JP5299617B2 - Method for producing hollow fiber membrane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hollow fiber membrane excellent in preservation stability, and quality stability even at high temperature in transportation, especially a permselective hollow fiber membrane suitable for a blood purifier. <P>SOLUTION: The hollow fiber membrane has an inner diameter of 100-300 &mu;m, a thickness of 10-60 &mu;m, and a porosity ratio of 50-90%, and is excellent in thermostability wherein a water permeability retention rate after sealing the hollow fiber membrane in an aluminum bag and leaving the membrane for 20hr at 80&deg;C is within 100&plusmn;10%. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a hollow fiber membrane having high porosity, high permselectivity, and high water permeability, which is excellent in storage stability of the hollow fiber membrane and in quality stability even at a high temperature during transportation. In particular, the present invention relates to a hollow fiber membrane suitable for a blood purifier.

  Hollow fiber membranes have been widely used in the field from reverse osmosis to microfiltration. Currently, hollow fiber membrane blood purifiers are often used to purify the blood of patients with renal failure. This is because a housing contains a large number of dialysis membranes, for example, hollow fiber membranes, the patient's blood is passed through the hollow portions, and the dialysate is passed through 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 the therapeutic effect can be enhanced by using a hollow fiber membrane for protein permeable hemodialysis and protein permeable hemofiltration dialysis.

  By the way, in recent years, it is related to long-term complications in dialysis patients, and the parathyroid gland is considered to be related to β2-microglobulin (β2-MG, molecular weight: 11,800), pruritus, and hyperlipidemia, which are considered to be causative agents of dialysis amyloidosis. Necessity of removal of toxic substances in the relatively medium high molecular weight region such as hormones (molecular weight: about 9,500), erythroblast-inhibiting factor involved in anemia, substances with molecular weight of 20,000 to 40,000 that are considered to be related to joint pain and bone pain Attention has been gathered. 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, a hollow fiber membrane that is excellent in the permeability of a substance having a molecular weight of 40 to 50,000 or less, has a good blocking property for a substance having a molecular weight of 60,000 or more, and has a good sharp cut property is desired.

  Thus, the hollow fiber membrane for blood processing must selectively permeate a specific substance according to the purpose. The performance is determined by the material of the hollow fiber membrane, the membrane structure, the porosity (pore size, number, etc.), the film thickness, and the like.

  In order to obtain the above-mentioned membrane performance, a hollow fiber membrane having as high a water permeability (UFR) as possible is required. 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, it is unclear whether the synthetic polymer membrane uses a hydrophilic polymer typified by polyvinylpyrrolidone or due to the membrane structure, but the dimensional stability of the hollow fiber membrane is low, It was very difficult to handle. In addition, since the hydrophilizing agent is hydrophilic, it may elute in the blood and gradually accumulate in the body, and there is a concern that the hydrophilizing agent that is originally a foreign substance may adversely affect the living body. The In order to eliminate concerns about such adverse effects, it was necessary to perform a treatment for suppressing the elution of the membrane for strengthening the washing and crosslinking, and the handling was complicated and the production was difficult.

  Further, the hollow fiber membrane is an ultrafine fiber having an inner diameter of about 200 μm and a film thickness of about 15 to 50 μm, which is slightly thicker than hair. Therefore, when exposed to high or low temperatures during transportation, the material itself constituting the hollow fiber membrane may be modified or altered, or the shape and microstructure may be deformed. May be. For this reason, it has been attempted to prevent oxidative degradation by controlling storage conditions (temperature, humidity) or devising a packaging form. In particular, since the internal temperature of the transport vehicle in summer increases to about 80 ° C., deterioration of quality or change in performance cannot be avoided. In the above-described polysulfone-based hollow fiber membranes, polyvinyl pyrrolidone is likely to be oxidized or thermally deteriorated, so that a hollow fiber membrane having stable quality and performance is required even at high or low temperatures. Conventionally, there has been no particular mention regarding the stability of quality and performance at high or low temperatures.

  Examples of the material used as the hollow fiber membrane include cellulose which is a natural material, cellulose diacetate and cellulose triacetate which are derivatives thereof, and polysulfone, polymethyl methacrylate, polyacrylonitrile and the like as synthetic polymers.

  For the purpose of efficient removal of the above-mentioned small molecular weight proteins, studies have been made to make the pore portion of the hollow fiber membrane larger, that is, to have a high porosity. However, when such a hollow fiber membrane is stored at a high temperature or a low temperature, there is a high possibility that the desired quality cannot be ensured due to a decrease in strength or decomposition of the polymer.

  As a method for improving such thermal stability, for example, deoxygenation + aluminum packaging is performed, or the storage temperature is set to a low temperature. However, this method has problems such as high cost and difficult management.

