JP4599934B2 - Hollow fiber membrane module - Google Patents

Description

  The present invention relates to a highly water-permeable hollow fiber membrane module for medical use that has high water permeability for use in the treatment of chronic renal failure, is small in size, and has high pressure-resistant durability with high reliability. .

  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.

  Blood purifiers that use hollow fiber membranes usually flow blood into the hollow space inside the hollow fiber, flow dialysate counter-currently to the outside, and transfer substances such as urea and creatinine by mass transfer based on diffusion from blood to dialysate. The main goal is to remove low molecular weight substances from the blood. Furthermore, with the increase in the number of long-term dialysis patients, dialysis complications have become a problem. In recent years, substances to be removed by dialysis are not only low molecular weight substances such as urea and creatinine, but also from medium molecular weights of several thousand to molecular weights of 1 to 20,000. It is required for blood purification membranes to expand to high molecular weight substances and to remove these substances. In particular, β2 microglobulin having a molecular weight of 11700 has been found to be a causative substance of carpal tunnel syndrome and is a removal target. In order to obtain a membrane used for the treatment of such high molecular weight substance removal, the pore diameter of the membrane is increased, the number of pores is increased, the porosity is increased, or the film thickness is increased as compared with the conventional dialysis membrane. It is preferable to reduce the thickness and increase the water permeability of the membrane.

  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.

  Blood purifiers that use hollow fiber membranes usually flow blood into the hollow space inside the hollow fiber, flow dialysate counter-currently to the outside, and transfer substances such as urea and creatinine by mass transfer based on diffusion from blood to dialysate. The main goal is to remove low molecular weight substances from the blood. Furthermore, with the increase in the number of long-term dialysis patients, dialysis complications have become a problem. In recent years, substances to be removed by dialysis are not only low molecular weight substances such as urea and creatinine, but also from medium molecular weights of several thousand to molecular weights of 1 to 20,000. It is required for blood purification membranes to expand to high molecular weight substances and to remove these substances. In particular, β2 microglobulin having a molecular weight of 11700 has been found to be a causative substance of carpal tunnel syndrome and is a removal target. In order to obtain a membrane used for the treatment of such high molecular weight substance removal, the pore diameter of the membrane is increased, the number of pores is increased, the porosity is increased, or the film thickness is increased as compared with the conventional dialysis membrane. It is preferable to reduce the thickness and increase the water permeability of the membrane.

  However, in order to increase the water permeability, as described above, improvements such as increasing the pore diameter of the membrane, increasing the number of pores, increasing the porosity, and reducing the film thickness are necessary. It is. When this improvement is made, the elution of the hydrophilic polymer increases, and the problems that the film strength is lowered arise. If elution of the hydrophilic polymer increases, the accumulation of the hydrophilic polymer, which is a foreign substance, in the human body during long-term dialysis increases, which may cause side effects and complications. In addition, the decrease in film strength leads to problems such as damage to the yarn during the manufacturing process, transportation process, and handling, breakage of the yarn, and blood leakage during treatment.

As means for suppressing blood leakage, a technique for further reducing the concentration of the organic solvent in the conventional aqueous solution containing an organic solvent and finding an appropriate range of the gas phase passage time after the nozzle discharge and the concentration of the core is disclosed. Yes. (For example, refer to Patent Document 1). That is, it is a method of forming a thin dense layer on the inner surface of the membrane while controlling water permeability. However, the formation state of the dense layer on the inner surface of the membrane significantly affects water permeability, making it difficult to narrow the range of water permeability.
JP 2000-107577 A

  Furthermore, increasing the pore diameter of the membrane, increasing the number of pores, or increasing the porosity increases the content of the hydrophilic polymer on the outer surface of the membrane, which allows dialysis. Endotoxin (endotoxin) contained in the solution is more likely to enter the blood side, leading to side effects such as fever, or hydrophilic polymers present on the outer surface of the membrane when the membrane is dried The hollow fiber membranes stick together (adhere) and cause problems such as deterioration in module assembly. In addition, when the hollow fiber itself is not crimped, the module assemblability deteriorates due to the displacement of the hollow fiber in the film in the manufacturing process.

Among the above-mentioned problems, with regard to the problem that endotoxin (endotoxin) enters the blood side, a method using the characteristic that endotoxin has a hydrophobic portion in its molecule and is easily adsorbed to hydrophobic materials. Is disclosed. (For example, refer to Patent Document 2). That is, it can be achieved by setting the ratio of the hydrophilic polymer to the hydrophobic polymer on the outer surface of the hollow fiber membrane to 5 to 25% by mass. Certainly, this method is a preferable method for suppressing the invasion of endotoxin into the blood side, but to impart this property, it is necessary to remove the hydrophilic polymer present on the outer surface of the membrane by washing. There is a problem that this cleaning requires a great deal 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 hydrophilic high molecular weight present on the outer surface of the membrane from the viewpoint of suppressing the invasion of endotoxin into the blood side. Therefore, when the dried hollow fiber membrane bundle is returned to a wet state, the familiarity with the physiological saline used for wetting becomes low. This is not preferable because it leads to the problem. As a method for improving this point, for example, a method of blending a hydrophilic compound such as glycerin is disclosed. (For example, refer to Patent Documents 3 and 4). However, if the method deviates from the proper concentration range, the hydrophilic compound acts as a foreign substance during dialysis, and the hydrophilic compound is susceptible to deterioration such as photodegradation, which adversely affects the storage stability of the module. Has the problem. In addition, there is also a problem of causing adhesive inhibition of the adhesive when the hollow fiber membrane bundle is fixed to the module in module assembly.
JP 2001-190934 A Japanese Patent No. 3193262

As a method for avoiding the sticking of the hollow fiber membranes, which is another problem described above, a method in which the porosity of the outer surface of the membrane is 25% or more is disclosed. (For example, refer to Patent Document 5). Certainly, this method is a preferable method for avoiding sticking, but has a problem that the membrane strength becomes low due to the high porosity and leads to the above-mentioned problem of blood leakage. Also disclosed is a method in which the porosity and area of the outer surface of the membrane are specified. (For example, refer to Patent Document 6). This method has a problem of low water permeability.
JP 2001-38170 A JP 2000-140589 A

Patent Document 7 discloses a technical requirement that, in a hydrophobic polymer hollow fiber membrane containing a hydrophilic polymer, elution of the hydrophilic polymer from the hollow fiber membrane is 10 ppm or less. However, in the prior art, no consideration is given to hemodiafiltration that requires higher pressure resistance and endotoxin exclusion compared to conventional hemodialysis. For example, there is no description regarding technical matters related to the content of polyvinylidyl pyrrolidone on the outer surface, burst pressure, open area ratio, average pore area, and in particular, technical matters related to important uneven thickness and burst pressure due to scratches are clearly indicated. There is no description.
JP 2001-170171 A

On the other hand, in recent years, the demand for hollow fiber membrane modules has also been diversified and sophisticated. For example, a small and high performance hollow fiber membrane module has been demanded due to demands for handling properties and transportation costs. In order to respond to these requirements, a technique relating to a blood treatment device that specifies the effective length of the hollow fiber membrane, the inner diameter of the hollow fiber membrane, the filling rate of the hollow fiber membrane, the bovine blood permeability coefficient and the pure water filtration coefficient has been disclosed (patent) Reference 8).
JP 2002-143298 A

In order to promote downsizing, it is necessary to reduce the diameter of the hollow fiber membrane and reduce the membrane thickness. Reducing the diameter of the hollow fiber membrane increases the pressure applied to the hollow fiber membrane during dialysis. On the other hand, reducing the membrane thickness leads to a decrease in pressure resistance of the hollow fiber membrane. Therefore, to meet the demand for miniaturization, it is necessary to improve the pressure resistance of the hollow fiber membrane. In particular, since the blood purifier is treated for a long time, not only the initial pressure resistance but also the pressure resistance reliability including the durability of the pressure resistance is required.
The technique disclosed in the above patent document is an effective method for promoting the miniaturization of the hollow fiber membrane module while maintaining high performance, but is another necessary characteristic required for miniaturization. No consideration is given to the reliability against pressure resistance.

  In order to reduce the size, the number of hollow fiber membranes focused in the module container is increased. However, when the number of hollow fiber membranes converging into the module container is increased, the membrane performance deteriorates due to a decrease in the effective membrane area due to the close contact between the hollow fiber membranes and the occurrence of drift, especially the permeation of small molecular weight substances such as urea. It is known to cause performance degradation. For this reason, various bulky processes are performed for the purpose of preventing adhesion and drift of the hollow fiber membranes. Among them, a method of directly bulking the hollow fiber is preferable in that the decrease in the effective area of the membrane is the least.

As a method of directly bulking the hollow fiber membrane, 3 or more and 10 or less hollow fibers after spinning, coagulation, water washing, glycerin treatment and drying are combined and wound on a bobbin at a crossing angle of 5 degrees or more. A method of applying crimp by heat-treating this at a temperature of 60 ° C. to 200 ° C. is disclosed. (For example, refer to Patent Document 9). In addition, a method of fixing a crimp by applying a crimp to a hollow fiber membrane in a non-dry state and then heat-treating the hollow fiber membrane to which the crimp has been applied in a non-dry state (see, for example, Patent Document 10) is proposed. However, in any case, after winding around a bobbin or the like to impart a crimp, heat treatment is performed at a temperature of 50 ° C. or more to fix the crimp. In such a method, the crimp cannot be fixed while the hollow fiber is running, and at the same time, the wavelength and amplitude of the crimp strongly correlate with the thermal characteristics of the hollow fiber and can hardly be controlled. Is as small as 0.15 mm or less and the wavelength is 10 mm or less. Furthermore, since the crimp is fixed by heat treatment, there is a problem that a hydrophilic polymer such as polyvinylpyrrolidone is decomposed and the amount of elution of PVP is increased.
Japanese Patent Publication No. 4-42022 JP-A-8-010322

Further, a method using a gear (for example, see Patent Document 11) has been proposed as a means for applying crimp at room temperature, but it is effective as a method for applying crimp to a film having a large film thickness and high yarn strength. However, when it is applied to a membrane having a thin film thickness and low yarn strength, the yarn is crushed, not only in terms of quality, but also cannot exhibit the performance as a hollow fiber membrane.
Japanese Patent Laid-Open No. 9-021024

As a method for solving the above-described problem, a method is disclosed in which a plurality of continuously supplied hollow fiber membrane rows are meandered between yarn guides that travel at regular intervals to provide crimp (patent). Reference 12). In this method, the hollow fiber membrane is separated by a separating plate in the crimping step, and crimping is applied. Therefore, there is a possibility that the hollow fiber membrane bundle is damaged by rubbing with the separating plate, and the reliability of the pressure resistance of the hollow fiber membrane is lowered. In this method, crimping is performed on the dried hollow fiber membrane. Dry hollow fiber membranes are prone to static electricity due to contact with members during running, increasing the entanglement of the hollow fiber membranes due to static electricity, and increasing the occurrence of scratches with the separating plate and between the hollow fiber membranes. And, it has the subject that it leads to the reliability fall of the pressure resistance of a hollow fiber membrane.
JP 2003-275549 A

  For example, the technique disclosed in Patent Document 8 described above lacks consideration regarding this drift countermeasure.

