JP6558063B2 - Hollow fiber membrane module and manufacturing method thereof - Google Patents

Description

The present invention relates to a hollow fiber membrane module and a method for producing the hollow fiber membrane module.

  In recent years, separation of substances by a hollow fiber membrane module incorporating a hollow fiber membrane has been actively performed. In particular, in blood purification therapy such as renal failure treatment, it is widely used as a blood purification device such as hemodialyzer, hemofilter, hemodialysis filter, etc. for the purpose of removing uremic toxins and waste products in the blood. .

  The hollow fiber membrane module has a wet type in which the container is filled with liquid and the hollow fiber membrane is completely filled with liquid, a semi-dry type in which the container is not filled with liquid but only the hollow fiber membrane is wet, hollow There is a dry type in which the yarn membrane hardly contains moisture. Among them, the dry type is advantageous in that it does not contain water and is light in weight, and has a low risk of performance deterioration due to freezing even in cold regions.

As hollow fiber membranes used for blood purification applications, high-performance hollow fiber membranes having a large pore diameter are mainly used. A membrane material made of a hydrophobic polymer is mainly used for removing a large amount of medium and high molecular weight pathogenic proteins such as β ₂ -microglobulin.

  However, when a hydrophobic polymer is used, since the membrane surface is highly hydrophobic, blood activation may occur and blood coagulation may progress when contacted with blood. Therefore, it is widely performed to improve the hydrophilicity of the film surface by adding a hydrophilic polymer.

  As a method of adding a hydrophilic polymer, a method of adding a hydrophilic polymer to a hollow fiber membrane forming raw solution, or a hollow fiber membrane obtained by immersing the formed hollow fiber membrane in a solution containing the hydrophilic polymer A method of imparting a hydrophilic polymer to the surface is common.

  Moreover, when using a hollow fiber membrane module for blood purification as mentioned above, since it is a medical device, it is indispensable to sterilize. As sterilization methods, there are techniques such as ethylene oxide gas sterilization and high-pressure steam sterilization. As a simple sterilization method capable of obtaining a high sterilization effect even in a packaged state, a sterilization method using radiation has been widely used in recent years. However, there is a concern that a degradation product is generated from the hollow fiber membrane or the potting agent by irradiation of the radiation, and the degradation product is eluted during clinical use, thereby causing side effects.

  A method for suppressing elution of hydrophilic polymer by irradiating a hollow fiber membrane module with water in a state filled with water is widely known. By irradiating with radiation in water, the hydrophilic polymer is cross-linked with the hydrophobic polymer constituting the membrane, thereby reducing the eluate. However, in this method, the hollow fiber membrane module has to be filled with water, resulting in problems such as a heavy module and poor handling. Therefore, a method of performing radiation sterilization without filling water has been proposed.

  Since the handling property of the hollow fiber membrane module can be increased and the risk of freezing during storage can be reduced, the dry-type hollow fiber membrane module containing no filling water is very useful. However, when performing sterilization by radiation in the absence of filling water, depending on the state of the atmosphere around the hollow fiber at the time of irradiation, the performance of the hollow fiber membrane deteriorates and the components constituting the hollow fiber membrane are eluted. There is a risk of coming.

  In Patent Document 1, reduction of eluate is achieved by irradiating radiation in a state where the oxygen concentration is 0.1% or more and 3.6% or less and the moisture content of the hollow fiber membrane is 4 to less than 300%. Yes.

  In patent document 2, the reduction | decrease of an elution is achieved by irradiating a radiation in the state whose moisture content is 3% or less and the relative humidity of hollow fiber membrane surrounding atmosphere is 40% or less.

  In Patent Document 3, the oxygen concentration is 0.001% or more and 0.1% or less, the moisture content relative to the weight of the hollow fiber membrane is 0.2 to 7% by weight or less, and the relative humidity at 25 ° C. is A method of irradiating radiation in a packaging bag atmosphere greater than 40% Rh is disclosed.

JP 2003-245526 A JP 2000-288085 A Japanese Patent No. 4846587

  According to the method described in Patent Document 1, the biocompatibility is reduced when the oxygen concentration is extremely low. In addition, as a result of studies by the present inventors, it has been found that when the water content is further lowered, the eluate tends to increase, and a reduction in the eluate at a higher level is required.

  In the method described in Patent Document 2, there is no description regarding the oxygen concentration at the time of radiation irradiation, and there is a fear that the hollow fiber membrane material is deteriorated due to the generation of oxygen radicals and the amount of eluate is increased as in the method of Patent Document 1.

  The method described in Patent Document 3 requires the use of an oxygen scavenger or the like that releases moisture in order to make the relative humidity greater than 40% Rh. For this reason, there is a limitation that it is necessary to use a packaging container having a low oxygen permeability and a low water vapor permeability. In addition, there was no mention of a solution to the problem of a decrease in biocompatibility when the oxygen concentration was low.

  Further, in the examination according to the present invention, when the water content at the time of radiation irradiation is low, the above elution problem cannot be solved simply by reducing the oxygen concentration when the hollow fiber membrane is irradiated with radiation. all right.

  An object of the present invention is to provide a hollow fiber membrane module which improves the drawbacks of the prior art and has less eluate even after radiation sterilization and is excellent in blood compatibility.

As a result of diligent investigations to solve the above problems, the present inventors have found that a hollow fiber membrane module with little eluate after radiation sterilization and high blood compatibility can be achieved by the following configuration. It was.
(1) A hollow fiber membrane satisfying the following conditions (A) and (B) in which a hydrophilic polymer having no hydrophobic unit is blended with a base material made of a hydrophobic polymer is incorporated,
A hollow fiber membrane module obtained by irradiating the hollow fiber membrane with radiation under a condition that the moisture content with respect to the mass of the hollow fiber membrane is 0% to 25% by mass.
(A) When measured by X-ray electron spectroscopy, the area percentage of the carbon peak derived from the ester group on the surface of the functional layer of the hollow fiber membrane is 1 to 10 (number of atoms) or less (B) exceeding 37 ° C When pure water is circulated at 200 mL / min for 4 hours, the amount of eluate eluted from the hollow fiber membrane is 1.0 mg / m ² or less. (2) The substrate made of a hydrophobic polymer does not have a hydrophobic unit. A step of producing a hollow fiber membrane from a membrane-forming stock solution containing a hydrophilic polymer, and a step of washing the hollow fiber membrane with a washing liquid containing 0.002% by mass or more and 0.05% by mass or less of a polymer containing an ester group When,
The hollow fiber membrane is built in the module, and the oxygen concentration in the atmosphere around the hollow fiber membrane is 0 to 1%, and the moisture content with respect to the mass of the hollow fiber membrane is 0 to 25% by mass. A method for producing a hollow fiber membrane module, wherein the hollow fiber membrane is irradiated with radiation.

  In the present invention, by providing an ester group-containing polymer to the surface of the functional layer of the hollow fiber membrane, it is possible to provide a hollow fiber membrane module that has less eluate and is excellent in blood compatibility even after radiation sterilization.

  In addition, the functional layer surface as used in the field of this invention is the surface of the outer surface and inner surface of a hollow fiber membrane in the side which contacts a to-be-processed substance. Taking the hollow fiber membrane for artificial kidneys as an example, the surface inside the hollow fiber through which blood as the liquid to be treated flows is the functional layer surface.

It is the schematic which shows an example of the hollow fiber membrane module which concerns on this invention.

  The hollow fiber membrane module of the present invention can separate the target substance and the waste substance that are desired to be recovered from the mixed solution. FIG. 1 is a schematic view showing an embodiment of the hollow fiber membrane module of the present invention. The hollow fiber membrane module preferably includes a case 11 and a hollow fiber membrane 13, and the case 11 preferably includes the hollow fiber membrane 13. Specifically, a bundle of hollow fiber membranes 13 cut to a required length is preferably stored in a cylindrical case 11. It is preferable that both ends of the hollow fiber membrane are fixed to both ends of the cylindrical case 11 by a potting material 17 or the like. At this time, it is preferable that both ends of the hollow fiber membrane are open.

  The hollow fiber membrane module preferably includes headers 14A and 14B at both ends of the case 11. The header 14A preferably includes a liquid inlet 15A to be processed. The header 14B preferably includes a liquid discharge port 15B to be processed. Further, the hollow fiber membrane module is preferably provided with nozzles 16A and 16B on the side surface portion of the case and in the vicinity of both end portions of the case as shown in FIG.

  Normally, the liquid to be processed is introduced from the liquid inlet 15A to be processed, passes through the inside of the hollow fiber membrane, and is discharged from the liquid outlet 15B. On the other hand, the processing liquid is usually introduced from the nozzle 16A (processing liquid inlet), passes through the outside of the hollow fiber membrane, and is discharged from the nozzle 16B (processing liquid outlet). That is, normally, the flow direction of the liquid to be treated is opposite to the flow direction of the treatment liquid.

