JP2010063605A - Blood purifier having excellent impact resistance - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood purifier having high water permeability and used for the treatment of chronic nephrosis, in which a hollow-fiber membrane does not get damaged and the performance of the hollow-fiber membrane does not fluctuate in response to repeated impacts anticipated in a clinical site. <P>SOLUTION: The blood purifier houses the hollow-fiber membrane. While the blood purifier is wet, one end of the blood purifier is fixed to an arm extending from a fulcrum arranged at a height of 30 cm, and the length of the arm is adjusted so that the other end of the blood purifier grounding makes an angle of 30° with the ground. The other end of the blood purifier is then dropped freely to the floor from a height of 20 cm and such impacts are given in the same direction for 50 times. The blood purifier is characterized by that the hollow-fiber membrane is not damaged even after such impacts. In addition, clearance of β2-microglobulin measured in plasma system after the impacts is maintained at 80% or more of the clearance before the impacts. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a blood purifier incorporating a hollow fiber membrane having extremely high water permeability and having impact resistance.

  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, with the increase in the number of long-term dialysis patients, dialysis complications have become a problem. In recent years, substances to be removed by dialysis are not only low molecular weight substances such as urea and creatinine, but also have molecular weights ranging from several thousand to 1,000 to 20,000 Blood purification membranes are required to expand to high molecular weight substances and to remove these substances. In particular, β2 microglobulin having a molecular weight of 11700 has been found to be a causative 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.

  However, as described above, the membrane pursuing such high performance is a hollow fiber membrane that increases the pore diameter of the membrane, increases the number of pores, increases the porosity, and reduces the film thickness. Development is underway at the expense of strength. If the strength of the hollow fiber membrane is weak, there is an increased risk of damage to the hollow fiber membrane due to impact during transportation or accidental dropping before use.

  As a method for increasing the strength of the hollow fiber membrane, there is an approach from a membrane structure in which the membrane structure is divided into a performance-expressing layer and a support layer, such as making the membrane structure an asymmetrical structure or a network structure and a spherical structure (for example, patent documents) 1 and 2).

  As an approach from the spinning conditions, a method of suppressing structural breakage at a low drawing and reducing the leak rate is disclosed (for example, see Patent Document 3). Further, there is a method of reducing the defects of the hollow fiber membrane and improving the breaking strength, breaking elongation, and burst pressure by purifying the hollow forming agent (see, for example, Patent Document 4).

  As an approach from the modularization technique, a method of improving impact resistance by coating the vicinity of the bonded portion of the hollow fiber membrane (for example, see Patent Document 5) or a method using a spacer filament (for example, see Patent Document 6) )

  If the structure of the membrane is significantly changed as described above, the design of the hollow fiber membrane having the target performance must be reviewed from the beginning, or the support layer must be thickened to increase the strength. There are pros and cons. In addition, the method of suppressing the membrane structure breakage by devising the spinning conditions is effective in reducing the defects of the membrane evaluated by burst pressure evaluation, etc., but it is effective against the strength of the entire membrane such as impact. The evaluation major was not enough. Furthermore, the use of coating and spacer filaments in modularization has the problem of increasing the number of processes and increasing costs.

In general, as a method for improving the strength of the yarn, there is a method of drawing during spinning (see, for example, Patent Document 7). However, in the case of a hollow fiber membrane that comes into contact with blood, such as a blood purifier, membrane structure breakage cannot be ignored even with slight stretching, and blood compatibility is significantly reduced. Particularly in the case of a highly water-permeable hollow fiber membrane, it is considered that high clearance is difficult to occur in the blood system due to the effect of stretching, and a film-forming method that suppresses structural destruction as much as possible without taking as much stretching as possible is taken. (For example, refer to Patent Document 8).
Japanese Patent Laid-Open No. 10-263375 WO03 / 106545 JP 2005-125131 A JP 2007-105700 A JP 2005-52716 A JP 2004-254941 A Japanese Patent Laid-Open No. 2003-210954 JP 2006-340977 A

  An object of the present invention is to provide a blood purifier having a built-in hollow fiber membrane having high water permeability and having sufficient strength against an impact in a defoaming operation such as a priming operation.

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) When the blood purifier with a hollow fiber membrane is wet and the arm is extended from the fulcrum provided at a height of 30 cm and one end of the blood purifier is fixed, and the other end of the blood purifier is grounded After adjusting the length of the arm so that the angle is 30 degrees, the blood purifier is dropped freely from the position of 20 cm in height from the other end of the blood purifier to the floor, and the impact is applied 50 times in the same direction. When added, there is no damage to the hollow fiber membrane, and the β2-microglobulin clearance measured in the plasma system after the impact is maintained at 80% or more of the clearance before the impact is applied. Blood purifier with rate.
(2) The blood purifier according to (1), wherein the hollow fiber membrane has a shear fracture rate of 70% or less.
(3) The blood purifier according to (1) or (2), wherein the yield strength when the hollow fiber membrane is measured in a wet state is 8 g / filament or more.
(4) The blood purifier according to any one of (1) to (3), wherein the average thickness of the hollow fiber membrane is 10 μm or more and 50 μm or less.
(5) The blood purifier according to any one of (1) to (4), wherein the hollow fiber membrane has a porosity of 70 to 90%.
(6) The blood purifier according to any one of (1) to (5), wherein the hollow fiber membrane has an average pore radius of 95 to 300 mm.
(7) the same direction 50 times shock blood purifier after adding (membrane area 1.5 m ²⁾ of the plasma system was measured using a β2- microglobulin clearance is is 45 ml / min or more (1) - ( 6) The blood purifier according to any one of the above.

  The blood purifier of the present invention has impact resistance and high water permeability. Therefore, the hollow fiber membrane is not easily damaged even when subjected to impacts due to transportation or excessive operation, and there is an advantage that there is less risk in the clinical field such as blood leak.

  Hereinafter, the present invention will be described in detail.

  In order to solve the above-mentioned problems, the present inventors have examined the manufacturing process, performance, and quality of a hollow fiber membrane used in a blood purifier. Hollow fiber membranes aiming at high water permeability have been developed in the direction of increasing the pores of the membrane as a whole, or reducing the film thickness, such as increasing the pore diameter of the membrane as described above. Such hollow fiber membranes focusing only on high water permeability must be sacrificed in terms of strength. When the strength of the hollow fiber membrane is weaker than that of the conventional one, the risk of damage to the hollow fiber membrane is increased in the manufacturing process, transportation process, and clinical site handling. In order to obtain a hollow fiber membrane with sufficient strength that does not hinder handling properties while achieving high water permeability, in the manufacturing process, active stretching before the membrane structure is formed and the membrane structure is formed. As a result, the present inventors have found that the non-stretching is closely related to the present invention.

