JP2012019891A - Method for manufacturing hollow fiber membrane for blood processing - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for manufacturing a hollow fiber membrane, which can bring about the hollow fiber membrane for blood processing, capable of reducing erroneous leak determination and fixing of the hollow fiber membranes to each other while maintaining a high membrane performance.SOLUTION: The method for manufacturing the hollow fiber membrane for the blood processing, wherein the hollow fiber membrane contains a polysulfone-based resin and a hydrophilic polymer, includes the step of using a spinning solution containing the polysulfone-based resin and the hydrophilic polymer with a molecular weight of 300,000 or more and an internal coagulation liquid containing 0.1-10 mass% of the hydrophilic polymer with a molecular weight of 300,000 or more, of simultaneously making the internal coagulation liquid flow out from an inside channel of a double annular nozzle and making the spinning solution flow out from an outside channel of the double annular nozzle, and of congealing them in an external coagulation liquid.

Description

  The present invention relates to a method for producing a hollow fiber membrane for blood treatment.

  In recent years, the application of hollow fiber membrane technology to medicine has progressed. For example, artificial kidneys used in hemodialysis therapy for patients with chronic renal failure, plasma separators used in plasma exchange therapy to replace patient plasma with fresh frozen plasma or albumin solution, or high molecular weight substances in patient plasma Hollow fiber membrane blood processing devices are frequently used in plasma fractionators and the like used for double filtration plasma exchange therapy for removing water.

  In the hollow fiber membrane blood treatment device, the container is filled with liquid and the hollow fiber membrane is completely filled with liquid (hereinafter sometimes referred to as wet product), and the container is not filled with liquid, A product in a dry state (the hollow fiber membrane contains almost no liquid) or a semi-dry state (the hollow fiber membrane is wetted with a liquid, but does not hold a liquid having a saturated liquid retention rate or more) (hereinafter “dry product”) ”). In particular, dry products have the advantage that they are not easily frozen during transportation and storage even in cold regions, and the products themselves are light.

  The hollow fiber membrane used in the hollow fiber membrane type blood treatment device has an unnecessary substance in the blood that is easily removed from the blood through the hollow fiber membrane, and the necessary substance in the blood passes through the hollow fiber membrane. Therefore, it is required to have a high substance selection performance such that the blood does not easily flow out of the blood and a high biocompatibility such that the blood does not easily adhere to the inner wall surface of the hollow fiber membrane. Therefore, in order to impart these performances to the hollow fiber membrane (hereinafter collectively referred to as “membrane performance”), for example, in Patent Documents 1 to 3, a polysulfone resin containing a hydrophilic polymer is used as the hollow fiber membrane. It is being considered for adoption.

  By the way, if pinholes (defects) are present in the hollow fiber membrane, substances that are not desired to pass through the hollow fiber membrane may leak out. Therefore, in the process of assembling the hollow fiber membrane blood treatment device, it is necessary to perform a leak test to confirm the presence or absence of pinholes in the hollow fiber membrane.

  For example, when the gas permeability of the hollow fiber membrane is low, the pressure of the gas is applied to one side of the space isolated by the hollow fiber membrane, and the rate at which the gas escapes to the other side is measured. Thus, the presence or absence of pinholes in the hollow fiber membrane can be determined. However, in the case of a hollow fiber membrane blood treatment device using a hollow fiber membrane having a high water permeability in recent years, the gas permeability of the hollow fiber membrane is very high. Is difficult.

  Therefore, in order to perform a leak test of a hollow fiber membrane having high water permeability and high gas permeability, the hollow fiber membrane is once wetted with a liquid, and after having made no gas permeation without a pinhole, A method of performing a leak test (Patent Document 4), or in a state where the hollow fiber membrane is completely immersed in a liquid, pressurizing the hollow portion of the hollow fiber membrane with a gas, and whether or not bubbles emerge from the hollow fiber membrane A method of detecting the presence or absence of pinholes (Patent Document 5) has been performed. As another leak test, there is a leak inspection method for a hollow fiber membrane module (Patent Document 6) in which a gas containing colorable particles is introduced under pressure into the hollow fiber membrane to detect leakage of the colored particles. .

JP-A-6-296686 JP-A-7-289866 JP 2005-329082 A Japanese Patent Laid-Open No. 2005-238096 JP 2003-190747 A JP 2009-183822 A

  However, as a result of studies by the present inventors, even if the hollow fiber membrane is wetted with a liquid, a hollow fiber membrane type blood treatment device without a pinhole is erroneously determined to have a pinhole in a leak test (in this specification, This is called “leak misjudgment”). The blood processing device in which this leak is erroneously determined is discarded even though it is normal, causing a significant reduction in production efficiency.

  Further, apart from the above problem, when a hollow fiber membrane bundle is produced by bundling a plurality of hollow fiber membranes, there is also a problem that the hollow fiber membrane bundle itself must be discarded if the hollow fiber membranes adhere to each other. When the hollow fiber membrane is fixed, irregularities may occur at the upper and lower ends of the hollow fiber bundle, which may cause problems such as difficulty in housing in the case, and reduced dialysis efficiency. For this reason, even if only a part of the hollow fiber membranes are fixed to each other, it is necessary to discard many other hollow fiber membranes that are not fixed, which causes a significant reduction in production efficiency as described above.

  Therefore, the present invention has been made in view of the above-described problems of the prior art, and obtains a hollow fiber membrane for blood treatment that can reduce misjudgment of leakage and adhesion between hollow fiber membranes while maintaining high membrane performance. An object of the present invention is to provide a method for producing a hollow fiber membrane.

In order to achieve the above object, the present invention provides the following [1] to [4].
[1] A method for producing a hollow fiber membrane for blood treatment, wherein the hollow fiber membrane contains a polysulfone resin and a hydrophilic polymer, and has a high hydrophilicity and a polysulfone resin and a molecular weight of 300,000 or more. Using a spinning stock solution containing molecules and an internal coagulating solution containing 0.1 to 10% by mass of a hydrophilic polymer having a molecular weight of 300,000 or more, the internal coagulating solution is double-circulated from the inner channel of the double annular nozzle. A method comprising a step of spinning a raw spinning solution from the outer flow path of a nozzle at the same time.
[2] The method according to [1] above, wherein the hydrophilic polymer is polyvinylpyrrolidone.
[3] The method according to [1] above, wherein the content of the hydrophilic polymer in the internal coagulation liquid is 0.1 to 1.0% by mass.
[4] The method according to [1] above, wherein the molecular weight of polyvinylpyrrolidone contained in the spinning dope and the internal coagulation liquid is 300,000 or more and 1,500,000 or less.

  ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the hollow fiber membrane which can obtain the hollow fiber membrane for blood processing which can reduce leak misjudgment and adhesion of hollow fiber membranes can be provided, maintaining a high membrane performance. It becomes possible.

It is a flowchart of the manufacturing method of the hollow fiber membrane which concerns on this embodiment. It is a schematic diagram which shows the manufacturing method of the hollow fiber membrane which concerns on this embodiment. It is a schematic cross section of the hollow fiber membrane type blood treatment device according to the present embodiment.

  Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the drawings as the case may be. In the drawings, the same or corresponding parts are denoted by the same reference numerals, and redundant description is omitted. Further, the dimensional ratios in the drawings are not limited to the illustrated ratios.

<Hollow fiber membrane>
First, the hollow fiber membrane that can be obtained by the production method according to a preferred embodiment of the present invention will be described. Here, the “hollow fiber membrane” is a membrane formed into a thread shape having a hollow communicating in the length direction. This membrane has the ability to separate substances by having a large number of fine pores, and exchanges substances between the liquid passing through the hollow area inside the yarn and the liquid passing through the outside. Can do.

The hollow fiber membrane according to the present embodiment includes a hydrophilic polymer and a polysulfone resin. The polysulfone-based resin, a sulfone bond - is a generic name for high molecular compounds having a sulfone bond _{(-SO 2) (-SO 2 -} ) is not particularly limited as long as it is a polymer compound containing a. For example, those having a structural unit containing a sulfone bond and an aromatic hydrocarbon group are preferable, and polysulfone-based resins having a structural unit represented by the following formula (1) or (2) are widely commercially available and easily available. Therefore, it is preferable. Especially, the polysulfone resin containing the structural unit represented by following (1) Formula is preferable. The polysulfone resin containing the structural unit represented by the following formula (1) is a product name of Udel from Solvay Advanced Polymers, and the polysulfone resin having the structure represented by the following formula (2) is a product of Ultrason from Buzzf. It is marketed by name. In addition, the polysulfone-based resin according to the present embodiment may include a part of the structural unit having no sulfone bond in addition to the structural unit including the sulfone bond.

  The hydrophilic polymer is a water-soluble polymer material. For example, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polypropylene glycol and the like can be exemplified, and those which are safe and less irritating to the living body are preferable. Polyvinyl pyrrolidone and polyethylene glycol are preferable from the viewpoints of safety and handling properties, and polyvinyl pyrrolidone is particularly preferable. For example, polyvinyl pyrrolidone with various molecular weights is commercially available from ISP under the trade name of Plusdon.

  The molecular weight of the hydrophilic polymer is 300,000 or more. Such a high molecular weight hydrophilic polymer has a large residual ratio in the film, and therefore tends to have a structure that satisfies the condition of the content ratio of a specific hydrophilic polymer as described later. In particular, when the hydrophilic polymer is polyvinyl pyrrolidone, the molecular weight is preferably 300,000 or more.

  The hollow fiber membrane according to the present embodiment performs substance exchange between liquids flowing inside and outside, and has a function (selective permeability) of selecting and transmitting a predetermined substance. Here, the selective permeability means, for example, a characteristic that allows only a water or a small molecule substance to permeate without passing a polymer substance contained in a liquid. Artificial dialysis refers to a function that does not permeate proteins such as albumin necessary for the body contained in the blood, but permeates water including wastes and the like to be discharged outside the body. The hollow fiber membrane does not need to be made of a material having selective permeability as a whole, and may be provided with a “dense layer” that exhibits selective permeability in part. Examples of the dense layer include those present in the vicinity of the inner surface of the hollow fiber membrane and having a network structure denser than the outer surface side. The hollow fiber membrane may have a gradient structure in which the density of the network structure decreases toward the outer surface side.

The hollow fiber membrane preferably has a hydrophilic polymer content of 2% by mass or more and 10% by mass or less in the entire hollow fiber membrane. Here, the “content ratio of the hydrophilic polymer in the entire hollow fiber membrane” is the ratio of the mass of the hydrophilic polymer to the total mass of the polysulfone resin and the hydrophilic polymer forming the membrane. Examples of the measurement method include a method using a measurement result by ¹ H-NMR. That is, in the method using ¹ H-NMR, the peak intensity derived from the proton of the group unique to the polysulfone resin and the intensity of the peak derived from the proton of the group unique to the hydrophilic polymer are determined. The molar ratio can be determined, and the content can be calculated based on the molar ratio.

  For example, when the polysulfone resin has a structural unit represented by the above formula (1) and the hydrophilic polymer is polyvinyl pyrrolidone, a hydrogen atom of one phenylene group in the structural unit of the polysulfone resin, Focusing on the hydrogen atoms in the structural units of polyvinylpyrrolidone and polyvinylpyrrolidone, the intensities (integrated values) of the peaks attributed to these are calculated. If the polysulfone-based resin is 100 moles, there are four phenylene group hydrogen atoms, and the peak strength derived from polyvinylpyrrolidone when the peak strength derived from it is 400, the polysulfone-based resin is 100 moles. This corresponds to the number of moles of polyvinylpyrrolidone. Based on these results, the mass ratio of both compounds can be calculated, and as a result, the content of the hydrophilic polymer in the entire hollow fiber membrane described above is determined.

  If the content of the hydrophilic polymer in the whole hollow fiber membrane is less than 2% by mass, the membrane becomes highly hydrophobic and the amount of protein adsorbed in blood increases, so the hollow fiber membrane is clogged. It tends to be easy to do. On the other hand, when the content is larger than 10% by mass, the amount of the eluted hydrophilic polymer tends to increase. From these viewpoints, 2% by mass or more and 9% by mass or less are more preferable, and 2% by mass or more and 8% by mass or less are more preferable.