  When the hollow fiber membrane module of the present invention is used for artificial kidney applications (blood purification applications), the blood to be treated is usually introduced from the treatment liquid inlet 15A, and the inside of the hollow fiber membrane is introduced inside the hollow fiber membrane. By passing, the blood is artificially dialyzed, and the purified blood, which is the collection target substance, is discharged from the liquid outlet 15B. That is, the flow path from the liquid inlet 15A to the liquid outlet 15B through the inside of the hollow fiber membrane is the liquid flow path (blood side flow path). Hereinafter, this channel may be simply referred to as “blood side channel”.

  On the other hand, the dialysis fluid as the treatment liquid is introduced from the nozzle 16A (treatment liquid inlet) and passes through the outside of the hollow fiber membrane to purify (dialyze) the liquid to be treated (blood), and the nozzle 16B (treatment liquid). From the discharge port, dialysate containing toxic components (waste substances) in the blood is discharged. That is, the flow path from the nozzle 16 </ b> A to the nozzle 16 </ b> B through the outside of the hollow fiber membrane becomes a flow path (dialysis liquid flow path) for the treatment liquid. Hereinafter, this channel may be simply referred to as “dialysate channel”.

  The hollow fiber membrane incorporated in the module is obtained by blending a hydrophilic polymer having no hydrophobic unit with a hydrophobic polymer as a base material. Here, the “base material” refers to a component having the highest content among the components constituting the hollow fiber membrane.

  In the present invention, the hydrophobic polymer refers to a polymer having a solubility in 100 g of water at 20 ° C. of less than 0.001 g. The hydrophilic polymer refers to a polymer having a solubility of 1 g or more in 100 g of water at 20 ° C. Further, in the following description, the hydrophobic unit refers to a 20 ° C. water of the polymer obtained when a polymer composed only of the monomer unit among the monomer units constituting the polymer is prepared. The solubility with respect to 100 g is less than 1 g, preferably 0.1 g or less. The hydrophilic unit is a monomer unit constituting a polymer, and when a polymer composed only of the monomer unit is prepared, the resulting polymer has a solubility of 1 g or more in 100 g of water at 20 ° C. Refers to things.

  Specific examples of the hydrophobic polymer include, but are not limited to, a polysulfone polymer, polystyrene, polyurethane, polyethylene, polypropylene, polyacrylonitrile, and the like. Among these, a polysulfone polymer is preferably used because it is easy to form a hollow fiber membrane. Furthermore, the polysulfone-based polymer is preferable because it can be easily coated with an ester group-containing polymer described later. Here, the polysulfone polymer is a polymer having an aromatic ring, a sulfonyl group and an ether group in the main chain, and examples thereof include polysulfone, polyethersulfone, and polyallylethersulfone. For example, a polysulfone polymer represented by the following chemical formula (1) or (2) is preferably used, but the present invention is not limited thereto. N in the formula is preferably 50 to 80, for example.

  Specific examples of polysulfone include Udel (registered trademark) Polysulfone P-1700, P-3500 (manufactured by Solvay), Ultrason (registered trademark) S3010, S6010 (manufactured by BASF), Victrex (registered trademark) (Sumitomo Chemical) ), Radel (registered trademark) A (manufactured by Solvay), and Ultrason (registered trademark) E (manufactured by BASF). Further, as the polysulfone, a polymer composed only of the repeating unit represented by the above formula (1) and / or (2) is preferable, but it is possible to co-polymerize with other monomers as long as the effects of the present invention are not hindered. It may be a combined or modified product. Although it does not specifically limit, it is preferable that another copolymerization monomer is 10 mass% or less.

  When forming a hollow fiber membrane, it is necessary to blend a hydrophilic polymer as a pore-forming agent and for adjusting the viscosity of the membrane-forming stock solution. Such a hydrophilic polymer does not have a hydrophobic unit. Specific examples include polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, and polypropylene glycol. Preferably, at least one hydrophilic polymer selected from polyvinyl pyrrolidone, polyethylene glycol and polyvinyl alcohol. Among these, when a polysulfone polymer is used as the hydrophobic polymer, polyvinylpyrrolidone is preferably used from the viewpoint of compatibility and safety.

However, the hydrophilic polymer blended in this way often causes an eluate after irradiation. The cause is considered to be that the hydrophilic polymer elutes because the interaction between the hydrophobic polymer and the hydrophilic polymer is weak. In particular, in the case of a dry type module having a low moisture content of the hollow fiber membrane, it is considered that the crosslinking reaction by radiation between the hydrophobic polymer and the hydrophilic polymer is less likely to occur, so that the elution is easier. Whether or not it contains a hydrophilic polymer can be measured using X-ray electron spectroscopy described later. For example, when the hydrophobic polymer is polysulfone and the hydrophilic group-containing polymer is polyvinylpyrrolidone, from the amount of nitrogen (c (number of atoms%)) and the measured amount of sulfur (d (number of atoms%)), The content (% by weight) of polyvinylpyrrolidone can be calculated by the following formula. Here, 111 is the molecular weight of the vinylpyrrolidone group, and 442 is the molecular weight of the repeating unit constituting the polysulfone.
Polyvinylpyrrolidone content (f) = 100 × (c × 111) / (c × 111 + d × 442).

  In addition, it is possible to extract the hydrophilic polymer in the hollow fiber membrane by dissolving the hollow fiber membrane in a good solvent of a hydrophobic polymer immiscible with water and then adding water. Thus, it can be confirmed whether the hydrophilic group containing polymer contains by measuring NMR and IR of the polymer extracted with water. For example, when the hydrophobic polymer is polysulfone and the hydrophilic group-containing polymer is polyvinylpyrrolidone, a good solvent for the hydrophobic polymer that is immiscible with water is dichloromethane.

  The present invention is characterized in that an ester group is present on the surface of the functional layer of the hollow fiber membrane. Due to the presence of ester groups on the surface of the functional layer of the hollow fiber membrane, protein and platelet adhesion is suppressed. Although the detailed mechanism is unknown, the hydrophilicity of the ester group is moderate, and the state of water on the surface of the functional layer and the state of water around the protein are almost the same, thereby preventing nonspecific adsorption of proteins. It is thought that it can be suppressed.

  From the above, it is important that the ester group exists on the surface of the functional layer of the hollow fiber membrane. The amount of ester groups on the surface of the hollow fiber membrane can be determined by measuring the amount of carbon derived from the ester groups on the surface of the hollow fiber membrane using X-ray electron spectroscopy (XPS). In order to exert the effect of suppressing the adhesion of proteins and platelets, when measured by X-ray electron spectroscopy (XPS), when the total peak area derived from carbon on the surface of the functional layer is 100 (atomic%) The percentage of the carbon peak area derived from the ester group is preferably 1 (number of atoms%) or more, preferably 1.2 (number of atoms%) or more, and more preferably 1.5 (number of atoms%) or more. On the other hand, if the amount of the ester group is too large, the performance of the film may be deteriorated. Therefore, the percentage of the carbon peak area derived from the ester group is 10 (atomic%) or less, and 5 (atomic%) or less. Is preferred.

  When the amount of carbon derived from ester groups on the surface of the hollow fiber membrane is determined by X-ray electron spectroscopy (XPS), a value measured at 90 ° is used as the measurement angle. When measured at a measurement angle of 90 °, a region having a depth of up to about 10 nm from the surface is detected. Moreover, it measures about three different places of a hollow fiber membrane, and uses the average value of these three places. The peak of the carbon derived from the ester group (COO) can be obtained by dividing the peak appearing at +4.0 to 4.2 eV from the main peak derived from CH of C1s or C—C. By calculating the ratio of the peak area derived from the ester group to the total peak area derived from carbon, the carbon amount (number of atoms%) derived from the ester group can be obtained. More specifically, the C1s peak is mainly derived from CHx, C—C, C═C, C—S, mainly derived from C—O, C—N, and π-π * satellite. It is composed of five components: a component, a component derived from C = O, and a component derived from COO. Peak splitting is performed on the above five components. The COO-derived component is a peak that appears at +4.0 to 4.2 eV from the main peak of CHx and C—C (near 285 eV). The peak area ratio of each component is calculated by rounding off the second digit of the decimal point. As a result of peak division, if the peak area percentage was 0.4% or less, it was set below the detection limit.

