Porous membrane, blood concentrator, and blood concentration method

Abstract

This porous membrane contains a hydrophobic polymer and a hydrophilic polymer. The molecular weight at which the sieve coefficient measured by a dextran sieve is 0.9 is 12,000-20,000, and the molecular weight at which the sieve coefficient is 0.1 is 30,000-80,000.

Description

Porous membrane, blood concentrator, and blood concentration method

[0001] The present invention relates to a porous membrane, a blood concentrator, and a blood concentration method.

[0002] Japanese Patent No. 7326403 (Patent Document 1) discloses a hemodialysis apparatus equipped with a hollow fiber membrane that can effectively retain albumin and large proteins while effectively removing uremic toxins with low molecular weights to contribute to blood purification.

[0003] Japanese Patent No. 7326403

[0004] When an artificial heart-lung machine is used in cardiac surgery (open-heart surgery) requiring extracorporeal circulation, blood is diluted by injection of cardioplegic solution or the like. For this reason, it is known that a blood concentrator (hemoconcentrator) for concentrating the blood by ultrafiltration and returning it to the body is used in the open-heart surgery. In this case, the blood concentrator is required to have a function of removing excess water and components such as electrolytes, and at the same time retaining components such as albumin and other proteins having relatively large molecular weights in the blood without leakage, that is, a function similar to the above-described hemodialysis apparatus. Accordingly, development is being advanced for porous membranes applied to the blood concentrator to enhance water permeability and enhance the performance of preventing components having relatively large molecular weights from leaking out.

[0005] In view of the above circumstances, an object of the present invention is to provide a porous membrane that can achieve both high water permeability and high performance of preventing components having relatively large molecular weights from leaking out at a high level, a blood concentrator including the same, and a blood concentration method using the porous membrane.

[0006] The present invention relates to a porous membrane, a blood concentrator, and a blood concentrating method as described below. [1] A porous membrane comprising a hydrophobic polymer and a hydrophilic polymer, wherein the molecular weight at which the sieving coefficient measured by a dextran sieve is 0.9 is 12,000 or more and 20,000 or less, and the molecular weight at which the sieving coefficient is 0.1 is 30,000 or more and 80,000 or less. [2] The porous membrane according to [1], wherein the molecular weight at which the sieving coefficient is 0.9 is greater than 14,000 and 20,000 or less. [3] The porous membrane according to [1] or [2], wherein the value obtained by subtracting the molecular weight at which the sieving coefficient is 0.9 from the molecular weight at which the sieving coefficient is 0.1 is 24,000 or more and 50,000 or less. [4] The porous membrane according to any one of [1] to [3], wherein the porous membrane is a hollow fiber membrane. [5] The porous membrane according to [4], wherein the hollow fiber membrane has a first inner surface and a second outer surface, and the hollow fiber membrane has a structure in which both or either the porosity and pore diameter are non-uniform in the direction from the first surface to the second surface, and the first surface has both or either the porosity and pore diameter smaller than the second surface. [6] The porous membrane according to [4] or [5], wherein the hollow fiber membrane has an average film thickness of 15 μm or more and 45 μm or less. [7] The porous membrane according to any one of [4] to [6], wherein the hollow fiber membrane has an average inner diameter of 180 μm or more and 220 μm or less. [8] The porous membrane according to any one of [1] to [7], wherein the hydrophobic polymer is both or either polysulfone and polyethersulfone. [9] The porous membrane according to any one of [1] to [8], wherein the hydrophilic polymer is either or both polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate.

[10] The porous membrane according to any one of [1] to [9], wherein the hydrophobic polymer is either or both polysulfone and polyethersulfone, the hydrophilic polymer is either or both polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate, and the ratio of the mass of the hydrophilic polymer to the mass of the hydrophobic polymer is 0.01 or more and 0.05 or less.

[11] A porous membrane according to any one of [1] to

[10] for use in blood concentration.

[12] A blood concentrator comprising a porous membrane according to any one of [1] to

[11] .

[13] A blood concentration method comprising a blood concentration step using a porous membrane according to any one of [1] to

[11] .

[0007] The present invention provides a porous membrane that can achieve a high level of both water permeability and the ability to prevent leakage of components having relatively large molecular weights, a blood concentrator containing the same, and a blood concentration method using the porous membrane.

