JP4843992B2 - Blood purifier - Google Patents

Description

  The present invention relates to a blood purifier having excellent blood compatibility, a good balance of separation characteristics, and high safety and stability of performance.

  In blood purification therapy for the treatment of renal failure, natural materials such as cellulose, cellulose diacetate, cellulose triacetate, synthetic polymers such as polysulfone, Modules such as hemodialyzers, hemofilters or hemodialyzers using dialysis membranes using polymers such as methyl methacrylate and polyacrylonitrile and ultrafiltration membranes as separation materials are widely used. In particular, modules using hollow fiber membranes as separation materials are important in the dialyzer field due to advantages such as reduction of the amount of blood circulating outside the body, high efficiency of removing substances in the blood, and productivity during module production. high.

  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 polyvinylpyrrolidone is attracting attention from the viewpoints 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 into 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 (referred to as the outer surface) on the opposite side 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 is increased. This is not preferable because side effects and complications occur 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. This leads to new problems, such as the fact that the polyvinyl pyrrolidone present on the outer surface intervenes when the membrane is dried, and the hollow fiber membranes stick together (adhere) and the module assemblability deteriorates. Conversely, lowering the amount of polyvinyl pyrrolidone present on the outer surface is preferable in terms of suppressing the entry of endotoxin into the blood side, but the hydrophilicity of the outer surface is reduced, so that assembly is performed after module assembly. When the dried hollow fiber membrane is returned to the wet state, the familiarity with the physiological saline is lowered, and this leads to the occurrence of the problem that the priming property, which is the expelling property of the air during the wet operation, is reduced. Absent.

  As a measure for solving the above problems, the content of polyvinylpyrrolidone 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 polyvinylpyrrolidone 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 problem that the priming property, which is another problem described above, is reduced, and improvement is necessary.

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 hollow fiber membrane, and it has not been possible to improve all of the above-mentioned problems caused by the content of polyvinylpyrrolidone on the outer surface.

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. When returning the dried hollow fiber membrane to the wet state, the familiarity with the physiological saline used for wetting becomes low, which leads to the problem that the priming property is lowered, which is not preferable. 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, since the hydrophilic compound acts as a foreign substance during dialysis, and the hydrophilic compound is susceptible to degradation such as light degradation, it leads to problems such as adversely affecting the storage stability of the module. In addition, there is also a problem of causing adhesive inhibition of the adhesive when fixing the hollow fiber membrane to the module in module assembly.
JP 2001-190934 A Japanese Patent No. 3193262

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

Further, the content of polyvinyl pyrrolidone on the inner surface 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, and creatinine, but also low molecular weight proteins with molecular weights of about 10,000 daltons from the middle molecular weight region around 5000 daltons. The removal object has spread to. 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. Further, it is described that the selective permeability with the effective protein removal rate is good and that the blood compatibility is excellent, but details regarding the effect are not mentioned. Furthermore, there is no mention at all regarding changes in these characteristics over time in hemodialysis, that is, stability over time, which is an important characteristic in practicality as a blood purifier. Therefore, development of a selectively permeable hollow fiber membrane with improved removal balance of both albumin and α1-microglobulin, blood compatibility, and improved stability over time of these properties is strongly desired.
Japanese Patent Laid-Open No. 11-309356 JP-A-7-289863

With regard to blood compatibility, which is one of the above problems, a technique for improving the characteristics by controlling the unevenness of the blood contact surface has been disclosed (see Patent Documents 18 and 19). In these techniques, the unevenness of the surface is defined from values measured by a white interference microscope. In Patent Document 1, it is considered preferable for the adhesion of platelets to be 10 ⁻⁶ cells / cm ² or less than the membrane area. A membrane having this characteristic is estimated to have a platelet retention rate (details will be described later) of approximately 100% in the present invention. However, in membranes with extremely high platelet retention, platelets activated by contact with the membrane are released into the blood, which triggers activation of the entire circulating blood in the body, resulting in biocompatibility. It may cause deterioration, which is not preferable. Also, there is no mention of stability over time.
JP 2000-126286 A JP-A-11-309353

  An object of the present invention is to provide a blood purifier having excellent blood compatibility, a good balance of separation characteristics, and high safety and stability of performance.

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 The blood purifier satisfies the following characteristics at the same time.
(1) Albumin sieving coefficient after 15 minutes when bovine blood at 37 ° C. with hematocrit of 30%, total protein concentration of 6-7 g / dl, and sodium citrate is added at 200 ml / min and filtration flow rate of 20 ml / min [A] is 0.01 or more and 0.1 or less. (2) The sieving coefficient [B] of albumin after 2 hours is 0.005 or more and less than 0.04. (3) When heparinized human whole blood was perfused at a flow rate of 150 mL / min into a blood purifier with a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard), the platelet retention after 60 minutes was 70% to 98%. The following.
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
Further, in this case, platelet factor 4 before and after blood perfusion when heparinized human whole blood was perfused at a flow rate of 150 mL / min into a blood purifier having a membrane area of 1.5 m ² (inside of hollow fiber membrane inner diameter). The concentration ratio (PF4 increase rate) is preferably 5 times or less.
In this case, 1000 mL of the solution containing the cationic dye is filled inside and outside the selectively permeable hollow fiber membrane of the blood purifier, and the remaining cationic dye solution is perfused through the blood purifier at a flow rate of 200 mL / min. In this case, the cationic dye adsorption rate after 5 minutes is preferably 40% or more and 70% or less.
In this case, 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%.

  The blood purifier of the present invention has a good balance of separation characteristics, high safety and stability of performance, and the selectively permeable hollow fiber membrane filled in the blood purifier of the present invention has an inner surface (blood contact). The cationic dye adsorption rate, which is a measure of the charge state of the side surface) and the hydrophilic-hydrophobic balance, is optimized, and the platelet retention rate during blood perfusion is within a predetermined range, so that blood compatibility, blood Performance retention at the time of contact use is realized at a high level.

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, for example, “Collidon” from BASF, “Prasdon” from ISP, “Pitz” from Daiichi Kogyo Seiyaku. 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 imparting hydrophilicity, 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 permselective hollow fiber membrane of the present invention is preferably produced using polyvinyl pyrrolidone 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 polyvinylpyrrolidone 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 only 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-A No. 2000-300663 is preferred. For example, 16 parts by mass of polyethersulfone (4800P, manufactured by Sumitomo Chemical Co., Ltd.) and 5 parts by mass of polyvinyl pyrrolidone (K-90, manufactured by BASF) disclosed in the patent document, 74 parts by mass of dimethylacetamide, 5 parts by mass of water Was dissolved and defoamed as a film-forming solution, and a 50% dimethylacetamide aqueous solution was used as a core solution, and this was simultaneously discharged from the outside and inside of the double-tube orifice, 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 above-described polysulfone-based polymer and polyvinyl pyrrolidone as constituents 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 facilitates control of the phase separation of polyvinylpyrrolidone with respect to the polysulfone polymer.

