JP2019018193A - Antiinflammatory hollow fiber membrane and manufacturing method for the same - Google Patents

Abstract

To suppress the production of an inflammatory reaction substance due to complement activity by dispersing an acrylic copolymer consisting of specific hydrophobic and hydrophilic side chain structures into the membrane.SOLUTION: This invention, which is a hollow fiber membrane containing a water insoluble (meth)acrylate copolymer consisting of polyaryl sulfonic polymer, polyvinyl pyrrolidone and alkyl (meth)acrylate and methoxy polyethylene glycol (meth)acrylate, is a hollow fiber membrane the percentage content of the (meth)acrylate copolymer being 0.5-5 mass% when the hollow fiber membrane is measured by using nuclear magnetic resonance spectroscopy, and the percentage content of the (meth)acrylate copolymer being 5-30 mass % when the inner face of the hollow fiber membrane is measured by using the X-ray photoelectron spectroscopy.SELECTED DRAWING: None

Description

  The present invention relates to a hollow fiber membrane and a hollow fiber membrane module having a membrane surface with improved biocompatibility, and methods for producing them.

  In hemodialysis, which is a maintenance therapy for patients with chronic renal failure, a hollow fiber membrane type blood purification device is widely used. In addition, examples of treatments such as continuous hemofiltration, continuous hemofiltration dialysis, and continuous hemodialysis are increasing as acute blood purification therapy for patients with serious pathological conditions such as acute renal failure and sepsis.

  In the blood purification treatment described above, when blood comes into contact with trace contaminants mixed in the membrane surface or dialysate such as endotoxin, the platelet system, coagulation system and complement system are activated, and various thrombotic reactions, inflammatory reactions and It is known that allergies and immune reactions are induced. In particular, chronic microinflammation and the accompanying accumulation of oxidative stress have occurred in the body of patients undergoing hemodialysis continuously for a long period of time. Inflammatory reactions and cardiovascular disorders in blood purification treatment In recent years, a lot of relations with risk have been pointed out.

  Against this background, there is an increasing demand for a hollow fiber membrane having a surface composition and a surface structure that are more biocompatible and capable of suppressing an inflammatory reaction.

  Generally, an organic polymer is used as a material for a hollow fiber membrane for blood purification. As a hollow fiber membrane material, a polyarylsulfone (PAS) polymer (specifically, polysulfone) is used from the viewpoint of having a high mechanical strength and chemical stability and easily obtaining a porous structure suitable for removing unnecessary substances in blood. , Polyphenylsulfone, and polyethersulfone) are widely used.

  Since the PAS polymer itself is a highly hydrophobic material, a thrombus formation reaction due to adsorption and activation of platelets on the material surface is likely to occur, and a phenomenon called residual blood tends to occur in the membrane. In addition, there is a drawback that membrane performance is likely to be lowered due to membrane pores being blocked by protein adsorption.

  Therefore, it cannot be said that the hollow fiber membrane itself made of a single PAS polymer is excellent for blood purification. Normally, when manufacturing a hollow fiber membrane using a PAS polymer, polyvinyl pyrrolidone (PVP), which is a water-soluble polymer known to form a compatible alloy with the PAS polymer, is blended in advance with the spinning dope. A method is adopted in which a compatible alloy film of a PAS polymer and PVP is prepared to impart hydrophilicity to the film surface and suppress protein adsorption.

  Such a PVP alloyed PAS polymer film is highly hydrophilic, and therefore, it is known that the adsorption of platelets is slight compared with a film of a PAS polymer alone. Furthermore, since the PVP-alloyed PAS polymer membrane has moderate wettability, water can be added to the dry membrane module that has been subjected to gamma ray sterilization without wet treatment of the hollow fiber membrane with a low surface tension solvent such as alcohol. Since the film spontaneously becomes wet, it can be used as it is for blood treatment, which is advantageous from the viewpoint of storage stability of the module and medical hygiene.

(1. Problems of PVP alloyed PAS polymer film)
However, the PVP alloyed PAS polymer film has at least two important problems from the viewpoint of blood compatibility.

  As a first problem, although PVP forms a compatible alloy with a PAS polymer, it is basically a water-soluble polymer, so that it may be eluted from the membrane surface into the blood in small amounts. . Therefore, it is necessary to highly wash the hollow fiber membrane with hot water and remove excess PVP during the membrane formation process and in the hollow fiber membrane module, but the elution of PVP from the hollow fiber membrane module product after the washing treatment The speed is not necessarily uniform in each product because it is affected by the cleaning know-how of each person skilled in the art and the storage period of the module. Moreover, although it is possible to wash | clean PVP with the solvent which swells a PAS type polymer film like alcohol, when it wash | cleans excessively, hydrophilicity will be lost from a PAS type polymer film.

  The second problem is that PVP is a homopolymer composed of highly polar N-vinylpyrrolidone units and has a high ability to activate the complement system. Activated complement is known to chemotactic macrophages and produce various inflammatory cytokines and radicals. These substances are circulated with the blood into the dialysis patient, causing inflammatory reactions and There is concern about the accumulation of oxidative stress.

  Regarding the ability of N-vinylpyrrolidone to activate complement, for example, there is Non-Patent Document 1, and when blood is passed through a polyethylene tube grafted with N-vinylpyrrolidone, leukocytes associated with complement activity on the tube wall It has been shown that the adsorption time increases and the duration until a thrombus is caused in the tube is shortened. On the other hand, it has been shown that the adsorption of leukocytes is not observed in the tube grafted with 2-hydroxyethyl methacrylate (HEMA), which has a low ability to activate complement.

  From the viewpoint of suppressing complement activation, it is known that a highly polar functional group such as the lactam structure in PVP is not preferable, and a hydrophobic surface is preferable. However, as described above, on the surface of normal hydrophobic polymers such as PAS polymer, polyethylene, silicone and the like, thrombus formation and residual blood phenomenon occur due to platelet adsorption and denaturation.

(2. Issues with other biocompatible polymers)
Thus, in order to reduce the inflammatory reaction and oxidative stress at the contact between blood and the membrane surface, it is considered that not only the platelet system but also a separation membrane surface capable of suppressing the activation of the complement system is necessary. Since there is no choice other than the PVP polymer structure for the hydrophilic polymer that can form a compatible alloy with the PAS polymer in the polymer polymer film, the applicability of other biocompatible polymers is fully It is hard to say that this has been done.

  As promising biocompatible polymers in addition to PVP, acrylic polymers such as polyhydroxyethyl methacrylate (PHEMA) have been developed as biocompatible coating materials for cardiopulmonary bypass and nerve regeneration induction tubes. Among them, as a polymer particularly excellent in suppressing complement activity, Patent Document 1 discloses a water-insoluble (meta-methacrylate) composed of a hydrophobic alkyl (meth) acrylate unit and a hydrophilic methoxypolyethylene glycol (meth) acrylate unit. ) Acrylate copolymers are disclosed.

  The acrylic copolymer is a flexible random copolymer consisting of a chemical structure having a hydrophobic alkyl side chain and a chemical structure of a hydrophilic polyethylene glycol side chain methylated at the end, Compared to homopolymers with a specific single side chain, for proteins and cells in the blood that show different interactions with certain material surfaces, such as the platelet system, complement system, coagulation system described above, It is considered to have a wide range of adsorption / activation suppression capabilities and is suitable as a biocompatible material.

  Patent Document 2 discloses a medical material treatment liquid in which a (meth) acrylate copolymer is dispersed in a mixed liquid composed of an organic solvent and water, and a medical material obtained by applying the treatment liquid to a blood contact surface. Is also disclosed.

  However, a coating solution in which the above (meth) acrylate copolymer is dissolved in an organic solvent such as ethanol is suitable for coating a medical product having a relatively simple structure such as a tube, but based on a precise molecular weight fraction. It has been difficult to apply to hollow fiber membranes that require the ability to adjust blood protein components. Specifically, when the coating method is applied to a hollow fiber membrane, if the polymer concentration of the solution is low, a non-uniform coating film is formed and sufficient biocompatibility cannot be obtained. Becomes relatively uniform, but the coating thickness increases, and the pore size distribution of the hollow fiber membrane changes. As a result, the balance between the water permeability of the membrane and the protein molecular weight cut-off fluctuated, and it was difficult to obtain sufficient performance reproducibility as a blood purification membrane product.

  Furthermore, the above (meth) acrylate copolymer includes an alkyl (meth) acrylate hydrophobic part in the structure based on the design concept of suppressing complement activity and preventing the polymer from eluting into the blood. Therefore, it has a relatively hydrophobic structure that is insoluble in water and insoluble in methanol. Therefore, the dry hollow fiber membrane module coated with the polymer alone has low wettability and does not get wet with water as it is, so it is necessary to perform a wet treatment with a solvent having a low surface tension such as alcohol. However, since the copolymer is easily dissolved in alcohol such as ethanol, there is a problem that the membrane performance cannot be maintained, and the processing steps are increased, thereby increasing the difficulty in ensuring the handling property and medical hygiene.

  Patent Document 3 discloses a hollow fiber membrane in which an acrylic homopolymer having a specific polyethylene glycol side chain is applied to a PVP alloyed PAS polymer membrane by a coating method, and a method for producing the hollow fiber membrane by a coating method Is disclosed.

  However, even in this technique, coating unevenness due to coating of the acrylic homopolymer with an alcohol solvent, reduction in water permeability when the coating liquid concentration is increased, and change in the fractionation characteristics of the hollow fiber membrane Are inherently difficult to avoid. In addition, since the composition of the coating solution changes with time due to the elution of PVP into the coating solution, it is not always easy to obtain the desired hollow fiber membrane economically with good reproducibility. Furthermore, since it is not a copolymer containing a hydrophobic alkyl side chain, it may not be sufficient for the activation of complement and the inhibitory effect of the inflammatory reaction associated therewith.