  As a method for producing a hollow fiber membrane, a membrane-forming solution is simultaneously discharged from a double tube spinneret together with a core liquid, and is guided into a coagulation bath through an idle running portion (air gap portion) to form a hollow fiber membrane. A winding method (dry and wet spinning method) is widely used. In this method, the composition of the film forming solution, the composition of the core solution, the draft ratio, the spinneret temperature, the air gap part environment, the composition of the coagulation bath, the temperature of the coagulation bath, the washing temperature, the draw ratio, the hydrophilization temperature, etc. It is a parameter that defines the characteristics of the obtained film. In particular, the draft ratio and the temperature of the washing tank are not less than the glass transition temperature of the polymer used, and greatly vary depending on the hydrophilization temperature and the stretch ratio.

  Patent Document 3 discloses a technique for improving water permeability and sieving coefficient of myoglobin (molecular weight 17000) after high-pressure steam sterilization by blending cellulose diacetate and cellulose triacetate in a specific range. Further, Patent Document 4 discloses a film that can be autoclaved by combining a heat-stable polymer and an unstable polymer, but it cannot be expected to have an effect under high-temperature storage for a long time.

  Moreover, in patent document 5, although it is supposed that intensity | strength will increase by applying high extending | stretching in hot water, since the core material of a hollow part is a non-solidification type | system | group, a structure is for the conventional uniform film | membrane, Performance change is expected due to high temperature storage stability.

In Patent Document 6 and Patent Document 7, it is said that blood compatibility is improved by performing high stretching, but the structure is a general asymmetric structure. There is.
Japanese Patent Publication No. 2-18695 Japanese Patent Publication No. 5-54373 JP-A-7-51553 Japanese Patent Laid-Open No. 9-135898 JP 54-134116 A JP 2004-305679 A JP 2004-313359 A

  An object of the present invention is to provide a hollow fiber membrane excellent in storage stability and quality stability even at a high temperature during transportation, particularly a hollow fiber membrane suitable for a blood purifier.

The present invention has the following configuration.
(1) A hollow fiber having an asymmetric structure in which a spinning stock solution containing a cellulosic polymer and water are discharged from a double pipe nozzle as a core liquid and immersed in the order of a coagulation step, a water washing step, and a plasticizer step through an aerial traveling section. In the method for producing a membrane,
(A) In the water washing step, a temperature of Tg or more of the cellulosic polymer is applied for 5 seconds or more,
(B) In the plasticizer step, a temperature of Tg or higher of the cellulosic polymer is applied for 1 sec or longer.
A method characterized by that.
(2) The method according to (1), wherein the temperature in the washing step is Tg + 50 ° C. or less.
(3) The method according to (1) or (2), wherein the temperature in the plasticizer step is Tg + 50 ° C. or less.
(4) The method according to any one of (1) to (3), wherein stretching in the water washing step and the plasticizer step is 0.3 to 10%.
(5) The method according to any one of (1) to (4), wherein the plasticizer step is a step of immersing the hollow fiber membrane in a glycerin aqueous solution.

  The hollow fiber membrane of the present invention is a hollow fiber membrane excellent in storage stability and quality stability even at high or low temperatures during transportation, and can be preferably used as a hollow fiber membrane particularly suitable for blood purifiers. .

  Conventionally, in the manufacture of hollow fiber membranes, consideration has been given to suppress deterioration of the membrane material. Further, in hollow fiber membranes comprising polysulfone resin and polyvinyl pyrrolidone (PVP), consideration is given for suppressing oxidative degradation of PVP during storage. However, when the temperature becomes high or low due to the influence of outside air during storage or transportation, the performance may deteriorate or the amount of effluent may increase, and the inherent performance and safety may be impaired. It may rise to 60-80 ° C in cars and warehouses during midsummer transportation. Even when allowed to stand at 80 ° C., it is required that the stability of performance, suppression of eluate, strength, and film thickness do not change substantially.

  In order to balance the performance and strength of the hollow fiber membrane, the cellulose acetate polymer concentration in the spinning dope is preferably set to 16% by mass or more and 25% by mass or less, and more preferably 17% by mass or more and 23% by mass or less. .

  Hemodialysis treatment generally requires 3 to 5 hours, but the fluctuation in performance over the treatment time is a clinical problem. Higher total protein leakage (TPL) than the initial setting can result in hypoalbuminemia and may affect patient prognosis. If the clearance of β2-microglobulin (CLβ2MG) is too lower than the initial setting, the risk of amyloidosis increases. In general, TPL and CLβ2MG have a certain degree of correlation with UFR, so it is possible to improve the heat resistance of the hollow fiber membrane by observing the change in UFR at high temperatures.

  If strength decreases from the time of shipment, there is an increased risk of leaks during dialysis. In the blood purifier, since both ends of the hollow fiber membrane are fixed with resin, the shrinkage of the hollow fiber membrane at a high temperature during the storage period or during transportation may cause fatal damage. In the present invention, it is preferable that the yield strength retention rate is 90% or more and 100% or less after the hollow fiber membrane is sealed in an aluminum bag with both ends being free and left at 80 ° C. for 1 week.