  As a method for introducing an ester group to the surface of the functional layer, a compound containing an ester group can be used relatively easily. The compound containing an ester group is preferably a polymer. From the viewpoint of the efficiency of introduction into the membrane, the part containing an ester group is preferably a hydrophobic unit. Specific examples of such a polymer include, but are not limited to, carboxylic acid vinyl esters such as vinyl acetate; acrylic acid esters such as methyl acrylate and methoxyethyl acrylate; methacrylic acid such as methyl methacrylate, ethyl methacrylate, and hydroxyethyl methacrylate. Examples include acid esters. Furthermore, it is preferable that the ester group-containing polymer is composed of a copolymer of a hydrophobic unit and a hydrophilic unit, and the hydrophobic unit contains an ester group. In particular, from the viewpoint of introduction efficiency into the membrane and blood compatibility, it is preferable to use a copolymer composed of vinyl acetate and vinylpyrrolidone, but it is not limited to this. In the copolymer of hydrophobic units and hydrophilic units, if the ratio of the hydrophobic units is small, the interaction with the hydrophobic polymer constituting the membrane is weakened, and the introduction efficiency is difficult to increase. On the other hand, if the ratio of the hydrophobic unit is large, the hydrophilicity of the inner surface of the hollow fiber membrane is lowered and blood compatibility is lowered. Therefore, the proportion of hydrophobic units is preferably 20 mol% or more, and more preferably 30% or more. The proportion of hydrophobic units is preferably 80 mol% or less, and more preferably 70 mol% or less.

  Examples of the method for introducing the ester group-containing polymer onto the surface of the functional layer include the following methods. A method of adding an ester group-containing polymer to a film-forming stock solution, a method of adding an ester group-containing polymer to a core solution that is flowed inward from a double ring cap when forming a hollow fiber membrane, and a hollow fiber membrane Examples include a method of coating the surface of the hollow fiber membrane with a solution to which an ester group-containing polymer is added later. Among these, a method of coating the hollow fiber membrane surface with a solution to which an ester group-containing polymer is added after film formation is preferably used. As will be described later, by coating the surface of the hollow fiber membrane with an ester group-containing polymer after film formation, it is possible to reduce eluate after irradiation.

  Next, among the methods for coating the surface of the hollow fiber membrane with the ester group-containing polymer after film formation, the most preferred embodiment will be described. In this embodiment, the hollow fiber membrane is washed using a washing liquid containing the ester group-containing polymer. The hydrophilic polymer blended in the film-forming stock solution may be in a state of being intertwined well with the hydrophobic polymer that constitutes the film or in a state of being only adsorbed on the surface of the film after the film formation. it is conceivable that. It is considered that the latter, that is, a hydrophilic polymer that is only adsorbed on the membrane surface, is likely to elute during use. Therefore, it is considered that the eluate can be reduced by removing the hydrophilic polymer in this state by washing. As the method, there is a method of washing with hot water or an organic solvent. However, when washed with hot water or an organic solvent, the hydrophilic compatibility of the membrane may be lowered due to a decrease in the hydrophilic polymer amount present on the membrane surface. Therefore, in this aspect, by adding the ester group-containing polymer to the cleaning liquid, the hydrophilic polymer that causes the eluate is washed, and the surface of the membrane has high blood compatibility. It has been found that it can be coated with a polymer, and as a result, it is possible to simultaneously achieve a reduction in eluate and an increase in biocompatibility.

  Since the ester group-containing polymer has a high affinity with the hydrophobic polymer that constitutes the membrane, the addition of the ester group-containing polymer to the cleaning liquid can reduce the affinity with the hydrophilic polymer that has a low affinity with the membrane. By performing the replacement, the cleaning efficiency is further increased. Further, since the added ester group-containing polymer is coated on the portion where the hydrophilic polymer is washed away by washing, it is possible to further improve the blood compatibility of the membrane.

  Since the material of the hollow fiber membrane is a hydrophobic polymer, the main interaction is a hydrophobic interaction. Therefore, by using an ester group-containing polymer having a hydrophobic unit, the affinity for the hydrophobic polymer is improved, and the efficiency of cleaning and coating of the film surface is improved.

  The ester group-containing polymer to be added to the washing solution is not particularly limited. However, as described above, the hydrophobic unit and the hydrophilic unit may be combined from the viewpoint of interaction with the hydrophobic polymer and from the viewpoint of blood compatibility. Polymers made of polymers are preferred. If the hydrophobicity is too strong, the blood compatibility of the coated membrane surface may be reduced. On the other hand, if the hydrophobicity is too weak, a sufficient cleaning effect may not be obtained. Examples of the cleaning liquid include water and organic solvents, and water is preferably used from the viewpoint of the hydrophobic interaction between the membrane material and the ester group-containing polymer. Therefore, a water-soluble hydrophilic polymer is preferably used as the ester group-containing polymer. A polymer containing an ester group in the side chain of the hydrophilic polymer or a polymer comprising a copolymer of a hydrophobic unit and a hydrophilic unit containing an ester group is useful. For example, when the membrane material hydrophobic polymer is a polysulfone resin and the hydrophilic polymer is polyvinyl pyrrolidone, the ester group-containing polymer added to the cleaning liquid is a polymer made of a copolymer of vinyl acetate and vinyl pyrrolidone. Preferably used.

  In addition, when water is used as the cleaning liquid, as a method for improving the hydrophobic interaction between the ester group-containing polymer and the membrane material, the hydrogen bonding hydration between the hydrophilic unit of the ester group-containing polymer and water is inhibited by ions. It is useful to stabilize. For example, when the hydrophilic unit of the ester group-containing polymer is vinylpyrrolidone, hydration is stabilized by a cation, but hydration is destabilized by an anion. That is, by making the aqueous solution anionic, the interaction between the ester group-containing polymer and water decreases, and the hydrophobic interaction between the ester group-containing polymer and the membrane material becomes relatively stronger. Thereby, the cleaning effect by the ester group-containing polymer and the introduction efficiency to the film surface are improved. Here, examples of the cation include lithium ions, and examples of the anion include fluorine ions, but are not limited thereto.

  In addition, it is known that ester groups such as vinyl acetate tend to generate radicals when irradiated with radiation. For this reason, it is considered that the ester group-containing polymer has a merit that it easily causes a crosslinking reaction with the material of the hollow fiber membrane even under conditions where the water content is low and the generation of radicals by water is small.

  When the amount of the ester group-containing polymer added to the cleaning liquid is too small, the cleaning effect cannot be sufficiently obtained, and blood compatibility cannot be sufficiently imparted, so 20 ppm or more is preferable, and more preferably 50 ppm. More preferably, it is 75 ppm or more. On the other hand, if the amount of the ester group-containing polymer to be added is too large, the added ester group-containing polymer itself may be eluted from the hollow fiber membrane, so 500 ppm or less is preferable, more preferably 300 ppm or less, 200 ppm or less is preferable.

  Examples of the method of flowing the cleaning liquid include a method in which the cleaning liquid is brought into contact only with the surface of the functional layer of the hollow fiber membrane, and a method of flowing the cleaning liquid in the film thickness direction from the functional layer surface of the hollow fiber membrane. From the viewpoint of improving the cleaning efficiency and introducing the ester group-containing polymer onto the surface of the functional layer, a method of flowing a cleaning liquid from the surface of the functional layer in the film thickness direction is preferably used. The cleaning time is preferably 10 seconds or more, and the flow rate of the cleaning liquid is preferably 200 to 1000 mL / min.

  The temperature of the cleaning liquid is preferably 100 ° C. or lower, more preferably 90 ° C. or lower, because if the temperature is too high, the performance of the hollow fiber membrane may be lowered. Increasing the temperature of the cleaning liquid is not preferable from the viewpoint of production efficiency because it requires equipment for heating. On the other hand, since the hydration becomes unstable when the temperature of the cleaning liquid is high, the hydrophobicity of the ester group-containing polymer is relatively increased, and the cleaning efficiency is increased. Therefore, the temperature of the cleaning liquid is preferably 25 ° C. or higher, more preferably 50 ° C. or higher, and further preferably 70 ° C. or higher. In particular, when an ester group-containing polymer having a cloud point is used, it is preferable to wash at a temperature equal to or higher than the cloud point.

In addition, it is desirable from the viewpoint of blood compatibility that the functional layer surface of the hollow fiber membrane is uniformly coated with an ester group-containing polymer. The distribution of the ester group-containing polymer on the surface of the functional layer can be measured by total reflection infrared spectroscopy (ATR). As an ATR measurement method, the measurement range is 3 μm × 3 μm, the number of integration is 30 times or more, and 25 infrared absorption spectra are measured. This 25-point measurement is performed on three hollow fiber membranes per module at three different locations for one hollow fiber membrane. In the obtained infrared absorption spectrum, a reference line is drawn at 1711 to 1759 cm ⁻¹ , and a part surrounded by the reference line and the positive part of the spectrum is defined as a polyvinylpyrrolidone-derived peak area (A _CCO ). Similarly, a reference line is drawn at 1549 to 1620 cm ⁻¹ , and a portion surrounded by the reference line and the positive portion of the spectrum is defined as a peak area derived from the polysulfone-derived benzene ring C═C (A _CC ), and a ratio between the two ( Calculate A _CCO ) / (A _CC ). This (A _CCO ) / (A _CC ) is preferably an average value of 0.01 or more, more preferably 0.03 or more, and still more preferably 0.05 or more. On the other hand, if the ratio of the ester group is too large, the hydrophobicity of the surface becomes strong and the blood compatibility may be lowered. Therefore, the average value is preferably 0.3 or less, more preferably 0.2 or less, Is preferably 0.15 or less.

