Hollow fiber membranes and hollow fiber membrane modules

Abstract

The present invention aims to provide a hollow fiber membrane that can maintain high mechanical strength while achieving the separation and removal of large molecular weight proteins. [Solution] The present invention sets the maximum porosity of the inner surface to X MAX The minimum porosity of the inner surface is X MIN When X MAX to X MIN The present invention provides a hollow fiber membrane in which the porosity ratio X, which is the value obtained by dividing by , is between 5 and 100.

Description

[Technical Field]

[0001] This invention relates to hollow fiber membranes and hollow fiber membrane modules. [Background technology]

[0002] Hollow fiber membranes have a hollow interior and exterior separated by a membrane, and porous hollow fiber membranes, in particular, which have a microporous structure, are suitable for use as separation membranes that screen out substances inside and outside. Among these, porous hollow fiber membranes are often used in blood purification therapies such as the treatment of renal failure, by being filled inside blood purification modules to remove uremic toxins and waste products from the blood.

[0003] Conventional blood purification therapies require the maximum removal of uremic substances with molecular weights smaller than albumin (molecular weight 66,000) while suppressing the leakage of albumin, a substance beneficial to the body. Polysulfone hollow fiber membranes are used as one of the ideal membranes to meet this need. Polysulfone hollow fiber membranes have a uniform pore size distribution and an asymmetric membrane structure. The uniform pore size results in sharp fractionation characteristics, and the asymmetric membrane structure forms a thin film in the film thickness direction, reducing the resistance to solute permeation.

[0004] On the other hand, data have been reported indicating that uremic proteins with molecular weights greater than albumin are involved in various complications in patients undergoing long-term blood purification therapy. Therefore, hollow fiber membranes with broadened fractionation characteristics by expanding the membrane pore size are needed to enable the separation of large molecular weight proteins with molecular weights greater than albumin (Non-patent documents 1 and 2).

[0005] Examples of hollow fiber membranes with enlarged pore sizes include polysulfone hollow fiber membranes (Patent Document 1), which have excellent performance in removing medium molecular weight substances, and regenerated cellulose hollow fiber membranes (Patent Document 2), which target substances such as β2-microglobulin (molecular weight 11,800). [Prior art documents] [Patent Documents]

[0006]

Patent Document 1

Patent Document 2

Non-Patent Document

[0007]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0008] However, although the above hollow fiber membrane has excellent performance in removing medium molecular weight substances, at present, there is no known hollow fiber membrane that targets large molecular weight proteins having a molecular weight greater than albumin for removal. Also, if the membrane pore size is simply enlarged to remove large molecular weight proteins, the entire hollow fiber membrane becomes a porous structure, and the mechanical strength of the hollow fiber membrane represented by the tensile modulus of elasticity is significantly reduced, and there is a concern that the spinning stability, the handling property during fiber processing, or the workability when inserting a bundle of hollow fiber membranes to form a hollow fiber membrane module deteriorates.

[0009] Therefore, an object of the present invention is to provide a hollow fiber membrane capable of maintaining high mechanical strength while achieving separation and removal of large molecular weight proteins.

Means for Solving the Problems

[0010] The present invention is (1) When the maximum pore opening ratio of the inner surface is X MAX , and the minimum pore opening ratio of the inner surface is X MIN , then X MAX is X MINProvided is a hollow fiber membrane in which the aperture ratio X, which is the value obtained by dividing by [specific value], is 5 to 100.

[0011] The present invention also provides the following hollow fiber membranes and hollow fiber membrane modules. (2) The above X MAX is 1.00 to 90.0%, and the above X MIN is 0.01 to 10.0%, the hollow fiber membrane according to (1) above. (3) The hollow fiber membrane according to (1) or (2) above, wherein the contour C of the inner surface in a cross section perpendicular to the longitudinal direction is irregular. (4) The hollow fiber membrane according to (3) above, wherein the contour C has 6 to 40 convex portions. (5) The hollow fiber membrane according to (4) above, wherein the above X MIN is observed at a site corresponding to the convex portion. (6) The hollow fiber membrane according to (4) or (5) above, wherein the convex portions are evenly present on the circumference of the circumscribed circle of the contour C. (7) The hollow fiber membrane according to any one of (1) to (6) above, which exhibits an inner dense asymmetric structure in a cross section perpendicular to the longitudinal direction. (8) The hollow fiber membrane according to any one of (1) to (7) above, which is mainly composed of a thermoplastic resin. (9) The hollow fiber membrane according to (8) above, wherein the thermoplastic resin is an amorphous polymer. (10) The hollow fiber membrane according to (9) above, wherein the amorphous polymer is a polysulfone-based polymer. (11) The hollow fiber membrane according to any one of (1) to (10) above, having an average membrane thickness of 10 to 80 μm. (12) A hollow fiber membrane module incorporating the hollow fiber membrane according to (1) or (2) above. (13) The hollow fiber membrane module according to (12) above, which is used for blood purification. (14) A method for producing a pharmaceutical product, comprising a purification step using the hollow fiber membrane module according to (12) above. [[Effect of the Invention]]

[0012] According to the present invention, it is possible to provide a hollow fiber membrane capable of simultaneously achieving separation and removal of high molecular weight proteins and high mechanical strength.

