JP2008284186A - Porous hollow-fiber membrane with superior stable permeability - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood purifier having high water permiation performance and used for treatment of chronic renal failure, which has stable treatment performance not influenced by concentration of the blood. <P>SOLUTION: This porous hollow-fiber membrane is provided for the blood purifier capable of exerting a certain level of performance despite of conditions of the blood and the performance is attained by controlling the filling state and the degree of freedom of substrate polymers. This hollow fiber membrane having such characteristic and suited to the blood purification membrane is acquired by controlling the membrane-forming conditions. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a hollow fiber membrane having high water permeability and excellent performance stability, and a blood purifier using the same. More specifically, the interaction between the polymers constituting the hollow fiber membrane was moderately moistened by the liquid to be treated such as blood.

  In blood purification methods for the treatment of renal failure, natural materials such as cellulose, cellulose diacetate, cellulose triacetate, and synthetic polymers such as polysulfone, Blood purifiers such as hemodialyzers, hemofilters or hemodialyzers using a dialysis membrane using a polymer such as methyl methacrylate or polyacrylonitrile or an ultrafiltration membrane as a separating material are widely used. Particularly, blood purifiers using hollow fiber membranes as separation materials are used in the field of blood purification due to advantages such as reduction of blood volume related to extracorporeal circulation, high efficiency in removing blood substances, and productivity of blood purifier assembly. The importance in is high.

  Blood purifiers that use hollow fiber membranes usually flow blood through the hollow part of the hollow fiber membrane, 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. Removes low molecular weight substances from the blood. Furthermore, with the increase in 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 have a molecular weight of several thousand and a molecular weight of 20,000 to 30,000. Blood purification membranes are required 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 accumulated substance of carpal tunnel syndrome and is a removal target. Membranes used for such high molecular weight substance removal treatments are called high performance membranes. They are larger than conventional dialysis membranes, increase the number of pores, increase the porosity, increase the porosity. The removal efficiency of medium to high molecular weight substances can be improved by reducing the thickness of the material.

However, although the membrane pursuing high performance as described above has excellent β2 microglobulin removal performance, it has a drawback of leaking albumin (molecular weight 66000), which is a useful blood protein. As a method for compensating for this drawback, it is conceivable to sharpen the fractionation characteristics of the film. As a method for producing a hollow fiber membrane having sharp fractionation characteristics, the hollow fiber membrane is made into a two-layer or multi-layer structure, at least a dense layer is provided on the inner surface of the hollow fiber membrane, and compared with a sieve coefficient in an aqueous solution system, If the rate of decrease in the sieving coefficient of medium and large molecules in the plasma system is below a certain value, the permeation due to filtration can be reduced without decreasing the permeation due to diffusion of medium and large molecules, and the fractionation characteristics are sharp. It is disclosed that a membrane can be produced. (For example, refer to Patent Document 1).
JP 10-127663 A

Also disclosed is a method for producing a membrane having a uniform structure by reducing the width of the pore size distribution by controlling the coagulation speed when coagulating the spinning stock solution by changing the composition of the raw material in the hollow fiber membrane production process. In other words, an invention has been disclosed in which sharp fractionation characteristics are obtained by reducing the width of the pore size distribution (see, for example, Patent Documents 2 and 3).
Japanese Patent Laid-Open No. 10-165774 JP 2000-153134 A

Furthermore, it is disclosed that sharp fractionation characteristics can be obtained by controlling the ratio of the sieving coefficient of albumin and β2-microglobulin to a certain condition by selecting a solvent during hollow fiber membrane formation (for example, (See Patent Document 4).
Japanese Patent Laid-Open No. 10-216489

  These inventions commonly have a dense layer on the inner surface of the hollow fiber membrane, thereby preventing clogging due to adsorption of blood proteins to the hollow fiber membrane and achieving sharp fractionation characteristics and maintenance of the characteristics. It is to be done.

In addition, the structure of the inner surface of the membrane is disclosed to improve smoothness for the purpose of preventing clogging by blood proteins, and it is described that the fractionation performance and stability over time are also improved by this technology. Yes. As a means for improving smoothness, it is supposed that dry and wet spinning using gas as a hollow forming material in the hollow fiber membrane spinning process (see, for example, Patent Document 5).
JP-A-10-108907

Separating the pore diameter of the hollow fiber membrane and the non-crystalline region and the crystalline region that compose the membrane, so that plasma protein has a specific adsorption form on the inner surface of the membrane when plasma and membrane come into contact with each other An efficient membrane is disclosed. (For example, refer to Patent Document 6).
JP 2000-300973 A

In addition, the structure of the active layer of the hollow fiber membrane is such that the pore diameter is set to a specific size according to the substance to be removed, and the number of pores is set in a specific range, while suppressing protein permeation, such as β2 microglobulin. It is disclosed that a substance can be removed efficiently (for example, refer to Patent Document 7).
Japanese Examined Patent Publication No. 6-42905

In order to improve the temporal stability of the hollow fiber membrane, it is disclosed that the surface of the hollow fiber membrane has a smooth structure and the inner diameter is reduced in order to improve the flow rate of blood flow (see, for example, Patent Document 8). ).
JP-A-8-970

As mentioned above, making the inner surface of the membrane dense, improving the smoothness, and keeping the pore diameter within a certain range can sharpen the fractionation characteristics and suppress the adsorption of blood proteins. It is said that there is an effect of suppressing a change in film performance with time. However, even a film having such a structural feature may not exhibit performance stability as expected in clinical use. For example, even if the smoothness of the inner surface is improved and the suppression of blood protein adsorption is expected, the blood state of patients undergoing blood purification therapy varies, and in particular, excessive water accumulated in the body during blood purification. In order to remove water, the protein concentration in the blood increases with the progress of treatment, and even in the same patient, a difference occurs in the treatment effect.
The same applies to setting the pore diameter within a certain range, and the target performance may not be obtained in a design that does not consider changes in the apparent pore diameter of the membrane due to contact with blood. In particular, changes in blood properties with the progress of treatment affect the temporal stability of membrane performance, and thus there is a problem in the reproducibility of treatment effects.
Such a phenomenon also becomes a problem in the manufacture of blood purifiers having different membrane areas using the same hollow fiber membrane, and in the development of a blood purification hollow fiber membrane, it was necessary to conduct and verify a huge blood experiment. .

  An object of the present invention is to provide a blood purifier having high water permeability and excellent performance stability with low influence of blood protein concentration.

As a result of intensive studies to solve the above-mentioned problems, that is, the blood properties, in particular, the problem of membrane performance degradation due to blood concentration due to water removal, the blood compatibility of the membrane is determined by the unevenness and fineness of the membrane. We found that not only the pore size but also the network structure between the polymers constituting the membrane, that is, the number of interactions and the number of interaction points, and the degree of freedom of the associated polymer, greatly affected the shape of the polymer constituting the membrane and the packing type. It was found that a hollow fiber membrane suitable for a blood purifier having excellent blood performance stability can be obtained by controlling the above.
That is, the present invention has the following configuration.
The present invention relates to a porous hollow fiber membrane having a porosity of 60% or more and a water permeability of pure water at 37 ° C. of 150 to 1500 mL / m ² / hr / mmHg, wherein the porous hollow fiber membrane is wet. The yield point is not seen in the SS curve obtained in the tensile test in the state.
It is preferable that a clear yield point is seen in the SS curve obtained in the tensile test of the hollow fiber membrane in the dry state.
When the tensile test is performed in a dry state, the yield strength is preferably 8.0 g / filament or more.
In the porous hollow fiber membrane, when the dry state and the wet state are compared, it is preferable that the yield strength is remarkably reduced with respect to changes in the breaking strength and breaking elongation in the wet state.
It is preferable that the yield strength ratio (wet / dry) of the wet state and the dry state is less than 0.7 and the ratio of break strength (wet / dry) is 0.7 to 1.3.
It is preferable to produce a blood purifier using the porous hollow fiber membrane.