  The present invention is a highly water-permeable hollow fiber membrane module for medical use that has high water permeability used for the treatment of chronic renal failure, and is small in size and excellent in permeation performance of small molecular weight substances, and is highly reliable in pressure resistance. Is to provide.

The present invention provides a dense layer on the inner surface side having an inner diameter of 190 to 250 μm, a film thickness of 10 to 60 μm, a thickness deviation of 0.6 or more, and a crimp having a wavelength of 10 mm or more and an amplitude of 0.2 mm or more. A hollow fiber membrane module in which a hollow fiber membrane having an asymmetric structure with a burst pressure of 0.5 to 2.0 MPa and a water permeability of 150 to 2000 ml / m ² / hr / mmHg is characterized. This is a hollow fiber membrane module.

  The hollow fiber membrane module of the present invention has high water permeability, is small in size and has high pressure resistance, and is highly reliable for treatment of chronic renal failure. It is suitable as a medical hollow fiber blood purifier having performance.

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。 The hollow fiber membrane used in the hollow fiber membrane module of the present invention is characterized in that it is composed of a hydrophobic polymer containing a hydrophilic polymer. Examples of the hydrophobic polymer material in the present invention include cellulose such as regenerated cellulose, cellulose acetate, and cellulose triacetate, polysulfone such as polysulfone and polyethersulfone, polyacrylonitrile, polymethyl methacrylate, and ethylene vinyl alcohol copolymer. However, it is preferable to use a cellulose or polysulfone type that can easily obtain a hollow fiber having a water permeability of 150 mL / m ² / hr / mmHg or more, and it is easy to reduce the film thickness. And cellulose triacetate are preferred. Polysulfone is particularly preferable. Polysulfone 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 hydrophilic polymer used in the present invention is not particularly limited, and a polymer that forms a micro phase separation structure in a solution with a polysulfone polymer is preferably used. Polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose, polyvinyl pyrrolidone and the like can be mentioned, but it is a preferred embodiment that polyvinyl pyrrolidone is used from the viewpoint of safety and economy. Polyvinyl pyrrolidone is a water-soluble polymer compound obtained by vinyl polymerization of N-vinyl pyrrolidone. For example, trade names of “Collidon” from BASF, “Prasdon” from ISP, and “Pittscall” from Daiichi Kogyo Seiyaku. There are products of various molecular weights. In general, it is preferable to use a low molecular weight in terms of hydrophilicity imparting efficiency, while it is preferable to use a high molecular weight from the viewpoint of lowering the elution amount. Selected. Those having a single molecular weight may be used, or two or more products having different molecular weights may be mixed and used. Moreover, you may use what refine | purified a commercial product and sharpened molecular weight distribution, for example. As the molecular weight of polyvinylpyrrolidone, those having a mass average molecular weight of 10,000 to 1,500,000 can be used. Specifically, for example, those having a molecular weight of 9,000 (K17) commercially available from BASF, and the same below, 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, they may be used alone or in combination of two or more. In the present invention, it is most preferable to use K90 alone.

The hollow fiber membrane used in the hollow fiber membrane module of the present invention has an inner diameter of 190 to 250 μm, a membrane thickness of 10 to 60 μm, a thickness deviation of 0.6 or more, a wavelength of 10 mm or more, and an amplitude of 0.2 mm or more. An asymmetric structure having a dense layer on the provided inner surface side is preferred. The hollow fiber membrane module of the present invention is a hollow fiber membrane module characterized by a burst pressure of 0.5 to 2.0 MPa and a water permeability of 150 to 2000 ml / m ² / hr / mmHg.

  The hollow fiber membrane of the present invention preferably has an inner diameter of 190 to 250 μm. The inner diameter is more preferably 193 to 240 μm, further preferably 196 to 230 μm. If the inner diameter is less than 190 μm, the pressure applied to the hollow fiber membrane during dialysis treatment increases, leading to a decrease in the pressure resistance of the hollow fiber membrane, and the burst pressure, which is a reliable pressure resistance, may be reduced. On the other hand, if it exceeds 250 μm, the pressure loss and shear rate of the blood flowing through the hollow portion will decrease and the permeability of blood waste will decrease, or the adhesion and deposition of blood components on the membrane surface will increase. Blood compatibility is reduced. Furthermore, the size of the blood purifier may become large, and it may not be possible to meet the demand for downsizing the blood purifier.

Moreover, it is preferable that film | membrane thickness is 10-60 micrometers. The film thickness is more preferably 15 to 55 μm, further preferably 20 to 50 μm. If the membrane thickness is less than 10 μm, the pressure resistance of the hollow fiber membrane is lowered, leading to a reduction in burst pressure which is the reliability of pressure resistance, which is not preferable. On the other hand, when the membrane thickness exceeds 60 μm, the size of the hollow fiber membrane module increases, which may cause problems such as an increase in transportation cost and a decrease in handling properties. If it exceeds 60 μm, even if the water permeability is high, it leads to a problem that the permeability of the medium to high molecular weight substance with a low moving speed is lowered.
From the viewpoint of miniaturization, the inner diameter is preferably as small as possible. However, when the inner diameter is reduced, the pressure applied to the hollow fiber membrane during dialysis treatment increases, and it becomes necessary to impart strong pressure resistance to the hollow fiber membrane. Although there is a method of increasing the film thickness as a method of increasing the pressure resistance, this method is not preferable because it goes against the downsizing. Rather, it has been found that the film thickness for imparting pressure resistance can be reduced by slightly increasing the inner diameter, and the present invention has been completed by finding the optimum range of the above range.

The hollow fiber membrane used in the hollow fiber membrane module of the present invention preferably has a thickness deviation of 0.6 or more. The thickness deviation in the present invention is a film thickness deviation of observing a 100 hollow fiber membrane cross-section of the hollow fiber membrane module, indicated by the ratio of the minimum and maximum values. In the present invention, the minimum thickness deviation of 100 hollow fiber membranes is 0.6 or more. If even one hollow fiber membrane includes a hollow fiber membrane with a thickness deviation of less than 0.6, the hollow fiber may cause a leak during clinical use. It represents not the average value but the minimum value of 100 lines. Higher unevenness increases the uniformity of the hollow fiber membrane, suppresses the appearance of latent defects and improves the burst pressure, more preferably 0.7 or more, more preferably 0.8 or more, even more Preferably it is 0.85 or more. If the uneven thickness is too low, latent defects are likely to be manifested, the burst pressure is lowered, and blood leakage is liable to occur.

  Means for achieving the thickness deviation of 0.6 or more are not limited. For example, it is preferable to make the slit width of the nozzle, which is the discharge hole for the spinning solution, strictly uniform. The spinning nozzle of the hollow fiber membrane is generally a tube-in-orifice type nozzle having an annular portion for discharging the spinning solution and a core liquid discharge hole serving as a hollow forming agent inside thereof. It refers to the width of the outer annular portion that discharges the spinning solution. By reducing the variation in the slit width, uneven thickness of the spun hollow fiber membrane can be reduced. Specifically, the ratio between the maximum value and the minimum value of the slit width is 1.00 or more and 1.11 or less, and the difference between the maximum value and the minimum value is preferably 10 μm or less, more preferably 7 μm or less, More preferably, it is 5 micrometers or less, More preferably, it is 3 micrometers or less. It is also preferable to optimize the nozzle temperature. The nozzle temperature is preferably 20 to 100 ° C. If it is less than 20 ° C., it is easily affected by the room temperature, the nozzle temperature is not stable, and the discharge spots of the spinning solution may occur. Therefore, the nozzle temperature is more preferably 30 ° C. or higher, further preferably 35 ° C. or higher, and further preferably 40 ° C. or higher. On the other hand, if the nozzle temperature exceeds 100 ° C., the viscosity of the spinning solution may be too low and ejection may become unstable, and thermal degradation / decomposition of the hydrophilic polymer may proceed. Therefore, the nozzle temperature is more preferably 90 ° C. or less, further preferably 80 ° C. or less, and still more preferably 70 ° C. or less.