  By reducing the wall thickness and inner diameter from the time of shipment, there is an increased possibility that residual blood may be generated due to blood flow stagnation during clinical use due to wrinkles on the inner surface of the hollow fiber membrane on the blood contact side. For these reasons, it is preferable that the retention ratio of the inner diameter and the film thickness is 90% or more and 100% or less after the hollow fiber membrane is sealed in an aluminum bag and left at 80 ° C. for 1 week.

As a means for confirming the influence of quality under high temperature, a dialyzer is put in an aluminum bag and sealed. Place it in a dryer at 80 ° C. Take them out at any time and check the impact on quality.

  When heat is applied to the film, the film structure changes. The heat causes shrinkage of the network between the polymers and decomposition of the polymer by the heat, so that the performance is lowered or increased. These are improved by an internal liquid coagulation system, and the film structure can be a network skin structure by setting the draft to 1.0 to 1.1.

  Furthermore, there are a water washing process in which a temperature of Tg or more is applied for 5 seconds or more and a plasticizer process in which a film having a network skin structure is applied for 5 seconds or more. The amount of heat applied to the film is an important point for manifesting this characteristic. In each step, a stronger structure is formed by stretching by 0.3 to 10%. If the stretching is too small, the effect of strength is reduced, and if it is too high, thread breakage occurs.

  The heat application start point is after the completion of solidification and from the step of washing the solvent and the non-solvent. The temperature is arbitrarily set depending on the polymer to be produced. This setting is set to Tg (glass transition point) or higher of the polymer, preferably Tg + 5 ° C or higher. If the temperature is too high, thermal shrinkage of the material will occur, leading to yarn breakage and film structure destruction. Therefore, Tg + 50 ° C or less is desirable. The time for applying heat needs to be set depending on the material, but it takes 5 seconds or more for the material to reach a substantially set temperature.

  Moreover, the heat addition in a plasticizer is arbitrarily set with the polymer to manufacture. This setting is set to Tg (glass transition point) or higher of the polymer, and preferably Tg + 5 ° C or higher. If the temperature is too high, thermal shrinkage of the material will occur, leading to yarn breakage and film structure destruction. Therefore, Tg + 50 ° C or less is desirable. Preferably it is Tg + 30 degrees C or less. The time for applying heat needs to be set depending on the material, but it takes 1 second or more for the material to reach a substantially set temperature. By carrying out in a plasticizer, the interpolymer network has a stronger structure and the yarn strength is increased. In the present invention, the term “in the plasticizer” refers to water, a glycerin aqueous solution, or the like.

  In the highly selective hollow fiber membrane of the present invention, the membrane structure preferably forms a network skin structure. Specifically, a skin layer is formed on the inner surface of the hollow fiber membrane and a rough layer is formed on the inner surface of the hollow fiber membrane at a magnification of 10,000 times using an electron microscope. It is an island and it is desirable to have a structure in which the sea exists on the island.

When the draft ratio is 1.1 or less in an internal liquid coagulation system, a network skin structure can be formed when phase separation is formed by the composition ratio of polymer and solvent, non-solvent and the concentration of the internal liquid coagulation liquid.
It is important that the polymer composition has a composition in which the composition of the internal solution also takes delayed phase separation behavior.
The solvent / non-solvent ratio is 8/2 or less, preferably 85/15. The composition ratio of the internal liquid is 5% or less, the same as the polymer composition ratio.

  When the heating temperature is Tg or more, looseness between polymers occurs, and thermal resistance is improved by orientation. The reason why Tg + 5 ° C or higher is required is that the looseness of the entire HF while traveling is evenly distributed. The reason why the temperature is Tg + 50 ° C. or lower is that structural change and thermal degradation occur due to heat.

  The reason for applying the washing temperature for 5 seconds or more is that the orientation is sufficiently stabilized. What is necessary is just to judge the time which adds heat from productivity. The same applies to the temperature at the plasticizer. The structure is stabilized by stretching and heat application in a plasticizer. Stretching and increasing the temperature increase the strength.

  The reason why the stretching is required to be 0.3% or more is that the structural change with respect to heat is eliminated by releasing the looseness of the polymer while being oriented. The effect will not be exerted unless at least 0.3% stretching is applied. However, thread breakage occurs when pulled more than 10%.

  As the structure of the hollow fiber membrane, there are a so-called homogeneous membrane structure, an asymmetrical structure, a finger void structure and the like, but any membrane structure may be used in the present invention. Those having a homogeneous membrane structure tend to have a small degree of effect of the present invention because the entanglement of the polymer is relatively stiff in the first place. A hollow fiber membrane having a relatively high porosity, an asymmetric structure, and a finger void structure is preferable because the effects of the present invention are easily exhibited.