  The blood purifier of the present invention has high water permeability and has a characteristic of having stability with low influence on protein concentration in blood system performance. Therefore, there is an advantage that a stable and reproducible therapeutic effect can be expected regardless of the blood state of the patient and throughout the treatment time.

  Hereinafter, the present invention will be described in detail.

  In order to solve the above-mentioned problems, the present inventors have studied the manufacturing process, performance, and physical properties of a hollow fiber membrane used in a blood purifier. Conventionally, hollow fiber membranes aimed at high water permeability have been developed in the direction of increasing the pore diameter, increasing the number of pores in the entire membrane, or reducing the film thickness. In such hollow fiber membranes focusing only on high water permeability, proteins in the blood are easily adsorbed on the surface of the membrane when hemodialysis is performed, and clogging is likely to occur, and the filtration efficiency deteriorates with time. In particular, unlike the model system (clearance measurement experiment conducted in the laboratory is a single pass and CBin is constant), it is remarkable in a clinical system in which plasma protein concentration increases with time due to water removal. Membranes that are prone to clogging have large fluctuations in intermembrane pressure and large changes in protein leak over time. Therefore, in clinical practice, the performance fluctuates depending on the blood state of the patient, and the removal performance decreases over time. In addition, hollow fiber membranes developed in the direction of increasing the number of pores in the entire membrane and reducing the film thickness make the yarn strength weaker than conventional hollow fiber membranes. It is also a serious weakness.

  In order to obtain a hollow fiber membrane that can reproduce a certain performance without depending on changes in the state of blood during blood purification (concentration of blood by water removal, etc.), from the start of blood circulation to the end of blood circulation It is important how to avoid the influence of blood protein on performance. In the present invention, in order to avoid the influence of blood concentration, attention was paid to the interaction between polymers constituting the membrane, the way of freedom, and the state of polymer filling. As a means for obtaining information such as the state of polymer interaction and the degree of freedom, it has been found that it is effective to determine the presence or absence of the yield point of the film. In order to obtain a hollow fiber membrane that achieves both target performance and handling properties, the pseudo-gelation of the dope in the film-forming process, the control of the actual gelation process, and stretching after the coagulation bath are closely related. As a result, the present invention was reached.

Permeability of water at 37 ° C. of the hollow fiber membrane of the present invention 150mL / m ² / hr / mmHg or more 1500mL / m ² / hr / mmHg or less is preferably in the range of. If it is less than 150 mL / m ² / hr / mmHg, it cannot be said to be the high water permeability aimed at by the present invention, and generally the permeation performance of medium molecular weight substances in the blood system is low. When the water permeability exceeds 1500 mL / m ² / hr / mmHg, the pore diameter becomes large, the amount of protein leak may increase excessively, and the stability targeted by the present invention may not be obtained. . Therefore, a more preferable range of water permeability is 200 mL / m ² / hr / mmHg or more and 1000 mL / m ² / hr / mmHg or less, more preferably 250 mL / m ² / hr / mmHg or more and 700 mL / m ² / hr / mmHg or less. is there.

The average film thickness of the hollow fiber membrane in the present invention is preferably 10 μm or more and 50 μm or less. If the film thickness is too thick, the permeability of the medium to high molecular weight substance may be lowered even if the water permeability is high. In addition, the merit of the hollow fiber membrane that accommodates a large membrane area in a small blood purifier may be impaired. A thinner film thickness is preferred because the material permeability is increased, more preferably 45 μm or less, and even more preferably 40 μm or less.
If the film thickness is too thin, it may be difficult to maintain the minimum film strength required for the blood purifier. Therefore, the average film thickness is more preferably 12 μm or more, and further preferably 14 μm or more.
The average film thickness here is an average value obtained by measuring five randomly sampled hollow fiber membranes. At this time, the difference between each value and the average value does not exceed 20% of the average value.

  In the present invention, the hollow fiber membrane preferably has an inner diameter of 100 to 300 μm. If the inner diameter is too small, the pressure loss of the blood flowing through the hollow fiber membrane is increased, which may cause hemolysis. In addition, when the inner diameter is too large, the shear rate of blood flowing through the hollow portion is reduced, and thus proteins in the blood are likely to be deposited on the inner surface of the membrane during filtration. The inner diameter in which the pressure loss and shear rate of the blood flowing through the hollow part are in an appropriate range is 150 to 250 μm.

  The hollow fiber membrane in the present invention is preferably a porous membrane having a porosity of 60% or more. In order to obtain the high water permeability performance aimed by the present invention, the porosity is more preferably 65% or more. If the porosity is too large, the strength of the hollow fiber membrane is weak, handling properties are poor, and when used as a separation membrane, it may not be able to withstand the form of use. Moreover, if the porosity is too small, the water permeability is low, and the high water permeability aimed by the present invention may not be obtained. Therefore, the porosity of the hollow fiber membrane is more preferably 65 to 95%, and further preferably 65 to 90%.

The hollow fiber membrane in the present invention has a characteristic that a clear yield point is not seen in an SS curve obtained by a tensile test in a wet state. The absence of a clear yield point means that elastic deformation can be ignored and plastic deformation occurs immediately after the start of the tensile test. In particular, it means that the interaction between the base polymers is weak in the wet state. That is, the hollow fiber membrane having such characteristics indicates that the polymer network constituting the membrane has a certain degree of freedom (flexibility), and the liquid to be treated such as blood and the hollow fiber membrane are in contact with each other. In this case, there is an advantage that the removed solute can easily pass through the gaps between the networks (when it becomes flexible). In addition, since clogging is less likely to occur, it has an effect of suppressing deterioration in performance over time.
On the other hand, even in the wet state, those having a characteristic of having a clear yield point mean that the base polymer cannot increase the degree of freedom by wetting in most of the film, and means a fixed polymer network structure. In such a structure, the pores through which the high molecular weight substance passes are small, and efficient separation of the high molecular weight substance cannot be expected, and it is not preferable from the viewpoint of stability of performance.

  In the present invention, it is preferable that a clear yield point is seen in the SS curve obtained in the tensile test of the hollow fiber membrane in the dry state. In the dry state, handling properties and processability (such as assembly of a blood purifier) are more important than physical properties necessary for developing permeation performance, and strength against elastic deformation is required.

  In the present invention, when the tensile test is performed in a dry state, the yield strength is preferably 8.0 g / filament or more. If the yield strength is too small, the physical properties of the hollow fiber membrane will change due to a force higher than the yield strength during transportation and processing into a blood purifier, and the expected performance will not be obtained when blood purification is performed. May cause problems. Therefore, the yield strength in the dry state is more preferably 8.5 g / filament or more, and further preferably 9.0 g / filament or more.

  In the hollow fiber membrane tensile test, when the hollow fiber membrane is compared between a dry state and a wet state, a decrease in yield strength is observed in the wet state. It is preferable that the change is small. In general fibers, a so-called plasticizing action in which the yield strength and the breaking strength are reduced by the wetting in the tensile test, and the breaking elongation is increased. The hollow fiber membrane of the present invention is assumed to be used in a wet state such as water treatment or blood treatment, and it is preferable that the hollow fiber membrane structure is not changed by the wetting and the breaking strength or breaking elongation is not greatly reduced. . On the other hand, the property that the breaking strength is reduced by wetting, which is a general fiber property, and the yarn that is undesirably high in elongation and easily stretched may change the designed performance in consideration of the usage form.