  The hollow fiber membrane used in the hollow fiber membrane module of the present invention preferably has a burst pressure of 0.5 MPa or more. The burst pressure of the hollow fiber membrane is an index of the pressure resistance performance of the hollow fiber membrane after being assembled into a module using the hollow fiber membrane as a blood purifier. The inside of the hollow fiber membrane is pressurized with gas, and the pressure is gradually increased. The pressure when the hollow fiber burst without being able to withstand the internal pressure. The higher the burst pressure, the less the hollow fiber membrane is cut and the occurrence of pinholes during use, so 0.5 MPa or more is preferred, 0.55 MPa or more is more preferred, and 0.6 MPa or more is even more preferred. If the burst pressure is less than 0.5 MPa, there may be a potential defect. The higher the burst pressure, the better. However, if the focus is on increasing the burst pressure and the film thickness is too high 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 safety of hollow fiber membranes in long-term dialysis cannot be sufficiently proved by blood leak characteristics governed by macro characteristics such as conventionally known membrane strength. That is, as a result of examining the physical properties of hollow fiber membranes used in blood purifiers, the hollow fiber membranes usually used for blood purification are confirmed to be defective in the hollow fiber membranes and blood purifiers at the final stage of production. Therefore, 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, microscopic scratches, crushing, and tears in the hollow fiber membrane that cannot be detected by a normal pressure leak test are the manufacturing process (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 hollow fiber membrane of the present invention preferably has a water permeability of 150 ml / m ² / hr / mmHg or more. If the water permeability is less than 150 ml / m ² / hr / mmHg, dialysis efficiency may be insufficient. In order to increase the dialysis efficiency, the pore diameter is increased or the number of pores is increased. However, this tends to cause a problem that the membrane strength is reduced or defects are formed. Therefore, it is preferable that the porosity of the support layer portion is optimized by optimizing the pore diameter of the outer surface, and the solute permeation resistance and membrane strength are balanced. A more preferable range of water permeability is 200 ml / m ² / hr / mmHg or more, more preferably 300 ml / m ² / hr / mmHg or more, particularly preferably 400 ml / m ² / hr / mmHg or more, most preferably 500 ml / m ^2. / Hr / mmHg or more. In addition, when the water permeability is too high, it becomes difficult to control water removal during hemodialysis, and therefore, 2000 ml / m ² / hr / mmHg or less is preferable. More preferably 1800 ml / m ² / hr / mmHg or less, further preferably 1500 ml / m ² / hr / mmHg or less, even more preferably 1300 ml / m ² / hr / mmHg or less, particularly preferably 1000 ml / m ² / hr / h / g. It is below mmHg.

  In the present invention, the thickness of the dense layer of the hollow fiber membrane is preferably 0.1 to 3 μm. The thinner the dense layer, the better the water permeability and solute permeability. However, defects in the hollow fiber membrane are likely to become obvious, which is disadvantageous in terms of manufacturing cost, such as the need to control manufacturing conditions severely. Sometimes. Therefore, the thickness of the dense layer is more preferably 0.15 μm or more, further preferably 0.2 μm or more, and further preferably 0.25 μm or more. On the other hand, if the thickness of the dense layer is too thick, the solute permeability may decrease or the fractionation characteristics may decrease. Therefore, the thickness of the dense layer is more preferably 2.5 μm or less, further preferably 2.0 μm or less, and further preferably 1.5 μm or less.

  In the present invention, the method for imparting the above-mentioned high water permeability to the hollow fiber membrane is not limited, but it is an asymmetric structure having a dense layer on the inner surface side and a structure in which the pore diameter increases toward the outer surface. Is an effective and preferred embodiment.

  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 hollow fiber membranes. That is, in the hollow fiber membrane of the present invention, the film thickness and the dense 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.

  Further, as a measure for increasing the burst pressure, it is also an effective method to reduce the potential defects by reducing the flaws on the surface of the hollow fiber membrane, the mixing of foreign matter and bubbles. As a method of reducing the occurrence of scratches, the material and surface roughness of rollers and guides in the manufacturing process of the hollow fiber membrane are optimized, the container and the hollow fiber membrane are inserted when the hollow fiber membrane bundle is inserted into the module container at the time of module assembly. It is effective to devise such that contact with the fiber or rubbing between the hollow fiber membranes is reduced. In the present invention, it is preferable to use a roller having a mirror-finished surface in order to prevent the hollow fiber membrane from slipping and scratching the surface of the hollow fiber membrane. Further, it is preferable to use a guide whose surface is textured or knurled in order to avoid contact resistance with the hollow fiber membrane as much as possible.

  In addition, an anti-scratch measure in the step of applying a crimp described later is also important. The first measure is to suppress the generation of static electricity due to the running of the hollow fiber membrane and to prevent the hollow fiber membranes from excessively rubbing by applying crimp to the wet hollow fiber membrane before drying. . The second method eliminates the splitting work in the crimping process, eliminates the generation of scratches with the splitting plate, and eliminates frictional charging with the splitting plate between the hollow fiber membranes due to static electricity. It is to suppress the occurrence of scratches. That is, a single yarn is used for spinning, coagulation, and water washing processes, and 3 to 10 single yarns are combined after the water washing process from the second half of the water washing process, and then continuously supplied to the crimping process to provide a crimp. It is preferably made of a thread membrane. This method solves the above-mentioned problems and enables efficient crimping by means of combined yarn. If the yarn is combined before the first half of the water washing step, it is not preferable because it leads to occurrence of sticking between the hollow fiber membranes.

In the present invention, as described above, it is preferable to apply crimp to the wet state hollow fiber membrane before drying, but the method is compared to the method of applying crimp to the dry state hollow fiber membrane. Crimp expression is slow. In order to avoid this problem, in the present invention, the breaking strength of the hollow fiber membrane is preferably 50 g / filament or less and the yield strength is preferably 30 g / filament or less. By this, it is possible to efficiently apply the crimp only by passing the process of partially giving deformation beyond the yield elongation of the hollow fiber membrane in the state of applying the crimp, and heat setting for immobilizing the crimp No processing is required.
When the breaking strength exceeds 50 g / filament and the yield strength exceeds 30 g / filament, the effect of adding the above characteristics decreases, and the polymer density in the hollow fiber membrane increases, so it may be difficult to increase the water permeability. . On the other hand, when the breaking strength and the yield strength are too low, there is a problem that the assembling property of the module is lowered. In addition, the burst pressure is reduced, and blood leakage may occur when using hemodialysis. Therefore, the breaking strength is preferably 15 g / filament or higher, and the yield strength is preferably 10 g / filament or higher, more preferably the breaking strength is 20 g / filament or higher, and the yield strength is 12 g / filament or higher.

  When the hollow fiber membrane bundle is inserted into the module container, the hollow fiber membrane bundle is not directly inserted into the module container, but a film whose contact surface with the hollow fiber membrane is processed with a satin finish, for example, is wound around the hollow fiber membrane bundle. It is preferable to use a method in which only the film is removed from the module container after being inserted into the module container. By this method, the workability of inserting into the module container can be improved, the occurrence of scratches on the hollow fiber membrane during the insertion is suppressed, and the burst pressure, which is a measure of the reliability of the pressure resistance of the hollow fiber membrane, is improved. The effect is expressed.

  In addition, as a measure for increasing the burst pressure, it is a preferable embodiment to suppress the mixing of foreign matters into the hollow fiber membrane. Specifically, a method of reducing foreign matters by filtering a spinning solution for spinning using a raw material with few foreign matters is effective. In the present invention, it is preferable to filter the spinning solution using a filter having a pore size smaller than the film thickness of the hollow fiber membrane. Specifically, the pore size provided while guiding the uniformly dissolved spinning solution from the dissolution tank to the nozzle. Pass through a 10-50 μm sintered filter. The filtration process may be performed at least once, but it is also a preferred embodiment that the filtration process is performed in several stages. The pore diameter of the filter is more preferably 10 to 45 μm, further preferably 10 to 40 μm, and still more preferably 10 to 35 μm. If the filter pore size is too small, the back pressure may increase and the quantitativeness may decrease. Further, as a method for suppressing the mixing of bubbles, it is effective to defoam a polymer solution for spinning. Depending on the viscosity of the spinning solution, static defoaming or vacuum defoaming can be used. Specifically, the inside of the dissolution tank is depressurized to −100 to −750 mmHg, and then the inside of the tank is sealed and allowed to stand for 5 to 30 minutes. This operation is repeated several times to perform defoaming treatment. If the degree of vacuum is too low, the treatment may take a long time because it is necessary to increase the number of defoaming times. On the other hand, when the degree of vacuum is too high, the cost for increasing the degree of sealing of the system may increase. The total treatment time is preferably 5 minutes to 5 hours. If the treatment time is too long, the hydrophilic polymer may be decomposed and deteriorated due to the effect of reduced pressure. If the treatment time is too short, the defoaming effect may be insufficient.

In addition, this is a preferred embodiment in improving the burst pressure, in which the spinning solution is filtered through a filter having a filtration accuracy of 25 μm or less. A filter having a filtration accuracy of 20 μm or less is more preferable, and a filter having a filtration accuracy of 15 μm or less is more preferable. Specifically, it is preferable to pass through a filter provided while the uniformly dissolved spinning solution is guided from the dissolution tank to the nozzle. The filtration process may be performed at least once, but it is preferable to divide the filtration process into several stages from the viewpoint of extending the filtration efficiency and the filter life. The filtration accuracy of the filter is measured according to JIS B8356: 1976, and the maximum glass bead particle size that has passed through the filter media is defined as filtration accuracy (μm). The material and structure of the filter are not limited as long as the filtration accuracy is satisfied. A wire mesh filter is generally used as a filter. Filtration capacity and miniaturization efficiency are improved by changing the shape of the weave such as plain weave, twill weave, plain tatami mat, twill tatami weave, the thickness of the line used and the laminated structure. It will change. Apart from these wire mesh filters, there is a type called a metal sintered filter, and there are two types, one that is powder sintered and one that is hardened without weaving metal like a nonwoven fabric. In particular, non-woven fabrics that have been hardened without weaving them are made by uniformly laminating and sintering micron-order stainless steel fibers. In addition to having high filtration accuracy, the porosity is higher than other metal filter media, so that the pressure loss is small and the foreign matter holding ability is higher than that of a wire mesh or metal powder sintered filter, which is preferable. Some wire mesh filters have improved performances that are equal to or better than improved weaving and lamination methods. The selection point is to select a filter with a low pressure loss and a high filtration capacity. The optimization of the filtration filter improves the uniformity of phase separation between the polysulfone-based polymer and the polyvinylpyrrolidone in the hollow fiber membrane as well as the suppression of foreign matter contamination due to the filtration effect. The uniformity of phase separation in the membrane is determined by microscopic observation of the outer surface of the hollow fiber membrane shown below.
[Uniformity of phase separation in hollow fiber membrane]
The measurement was evaluated using a real surface view microscope VE-7800 (manufactured by Keyence Corporation). Hollow fiber membranes were arranged on a sample stage at a pitch of 3 mm and fixed with double-sided tape, and a total length of 1 m was confirmed while scanning for the presence or absence of foreign matter at a magnification of 200 times. In addition, the void was observed by obliquely cutting the hollow fiber membrane with a razor, fixing the sample surface with double-sided tape so that the cut surface faces upward, and observing 30 fields of view at a magnification of 300 times to confirm the presence or absence of voids. .