  The material of the highly selective hollow fiber membrane of the present invention includes cellulose-based polymers such as cellulose, cellulose diacetate, and cellulose triacetate, polysulfone-based polymers such as polysulfone and polyethersulfone, and acrylic-based materials such as polymethyl methacrylate and polyacrylonitrile. Materials conventionally used as blood purification membrane materials such as polymers, vinyl alcohol polymers such as vinyl acetate and ethylene-vinyl alcohol copolymer are widely available, but cellulose diacetate, cellulose triacetate, etc. The cellulose derivatives are suitable and preferable for obtaining the above preferable characteristics.

  In the conventional method for obtaining a cellulose acetate-based hollow fiber membrane, the polymer concentration in the spinning dope needs to be 15% or less in order to ensure the fluidity of the spinning dope and obtain the desired performance and quality. However, lowering the polymer concentration in the spinning dope results in a lower polymer density in the formed hollow fiber membrane, leading to a decrease in the strength of the hollow fiber membrane. In particular, there is a problem that the strength, which is important in module production, is likely to be insufficient. When a module is manufactured using such a low-strength hollow fiber membrane, the hollow fiber membrane breaks without being able to withstand friction when the bundle of hollow fiber membranes is loaded into the module case, or the module end is filled with resin. When the core liquid in the hollow portion is removed, the hollow fiber membrane is not able to withstand the centrifugal force, causing a problem that causes a decrease in module productivity.

Therefore, in order to ensure module productivity while expressing the performance required for hollow fiber membranes for artificial kidneys, the hollow fiber obtained by setting the polymer concentration in the spinning dope to a relatively high value of 15% to less than 30% The film strength was ensured. Furthermore, the water permeability (UFR) is 200 ml / (hr · mmHg · m ² ) or more, β2MG clearance is 50 ml / min. (1.5 m ² ) or more, and the leakage of useful proteins such as albumin is 3 g / (3 L We examined to develop the following performance (at the time of water removal).

  Generally, when the polymer concentration is increased, the viscosity of the spinning dope increases and the fluidity decreases, so it is necessary to set the nozzle temperature relatively high to ensure the fluidity of the spinning dope. In particular, in the case of a cellulose acetate polymer, the spinning dope viscosity is much higher even at the same polymer concentration as compared to a polysulfone polymer. In the case of a spinning stock solution using a polysulfone-based polymer, the viscosity of the spinning stock solution is relatively low, so even if the polymer concentration is increased, it can be sufficiently discharged from the nozzle. However, in the case of a cellulose acetate-based polymer, the polymer concentration is at most However, it is necessary to raise the nozzle temperature to 100 ° C or higher even if it is about 15%. Although there is no particular difficulty in setting the nozzle temperature to 100 ° C. or higher, it is necessary to use an aqueous solution as a core liquid in order to form a dense layer on the inner surface of the hollow fiber membrane, and the nozzle is used to prevent boiling of the aqueous solution. The temperature should be at least 90 ° C or lower.

  In order to obtain a high-strength cellulose acetate asymmetric hollow fiber membrane, the above technical problems must be solved. Therefore, as a result of intensive investigations to prevent the core liquid from boiling while ensuring the fluidity of the spinning raw liquid, the present inventors separately control the temperature until immediately before discharging the spinning raw liquid and the core liquid from the nozzle. Found a means. Specifically, by using the means as described later, the fluidity of the spinning dope was secured while preventing boiling of the core solution, and the present invention was finally completed.

  For example, in order to produce a hollow fiber membrane for blood purification, a plurality of double tube nozzles having a slit outer diameter of 300 to 1000 μm, a slit inner diameter of 200 to 900 μm, and a core liquid discharge port diameter of 100 to 600 μm are generally provided in the nozzle block. Set and use. As described above, since the width of the spinning raw solution discharge hole and the diameter of the core liquid discharging hole are only several hundred μm, it is very difficult to precisely control the temperature until the spinning raw solution and the core liquid are discharged from the nozzle. The present inventors solved this problem by using a structure in which a heat medium (refrigerant) can be circulated in the nozzle block so that the temperature of the spinning dope and the core solution can be controlled separately until immediately before discharge. did. One nozzle block usually has several tens to several hundreds of nozzles incorporated therein, and it is necessary to take into consideration temperature control of them uniformly. This technical difficulty has been cleared and the present invention has been achieved.

  Conventional cellulose acetate polymers include various cellulose acetate polymers with different degrees of acetylation and polymerization such as L-20, 30, 40, 50, 70, LT-35, 55, 105 from Daicel Chemical Industries. A cellulose triacetate having a 6% viscosity of 250 mPa · s to 300 mPa · s has been conventionally used. By processing the nozzle block, it is possible to perform spinning even when the polymer concentration exceeds 15% using such a high viscosity polymer, and it is possible to ensure the strength of the hollow fiber membrane. However, 6% viscosity is relatively low, more than 140mPa · s and less than 200mPa · s, in order to achieve further improvement in hollow fiber membrane performance and spinning stability, module productivity and especially storage stability during transportation. The use of a cellulose acetate polymer having a viscosity was studied. Finally, by using the low-viscosity polymer and further increasing the polymer concentration in the spinning dope, it became possible to ensure the strength of the hollow fiber membrane, maintain and improve the membrane performance, and optimize the balance between them. .