  In the present invention, in a wet state, the arm is extended from a fulcrum provided at a height of 30 cm, the blood purifier end is fixed, and the angle at which the opposite blood purifier end contacts the floor is 30 degrees. With the length adjusted, the impact applied by allowing the blood purifier to fall freely from the position of 20 cm in height from the end of the blood purifier that contacts the floor to the floor is applied 50 times in the same direction. It is preferable that there is no damage site in the thread membrane portion. In the use of a blood purifier, when foaming occurs during priming, the work is often performed to remove the foam by applying an impact such as tapping the blood purifier while flowing physiological saline through the blood purifier. Since the number of impacts at this time ranges from several to several tens, the number of repeated impacts is preferably 50 or more.

  Furthermore, it is preferable that the clearance of β 2 -microglobulin measured in the plasma system after repeated impacts is a retention rate of 80% or more as compared with the value before impact. More preferably, it is 85% or more. If the retention ratio of the clearance β2-microglobulin after impact is less than 80%, even if the hollow fiber membrane built in the blood purifier does not reach damage by giving repeated impacts, It is considered that the blood compatibility deteriorated due to deformation such as stretching and bending toward one end and changes in the membrane structure. The plasma clearance β 2 -microglobulin can be measured by a method according to a method defined by the Dialysis Medical Association, which will be described later.

  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, a hollow fiber membrane having relatively high water permeability and high impact resistance can be obtained, but the permeability of medium to high molecular weight substances may be insufficient. In addition, in the design of the blood purifier, if the film thickness is large when the membrane area is increased, the size of the blood purifier increases, which is not appropriate. A thinner film thickness is preferred because the material permeability is increased, more preferably 45 μm or less, and even more preferably 40 μm or less. If the average film thickness is too thin, it may be difficult to maintain the minimum film strength necessary for the blood purifier in evaluating defects such as burst pressure. Therefore, the average film thickness is more preferably 12 μm or more, and further preferably 13 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.

  The hollow fiber membrane preferably has an inner diameter of 100 to 300 μm. If the inner diameter is too small, the pressure loss of the fluid flowing through the hollow portion of the hollow fiber membrane increases, which may cause hemolysis. 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.

In the present invention, the hollow fiber membrane preferably has an average pore radius of 95 to 300 mm. More preferably, it is 150 to 300 mm, and more preferably 150 to 280 mm. By setting this range, even if the apparent pore size is reduced after contact with blood, the effect on the permeation performance of the substance to be removed such as β2-microglobulin is considered to be small. If the average pore radius is too small, there is a possibility that performance deterioration due to blood components will be remarkable, and the change with time will be large. In addition, if the average pore radius is too large, the amount of albumin leak may be excessive. Here, in the present invention, the average pore radius of the hollow fiber membrane is defined as an average pore radius measured using a thermal analysis (DSC) described later, for example, albumin (Stokes radius) It is different from the one obtained from the sieve coefficient of 35mm), and the size of the pores in the membrane is defined and calculated from the state of water in the membrane.
The pore size determined by DSC is a combination of the Laplace and Gibbs-Duhem equations.
r = (2σiw × Vm × To × cos θ) / (ΔT × ΔHm)
r: pore radius σiw: interfacial energy between water and ice (0.01 N / m)
Vm: molar volume of water
To: melting point of bulk water θ: contact angle ΔT: melting point drop ΔHm: molar melting enthalpy, where σiw was 0.01 N / m. Further, ΔT handled in the present invention is the peak top of water with a freezing point drop observed by DSC measurement, and is not strictly an average value. Further, the pore volume porosity is obtained from the amount of water whose freezing point is lowered. Thus, the pore in DSC measurement is defined and calculated from the state of water in the membrane.

In the present invention, the water permeability of pure water at 37 ° C. of the hollow fiber membrane is preferably in the range of 200 ml / m ² / hr / mmHg to 1500 ml / m ² / hr / mmHg. If the water permeability is less than 200 ml / m ² / hr / mmHg, it cannot be said that the object of the present invention is high water permeability, and generally the permeation performance of medium molecular weight substances in the blood system is also low. If the water permeability is too large, the pore diameter increases and the amount of protein leak may increase. Therefore, a more preferable range of water permeability is 200 ml / m ² / hr / mmHg to 1200 ml / m ² / hr / mmHg, more preferably 200 ml / m ² / hr / mmHg to 1000 ml / m ² / hr / mmHg. is there.

  In the present invention, the shear failure rate of the hollow fiber membrane is preferably 70% or less. 65% or less is more preferable, and 60% or less is more preferable. The shear fracture rate is an evaluation of the probability of fracture at the interface of the resin fixing part in a fracture test of a hollow fiber membrane partially fixed with resin. The fracture at the interface of the resin fixing part is evaluated as a shear fracture because the fracture section is observed without observing the fracture cross section and accompanied by the elongation deformation in which the hollow fiber membrane is elongated and thinned. Conversely, the fracture cross-section of the hollow fiber membrane that is broken near the center of the hollow fiber membrane that is not the resin fixing portion is a tensile failure accompanied by a tensile deformation due to the reduced diameter of the hollow fiber membrane. The fracture of the hollow fiber membrane due to impact or the like is a shear fracture, and when the shear fracture rate exceeds 70%, the shear fracture is likely to occur, and the hollow fiber membrane is likely to be damaged by a slight repeated impact.

  In the present invention, the yield strength of the wet hollow fiber membrane is preferably 8 g / filament or more. Furthermore, 8.5 g / filament or more is preferable. The damage mechanism of the hollow fiber membrane due to slight repeated impacts is shear fracture that receives damage without stretching from observation of the fracture cross section of the hollow fiber membrane. The shear fracture rate has a correlation with the Young's modulus. Furthermore, Young's modulus is a function of yield strength. For this reason, it is considered that one can withstand shear fracture due to a slight impact as long as the yield strength is maintained above a certain level. Considering the total weight of the blood purifier when the hollow fiber membrane built in the blood purifier is filled with water, even if it is a small impact, a greater gravitational acceleration is applied than in the dry state, and the wet state If the yield strength is less than 8g / filament, there is a high risk of shear failure due to slight repeated impact. Usually, the yield strength of wet hollow fiber membranes is smaller than the yield strength in the dry state, but water has some plasticizing effect, and the rate of decrease is generally constant depending on the membrane material and membrane structure. In addition, it is difficult to predict the yield strength in the wet state from the yield strength in the dry state.

