JP2013144162A - Blood purifier excelling in replacement characteristic of large amount of liquid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a blood purifier having replacement characteristics of a large amount of liquid and excelling in performance stability.SOLUTION: A method for producing a hollow fiber membrane includes ejecting a spinning dope and a core liquid from a tube-in orifice type nozzle and allowing them to pass through a coagulation bath via an aerial traveling part for water washing. (1) A temperature difference (I) between the spinning dope and the inside of the nozzle is 40°C or higher and 110°C or lower, and a temperature difference (J) between the spinning dope and the core liquid in the nozzle is 10°C or higher and 90°C or lower. (2) The product (I×J) of I and J is 1,600-5,000. (3) As to water washing, an inlet temperature of a water washing bath is 60-90°C.

Description

  The present invention relates to a blood purifier having a large volume liquid replacement characteristic and excellent performance stability.

  In blood purification methods for the treatment of renal failure, for the purpose of removing uremic toxins and waste products in the blood, cellulose, which is a natural material, and its derivatives, cellulose diacetate, cellulose triacetate, synthetic polymers such as polysulfone, Blood purifiers such as hemodialyzers, hemofilters or hemodialyzers using a dialysis membrane using a polymer such as methyl methacrylate or polyacrylonitrile or an ultrafiltration membrane as a separating material are widely used. In particular, blood purifiers that use hollow fiber membranes as separators are blood purifiers due to advantages such as reduction of circulating blood volume related to extracorporeal circulation, high substance removal efficiency in blood, and productivity of blood purifier assembly. High importance in the field.

  Blood purifiers that use hollow fiber membranes usually flow blood through the hollow part of the hollow fiber membrane, flow dialysate counter-currently to the outside, and transfer substances such as urea and creatinine by mass transfer based on diffusion from blood to dialysate. The main goal is to remove low molecular weight substances from the blood. Furthermore, as dialysis complications become a problem as the number of long-term dialysis patients increases, not only low molecular weight substances such as urea and creatinine are removed by dialysis, but also high molecular weights with a molecular weight of several thousand to a molecular weight of 1 to 20,000. It is required for blood purification membranes to expand to these substances and to remove these substances. In particular, β2 microglobulin with a molecular weight of 11700 has been found to be the main accumulation substance of carpal tunnel syndrome and is a removal target. Membranes used for such high molecular weight substance removal treatments are called high performance membranes. They are larger than conventional dialysis membranes, increase the number of pores, increase the porosity, increase the porosity. It is possible to improve the removal efficiency of high molecular weight substances by reducing the thickness.

  Furthermore, in recent years, it has been reported that a treatment method that removes a substance having a higher molecular weight than β2 microglobulin has the effect of reducing the survival risk of dialysis patients, and the removal of a substance having a higher molecular weight than β2 microglobulin has attracted attention. ing. In order to increase the removal efficiency of a substance having a low molecular weight with such a diffusion alone, mass transfer based on filtration is effective. From the above background, an invention for increasing the filtration effect in a normal treatment mode in a blood purifier using a hollow fiber membrane is disclosed. For example, a technique for enhancing internal filtration in a blood purifier by providing a narrow portion of a hollow fiber bundle at the center of the blood purifier has been disclosed (for example, see Patent Document 1). As another means, high performance is disclosed for a blood purifier in which the effective length of the hollow fiber membrane of the blood purifier is increased, the diameter is reduced, and the filling rate of the hollow fiber membrane is increased (for example, patents). References 2 and 3).

  However, just pursuing the filtration effect in the normal dialysis mode as described above, the expected liquid replacement amount is not sufficient, and the life risk of dialysis patients does not change much compared to normal dialysis. Treatment involving filtration is expected. Dialysis and filtration treatment usually involves dialysis and filtration of blood for 4 hours or more, but the lifetime of the blood purifier is a problem here. The lifetime of a blood purifier is generally greatly affected by the filtration flow rate. The main factor that shortens the lifetime is clogging of the blood purification membrane, which is clogged by blood components, increasing the transmembrane pressure difference of the blood purification device during treatment, and the desired filtration efficiency. May not be obtained, or the performance may be adversely affected. As a means for preventing an increase in the transmembrane pressure difference of the blood purifier with respect to a constant filtration flow rate, an invention such as increasing the inner diameter of the hollow fiber membrane and designing the interfacial tension within the membrane within a specific range is disclosed. (For example, see Patent Document 4). Moreover, the technique which avoids a pressure rise by making the sieve coefficient of a blood purification film into a specific range is also disclosed (for example, refer patent document 5). Furthermore, by making the inner surface of the blood purification membrane dense, the effect of not increasing the transmembrane pressure difference even when filtration is performed (for example, see Patent Document 6), and the inner surface of the blood purification membrane is made uniform. The effect of not reducing the ultrafiltration coefficient is disclosed (for example, see Patent Document 7), and the effect of not reducing the ultrafiltration coefficient by making the inner surface smooth is disclosed (for example, see Patent Document 8). ing.

  The increase in transmembrane pressure difference due to clogging in blood filtration is greatly affected by blood flow rate and filtration flow rate. One of the factors that increase the transmembrane pressure difference is to increase the filtration flow rate. As a result of the removal of water from the blood, the blood concentration increases, the blood fluidity deteriorates, and the filtration efficiency decreases. It is in. An invention has been disclosed in which hematocrit is focused on as an indicator of blood concentration (blood cell concentration), and filtration characteristics are improved assuming a region where hematocrit is high (see, for example, Patent Documents 9 and 10).

  In this way, inventions for improving filtration characteristics have been made, but none of the targeted filtration characteristics has a ratio of filtration flow rate to blood flow rate exceeding 30%. This is because in blood filtration dialysis, the critical value of reaching the limit value of the transmembrane pressure difference due to blood concentration and clogging in the conventional blood purification membrane is in the region where the ratio of the filtration flow rate to the blood flow rate is 30% or less, This confirms that it was impossible to perform hemofiltration dialysis for several hours in the region where the ratio of the filtration flow rate to the blood flow rate was high. However, it has been reported that in the case of a large-volume liquid replacement therapy that filters a large amount of blood, the survival risk of the patient is significantly reduced in the case of 25L replacement. For example, assuming that the actual filtration time for a 20 L large-volume liquid replacement therapy is 5 hours, the filtration flow rate is 67 ml / min. Here, when 300 ml / min, which is a large amount of blood flow for Japanese people, can be secured, the blood flow ratio is 22%, but the blood flow rate is 200 ml / min, which is the average value of Japanese people. In some cases, the current critical value will be exceeded, 33%. As described above, in a patient whose blood flow volume cannot be sufficiently secured, large-volume liquid replacement therapy has been difficult to implement with the blood purification membranes developed so far.