  In the present invention, the yield strength ratio (wet / dry) between the wet state and the dry state in the tensile test of the hollow fiber membrane is preferably 0.7 or less. The greater the difference in yield strength between wet and dry conditions, the greater the degree of freedom of the polymer network due to the presence of water, and the smaller the number of interaction points between the polymers, the smaller the molecular weight to high molecular weight substances that can pass through. Since it is considered that there are sufficient pores, it is preferable because it is advantageous for separation and stability of a high molecular weight substance. More preferably, it is 0.65 or less, More preferably, it is 0.6 or less. If the yield strength ratio is too large, the interaction between the polymers is too strong and the mobility of the polymer network through which the high molecular weight substance can pass is not sufficient, so that high performance cannot be expected and stability may be disadvantageous. The yield strength ratio (wet / dry) between the wet state and the dry state is preferably 0.1 or more. 0.2 or more is more preferable, 0.3 or more is more preferable, and 0.35 or more is even more preferable. If it is less than 0.1, the strength of the yarn in a wet state is too weak, and the physical properties of the yarn may change due to the load applied in the process of assembling the blood purifier. Here, even if the yield point in the wet state is not clear, it is assumed that it has been read as much as possible.

In the tensile test of the hollow fiber membrane in the present invention, the average value of n = 5 of the breaking strength ratio (wet / dry) between the wet state and the dry state is preferably in the range of 0.7 to 1.3. Within this ratio range, the respective values are almost equal, and there is no fear of a decrease in breaking strength due to the presence of water, which is preferable. More preferably, it is the range of 0.8-1.2, More preferably, it is 0.9-1.2. If the breaking strength ratio is too small, the reduction in breaking strength due to the presence of water may cause a problem in use in terms of stability and strength of the separation membrane performance due to plasticizing action. On the other hand, if the breaking strength ratio is too large, there is a possibility that the interaction between the polymers becomes too strong, and when clogged, the hollow fiber membrane is stretched and the shape of the hole is deformed to deteriorate the performance.
The dry state means a state where the moisture content of the hollow fiber membrane is less than 30%. The wet state means a state where the moisture content of the hollow fiber membrane is 60% or more.

  As the hollow fiber membrane in the present invention, it is preferable to use a polymer material having a glass transition temperature Tg in a glass state that is 20 ° C. higher than normal temperature and use temperature. Since the hollow fiber membrane in the present invention controls the separation characteristics according to the degree of interaction between the base polymers and the filling state of the polymer unit, the structure of the polymer unit has changed near normal temperature or use temperature, The structure at the time of film formation cannot be maintained, and a rubber-like structure is not preferable because the desired separation characteristics cannot be reproduced.

As described above, the porous hollow fiber membrane of the present invention does not have a clear yield point in the SS curve obtained in the tensile test conducted in a wet state. That is, since the polymer network constituting the hollow fiber membrane has a degree of freedom (flexibility), it has a characteristic that the solute easily passes through the gaps in the network. Because of these characteristics, modules made using the hollow fiber membrane have the property of not causing clogging even when processing liquids containing a lot of protein components such as blood. Can be expressed. In the present application, as described later, clogging is less likely to occur by measuring clearance using a liquid to be treated containing various concentrations of β2 microglobulin (β2MG). The total protein concentration in the liquid to be treated is 6.5 g / dl, as described in the evaluation method for blood purifiers established by the Japanese Dialysis Medical Association (Vol. 29, No. 8, 1996, p.1239-1245) Represents standard measurement conditions. On the other hand, by setting the total protein concentration in the solution to be treated to 8.0 g / dl, it is possible to confirm the suppression of clogging under higher solute concentrations, and between patients with different nutritional status. It is possible to reduce the performance difference.
In the present invention, the clearance (β2MG) reduction rate is preferably 20% or less when measured under the condition (8.0 g / dl) where the total protein concentration is high with respect to the standard condition (6.5 g / dl). . More preferably, it is 15% or less, more preferably 10% or less, and still more preferably 5% or less.

As the material of the hollow fiber membrane in the present invention, cellulose-based polymers such as cellulose acetate (Tg 80 to 185 ° C.) and cellulose triacetate (Tg 174 ° C.), and polysulfones such as polysulfone (Tg 190 ° C.) and polyether sulfone (Tg 225 ° C.) Polymers, polyacrylonitrile (Tg105 ° C), polymethylmethacrylate (Tg115 ° C), ethylene vinyl alcohol copolymer (Tg85 ° C), etc., hollow fiber membranes with water permeability of 150 ml / m ² / hr / mmHg or more Cellulose-based and polysulfone-based materials that are easy to obtain are preferable. In particular, cellulose diacetate or cellulose triacetate is preferable for cellulose, and polysulfone or polyethersulfone is preferable for polysulfone because it is easy to reduce the film thickness.

  The idea in the present invention is to pursue in what state the base polymer that forms the hollow fiber membrane can be obtained. In the image of the entire hollow fiber membrane, the base polymer that forms the hollow fiber membrane is designed to have a certain porosity in order to have high water permeability. It has a filling structure that interacts at regular intervals. Considering the interaction between polymers as a network between polymers, for example, assuming a network-like network, the larger the number of network points, the smaller the size of the pores through which the substance to be separated permeates. Also, in such a state, the polymer-to-polymer network is severely constrained, and even in conditions where the degree of freedom of the polymer increases, such as in a wet state, it tries to maintain its original structure, so that the network between polymers is about to break. Little change in elastic deformation. In plastic deformation with a force greater than elastic deformation, once the polymer network begins to break, it is considered that the breaking strength decreases because the network is broken in a chain. In such a state, the basis of the present invention is that it has been found that the performance change due to the interaction between the membrane and the protein occurs remarkably.

  On the other hand, when designing a hollow fiber membrane with a polymer-packed structure that roughens the network between the polymers and is rich in mobility, water that increases the degree of freedom can be found where the constraints between the polymers are not strong. If there is, the elastic deformation hardly occurs, or when the yield point is forcibly read from the SS curve whose yield point is not clear, the yield strength is lower than that in the dry state. In addition, when the network between the polymers is rough, the packing of the polymer is not dense, the size of the pores through which the substance to be separated passes increases, and the membrane structure is advantageous for separating high molecular weight substances. It has been found that even when proteins interact, the original stable separation performance derived from the membrane structure can be expressed. In the plastic deformation of such a film, since the polymer interaction is originally weak, there is almost no difference in the force required to break the structure in the wet state and the dry state. The dry ratio is close to 1.

  The hollow fiber blood purifier of the present invention is suitable as a blood purifier used for the treatment of renal failure, such as hemodialysis, hemodiafiltration and hemofiltration. In addition, since the network between the polymers is designed to be relatively loose, it is excellent in the penetration of pore diameter retainers and can keep the shape of the pores stable. The risk of crushing is low, which is preferable for product safety. In addition, because the polymer structure is designed with a high degree of freedom in the polymer filling state and wet state, even in special environments such as blood, for example, when protein adsorbs or enters the pores, Because of its flexibility, protein immobilization is unlikely to occur, and clogging and adsorption are unlikely to occur, so stable treatment is possible regardless of the patient's health, symptoms and plasma protein concentration during blood purification. It is preferable in that it can be expected.