JP 2007-146133 A JP 2007-264266 A WO2016 / 208642A1

H. Fukumura, “Complement-induced thrombus formation on the surface of poly (N-vinylpyrrolidone) -grafted polyethylene”, Biomaterials, 1987, vol. 8, January.

  The present invention has been made in view of such problems of the prior art, and the production of inflammatory reaction substances due to complement activity, which has been a problem of conventional PVP-alloyed PAS polymer membranes, has a specific hydrophobicity and hydrophilicity. It is the first object to suppress by providing a (meth) acrylate copolymer having a side chain structure. Furthermore, it improved the low film wettability, which was a problem when applying the water-insoluble (meth) acrylate copolymer to hollow fiber membranes, and solved the problem of fluctuations in membrane performance that occurred when the coating method was adopted. The second purpose is to do. As a result of achieving these two objectives, an attempt is made to provide a hollow fiber membrane, a hollow fiber membrane module, and a method for producing the same, which are excellent in anti-inflammatory reactivity, and further excellent in separation performance and separation performance reproducibility, and easy to produce. To do.

  The present inventor has intensively studied to achieve the above object, and has completed the invention based on the following knowledge.

  Since the (meth) acrylate copolymer having a specific structure described in Patent Document 1 was insoluble in water and methanol, a coating liquid was prepared with an ethanol solvent as described in Patent Document 2, A bundle of hydrophobic PAS polymer hollow fiber membranes to which no PVP was applied was dip coated and air-dried. The obtained hollow fiber membrane did not have sufficient wettability to water. Further, as the polymer concentration of the coating solution is increased, the water permeability is lowered, and it is difficult to obtain reproducibility of the separation performance.

  Next, this (meth) acrylate copolymer ethanol solution was dip-coated on a PVP alloyed PAS polymer film and air-dried. Although the obtained hollow fiber membrane maintained wettability, the water permeability decreased according to the polymer concentration of the coating solution, and it was difficult to obtain reproducibility. Furthermore, as a problem, it was found that PVP that is readily soluble in ethanol elutes into the coating solution, and therefore, when the hollow fiber membrane bundle is repeatedly treated, the coating solution gradually changes in composition. Therefore, the coating solution needs to be updated frequently, which is difficult from an economic viewpoint.

  Thus, several problems were confirmed in the coating method. The present inventor has tried to apply a polymer blend method by paying attention to the point that the above PVP and (meth) acrylate copolymer have water-soluble and water-insoluble characteristics. That is, in the spinning process of the hollow fiber membrane, a spinning stock solution composed of a PAS polymer and a PVP-compatible two-component polymer was prepared, and the acrylic copolymer was added thereto. Here, it is known that the PAS polymer and PVP are compatible, and a uniform and transparent spinning solution can be obtained in a solvent of dimethylacetamide, dimethylformamide, or N-methyl-2-pyrrolidone. On the other hand, the (meth) acrylate copolymer was soluble in the solvent, but was incompatible with the PAS polymer and PVP. By adding the (meth) acrylate copolymer, the spinning dope became a milky white translucent dispersion.

  It is known that a dispersion spinning stock solution containing such an incompatible polymer component is generally not good in spinnability (to obtain a hollow fiber membrane stably without trouble of yarn breakage). Therefore, the present inventor adjusted the addition amount of the (meth) acrylate copolymer roughly to 1% by mass or less of the whole spinning dope and about 1/10 to 1/3 of the addition amount of PVP. Spinning stability could be obtained. Furthermore, except for adding the (meth) acrylate copolymer in this way, a hollow fiber membrane could be easily obtained by a conventional film forming method.

  The hollow fiber membrane of the present invention thus obtained has a droplet-like void structure (hereinafter referred to as a sponge-like asymmetric membrane composed of a two-component system of a PAS polymer and PVP in its cross-sectional structure). , Referred to as “pool”). This structure is due to the fact that the (meth) acrylate copolymer is incompatible with the PAS polymer and PVP, is liquid at room temperature, and is insoluble in water (water insoluble). This is what happens. Specifically, the pool is considered to be formed by the following mechanism.

  In the spinning dope composed of the three component polymers, the solution phase of the (meth) acrylate copolymer component exists in a state separated from the solution phase composed of the two components of the PAS polymer and PVP, and many drops It becomes a let phase and is dispersed throughout the spinning dope. In the process of forming the hollow fiber membrane by phase separation, the liquid droplets of these (meth) acrylate copolymers are left in a state of being dispersed throughout the hollow fiber membrane formed from the PAS polymer and PVP. From the large and small pools formed in this way, the (meth) acrylate copolymer is water-insoluble and liquid, so that it does not elute out of the membrane (core liquid or external coagulation liquid). It is considered that it is released and dispersed on the porous structure surface of the yarn membrane, and as a result, the entire hollow fiber membrane is polymer-coated.

  Subsequent to the spinning step and in the module washing step, after the excess PVP is washed from the hollow fiber membrane by hot water washing at 70 to 95 ° C., the dried hollow fiber membrane is subjected to deuterated dimethyl After dissolving in sulfoxide, this solution was measured by nuclear magnetic resonance spectroscopy (NMR), and the composition of the hollow fiber membrane was evaluated (weight fraction of the three-component polymer). As a result, the water-soluble PVP is reduced to one-fifth to one-tenth of the charged amount, and the hollow fiber membrane extract when the test defined by the dialysis-type artificial kidney device manufacturing approval standard is carried out It was found that the absorbance of ultraviolet absorption (UV wavelength: 220 to 350 nm) was sufficiently below the reference value of 0.10. On the other hand, surprisingly, the above-mentioned water-insoluble (meth) acrylate copolymer is almost free from elution even after high temperature hot water washing at 95 ° C. I understood.

  Next, when the surface composition of this hollow fiber membrane was evaluated by X-ray photoelectron spectroscopy (ESCA) for the inner / outer surfaces with which blood and dialysate contact each other, PVP and the (meth) acrylate copolymer were It was found that the hollow fiber membranes were unevenly distributed on the inner / outer surface of the hollow fiber membrane at a substantially the same polymer amount ratio and were uniformly distributed over the entire surface.

  Evaluation of water permeability for blood purification (UFR: Ultra Filtration Rate) and β2 microglobulin or myoglobulin protein blocking performance revealed that hollow fiber membrane performance with or without the addition of the (meth) acrylate copolymer was Almost no difference could be confirmed, and it was possible to obtain good basic performance with good reproducibility for blood purification.

  Further, the hollow fiber membrane module which was dried and subjected to γ sterilization treatment maintained the moderate wettability derived from PVP and could retain the property of being spontaneously wetted by water.

  Furthermore, the inventor conducted a blood evaluation test, which will be described later, as a confirmation of the effect of applying a specific (meth) acrylate copolymer excellent in blood compatibility to the hollow fiber membrane. The amount of residual blood after the circulation test was smaller than that of the conventional PVP alloyed PAS polymer membrane. Furthermore, as a result of an attempt to evaluate inflammatory response cytokines (particularly TNF-α and IL-6) produced by activation of complement in blood as a marker of anti-inflammatory imparting effect in the present invention, a hollow fiber membrane module was obtained. It was found that the increase rate of the inflammatory cytokine before and after human blood circulation was almost halved compared with the conventional PVP alloyed PAS polymer membrane.

The present invention has been completed based on the above findings, and has the following configurations (1) to (9).
(1) A water-insoluble solution comprising a polyarylsulfone-based polymer, polyvinylpyrrolidone, and an alkyl (meth) acrylate represented by the following general formula (I) and a methoxypolyethylene glycol (meth) acrylate represented by the following general formula (II) A hollow fiber membrane containing a (meth) acrylate copolymer, and the content of the (meth) acrylate copolymer is 0.5 to 5 when the hollow fiber membrane is measured using nuclear magnetic resonance spectroscopy. The hollow fiber membrane which is mass% and whose content of the (meth) acrylate copolymer is 5 to 30 mass% when the inner surface of the hollow fiber membrane is measured using X-ray photoelectron spectroscopy.
(Wherein R ₁ is an alkyl group or aralkyl group having 2 to 30 carbon atoms, R ₂ and R ₃ are hydrogen atoms or methyl groups, k is an integer of 1 to 1000, and m and n are Indicates the ratio of polymerization, m + n = 1.)
(2) The alkyl (meth) acrylate is represented by the following general formula (III), and the methoxypolyethylene glycol (meth) acrylate is represented by the following general formula (IV). Hollow fiber membrane.
(3) The hollow fiber membrane according to (2), wherein in the general formulas (III) and (IV), m = 0.5 to 0.9 and n = 0.1 to 0.5.
(4) When the hollow fiber membrane is measured using nuclear magnetic resonance spectroscopy, the content of polyvinylpyrrolidone in the hollow fiber membrane is 0.5 to 5% by mass, and the inner surface of the hollow fiber membrane is X-rayed. The hollow fiber membrane in any one of (1)-(3) whose content rate of polyvinylpyrrolidone is 5-30 mass% when measured using a photoelectron spectroscopy.
(5) The hollow fiber membrane according to any one of (1) to (4), wherein the polyarylsulfone-based polymer is polyethersulfone.
(6) The hollow fiber membrane according to any one of (1) to (5), wherein the hollow fiber membrane is for blood purification.
(7) A hollow fiber membrane module loaded with the hollow fiber membrane according to any one of (1) to (6), wherein two or more fluid inlets / outlets communicating with the lumen of the hollow fiber membrane and the outside of the hollow fiber membrane A hollow fiber membrane module comprising two or more fluid inlets and outlets communicating with a cavity.
(8) A method for producing the hollow fiber membrane according to any one of (1) to (6), wherein a polyarylsulfone-based polymer, polyvinylpyrrolidone, a (meth) acrylate copolymer, and a solvent are mixed. A method comprising discharging the obtained spinning solution together with a core solution from a double ring nozzle and immersing in an external coagulation solution.
(9) The spinning dope includes 10 to 50% by mass of a polyarylsulfone-based polymer, 1 to 10% by mass of polyvinylpyrrolidone, and 0.1 to 1.5% by mass of a (meth) acrylate copolymer. ). The method for producing a hollow fiber membrane according to

  The hollow fiber membrane and the hollow fiber membrane module of the present invention are made of a specific biocompatible (meth) acrylate copolymer excellent in complement activity inhibiting effect while maintaining the wettability of the PAS polymer membrane by PVP alloying. It is imparted to the surface and can achieve both excellent anti-inflammatory properties and handleability. Furthermore, the method for producing a hollow fiber membrane of the present invention is a simple one that can be formed as in the conventional method by a polymer blend method in which a very small amount of the (meth) acrylate copolymer is added, compared with the coating method. Also, since there is no fluctuation in the water permeability and protein separation performance of the membrane, it also has the advantage that it is easy and economical to produce.