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. A low degree of acetylation indicates that there are many hydroxyl groups in the polymer chain, which may be disadvantageous in terms of biocompatibility such that complements are easily activated when the polymer comes into contact with blood. The theoretical upper limit of the degree of acetylation is 62.5%, but if the degree of acetylation is too high, the solubility and moldability may be reduced. 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.

  A hollow fiber membrane with an asymmetric structure that has a thin dense layer on the inner surface and the pore diameter increases toward the outside. The thin dense layer has a fractionation characteristic (β2 microglobulin permeates and albumin does not permeate). In other words, the portion (support layer) other than the dense layer has a large pore diameter, so that it does not have resistance to substance permeation, and it is possible to improve the removability of low molecular weight proteins typified by β2 microglobulin. The support layer mainly plays a role of maintaining the strength of the film. Therefore, as the thickness of the support layer is increased, the strength of the resulting hollow fiber membrane can be increased and the heat resistance can be increased, but this increases the possibility that the desired membrane performance cannot be expressed. On the other hand, if the thickness of the support layer is reduced, the membrane performance can be improved, but this is a trade-off phenomenon that the strength and heat resistance are sacrificed.

In order to balance the performance of the hollow fiber membrane and the strength of the membrane and increase the thermal stability during storage, it is more preferable to set the cellulose acetate polymer concentration in the spinning dope to 16% by mass or more and 25% by mass or less. More preferably, the content is 17% by mass or more and 23% by mass or less.
The viscosity of the spinning dope when discharged from the nozzle is N-methylpyrrolidone (NMP) as a solvent, triethylene glycol (TEG) as a non-solvent, and cellulose acetate polymer / NMP / TEG = 16-25 / It is preferable that the viscosity when measured at 49 to 77/7 to 26 is 50 to 9000 mPa · s (50 ° C.).

  As described above, the structure of the hollow fiber membrane is a two-layer structure comprising an ultrathin dense layer that governs the separation and permeation characteristics of a substance and a support layer that retains mechanical strength and hardly affects the permeation of the substance. Or a multilayer structure is preferable. In particular, when blood is allowed to flow through the hollow portion of the hollow fiber membrane and the substance permeates from the inside to the outside of the hollow fiber membrane, it is desirable that there is a dense layer at least on the inner surface side of the hollow fiber membrane. If there is no dense layer on the inner surface side, blood protein tends to adhere to the portion, or it tends to enter into the pores, which may impede substance permeation.

  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. 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 a module (blood purifier) to compensate for the lack of membrane performance There is a possibility that the convenience of use may be impaired, such as having to increase the size. 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 thickness of the hollow fiber membrane is too thin, the permeation performance is improved, but it may be difficult to maintain the required strength. On the other hand, if the film thickness is too large, the permeation resistance of the substance increases and the permeability of the removed substance 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 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.

  In the present invention, it is preferable to use N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like as the solvent for the cellulose acetate polymer. These solvents have good compatibility with water and exhibit coagulability with respect to the cellulose acetate polymer. Non-solvents include ethylene glycol, triethylene glycol, polyethylene glycol, glycerin, propylene glycol, and alcohols.

  In the present invention, as the core liquid, an aqueous solution composed of the above-mentioned solvent, non-solvent and water can be generally used, but may further contain a swelling agent and other additives. Examples of swelling agents include formamide, urea, triethyl phosphate, glyoxal, butanol, isopropanol and the like.

  When a relatively high viscosity cellulose acetate polymer is used as a raw material, if the water content of the core liquid is too low, the coagulation property of the polymer is lowered. The formation and porosity of the ultrathin dense layer to be determined tends to be non-uniform. Therefore, the water content in the core liquid is preferably 10% by mass or more. It is more preferably 30% by mass or more, further preferably 50% by mass or more, still more preferably 70% by mass or more, and particularly preferably water alone. On the other hand, if the water content of the core liquid becomes too high, the spinning dope discharged from the nozzle is rapidly solidified, so that the spinnability is deteriorated and yarn breakage or deformation of the hollow fiber membrane occurs. Is likely to occur. Here, when the low-viscosity cellulose acetate-based polymer described above is used, the reason is not well understood, but it is found that even if the water content of the core liquid is increased, good spinning stability without occurrence of yarn breakage can be obtained. It was.