Embodiment for Carrying Out the Invention

[0013] The hollow fiber membrane can be produced, for example, by ejecting an injection liquid or an injection gas from a circular tube inside a double-tube die and discharging a spinning dope from a slit outside. At this time, the structure of the hollow fiber membrane can be controlled by appropriately adjusting the spinning conditions such as the composition of the spinning dope, the type or temperature of the injection liquid or injection gas.

[0014] The hollow fiber membrane of the present invention has a maximum pore opening rate on the inner surface of X MAX and a minimum pore opening rate on the inner surface of X MIN When these are defined, the pore opening rate ratio X, which is the value obtained by dividing X MAX by X MIN is characterized by being 5 to 100.

[0015] Here, the "maximum pore opening rate on the inner surface" refers to the pore opening rate that shows the maximum value when the pore opening rate is measured along the direction perpendicular to the longitudinal direction (corresponding to the circumferential direction of the hollow fiber membrane) on the inner surface exposed by cutting the hollow fiber membrane in the longitudinal direction. The "minimum pore opening rate on the inner surface" refers to the pore opening rate that shows the minimum value when the pore opening rate is measured in the same manner as the "maximum pore opening rate on the inner surface".

[0016] The pore opening rate on the inner surface can be calculated by observing the inner surface of the hollow fiber membrane with a scanning electron microscope (SEM) and performing image analysis. The observation magnification and conditions at that time can be appropriately determined so that the number of pores observed per field (image) is 20 to 2000 in a state where the pore diameter can be measured.

[0017] The hollow fiber membrane of the present invention secures a flow path through which high molecular weight proteins with a molecular weight of tens of thousands to hundreds of thousands, such as transferrin and IgG, can permeate, and from the viewpoint of increasing the permeation coefficient, the above X MAXIt is preferable that the amount be 1.00% or more, more preferably 2.00% or more, and even more preferably 4.00% or more. On the other hand, in order to further improve spinning stability, handling during fiber processing, or the ease of inserting the hollow fiber membrane bundle into the case when constructing a hollow fiber membrane module, the above X MAX The percentage is preferably 90.00% or less, more preferably 75.00% or less, and even more preferably 60.00% or less. Furthermore, from the viewpoint of increasing the mechanical strength of the hollow fiber membrane, the above X MIN The amount is preferably 10.00% or less, more preferably 8.00% or less, and even more preferably 5.00% or less. On the other hand, from the viewpoint of maintaining the permeability of the hollow fiber membrane, the above X MIN The amount is preferably 0.01% or more, more preferably 0.05% or more, and even more preferably 0.10% or more.

[0018] To improve the separation and removal performance of large molecular weight proteins while ensuring sufficient mechanical strength of the hollow fiber membrane, the porosity ratio X is preferably 10 to 90.

[0019] Furthermore, the hollow fiber membrane of the present invention generates a difference in the porosity in the direction perpendicular to the longitudinal direction of the hollow fiber membrane in response to changes in shape, as described above X MAX and the above X MIN From the viewpoint of making control easier, the inner surface contour C in a cross section perpendicular to the longitudinal direction is preferably circular or irregular in shape, and more preferably irregular in shape. Here, "irregular shape" refers to a shape other than a perfect circle. The irregular shape may be a shape that maintains symmetry such as line symmetry or point symmetry, or it may be an asymmetrical shape.

[0020] If the deformed shape maintains symmetry, the inscribed circle is the circle inscribed within the contour C of the deformed shape, and the circumscribed circle is the circle circumscribed around the contour C of the deformed shape. Specifically, by observing a cross-section perpendicular to the longitudinal direction of the hollow fiber membrane, selecting the vertices of the irregularities in the contour C of the inner surface of the hollow fiber membrane, and drawing approximate circles with respect to those vertices, the inscribed or circumscribed circle can be determined.

[0021] On the other hand, if the shape of the deformity is asymmetrical, the center of the cross-section perpendicular to the longitudinal direction of the hollow fiber membrane is determined, and the circle containing the point on the contour of the deformity closest to that center is defined as the inscribed circle. The circle containing the point on the contour of the deformity furthest from the center is defined as the circumscribed circle.

