, it is preferable that the hollow fiber membrane having the above characteristics is provided with radiation. In the above patent document, it is considered that the carboxyl group in the hollow fiber membrane is mainly generated by hydrolysis of the pyrrolidone ring of polyvinylpyrrolidone (PVP). It is presumed to be generated by reaction. Although the detailed mechanism of action of the carboxyl group on platelet activation is unknown, if the content is too high, the amount of platelet adhesion to the membrane increases. When platelets recognize xenobiotics, they adhere to the surface and lead to thrombus formation. Therefore, it can be said that the increase in carboxyl groups by irradiation is a bad direction for antithrombogenicity. On the other hand, when the carboxyl group content is too low, it means that the radiation dose of the film is not sufficient, leading to an increase in the elution amount of PVP and a decrease in sterilization efficiency, which is not desirable for medical use. Accordingly, the carboxyl group content needs to be suppressed to a range of 100 nmol / g or more and less than 800 nmol / g. In general, an anticoagulant is administered for the purpose of preventing blood coagulation during clinical use. However, since it is desirable to reduce the amount used, it is more preferably 100 to 600 nmol / g. More preferably, ˜400 nmol / g.

  Moreover, it is preferable that the peroxide content in a hollow fiber membrane is 200 nmol / g or less. Like the carboxyl group, the peroxide in the film is also generated in the main chain of PVP by irradiation and is considered to decompose during long-term storage due to its chemical instability. Further, PVP already contains a peroxide at the stage of manufacturing raw materials, and may be taken into the film as it is. When irradiated in this state, radicals generated by irradiation are triggered and decomposed, and as a result, PVP depolymerized by molecular cleavage starting from peroxide is detached from the film, and the film surface is used during use. The upper PVP is reduced and the antithrombogenicity is reduced. In order to substantially eliminate the influence of decomposition, the peroxide content is more preferably 150 nmol / g or less, and even more preferably 100 nmol / g or less.

  In order to satisfy these characteristics, conventionally, the above-mentioned characteristics have been achieved by irradiation with radiation in the presence of a radical scavenger by a method applied to a wet type blood purifier. There was a problem and the improvement was desired. An object of the present invention is to provide a dry type blood purifier that solves the above-mentioned problems and a method that can avoid the above problems even if irradiation is performed in the absence of a radical scavenger.

  Therefore, in the present invention, the moisture content in the selectively permeable hollow fiber membrane bundle is preferably 600% by mass or less, and it is preferable that no radical scavenger is contained in the blood purifier when irradiated with radiation.

  When the water content exceeds 600% by mass, the weight of the blood purifier increases, resulting in problems such as reduced handling and increased transportation costs, easy generation of bacteria, and freezing in cold regions. 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, if the water content is too low, the detailed reason is not known, but the degradation of polyvinylpyrrolidone by irradiation is promoted, the production of hydrogen peroxide, carboxyl groups and peroxides is increased, and the dialysis artificial kidney device approval criteria May cause an increase in UV (220-350 nm) absorbance, long-term storage stability, blood compatibility, and a decrease in the stability of the hollow fiber membrane extract when the test defined by is performed. Therefore, 0.8-300 mass% is more preferable, and 1.5-200 mass% is further more preferable.

  It is difficult to suppress the degradation of the hollow fiber membrane material due to radiation irradiation in the dry state and in the absence of the radical scavenger, which is the object of the present invention. Conventionally, it is unavoidable that the wet method is used, and in the presence of the radical scavenger. It was carried out in. The present inventors diligently studied to solve the problem, and the degradation reaction was promoted by oxygen gas adsorbed on the localized portion of the polyvinyl pyrrolidone of the polysulfone-based selectively permeable hollow fiber membrane, and the local reaction of the polyvinyl pyrrolidone. The present invention was completed by finding a method for suppressing the degradation reaction of polyvinylpyrrolidone based on the presumed mechanism of being suppressed by water adsorbed on the existing portion. Although it is a well-known phenomenon that the above degradation reaction is affected by oxygen, the present inventors have found for the first time that the degradation reaction is suppressed by a trace amount of water adsorbed on the localized portion of polyvinylpyrrolidone. Phenomenon. Preferred embodiments are described below.

  The inventors of the present invention, when using a selectively permeable hollow fiber membrane having the above-mentioned properties, when irradiating with radiation in a dry state, the water content of the hollow fiber membrane is 5% by mass or more, and the water is degassed. It was found that the degradation reaction of polyvinyl pyrrolidone 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 selectively permeable hollow fiber membrane bundle containing polyvinylpyrrolidone whose water content was adjusted to 5 to 600% by mass using deaerated water were sealed. It is preferable to irradiate with radiation by sealing with a packaging bag that blocks outside air and water vapor in the state.

  In the present invention, the deaerated water present in and around the selectively permeable hollow fiber membrane is preferably deoxygenated water. Moreover, it is more preferable that it is an inert gas saturated water.

  The deoxygenated water and the inert gas saturated water are 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. Here, the dissolved oxygen in water can be measured using, for example, a dissolved oxygen meter OM-51-L1 manufactured by HORIBA Ltd.

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

  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 may oxidize and degrade polyvinylpyrrolidone. 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 the state in which the concentration of oxygen contained in water is low is reduced. 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 the introduction of inert gas. It is also preferable to dissolve the active gas. Specifically, oxygen is removed by bubbling an inert gas in water from which oxygen has been removed in advance by a heat degassing method, a vacuum degassing method, a membrane degassing method, a reducing agent addition method, or the like, and the inert gas is dissolved. Is done efficiently. Here, the dissolved oxygen amount of the inert gas saturated water is preferably 0.5 ppm or less, more preferably 0.2 ppm or less, and further preferably 0.1 ppm or less. The water used here is preferably RO-treated water.

  By using the deaerated water, the deterioration of the hollow fiber membrane due to radiation irradiation, particularly the degradation reaction of polyvinylpyrrolidone, is more effectively suppressed than when non-deaerated water is used. Increase in UV (220-350 nm) absorbance in the extract of hollow fiber membranes when the test specified by the approval standard for dialysis-type artificial kidney device manufacturing is increased, anti-thrombogenicity, long-term The effect of suppressing an undesirable deterioration reaction that causes a decrease in storage stability and performance development during priming is increased.

  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 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 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.

  In the present invention, the oxygen concentration in the blood purifier before sterilization is 3.6% 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. Is preferred. 3.0% by volume or less is more preferable, and 2.5% by volume or less is more preferable. When the oxygen concentration exceeds 3.6% by volume, the oxygen gas present in the space in the blood purifier dissolves in the deaerated water present on the surface of the hollow fiber membrane, When irradiated with an electron beam, the hollow fiber membrane, particularly polyvinylpyrrolidone, may be deteriorated. The expression of the effect of the present invention is further stabilized by adjusting the oxygen concentration.

  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, the blood purifier is assembled using the hollow fiber membrane bundle dried by the above-described method, deoxygenated water is injected and filled into the blood purifier, and the air present in the blood purifier is expelled. A method of simultaneously performing deoxygenation and oxygen concentration reduction by injecting and filling an inert gas into the blood purifier after filling the water in the hollow fiber membrane and the periphery of the hollow fiber membrane with deoxygenated water is preferable. . Nitrogen gas is preferably used as the inert gas from the viewpoint of economy.

  In the above method, it is preferable to seal all the blood and dialysate inlet / outlet of the blood purifier after adjusting the water content and oxygen concentration in the blood purifier. By this method, volatilization of moisture from the hollow fiber membrane filled in the blood purifier can be suppressed, and invasion of germs into the blood purifier can be prevented. Moreover, since volatilization of moisture from the hollow fiber membrane is suppressed, shrinkage of the hollow fiber membrane and deterioration of the membrane characteristics due to drying 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.

  When inert gas saturated water is used, the barrier effect against the transfer of oxygen gas from the periphery of the hollow fiber membrane to the surface of the hollow fiber membrane is large. Even if the oxygen concentration is not lowered, the effect of suppressing the deterioration reaction due to radiation irradiation can be exhibited.

  When the water content is less than 5% by mass, the amount of water selectively adsorbed around the polyvinyl pyrrolidone is reduced, so that the effect of suppressing the deterioration of the polyvinyl pyrrolidone by the adsorbed water is reduced. It becomes difficult to suppress the degradation of polyvinyl pyrrolidone due to. The present inventors diligently studied to solve the problem and found that the deterioration of polyvinyl pyrrolidone due to radiation irradiation can be suppressed by optimizing the oxygen concentration and humidity of the atmosphere surrounding the hollow fiber membrane. The first requirement in the method is a requirement relating to the oxygen concentration of the atmosphere surrounding the selectively permeable hollow fiber membrane during sterilization. Radiation irradiation is preferably performed in a state where the oxygen concentration is 3.6% by volume or less. When the water content of the hollow fiber membrane is less than 5% by mass, the amount of water adsorbed on the polyvinyl pyrrolidone decreases, so that the opportunity for contact between oxygen and polyvinyl pyrrolidone increases as compared with the case where the water content is 5% by mass or more. . Therefore, when the moisture content of the hollow fiber membrane is low, the oxygen concentration in the atmosphere surrounding the hollow fiber membrane is more preferably 1% by volume or less, and further preferably 0.1% by volume or less. If it exceeds 3.6% by volume, hydrogen peroxide production due to deterioration of polyvinylpyrrolidone may increase. If the oxygen concentration is less than 0.001%, the substantial sterilization effect is inhibited, so a very small amount of oxygen concentration is necessary.

  The second requirement in the case where the moisture content of the hollow fiber membrane is less than 5% by mass is a requirement relating to water adsorbed on the polyvinylpyrrolidone in the hollow fiber membrane. It is preferable to optimize the moisture content in the hollow fiber membrane and the humidity in the packaging bag. The water content is preferably 0.8% by mass or more. 1 mass% or more is more preferable. Further, the humidity in the packaging bag is preferably such that the relative humidity at 25 ° C. exceeds 40% RH. The relative humidity of the space in the packaging bag is more preferably 50 to 90% RH (25 ° C.), and further preferably 60 to 80% RH (25 ° C.). When the water content is less than 0.8% by mass, it is difficult to suppress the degradation of polyvinyl pyrrolidone even in the humidity range.