  The hollow fiber membrane preferably has a hydrophilic polymer abundance ratio of 40% by mass or more and 100% by mass or less on the inner surface of the hollow fiber membrane. Here, the abundance ratio of the hydrophilic polymer on the inner surface of the hollow fiber membrane refers to the polysulfone resin and the hydrophilicity in the outermost layer portion inside the hollow fiber membrane (that is, the surface where blood contacts the hollow fiber membrane). The ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer. Examples of the measurement method include a method using a measurement result by X-ray photoelectron spectroscopy (XPS). That is, the inner surface of the hollow fiber membrane is measured by XPS, and the ratio of the number of each atom on the surface is obtained from the peak intensity of atoms peculiar to the polysulfone resin and the hydrophilic polymer, respectively. The abundance ratio can be calculated from the mass ratio of the compound.

Specifically, when polyvinyl pyrrolidone is used as the hydrophilic polymer, it is determined from the number of nitrogen atoms (derived from polyvinyl pyrrolidone) and the number of sulfur atoms (derived from polysulfone resin) at the inner surface of the hollow fiber membrane. It is done. For example, when the polysulfone-based resin is composed of the structural unit represented by the above formula (1), the abundance of polyvinyl pyrrolidone on the inner surface of the hollow fiber membrane can be determined by the following formula (3).

  If the abundance of the hydrophilic polymer on the inner surface of the membrane is less than 40% by mass, the above-described leak misjudgment may increase. The upper limit of this abundance is 100% by mass, but if the value is large, the amount of the eluted hydrophilic polymer tends to increase. Therefore, the abundance ratio is preferably 40% by mass to 90% by mass, and more preferably 40% by mass to 80% by mass.

Furthermore, in the hollow fiber membrane, the ratio of the abundance of the hydrophilic polymer on the inner surface of the hollow fiber membrane to the hydrophilic polymer content in the entire hollow fiber membrane is 8.0 or more and 50 or less. It is preferable that it is. Here, the ratio of the abundance of the hydrophilic polymer on the inner surface of the hollow fiber membrane to the content of the hydrophilic polymer in the entire hollow fiber membrane is obtained by the following equation (4).
(Ratio of the abundance of the hydrophilic polymer on the inner surface of the hollow fiber membrane to the content of the hydrophilic polymer in the entire hollow fiber membrane) = (Abundance of the hydrophilic polymer on the inner surface of the hollow fiber membrane) / (Content of hydrophilic polymer in the entire hollow fiber membrane) (4)

  When the ratio of the hydrophilic polymer content in the inner surface of the hollow fiber membrane to the hydrophilic polymer content in the entire hollow fiber membrane is less than 8.0, the hydrophilicity of the inner surface of the membrane Since there are few polymers, there is a tendency for leak misjudgment to increase, or there is too much hydrophilic polymer in the membrane and the hollow fiber membranes tend to stick together. In addition, the permeability of solute from blood may be lowered. On the other hand, if it is larger than 50, there are too many hydrophilic polymers on the inner surface of the membrane and the amount of hydrophilic polymer eluate increases, or there are few hydrophilic polymers contained in the entire membrane, causing protein adsorption and clogging. It tends to occur easily. The internal surface of the hollow fiber membrane with respect to the hydrophilic polymer content in the entire hollow fiber membrane, due to the balance of the leak determination accuracy, the low adhesion between the hollow fiber membranes, and the permeability of the solute from blood The ratio of the abundance ratio of the hydrophilic polymer in is more preferably 8.5 or more and 45 or less, and further preferably 10 or more and 40 or less.

<Method for producing hollow fiber membrane>
Next, the manufacturing method of the hollow fiber membrane which concerns on suitable embodiment is demonstrated. The hollow fiber membrane according to the present embodiment undergoes a process (spinning process) in which the internal coagulation liquid is simultaneously discharged from the inner flow path of the double annular nozzle and the spinning raw solution is simultaneously discharged from the outer flow path of the double annular nozzle. Can be manufactured. In this step, a spinning solution containing a polysulfone resin and a hydrophilic polymer having a molecular weight of 300,000 or more is used, and a hydrophilic polymer having a molecular weight of 300,000 or more is 0.1 to 10 mass as an internal coagulation liquid. % Containing.

  More specifically, as shown in the flowchart of FIG. 1, the hollow fiber membrane (hollow fiber membrane bundle) includes a spinning dope preparation process, an internal coagulation liquid preparation process, a spinning process, a coagulation process, a water washing process, a drying process, a winding process, and the like. It can be manufactured by a method having a taking process and a bundle forming / cutting process.

  Hereinafter, each process will be described in detail with reference to FIG.

(Spinning stock solution preparation process)
A polysulfone resin and a hydrophilic polymer are dissolved in a solvent to prepare a spinning dope 31. The hydrophilic polymer has a molecular weight of 300,000 or more, preferably 450,000 or more, more preferably 800,000 or more. Among the hydrophilic polymers, it is particularly preferable to use polyvinyl pyrrolidone. Examples of the solvent include dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) and the like.

  The content of the hydrophilic polymer in the spinning dope 31 is preferably 1 to 10% by mass and more preferably 2 to 6% by mass with respect to the total mass of the polysulfone resin and the hydrophilic polymer. If it carries out like this, it exists in the tendency which becomes easy to obtain the hollow fiber membrane which has favorable biocompatibility.

(Internal coagulation liquid preparation process)
A hydrophilic polymer is mixed with a solvent to prepare the internal coagulation liquid 32. As the solvent, the same solvent as used for the spinning dope can be used, and DMAc is preferable. The hydrophilic polymer has a molecular weight of 300,000 or more, preferably 450,000 or more, more preferably 800,000 or more. Among the hydrophilic polymers, it is particularly preferable to use polyvinyl pyrrolidone.

  The content of the hydrophilic polymer in the internal coagulation liquid is 0.01% by mass to 10% by mass, preferably 0.01% by mass to 5.0% by mass, and 0.05% by mass to 2.% by mass. More preferably, it is 0 mass%, and it is further more preferable that it is 0.1 mass%-1.0 mass%.

  By setting the content of the hydrophilic polymer in the internal coagulation liquid in such a range, the content of the hydrophilic polymer in the entire hollow fiber membrane as described above is 2% by mass or more and 10% by mass or less. In the inner surface of the hollow fiber membrane, the abundance ratio of the hydrophilic polymer on the inner surface of the hollow fiber membrane is 40% by mass or more and 100% by mass or less, and the content of the hydrophilic polymer in the entire hollow fiber membrane is It becomes easy to obtain a hollow fiber membrane that satisfies the specific condition that the ratio of the abundance ratio of the hydrophilic polymer is 8.0 or more and 50 or less.