Example of NMR spectrum of (meth) acrylate copolymer Another NMR spectrum example of (meth) acrylate copolymer Example of NMR spectrum of hollow fiber membrane of the present invention Another NMR spectrum example of the hollow fiber membrane of the present invention Example of correspondence between polyethersulfone and NMR peak Example of correspondence between polyvinylpyrrolidone and NMR peak Corresponding example of (meth) acrylate copolymer and NMR peak Example of peak separation of C1s spectrum in ESCA measurement of hollow fiber membrane The figure which shows an example of the hollow fiber membrane module of this invention Evaluation results of anti-inflammatory properties using the hollow fiber membranes of Example 1 and Comparative Example 5 Evaluation results of dialysis performance using modules of Examples and Comparative Examples

  Hereinafter, the present invention will be described in detail. The hollow fiber membrane of the present invention comprises a polyarylsulfone (PAS) polymer containing polyvinyl pyrrolidone (PVP), which is a water-soluble hydrophilic polymer, as a basic component, and a specific (meth) acrylate copolymer as a third component polymer. It is characterized by containing a polymer.

(Polyarylsulfone polymer)
The polyarylsulfone-based polymer is a general term for aromatic polymers having a sulfone bond, and among them, it is preferable to use a polyarylsulfone-based polymer that is compatible with PVP. Specifically, polysulfone and polyethersulfone having repeating units represented by the following general formula (V) and general formula (VI) are preferable because they are compatible with PVP and are easily available. The molecular weight is preferably a weight average molecular weight of 20,000 or more from the viewpoint of obtaining a preferable porous structure and spinning stability. More preferably, it is 40,000 or more.

(Polyvinylpyrrolidone)
The main purpose of PVP is to increase the hydrophilicity of the film surface and to impart wettability to water by blending with a PAS polymer film. The following general formula (VII) shows the repeating unit structure of PVP. As the molecular weight of PVP, those having a weight average molecular weight of 10,000 to 1,500,000 can be used. For example, those having a weight average molecular weight of 9,000 (K17), 45,000 (K30), 450,000 (K60), 900,000 (K80), 1,200,000 (K90) from BASF are used. it can. From the viewpoint of imparting an appropriate thickening effect to the spinning dope and obtaining an appropriate film structure and PVP detergency by hot water washing described later, it is preferable to use a high molecular weight type of K60 or higher.

((Meth) acrylate copolymer)
In the present invention, the (meth) acrylate copolymer is composed of a hydrophobic alkyl (meth) acrylate represented by the general formula (I) and a methoxypolyethylene glycol (meth) acrylate of the hydrophilic portion represented by the general formula (II). A water-insoluble (water-insoluble) (meth) acrylate copolymer is preferable.
(In the formula, R ₁ is an alkyl group or aralkyl group having 2 to 30 carbon atoms, R ₂ and R ₃ are hydrogen atoms or methyl groups, k is an integer of 1 to 1000, and m and n are copolymerization ratios. And m + n = 1.)

In order to increase the inhibitory effect on the adsorption and activation of complement, it is necessary to form a polymer surface having a high polymer hydrophobicity and a low glass transition temperature (that is, high molecular mobility and high fluidity). Therefore, R ₁ of the alkyl (meth) acrylate (I) in the hydrophobic portion is an alkyl group or aralkyl group having 2 to 30 carbon atoms, and R ₂ is a hydrogen atom or a methyl group from the viewpoint of increasing hydrophobicity. Is preferred. Further, it is more preferable to lower the glass transition temperature to increase molecular mobility. With regard to this point, for example, referring to the knowledge of “Acrylic Resin Synthesis / Design and New Application Development Chubu Management Development Center Issued in 1985” and “Acrylic Acid Ester and its Polymer [II] Showa-do Inc. Issued in 1975” Then, as the carbon number of the alkyl (meth) acrylate increases, the glass transition temperature of the polymer tends to decrease and tends to increase after reaching a certain minimum value. Is 8 (in n-alkyl methacrylate, the number of carbon atoms is 12). Therefore, it is more preferable that the structure of the alkyl (meth) acrylate of the hydrophobic portion is adjusted to 8 carbon atoms as in the following general formula (III).

On the other hand, in order to suppress the adsorption / activation of platelets, it is preferable to introduce appropriate hydrophilicity into the polymer structure. It is preferable to select a sex structure. From this viewpoint, methoxypolyethylene glycol (meth) acrylate of the general formula (II) is preferable, R ₃ is preferably a hydrogen atom or a methyl group, and k is preferably in the range of 1 to 1000. More preferably, one represented by the general formula (IV) is used. When k is larger than this range, the hydrophilicity becomes too high and the complement activity cannot be suppressed, or the polymer may be eluted at the same time in the hot water washing treatment step of PVP. On the other hand, if k is smaller than this range, sufficient hydrophilicity cannot be obtained, and platelet adsorption may easily occur.

  In the present invention, m in the general formula (III) is preferably in the range of 0.5 to 0.9. When the copolymerization ratio m is smaller than this range, the hydrophilicity of the whole polymer increases, so that the effect of suppressing complement activation is reduced and the polymer is easily eluted in the PVP hot water washing treatment step. On the other hand, if m is larger than this range, the polymer becomes too hydrophobic and the degree of platelet adsorption / activation increases, and it becomes difficult to dissolve in the solvent of the spinning dope.

  In the present invention, the molecular weight of the (meth) acrylate copolymer is not particularly limited, but is preferably a number average molecular weight of 2,000 or more from the viewpoint of ease of purification by reprecipitation after polymerization. More preferably, it is 5,000 or more.

  In the present invention, the (meth) acrylate copolymer may be any of a random copolymer, a block copolymer, and a graft copolymer, but a random copolymer is preferable because of easy polymerization. The reaction method for producing the copolymer is not particularly limited, and a known method such as a radical polymerization method can be used.

(Preparation of spinning dope)
In the present invention, the spinning dope is prepared by dissolving the PAS polymer and PVP in one or more aprotic polar solvents selected from dimethylacetamide, dimethylformamide, and N-methyl-2-pyrrolidone (NMP). The (meth) acrylate copolymer can be added and kneaded. The order of addition of the polymers and the kneading method are not particularly limited.

  In the present invention, the polymer concentration in the spinning dope is 10 to 50% by mass of the PAS polymer, 1 to 10% by mass of PVP, and 0.1 to 1.5% by mass of the (meth) acrylate copolymer. Is preferred. In this range, the PAS polymer and PVP can optimize the porous structure of the hollow fiber membrane for blood purification applications and impart appropriate membrane wettability. Moreover, the addition amount of the (meth) acrylate copolymer is preferable in this range because it is possible to ensure spinnability and to impart sufficient anti-inflammatory reactivity.

(Method for producing hollow fiber membrane)
For the method for producing the hollow fiber membrane of the present invention, known means can be used, but it is preferable to use a dry and wet spinning method. Specifically, a spinning stock solution in which a PAS polymer, PVP, a (meth) acrylate copolymer, a solvent, and a non-solvent as necessary is kneaded and dissolved is discharged from the slit portion of the double-tube nozzle, and from the center portion. By simultaneously discharging the core liquid and immersing it in the coagulation bath through an air gap, a hollow fiber membrane excellent in water permeability and protein fractionation characteristics can be obtained.

  In the present invention, it is preferable to use a liquid mainly composed of a solvent and / or a non-solvent contained in the spinning dope as the core liquid used in forming the hollow fiber membrane. Therefore, it is preferable to use any of a mixed solution of a solvent and a non-solvent, a non-solvent alone, a mixed solution of a solvent and water, a mixed solution of a non-solvent and water, or a mixed solution of a solvent, a non-solvent, and water. More preferably, it is preferable to prepare a mixed solution having the same solvent / non-solvent ratio of the spinning dope and dilute it with water. At this time, the organic component concentration is preferably 10 to 80% by mass. If the organic component concentration is less than 10% by mass, solidification tends to proceed, the structure inside the membrane becomes too dense, and the water permeation performance may deteriorate. When the organic component concentration is more than 80% by mass, pores having a large pore diameter are likely to be generated, and there is a high possibility that the separation characteristics and the strength are reduced.