  As described above, by changing the shape of the blood purification membrane, the internal filtration flow rate is increased, the removal efficiency of the substance to be removed is increased, the inner surface of the membrane is made dense, the smoothness is improved, and the filtration characteristics are improved. Although it has been raised, the mass filtration properties, which are areas of mass fluid replacement therapy, are still not sufficient to apply to all patients. The current situation is that there is no blood purifier capable of performing large-volume liquid replacement therapy especially for patients who cannot obtain a large amount of blood flow. As a result of intensive studies on hollow fiber membranes used in blood purifiers in order to solve the above-mentioned problems, the present inventors found that after molding the hollow fiber membranes in the pre-phase separation state, they were further immersed in a water bath at a temperature higher than the glass transition temperature. It was found that by re-forming, clogging due to mass filtration can be effectively suppressed, and a blood purification membrane suitable for a blood purifier excellent in performance stability can be obtained.

Japanese Patent No. 3257999 JP 2002-143298 A JP-A-2005-131123 JP 2006-305333 A JP-A-10-108907 Japanese Patent Laid-Open No. 10-248925 JP 09-154936 A Japanese Patent Application Laid-Open No. 08-970 JP 2006-288414 A JP 2006-288413 A

  An object of the present invention is to provide a blood purifier having a large-volume liquid replacement characteristic and excellent in performance stability.

As a result of intensive studies in order to solve the above problems, the present inventors finally reached the present invention. That is, the present invention has the following configuration.
(1) A method for producing a hollow fiber membrane comprising discharging a spinning stock solution and a core solution from a tube-in-orifice nozzle, passing through a solidified bath through an aerial traveling section, and washing with water.
(A) The difference (I) between the keep temperature of the spinning dope and the temperature in the nozzle is 40 ° C. or more and 110 ° C. or less, and the temperature difference (J) between the spinning dope and the core solution in the nozzle is 10 ° C. or more and 90 ° C. (B) The product of I and J (I × J) is 1600 to 5000 (c) The water washing is performed at a water bath temperature of 60 to 90 ° C.
(2) The method according to (1), wherein the spinning dope contains a cellulosic polymer.
(3) The method according to (1) or (2), wherein the core liquid is water.

  The blood purifier of the present invention has a large-volume liquid replacement characteristic and a characteristic that has stability in blood system performance. Therefore, regardless of the patient's blood condition and the blood flow volume that can be secured, all patients can be subjected to large-volume liquid replacement therapy such as pre-dilution and post-dilution, such as online HDF therapy, to reduce the patient's life risk. There is an advantage that can be.

The schematic diagram of the film | membrane cross section which shows the particle filling state of the hollow fiber membrane of this invention. The figure which shows the relationship between the filtration time in Qf90ml / min, and the change of TPL. The figure which shows the relationship between IxJ value and ultrafiltration coefficient ratio (B / A, D / C).

  Hereinafter, the present invention will be described in detail.

  In order to solve the above-mentioned problems, the present inventors have studied the manufacturing process and performance of hollow fiber membranes used in blood purifiers, particularly the filtration characteristics. Hollow fiber membranes aiming to be able to filter stably with a large amount of liquid replacement, that is, at a high flow rate, increase the pore size of the membrane as a whole, such as increasing the pore size of the membrane as described above, or reducing the film thickness Has been developed in the direction to. Such hollow fiber membranes focusing only on high water permeation performance tend to clog because proteins in the blood are easily attached and adsorbed on the surface of the membrane when hemodialysis or hemodiafiltration is performed. When clogging begins to occur, the transmembrane pressure difference gradually or rapidly increases with time, and it may be difficult to continue blood purification further, or dialysis efficiency and filtration efficiency may deteriorate. A membrane that easily causes clogging has a great influence on the performance. For example, the retention rate of clearance may be low, or the change in protein leak over time may be large. In order to obtain a hollow fiber membrane that can be stably filtered at a high flow rate even when the blood flow rate is low, that is, clogging is difficult, clearance retention is high, and protein leaks change slowly over time, The present inventors have found that phase separation and subsequent process control before the hollow fiber membrane is completely solidified are closely related.

Evaluation of clogging in the present invention is carried out by adding bovine blood prepared by adding citric acid to suppress coagulation to a hematocrit of 27-33% and a protein concentration of 6-7 g / dl, or a protein concentration of 6-7 g / dl. Using the prepared bovine plasma at 37 ° C., the blood was sent to a blood purifier with a membrane area of 1.5 m ^{2 at} an inlet flow rate (Qbin) of 200 ml / min, and blood at a predetermined filtration flow rate (Qf: ml / min). Is filtered. At this time, the filtrate is returned to the original blood batch to form a circulatory system. In the variable speed filtration experiment, Qf is changed every 15 minutes as 15 → 30 → 45 → 60 → 90 → 60 → 45 → 30 → 15 → 0 ml / min. Immediately before changing Qf, measure the flow rate of the filtrate, measure the inlet pressure (Pbin), outlet pressure (Pbout), and filtrate outlet pressure (Pfout) of the blood purifier.
Transmembrane pressure at each filtration flow rate (TMP) [mmHg] = (Pbin + Pbout) / 2-Pfout
TMP at Qf = 0m / min is the osmotic pressure of the colloid and is π.
Blood ultrafiltration coefficient (ml / m ² / hr / mmHg) = Qf (ml / min) × 60 / (TMP−π) / membrane area Here, Qf uses a measured value.

The ratio (B / A) between the value (A) at the first Qf = 15 ml / min and the value (B) at the last Qf = 15 ml / min is 80% for the ultrafiltration coefficient thus determined. The above is desirable. Furthermore, 83% or more is more preferable, and 86% or more is more preferable. In this evaluation, for a blood purifier having a membrane area of 1.5 m ² , the filtration flow rate was increased to 90 ml / min (filtration rate ratio 45%) with respect to a blood flow rate of 200 ml / min, and then the filtration flow rate was gradually decreased. In the clinical setting, the filtration rate is gradually increased while observing the patient's condition, or the filtration rate planned for various circumstances is changed ( This is a measure that evaluates clogging due to mass filtration. This assessment relates to the filtration of blood that has not been concentrated or diluted and corresponds to what is clinically referred to as post-dilution diafiltration (postHDF). From this background, if the storage rate of the ultrafiltration coefficient in this evaluation is less than 80%, the ultrafiltration performance of the membrane blood against the initial 20% or more is clogged and no longer functions. This means that the intended treatment is not actually performed, but this is not preferable because it reduces the therapeutic effect.

  In this evaluation, the influence of clogging can also be evaluated for the retention rate of the substance permeation performance. For the same blood purifier, after one blood evaluation was performed, the other one remained new, the clearance (CLmyo) of myoglobin (molecular weight 17000) was measured, and the retention rate (after blood evaluation / new) X100%). The CLmyo retention rate is desirably 50% or more, more desirably 60% or more, and still more desirably 70% or more. If the CLmyo retention rate is too low, the ability to remove other medium molecular weight proteins is also expected to decrease, and the desired therapeutic efficiency may not be achieved. The upper limit of the clearance value depends on the blood flow volume. When the blood flow volume is 200 ml / min, the maximum CLmyo value is 200 ml / min.