  Conventionally, the condition of the content ratio of the hydrophilic polymer in the hollow fiber membrane tends to be difficult to adjust unless the conditions of each step in spinning are set very strictly. However, as a result of the study by the present inventors, surprisingly, by using a liquid containing the above-mentioned specific amount of hydrophilic polymer as the internal coagulation liquid, other spinning conditions are not controlled so strictly. It has also been found that a hollow fiber membrane that satisfies the specific conditions as described above can be obtained.

  The internal coagulation liquid is removed by washing in the manufacturing process of the hollow fiber membrane in order to form a hollow structure inside the hollow fiber membrane, but the hydrophilic polymer is very likely to flow out by washing. . Therefore, conventionally, it has been considered that components in the internal coagulation liquid have no influence on the hollow fiber membrane. However, as a result of the study by the present inventors, it is possible to adjust the content ratio of the hydrophilic polymer in the hollow fiber membrane by including the hydrophilic polymer in the internal coagulation liquid under the specific conditions described above. It has been found. This is considered to be due to factors such as the diffusion of an appropriate amount of hydrophilic polymer from the internal coagulation liquid to the spinning dope, but the action is not limited thereto.

  Here, conventionally, from the viewpoint that the hydrophilic polymer was likely to flow out by washing, normally, the hydrophilic polymer added to the internal coagulating liquid is a low diffusion rate having a high diffusion rate toward the spinning dope. The molecular weight is considered good. The reason for this is that if the hydrophilic polymer in the internal coagulating liquid immediately diffuses to the spinning dope immediately after ejection from the nozzle, the diffusion of the hydrophilic polymer from the internal coagulating liquid to the spinning dope and the spinning dope Can be coagulated in a state where sufficient concentration equilibrium is formed with the diffusion of the hydrophilic polymer from the inside to the internal coagulation liquid, and as a result, the hydrophilic polymer adheres well to the inner surface of the hollow fiber membrane. Because it can.

  However, as a result of the study by the present inventors, the hydrophilic polymer is not a low molecular weight expected as described above, but conversely, when a polymer having a high molecular weight of 300,000 or more is used. It has been found that a hollow fiber membrane satisfying the above-described content ratio of the specific hydrophilic polymer can be obtained. The reason for this is not necessarily clear, but hydrophilic polymers having such a large molecular weight can remain in the boundary portion with the spinning dope, and as a result, hydrophilic polymers are formed on the inner surface of the hollow fiber membrane. It is estimated that this is because an intertwined state is formed at a high retention rate.

  In addition, by setting the content of the hydrophilic polymer in the internal coagulation liquid to a small amount as described above (particularly around 1% by mass), the hollow satisfies the condition for the content ratio of the specific hydrophilic polymer described above. It is also surprising that a yarn membrane is easily obtained. In order to retain the hydrophilic polymer inside the hollow fiber membrane, it is considered that a large amount of hydrophilic polymer is usually contained in the internal coagulation liquid. On the other hand, the reason why it is preferable that the content of the hydrophilic polymer in the internal coagulation liquid is small as in the present embodiment is not necessarily clear, but by making the hydrophilic polymer a small amount, It is considered that the hydrophilic polymer does not take a lump structure on the inner surface of the thread membrane and is uniformly diffused over the entire membrane surface.

(Spinning process)
The spinning solution is discharged from the outer tube (outer channel) of the annular slit base 33 (double annular nozzle) having a double tube structure, and at the same time, the inner coagulation solution is discharged from the inner tube (inner channel). Spin. For example, the extruded spinning solution is allowed to travel a distance of 5 cm to 1 m in the air. The extruded spinning solution is preferably sufficiently solidified before being immersed in a coagulation bath 34 described later. In order to obtain a hollow fiber membrane having a desired film thickness and inner diameter, the discharge amounts of the spinning stock solution 31 and the internal coagulation solution 32 may be appropriately adjusted.

(Coagulation process)
The spinning dope extruded from the annular slit base 33 is then immersed in the coagulation bath 34. From the viewpoint of coagulating the extruded spinning solution more sufficiently and elution of the internal coagulating solution, water at 40 to 70 ° C. may be used for the coagulation bath. The immersion speed of the extruded spinning solution is preferably 10 to 100 m / min.

(Washing, drying, winding process)
The hollow fiber membrane 30 that has been immersed in the coagulation bath is washed in a washing bath 35 as necessary, and then dried in a dryer 36 whose internal temperature is set to 100 to 150 ° C. Winding is performed by a roller 37. The hollow structure of the hollow fiber membrane is formed by elution of only the internal coagulation liquid with water or the like in the coagulation step or the water washing step. The hollow fiber membrane 30 thus obtained may be further washed with warm water or the like in order to remove the unwashed residual solvent, and may be dried by attaching a pore diameter retaining agent such as glycerin as necessary.

(Bundling, cutting process)
After the winding process, the obtained bundle of hollow fiber membranes is cut. Thus, the hollow fiber membrane bundle 40 which consists of a some hollow fiber membrane can be manufactured.

  Since the hollow fiber membrane according to the present embodiment is less likely to stick between the hollow fiber membranes, the hollow fiber membranes produced particularly when the hollow fiber membrane bundle 40 composed of a plurality of hollow fiber membranes is bundled and cut. Unevenness of the hollow fiber membranes due to fixation can be reduced. Thereby, discard of a hollow fiber membrane bundle decreases and productivity improves. Further, since the hollow fiber membrane according to the present embodiment has a high level of membrane performance such as permeation selectivity and biocompatibility of substances, it is expected to make a high contribution to the medical field as a hollow fiber membrane for blood treatment. it can.

<Hollow fiber membrane blood treatment device>
Subsequently, a preferred embodiment of a hollow fiber type blood treatment device including a hollow fiber membrane (hollow fiber membrane bundle) obtained by the above-described production method will be described.

  The hollow fiber type blood treatment device of this embodiment includes a container, a hollow fiber membrane bundle composed of a plurality of hollow fiber membranes inserted into the container, and both ends of the hollow fiber membrane bundle at both ends of the container. A partition wall that is liquid-tightly fixed, a treatment liquid inlet and a treatment liquid outlet that communicate with the space in the container, and a blood inlet and a blood stream that are attached to both ends of the container and communicate with the space inside the hollow fiber membrane, respectively. The hollow fiber membrane includes the above-described embodiment.