  When the moisture content in the hollow fiber membrane is 0.8 to 5% by mass, oxygen present in a trace amount when irradiated with radiation when the relative humidity of the space in the packaging bag is 40% RH (25 ° C.) or less. Deterioration of polyvinyl pyrrolidone is caused by the gas, and hydrogen peroxide is generated, which leads to the above-described undesirable deterioration reaction. On the other hand, when the relative humidity exceeds 90% RH (25 ° C.), condensation may occur in the packaging bag and the quality of the blood purifier may be lowered.

  The relative humidity referred to in the present invention is represented by the formula of relative humidity (% RH) = p / P × 100 using a water vapor partial pressure (p) at 25 ° C. and a saturated water vapor pressure (P) at 25 ° C. The measurement was performed by inserting and sealing a sensor of a temperature / humidity measuring device (Ondotori RH type, manufactured by T & D) into the packaging bag.

When the water content in the hollow fiber membrane is 0.8 to 5% by mass, the mechanism that suppresses the degradation of polyvinylpyrrolidone by making the relative humidity of the space in the packaging bag more than 40% RH (25 ° C.) I guess as follows.
By making the relative humidity of the space inside the packaging bag more than 40% RH (25 ° C.), the amount of water adsorbed around the polyvinyl pyrrolidone that has been insufficient due to the low moisture content in the hollow fiber membrane increases, It is presumed that the adsorbed water blocks the attack of oxygen activated by radiation irradiation on polyvinylpyrrolidone and suppresses the degradation reaction.
On the other hand, it is known that a hollow fiber membrane containing polyvinylpyrrolidone has a humidity control function, that is, moisture absorption / release characteristics (see, for example, JP-A-2004-97918). Therefore, when the relative humidity in the packaging bag is low, the moisture adsorbed on the polyvinylpyrrolidone present on the surface of the hollow fiber membrane is released to the space inside the packaging bag, and in particular, the polyvinylpyrrolidone present on the pole surface that is subject to the above-mentioned deterioration It is presumed that the amount of adsorbed water becomes low and is oxidized and deteriorated during irradiation. Therefore, it is presumed that the effect of suppressing oxidative degradation is manifested by increasing the humidity.

In the case where the moisture content in the hollow fiber membrane is 0.8 to 5% by mass, as a method for suppressing the deterioration of polyvinylpyrrolidone due to radiation irradiation, for example, the hollow fiber membrane having a moisture content of 0.8 to 5% by mass The blood purifier filled with the bundle had an oxygen permeability of 10 cm ³ / m ² · 24 h · MPa (20 ° C., 90% RH) or less together with an oxygen scavenger and a water vapor permeability of 50 g / m ² · 24 h · MPa (40 (° C., 90% RH) or less, and a method of irradiating with radiation in a state where the relative humidity at 25 ° C. of the atmosphere in the packaging bag exceeds 40% RH.

  The oxygen scavenger is used to absorb oxygen in the packaging bag and form a substantial oxygen scavenging state. Therefore, it is not limited as long as it has a deoxygenating 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 as an oxygen-absorbing main agent, which can be appropriately selected. In addition, oxygen scavengers for metal powders are used as an oxidation catalyst, if necessary, such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium bromide, odor. One or two kinds of metal halides such as potassium iodide, magnesium bromide, calcium bromide, iron bromide, nickel bromide, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, iron iodide, etc. The above may be added. Moreover, adding a deodorant, a deodorant, and another functional filler is not restrict | limited at all. Further, the shape of the oxygen scavenger is not particularly limited, and may be any of powder, granule, lump, sheet, etc., or a sheet in which various oxygen absorbent compositions are dispersed in a thermoplastic resin or A film-like oxygen scavenger may be used.

The packaging bag used in the method of reducing the oxygen concentration by the oxygen scavenger described above needs a function of forming a space deoxygenated by the oxygen scavenger and maintaining the deoxygenated state for a long 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, the packaging bag in the present invention is preferably made of a material having a low water vapor permeability. 50 g / m ² · 24 h · MPa (40 ° C., 90% RH) or less is preferable. 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. When the pressure 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. This is not preferable because the preferable water content cannot be maintained.

  The material and configuration of the packaging bag are not limited as long as they have the above characteristics. In a preferred embodiment, the material is made of an impermeable material for both oxygen gas and water vapor such as aluminum foil, aluminum vapor deposited film, inorganic oxide vapor deposited film such as silica and / or alumina, and vinylidene chloride polymer composite film. is there. Further, the sealing method in the packaging bag is not limited and is arbitrary, and examples thereof include a heat sealing method, an impulse sealing method, a fusing sealing method, a frame sealing method, an ultrasonic sealing method, and a high frequency sealing method. A composite material composed of a composite of the film material and the above-described impermeable material is preferable. In particular, both the impervious and heat-sealable functions, in which the outer layer is made of polyester film, the intermediate layer is made of aluminum foil, and the inner layer is made of polyethylene film, are made of aluminum foil that can substantially block oxygen gas and water vapor. It is preferable to apply a laminated sheet having the same.

  Moreover, the method of making relative humidity of the space in a packaging bag over 40% RH (25 degreeC) is not limited. For example, (1) When a blood purifier is sealed with a packaging bag, a humidity-controlled gas is injected into the packaging bag or sealed in a conditioned environment. (2) Depending on the moisture content of the selectively permeable hollow fiber membrane Examples thereof include a method of adjusting, (3) using a deoxidizing agent that releases moisture, and (4) simultaneously sealing a humidity control agent together with the deoxidizing agent.

  A humidity control agent will not be restrict | limited, if it has the characteristic which makes the relative humidity of the space in a packaging bag the said range by a moisture absorption / release function. As the humidity control agent, B-type silica gel is widely used, but is not limited. For example, as a humidity control agent similar to B-type silica gel, absorption and release can be achieved by sharpening the pore distribution of silica gel or by combining a humidity control agent composed of an alkali metal compound or an alkaline earth metal compound. Examples thereof include porous inorganic particles such as improved B-type silica gel, mesoporous silica alumina gel, mesoporous hollow aluminum silicate, zeolite and the like having improved wet characteristics. Also, particles made of water-absorbing polymer such as sodium acrylate cross-linked polymer, polyethylene glycol chain, polyvinylpyrrolidone chain, etc., blended or alloyed, composite particles in which the water-absorbing polymer is combined with inorganic microcapsules, etc. It may be. The shape of the humidity control agent is not particularly limited, and may be any of powder, granule, lump, sheet, and the like. It is preferable to use powdery and granular materials by packaging them with a moisture-permeable packaging material. Moreover, you may use as a composite_body | complex combined with a film, a sheet | seat, paper, a nonwoven fabric, a woven fabric, etc. In this case, the composite substrate is preferably made of a hydrophilic material. Further, the humidity control agent particles may be combined with a hydrophilic binder and combined with a base material made of a general-purpose material such as polyester or polyolefin. In the case of a humidity control agent comprising a water-absorbing polymer, the polymer may be used directly as a film or sheet. Moreover, you may use in shapes, such as paper, a nonwoven fabric, and a woven fabric, as a fiber. Moreover, you may use it as a shape of a foam sheet or a home using a foaming agent. For example, humidity control sheets impregnated with water-absorbing sheets (paper, non-woven fabrics, woven fabrics) with inorganic salt humidity control agents such as ammonium chloride, water, surfactants, etc., sodium polyacrylate, inorganics such as magnesium metasilicate aluminate A sheet-like hydrogel fixed with a network-structured water-absorbing polymer crosslinked with a crosslinking agent can be suitably used.

  It is preferable to use the humidity control agent after seasoning in an environment of a relative humidity of 80 to 90% RH at 25 ° C. in advance.

  In the case where the oxygen concentration is reduced by the oxygen scavenger described above, it is necessary to adjust the oxygen concentration and humidity of the atmosphere around the hollow fiber membrane after sealing the blood purifier with a packaging bag. The opening must be open.

  The above-described method using deaerated water is referred to as a deaerated water method, and the method using an oxygen scavenger is referred to as an oxygen scavenger method.

  In the present invention, the requirements of the oxygen scavenger method may be applied to the degassing water method. For example, when the deaerated water method is used, the sealed blood purifier may be sealed with a 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 this method, the container may be simply sealed, but an oxygen scavenger may be enclosed at the same time when the packaging bag is sealed to lower the atmosphere in the packaging bag. By carrying out the method, it is possible to suppress the growth of various germs mixed after sterilization.

  In the present invention, in the oxygen scavenger method, it is preferable to irradiate the radiation after sealing the packaging bag, or in the case of the degassing water method, 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 or sealing is too long, miscellaneous bacteria may grow. Therefore, it is preferable to perform the irradiation within 10 days after sealing or 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. If the irradiation treatment is performed in a state of less than 48 hours, the expression of water permeability performance during priming may be reduced.

  The reason why the expression of water permeability during priming changes depending on the elapsed time until irradiation treatment is unknown, but in the oxygen scavenger method, the trace amount of oxygen adsorbed on the hollow fiber membrane surface is deoxygenated. Desorption due to the deoxygenation effect by the agent, and in the case of the degassing water method, the method moves to the degassing water method localized around the trace amount of oxygen adsorbed on the hollow fiber membrane surface. Therefore, it is presumed that this is caused by suppressing the deterioration reaction that inhibits the affinity between the film 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, and ion beams are used. From the viewpoint of sterilization efficiency and ease of handling, γ rays or electron rays are used. Preferably used. The irradiation dose of radiation is not particularly limited as long as it is a dose capable of sterilization and crosslinking, but generally 10 to 30 kGy is preferable.

  The selectively permeable hollow fiber membrane used in the present invention divides the hollow fiber membrane into 10 in the longitudinal direction by the length unit filled in the blood purifier, and the elution amount of hydrogen peroxide when measured for each part is The preferred embodiment is 5 ppm or less.

  Conventionally, the amount of eluate from the hollow fiber membrane is determined by the dialysis-type artificial kidney device manufacturing approval standard. In the dialysis artificial kidney device manufacturing approval standard, the amount of eluate from the membrane is quantified by UV absorbance. As a result of detailed studies on the elution behavior from the membrane, the present inventors have conducted a study determined by the above-mentioned dialysis-type artificial kidney device manufacturing approval criteria in a hollow fiber membrane mainly composed of a polysulfone polymer and polyvinylpyrrolidone. It has been found that hydrogen peroxide that cannot be measured by a conventionally known UV absorbance is contained in the extract extracted by the method. In the presence of the hydrogen peroxide, for example, the hydrogen peroxide becomes an initiator even when irradiated by the above-described method, and the irradiation reaction induces a degradation reaction of polyvinyl pyrrolidone, thereby generating carboxyl groups and peroxides. Occurs and it becomes difficult to satisfy the content of the present invention.