  The uniformity of phase separation is improved by the above method when the spinning solution is filtered through a specified filter, and the effect of dispersing the poorly dispersed portion of polyvinylpyrrolidone present in the spinning solution by passing through the filter. It is assumed that this is caused by the removal of the defective part.

  By adopting the above method, the uniformity of the phase separation between the polysulfone polymer constituting the hollow fiber membrane and the polyvinylpyrrolidone is improved, and the phase separation in the membrane can be achieved even if the film thickness and dense layer are very thin. The formation of the defect part of the film strength reduction due to the non-uniformity is suppressed and the burst pressure is improved.

  It is also important to optimize the nozzle temperature. The nozzle temperature is preferably 20 to 90 ° C. If it is less than 20 ° C., it is easily affected by the room temperature, the nozzle temperature is not stable, and the discharge stock of the spinning stock solution may occur. Therefore, the nozzle temperature is more preferably 30 ° C. or higher, further preferably 35 ° C. or higher, and further preferably 40 ° C. or higher. On the other hand, if the temperature exceeds 90 ° C., the viscosity of the spinning dope may be too low and ejection may become unstable, and polyvinylpyrrolidone may be thermally deteriorated or decomposed. Therefore, the nozzle temperature is more preferably 85 ° C. or less, and further preferably 80 ° C. or less.

  It is also a preferred embodiment that the spinning dope has a viscosity of 2000 to 6000 cps. 3000-5000 cps is more preferable. By setting the viscosity range, the stirring efficiency of the undiluted solution is improved, so that the effects such as uniform phase separation, reduction of discharge spots from the nozzle and ease of defoaming are expressed, and the burst pressure is improved. Connected.

The hollow fiber membrane module in the present invention is preferably loaded in a module container with a filling rate of the hollow fiber membrane of 40 to 60% by volume. If the filling rate of the hollow fiber membrane is too small, useless space volume in the module is increased, the diameter of the container is increased, and this is unfavorable for downsizing. In addition, the dialysis fluid drifts and leads to a decrease in dialysis efficiency. Therefore, the filling rate is more preferably 43% by volume or more, and further preferably 45% by volume or more. On the other hand, if the filling rate of the hollow fiber membrane is too high, the workability of loading into the container is lowered, and the burst pressure is reduced due to scratches on the hollow fiber membrane due to friction between the container and the hollow fiber membrane during the loading operation. This is not preferable because it leads to blood leakage. Further, in the bonding step of fixing the hollow fiber membrane in the container, the permeability of the adhesive into the space between the hollow fiber membranes is reduced, which leads to an increase in the number of defective adhesion points. Therefore, the filling rate is more preferably 58% by volume or less, and further preferably 55% by volume or less. In addition, this filling rate is calculated | required with the sum total of the cross-sectional area of the outer diameter reference | standard of the hollow fiber membrane with respect to the cross-sectional area of a module container.
The filling rate is preferably as high as possible from the viewpoint of miniaturization of the blood purifier, which is one of the objects of the present invention, but the above range is preferable in terms of the balance with the point of improving the reliability of pressure resistance.

  In the present invention, the filling rate of the hollow fiber membrane is set in a relatively low range as described above. If the filling rate is within this range, the dialysate drifts and the dialysis efficiency is liable to be reduced. Examples of the drift prevention measure include a method of inserting a spacer together with the hollow fiber membrane, a method of imparting crimp to the hollow fiber membrane, and the like. The former method is not preferable because it increases the filling volume and goes against miniaturization. Therefore, the latter is preferable.

  The hollow fiber membrane used in the hollow fiber membrane module of the present invention is preferably provided with a crimp having a wavelength of 10 mm or more and an amplitude of 0.2 mm or more. When the crimp of the hollow fiber membrane is 10 mm or less and the amplitude is 0.2 mm or less, the module assembly process deteriorates due to the displacement of the hollow fiber membrane in the film in the module assembly process, the hollow fiber membranes adhere to each other, and the dialysate drifts This may cause a decrease in permeation performance of small molecular weight substances such as urea. On the other hand, if the crimp wavelength and amplitude become too high, the resistance when inserting the bundle of hollow fiber membranes into the module case becomes too large in the module assembly process, resulting in damage to the hollow fiber membrane surface and leakage. End up. Accordingly, the crimp preferably has a wavelength of 50 mm or less and an amplitude of 5 mm or less, more preferably a wavelength of 40 mm or less and an amplitude of 4 mm or less.

  Examples of the method of applying crimp in the present invention include (1) a method of passing between a plurality of cylindrical bodies having a certain clearance or pulleys with rollers, and (2) a plurality of cylindrical bodies having a certain clearance. Or a method of passing between a timing belt or chain with a roller, (3) a method of passing between a plurality of timing belts having a certain clearance, and (4) a plurality of surfaces having a certain clearance. There is a method of passing between the belts with irregularities. In any case, the method according to the present invention must be capable of being deformed by partial stretching intermittently in a part of one side in the circumferential direction of the hollow fiber membrane and in the length direction.

  The size of the crimp of the hollow fiber membrane obtained according to the present invention and the number of crimps per unit length are the cylinder for use in applying the crimp, the diameter of the cylinder such as a roller or a timing belt with a convex part, or the distance between the rollers. Or it can change freely by changing the shape of a convex part, a cylindrical body, a roller, or the meshing depth of a convex part. (See FIGS. 1 and 2).

  The crimping is preferably performed after the hollow fiber membrane structure is substantially fixed. The state in which the hollow fiber membrane structure is substantially fixed refers to a state in which the spinning solution is discharged from a nozzle, solidified in a coagulation bath, and the hollow fiber membrane structure is not physically changed after a water washing step. Therefore, it is preferable to carry out after the yarns are combined after the water washing step.

  The hollow fiber membrane that has passed through the washing bath needs to have a burst pressure within a specific range in order to ensure the reliability of pressure resistance as described above. For this purpose, the hollow fiber membrane can be damaged. It is necessary to reduce as much as possible. Therefore, in order to prevent the hollow fibers from excessively rubbing with each other even in the step of applying the crimp described above, in the step of applying the crimp to the hollow fiber membrane, a plurality of hollow fiber membrane rows continuously supplied In a hollow fiber membrane that is provided with crimps by meandering between yarn guides that run at a constant interval, it is preferable that a plurality of hollow fiber membrane rows between the yarn guides are run while being divided in the width direction. . The crimping method will be described in detail. The yarn guide is a guide that conveys the hollow fiber membrane while undulating it. The crimp means a waveform shape with respect to a straight line. The width direction means a direction perpendicular to the advancing direction of the hollow fiber membrane, and the division means a state in which a plurality of hollow fiber membranes are divided every predetermined number. Meander means a state of moving while maintaining the waveform shape, and traveling means a state of moving the yarn guide or the hollow fiber membrane. If a plurality of hollow fiber membrane rows between the yarn guides are divided in the width direction and run to be crimped, the hollow fiber membrane rows that are not divided meander between the yarn guides that run at regular intervals. Even if crimping is performed, the module assembly property is deteriorated in the manufacturing process due to the displacement of the hollow fiber in the film in the manufacturing process. In the prior art, the division is performed by performing a fiber separation process in the crimping step. This method has the problems as described above. In the present invention, as described above, the single yarn that has been spun before being supplied to the crimping step is combined and then supplied to the crimping step in units of the combined yarn to avoid this problem.

  After the hollow fiber membrane structure is fixed, a specific example for giving a partial deformation is that the yarn travels between the two belts having convex portions fixed on the timing belt while the belt runs. It is obtained by passing. At this time, the shape of the convex portion is preferably a semicircular shape or a parabolic shape at a portion where the yarn contacts, and in the case of a square shape, the hollow fiber is often damaged, such as deformed or blocked. A roller holding a circular roller or a pin may be used instead of the convex portion, and a roller that rotates freely is more preferable because unnecessary stretching of the yarn at the entrance can be prevented. When used with non-rotating teeth or the like, it is desirable to reduce the frictional resistance by using a material with less friction between the surface of the teeth and the yarn or surface treatment.

  In the method according to the present invention, the hollow fiber membrane is crimped because the yarn sandwiched between the upper and lower two sets of convex portions or cylindrical bodies is formed on the surface of the circular or parabolic convex portions or cylindrical bodies. By being pressed along, the hollow fiber membrane of the outer part on the circumference requires a longer distance from the surface of the hollow fiber on the side in contact with the convex part or the cylinder. Therefore, the radius of the semicircular convex part or cylindrical body is sufficient to give a deformation exceeding the yield elongation on the side opposite to the contact side when the hollow fiber membrane is pressed along the convex part or cylinder. If the diameter is smaller than necessary, the hollow fiber is damaged such as flattening, deforming, or blocking. Therefore, it is desirable to have a diameter that can give deformation of 2 to 9 times the yield elongation. Furthermore, it is more desirable for the diameter to be able to give a deformation of 3 to 8 times the yield elongation in order to reduce flattening, deforming or blocking, and to obtain sufficient crimp fixation.

  In applying the crimp in the present invention, in order to prevent the hollow fiber from being flattened, deformed, or blocked, the hollow fiber may be treated in the presence of the hollow forming material substantially enclosed. In this case, it is more desirable that the hollow forming material is liquid at the temperature of the crimping process.