  In the present invention, the hollow fiber membrane preferably has a porosity of 70% or more and 90% or less. More preferably, the porosity is 72% or more and 89% or less, and further preferably the porosity is 74% or more and 88% or less. Usually, the porosity is correlated with the water permeability of the hollow fiber membrane, and the porosity is increased to obtain high water permeability. The lower the porosity, the more the polymer occupies and the strength of the hollow fiber membrane increases. However, there is a possibility that the high water permeability targeted in the present invention cannot be obtained. On the other hand, when the porosity is increased, the portion occupied by the polymer is reduced accordingly, so that the strength of the hollow fiber membrane is lowered, the handling property is deteriorated, and the modularization process may be hindered.

In the present invention, in a wet state, the arm is extended from a fulcrum provided at a height of 30 cm, the blood purifier end is fixed, and the angle at which the opposite blood purifier end contacts the floor is 30 degrees. After adjusting the length, after applying the impact of dropping the blood purifier freely from the position of the height of 20 cm from the end of the blood purifier in contact with the floor to the floor more than 50 times in the same direction it is preferred values of clearance β2- microglobulin blood purifier of the membrane area 1.5 m ² is 45 ml / min or more. It is more preferably 50 ml / min, and further preferably 55 ml / min or more.

Examples of the material of the hollow fiber membrane in the present invention include cellulose polymers such as regenerated cellulose, cellulose acetate, and cellulose triacetate, polysulfone polymers such as polysulfone and polyethersulfone, polyacrylonitrile, polymethyl methacrylate, ethylene vinyl alcohol copolymer Examples thereof include cellulose and polysulfone, which are easy to obtain a hollow fiber membrane having a water permeability of 200 ml / m ² / hr / mmHg or more. In particular, cellulose diacetate or cellulose triacetate is preferable for cellulose, and polysulfone or polyethersulfone is preferable for polysulfone because it is easy to reduce the film thickness.

  The blood purifier of the present invention is suitable as a blood purifier used for the treatment of renal failure such as hemodialysis, hemodiafiltration and blood filtration. In addition, even though it has high water permeability, even if it receives a slight repetitive impact during use, there is no damage to the hollow fiber membrane, and there is no change in performance due to deflection of the hollow fiber membrane. Excellent in that it can be treated safely.

  As a method for producing a hollow fiber membrane used in such a blood purifier, the following conditions are preferable. In order to obtain high water permeability, the polymer concentration of the spinning solution may be lowered, and depending on the type of polymer, etc., in the case of the aforementioned polymer, it is preferably 20% by mass or less, more preferably 19.5% by mass or less. . The spinning solution is preferably filtered immediately before nozzle discharge for the purpose of removing insoluble components and gel in the spinning solution. The pore diameter of the filter is preferably small, and specifically, it is preferably not more than the thickness of the hollow fiber membrane, 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. In addition, if there is no filter or the filter pore size exceeds the thickness of the hollow fiber membrane, partial voids due to the insoluble components in the spinning solution or the inclusion of gel, etc., and the texture of the surface structure in units of several tens of μm It tends to cause fineness (such as pulling or partial wrinkling). The generation of partial voids in a hollow fiber membrane having a high porosity can cause a decrease in the strength of the hollow fiber membrane, and is one of the specific requirements for achieving the present invention. In addition, remarkably disturbing the fineness of the surface of the hollow fiber membrane in units of several tens of μm leads to activation of blood, increasing the possibility of inducing thrombus and residual blood. It is thought that activating blood has a great influence on performance expression. Filtration of the stock solution for spinning may be carried out a plurality of times before discharging, which is preferable because the life of the filter can be extended.

  The spinning dope treated as described above is discharged using a tube-in-orifice type nozzle having an annular portion on the outside and a hollow forming material discharge hole on the inside. By reducing 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 film thickness of the hollow fiber membrane to be obtained, and the type of hollow forming material, but a large variation in nozzle slit width causes uneven thickness and is thin even at normal blood pressure. The part may tear or rupture, causing a leak.

  The flow rate for discharging the spinning dope (dope discharge rate) is preferably 1.2 ml / min or more. Furthermore, 1.25 ml / min or more is more preferable. When the discharge rate of the spinning dope is 1.2 ml / min, the membrane structure will tend to be denser. By combining with the solidification conditions in the subsequent solidification process, stronger characteristics against shear fracture are obtained. can do. When the flow rate for discharging the spinning dope does not reach 1.2 ml / min, there is a possibility that it is weak against shear fracture, inferior in impact resistance, or the performance retention rate after impact is lowered.

  A smaller draft ratio is preferable. Specifically, it is preferably 1 or more and 10 or less, and more preferably 8 or less. The draft ratio referred to here is the ratio of the discharge linear velocity of the spinning dope discharged from the nozzle to the hollow fiber membrane take-up speed. If the draft ratio is too large, tension is applied when forming the pores of the membrane, making it difficult to control the shape of the hollow fiber membrane.

  The nozzle temperature at the time of discharging the spinning dope is preferably lower than the general hollow fiber membrane production conditions in order to obtain a sufficient effect in the aerial running part of the next step. Specifically, 50 ° C. or higher and 130 ° C. or lower, and 55 ° C. or higher and 120 ° C. or lower are more preferable. If the nozzle temperature is too low, the viscosity of the dope increases, so the pressure applied to the nozzle increases and the spinning dope may not be discharged stably. Further, if the nozzle temperature is too high, there is a possibility that the pore size becomes too large due to the influence of the membrane structure by phase separation. These can also be a factor affecting the strength (shear fracture) of the hollow fiber membrane.

  The discharged spinning solution is immersed in the coagulating liquid through the aerial traveling section. At this time, it is preferable that the aerial traveling section is surrounded by a member (spinning tube) that shields it from the outside air, and the temperature is lowered. Specifically, it is preferably 15 ° C. or less, more preferably 13 ° C. or less, by actual measurement. As a method of controlling the aerial traveling section at a relatively low temperature, there are a method of circulating a refrigerant through a spinning tube and a method of flowing a cooled wind. Cooling of the refrigerant and cooling of the wind can be controlled using liquid nitrogen, dry ice, etc., but considering the workability, the temperature of the air travel part is preferably −20 ° C. or higher, and −10 ° C. or higher. Is more preferable, 0 ° C. or higher is more preferable, and 5 ° C. or higher is even more preferable. In addition, the atmosphere of the aerial traveling section is desirably kept uniform because it affects the phase separation of the spinning dope, and it is preferable to prevent the temperature and wind speed from becoming uneven by covering with an enclosure or the like. Unevenness in the atmosphere, temperature, and wind speed of the aerial traveling part is not appropriate because it causes variations in the microscopic membrane structure and causes problems in performance and strength (shear fracture). As will be described later, gelation can be promoted and the solidification rate of the solidification process in the subsequent step can be controlled appropriately by lowering the temperature of the aerial traveling section.

