JP5212837B2 - Permselective hollow fiber membrane - Google Patents

Description

  The present invention relates to a hollow fiber membrane made of a cellulose acetate polymer. Specifically, the present invention has been conventionally achieved by forming a thin separation active layer (dense layer) at least on the inner surface side of the hollow fiber membrane and providing a specific dense structure in the direction from the inner surface side to the outer surface side. The present invention relates to a hollow fiber membrane having high solute permeability, filtration stability and high strength.

  Hollow fiber membranes have been widely used in the field from reverse osmosis to microfiltration. Currently, hollow fiber modules are often used to purify the blood of patients with renal failure. This is because the housing contains a large number of separation membranes, for example, hollow fiber membranes, the patient's blood is flowed through the hollow portions, and the dialysate is flowed into the outside, that is, the hollow fiber membrane gaps. By removing the waste products in the blood by dialysis through the filter, the electrolyte concentration is corrected, and the medium molecular weight substances and excess water in the blood are removed by filtration by applying a pressure difference inside and outside the hollow fiber membrane. It is. Furthermore, a hollow fiber membrane may be used to separate only plasma from blood or remove specific components from the plasma to treat autoimmune diseases and the like. Recently, it has been confirmed that a therapeutic effect can be obtained by using a hollow fiber membrane for protein permeable hemodialysis or protein permeable hemofiltration dialysis.

  By the way, in recent years, parathyroid hormone is considered to be related to β2 microglobulin (β2MG, molecular weight: 11,800), pruritus, and hyperlipidemia, which are related to long-term complications of dialysis patients and are considered as causative substances of dialysis amyloidosis. (Molecular weight: about 9,500), erythroblast-inhibiting factor involved in anemia, arthralgia, substance having a molecular weight of 20,000 to 40,000, for example, α1 microglobulin (α1MG, molecular weight: 33,000) The necessity of removing toxic substances in the relatively high molecular weight region is screamed. On the other hand, the loss of albumin (molecular weight: 66,000) useful for the human body must be avoided as much as possible. That is, there is a demand for a selectively permeable membrane excellent in the permeability of a substance having a molecular weight of 20,000 to 40,000 and having a high molecular weight of 60,000 or more and having a good molecular weight and sharp-cut property.

  As described above, a hollow fiber membrane for blood treatment must selectively permeate a specific substance depending on the purpose, and its performance depends on the material of the hollow fiber membrane, the membrane structure, and the porosity (pore size). And the number) and the film thickness.

  In order to obtain the above-mentioned membrane performance, a hollow fiber membrane having as high a water permeability (UFR) as possible is necessary. Conventionally, synthetic polymers such as polysulfone, as seen in Patent Documents 1 and 2, for example, The thing which comparatively satisfy | filled the said request | requirement is obtained. However, these patent documents do not describe the removal efficiency of α1-microglobulin.

  In addition, as shown in Patent Document 3, the liquid used when wet spinning a hollow fiber membrane uses a liquid paraffin, higher alcohol, isopropyl myristate, or the like that has no solidification (low) for cellulose acetate polymers. In this case, the asymmetric structure as described above could not be obtained.

  For example, Patent Documents 4 and 5 disclose cellulose triacetate films having an asymmetric structure having a dense layer on the inner surface. In these patent documents, an aqueous solution having a solidification property is used as an internal solution, and a two-layer or multi-layer film structure which has been conventionally realized with a synthetic polymer can be obtained. However, it is described that it is very difficult to stabilize the hollow fiber membrane production because the spinnability is lowered when the aqueous solution concentration of the internal solution is lowered. Thus, in order to use as a hemodialyzer, not only the productivity of the hollow fiber membrane is ensured, but the total productivity cannot be improved unless the assembly property of the module is also secured. Therefore, there is room for improvement in order to improve the overall productivity.

  In addition, the pore diameter of the micropores in the layer near the surface of the inner wall of the membrane is 500 nm or less, and has at least one maximum pore size in the pore size distribution distributed in the cross section in the film thickness direction. The pore diameter of the layer near the surface is 1.2 times or more and the pore diameter of the layer near the surface of the outer membrane wall is 0.6 or more and less than 1.2 times the pore diameter of the layer near the membrane inner wall surface. A hollow fiber separation membrane is disclosed. (See Patent Document 6). However, the hollow fiber membrane described in this patent document has a water permeability that may be because the pore diameter of the layer near the surface of the outer wall of the membrane is relatively small for the purpose of preventing reverse entry of endotoxin from the dialysate into the blood. It is too low to increase the removability of low molecular weight proteins typified by β2MG.

  Also disclosed is a hollow fiber membrane comprising a cellulose derivative and having a dense layer at least on the inner surface and a porous layer on the outer layer, and a method for producing the same. (See Patent Documents 7 to 10). However, the hollow fiber membranes described in these patent documents have a large thickness in order to ensure the membrane strength, and the compactness that is the merit of the hollow fiber membrane type module is impaired.

  Patent Document 11 discloses a technique related to a hollow fiber membrane having an asymmetric structure made of a cellulose acetate polymer. Although the hollow fiber membrane described in this patent document has a high membrane strength for a thin film thickness and a relatively high β2MG permeability, it achieves performance up to type IV of the dialyzer function classification. It ’s just that.

JP 58-104940 A JP 61-93801 A JP 54-88881 A Japanese Patent Laid-Open No. 10-263375 Japanese Patent Laid-Open No. 10-165775 Japanese Patent Laid-Open No. 9-47645 JP-A-10-66725 Japanese Patent Laid-Open No. 10-85569 JP 10-85570 A Japanese Patent Laid-Open No. 10-165775 JP 2008-178814 A

Akiba et al., Dialysis Society 41 (3), p159-167, 2008

  The present invention aims to solve such problems of the prior art. Specifically, the present invention provides a specific dense structure in the film thickness direction of the hollow fiber membrane, and has high water permeability and molecular weight content. It imparts image characteristics and solute permeability. In particular, it is an object of the present invention to provide a hollow fiber membrane that can enhance removal of harmful substances having a size of β2MG to α1MG and outflow prevention of useful substances such as albumin in hemodialysis and hemodiafiltration. To do.

  As a result of intensive studies to achieve the above object, the present inventors have finally completed the present invention.