  The blood purifier of the present invention is a 37 ° C. cow with 30% hematocrit, a total protein concentration of 6-7 g / dl, and sodium citrate added to a module made by loading a selectively permeable hollow fiber membrane having the above composition. When blood was flowed at 200 ml / min and a filtration flow rate of 20 ml / min, the sieving coefficient [A] of albumin after 15 minutes was 0.01 or more and 0.1 or less, 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 coefficients of albumin after 15 minutes and 2 hours are 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, if 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 clinically that the amount of albumin leakage per one hemodialysis treatment (water removal amount 3 L) is 3 g or less. 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 vivo, and even if the amount of albumin leakage is too small, it may cause various disorders. Accordingly, 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, it is a more preferable embodiment that the sieving coefficient [B] of albumin after 2 hours is smaller than the sieving coefficient [A] of albumin after 15 minutes (requirement 2). By satisfying the requirements, the effects of the present invention can be remarkably exhibited. Furthermore, the relationship between the sieving coefficient [A] of albumin after 15 minutes and the sieving coefficient [B] of albumin after 2 hours satisfies [B] / [A] = 0.1 to 0.4. This is a preferred embodiment (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, so that 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 pre-primed with physiological saline before coming into contact with blood, and the filtrate side in the membrane and the module 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 should be 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 cannot be maintained over the entire treatment time, which is not preferable. 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 if 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 module made by loading a selectively permeable hollow fiber membrane made of a polysulfone polymer and polyvinyl pyrrolidone into 30% hematocrit, When 37 ° C. bovine blood with a total protein concentration of 6-7 g / dl and sodium citrate was 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 was 0.01. Optimum conditions for a selectively permeable hollow fiber membrane having a characteristic that the sieving coefficient [B] of albumin after 2 hours falls within the range of 0.005 or more and less than 0.04 in the range of 0.1 or less I found out. In order to manufacture a separation membrane with such optimum conditions, it is important to control various materials, specifications, manufacturing processes, drying conditions, etc. One method is to analyze the relationship between the sieving coefficients.

  The content of polyvinyl pyrrolidone on the innermost surface of the hollow fiber membrane [C] and the content of polyvinyl pyrrolidone on the outermost surface of the outer surface [D], which are one of the most typical characteristics 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 separation membrane can be obtained which is properly within the range of 0.01 or more and 0.1 or less and 0.005 or more and less than 0.04 and has a balance between albumin and α1 microglobulin. Of course, the molecular weight of polyvinylpyrrolidone and the content in the separation membrane are considered to affect the albumin sieving coefficient. However, within the range verified in this example, [D] / [C] is over 1.1. 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), When [D] / [C] is more than 1.1, [B] / [A] fits in the range of 0.1 to 0.4. , Distribution greatly deviates.

  In the present invention, the method for imparting the above-described protein separation selectivity balance to the selectively permeable hollow fiber membrane is not limited, but the blood purification 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 manifest, making it impossible to suppress leakage of albumin, a useful protein, and making it 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.

  Further, in the above production method, the film-forming solution comprises 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 hollow forming agent is an amide solvent. It is also an aqueous solution containing 30 to 60% by mass, and it is also preferable that the liquid temperature of the hollow forming agent is lower by 30 to 60 ° C. than the liquid temperature of the film forming solution and the liquid temperature is discharged under the condition of 0 to 40 ° C. This is an embodiment. 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 of the hollow forming agent is more preferably 32 to 58% by mass, further preferably 34 to 56% by mass, and still more preferably 35 to 54% by mass. The difference between the liquid temperature of the hollow forming agent and the liquid temperature of the film forming solution is more preferably 30 to 60 ° C, further preferably 30 to 55 ° C, and still more preferably 35 to 50 ° C. The liquid temperature of the hollow forming agent is more preferably 0 to 35 ° C, further preferably 5 to 30 ° C, and still more preferably 10 to 30 ° C. By selecting these conditions, the skin layer thickness of the selectively permeable hollow fiber membrane, the inner surface characteristics 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 hollow forming agent within the above range, it is possible to suppress the dissolved gas that has dissolved into bubbles when the hollow forming agent is discharged from the nozzle. That is, by suppressing the bubble formation of the dissolved gas in the hollow forming agent, there is also a secondary effect of suppressing the yarn breakage directly under the nozzle and the generation of the knob.

  There is no limitation on the method of making a temperature difference between the liquid temperature of the hollow forming agent and the liquid temperature of the film forming solution, but a tube-in-orifice type nozzle is provided with a heat exchanger in the pipe and nozzle block from the hollow forming agent tank to the nozzle. It is a preferred embodiment to use a hollow forming agent heating medium circulating block capable of adjusting the liquid temperature separately from the temperature of the film forming solution.

  In addition, as a 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 protein permeability is increased, and as the dialysis progresses (the passage of blood), the swelling of polyvinylpyrrolidone in the selectively permeable hollow fiber membranes progresses, so that the albumin permeability increases over time. The effect of improving the selectivity of protein separation by lowering the concentration is utilized. 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 the insoluble component 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 slightly cross-linking (insolubilizing), it is possible to exert a secondary effect of reducing the amount of the eluate without adversely affecting the residual blood during blood flow. 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 the present invention, the thickness of the selectively permeable hollow fiber membrane is preferably 25 to 50 μm (Requirement 7). If the film thickness is too thin, the pressure resistance may decrease. In addition, the permselective hollow fiber membrane may become weak, leading to a problem that the assemblability of the module is lowered. Therefore, the film thickness is more preferably 26 μm or more, and further preferably 27 μm or more. On the other hand, if the film thickness is too thick, it leads to a decrease in clearance 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 possibility of losing the merit that the module is compact. Therefore, the film thickness is more preferably 47 μm or less, further preferably 43 μm or less, and still more preferably 40 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 the content of polyvinyl pyrrolidone in the outermost layer is too small, the hydrophilicity of the inner surface of the hollow fiber membrane is low and blood compatibility is deteriorated, and blood coagulation is likely to occur on the surface of the hollow fiber membrane. Occlusion may occur and the separation performance of the hollow fiber membrane may decrease, or 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, if the polyvinyl pyrrolidone content in the outermost layer is too large, the amount of polyvinyl pyrrolidone eluted in the blood increases, and side effects and complications due to long-term accumulation of the eluted polyvinyl pyrrolidone in the body 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 hollow forming agent. Therefore, it is important that the liquid temperature of the hollow forming agent is 30 to 60 ° C. lower than the liquid temperature of the film-forming solution and the liquid temperature is 0 to 40 ° C. This optimizes the content of the innermost surface polyvinylpyrrolidone on the inner surface. 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 blood contact 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. As a matter of course, since ionic substances are 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 effect of preventing dialysis complications and 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, and gradually with the progress of dialysis. The problem that blood compatibility falls will generate | occur | produce. The present invention has been completed based on the technical idea that this problem is solved by replenishing the polyvinyl pyrrolidone present in the layer near the surface by movement 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 surface outermost layer in the selectively permeable hollow fiber membrane is 25 to 50% by mass, and (content of polyvinylpyrrolidone in the outermost surface outermost layer) / (the innermost surface outermost layer) The content of polyvinyl pyrrolidone) is preferably ≧ 1.1 (Requirement 11). If the content of polyvinyl pyrrolidone in the outermost surface layer of the outer surface is too small, the blood protein adsorption amount to the support layer portion of the hollow fiber membrane increases, so that blood compatibility and permeation performance may be lowered. In the case of a dry film, the priming property may be deteriorated. Accordingly, 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 may enter the blood side, leading to side effects such as fever, When it is dried, polyvinyl pyrrolidone present on the surface intervenes, and the hollow fiber membranes are fixed to each other, which may cause problems such as deterioration in module assembly. The content of polyvinylpyrrolidone on the outer surface is more preferably 43% by mass or less, further preferably 41% by mass or less, and further preferably 39% by mass or less.

In addition, the content of polyvinyl pyrrolidone on the outermost surface layer is preferably 1.1 times or more the content of polyvinyl pyrrolidone on the outermost surface layer on the inner surface. The content of polyvinyl pyrrolidone affects the shrinkage rate of the hollow fiber membrane after film formation. That is, as the content of polyvinyl pyrrolidone increases, the shrinkage rate of the hollow fiber membrane 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, micro wrinkles are formed on the inner surface side due to the difference in shrinkage between the inner surface side and the outer surface side. May occur 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 polyvinyl pyrrolidone 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. Therefore, it is more preferably 1.9 times or less, further preferably 1.8 times or less, and still more preferably 1.7 times or less.