  In the present invention, the amount of hydrogen peroxide eluted from the 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, even if the above-described means for suppressing the degradation reaction due to the irradiation is taken, the hydrogen peroxide promotes the degradation reaction due to the radiation irradiation. It becomes difficult to bring the carboxyl group and peroxide content of the present invention within the range of the present invention.

  The elution amount of hydrogen peroxide in the present invention is quantified with respect to 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 hollow fiber membrane, and 1.0 g is measured in a dry state. 100 ml of RO water is added to this, and extraction is performed at 70 ° C. for 1 hour.

  As a method for controlling the elution amount of hydrogen peroxide to 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 generated 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, since the contribution of the production in the drying process when producing the hollow fiber membrane is large, it is important to optimize the drying conditions. In particular, the optimization of the drying conditions is an effective means for reducing the fluctuation of the elution amount in the longitudinal direction of the hollow fiber membrane.

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

  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 suppressing contact with oxygen, such as in an atmosphere substituted with an inert gas, even during kneading. It is preferable to carry out in a separate line. The method of kneading only polyvinylpyrrolidone and a 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 may be carried out by providing a kneading line separately from the dissolving tank and supplied to the dissolving tank, or both kneading and dissolving may be performed in a dissolving tank having a kneading function. The type and form of the kneading apparatus in the former separate apparatus are not limited. Either a batch system or a continuous system may be used. A static method such as a static mixer 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. Recommended. For example, a planetary mixer or a trimix manufactured by Inoue Seisakusho Co., Ltd. corresponds to this method.

  The ratio of the resin component such as polyvinyl pyrrolidone or polysulfone 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 polymer are kneaded in separate lines, this requirement may be applied to the polysulfone polymer kneading line. The efficiency of kneading and dissolution and heat generation are two contradictory phenomena. Selection of an apparatus and conditions that avoid the trade-off as much as possible is an important element of the present invention. In this sense, the cooling method in the kneading mechanism is important and needs attention.

Subsequently, the material kneaded by the above method is dissolved. Although the dissolution method is not limited, for example, a dissolution method using a stirring type dissolution apparatus can be applied. In order to dissolve at a low temperature for a short time (within 3 hours), the Froude number (Fr = n ² d / g) is 0.7 to 1.3 and the stirring Reynolds number (Re = nd ² ρ / μ) is It is preferable that it is 50-250. Where n is the blade rotation speed (rps), ρ is the density (Kg / m ³ ), μ is the viscosity (Pa · s), g is the gravitational acceleration (= 9.8 m / s ² ), and d is the stirring blade diameter. (M). If the Froude number is too large, the inertial force becomes strong, so that the raw material scattered in the tank adheres to the walls and ceiling, and the desired film-forming solution composition may not be obtained. Therefore, the fluid number is more preferably 1.25 or less, further preferably 1.2 or less, and further preferably 1.15 or less. On the other hand, if the fluid number is too small, the inertial force is weakened, so that the dispersibility of the raw material is lowered. 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 is reduced. It has been found that this causes problems such as decreased sex and burst pressure. Defoaming of the spinning solution is an effective countermeasure, but it may be accompanied by changes in the composition of the spinning solution due to viscosity control of the spinning solution or evaporation of the solvent, so careful handling is necessary when defoaming. .

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

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

  In order to suppress the elution amount of hydrogen peroxide and its fluctuation, it is further preferable that the hollow fiber membrane is not completely dried. If it is completely dried, the deterioration of polyvinylpyrrolidone increases and the production of hydrogen peroxide is greatly increased, which is not preferable. In addition, wettability may be reduced during re-wetting during use, and polyvinyl pyrrolidone may be less likely to absorb water and may be easily eluted from the hollow fiber membrane. The moisture content of the hollow fiber membrane after drying is preferably 0.5% by mass or more, more preferably 0.7% by mass or more, and further preferably 1.0% by mass or more. On the other hand, in the present invention, it is preferable that polyvinylpyrrolidone is substantially non-crosslinked as described above. For example, when used for a blood purifier, sterilization by γ-ray irradiation is performed, and polyvinylpyrrolidone is crosslinked by the γ-ray irradiation. In the present invention, it is a preferred embodiment to minimize the crosslinking of polyvinyl pyrrolidone by γ-ray irradiation. The crosslinking reaction of the polyvinyl pyrrolidone is affected by the water content of the hollow fiber membrane. When the water content exceeds 10% by mass, the crosslinking reaction becomes remarkable. Therefore, the water content is preferably 10% by mass or less. It is more preferably less than 7% by mass, and still more preferably less than 4% by mass.

  With respect to the drying process, in the prior art, for example, as disclosed in JP 2000-300663 A, a hollow fiber membrane is obtained by passing air at 60 ° C. in the longitudinal direction of the hollow fiber membrane bundle for about 20 hours from one direction. The bundle was allowed to dry. However, in this method, fluctuations in the longitudinal direction of the hollow fiber membrane bundle eluted with hydrogen peroxide are large, and many portions exceeding the preferred range occur, and the present invention cannot be satisfied. I do not know the reason for this well, but when air is ventilated from a certain direction and the hollow fiber membrane bundle is dried, the air inlet portion of the hollow fiber membrane bundle is sequentially dried from the air inlet portion to the outlet portion. Then, the drying is completed quickly, and the drying is completed with a delay at the air outlet. That is, the hollow fiber membrane bundle becomes excessively dried at the air inlet portion, so that degradation of the hollow fiber membrane bundle material proceeds.As a result, the inlet portion is made of the constituent material of the hollow fiber membrane bundle, particularly polyvinylpyrrolidone. It is presumed that it was caused by an increase in oxidative degradation. Therefore, the present inventors aim to prevent partial overdrying of the hollow fiber membrane bundle and to dry it uniformly, and the direction of air during drying is set to 180 at regular intervals (for example, every hour or every 30 minutes). The hollow fiber membrane bundle was dried while being inverted. As another object, the hollow fiber membrane bundle of the present invention is reduced by reducing the temperature in the dryer and the temperature of the drying air from the conventional 60 ° C. to 40 ° C. in order to suppress the oxidation reaction rate due to heat during drying. Could get. As described above, it is presumed that oxidative degradation is a fluctuation factor of the hydrogen peroxide elution amount. Therefore, a method of carrying out by replacing the atmosphere during drying with an inert gas such as nitrogen gas is also effective.

  The air volume and speed in the dryer may be adjusted by the ventilation dryer according to the amount of the hollow fiber membrane bundle and the total water content. Usually, the air volume is 0.01 to 5 L / sec (one hollow fiber membrane bundle). ) Is enough. As the ventilation medium, it is preferable to use an inert gas. However, when normal air is used, it is preferable to use a dehumidified medium. The drying temperature may be 20 to 80 ° C. However, if the temperature is increased, damage to the hollow fiber membrane bundle is increased, and drying tends to become partially unbalanced. It is preferable to do this. For example, in a state where the water content is 200 to 1000% by mass, drying is possible at a relatively high temperature of 60 to 80 ° C., but when the drying proceeds, for example, when the water content is reduced to about 1 to 50% by mass, It is preferable to dry in the range of normal temperature having a low target temperature to a maximum of about 60 ° C. Ideally, the moisture content of the center portion and the outer peripheral portion of the hollow fiber membrane bundle, as well as the center portion and the outer peripheral portion of the hollow fiber membrane bundle in which the drying is performed, is ideally unchanged. Actually, there is a slight difference in the moisture content between the center portion and the outer peripheral portion of the hollow fiber membrane or hollow fiber membrane bundle. And since it is a preferable embodiment for producing a good quality product that the difference in moisture content of the hollow fiber membrane bundle such as the central part, the intermediate part and the outer peripheral part is small, it is technical to the drying method for producing it. It is necessary to give special consideration. For example, when an inert gas such as nitrogen gas or argon gas is used as the ventilation medium, since the drying is performed in a substantially oxygen-free state, the degradation and decomposition of the hydrophilic polymer hardly occur, and the drying temperature is increased. It is possible.

  The air volume and the drying temperature are determined by the water content contained in the hollow fiber membrane bundle. When the moisture content is high, the air volume is set to a relatively high value of, for example, 0.1 to 5 L / sec (one hollow fiber membrane bundle), and the temperature is set to a relatively high value of 50 to 80 ° C. When drying progresses and the moisture content of the hollow fiber membrane bundle becomes low, the air volume is adjusted to gradually reduce the air volume to, for example, 0.1 L / sec (one hollow fiber membrane bundle) or less. One of the ideas of drying is to adopt a drying method that gradually moves it to room temperature in conjunction with it. The fact that the difference in moisture content at the center, middle, and outer periphery of the hollow fiber membrane bundle is small means that the drying of each part is simultaneously and uniformly progressed. For this reason, to alternately reverse the blowing direction when the hollow fiber membrane bundle is air-dried is to alternately blow air from the direction in which the air blowing direction with respect to the hollow fiber membrane bundle in the air-drying is changed by 180 degrees. Of course, there is a case where the device is devised so that the reversal of the blowing direction is alternately reversed by 180 degrees with respect to the air flow direction as the contents of the hollow fiber membrane bundle itself. Further, there is a method in which a hollow fiber membrane bundle for drying is fixed, and a blower is devised to blow air from the direction in which the ventilation direction is alternately changed by about 180 degrees. However, the blower means is not particularly limited. In particular, in the case of a circulation type blower / dryer, an apparatus that alternately inverts the hollow fiber membrane bundle of the contents itself by 180 degrees functions not only in design but also in operation. The drying method of the present invention including this seemingly common inversion is an anticipation not seen in the drying of general-purpose materials, particularly in the special control of hollow fiber membrane bundles, in quality control to prevent partial bundle fixing. It was that we were able to achieve unexpected results.