That is, the present invention has the following configurations (1) to (4).
(1) A hollow fiber membrane having an asymmetric structure made of a cellulose acetate polymer, wherein the hollow fiber membrane is observed at a magnification of 10,000 using a scanning electron microscope.
(A) The presence rate of pores of 300 nm or more on the inner surface is 0.5% or less ,
(B) In the cross section of the hollow fiber membrane, the porosity of the region from the inner surface to 20% of the film thickness is 0.1 to 5%, and the porosity of the region from the outer surface to 20% of the film thickness is 22 ~ 30%, the porosity of the other intermediate region is 10-20%,
When a module having a membrane area of 1.5 m ² based on the inner diameter standard is produced using a hollow fiber membrane , human β2MG (molecular weight 18,000) is adjusted to a concentration of 0.05 to 0.1 mg / l on the blood channel side. The total protein concentration added was 6.5 ± 0.5 g / dl, ACD-added bovine plasma kept at 37 ° C. was flowed at a flow rate of 200 ml / min, dialysate was flowed to the dialysate side at 500 ml / min, and the filtration flow rate was 15 ml / min. The clearance of β2MG at the time of 60 minutes and 240 minutes after the start of dialysis is 65 ml / min or more, and
A structure in which the initial hole area ratio increases from the inner surface toward the outer surface, the hole area ratio remains almost constant from the middle part to the vicinity of the outer surface, and the hole area ratio increases again near the outer surface. the hollow fiber membrane according to claim <br/> to have.
(2) The hollow fiber membrane according to (1), wherein the average surface roughness on the inner surface is 10 nm or less.
(3) The hollow fiber membrane according to (1) or (2), wherein the porosity of the inner surface is 0.5% or less.
(4) The hollow fiber membrane according to any one of (1) to (3), including a step of discharging the membrane-forming stock solution and the internal solution from a double tubular nozzle and then allowing the membrane to pass through an air gap and then coagulating in a coagulation bath. In the manufacturing method of
(A) The film-forming stock solution comprises a cellulose acetate polymer, a solvent of the polymer and a non-solvent,
(B) The content of water in the internal solution is 95% by weight or more and 100% by weight or less,
(C) The temperature of the film-forming stock solution at the nozzle part is 70 ° C. or higher and 110 ° C. or lower, and the temperature of the internal solution is 0 ° C. or higher and 40 ° C. or lower,
(D) the solvent concentration of the coagulation bath is 40 wt% or more and 60 wt% or less;
(E) the nozzle draft ratio is 0.9 to 1.3;
(F) The nozzle slit outer diameter is 220 to 330 μm, and the slit inner diameter is 150 to 270 μm.
A method characterized by.

  The hollow fiber membrane of the present invention is a so-called asymmetric structure membrane having a dense layer at least on the inner surface side. However, the intermediate portion of the membrane has a structure close to a homogeneous structure, and the inner surface is smooth and has an appropriate porosity. As a result, the strength of the hollow fiber membrane, the stability of solute removal, and the suppression of leakage of useful proteins are compatible at a high level even though it is a very thin film. Therefore, there is an effect that it can be suitably used not only for hemodialysis but also for hemodiafiltration and blood filtration.

An example of the SS curve which shows the measurement result of the strong elongation per dry hollow fiber membrane is shown. An example when the cross section of the hollow fiber membrane of the present invention is observed with a scanning electron microscope at a magnification of 5,000 times is shown. An example is shown when the inner surface of the hollow fiber membrane of the present invention is observed with a scanning electron microscope at a magnification of 10,000 times. An example when the outer surface of the hollow fiber membrane of the present invention is observed with a scanning electron microscope at a magnification of 10,000 times is shown. An example when a cross section of a conventional asymmetric hollow fiber membrane is observed with a scanning electron microscope at a magnification of 2,000 times is shown.

  Conventionally, as a separation membrane, a homogeneous structure membrane having a substantially uniform membrane structure from one membrane surface to the other membrane surface, or a dense layer on one surface so that the pore diameter gradually increases toward the other surface. Asymmetric structure films are the mainstream. In a hollow fiber membrane for blood purification, in the case of an asymmetric structure that has a thin dense layer on the inner surface side and the pore diameter increases toward the outer surface side, only the thin dense layer contributes to the permeation of the removed substance. The portion other than the dense layer (support layer) is not advantageous in permeation due to its large pore size, and is advantageous for enhancing the removability of low molecular weight proteins typified by β2 microglobulin (β2MG). The support layer mainly plays a role of maintaining the strength of the film. However, in the blood purification membrane, the thickness of the dense layer is usually very thin, about 0.1 to several μm, so that the influence of the pore distribution cannot be absorbed, and fractionation (removal of β2MG and albumin) There was a limit in improving leakage control.

  The hollow fiber membrane of the present invention belongs to a so-called asymmetric structure membrane in that it has a dense layer on the inner surface side and the outer surface side has an enlarged pore diameter compared to the inner surface side. When the hollow fiber membrane is observed at a magnification of 10,000 using a scanning electron microscope (SEM), no pores are substantially observed on the inner surface. Moreover, it is preferable that average surface roughness (Ra) showing the arithmetic average of the unevenness | corrugation of all the measurement points with respect to the reference point at the time of measuring the unevenness | corrugation of the film | membrane surface with an atomic force microscope is 10 nm or less.

  The fact that pores are not substantially observed means that the abundance ratio of pores having a major axis of 3 mm or more, that is, pores having a diameter of 300 nm or more on the inner surface is 0.5% or less in a photograph at a magnification of 10,000. Most preferably, no pores or irregularities are observed when observed at a magnification of 10,000 times. However, if the abundance of the pores is about 0.5% or less and the Ra value is 10 nm or less, clogging of the film in actual use This is advantageous in suppressing the generation of so-called secondary layers and improving the temporal stability of ultrafiltration speed and solute separation performance.

  Furthermore, when the membrane structure of the support layer portion is closely observed, the hollow fiber membrane of the present invention increases in the initial porosity from the inner surface to the outer surface, and passes through the intermediate portion as it is to the vicinity of the outer surface. This is different from the conventional asymmetric structure film in that the porosity changes substantially constant and the porosity increases again near the outer surface. That is, having a dense layer on the inner surface side means that the dense layer on the inner surface defines fractionation (preventing the outflow of albumin, which is a useful substance), and the intermediate layer has permeability (removal of β2MG, etc.). The contribution to the fractionation and permeability means that the dense layer on the inner surface side is the main and the intermediate part and the outer surface side are the subordinates. When a fluid such as blood is processed, shearing force due to the fluid is generated on the inner surface, so that it is easy to avoid accumulation of protein in the blood on the surface. At this time, the effect is further enhanced by the presence of the dense layer on the surface. In addition, it is advantageous that the portion behind the dense layer is a sponge-like support layer having a large pore diameter and a large porosity because the fluid resistance is low and high permeability can be easily obtained. However, if it does so, it will be necessary to make a film thickness thick in order to ensure the required film | membrane intensity | strength, and there exists a problem by which the compactness which is the merit of a hollow fiber membrane type module is impaired. Therefore, in the present invention, not only a dense layer is provided on the inner surface side, but also a relatively dense structure in which the pore diameter and porosity of the layer in the vicinity of the middle part of the film thickness portion do not become the permeation resistance of the removed substance. By doing so, it became possible to ensure high solute removal property and strength without increasing the film thickness.

  The structure of the hollow fiber membrane of the present invention as described above can be confirmed by observing the cross section of the hollow fiber membrane with a scanning electron microscope of 10,000 times. That is, when the cross section of the hollow fiber is divided almost equally into 5 from the inside to the outside and the open area ratio of each (sections 1, 2, 3, 4, 5) is measured, 1 to 5%, 10 to 20% in the cross sections 2 to 4, and 22 to 30% in the cross section 5. Of course, the open area ratio does not change discontinuously between the cross sections 1 and 2 or the cross sections 4 and 5, and the open area ratio changes continuously in the cross section direction even when viewed from the manufacturing conditions of the hollow fiber membrane. ing. However, the hollow fiber membrane of the present invention has acquired a stepwise gradient structure rather than a linear gradient structure like a general asymmetric structure membrane by adjusting the phase separation conditions. By giving such a structure to the separation membrane, it is possible to achieve both high performance and high strength while being a very thin film.

  In the present invention, in order to ensure blood flow stability, the inner diameter of the hollow fiber membrane is preferably 150 μm or more and 300 μm or less. If the inner diameter of the hollow fiber membrane is too small, the blood flow linear velocity increases, and the blood cell component may be damaged. On the other hand, if the hollow fiber membrane is too large in diameter, the blood shear rate and pressure loss will not increase, the filtration effect contributing to the permeation of medium high molecular weight substances will be reduced, and the module (blood There is a possibility that the convenience of use is impaired, for example, the size of the purifier must be increased unnecessarily. Therefore, the inner diameter of the hollow fiber membrane is more preferably 160 μm or more and 280 μm or less, and further preferably 170 μm or more and 260 μm or less.