  It should be noted that, even when the core liquid is water, good productivity is ensured without affecting the stringiness. The fact that the water content of the core liquid can be increased means that it is easy to have a difference in solvent concentration between the core liquid and the spinning dope, that is, the thickness and structure of the dense layer on the inner surface of the hollow fiber membrane. This leads to a wider range of control. Moreover, since the core liquid can be easily washed and removed after the production of the hollow fiber membrane, there are secondary effects such as reduction of work man-hours, cost reduction for washing treatment, and wastewater treatment.

  As described above, it is possible to increase the discharge temperature of the spinning dope by separately controlling the temperature of the spinning dope and the core solution, and the polymer concentration in the spinning dope can be increased by using a relatively low viscosity polymer. As an effect that can be enhanced, the strength of the obtained hollow fiber membrane was improved. Another effect of using a relatively low-viscosity polymer is that a hollow fiber membrane with a high Young's modulus, which is an index of hardness, improves the polymer density (packing property) per unit volume of the hollow fiber membrane. It became possible to get.

  Further effects could be confirmed by using a spinning dope comprising a low viscosity cellulose acetate polymer. By improving the fluidity of the spinning dope, the setting range of the nozzle temperature, which is one of the means for adjusting the performance of the hollow fiber membrane, has been widened, and it has become easier to control the balance between coagulation and phase separation of the spinning dope. Controlling the balance between coagulation and phase separation means balancing the pore diameter and thickness of the dense layer of the hollow fiber membrane and the porosity of the support layer, specifically while enhancing the removability of β2 microglobulin. It leads to suppressing leakage of useful proteins represented by albumin as much as possible. Moreover, it leads also to the ensuring of the intensity | strength of the hollow fiber membrane which contributes to the improvement of the washing | cleaning removal property of the solvent in the hollow fiber membrane manufacture mentioned later, and a non-solvent, and module assembly property. With conventional spinning stock solutions consisting of high-viscosity polymers, the nozzle temperature could only be lowered to around 100 ° C even if the following measures were taken, but by using low-viscosity polymers, the nozzle temperature was reduced to around 40 ° C. However, the spinning dope can be discharged uniformly and stably.

In the present invention, the outer surface porosity of the hollow fiber membrane is preferably 15% or more and 30% or less. Further, the average pore area per hole on the outer surface of the hollow fiber membrane is preferably 0.01 μm ² or more and 0.05 μm ² or less. If the outer surface open area ratio or average pore area is too large, the porosity of the entire support layer generally increases, so that the strength required for the hollow fiber membrane cannot be ensured, or the retainability of the membrane pore retainer may be reduced. There is. On the other hand, if the outer surface open area ratio or average pore area of the hollow fiber membrane is too small, the asymmetry of the pores is lost and the structure approaches a homogeneous structure, so that the permeability and filtration stability of the substance are reduced. Sometimes. 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 16% or more and 28% or less, and further preferably 17% or more and 26% or less. The average pore area is more preferably 0.01 [mu] m ² or more 0.04 .mu.m ² or less, more preferably 0.02 [mu] m ² or more 0.04 .mu.m ² or less.
Here, the membrane pore-retaining agent refers to pores that are temporarily removed when an air leak test is performed to prevent the pores from shrinking when the hollow fiber membrane is dried or to test the integrity of a module such as a blood purifier. It plays the role of blocking the Specific examples of the membrane pore retainer include glycerin, glycerin derivatives, polyethylene glycol, and the like. In the present invention, it is preferable to use glycerin.

  Conventionally, some hollow fiber membranes having a uniform structure have been filled with a membrane pore retainer in the pores in order to prevent shrinkage of the pores. However, in hollow fiber membranes having a so-called asymmetric structure, the pore diameter and porosity are too high, so there is a problem that the membrane pore retainer leaks from the pores, and the membrane pore retainer cannot be used. It was. In particular, a hollow fiber membrane made of a cellulose acetate-based polymer is likely to shrink due to heat during drying or storage, and a membrane design that assumes shrinkage in advance is required. In the hollow fiber membrane of the present invention, by preparing a relatively high concentration spinning stock solution using a relatively low viscosity polymer, it is possible to obtain a hollow fiber membrane having higher strength than conventional membranes. Leakage from the pores of the membrane pore retainer due to shrinkage is suppressed. In addition, when the porosity and the average pore area are reduced, the permeation resistance of the substance is increased, and thus the permeability of the substance in the low molecular protein region is lowered, but the thickness of the hollow fiber membrane of the present invention can be reduced. Therefore, the transmission performance can be improved accordingly.