  The composition of the external coagulation liquid is preferably a mixture of a solvent and a non-solvent contained in the spinning dope and water. At this time, the ratio of the solvent and the non-solvent is preferably the same as the solvent / non-solvent ratio of the spinning dope. Preferably, the same solvent and non-solvent used in the spinning dope are mixed in the same ratio as in the spinning dope and diluted by adding water. The organic component concentration of the external coagulation liquid is preferably 10 to 70% by mass. When the organic component concentration is low, solidification tends to proceed, the membrane structure becomes too dense, and the permeability may decrease. Further, when the concentration of the organic component is large, pores having a large pore diameter are likely to be generated, and the separation characteristics and strength may be reduced. Moreover, it is preferable that the temperature of an external coagulation liquid shall be 30-80 degreeC. If the temperature is low, solidification tends to proceed, and the membrane structure may become too dense, resulting in a decrease in permeability. Further, when the temperature is high, pores having a large pore diameter are likely to be generated, and the possibility that the separation characteristics and the strength are lowered is increased.

  One factor that controls water permeability is the temperature of the nozzle. If the nozzle temperature is low, solidification tends to proceed, the membrane structure becomes too dense, and the permeability decreases. Moreover, when the temperature of the nozzle is high, pores having a large pore diameter are likely to be generated, and the possibility of causing a reduction in separation characteristics and strength is increased. A suitable nozzle temperature is 40-80 ° C.

  The spinning stock solution (hollow fiber membrane), in which the spinning solution discharged from the double tube nozzle together with the core solution is led into the external coagulation solution through the air gap, is solidified from the outside while solidification from the core solution proceeds. Comes into contact with the external coagulation liquid in a state that is suppressed to some extent. During the passage of the external coagulation liquid, the hollow fiber membrane completes coagulation and a structure is formed.

  The spinning speed (spinning speed) is not particularly limited as long as a hollow fiber membrane having no defect is obtained and productivity can be secured, but it is preferably 5 to 100 m / min. If the spinning speed is lower than this, the productivity is lowered. If the spinning speed is higher than this, the phase separation structure may not be sufficiently developed in the solidification process.

(PVP cleaning process with hot water)
The hollow fiber membrane that has been solidified is preferably washed with hot water to remove excess PVP contained in the membrane. In the PVP alloyed with the PAS polymer, the molecular chain is constrained to the matrix phase of the PAS polymer, and the mobility is considered to be low. In fact, it is possible to obtain a higher cleaning effect of PVP by washing with hot water than washing with room temperature water. The temperature of the hot water is preferably 70 ° C. or higher, more preferably 80 to 95 ° C. If the temperature is lower than this, the cleaning effect becomes insufficient, and if the temperature is higher than this, the energy cost becomes high and the cleaning effect is not necessarily improved.

(Drying and bundling process)
The hollow fiber membrane obtained through hot water washing is cut into an appropriate length and bundled into a bundle shape. For the purpose of draining the liquid present in the hollow portion, the bundle is left standing for 30 minutes to 2 hours. If it is shorter than 30 minutes, the liquid in the hollow portion is not sufficiently removed, which is not preferable. If left for more than 2 hours, the bundle may buckle due to its own weight when the liquid is drained while standing.

  As a method for drying the hollow fiber membrane, a commonly used drying method such as air drying, reduced pressure drying, hot air drying, microwave drying, or the like can be used. Hot air drying is preferably used in that a large amount of hollow fiber membranes can be efficiently dried with a simple apparatus. The hot air temperature at the time of hot air drying is not particularly limited, but is preferably 25 to 100 ° C, more preferably 30 to 80 ° C. If the temperature is lower than this, it takes a long time to dry, and if the temperature is higher than this, the energy cost for generating hot air increases.

(Module manufacturing process)
The module is made by inserting the hollow fiber membrane bundle into a container, injecting a potting agent such as polyurethane into both ends of the bundle and sealing both ends, and then cutting off and removing the excess potting agent to open the end surface of the hollow fiber membrane. This can be done by attaching a header.

  The module 1 is loaded with a hollow fiber membrane bundle 3 in a cylindrical container 2, both ends of the hollow fiber membrane bundle 3 are fixed to both ends of the container 2 with an adhesive 4 or the like, and caps are attached to both ends of the container 2. 5a and 5b are attached. A dialysate inlet 6a for introducing dialysate into the container 2 is formed in the vicinity of one end of the container 2, and a dialysate discharge port 6b for discharging the dialysate is formed in the vicinity of the other end. It is. One cap 5a is formed with a blood introduction port 7a for introducing blood into the container 2, and the other cap 5b is formed with a blood discharge port 7b for discharging blood (FIG. 9).

  The blood enters the space formed by the cap 5a and one end face of the hollow fiber membrane bundle 3 from the blood introduction port 7a as shown by the arrow A, and the hollow fiber membrane of the hollow fiber membrane bundle 3 is hollow. Passes through the part, enters the space formed by the other end face of the hollow fiber membrane bundle 3 and the cap 5b, and is discharged from the blood outlet 7b as indicated by the arrow B. On the other hand, the dialysate enters the container 2 from the dialysate introduction port 6a as shown by the arrow C, flows outside the hollow fiber membrane of the hollow fiber membrane bundle 3, and as shown by the arrow D, the dialysate discharge port. It is discharged from 6b. At this time, the flow of blood to be dialyzed and the flow of dialysate are preferably opposite so-called opposite flows. During this time, waste in the blood flowing in the hollow fiber membrane is dialyzed into the outer dialysate through the hollow fiber membrane.

(Module hot water treatment process)
In addition to the hot water washing in the membrane forming step, it is preferable that the modularized hollow fiber membrane bundle is also subjected to hot water treatment. By these washing steps, the amount of eluate extracted from the module by the method defined in the dialysis-type artificial kidney device manufacturing approval standard at the stage of final use for treatment is 0. UV absorption (220-350 nm). A level of 1 or less can be achieved, which is preferable.

(Module sterilization)
The completed module is sterilized from the viewpoint of medical hygiene. The module is preferably sealed in a packaging bag together with an oxygen scavenger and sterilized by irradiation with radiation and / or electron beams in a state where the space inside the module is dry. Examples of the radiation or electron beam include α-rays, β-rays, γ-rays, and electron beams, and γ-rays or electron beams are preferably used from the viewpoint of sterilization efficiency and ease of handling. The irradiation dose of radiation or electron beam is not particularly limited as long as it can be sterilized, but generally 10 to 30 kGy is preferable.

(Polymer composition ratio of hollow fiber membrane)
By completely dissolving the hollow fiber membrane in a mixed solvent containing deuterated dimethyl sulfoxide (DMSO-d ₆ ) or DMSO-d ₆ and performing spectrum measurement by proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR), The weight ratio of the three components of the PAS polymer, PVP and (meth) acrylate copolymer calculated from the integration ratio of the corresponding peak can be evaluated. The composition ratio obtained by this method is an average value in the entire hollow fiber membrane.

The NMR measurement method and analysis method are not particularly limited, and known means may be used. In order to correctly evaluate the composition ratio, it is preferable to perform measurement by the following procedures (1) to (3). (1) NMR measurement of (meth) acrylate copolymer alone Since PAS polymer and PVP are readily soluble in DMSO-d ₆ , NMR measurement of hollow fiber membranes is basically carried out with DMSO-d ₆ solvent. The (meth) acrylate copolymer used in the present invention has low solubility in DMSO-d ₆ depending on the copolymer composition. In that case, for example, a completely dissolved state can be obtained by adding 80 parts by volume of NMP to 20 parts by volume of DMSO-d ₆ .

The (meth) acrylate copolymer is easily soluble in deuterated chloroform (CDCl ₃ ). Therefore, NMR of the (meth) acrylate copolymer alone is measured for the CDCl ₃ solution and the DMSO-d ₆ / NMP solution. Examples of NMR spectra of a specific (meth) acrylate copolymer (FIG. 7) are shown in FIGS. From both spectra, a characteristic peak of the (meth) acrylate copolymer that is not interfered with by the peak of NMP can be selected. For example, a peak (C in FIG. 1) derived from the methyl group of alkyl (meth) acrylate around 0.9 ppm can be used for evaluation.

(2) NMR measurement of hollow fiber membrane (DMSO-d ₆ solvent)
The weight ratio of the two components of the PAS polymer and PVP in the hollow fiber membrane can be evaluated from the NMR spectrum of the DMSO-d ₆ solution. An example of an NMR spectrum of a DMSO-d ₆ solution when polyethersulfone is used as the PAS polymer is shown in FIG. As an independent peak derived from polyethersulfone (FIG. 5), A (hydrogen number 4H) in the vicinity of 8 ppm in FIG. 3 is used, and a plurality of peaks derived from PVP (FIG. 6) is from 1.1 to 2.3 ppm. The weight ratio of the PAS polymer and PVP is calculated by employing the peak group B (hydrogen number 6H). At this time, since the peak group B of the PVP includes the peak group C ′ of the (meth) acrylate copolymer, the integration ratio of the NMR spectrum of the (meth) acrylate copolymer alone (FIG. 1: 0.9 ppm). Based on the integral value ratio Δ) of the nearby independent peak C and the peak group C ′ near 1.1 to 2.3 ppm, this is removed and the integral value B of the net PVP is calculated.

(3) NMR measurement of hollow fiber membrane (DMSO-d ₆ / NMP mixed solvent)
When the solubility of the (meth) acrylate copolymer in DMSO-d ₆ is not sufficient, NMR measurement of a DMSO-d ₆ / NMP mixed solvent is also performed on the same hollow fiber membrane sample. An example NMR spectrum is shown in FIG. In this measurement, since the (meth) acrylate copolymer is completely dissolved, the weight ratio of the PAS polymer and the (meth) acrylate copolymer can be determined. The PVP peak is excluded from the analysis because it almost overlaps the NMP peak. From the integral ratio of the independent peak A derived from the PAS polymer (polyethersulfone) near 8 ppm and the independent peak C derived from the (meth) acrylate copolymer near 0.9 ppm, the weight ratio of both can be calculated. . However, since the integral value of C is derived from the hydrophobic portion of the (meth) acrylate copolymer, the weight ratio of the entire polymer including the hydrophilic portion is calculated based on the copolymerization ratio (FIG. 7).