  The hollow forming material is preferably an inert liquid or gas although it depends on the spinning dope used. Specific examples of such a hollow forming material include liquid paraffin, isopropyl myristate, nitrogen, argon, and the like. Non-solvents such as glycerin, ethylene glycol, triethylene glycol, and polyethylene glycol can be added to these hollow forming materials as necessary. The hollow forming material is an important factor affecting the membrane structure, and can be said to have a great influence on membrane performance and membrane strength. There is a concern that the use of a hollow forming material that is inert to the spinning dope may be slightly disadvantageous in terms of the balance between the membrane performance and membrane strength of the hollow fiber membrane, but in the present invention the membrane strength is increased. Overcoming the disadvantages by taking care of.

  The film that has been gelled through the aerial traveling part undergoes a coagulation step by passing through the coagulation bath. The coagulation bath is preferably an aqueous solution of the solvent used in preparing the spinning dope. In the case where the coagulation bath is water, it is difficult to control the strength application in the coagulation bath which solidifies rapidly and is one of the means for achieving the present invention. It is preferable that the coagulation bath is a mixed solution of a solvent and water because the control of the coagulation time can be easily adjusted. The solvent concentration of the coagulation bath is preferably 70% by mass or less, and more preferably 50% by mass or less. However, if the solvent concentration in the coagulation bath is too low, it is difficult to control the concentration during spinning, so the lower limit of the solvent concentration is preferably 1% by mass or more. The temperature of the coagulation bath is preferably 4 ° C. or more and 50 ° C. or less for controlling the coagulation rate. Furthermore, 10 degreeC or more and 45 degrees C or less are preferable. A non-solvent such as glycerin, ethylene glycol, triethylene glycol, and polyethylene glycol 200 and 400, and additives such as an antioxidant and a lubricant can be added to the coagulation bath as necessary.

  For the hollow fiber membrane that has undergone the coagulation bath under such conditions, when a tensile test was performed, undulations (a tendency to decrease the y-axis value) were seen in the SS curve, and the membrane structure was found in the completed hollow fiber membrane. There was no tendency for the test force (SS curve vertical axis) to continue increasing until just before the break point. Further, the elongation to break (breaking elongation) was higher than that of the hollow fiber membrane that had been subjected to a washing bath under the same conditions. That is, it is considered that the film structure has not been completely determined immediately after leaving the coagulation bath. In the manufacturing process of a highly water-permeable blood purification membrane, it is considered important not to destroy the membrane structure in order to improve blood compatibility, and active stretching during the process has been avoided. However, stretching when the membrane structure is not completely determined in the coagulation bath does not affect the membrane structure destruction, that is, the deterioration of blood performance, and is a weak point of a hollow fiber membrane having high water permeability. It was found that high strength can be imparted. The higher the stretching ratio in the coagulation bath, the better the strength imparting efficiency. Specifically, it is preferably 5% or more, more preferably 8% or more, and more preferably 10% or more. By stretching in the coagulation bath before the film structure is determined, it is considered that the strength is improved because the polymer chain network is formed more firmly. If the stretch ratio is increased too much, the spinnability is lowered, so the upper limit is preferably 50% or less, more preferably 40% or less, further preferably 30% or less, and even more preferably 20% or less. The stretching ratio here is the ratio of the second coagulation bath inlet roller speed and the second coagulation bath outlet roller speed.

  In addition, the degree of film formation immediately after leaving the coagulation bath varies depending on the temperature in the aerial traveling section of the previous step even at the same stretching ratio. In other words, when the air travel part was not cooled, in the tensile test using the hollow fiber membrane after leaving the coagulation bath, the swell of the SS curve immediately before reaching the break point was very large (the break point was the first). Exceeds the peak), and the elongation at break exceeds 100% (SS curve horizontal axis). However, under the same conditions, when cooling in the aerial traveling part is applied, in the tensile test of the hollow fiber membrane after leaving the coagulation bath, the swell of the SS curve just before reaching the breaking point is small (the breaking point is the first) The elongation is not more than 100%. The inventors of the present invention have found that the hollow fiber membrane in the state of leaving the coagulation bath is in the state immediately before the structure determination having the characteristics shown by such an S-S curve is the point of the permeation performance. A hollow fiber membrane (with SS curve and rupture elongation of 100% or more) in a state where the structure immediately after leaving the coagulation bath is almost undefined, as in the case where there is no cooling in the aerial running section. When entering the washing bath, solidification from the outer surface layer occurs instantaneously, a dense structure is formed in the outer surface layer, and a solidification reaction from the outer surface layer to the inner surface layer also occurs quickly, and the pores of the membrane become dense Therefore, it is considered that the desired high transmission performance cannot be achieved.

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

  In order to achieve both the suppression of the deformation of the hollow fiber membrane and the washability, it is effective to flow the cleaning liquid and the hollow fiber membrane in parallel flow. As a specific aspect of the washing step, for example, a facility in which the washing bath is inclined and the hollow fiber membrane is lowered is preferable. Specifically, the inclination of the bath is preferably 1 to 3 degrees. If it is 3 degrees or more, the flow rate of the cleaning liquid becomes too fast, and the running resistance of the hollow fiber membrane may not be suppressed. If it is less than 1 degree, the cleaning failure of the hollow fiber membrane due to the retention of the cleaning liquid may occur. Thus, by suppressing the resistance to the hollow fiber membrane in the cleaning bath, the traveling speed of the hollow fiber membrane at the inlet of the cleaning bath and the traveling speed of the outlet can be made substantially the same. Specifically, the stretching ratio from the coagulation bath to the final winding step is preferably 10% or less. 8% or less is more preferable, and 5% or less is more preferable. The stretching ratio here is specifically the ratio between the traveling speed of the hollow fiber membrane at the coagulation bath outlet and the winding speed at the end of the spinning process. In order to further increase the cleaning efficiency, the cleaning baths are preferably arranged in multiple stages. The number of stages needs to be set as appropriate depending on the balance with the washability and yarn quality. For example, if the purpose is to remove the solvent, non-solvent, hydrophilizing agent, etc. used in the present invention, 3 to 30 It can be said that it is enough if there is a step.