  In the present invention, the thickness of the hollow fiber membrane is preferably 10 μm or more and less than 30 μm. If the hollow fiber membrane is too thin, the permeation performance will increase, but it may be difficult to maintain the required strength.If the membrane is too large, the permeation resistance of the substance will increase and the permeability of the removed substance will increase. It may be insufficient. In addition, there is a possibility that the convenience of use may be impaired because the size of the module needs to be increased. Therefore, the film thickness of the hollow fiber membrane is more preferably 12 μm or more and 28 μm or less, and further preferably 13 μm or more and 26 μm or less.

  As basic production conditions for obtaining the hollow fiber membrane of the present invention, conditions as described in Patent Documents 7 to 11 can be adopted. Using a film-forming stock solution consisting of a polymer, a polymer solvent and a non-solvent, and an internal solution solidifying with respect to the polymer, it is discharged simultaneously from a double tubular nozzle, passed through an air gap, and then coagulated bath To solidify and fix the hollow fiber membrane shape. Excess solvent and non-solvent are removed from the obtained hollow fiber membrane in a washing bath, a membrane pore retainer is impregnated in the pores, and then dried and wound up.

  In the conventional method for obtaining an asymmetric membrane, it is necessary to adjust the viscosity of the film-forming stock solution within the spinning range in order to ensure the fluidity of the film-forming stock solution and obtain the desired performance. However, decreasing the polymer concentration in the membrane forming stock solution to adjust the viscosity results in a decrease in the polymer density in the formed hollow fiber membrane, leading to a decrease in the strength of the hollow fiber membrane.

  Generally, when the polymer concentration is increased, the viscosity of the film-forming stock solution is increased and the fluidity is lowered. Therefore, it is necessary to set the nozzle temperature relatively high to ensure the fluidity of the film-forming stock solution. Increasing the nozzle temperature itself is not particularly difficult, but in order to form a dense layer on the inner surface of the hollow fiber membrane, it is necessary to use an aqueous solution as the internal solution, and the nozzle temperature is set to prevent boiling of the aqueous solution. Must be set. Accordingly, as a result of intensive investigations to prevent the boiling of the internal solution while ensuring the fluidity of the film forming stock solution, the present inventors separately control the temperature until immediately before discharging the film forming stock solution and the internal solution from the nozzle. Found a means. Specifically, it has succeeded in securing the fluidity of the film-forming stock solution while preventing the boiling of the internal solution by using the means described later.

  In the present invention, a cellulose acetate polymer is used as a material for a separation membrane for blood purification. Cellulose acetate polymers are capped with hydroxyl groups to some extent, have excellent blood compatibility such as suppression of complement activity and good blood return without blood clotting, and are suitable for blood purification applications.

  As the cellulose acetate polymer, for example, various cellulose acetate polymers having different degrees of acetylation and polymerization such as L-20, 30, 40, 50, 70, LT-35, 55, 105 are commercially available from Daicel Chemical Industries. (See Table 1). If the nozzle block is processed, spinning can be performed even if such a high-viscosity polymer is used at a polymer concentration exceeding 15%, and the strength of the hollow fiber membrane can be ensured. However, in order to achieve further improvements in hollow fiber membrane performance, spinning stability, and module productivity, a relatively low viscosity cellulose acetate polymer having a 6% viscosity of over 140 mPa · s and less than 200 mPa · s should be used. It was investigated. As a result, it became possible to secure the strength of the hollow fiber membrane, improve the membrane performance, and optimize the balance by using a relatively low viscosity polymer and further increasing the polymer concentration in the spinning dope. . In the present invention, in order to balance the performance of the hollow fiber membrane and the strength of the membrane, the concentration of the cellulose acetate polymer in the membrane forming stock solution is preferably set to 16% by mass or more and 25% by mass or less, and preferably 17% by mass or more. 23 mass% or less is more preferable.

  In the present invention, the acetylation degree of the cellulose acetate polymer is preferably 53 to 62%. Here, the degree of acetylation represents the degree of acetate group substitution of hydroxyl groups in cellulose. If the degree of acetylation is too low, the number of hydroxyl groups in the polymer chain increases, which may be disadvantageous in terms of biocompatibility such that complements are easily activated when the polymer comes into contact with blood. Moreover, although the theoretical upper limit of the acetylation degree is 62.5%, if the acetylation degree is too high, solubility and moldability may be lowered. Therefore, the acetylation degree of the cellulose acetate polymer is more preferably 61.5% or less. The lower the degree of acetylation, the better the solubility and moldability of the polymer, but the blood compatibility represented by complement activity tends to decrease as the number of hydroxyl groups increases. Therefore, the acetylation degree is more preferably 55% or more, and further preferably 58% or more.

  In the present invention, the cellulose acetate polymer is dissolved in a solvent and a non-solvent to prepare a film forming stock solution. As the solvent, it is preferable to use N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, or the like. These solvents have good compatibility with water. Examples of the non-solvent include ethylene glycol, triethylene glycol, polyethylene glycol 200 and 400, glycerin, propylene glycol, alcohols, and the like, and each may be used alone or in combination. When N-methylpyrrolidone (NMP) is used as a solvent and triethylene glycol (TEG) is used as a non-solvent, mixing is performed at a mass ratio of cellulose acetate polymer / NMP / TEG = 16-25 / 49-77 / 7-26. And preferably used.

  Although the hollow fiber membrane of the present invention is an asymmetric structure membrane as described above, the thickness can be made thinner than before, and consideration is given to making the permeation resistance of the removed substance as small as possible. In addition, by taking into account the suppression of the formation of secondary layers and clogging of the pores by increasing the smoothness of the inner surface that can be said to be the entrance of the hollow fiber membrane when the removed substance moves from the blood to the dialysate side Yes. That is, in order to improve the smoothness of the inner surface, after the film-forming solution is discharged from the nozzle, the inner surface is quickly solidified (fixed) before being affected by disturbance, so that phase separation does not proceed excessively. Examples thereof include not applying an external force such as stretching the inner surface after being solidified and solidified, and suppressing fluctuations in the inner diameter after the hollow fiber membrane structure is fixed as much as possible.

  In order to rapidly solidify the inner surface, an internal solution having a high coagulation property with respect to the film-forming stock solution, or a film-forming stock solution composition and temperature conditions that easily coagulate can be used. In the present invention, it is preferable to use an internal liquid mainly composed of water having a high coagulation property with respect to the cellulose acetate film-forming stock solution. In addition to water, ethylene glycol, triethylene glycol, polyethylene glycol 200 or 400, glycerin, propylene glycol, etc., which are generally used as non-solvents for cellulose acetate polymers, can be used alone or in combination. When using an internal liquid mainly composed of water, the upper limit is 5% by weight as components other than water, such as N-methylpyrrolidone, dimethylacetamide, dimethylformamide, and dimethylsulfoxide, which are solvents for the non-solvent and cellulose triacetate polymers. Can be added as

  In addition, as described above, the technology for providing a temperature difference between the film-forming stock solution and the internal solution when the film-forming stock solution and the internal solution are discharged from the double tubular nozzle has been developed. It is an important point in increasing the speed. The lower the temperature of the inner solution relative to the stock solution, the higher the coagulation (the solidification rate increases). However, it is technically difficult to provide a temperature difference between the stock solution and the internal solution. Accompany. As a result of diligent investigation on this point, the present inventor has processed a structure in which a heat medium (refrigerant) can be circulated in the nozzle block so that the temperature of the raw film forming solution and the internal solution can be controlled separately until immediately before discharge. By using it, this problem was solved. One nozzle block usually has several tens of nozzles incorporated therein, and it is necessary to consider the temperature control of these nozzles uniformly. This technical difficulty has been cleared.