  As the second clogging evaluation in the present invention, predilution diafiltration (preHDF) is assumed. The evaluation method uses the diluted plasma obtained by diluting bovine plasma prepared at a protein concentration of 6 to 7 g / dl with physiological saline twice, and the last Qf = 15 ml / min for the ultrafiltration coefficient in the above method. This is a method for evaluating a ratio of values (last value / first value) when Qf = 15 ml / min. preHDF is a treatment method that is used when a larger amount of fluid replacement is required in a large-volume fluid replacement therapy, and is a treatment method that dilutes blood with a replacement fluid before blood enters the blood purifier. In this evaluation, it is assumed that plasma is diluted before passing through the blood purifier, that is, because the blood protein and other blood components are in a diluted state, clogging of the hollow fiber membrane is slight. However, in practice, clogging phenomenon similar to that of normal blood is confirmed. For the blood purifier of the present invention, the storage rate of the ultrafiltration coefficient with diluted plasma (the ratio between the first Qf = 15 ml / min value (C) and the last Qf = 15 ml / min value (D) (D / C) is preferably 80% or more, more preferably 85% or more, more preferably 90% or more, still more preferably 95% or more, and when the storage rate is less than 80%, This means that the ultrafiltration performance of the membrane against blood is more than 20% of the initial level, and it is in a state where it is not functioning due to clogging. Therefore, there is a possibility that the therapeutic effect is not obtained.

  In this evaluation, the degree of clogging can also be evaluated for the retention rate of the substance permeation performance. For exactly the same blood purifier, after one blood evaluation was performed, the other remained as new, the myoglobin clearance (CLmyo) was measured, and the retention rate (after blood evaluation / new product x 100%) Ask for. The CLmyo retention rate is desirably 50% or more, more desirably 60% or more, and still more desirably 70% or more. If the CLmyo retention rate is too low, the performance of other medium molecular weight proteins is predicted to decrease, and the desired therapeutic efficiency may not be achieved.

The third evaluation of clogging in the present invention is the temporal stability of constant-speed mass filtration. As an evaluation method, bovine blood prepared by adding citric acid and suppressing coagulation to a hematocrit of 27 to 33% and a protein concentration of 6 to 7 g / dl, or a cow prepared to a protein concentration of 6 to 7 g / dl. Using plasma, at 37 ° C., a blood purifier having a membrane area of 1.5 m ² is fed at an inlet flow rate (Qbin) of 200 ml / min, and blood is filtered at a filtration flow rate (Qf) of 90 ml / min. The measurement is continued for 120 minutes. From the start of the experiment, measure the transmembrane pressure and sample the filtrate. It is preferable that the ratio (H / G) of the 15 minute value (G) and the 120 minute value (H) of the ultrafiltration coefficient is 80% or more. Further, it is preferably 85% or more. When plasma with a protein concentration of 6.5 g / dl is filtered at a flow rate of 90 ml / min, the plasma inside the blood purifier is concentrated to a protein concentration of 18 g / dl and the viscosity of whole blood to 23 cP. The fact that such highly concentrated and highly viscous blood is continuously filtered for 120 minutes and the original ultrafiltration coefficient is maintained at 80% or more means that clogging in the ultrafiltration performance hardly occurs. The ratio of the 120 minute value / 15 minute value of the ultrafiltration coefficient being less than 80% means that the ultrafiltration coefficient for blood has decreased, and is a normal treatment time of 4 to 5 hours. Later, most of the performance of the blood purification membrane may be lost due to clogging.

  Regarding the time course change of protein leak in the above-mentioned constant-speed mass filtration (Qb 200 ml / min, Qf 90 ml / min), the ratio (F / E) of 15-minute value (E) to 120-minute value (F) is 30% or more. desirable. Regarding protein leakage in blood purification, even when the ratio of the ultrafiltration coefficient between the beginning and the end is high, there is a difference between the start and end of blood filtration, and it is usually not constant from the beginning to the end. . For this reason, the protein leak ratio is an index for knowing performance fluctuations due to clogging with higher sensitivity than the ultrafiltration coefficient ratio. The change over time in protein leak is due to adsorption or clogging of blood components, and the change over time may occur rapidly depending on the degree of interaction and reaction rate. This time-dependent change also depends on the flow rate of filtration, and a small rate of protein leak change with time even for large-scale filtration means that it is less affected by blood performance fluctuations, which is a desirable characteristic. . Moreover, when the ratio (F / E) of the 15-minute value (E) and the 120-minute value (F) is less than 30% with respect to the change over time of protein leak, the initial change over time is large, that is, the patient at the start of treatment. This is a phenomenon in which protein (mainly albumin) is rapidly removed from the blood, which may increase the burden on the patient. F / E is more preferably 40% or more, and further preferably 50% or more.

  Moreover, it is preferable that the protein leak amount in terms of 20 L water removal at the time of the above-mentioned constant-speed mass filtration (Qb 200 ml / min, Qf 90 ml / min) is 5 g or less. It is more preferably 4 g or less, and further preferably 3 g or less. Also, if it is greater than 5 g, it is serious for patients with poor nutritional status and may cause hypoalbuminemia, so it is desirable that the protein loss be reasonably low. However, if the amount of protein leak is too small, the removal of unnecessary substances having a molecular weight larger than β2MG may be reduced, and the lower limit of the protein leak amount in terms of 20 L water removal is preferably 0.5 g or more, and 0.7 g or more. Is more preferably 1.0 g or more, and even more preferably 1.5 g or more.

  The blood purifier of the present invention is suitable as a blood purifier used for the treatment of renal failure, such as hemodialysis (HD), hemofiltration dialysis (HDF, online HDF, etc.), blood filtration (HF), and the like. In addition, regardless of the blood flow volume that can be secured, large-scale filtration can be stably performed by pre-dilution and post-dilution, so the intended treatment of large-volume liquid replacement therapy is safe regardless of the patient's health condition and symptoms. It is excellent in that it can be done.

In the present invention, the ultrafiltration coefficient of pure water at 37 ° C. of the hollow fiber membrane is preferably in the range of 150 mL / m ² / hr / mmHg to 800 mL / m ² / hr / mmHg. When the ultrafiltration coefficient is less than 150 mL / m ² / hr / mmHg, the permeation performance of medium molecular weight substances in the blood system targeted by the present invention may be low. When the ultrafiltration coefficient is too large, the pore diameter becomes large, and clogging and protein leakage may increase. Therefore, a more preferable range of the ultrafiltration coefficient is 150 mL / m ² / hr / mmHg or more and 750 mL / m ² / hr / mmHg or less, more preferably 150 mL / m ² / hr / mmHg or more and 700 mL / m ² / hr / mmHg. It is as follows.

  In the present invention, the average thickness of the hollow fiber membrane is preferably 10 μm or more and 50 μm or less. If the average film thickness is too large, the load during filtration may become too large. Further, in the design of the blood purifier, if the film thickness is increased when the membrane area is increased, the size of the blood purifier is increased, which is not appropriate. A thinner film thickness is preferred because the material permeability increases, more preferably 45 μm or less, and even more preferably 40 μm or less. If the average film thickness is too thin, it may be difficult to maintain the minimum film strength required for the blood purifier. Therefore, the average film thickness is more preferably 12 μm or more, and further preferably 14 μm or more. An average film thickness here is an average value when five hollow fiber membranes sampled at random are measured. At this time, the difference between each value and the average value does not exceed 20% of the average value.