[0008] Figure 1 is an electron microscope image illustrating a cross-section of the porous membrane (hollow fiber membrane) according to this embodiment and the direction in which water permeates the porous membrane (hollow fiber membrane). Figure 2 is a logarithmic graph illustrating the characteristics of the porous membrane (hollow fiber membrane) according to this embodiment, such as the narrow difference between MWRO and MWCO. Figure 3 is an explanatory diagram illustrating extracorporeal circulation during open-heart surgery using a cardiopulmonary bypass machine, including a hemoconcentrator to which the porous membrane according to this embodiment is applied. Figure 4 is a schematic diagram illustrating an example of a method for manufacturing the porous membrane according to this embodiment.

[0009] One embodiment of the present invention (hereinafter also referred to as "this embodiment") is described below, but the present invention is not limited thereto. In this specification, the notation of the form "A to B" means the upper and lower limits of a range (i.e., A or more and B or less), and if no unit is specified for A and only a unit is specified for B, the unit for A and the unit for B are the same.

[0010] In this specification, "hydrophilic" is defined as a substance whose elution rate in water at 25°C is 5% by mass or more. In this specification, "hydrophobic" is defined as a substance whose elution rate in water at 25°C is 1% by mass or less.

[0011] The elution rate of the target substance is calculated from the difference in mass of the target substance before and after immersion in water. Specifically, first, the target substance is mixed with 90 parts by mass of deionized water at 25°C so that the amount of the target substance is 10 parts by mass. The mixture obtained is shaken at 24°C for 1 hour and then allowed to stand for 24 hours. Next, the mixture is filtered using a 5 μm syringe filter, and the mass (W1) of the solid obtained by heating the filtrate at 130°C for 1 hour is measured, and the elution rate of the target substance is calculated using the following formula: Elution rate of target substance (mass %) = (W1 / mass of target substance used for measurement) × 100

[0012] The molecular weight at which the sieving coefficient measured by a dextran sieve is 0.9 is also called the molecular weight retention onset (MWRO). The molecular weight at which the sieving coefficient is 0.1 is also called the molecular weight cut-off (MWCO). In this specification, the molecular weight at which the sieving coefficient is 0.9 may be written as "MWRO," and the molecular weight at which the sieving coefficient is 0.1 may be written as "MWCO."

[0013] [Porous Membrane] The porous membrane according to this embodiment includes a hydrophobic polymer and a hydrophilic polymer. In the above porous membrane, the molecular weight at which the sieving coefficient measured by a dextran sieve is 0.9 is 12,000 to 20,000, and the molecular weight at which the sieving coefficient is 0.1 is 30,000 to 80,000. In the above porous membrane, the molecular weight at which the sieving coefficient is 0.9 may be between 14,000 and 20,000. In particular, in the above porous membrane, the value obtained by subtracting the molecular weight at which the sieving coefficient is 0.9 from the molecular weight at which the sieving coefficient is 0.1 may be between 24,000 and 50,000. The above porous membrane may be a hollow fiber membrane. A porous membrane having these characteristics can achieve a high level of both water permeability and the ability to prevent leakage of components with relatively large molecular weights.

[0014] The present inventors diligently conducted research to solve the above problems and arrived at the present invention. Specifically, a porous membrane having an MWCO that prevents leakage of albumin (weight-average molecular weight: 66,700), a type of blood protein, and an MWRO that is desirable for high water permeability was conceived. It was found that this porous membrane does not allow leakage of albumin, has a large ultrafiltration coefficient (UFR) for pure water, and maintains a low transmembrane pressure difference (TMP), thus completing the present invention. Hereinafter, the porous membrane according to this embodiment will be explained by illustrating a porous membrane having a hollow fiber membrane configuration.

[0015] <Hydrophobic Polymer> The porous membrane described above contains a hydrophobic polymer. The hydrophobic polymer may include at least one selected from the group consisting of polysulfone-based polymers such as polysulfone and polyethersulfone, cellulosonic polymers such as cellulose acetate and cellulose derivatives, and polyolefin-based polymers such as polyethylene. The hydrophobic polymer may be both or either polysulfone and polyethersulfone. The hydrophobic polymer may be, for example, polyethersulfone. This polyethersulfone is a compound containing the structural unit shown in the following formula (1).

[0016]

[0017] Specific examples of polyethersulfones include, for example, BASF's Ultrazone® E2020P and E6020P, or Sumitomo Chemical's Sumika Excel® 3600P, 4100P, 4800P, 5200P, and 7600P. The polyethersulfone may be E6020P, 4800P, or 5200P. These may be used individually or in combination.