  As a method for producing a hollow fiber membrane used in such a blood purifier, the following conditions are preferable. In order to obtain high porosity and water permeability, the polymer concentration of the spinning solution is 30% by mass or less, more preferably 20% by mass or less. The dissolution temperature of the spinning solution is a balance between the composition of the polymer, the solvent, and the non-solvent. For example, in the case of cellulose triacetate, a range of 150 ° C. to 190 ° C. is preferable. After mixing, the spinning solution is uniformly dissolved and pushed out to the nozzle. During this time, it is preferable to provide a cooling step in order to control subsequent film formation.

  Although the effect of the cooling process is not clear, if the dope is protruded from the nozzle and the solidification process is performed in one step, the size of the polymer network will be uniform and the shape will be uniform, resulting in a strong network. I can guess. On the other hand, when the coagulation process is divided into two or more times under two or more conditions, the size of the polymer network becomes irregular and it is presumed that its strength is inferior compared to the former case. For example, cellulose triacetate dissolved at 160 ° C. is once cooled to 130 ° C. The cooling temperature is preferably 20 ° C to 100 ° C lower than the melting temperature. Cooling effect within 20 ℃ is hardly seen. Cooling at 100 ° C. or higher is not appropriate because the stock solution for spinning is completely gelled, which leads to subsequent clogging of the stock solution transport line and increased filter pressure. The spinning solution is preferably treated with a filter immediately before nozzle discharge for the purpose of removing insoluble components and gel in the spinning solution. The pore diameter of the filter is preferably small, and specifically, it is preferably less than the thickness of the hollow fiber membrane, more preferably 1/2 or less of the thickness of the hollow fiber membrane. When there is no filter or when the pore diameter of the filter exceeds the film thickness of the hollow fiber membrane, a part of the nozzle slit may be clogged, resulting in occurrence of uneven thickness yarn. Furthermore, if there is no filter or the filter pore size exceeds the film thickness of the hollow fiber membrane, partial voids due to the insoluble components in the spinning solution or the inclusion of gel, etc., and the texture of the surface structure in units of several tens of μm It causes the fineness to be disturbed (scratched or partially wrinkled). Partial voids in hollow fiber membranes with high porosity cause a reduction in the physical strength of the membrane. In addition, when the fineness of the surface of the hollow fiber membrane in units of several tens of μm is significantly disturbed, for example, when used as a blood purification membrane, the blood is activated and is likely to cause thrombus and residual blood. . It is considered that activating blood affects the performance stability. Filtration of the stock solution for spinning may be carried out a plurality of times before discharging, which is preferable because the life of the filter can be extended.

  The spinning dope treated as described above is discharged using a tube-in-orifice type nozzle having an annular portion on the outside and a hollow forming material discharge hole on the inside. By reducing variations in the slit width of the nozzle (the width of the annular portion that discharges the spinning dope), uneven thickness of the spun hollow fiber membrane can be reduced. Specifically, the difference between the maximum value and the minimum value of the slit width of the nozzle is preferably 10 μm or less. The slit width varies depending on the viscosity of the spinning dope used, the film thickness of the hollow fiber membrane to be obtained, and the type of hollow forming material, but if the nozzle slit width varies greatly, uneven thickness will be caused and the thin part will be torn. If it is ruptured and causes a leak, and the uneven thickness is remarkable, it may cause a failure to obtain an appropriate strength as a blood purification film.

  The nozzle temperature at the time of discharging the spinning dope is preferably lower than the general hollow fiber membrane production conditions in order to obtain a sufficient effect in the aerial running part of the next step. Specifically, 50 ° C. or higher and 130 ° C. or lower, and 55 ° C. or higher and 120 ° C. or lower are more preferable. If the nozzle temperature is too low, the viscosity of the dope increases and the pressure applied to the nozzle increases, and the spinning dope may not be stably discharged. On the other hand, if the nozzle temperature is too high, excessive mobility may be formed due to the high mobility of the polymer unit during the formation of the phase separation membrane.

  The discharged spinning solution is immersed in the coagulating liquid through the aerial traveling section. At this time, it is preferable that the aerial traveling section is surrounded by a member (spinning tube) that shields it from the outside air and is kept at a low temperature. Specifically, it is preferably 15 ° C. or less, more preferably 13 ° C. or less, by actual measurement. The low-temperature control of the aerial traveling unit is performed by a method of circulating a refrigerant through a spinning tube or a method of flowing a cooled wind. Cooling of the refrigerant and cooling of the wind can be controlled using liquid nitrogen or dry ice. In addition, the atmosphere of the aerial travel section is desirably kept uniform because it affects the phase separation of the spinning dope, and it is preferable not to cause unevenness by covering with an enclosure or the like. Unevenness in the atmosphere of the aerial traveling part is not appropriate because it causes variations in the microscopic membrane structure and causes problems in performance. As a method for preventing unevenness in the temperature and wind power of the aerial traveling portion, it is effective to make a hole of an appropriate size in the enclosure of the aerial traveling portion so that the cooled wind flows uniformly. The gelation rate in the film forming process can be controlled to be constant by appropriately reducing the nozzle temperature and keeping the temperature of the aerial traveling section low. In addition, by setting the aerial running part at a lower temperature than usual, abrupt gelation is promoted on the outer surface of the hollow fiber membrane. A three-layer structure having a dense layer is formed. In addition, it is considered that the polymer network structure excluding the innermost and outer layers can be relaxed by the effect of once cooling after completely dissolving the dope, and the characteristics of the present application can be imparted.

  A smaller draft ratio is preferable. Specifically, it is preferably 1 or more and 10 or less, and more preferably 8 or less. The draft ratio referred to here is the ratio of the discharge linear velocity of the spinning dope discharged from the nozzle to the hollow fiber membrane take-up speed. If the draft ratio is too large, tension may be applied during the formation of pores in the membrane, and the shape of the pores may be distorted, resulting in a decrease in permeation performance.

  The hollow forming material discharged from the nozzle together with the spinning dope has an important influence on the structure formation of the inner surface of the hollow fiber membrane. In order to design an ideal membrane structure, it was found that the composition of the hollow forming material, the nozzle temperature, the draft ratio, and low drawing in the spinning process are important. It is considered that the phase separation of the inner surface can be controlled by adjusting these conditions. Although the hollow forming material depends on the spinning dope used, it is preferable to use a liquid or gas that is inert to the spinning dope when phase separation is to be promoted. Specific examples of such a hollow forming material include liquid paraffin, isopropyl myristate, nitrogen, argon, and the like. In addition, in order to form a dense layer, an aqueous solvent solution or water used for preparing the spinning dope can be used. To these hollow forming materials, non-solvents such as glycerin, ethylene glycol, triethylene glycol, and polyethylene glycol, and additives such as antioxidants and lubricants can be added as necessary. In order to control the polymer network and control the performance, it is effective to cool the aerial traveling part. When the dope discharged from the nozzle is rapidly cooled in the aerial traveling part, the dense layer of the polymer network formed by the phase separation proceeding from the outer surface of the membrane, as the secondary separation layer, exhibits the fractionation characteristics. This is thought to contribute to sharpening.