  Moreover, it is preferable that the internal diameter of a hollow fiber membrane is 100-300 micrometers. If the inner diameter is too small, the pressure loss of the fluid flowing through the hollow portion of the hollow fiber membrane increases, which may cause hemolysis. Further, when filtration is performed in a region where the flow rate is large, the transmembrane pressure difference becomes large, and even a slight clogging may cause a rapid increase in pressure. On the other hand, if the inner diameter is too large, the shear rate of blood flowing through the hollow portion of the hollow fiber membrane becomes small, so that proteins in the blood easily accumulate on the inner surface of the membrane over time. The inner diameter at which the pressure loss and shear rate of the blood flowing inside the hollow fiber membrane is in an appropriate range is 150 to 250 μm.

  The hollow fiber membrane of the present invention has a thin dense layer on the inner surface side and an asymmetric structure in which the pore diameter increases toward the outer side, so that the thin dense layer has a fractionation characteristic (β2 microglobulin is permeable). However, the portion other than the dense layer (support layer) has a large pore size, so it does not have resistance to substance permeation and improves the removability of low molecular weight proteins typified by β2 microglobulin. It is possible. The support layer mainly plays a role of maintaining the strength of the film.

In the present invention, the outer surface area 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 0.005 μm ² or more and 0.05 μm ² or less. If the outer surface porosity or average pore area is too large, the overall porosity of the support layer will be high, so the strength required for the hollow fiber membrane cannot be secured, or the retention of membrane pore retention agents such as glycerin will be reduced. there's a possibility that. 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 0.045 .mu.m ² or less, more preferably 0.01 [mu] m ² or more 0.04 .mu.m ² or less.

In the present invention, the Young's modulus per single yarn of the hollow fiber membrane is preferably 4500 kg / cm ² or more and the yield strength is preferably 20 g or more. A high Young's modulus and yield strength mean that the polymer constituting the hollow fiber membrane has a high density or a strong entanglement of polymer chains. In the assembly of a module such as a blood purifier, the end portion of the hollow fiber membrane and the end portion of the module case are bonded with an adhesive resin, and at that time, the adhesive resin is filled using centrifugal force. At this time, if the Young's modulus of the hollow fiber membrane is low, the hollow fiber membrane may bend or bend due to centrifugal force. A module in which such a phenomenon has occurred can cause non-passage or residual blood when blood flows through the hollow fiber membrane, and can no longer be shipped as a product. Since the centrifugal force (RCF) used for filling the adhesive resin is about 40 × g, the Young's modulus and yield strength of the hollow fiber membrane are set to 4500 kg / cm ² or more and 20 g or more, respectively, in anticipation of the safety factor. Young's modulus is more preferably 5000 kg / cm ² or more, 5500kg / cm ² or more is more preferable. The yield strength is more preferably 23 g or more, and further preferably 25 g or more. Higher Young's modulus and yield strength are preferred, but in the case of a hollow fiber membrane for blood purification, the upper limit is considered to be about 7000 kg / cm ^{2 and} about 40 g, respectively, depending on the relationship with performance and porosity. .

Examples of the material of the hollow fiber membrane in the present invention include cellulosic polymers such as regenerated cellulose, cellulose acetate, and cellulose triacetate. A hollow fiber membrane having an ultrafiltration coefficient of 150 ml / m ² / hr / mmHg or more is used. Cellulosic materials that are easy to obtain are preferred. In particular, cellulose diacetate and cellulose triacetate are preferable for the cellulose type because the film thickness can be easily reduced.

  As a method for producing a hollow fiber membrane used in such a blood purifier, the following conditions are preferable. In order to obtain a high ultrafiltration coefficient, the polymer concentration of the spinning dope is preferably 26% by mass or less, more preferably 25% by mass or less, depending on the type of polymer. Further, if the polymer concentration is too low, it is difficult to obtain the necessary yarn strength, so the content is preferably 15% by weight or more, and more preferably 17% by weight or more.

  The spinning dope is preferably filtered immediately before nozzle discharge for the purpose of removing insoluble components and gel in the spinning dope. The pore diameter of the filter is preferably small. Specifically, the pore diameter is preferably not more than the thickness of the hollow fiber membrane, and more preferably not more than 1/2 of the thickness of the hollow fiber membrane. When there is no filter or when the pore diameter of the filter exceeds the film thickness of the hollow fiber membrane, a part of the nozzle slit may be clogged, resulting in occurrence of uneven thickness yarn. Furthermore, if there is no filter or the filter pore size exceeds the thickness of the hollow fiber membrane, partial voids due to insoluble components or gels in the spinning dope and surface structure texture in units of several tens of μm It tends to cause fineness (such as pulling or partial wrinkling). In hollow fiber membranes having a high porosity, the generation of partial voids can cause a reduction in the physical strength of the membrane. Moreover, remarkably disturbing the fineness of the surface of the hollow fiber membrane leads to activation of blood, increasing the possibility of inducing thrombus and residual blood. Activating blood is thought to have an adverse effect on filtration characteristics. Filtration of the spinning solution may be carried out a plurality of times before discharging, and this is preferable because it can extend the life of the filter.

  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 a swelling agent and other additives may be included in addition. Examples of swelling agents include formamide, urea, triethyl phosphate, glyoxal, butanol, isopropanol and the like. The water content in the core liquid is preferably 50% by weight or more. 70% by weight or more is more preferable, 90% by weight or more is more preferable, and it is even more preferable to use water alone. On the other hand, if the water content of the core liquid becomes too high, solidification of the spinning dope discharged from the nozzle rapidly progresses, so that the spinnability deteriorates, and breakage such as thread breakage or deformation of the hollow fiber membrane occurs. It tends to occur. However, in the present invention, as described later, by improving the nozzle, the spinning dope and the core liquid temperature can be controlled separately and accurately, so that even if the water content of the core liquid is increased, there is no occurrence of yarn breakage. Stability can be obtained.

  The spinning dope treated as described above is discharged using a tube-in-orifice nozzle having an annular part on the outside and a core liquid discharge hole on the inside. By reducing the variation in the slit width of the nozzle (the width of the annular portion that discharges the spinning dope), uneven thickness of the spun hollow fiber membrane can be reduced. Specifically, the difference between the maximum value and the minimum value of the slit width of the nozzle is preferably 10 μm or less. The slit width varies depending on the viscosity of the spinning dope used, the thickness of the hollow fiber membrane to be obtained, and the type of core liquid. If the nozzle slit width varies greatly, uneven thickness will be caused, and the thin part will tear or rupture. Cause leaks. Moreover, when uneven thickness is remarkable, it becomes a cause by which appropriate intensity | strength as a blood purification film cannot be obtained.