  The hollow fiber membrane that has undergone the washing step is subjected to glycerin treatment as necessary. For example, in the case of a hollow fiber membrane made of cellulosic polymer, after passing through a glycerin bath, it is wound through a drying step. In this case, the glycerin concentration is preferably 30 to 80% by mass. If the glycerin concentration is too low, the hollow fiber membrane tends to shrink during drying, and storage stability may deteriorate. 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 40 ° C or higher and 80 ° 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 structure of the hollow fiber membrane thus obtained has an average pore size of 95 to 300 mm, and the water permeability of pure water at 37 ° C. is from 200 ml / m ² / hr / mmHg to 1500 ml / m ² / hr. / MmHg or less, the yield strength in the wet state is 8 g / filament or more, the hollow fiber membrane is not damaged after 50 or more repeated impact tests, and the clearance β2-microglobulin retention rate is 80% or more. .

  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. Repeated impact test The blood purifier is primed with pure water, the inner side of the hollow fiber membrane (blood side) is capped, and the water on the outer side of the hollow fiber membrane (dialysate side) is naturally removed with the blood purifier standing. Liquid cap. The arm was extended from the fulcrum provided with the blood purifier in this state at a height of 30 cm, the module end was fixed, and the length of the arm was adjusted so that the angle at which the opposite module end contacts the floor was 30 degrees. In this state, 50 times of impacts are applied in the same direction by allowing the module to fall freely from a position 20 cm high from the end of the module that contacts the floor to the floor. After that, when the filling water on the blood side is drained and the blood purifier is submerged, air is blown from the dialysate side at 1.5 kgf / cm ² , and if air bubbles come out from the blood side, the hollow fiber membrane is damaged. It is determined that it has been received.

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

3. Calculation of membrane area The membrane area of the blood purifier 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 blood purifier, 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 blood purifier .

4). β2-microglobulin clearance (CLβ2MG)
Plasma with a protein concentration of 6-7 g / dl is separated from ACD calf blood by centrifugation. About 0.05 mg / dl of heparin sodium (2000 to 4000 units / L) and β2-microglobulin (genetical recombination product Wako Pure Chemical Industries, Ltd.) are added to the plasma used in the dialysis experiment. Only heparin sodium is added to circulating plasma. Prepare at least 2L of circulating plasma per blood purifier to be measured. Circulating plasma is flowed at a flow rate of 200 ml / min through a blood purifier primed with dialysate and moistened. At this time, the filtrate is filled on the dialysate side while filtering at a Qf of 15 ml / min. After the filtrate is filled, the cap is capped and plasma is circulated only for 1 hour on the blood side. After circulation, switch to dialysis experimental plasma membrane area 1.5 m ² of as long as a blood purifier Qbin200ml / min, while flowing plasma in a single pass while applying filtering to a Qbout185ml / min, the dialysate Qdin500ml / min (The filtration flow rate is 10 ml / min / m ² ). Sample Qbout 4 minutes after the start of dialysis. The blood purifier clearance (CLβ2, ml / min) is calculated from the β2MG concentration (Cbin) of the plasma stock solution, the β2MG concentration (Cbout) of the fluid that has passed through the blood purifier, and the flow rate. All operations are performed at 37 ° C.
CLβ2MG = (Cbin × Qbin−Cbout × Qbout) / Cbin

5). Retention rate Two blood purifiers of the same type, the same lot, and the same membrane area are prepared, and one measures CLβ2MG by the above method. The other is subjected to repeated impact tests by the method described above, and then CLβ2MG is measured. When there is no change in performance due to the impact test, the CLβ2MG values of the two blood purifiers are equal and the retention rate is 100%.
Retention rate (%) = CLβ2MG after impact test / CLβ2MG × 100 not subjected to impact test

6). Measurement of pore volume porosity and average pore radius of hollow fiber membranes Dozens of hollow fiber membranes that have been sufficiently wetted with pure water are cut to about 5 mm, excess water is removed with filter paper, and sealed pans are used. Next, measure the melting curve with DSC (DSC-7 or Pyris 1 manufactured by Perkin-Elmer, a differential scanning calorimeter). The measurement is carried out in the range of −45 ° C. to 15 ° C. at a heating rate of 2.5 ° C./min. The water present in the pores has a freezing point drop due to the influence of the base material, and shows a peak at a place different from free water (melted at around 0 ° C.) (temperature range lower than free water). The amount of heat of fusion (ΔHp) in the region surrounded by the peak of the portion where the freezing point is lowered and the baseline is obtained, and the amount of pore water (Wp) is calculated from the amount of heat of fusion (ΔHm) per unit weight of water. The sample subjected to DSC measurement is absolutely dried, and the weight of evaporated water (total water content Wt) is obtained. From these values, Vp (pore volume porosity) is calculated by the following equation.
Wp = ΔHp / ΔHm
Vp (%) = Wp / (Wt + Mp / ρp) × 100
Mp: polymer weight = sample weight-total water content ρp: polymer specific gravity From the melting curve obtained as described above, the peak top of the peak with the freezing point lowered is read, and the freezing point due to capillary condensation of water in the pores ( The pore radius (r) can be simply calculated from the degree of freezing) using the following equation. In the present invention, the value obtained by this measurement method is defined as the average pore radius.
r (Å) = Degree of freezing point (° C.) / 164

7). The blood outlet circuit of the water-permeable blood purifier (the outlet side from the pressure measurement point) 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 blood purifier kept at 37 ° C constant temperature bath, and the amount of filtrate that flows out from the dialysate side Was measured. The transmembrane pressure difference (TMP) is
TMP = (Pi + Po) / 2
And Here, Pi is the blood purifier inlet side pressure, and Po is the blood purifier outlet side pressure. The TMP was changed at four points, the filtration flow rate was measured, and the water permeability (ml / hr / mmHg) was calculated from the slope of the relationship. At this time, the correlation coefficient between TMP and filtration flow rate must be 0.99 or more. In order to reduce the pressure loss error due to the circuit, TMP is measured in the range of 100mmHg or less. The water permeability of the hollow fiber membrane is calculated from the membrane area and the water permeability of the blood purifier.
UFR (H) = UFR (D) / A
Where UFR (H) is the permeability of the hollow fiber membrane (ml / m ² / hr / mmHg), UFR (D) is the permeability of the blood purifier (ml / hr / mmHg), and A is the membrane of the blood purifier the area (m ^2).

8). Yield strength Measured using Tensilon UTMII manufactured by Toyo Baldwin.
The hollow fiber membrane wetted with water was measured at a pulling speed of 20 mm / min and a distance between chucks of 20 mm, and the hollow fiber membrane immediately after the coagulation bath was measured under a pulling speed of 200 mm / min and a distance between chucks of 100 mm.