  If the water content of the hollow fiber membrane filled in the hollow fiber membrane module is too large, there is a concern about the growth of bacteria during storage, and when the hollow fiber membrane is frozen, the performance may be lowered. On the other hand, if the dry type has a low water content, the hollow fiber membrane module can be reduced in weight, and the transportation cost and safety can be improved. Moreover, in the hollow fiber membrane module in which the hollow fiber membrane is substantially dry, the bubble removal property during use is improved. From the above, the moisture content of the present hollow fiber membrane is preferably 25% by mass or less, more preferably 10% by mass or less, and further preferably 4% by mass or less.

  Here, the moisture content in the present invention is the mass (a) of the hollow fiber membrane module, the mass (b) of the hollow fiber membrane module after the hollow fiber membrane is dried to the absolutely dry state, and the hollow fiber membrane in the absolutely dry state. The mass (c) is measured, and the moisture content (% by mass) = 100 × (ab) / c is calculated.

  Moreover, when measuring in the state of a hollow fiber membrane bundle, the mass (d) of the hollow fiber bundle before drying and the mass (e) of the hollow fiber membrane bundle in an absolutely dry state are measured, and the moisture content (mass%). = 100 × (d−e) / e In either case, the measured value is rounded off to the first decimal place.

  Examples of the method for drying the hollow fiber membrane include a method in which a gas such as compressed air or nitrogen is allowed to flow into the hollow fiber membrane module, a method in which the hollow fiber membrane is dried by irradiation with microwaves, and a method in which drying is performed under reduced pressure.

  Next, the manufacturing method of a hollow fiber membrane is demonstrated. The hollow fiber membrane is preferably a membrane having an asymmetric structure composed of a functional layer contributing to separation performance and a support layer contributing to mechanical strength of the membrane from the viewpoint of water permeability and separation performance.

  Such a hollow fiber membrane is formed by feeding a membrane-forming stock solution containing a hydrophobic polymer and its good solvent, a poor solvent and a hydrophilic polymer containing no hydrophobic unit from the slit portion of the double tube cap from the circular tube portion. It is preferable to produce by discharging the liquid and allowing it to pass through a dry part and then solidify in a coagulation bath.

  Here, the good solvent is a solvent that dissolves the hydrophobic polymer in the film-forming stock solution. Although there is no particular limitation, when a polysulfone polymer is used, N, N-dimethylacetamide is preferably used because of its solubility. On the other hand, the poor solvent is a solvent that does not dissolve the hydrophobic polymer at the film forming temperature. Although it does not specifically limit, water is used suitably.

  By increasing the concentration of the hydrophobic polymer in the membrane forming stock solution, the mechanical strength of the hollow fiber membrane can be increased. On the other hand, if the concentration of the hydrophobic polymer is too high, a poor solubility or a discharge failure due to an increase in the viscosity of the film-forming stock solution may occur. Moreover, the water permeability and fractional molecular weight of the resulting hollow fiber membrane can be adjusted by the concentration of the hydrophobic polymer in the membrane-forming stock solution. When the concentration of the hydrophobic polymer is increased, the density of the inner surface of the hollow fiber membrane is increased, so that the water permeability and the molecular weight cut off are decreased. In view of the above, the concentration of the hydrophobic polymer in the film-forming stock solution is preferably 14% by mass or more, and more preferably 24% by mass or less.

  The hydrophilic polymer having no hydrophobic unit blended in the membrane-forming stock solution functions as a pore-forming agent, and can be expected to improve the water permeability and hydrophilicity of the resulting hollow fiber membrane. Moreover, it is possible to adjust the viscosity of the membrane-forming stock solution by blending a hydrophilic polymer, and it is possible to suppress the formation of macrovoids that cause a decrease in the strength of the hollow fiber membrane. However, if the blending amount of the hydrophilic polymer in the film-forming stock solution is too large, a decrease in solubility or a discharge failure may occur due to an increase in the viscosity of the film-forming stock solution. Moreover, when a large amount of hydrophilic polymer remains in the hollow fiber membrane, there is a risk that water permeability may be lowered due to an increase in permeation resistance. The optimum amount of the hydrophilic polymer added to the stock solution is preferably 1% by mass or more, and more preferably 15% by mass or less, depending on the type and target performance. The hydrophilic polymer added to the film-forming stock solution is not particularly limited, but when a polysulfone resin is used as the hydrophobic polymer, polyvinyl pyrrolidone is preferably used because of high compatibility. Moreover, a hydrophilic polymer may be used individually by 1 type, and 2 or more types may be mixed and used for it.

  Furthermore, in order to improve the water permeability of the hollow fiber membrane, it is preferable to use a hydrophilic polymer having a relatively low molecular weight because the pore forming action is enhanced. On the other hand, when a low molecular weight hydrophilic polymer is used, elution from the hollow fiber membrane is likely to occur.

  When the polymer is dissolved in order to obtain a film-forming stock solution, it is preferable to dissolve at a high temperature in order to improve the solubility, but there is a concern that the polymer may be modified by heat or the composition may be changed by evaporation of the solvent. Therefore, the melting temperature is preferably 30 ° C. or higher and 120 ° C. or lower. However, these optimum ranges may differ depending on the type of hydrophobic polymer and additive.

  The core solution used for hollow fiber membrane formation is preferably a mixed solution of a good solvent and a poor solvent, and the water permeability and fractional molecular weight of the hollow fiber membrane can be adjusted by the ratio. Although it does not specifically limit as a poor solvent, Water is used suitably. Although it does not specifically limit as a good solvent, N, N- dimethylacetamide is used suitably.

  When the membrane-forming stock solution and the core solution are in contact with each other, phase separation of the membrane-forming stock solution is induced by the action of the poor solvent, and solidification proceeds. When the ratio of the poor solvent in the core liquid is too high, the water permeability and the molecular weight cut off of the membrane are lowered. On the other hand, when the ratio of the poor solvent is too low, the hollow fiber membrane cannot be obtained because it is dropped as a liquid. The appropriate ratio between the two in the core liquid varies depending on the types of the good solvent and the poor solvent, but the poor solvent is preferably 10% by mass or more in the core liquid, and more preferably 80% by mass or less.

  Moreover, when the density | concentration of the good solvent in a core liquid is low, coagulation | solidification of an inner surface is accelerated | stimulated and there exists a possibility that the performance of a hollow fiber membrane may fall. On the other hand, when the concentration of the good solvent in the core liquid is high, solidification of the inner surface is suppressed, and spinnability may be reduced. Therefore, the concentration of the good solvent in the core liquid is preferably 40% by mass or more, more preferably 50% by mass or more, while the concentration of the good solvent is preferably 90% by mass or less, more preferably 80% by mass or less. More preferably, it is 70% or less.

  The temperature of the double tube cap at the time of discharge can affect the viscosity and phase separation behavior of the film-forming stock solution and the diffusion rate of the core liquid into the film-forming stock solution. Generally, the higher the temperature of the double tube cap, the greater the water permeability and the molecular weight cut off of the resulting hollow fiber membrane. However, if the temperature of the double tube cap is too high, the spinnability is lowered because the discharge becomes unstable due to a decrease in the viscosity of the film-forming stock solution and a decrease in the coagulation property. On the other hand, if the temperature of the double tube cap is low, moisture may adhere to the double tube cap due to condensation. Therefore, the temperature of the double tube cap is preferably 20 ° C. or higher, while 90 ° C. or lower is preferable.

  After the film-forming stock solution is discharged from the double tube cap, it passes through the dry part, is immersed in a coagulation bath, and is coagulated. In the dry section, the outer surface of the membrane-forming stock solution comes into contact with air, so that moisture in the air is taken in and becomes a poor solvent, so that phase separation of the membrane-forming stock solution proceeds. Therefore, by controlling the dew point of the dry part, it is possible to adjust the open area ratio of the outer surface of the obtained hollow fiber membrane. When the dew point of the dry part is low, phase separation may not proceed sufficiently, the outer surface open area ratio decreases, the friction of the hollow fiber membrane increases, and the spinnability may deteriorate. On the other hand, if the dew point of the dry part is too high, the outer surface may solidify and the aperture ratio may decrease. The dew point of the dry part is preferably 60 ° C. or lower, while 10 ° C. or higher is preferable.

  If the dry length is too short, the film-forming stock solution is solidified before the phase separation sufficiently proceeds, and the water permeation performance and fractionation performance deteriorate. The dry length is preferably 50 mm or more, and more preferably 100 mm or more. On the other hand, if the dry length is too long, the spinning stability may decrease due to yarn swinging or the like, so 600 mm or less is preferable.