The alternating inversion time of ventilation in drying is of a nature that varies depending on factors such as the total moisture content of the hollow fiber membrane bundle for drying and the wind speed, air volume, drying temperature, degree of dehumidification of air, but if uniform drying is desired, It is preferable to reverse the blowing direction frequently. The wind direction reversal time that is practically set industrially affects the moisture content after the start of drying, for example, at a high temperature of about 60 to 80 ° C., for example, at 65 ° C. for 1 to 4 hours, at 25 to 60 ° C. When the total drying time of 24 hours is set at about 30 ° C. for 1 to 20 hours, the wind direction can be mechanically reversed at intervals of about 30 to 60 minutes. In the initial drying stage where the total amount of moisture is large, for example, when drying at a high temperature of about 60 to 80 ° C. and under a relatively large air volume of about 0.1 to 5 L / sec (one hollow fiber membrane bundle), Since the portion where the wind directly hits is dried relatively quickly, the reversal of the wind direction is repeated for about 1 to 5 hours at intervals of about 10 to 120 minutes. In particular, in the first stage, it is preferable to reverse the wind direction at intervals of 10 to 40 minutes. As the moisture content difference between the center and the outer periphery of the hollow fiber membrane bundle becomes smaller, the drying temperature gradually approaches the room temperature of about 30 ° C., and the reversal of the wind direction is repeated at intervals of about 30 to 90 minutes. Can do. Switching of the air volume and temperature at that time can be arbitrarily determined in consideration of the moisture content of the hollow fiber membrane bundle. If it shows more quantitatively, the moisture content of the center part and the outer peripheral part of the hollow fiber membrane bundle is based on the calculation, and when the moisture content is about 50 to 100% by mass or less, the drying is performed while observing the drying condition. The time and the inversion time can be changed as appropriate.
Drying can be performed by mechanically setting the wind direction reversal time at fixed time intervals. On the other hand, there are factors that rely on situation judgments and empirical rules to determine the wind direction inversion time and total drying time while observing the degree of progress of drying.

  Moreover, it is one of effective means to dry by irradiating microwaves under reduced pressure.

  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, the frequency of this microwave is 1,000-5,000 MHz, and it is a preferable embodiment that the highest ultimate temperature of the hollow fiber membrane bundle during a drying process is 90 degrees C or less. If a means of decompression is also provided, drying of moisture will be promoted by itself, so there is an advantage that the microwave irradiation output can be reduced and the irradiation time can be shortened, but the temperature rise can also be made relatively low. Overall, there is little influence on the performance degradation of the hollow fiber membrane bundle. 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 degradation degradation of polyvinylpyrrolidone can be remarkably suppressed. An appropriate drying temperature is sufficient from 20 to 80 ° C. More preferably, it is 20-60 degreeC, More preferably, it is 20-50 degreeC, More preferably, it is 30-45 degreeC.

  The accompanying decompression means that the decompression is uniformly applied to the center part and the outer peripheral part of the hollow fiber membrane bundle, the evaporation of moisture is promoted uniformly, and the hollow fiber membrane is uniformly dried. Therefore, the failure of the hollow fiber membrane bundle due to non-uniform drying is corrected. In addition, heating by microwaves also acts almost equally on the entire center and outer periphery of the hollow fiber membrane bundle, so it functions synergistically in uniform heating, and is unique in drying the hollow fiber membrane bundle. It will be of significance. The degree of vacuum may be set as appropriate depending on the output of the microwave, the total moisture content of the hollow fiber membrane bundle and the number of hollow fiber membrane bundles, but in order to prevent temperature rise of the hollow fiber membrane bundle during drying, the degree of vacuum is It is performed at 20 kPa or less, more preferably 15 kPa or less, and further preferably 10 kPa or less. If it is 20 kPa or more, not only the water evaporation efficiency is lowered, but also the temperature of the polymer constituting the hollow fiber membrane bundle 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 membrane bundles containing polyvinylpyrrolidone, degradation or decomposition of polyvinylpyrrolidone occurs due to overdrying or overheating, or wettability during use. It is preferable not to increase the output much because there is a problem such as a decrease. Further, the hollow fiber membrane bundle can be dried even with an output of less than 0.1 kW, but there is a possibility that a problem of reduction in throughput due to an increase in drying time may occur. The optimum value of the combination of the degree of decompression and the microwave output varies depending on the water content of the hollow fiber membrane bundle and the number of processed hollow fiber membrane bundles, and it is preferable to obtain a set value as appropriate through trial and error.
For example, as a temporary guide for carrying out the drying conditions of the present invention, when 20 hollow fiber membrane bundles having a moisture content of 50 g per hollow fiber membrane bundle are dried, the total moisture content is 50 g × 20 fibers = 1,000 g. At this time, it is appropriate that the microwave output is 1.5 kW and the decompression degree is 5 kPa.

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

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

  In another aspect, when the water content of the hollow fiber membrane bundle is 400% by mass or less, irradiation with a low-power microwave of 12 kW or less may be excellent. For example, when the water content of the total amount of the hollow fiber membrane bundle is about 1 to 7 kg, an output of 12 kW or less, for example 1 10 to 240 minutes with a microwave of about 5 kW, about 1 to 240 minutes with a microwave of less than 0.5 to 1 kW, more preferably about 3 to 240 minutes, 1 with a microwave of 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 for about 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 according to the present invention. Of course, it is necessary to always consider the uniform irradiation and exhaust of the microwave in the microwave irradiation apparatus.

  The drying of hollow fiber membrane bundles can be achieved by irradiating with microwaves under reduced pressure and using a drying method that alternately reverses the direction of ventilation. 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 alternate 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 that alternately reverses the ventilation direction 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 permselective 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 complexity and complexity of the apparatus and high price. 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 bundle during drying can be measured by applying an irreversible thermolabel to the side of the film that protects the hollow fiber membrane bundle, drying, and checking the display after taking out the drying. . At this time, the maximum reached temperature of the hollow fiber membrane bundle during drying is preferably 90 ° C. or lower, more preferably 80 ° C. or lower. More preferably, it is 70 degrees C or less. If the maximum temperature reached exceeds 90 ° C., the film structure is likely to change, which may cause performance degradation or oxidative degradation. In particular, in a hollow fiber membrane 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. Although the method is not limited and is arbitrary, for example, a method in which a reflecting plate is provided in an oven disclosed in Japanese Patent Application Laid-Open No. 2000-340356 to reflect reflected waves and make heating uniform is a preferred embodiment. 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 perform heating (ventilation) drying 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, the hollow fiber membrane. As the moisture content decreases, there is a problem that it is susceptible to degradation and decomposition 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, it is inexpensive to use a far-infrared radiator in which austenitic stainless steel powder is coated with an oxide metal such as Al ₂ O ₃ , Fe ₂ O ₃ , TiO ₂ , CaO, MgO, K ₂ O, and Na ₂ O. This is a more preferable embodiment because far infrared rays can be extracted efficiently.

  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 bundle, the surface roughness, bending, cracking, smoothness and soft feeling.

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.

  As described above, the far-infrared irradiation may be started after the microwave irradiation is completed, or may be performed at the time of the microwave irradiation, and the microwave drying and the 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 the far-infrared irradiation while maintaining the 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 increased 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 applied 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. There is a risk that a structure that can cope with pressure cannot be guaranteed. 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 hollow fiber membrane bundle by the far infrared ray is promoted, and the microwave drying and the far infrared drying increase the 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 bundle is high, so when returning the inside of the drying chamber to atmospheric pressure, when a gas containing oxygen such as air is fed, in the case of a hollow fiber membrane containing polyvinylpyrrolidone, polyvinylpyrrolidone May undergo oxidative degradation due to the effects 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 bundle 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 an unlimited time does not affect the quality. This is because the influence of thermal deterioration of the polysulfone resin constituting the hollow fiber membrane bundle or of the polyvinylpyrrolidone material 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 industrial productivity, the inventors of the present invention are 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, thread collapse may occur due to the weight of the hollow fiber membrane, and adhesion failure of the adhesive may occur during assembly of the blood purifier. Therefore, the moisture 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 bundle, 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. To do. The difference between before and after drying is determined as% (g) based on the weight (g) after drying. The water content is determined by the following formula.
(Weight loss / mass after drying) × 100 = moisture content (mass%)

  As described above, the main items constituting the present invention and important points necessary for achieving the requirements have been described, but the spinning and post-treatment for obtaining the hollow fiber membrane of the present invention will be described in more detail with specific examples. To do.

  In the film forming solution, a polymer and a solvent, and if necessary, non-solvent components are used. The hollow inner liquid is preferably a mixed liquid composed of the same solvent and water as used for the film-forming solution, but a non-solvent may be appropriately added in order to obtain the desired film performance and film characteristics. As the polysulfone polymer, not only polysulfone and polyethersulfone but also two kinds of polymers can be mixed and used. As the solvent, it is preferable to use a solvent that dissolves both the polysulfone polymer and polyvinylpyrrolidone. Specifically, for example, dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dimethylformamide and the like can be used. Dimethylacetamide and N-methyl-2-pyrrolidone are more preferable. In the present invention, the non-solvent means a solvent that can be mixed to some extent at an arbitrary ratio but has no ability to dissolve the polysulfone polymer. In the present invention, water, ethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, 1,3-butylene glycol, glycerin, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether and the like are preferable. Water, triethylene glycol, and polyethylene glycol are more preferable from the viewpoints of work safety, availability, and cost.

  The membrane-forming solution is discharged from a tube-in-orifice double tube nozzle heated to room temperature to 130 ° C., and a membrane is formed by a so-called dry and wet spinning method. The film-forming solution and the hollow inner liquid for coagulating the film-forming solution are simultaneously extruded from the nozzle into the air, and after passing through the air blocked from the outside air, led to the coagulation bath provided directly under the nozzle, and the membrane is formed by microphase separation. Let it form. The resulting hollow fiber membrane is subsequently passed through a water washing tank to remove excess solvent / non-solvent / polyvinylpyrrolidone from the membrane. A certain number is wound around a bag and inserted into a film that protects the hollow fiber membrane bundle, and then cut into a certain length. Further, after removing the internal liquid by centrifugation, washing is performed again to remove excess polyvinylpyrrolidone and degraded degradation products and to control the content in the membrane. The obtained hollow fiber membrane is dried at a low temperature.

  It is preferable that the film forming solution discharge hole width of the nozzle is 100 μm or less. More preferably, it is 80 micrometers or less, More preferably, it is 60 micrometers or less. The smaller discharge hole width is preferable because the film thickness can be reduced. However, if the discharge hole width is too small, nozzle clogging is likely to occur, or problems such as difficulty in cleaning may occur. More preferred. Further, as described above, the L / D value, which is the ratio between the discharge outer diameter (D) and the land length (L) of the film forming solution flow path, is preferably 2 to 6. Correspondingly, the orientation of polyvinyl pyrrolidone on the inner surface of the hollow fiber membrane is within a preferred range.