9. Shear Fracture Rate A resin is uniformly applied to the hollow fiber membrane with a width of 5 mm at the center of about 150 mm of the dried hollow fiber membrane and dried. As the resin, a two-component urethane resin, an epoxy resin, or a one-component urethane resin is used. The drying time is 24 hours. Drying and breaking tests are performed at 20 ° C and 65% humidity. The hollow fiber membrane from which the resin was dried was subjected to a tensile test using Tensilon UTMII manufactured by Toyo Baldwin. Measure under conditions of a pulling speed of 200mm / min and a distance between chucks of 100mm, and record the broken part. Measure 10 or more samples.
Shear fracture rate (%) = number of fractures near the resin (shear fracture) / number of elongation fractures × 100

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

Example 1
15% by mass of cellulose triacetate (manufactured by Daicel Chemical Industries), 59.5% by mass of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical) and 25.5% by mass of triethylene glycol (TEG, manufactured by Mitsui Chemicals) It heated and melt | dissolved uniformly, and the defoaming of the obtained film forming solution was performed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged from a tube-in orifice nozzle heated to 100 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After being cut off from the outside by a tube and passing through a 70 mm dry section adjusted to 12 ° C., it was coagulated in a 15 mass% NMP / TEG (7/3) aqueous solution at 45 ° C., and after passing through a 30 ° C. water washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.3 ml / min, and the draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 2 degrees so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretching was 10%, the SS curve of the hollow fiber immediately after the coagulation bath had some undulations, but did not exceed the strong peak at the breaking point, and the breaking elongation was 60%. The stretch from the coagulation bath to winding was 4%.

  The resulting hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 16 μm, a porosity of 80%, a wet yield strength of 9.0 g, a shear fracture rate of 40%, and an average pore radius of 280 mm ( Table 1).

A blood purifier was assembled using the obtained hollow fiber membrane so that the membrane area was 1.5 m ² . The blood purifier primed with pure water was repeatedly subjected to an impact test (50 times). After that, it was examined whether the hollow fiber membrane had any damaged site, and there was no damaged site. The plasma clearance β2-microglobulin of this blood purifier was 63 ml / min. Since the plasma clearance β2-microglobulin of the blood purifier not subjected to the repeated impact test of the same lot was 75 ml / min, the plasma clearance β2-microglobulin retention rate can be calculated as 84%. In addition to high performance, it had sufficient strength and performance retention against repeated impacts.

(Example 2)
16% by mass of cellulose triacetate (manufactured by Daicel Chemical), 58.8% by mass of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical) and 25.2% by mass of triethylene glycol (TEG, manufactured by Mitsui Chemicals) It heated and melt | dissolved uniformly, and the defoaming of the obtained film forming solution was performed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged from a tube-in orifice nozzle heated to 98 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After passing through a 50 mm dry section adjusted to 5 ° C. after being blocked from outside air by a tube, it is solidified in a 40% by weight 15% by mass NMP / TEG (7/3) aqueous solution, and after passing through a 30 ° C. water washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.3 ml / min, and the draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 8 μm. In addition, the water washing bath was adjusted to have an inclination of 3 degrees so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretch was 11%, and the SS curve of the hollow fiber immediately after the coagulation bath was slightly waved but did not exceed the strong peak at the breaking point, and the breaking elongation was 55%. The stretch from the coagulation bath to winding was 4%.

  The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 16 μm, a porosity of 78%, a wet yield strength of 10.0 g, a shear fracture rate of 30%, and an average pore radius of 270 mm ( Table 1).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 1. No hollow fiber damage was observed after the repeated impact test. The plasma clearance β2-microglobulin of the blood purifier after repeated impact tests was 67.5 ml / min. Since the plasma clearance β2-microglobulin of the blood purifier not subjected to the repeated impact test of the same lot was 71 ml / min, the plasma clearance β2-microglobulin retention rate was 95%. In addition to high performance, it had sufficient strength and performance retention against repeated impacts.

(Example 3)
20% by mass of polyethersulfone (manufactured by Sumitomo Chemical Co., Ltd., Polyethersulfone 7300P), 2% by mass of polyvinylpyrrolidone (PVP K-90 manufactured by BASF), N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) 48% by mass and 30% by mass of polyethylene glycol (PEG200, manufactured by Daiichi Kogyo Seiyaku) were uniformly dissolved, and then the film-forming solution was defoamed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then simultaneously discharged together with nitrogen gas as a hollow forming material from a tube-in orifice nozzle heated to 110 ° C. After passing through a 5 mm dry section that was cut off and adjusted to 10 ° C., it was solidified in a 40 mass% NMP / PEG 200 (6/4) aqueous solution at 40 ° C., passed through a 50 ° C. water-washing bath, 50 ° C., 60 ° C. It was passed through a mass% glycerin bath, dried with a dryer, and wound up. The dope discharge speed was 1.4 ml / min, and the draft ratio of the film forming solution was 5. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 1 degree so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 5 steps. The solidification bath stretching was 20%, and the SS curve of the hollow fiber immediately after the coagulation bath was slightly waved but did not exceed the strong peak at the breaking point, and the breaking elongation was 60%. The stretch from the coagulation bath to winding was 5%.

  The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 20 μm, a porosity of 76%, a wet yield strength of 15.0 g, a shear failure rate of 0%, and an average pore radius of 170 mm ( Table 1).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 1. No hollow fiber damage was observed after the repeated impact test. The plasma clearance β2-microglobulin of the blood purifier after repeated impact tests was 55 ml / min. Since the plasma clearance β2-microglobulin of the blood purifier not subjected to the repeated impact test of the same lot was 64 ml / min, the plasma clearance β2-microglobulin retention rate was 86%. In addition to high performance, it had sufficient strength and performance retention against repeated impacts.

Example 4
Cellulose triacetate (manufactured by Daicel Chemical Industries) 19% by mass, N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) 56.7% by mass and triethylene glycol (TEG, manufactured by Mitsui Chemicals) 24.3% by mass It heated and melt | dissolved uniformly, and the defoaming of the obtained film forming solution was performed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged from a tube-in orifice nozzle heated to 100 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After passing through a 50 mm dry section adjusted to 5 ° C. after being blocked from outside air by a tube, it is solidified in a 40% by weight 15% by mass NMP / TEG (7/3) aqueous solution, and after passing through a 30 ° C. water washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.4 ml / min, and the draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 2 degrees so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretching was 12%, the SS curve of the hollow fiber immediately after the coagulation bath had some undulations, but did not exceed the strong peak at the breaking point, and the breaking elongation was 50%. The stretch from the coagulation bath to winding was 4%.