  The analysis method in (1) to (3) above and the range of chemical shift for integration depend on the type of PAS polymer selected in the present invention, the composition / composition ratio of the (meth) acrylate copolymer, and the solvent composition. It can vary somewhat. Further, when additives and contaminant components other than the above three polymer components are mixed in the hollow fiber membrane, it is necessary to appropriately perform the peak identification and integral value removal processing.

  In the average composition of the hollow fiber membranes evaluated by the above measurements, when the weight fraction was determined for the three components of the PAS polymer, PVP and (meth) acrylate copolymer, the PVP was 1.0-5. If 0 mass% and the (meth) acrylate copolymer are in the range of 0.5 to 5.0 mass%, the anti-inflammatory property in blood purification therapy is good, which is preferable. More preferably, PVP is 1.5 to 4.8% by mass and (meth) acrylate copolymer is 1.0 to 4.7% by mass. When there is more PVP than this range, there exists a possibility that the PVP elution rate at the time of blood purification therapy may become large. If the PVP is less than this range, sufficient wettability may not be imparted to the hollow fiber membrane. Further, when the (meth) acrylate copolymer is less than this range, the anti-inflammatory property may not be sufficiently exhibited. In addition, when the amount of (meth) acrylate copolymer is larger than this range, not only the anti-inflammatory property is improved, but too much (meth) acrylate copolymer adheres to the membrane surface, so In addition, the dialysis performance may be deteriorated by narrowing the flow path or blocking the pores.

(Evaluation of composition ratio of inner / outer surface of hollow fiber membrane by ESCA)
For composition evaluation of the inner surface and outer surface of the hollow fiber membrane in contact with blood and dialysate, elemental composition measurement by X-ray photoelectron spectroscopy (ESCA) is preferably used. When the weight fraction of the three components PAS polymer, PVP and (meth) acrylate copolymer calculated from the peak integration ratio is evaluated, the PVP is 5.0 to 30% by mass, and the (meth) acrylate copolymer Are preferably in the range of 5.0 to 30% by mass. More preferably, PVP is 10 to 30% by mass and (meth) acrylate copolymer is 5.0 to 25% by mass. Further, the PVP and (meth) on the inner surface of the hollow fiber membrane evaluated by this method, rather than the weight fraction of PVP and (meth) acrylate copolymer as an average composition evaluated by the H-NMR measurement. It is preferable that the weight fraction of the acrylate copolymer is larger. Under these conditions, PVP and (meth) acrylate copolymer are appropriately mixed and dispersed on the surface of the hollow fiber membrane, and there is little variation in the distribution of the two-component polymer on the membrane surface. Therefore, the anti-inflammatory effect mentioned later becomes high. On the other hand, when the weight fraction of PVP and (meth) acrylate copolymer is less than this range, sufficient wettability may not be imparted to the hollow fiber membrane, and anti-inflammatory properties may not be imparted sufficiently. On the other hand, if it is larger than this range, the weight fraction of the PAS polymer that is the matrix phase of the hollow fiber membrane becomes too small, and the mechanical strength of the membrane may not be sufficiently obtained.

  As a method for imparting a (meth) acrylate copolymer to a hollow fiber membrane, a hollow fiber membrane produced by a known method is immersed in a solution in which a (meth) acrylate copolymer is dissolved or dispersed, and is applied to the membrane surface. Examples thereof include a method of attaching a (meth) acrylate copolymer (coating method) and a method of manufacturing a hollow fiber membrane using a spinning stock solution to which a (meth) acrylate copolymer is added (blend method). However, the (meth) acrylate copolymer used in the present invention is not compatible with the PAS polymer and PVP, and is insoluble in water. Therefore, when the coating method is employed, a relatively large amount of the copolymer can be attached to the inner surface and the outer surface of the hollow fiber membrane, but there is a problem that it is difficult to penetrate into the membrane. In addition, if the polymer excessively adhering to the inner surface and the outer surface of the membrane is removed by washing after allowing a sufficient amount of the polymer to penetrate into the membrane, it is insoluble in water. It becomes necessary to use a cleaning solution. Then, PVP may fall off from the hollow fiber membrane, or the membrane structure may be destroyed or defective due to partial dissolution of the hollow fiber membrane, and a low protein leak can be achieved while achieving high β2MG clearance. Disappear. On the other hand, in the case of the blend method, by selecting appropriate spinning conditions, the content ratio of the (meth) acrylate copolymer in the entire film and the content ratio of the (meth) acrylate copolymer on the inner surface are within an appropriate range. It is possible to prepare.

(Evaluation of anti-inflammatory properties of hollow fiber membranes by human blood)
Regarding the evaluation of the degree of the inflammatory reaction caused by contact between the hollow fiber membrane and blood, fresh human blood is circulated through the hollow fiber membrane (micromodule), and inflammatory cytokines (TNF-α and This can be done by comparing the increase rate of IL-6). The evaluation is preferably performed using human blood. In the evaluation with commercially available animal blood such as bovine blood and pig blood, the above-mentioned inflammatory cytokine has an extremely large initial value and cannot be evaluated with good reproducibility.

  As human blood, blood from several healthy individuals collected by medical personnel at medical facilities is used. A circuit is constructed using a membrane module having a specific membrane area and a tube of a certain length, and after passing physiological saline on the dialysate side and a human blood sample on the blood side at a constant flow rate, blood is collected. . The collected blood is requested to be evaluated by a specialized medical contractor for inflammatory cytokine tests and general peripheral blood tests.

  Regarding the evaluation of anti-inflammatory properties, the reason for evaluating the blood levels of TNF-α and IL-6 is as follows.

  Inflammatory cytokines are produced from activated complements, particularly macrophages chemotilized by anaphylatoxin C5a, etc., and when these are refluxed into the patient's body together with blood and accumulated in the liver and bone marrow, liver damage and bone damage It has been pointed out that it may cause Therefore, after the blood comes into contact with the hollow fiber membrane, the degree of inflammatory reaction caused by the contact between the hollow fiber membrane and the blood is examined by confirming the rate of increase in the concentration of TNF-α and IL-6 in the blood. be able to.

  On the other hand, as a blood compatibility evaluation on the surface of the hollow fiber membrane, there is a method of evaluating complement value and activated complement (particularly, anaphylatoxins C3a and C5a). However, as a conventional evaluation method, for example, fine glass beads are coated with a biocompatible polymer, put in a test tube, incubated with serum, and then measured for complement value and anaphylatoxin production. However, in a hollow fiber membrane, it is difficult to perform an accurate test for such measurement. Specifically, in hemodialysis and the like, unnecessary proteins, lipids, urea and the like are discharged between the blood separated from the hollow fiber membrane and the dialysate. The activated complements C3a (molecular weight about 9,000) and C5a (molecular weight about 11,000) have a low molecular weight and are less than or equal to the unnecessary protein β2 microglobulin (molecular weight about 11,000). In particular, in a high-flux type hollow fiber membrane, a considerable amount permeates from the blood side to the dialysate side, and it is difficult to accurately evaluate the rate of increase in blood concentration. On the other hand, TNF-α (molecular weight about 25,900) and IL-6 (molecular weight about 23,700) produced by phagocytic cells such as macrophages chemotilized by activated complement penetrate the hollow fiber membrane because of their large molecular weight. The possibility of staying on the blood side and returning to the body as it is is high. Therefore, as a more direct method for evaluating the anti-inflammatory properties of the hollow fiber membrane of the present invention, the blood concentration of the inflammatory cytokine is evaluated.

  Examples and specific effects of the present invention will be described below, but the present invention is not limited thereto.

(Number average molecular weight measurement of (meth) acrylate copolymer)
To 15 mg of the polymer sample, 3 mL of a mobile phase for GPC measurement was added and dissolved, followed by filtration with a 0.45 μm hydrophilic polytetrafluoroethylene membrane (Millex-LH, Nihon Millipore). GPC measurement uses 510 high pressure pump, 717plus automatic injection device (Nihon Waters), RI-101 (Showa Denko) measuring device, column PLgel 5 μMIXED-D (600 × 7.5 mm) (Polymer Laboratories), column temperature at room temperature As the mobile phase, tetrahydrofuran (THF) to which 0.03% by mass of dibutylhydroxytoluene (BHT) was added was used. Detection was performed with RI, and 50 μL was injected. The molecular weight structure was determined by monodispersed PMMA (EasiCal: Polymer Laboratories).

(Solvent solubility test of (meth) acrylate copolymer)
Prepare 10 mL vials with 500 mg of sample as many as the number of solvent species, add 2 mL of water, methanol, ethanol, and 2-propanol to each vial and mix well using a magnetic stirrer. Dissolution was confirmed.

(Measurement of glass transition temperature)
Using a differential scanning calorimeter (Shimadzu DSC-50), 10 mg of sample is packed in an aluminum sample pan (6 mmφ), covered, crimped and sealed with a sealer crimper, and then set on a measuring instrument for measurement. went. The measurement was carried out from −150 ° C. to 60 ° C. under a N ₂ gas stream at a heating rate of 5 ° C./min after cooling with liquid nitrogen.

(Calculation of hollow fiber membrane area)
The membrane area A of the hollow fiber membrane module was determined by the following formula on the basis of the inner diameter of the hollow fiber membrane.
A = n × π × d × L (m ² )
Here, n is the number of hollow fiber membranes in the module, π is the circumference ratio, d is the inner diameter (m) of the hollow fiber, and L is the effective length (m) of the hollow fiber in the module.