  FIG. 3 is a schematic cross-sectional view of a hollow fiber membrane blood treatment device according to the present embodiment. The hollow fiber membrane blood processor 10 is loaded with a hollow fiber membrane bundle made of a plurality of hollow fiber membranes 1 along the longitudinal direction of the cylindrical container 2. The hollow fiber membrane bundle has resin 3a and 3b (partition walls) at both ends so as to isolate the inner side (first flow path 1a) and the outer side (second flow path 11) of the hollow fiber membrane 1. Is fixed to both ends of the cylindrical container 2. The second flow path 11 includes a space between the plurality of hollow fiber membranes 1 as well as a space formed between the outside of the hollow fiber membrane 1 and the inner surface of the cylindrical container 2.

  The end surface of the hollow fiber membrane 1 is open, and the liquid to be treated such as blood can flow into the first flow path 1a through the space 8 from the direction of the arrow Fb through this opening. Then, the liquid to be processed such as blood that has passed through the first flow path 1a can flow out from the other opening. At both ends of the cylindrical container 2, nozzles 6 a and 6 b that serve as inflows and outflows of the liquid to be processed such as blood, facing the end surfaces of the resins 3 a and 3 b having the openings of the hollow fiber membrane 1 on the surface. Header caps 7a and 7b provided with are provided.

  Ports 2 a and 2 b that serve as inflow and outflow of a treatment liquid such as a dialysis liquid are provided on side surfaces of both ends of the cylindrical container 2. When a treatment liquid such as dialysate flows in from the direction of the arrow Fa from the port 2b, for example, it can pass through the inside of the second flow path 11 and flow out from the port 2a. A treatment liquid such as dialysate passes from the liquid to be treated such as blood flowing in the first flow path 1a through the hollow fiber membrane 1 while passing through the second flow path 11, for example, waste products. Can be removed.

  The hollow fiber membrane blood treatment device according to the present embodiment includes, for example, a hemodialyzer, a hemodialysis filter, a hemofiltration device, a continuous hemodiafiltration device, a continuous hemofiltration device, a plasma separator, and a plasma component component. For example, a medical device that uses the filtration characteristics of a hollow fiber membrane, such as a separator, a plasma component adsorber, a virus remover, a blood concentrator, a plasma concentrator, an ascites filter, and an ascites concentrator. Included in blood processor.

  Note that the target of the leak test method to be described later includes both a hollow fiber membrane blood processor in a dry state or a semi-dry state. The hollow fiber membrane of the present embodiment is particularly suitable for use in these dry products because it is difficult for erroneous determination in the leak test method to occur.

<Method for producing hollow fiber membrane blood treatment device>
Next, an example of the manufacturing method of the hollow fiber blood processing device having the above configuration will be described.

  After the formed hollow fiber membrane 1 is bundled every several thousand to several tens of thousands, it is loaded into a plastic cylindrical container 2 designed to have an effective membrane area of a predetermined hollow fiber membrane, The both ends are bonded and fixed with urethane resin or the like (resins 3a and 3b), and then both end surfaces are cut to form the open ends of the hollow fiber membranes. Subsequently, distilled water as a coating solution is injected from the opening end into the first flow path 1a in the hollow fiber membrane 1 at a predetermined speed, and flushed (blowed off) with air, and then the header caps at both ends. 7a, 7b can be attached, and the hollow fiber membrane type blood processing device 10 can be manufactured.

  Then, after a leak test is performed on the obtained hollow fiber membrane blood processing device 10, the blood processing device 10 is housed in an impermeable packaging container together with an oxygen scavenger, and is allowed to stand for a certain time. After the inside of the impermeable packaging container becomes oxygen-free, the blood processing device contained in the packaging container is sterilized by irradiation with radiation. As the radiation to be irradiated, γ rays of about 20 to 50 Gy can be used.

  In this way, by irradiating the hollow fiber membrane-type blood treatment device 10 with radiation, “the mass of the hydrophilic polymer soluble in water out of the total mass of the hydrophilic polymer contained in the hollow fiber membrane” The “ratio” can be set to 1% by mass or more and 10% by mass or less. This is considered to be because the hydrophilic polymer becomes a half-crosslinked state with respect to the polysulfone resin by irradiation with radiation. The half-crosslinked state is considered to be a state in which only one end of the hydrophilic polymer is bonded to the polysulfone resin.

  Here, the ratio of the mass of the hydrophilic polymer soluble in water in the total mass of the hydrophilic polymer contained in the hollow fiber membrane can be measured by the following method. Distilled water for injection is allowed to flow through the first flow path 1a of the hollow fiber membrane 1 of the hollow fiber membrane-type blood treatment device 10 at a predetermined flow rate, and then the nozzle 6b is closed to hollow the distilled water for injection at the same flow rate. It is made to flow through the second flow path 11 of the thread membrane 1 and subjected to ultrafiltration to be washed, and thereafter, distilled water for injection in the hollow fiber membrane blood processor 10 (module) is discharged under pressure. Next, the heated distilled water for injection is circulated through the first flow path 1a of the hollow fiber membrane 1 at a predetermined flow rate for a predetermined time, and after the circulation, all of the distilled water for injection in the module is recovered. Is the extract. The concentration of the hydrophilic polymer in the extract can be determined by liquid chromatography. The absolute amount of the hydrophilic polymer was calculated from the concentration of the hydrophilic polymer, and the value obtained by dividing by the mass of the hydrophilic polymer contained in the membrane was taken as the content of the hydrophilic polymer soluble in water.

  In the hollow fiber membrane 1 according to this embodiment, the ratio of the hydrophilic polymer soluble in water to the total mass of the hydrophilic polymer contained in the hollow fiber membrane is remarkably reduced. The amount is significantly suppressed. Therefore, for example, it is possible to provide a high blood treatment device that can exhibit extremely stable performance with very little hydrophilic polymer falling off from the hollow fiber membrane during dialysis treatment.

<Performance test of hollow fiber membrane blood treatment device>
As described above, the hollow fiber type blood treatment device cannot be used satisfactorily when it is determined that there is a pinhole in the leak test or the hollow fiber membranes are stuck to each other. During the manufacture of the vessel, it is necessary to evaluate whether or not these inconveniences have occurred by extracting several samples. Hereinafter, these evaluation methods will be described.