  The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 17 μm, a porosity of 76%, a wet yield strength of 13.0 g, a shear fracture rate of 0%, and an average pore radius of 250 mm ( Table 1).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 1. No hollow fiber damage was observed after the repeated impact test. The plasma clearance β2-microglobulin in the blood purifier after the repeated impact test was 65 ml / min. Since the plasma clearance β2-microglobulin of the blood purifier not subjected to the repeated impact test of the same lot was 65 ml / min, the plasma clearance β2-microglobulin retention rate was 100%. In addition to high performance, it had sufficient strength and performance retention against repeated impacts.

(Example 5)
Cellulose triacetate (Daicel Chemical) 18% by mass, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical) 57.4% by mass and triethylene glycol (TEG, Mitsui Chemicals) 24.6% by mass It heated and melt | dissolved uniformly, and the defoaming of the obtained film forming solution was performed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged from a tube-in orifice nozzle heated to 110 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After passing through a 50 mm dry section adjusted to 5 ° C. after being blocked from outside air by a tube, it is solidified in a 40% by weight 15% by mass NMP / TEG (7/3) aqueous solution, and after passing through a 30 ° C. water washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.25 ml / min, and the draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 2 degrees so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretching was 15%, and the SS curve of the hollow fiber immediately after the coagulation bath had some undulations, but did not exceed the strong peak at the breaking point, and the breaking elongation was 50%. The stretch from the coagulation bath to winding was 5%.

  The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 15 μm, a porosity of 78%, a wet yield strength of 12.0 g, a shear fracture rate of 70%, and an average pore radius of 270 mm ( Table 1).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 1. No hollow fiber damage was observed after the repeated impact test. The plasma clearance β2-microglobulin of the blood purifier after repeated impact tests was 56.5 ml / min. Since the plasma clearance β2-microglobulin of the blood purifier not subjected to the repeated impact test of the same lot was 69 ml / min, the plasma clearance β2-microglobulin retention rate was 82%. In addition to high performance, it had sufficient strength and performance retention against repeated impacts.

(Example 6)
Cellulose triacetate (Daicel Chemicals) 18.5% by mass, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical) 57.1% by mass and triethylene glycol (TEG, Mitsui Chemicals) 24.4% by mass % Was heated and dissolved uniformly, and then the resulting film forming solution was defoamed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged from a tube-in orifice nozzle heated to 102 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After passing through a 50 mm dry section adjusted to 5 ° C. after being blocked from outside air by a tube, it is solidified in a 40% by weight 15% by mass NMP / TEG (7/3) aqueous solution, and after passing through a 30 ° C. water washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.3 ml / min, and the draft ratio of the film forming solution was 7. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the water washing bath was adjusted to have an inclination of 3 degrees so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretching was 15%, and the SS curve of the hollow fiber immediately after the coagulation bath had some undulations, but did not exceed the strong peak at the breaking point, and the breaking elongation was 50%. The stretch from the coagulation bath to winding was 4%.

  The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 16 μm, a porosity of 78%, a wet yield strength of 12.5 g, a shear fracture rate of 60%, and an average pore radius of 270 mm ( Table 1).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 1. No hollow fiber damage was observed after the repeated impact test. The plasma clearance β2-microglobulin of the blood purifier after the repeated impact test was 59 ml / min. Since the plasma clearance β2-microglobulin of the blood purifier not subjected to the repeated impact test of the same lot was 68 ml / min, the plasma clearance β2-microglobulin retention rate was 87%. In addition to high performance, it had sufficient strength and performance retention against repeated impacts.

(Comparative Example 1)
16% by mass of cellulose triacetate (manufactured by Daicel Chemical), 58.8% by mass of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical) and 25.2% by mass of triethylene glycol (TEG, manufactured by Mitsui Chemicals) It heated and melt | dissolved uniformly, and the defoaming of the obtained film forming solution was performed. The obtained film-forming solution was passed through a two-stage sintered filter of 20 μm and 20 μm in order, and then discharged from a tube-in orifice nozzle heated to 105 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After being cut off from the outside by a tube and passing through a 70 mm dry part adjusted to 12 ° C., it is solidified in a 20 mass% NMP / TEG (7/3) aqueous solution at 40 ° C., and after passing through a 30 ° C. water-washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.1 ml / min, and the draft ratio of the film forming solution was 11. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 1 degree so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretching was 4%, and the SS curve of the hollow fiber immediately after the coagulation bath had a large undulation and exceeded the strong first peak at the breaking point. Furthermore, the elongation at break was 100%. The stretch from the coagulation bath to winding was 5%.

  The resulting hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 16 μm, a porosity of 80%, a wet yield strength of 6.0 g, a shear fracture rate of 90%, and an average pore radius of 300 mm ( Table 2).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 2. Numerous hollow fiber damages were observed in the blood purifier after repeated impact tests. The plasma clearance β2-microglobulin of a blood purifier not subjected to the repeated impact test of the same lot had a high performance of 71 ml / min, but did not have sufficient strength against repeated impact.

(Comparative Example 2)
Cellulose triacetate (Daicel Chemical) 17.5% by mass, N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical) 57.75% by mass and triethylene glycol (TEG, Mitsui Chemicals) 24.75% by mass % Was heated and dissolved uniformly, and then the resulting film forming solution was defoamed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 5 μm in order, and then discharged from a tube-in orifice nozzle heated to 105 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After being cut off from the outside by a tube and passing through a 50 mm dry part adjusted to 30 ° C., it is solidified in a 20 mass% NMP / TEG (7/3) aqueous solution at 40 ° C., and after passing through a 30 ° C. water-washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.1 ml / min, and the draft ratio of the film forming solution was 11. The difference between the maximum value and the minimum value of the nozzle slit width was 10 μm. In addition, the washing bath was adjusted to have an inclination of 3 degrees so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in opposite directions. The washing bath was 5 steps. The solidification bath stretching was 4%, and the SS curve of the hollow fiber immediately after the coagulation bath had a large undulation and exceeded the strong first peak at the breaking point. Furthermore, the elongation at break was 120%. The stretching from the coagulation bath to winding was 20%.

  The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 15 μm, a porosity of 79%, a wet yield strength of 8.0 g, a shear fracture rate of 50%, and an average pore radius of 280 mm ( Table 2).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 2. No hollow fiber damage was observed in the blood purifier after the repeated impact test, but the plasma clearance β2-microglobulin of the blood purifier after the repeated impact test was 41 ml / min. Since the blood clearance β2-microglobulin of the blood purifier not subjected to the repeated impact test of the same lot was 54 ml / min, the plasma clearance β2-microglobulin retention rate was 76%. Since the stretching after the coagulation bath was high, the yield strength in the wet state was improved and it was able to withstand repeated impact tests. However, because the stretching was after the formation of the structure, both the blood performance and the retention rate were low.