  In the present invention, it is possible to prevent the above-described elution amount of polyvinyl pyrrolidone and endotoxin, which is an endotoxin, from entering the blood side, or to prevent the hollow fiber membranes from adhering to each other from being dried. In order to balance, it is required that the content of polyvinyl pyrrolidone on the outer surface of the hollow fiber membrane be in 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 polymer 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. As film forming conditions, optimization of stretching conditions, coagulation bath temperature, composition ratio of solvent and non-solvent in the coagulation liquid, etc., and effective washing methods include warm water washing, alcohol washing, and centrifugal washing. It is.

The hollow fiber membrane that has passed through the 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 washing 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 from 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 three or four 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 centrifugal washing is performed 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 of the methods, if 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 cleaning, it is possible to optimize the content of the outer surface polyvinyl pyrrolidone, thereby suppressing sticking and reducing the amount of eluate.

  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. Albumin sieving coefficient (preparation of 1% bovine plasma albumin solution)
Solution A: 53.72 g of Na ₂ HPO ₄ · 12H ₂ O and 26.30 g of NaCl are dissolved in 3 L of pure water.
Liquid B: 20.42 g of KH ₂ PO ₄ and 26.30 g of NaCl are dissolved in 3 L of pure water.
Add solution B to solution A and adjust to pH = 7.5 ± 0.1. 30 g of bovine plasma albumin (manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in 3 L of this phosphate buffer. After dissolution, adjust the pH to 7.5 ± 0.1 again using 1N-NaOH.
(Liquid flow)
Pure water was passed through the dialysate side channel of the blood purifier at 500 mL / min for 5 minutes, and then passed through the blood side channel at 200 mL / min for 5 minutes. Then, the phosphate buffer solution 500 mL / min was passed through the dialysate side channel of the blood purifier for 5 minutes, and then the blood side channel was passed at 200 mL / min for 5 minutes. Thereafter, the solution was passed for 3 minutes while filtering from the blood side to the dialysate side.
(Measurement)
Connect the circuit to the blood side and discard the priming solution (phosphate buffer) on the dialysate side. The blood purifier is placed in a constant temperature bath at 37 ° C., the dialysate side is sealed, and the blood side flow rate is passed at 200 mL / min for 1 minute to remove the priming solution remaining on the blood side. Next, a circuit is connected to the dialysate inlet, the blood side 200 mL / min, the flow rate of the filtration circuit connected to the dialysate inlet is set to 30 mL / min, and the blood permeate and filtrate are both returned to the test solution. Conduct the test. A test solution, a blood side permeate, and a filtrate 15 minutes after the start of circulation were collected. The collected sample was diluted 10 times with pure water (the filtrate is preferably undiluted), and the absorbance was measured with a spectrometer at a wavelength of 280 nm. The sieving coefficient of albumin was calculated from each absorbance using the following formula.
SCalb = 2 × Cf / (Cb + Co)
Here, Cf represents the absorbance of the filtrate, Cb represents the absorbance of the test solution, and Co represents the absorbance of the blood side permeate, and when diluted, the respective dilution factors are multiplied.

2. Clearance of α1 microglobulin Human α1 microglobulin (Catalog # 133007, Cosmo Bio) was dissolved in bovine blood (sodium citrate added, hematocrit 30%, adjusted to a total protein concentration of 6-7 g / dl). Prepare to a concentration of L. This bovine blood was heated to 37 ° C., sent to the blood side (inside the hollow fiber) of a 1.0 m ² blood purifier with an internal diameter standard at a rate of 10 ml / min, and the dialysate side was heated to 37 ° C. Similarly, dialysate is allowed to flow in the counterflow direction with the blood at 25 ml / min. Further, the blood side outlet flow rate is maintained at 10 ml / min. After setting the flow rate, sampling was performed 30 minutes later from the blood side inlet / outlet and the dialysate side outlet. The concentration of α1MG was measured by the ELISA method, and the clearance CL was calculated by the following formula.
CL = (Cbi−Cbout) / Cbi × Qb
Where CL: clearance (ml / min)
Cbi: Blood side inlet concentration Cbout: Blood side outlet concentration Qb: Blood flow rate (ml / min)

3. Measurement of α1 microglobulin adsorption (preparation of 100mg / Lα1MG solution)
Solution A: Dissolve 53.72 g of Na ₂ HPO ₄ · 12H ₂ O and 26.30 g of NaCl in 3 L of pure water.
Solution B: Dissolve 20.42 g of KH ₂ PO ₄ and 26.30 g of NaCl in 3 L of pure water.
Add solution B to solution A and adjust to pH = 7.5 ± 0.1. 300 mg of bovine plasma albumin (manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in 3 L of this phosphate buffer. After dissolution, adjust to pH = 7.5 ± 0.1 again using 1N-NaOH.
(Liquid flow)
Pure water was allowed to flow at 500 mL / min for 5 minutes through the dialysate side channel of the blood purifier, and then passed through the blood side channel at 200 mL / min for 5 minutes. Subsequently, the phosphate buffer solution 500 mL / min was passed for 5 minutes through the dialysate side flow path of the blood purifier, and then passed through the blood side flow path at 200 mL / min for 5 minutes. Thereafter, the solution was passed for 3 minutes while filtering from the blood side to the dialysate side.
(Measurement)
Connect the measuring solution circuit to the blood side and discard the priming solution (phosphate buffer solution) on the dialysate side. The blood purifier is placed in a 37 ° C. thermostat, the dialysate side is sealed, and the blood side flow rate is 200 mL / min for 1 minute to remove the priming solution remaining on the blood side. Next, connect the circuit to the dialysate inlet, set the flow rate on the blood side to 200 mL / min, set the flow rate of the filtration circuit connected to the dialysate inlet to 30 mL / min, and return both the blood-side permeate and filtrate to the test solution. Perform the test in the circulatory system. Test solutions at the start of circulation and after 15 minutes were collected. The concentration of the collected sample was determined by the Eliser method, and the adsorption amount was determined.
α1MG adsorption amount (mg) = Cb0 x test liquid volume-Cb15 x test liquid volume where Cb0 and Cb15 represent the concentration of the test liquid at the start of circulation and 15 minutes later, respectively, and when diluted, the respective dilution factor Shall be multiplied.

4. Water permeability The blood outlet circuit (outlet side from the pressure measurement point) of the blood purifier is stopped by forceps and is subjected to total filtration. Purified water kept at 37 ° C is placed in a pressurized tank and the pressure is controlled by a regulator. The pure water is sent to a blood purifier kept in a high temperature bath at 37 ° C, and the amount of filtrate flowing out from the dialysate side is measured with a graduated cylinder. taking measurement. The transmembrane pressure difference (TMP) is TMP = (Pi + Po) / 2
And Here, Pi is the blood purifier inlet side pressure, and Po is the blood purifier 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 blood purifier (mL / hr / mmHg), and A is the membrane area of the dialyzer. (M ² ).

5. Calculation of membrane area The membrane area of the blood purifier is determined 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 blood purifier, 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 blood purifier. .

6. Blood Leak Test A 37 ° C. bovine blood to which citric acid is added and coagulation is suppressed is fed to a blood purifier at 200 mL / min, and the blood is filtered at a rate of 20 mL / min. At this time, the filtrate is returned to blood to be a circulatory system. After 60 minutes, the filtrate from the blood purifier is collected, and the red color resulting from red blood cell leakage is visually observed. In this blood leak test, 30 blood purifiers were used in each example and comparative example, and the number of blood purifiers that had leaked blood was examined.

7. Content of polyvinyl pyrrolidone (PVP) in outermost layer of inner and outer surfaces of hollow fiber membrane It was determined by X-ray photoelectron spectroscopy (ESCA method).
One hollow fiber membrane was attached to the sample stage and measured by ESCA. The measurement conditions are as follows.
Measuring device: ULVAC-Phi ESCA5800
Excitation X-ray: MgKα ray X-ray output: 14 kV, 25 mA
Photoelectron escape angle: 45 °
Analysis diameter: 400μmφ
Pass energy: 29.35 eV
Resolution: 0.125 eV / step
Degree of vacuum: about 10 ⁻⁷ Pa or less From the measured value (N) of nitrogen and the measured value (S) of sulfur, the PVP content on the surface was calculated by the following formula.
<In case of PVP-added PES (polyethersulfone) membrane>
PVP content (Hpvp) [mass%]
= 100 × (N × 111) / (N × 111 + S × 232)
<In the case of PVP-added PSf (polysulfone) membrane>
PVP content (Hpvp) [mass%]
= 100 × (N × 111) / (N × 111 + S × 442)

8. Measuring method of PVP content in the whole hollow fiber membrane The sample was dried at 80 ° C. for 48 hours using a vacuum dryer, and 10 mg of the sample was measured with a CHN coder (manufactured by Yanaco Analytical Industries, Model MT-6). Analysis was made and the content of PVP was calculated from the nitrogen content by the following formula.
PVP content (mass%) = nitrogen content (mass%) × 111/14

9. The content of PVP in the surface vicinity layer of the inner surface of the hollow fiber membrane was measured by an ATR (Attenuated Total Reflection) method using a Fourier transform infrared spectrophotometer (IRμs / SIRM manufactured by SPECTRA TECH). Using a measurement sample prepared by the same method as in 7 above, an infrared absorption spectrum was measured using diamond 45 ° as an internal reflection element. In the infrared absorption spectrum, the ratio Ap / As of the peak absorption intensity Ap derived from C═O of PVP near 1675 cm ⁻¹ and the peak absorption intensity As derived from polysulfone-based polymer near 1580 cm ⁻¹ was determined. In the ATR method, since the absorption intensity depends on the measured wave number, a ratio υp / υs between the peak position υs of the polysulfone polymer and the peak position υp (wave number) of the PVP was applied to the measured value as a correction value. The content of PVP in the layer near the blood contact surface was calculated by the following formula.
Content (mass%) of PVP in the near surface layer = Cav × Ap / As × υp / υs
Cav is the PVP content (mass%) determined in 8 above.

10. Opening ratio of outer surface of hollow fiber membrane The outer surface of the hollow fiber membrane is observed with an electron microscope of 10,000 times and a photograph (SEM photograph) is taken. The image was processed with image analysis processing software to obtain the porosity of the outer surface of the hollow fiber membrane. The image analysis processing software is measured using, for example, Image Pro Plus (Media Cybernetics, Inc.). The emphasis / filtering operation is performed on the captured image so that the hole and the blockage are identified. Thereafter, the holes were counted. At that time, if the lower layer polymer chain could be seen inside the hole, the lower layer polymer chain was ignored and counted. The area (A) of the measurement range and the cumulative area (B) of the areas of the pores within the measurement range were determined, and the area ratio (%) = B / A × 100. This was carried out for 10 views and the average was obtained. Scale setting is performed as an initial operation, and holes on the measurement range boundary are not excluded during counting.