  The gelled film is allowed to solidify by passing through a coagulation bath through the air running part. The coagulation bath is preferably an aqueous solution of the solvent used in preparing the spinning dope. When the coagulation bath is water, it solidifies rapidly and a dense layer is formed on the outer surface of the hollow fiber membrane. The rapidly solidified surface has a low porosity, but it is difficult to control the surface roughness. It is preferable to use a coagulation bath as a mixed solution of a solvent and water because the coagulation time can be easily controlled and the surface roughness of the hollow fiber membrane can be appropriately adjusted. The solvent concentration of the coagulation bath is preferably 70% by mass or less, and more preferably 50% by mass or less. Further, since the structure is greatly changed from the case of water alone because the solvent is contained even at 1% by mass, the lower limit of the solvent concentration is 1% by mass or more. The temperature of the coagulation bath is preferably 4 ° C. or more and 50 ° C. or less for controlling the coagulation rate. Furthermore, 10 degreeC or more and 45 degrees C or less are preferable. Thus, a hollow fiber membrane having a moderate size, distribution, and number of pores can be obtained by gently forming the hollow fiber membrane with the air running portion and the coagulation bath. A non-solvent such as glycerin, ethylene glycol, triethylene glycol, or polyethylene glycol, or an additive such as an antioxidant or a lubricant can be added to the coagulation bath as necessary. Further, since the film is in an initial stage in which the film is formed in the coagulation bath, prevention of stretching here is important for forming the film structure which is the object of the present application. The water flow in the coagulation bath is preferably in the same direction as the traveling direction of the hollow fiber membrane. The purpose is to reduce the resistance of the water flow to the hollow fiber membrane in order not to break or deform the membrane structure designed under various conditions set up to the coagulation bath. Furthermore, for the same reason, it is preferable that the stretching of the hollow fiber membrane after the coagulation bath is low. Specifically, the stretching ratio in the coagulation bath is preferably 0 or more and 10 or less, more preferably 5 or less, and even more preferably 2.5 or less.

  The hollow fiber membrane that has passed through the coagulation bath is washed away with unnecessary components such as a solvent through a washing step. The cleaning liquid used at this time is preferably water, and a temperature of 20 to 80 ° C. is preferable because the cleaning effect is enhanced. If it is less than 20 ° C., the cleaning efficiency is poor, and if it exceeds 80 ° C., the thermal efficiency is poor, and the burden on the hollow fiber membrane is large, which affects the storage stability and performance. In addition, the membrane is still active after the coagulation bath process, and if a force is applied from the outside in the washing bath, the membrane structure, surface shape and pore shape may be deformed. It is necessary to devise so that resistance is not applied as much as possible. In order to remove unnecessary components such as solvents and additives from the hollow fiber membrane, it is preferable to increase the renewal of the liquid. Conventionally, for example, the hollow fiber membrane is run in the shower of the cleaning liquid, or the flow of the cleaning liquid Cleaning efficiency was improved by making the running of the hollow fiber membrane counter-current. However, when such a cleaning method is adopted, the running resistance of the hollow fiber membrane increases, so that it has been necessary to prevent the hollow fiber membrane from being stretched and loosened or drooped.

  The inventors of the present invention have intensively studied in order to achieve both suppression of deformation of the hollow fiber membrane and cleanability, and as a result, have found that it is effective to flow the cleaning liquid and the hollow fiber membrane in the same direction (cocurrent flow).

  As a specific aspect of the washing step, for example, a facility in which the washing bath is inclined and the hollow fiber membrane is lowered is preferable. Specifically, the inclination of the bath is preferably 1 to 3 degrees. If it is 3 degrees or more, the flow rate of the cleaning liquid becomes too fast, and the liquid immersion necessary for solvent cleaning from the hollow fiber membrane may not be sufficient. If it is less than 1 degree, the cleaning failure of the hollow fiber membrane due to the retention of the cleaning liquid may occur. Thus, by suppressing the resistance to the hollow fiber membrane in the cleaning bath, the traveling speed of the hollow fiber membrane at the inlet of the cleaning bath and the traveling speed of the outlet can be made substantially the same. Specifically, the stretching ratio in the washing bath is preferably 0 or more and 10 or less, more preferably 5 or less, and even more preferably 2.5 or less. In order to further increase the cleaning efficiency, the cleaning baths are preferably arranged in multiple stages. The number of stages needs to be set as appropriate depending on the balance with detergency. For example, if the purpose is to remove the solvent, non-solvent, hydrophilizing agent, etc. used in the present invention, there are about 3 to 30 stages That's enough.

  The hollow fiber membrane that has undergone the washing step is subjected to glycerin treatment as necessary. For example, in the case of a hollow fiber membrane made of cellulosic polymer, after passing through a glycerin bath, it is wound through a drying step. In this case, the glycerin concentration is preferably 30 to 80% by mass. If it is less than 30% by mass, the hollow fiber membrane tends to shrink during drying and storage stability is poor. On the other hand, if it exceeds 80% by mass, excess glycerin tends to adhere to the hollow fiber membrane, and the adhesiveness at the end of the hollow fiber membrane may be deteriorated when assembled into a blood purifier. The temperature of the glycerin bath is preferably 40 ° C or higher and 80 ° C or lower. Below 40 ° C, the viscosity of the glycerin aqueous solution is high, and the glycerin aqueous solution may not reach all the pores of the hollow fiber membrane. Above 80 ° C, the hollow fiber membrane may be denatured by heat.

  In the spinning process as a whole, the tension applied to the hollow fiber membrane affects the structure of the membrane. Therefore, it is preferable not to stretch as much as possible in order not to change the membrane structure. This is because the membrane is still active after the coagulation bath process, and when an external force is applied in the washing bath, the membrane structure, surface structure and pore shape are deformed. In particular, the stretching causes the pore shape of the membrane to be deformed from a perfect circle to an ellipse, and therefore has a great influence on the permeation performance. Specifically, the ratio of the traveling speed of the hollow fiber membrane at the inlet of the coagulation bath to the winding speed at the end of the spinning process is preferably 1 or more and 10 or less, more preferably 1.5 or more and 7 or less, and even more preferably 5 or less.

  Unlike the intermediate layer, the innermost surface structure of the hollow fiber membrane thus obtained has a dense structure of the polymer network, which becomes the primary separation layer, and has a fractionation characteristic. It will be a part that determines the majority. In addition, the cooling of the aerial traveling portion affects the uniformity of the polymer network, and thus has a function of further sharpening the fractionation characteristics. On the other hand, when viewed as a whole membrane, the polymer network has a morphologically uniform but loose network structure, so that the pores between the base polymers are large, and the function of widening the water permeability and clogging tolerance is widened. Have

  Hereinafter, the effectiveness of the present invention will be described with reference to examples, but the present invention is not limited thereto. In addition, the evaluation method of the physical property in the following examples is as follows.

1. Measurement of inner diameter, outer diameter, and film thickness of hollow fiber membrane A sample of the cross section of the hollow fiber membrane can be obtained as follows. For the measurement, it is preferable to observe the dried hollow fiber membrane after the hollow forming material is washed and removed. There is no limitation on the drying method. However, when the shape changes remarkably by drying, it is preferable to clean and remove the hollow forming material and then completely replace with pure water, and then observe the shape in a wet state. The inner diameter, outer diameter, and film thickness of the hollow fiber membrane are cut through a razor on the upper and lower surfaces of the slide glass so that the hollow fiber membrane does not fall out into a hole of φ3mm in the center of the slide glass. Then, after obtaining a hollow fiber membrane cross-section sample, it is obtained by measuring the short diameter and long diameter of the hollow fiber membrane cross section using a projector Nikon-V-12A. Measure the short axis and long axis in two directions for each cross section of hollow fiber membrane, and calculate the arithmetic average value of each as the inner diameter and outer diameter of one hollow fiber membrane cross section. The film thickness is calculated as (outer diameter-inner diameter) / 2. did. The same measurement was performed on five cross sections, and the average value was defined as the inner diameter and film thickness.