  The coagulation bath contains a poor solvent as a main component, and a good solvent is added as necessary. Water is preferably used as the poor solvent. When the film-forming stock solution enters the coagulation bath, the film-forming stock solution is solidified by a large amount of poor solvent in the coagulation bath, and the film structure is fixed. As the temperature of the coagulation bath is increased, coagulation is suppressed, so that the water permeability and the molecular weight cut off are increased.

  The hollow fiber membrane obtained by coagulation in a coagulation bath contains excess hydrophilic polymer derived from a solvent or stock solution, and therefore needs to be washed with water.

  If washing with water at the time of film formation is insufficient, the washing before using the hollow fiber membrane module becomes complicated, and inflow of the eluate into the processing solution may become a problem. Since the washing efficiency increases by raising the washing temperature, the washing temperature is preferably 50 ° C. or higher.

  As the film thickness of the hollow fiber membrane becomes thinner, the material removal performance of the hollow fiber membrane is improved because the membrane mass transfer coefficient can be reduced. On the other hand, if the film thickness is too thin, yarn breakage and dry crushing are likely to occur, which may cause problems in production. The ease of collapsing the hollow fiber membrane correlates with the film thickness and the inner diameter of the hollow fiber membrane. Therefore, the thickness of the hollow fiber membrane is preferably 20 μm or more, and more preferably 25 μm or more. On the other hand, it is preferably 50 μm or less, more preferably 45 μm or less. The inner diameter of the hollow fiber membrane is preferably 80 μm or more, more preferably 100 μm or more, further preferably 120 μm or more, while 250 μm or less is preferable, more preferably 200 μm or less, and still more preferably 160 μm.

The hollow fiber membrane inner diameter is obtained by measuring the film thickness of 16 randomly selected hollow fiber membranes with a 1000 × lens (VH-Z100; KEYENCE, Inc.) of a microwatcher to obtain an average value a, The value calculated from the equation. The hollow fiber membrane outer diameter means an average value obtained by measuring the outer diameters of 16 randomly selected hollow fiber membranes with a laser displacement meter (for example, LS5040T; KEYENCE Inc.).
Hollow fiber membrane inner diameter (μm) = hollow fiber membrane outer diameter−2 × film thickness A hollow fiber membrane module is obtained by incorporating the hollow fiber membrane thus obtained in a case. The method of incorporating the hollow fiber membrane in the case is not particularly limited, but an example is as follows. First, the hollow fiber membrane is cut into a required length, bundled in the required number, and then put into a cylindrical case. Then, a temporary cap is put on both ends, and a potting agent is put on both ends of the hollow fiber membrane. At this time, the method of putting the potting agent while rotating the module with a centrifuge is a preferable method because the potting agent can be filled uniformly. After the potting agent is solidified, both ends are cut so that both ends of the hollow fiber membrane are open. A hollow fiber membrane module is obtained by attaching headers to both ends of the case and plugging the header and the nozzle part of the case.

The water permeability of the hollow fiber membrane is preferably 100 ml / hr / mmHg / m ² or more, more preferably 200 ml / hr / mmHg / m ² or more, and further preferably 300 ml / hr / mmHg / m ² or more. In the case of artificial kidney use, if water permeability is too high, a phenomenon such as residual blood may be observed. Therefore, it is preferably 2000 ml / hr / mmHg / m ² or less, more preferably 1500 ml / hr / mmHg / m ^2. It is as follows.

  Hollow fiber membrane modules for blood purification applications such as artificial kidneys need to be sterilized, and radiation sterilization methods are frequently used from the viewpoint of low residual toxicity and simplicity. In the present invention, since it aims at obtaining a dry type hollow fiber membrane module, the moisture content with respect to the mass of the hollow fiber membrane built in the module is 25 mass% or less, preferably 10 mass% or less, more preferably Irradiation is performed in a state of 4% by mass or less. As radiation to be used, α rays, β rays, γ rays, X rays, ultraviolet rays, electron beams, and the like are used. Among them, γ rays and electron beams are preferably used from the viewpoint of little residual toxicity and simplicity. In addition, the ester group-containing polymer incorporated in the inner surface of the hollow fiber can be fixed by causing cross-linking with the membrane material by irradiation with radiation, and also leads to reduction of the eluate. Therefore, irradiation with radiation is preferable. If the radiation dose is low, the sterilization effect is low. On the other hand, if the radiation dose is high, degradation of the ester group-containing polymer or membrane material occurs and blood compatibility is lowered. Therefore, the irradiation dose is preferably 15 kGy or more, and preferably 100 kGy or less.

  When irradiating with radiation, if the oxygen concentration around the hollow fiber membrane is high, oxygen radicals are likely to be generated by radiation irradiation, and if the water content of the hollow fiber membrane is low, the membrane may deteriorate or increase the amount of eluate. There is. Radiation is preferably irradiated under the condition that the oxygen concentration in the atmosphere around the hollow fiber membrane is 1% or less, more preferably 0.5% or less, further 0.2% or less, and particularly preferably 0.1%. It is as follows. A method for measuring the oxygen concentration will be described later in Examples.

  In Patent Document 1, from the viewpoint of biocompatibility, it is preferable to have a certain amount of oxygen concentration at the time of γ-ray irradiation. However, in the present invention, since the functional layer surface has an ester group, the oxygen concentration at the time of γ-ray irradiation. It was found that high biocompatibility can be maintained even in a low state.

  Examples of a method for reducing the oxygen concentration in the hollow fiber membrane module include a method of flowing an inert gas into the hollow fiber membrane module and a method using an oxygen scavenger. However, in the method using an oxygen scavenger, the cost of the oxygen scavenger is high, and a hollow fiber membrane packaging container having a low oxygen permeability must be used. Therefore, a method of filling with an inert gas is preferable. After inflowing the inert gas, all the inlets of the hollow fiber membrane module are tightly plugged, or the hollow fiber membrane module is sealed in a packaging container with low oxygen permeability into the inert gas. The atmosphere around the film can be brought into a low oxygen concentration state using an inert gas.

  In addition, when the humidity around the hollow fiber membrane and in the packaging container is too high, it may cause condensation or freezing at low temperatures, which may lead to performance degradation. Therefore, the relative humidity at 25 ° C. around the hollow fiber membrane and in the packaging container is preferably less than 80% Rh, more preferably 60% Rh, and further preferably less than 40 Rh%. Here, the relative humidity is expressed by the formula of relative humidity (% Rh) = 100 × p / P using the partial pressure of water vapor (p) at room temperature and the saturated water vapor pressure (P) at room temperature.

  In the present invention, since it has an ester group on the surface of the functional layer of the hollow fiber membrane, it is considered that a cross-linking reaction with the membrane material is likely to occur at the time of irradiation even under a low relative humidity condition, and as a result, the elution of the amount of the eluate is suppressed. It is thought.

If the amount of the high molecular weight substance eluted from the hollow fiber membrane module is large, when used for blood purification such as dialysis, the eluate may be mixed into the blood and cause side effects and complications. Therefore, the amount of the high molecular weight substance to be eluted is preferably 1.0 mg / m ² or less, more preferably 0.75 mg / m ² , further preferably 0.5 mg / m ² or less, most preferably 0 mg / m ^2. It is. However, in some cases, less than 0.1 mg / m ² cannot be achieved.

In the present invention, the amount of eluate contained in the water circulated through the hollow fiber membrane module for 4 hours is defined as the amount of eluate in the hollow fiber membrane module. Here, the water circulated for 4 hours means that ultrapure water heated to 37 ° C. was passed through the flow path on the inner surface side of the hollow fiber membrane of the hollow fiber membrane module for 7 minutes at 100 mL / min, and then hollowed in the same manner. After passing through the flow path on the outer surface side of the yarn membrane at 500 mL / min for 5 minutes, again passing through the flow channel at the inner surface of the hollow fiber membrane for 3 minutes at 100 mL / min, and washing, the inner surface side of the hollow fiber membrane 4 L of ultrapure water heated to 37 ° C. was circulated at 200 mL / min for 4 hours while collecting water after circulation for 4 hours. The eluate eluted in water can be measured using gel filtration chromatography or the like using a liquid obtained by concentrating the water circulated for 4 hours 100 times as a measurement sample. The amount of eluate (mg / m ² ) in the present invention is calculated as follows.
Details of the measuring method are as described later in the examples. The hydrophilic high molecular weight (mg) in 4 L of water after 4 hours of circulation obtained in this way was divided by the total value (m ² ) of the inner surface area of the hollow fiber membrane packed in the measured hollow fiber membrane module. The value was defined as the amount of eluate (mg / m ² ) in the present invention. The calculated value is rounded off to the second decimal place.
Elution amount (mg / m ² ) = Hydrophilic high molecular weight in 4 L (mg) / Total value of inner surface area of hollow fiber membrane (m ² )
The total value of the inner surface area of the hollow fiber membrane is obtained by the following formula.
Total value of the inner surface area of the hollow fiber membrane (m ² ) = π × hollow fiber membrane inner diameter (m) × effective length (m) × number of yarns (number)
Here, the effective length refers to a portion where the potting material is not attached to the hollow fiber membrane filled in the hollow fiber membrane module.