In order to make the outer surface open area ratio and average pore area within the scope of the present invention, the polymer concentration in the spinning dope and the nozzle temperature are affected, but in addition, the spinning dope discharged from the nozzle is immersed in the coagulation bath. It is preferable that the length of the aerial traveling portion until the distance is 10 mm or more and 600 mm or less. Moreover, it is preferable to block the aerial travel 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, the growth of polymer nuclei on the outer surface side of the spinning dope discharged from the nozzle can be promoted. On the other hand, on the inner surface side of the spinning dope, it is possible to complete the coagulation of the polymer with 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 portion is more preferably 10 mm or more and 300 mm or less, and 10 mm or more and 150 mm or less is more preferable in order to offset the influence of the spinning spot discharged from the spinneret. The temperature of the aerial traveling section is preferably 3 ° C. or higher and 45 ° C. or lower in terms of easy control, and in view of performance, it is more preferably 5 ° C. or higher and 40 ° C. or lower in order to suppress the amount of useful protein leak.
The appropriate range for the length and temperature of the aerial running section varies depending on the nozzle draft and spinning speed. The scope of the present invention assumes that the nozzle draft is about 1 to 5 and the spinning speed is 30 to 90 m / min. doing.

  In the present invention, in order to obtain an appropriate outer surface of the hollow fiber membrane, it is also an important requirement to optimize the conditions of the coagulation bath. 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, it is possible to grow polymer nuclei generated in the aerial traveling section, and it is possible to expand the hole area ratio and the hole diameter. In order to set the open area ratio to 15% or more and 30% or less, the solvent concentration in the coagulation bath is preferably 50% by weight to 80% by weight and the coagulation bath temperature is preferably 20 ° C. or more and 70 ° C. or less. The solvent concentration should be 55% to 77% by weight and the coagulation bath temperature should be 30 ° C or more and 50 ° C or less, in order to ensure the hollow fiber membrane from the coagulation bath and the ease of temperature control of the running part in the air. More preferably, the solvent concentration is 60 wt% or more and 75 wt% or less, and the coagulation bath temperature is 35 ° C. or more and 45 ° C. or less.

  Hereinafter, the effectiveness of the present invention will be described with reference to examples, but the present invention is not limited thereto.

(Measurement of polymer viscosity)
Dissolve each desired spinning dope for 4 hours at 180 ° C. in a nitrogen atmosphere. After confirming that the solution was uniformly dissolved visually, a sample was taken and a B-type viscometer (B-8H-HH) [ Measure the viscosity at a temperature of 50 ° C with Tokyo Keiki].

(Hole ratio of hollow fiber membrane outer surface)
Observe the outer surface of the hollow fiber membrane with a 10,000x electron microscope and take a photograph (SEM photograph). The image is processed with image analysis software to determine the porosity of the outer surface of the hollow fiber membrane. The image analysis software is measured using, for example, Image Pro Plus (Media Cybernetics, Inc.). The emphasis / filtering operation is performed on the captured image so that the hole and the blockage are identified. Thereafter, the holes are counted, and when the lower polymer chain can be seen inside the holes, the holes are combined and counted as one hole. The area (A) of the measurement range and the 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 10 views 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.

(Average pore area of the hole on the outer surface of the hollow fiber membrane)
Count as in the previous section to determine the area of each hole. Also, holes on the measurement range boundary are excluded during counting. This is carried out for 10 fields of view and the average of all the hole areas is obtained.

(Water permeability)
The blood outlet circuit (outlet side from the pressure measurement point) of the dialyzer was sealed with forceps. Purified water kept at 37 ° C is placed in a pressurized tank, and the pressure is controlled by a regulator. The pure water is sent to the blood flow path side of the dialyzer kept in a 37 ° C constant temperature bath, and the amount of filtrate flowing out from the dialysate side is measured. It was 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 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 should be 0.999 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 from the membrane area and the water permeability of the dialyzer.
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 ).

(Yielding strength)
Using Tensilon UTMII manufactured by Toyo Baldwin, the tensile speed was 100 mm / min and the distance between chucks was 100 mm.

(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 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.

(UV)
Add 100 ml of water to 1 g of hollow fiber membrane according to the dialysis artificial kidney device manufacturing approval standard. Heat to a 70 ° C bath for 1 hr. Thereafter, the maximum absorption peak value of UV (220 to 360 nm) of the sample liquid is defined as the UV value.

(H ₂ O ₂ )
Add 100 ml of water to 1 g of hollow fiber membrane. Heat to 70 ° C bath for 1 hour. Thereafter, the hydrogen peroxide concentration in the sample solution is measured, and the amount relative to the weight of the hollow fiber membrane is calculated.

Example 1
Cellulose triacetate (6% viscosity = 162 mPa · s, Daicel Chemical Industries) 19.0 mass%, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical) and triethylene glycol (TEG, Mitsui Chemicals) 85:15 The solution was uniformly dissolved at a ratio, and then the spinning solution was defoamed. The obtained spinning dope was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then simultaneously discharged together with water degassed in advance as a core solution from a double tube nozzle heated to 85 ° C. At that time, the core liquid was cooled by flowing a 5 ° C. refrigerant through the nozzle block. The spinning dope was kept warm by circulating a heating medium at 80 ° C. in the block. After passing through the aerial traveling section , which was blocked from the outside air by a spinning tube, it was solidified in a 70 mass% NMP / TEG (85/15) aqueous solution at 44 ° C. The hollow fiber membrane pulled out from the coagulation tank is subjected to a 90 ° C x 0.3% stretched water washing process for 10 seconds, then passed through a glycerin bath of 85 ° C x 88 mass% x stretched 1.0% for 3 seconds, dried with a dryer, and spinning speed. Winding up at 60 m / min.