[0022] In the hollow fiber membrane of the present invention, when IDi is the diameter of the inscribed circle (μm) of the inner surface contour and IDo is the diameter of the circumscribed circle (μm) of the inner surface contour, the value obtained by dividing IDo by IDi, i.e., "IDo / IDi", is defined as the degree of irregularity.

[0023] IDi is preferably 90 μm or larger, more preferably 120 μm or larger, and even more preferably 150 μm or larger, in order to reduce the shear stress of blood flowing through the hollow fiber membrane and suppress the activation of blood cell components, etc. On the other hand, in order to improve the removal efficiency by diffusion, it is preferably 1000 μm or smaller, more preferably 500 μm or smaller, and even more preferably 300 μm or smaller.

[0024] For similar reasons, IDo is preferably 100 μm or larger, more preferably 120 μm or larger, and even more preferably 150 μm or larger. On the other hand, it is preferably 1100 μm or smaller, more preferably 600 μm or smaller, and even more preferably 400 μm or smaller.

[0025] The value obtained by dividing IDo by IDi, i.e., "IDo / IDi", is preferably 1.05 or higher, more preferably 1.08 or higher, and even more preferably 1.10 or higher, in order to increase the effective membrane area on the inner surface of the hollow fiber membrane. On the other hand, in order to suppress platelet adhesion to depressions on the inner surface, it is preferably 1.6 or lower, more preferably 1.5 or lower, and even more preferably 1.4 or lower.

[0026] Regarding the difference between IDo and IDi, a difference of 5 μm or more is preferable, and 10 μm or more is preferable, in order to increase the effective membrane area on the inner surface of the hollow fiber membrane. On the other hand, a difference of 100 μm or less is preferable, and 80 μm or less is preferable, in order to suppress platelet adhesion to depressions on the inner surface.

[0027] The hollow fiber membrane of the present invention preferably has 6 to 40 convex portions in the contour C of its inner surface. The concave and convex portions of the contour C of the inner surface refer to the portions that are convex toward the center of the cross-section in a cross-section perpendicular to the longitudinal direction of the hollow fiber membrane, and the portions that are concave toward the center of the cross-section. The number of convex portions in the contour C of the inner surface is preferably 6 or more, and more preferably 8 or more, in order to increase the effective membrane area of ​​the inner surface of the hollow fiber membrane. On the other hand, from the viewpoint of preventing adhesion or contact between convex portions, or limiting the processing accuracy of the spinneret, it is preferably 40 or less, and more preferably 36 or less.

[0028] The hollow fiber membrane of the present invention is the above X MIN It is preferable that this is observed in the area corresponding to the above-mentioned protrusion. MIN "Observed at the portion corresponding to the above-mentioned protrusion" means that, assuming that the direction in which the porosity is measured (circumferential direction of the hollow fiber membrane) coincides with the contour C of the inner surface when the hollow fiber membrane is cut in the longitudinal direction and exposed, the above X MIN This refers to the area where the phenomenon is observed corresponding to the convex portion mentioned above.

[0029] It is preferable that the above-mentioned protrusions are evenly distributed on the circumference of the above-mentioned circumscribed circle. The even distribution of the protrusions suppresses structural irregularities in the hollow fiber membrane, and stabilizes the performance of the hollow fiber membrane. Here, "evenly distributed" means that each protrusion has approximately point symmetry. For example, for a group of values ​​in which the distance between the vertices of adjacent protrusions is measured, it is preferable that the coefficient of variation is 0.3 or less, and more preferably 0.2 or less.

[0030] Hollow fiber membranes can have two types of structures: a symmetrical structure in which the pore diameter remains substantially constant in the film thickness direction of a cross section perpendicular to the longitudinal direction, and an asymmetrical structure in which the pore diameter changes continuously or discontinuously. The hollow fiber membrane of the present invention preferably exhibits an asymmetrical structure in which the pore diameter is smaller on the inside than on the outside in the film thickness direction of a cross section perpendicular to the longitudinal direction. A hollow fiber membrane exhibiting an asymmetrical structure allows for a thinner layer of small pores that contribute to size exclusion, making it possible to improve permeability while reducing the permeability resistance of water and permeable substances. Furthermore, for hollow fiber membranes used for blood purification, since blood components are often passed through the inside of the hollow fiber membrane, it is preferable to exhibit an asymmetrical structure with a dense interior in order to suppress fouling of the inner surface of the hollow fiber membrane.