11. Thickness measurement of hollow fiber membrane A cross-section of the hollow fiber membrane is projected by a projector with a magnification of 200 times, and the inner diameter (A) and outer diameter of the hollow fiber membrane of maximum, minimum, and medium sizes in each field of view. (B) is measured, and the film thickness of each hollow fiber membrane is determined by the following equation:
Film thickness = (B−A) / 2
The average film thickness of five hollow fiber membranes per field of view was calculated.

12. Measurement of skin layer thickness The thickness of the skin layer of the hollow fiber membrane in the present invention was determined as follows.
The cross section of the hollow fiber membrane was observed with a scanning electron microscope (SEM) at a magnification of 3000 times, and the portion where no pore was clearly observed was defined as the skin layer, and the thickness was measured.

13. Measurement of carboxyl group content in hollow fiber membrane A dry hollow fiber membrane bundle was cut into a length of about 1 cm and weighed 0.75 g. This membrane was immersed in 25 cc of a methanol solution containing 0.01% by mass of 9-anthryldiazomethane (manufactured by Funakoshi Co., Ltd.) and allowed to stand at room temperature for 1 hour. The membrane was then filtered and immersed in methanol and filtered repeatedly to remain. The reagent was washed away. Next, the membrane was immersed in 25 cc of methanol containing 1N sodium hydroxide and hydrolyzed at room temperature for 2 hours. The fluorescence intensity of the supernatant was measured at an excitation wavelength of 365 nm and an emission wavelength of 412 nm, and the carboxyl group content in the film was calculated using anthracene methanol as a standard.

14. Measurement of peroxide content in hollow fiber membrane A dry hollow fiber membrane bundle was cut into a length of about 5 cm and weighed 0.3 g. This film was filled in a glass test tube, 4 cc of a color developing solution was added, and the mixture was reacted at 37 ° C. for 8 hours in the dark. As the coloring reagent, a solution obtained by dissolving a coloring agent attached to a commercially available peroxide measurement kit (Determiner LPO: manufactured by Kyowa Medix Co., Ltd.) with a dedicated solution was used. After completion of the reaction, the membrane was separated by filtration, the absorbance of the filtrate was measured at a wavelength of 675 nm, and the peroxide content in the membrane was calculated using cumene hydroperoxide as a standard.

15. Platelet adhesion test to hollow fiber membrane (LDH activity)
A small blood purification device having a length of 15 cm was prepared from 50 hollow fiber membranes, and heparinized human fresh blood was passed through the blood purification device at a linear velocity of 1.0 cm / sec for 15 minutes. After washing the blood purifier with physiological saline, the hollow fiber membrane is chopped and subjected to ultrasonic treatment in 0.5 cc physiological saline containing 0.5% polyethylene glycol alkylphenyl ether (trade name Triton X100). The activity of lactate dehydrogenase (hereinafter referred to as LDH) released from platelets attached to the surface was measured. LDH activity was measured using a commercially available colorimetric kit (LDH monotest kit: Boehringer Mannheim, manufactured by Yamanouchi Co., Ltd.), and the LDH activity per membrane area was calculated. In addition, the membrane which does not contain PVP at all was used as a positive control with severe platelet adhesion, and compared with the test product. The positive control LDH activity was 15.0 to 15.5 U / m ² .

16. Measurement of oxygen concentration in packaging bag and water Measurement of oxygen concentration in packaging bag was carried out 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.

17. Endotoxin permeability Dialysate with an endotoxin concentration of 200 EU / L is fed at a flow rate of 500 ml / min from the dialysate inlet of the blood purifier, and dialysate containing endotoxin is passed from the outside to the inside of the hollow fiber membrane at a filtration rate of 15 ml / Filtration was performed for 2 hours at min, 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).

18. Measurement of PVP insoluble matter amount Insolubilization by crosslinking of polyvinylpyrrolidone in the present invention is determined by solubility in dimethylformamide in the crosslinked membrane. That is, 10 g of the crosslinked film is taken, and the turbidity of the solution dissolved in 100 ml of dimethylformamide is visually observed. If turbidity is present, crosslinking is observed. It was determined that there was no crosslinking.

19. Hydrogen peroxide elution amount An extract was obtained by the method defined in the dialysis artificial kidney device production standard, and hydrogen peroxide in the extract was quantified by a colorimetric method. The quantification was carried out for each part by equally dividing the hollow fiber membrane into 10 pieces in the longitudinal direction by the length unit filled in the blood purifier.
From each part, 1 g of dry hollow fiber membrane was weighed, 100 ml of pure water was added, and extraction was performed at 70 ° C. for 1 hour. Mixing of 2.6 ml of the resulting extract with 0.2 ml of ammonium chloride buffer (pH 8.6) in an equimolar ratio and a hydrogen chloride solution of TiCl ₄ and an aqueous Na salt solution of 4- (2-pyridylazo) resorcinol 0.2 ml of a coloring reagent adjusted to 0.4 mM was added, heated at 50 ° C. for 5 minutes, cooled to room temperature, and the absorbance at 508 nm was measured. The elution amount of hydrogen peroxide was quantified using a calibration curve obtained by measuring in the same manner using a sample.

20, Elution amount of polyvinylpyrrolidone (PVP) To 2.5 ml of the extract extracted by the above method, add 1.25 ml of 0.2 mol citric acid aqueous solution and 0.5 ml of 0.006 normal iodine aqueous solution and mix well. The absorbance at 470 nm was measured after standing for a minute. Quantification was performed with a calibration curve obtained according to the above method using a standard polyvinylpyrrolidone.

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

22. Performance expression during priming Saline was flowed from the blood side inlet port of the blood purifier, and the water permeability after 10 minutes and 24 hours was evaluated by the above evaluation method, and 10 minutes with respect to the water permeability after 24 hours. The ratio of the water permeability after was calculated | required, and the following references | standards determined. After measuring the water permeability after 10 minutes, the blood purifier was filled with water and kept at room temperature for up to 24 hours.
90% or more: ○
Less than 90%: ×

23, Water Content of Hollow Fiber Membrane The water content of the selectively permeable hollow fiber membrane in the present invention was calculated by the following equation.
Moisture content (mass%) = 100 × (Ww−Wd) / Wd
Here, Ww is the mass of the selectively permeable hollow fiber membrane (g), and Wd is the mass of the selectively permeable hollow fiber membrane (g) after drying for 2 hours in a dry heat oven at 120 ° C. (after absolutely dry). Moreover, by setting Ww within the range of 1 to 2 g, it can be brought into a completely dry state (a state in which there is no further change in mass) after 2 hours.

Example 1
18% by mass of polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (registered trademark) 5200P), 3% by mass of polyvinylpyrrolidone (Collidon (registered trademark) K-90, manufactured by BASF), 27% by mass of dimethylacetamide (DMAc) It knead | mixed with the biaxial screw type kneader. The obtained kneaded material was put into a stirring type dissolution tank charged with 47.5% by mass of DMAc and 4.5% by mass of water, and dissolved by stirring for 3 hours. The kneading and dissolution were performed while cooling so that the solution temperature did not exceed 30 ° C. Then, after the pressure in the dissolution tank was reduced to −500 mmHg using a vacuum pump, the dissolution tank was immediately sealed and allowed to stand for 15 minutes so that the solvent and the like would not evaporate and change the film forming solution composition. This operation was repeated three times to degas the film forming solution. The hydrogen peroxide content of polyvinyl pyrrolidone was 100 ppm. The supply tank of the raw material supply system and the inside of the dissolution tank were replaced with nitrogen gas. Further, the Froude number and the stirring Reynolds number at the time of dissolution were 1.1 and 120, respectively. The obtained film-forming solution was sequentially passed through a two-stage sintered filter of 15 μm and 10 μm, and then discharged from a tube-in orifice nozzle heated to 70 ° C. at a discharge rate of 2.3 cc / min. -A 46% by mass DMAc aqueous solution at 25 ° C deaerated at 700 mmHg for 30 minutes was discharged, passed through a 700 mm dry part (air gap part) blocked from the outside air by a spinning tube, and then a 20% by mass DMAc aqueous solution at 70 ° C. It was solidified inside and rolled up in a wet state. At this time, the pressure loss in the nozzle is 2.9 × 10 ⁸ Pa · s, the shear stress in the film forming solution channel is 1.5 × 10 ⁶ s ⁻¹ , and the channel passage time is 1.3 ×. Calculated as 10 ^-3 sec. The draft ratio was 1.3.

  A polyethylene film is wound around a bundle of about 10,000 hollow fiber membranes, then cut to a length of 27 cm (hereinafter referred to as a bundle), and washed in water at 121 ° C. for 30 minutes × 3 times. Excess polyvinylpyrrolidone, solvent, and endotoxin (fragment) contained in the membrane were removed.

The obtained wet hollow fiber membrane bundle was introduced into a microwave dryer having an exhaust system for reducing the pressure of the far infrared heater and the oven, 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, the microwave was irradiated and the hollow fiber membrane bundle was heated at an output of 0.5 kW for 10 minutes, 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 for 8 minutes at an output of 0.2 kW to heat the hollow fiber membrane bundle. After the microwave cutting, the degree of vacuum was increased to 0.5 kPa, and only the far infrared rays were irradiated and maintained for 10 minutes to complete the drying of the hollow fiber membrane bundle. During drying, the output of the far-infrared heater was adjusted so that the temperature detected by a thermocouple provided at the center of the drying oven was 50 ° C. over the entire period.
The maximum temperature reached on the surface of the hollow fiber membrane bundle at this time was 65 ° C. The moisture content of the hollow fiber membrane bundle before drying is 330% by mass, the moisture content of the hollow fiber membrane bundle after the first stage is 34% by mass, and the moisture content of the hollow fiber membrane bundle after the second stage is 11% by mass. The water content of the hollow fiber membrane bundle after the third stage was 3.0% by mass. The resulting hollow fiber membrane had an inner diameter of 199 μm and a film thickness of 28 μm. The skin layer thickness was 0.9 μm.

  The obtained hollow fiber membrane bundle was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of the hollow fiber membrane bundle in a dry state was weighed from each part to quantify hydrogen peroxide. Hydrogen peroxide was stable at a low level at all sites, and the maximum value was 2 ppm.