The hollow fiber membrane to which the crimp is applied is wound into a cocoon in a wet state to form a bundle of 3,000 to 20,000. Next, the obtained hollow fiber membrane bundle is washed to remove excess solvent and hydrophilic polymer. As a method for washing the hollow fiber membrane bundle, in the present invention, it is preferable to treat the hollow fiber membrane bundle by immersing it in hot water at 70 to 130 ° C. or 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 bundle is immersed in excess water and treated at 70 to 90 ° C. for 15 to 60 minutes, and then the hollow fiber membrane bundle is taken out and subjected to centrifugal dehydration. This operation is repeated three or four times while renewing the water to perform the cleaning process.
(2) A method of treating a hollow fiber membrane bundle immersed in excess 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 preferable that the hollow fiber membrane bundle is radially arranged in the centrifugal washer, and the centrifugal washing is performed for 30 minutes to 5 hours as a total time while spraying washing water at 40 ° C. to 90 ° C. from the rotation center in a shower shape. Is the method.
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, when the treatment temperature is too high, the decomposition of the hydrophilic polymer is accelerated, and conversely, the cleaning efficiency may be lowered. By performing the above washing, it is possible to optimize the content of the hydrophilic polymer on the outer surface, to suppress sticking and to reduce the amount of eluate.

  The hollow fiber membrane of the present invention preferably has a porosity of 60 to 80%. If the porosity is less than 60%, the water permeability may be low. Therefore, the porosity is more preferably 63% or more, and further preferably 65% or more. On the other hand, when it exceeds 80%, the strength of the hollow fiber membrane is lowered, which may lead to a decrease in burst pressure or the like. Therefore, the porosity is more preferably 77% or less, and further preferably 75% or less.

In the present invention, the hole area ratio of the outer surface of the hollow fiber membrane is 8 to 25%, and the average hole area of the hole portion on the outer surface of the hollow fiber membrane is 0.3 to 1.0 μm ² . This is effective for imparting the above-mentioned characteristics and is a preferred embodiment. If the open area ratio is less than 8% or the average pore area is less than 0.3 μm ² , the water permeability may decrease. Therefore, the open area ratio is more preferably 9% or more, and further preferably 10% or more. The average pore area is more preferably 0.4 μm ² or more, further preferably 0.5 μm ² or more, and further preferably 0.6 μm ² or more. Further, when the membrane is dried, the hydrophilic polymer existing on the outer surface of the membrane is interposed, and the hollow fiber membranes are fixed to each other, causing problems such as deterioration in module assemblability. On the contrary, when the open area ratio exceeds 25% or the average pore area exceeds 1.0 μm ² , the burst pressure may decrease. Therefore, the porosity is more preferably 23% or less, further preferably 20% or less, still more preferably 17% or less, and particularly preferably 15% or less. The average pore area is more preferably 0.95 .mu.m ² or less, more preferably 0.90 .mu.m ² or less.

  The method for imparting the above properties is not limited, but it is preferably achieved by optimizing the following various requirements. Specifically, it is possible to impart a preferable porosity to the hollow fiber membrane by appropriately controlling the three conditions of the spinning solution composition, the air gap condition, and the coagulation condition.

  As the spinning dope, it is preferable to use a polysulfone-based polymer and a hydrophilic polymer, a solvent, and, if necessary, a non-solvent three to four-component spinning dope. In order to set the void ratio of the hollow fiber membrane to 60 to 80%, a spinning stock solution having a combined content of polysulfone polymer + hydrophilic polymer as polymer components of 10.5 to 37.5% by mass is used. Is preferred.

  The absolute humidity inside the air gap is preferably controlled with 0.01 to 0.3 kg / kg dry air. In order to control the humidity inside the air gap, it is a preferred embodiment that the hollow fiber membrane passage portion is surrounded by a member for blocking the outside air. The humidity inside the air gap is preferably adjusted by the spinning solution composition, nozzle temperature, air gap length, external coagulating liquid temperature, and composition. For example, a spinning solution composed of polyethersulfone / polyvinylpyrrolidone / dimethylacetamide / RO water = 10-25 / 0.5-12.5 / 52.5-89.5 / 0-10.0 It becomes easy to set to the said range by discharging from a nozzle, passing an air gap of 100-1000 mm, and using the external coagulation liquid of density | concentration 0-70 mass% and temperature 50-80 degreeC. It is also an embodiment of the present invention to devise a device that can forcibly humidify or dehumidify. By adjusting to such a range, it becomes possible to control the outer surface porosity, the outer surface average pore area, and the outer surface hydrophilic polymer content to an appropriate range, and consequently the porosity of the hollow fiber membrane. A desired range can be set.

  As the internal coagulation liquid, a 0 to 80% by mass dimethylacetamide (DMAc) aqueous solution is preferable. If the concentration of the internal coagulation solution is too low, the dense layer on the blood contact surface becomes thick, which may reduce the solute permeability. A more preferable internal coagulation liquid concentration is 15% by mass or more, further preferably 25% by mass or more, and still more preferably 30% by mass or more. On the other hand, if the concentration of the internal coagulating liquid is too high, the formation of the dense layer tends to be incomplete, and the fractionation characteristics may deteriorate. The concentration of the internal coagulation liquid is more preferably 70% by mass or less, further preferably 60% by mass or less, and still more preferably 50% by mass or less.

  The external coagulation liquid is preferably a 0 to 50% by weight DMAc aqueous solution. If the concentration of the external coagulation liquid is too high, the outer surface open area ratio and the outer surface average pore area will be too large, and the void ratio of the hollow fiber membrane will increase. There is also a possibility that the burst pressure will decrease. Therefore, the external coagulation liquid concentration is more preferably 40% by mass or less, further preferably 30% by mass or less, and still more preferably 25% by mass or less. If the concentration of the external coagulation liquid is too low, it is necessary to use a large amount of water to dilute the solvent brought in from the spinning solution, and the cost for waste liquid treatment increases. Therefore, the lower limit of the external coagulation liquid concentration is more preferably 3% by mass or more, and further preferably 5% by mass or more.

  In the production of the hollow fiber membrane of the present invention, it is preferable that stretching is not substantially applied before the hollow fiber membrane structure is completely fixed. “Substantially no stretching” means that the roller speed during the spinning process is controlled so that the spinning dope discharged from the nozzle is not loosened or excessively tensioned. The discharge linear speed / coagulation bath first roller speed ratio (draft ratio) is preferably in the range of 0.7 to 1.8. If the ratio is less than 0.7, the running hollow fiber membrane may be loosened, leading to a decrease in productivity. Therefore, the draft ratio is more preferably 0.8 or more, further preferably 0.9 or more, and More preferably 95 or more. If it exceeds 1.8, the membrane structure may be destroyed, for example, the dense layer of the hollow fiber membrane is torn. Therefore, the draft ratio is more preferably 1.7 or less, still more preferably 1.6 or less, still more preferably 1.5 or less, and particularly preferably 1.4 or less. By adjusting the draft ratio to this range, deformation and destruction of the pores can be prevented, clogging of blood protein into the membrane pores can be prevented, and performance stability over time and sharp fractionation characteristics can be expressed. Is possible.

  In the present invention, the effective length of the hollow fiber membrane is preferably 15 to 30 cm. When the hollow fiber membrane area is constant, when the effective length of the hollow fiber membrane is short, the pressure loss and shear rate of the treatment liquid flowing through the hollow portion of the hollow fiber membrane are small. Reduces the risk of hemolysis and the occurrence of problems such as rupturing of the hollow fiber membrane, but decreases the ability to remove larger molecular weight substances because the amount of exchange fluid between the blood and dialysate decreases. There is. Therefore, the effective length of the hollow fiber membrane is more preferably 17 cm or more, further preferably 19 cm or more, and further preferably 21 cm or more. On the other hand, if the effective length of the hollow fiber membrane is too long, the transportation cost and handleability may decrease, and the pressure loss of the treatment liquid may increase, which may cause problems of leakage and hemolysis. Therefore, the effective length of the hollow fiber membrane is more preferably 28 cm or less, and further preferably 26 cm or less.

The urea clearance measured using the hollow fiber membrane module having the above configuration is preferably 150 mL / min (1.5 m ² ) or more. If the urea clearance is too low, for example, when used for blood purification, a sufficient therapeutic effect may not be obtained. Therefore, the urea clearance 155mL / min (1.5m ²⁾ or more preferably, 160mL / min (1.5m ²⁾ or more preferably, 165mL / min (1.5m ²⁾ or more preferably more. The upper limit of urea clearance is determined by the blood flow rate. When the blood flow rate is 200 mL / min, the upper limit of clearance is 200 mL / min.

  Since the hollow fiber membrane module of the present invention has the above characteristics, it is preferably used for blood purification.

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

2. Calculation of membrane area The membrane area of the dialyzer was determined based on the inner diameter of the hollow fiber.
A = n × π × d × L
Here, n is the number of hollow fibers in the dialyzer, π is the circumference, d is the inner diameter (m) of the hollow fiber, and L is the effective length (m) of the hollow fiber in the dialyzer.

3. Burst pressure Fill the dialysate side of a module consisting of about 10,000 hollow fiber membranes with water and plug it. Dry air or nitrogen is fed from the blood side at room temperature and pressurized at a rate of 0.5 MPa per minute. The pressure was increased, and the air pressure when the hollow fiber membrane burst (burst) with pressurized air and bubbles were generated in the liquid filled on the dialysate side was defined as the burst pressure.

4). Unevenness of thickness A cross section of 100 hollow fibers is observed with a 200 times projector. In one field of view, the thickness of the thickest part and the thinnest part was measured for one yarn cross section with the largest film thickness difference.
Thickness unevenness = thinnest part / thickest part thickening degree = 1, and the film thickness is perfectly uniform.

5). Elution amount of hydrophilic polymer An example of the measurement method when polyvinylpyrrolidone is used as the hydrophilic polymer is shown below.
Extraction was performed by the method defined in the dialysis artificial kidney device production standard, and polyvinylpyrrolidone in the extract was quantified by a colorimetric method.
That is, 100 ml of pure water was added to 1 g of the hollow fiber membrane and extracted at 70 ° C. for 1 hour. To 2.5 ml of the resulting extract, 0.25 ml of a 0.2 molar citric acid aqueous solution and 0.5 ml of 0.006 N iodine aqueous solution were added and mixed well, and after standing at room temperature for 10 minutes, the absorbance at 470 nm was measured. . Quantification was performed with a calibration curve obtained according to the above method using a standard polyvinylpyrrolidone.
In the case of the wet hollow fiber membrane module, physiological saline was passed through the dialysate side channel of the module at 500 mL / min for 5 minutes, and then passed through the blood side channel at 200 mL / min. Thereafter, the solution was 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.