  Regarding the innermost surface layer and the inner surface vicinity layer, the difference between the two layers in detail is a two-layer structure due to the difference in the content of the hydrophilic polymer. The permselective hollow fiber membrane is generally a skin on the inner surface. 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 vicinity of the surface may be formed. The thickness of each layer and its boundary line are arbitrarily changed depending on the manufacturing conditions of the selectively permeable hollow fiber membrane, and the structure of the layer 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 behaviors because of the fault in the distribution curve of the content of the hydrophilic polymer. The content of polyvinyl pyrrolidone is 20-40% by mass on the outermost layer and 5-20% by mass on the surface vicinity layer as the optimum range, but polyvinyl pyrrolidone is changed from the surface vicinity layer to the outermost layer. 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 polyvinyl pyrrolidone present in the two layers. As the appropriate difference value, that is, the ratio of the outermost layer polyvinylpyrrolidone content to the surface vicinity layer polyvinylpyrrolidone content is 1.1 times or more, specifically, the content of the two layers of polyvinylpyrrolidone If the difference in the amount is about 1 to 35% by mass, and 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 innermost and outermost surface layers of the polyvinyl pyrrolidone is measured and calculated by the ESCA method as described later, and the content of the outermost surface layer portions (the depth from the surface layer to several tens of feet) on the inner and outer surfaces. This is the absolute value of the quantity. Usually, the ESCA method can measure the polyvinylpyrrolidone content up to about 10 nm (100 mm) deep from the surface. The content of polyvinyl pyrrolidone 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 polyvinyl pyrrolidone on the innermost and outermost surface layers may be related to the molecular weight of polyvinyl pyrrolidone. 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 relative to the polysulfone-based polymer within the above-described range, and the conditions for forming a 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 and the surface vicinity layer. That is, although the detailed reason is not known, the outermost surface layer of the inner surface of the hollow fiber membrane can be obtained by setting the mass ratio of the polysulfone polymer and polyvinylpyrrolidone in the membrane forming solution and the concentration and temperature of the hollow forming agent within the ranges described later. There is a difference in the solidification rate and / or phase separation rate between the surface vicinity layer and the surface separation layer, and the difference in solubility between the polysulfone polymer and the polyvinylpyrrolidone in the solvent / water may express the above-mentioned characteristics. For requirement 9, it is important to optimize the drying conditions. That is, when the wet hollow fiber membrane is dried, polyvinylpyrrolidone dissolved in water moves from the inside of the hollow membrane to the surface side as the water moves. 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 increases, and the selectively permeable hollow fiber of the present invention increases. It is assumed that requirement 9 which is a characteristic of the film can be achieved. Further, for achieving 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). When the open area ratio is too small, there is a possibility that sticking between the hollow fiber membranes is likely to occur. Therefore, the porosity of the outer surface is more preferably 27% or more, and even more preferably 29% or more. Conversely, if the open area ratio is too large, the porosity of the selectively permeable hollow fiber membrane will increase, making it difficult to obtain the desired burst pressure, and it may not be possible to suppress leakage of albumin, which is a useful protein. There is sex. Therefore, the porosity of the outer surface is more preferably 33% or less, and even more preferably 31% or less.

  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 burst pressure of the selectively permeable hollow fiber membrane cannot be cleared to 0.5 MPa or more (requirement 13), it is necessary to introduce a measure for solving this problem. The burst pressure of the selectively permeable hollow fiber membrane is an index of pressure resistance performance of the selectively permeable hollow fiber membrane. The inside of the hollow fiber membrane is pressurized with gas, and the pressurized pressure is gradually increased. Is the pressure when bursting without being able to withstand the internal pressure. The higher the burst pressure, the less the cutting of the hollow fiber membrane and the generation of pinholes during use, so 0.55 MPa or more is more preferable, and 0.6 MPa or more is more preferable. 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 focus is on increasing the burst pressure and the film thickness is too thick or the porosity is too low, 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 based on the knowledge that the blood leak characteristics governed by the conventionally known macro characteristics such as the membrane strength cannot sufficiently prove the safety of the hollow fiber membrane in long-term dialysis. 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 a hollow fiber type blood purification membrane having a particularly high water permeability, minute scratches, crushing, and tearing of the hollow fiber membrane that cannot be detected by a normal pressure leak test are caused by manufacturing processes (mainly sterilization) after the leak test. Or packing), transportation process, or clinical handling (unpacking, priming, etc.), leading to the occurrence of hollow fiber breakage or pinholes, which may cause blood leaks during treatment. The present inventors have found that. 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 blood purifier of the present invention has a flow rate of 150 mL / min of heparinized human whole blood on the blood contact side of a blood purifier having a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard) prepared using the hollow fiber membrane. When the solution is perfused, the platelet retention after 60 minutes is preferably 70% or more and 98% or less.

  As an index indicating blood compatibility, there is a method for evaluating adhesion of platelets when contacted with blood. Conventionally, in order to improve blood compatibility, studies have been made with the goal of reducing the amount of platelet adhesion (improving platelet retention). Activation is considered unavoidable in some sense, even if the degree of difference. In the case of a membrane with a very high platelet retention rate, the apparent blood compatibility is judged to be good, but if the view is changed, even the platelets activated by contact with foreign materials are in the blood. May have been released. From such a viewpoint, as a result of further intensive studies, it was found that the retention rate of platelets is actually preferably 70% to 98%, and the present invention has been achieved. If the platelet retention rate is less than this range, the amount of platelet adhesion increases, and blood clots may be easily formed or the blood purification function may be reduced. Therefore, the platelet retention rate is more preferably 74% or more, and further preferably 78% or more. In addition, if it is larger than this range, activated platelets are also released into the blood, so blood components such as blood cells and plasma circulating in the living body are stimulated, and the whole blood in the living body is activated Therefore, there is no denying the tendency to clot and in some cases the risk of embolization. Therefore, the platelet retention is more preferably 97% or less, still more preferably 96% or less, and even more preferably 95% or less.

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

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

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

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

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

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

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

  It is thought that polyvinyl pyrrolidone, which is the outermost layer on the inner surface, contributes mainly to the above blood compatibility and performance stability. In the hollow fiber membrane of the present invention, the content of polyvinyl pyrrolidone on the innermost outermost layer is preferably 5 to 50% by weight, more preferably 10 to 40% by weight, and further preferably 15 to 40% by weight. A preferable content of the polyvinyl pyrrolidone is wider than a range suitable for imparting the selective permeability described above. Therefore, it is preferable that it is 20-40 mass% which is the above-mentioned preferable range. By setting this range, both characteristics can be satisfied simultaneously.

  Polyvinyl pyrrolidone whose structure is partially modified by treatment such as cross-linking may behave slightly different from the properties inherent to the polyvinyl pyrrolidone. In order to ensure the performance retention at the time of blood contact use, it is preferable that the polyvinylpyrrolidone contained in the hollow fiber membrane of the present invention is not substantially insolubilized. This point is also consistent with the preferred embodiment for imparting the selective permeability described above.

  Examples of specific means for obtaining a hollow fiber membrane excellent in blood compatibility intended by the present invention include the following techniques. By appropriately combining these techniques, a hollow fiber membrane having excellent blood compatibility can be obtained.

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

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

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

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

5). Use of alkaline earth metal-containing water It is preferable that the amount of alkaline earth metal contained in the water used in the production process of the hollow fiber membrane such as a hollow forming agent, a coagulation tank, and a washing tank is within a predetermined range. Although the detailed mechanism is unknown, the alkaline earth metal existing as a divalent cation functions to gently bridge oxygen atoms such as carbonyl group, hydroxyl group, ether bond of weakly negatively charged polyvinylpyrrolidone. It is presumed that the static and / or dynamic existence state of polyvinylpyrrolidone in the membrane is optimized. It is considered that this optimizes the function of polyvinylpyrrolidone as a hydrophilicity imparting agent and at the same time suppresses elution and contributes to optimization of the charged state of the hollow fiber membrane surface. The total amount of alkaline earth metal contained is preferably 0.02 to 1 ppm, more preferably 0.03 to 0.5 ppm. The method for obtaining such water is not particularly limited. The water used for film formation is preferably purified with an RO membrane or the like in order to remove impurities. For example, a method of adding a metal salt to the purified water is exemplified. In addition, there is a method of using ion-exchanged water as the raw water supplied to the RO membrane in order to thoroughly avoid contamination by impurities in the purification process. For example, ordinary raw water is used for this raw water. A method of leaving a trace amount of alkaline earth metal is also exemplified. In the method of adding a metal salt to the purified water, it is preferable to use the metal ion-adjusted water after ultrafiltration to remove impurities.