[0031] The hollow fiber membrane of the present invention preferably has a thermoplastic resin as its main component. Here, "thermoplastic resin" refers to a polymer that is difficult to deform and elastic at room temperature (20±15℃) and does not exhibit plasticity, but becomes plastic and moldable when heated above room temperature, and undergoes a reversible change to return to its original elastic state when cooled and the temperature drops, without causing any chemical changes such as molecular structure during this process. The "main component of the hollow fiber membrane" refers to the component that is most frequently detected when the hollow fiber membrane is analyzed by infrared spectroscopy or mass spectrometry. The method of component analysis is not particularly limited, but infrared spectroscopy or mass spectrometry is preferably used.

[0032] As the thermoplastic resin, amorphous polymers are preferred. Here, "amorphous polymer" refers to a polymer that does not crystallize, and more specifically, a polymer that does not exhibit an exothermic peak due to crystallization when measured with a differential scanning calorimeter.

[0033] Examples of amorphous polymers include polystyrene, polycarbonate, polyacrylonitrile, polymethyl methacrylate, polyvinyl chloride, or polysulfone, but polysulfone is preferred because it is easier to control the pore size.

[0034] Examples of polysulfones include "Udel" (registered trademark) polysulfone P-1700 and P-3500 (manufactured by Solvay), and "Ultrasone" (registered trademark) S3010 or S6010 (manufactured by BASF).

[0035] The average film thickness of the hollow fiber membrane of the present invention is preferably 10 to 80 μm or less. Here, "average film thickness" refers to the average value of the maximum and minimum film thicknesses in the hollow fiber membrane. To ensure membrane strength that can withstand the pressure used for blood purification applications, the average film thickness of the hollow fiber membrane is preferably 10 μm or more, and more preferably 20 μm or more. On the other hand, to reduce permeation resistance, it is preferably 80 μm or less, and more preferably 60 μm or less.

[0036] To manufacture the hollow fiber membrane of the present invention, for example, the shape of the discharge port of the double-tube nozzle is important. For example, the shape of the discharge port on the inside of the double-tube nozzle is preferably circular or irregular, and more preferably irregular. Also, the X on the inner surface of the hollow fiber membrane MAX and X MIN From the viewpoint of increasing the difference between the two, it is more preferable that the ratio of the circumscribed circle diameter to the inscribed circle diameter of the irregularly shaped discharge port is 1.1 or greater.

[0037] One example of a method for manufacturing a hollow fiber membrane according to the present invention is a manufacturing method comprising: an extrusion step of extruding a spinning stock solution from a slit formed in a double-tube nozzle; a cooling step of passing the material through a dry section consisting of a gas phase; and a solidification step of solidifying the material in a solidification bath after the drying step. When phase separation is induced by heat, a method of rapid cooling in the solidification step is used. When phase separation is induced by a poor solvent, a method of extruding a poor solvent relative to the main component of the spinning stock solution as an injection solution, and then solidifying the material in a solidification bath containing a poor solvent relative to the main component is used. When phase separation is induced by a poor solvent, the poor solvent is supplied by diffusion in the direction of film thickness, resulting in a concentration difference of the poor solvent in the direction of film thickness, which tends to result in an asymmetric structure of the hollow fiber membrane. Therefore, it is preferable for the solidification solution containing the poor solvent to come into contact with the spinning stock solution in the dry section. In this case, by adding a good solvent to the solidification solution to adjust the concentration of the poor solvent, the coagulation properties change, and the pore size of the surface can be made appropriate while maintaining spinnability.

[0038] Here, "poor solvent" refers to a solvent that does not dissolve the main component of the spinning solution at the temperature of the double-tube nozzle in the dispensing process. When the main component of the spinning solution is polysulfone, water is preferred as the poor solvent. As a good solvent, for example, N,N-dimethylacetamide is preferred. The concentration of the good solvent is preferably 40 to 80% by mass, and more preferably 50 to 70% by mass.

[0039] The temperature of the double-tube spinneret during the extrusion process affects the viscosity of the spinning solution and the phase separation behavior of the hollow fiber membrane. Generally, the higher the spinneret temperature, the greater the water permeability and molecular weight cutoff of the resulting porous membrane. However, to maintain spinnability, the temperature of the double-tube spinneret is preferably 90°C or lower. On the other hand, to prevent moisture from adhering to the double-tube spinneret due to condensation, the temperature of the double-tube spinneret is preferably 20°C or higher.

[0040] The temperature of the solidification bath in the solidification process is preferably in the range of 20 to 90°C.

[0041] After the solidification process, the hollow fiber membrane is preferably passed through a water rinsing bath to remove residual solvents and other contaminants. The water rinsing bath temperature is preferably 60 to 90°C to improve washing efficiency.

[0042] The hollow fiber membrane may be dried further. Examples of drying methods include drying with hot air, drying with microwaves, or drying under reduced pressure, but drying with hot air is preferred.