Further, as another indicator of the amount of organic matter eluted from the hollow fiber membrane, the consumption of potassium permanganate in the initial cleaning liquid of the hollow fiber membrane module can be used. The initial cleaning liquid here refers to water sampled from the first 25 mL of cleaning liquid that has flowed out when the hollow fiber membrane module is filled with water when ultrapure water is allowed to flow inside the hollow fiber membrane at a flow rate of 100 mL / min. I mean. The eluate contained in the initial cleaning solution was measured by adding 20 mL of a 2.0 × 10 ⁻³ mol / L potassium permanganate aqueous solution to 1 mL of the initial cleaning solution and adding 1 mL of 10 vol% sulfuric acid and boiling stone for 3 minutes. Boil. The mixture is then cooled to room temperature. 1 mL of 10 mass% potassium iodide aqueous solution is added there, and after stirring well at room temperature, it is left to stand for 10 minutes and titrates with 1.0 * 10 ^<-2 > mol / L sodium thiosulfate aqueous solution. When the color of the solution becomes light yellow, add 0.5 mL of 1% by weight starch aqueous solution and stir well at room temperature. Thereafter, titration is further performed with an aqueous sodium thiosulfate solution until the color of the solution becomes transparent. 1.0 × ¹⁰ -2 mol / L sodium thiosulfate required for the hollow fiber membrane 1.0 × ¹⁰ -2 mol / L aqueous solution of sodium thiosulfate quantity used in ultra pure water titration non through modules and titration of the initial washing liquid The difference in the amount of the aqueous solution was used as an index of the amount of the eluate. The index of the amount of eluate obtained by measuring the circulating fluid for 4 hours represents the amount of the eluate when the hollow fiber membrane module is used. It represents the amount of eluate in the initial state of the module.

For example, when the hollow fiber membrane module is used as an artificial kidney in hemodialysis, it is preferable that the amount of potassium permanganate consumed is small. The eluate test of the circuit in the dialysis-type artificial kidney approval standard is to perform titration with 2.0 × 10 ⁻³ mol / L potassium permanganate aqueous solution using 10 ml of the initial washing solution, and permanganic acid at the time of titration The same standard stipulates that the consumption of aqueous potassium solution is 1 ml or less. Since this standard is a circuit eluate test and is a stricter standard than the dialyzer approval standard, it is not necessary in the present invention for the hollow fiber membrane module to meet the standard, but the initial washing liquid potassium permanganate Is 3 mL or less per 1 m ² of membrane area, more preferably 2 mL or less, and further preferably 1 mL or less.

(1) X-ray electron spectroscopy (XPS) measurement The hollow fiber membrane was cut into a semi-cylindrical shape with a single blade, and three points on the functional layer surface (inner surface) of the hollow fiber membrane were measured. The measurement sample was rinsed with ultrapure water, dried at room temperature and 0.5 Torr for 10 hours, and then subjected to measurement. Measurement equipment and conditions are as follows.

Measuring device: ESCALAB220iXL
Excitation X-ray: monochromatic Al Kα1,2 line (1486.6 eV)
X-ray diameter: 0.15mm
Photoelectron escape angle: 90 ° (inclination of detector with respect to sample surface)
The C1s peak is mainly derived from CHx, C—C, C═C, C—S, mainly derived from C—O, C—N, π-π * satellite-derived component, C = O derived And five components derived from COO. The peak is divided into the above five components. The COO-derived component is a peak that appears at +4.0 to 4.2 eV from the main peak of CHx and C—C (near 285 eV). The peak area ratio of each component was calculated by rounding off the first decimal place. In addition, if the peak area percentage was 0.4% or less as a result of the peak division, it was set to the detection limit or less.

(2) Measurement of moisture content The hollow fiber membrane module before washing was placed in a vacuum dryer set at 50 ° C. and dried at 0.5 Torr for 12 hours. b). Further, as a washing step, a washing liquid at 25 ° C. is passed through the hollow fiber membrane inner surface side inlet 15A from the hollow fiber membrane inner surface side inlet 15A to the outlet 15B for 1 minute at 500 mL / min, and further from the hollow fiber membrane inner surface side inlet 15A to the hollow fiber. Water was passed through the outer membrane surface side nozzle 16A in the film thickness direction at 500 mL / min for 1 minute. Next, the liquid filled into the inner surface side inlet 15A is pushed out from the hollow fiber membrane outer surface side nozzle 16A with compressed air of 100 kPa, and then the filling liquid on the inner surface side of the hollow fiber membrane is blown in the direction from 15B to 15A, After only the membrane was wetted, the hollow fiber membrane module was dried using compressed air or microwave. The mass of the hollow fiber membrane module in this state was measured to obtain the mass (a) of the hollow fiber membrane module before absolute drying. Further, another module prepared in the same manner was disassembled and the hollow fiber membrane was taken out and dried under reduced pressure at 50 ° C. and 0.5 Torr for 12 hours. The measured mass was the mass of the hollow fiber membrane when completely dried (c) It was. The moisture content of the hollow fiber membrane is calculated from the following formula, and the measured value is a value obtained by rounding off the second decimal place.
Moisture content (mass%) = 100 × (ab) / c
Here, a: hollow fiber membrane module mass (g) before absolute drying, b: hollow fiber membrane module mass (g) after absolute drying, c: hollow fiber membrane mass when absolutely dry.

(3) Oxygen concentration measurement Nitrogen or a gas adjusted to a predetermined oxygen concentration was simultaneously flowed into the hollow fiber membrane module from the inside of the hollow fiber membrane and the outside of the hollow fiber membrane to sufficiently replace the gas in the hollow fiber membrane module. Thereafter, the hollow fiber membrane module was sealed with a rubber cap made of a material having low oxygen permeability. Thereafter, the oxygen concentration in the hollow fiber membrane module was measured using IS-300 manufactured by Iijima Electronics Co., Ltd. If the hollow fiber membrane module is not tightly sealed, use a packaging bag with low oxygen permeability, replace the inside of the packaging bag with nitrogen or a gas adjusted to a predetermined oxygen concentration, and then replace the gas as described above. The membrane module was placed and the packaging bag was sealed. Thereafter, the oxygen concentration in the packaging bag was measured in the same manner. The value was rounded off to the second decimal place.

(4) Eluate test Ultrapure water heated to 37 ° C was passed through the flow path on the inner surface side of the hollow fiber membrane module for 7 minutes at 100 mL / min, and then the outer surface side of the hollow fiber membrane was similarly used. Then, the solution was passed through the flow channel at 500 mL / min for 5 minutes, and again through the hollow fiber membrane inner surface flow channel at 100 mL / min for 3 minutes to perform washing. Thereafter, 4 L of ultrapure water heated to 37 ° C. was passed through the inner surface of the hollow fiber membrane while circulating at 200 mL / min for 4 hours. The water after circulation for 4 hours was collected to obtain a sample solution. Since the obtained sample solution was dilute, it was freeze-dried, concentrated 100 times, and then subjected to gel filtration chromatography measurement. Gel filtration chromatography was measured under the following conditions. First, several kinds of aqueous solutions in which polyvinylpyrrolidone (K90 manufactured by ISP Co., Ltd.) was dissolved by changing the concentration were used as standard samples and measured using gel filtration chromatography. A calibration curve of the relationship between the peak area of the standard sample polyvinylpyrrolidone and the prepared concentration was prepared. Next, the concentration of the eluate in the sample solution was calculated from the total value of all peak areas obtained by measuring the sample solution and the calibration curve.

Subsequently, the hydrophilic high molecular weight contained in 4 L of ultrapure water after circulation for 4 hours was calculated by the following formula. At this time, calculation was performed by approximating 1 L of pure water to 1 kg. The calculated value was rounded off to the second decimal place.
Hydrophilic high molecular weight (mg) in 4 L = Hydrophilic high polymer concentration in measurement sample (ppm) × 4 (kg) / 100
Hollow fiber membrane inner surface side area (m ² ) = π × hollow fiber membrane inner diameter (m) × effective length (m) × number of yarns (pieces)
The effective length in the present invention refers to a portion where the potting material is not attached to the hollow fiber membrane filled in the hollow fiber membrane module.
Elution amount (mg / m ² ) = Hydrophilic high molecular weight in 4 L (mg) / Inside surface area of hollow fiber membrane (m ² )
Column: TSKgel GMPWXL (manufactured by Tosoh Corporation)
Solvent: 0.1 mol / L lithium nitrate, water / methanol: 50 vol / 50 vol
Flow rate: 0.5 mL / min
Column temperature: 40 ° C
Detector: differential refractometer RI-8010 (manufactured by Tosoh Corporation).