  In order to produce the hollow fiber membrane of the present invention, it is preferable to set the temperature of the membrane forming stock solution to 70 to 110 ° C and the temperature of the internal solution to 0 to 40 ° C. Moreover, it is preferable to provide a temperature difference of 50 ° C. or more and 100 ° C. or less between the film forming stock solution and the internal solution. Even if the temperature difference is set too large, heat conduction cannot actually be suppressed, and if the temperature difference is too small, solidification cannot be promoted. Therefore, the temperature difference is preferably 40 ° C. or more and 90 ° C. or less, more preferably 50 ° C. or more. 85 ° C. or lower is more preferable.

The size of the double tubular nozzle is particularly important in order not to apply an external force such as stretching on the solidified inner surface and the solidified inner surface. The inner diameter of the membrane-forming solution discharge (slit inner diameter) is the inner diameter of the hollow fiber membrane to be formed. It is necessary to make it the same size as. Although it is desirable to make the outer diameter of the membrane-forming stock solution discharge outer diameter (slit outer diameter) equal to the outer diameter of the hollow fiber membrane to be formed, it is difficult to meet the demand due to the processing limit of the nozzle. It is desirable to use a nozzle with the smallest diameter that the processing accuracy allows. As described above, the hollow fiber membrane of the present invention has an inner diameter of about 140 to 260 μm and a film thickness of about 10 to 30 μm. The nozzle used in this case has a slit outer diameter of 220 to 330 μm and a slit inner diameter of about 150 to 270 μm. Is preferable. By adopting such a nozzle, it becomes possible to reduce the interfacial friction between the discharged film-forming stock solution and the internal solution, and the discharge linear speed and take-up speed of the film-forming stock solution can be made substantially the same, so that it is hollow. It becomes possible to prevent roughening of the inner surface of the yarn film. In the present invention, the take-off speed refers to the outlet roller speed of the coagulation bath, and the ratio of the discharge linear speed to the take-off speed (discharge linear speed / take-off speed = nozzle draft ratio) is 0.9 to 1.3. Is preferred. More preferably, it is 1.0-1.2. In the present invention, the ability to use an unprecedented small-diameter nozzle leads to further performance improvement.
Here, the discharge linear velocity at the time of discharging the film forming stock solution is obtained by dividing the film forming stock solution discharge amount by the slit cross-sectional area obtained using the nozzle slit outer diameter (a) and the nozzle slit inner diameter (b).
Discharge linear velocity of film forming stock solution [m / min] = film forming stock solution discharge amount / [π {(a / 2) ^ 2− (b / 2) ^ 2}]

  In addition, after the hollow fiber membrane is solidified, it is preferable that the hollow fiber membrane is not stretched as much as possible in the steps after washing with water. The present inventor pays attention to washing the hollow fiber membrane without stretching and performs washing without stretching the hollow fiber membrane as much as possible by flowing washing water in the same direction as the traveling direction of the hollow fiber membrane. I arrived at the idea. In the cleaning of the hollow fiber membrane, conventionally, the cleaning liquid is flowed in the direction opposite to the traveling direction of the hollow fiber membrane in order to improve the cleaning efficiency by surface renewal. The resistance increased, and as a result, it was necessary to apply stretching to absorb the elongation of the hollow fiber membrane. However, by flowing the hollow fiber membrane and the cleaning liquid in the same direction, the elongation of the hollow fiber membrane can be minimized, and it is not necessary to absorb the amount of elongation of the hollow fiber membrane in the water washing step, and the water washing step is substantially effective. It became possible to make it unstretched. In addition, being substantially unstretched means that the roller speed at the entrance of the washing step and the roller speed at the exit are substantially the same.

  Moreover, it is important to suppress the shrinkage of the hollow fiber membrane particularly in the drying process for suppressing the inner diameter fluctuation after the hollow fiber membrane structure is fixed as much as possible. Conventionally, in the production of a homogeneous structure film using liquid paraffin as an internal liquid, radial shrinkage can be suppressed relatively effectively by the body expansion of liquid paraffin by heating during drying. However, in the case of using an internal liquid that easily passes through the pores of the hollow fiber membrane, there is no other way than to give the membrane itself the strength to withstand shrinkage. As described above, the hollow fiber membrane of the present invention has a very thin film thickness while having an asymmetric structure. Therefore, a relatively dense layer is provided also in the middle of the membrane cross section and in the vicinity of the outer surface to provide strength. doing. The hollow fiber membrane of the present invention achieves a breaking strength per single yarn of 30 to 40 g, a breaking elongation of 19 to 30%, a yield strength of 18 to 30 g, and a yield elongation of 2.3 to 3.0%. ing.

  In the present invention, in order to make the high elongation of the hollow fiber membrane within the above range, it is effective to optimize the coagulation conditions in addition to the polymer concentration and the nozzle temperature in the spinning dope. As the composition of the coagulation bath, it is preferable to use a mixed solution comprising a solvent, a non-solvent, and water. As the solvent and non-solvent, it is preferable to use the same solvent as that used for the preparation of the stock solution. Although addition of a non-solvent to the coagulation bath is not particularly required, it is preferable to match the solvent / non-solvent ratio in the spinning dope from the viewpoint of suppressing changes in the coagulation bath composition.

  In the present invention, the porosity of the outer surface of the hollow fiber membrane is preferably 7% or more and 30% or less. If the outer surface open area ratio is too large, the porosity of the intermediate (support) layer generally increases, so that the strength required for the hollow fiber membrane cannot be secured, or the retainability of the membrane pore retainer may be reduced. . On the other hand, if the outer surface open area ratio of the hollow fiber membrane is too small, the asymmetry of the pores is lost and it approaches a homogeneous structure, so that the permeability and filtration stability of the substance may be lowered. Moreover, since the permeation | diffusion characteristic of a hollow fiber membrane falls, online washing | cleaning efficiency may fall. Therefore, the outer surface open area ratio of the hollow fiber membrane is more preferably 8% or more and 25% or less, further preferably 20% or less, and particularly preferably 18% or less.

  In order to make the outer surface area porosity within the above range, the polymer concentration in the film forming stock solution and the nozzle temperature are affected, but in addition, the spinning stock solution discharged from the nozzle is immersed in the coagulation bath. It is preferable that the length of the aerial traveling unit is 10 mm or more and 150 mm or less. Moreover, it is preferable to block the aerial traveling part from the outside air and set the interior to 0 ° C. or more and 50 ° C. or less. By setting the length and temperature of the aerial traveling portion within the above ranges, it is possible to promote the growth of polymer nuclei on the outer surface side of the film-forming stock solution discharged from the nozzle. On the other hand, on the inner surface side of the film-forming stock solution, it is possible to complete the solidification of the polymer by the core solution and form a dense layer before being affected by the solvent removal from the outer surface side. In order to improve the stability of the spinning film formation, the length of the aerial traveling section is more preferably 10 mm or more and 100 mm or less, and more preferably 15 mm or more and 80 mm or less in order to offset the influence of the discharge spots of the spinning stock solution from the spinneret.