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

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

  The above-described suppression of overdrying of the hollow fiber membrane is largely due to controlling the UV absorbance of the extract from the hollow fiber membrane, which will be described later, within the preferable range regulated by the present invention and greatly affecting partial sticking suppression. The effect is great because of the heavy effect.

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

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

  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 inventors of the present invention conducted a hollow fiber membrane mainly composed of a polysulfone polymer and polyvinyl pyrrolidone, and a test defined by the above dialysis-type artificial kidney device manufacturing approval criteria. It has been found that hydrogen peroxide which cannot be measured by a conventionally known UV absorbance is contained in the extract extracted by the method. It has been found that the presence of the hydrogen peroxide accelerates the oxidative degradation of, for example, polyvinyl pyrrolidone, and the storage stability of the polyvinyl pyrrolidone elution increases when the hollow fiber membrane is stored. Moreover, in the prior art, all were evaluated about the specific site | part of the hollow fiber membrane. For example, when processing such as drying the hollow fiber membrane in module assembly or the like, it is found that the hydrogen peroxide elution amount greatly varies in the length direction of the hollow fiber membrane due to the influence of variation in drying conditions, etc. It was clarified that the evaluation of only the specific part mentioned above cannot answer the high safety requirement. In particular, even when hydrogen peroxide revealed by the present inventors is present at a specific portion of the hollow fiber membrane, the degradation reaction of the hollow fiber membrane material is started from that location and propagates throughout the hollow fiber membrane. . Accordingly, the content of hydrogen peroxide in the length direction of the hollow fiber membrane to be used needs to be maintained below a certain amount over the entire region.

  In the present invention, the hollow fiber membrane is divided into 10 in the longitudinal direction, and the elution amount of hydrogen peroxide when measured using an extract extracted according to the dialysis artificial kidney device manufacturing approval standard is 5 ppm at all sites. The following is preferable. 4 ppm or less is more preferable, and 3 ppm or less is more preferable. If the elution amount of the hydrogen peroxide is too large, the storage stability deteriorates due to oxidative degradation of the hollow fiber membrane material (particularly polyvinylpyrrolidone) due to the hydrogen peroxide. For example, the elution amount of polyvinylpyrrolidone when stored for a long period of time. May increase. In terms of storage stability, the increase in the amount of polyvinylpyrrolidone eluted is the most prominent phenomenon. In addition, deterioration of the polysulfone-based polymer causes the hollow fiber membrane to become brittle, or polyurethane-based adhesive used for module assembly. There is a possibility that the deterioration of the agent is promoted, the amount of elution of the deteriorated product is increased, and the safety is lowered. The increase in the amount of eluate caused by deterioration caused by the oxidizing action of hydrogen peroxide during the long-term storage can be evaluated by measuring UV (220-350 nm) absorbance set by the dialysis artificial kidney device manufacturing approval standard.

  Here, the elution amount of hydrogen peroxide is quantified with respect to the extract extracted by a method according to the elution test method of the dialysis artificial kidney device manufacturing approval standard. That is, a hollow fiber membrane is arbitrarily taken out from the hollow fiber membrane, and 1.0 g is weighed 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 variation in 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 decomposition of polyvinylpyrrolidone, and eventually blends the degradation product of polyvinylpyrrolidone into the hollow fiber membrane, so that it can be obtained, for example. When hollow fiber membranes were used 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 carried out in a dissolving tank having a kneading function. The type and form of the kneading apparatus in the former separate apparatus are not limited. Either a batch system or a continuous system may be used. A static method such as a static mixer may be used, or a dynamic method such as a kneader or a stirring kneader may be used. The latter is preferred from the efficiency of kneading. The kneading method in the latter case is not limited, and any type such as a pin type, a screw type, and a stirrer type may be used. Screw type is preferred. What is necessary is just to select suitably the shape and rotation speed of a screw from the balance of kneading | mixing efficiency and heat_generation | fever. On the other hand, the type of dissolution tank when using a dissolution tank having a kneading function is not limited. 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 they are 50 or more and 250 or less. Where n is the blade rotation speed (rps), ρ is the density (Kg / m ³ ), μ is the viscosity (Pa · s), g is the gravitational acceleration (= 9.8 m / s ² ), and d is the stirring blade diameter. (M). If the Froude number is too large, the inertial force becomes strong, so that the raw material scattered in the tank adheres to the walls and ceiling, and the desired film-forming solution composition may not be obtained. Therefore, the fluid number is more preferably 1.25 or less, further preferably 1.2 or less, and further preferably 1.15 or less. On the other hand, if the fluid number is too small, the inertial force is weakened, so that the dispersibility of the raw material is lowered. Particularly, polyvinylpyrrolidone becomes lumpy and it becomes difficult to dissolve further, or it takes a long time for uniform dissolution. Sometimes. Therefore, the fluid number is more preferably 0.75 or more, and further preferably 0.8 or more.

  Since the film-forming solution in the present invention is a so-called low-viscosity fluid, if the stirring Reynolds number is too large, a long defoaming time or insufficient defoaming occurs due to entrapment of bubbles in the film-forming solution during stirring. Problems may occur. Therefore, the stirring Reynolds number is more preferably 240 or less, further preferably 230 or less, and still more preferably 220 or less. On the other hand, when the stirring Reynolds number is too small, the stirring force becomes small, so that dissolution may be easily made nonuniform. Therefore, the stirring Reynolds number is more preferably 35 or more, further preferably 40 or more, still more preferably 55 or more, and particularly preferably 60 or more. Furthermore, when a hollow fiber membrane is formed with such a spinning solution, the operability is deteriorated due to a decrease in spinnability due to bubbles, and in terms of quality, the portion becomes defective due to the entrapment of bubbles in the hollow fiber membrane, and the airtightness of the membrane 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 can be mentioned, but 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 polyvinyl pyrrolidone increases, and the production of hydrogen peroxide is 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 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 polyvinylpyrrolidone 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.

  Regarding 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 were large and many portions exceeding the preferred range occurred, and the present invention could not 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 finished quickly, and the drying is finished with a delay at the air outlet. That is, when the hollow fiber membrane bundle is overdried at the air inlet portion, degradation of the hollow fiber membrane bundle material proceeds, and 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 produced by lowering 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 variable factor for the elution amount of hydrogen peroxide, and therefore a method of 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 where the target temperature is low to maximum 60 ° C. Ideally, the moisture content of the center portion and the outer peripheral portion of the hollow fiber membrane bundle, as well as the center portion and the outer peripheral portion of the hollow fiber membrane bundle in which the drying is performed, is ideally unchanged. Actually, there is a slight difference in the moisture content of the center portion and the outer periphery of the hollow fiber membrane or the 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 moisture content of 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 lower 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 to room temperature in conjunction with it. The small difference in the moisture content of the hollow fiber membrane bundle such as the central part, the intermediate part and the outer peripheral part means that the drying of each part is simultaneously and uniformly progressed. For this reason, alternately reversing the blowing direction when the hollow fiber membrane bundle is air-dried means alternately blowing air from the direction in which the air blowing direction with respect to the hollow fiber membrane bundle 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 the blower is devised to blow air from the direction in which the ventilation direction is alternately changed by about 180 degrees, but the blower means is not particularly limited. In particular, in the case of a circulation type blower / dryer, an apparatus that alternately inverts the hollow fiber membrane bundle of the content 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. The water content (% by mass) of the present invention is determined by measuring the mass (a) of the hollow fiber membrane before drying, the mass (b) of the hollow fiber membrane after drying,
Moisture content (mass%) = (ab) / b × 100
Can be easily calculated.