  A feature of the present invention is that the temperature of the spinning solution and the core solution are separately controlled, and the phase separation reaction is performed under a certain condition. In the spinning process for producing a hollow fiber membrane for normal blood purification, a plurality of double tube nozzles are set in a nozzle block, and the width of the spinning solution discharge hole and the core solution discharge hole is several hundred μm. Therefore, it is very difficult to precisely control the temperature of the spinning solution and the core solution until just before they are discharged from the nozzle. The present inventors have solved the general 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 solution and the core solution can be individually controlled until immediately before discharge. Dozens of nozzles are usually incorporated in one nozzle block, and it is necessary to consider the temperature control of these nozzles uniformly. This technical difficulty has been cleared and the present invention has been achieved.

As a result of intensive studies on the phase separation conditions before and after nozzle discharge, it was found that the present invention can be achieved when the temperature control conditions are as follows. The stock solution for spinning is kept warm at 100 ° C. or higher after dissolution. On the other hand, the spinning dope in the nozzle is set to be constant in the range of 40 ° C. to 100 ° C. Further, the temperature of the core liquid in the nozzle is set to be constant in the range of 5 ° C. or more and 40 ° C. or less. It is preferable that both the temperature drop in the spinning solution in the nozzle and the temperature difference between the spinning solution and the core solution in the nozzle are large, because a pre-phase separation state due to a rapid temperature gradient can be created. The difference (I) between the spinning solution and the temperature in the nozzle is preferably 40 ° C. or higher and 110 ° C. or lower, more preferably 50 ° C. or higher and 100 ° C. or lower, and further preferably 55 ° C. or higher and 80 ° C. or lower. The temperature difference (J) between the temperature of the spinning dope in the nozzle and the core liquid is preferably 10 ° C. or higher and 90 ° C. or lower, more preferably 20 ° C. or higher and 80 ° C. or lower, and further preferably 20 ° C. or higher and 60 ° C. or lower. Further, I × J is preferably 1500 to 8000. I × J is more preferably 1600 to 6500, further preferably 1600 to 5000. As I × J increases, the ultrafiltration coefficient ratio tends to increase. However, if I × J becomes too large, the detailed reason is unknown, but I × J tends to become smaller.
Specifically, the spinning dope is kept at a temperature of 110 ° C. or more and 180 ° C. or less, the spinning dope in the nozzle is constantly controlled in the range of 45 ° C. or more and 90 ° C. or less, and the temperature of the core solution is 10 ° C. or more and 35 ° C. or less. More preferably, it is controlled to be constant within the range. Here, “constant” refers to control within about ± 3 ° C. If each temperature control is out of the setting, the viscosity of the spinning dope becomes high and the spinning dope cannot be discharged stably, or the pore size becomes too large due to different phase separation conditions, and the yarn cannot be spun out. Problems can arise.

The discharged spinning solution is coagulated by passing through a coagulation bath through an aerial traveling section. 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 section is 5 mm or more and 200 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, 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 section is more preferably 7 mm or more and 150 mm or less, and more preferably 10 mm or more and 100 mm or less in order to offset the influence of the spinning spot discharged from the spinneret. The temperature of the aerial traveling part is preferably 3 ° C. or higher and 45 ° C. or lower, and more preferably 5 ° C. or higher and 40 ° C. or lower in order to suppress the leakage of useful protein in terms of performance.
The appropriate range of the length and temperature of the aerial traveling 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.

  The coagulation bath is preferably an aqueous solution of the solvent used in preparing the spinning dope. If necessary, a non-solvent can be added. When the coagulation bath is water, coagulation proceeds rapidly, so that a dense layer is easily formed on the outer surface of the hollow fiber membrane. It is preferable to use a coagulation bath as a mixed solution of a solvent, a non-solvent and water because the coagulation time can be easily controlled. The concentration of the solvent and non-solvent in the coagulation bath is preferably 50% by mass or more, and more preferably 60% by mass or more. However, less than 50% by mass is not preferable because it is difficult to control the coagulation time. The temperature of the coagulation bath is related to the composition and temperature of the spinning dope discharged from the nozzle, but is preferably 4 ° C. or more and 60 ° C. or less for controlling the coagulation rate. 10 degreeC or more and 55 degrees C or less are more preferable. Thus, by controlling the phase separation and coagulation precisely, a hollow fiber membrane having a Young's modulus and a yield strength of the hollow fiber membrane within the above ranges and improved filtration characteristics can be obtained.

  The hollow fiber membrane that has passed through the coagulation bath is washed away with unnecessary components such as a solvent through a washing step. The washing liquid used at this time is preferably water, and the inlet water temperature of the washing bath is preferably 60 to 90 ° C. The glass transition temperature of wet cellulose acetate is said to be around 70 ° C, and polymer particles are reorganized by passing a temperature above the glass transition temperature in the water washing process, resulting in a defect structure present in the hollow fiber membrane. It is considered that the film is reset and the film is less likely to be clogged with blood. The outlet water temperature of the washing bath is preferably 50 to 90 ° C. in order to improve the washing efficiency or to suppress the loosening of the hollow fiber membrane during running. If it is less than 50 degreeC, cleaning efficiency may fall, and if it exceeds 90 degreeC, thermal efficiency may fall.

  The hollow fiber membrane that has undergone the washing step passes through a glycerin bath, and the holes and hollow portions of the hollow fiber membrane are replaced with an aqueous glycerin solution. Then, it winds up through a drying process. In this case, the glycerin concentration is preferably 50 to 95% by mass. If the glycerin concentration is too low, the glycerin substitution concentration of the core liquid may not be sufficient, and the hollow fiber membrane may shrink or collapse during drying, resulting in poor storage stability. Also, if the glycerin concentration is too high, excess glycerin tends to adhere to the hollow fiber membrane, and the adhesiveness at the end of the hollow fiber membrane may deteriorate when assembled into a blood purifier. The temperature of the glycerin bath is preferably 50 ° C. or higher and 100 ° C. or lower. When the temperature of the glycerin bath is too low, the viscosity of the glycerin aqueous solution is high, and there is a possibility that the glycerin aqueous solution does not reach all the pores of the hollow fiber membrane. If the temperature of the glycerin bath is too high, the hollow fiber membrane may be denatured and altered by heat.