(Example 2)
Cellulose triacetate (manufactured by Daicel Chemical Industries) 19.0% by mass, N-methyl-2-pyrrolidone (NMP) and triethylene glycol (TEG) were uniformly dissolved in a ratio of 85:15, and then the spinning solution was defoamed. . The obtained spinning dope is passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged simultaneously with water previously deaerated as a core solution from a double tube nozzle heated to 85 ° C. After passing through the aerial traveling section that is blocked from the outside air, it is coagulated in a 70 mass% NMP / TEG (85/15) aqueous solution at 44 ° C, followed by a water washing step of 95 ° C x stretching 0.3% for 10 seconds, then 90 ° C x A glycerin bath of 88% by mass × stretching 1.0% was passed through for 3 seconds, dried with a dryer, and wound up at a spinning speed of 60 m / min.

(Example 3)
Cellulose triacetate (manufactured by Daicel Chemical Industries) 19.0% by mass, N-methyl-2-pyrrolidone (NMP) and triethylene glycol (TEG) were uniformly dissolved in a ratio of 85:15, and then the spinning solution was defoamed. . The obtained spinning dope is passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged simultaneously with water previously deaerated as a core solution from a double tube nozzle heated to 85 ° C. After passing through the aerial traveling section , which is blocked from the outside air, it is solidified in a 70 mass% NMP / TEG (85/15) aqueous solution at 44 ° C, and after 95 seconds of water washing process of 95 ° C x 5% stretch, 95 ° C x The mixture was passed through a glycerin bath of 88% by mass × stretching 3.0% for 3 seconds, dried with a dryer, and wound up at a spinning speed of 60 m / min.

(Comparative Example 1)
Cellulose triacetate (manufactured by Daicel Chemical Industries) 19.0% by mass, N-methyl-2-pyrrolidone (NMP) and triethylene glycol (TEG) were uniformly dissolved in a ratio of 85:15, and then the spinning solution was defoamed. . The obtained spinning dope is passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged simultaneously with water previously deaerated as a core solution from a double tube nozzle heated to 85 ° C. After passing through the aerial traveling part that is blocked from the outside air, it is solidified in a 70 mass% NMP / TEG (85/15) aqueous solution at 44 ° C, and after passing through a water washing step of 55 ° C x stretching 0.3%, 65 ° C x The mixture was passed through a glycerin bath of 88% by mass × stretching 1.0% for 3 seconds, dried with a dryer, and wound up at a spinning speed of 60 m / min.

(Comparative Example 2)
Cellulose triacetate (manufactured by Daicel Chemical Industries) 19.0% by mass, N-methyl-2-pyrrolidone (NMP) and triethylene glycol (TEG) were uniformly dissolved in a ratio of 85:15, and then the spinning solution was defoamed. . The obtained spinning dope is passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged simultaneously with water previously deaerated as a core solution from a double tube nozzle heated to 85 ° C. After passing through the aerial traveling part that is blocked from the outside air, it is solidified in a 70 mass% NMP / TEG (85/15) aqueous solution at 44 ° C, and after passing through a water washing step of 55 ° C x stretching 0.3%, 65 ° C x The mixture was passed through a glycerin bath of 88% by mass × 0.0% of stretching for 3 seconds, dried with a dryer, and wound up at a spinning speed of 60 m / min.

  The hollow fiber membrane of the present invention is excellent in stability of quality even when exposed to high temperatures during storage and transportation, and therefore excellent in performance of desired performance even in clinical use. Therefore, it is important to contribute to industrial development.

Claims (5)

Production of a hollow fiber membrane having an asymmetric structure in which a spinning stock solution containing a cellulosic polymer and water are discharged from a double pipe nozzle as a core liquid and are immersed in the order of a coagulation step, a water washing step, and a plasticizer step through an aerial traveling section. In the method
(A) In the water washing step, a temperature of Tg or more of the cellulosic polymer is applied for 5 seconds or more,
(B) In the plasticizer step, a temperature of Tg or higher of the cellulosic polymer is applied for 1 sec or longer.
A method characterized by that. The method according to claim 1, wherein the temperature in the washing step is Tg + 50 ° C. or less. The method according to claim 1, wherein the temperature in the plasticizer step is Tg + 50 ° C. or less. The method according to any one of claims 1 to 3, wherein the stretching in the washing step and the plasticizer step is 0.3 to 10%. The method according to claim 1, wherein the plasticizer step is a step of immersing the hollow fiber membrane in a glycerin aqueous solution.