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

7. 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 are counted, and when the lower polymer chain can be seen inside the holes, the holes are combined and counted as one hole. 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.

8. Average pore area of the hole portion on the outer surface of the hollow fiber membrane Counting was performed in the same manner as in the previous section to obtain the area of each pore. In addition, holes on the measurement range boundary were excluded during counting. This was carried out for 10 fields of view, and the average of all pore areas was determined.

9. Porosity 10000 hollow fiber membranes are wrapped with a polyethylene film and cut to a length of 25 cm (hereinafter referred to as a bundle). The bundle was completely immersed in water at 20 ° C. and allowed to stand for 30 minutes under a reduced pressure of −700 mmHg. This operation was repeated 5 times, changing the water each time. Thereafter, the bundle was installed along the radial axis of the rotary table at a location 12 cm away from the center of rotation (in the case of a plurality of concentric circles), and liquid removal was performed at 200 rpm for 15 minutes. Only the hollow fiber membrane was extracted from the bundle immediately after liquid removal, and its mass A (g) was measured. The hollow fiber membrane was freeze-dried, and the mass B (g) of the dried hollow fiber membrane was measured. Using the obtained measured value, the porosity of the hollow fiber membrane was calculated by the following formula.
Porosity (%) = ((A−B) / ((A−B) + B / δ)) × 100
Here, δ is the specific gravity of the polysulfone polymer.

10. Thickness measurement of the 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.

11. Measurement of dense layer thickness The thickness of the dense 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 a portion where no pore was clearly observed was defined as a dense layer.

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

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

14. Adhesiveness of hollow fiber membrane About 10,000 hollow fibers were bundled, loaded into a blood purifier container of 30 mmφ to 35 mmφ, and sealed with a two-component polyurethane resin to prepare a blood purifier. A leak test was conducted at five levels for each level, and the number of blood purifiers that failed to seal the urethane resin was counted.

15. Residual blood of the hollow fiber membrane Fill the dialysate side of the blood purifier with a membrane area of 1.5m ² with physiological saline, fill the blood bag with 200ml of heparinized blood collected from a healthy person, and connect the blood bag and module to the tube. And circulate at 37 ° C. for 1 hour at a blood flow rate of 100 ml / min. Blood samples before the start of circulation and 60 minutes of circulation are sampled, and the white blood cell count and platelet count are measured. The measured value is corrected with the value of hematocrit.
Correction value = measured value (60 minutes) x hematocrit (0 minutes) / hematocrit (60 minutes)
The rate of change of white blood cells and platelets is calculated from the correction value.
Change rate = correction value (60 minutes) / value before circulation start × 100
After the circulation for 60 minutes, the blood was returned with physiological saline, and the number of remaining blood was counted. The evaluation was carried out with the number of remaining blood threads being 10 or less, ◯, 11 to 30 threads as Δ, and 31 or more threads as ×.

16. Priming property With the lid on the dialysate side port of the blood purifier, 10 seconds have passed since the distilled water for injection was flowed from the blood side inlet port at 200 mL / min and the distilled water for injection reached the outlet port. In the meantime, the blood purifier container was tapped 5 times with forceps to defoam, and the number of bubbles passed for 1 minute was visually confirmed. The determination was made according to the following criteria.
10 / min or less: ○
11 / min or more and less than 30 / min: △
30 pieces / minute or more: ×

17. Urea clearance Using a blood purifier with a membrane area of 1.5 m ² , urea clearance is measured according to the dialyzer performance evaluation standard issued by the Japanese Dialysis Medical Association at a blood flow rate of 200 ml / min and a dialysate flow rate of 500 ml / min. .

18. Breaking strength and yield strength Breaking strength and yield strength were measured using a yarn tensile tester (Instron (Model No. TM) manufactured by Instron Engineering Corporation). A single yarn having a total length of 15 cm was fixed to a chuck (10 cm between chucks) immersed in water, and a full-scale 100 g cell connected to the chuck was raised at a speed of 20 mm / min. The breaking elongation and breaking strength at which the yarn was cut from the chart paper were read and used as the SS curve. When there is no maximum point as shown in FIG. 3, an auxiliary line with an extended initial slope is provided. The point where two auxiliary lines intersect is defined as the yield point, and the strength at that point is the yield strength and the elongation is the yield elongation. In addition, when there is a maximum point as shown in Fig. 4, the point where the auxiliary line with the initial slope extended and the auxiliary line with zero slope at the maximum point intersect is defined as the yield point, and the strength at that point is the yield strength, Degree is the yield elongation.

19, Crimp wavelength and amplitude The crimp wavelength represents the length from the top of the mountain shown in FIG. 5 to the top of the next mountain, and in actual measurement, it is counted how many periods exist in the length of 100 mm. The number is displayed by dividing 100 mm. In addition, the amplitude was measured by measuring the wave height from the top of the mountain to the bottom of the valley, and was set to a half value thereof.

Example 1
Polyethersulfone (Sumika Chemtex, Sumika Excel (R) 5200P) 17% by mass, Polyvinylpyrrolidone (BASF Kollidon (R) K-90) 2.8% by mass, Dimethylacetamide (DMAc) 77.2% %, 3% by mass of RO water at 50 ° C., and after reducing the pressure in the system to −500 mmHg using a vacuum pump, immediately in the system so that the solvent etc. evaporates and the spinning solution composition does not change. Sealed and left for 15 minutes. This operation was repeated three times to degas the film forming solution. The film-forming solution was passed through a three-stage sintered filter of 15 μm, 15 μm, and 15 μm in order, and then degassed for 30 minutes at −700 mmHg as a hollow forming agent in advance from a tube-in orifice nozzle heated to 80 ° C. After discharging with a DMAc aqueous solution and passing through a 450 mm dry part cut off from the outside air by a spinning tube, it was solidified in a 20% by mass DMAc aqueous solution at 60 ° C., and the hollow fiber membrane after passing through the water washing bath was taken out of the water washing bath. This is a chain of freely rotating rollers, which is set so that four yarns are united, and the pitch between rollers is 10 mm, the roller diameter is 5 mm, and the width of the thread meandering is 5 mm without going through the drying process. The yarn was run at room temperature along with the running of the chain. In the step of crimping the hollow fiber membranes, the continuously supplied hollow fiber membranes were divided and run in the width direction in units of combined yarns, and were rolled up in a wet state. The nozzle slit width of the tube-in-orifice nozzle used is an average of 60 μm, the maximum is 61 μm, the minimum is 59 μm, the ratio of the maximum and minimum slit width is 1.03, the draft ratio of the spinning solution is 1.1, and the dry part The absolute humidity was 0.18 kg / kg dry air. During the spinning process, the roller in contact with the hollow fiber membrane was made of stainless steel whose surface was mirror-finished, and the guides were all made of stainless steel whose surface was textured.

  A polyethylene film with a hollow surface on the hollow fiber bundle side surface is wrapped around about 10,000 bundles of the hollow fiber membrane, and then washed in hot water at 80 ° C. for 30 minutes × 4 times to complete the washing. Thereafter, drying treatment was performed in a nitrogen atmosphere at 40 ° C. During the spinning process, the roller contacted with the hollow fiber membrane was a mirror-finished surface, and the guides were all treated with a satin finish. The resulting hollow fiber membrane had an inner diameter of 198 μm and a film thickness of 27 μm. Further, the asymmetric structure had a dense layer on the inner surface side, and the dense layer thickness was 0.9 μm. It was 6.7 mass% when the content rate of PVP in a hollow fiber membrane was measured.

Insert the hollow fiber membrane bundle prepared by the above method into a polycarbonate module container at a filling rate of 50% by volume, fix both ends with urethane resin and cut the resin end to open the hollow fiber membrane hollow part, A cap having an inflow port was attached to produce a hollow fiber membrane module having a hollow fiber membrane effective length of 255 mm and a membrane area of 1.5 m ² . The hollow fiber membrane module was filled with pure water and sterilized by irradiation with 25 KGy of γ rays in an oxygen-free environment. The priming property of the obtained blood purifier was good.

  When the hollow fiber membrane was cut out from the hollow fiber membrane module after γ-irradiation and subjected to the eluate test, the amount of PVP elution was 4 ppm, which was a satisfactory level.

The hollow fiber membrane module was filled with pressurized air at a pressure of 0.1 MPa, and a product that passed the leak test with a pressure drop for 10 seconds of 30 mmAq or less was used in the subsequent tests. 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. In addition, citrated fresh bovine blood was passed through the blood purifier at a blood flow rate of 200 mL / min and a filtration rate of 10 mL / min (1 m ² ), but no blood cell leak was observed. Endotoxin filtered from the outer side of the hollow fiber to the inner side of the hollow fiber was below the detection limit and was at a level with no problem.

  Further, when the hollow fiber membrane was taken out from the module and the outer surface was observed with a microscope, no defects such as scratches were observed. All of the characteristics were good and the module for blood purification was highly practical. The evaluation results are shown in Table 1.

  The yield elongation of the hollow fiber membrane taken out from the hollow fiber membrane module was measured and found to be 2.5%. Further, the outer diameter of the hollow fiber membrane was 252 μm, and the outermost stretching on the side opposite to the side of the hollow fiber membrane calculated from the roller diameter was 10.4% when flattening was ignored. As a result of measuring the crimp in the non-tensioned state of the hollow fiber membrane, a crimp having an amplitude of 2.2 mm and an average wavelength of 25 mm was fixed.