  The present invention is achieved by a combination of control of the phase separation reaction by precise temperature control before discharging the film forming solution from the nozzle and reconfiguration of the structure by the subsequent water washing step. When schematically illustrating the present invention, at the time of film formation, before the film-forming solution is discharged from the nozzle, the keeping temperature of the spinning dope, the temperature in the nozzle, and the core liquid temperature are accurately controlled, and an appropriate temperature difference is provided for each. In this state, phase separation is caused by a rapid temperature change. Thereafter, it is solidified in a coagulation bath, where the hollow fiber membrane forms a dense structure having a dense layer on at least the inner surface. Although it is difficult to observe the details with the current analysis means, it is considered that the image forms a structure filled with polymer particles. However, at this point, the structure filled with the particles is not completely formed, and the individual particles move slightly by passing through a water bath above the glass transition temperature in the next step. Thus, the structure is corrected in a fine area. That is, there is an effect that the polymer particles are loosened in a high-temperature water washing step to reorganize the particle filling structure, and as a result, the gaps between the particles formed by the previous phase separation are filled. An image diagram was posted. FIG. 1 is a schematic diagram of a cross section of a membrane showing the particle filling state of the hollow fiber membrane of the present invention. Before the water washing step, there is a portion where the particle filling state is not uniform. For example, when a portion in such a state exists on the inner surface, an adsorption reaction of a blood component to a portion in which the filling state is not uniform is promoted, and it is considered that an adverse effect on blood performance such as clogging occurs. On the other hand, passing through a high-temperature water washing bath causes fine correction by rearrangement of the particles, and the particle filling state is considered to be uniform as compared with that before the high-temperature water washing treatment. A blood purifier comprising a hollow fiber membrane having a particle-packed structure rearranged in this way has a high filtration characteristic that is less likely to be clogged than a conventional blood purifier.

  FIG. 2 is a graph showing experimental results comparing the amount of protein leakage in a blood filtration experiment for the hollow fiber membrane of the present invention (Example 3) and a polysulfone-based hollow fiber membrane having a general asymmetric structure. Since the polysulfone polymer is highly hydrophobic, it cannot completely suppress the adsorption of blood components when it comes into contact with blood. That is, the polysulfone-based hollow fiber membrane is preliminarily designed with a larger pore size assuming the adsorption and accumulation of blood components on the membrane surface and in the pores when contacted with blood. On the other hand, the hollow fiber membrane of the present invention has the feature that the change in performance over time is small because it suppresses the adsorption of blood components to the membrane surface and the penetration into the pores (clogging). Since it has such features, it has excellent performance stability even in large-volume liquid replacement therapy.

  Fig. 3 shows the product (I x J) of the "difference between the keep temperature of the spinning dope and the temperature in the nozzle" and the "difference between the spinning dope temperature in the nozzle and the core solution temperature" on the horizontal axis, and the vertical axis. The data of an Example are plotted by taking ultrafiltration coefficient ratio (B / A and D / C). It can be understood that the change in performance is small when I × J falls within a specific range.

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

1. Measurement of inner diameter, outer diameter and film thickness of hollow fiber membrane A sample of the cross section of the hollow fiber membrane can be obtained as follows. For the measurement, it is preferable to observe 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 due to drying, it is preferable to wash and remove the core liquid, completely replace with pure water, and then observe the form in a wet state. The hollow fiber membrane has an inner diameter, an outer diameter, and a film thickness that are appropriate for the hollow fiber membrane so that the hollow fiber membrane does not fall out into a 3 mm hole in the center of the slide glass, and is cut with a razor on the upper and lower surfaces 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 cross section of the hollow fiber membrane 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. did. The same measurement was performed on five cross sections, and the average value was defined as the inner diameter and film thickness.

2. Ultrafiltration coefficient The blood outlet circuit of the dialyzer (the outlet side from the pressure measurement point) is sealed with forceps. Purified water kept at 37 ° C is put into a pressurized tank, and while controlling the pressure with a regulator, pure water is sent to the blood flow path side of the dialyzer kept at 37 ° C constant temperature bath, and the amount of filtrate flowing out from the dialysate side is measured. taking measurement. 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 ultrafiltration coefficient (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 0.99 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 ultrafiltration coefficient of the hollow fiber membrane is calculated from the membrane area and the ultrafiltration coefficient of the dialyzer.
UFR (h) = UFR (d) / a
Where UFR (h) is the ultrafiltration coefficient of the hollow fiber membrane (mL / m ² / hr / mmHg), UFR (d) is the ultrafiltration coefficient of the dialyzer (mL / hr / mmHg), and a is the dialyzer Is the membrane area (m ² ).

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

4). Evaluation of blood system (1) Blood to be used Bovine blood prepared by adding citric acid and suppressing coagulation to hematocrit 27-33% and protein concentration 6-7 g / dl, or protein concentration 6-7 g / dl Use bovine plasma prepared in dl. When the circulation test is performed by diluting the plasma by half, bovine plasma prepared to a protein concentration of 6 to 7 g / dl is diluted 2 times with physiological saline and used.
(2) Blood purifier A blood purifier having a membrane area of 1.5 m ² is washed and primed with 1 L of physiological saline and heated to 37 ° C.
(3) Circulation test After 5L of circulating blood or plasma was adjusted to 37 ° C, the primed blood purifier was fed at an inlet flow rate (Qbin) of 200ml / min, and a predetermined filtration flow rate (Qf: ml / min) ) To filter the blood. At this time, the filtrate is returned to the original blood batch to form a circulatory system. In the variable speed filtration experiment, Qf is changed every 15 minutes as 15 → 30 → 45 → 60 → 90 → 60 → 45 → 30 → 15 → 0 ml / min. Immediately before changing Qf, the filtrate flow rate is measured, and the blood pressure inlet pressure (Pbin), outlet pressure (Pbout), and filtrate outlet pressure (Pfout) are measured. In the constant speed filtration experiment, the filtrate flow rate is measured and the filtrate is sampled every 15 minutes after the start of filtration.
(4) Ultrafiltration coefficient of blood Differential pressure between membranes at each filtration flow rate (TMP) (mmHg) = (Pbin + Pbout) / 2-Pfout
TMP at Qf = 0m / min is the osmotic pressure of the colloid and is π. π is approximately 22 mmHg at a protein concentration of 6.5 g / dl.
Blood ultrafiltration coefficient (ml / m ² / hr / mmHg) = Qf (ml / min) × 60 / (TMP−π) / membrane area Here, Qf uses a measured value.
(5) Calculation of protein leak amount In a constant-speed filtration experiment, the filtration flow rate is measured every 15 minutes, and the filtrate of the blood purifier is collected. The concentration of protein contained in the filtrate is measured. Measurement of protein concentration in plasma is performed using an in vitro diagnostic kit (MicroTP-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.). Based on the data for up to 2 hours, calculate the average protein leak amount from the following formula and calculate the target protein leak amount (TPL) when converted to water removal.
Integrated filtration volume (ml) = t ₁ (min) x C _t1 (ml / min) + (t ₂ -t ₁ ) (min) x C _t2 (ml / min) + (t ₃ -t ₂ ) (min) × C _t3 (ml / min) ··· (t ₁₂₀ -t _n ) (min) × C _{120 min} (ml / min)
t: Measurement time (min)
C: Filtration flow rate (ml / min)
Filtrate protein concentration = a x Ln (total filtration volume) + b
Determine a and b from the protein concentration of the filtrate at each measurement point and Ln (total filtration amount).
TPL (average) = -a + b + a x Ln (integrated filtration rate x 2)
For example, in the case of 20L water removal conversion,
TPL (20L dewatering equivalent) (g) = TPL (average) x 200/1000
For evaluation of reproducibility of blood performance and performance stability, Qf = 90 ml / min, TPL value in terms of 20 L water removal was used as an index.
TPL ratio = TP concentration 120 minutes / TP concentration 15 minutes.