[0043] When the hollow fiber membrane is dried, crimps are imparted to it, which is preferable because it improves the flow of dialysate when it is incorporated into a module. The crimp pitch is preferably in the range of 5 to 30 mm, and the amplitude is preferably in the range of 0.2 to 3.0 mm.

[0044] If the hollow fiber membrane is not dried, it may be impregnated with a moisturizing component to maintain the pore size. It is preferable that the moisturizing component be impregnated after passing through a water bath. Examples of moisturizing components include glycerin or an aqueous solution thereof.

[0045] The hollow fiber membrane of the present invention can be suitably used for blood purification applications.

[0046] Furthermore, the hollow fiber membrane module of the present invention, for example, a blood purification module, is characterized by having the hollow fiber membrane of the present invention incorporated within it.

[0047] A method for manufacturing a hollow fiber membrane module, such as a blood purification module, involves bundling the required number of hollow fiber membranes of the present invention, cut to appropriate lengths, placing them in a cylindrical case, potting both ends with a potting agent, cutting both ends so that the ends of the hollow fiber membranes are open, and then attaching headers to both ends. To uniformly fill the module with the potting agent, it is preferable to inject the potting agent while rotating the module containing the hollow fiber membranes in a centrifuge.

[0048] For the hollow fiber membrane of the present invention to be used for blood purification purposes, it is preferable that the hollow fiber membrane has excellent biocompatibility. Here, "excellent biocompatibility" means, for example, that when human blood is brought into contact with the inner surface of the hollow fiber membrane, a small number of platelets adhere to it. If a small number of platelets adhere, the platelets will not be activated, and the inflammatory response caused by the release of platelet activating factors, etc., can be suppressed. The number of platelets that adhere to the hollow fiber membrane when human blood is brought into contact with it is 20 / (5.2 × 10⁻⁶). 3 μm 2 Preferably 15 pieces / (5.2 × 10 3 μm 2 ) or less is more preferable, 10 pieces / (5.2 × 10 3 μm 2 The following are even more preferable.

[0049] To improve the biocompatibility of hollow fiber membranes or suppress protein fouling, certain polymers may be present on the surface of the hollow fiber membrane, provided that the performance of the hollow fiber membrane is not altered. One way to present polymers on the surface of the hollow fiber membrane is to coat the surface with the polymer. Methods for coating the surface of the hollow fiber membrane with the polymer include adding the polymer to the spinning solution, adding the polymer to the injection solution in the extrusion process, or coating the surface with the polymer after the hollow fiber membrane has been formed. Water is preferred as the solution used for coating.

[0050] Furthermore, the presence of compounds having ester groups on the hollow fiber membrane surface inhibits the adhesion of proteins and platelets. Examples of polymers include vinyl carboxylate esters such as vinyl acetate, acrylic acid esters such as methyl acrylate or methoxyethyl acrylate, methacrylic acid esters such as methyl methacrylate, ethyl methacrylate or hydroxyethyl methacrylate, polyvinyl alcohol with a degree of saponification of less than 99%, vinylpyrrolidone-vinyl acetate copolymer, vinylpyrrolidone-vinyl propanoate copolymer, vinylpyrrolidone-vinyl butyrate copolymer, vinylpyrrolidone-vinyl pentanoate copolymer, vinylpyrrolidone-vinyl pivalate copolymer, vinylpyrrolidone-vinyl caprolactam copolymer, or vinylpyrrolidone-vinyl alcohol copolymer. However, vinylpyrrolidone-vinyl acetate copolymer, vinylpyrrolidone-vinyl propanoate copolymer, vinylpyrrolidone-vinyl butyrate copolymer, vinylpyrrolidone-vinyl pentanoate copolymer, or vinylpyrrolidone-vinyl pivalate copolymer are preferred.

[0051] It is preferable that the polymer used for coating is immobilized on the hollow fiber membrane surface by chemical bonding. Methods for immobilizing the polymer by chemical bonding include, for example, irradiating the hollow fiber membrane with radiation after contacting the polymer, or introducing reactive groups such as amino groups or carboxyl groups to both the coating polymer and the surface of the hollow fiber membrane to be immobilized, and then reacting the two.

[0052] Blood purification modules require prior sterilization, and radiation sterilization is frequently used because it has low residual toxicity and is simple. Examples of radiation used for radiation sterilization include alpha rays, beta rays, gamma rays, X-rays, ultraviolet rays, or electron beams, but gamma rays or electron beams are preferred because they have lower residual toxicity and are simpler. Furthermore, if the hollow fiber membrane contains polymers with hydrophilic groups, there is a risk that these polymers may leach out from the hollow fiber membrane afterward, but such polymers can be immobilized on the inner surface of the hollow fiber membrane by a cross-linking reaction caused by radiation irradiation. To ensure sterilization effectiveness while preventing the decomposition of polymers contained in the hollow fiber membrane, an irradiation dose of 15k to 100kGy is preferred.