(5) Microscopic ATR method A hollow fiber membrane was cut into a semi-cylindrical shape with a single blade, rinsed with ultrapure water, and then dried at room temperature and 0.5 Torr for 10 hours to obtain a sample for surface measurement. Each surface of the dry hollow fiber membrane was measured by a microscopic ATR method using an IRT-3000 manufactured by JASCO. The measurement was performed with a field of view (aperture) of 100 μm × 100 μm, a measurement range of 3 μm × 3 μm, 30 times of integration, and a total of 25 points of 5 points each in length and width. A reference line was drawn at a wavelength of 1549 to 1620 cm ⁻¹ of the obtained spectrum, and a part surrounded by the reference line and the positive part of the spectrum was defined as a peak area derived from the polysulfone-derived benzene ring C═C (A _CC ). . Similarly, a reference line was drawn at 1711 to 1759 cm ⁻¹ , and the peak area derived from the ester group was defined as (A _COO ) in the part surrounded by the reference line and the positive part of the spectrum.

The above operation was performed at three different locations of the same hollow fiber, the average of (A _COO ) / (A _CC ) was calculated, and the value rounded to the third decimal place was used.

(6) Human platelet adhesion test method A double-sided tape was affixed to an 18 mmφ polystyrene circular plate, and a hollow fiber membrane was fixed thereto. The attached hollow fiber membrane was cut into a semicylindrical shape with a single blade to expose the inner surface of the hollow fiber membrane. If dirt, scratches, folds, or the like are present on the inner surface of the hollow fiber membrane, platelets will adhere to that portion, so that it may not be possible to make a correct evaluation. The circular plate was attached to a Falcon (registered trademark) tube (18 mmφ, No. 2051) cut into a cylindrical shape so that the surface on which the hollow fiber membrane was attached was inside the cylinder, and the gap was filled with parafilm. . The cylindrical tube was washed with physiological saline and then filled with physiological saline. Immediately after collecting human venous blood, heparin was added to a concentration of 50 U / mL. After discarding the physiological saline in the cylindrical tube, 1.0 mL of the blood was added to the cylindrical tube within 30 minutes after blood collection, and shaken at 37 ° C. for 1 hour. Thereafter, the hollow fiber membrane was washed with 10 mL of physiological saline, 2.5% glutaraldehyde physiological saline was added and allowed to stand, and blood components adhering to the hollow fiber membrane were immobilized on the hollow fiber membrane. After 1 hour or more, it was washed with 20 mL of distilled water. The washed hollow fiber membrane was dried under reduced pressure at room temperature and 0.5 Torr for 10 hours. This hollow fiber membrane was attached to a sample stage of a scanning electron microscope with a double-sided tape. Thereafter, a thin film of Pt—Pd was formed on the hollow fiber surface by sputtering to obtain a measurement sample. The inner surface of the hollow fiber membrane was observed with a field emission type scanning electron microscope (S-800 manufactured by Hitachi, Ltd.) at a magnification of 1500 times, and platelets adhered in one field of view (4.3 × 10 ³ μm ² ). I counted the number. In the vicinity of the center in the longitudinal direction of the hollow fiber, the average value of the number of adhered platelets in 10 different visual fields was defined as the number of adhered platelets (pieces / 4.3 × 10 ³ μm ² ). When the number exceeded 50 / 4.3 × 10 ³ μm ² in one visual field, it was counted as 50. The end portion of the hollow fiber in the longitudinal direction was easily excluded from the measurement of the number of platelet adhesion because blood pools were easily formed.

(7) Measurement of the amount of eluate with an aqueous potassium permanganate solution Ultrapure water was flowed as an initial washing liquid at a flow rate of 100 mL / min inside the hollow fiber of the measurement hollow fiber membrane module, and the hollow fiber membrane module was filled with water and flowed first. Of 25 mL of water was sampled. 10 mL was taken out from this sample, 20 mL of a 2.0 × 10 ⁻³ mol / L potassium permanganate aqueous solution was added, 1 mL of 10 vol% sulfuric acid and boiling stone were added and boiled for 3 minutes. Then, it cooled to room temperature, added 1 mL of 10 mass% potassium iodide aqueous solution, stirred well at room temperature, left to stand for 10 minutes, and titrated with 1.0 * 10 ^<-2 > mol / L sodium thiosulfate aqueous solution. When the color of the solution became pale yellow, 0.5 mL of 1% by mass starch aqueous solution was added, and stirred well at room temperature. Thereafter, titration was continued with an aqueous sodium thiosulfate solution until the color of the solution became transparent. For ultrapure water that did not pass through the hollow fiber membrane module, the same titration as in the measurement sample was performed. 1.0 × ¹⁰ -2 mol / L sodium thiosulfate required for the hollow fiber membrane 1.0 × ¹⁰ -2 mol / L aqueous solution of sodium thiosulfate quantity used in ultra pure water titration non through modules and titration of the initial washing liquid The difference in the amount of the aqueous solution was used as an index of the amount of the eluate. The average value of two measurements was calculated, and the value rounded to the third decimal place was used.

(8) Measurement of relative humidity A thermo-hygrometer (manufactured by Vaisala Co., Ltd., indicator HM141, probe HMP42) was inserted into a sealed hollow fiber membrane module, and measurement was performed.

[Example 1]
16% by mass of polysulfone ("Udel (registered trademark)" P-3500 manufactured by Solvay), 4% by mass of polyvinylpyrrolidone (manufactured by International Special Products; hereinafter referred to as ISP K30) and 2% of polyvinylpyrrolidone (K90 manufactured by ISP) Mass%, 77% by mass of N, N-dimethylacetamide, and 1% by mass of water were dissolved by heating to obtain a film-forming stock solution. A solution containing 63% by mass of N, N-dimethylacetamide and 37% by mass of water was used as a core solution.

  The film-forming stock solution and the core solution are respectively sent to the spinneret part at a temperature of 50 ° C., and discharged from the outer pipe of the orifice type double pipe base having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of the annular slit part. It discharged from the inner tube. The discharged film-forming stock solution is passed through a dry zone atmosphere having a dry length of 350 mm, a temperature of 30 ° C., and a dew point of 28 ° C., and then led to a coagulation bath of 100% water and a temperature of 40 ° C. A hollow fiber membrane was obtained through a 90-second washing step, a drying step at 130 ° C. for 2 minutes, and a crimping step at 160 ° C. The obtained hollow fiber membrane was wound up to obtain a hollow fiber membrane bundle. The hollow fiber membrane had an inner diameter of 200 μm and an outer diameter of 280 μm.

The hollow fiber membrane 13 was filled in the case 11 so that the inner surface area of the hollow fiber membrane was 1.5 m ² , and both ends of the hollow fiber were fixed to the case end by the potting material 17. Further, a part of the end portion of the potting material was cut to open both sides of the hollow fiber membrane, and headers 14A and 14B were attached to both sides of the case to obtain a hollow fiber membrane module.

  Next, as a washing step, a partially saponified polyvinyl alcohol (PVA417 manufactured by Kuraray Co., Ltd.) of 0.01% by mass of an aqueous solution at 25 ° C. is applied from a treatment liquid inlet (hollow fiber membrane inner surface side inlet) 15A of the hollow fiber membrane module. The treatment liquid discharge port (hollow fiber membrane inner surface side outlet) 15B is passed through at a rate of 500 mL / min for 1 minute, and further from the treatment liquid injection port 15A to the nozzle (treatment liquid injection port) 16A at 500 mL / min in the film thickness direction. Water was passed for 1 minute. Next, the liquid filled into the liquid inlet 15A from the nozzle 16A is pushed out with compressed air of 100 kPa, and then the filling liquid on the inner surface side of the hollow fiber membrane is blown with compressed air in the direction of 15B to 15A, and only the hollow fiber membrane is blown. Was in a wet state. Further, the inner surface side and the outer surface side of the hollow fiber membrane were simultaneously blown with compressed air to dry the hollow fiber membrane. Here, the moisture content of the hollow fiber membrane module was measured as described above from the mass of the hollow fiber membrane module before washing and the mass after drying.

  After the inside of the hollow fiber membrane module was replaced with nitrogen, the hollow fiber membrane module 1 was obtained by capping with a rubber stopper that does not transmit oxygen and irradiating γ rays with an irradiation dose of 25 kGy. The amount of eluate in the obtained hollow fiber membrane module, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet count, and potassium permanganate consumption of the initial washing solution were measured. The results are shown in Table 1. The ester group was uniformly present on the inner surface of the hollow fiber, and a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained.