  Moreover, it is one of the effective means to dry by irradiating a microwave under reduced pressure. As a drying condition of the drying method, it is a preferred embodiment to irradiate microwaves having 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 additionally provided, drying of moisture is promoted by itself, so there is an advantage that the output of microwave irradiation can be suppressed and the irradiation time can be shortened, but the rise in temperature can also be suppressed relatively small. Therefore, the influence on the performance degradation of the hollow fiber membrane bundle is small as a whole. Furthermore, drying accompanied by means of reduced pressure has the advantage that the drying temperature can be relatively lowered, and has a significant point that deterioration and decomposition of the hydrophilic polymer can be remarkably suppressed. An appropriate drying temperature is sufficient from 20 to 80 ° C. More preferably, it is 20-60 degreeC, More preferably, it is 20-50 degreeC, More preferably, it is 30-40 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, since heating by microwaves acts almost equally on the center and the entire outer periphery of the hollow fiber membrane bundle, uniform heating and reduced pressure function synergistically, which is unique in drying the hollow fiber membrane bundle. The effect of. The degree of vacuum may be appropriately set according to the output of the microwave, the total moisture content of the hollow fiber membrane bundle, and the number of hollow fiber membrane bundles, but the degree of vacuum is 20 kPa to prevent the temperature of the hollow fiber membrane bundle during drying. Hereinafter, it is performed more preferably at 15 kPa or less, and further preferably at 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 forming 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 raises temperature rise suppression and drying efficiency, since the cost concerning maintaining the sealing degree of an apparatus becomes high, 0.1 kPa or more is preferable. More preferably, it is 0.25 kPa or more, and further preferably 0.4 kPa or more.

In consideration of shortening the drying time, a higher microwave output is preferable.For example, in hollow fiber membrane bundles containing polyvinylpyrrolidone, degradation or decomposition of polyvinylpyrrolidone occurs due to overdrying or overheating, and wettability decreases during use. Therefore, it is preferable not to increase the output so much. 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 the throughput will be reduced due to the extended drying time. 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 membranes and the total water content, but when suddenly high-power microwaves are irradiated, drying is completed in a short time, but the hollow fiber membrane is partially denatured. And 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 consideration of the influence on the hollow fiber membrane, especially under conditions under reduced pressure, conventionally, irradiation with microwaves under reduced pressure was not intended. Irradiation of microwaves under reduced pressure according to the present invention means that the evaporation of aqueous liquid is active even in a relatively low temperature state, so that degradation of polyvinylpyrrolidone and deformation of hollow fiber membranes due to high output microwaves and high temperatures Thus, a double effect of preventing damage to the hollow fiber membrane is obtained.

  In the present invention, drying by microwave irradiation under reduced pressure enables one-stage drying with a constant microwave output, but as another embodiment, the microwave output is sequentially stepped in accordance with the progress of drying. Therefore, so-called multistage drying is included as a preferred embodiment. Therefore, the significance of multi-stage drying will be described as follows. When drying with microwaves at a relatively low temperature of about 30 to 90 ° C. under reduced pressure, multi-stage drying in which the output of the microwaves is sequentially reduced in accordance with the progress of drying of the hollow fiber membrane bundle. The method is excellent. The degree of pressure reduction, temperature, microwave output, and irradiation time may be determined in consideration of the total amount of hollow fiber membranes to be dried, industrially acceptable drying time, and the like. Multistage drying can be performed in any number of stages, for example, 2 to 6 stages, but it is appropriate to use 2 to 4 stages for industrially acceptable 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 difference of the microwave is large, for example, 90 kW at the high stage and 0.1 kW at the low stage, the number of stages to reduce 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 art, thus making the effects of the present invention significant.

  To explain another aspect, when the moisture 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 total amount of water of the hollow fiber membrane bundle to be dried at a time is as relatively small as about 1 to 7 kg, it is 12 kW under a reduced pressure of 3 to 10 kPa at a temperature of 80 ° C. or lower, preferably 60 ° C. or lower. After heating the hollow fiber membrane bundle uniformly for 10 to 240 minutes with a microwave of the following output, for example, 1 to 5 kW, the microwave irradiation is stopped, and at the same time, the degree of vacuum is increased to 1 to 3 kPa to evaporate water. When the temperature of the hollow fiber membrane bundle decreases and it becomes difficult for water to evaporate, the degree of vacuum is returned to 3 to 10 kPa, the microwave irradiation is resumed, and the hollow fiber membrane bundle is resumed for 1 to 240 minutes with a microwave of less than 0.5 to 1 kW. Heat. When the temperature of the hollow fiber membrane bundle rises, microwave irradiation is stopped, the degree of vacuum is increased to 0.5 to 1.5 kPa, and the water is evaporated. If the moisture is less likely to evaporate than the hollow fiber membrane bundle, the degree of vacuum is reduced again to 3-10 kPa, irradiated with microwaves of less than 0.1-0.5 kW and heated for 1-240 minutes, depending on the degree of drying If the irradiation power and the irradiation time of the microphone mouth wave are adjusted, drying is performed uniformly. The degree of vacuum is set to 0.1 to 20 kPa for each stage, but the first stage having a relatively high moisture content of the hollow fiber membrane is increased to 0.1 to 5 kPa, for example, and the microwave output is increased. The so-called depressurization degree of each stage is such that microwaves are irradiated at a slightly higher pressure 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. Appropriate adjustment and change according to the situation can be arbitrarily set in consideration of the transition of 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 the hollow fiber membrane bundle is performed by irradiating with microwaves under reduced pressure, and using a drying method that alternately reverses the direction of ventilation also makes the process complicated in drying, but an effective drying method It is. The microwave irradiation method and the alternating ventilation reverse method also have merits and demerits, and these can be used together when high quality is required. In the first stage, when the air flow alternating reversal method is adopted and the moisture content proceeds to about 20 to 60% by mass, it can be dried by irradiating microwaves under reduced pressure in the next stage. In this case, after drying by irradiating microwaves, it is possible to use a drying method in which the ventilation direction is reversed alternately. These can be determined in consideration of the quality of the hollow fiber membrane produced by drying, particularly the quality of the polysulfone-based hollow fiber membrane bundle having no partial fixation in the length direction of the hollow fiber membrane. These drying methods can be performed simultaneously, but are not practical because of disadvantages such as the complexity and complexity of the apparatus and the price increase. However, the combined use of 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 reaches 90 ° C. or higher, 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, non-uniform heating due to reflected waves generated during microwave irradiation occurs, so it is important to take measures to reduce non-uniform heating due to the reflected waves. The method is not limited and is arbitrary. For example, a method of providing a reflector in an oven disclosed in Japanese Patent Application Laid-Open No. 2000-340356 to reflect reflected waves and uniformize heating is a preferred embodiment. One.

  As described above, the main matters 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. As the hollow forming agent, it is preferable to use the same mixed solution 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 refers to a solvent that can be mixed at an arbitrary ratio to some extent but does not have the 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. A membrane-forming solution and a hollow forming agent for coagulating the membrane-forming solution are extruded from the nozzle into the air at the same time. Let it form. The obtained hollow fiber membrane is subsequently passed through a 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 hollow forming agent by centrifugation, washing is performed again to remove excess polyvinyl pyrrolidone and degraded degradation products and to control the content in the membrane. The obtained hollow fiber membrane is dried at a low temperature.

  The width of the film forming solution discharge hole of the nozzle is preferably 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 liable 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.