[Leak test method for hollow fiber membrane blood processor]
The leak test method applicable to the hollow fiber membrane blood treatment device of the present embodiment includes a step of coating a hollow fiber membrane with a liquid harmless to a living body represented by water, for example, and a gas permeation of the hollow fiber membrane after coating. And a leak test process for measuring performance.

(Process to coat the hollow fiber membrane)
The liquid that coats the hollow fiber membrane is preferably a hydrophilic liquid (coating liquid) that is harmless to the living body, such as water and ethanol. These liquids are removed by drying the hollow fiber membrane after the leak test, but even if they remain to some extent, they can be easily removed by washing the hollow fiber membrane with a physiological saline solution or the like before use.

  As a method for coating the above-mentioned coating solution on the hollow fiber membrane or a dense layer formed in the vicinity of the inner surface of the hollow fiber membrane, for example, the coating solution is applied to the inside of the hollow fiber membrane 1 (first flow). A method of passing the liquid through the path 1a) can be employed. By this method, the coating solution contacts at least the inner surface of the hollow fiber membrane. Excess solution can be removed by flushing (blowing away) with gas or the like, or removing liquid by applying centrifugal force. By impregnating the above-mentioned coating solution into the hollow fiber membrane by such a method, the gas permeability of the hollow fiber membrane can be greatly reduced, and it is easy to determine the presence or absence of pinholes in the leak test process described later It becomes.

(Leak test process for measuring gas permeability)
As described above, a leak test is performed after coating the coating solution on the hollow fiber membrane or the dense layer formed on the inner surface of the hollow fiber membrane and in the vicinity of the inner surface. In the leak test, the presence or absence of pinholes in the hollow fiber membrane is determined. For example, a method of applying a gas pressure to the hollow fiber membrane, measuring the velocity of the gas passing through the hollow fiber membrane, and determining the presence or absence of a pinhole based on the measured velocity can be exemplified. More specifically, after applying a certain air pressure to the inside of the hollow fiber membrane 1 (first flow path 1a), the pressurization is stopped and the opening is closed, and the pressure drop inside the hollow fiber membrane 1 is measured. And check for pinholes. When the pressure drop exceeds a normal level, it can be determined that a pinhole exists and a leak has occurred.

  However, when the gas permeability of the hollow fiber membrane is high, even if the above-mentioned coating is performed, the inner surface of the hollow fiber membrane is not sufficiently coated, resulting in a pressure drop, which causes a leak error. Judgment is triggered. Therefore, conventionally, it has been difficult to perform an accurate leak test on a hollow fiber membrane having a high gas permeability. In contrast, in the hollow fiber membrane obtained by the manufacturing method of the above-described embodiment, first, the hydrophilic polymer abundance ratio on the inner surface of the membrane is 40% by mass or more and 100% by mass or less. The surface is easily wetted by the coating solution, whereby the gas permeability of the hollow fiber membrane can be easily reduced. As a result, it is possible to reduce leak misjudgment.

  On the other hand, even if only the abundance of the hydrophilic polymer on the inner surface of the hollow fiber membrane is defined, it is difficult to sufficiently stabilize the result of the leak test. The cause is not necessarily clear, but it is estimated that there is a difference in the shrinkage rate of the hollow fiber membrane due to the bias in the proportion of hydrophilic polymer in the whole hollow fiber membrane, and that the structure of the membrane surface has changed. Is done.

  In contrast, the hollow fiber membrane obtained by the manufacturing method of the above-described embodiment has a hydrophilic polymer content of 2% by mass or more and 10% by mass or less in the entire hollow fiber membrane, and is further hydrophilic in the entire hollow fiber membrane. Since the ratio of the abundance of the hydrophilic polymer on the inner surface of the hollow fiber membrane to the content of the conducting polymer is 8.0 or more and 50 or less, the result of the leak test becomes extremely stable. In other words, the hollow fiber membrane obtained by the production method of the above embodiment, in addition to the conditions for the abundance of the hydrophilic polymer on the inner surface thereof, satisfying a combination of these conditions, there are fewer leak misjudgments, Results with good reproducibility can be obtained.

  Thus, the content rate of the hydrophilic polymer in the whole hollow fiber membrane is 2% by mass or more and 10% by mass or less, and the hydrophilic polymer existing rate on the inner surface of the membrane is 40% by mass or more and 100% by mass or less. In the hollow fiber membrane in which the ratio of the hydrophilic polymer content on the inner surface of the hollow fiber membrane to the content of the hydrophilic polymer in the entire hollow fiber membrane is 8.0 or more and 50 or less, as described above The reason why the effect is obtained is estimated as follows. That is, when these conditions are satisfied, the surface state inside the hollow fiber membrane (or the dense layer of the hollow fiber membrane) (specifically, the presence of the polysulfone resin and the hydrophilic polymer, the unevenness of the pore diameter and the thickness) This is presumably because spots are easily masked by the coating solution.

  Note that the degree of occurrence of erroneous leak determination can be evaluated by the occurrence rate of leak erroneous determination (leak erroneous detection rate), and the leak erroneous detection rate can be calculated by, for example, the following method. That is, the leak test method described above is performed on a plurality of hollow fiber membrane blood processors, and the number of pinholes determined to have a pinhole is calculated. Thereafter, the leak test method described above is performed again for those determined to have pinholes. In this case, when it is determined that there is a pinhole for the first time, but it is determined that there is no pinhole for the second time, a leak error determination is made. Therefore, the ratio of the number of samples that caused a leak misjudgment to the number of samples determined to have pinholes for the first time is the leak misdetection rate, and a larger value means that a leak misjudgment is more likely to occur. To do. Instead of the second leak test, immerse the one that was determined to have pinholes in the first time, enclose air in the hollow fiber membrane blood treatment device, and generate bubbles from the hollow fiber membrane. The presence or absence of a pinhole may be confirmed by confirming the presence or absence.

[Method for measuring the number of sticking of the hollow fiber membrane blood treatment device]
The measurement of the number of hollow fiber membranes fixed in the hollow fiber membrane blood processor 10 is, for example, by separating a bundle of hollow fiber membranes made of about 10,000 hollow fiber membranes 1 and visually counting the adhered hollow fiber membranes. Can be performed. For example, when two hollow fiber membranes are fixed to each other, the number of fixings is counted as two, and when three hollow fiber membranes are fixed to each other, the number of fixings is counted as three. Moreover, when the sticking of the hollow fiber membranes is observed at a plurality of locations, after counting the number of the stuck hollow fiber membranes, the total number is taken as the sticking number.