[0053] The hollow fiber membrane of the present invention has a wide variety of applications, not limited to blood purification. For example, it can be used as a filter for various fluids, regardless of whether they are in the gas or liquid phase, as a thermal insulation material, sound-absorbing material, shock-absorbing material, substrate for cell culture, carrier for regenerative medicine, and in the manufacturing of biopharmaceuticals. When the hollow fiber membrane of the present invention is used in the manufacturing of biopharmaceuticals, for example, a hollow fiber membrane module containing the hollow fiber membrane of the present invention can be used to purify the raw material for pharmaceuticals. Furthermore, in medical applications, it is suitably used to remove pathogenic proteins, bacteria, viruses, endotoxins, glycans, autoantibodies, immune complexes, free light chains, potassium, bilirubin, bile acids, creatinine, phosphorus compounds, drugs, etc., from blood, plasma, and body fluids, and is particularly suitable for blood purification. In addition, when used in water treatment applications, it is suitably used to remove humic substances, metal corrosive substances, etc.

[0054] The water permeability performance of the hollow fiber membrane of the present invention is set to 100-3000 mL / hr / m³ in order to ensure sufficient permeability and filtration capacity while suppressing the risk of leakage of useful proteins and other substances and irritation to blood cell components. 2 A range of 200-2500 (mL / hr / m³) is preferred, with a range of 200-2500 (mL / hr / m³). 2 / mmHg) is more preferable. The permeability performance (UFR) can be calculated using the following formula (1).

[0055] UFR (mL / hr / m) 2 / mmHg) = Qw / (P×T×A) ···(1) Here, Qw: Filtration volume (mL), T: Flow time (hr), P: Pressure (mmHg), A: The inner surface area (m²) of the hollow fiber membrane 2 ) [Examples]

[0056] (1) Observation of the cross-section of the hollow fiber membrane Eight randomly selected hollow fiber membranes were used as samples, and each was cut at a random position to expose a cross-section perpendicular to the longitudinal direction. The contour C of the inner surface of each cross-section was observed using a digital microscope (RH-2000; manufactured by HIROX Corporation).

[0057] (2) Observation of the inner surface of the hollow fiber membrane Double-sided tape was attached to the sample stage of a scanning electron microscope, and a hollow fiber membrane was fixed to it. The fixed hollow fiber membrane was then cut longitudinally with a single blade so that it became a semi-cylindrical shape, exposing the inner surface of the hollow fiber membrane. Next, the hollow fiber membrane was spread out into a flat film and fixed to the double-sided tape, and a thin film of Pt was formed on the inner surface of the hollow fiber membrane by sputtering, which was used as the sample.

[0058] Using a scanning electron microscope (Merlin; Carl Zeiss), magnified images were continuously captured from one end to the other of the hollow fiber membrane sample's inner surface, perpendicular to the longitudinal direction (corresponding to the circumferential direction of the hollow fiber membrane), in order to calculate the porosity. The magnification was set to 30,000 to 50,000 times.

[0059] (3) Measurement of the open area ratio For magnified images of the inner surface of the captured hollow fiber membrane, a general image analysis software (e.g., ImageJ; Wayne Rasband) was used to perform binarization so that the pore areas were black and the structural areas were white. The porosity was then calculated from the total area of ​​the pores within the entire image. If binarization of the pore and structural areas was difficult due to the contrast difference in the magnified image, as described in International Publication 2001 / 53213, a transparent sheet was placed over a printed copy of the magnified image, the pore areas were blackened with a black marker, and this transparent sheet was copied onto white paper and then binarized using general image analysis software. The porosity was calculated for each of the magnified images taken sequentially for a single sample, and the value with the highest result was set as the maximum porosity of the inner surface, X. MAX The one with the smallest value is the minimum open area ratio of the inner surface, X MIN That's what I decided.

[0060] (4) Permeability measurement using dextran Forty hollow fibers were bundled together and filled into a cylindrical polystyrene case with a diameter of 5 mm and a length of 17 cm. Both ends of the hollow fiber bundle were fixed to the ends of the case by potting with a potting agent (Quick Mender; manufactured by Konishi Co., Ltd.), and a portion of the ends of the potting agent was cut to create openings at both ends of the hollow fiber membrane. Headers were then attached to both sides of the case to obtain a hollow fiber membrane module.

[0061] Next, six types of dextran with different molecular weights (all manufactured by FULKA) were prepared (a: molecular weight 1,200, b: molecular weight 6,000, c: molecular weight 15,000-20,000, d: molecular weight 40,000, e: molecular weight 56,000, f: molecular weight 220,000), and aqueous solutions of each dextran were prepared at a concentration of 0.5 mg / mL.