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

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

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

  In the production of the hollow fiber membrane of the present invention, it is preferable that stretching is not substantially applied before the hollow fiber membrane structure is completely fixed. The fact that the film is not substantially stretched means that the roller speed during the spinning process is controlled so that excessive slack or tension does not occur in the film forming solution discharged from the nozzle. The discharge linear speed / coagulation bath first roller speed ratio (draft ratio) is preferably in the range of 0.7 to 2.0. If the ratio is less than 0.7, the running hollow fiber membrane may be loosened, leading to a decrease in productivity. Therefore, the draft ratio is more preferably 0.8 or more, further preferably 0.9 or more, and More preferably 95 or more. When it exceeds 2.0, the membrane structure may be destroyed, for example, the dense layer of the hollow fiber membrane is torn. Therefore, the draft ratio is more preferably 1.9 or less, and still more preferably 1.8 or less. By adjusting the draft ratio to this range, deformation and destruction of the pores can be prevented, clogging of blood protein into the membrane pores can be prevented, and performance stability over time and sharp fractionation characteristics can be expressed. As a result of a synergistic effect with the optimization of the liquid temperature of the hollow forming agent described above, streaky irregularities that are continuous in the longitudinal direction of the hollow fiber membrane are formed on the surface of the inner surface, so Since it leads to increase of quantity, it is preferable.

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

  In the present invention, the elution amount of the polyvinyl pyrrolidone and the endotoxin, which is an endotoxin, are prevented from entering the blood, and the hollow fiber membranes are prevented from sticking to each other when the hollow fiber membranes are 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 with respect to the polysulfone polymer to the above-mentioned range or optimizing the film forming conditions of the hollow fiber membrane. It is also an effective method to wash the formed hollow fiber membrane. As film forming conditions, optimization of stretching conditions, temperature of coagulation bath, composition ratio of solvent and non-solvent in coagulating liquid, etc. Also effective cleaning methods include hot water cleaning, alcohol cleaning and centrifugal cleaning. It is.

As a method for cleaning the hollow fiber membrane, in the present invention, it is preferable to treat the hollow fiber membrane by immersing it in hot water at 70 to 130 ° C., or at room temperature to 50 ° C. and 10 to 40 vol% ethanol or isopropanol aqueous solution.
(1) In the case of hot water washing, the hollow fiber membrane is immersed in excess RO water and treated at 70 to 90 ° C. for 15 to 60 minutes, and then the hollow fiber membrane is taken out and subjected to centrifugal dehydration. This operation is repeated 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 centrifugally washed for 30 minutes to 5 hours while spraying washing water at 40 ° C. to 90 ° C. from the rotation center in a shower shape.
Two or more cleaning methods may be combined. In any 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.

  In the present invention, when the hollow fiber membrane is stored in a dry state, it is preferably stored at a temperature of 20 ° C. or lower in order to suppress the generation of hydrogen peroxide. It is also a preferred embodiment to carry out hermetic packaging in a deoxygenated state. For example, an outer layer composed of an aluminum foil that can substantially block oxygen gas and water vapor is composed of a polyester film, an intermediate layer is an aluminum foil, and an inner layer is made of a material having both impermeability and heat sealability. The packaging bag may be sealed in an inert gas or in the presence of an oxygen scavenger. In this case, it is preferable to store the hollow fiber membrane with a moisture content of 1% by mass to a saturated moisture content. More preferably, it is 1-10 mass%, More preferably, it is 1-7 mass%. If the water content of the hollow fiber membrane is less than 1% by mass, store it in a state where the relative humidity at room temperature of the atmosphere in the packaging bag is 50% RH or more, or bundle a moisture releasing oxygen scavenger. Is preferred.

  In the present invention, when sterilizing by γ-ray or electron beam irradiation, it is preferable to carry out the hollow fiber membrane bundle in a dry state in order to suppress the crosslinking reaction of polyvinylpyrrolidone. In this method, it is preferable to carry out the same method as described in the above storage method in order to suppress the production of hydrogen peroxide due to the degradation of polyvinyl pyrrolidone by γ-ray or electron beam irradiation.

  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. Subsequently, the phosphate buffer solution 500 mL / min was passed through the dialysate side channel of the module 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 module 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, 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), and 100 mL / Prepare to a concentration of L. This bovine blood is heated to 37 ° C., sent to the blood side (inside the hollow fiber) of the module of 1.0 m ^{2 on} the basis of the inner diameter with a small pump at 10 ml / min, and the dialysate side is heated to 37 ° C. In the same direction 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 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: 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.
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 through the dialysate side channel of the module 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 measuring solution circuit to the blood side and discard the priming solution (phosphate buffer solution) on the dialysate side. The module is placed in a constant temperature bath at 37 ° C., 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 amount of adsorption 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 mouth 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 leaked modules was examined.

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

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

15, PF4 increase rate Japanese standard product classification number issued by the company using EIA (sandwich method) platelet factor 4 (PF4) measurement reagent manufactured by Roche Diagnostics, Inc .: Approval number: 16200EZY0045300, 2002 (Revised version) Measured according to the measurement method described.

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

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. Priming property Distilled water for injection is allowed to flow at 200 mL / min from the blood side inlet port with the lid on the dialysate side port of the blood purifier, and the water is injected for 10 seconds after the distilled water for injection reaches the outlet side port. Then, the blood purifier case was tapped 5 times to defoam, and the number of bubbles passed for 1 minute was visually confirmed.
Judgment was made according to the following criteria.
10 / min or less: ○
11-30 pieces / min: △
30 or more / minute: ×

19, Measurement of the amount of insoluble PVP When the blood purifier is filled with liquid, the filling liquid is first withdrawn, then pure water is allowed to flow through the dialysate side flow path at 500 mL / min for 5 minutes, In the same way, pure water is allowed to flow at 200 mL / min for 5 minutes. Finally, 200 mL / min of pure water is passed through the membrane from the blood side to the dialysate side to finish the washing process. A hollow fiber membrane bundle was taken out from the obtained blood purifier and freeze-dried to obtain a sample for measuring insoluble components. In the case of a dry hollow fiber membrane blood purifier, the same washing treatment was performed to obtain a measurement sample.
Insolubilization due to crosslinking of polyvinylpyrrolidone in the present invention is determined by solubility in dimethylformamide in the crosslinked film. That is, 10 g of the crosslinked film was taken, and the turbidity of the solution dissolved in 100 ml of dimethylformamide was observed with the naked eye, and the turbid case was determined to be cross-linked and the non-turbid case was determined to be non-cross-linked.

20, Hydrogen peroxide elution amount An extract was obtained by a method defined in the manufacturing standard of dialysis artificial kidney device, 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 of 2.7 cm in the longitudinal direction.
In the case of a dry hollow fiber membrane, 100 ml of pure water was added to 1 g of a hollow fiber membrane bundle and extracted 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 Add 0.2 ml of coloring reagent adjusted to 0.4 mM, heat at 50 ° C. for 5 minutes, cool to room temperature, and measure absorbance at 508 nm. The elution amount of hydrogen peroxide was quantified using a calibration curve obtained by measuring in the same manner using a sample.
In the case of the wet hollow fiber membrane blood purifier, physiological saline was passed through the dialysate side flow path of the blood purifier at 500 ml / min for 5 minutes, and then passed through the blood side flow path at 200 ml / min. Thereafter, the solution was allowed to pass through for 3 minutes while filtering from the blood side to the dialysate side at 200 ml / min, and then freeze-dried to obtain a dry membrane, and the above quantification was performed using the dry membrane.

21, Polyvinylpyrrolidone (PVP) elution amount To 2.5 ml of the extract extracted by the above method, 1.25 ml of 0.2 mol citric acid aqueous solution and 0.5 ml of 0.006 normal iodine aqueous solution were added and mixed 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.