(Comparative Example 1)
In the method of Example 1, the filter used for filtering the spinning solution was changed to a 30 μm 1-stage sintered filter, and the nozzle slit width of the tube-in orifice nozzle was an average of 60 μm, a maximum of 67 μm, a minimum of 53 μm, and a slit A hollow fiber membrane and a hollow fiber membrane module were obtained in the same manner as in Example 1 except that the ratio between the maximum value and the minimum value of the width was changed to 1.26.
The characteristics of the obtained hollow fiber membrane and hollow fiber membrane module are shown in Table 1. The hollow fiber membrane module obtained in this comparative example has a low burst pressure because the unevenness of the hollow fiber membrane and the uniformity of phase separation are low. In the blood leak test using bovine blood, among 30 modules, Blood cell leaks were observed in five, and the module obtained in this comparative example was not practical for blood purification.

(Comparative Example 2)
In the method of Example 1, the nozzle slit width of the tube-in-orifice nozzle is an average of 80 μm, a nozzle having a maximum ratio of 81 μm, a minimum of 79 μm, a maximum value of the slit width and a minimum value of 1.03, and a draft ratio of 1 30, and the crimping step was omitted to obtain a hollow fiber membrane having an inner diameter of 180 μm and a membrane thickness of 30 μm without crimping. A hollow fiber membrane module was obtained in the same manner as in Example 1 except that the filling rate of the hollow fiber membrane prepared in the above method into a polycarbonate container was changed to 70% by volume. The hollow fiber membrane module was sterilized by irradiation with 25 KGy of γ rays in an oxygen-free environment.
The hollow fiber membrane module obtained in this comparative example had a high filling rate into the module container, and the hollow fiber membrane was rubbed and scratched when the hollow fiber membrane was loaded into the container. Therefore, the obtained hollow fiber membrane module had a low burst pressure.

(Comparative Example 3)
In the method of Comparative Example 1, the hollow fiber membrane of Comparative Example 3 was obtained in the same manner as in Comparative Example 1 except that the crimp application step was omitted and a change was made so as to obtain a hollow fiber membrane to which no crimp was applied. . Using the hollow fiber membrane obtained in this Comparative Example, a hollow fiber membrane module was produced in the same manner as in Example 1. In addition to the problems of the hollow fiber membrane module obtained in Comparative Example 1, the hollow fiber membrane module obtained in this comparative example has a low filling rate and is not provided with crimps. Happened and urea clearance performance was poor. Moreover, the performance variation between modules was also large.

(Example 2)
18% by mass of polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (R) 4800P), 3.5% by mass of polyvinylpyrrolidone (Collidon (R) K-90, manufactured by BASF), 73.5% by mass of DMAc, 5% by mass of water % Was melted at 50 ° C., and the inside of the system was reduced to −700 mmHg using a vacuum pump. The inside of the system was immediately sealed and allowed to stand for 10 minutes so that the solvent and the like were volatilized and the film forming solution composition did not change. This operation was repeated three times to degas the film forming solution. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and then degassed in advance at −700 mmHg for 2 hours as a hollow forming agent from a tube-in orifice nozzle heated to 70 ° C. for 2 hours. At the same time, it was discharged, passed through a 300 mm air gap portion that was blocked from outside air by a spinning tube, and then solidified in water at 60 ° C. The nozzle slit width of the tube-in-orifice nozzle used is an average of 45 μm, the maximum is 45.5 μm, the minimum is 44.5 μm, the ratio of the maximum and minimum slit width is 1.02, the draft ratio is 1.06, and the dry type The absolute humidity of the part was 0.12 kg / kg dry air. 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 hydrophilic polymer. Crimping was performed in the same manner as in Example 1, and the product was rolled up in a wet state. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface.

  A polyethylene film having a textured finish similar to that of Example 1 was wrapped around a bundle of about 10,000 hollow fiber membranes, and then immersed and washed in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes × 2 times. Then, it replaced with water and dried in 60 degreeC nitrogen stream. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 29 μm. Moreover, it was an asymmetrical structure which has a dense layer on the inner surface side, and the dense layer thickness was 0.7 μm. The content of the hydrophilic polymer in the hollow fiber membrane was measured and found to be 7.3% by mass. Using the thus obtained hollow fiber membrane, a hollow fiber membrane module was assembled in the same manner as in Example 1. As a result of the leak test, no adhesion failure caused by the sticking of the hollow fibers was found. When the hollow fiber membrane was cut out from the hollow fiber membrane module and subjected to the eluate test, the PVP elution amount was as good as 6 ppm. Further, when the hollow fiber membrane was taken out from the hollow fiber membrane module and the outer surface was observed with a microscope, defects such as scratches were not observed. No blood cell leak was found in the blood leak test using bovine blood. In addition, as a result of the endotoxin permeation test, endotoxin filtered from the outside of the hollow fiber to the inside of the hollow fiber was below the detection limit and was at a level with no problem. The other analysis results are shown in Table 1.

(Example 3)
Polysulfone (Amoco P-3500) 18% by mass, Polyvinylpyrrolidone (BASF Kollidon (R) K-60) 9% by mass, DMAc 68% by mass, water 5% by mass were dissolved at 50 ° C., and then a vacuum pump was used. After the pressure inside the system was reduced to −300 mmHg, the system was immediately sealed and left for 15 minutes so that the solvent and the like would volatilize and the film forming solution composition would not change. This operation was repeated three times to degas the film forming solution. The obtained film-forming solution was passed through two types of filters of 15 μm and 15 μm, and then discharged from a tube-in orifice nozzle heated at 40 ° C. simultaneously with a 35 mass% DMAc aqueous solution degassed in advance as a hollow forming agent, After passing through a 600 mm air gap portion cut off from the outside air by a spinning tube, it was solidified in water at 50 ° C. The average nozzle slit width of the tube-in-orifice nozzle used is 60 μm, the maximum is 61 μm, the minimum is 59 μm, the ratio of the maximum and minimum slit width is 1.03, the draft ratio is 1.01, the absolute humidity of the dry section Was 0.06 kg / kg dry air. 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 hydrophilic polymer. Crimping was performed in the same manner as in Example 1, and the product was rolled up in a wet state. A bundle of about 10,000 hollow fiber membranes was immersed in pure water and washed in an autoclave at 121 ° C. for 1 hour. A polyethylene film similar to that of Example 1 was wound around the hollow fiber membrane bundle after washing, and then dried in a nitrogen stream at 45 ° C. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. The resulting hollow fiber membrane had an inner diameter of 197 μm and a film thickness of 41 μm. The asymmetric structure had a dense layer on the inner surface side, and the dense layer thickness was 1.2 μm. The content of the hydrophilic polymer in the hollow fiber membrane was measured and found to be 9.8% by mass.

As a result of producing a module from the obtained hollow fiber membrane and conducting a leak test, no adhesion failure caused by the sticking of the hollow fibers was observed. Using the thus obtained hollow fiber membrane, a hollow fiber membrane module was assembled in the same manner as in Example 1. The hollow fiber membrane module was filled with pure water and irradiated with γ rays at an absorbed dose of 25 kGy to carry out a crosslinking treatment. When the hollow fiber membrane was cut out from the hollow fiber membrane module after γ-irradiation and subjected to the eluate test, the PVP elution amount was 7 ppm, which was at a satisfactory level. The hollow fiber membrane module was filled with pressurized air at a pressure of 0.1 MPa, and a product that passed the leak test with a pressure drop for 10 seconds of 30 mmAq or less was used in the subsequent tests. Further, when the hollow fiber membrane was taken out from the hollow fiber membrane module and the outer surface was observed with a microscope, defects such as scratches were not observed. In addition, citrated fresh bovine blood was passed through the blood purifier at a blood flow rate of 200 mL / min and a filtration rate of 10 mL / min (1 m ² ), but no blood cell leak was observed. Endotoxin filtered from the outer side of the hollow fiber to the inner side of the hollow fiber was below the detection limit and was at a level with no problem. The other analysis results are shown in Table 1.

Example 4
Polysulfone (Amoco P-1700) 17% by mass, polyvinyl pyrrolidone (BASF Koridone (R) K-60) 5% by mass, DMAc 73% by mass, water 5% by mass were dissolved at 50 ° C., and then a vacuum pump was used. After the pressure inside the system was reduced to −400 mmHg, the inside of the system was immediately sealed and left for 30 minutes so that the solvent and the like were volatilized and the film forming solution composition did not change. This operation was repeated three times to degas the film forming solution. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and then discharged from a tube-in orifice nozzle heated to 40 ° C. simultaneously with a 35 mass% DMAc aqueous solution degassed under reduced pressure as a hollow forming agent. After passing through a 600 mm air gap portion cut off from the outside air by a spinning tube, it was solidified in water at 50 ° C. The average nozzle slit width of the tube-in-orifice nozzle used is 60 μm, the maximum is 61 μm, the minimum is 59 μm, the ratio of the maximum and minimum slit width is 1.03, the draft ratio is 1.01, the absolute humidity of the dry section Was 0.07 kg / kg dry air. The hollow fiber membrane pulled up from the coagulation bath is passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess hydrophilic polymer, and then crimped in the same manner as in Example 1, and remains wet. I rolled it up in a bag. A bundle of about 10,000 hollow fiber membranes was immersed in pure water and washed in an autoclave at 121 ° C. for 1 hour. A polyethylene film having a matte finish was wound around the hollow fiber membrane bundle after washing, and then dried in a nitrogen stream at 45 ° C. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 44 m. The asymmetric structure had a dense layer on the inner surface side, and the dense layer thickness was 1.4 μm. The PVP content in the hollow fiber membrane was 5.2% by mass.