(Production of hollow fiber membrane module)
A bundle of 10,000 hollow fiber membranes is filled in a module case having an inner diameter of 30 to 35 mmφ, and both ends are sealed with a two-component curable polyurethane resin, and the membrane area (hollow fiber membrane inner diameter standard) 1 A hollow fiber membrane module of 5 m ² was produced. At a general blood flow rate of 200 mL / min in hemodialysis, the linear velocity of blood flow inside the hollow fiber membrane of this module was adjusted to 1.0 cm / s.

(Measurement of ultrafiltration coefficient UFR of pure water)
The blood outlet circuit of the hollow fiber membrane module was sealed to obtain dead-end total filtration. Filling the pressurized tank with pure water kept at 37 ° C and controlling the pressure with a regulator, sending pure water to the inside of the hollow fiber membrane of the hollow fiber membrane module in the thermostatic bath kept at 37 ° C, outside the hollow fiber membrane The amount of the filtrate flowing out from the was measured with a graduated cylinder. The transmembrane pressure difference TMP was set to TMP = (Pi + Po) / 2. Here, Pi is the module inlet pressure, and Po is the module outlet pressure. The filtration flow rate at four points was measured while changing TMP, and the water permeability UFR (D) (mL / (h · mmHg)) of the module was calculated from the slope of these straight lines. At this time, the correlation coefficient between TMP and the filtration flow rate must be 0.999 or more. In order to reduce the pressure loss error due to the circuit, TMP was measured in the range of 100 mmHg or less. The water permeability UFR (H) of the hollow fiber membrane was calculated by the following formula from the membrane area and the water permeability of the module.
UFR (H) (mL / (m ² · h · mmHg)) = UFR (D) / A

(Evaluation of clearance of β2 microglobulin (β2MG))
It was carried out according to the module performance evaluation criteria shown in Dialysis Society Journal 41 (3), p159-167 (2008). For the module with a membrane area of 1.5 m ² , ACD (acid-citrate-dextrose) -added bovine plasma kept at 37 ° C. with a total protein concentration of 6.5 ± 0.5 g / dL at a blood side flow rate of 200 mL / min. Circulated for 1 hour. Then, ACD with a total protein concentration of 6.5 ± 0.5 g / dL is added so that human β2 microglobulin (β2MG, genetically modified product, manufactured by Wako Pure Chemical Industries, Ltd.) has a concentration of 0.05 to 0.1 mg / L. What was added to the bovine plasma was allowed to flow to the blood side at a blood flow rate of 200 mL / min, and dialysis was performed at a commercial dialysate of 500 mL / min and a filtration flow rate of 15 mL / min. The evaluation was conducted with a single pass. After the start of dialysis, the β2MG concentration of the test solution collected from the blood inlet, outlet and dialysate outlet at 60 minutes is measured. The clearance (CL) was calculated by the following formula.
CLβ2MG (mL / min) = 200 × [(200 × C _Bi ) − (185 × C _Bo )] / (200 × C _Bi )
Here, C _Bi represents the blood inlet portion concentration, and C _Bo represents the blood outlet portion concentration.

(Calculation of protein leak (TPL))
Prepared bovine blood by adding citric acid to suppress coagulation to a hematocrit of 25-30% and a protein concentration of 6-7 g / dL, sent to a hollow fiber membrane module at 37 ° C. at a rate of 200 mL / min, and a filtration flow rate of 15 mL The blood was filtered at / min. At this time, the filtrate was returned to the blood to form a circulatory system. The filtration flow rate was measured every 15 minutes, and the filtrate of the hollow fiber membrane module was collected. The concentration of protein contained in the filtrate was measured. Measurement of protein concentration in plasma was performed using an in vitro diagnostic kit (Micro TP-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.). Based on the data for up to 2 hours, the average amount of protein leak was calculated, and the amount of protein leak TPL at the time of 3L water removal conversion was calculated and used as the evaluation value.

(Measurement of PVP elution amount of hollow fiber membrane)
The hollow fiber membrane was extracted by the method defined in the dialysis artificial kidney device production standard, and PVP in the extract was quantified by a colorimetric method. Specifically, for the dry hollow fiber membrane module, 1 g of the hollow fiber membrane was taken out, added to 100 mL of pure water, and extracted at 70 ° C. for 1 hour. The obtained extract (2.5 mL), 0.2 mol citric acid aqueous solution (1.25 mL) and 0.006 N iodine aqueous solution (0.5 mL) were mixed well and allowed to stand at room temperature for 10 minutes. About this extract, the light absorbency of wavelength range 200-350 nm was measured using the spectrophotometer (the Hitachi, Ltd. make, U-3000), and the maximum light absorbency in this wavelength range was calculated | required. When the hollow fiber membrane sample was taken out from the module, it was equally divided into 10 pieces in the longitudinal direction of the yarn, 1 g of the hollow fiber membrane in a dry state was weighed from each part, and all the samples were measured, and the average value was obtained. .

(Evaluation of anti-inflammatory properties of hollow fiber membranes)
(1. Fabrication of micromodule)
A polycarbonate micromodule having an inner diameter of 8 mm, an overall length of 95 mm, and an inlet port and an outlet port on the dialysate side (outside of the hollow fiber membrane) is prepared. This has a hollow fiber effective length of 75 mm, an inner diameter standard membrane area of 24 cm ² , blood The hollow fiber membrane was filled so that the linear velocity inside the hollow fiber was 1.0 cm / s when the circulation flow rate was 1.0 mL / min. Both ends were potted with urethane resin, and after curing, both ends of the hollow fiber were opened with a knife, and respective lids with ports were attached. The number of yarns varies somewhat depending on the inner diameter of the hollow fiber membrane. For example, when the inner diameter was 200 μm, the number of yarns was 51.

  The micromodule was cleaned before use. 5 mL of physiological saline was added to the blood side (inside the hollow fiber membrane) with a syringe, and 5 mL of physiological saline was similarly added to the dialysis side (outside of the hollow fiber membrane). Thereafter, the physiological saline on the blood side was pushed out with a syringe. Next, as a leak test, insert a syringe into the port on one end face on the blood side, seal the other side, push out air with the syringe, and check if bubbles due to membrane leak occur outside the hollow fiber membrane It was confirmed.

(2. Preparation of human blood sample)
Blood samples were collected from multiple volunteers (50 mL each) at Toyobo Research Institute Clinic, and then 2 mL of heparin was added to the sample, and then placed in a centrifuge tube and measured in a thermostatic chamber at 37 ° C. The temperature was adjusted until the time and subjected to evaluation promptly.

(3. Evaluation of the amount of inflammatory cytokines after tube circuit circulation)
A clear increase in the amount of inflammatory cytokines in the blood was confirmed not only by the hollow fiber membrane but also by contact between the tube circuit and blood. Therefore, after circulating the blood under the conditions in which the material and the tube circuit length were fixed in advance, the amount of inflammatory cytokine was measured, and this was evaluated as a blank. Specifically, a silicone tube having an inner diameter of 1 mm, an outer diameter of 3 mm, and a length of 70 cm is prepared, and this is attached to a micro tube pump (EYELA MP-3), and the tube is left in a constant temperature bath at 37 ° C. Circulation was performed by adjusting the flow rate to 1.0 mL / min using physiological saline. Thereafter, the human blood sample was circulated in the tube at a flow rate of 1.0 mL / min for 15 minutes. The blood after circulation was collected in a vacuum blood collection tube (TERUMO Beneject II vacuum blood collection tube (sterile product)), and a 4 mL sample and a 2 mL sample were collected, respectively, and highly sensitive IL-6 and TNF-α tests and peripheral blood in general. The inspection was conducted at the Kinki Institute for Preventive Medicine.

(4. Evaluation of amount of inflammatory cytokine after circulation of micromodule)
The silicone tube circuit 70 cm in which blood was circulated through the washed micromodule in the procedure (3) was cut into 50 cm and 20 cm, and promptly connected to the blood side inlet port and outlet port of the micromodule. Thereafter, the micromodule and the tube circuit were placed in a constant temperature bath at 37 ° C., and the same blood sample was circulated for 15 minutes at a flow rate of 1.0 mL / min using a microtube pump. The blood after circulation was subjected to high sensitivity IL-6 and TNF-α tests and peripheral blood general tests in the same manner as described above.

The inflammatory cytokine increase rate RI was determined from the blood concentration of the inflammatory cytokine thus obtained (and each item in the peripheral blood general examination if necessary) using the following formula. RI (%) = 100 × (C _total −C _tube ) / C _tube
Where C _total is the concentration of IL-6 or TNF-α in the blood (pg / ml) after circulating through the entire system consisting of micromodules and tubes, and C _tube is only after circulating through the tube circuit. Concentration of IL-6 or TNF-α (pg / mL).

(5. Evaluation of the amount of inflammatory cytokines in untreated blood)
The blood sample before the circulation treatment was directly taken into a vacuum blood collection tube and similarly subjected to high-sensitivity IL-6 and TNF-α analysis and general peripheral blood examination as necessary.

  In the above procedures 3 to 5, the peripheral blood general test was performed at the same time, and this was performed as a reference for confirming whether or not there were any abnormal values in the white blood cell count and platelet count in the blood sample of this evaluation.

(Evaluation of residual blood properties of hollow fiber membrane modules)
The module after blood circulation to the micromodule was disassembled, the remaining blood was counted, and the number of threads dyed red was counted. The remaining blood threads were evaluated as 0 (excellent) for 0-2, 3 (circle) for 3-5, Δ (fair) for 6-10, and x (bad) for 11 or more.