  In the present invention, in order to obtain an appropriate outer surface of the hollow fiber membrane, it is one effective means to optimize the coagulation conditions. In order to increase the porosity of the outer surface, it is effective to increase the solvent concentration in the coagulation bath and increase the temperature. By increasing the solvent concentration and temperature, polymer nuclei generated in the aerial traveling part can be further grown, and the hole area ratio and the hole diameter can be increased. In order to set the open area ratio within the above range, the solvent concentration in the coagulation bath is preferably 40% by weight to 60% by weight and the temperature is preferably 30 ° C. or more and 60 ° C. or less. In order to ensure that the hollow fiber membrane is pierced from the coagulation bath, the solvent concentration is preferably 45% by weight or more and 60% by weight or less, the temperature is preferably 30 ° C. or more and 50 ° C. or less, and the solvent concentration is 45% by weight or more and 55% by weight. %, And the temperature is more preferably 35 ° C. or higher and 45 ° C. or lower.

  The hollow fiber membrane squeezed out from the coagulation bath is subsequently washed in a water washing bath to remove excess solvent and non-solvent. In order to perform cleaning in a short time, it is better to raise the temperature of the washing bath as much as possible. However, if the temperature is too high, the film constituent material may be deteriorated and the film shape and the film structure may be defective. Therefore, it is preferable to perform the cleaning at about 50 to 90 ° C, more preferably 60 to 90 ° C. 70-85 degreeC is further more preferable.

  The hollow fiber membrane that has undergone the water washing step is then transferred to the step of filling the pores with the hydrophilizing agent. In the present invention, the hollow fiber membrane is immersed in the glycerin aqueous solution and drained repeatedly to fill the pores with the glycerin aqueous solution as a hydrophilizing agent. Here, the concentration of glycerin is preferably 70 to 95% by weight. If the glycerin concentration is too low, the pore diameter may be reduced and the hollow fiber membrane shape may be deformed (crushed or flattened) due to moisture evaporation in the subsequent hollow fiber membrane drying step. On the other hand, if the glycerin concentration is too high, the fluidity is lowered and filling and replacement may be insufficient. Therefore, the glycerin concentration is more preferably 75 to 95% by weight, and further preferably 80 to 90% by weight. The temperature of the glycerin aqueous solution depends on the glycerin concentration, but is preferably about 80 to 95 ° C. within the above range. If it is such a temperature range, the fluidity | liquidity of glycerin aqueous solution will be ensured and it is preferable at the surface of a filling property or substitution property. In the present invention, the time and frequency of immersing in the glycerin aqueous solution and draining are not unambiguous because they relate to the inner diameter, film thickness, and membrane structure of the hollow fiber membrane, but in the case of the hollow fiber membrane of the present invention It can be said that it is sufficient to perform immersion and liquid draining for about 3 to 10 seconds each, and performing immersion and liquid draining for about 3 to 10 times as one step. A hollow fiber membrane filled with an aqueous glycerin solution inside the pores is wound around a bobbin in a cheese shape through a drying process.

When a module having a membrane area of 1.5 m ² based on the inner diameter standard is produced using the hollow fiber membrane of the present invention, human β2MG (molecular weight 18,000) is added to the blood flow channel side at a concentration of 0.05 to 0.1 mg / l. The total protein concentration so added was 6.5 ± 0.5 g / dl, the ACD-added bovine plasma kept at 37 ° C. was flowed at 200 ml / min, the dialysate on the dialysate side was 500 ml / min, and the filtration flow was 15 ml / min. , The clearance of β2MG at 60 minutes and 240 minutes after the start of dialysis (respectively CLβ15 [60] and CLβ15 [240]) can reach 65 ml / min or more. It is also possible to develop V-type performance. It is preferable that CLβ15 [240] / CLβ15 [60] ≧ 0.93 is satisfied.

  In addition, the hollow fiber membrane of the present invention is not only capable of enhancing the permeability of low molecular weight proteins typified by β2MG, because it has taken into consideration the suppression of pore clogging and the formation of secondary layers. It became possible to improve the stability of permeation performance and the stability over time when the filtration flow rate was increased. That is, in the test, the ratio (CLβ45 [60]) of β2MG clearance (CLβ15 [60]) when the filtration flow rate is 15 ml / min and β2MG clearance (CLβ45 [60]) when the filtration flow rate is 45 ml / min. / CLβ15 [60]) is 1.05 or more.

  Furthermore, the hollow fiber membrane of the present invention achieves a very low amount of protein leakage of 3 g or less (equivalent to general hemodialysis therapy) of protein leakage of 2 g or less when tested at a filtration flow rate of 15 ml / min. doing. Further, when tested under the condition of a filtration flow rate of 45 ml / min, it is also possible to achieve a protein leak amount of 5 g or less in terms of water removal amount of 10 L (corresponding to blood filtration dialysis therapy).

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited at all by these Examples.

(Measurement of hollow fiber membrane inner diameter, outer diameter, film thickness)
A sample of the cross section of the hollow fiber membrane can be obtained as follows. For the measurement, it is preferable to observe in a form in which the hollow fiber membrane is dried after washing and removing the core liquid. There is no limitation on the drying method, but when the form changes remarkably by drying, it is preferable to observe the form in a wet state after washing and removing the core liquid and replacing with pure water. The hollow fiber membrane has an inner diameter, an outer diameter, and a film thickness. The hollow fiber membrane is cut through a razor on the top and bottom surfaces of the slide glass so that the hollow fiber membrane does not fall out into a hole of φ3 mm in the center of the slide glass. And after obtaining the hollow fiber membrane cross-section sample, it is obtained by measuring the minor axis and major axis 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 the hollow fiber membrane, and calculate the arithmetic average value of each of the cross section of the hollow fiber membrane as the inner diameter and outer diameter of one hollow fiber membrane. To do. The same measurement is performed for five cross sections, and the average value is defined as the inner diameter and film thickness.

(Measurement of open area of hollow fiber membrane)
The hollow fiber membrane is observed with a scanning electron microscope of 10,000 times, and a photograph (SEM photograph) is taken. An area of 762 pixels in the vertical direction and 620 pixels in the horizontal direction is cut out from the image, and then the image is binarized into white / black using image analysis software to obtain the hollow fiber membrane surface and the open area ratio of each cross section. 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 total area (B) of the holes in the measurement range are obtained to obtain the hole area ratio (%) = B / A × 100. This is carried out for 10 visual fields and the average is obtained. Scale setting is performed as an initial operation, and holes on the measurement range boundary are not excluded during counting.
To measure the open area ratio of the cross section, the hollow fiber cross section is divided into five sections of substantially equal length from the inside to the outside (the sections 1, 2, 3, 4 and 5 are sequentially formed from the inner surface to the outer surface). Then, the respective aperture ratios are measured.

(Measurement of average surface roughness (Ra value))
A sample in which the inner surface of the hollow fiber membrane to be evaluated was exposed was used. The morphology was observed with an atomic force microscope SPI3800 (manufactured by Seiko Instruments Inc.). The observation mode at this time is the DFM mode, the scanner is FS-20A, the cantilever is DF-3, and the observation field is 3 μm square. Ra value represents the arithmetic average of the unevenness | corrugation of all the measurement points with respect to the reference point at the time of measuring the unevenness | corrugation of the film | membrane surface.