2. Unevenness of wall Observe the cross section of 100 hollow fiber membranes with a 200x projector. In one field of view, the thickness of the thickest part and the thinnest part is measured with respect to one yarn cross section having the largest film thickness difference.
Thickness unevenness = thinnest part / thickest part thickening degree = 1, and the film thickness is perfectly uniform.

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

4, porosity
A hollow fiber membrane bundle immersed in pure water for 1 hour or more is centrifuged for 5 minutes at a rotation speed of 900 rpm, and the weight is measured. Then, it is completely dried in a dryer and the weight is measured (Mp).
Wt (weight of water clogged in holes) = weight of yarn bundle after centrifugation-Mp
Volume porosity (Vt)% = Wt / (Wt + Mp / polymer density) × 100

5. Yield strength, breaking strength, breaking elongation Using a Tensilon UTMII manufactured by Toyo Baldwin, the tensile speed was 100 mm / min and the distance between chucks was 100 mm. Samples were measured at n = 5 and average values were used.

6. Water permeability
Purified water kept at 37 ° C is placed in a pressurized tank, and the pressure is controlled by a regulator. Purified water is sent to the blood flow channel side of the dialyzer kept in a 37 ° C constant temperature bath. The pure water permeation rate of ml / hr was measured. At this time, the blood outlet circuit of the dialyzer (the outlet side from the pressure measurement point) is sealed with forceps to measure water permeability by the stop method. 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 was changed at four points, the filtration flow rate was measured, and the water permeability (ml / hr / mmHg) was calculated from the slope of the relationship. At this time, the correlation coefficient between TMP and filtration flow rate must be 0.99 or more. In order to reduce the pressure loss error due to the circuit, TMP is measured in the range of 100mmHg or less. The water permeability of the hollow fiber membrane is calculated by converting the water permeability of the dialyzer into a membrane area.
UFR (H) = UFR (D) / A
Where 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 ( m ² ).

7. Clearance (β2 microglobulin)
Plasma is separated from the bovine blood collected by adding citric acid and sodium heparin (suppressed clotting) by centrifugation. About 0.01 mg / dl of heparin sodium and β2 microglobulin (genetical recombination product Wako Pure Chemical Industries) are added as plasma for dialysis experiments. Only heparin sodium is added to circulating plasma. The separated plasma was diluted or concentrated so that the total protein concentrations were 6.5 g / dl and 8.0 g / dl, respectively. Prepare at least 2L of circulating plasma per blood purifier to be measured. Circulating plasma is flowed at a flow rate of 200 ml / min through the blood purifier (membrane area (A) 1.5 m ² ) primed one hour ago. At this time, one side on the dialysate side is plugged, and from one side, the filtrate is filled on the dialysate side while filtering at a Qf of 15 ml / min. After the filtrate is filled, the stopper is capped and plasma is circulated only for 1 hour on the blood side. After circulation, switch to plasma for dialysis experiment, and flow the dialysate at Qdin500ml / min while flowing the plasma in a single pass while filtering to Qbin200ml / min, Qbout185ml / min. Sample Qbout 4 minutes after starting diafiltration. The clearance (CLβ2) of the blood purifier is calculated from the β2MG concentration (Cbin) of the plasma stock solution, the β2MG concentration (Cbout) of the fluid that has passed through the blood purifier, and the flow rate. All operations are performed at 37 ° C.
CLβ2 = (Cbin x Qbin-Cbout x Qbout) / Cbin
The stability of blood performance and permeation performance was measured by using anticoagulant-added plasma adjusted so that the total protein concentrations were 6.5 g / dl and 8.0 g / dl, respectively.
According to the evaluation criteria of the Dialysis Medical Society, the total protein concentration of plasma used for the evaluation is 6.5 ± 0.5 g / dl, but it is 8.0 g / assuming the nutritional status of patients in the clinic and changes in the total protein concentration during dialysis. The concentration of dl was also evaluated.

8. Calculation of the amount of protein leak Prepared bovine blood to which citric acid was added and suppressed clotting to a hematocrit of 25-30% and a protein concentration of 6-7 g / dl, and sent to a blood purifier at 37 ° C at 200 mL / min The blood is filtered at a constant flow rate (Qf: ml / min). At this time, the filtrate is returned to blood to be a circulatory system. Measure the filtration flow rate every 15 minutes and collect the blood purifier filtrate. Measure the protein concentration in the filtrate. Measurement of protein concentration in plasma is performed using an in vitro diagnostic kit (MicroTP-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.). Based on the data up to 2 hours, calculate the average amount of protein leak from the formula below and calculate the amount of protein leak (TPL) when converted to 3L water removal.
Integrated filtration rate (ml) = t ₁ (min) x C _t1 (ml / min) + (t ₂ -t ₁ ) (min) x C _t2 (ml / min) + (t _3- t ₂ ) (min) × C _t3 (ml / min) ・ ・ ・ ・ ・ ・ (t ₁₂₀ -t _n ) (min) × C _120min (ml / min)
t: Measurement time (min)
C: Filtration flow rate (ml / min)
Protein concentration of filtrate = a × Ln (total filtration amount) + b
Obtain a and b from the protein concentration of the filtrate at each measurement point and Ln (integrated filtration rate).
TPL (average) = -a + b + a x Ln (integrated filtration rate x 2)
TPL (3L water removal equivalent) (g) = TPL (average) x 30/1000
For evaluation of reproducibility of blood performance and performance stability, TPL value converted to 3L water was used as an index.

9. Tg measurement
Tg was measured by DSC or referred to the literature.
References: Cellulose Dictionary (Asakura Shoten, November 10, 2000, first edition)
DSC was measured at a heating rate of 10 ° C / min.

10. Measurement of moisture content of hollow fiber membrane After measuring the mass of the hollow fiber membrane to be measured, it is dried in an oven at 105 ° C for 3 hours and then weighed again.
Calculated from the following formula.
Moisture content (%) = (mass before drying−mass after drying) / mass after drying × 100

Example 1
After mixing cellulose triacetate (manufactured by Daicel Chemical Industries) 19% by mass, N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) at a ratio of 75:25, a kneader The solution was uniformly dissolved while heating to 175 ° C., and then the film forming solution was defoamed. The obtained film-forming solution was aged in a line kept at a temperature of 145 ° C., 30 ° C. lower than the dissolution temperature, supplied to a 10 μm sintered filter, filtered, and then heated to 110 ° C. It is simultaneously discharged from the tube-in orifice nozzle together with liquid paraffin that has been degassed in advance as a hollow forming material, cut off from the outside air by a spinning tube, and after passing through a 70 mm air gap adjusted to 12 ° C, 20 mass at 40 ° C % NMP / TEG (75/25) coagulant was used. After running 50 cm in the coagulation bath, the water flow in the coagulation bath at this time was circulated in the same direction as the running direction of the membrane so as not to impose a burden on the hollow fiber membrane, and then a 30 ° C water washing bath After passing through, it was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up at a spinning speed of 70 m / min. The draft ratio of the film forming solution was 6. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 2.5 degrees and the washing water gradually descended, and the water was allowed to flow in the same direction as the hollow fiber membrane, and the washing bath had five stages. The draw ratio in the coagulation bath was 2.0%, and the draw ratio in the water washing bath was 0.1%. The draw ratio from the entrance of the coagulation bath to winding was 3.5%. The obtained hollow fiber membrane had an inner diameter of 200.3 μm, a film thickness of 15.8 μm, a thickness deviation of 0.7, and a porosity of 74.5%. The results of measuring the yarn quality of the hollow fiber membrane are shown in Table 1. The Tg of cellulose triacetate used was 174 ° C.