6). Clearance myoglobin (CLmyo)
A blood purifier (membrane area (A ′) 1.5 m ² ) primed with physiological saline and wetted with 0.01% myoglobin (Sigma-Aldrich Chemical Co.) dialysate aqueous solution, blood flow rate (Qbin) 200 ml The dialysate is flowed at a dialysate side flow rate (Qd) of 500 ml / min while flowing in a single pass without filtration at / min. From the myoglobin concentration (Cbin) of the first myoglobin stock solution and the myoglobin concentration (Cbout) of the fluid that has passed through the blood purifier, the clearance (CLmyo: ml / min) of the blood purifier is calculated. The measurement is carried out at 37 ° C.
CLmyo = (Cbin−Cbout) / Cbin × Qbin

7. Clearance myoglobin retention rate Prepare ^two blood purifiers of the same type and the same lot (membrane area 1.5 m ^{2 based on the} inner diameter of the hollow fiber membrane), and measure the CLmyo by the method described above. The remaining one is tested with blood in the manner described above. Thereafter, the blood purifier is thoroughly washed with water at the same flow rate as the measurement. CLmyo is measured by the same method for the blood purifier washed with water, and the ratio with the first value is calculated. When there is no performance change due to the blood experiment, the CLmyo values of the two blood purifiers are equal and the retention rate is 100%.
Retention rate (%) = CLmyo after plasma circulation / normal CLmyo × 100

8). Opening ratio of outer surface of hollow fiber membrane The outer surface of the hollow fiber membrane is observed with an electron microscope of 10,000 times, and a photograph (SEM photograph) is taken. The image 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 (K) of the measurement range and the total (L) of the area of the holes in the measurement range are obtained to obtain the open area ratio (%) = L / K × 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.

9. The average pore area of the apertures on the outer surface of the hollow fiber membrane is counted in the same manner as in the previous section, and the area of each pore is determined. Also, holes on the measurement range boundary are excluded during counting. This is carried out for 10 visual fields, and the average of all the hole areas is obtained.

10. Young's modulus (kg / cm ² )
The breaking strength and yield strength are measured using a yarn tensile tester (Instron (Model No. TM) manufactured by Instron Engineering Corporation). A single yarn having a total length of about 15 cm is fixed to a chuck (10 cm between chucks), and a full-scale 100 g cell connected to the chuck is raised at a speed of 20 mm / min. The breaking elongation and breaking strength at which the hollow fiber is cut from the chart paper are read and taken as SS curve. If there is no maximum point, an auxiliary line with an extended initial slope is provided. The point where two auxiliary lines intersect is defined as the yield point, and the strength at that point is the yield strength and the elongation is the yield elongation. In addition, if there is a maximum point, the point where the auxiliary line with an extended initial slope and the auxiliary line with zero slope at the maximum point intersect is defined as the yield point, the strength at that point is the yield strength, and the elongation is the yield elongation. And Using these values, the Young's modulus is calculated by the following formula: Young's modulus = yield strength / yarn cross-sectional area / yield elongation.

Example 1
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries, Ltd.) 18 wt% of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) Was uniformly dissolved in a mixed solution of 85:15 as a spinning stock solution at 120 ° C., and discharged from the outer annular portion of the double tube nozzle, and at the same time, water was discharged as a core solution. At that time, the core liquid was cooled by flowing a 25 ° C. refrigerant through a block in which the nozzle was set. The spinning dope was kept warm by circulating a heating medium at 50 ° C. in the nozzle block.
The spinning dope discharged from the nozzle was passed through a 13 mm, 30 ° C. idle running portion, and then the NMP / TEG = 85/15 mixed solution was diluted to 70 wt% with water in a 44 ° C. coagulating solution. Then, it was washed with hot water having an inlet temperature of 90 ° C. (outlet temperature of 60 ° C.), adhered and replaced with glycerin, dried and wound up. The hollow fiber membrane had an inner diameter of 206 μm and a film thickness of 22 μm. The obtained hollow fiber membranes were bundled and inserted into a blood purifier case, and both ends were bonded and fixed with polyurethane, and various hemodialyzers having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared. It used for evaluation. The spinning conditions are summarized in Table 1, and the evaluation results are summarized in Tables 2 and 3.

  The ultrafiltration coefficient ratio and CLmyo retention were high, and the filtration characteristics were excellent. In addition, large-volume constant-speed filtration with a Qf of 90 ml / min showed a large TP ratio and stable performance over time.

(Example 2)
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries, Ltd.) 23% by weight of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) Was uniformly dissolved in a 80:20 mixed solution, and was discharged from the outer annular portion of the double tube nozzle while keeping the spinning stock solution at 160 ° C., and at the same time, water was discharged as a core solution. At that time, the core liquid was cooled by flowing a 30 ° C. refrigerant through a block in which the nozzle was set. The spinning dope was kept warm by circulating a heat medium at 85 ° C. in the block.
The spinning dope discharged from the nozzle was allowed to pass through a 20 mm, 30 ° C. idle running portion, and then the NMP / TEG = 80/20 mixed solution was diluted to 70 wt% with water in a 45 ° C. coagulating solution. Then, it was washed with hot water having an inlet temperature of 80 ° C. (outlet temperature of 80 ° C.), adhered and replaced with glycerin, dried and wound up. The hollow fiber membrane had an inner diameter of 205 μm and a film thickness of 23 μm. The obtained hollow fiber membranes were bundled and inserted into a blood purifier case, and both ends were bonded and fixed with polyurethane, and various hemodialyzers having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared. It used for evaluation. The spinning conditions are summarized in Table 1, and the evaluation results are summarized in Tables 2 and 3.

  The ultrafiltration coefficient ratio and CLmyo retention were high, and the filtration characteristics were excellent. In addition, large-volume constant-speed filtration with a Qf of 90 ml / min showed a large TP ratio and stable performance over time. The TPL value was also low.

(Example 3)
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries, Ltd.) 21 wt% of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) Was uniformly dissolved in an 80:20 mixed solution while being kept at 110 ° C. as a spinning stock solution and discharged from the outer annular portion of the double tube nozzle, and at the same time, water was discharged as a core solution. At that time, the core liquid was cooled by flowing a 10 ° C. refrigerant through a block in which the nozzle was set. The spinning dope was kept warm by circulating a heat medium at 50 ° C. in the block.
The spinning dope discharged from the nozzle was passed through a 13 mm, 30 ° C. idle running portion, and then the NMP / TEG = 80/20 mixed solution was diluted with water to 60% by weight in a 40 ° C. coagulating solution. Then, it was washed with hot water having an inlet temperature of 70 ° C. (outlet temperature of 70 ° C.), adhered and replaced with glycerin, dried and wound up. The hollow fiber membrane had an inner diameter of 206 μm and a film thickness of 22 μm. The obtained hollow fiber membranes were bundled and inserted into a blood purifier case, and both ends were bonded and fixed with polyurethane, and various hemodialyzers having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared. It used for evaluation. The spinning conditions are summarized in Table 1, and the evaluation results are summarized in Tables 2 and 3.