Using the obtained hollow fiber membrane, a hollow fiber membrane module was assembled in the same manner as in Example 1, and a leak test was performed. As a result, no adhesion failure due to adhesion between the hollow fiber membranes was found. A blood purifier was assembled using the hollow fiber membrane thus obtained. When the hollow fiber membrane was cut out from the hollow fiber membrane module and subjected to the eluate test, the PVP elution amount was 7 ppm, which was a satisfactory level. The hollow fiber membrane module was filled with pressurized air at a pressure of 0.1 MPa, and a product that passed the leak test with a pressure drop for 10 seconds of 30 mmAq or less was used in the subsequent tests. Further, when the hollow fiber membrane was taken out from the hollow fiber membrane module and the outer surface was observed with a microscope, defects such as scratches were not observed. In addition, citrated fresh bovine blood was passed through the blood purifier at a blood flow rate of 200 mL / min and a filtration rate of 10 mL / min (1 m ² ), but no blood cell leak was observed. Endotoxin filtered from the outside of the hollow fiber membrane to the inside of the hollow fiber membrane was below the detection limit, and was at a level with no problem. The other analysis results are shown in Table 1.

(Comparative Example 4)
Polyethersulfone (Sumika Chemtex, Sumika Excel (R) 5200P) 16% by mass, polyvinyl pyrrolidone (BASF Koridone (R) K-90) 6% by mass, DMAc 75% by mass, water 3% by mass at 50 ° C. Then, the system was depressurized to -500 mmHg using a vacuum pump, and the system was immediately sealed and allowed to stand for 15 minutes so that the solvent and the like were volatilized and the film forming solution composition did not change. This operation was repeated three times to degas the film forming solution. This membrane-forming solution was passed through a 30 μm filter, and simultaneously discharged and spun from a tube-in orifice nozzle heated to 60 ° C. using a 30 mass% DMAc aqueous solution previously degassed at −700 mmHg for 2 hours as a hollow forming agent. After passing through a 600 mm dry part cut off from the outside air by a tube, it was solidified in a DMAc aqueous solution having a concentration of 10% by mass and 60 ° C. The nozzle slit width of the tube-in-orifice nozzle used is an average of 100 μm, the maximum is 110 μm, the minimum is 90 μm, the ratio of the maximum and minimum slit width is 1.22, the draft ratio is 2.41, the absolute humidity of the dry section Was 0.11 kg / kg dry air. The obtained hollow fiber membrane was passed through a water washing tank at 40 ° C. for 45 seconds to remove the solvent and excess hydrophilic polymer, and then crimped in the same manner as in Example 1 to wind it up in a wet state in air. Dried at ℃. The resulting hollow fiber membrane had an inner diameter of 198 μm and a film thickness of 27 μm. Further, the asymmetric structure had a dense layer on the inner surface side, and the dense layer thickness was 0.9 μm. The PVP content in the hollow fiber membrane was 8.2% by mass.

  A hollow fiber membrane module was assembled using the hollow fiber membrane thus obtained. In a state where the hollow fiber membrane module was filled with pure water, γ-rays were irradiated at an absorbed dose of 25 kGy to carry out a crosslinking treatment. When the hollow fiber membrane was cut out from the blood purifier after γ-irradiation and subjected to the eluate test, the elution amount of PVP was 12 ppm. The poor cleaning of the hollow fiber membrane was considered. The blood purifier was filled with pressurized air at a pressure of 0.1 MPa, and a module having a pressure drop for 10 seconds of 30 mmAq or less was used for the test. In the blood leak test using bovine blood, 7 of 30 modules showed blood cell leaks. From the fact that the uneven thickness is small and the outer surface hole diameter is too large, it seems that pinholes are generated and / or broken. As a result of the endotoxin permeation test, endotoxin filtered from the outside of the hollow fiber to the inside of the hollow fiber was detected. It is presumed that endotoxin is easily permeated due to the large amount of outer surface PVP and the large open area ratio. The other analysis results are shown in Table 1.

(Comparative Example 5)
In the method of Comparative Example 1, the hollow fiber membrane and the hollow fiber membrane module of Comparative Example 6 were obtained in the same manner as Comparative Example 1 except that the number of washings with 50 vol% isopropanol aqueous solution was changed to 6. The characteristics of the obtained hollow fiber membrane and hollow fiber membrane module are shown in Table 1.

  In addition to the problems of the hollow fiber membrane module obtained in Comparative Example 1, the hollow fiber membrane module obtained in this Comparative Example has a strong hydrophobicity due to a decrease in the content of polyvinyl pyrrolidone on the outer surface due to enhanced washing. As a result, the priming property deteriorates.

(Comparative Example 6)
30% by mass of polyethersulfone (Sumika Chemtex (R) 4800P manufactured by Sumika Chemtex Co., Ltd.), 3% by mass of polyvinylpyrrolidone (Collidon (R) K-90 manufactured by BASF), 13.4% by mass of triethylene glycol (Mitsui Chemicals) And 53.6% by mass of N-methyl 2-pyrrolidone (Mitsubishi Chemical Corporation) were mixed and stirred to prepare a uniform transparent film-forming solution. The system was then depressurized to -500 mmHg using a vacuum pump, and the system was immediately sealed and allowed to stand for 15 minutes so that the solvent and the like would volatilize and the film forming solution composition would not change. This operation was repeated three times to degas the film forming solution. After passing this membrane-forming solution through a 30 μm filter, it was simultaneously discharged from a tube-in orifice nozzle heated to 120 ° C. using liquid paraffin as a hollow forming agent, and passed through a 70 mm dry section cut off from the outside air by a spinning tube. Thereafter, the solution was coagulated in an aqueous solution of N-methyl-2-pyrrolidone / triethylene glycol / water = 16/4/80. The nozzle slit width of the tube-in-orifice nozzle used was an average of 100 μm, the maximum was 110 μm, the minimum was 90 μm, the ratio between the maximum and minimum slit widths was 1.22, and the draft ratio was 2.6. The obtained hollow fiber membrane was passed through a 40 ° C. water washing tank for 45 seconds to remove the solvent and excess hydrophilic polymer, and then passed through a 45% by mass glycerin aqueous solution at 50 ° C. In the same manner, crimping was performed, and a hot air drying process at 100 ° C. was passed and wound up. The obtained hollow fiber membrane had an inner diameter of 198 μm and a film thickness of 21.5 μm. Further, the entire hollow fiber membrane has a symmetric structure having a dense structure, and the thickness of the dense layer could not be clearly determined. The PVP content in the hollow fiber membrane was 7.4% by mass.

(Comparative Example 7)
A hollow fiber membrane of Comparative Example 7 was obtained in the same manner as Comparative Example 1 except that the method of Comparative Example 1 was changed so that the hollow fiber membrane was not washed. The obtained hollow fiber membrane was observed to adhere to the hollow fiber membrane bundle after drying, and when assembling the hollow fiber membrane module, the end part adhesive resin did not enter between the hollow fiber membranes, and the hollow fiber membrane module was assembled. I couldn't.

(Comparative Example 8)
The hollow fiber membrane obtained by changing the drying method of the hollow fiber membrane to the in-line drying method and continuously supplying the hollow fiber membrane obtained through the spinning, coagulation and water washing steps to the drying step without combining yarns. Is continuously supplied to the crimping step, and in the crimping step, the hollow fiber membranes are split into four in the splitting plate so that the crimping is performed. The hollow fiber membrane and hollow fiber membrane module of Comparative Example 8 were obtained in the same manner as in Example 2. In the hollow fiber membrane obtained in this comparative example, the occurrence of scratches in the hollow fiber membrane in the crimping process was increased as compared with Comparative Example 2. As a result, the burst pressure further deteriorated to 0.2 MPa.

  The hollow fiber membrane module of the present invention has high water permeability, is small in size and has high pressure resistance, and is highly reliable for treatment of chronic renal failure. It is suitable as a medical hollow fiber blood purifier having performance. Therefore, it is important to contribute to industrial development.

It is a figure which shows the principal part for crimping of the apparatus of this invention. It is an enlarged view of FIG. It is a figure which shows how to obtain | require the yield point in the case of not having a local maximum point. It is a figure which shows how to obtain | require a yield point in the case of having a local maximum point. It is a schematic diagram of the wavelength and amplitude of the crimp in the present invention.

Claims (11)

It consists of a polysulfone polymer and polyvinylpyrrolidone, has an inner diameter of 190 to 250 μm, a membrane thickness of 10 to 60 μm, a thickness deviation of 0.6 or more , a porosity of 60 to 80% , a wavelength of 10 mm or more, and an amplitude of 0.2 mm. A hollow fiber membrane module in which a hollow fiber membrane having an asymmetric structure having a dense layer on the inner surface side to which the above crimp is applied is inserted, and has a burst pressure of 0.5 to 1.5 MPa and a water permeability of 150. the hollow fiber membrane module, which is a ^{~ 1000 ml / m 2 / hr} / mmHg.   The hollow fiber membrane module according to claim 1, wherein a filling rate of the hollow fiber membrane is 40 to 60% by volume.   The hollow fiber membrane module according to claim 1 or 2, wherein the effective length of the hollow fiber membrane is 15 to 30 cm.   The hollow fiber membrane is run as a single yarn until the spinning, coagulation and water washing steps, and 3 to 10 single yarns are combined after the water washing step after the water washing step and continuously supplied to the crimping step. It is provided, The hollow fiber membrane module in any one of Claims 1-3 characterized by the above-mentioned.   A plurality of hollow fiber membrane rows to which the hollow fiber membranes are continuously supplied are crimped by meandering between yarn guides that travel at regular intervals. 4. The hollow fiber membrane module according to any one of 4 above.   The hollow fiber membrane module according to any one of claims 1 to 5, wherein the breaking strength of the hollow fiber membrane is 50 g / filament or less, and the yield strength is 30 g / filament or less. The hollow fiber membrane module according to any one of claims 1 to 6 , wherein a porosity of an outer surface of the hollow fiber membrane is 8 to 25%. The hollow fiber membrane module according to any one of claims 1 to 7 , wherein an average pore area on an outer surface of the hollow fiber membrane is 0.3 to 1.0 µm ² . The hollow fiber membrane module according to any one of claims 1 to 8 , wherein the thickness of the dense layer of the hollow fiber membrane is 0.1 to 3 µm. The hollow fiber membrane module according to any one of claims 1 to 9, wherein the content of polyvinyl pyrrolidone in the hollow fiber membrane is 1 to 20% by mass. It is used for blood purification, The hollow fiber membrane module in any one of Claims 1-10 characterized by the above-mentioned.

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