The obtained hollow fiber membrane bundle was loaded into the blood purifier housing at a filling rate of 60% by volume, the end was adhered with urethane resin, the resin was cut out, and the hollow fiber membrane end was opened to assemble the blood purifier. . As a result of conducting a leak test of the obtained blood purifier, no adhesion failure caused by the sticking of the hollow fiber membranes was observed. The blood purifier is composed of two general-purpose oxygen scavengers (TAMOTSU (registered trademark) manufactured by Oji Tac Co., Ltd.), a pore volume of 1.05 cc / g, a surface area of 320 m ² / g, and a silica gel having a particle size of 8 mesh and calcium chloride. An oxygen transmission rate and a water vapor transmission rate of 1 cm ³ / m ² each consisting of a modified silica gel B loaded with 10% by mass of a silica gel B in a paper pack and an outer layer made of polyester film, an intermediate layer made of aluminum foil, and an inner layer made of polyethylene film. -Sealed by a heat sealing method and sealed in a packaging bag made of an aluminum laminate sheet of 24 h · MPa (20 ° C, 90% RH) or less and 5 g / m ² · 24 h · MPa (40 ° C, 90% RH) or less. The humidity control agent used was seasoned in advance in an environment with a relative humidity of 85% RH for 24 hours. The package was stored at room temperature for 72 hours and then sterilized by irradiation with 25 kGy of γ rays. The oxygen concentration in the packaging bag of the package sealed simultaneously with the sterilized product was measured. It was substantially oxygen-free at 0.1% by volume or less. The relative humidity was 75% RH.

The hollow fiber membrane bundle was taken out from the sterilized blood purifier, and the carboxyl group and peroxide contents in the hollow fiber membrane were measured. Further, LDH activity was evaluated immediately after sterilization and after storage for 2 weeks in a sealed state in a packaging bag. The above evaluation was performed using a plurality of blood purifiers produced simultaneously.
The carboxyl group and peroxide contents in the hollow fiber membrane were appropriate, the LDH activity was low, and the antithrombogenicity was good. In addition, the sieving coefficient of albumin, the clearance of α1 microglobulin, and the amount of α1 microglobulin adsorbed were evaluated. These selective permeabilities were good.

When the hollow fiber membrane was taken out from the blood purifier and the outer surface was observed with a microscope, no defects such as scratches were observed. In addition, citrated fresh bovine blood was passed through the blood purifier at a blood flow rate of 200 mL / min and a filtration rate of 10 mL / min / m ² , but no blood cell leak was observed. Endotoxin filtered from the outside of the hollow fiber membrane to the inside of the hollow fiber membrane was below the detection limit, and was at a level with no problem.

  Moreover, the amount of polyvinylpyrrolidone eluted from the selectively permeable hollow fiber membrane of the blood purifier was low, and the water permeability at the time of priming was also good, so that it was highly practical as a blood purifier.

  These evaluation results are shown in Table 1.

(Comparative Example 1)
In the method of Example 1, the composition of the film-forming solution was polyethersulfone (Sumika Excel (registered trademark) 5200P manufactured by Sumika Chemtex Co., Ltd.) 18.0% by mass, polyvinylpyrrolidone (Collidon (registered trademark K-90 manufactured by BASF)) Example 1 except that 0.5% by mass, dimethylacetamide (DMAc) 77.0% by mass, RO water 4.5% by mass, the temperature of the internal solution was changed to 50 ° C., and the coagulation solution was changed to RO water. In the same manner, a hollow fiber membrane and a blood purifier of Comparative Example 1 were obtained. The ratio of polyvinylpyrrolidone to the polysulfone polymer in the film-forming solution was 2.8% by mass, and the temperature difference between the film-forming solution temperature and the internal liquid at the time of nozzle discharge was 20 ° C. The characteristic values are shown in Table 2.

  The hollow fiber membrane obtained in this comparative example was inferior in the selective permeability of the protein because the content of polyvinyl pyrrolidone on the innermost surface layer of the hollow fiber membrane was too low and the skin layer was thick. Moreover, since the content of polyvinylpyrrolidone on the inner surface was too low, the residual blood property was inferior. Furthermore, since the content of polyvinyl pyrrolidone on the inner surface and outer surface of the hollow fiber membrane was low, the priming property was not good. Therefore, the blood purifier obtained in this comparative example has a low practicality.

(Comparative Example 2)
In the method of Example 1, the composition of the film-forming solution was polyethersulfone (Sumika Excel (registered trademark) 5200P manufactured by Sumika Chemtex Co., Ltd.) 18.0% by mass, polyvinylpyrrolidone (Collidon (registered trademark K-90 manufactured by BASF)) Example 1 except that 10.0% by mass, 67.5% by mass of dimethylacetamide (DMAc), 4.5% by mass of RO water, 65% by mass of the internal liquid, and 45 ° C. of the liquid temperature were changed. Similarly, a blood purifier of Comparative Example 2 was obtained. The ratio of polyvinyl pyrrolidone to polysulfone polymer in the film forming solution was 55.5% by mass. The characteristic values are shown in Table 2.

  The blood purifier obtained in this Comparative Example was inferior in protein permselectivity due to the high content of polyvinylpyrrolidone on the inner surface of the filled hollow fiber membrane and the large pore diameter. Moreover, the elution amount of polyvinylpyrrolidone was high. Regarding the low protein selectivity, in addition to the high content of polyvinylpyrrolidone on the inner surface, other factors affecting the protein permeability such as the average pore size and pore size distribution on the inner surface were also implemented. This is different from the hollow fiber membrane filled in the blood purifier of Example 1, and this is also presumed to have an influence. Further, since the content of polyvinyl pyrrolidone on the outer surface of the hollow fiber membrane was high, the hollow fiber membranes adhered to each other. In addition, permeation of endotoxin was observed.

  In addition, as a result of the air leak test, the blood purifier obtained in this comparative example was found to generate bubbles from the blood purifier bonding portion. It seems that the adhesion failure resulting from fixation of hollow fiber membranes was caused. Therefore, the blood purifier obtained in this comparative example has a low practicality.

(Comparative Example 3)
In Example 1, except that the combined use of the humidity control agent was stopped, the blood purifier and the oxygen scavenger were sealed in a packaging bag, and sterilized by γ-ray irradiation. A blood purifier was obtained. The relative humidity in the packaging bag was 35% RH. Table 2 shows the characteristics of the obtained blood purifier. The blood purifier obtained in Comparative Example 3 had a high carboxyl group and peroxide content in the hollow fiber membrane after receiving γ-ray irradiation, a large LDH activity, and an inferior antithrombogenicity. This is considered to be caused by the deterioration of the polyvinyl pyrrolidone in the hollow fiber membrane bundle due to the irradiation of γ rays because the humidity in the atmosphere around the hollow fiber membrane bundle at the time of γ ray irradiation is low.

(Comparative Example 4)
In Example 1, a blood purifier was obtained in the same manner as in Example 1 except that the sterilization treatment was performed without the oxygen scavenger in the packaging bag. Table 2 shows the characteristics of the obtained blood purifier. The blood purifier obtained in Comparative Example 4 was of low quality, as was the blood purifier obtained in Comparative Example 3. In this comparative example, since the oxygen scavenger is not enclosed, the oxygen concentration in the atmosphere around the hollow fiber membrane bundle at the time of γ-ray irradiation is not high so that oxidation is not suppressed. This is considered to be caused by the deterioration of the polyvinylpyrrolidone in the bundle.

(Example 2)
In the same manner as in Example 1, polyethersulfone (Sumikaexex (registered trademark) 4800P manufactured by Sumika Chemtex Co., Ltd.) 18.0% by mass, polyvinylpyrrolidone (Collidon (registered trademark) K-90 manufactured by BASF) 2.5 A film forming solution consisting of 5% by mass, 74.5% by mass of dimethylacetamide (DMAc) and 5.0% by mass of RO water was prepared. The ratio of polyvinyl pyrrolidone to polysulfone polymer in the film forming solution was 13.8% by mass. The hydrogen peroxide content of the raw material polyvinylpyrrolidone was 100 ppm. The obtained film-forming solution was sequentially passed through a two-stage sintered filter of 15 μm and 10 μm, and then discharged from a tube-in orifice nozzle heated to 70 ° C. at a rate of 2.1 cc / min. A 50% by mass DMAc aqueous solution at 30 ° C. that had been degassed in advance was discharged as a liquid, passed through a 750 mm air gap portion that was blocked from the outside air by a spinning tube, and then coagulated in a 25% by mass DMAc aqueous solution at 65 ° C. I lifted it up in the state. The draft ratio was 1.3. The pressure loss of the film forming solution in the nozzle is 2.15 × 10 ⁸ Pa · s, the shear stress is 1.1 × 10 ⁶ s ⁻¹ , and the passage time is 1.2 × 10 ⁻³ sec. there were. The hollow fiber membrane pulled up from the coagulation bath was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up.

A polyethylene film similar to that in Example 1 was wrapped around a bundle of about 10,000 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 selective permeable hollow fiber membrane bundle was dried in the same manner as in Example 1. The water content after drying was 1.7% by mass. The resulting hollow fiber membrane had an inner diameter of 202 μm and a film thickness of 29 μm. The skin layer thickness was 0.8 μm.

The obtained dry permselective hollow fiber membrane bundle was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of the hollow fiber membrane bundle in a dry state was weighed from each part, and the hydrogen peroxide elution amount was quantified. . The hydrogen peroxide elution amount was stable at a low level in all the sites, and was 2 ppm at the maximum.
Using the hollow fiber membrane bundle thus obtained, a blood purifier was assembled and sterilized in the same manner as in Example 1. The obtained blood purifier was of high quality and high practicality like the blood purifier obtained in Example 1. These evaluation results are shown in Table 1.

(Example 3)
In the same manner as in Example 1, 18.5% by mass of polysulfone (P-3500 manufactured by Amoco), 3.0% by mass of polyvinylpyrrolidone (Collidon (registered trademark) K-60 manufactured by BASF), dimethylacetamide (DMAc) A film forming solution consisting of 74.5% by mass and RO water 4.0% by mass was obtained. The ratio of polyvinyl pyrrolidone to the polysulfone polymer in the membrane forming solution was 16.2% by mass, and the hydrogen peroxide content in the raw material polyvinyl pyrrolidone was 150 ppm. The obtained film-forming solution was passed through a two-stage sintered filter of 15 μm and 10 μm in order, and then discharged from a tube-in orifice nozzle heated to 50 ° C. at a discharge rate of 2.4 cc / min. -A 35 mass% DMAc aqueous solution at 15 ° C degassed for 30 minutes at -700 mmHg was discharged, passed through a 650 mm air gap portion that was blocked from the outside air by a spinning tube, and then coagulated in a 15 mass% DMAc aqueous solution at 60 ° C. Then, it 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 pressure loss of the film forming solution in the nozzle was 2.3 × 10 ⁸ Pa · s, and the shear stress was 1.2 × 10 ⁶ s ^−1. The passage time was 1.5 × 10 ⁻³ sec. The draft ratio was 1.3.