[0018] <Hydrophilic Polymer> The porous membrane described above contains a hydrophilic polymer. The hydrophilic polymer may include at least one selected from the group consisting of polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate (hereinafter also referred to as "vinylpyrrolidone polymer"), polyvinyl alcohol, polyethylene glycol, polyacrylic acid, cellulose, methylcellulose, and chitosan. The hydrophilic polymer may be both or either polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate. The vinylpyrrolidone polymer refers to a polymer of monomers containing at least N-vinylpyrrolidone.

[0019] Vinylpyrrolidone polymers may contain structural units represented by, for example, the following formula (2).

[0020]

[0021] Examples of vinylpyrrolidone polymers include Kollidon® 30, 90, or Luvitec® K30, K80, K85, K90, VA64, all commercially available from BASF, and K-90, K-85, K-30, all commercially available from Nippon Shokubai Co., Ltd.

[0022] In the porous membrane described above, the hydrophobic polymer may be both or either polysulfone and polyethersulfone, and the hydrophilic polymer may be both or either polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate. Furthermore, the ratio of the mass of the hydrophilic polymer to the mass of the hydrophobic polymer may be 0.01 or more and 0.05 or less. In other words, the content ratio (mass ratio) of the hydrophobic polymer / hydrophilic polymer in the entire porous membrane may be 95 to 99 / 1 to 5. The content ratio (mass ratio) may also be 97 to 99 / 1 to 3.

[0023] <Hollow Fiber Membrane> Figure 1 is an electron microscope image illustrating a cross-section of the porous membrane (hollow fiber membrane) according to this embodiment and the direction in which water permeates the porous membrane (hollow fiber membrane). As shown in Figure 1, the porous membrane may be a hollow fiber membrane 1. In Figure 1, the hollow fiber membrane 1 has a first surface 11 and a second surface 12. The first surface 11 may be the inner surface on the hollow side of the hollow fiber membrane 1, and the second surface 12 may be the outer surface of the hollow fiber membrane 1. The arrows shown in Figure 1 indicate the direction from the first surface 11 to the second surface 12.

[0024] The hollow fiber membrane 1 may have an average film thickness of 15 μm or more and 45 μm or less. The hollow fiber membrane 1 may have an average film thickness of 20 μm or more and 40 μm or less, an average film thickness of 25 μm or more and 35 μm or less, or an average film thickness of 26 μm or more and 34 μm or less. In this specification, the "average film thickness" of the hollow fiber membrane 1 means the average value of the distance from the first surface 11 to the second surface 12 in the cross-section revealed by cutting the hollow fiber membrane 1 parallel to the radial direction of the hollow fiber membrane 1, measured at four points approximately equally spaced in the circumferential direction.

[0025] The hollow fiber membrane 1 may have an average inner diameter of 180 μm or more and 220 μm or less. The hollow fiber membrane 1 may have an average inner diameter of 190 μm or more and 210 μm or less, and may have an average inner diameter of 195 μm or more and 205 μm or less. In this specification, the "average inner diameter" of the hollow fiber membrane 1 means the average value of the distances measured in the X-X direction and Y-Y direction (two substantially orthogonal directions on the cross-section) of the internal space including the first surface 11 in the cross-section revealed by cutting the hollow fiber membrane 1.

[0026] (Structure that is non-uniform in the film thickness direction) The hollow fiber membrane 1 has a structure in which both or either of the porosity and pore diameter are non-uniform in the direction from the first surface 11 to the second surface 12 (film thickness direction). In particular, the first surface 11 may have both or either of the porosity and pore diameter smaller than the second surface 12. The above "structure that is non-uniform in the film thickness direction" may mean, for example, in the hollow fiber membrane 1, that the density of the first surface 11 is greater than that of the interior of the hollow fiber membrane 1 and the second surface 12 because the first surface 11 has both or either of the porosity and pore diameter smaller than that of the interior of the hollow fiber membrane 1 and the second surface 12. The above "structure that is non-uniform in the film thickness direction" may mean, for example, that the density is high on the side of the first surface 11 of the hollow fiber membrane 1, and that the density tends to decrease along the direction from the side of the first surface 11 to the side of the second surface 12. This allows for a higher level of balance between water permeability and the ability to prevent leakage of components with relatively large molecular weights.

[0027] In this specification, "showing a tendency for the density to decrease along the direction from the first surface 11 to the second surface 12" means that there should be a portion in the direction from the first surface 11 to the second surface 12 in which both or either of the porosity and pore diameter are larger. Furthermore, if the vicinity of the first surface 11 is X and the vicinity of the second surface 12 is Y, then measuring the porosity and pore diameter at these locations will mean that there is at least one of the following distributions: porosity of X < porosity of Y, or pore diameter of X < pore diameter of Y.