(Measurement of water permeability (UFR))
The blood outlet circuit of the dialyzer (the outlet side from the pressure measurement point) is sealed with forceps. Pure 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. in a constant temperature bath, and the flow rate of the filtrate flowing out from the dialysate side is measured. The transmembrane pressure difference (TMP) is TMP = (Pi + Po) / 2
And Here, Pi is the dialyzer inlet side pressure, and Po is the dialyzer outlet side pressure. The TMP is changed at four points, the filtration flow rate is measured, and the water permeability (mL / hr / mmHg) is calculated from the slope of the relationship. At this time, the correlation coefficient between TMP and the filtration flow rate must be 0.999 or more. In order to reduce the pressure loss error due to the circuit, TMP is measured in the range of 100 mmHg or less. The water permeability of the hollow fiber membrane is calculated from the membrane area and the water permeability of the dialyzer.
UFR (H) = UFR (D) / A
Here, UFR (H) is the water permeability of the hollow fiber membrane (mL / m ² / hr / mmHg), UFR (D) is the water permeability of the dialyzer (mL / hr / mmHg), and A is the membrane area of the dialyzer (mL m ² ).

(Measurement of β2MG clearance)
It carries out according to the blood purifier performance evaluation criteria shown in Non-Patent Document 1. ACD (acid-citrate-dextrose) -added cow adjusted to a total protein concentration of 6.5 ± 0.5 g / dl and kept at 37 ° C. in a blood purifier having a membrane area of 1.5 m ² (inside of hollow fiber membrane inner diameter) Plasma is circulated for 1 hour at a blood flow rate of 200 ml / min. Next, human β2MG (genetical recombination product, manufactured by Wako Pure Chemical Industries, Ltd.) was added to a concentration of 0.05 to 0.1 mg / l, and the total protein concentration was adjusted to 6.5 ± 0.5 g / dl. The kept ACD-added bovine plasma is flowed to the blood side at a blood flow rate of 200 ml / min, and dialysis is performed at a commercial dialysate of 500 ml / min and a filtration flow rate of 15 ml / min or 45 ml / min. This clearance evaluation is performed with a single pass. After the start of dialysis, the β2MG concentration of the test solution collected from the blood inlet / outlet and the dialysate outlet at 60 minutes and 240 minutes is measured. The clearance is calculated using the following formula.
Filtration flow rate 15 ml / min, clearance at 60 minutes and 240 minutes (CLβ15 [60], [240])
CLβ15 (ml / min) = 200 × [(200 × CBi) − (185 × CBo)] / (200 × CBi)
Filtration flow rate 45 ml / min, clearance at 60 minutes and 240 minutes (CLβ45 [60], [240])
CLβ45 (ml / min) = 200 × [(200 × CBi) − (155 × CBo)] / (200 × CBi)
Here, CBi: blood inlet concentration, CBo: blood outlet concentration.

(Measurement of protein leak)
Bovine blood to which citric acid was added and coagulation was suppressed was adjusted to a hematocrit of 25 to 30% and a protein concentration of 6 to 7 g / dl, and sent to a blood purifier at 37 ml at a rate of 200 ml / min, and a filtration flow rate of 15 ml / min. Alternatively, the blood is filtered at 45 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 filtrate from the blood purifier. Measure the protein concentration in the filtrate. Measurement of protein concentration in plasma is performed using an in vitro diagnostic kit (Micro TP-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.). Based on the data for up to 2 hours, the average protein leak amount is obtained from the following formula, and the protein leak amount (TPL) at the time of 3 L water removal conversion is calculated.
Integrated filtration amount (ml) = t ₁ (min) × C _t1 (ml / min) + (t ₂ −t ₁ ) (min) × C _t2 (ml / min) + (t ₃ −t ₂ ) (min) × C _t3 (ml / min)... (T ₁₂₀ −t _n ) (min) × C _{120 min} (ml / min)
t: Measurement time (min), C: Filtration flow rate (ml / min)
Protein concentration in the filtrate = a × Ln (integrated filtration amount) + b
A and b are determined from the protein concentration of the filtrate at each measurement point and Ln (integrated filtration amount).
TPL (average) = − a + b + a × Ln (integrated filtration amount × 2)
TPL (converted to 3L water removal) (g) = TPL (average) × 30/1000
TPL (converted to 10L water removal) (g) = TPL (average) × 100/1000

(Measurement of breaking strength and yield strength)
The tensile strength of the hollow fiber membrane was determined by using a Tensilon universal testing machine (UTMII manufactured by Toyo Baldwin) to cut one dried hollow fiber membrane into a length of about 15 cm and loosening between the chucks (distance about 10 cm). The hollow fiber membrane was pulled at a crosshead speed of 10 cm / min in a temperature and humidity environment of 20 ± 5 ° C. and 60 ± 10% RH, and measurement was performed. The breaking elongation and breaking strength at which the hollow fiber membrane is cut are read from the obtained chart paper. As shown in FIG. 1, an auxiliary line is provided from the SS curve, a point where two auxiliary lines intersect is defined as a yield point, and the strength at that point is defined as yield strength and the elongation as yield elongation.

(Module production yield)
About 10,000 of the spun hollow fiber membranes are wound into a bundle, the wound hollow fiber membrane bundle is inserted into a transparent module case, and then the end of the case is made of a resin such as urethane or epoxy, The hollow fiber membrane bundle and the case are bonded in a liquid-tight manner, and then the bonded portion is cut so that the hollow portion of the hollow fiber membrane is opened, thereby producing a hollow fiber membrane module. The appearance of the completed hollow fiber membrane module is visually inspected, and the production yield is calculated based on whether or not the hollow fiber membrane is bent, cut, twisted, or crushed. In the present invention, the module production yield is preferably 96% or more.

Example 1
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries) 17% by weight, N-methylpyrrolidone (NMP, manufactured by Mitsubishi Chemical) 58.1% by weight, triethylene glycol (TEG, manufactured by Mitsui Chemicals) A solution obtained by uniformly dissolving 24.9% by weight was discharged as a film-forming stock solution from the slit portion of a double-tube nozzle having a slit outer diameter of 270 μm and a slit inner diameter of 200 μm, and at the same time, water was discharged as the inner liquid. At that time, the internal liquid was cooled by flowing a 15 ° C. refrigerant through the nozzle block. The film-forming stock solution was heated by circulating a heating medium at 92 ° C. in the block.
The film-forming stock solution discharged from the nozzle is allowed to pass through a 20 mm air gap, and then guided into a 45 ° C. coagulation bath consisting of NMP / TEG / water = 49/21/30, solidified, washed with water, and treated with glycerin. After that, it was dried and wound up. The nozzle draft ratio was 1.15. In addition, the water washing process followed the conventional method in which a hollow fiber membrane and washing water are made to flow countercurrently. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 1.0%. The total stretching from the coagulation bath outlet to winding was 6%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 19 μm. The obtained hollow fiber membrane was bundled and inserted into a case, and both ends were bonded and fixed with polyurethane resin, and a module having a hollow fiber membrane inner diameter standard membrane area of 1.5 m ² was produced and subjected to various evaluations. . The evaluation results are summarized in Table 2.