(Comparative Example 3)
15% by mass of cellulose triacetate (manufactured by Daicel Chemical Industries), 59.5% by mass of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical) and 25.5% by mass of triethylene glycol (TEG, manufactured by Mitsui Chemicals) It heated and melt | dissolved uniformly, and the defoaming of the obtained film forming solution was performed. The obtained film-forming solution was passed through a two-stage sintered filter of 20 μm and 20 μm in order, and then discharged from a tube-in orifice nozzle heated to 105 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After being cut off from the outside by a tube and passing through a 70 mm dry part adjusted to 12 ° C., it is solidified in a 20 mass% NMP / TEG (7/3) aqueous solution at 40 ° C., and after passing through a 30 ° C. water-washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.3 ml / min, and the draft ratio of the film forming solution was 11. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 1 degree so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretching was 4%, and the SS curve of the hollow fiber immediately after the coagulation bath had a large undulation and exceeded the strong first peak at the breaking point. Furthermore, the elongation at break was 100%. The stretch from the coagulation bath to winding was 5%.

  The resulting hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 15 μm, a porosity of 79%, a wet yield strength of 6.5 g, a shear fracture rate of 80%, and an average pore radius of 290 mm ( Table 2).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 2. In the blood purifier after repeated impact tests, hollow fiber damage was observed in 9 out of 10 blood purifiers. Since the stretching before the structure formation was low, the strength against repeated impacts was weak. When the plasma clearance was measured for one of the fibers in which no damage to the hollow fiber was observed, the retention rate was 59%.

(Comparative Example 4)
Cellulose triacetate (manufactured by Daicel Chemical Industries) 17% by mass, N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation) 58.1% by mass and triethylene glycol (TEG, manufactured by Mitsui Chemicals) 24.9% by mass It heated and melt | dissolved uniformly, and the defoaming of the obtained film forming solution was performed. The obtained film-forming solution was passed through a two-stage sintered filter of 20 μm and 20 μm in order, and then discharged from a tube-in orifice nozzle heated to 105 ° C. with liquid paraffin previously deaerated as a hollow forming material, and spinning. After being cut off from the outside by a tube and passing through a 70 mm dry part adjusted to 12 ° C., it is solidified in a 20 mass% NMP / TEG (7/3) aqueous solution at 40 ° C., and after passing through a 30 ° C. water-washing bath, It was passed through a glycerin bath at 50 ° C. and 60% by mass, dried with a dryer, and wound up. The dope discharge speed was 1.1 ml / min, and the draft ratio of the film forming solution was 11. The difference between the maximum value and the minimum value of the nozzle slit width was 7 μm. In addition, the washing bath was adjusted to have an inclination of 1 degree so that the washing water slowly descended, and the washing water and the hollow fiber membrane flowed in the same direction. The washing bath was 7 steps. The solidification bath stretch was 20%, and the SS curve of the hollow fiber immediately after the coagulation bath had less undulation. Furthermore, the elongation at break was 80%. The stretch from the coagulation bath to winding was 5%.

  The obtained hollow fiber membrane had an inner diameter of 200 μm, a film thickness of 15 μm, a porosity of 78%, a wet yield strength of 7.5 g, a shear fracture rate of 80%, and an average pore radius of 270 mm ( Table 2).

  Evaluation was conducted in the same manner as in Example 1 using the obtained hollow fiber membrane. The results are shown in Table 2. Hollow fiber damage was observed in the blood purifier after repeated impact tests. Although the stretching before the structure formation was increased, the dope supply amount was not sufficient, so the strength against repeated impacts was weak.

(Comparative Example 5)
Cellulose triacetate (manufactured by Daicel Chemical Industries) 19% by mass, NMP 56.7% by mass, and TEG 24.3% by mass were uniformly dissolved, and then the film-forming solution was defoamed. The obtained film-forming solution was passed through a two-stage sintered filter of 10 μm and 15 μm in order, and simultaneously discharged together with liquid paraffin previously degassed as a hollow forming material from a tube-in orifice nozzle heated to 105 ° C., After passing through a 50 mm dry section cut off from the outside air by a spinning tube and adjusted to a uniform atmosphere at 30 ° C., it was solidified in a 30 mass% NMP / TEG (7/3) aqueous solution at 50 ° C. When the coagulation bath stretching was 60%, yarn breakage occurred and spinning could not be performed.

  The hollow fiber blood purifier of the present invention does not damage the hollow fiber membrane even when subjected to repeated impacts assuming priming, etc., and there is no fluctuation in blood system permeation performance even after receiving the impacts. It has the characteristics of high water permeability. Therefore, there is an advantage that it can be expected that there is little risk of blood leak and stable performance even when subjected to an impact in handling in the clinical field. Therefore, it can greatly contribute to industrial development.

The schematic diagram which shows one method of the impact test of this invention.

Claims (7)

  In a blood purifier with a hollow fiber membrane built-in, the angle when the arm is extended from a fulcrum provided at a height of 30 cm and one end of the blood purifier is fixed and the other end of the blood purifier is grounded to the floor in a wet state. After adjusting the length of the arm so that it is 30 degrees, when the blood purifier is dropped freely from the position of 20 cm from the other end of the blood purifier to the floor and 50 impacts are applied in the same direction In addition, there is no damage to the hollow fiber membrane, and the clearance of β2-microglobulin measured in the plasma system after the impact has a retention rate of 80% or more with respect to the clearance before the impact is applied. Blood purifier.   The blood purifier according to claim 1, wherein the hollow fiber membrane has a shear fracture rate of 70% or less.   The blood purifier according to claim 1 or 2, wherein the yield strength when the hollow fiber membrane is measured in a wet state is 8 g / filament or more.   The blood purifier according to any one of claims 1 to 3, wherein the average thickness of the hollow fiber membrane is 10 µm or more and 50 µm or less.   The blood purifier according to any one of claims 1 to 4, wherein the hollow fiber membrane has a porosity of 70 to 90%.   The blood purifier according to any one of claims 1 to 5, wherein the hollow fiber membrane has an average pore radius of 95 to 300 mm. 7. The plasma β2-microglobulin clearance measured using a blood purifier (membrane area 1.5 m ² ) after 50 impacts in the same direction is 45 ml / min or more. The blood purifier described.

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