  The ultrafiltration coefficient ratio and CLmyo retention were high, and the filtration characteristics were excellent. In addition, even with a large volume constant speed filtration of Qf 90 ml / min, the TP ratio was large and the performance was stable over time. The TPL value was also low.

(Comparative Example 1)
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries, Ltd.) 21 wt% of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) Was uniformly dissolved in an 80:20 mixed solution, and was discharged from the outer annular portion of the double tube nozzle while keeping the spinning stock solution at 185 ° C., and at the same time, water was discharged as a core solution. At that time, the core liquid was cooled by flowing a 0 ° C. refrigerant through a block in which the nozzle was set. The spinning dope was kept warm by circulating a heat medium at 100 ° C. in the block.
The spinning dope discharged from the nozzle was passed through a 20 mm, 30 ° C. idle running portion, and then the NMP / TEG = 80/20 mixed solution was diluted with water to 60% by weight in a 40 ° C. coagulating solution. Then, it was washed with hot water having an inlet temperature of 60 ° C. (outlet temperature of 40 ° C.), adhered and replaced with glycerin, dried and wound up. The hollow fiber membrane had an inner diameter of 206 μm and a film thickness of 23 μm. The obtained hollow fiber membranes were bundled and inserted into a blood purifier case, and both ends were bonded and fixed with polyurethane, and various hemodialyzers having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared. It used for evaluation. The spinning conditions are summarized in Table 1, and the evaluation results are summarized in Tables 2 and 3.

  Since the combination of the phase separation condition and the water washing process condition is not the optimum condition, the rearrangement of the polymer particles is insufficient, the ultrafiltration coefficient ratio is low, and the membrane is likely to be clogged due to fluctuations in the filtration flow rate. Also, the constant-rate filtration experiment with Qf of 90 ml / min could not be carried out until 120 minutes due to pressure increase.

(Comparative Example 2)
Cellulose triacetate (6% viscosity = 154 mPa · s, manufactured by Daicel Chemical Industries) 18% by weight of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) Was uniformly dissolved in an 80 to 20 mixed solution, while being kept at 120 ° C. as a spinning stock solution, and discharged from the outer annular portion of the double tube nozzle, and at the same time, water was discharged as a core solution. At that time, the core liquid was cooled by flowing a 50 ° C. refrigerant through a block in which the nozzle was set. The spinning dope was kept warm by circulating a 110 ° C. heating medium in the block.
The spinning dope discharged from the nozzle was allowed to pass through a 20 mm, 30 ° C. idle running portion, and then the NMP / TEG = 80/20 mixed solution was diluted with water to 70% by weight in a 40 ° C. coagulating solution. Then, it was washed with hot water having an inlet temperature of 50 ° C. (outlet temperature of 45 ° C.), adhered and substituted with glycerin, dried and wound up. The hollow fiber membrane had an inner diameter of 206 μm and a film thickness of 23 μm. The obtained hollow fiber membranes were bundled and inserted into a blood purifier case, and both ends were bonded and fixed with polyurethane, and various hemodialyzers having an effective area of 1.5 m ^{2 based} on the hollow fiber membrane inner diameter standard were prepared. It used for evaluation. The spinning conditions are summarized in Table 1, and the evaluation results are summarized in Tables 2 and 3.

  The combination of the phase separation conditions and the washing process conditions is not the optimal condition, so the rearrangement of polymer particles is insufficient, the ultrafiltration coefficient ratio is low, and the CLmyo retention rate is low. The film was prone to clogging. Also, the constant-rate filtration experiment with Qf of 90 ml / min could not be carried out until 120 minutes due to pressure increase.

(Comparative Example 3)
Cellulose triacetate (6% viscosity = 162 mPa · s, manufactured by Daicel Chemical Industries, Ltd.) 21 wt% of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) and triethylene glycol (TEG, manufactured by Mitsui Chemicals) Was uniformly dissolved in a 80:20 mixed solution as a stock solution for spinning at 90 ° C., and discharged from the outer annular portion of the double tube nozzle, and at the same time, water was discharged as a core solution. At that time, the core liquid was cooled by flowing a 35 ° C. refrigerant through a block in which the nozzle was set. The spinning dope was kept warm by circulating a heat medium at 30 ° C. in the block. The spinning stock solution was poor in fluidity and could not be spun.

(Reference Example 1)
Various evaluations were performed using a blood purifier (FPX140) manufactured by Fresenius. The results are summarized in Table 2.

  Since the ultrafiltration coefficient ratio in the variable speed filtration and the CLmyo retention rate were low, clogging due to fluctuations in the filtration flow rate was observed. In the Qf 90 ml / min constant-speed filtration experiment, three dialyzers were tried, but only one was measurable up to 120 minutes, and the change in TPL with time was large.

(Reference Example 2)
Various evaluations were performed using a blood purifier (APS-15SA) manufactured by Asahi Kasei Medical. The results are summarized in Table 2.

  Since the ultrafiltration coefficient ratio in the variable speed filtration and the CLmyo retention rate were low, clogging due to fluctuations in the filtration flow rate was observed. In particular, the retention rate of CLmyo was low. In addition, in the Qf 90 ml / min constant speed filtration experiment, three dialyzers were tried, but only one was measurable until 120 minutes, the change in TPL with time was large, and the TPL value was also high.

(Reference Example 3)
Various evaluations were performed using a Nipro blood purifier (FB-150Uβ). The results are summarized in Table 2.

  In a variable speed filtration experiment with undiluted blood, the Qf could only be increased to 60 ml / min due to pressure increase. Therefore, a constant-rate filtration experiment with a Qf of 90 ml / min could not be performed. Clogging due to mass filtration was significant. The hollow fiber membrane constituting the dialyzer is thought to have been greatly affected by clogging due to blood components because the inner surface structure is not dense.

  The blood purifier excellent in the mass liquid replacement characteristic of the present invention has a characteristic that the influence of clogging and the like is small even if mass filtration with a filtration flow rate exceeding 30% with respect to the blood flow rate is performed. Therefore, there is an advantage that treatment for large-volume liquid replacement is possible even for a patient whose blood flow volume cannot be sufficiently secured. Therefore, it can greatly contribute to industrial development.

Claims (3)

A method for producing a hollow fiber membrane comprising discharging a spinning stock solution and a core solution from a tube-in-orifice nozzle, passing through a solidified bath through an aerial traveling unit, and washing with water,
(A) The difference (I) between the keep temperature of the spinning dope and the temperature in the nozzle is 40 ° C. or more and 110 ° C. or less, and the temperature difference (J) between the spinning dope and the core solution in the nozzle is 10 ° C. or more and 90 ° C. (B) The product of I and J (I × J) is 1600 to 5000 (c) The water washing is performed at a water bath temperature of 60 to 90 ° C.   The method according to claim 1, wherein the spinning dope comprises a cellulosic polymer.   The method according to claim 1 or 2, wherein the core liquid is water.