(Example 2)
17% by weight of cellulose triacetate (6% viscosity = 154 mPa · s, manufactured by Daicel Chemical Industries), 58.1% by weight of N-methylpyrrolidone (manufactured by Mitsubishi Chemical) and 24.9% by weight of triethylene glycol (manufactured by Mitsui Chemicals) % As a film-forming stock solution was discharged from a slit portion of a double-tube nozzle having a slit outer diameter of 270 μm and a slit inner diameter of 200 μm, and water was simultaneously discharged as an inner liquid. At that time, the internal liquid was cooled by flowing a 35 ° C. refrigerant through the nozzle block. The film-forming stock solution was heated by circulating a heating medium at 92 ° C. in the block.
The film-forming stock solution discharged from the nozzle is allowed to pass through a 20 mm air gap, and is then solidified by being guided into a 40 ° C. coagulation bath consisting of NMP / TEG / water = 49/21/30, followed by washing with water and glycerin adhesion treatment. After that, it was dried and wound up. The nozzle draft ratio was 1.15. The washing tank was adjusted to have an inclination of 2.5 degrees so that the washing water gradually descended, and the washing water was allowed to flow in the same co-current as the hollow fiber membrane. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 0%. The total stretching from the coagulation bath outlet to winding was 4%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 20 μm. The obtained hollow fiber membranes were bundled and inserted into a case, and both ends were bonded and fixed with polyurethane, and modules having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared for various evaluations. The evaluation results are summarized in Table 2.

(Example 3)
Cellulose triacetate (6% viscosity = 154 mPa · s, manufactured by Daicel Chemical Industries) 18% by weight, N-methylpyrrolidone (Mitsubishi Chemical Co., Ltd.) 57.4% by weight and triethylene glycol (Mitsui Chemicals) 24.6% by weight % As a film-forming stock solution was discharged from a slit portion of a double-tube nozzle having a slit outer diameter of 270 μm and a slit inner diameter of 200 μm, and water was simultaneously discharged as an inner liquid. At that time, the internal liquid was cooled by flowing a 15 ° C. refrigerant through the nozzle block. The film-forming stock solution was heated by circulating a heating medium at 103 ° C. in the block.
The film-forming stock solution discharged from the nozzle passes through a 45 mm air gap, and is then solidified by being guided into a 45 ° C. coagulation bath consisting of NMP / TEG / water = 49/21/30, followed by washing with water and glycerin adhesion treatment. After that, it was dried and wound up. The nozzle draft ratio was 1.15. The washing tank was adjusted to have an inclination of 2.5 degrees so that the washing water gradually descended, and the washing water was allowed to flow in the same co-current as the hollow fiber membrane. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 0%. The total stretching from the coagulation bath outlet to winding was 4%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 19 μm. The obtained hollow fiber membranes were bundled and inserted into a case, and both ends were bonded and fixed with polyurethane, and modules having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared for various evaluations. The evaluation results are summarized in Table 2.

Example 4
Cellulose triacetate (6% viscosity = 154 mPa · s, manufactured by Daicel Chemical Industries, Ltd.) 16.5% by weight, N-methylpyrrolidone (Mitsubishi Chemical Co., Ltd.) 54.3% by weight, and triethylene glycol (Mitsui Chemicals, Inc.) 29. A solution obtained by uniformly dissolving 2% by weight of the mixture was discharged as a film-forming stock solution from the slit portion of a double tube nozzle having a slit outer diameter of 270 μm and a slit inner diameter of 200 μm, and at the same time, water was discharged as the inner liquid. At that time, the internal liquid was cooled by flowing a 30 ° C. refrigerant through the nozzle block. The film forming stock solution was heated by circulating a heat medium at 85 ° C. in the block.
The film-forming stock solution discharged from the nozzle passes through a 15 mm air gap, and is then solidified by guiding it into a 35 ° C. coagulation bath consisting of NMP / TEG / water = 42/23/35, followed by washing with water and glycerin adhesion treatment. After that, it was dried and wound up. The nozzle draft ratio was 1.1. In addition, the water washing process followed the conventional method in which a hollow fiber membrane and washing water are made to flow countercurrently. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 1.0%. The total stretching from the coagulation bath outlet to winding was 6%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 21 μm. The obtained hollow fiber membranes were bundled and inserted into a case, and both ends were bonded and fixed with polyurethane, and modules having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared for various evaluations. The evaluation results are summarized in Table 2.

(Example 5)
Cellulose triacetate (6% viscosity = 154 mPa · s, manufactured by Daicel Chemical Industries) 17.5% by weight, N-methylpyrrolidone (Mitsubishi Chemical) 57.8% by weight and triethylene glycol (Mitsui Chemicals) 24. A solution in which 7% by weight of the mixture was uniformly dissolved was discharged from a slit portion of a double tube nozzle having a slit outer diameter of 270 μm and a slit inner diameter of 200 μm as a film forming stock solution, and at the same time, water was discharged as an inner liquid. At that time, the internal liquid was cooled by flowing a 15 ° C. refrigerant through the nozzle block. The film forming stock solution was heated by circulating a 97 ° C. heating medium in the block.
The film-forming stock solution discharged from the nozzle passes through a 45 mm air gap, and is then solidified by being guided into a 45 ° C. coagulation bath consisting of NMP / TEG / water = 49/21/30, followed by washing with water and glycerin adhesion treatment. After that, it was dried and wound up. The nozzle draft ratio was 1.15. The washing tank was adjusted to have an inclination of 2.5 degrees so that the washing water gradually descended, and the washing water was allowed to flow in the same co-current as the hollow fiber membrane. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 0%. The total stretching from the coagulation bath outlet to winding was 4%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 19 μm. The obtained hollow fiber membranes were bundled and inserted into a case, and both ends were bonded and fixed with polyurethane, and modules having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared for various evaluations. The evaluation results are summarized in Table 2.

(Example 6)
17% by weight of cellulose triacetate (6% viscosity = 172 mPa · s, manufactured by Daicel Chemical Industries), 58.1% by weight of N-methylpyrrolidone (manufactured by Mitsubishi Chemical) and 24.9% by weight of triethylene glycol (manufactured by Mitsui Chemicals) % As a film-forming stock solution was discharged from the slit portion of a double-tube nozzle having a slit outer diameter of 250 μm and a slit inner diameter of 185 μm, and water was simultaneously discharged as the inner liquid. At that time, the internal liquid was cooled by flowing a 15 ° C. refrigerant through the nozzle block. The film-forming stock solution was heated by circulating a heating medium at 92 ° C. in the block.
The film-forming stock solution discharged from the nozzle is allowed to pass through a 20 mm air gap, and then guided into a 45 ° C. coagulation bath consisting of NMP / TEG / water = 49/21/30, solidified, washed with water, and treated with glycerin. After that, it was dried and wound up. The nozzle draft ratio was 1.07. In addition, the water washing process followed the conventional method in which a hollow fiber membrane and washing water are made to flow countercurrently. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 1.0%. The total stretching from the coagulation bath outlet to winding was 6%. The obtained hollow fiber membrane had an inner diameter of 185 μm and a film thickness of 16 μm. The obtained hollow fiber membranes were bundled and inserted into a case, and both ends were bonded and fixed with polyurethane, and modules having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared for various evaluations. The evaluation results are summarized in Table 2.