Using the obtained hollow fiber membrane, a blood purifier was assembled so that the membrane area was 1.5 m ² . The effective length of the hollow fiber membrane filled in the module was 22.5 cm. This blood purifier was tested for water permeability, clearance by blood with different protein concentrations (β2 microglobulin), and protein leak test. The results are shown in Table 2. Clearance values in systems with different protein concentrations were reproducible and both were 55 ml / min or higher. The protein leak value was 0.7 g, which was sufficiently low.

(Example 2)
After mixing cellulose triacetate (Daicel Chemicals) 17.5% by mass, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical) and triethylene glycol (TEG, Mitsui Chemicals) at a ratio of 70:30, kneader The solution was uniformly dissolved while heating to 180 ° C., and then the film forming solution was defoamed. The obtained film-forming solution was aged in a line kept at 150 ° C with a heating medium 30 ° C lower than the dissolution temperature, supplied to a 10 µm sintered filter, filtered, and then heated to 105 ° C From the tube-in-orifice nozzle, discharged together with liquid paraffin previously degassed as a hollow forming material, blocked from the outside air by a spinning tube, passed through a 70 mm air gap adjusted to 11 ° C, and then 30 mass at 35 ° C % NMP / TEG (70/30) coagulation solution. After running 50 cm in the coagulation bath, the water flow in the coagulation bath at this time was circulated in the same direction as the running direction of the membrane so as not to impose a burden on the hollow fiber membrane, and then a 30 ° C water washing bath After passing through, it was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up at a spinning speed of 70 m / min. The draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 2 degrees so that the washing water slowly descended, and the water was allowed to flow in the same direction as the hollow fiber membrane, and the washing bath had five stages. The stretching ratio in the coagulation bath was 1.5%, and the stretching ratio in the water washing bath was 1.5%. The draw ratio from the entrance of the coagulation bath to winding was 2.0%. The obtained hollow fiber membrane had an inner diameter of 200.7 μm, a film thickness of 15.5 μm, a thickness deviation of 0.7, and a porosity of 83.5%. The results of measuring the yarn quality of the hollow fiber membrane are shown in Table 1.

Using the obtained hollow fiber membrane, a blood purifier was assembled so that the membrane area was 1.5 m ² . The effective length of the hollow fiber membrane filled in the module was 22.5 cm. This blood purifier was tested for water permeability, clearance by blood with different protein concentrations (β2 microglobulin), and protein leak test. The results are shown in Table 2. Reproducibility was good even in systems with different protein concentrations, and both clearance values were as high as 64 ml / min. The protein leak value was as low as 1.4 g.

(Example 3)
After mixing cellulose triacetate (Daicel Chemical Co., Ltd.) 20.0% by mass, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical Co., Ltd.) and triethylene glycol (TEG, Mitsui Chemicals Co., Ltd.) in a ratio of 70:30, kneader The solution was uniformly dissolved while heating to 180 ° C., and then the film forming solution was defoamed. The obtained film-forming solution was aged in a line kept at 160 ° C with a heating medium 20 ° C lower than the dissolution temperature, supplied to a 10 µm sintered filter, filtered, and then heated to 120 ° C It is simultaneously discharged from the tube-in orifice nozzle together with liquid paraffin that has been degassed in advance as a hollow forming material, cut off from the outside air by a spinning tube, and after passing through a 70 mm air gap adjusted to 12 ° C, 20 mass at 40 ° C % NMP / TEG (70/30) coagulation solution. After running 50 cm in the coagulation bath, the water flow in the coagulation bath at this time was circulated in the same direction as the running direction of the membrane so as not to impose a burden on the hollow fiber membrane, and then a 30 ° C water washing bath After passing through, it was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up at a spinning speed of 70 m / min. The draft ratio of the film forming solution was 6. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 2 degrees so that the washing water slowly descended, and the water was allowed to flow in the same direction as the hollow fiber membrane, and the washing bath had five stages. The stretch ratio in the coagulation bath was 2.0%, and the stretch ratio in the washing bath was 2.0%. The draw ratio from the entrance of the coagulation bath to winding was 4.0%. The resulting hollow fiber membrane had an inner diameter of 200.5 μm, a film thickness of 15.3 μm, a thickness deviation of 0.8, and a porosity of 68.0%. The results of measuring the yarn quality of the hollow fiber membrane are shown in Table 1.

Using the obtained hollow fiber membrane, a blood purifier was assembled so that the membrane area was 1.5 m ² . The effective length of the hollow fiber membrane filled in the module was 22.5 cm. This blood purifier was tested for water permeability, clearance by blood with different protein concentrations (β2 microglobulin), and protein leak test. The results are shown in Table 2. Reproducibility was good even in systems with different protein concentrations, and both clearance values were as high as 50 ml / min and high performance. The protein leak value was as low as 0.4 g.

Example 4
After mixing cellulose triacetate (Daicel Chemicals) 16.5% by mass, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical) and triethylene glycol (TEG, Mitsui Chemicals) at a ratio of 80:20, kneader The solution was uniformly dissolved while heating to 175 ° C., and then the film forming solution was defoamed. The obtained film-forming solution was aged on a line kept warm with a 145 ° C heating medium 30 ° C lower than the dissolution temperature, supplied to a 10 µm sintered filter, filtered, and then heated to 105 ° C It is simultaneously discharged together with liquid paraffin previously degassed as a hollow forming material from the tube-in orifice nozzle, cut off from the outside air by a spinning tube, passed through a 70 mm air gap adjusted to 10 ° C, and then 30 mass at 35 ° C % NMP / TEG (70/30) coagulation solution. After running 50 cm in the coagulation bath, the water flow in the coagulation bath at this time was circulated in the same direction as the running direction of the membrane so as not to impose a burden on the hollow fiber membrane, and then a 30 ° C water washing bath After passing through, it was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up at a spinning speed of 70 m / min. The draft ratio of the film forming solution was 6. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 2 degrees so that the washing water slowly descended, and the water was allowed to flow in the same direction as the hollow fiber membrane, and the washing bath had five stages. The stretching ratio in the coagulation bath was 1.5%, and the stretching ratio in the water washing bath was 1.5%. The draw ratio from the entrance of the coagulation bath to winding was 2.0%. The resulting hollow fiber membrane had an inner diameter of 200.8 μm, a film thickness of 15.6 μm, a thickness deviation of 0.7, and a porosity of 86.2%. The results of measuring the yarn quality of the hollow fiber membrane are shown in Table 1.

Using the obtained hollow fiber membrane, a blood purifier was assembled so that the membrane area was 1.5 m ² . The effective length of the hollow fiber membrane filled in the module was 22.5 cm. This blood purifier was tested for water permeability, clearance by blood with different protein concentrations (β2 microglobulin), and protein leak test. The results are shown in Table 2. Reproducibility was good even in systems with different protein concentrations, and both clearance values were 74 ml / min and high performance. The protein leak value was 2.5 g.