  A polyethylene film similar to that of Example 1 was wrapped around a bundle of about 10,000 hollow fiber membranes, and then immersed and washed in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes × after washing treatment. The hollow fiber membrane bundle was lightly rinsed with RO water to replace isopropanol with water, and then drained for 600 rpm × 5 min with a centrifugal dehydrator. The obtained wet hollow fiber membrane bundle was dried in the same manner as in Example 1. The moisture content after drying was 2.0% by mass. The obtained hollow fiber membrane had an inner diameter of 199 μm and a film thickness of 30 μm. The skin layer thickness was 0.7 μm. The characteristic values of the obtained hollow fiber membrane are shown in Table 1.

  The obtained hollow fiber membrane was equally divided into 10 pieces of 2.7 cm in the longitudinal direction, and 1 g of the dried hollow fiber membrane was weighed from each site, and the hydrogen peroxide elution amount was quantified. The hydrogen peroxide elution amount was 2 ppm or less at the maximum value.

  Using the hollow fiber membrane prepared by the above method, a blood purifier was assembled and sterilized in the same manner as in Example 1. The obtained blood purifier was of high quality and high practicality like the blood purifier obtained in Example 1. These evaluation results are shown in Table 1.

Example 4
In the method of Example 1, the oxygen scavenger is switched to the moisture-releasing type AGELESS Z-200PT (registered trademark) manufactured by Mitsubishi Gas Chemical Co., and the use of the humidity control agent is stopped, and the packaging bag is sealed and stored until sterilization. A blood purifier was obtained in the same manner as in Example 1 except that the time was changed to 50 hours so that sterilization was performed. The obtained blood purifier was of high quality and high practicality like the blood purifier obtained in Example 1. These evaluation results are shown in Table 1.

(Example 5)
A blood purifier was assembled using a dry selectively permeable hollow fiber membrane bundle obtained in the same manner as in Example 1. After the RO side was filled with deoxygenated water having a dissolved oxygen concentration of 0.05 ppm obtained by passing RO water through the hollow fiber membrane deaerated blood purifier, the blood side was filled at 200 ml / min for 5 minutes, and then the blood side Then, the water content in the hollow fiber membrane was adjusted to 10% by mass by expelling the filling water with nitrogen gas at 60 ° C. at a pressure of 0.1 MPa and continuing the ventilation. The above operation was performed in a nitrogen atmosphere. The oxygen concentration in the blood purifier was 0.5% by volume. In this environment, all the blood and dialysate entrances and exits of the dried blood purifier are sealed with a cap made of an ethylene-propylene synthetic rubber, and the outer layer is a biaxially stretched polyamide film having a thickness of 25 μm and the inner layer is not yet having a thickness of 50 μm. It sealed in the packaging bag which consists of a laminated body of an extending | stretching polyethylene film.

  After sealing and storing at room temperature for 120 hours, sterilization was performed by irradiation with 25 kGy of γ rays. The resulting blood purifier has a slightly lower selective permeability than the blood purifier obtained in Example 1 because polyvinylpyrrolidone is slightly cross-linked, but is of high quality and high practicality. It was. These evaluation results are shown in Table 1.

(Example 6)
A blood purifier was assembled using a dry selectively permeable hollow fiber membrane bundle obtained in the same manner as in Example 1. Nitrogen was bubbled into deoxygenated water having a dissolved oxygen concentration of 0.05 ppm by passing RO water through the blood purifier through a hollow fiber membrane degassed blood purifier to prepare nitrogen-saturated water. After filling the blood side of the blood purifier with this nitrogen-saturated water at 200 ml / min for 5 minutes, the blood side is stopped, and the filling water is expelled with 60 ° C. air at a pressure of 0.1 Pa, and the ventilation is continued. Thus, the water content in the hollow fiber membrane was adjusted to 10% by mass. The blood and dialysate inlet / outlet of the blood purifier dried under the above 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. 50 hours after sealing, it was changed to γ-rays and sterilized by irradiation with an electron beam using an electron beam irradiation machine having an acceleration voltage of 5000 KV. The obtained blood purifier has a slightly lower selective permeability than the blood purifier obtained in Example 1 because polyvinylpyrrolidone is slightly cross-linked, but it has high quality and high practicality. It was. These evaluation results are shown in Table 1.

(Examples 7 and 8)
In the method of Example 1, a blood purifier was obtained in the same manner as in Example 1 except that each was sealed and then allowed to stand at room temperature for 24 hours and 40 hours and then sterilized by γ-ray irradiation. These characteristics are shown in Table 1. The permselectivity and blood compatibility were high quality as in the blood purifier obtained in Example 1. However, since the time from sealing to γ-ray treatment is short, the blood purifier obtained in Example 1 is slightly inferior in the performance of water permeability during priming. It was shown that the elapsed time until γ-ray irradiation has an influence on the performance.

(Comparative Example 9)
In Example 1, polyvinyl pyrrolidone having a hydrogen peroxide content of 500 ppm was used as a raw material, the kneading and dissolution temperature was 85 ° C., nitrogen gas replacement in the raw material supply system and dissolution tank was stopped, and the number of washings of the hollow fiber membrane bundle was 1 Example 1 except that the wet and selectively permeable hollow fiber membrane bundle was changed to dry under a normal pressure by irradiating microwaves until the moisture content became 0.5% by mass. A dry hollow fiber membrane bundle was obtained by the same method. The maximum value and the average value of the hydrogen peroxide content in the obtained dry hollow fiber membrane bundle were 10 and 5.6 ppm, respectively. A blood purification membrane was assembled using the dried hollow fiber membrane in the same manner as in Example 1. The blood purification membrane was filled with RO water and irradiated with γ rays in a wet state. The resulting blood purification membrane was poor in permselectivity because of the crosslinking of polyvinylpyrrolidone in the hollow fiber membrane by γ-ray irradiation. In addition, since the hollow fiber membrane used in this comparative example has a high hydrogen peroxide content, degradation of polyvinyl pyrrolidone occurs due to γ-ray irradiation despite γ-ray irradiation in a wet state, and carboxyl groups and peroxidation are caused. Many products were produced and blood compatibility was poor. It is inferred that the degradation reaction of polyvinylpyrrolidone by the γ-ray irradiation was induced by hydrogen peroxide contained in the hollow fiber membrane.

  Since the blood purifier of the present invention is excellent in selective permeability and is of a dry type, it has advantages such as being light, not freezing, and difficult to propagate various bacteria. In addition, since the polysulfone-based selectively permeable hollow fiber membrane loaded in the blood purifier of the present invention does not contain a radical scavenger, the radical scavenger is washed and removed in advance when used for blood purification. There is an advantage that the operation to perform is unnecessary. Furthermore, in the present invention, even in the dry state and in the absence of a radical scavenger, even if irradiated with radiation, the degradation of the selectively permeable hollow fiber membrane due to irradiation is suppressed, an effect that cannot be achieved with the prior art. Therefore, the production of the carboxyl group and peroxide caused by the deterioration reaction is small, and the blood purifier of the present invention has the advantage of excellent antithrombotic properties. Therefore, it is important to contribute to the industry.

The schematic diagram of the tube-in orifice nozzle used by this invention is shown. It is a schematic diagram showing the relationship between the PVP content ratio of the inner and outer surfaces of the hollow fiber membrane and the albumin sieving coefficient. It is a schematic diagram showing the relationship between the PVP content ratio of the inner and outer surfaces of the hollow fiber membrane and the change with time of the albumin sieving coefficient.

Explanation of symbols

1: Inner liquid discharge hole 2: Film-forming stock solution discharge hole L: Land length D: Nozzle outer diameter

Claims (8)

  It is mainly composed of a polysulfone-based polymer and polyvinylpyrrolidone, has a skin layer having a thickness of 0.1 to 1.2 μm, the content of polyvinylpyrrolidone on the outermost surface layer is 25 to 50% by mass, and (the outermost surface Content of polyvinyl pyrrolidone on the surface layer) / (Content of polyvinyl pyrrolidone on the innermost surface layer) ≧ 1.1 In a blood purifier made using a selectively permeable hollow fiber membrane, hematocrit 30%, total When bovine blood at 37 ° C. with a protein concentration of 6-7 g / dl and sodium citrate is added at a flow rate of 200 ml / min and a filtration flow rate of 20 ml / min, the sieving coefficient [A] of albumin after 15 minutes is 0.01 or more. The sieving coefficient [B] of albumin after 2 hours at 0.1 or less is 0.005 or more and less than 0.04, and the carboxyl group content in the selectively permeable hollow fiber membrane is 10 Blood purifier, which is a ~800nmol / g.   The blood purifier according to claim 1, wherein the sieving coefficient [B] of albumin after 2 hours is smaller than the sieving coefficient [A] of albumin after 15 minutes. The blood purifier according to claim 1 or 2, wherein the relationship between the sieving coefficient [A] of albumin after 15 minutes and the sieving coefficient [B] of albumin after 2 hours satisfies the following formula.
[B] / [A] = 0.1 to 0.4   The blood purifier according to any one of claims 1 to 3, wherein a peroxide content in the selectively permeable hollow fiber membrane is 200 nmol / g or less.   The blood purifier according to any one of claims 1 to 4, wherein the selectively permeable hollow fiber membrane has a thickness of 25 to 50 µm.   The blood purifier according to any one of claims 1 to 5, wherein the porosity of the outer surface of the selectively permeable hollow fiber membrane is 20 to 35%.   The blood purifier according to any one of claims 1 to 6, wherein the moisture content of the selectively permeable hollow fiber membrane is 600 mass% or less.   When the permselective hollow fiber membrane bundle before irradiation is divided into 10 pieces in the longitudinal direction by the length unit to be filled in the blood purifier, and each of them is subjected to the test defined by the dialysis-type artificial kidney device manufacturing approval criteria The blood purifier according to any one of claims 1 to 7, wherein the concentration of hydrogen peroxide in all the extracts is 5 ppm or less.

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