(Measurement method of polymer and hollow fiber membrane by ¹ H-NMR)
The measurement was performed with the following apparatus and conditions.
(Apparatus): Fourier transform nuclear magnetic resonance apparatus (AVANCE500 manufactured by Bruker BioSpin, magnet manufactured by Oxford)
(Measurement solution): 5 to 50 mg of a sample was dissolved in 0.6 mL of deuterated dimethyl sulfoxide (other solvent).
( ¹ H resonance frequency): 500.13 MHz
(Flip angle of detection pulse): 45 °
(Data acquisition time): 4.0 seconds (delay time): 1.0 seconds (number of integration): 5 to 200 times (measurement temperature): room temperature or 40 ° C.

(Evaluation of composition ratio of (meth) acrylate copolymer)
A polymer sample of 15 mg dissolved in 0.6 mL of deuterated chloroform was injected into an NMR test tube, and NMR measurement was performed and calculated using the above measuring apparatus and measurement conditions.

(Composition analysis of hollow fiber membrane inner / outer surface by X-ray photoelectron spectroscopy (ESCA))
The outer surface of the hollow fiber membrane sample was measured as it was, and the inner surface was measured with a knife opened. The apparatus and measurement conditions were as follows.
(Apparatus): K-Alpha ⁺ (Thermo Fisher Scientific)
[Measurement condition]
(Excitation X-ray): Monochrome Al Kα ray (X-ray output): 12 kV, 2.5 mA
(Photoelectron escape angle): 90 °
(Spot size): About 200μmφ
(Pass energy): 50 eV
(Step): 0.1 eV

The analysis was performed as follows. The weight fraction of each component on the surface is the N element (derived from PVP), the S element (derived from the PAS polymer), the C element derived from the COO structure ((meth) acrylate copolymer) evaluated by the ESCA measurement. Derived) and the unit formula amount of each polymer. C element of COO structure has C1s spectrum as follows: (1) CHx, C—C, C═C, C—S component, (2) C—O, C—N component, (3) C = Calculation was performed based on the results of peak splitting for the five components of O-derived component, (4) COO-derived component, and (5) π-π ^* -derived component (FIG. 8). The peak derived from COO refers to a peak appearing on the high binding energy side of about 4 eV from the main peak derived from C—C or the like. Background subtraction was performed by the linear method. The weight fraction of each component on the sample surface was the average value of the measurement results at three or more locations. However, the analysis method was adjusted as appropriate because the method may vary somewhat depending on the type of PAS polymer used in the present invention and the copolymerization ratio of the (meth) acrylate copolymer.

[Example 1]
(Preparation of (meth) acrylate copolymer)
(Meth) acrylate copolymers represented by the above chemical formulas (III) and (IV) were prepared as follows. 0.445 g of azobisisobutyronitrile (AIBN) was added to 151.0 g of methoxytriethylene glycol acrylate (MTEGA) and 297.0 g of 2-ethylhexyl acrylate (EHA), and the mixture was stirred at 80 ° C. for 20 hours in 1800 g of ethyl acetate. The polymerization reaction was performed under the conditions. After the completion of the polymerization reaction, the reaction solution was added dropwise to methanol and precipitated to isolate the product. The product was dissolved in tetrahydrofuran (THF) and purified by performing dropwise addition to methanol twice. This was dried under reduced pressure at 60 ° C. all day and night to obtain the desired (meth) acrylate copolymer. The copolymerization ratio of the hydrophobic part (EHA) and the hydrophilic part (MTEGA) was 0.68: 0.32. The glass transition temperature of the polymer was −58 ° C., and the number average molecular weight was 14,000.

(Preparation of spinning dope)
As the PAS polymer, 16.5% by mass of polyethersulfone (BASF, 6020P), 3.0% by mass of PVP (Collidon K-90, BASF), 0.30 of the above (meth) acrylate copolymer. A spinning dope was prepared by kneading and dissolving 75.2% by mass of dimethylacetamide as a solvent and 5.0% by mass of RO water as a non-solvent at 60 ° C.

(Method for producing hollow fiber membrane)
The obtained spinning dope is discharged together with a core liquid (50% by mass dimethylacetamide aqueous solution) from a double tube nozzle heated to 60 ° C., and after passing through a 400 mm dry part cut off from the outside air by the spinning tube, 70 ° C. The solution was coagulated in an aqueous 30% by mass dimethylacetamide solution and passed through a 75 ° C. water-washing bath, and then rolled up at a speed of 30 m / min.

(Drying and bundling process)
The bundle of about 10,000 obtained hollow fiber membranes was cut into a length of 40 cm, wound with gauze, and then dried at 60 ° C. for 18 hours with a hot air dryer.

(Module manufacturing process)
After the obtained hollow fiber membrane bundle was inserted into the module case, the end portion of the hollow fiber membrane bundle and the case were bonded in a liquid-tight manner with a polyurethane resin. After the polyurethane resin was cured, a part of the adhesive part was cut so that the hollow part opened, and a module was prepared by attaching a header. The module thus produced was sterilized by irradiating with γ rays at an absorbed dose of 25 kGy. The results obtained by subjecting this module to the measurement evaluation as described above are shown in Table 1 and FIG.

(Micro module manufacturing process)
A polycarbonate micromodule having an inner diameter of 8 mm, an overall length of 95 mm, and an inlet port and an outlet port on the dialysate side (outside of the hollow fiber membrane) is prepared. This has a hollow fiber effective length of 75 mm, an inner diameter standard membrane area of 24 cm ² , blood The hollow fiber membrane was filled so that the linear velocity inside the hollow fiber was 1.0 cm / s when the circulation flow rate was 1.0 mL / min. Both ends were potted with urethane resin, and after curing, both ends of the hollow fiber were opened with a knife, and respective lids with ports were attached. The results obtained by subjecting this micromodule to the measurement evaluation as described above are shown in Table 1, Table 2, and FIG.

[Example 2]
In the production of the spinning dope, 16.5% by mass of polyethersulfone (BASF, 6020P) as a PAS polymer, 3.0% by mass of PVP (Collidon K-90, BASF), and the above (meth) acrylate Example 1 except that 0.90% by mass of a polymer, 74.6% by mass of dimethylacetamide as a solvent, and 5.0% by mass of RO water as a non-solvent were kneaded and dissolved at 60 ° C. to prepare a spinning dope. Modules and micromodules were produced in the same manner as described above. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 3]
Modules and micromodules were produced in the same manner as in Example 1 except that the hollow fiber membrane production method was passed through a 90 ° C. water-washing bath. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 4]
In preparing the (meth) acrylate copolymer, 0.445 g of azobisisobutyronitrile (AIBN) was added to 174.7 g of methoxytriethylene glycol acrylate (MTEGA) and 273.3 g of 2-ethylhexyl acrylate (EHA), A polymerization reaction was conducted in 1800 g of ethyl acetate at 80 ° C. for 20 hours, except that the copolymerization ratio of hydrophobic part (EHA) and hydrophilic part (MTEGA) was 0.61: 0.39. Produced a module and a micromodule in the same manner as in Example 1. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 5]
In the preparation of the spinning dope, 21.0% by mass of polyethersulfone (BASF, 6020P) as a PAS polymer, 3.5% by mass of PVP (Collidon K-90, BASF), (meth) acrylate co-polymer Example 1 except that 0.40% by mass of the coalescence, 70.4% by mass of a dimethylacetamide solvent as a solvent, and 4.7% by mass of RO water as a non-solvent were dissolved at 60 ° C. for 4 hours to prepare a spinning dope. Modules and micromodules were produced in the same manner as described above. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 6]
In preparing the spinning dope, 25.6% by mass of polyethersulfone (BASF, 6020P) as a PAS polymer, 4.0% by mass of PVP (Collidon K-90, manufactured by BASF), (meth) acrylate copolymer Example 3 except that the combined solution was 0.60% by mass, 65.4% by mass of a dimethylacetamide solvent as a solvent, and 4.4% by mass of RO water as a non-solvent was kneaded and dissolved at 60 ° C. to prepare a spinning dope. Modules and micromodules were produced in the same manner as described above. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 7]
In preparing the spinning dope, 34.5% by mass of polyethersulfone (BASF, 6020P) as a PAS polymer, 5.9% by mass of PVP (Collidon K-90, BASF), (meth) acrylate co-polymer 0.60% by mass of the coalescence, 35.4% by mass of N-methyl-2-pyrrolidone solvent as a solvent, and 23.6% by mass of triethylene glycol as a non-solvent were kneaded and dissolved at 60 ° C. to prepare a spinning dope. Except for the above, a module and a micromodule were produced in the same manner as in Example 6. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 8]
In the production of the spinning dope, 17.0% by mass of polysulfone (manufactured by SOLVAY, Udel P-1700) as a PAS polymer, 3.0% by mass of PVP (Collidon K-90 manufactured by BASF), and (meth) acrylate Except for preparing a spinning stock solution by kneading and dissolving 0.30% by mass of a polymer, 74.7% by mass of a dimethylacetamide solvent as a solvent, and 5.0% by mass of RO water as a non-solvent at 60 ° C. In the same manner as in No. 1, a module and a micromodule were produced. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 9]
In the preparation of the (meth) acrylate copolymer, 0.445 g of azobisisobutyronitrile (AIBN) was added to 100.3 g of methoxytriethylene glycol acrylate (MTEGA) and 339.2 g of 2-ethylhexyl acrylate (EHA), A polymerization reaction was carried out in 1800 g of ethyl acetate at 80 ° C. for 20 hours, and a copolymer having a hydrophobic part (EHA) and hydrophilic part (MTEGA) copolymerization ratio of 0.79: 0.21 was used. Produced a module and a micromodule in the same manner as in Example 1. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Example 10]
In the preparation of the spinning dope, 14.5% by mass of polyethersulfone (BASF, 6020P) as a PAS polymer, 5.0% by mass of PVP (Collidon K-90, BASF), (meth) acrylate co-polymer Example 1 except that the combined stock was 0.30% by mass, 75.2% by mass of dimethylacetamide solvent as a solvent, and 5.0% by mass of RO water as a non-solvent was dissolved at 60 ° C. for 4 hours to prepare a spinning stock solution. Modules and micromodules were produced in the same manner as described above. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Comparative Example 1]
(Preparation of spinning dope)
16.5% by mass of polyethersulfone (BASF, 6020P) as a PAS polymer, 3.0% by mass of PVP (Collidon K-90, BASF), 75.5% by mass of a dimethylacetamide solvent as a solvent, As a non-solvent, 5.0% by mass of RO water was kneaded and dissolved at 60 ° C. to prepare a spinning dope.