(Comparative Example 1)
After mixing cellulose triacetate (manufactured by Daicel Chemical Industries) 19% by mass, N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) at a ratio of 70:30, kneader The solution was uniformly dissolved while heating to 175 ° C., and then the film forming solution was defoamed. The obtained film-forming solution was supplied to a line maintained at 145 ° C with a heat medium and a 20 µm sintered filter, filtered, and then degassed in advance as a hollow forming material from a tube-in orifice nozzle heated to 105 ° C. It is discharged simultaneously with the treated liquid paraffin, cut off from the outside air by a spinning tube, and after passing through a 70mm air gap adjusted to 12 ° C, it becomes a solidified solution of 20% NMP / TEG (70/30) at 40 ° C. Provided. After running 50 cm in the coagulation bath, run in the direction opposite to the circulation in the coagulation bath through the guide, then go through a 30 ° C water washing bath, pass through a glycerin bath at 50 ° C and 60% by mass, and with a dryer It was dried and wound up at a spinning speed of 85 m / min. The draft ratio of the film forming solution was 11. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 0.5 degrees and the washing water slowly rose, the water was allowed to flow in a countercurrent flowing in the opposite direction to the hollow fiber membrane, and the washing bath had seven stages. The stretching ratio in the coagulation bath was 12%, and the stretching ratio in the water washing bath was 12%. The draw ratio from the entrance of the coagulation bath to winding was 20%. The resulting hollow fiber membrane had an inner diameter of 198.9 μm, a film thickness of 14.8 μm, a thickness deviation of 0.7, and a porosity of 75.7%. The results of measuring the yarn quality of the hollow fiber membrane are shown in Table 1.

Using the obtained hollow fiber membrane, a blood purifier was assembled so that the membrane area was 1.5 m ² . The effective length of the hollow fiber membrane filled in the module was 22.5 cm. This blood purifier was tested for water permeability, clearance by blood with different protein concentrations (β2 microglobulin), and protein leak test. The results are shown in Table 2. Since stretching was applied, the water permeability was 282 mL / hr / mmHg / m ² , whereas the clearance values were as low as 49 and 42 ml / min.

(Comparative Example 2)
After mixing cellulose triacetate (manufactured by Daicel Chemical Industries) 19% by mass, N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) at a ratio of 70:30, kneader The solution was uniformly dissolved while heating to 175 ° C., and then the film forming solution was defoamed. The obtained film-forming solution was supplied to a line maintained at 145 ° C. with a heat medium and a 20 μm sintered filter, filtered, and then degassed in advance as a hollow forming material from a tube-in orifice nozzle heated to 135 ° C. It is discharged simultaneously with the treated liquid paraffin, cut off from the outside air by a spinning tube, passed through a 70mm air gap adjusted to 20 ° C, and then into a coagulating liquid of 20% by mass NMP / TEG (70/30) at 40 ° C. Provided. After running 50 cm in the coagulation bath, run in the direction opposite to the circulation in the coagulation bath through the guide, then go through a 30 ° C water washing bath, pass through a glycerin bath at 50 ° C and 60% by mass, and with a dryer It was dried and wound up at a spinning speed of 70 m / min. The draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. The washing bath was adjusted to have an inclination of 2.0 degrees, so that the washing water slowly descended, and the water was made to flow in the same direction as the hollow fiber membrane, and the washing bath was composed of 5 stages. The stretching ratio in the coagulation bath was 1.5%, and the stretching ratio in the water washing bath was 1.5%. The draw ratio from the entrance of the coagulation bath to winding was 2.0%. The obtained hollow fiber membrane had an inner diameter of 200.4 μm, a film thickness of 15.3 μm, a thickness deviation of 0.7, and a porosity of 76.4%. The results of measuring the yarn quality of the hollow fiber membrane are shown in Table 1.

Using the obtained hollow fiber membrane, a blood purifier was assembled so that the membrane area was 1.5 m ² . The effective length of the hollow fiber membrane filled in the module was 22.5 cm. This blood purifier was tested for water permeability, clearance by blood with different protein concentrations (β2 microglobulin), and protein leak test. The results are shown in Table 2. The protein leak amount was as high as 2.4 g due to the high temperature in the air running section from the nozzle, and the clearance value changed from 45 to 54 ml / min depending on the protein concentration in the blood.

(Comparative Example 3)
After mixing cellulose triacetate (Daicel Chemicals) 17.5% by mass, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical) and triethylene glycol (TEG, Mitsui Chemicals) at a ratio of 70:30, kneader The solution was uniformly dissolved while heating to 180 ° C., and then the film forming solution was defoamed. The obtained film-forming solution was supplied to a line maintained at 180 ° C. with a heat medium and a 20 μm sintered filter, filtered, and then degassed in advance as a hollow forming material from a tube-in orifice nozzle heated to 120 ° C. It is discharged simultaneously with the treated liquid paraffin, cut off from the outside air by a spinning tube, passed through a 70mm air gap adjusted to 13 ° C, and then into a coagulating liquid of 20% NMP / TEG (70/30) at 40 ° C. Provided. After running 50 cm in the coagulation bath, run in the same direction as the circulation in the coagulation bath through a guide, then pass through a water washing bath at 30 ° C, then pass through a glycerin bath at 50 ° C and 60% by mass, with a dryer It was dried and wound up at a spinning speed of 75 m / min. The draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. The washing bath was adjusted to have an inclination of 2.0 degrees, so that the washing water slowly descended, and the water was made to flow in the same direction as the hollow fiber membrane, and the washing bath was composed of 5 stages. The stretching ratio in the coagulation bath was 2.0%, and the stretching ratio in the water washing bath was 1.5%. The draw ratio from the entrance of the coagulation bath to winding was 3.5%. The obtained hollow fiber membrane had an inner diameter of 200.4 μm, a film thickness of 14.9 μm, a thickness deviation of 0.7, and a porosity of 85.7%. The results of measuring the yarn quality of the hollow fiber membrane are shown in Table 1.

Using the obtained hollow fiber membrane, a blood purifier was assembled so that the membrane area was 1.5 m ² . The effective length of the hollow fiber membrane filled in the module was 22.5 cm. This blood purifier was tested for water permeability, clearance by blood with different protein concentrations (β2 microglobulin), and protein leak test. The results are shown in Table 2. Since the dope cooling and aging processes were not provided, the polymer network structure was not ideal and the clearance value was on the order of 50 ml / min, whereas the protein leak amount was as high as 1.5 g, blood The clearance value varied from 50 to 59 ml / min depending on the protein concentration in the medium.

  The hollow fiber blood purifier of the present invention has a high water permeability and a characteristic of having stable blood performance. Therefore, there is an advantage that a stable therapeutic effect that does not depend on a change in the blood concentration of the patient can be expected. Therefore, it can greatly contribute to industrial development.

The figure which shows the result (S-S curve) of the thread | yarn test of the hollow fiber membrane obtained in Example 2. FIG. The figure which shows the result (S-S curve) of the yarn test of the hollow fiber membrane obtained in Comparative Example 1.

Claims (6)

A porous hollow fiber membrane having a porosity of 60% or more and a water permeability of pure water at 37 ° C. of 150 to 1500 mL / m ² / hr / mmHg, wherein the porous hollow fiber membrane is pulled in a wet state A porous hollow fiber membrane excellent in permeation performance stability, characterized in that no yield point is observed in the SS curve obtained in the test.   The porous hollow fiber membrane excellent in permeation performance stability according to claim 1, wherein a clear yield point is observed in an SS curve obtained in a tensile test of the hollow fiber membrane in a dry state.   The porous hollow fiber membrane excellent in permeation performance stability according to claim 1 or 2, wherein a yield strength is 8.0 g / filament or more when a tensile test is performed in a dry state.   The permeation performance stability according to any one of claims 1 to 3, wherein when the wet state and the dry state are compared, the yield strength is significantly reduced with respect to changes in the breaking strength and breaking elongation in the wet state. Excellent porous hollow fiber membrane.   The ratio of wet strength to dry strength (wet / dry) is less than 0.7, and the ratio of break strength (wet / dry) is 0.7 to 1.3. Item 5. A porous hollow fiber membrane excellent in permeation performance stability according to any one of Items 1 to 4. A blood purifier produced using the porous hollow fiber membrane according to any one of claims 1 to 5.

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