  The cause of sticking is thought to be due to the high proportion of hydrophilic high split yarn present on the outer surface of the hollow fiber membrane, so that the proportion of hydrophilic polymer present on the outer surface is small. Is preferred. However, conventionally, it is difficult to adjust only the ratio of the hydrophilic polymer on the outer surface of the membrane, and the outer surface of the hollow fiber membrane is not in contact with blood, so that biocompatibility is not directly affected. Therefore, strictly controlling only the abundance ratio of the hydrophilic polymer on the outer surface is not very desirable from the viewpoint of avoiding an excessive load in the manufacturing process.

  On the other hand, as a result of intensive studies by the present inventors, according to the production method of the embodiment described above, the content of the hydrophilic polymer in the entire hollow fiber membrane is 2% by mass or more and 10% by mass or less, and the membrane The presence of the hydrophilic polymer on the inner surface of the hollow fiber membrane with respect to the content of the hydrophilic polymer in the whole hollow fiber membrane, wherein the abundance of the hydrophilic polymer on the inner surface of the fiber is 40% by weight or more and 100% by mass or less A hollow fiber membrane that satisfies the condition that the ratio of the ratios is 8.0 or more and 50 or less is obtained, and according to such a hollow fiber membrane, only the ratio of the hydrophilic polymer on the outer surface of the membrane is selectively controlled. Even without this, it has been found that the sticking of the hollow fiber membranes is remarkably suppressed, and further, the hollow fiber membrane bundle can be stably stored in the module.

  The reason why the hollow fiber membranes are prevented from adhering to each other in the hollow fiber membrane satisfying the condition of the existence ratio of the specific hydrophilic polymer as described above is not necessarily clear, but the outer surface structure of the hollow fiber membrane satisfying this condition Has a stable surface structure, and it is presumed that the hydrophilic polymer existing on the outer surface of the membrane is difficult to adhere to the adjacent outer surface of the hollow fiber membrane.

  As mentioned above, the manufacturing method of the hollow fiber membrane for blood processing which concerns on this invention, the hollow fiber membrane obtained by this, the hollow fiber membrane type | mold blood processing apparatus provided with it, and suitable embodiment of the manufacturing method in detail are described in detail. Although described, the present invention is not limited to the above-described embodiment.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example.

Example 1
<Production of hollow fiber membrane>
[Spinning stock solution preparation process]
17 parts by mass of a polysulfone-based resin represented by the above formula (1) (hereinafter sometimes referred to as “PSF”: Solvay Advanced Polymers, trade name: P-1700), and polyvinylpyrrolidone (hereinafter referred to as “PSF”) , “PVP”: BASF, trade name: LUVITEC K-85, molecular weight 1,100,000) 4 parts by mass of dimethylacetamide (hereinafter sometimes referred to as “DMAc”) A uniform spinning stock solution was prepared by dissolving in 79 parts by mass.

[Internal coagulation liquid preparation process]
0.01% by mass of PVP (manufactured by BASF, trade name: LUVITEC K-85, molecular weight 1,100,000) as a hydrophilic polymer was added to a 42% DMAc aqueous solution to prepare an internal coagulation liquid.

[Spinning process]
The spinning stock solution maintained at 40 ° C. was flowed from the outer flow path of the annular slit base, and simultaneously the internal coagulation liquid was flowed from the inner flow path, whereby the spinning raw solution and the internal coagulation liquid were discharged from the annular slit base. At this time, the discharge amounts of the above spinning raw solution and internal coagulating liquid were adjusted so that the thickness of the hollow fiber membrane after the drying step was 35 μm and the inner diameter was 185 μm.

[Coagulation, washing, drying, winding process]
The discharged spinning dope is immersed in a coagulation bath made of water at 60 ° C. provided approximately 50 cm below the nozzle, passed through the coagulation bath at a speed of 30 m / min, then washed with water, introduced into a drier, 160 Dry at 0C. Thereafter, crimping was applied and the hollow fiber membrane was wound up.

[Bundling and cutting process]
A bundle of 10,000 hollow fiber membranes wound up was cut at an interval of about 30 cm to produce a hollow fiber membrane bundle.

(Example 2)
A hollow fiber membrane was formed in the same manner as in Example 1 except that the concentration of PVP in the internal coagulation liquid was 0.1% by mass.

(Example 3)
A hollow fiber membrane was formed in the same manner as in Example 1 except that the PVP concentration in the internal coagulation liquid was changed to 0.5% by mass.

Example 4
A hollow fiber membrane was formed in the same manner as in Example 1 except that the concentration of PVP in the internal coagulation liquid was 1.0% by mass.

(Example 5)
As a hydrophilic polymer to be added to the spinning dope and the internal coagulating liquid, PVP having a molecular weight of 450,000 (manufactured by BASF, trade name: LUVITEC K60) was used, and the PVP concentration in the internal coagulating liquid was set to 10% by mass. Except for the above, a hollow fiber membrane was prepared in the same manner as in Example 1.

(Comparative Example 1)
A hollow fiber membrane was formed in the same manner as in Example 1 except that PVP was not contained in the internal coagulation liquid.

(Comparative Example 2)
A hollow fiber membrane was formed in the same manner as in Example 1 except that the concentration of PVP in the internal coagulation liquid was 15% by mass.

(Comparative Example 3)
As a hydrophilic polymer to be added to the spinning dope and the internal coagulation liquid, PVP having a molecular weight of 50,000 (manufactured by BASF, trade name: LUVITEC K30) is used, and the PVP concentration in the internal coagulation liquid is 0.5 mass% A hollow fiber membrane was prepared in the same manner as in Example 1 except that it was changed.

(Comparative Example 4)
As a hydrophilic polymer to be added to the spinning dope, PVP having a molecular weight of 450,000 (manufactured by BASF, trade name: LUVITEC K60) was used, and as a hydrophilic polymer to be added to the internal coagulation liquid, PVP having a molecular weight of 50,000 ( A hollow fiber membrane was prepared in the same manner as in Example 1 except that BASF, trade name: K30) was used, and the PVP concentration in the internal coagulation liquid was changed to 0.5% by mass.