(Method for producing hollow fiber membrane)
The obtained film-forming stock solution was discharged as a core solution together with a 50% by mass dimethylacetamide aqueous solution from a double-tube nozzle heated to 60 ° C., passed through a 400 mm dry section cut off from the outside air by a spinning tube, and then passed through 70 ° C. The solution was coagulated in an aqueous 30% by mass dimethylacetamide solution and passed through a 75 ° C. water-washing bath, and then rolled up at a speed of 30 m / min.

(Drying and bundling process)
The bundle of about 10,000 obtained hollow fiber membranes was cut into a length of 40 cm, wound with gauze, and then dried at 60 ° C. for 18 hours with a hot air dryer.

((Meth) acrylate copolymer coating)
The obtained hollow fiber membrane was dip-coated with a 0.05% by mass ethanol aqueous solution of a (meth) acrylate copolymer and air-dried.

(Module manufacturing process)
After the obtained hollow fiber membrane bundle was inserted into the module case, the end portion of the hollow fiber membrane bundle and the case were bonded in a liquid-tight manner with a polyurethane resin. After the polyurethane resin was cured, a part of the adhesive part was cut so that the hollow part opened, and a module was prepared by attaching a header. The module thus produced was sterilized by irradiating with γ rays at an absorbed dose of 25 kGy. The results obtained by subjecting this module to the measurement evaluation as described above are shown in Table 1 and FIG.

(Micro module manufacturing process)
A polycarbonate micromodule having an inner diameter of 8 mm, an overall length of 95 mm, and an inlet port and an outlet port on the dialysate side (outside of the hollow fiber membrane) is prepared. This has a hollow fiber effective length of 75 mm, an inner diameter standard membrane area of 24 cm ² , blood The hollow fiber membrane was filled so that the linear velocity inside the hollow fiber was 1.0 cm / s when the circulation flow rate was 1.0 mL / min. Both ends were potted with urethane resin, and after curing, both ends of the hollow fiber were opened with a knife, and respective lids with ports were attached. Table 1 shows the results obtained by subjecting the micromodule to the measurement evaluation as described above.

[Comparative Example 2]
In the coating of the (meth) acrylate copolymer, the module and the micromodule were prepared in the same manner as in Comparative Example 1 except that the (meth) acrylate copolymer 0.5 mass% ethanol aqueous solution was dip coated and air-dried. Produced. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Comparative Example 3]
In the coating of the (meth) acrylate copolymer, the module and the micromodule were prepared in the same manner as in Comparative Example 1 except that the (meth) acrylate copolymer 0.15 mass% ethanol aqueous solution was dip coated and air-dried. Produced. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Comparative Example 4]
A hollow fiber membrane and a module were prepared in the same manner as in Comparative Example 1 except that in the coating of the (meth) acrylate copolymer, a 1.0% by mass ethanol solution of the (meth) acrylate copolymer was dip-coated and air-dried. Was made. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Comparative Example 5]
In preparing the spinning dope, 16.5% by mass of polyethersulfone (BASF, 6020P) as a PAS polymer, 3.0% by mass of PVP (Collidon K-90, BASF), and a dimethylacetamide solvent as a solvent. A module and a micromodule were prepared in the same manner as in Example 1 except that 75.5% by mass and 5.0% by mass of RO water as a non-solvent were kneaded and dissolved at 60 ° C. to prepare a spinning stock solution. Tables 1 and 2 and FIGS. 10 and 11 show the results obtained for the measurement evaluation as described above.

[Comparative Example 6]
In the production of the (meth) acrylate copolymer, 0.445 g of azobisisobutyronitrile (AIBN) was added to 448.0 g of methoxytriethylene glycol acrylate (MTEGA), and the mixture was stirred at 80 ° C. for 20 hours in 1800 g of ethyl acetate. A module and a micromodule were produced in the same manner as in Example 1 except that a polymerization reaction was performed under the conditions and a hydrophilic part (MTEGA) having a 100% content was used. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

[Comparative Example 7]
In the preparation of the (meth) acrylate copolymer, 0.445 g of azobisisobutyronitrile (AIBN) was added to 448.0 g of 2-ethylhexyl acrylate (EHA), and the conditions of 80 ° C. and 20 hours in 1800 g of ethyl acetate were added. A hollow fiber membrane and a module were produced in the same manner as in Example 1 except that a polymerization reaction was performed and a hydrophobic part (EHA) of 100% was used. The results obtained for the measurement evaluation as described above are shown in Table 1 and FIG.

  As is apparent from the results of Tables 1 and 2 and FIGS. 10 and 11, Example 1-10 has a hollow fiber membrane that is excellent in dialysis performance balance and excellent in anti-inflammatory properties. On the other hand, in Comparative Example 1-4, as a result of dip coating the (meth) acrylate copolymer after hollow fiber membrane formation, the amount of the copolymer attached to the membrane surface increased, Permeability (removability) of β2 microglobulin was lower than the amount of water permeated to block the pores. In Comparative Example 5, the increase rate RI of inflammatory cytokines (TNF-α and IL-6), which is an anti-inflammatory index, was larger than that of the Examples as a result of not giving the (meth) acrylate copolymer. became. In addition, the number of residual blood modules increased slightly. In Comparative Example 6, as a result of producing a hollow fiber membrane by adding a hydrophilic acrylate homopolymer to the spinning dope, the increase rate RI of inflammatory cytokines (TNF-α and IL-6), which are anti-inflammatory indicators, is It became large compared with the Example. In addition, the number of residual blood modules increased slightly. Furthermore, the UV absorbance of the extract increased. In Comparative Example 7, a homopolymer of hydrophobic acrylate was added to the spinning dope to produce a hollow fiber membrane. As a result, the increase rate RI of inflammatory cytokines (TNF-α and IL-6), which are anti-inflammatory indicators, was It became large compared with the Example. In addition, the number of residual blood modules increased slightly.

  The hollow fiber membrane of the present invention has a long-term hemodialysis history because it not only excels in water permeability and waste removal, but can also suppress the production of inflammatory reaction substances when in contact with blood. It can be applied to patients with peace of mind.

1: Module 2: Module case 3: Hollow fiber membrane 4: Adhesive 5: Cap 6a: Dialysate inlet 6b: Dialysate outlet 7a: Blood inlet 7b: Blood outlet

Claims (9)

A water-insoluble (meth) comprising a polyarylsulfone-based polymer, polyvinylpyrrolidone, and an alkyl (meth) acrylate represented by the following general formula (I) and a methoxypolyethylene glycol (meth) acrylate represented by the following general formula (II) A hollow fiber membrane comprising an acrylate copolymer, wherein the content of the (meth) acrylate copolymer is 0.5 to 5% by mass when the hollow fiber membrane is measured using nuclear magnetic resonance spectroscopy A hollow fiber membrane having a (meth) acrylate copolymer content of 5 to 30% by mass when the inner surface of the hollow fiber membrane is measured using X-ray photoelectron spectroscopy.
(Wherein R ₁ is an alkyl group or aralkyl group having 2 to 30 carbon atoms, R ₂ and R ₃ are hydrogen atoms or methyl groups, k is an integer of 1 to 1000, and m and n are Indicates the ratio of polymerization, m + n = 1.) The hollow fiber according to claim 1, wherein the alkyl (meth) acrylate is represented by the following general formula (III), and the methoxypolyethylene glycol (meth) acrylate is represented by the following general formula (IV). film.
  The hollow fiber membrane according to claim 2, wherein in the general formulas (III) and (IV), m = 0.5 to 0.9 and n = 0.1 to 0.5.   When the hollow fiber membrane was measured using nuclear magnetic resonance spectroscopy, the content of polyvinylpyrrolidone in the hollow fiber membrane was 0.5 to 5% by mass, and the inner surface of the hollow fiber membrane was subjected to X-ray photoelectron spectroscopy. The hollow fiber membrane in any one of Claims 1-3 whose content rate of polyvinylpyrrolidone is 5-30 mass% when measured using this.   The hollow fiber membrane according to any one of claims 1 to 4, wherein the polyarylsulfone-based polymer is polyethersulfone.   The hollow fiber membrane according to any one of claims 1 to 5, wherein the hollow fiber membrane is for blood purification.   A hollow fiber membrane module loaded with the hollow fiber membrane according to any one of claims 1 to 6, wherein the two or more fluid inlets and outlets communicate with the inner cavity of the hollow fiber membrane and the outer cavity of the hollow fiber membrane. A hollow fiber membrane module comprising the above fluid inlet / outlet.   A method for producing the hollow fiber membrane according to any one of claims 1 to 6, wherein the spinning dope is obtained by mixing a polyarylsulfone-based polymer, polyvinylpyrrolidone, a (meth) acrylate copolymer, and a solvent. And a step of discharging the core liquid together with the core liquid from a double ring nozzle and immersing in an external coagulation liquid.   The said spinning dope contains 10-50 mass% of polyaryl sulfone type polymers, 1-10 mass% of polyvinylpyrrolidone, and 0.1-1.5 mass% of (meth) acrylate copolymers. A method for producing a hollow fiber membrane.