[0062] The above dextran aqueous solution is poured into the hollow fiber membrane module at a flow rate of 100 mL / min·m 2 ), filtration rate 20mL / (min m 2After passing the solution through the membrane for 20 minutes to reach equilibrium, 10 mL samples were taken of the stock solution, the effluent discharged from the hollow fiber membrane module, and the filtrate. The dextran concentrations in each of the following solutions, namely Cbin in the stock solution, Cbout in the effluent discharged from the hollow fiber membrane module, and Cf in the filtrate, were determined using the method described below.

[0063] Specifically, the sampled dextran aqueous solution was passed through a "Myshori Disc" W-13-5 (manufactured by Tosoh Corporation) and then placed in a sample bottle. The concentration of each solution was measured using HPLC (AK-216-001; manufactured by Tosoh Corporation) and a column (TSKgel-G3000PWXL; manufactured by Tosoh Corporation). A differential refractometer (RI-8020; manufactured by Tosoh Corporation) was used for detection, with a slice time of 0.02 min and a baseline range of 4.5 to 11.0 min.

[0064] The dextran sieving coefficient (SC) was calculated from each dextran concentration using the following formula (2).

[0065] SC=2×Cf / (Cbin+Cbout)) (2) Here, assuming a molecular weight of β2-microglobulin of 11,800 and a molecular weight of albumin (Alb) of 66,000, the corresponding dextran sieving coefficient was calculated.

[0066] (5) Tensile modulus (MPa) Under conditions of 20°C and 65% humidity, a tensile testing machine (RTM-100; manufactured by Orientec Co., Ltd.) was used to measure the sample length of 50 mm and the tensile speed of 50 mm / min. Other conditions followed the method specified in "JIS L 1013:2010 Chemical Fiber Filament Yarn Test Methods, 8.10 Initial Tensile Resistance," and the apparent Young's modulus was calculated from the initial tensile resistance. This was repeated 10 times, and the average value was taken as the tensile modulus of elasticity (MPa).

[0067] [Example 1] 18% by mass of polysulfone ("Udel" (registered trademark) P-3500; manufactured by Solvay) was added to a mixed solvent of 81.67% by mass of N,N-dimethylacetamide and 0.33% by mass of water, and heated at 90°C for 6 hours to dissolve and obtain a spinning solution. This spinning solution was extruded from an annular slit of a circular double-tube cylindrical nozzle. The outer diameter of the annular slit was 0.35 mm and the inner diameter was 0.25 mm. As the injection solution, a solution consisting of 61% by mass of N,N-dimethylacetamide and 39% by mass of water was extruded from the inner tube. The nozzle was kept warm at 50°C. The extruded spinning solution passed through a 350 mm dry section with a dew point of 26°C (temperature 30°C, humidity 80%) in 0.7 seconds, then was guided to a 40°C water bath (coagulation bath) to solidify. After solidification, it was taken up at a speed of 30 m / min by a first roller outside the coagulation bath, washed in a 60°C water bath, and then wound up. By adjusting the extrusion rate of the spinning solution and the injection solution, porous hollow fiber membranes with a dense, asymmetrical structure were obtained. The obtained hollow fiber membranes were measured for fiber diameter, observed for inner surface, and measured for porosity, and the results are shown in Table 1.

[0068] Furthermore, hollow fiber membrane modules were obtained using the acquired hollow fiber membranes, and their permeability performance with dextran was measured. The results are shown in Table 1.

[0069] [Example 2] 16% by mass of polysulfone (Solvay; "Udel" (registered trademark) P-3500), 4% by mass of polyvinylpyrrolidone (K30; International Special Products K30), and 2% by mass of polyvinylpyrrolidone (K90; International Special Products) were added to a mixed solvent of 77% by mass of N,N-dimethylacetamide and 1% by mass of water, and heated and dissolved at 90°C for 6 hours to obtain a spinning solution.

[0070] The spinning stock was extruded from an annular slit of a double-tube cylindrical nozzle with an irregular shape. The outer diameter of the annular slit was 0.62 mm, the inner diameter of the recess was 0.45 mm, and the convex portion was 0.27 mm. As the injection solution, a solution consisting of 63% by mass of N,N-dimethylacetamide and 37% by mass of water was extruded from the inner tube. Hollow fiber membranes with a dense, asymmetrical structure were obtained using the same method as in Example 1, except as described above. The evaluation results of the obtained hollow fiber membranes are shown in Table 1.