(Comparative Example 5)
As a hydrophilic polymer to be added to the spinning dope, PVP having a molecular weight of 50,000 (manufactured by BASF, trade name: LUVITEC K60) is used, and as a hydrophilic polymer to be added to the internal coagulating liquid, PVP having a molecular weight of 50,000 ( A hollow fiber membrane was prepared in the same manner as in Example 1 except that BASF Corporation, trade name: LUVITEC K30) was used, and the PVP concentration in the internal coagulation liquid was changed to 11% by mass.

<Production and evaluation of hollow fiber membrane blood treatment device>
A bundle of hollow fiber membranes each having 10,000 hollow fiber membranes produced in Examples 1 to 5 and Comparative Examples 1 to 5 is designed so that the effective membrane area of the hollow fiber membrane is 1.5 m ^2. The plastic cylindrical container was loaded, both ends thereof were bonded and fixed with urethane resin, and both ends were cut to form the open ends of the hollow fiber membranes.

From one of the open ends, 60 mL of distilled water as a coating solution is injected into the hollow fiber membrane at a speed of 5 mm / s, flushed with 0.3 MPa air for 10 seconds, and then blood inlets are provided at both ends. A header cap having a (nozzle) and an outlet (nozzle) was attached to provide hollow fiber membrane blood treatment devices of Examples 1 to 5 and Comparative Examples 1 to 5 having the structure shown in FIG. The obtained hollow fiber membrane blood treatment device was evaluated as follows. The obtained results are shown in Tables 1 and 2.
[Leak test]
In the leak test, first, using a Cosmo leak tester (manufactured by Cosmo Keiki Co., Ltd., product name: COSMO AIR LEAK TESTER LS-1842), with the outlet closed, gas was sealed from the inlet on the opposite side. A pressure of 250 kPa was applied to the inside of the hollow fiber membrane. After 2.5 seconds, the inlet was closed, and the pressure fluctuation (drop) inside the hollow fiber membrane was measured for 3.5 seconds thereafter. The measurement environment temperature was 25 ° C. In this determination, a criterion for determining that there is no pinhole in the hollow fiber membrane if the pressure drop is less than 580 Pa and that there is a pinhole if the pressure drop is 580 Pa or more is used. This criterion is an experimental value obtained while confirming whether hemoglobin in the blood leaks or does not leak in the hollow fiber membranes used in the examples and comparative examples.

[Judgment of false detection of leak]
(1) 100 hollow fiber membrane blood treatment devices 10 were prepared, and a leak test was performed in the same manner as the leak test.
(2) The hollow fiber membrane blood treatment device judged to have a pinhole in (1) was submerged in a water tank containing water, and the hollow fiber membrane blood treatment device was filled with water. One end of the blood inlet was pressed, air was fed from the other end, and it was visually confirmed whether bubbles were generated from the hollow fiber membrane. It was judged that there was a pinhole when the bubble was generated.
(3) The leak detection rate was calculated by the following formula (5).
Leak false detection rate (%) = 100 × {(number of pinholes determined in (1)) − (number of pinholes determined in (2))} / (pinhole in (1) Number determined to be ...) (5)
In addition, the level of leak detection error was judged according to the following criteria.
(A) Low leak detection rate: The leak detection rate is 1% or less.
(B) High leak detection rate: The leak detection rate is higher than 1%.

[Evaluation of adhesion of hollow fiber membrane]
The hollow fiber membrane bundle which consists of 10000 hollow fiber membranes in each hollow fiber membrane type blood treatment device obtained in Examples 1 to 5 and Comparative Examples 1 to 5 is separated, and the number of hollow fiber membranes adhered is visually observed. I counted. At this time, for example, when two hollow fiber membranes were fixed to each other, the number of fixed members was two, and when three hollow fiber membranes were fixed to each other, the number of fixed members was three. Moreover, when the sticking of the hollow fiber membranes was observed at a plurality of locations, after counting the number of the stuck hollow fiber membranes, the total number was taken as the sticking number. The case where the number of fixings was less than 10 was determined as “low fixing property”, and the case where the number was 10 or more was determined as “high fixing property”.

  As shown in Tables 1 and 2, the hollow fiber membrane blood treatment devices obtained in Examples 1 to 5 are less likely to cause erroneous leak determination than Comparative Examples 1 to 5, and the hollow fiber membranes are It was proved that the sticking of the film hardly occurs.

  As is clear from the above results, according to the method for producing a hollow fiber membrane for blood treatment of the present invention, it is possible to obtain a hollow fiber membrane and a hollow fiber membrane type blood treatment device in which leak misjudgment is unlikely to occur. Efficiency can be ensured. In addition, since the sticking of the hollow fiber membranes is suppressed, the hollow fiber membranes are stuck to each other and unevenness of the hollow fiber membrane bundle does not occur, thereby ensuring high production efficiency.

DESCRIPTION OF SYMBOLS 1, 30 ... Hollow fiber membrane, 1a ... 1st flow path, 2 ... Cylindrical container, 2a, 2b ... Port, 3a, 3b ... Sealing resin, 6a, 6b ... Nozzle, 7a, 7b ... Header cap, 10 DESCRIPTION OF SYMBOLS ... Hollow fiber membrane type | mold blood processing device, 11 ... 2nd flow path, Fa ... Flow direction of process liquid (blood), Fb ... Flow direction of to-be-processed liquid (blood), 31 ... Spinning undiluted solution, 32 ... Internal coagulation liquid 33 ... Annular slit cap, 34 ... Coagulation bath, 35 ... Washing bath, 36 ... Dryer, 37 ... Winding roll, 40 ... Hollow fiber membrane bundle.

Claims (4)

A method for producing a hollow fiber membrane for blood treatment,
The hollow fiber membrane contains a polysulfone resin and a hydrophilic polymer,
Using a spinning dope containing the polysulfone-based resin and the hydrophilic polymer having a molecular weight of 300,000 or more, and an internal coagulation liquid containing 0.1 to 10% by mass of the hydrophilic polymer having a molecular weight of 300,000 or more,
The method comprising the step of spinning the inner coagulation liquid from the inner flow path of the double annular nozzle and the spinning solution from the outer flow path of the double annular nozzle.   The method according to claim 1, wherein the hydrophilic polymer is polyvinylpyrrolidone.   The method according to claim 1 or 2, wherein a content of the hydrophilic polymer in the internal coagulation liquid is 0.1 to 1.0% by mass. The method according to any one of claims 1 to 3, wherein the molecular weight of the hydrophilic polymer contained in the spinning dope and the internal coagulation solution is 300,000 or more and 1,500,000 or less. .

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