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

23, Moisture Content The moisture 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
Polyethersulfone (Suika Chemtex Co., Ltd. Sumika Excel (registered trademark) 5200P) 18% by mass, Polyvinylpyrrolidone (BASF Koridone (registered trademark) K-90) 3% by mass, Dimethylacetamide (DMAc) 27% by mass 2 It knead | mixed with the screw type kneading machine of the axis | shaft. The obtained kneaded material was charged 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 rise above 30 ° C. Subsequently, the film forming solution was defoamed. 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. At this time, the oxygen concentration in the dissolution tank was 0.06%. 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 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 70 ° C. at a discharge rate of 2.3 cc / min. A 46% by mass DMAc aqueous solution at 25 ° C. that had been degassed in advance was discharged, passed through a 700 mm dry part (air gap part) blocked from the outside air by a spinning tube, and then solidified in a 20% by mass DMAc aqueous solution at 70 ° C. Then, it was rolled up in a wet state. The nozzle slit width is 60 μm on average, 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 The transit time was calculated to be 1.3 × 10 ⁻³ sec. The draft ratio was 1.04. The linear velocities immediately after discharge were 17790 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.7. All the water used in the spinning process is prepared by adding calcium nitrate and magnesium nitrate to the RO water so that the calcium content is 0.04 ppm and the magnesium content is 0.04 ppm, and water that has passed through an ultrafiltration membrane is used. did. During the spinning process, the guide and roller with which the hollow fiber membrane bundle contacts were surface-treated with Teflon (registered trademark). Moreover, mist-like water was sprayed on the hollow fiber membrane bundle under running just before winding. Some of these manufacturing conditions are shown in Table 1.

  A polyethylene film is wound around the bundle of about 10,000 hollow fiber membranes, and then immersed and washed in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes × 2 times. After rinsing lightly with RO water to replace isopropanol with water, the solution was removed with a centrifugal separator for 600 rpm × 5 min. The obtained wet hollow fiber membrane bundles were set in 12 × 2 stages on a rotary table in a drying apparatus, 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 at the same time the degree of reduced pressure was increased to 1.5 kPa and maintained for 3 minutes. Subsequently, the degree of vacuum was returned to 7 kPa, and at the same time, microwaves were applied to heat the hollow fiber membrane bundle 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 at an output of 0.2 kW for 8 minutes to heat the hollow fiber membrane bundle. After microwave cutting, the degree of vacuum was raised to 0.5 kPa and maintained for 5 minutes to condition the hollow fiber membrane bundle and finish drying. 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 310% by mass, the moisture content of the hollow fiber membrane bundle after the first stage is 38% by mass, and the moisture content of the hollow fiber membrane bundle after the second stage is 14% by mass. The moisture content of the hollow fiber membrane bundle after the third stage was 2.3% by mass. The obtained hollow fiber membrane had an inner diameter of 199 μm, a film thickness of 28 μm, and a skin layer thickness of 0.9 μm.

A cap having an inflow port by inserting the hollow fiber membrane bundle prepared by the above method into a blood purifier case made of polycarbonate, fixing both ends with urethane resin, cutting the resin end portion and opening the hollow portion of the hollow fiber membrane A blood purifier having a membrane area of 1.5 m ² was prepared. This blood purifier was sterilized by irradiation with 25 kGy of γ rays. The priming property of the obtained blood purifier was good.

  When hollow fiber membranes after γ-ray sterilization were cut out and subjected to the eluate test, the polyvinyl pyrrolidone elution amount was 5 ppm, and the maximum hydrogen peroxide elution amount was 2 ppm. It was suppressed.

  A plurality of blood purifiers were produced, two of the completed blood purifiers were broken, 10 hollow fiber membranes were taken out to form a bundle of 10 micromodules, and blood compatibility tests and cationic dye adsorption rates were measured. The cationic dye adsorption rate had an appropriate value, negative charge control was appropriate, and blood compatibility 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. In addition, blood leakage and endotoxin permeability were good.

  Further, when the hollow fiber membrane was taken out from the blood purifier and the outer surface was observed with a microscope, defects such as scratches were not observed, and the burst pressure was good. All the characteristics were good and the blood purifier was highly practical. The evaluation results are shown in Table 2.

(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 except that 0.5% by mass, dimethylacetamide (DMAc) 77.0% by mass, RO water 4.5% by mass, the temperature of the hollow forming agent is changed to 50 ° C., and the coagulation liquid is changed to RO water. In the same manner as in Example 1, the hollow fiber membrane and module 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 hollow forming agent at the time of nozzle discharge was 20 ° C. Tables 1 and 2 show some of the manufacturing conditions and characteristic values.

  The hollow fiber membrane obtained in this comparative example was inferior in protein permselectivity 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, the priming property was not good because the content of polyvinyl pyrrolidone on the inner surface and outer surface of the hollow fiber membrane was low. 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, the concentration of the hollow forming agent was changed to 65% by mass, and the liquid temperature was changed to 45 ° C. In the same manner, 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. Tables 1 and 2 show some of the manufacturing conditions and characteristic values.

  The blood purifier obtained in this comparative example was inferior in protein permselectivity because of the high content of polyvinylpyrrolidone in the innermost surface layer 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. It is different from the hollow fiber membrane filled in the blood purifier of Example 1, and this is 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.

  Further, as a result of the air leak test, the blood purifier obtained in this comparative example was found to generate bubbles from the module adhesion part. 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 Examples 3 and 4)
In Example 1, the hollow forming agent discharge linear velocity was changed to 12100 and 53240 cm / min, respectively, the linear velocity ratio was 2.5 and 11.0, respectively, and the guide of the spinning process and the Teflon (registered trademark) processing of the roller surface were performed. Example, except that it is omitted and a metal one is used, and the spraying of mist water during winding of the spinning process and the slow current treatment during loading of the hollow fiber membrane bundle into the module housing are omitted. The hollow fiber membrane bundle and blood purifier of Comparative Examples 3 and 4 were obtained in the same manner as in Example 1. Tables 1 and 2 show part of the manufacturing conditions and the evaluation results of the blood purifier, respectively.
The hollow fiber membranes obtained in both comparative examples were inferior in blood compatibility. The hollow fiber membrane obtained in Comparative Example 3 can be controlled to an appropriate negative charge such that the ratio of the linear velocity immediately after ejection is as low as 2.5 times, and friction at the interface between the dope and the hollow forming agent is not sufficient. It is thought that the contribution of what could not be done was significant. On the other hand, in the hollow fiber membrane obtained in Comparative Example 4, the ratio of the linear velocity immediately after discharge is as high as 11.0 times, the friction at the interface between the dope and the hollow forming agent is excessive, and is controlled to an appropriate negative charge. In addition, since stable spinning could not be performed, a uniform hollow fiber membrane could not be obtained, and it was considered that the contribution of the deterioration of the inner surface state was great.

(Comparative Example 5)
In Comparative Example 3, all the water used for the production of the hollow fiber membrane is RO water, the calcium content and the magnesium content are not adjusted, the treatment with the ultrafiltration membrane is not performed, and the γ-ray irradiation is performed in the air. A blood purifier was obtained in the same manner as in Comparative Example 3 except that the above was changed. The calcium content and magnesium content of the water used were both 0.005 ppm or less. Table 3 shows the characteristics of the obtained blood purifier. The hollow fiber membrane obtained in this Comparative Example was worse in blood compatibility than Comparative Example 3 because the calcium and magnesium contents of water used for the production of the hollow fiber membrane were not adjusted. This is considered to be caused by the deterioration of the charged state of the hollow fiber membrane. In addition, the storage stability of the blood purifier was inferior because polyvinylpyrrolidone was deteriorated by γ-ray irradiation and hydrogen peroxide increased. Tables 1 and 2 show part of the manufacturing conditions and the evaluation results of the blood purifier, respectively.

(Comparative Example 6)
In Comparative Example 2, the hollow forming agent discharge linear velocity was changed to 12100 cm / min, the linear velocity ratio was 2.5, the spinning step guide and the Teflon (registered trademark) processing of the roller surface were omitted, and the metallic one Used, omits the spraying of mist water during winding of the spinning process and the slow current treatment at the time of loading the hollow fiber membrane bundle into the module housing, and filling the blood purifier with RO water and irradiating with γ rays A blood purifier of Comparative Example 6 was obtained in the same manner as in Comparative Example 1 except that the above was changed. Tables 1 and 2 show part of the manufacturing conditions and the evaluation results of the blood purifier, respectively.
The blood purifier obtained in this comparative example was inferior in blood compatibility for the same reason as in Comparative Example 3 in addition to the problem of the blood purifier obtained in Comparative Example 2. Further, since the hollow fiber membrane filled in the blood purifier obtained in this comparative example was irradiated with γ-rays in a wet state, the cross-linking of polyvinyl pyrrolidone progressed, so that the selective permeability was comparative example 2. It was even lower.