[0071] [Example 3] A hollow fiber membrane with a dense, asymmetrical structure was obtained using the same method as in Example 2, except that the extruded spinning solution was passed through a 350 mm dry section with a dew point of 26°C (temperature 30°C, humidity 80%) for 1.05 seconds, and then guided to a 40°C water bath (coagulation bath) for solidification. The evaluation results of the obtained hollow fiber membrane are shown in Table 1.

[0072] [Example 4] A hollow fiber membrane with a dense, asymmetric structure was obtained in the same manner as in Example 2, except that a solution consisting of 50% by mass of N,N-dimethylacetamide and 50% by mass of water was discharged from the inner tube as the injection solution and the nozzle was kept warm at 60°C. The evaluation results of the obtained hollow fiber membrane are shown in Table 1.

[0073] [Example 5] A hollow fiber membrane with a dense, asymmetrical structure was obtained using the same method as in Example 2, except that the extruded spinning solution was guided to a 40°C water bath (coagulation bath) to solidify, washed with a 60°C water bath, dried with 100°C hot air, and then wound up. The evaluation results for the obtained hollow fiber membrane are shown in Table 1.

[0074] [Example 6] A hollow fiber membrane with a dense, asymmetrical structure was obtained using the same method as in Example 4, except that the extruded spinning solution was guided to a 45°C water bath (coagulation bath) and solidified. The evaluation results of the obtained hollow fiber membrane are shown in Table 1.

[0075] [Comparative Example 1] A hollow fiber membrane with a dense, asymmetrical structure was obtained using the same method as in Example 2, except that an annular slit of a double-tube cylindrical end cap with an outer diameter of 0.35 mm and an inner diameter of 0.25 mm was used for the annular slit. The evaluation results of the obtained hollow fiber membrane are shown in Table 1.

[0076] [Comparative Example 2] A hollow fiber membrane with a dense, asymmetrical structure was obtained in the same manner as in Example 2, except that a solution consisting of 50% by mass of N,N-dimethylacetamide and 50% by mass of water was discharged from the inner tube as the injection solution. The evaluation results of the obtained hollow fiber membrane are shown in Table 1.

[0077] [Comparative Example 3] A hollow fiber membrane with a dense, asymmetric structure was obtained in the same manner as in Comparative Example 1, except that a solution consisting of 50% by mass of N,N-dimethylacetamide and 50% by mass of water was discharged from the inner tube as the injection solution. The evaluation results of the obtained hollow fiber membrane are shown in Table 1.

[0078] [Comparative Example 4] Except for adjusting the discharge volume of the stock solution and the discharge volume of the injected solution to set the inner diameter of the hollow fiber membrane to 197.9 μm and the film thickness to 39.3 μm, a hollow fiber membrane with a dense, asymmetric structure was obtained using the same method as in Comparative Example 2. The evaluation results for the obtained hollow fiber membrane are shown in Table 1.

[0079] [Table 1]

Claims

1. The maximum porosity of the inner surface is X ＭＡＸ , The minimum porosity of the inner surface is X ＭＩＮ When that is the case, X ＭＡＸ to X ＭＩＮ A hollow fiber membrane in which the porosity ratio X, which is the value obtained by dividing by , is between 5 and 100.

2. The aforementioned X ＭＡＸ However, the percentage ranges from 1.00% to 90.00%. The aforementioned X ＭＩＮ The hollow fiber membrane according to claim 1, wherein the content is 0.01 to 10.00%.

3. The hollow fiber membrane according to claim 1 or 2, wherein the contour C of the inner surface in a cross section perpendicular to the longitudinal direction is irregularly shaped.

4. The hollow fiber membrane according to claim 3, wherein the contour C has 6 to 40 protrusions.

5. The aforementioned X ＭＩＮ However, the hollow fiber membrane according to claim 4 is observed in the portion corresponding to the convex portion.

6. The hollow fiber membrane according to claim 4, wherein the convex portions are uniformly distributed on the circumference of the circumscribed circle of the contour C.

7. The hollow fiber membrane according to claim 1 or 2, which exhibits an internally dense, asymmetrical structure in a cross section perpendicular to the longitudinal direction.

8. A hollow fiber membrane according to claim 1 or 2, comprising a thermoplastic resin as the main component.

9. The hollow fiber membrane according to claim 8, wherein the thermoplastic resin is an amorphous polymer.

10. The hollow fiber membrane according to claim 9, wherein the amorphous polymer is a polysulfone polymer.

11. The hollow fiber membrane according to claim 1 or 2, wherein the average film thickness is 10 to 80 μm.

12. A hollow fiber membrane module having a hollow fiber membrane according to claim 1 or 2.

13. A hollow fiber membrane module according to claim 12, for use in blood purification.

14. A method for producing a pharmaceutical product, comprising a purification step using the hollow fiber membrane module described in claim 12.

Images