[Example 2]
Example 1 except that a vinylpyrrolidone / vinyl acetate (5/5) random copolymer (“Luviscol” (registered trademark) VA55I, manufactured by BASF) was used as a cleaning liquid used in the cleaning step, and an aqueous solution of 0.01% by mass at 25 ° C. A hollow fiber membrane module 2 was obtained by performing the same experiment as described above. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet adhesion number, consumption of potassium permanganate in the initial washing solution were measured. The results are shown in Table 1. As in Example 1, a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained.

[Example 3]
A hollow fiber membrane module 2 was obtained by performing the same experiment as in Example 2 except that the temperature of the cleaning liquid was 50 ° C. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet adhesion number, consumption of potassium permanganate in the initial washing solution were measured. The results are shown in Table 1. As in Example 2, a hollow fiber membrane module with a small number of platelets attached and a further reduced amount of the eluate was obtained.

[Example 4]
Example 1 except that a vinylpyrrolidone / vinyl acetate (7/3) random copolymer (“Luviskol” (registered trademark) VA73, manufactured by BASF) was used as a cleaning liquid used in the cleaning step, and a 0.01% by mass aqueous solution at 50 ° C. The same experiment was performed to obtain a hollow fiber membrane module 4. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet adhesion number, consumption of potassium permanganate in the initial washing solution were measured. The results are shown in Table 1. As in Example 1, a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained.

[Example 5]
Example except that vinylpyrrolidone / vinyl acetate (6/4) random copolymer (“KOLLIDON” (registered trademark) VA64 manufactured by BASF) 0.01% by mass aqueous solution at 25 ° C. was used as the cleaning liquid used in the cleaning process. The same experiment as 1 was performed to obtain a hollow fiber membrane module 5. The amount of eluate in the obtained hollow fiber membrane module, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet count, and potassium permanganate consumption of the initial washing solution were measured. The results are shown in Table 1. The ester group was uniformly present on the inner surface of the hollow fiber, and a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained.

[Example 6]
Except for using 0.02% by mass of 25 ° C. aqueous solution of vinylpyrrolidone / vinyl acetate (6/4) random copolymer (BASF “KOLLIDON” (registered trademark) VA64) as the cleaning liquid used in the cleaning process. The same experiment as in Example 1 was performed to obtain a hollow fiber membrane module 6. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet adhesion number, consumption of potassium permanganate in the initial washing solution were measured. The results are shown in Table 1. As in Example 1, a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained.

[Example 7]
As the cleaning liquid used in the cleaning process, a vinylpyrrolidone / vinyl acetate (6/4) random copolymer (BASF "KOLLIDON" (registered trademark) VA64) of 0.01% by mass aqueous solution at 80 ° C is used, and a hollow fiber membrane A hollow fiber membrane module 7 was obtained by performing the same experiment as in Example 1 except that the concentration of oxygen in the module was adjusted to 1% and γ rays were applied. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet adhesion number, consumption of potassium permanganate in the initial washing solution were measured. The results are shown in Table 1. As in Example 1, a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained.

[Example 8]
A hollow fiber membrane module 8 was obtained by performing the same experiment as in Example 1 except that the moisture content of the hollow fiber membrane during γ-ray irradiation was 20% by mass. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, XPS on the inner surface of the hollow fiber membrane, microscopic ATR, platelet adhesion number, consumption of potassium permanganate in the initial washing solution were measured. The results are shown in Table 1. As in Example 1, a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained. In addition, there was no problem with the bubble removal property during washing.

[Example 9]
Example except that vinylpyrrolidone / vinyl acetate (6/4) random copolymer (BASF “KOLLIDON” (registered trademark) VA64) 0.01 mass% aqueous solution at 60 ° C. was used as the cleaning liquid used in the cleaning process. The same experiment as 1 was performed to obtain a hollow fiber membrane module 9. In the obtained hollow fiber membrane module, in the elution from the hollow fiber membrane, the amount from the hollow fiber membrane, the XPS on the inner surface of the hollow fiber membrane, the microscopic ATR, the platelet adhesion number, the consumption amount of potassium permanganate in the initial washing liquid It was measured. The results are shown in Table 1. As in Example 1, a hollow fiber membrane module with a small number of platelets attached and a small amount of eluate was obtained.

[Comparative Example 1]
A hollow fiber membrane module 10 was obtained by performing the same experiment as in Example 1 except that the oxygen concentration in the hollow fiber membrane module was adjusted to 2.5% and γ rays were irradiated. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, and XPS, microscopic ATR, and platelet adhesion number on the inner surface of the hollow fiber membrane were measured. The results are shown in Table 1. As in Example 1, the platelet adhesion number was small, but the amount of high molecular weight eluted was increased due to the high oxygen concentration.

[Comparative Example 2]
A hollow fiber membrane module 11 was obtained by performing the same experiment as in Example 1 except that 80 ° C. water was used as the cleaning liquid used in the cleaning process. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, and XPS, microscopic ATR, and platelet adhesion number on the inner surface of the hollow fiber membrane were measured. The results are shown in Table 1. Since there was no ester group on the surface of the functional layer, the number of platelets adhered was large and the amount of eluate was also large.

[Comparative Example 3]
Except using 0.001 mass% 25 degreeC aqueous solution of a vinylpyrrolidone / vinyl acetate (6/4) random copolymer (BASF "KOLLIDON" (registered trademark) VA64) as a cleaning liquid used in the cleaning process. The same experiment as in Example 1 was performed to obtain a hollow fiber membrane module 12. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, and XPS, microscopic ATR, and platelet adhesion number on the inner surface of the hollow fiber membrane were measured. The results are shown in Table 1. Similar to Example 1, the platelet adhesion number was small. However, the amount of the eluate was large in connection with the small amount of ester groups present on the surface.

[Reference example]
The hollow fiber membrane module 13 was obtained by the method described in Example 3 of JP2011-78974. In the obtained hollow fiber membrane module, the amount of eluate from the hollow fiber membrane, and XPS, microscopic ATR, and platelet adhesion number on the inner surface of the hollow fiber membrane were measured. The results are shown in Table 1. Although the amount of ester groups on the surface is small, since the water content of the hollow fiber membrane during γ-ray irradiation is high, the amount of eluate can be suppressed.

11 Cylindrical Case 13 Hollow Fiber Membrane 14A Header 14B Header 15A Processed Liquid Inlet (Hollow Fiber Membrane Inner Entrance)
15B Processed liquid outlet (hollow fiber membrane outlet)
16A nozzle (treatment liquid inlet)
16B nozzle (treatment liquid outlet)
17 Potting material

Claims (7)

A method for producing a hollow fiber membrane module incorporating a hollow fiber membrane,
The hollow fiber membrane is a mixture of a hydrophilic polymer not having a hydrophobic unit in a base material made of a hydrophobic polymer,
The hydrophobic polymer is a polysulfone polymer,
Satisfy the following conditions (A) and (B) ,
(A) when measured by X-ray photoelectron spectroscopy, the area percentage of carbon peak derived from an ester group in the functional layer surface of the hollow fiber membrane 10 (atomic%) or less, the carbon derived from the ester group The peak is derived from an ester group in the ester group-containing polymer introduced on the functional layer surface,
(B) When the 37 ° C. of ultrapure water was circulated for 4 hours at 200 mL / min, that eluted amount eluted from the hollow fiber membrane is 1.0 mg / ^{m 2} or less,
further,
Washing the hollow fiber membrane with a washing liquid containing 0.002% by mass or more and 0.05% by mass or less of the ester group-containing polymer;
The condition that the hollow fiber membrane is built in the module, the oxygen concentration in the atmosphere around the hollow fiber membrane is 0.02 to 1%, and the water content with respect to the mass of the hollow fiber membrane is 0 to 25% by mass under a step of irradiating radiation to the hollow fiber membrane,
That having a method of manufacturing a hollow fiber membrane module. The method for producing a hollow fiber membrane module according to claim 1, wherein the atmosphere is an inert gas. The method for producing a hollow fiber membrane module according to claim 1 or 2, wherein the hydrophilic polymer having no hydrophobic unit is at least one selected from polyvinyl pyrrolidone, polyethylene glycol, and polyvinyl alcohol. The method for producing a hollow fiber membrane module according to any one of claims 1 to 3 , wherein the ester group-containing polymer is a copolymer of a hydrophobic unit and a hydrophilic unit. The ester group-containing polymer, carboxylic acid vinyl esters, acrylic acid esters or methacrylic acid esters, the production method of the hollow fiber membrane module according to any of claims 1-4. The method for producing a hollow fiber membrane module according to any one of claims 1 to 5 , wherein the ester group-containing polymer is a copolymer of vinyl acetate and vinyl pyrrolidone. Said radiation, the irradiated hollow fiber membranes sealed state or the hollow fiber membrane module all inlet module while sealed in the packaging bag, the hollow fiber according to any one of claims 1 to 6 Membrane module manufacturing method.

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