(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 film-forming stock solution discharge rate of 2.1 cc / min. As a forming agent, a 50% by mass DMAc aqueous solution at 30 ° C. that had been degassed in advance was discharged, passed through a 750 mm air gap portion that was blocked from outside air by a spinning tube, and then solidified in a 25% by mass DMAc aqueous solution at 65 ° C. It was rolled up in a wet state. The nozzle slit width is 60 μm on average, 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 It was 1.2 × 10 ⁻³ sec. The draft ratio was 1.06. The linear velocities immediately after discharge were 17790 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.6. All the water used in the spinning process is prepared by adding calcium nitrate and magnesium nitrate to the RO water so that the calcium content is 0.04 ppm and the magnesium content is 0.04 ppm, and water that has passed through an ultrafiltration membrane is used. did. 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. Some of these manufacturing conditions are shown in Table 1.

  A polyethylene film is wound around the bundle of about 10,000 hollow fiber membranes, and then immersed and washed in a 30 vol% ethanol aqueous solution at 30 ° C. for 30 minutes × 3 times. After rinsing lightly with RO water and replacing ethanol with water, the solution was removed with a centrifugal separator for 600 rpm × 5 min. The obtained wet hollow fiber membrane bundle was dried for 3 hours at 65 ° C. and a flow rate of 0.3 L / sec in a ventilator having a flow path in the longitudinal direction, and then 20 ° C. and a flow rate of 0.05 L / sec. Let dry for hours. From the start of drying to the end of drying, drying was carried out by reversing the direction of ventilation by 180 degrees every 20 minutes for the first 3 hours and every hour for the next 20 hours. The moisture content of the hollow fiber membrane bundle before drying is 290% by mass, the moisture content of the hollow fiber membrane bundle after 3 hours of drying is 67% by mass, and the moisture content of the hollow fiber membrane bundle after drying is 2.4% by mass. there were. At this time, nitrogen gas was used as the ventilation medium. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 29 μm. The skin layer thickness was 0.7 μm.

  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 2.

(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. In addition, the hydrogen peroxide content in the raw material polyvinylpyrrolidone 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 that had been degassed in advance was discharged, passed through a 650 mm air gap portion that was blocked from the outside air by a spinning tube, and then solidified in a 15 mass% DMAc aqueous solution at 60 ° C. I whispered to the wall. 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, 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. The linear velocities immediately after discharge were 17790 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.6. All the water used in the spinning process is prepared by adding calcium nitrate and magnesium nitrate to the RO water so that the calcium content is 0.04 ppm and the magnesium content is 0.04 ppm, and water that has passed through an ultrafiltration membrane is used. did. Some of these manufacturing conditions are shown in Table 1.

  A polyethylene film is wound around the bundle of about 10,000 hollow fiber membranes, and then immersed and washed in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes × 2 times. After rinsing lightly with RO water to replace isopropanol with water, the solution was removed with a centrifugal separator for 600 rpm × 5 min. The obtained wet hollow fiber membrane bundle was set in a 48 × 2 stage on a rotary table in a drying apparatus provided with a microwave reflector in the apparatus so that it could be heated uniformly, and dried under the following conditions. Under a reduced pressure of 7 kPa, a microwave was irradiated with an output of 12 kW, and heat treatment was performed for 15 minutes. Subsequently, the microwave irradiation was stopped and the degree of vacuum was increased to 1 kPa and maintained for 3 minutes to evaporate water. Next, the degree of decompression was returned to 7 kPa, and microwaves were applied, and heat treatment was performed for 7 minutes at an output of 3.5 kW. After heating, microwave irradiation was stopped, the degree of vacuum was increased to 0.7 kPa, and maintained for 3 minutes. Furthermore, the degree of vacuum was returned to 7 kPa, microwave irradiation was resumed, the output was reheated at 2.5 kW for 6 minutes, microwave irradiation was stopped, the degree of vacuum was raised to 0.5 kPa, and drying was performed for 7 minutes. It was. The hollow fiber membrane bundle was further subjected to a water content homogenization treatment at 35 ° C. for 3 hours in an air dryer. The moisture content of the hollow fiber membrane bundle before microwave drying is 306% by mass, the moisture content after the first stage is 33% by mass, the moisture content after the second stage is 16% by mass, and the moisture content after the third stage is finished. The rate was 6% by mass, and the water content after completion of ventilation drying was 1.7% by mass. The highest temperature reached of the hollow fiber membrane bundle during the drying process was 54 ° C. 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.

  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 2.

  Moreover, the schematic diagram showing the relationship between the discharge linear velocity ratio obtained by the result of the said Example and comparative example and platelet retention is shown in FIG. From these figures, it can be understood that the limited range of the present invention is a critical range.

  The blood purifier of the present invention has a good balance of separation characteristics, high safety and stability of performance, and the hollow fiber membrane filled in the blood purifier of the present invention has an inner surface (blood contact side surface). The cationic dye adsorption rate, which is a measure of the state of charge and hydrophilicity-hydrophobicity balance, is optimized, and the platelet retention rate during blood perfusion is within a predetermined range, so that blood compatibility and blood contact are used. Performance retention is achieved at a high level. 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. It is a schematic diagram showing the relationship between a discharge linear velocity ratio and platelet retention.

Explanation of symbols

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

Claims (6)

Ri mainly Na than polysulfone-based polymer and polyvinyl pyrrolidone, open porosity 25 to 35% of the outer surface, the skin layer thickness 0.1 to 0.9 mu m, the content of the uppermost layer of the outer surface polyvinylpyrrolidone 25 -50% by mass, and (the content of polyvinyl pyrrolidone in the outermost surface outermost layer) / (content of the polyvinyl pyrrolidone in the outermost inner surface layer) ≧ 1.1. A blood purifier comprising: a blood purifier satisfying the following characteristics simultaneously:
(1) Albumin sieving coefficient after 15 minutes when bovine blood at 37 ° C. with hematocrit of 30%, total protein concentration of 6-7 g / dl, and sodium citrate is added at 200 ml / min and filtration flow rate of 20 ml / min [A] is 0.01 or more and 0.1 or less.
(2) The sieving coefficient [B] of albumin after 2 hours is 0.005 or more and less than 0.04.
(3) When heparinized human whole blood is perfused at a flow rate of 150 mL / min into a blood purifier having a membrane area of 1.5 m ² (inside of hollow fiber membrane inner diameter), the platelet retention after 60 minutes is 70% to 98%. The following.   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 [B] of albumin after 2 hours and the sieving coefficient [A] of albumin after 15 minutes satisfies the following formula.
[B] / [A] = 0.1 to 0.4 150m of heparinized human whole blood in a blood purifier with a membrane area of 1.5m ² (inside of hollow fiber membrane inner diameter)
The blood purification according to any one of claims 1 to 3, wherein the concentration ratio (PF4 increase rate) of platelet factor 4 before and after blood perfusion when perfused at a flow rate of L / min is 5 times or less. vessel.   After 5 minutes when 1000 mL of the solution containing the cationic dye was filled inside and outside the selectively permeable hollow fiber membrane of the blood purifier and the remaining cationic dye solution was perfused through the blood purifier at a flow rate of 200 mL / min. The blood purifier according to any one of claims 1 to 4, wherein the adsorption rate of the cationic dye is 40% or more and 70% or less.   The blood purifier according to any one of claims 1 to 5, wherein the selectively permeable hollow fiber membrane has a thickness of 25 to 50 µm.

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