(Comparative Example 1)
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries) 17% by weight, N-methylpyrrolidone (NMP, manufactured by Mitsubishi Chemical) 58.1% by weight, triethylene glycol (TEG, manufactured by Mitsui Chemicals) A solution obtained by uniformly dissolving 24.9% by weight was discharged as a film-forming stock solution from the slit portion of a double-tube nozzle having a slit outer diameter of 270 μm and a slit inner diameter of 200 μm, and simultaneously a 10% by weight NMP aqueous solution was discharged as the inner liquid. At that time, the internal liquid did not flow through the block and was not cooled. The film-forming stock solution was heated by circulating a heating medium at 92 ° C. in the block.
After the film-forming stock solution discharged from the nozzle passes through an air gap of 20 mm, it is solidified by being guided into a 45 ° C. coagulation bath composed of NMP / TEG / water = 63/7/30, washed with water, and treated with glycerin. After that, it was dried and wound up. The nozzle draft ratio was 1.15. In addition, the water washing process followed the conventional method in which a hollow fiber membrane and washing water are made to flow countercurrently. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 1.0%. The total stretching from the coagulation bath outlet to winding was 6%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 19 μm. The obtained hollow fiber membrane was bundled and inserted into a case, and both ends were bonded and fixed with polyurethane resin, and a module having a hollow fiber membrane inner diameter standard membrane area of 1.5 m ² was produced and subjected to various evaluations. . The evaluation results are summarized in Table 2.

(Comparative Example 2)
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries) 17% by weight, N-methylpyrrolidone (Mitsubishi Chemical) 58.1% by weight, triethylene glycol (Mitsui Chemicals) 24.9% % As a film-forming stock solution was discharged from the slit portion of a double-tube nozzle having a slit outer diameter of 400 μm and a slit inner diameter of 250 μm, and water was simultaneously discharged as the inner liquid. At that time, the internal liquid did not flow through the block and was not cooled. The film-forming stock solution was heated by circulating a heating medium at 92 ° C. in the block.
The film-forming stock solution discharged from the nozzle is allowed to pass through a 20 mm air gap, and is then solidified by being guided into a 45 ° C. coagulation bath consisting of NMP / TEG / water = 56/14/30, followed by washing with water and glycerin adhesion treatment. After that, it was dried and wound up. The nozzle draft ratio was 1.7. The washing tank was adjusted to have an inclination of 2.5 degrees so that the washing water gradually descended, and the washing water was allowed to flow in the same co-current as the hollow fiber membrane. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 0%. The total stretching from the coagulation bath outlet to winding was 4%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 18 μm. The obtained hollow fiber membrane was bundled and inserted into a case, and both ends were bonded and fixed with polyurethane resin, and a module having a hollow fiber membrane inner diameter standard membrane area of 1.5 m ² was produced and subjected to various evaluations. . The evaluation results are summarized in Table 2.

(Comparative Example 3)
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries) 18% by weight, N-methylpyrrolidone (Mitsubishi Chemical) 65.6% by weight, triethylene glycol (Mitsui Chemicals) 16.4% by weight % As a film-forming stock solution was discharged from the slit portion of a double-tube nozzle having a slit outer diameter of 400 μm and a slit inner diameter of 250 μm, and water was simultaneously discharged as the inner liquid. At that time, the internal liquid was cooled by flowing a 0 ° C. refrigerant through the nozzle block. Moreover, the film-forming stock solution was heated by circulating a heating medium at 80 ° C. in the block.
The film-forming stock solution discharged from the nozzle is passed through an air gap of 80 mm, and then guided into a 45 ° C. coagulation bath consisting of NMP / TEG / water = 57.6 / 14.4 / 28, solidified, and washed with water. After the glycerin adhesion treatment, it was dried and wound up. The nozzle draft ratio was 1.4. In addition, the water washing process followed the conventional method in which a hollow fiber membrane and washing water are made to flow countercurrently. The flow rate of the washing water was adjusted to 0.35 m / min, and the washing tank was 5 stages. The stretching of the hollow fiber membrane in the water washing step was 1.0%. The total stretching from the coagulation bath outlet to winding was 6%. The resulting hollow fiber membrane had an inner diameter of 200 μm and a film thickness of 19 μm. The obtained hollow fiber membrane was bundled and inserted into a case, and both ends were bonded and fixed with polyurethane resin, and a module having a hollow fiber membrane inner diameter standard membrane area of 1.5 m ² was produced and subjected to various evaluations. . The evaluation results are summarized in Table 2.

  As is clear from Table 2, Examples 1 to 6 in which the open area ratios of the cross sections (2 to 4) are in an appropriate range not only have good performance stability and good fractionability, but also have high elongation. Since it is high, the module manufacturing yield is good. On the other hand, Comparative Examples 1 to 3 in which the cross-sectional area ratio is outside the proper range have problems such as low performance stability over time, a large amount of protein leak, and low filtration performance. In Comparative Examples 1 to 3, the yield of module production is low because the high elongation of the hollow fiber membrane is low.

  The hollow fiber membrane of the present invention is a so-called asymmetric structure membrane having a dense layer at least on the inner surface side. However, the intermediate portion of the membrane has a structure close to a homogeneous structure, and the inner surface is smooth and has an appropriate porosity. As a result, the strength of the hollow fiber membrane, the stability of solute removal, and the suppression of leakage of useful proteins are compatible at a high level even though it is a very thin film. Therefore, it can be suitably used not only for hemodialysis but also for hemodiafiltration and blood filtration, and contributes to industrial development.

Claims (4)

A hollow fiber membrane having an asymmetric structure made of a cellulose acetate polymer, when the hollow fiber membrane is observed at a magnification of 10,000 times using a scanning electron microscope,
(A) The presence rate of pores of 300 nm or more on the inner surface is 0.5% or less ,
(B) In the cross section of the hollow fiber membrane, the porosity of the region from the inner surface to 20% of the film thickness is 0.1 to 5%, and the porosity of the region from the outer surface to 20% of the film thickness is 22 ~ 30%, the porosity of the other intermediate region is 10-20%,
When a module having a membrane area of 1.5 m ² based on the inner diameter standard is produced using a hollow fiber membrane , human β2MG (molecular weight 18,000) is adjusted to a concentration of 0.05 to 0.1 mg / l on the blood channel side. The total protein concentration added was 6.5 ± 0.5 g / dl, ACD-added bovine plasma kept at 37 ° C. was flowed at a flow rate of 200 ml / min, dialysate was flowed to the dialysate side at 500 ml / min, and the filtration flow rate was 15 ml / min. The clearance of β2MG at the time of 60 minutes and 240 minutes after the start of dialysis is 65 ml / min or more, and
A structure in which the initial hole area ratio increases from the inner surface toward the outer surface, the hole area ratio remains almost constant from the middle part to the vicinity of the outer surface, and the hole area ratio increases again near the outer surface. the hollow fiber membrane according to claim <br/> to have.   The hollow fiber membrane according to claim 1, wherein an average surface roughness on the inner surface is 10 nm or less.   The hollow fiber membrane according to claim 1 or 2, wherein the porosity of the inner surface is 0.5% or less. In the method for producing a hollow fiber membrane according to any one of claims 1 to 3, comprising a step of solidifying in a coagulation bath after passing through the air gap after discharging the membrane-forming stock solution and the internal solution from the double tubular nozzle.
(A) The film-forming stock solution comprises a cellulose acetate polymer, a solvent of the polymer and a non-solvent,
(B) The content of water in the internal solution is 95% by weight or more and 100% by weight or less,
(C) The temperature of the film-forming stock solution at the nozzle part is 70 ° C. or higher and 110 ° C. or lower, and the temperature of the internal solution is 0 ° C. or higher and 40 ° C. or lower,
(D) the solvent concentration of the coagulation bath is 40 wt% or more and 60 wt% or less;
(E) the nozzle draft ratio is 0.9 to 1.3;
(F) The nozzle slit outer diameter is 220 to 330 μm, and the slit inner diameter is 150 to 270 μm.
A method characterized by.