[0028] Therefore, in the direction from the first surface 11 to the second surface 12, there may be portions where both or either of the porosity and pore diameter are larger, and where there is a distribution where the porosity of X < the porosity of Y, or a distribution where the pore diameter of X < the pore diameter of Y, as long as these portions are present, there may be portions where both or either of the porosity and pore diameter are constant in the direction from the first surface 11 to the second surface 12. Furthermore, there may be portions where both or either of the porosity and pore diameter are smaller in the direction from the first surface 11 to the second surface 12.

[0029] The above "porosity" is calculated from the difference between the mass of the hollow fiber membrane when water is added to the void portion and the mass of the dried hollow fiber membrane. Specifically, the above "porosity" refers to the value obtained by measuring the hollow fiber membrane using the following procedure (1) to (5). (1) The portion corresponding to the area where the porosity is to be measured (the sample to be measured) is removed from the hollow fiber membrane. (2) After the sample to be measured is thoroughly immersed in pure water, it is dehydrated by centrifugation at a rotation speed of 900 rpm (gravitational acceleration 116 G) for 5 minutes. (3) The mass (W) of the sample to be measured after dehydration is measured. (4) The mass (P) of the sample to be measured after being completely dried in a dryer is measured. (5) The porosity (ψ) is calculated using the following formula. ψ(%) = W / (W + P / polymer density) × 100 The above "polymer density" refers to the density of the polymer species (hydrophobic polymer) with the highest content in the hollow fiber membrane. For example, the density of polyethersulfone is 1.37 g / cm³. ３ That is the case.

[0030] The porosity of the hollow fiber membrane may be 70% to 98%, 72% to 96%, or 74% to 94%. If the porosity is too high, the strength of the hollow fiber membrane may be insufficient. On the other hand, if the porosity of the hollow fiber membrane is too low, the water permeability may be reduced. When the porosity of the hollow fiber membrane is within the above range, it is possible to achieve both water permeability and strength against filtration pressure.

[0031] The above "pore size" can be confirmed, for example, by observation using the following procedure with an SEM (scanning electron microscope). (1) The hollow fiber membrane as a sample is lightly washed with water, the sample is frozen with liquid nitrogen, and then cut. (2) The cut sample is fixed to a sample stage so that the cut surface (fracture surface) of the sample can be observed, and osmium staining is performed using an osmium coater (Neoc-stb, manufactured by Meiwa Farsis). (3) The osmium-stained sample is observed using a scanning electron microscope (Hitachi "S-2500") at an acceleration voltage of 10 kV, and an SEM image is acquired. In this case, the SEM image may be acquired at a magnification such that approximately 100 pores can be observed in one field of view. (4) Finally, the diameters of 100 pores are measured in the SEM image, and the average value is determined as the pore size of the hollow fiber membrane.

[0032] Furthermore, the density of the hollow fiber membrane in the film thickness direction can also be confirmed by visually determining the porosity and pore size in the SEM image described above.

[0033] <MWRO and MWCO> In the porous membrane described above, the molecular weight (MWRO) at which the sieving coefficient measured by a dextran sieve is 0.9 is between 12,000 and 20,000. The molecular weight (MWCO) at which the sieving coefficient is 0.1 is between 30,000 and 80,000. This allows for a higher level of compatibility between water permeability and the ability to prevent the permeation of components with relatively large molecular weights. In this specification, the values ​​of "MWRO" and "MWCO" described above are values ​​measured before the porous membrane comes into contact with blood.

[0034] In the porous membrane described above, the MWRO is between 12,000 and 20,000. This means that molecules with a molecular weight between 12,000 and 20,000 pass through the porous membrane with a probability of 90% by mass. The MWRO may be between 14,000 and 20,000. The MWRO may be between 15,000 and less than 20,000. As a result, not only water in the blood but also components with relatively small molecular weights (for example, unwanted components such as electrolytes) can pass through the porous membrane, thus enabling the porous membrane to have excellent water permeability.

[0035] In the porous membrane described above, the MWCO is between 30,000 and 80,000. This means that molecules with a molecular weight between 30,000 and 80,000 can only pass through the porous membrane with a probability of 10% by mass. The MWCO may be between 40,000 and 68,000. The MWCO may be greater than 40,000 and less than 68,000. This allows the porous membrane to be superior in preventing leakage of relatively large molecular weight components in the blood, such as albumin (and protein components such as globulin in addition to albumin).

[0036] In the porous membrane described above, the value obtained by subtracting MWRO from MWCO may be between 24,000 and 50,000. Alternatively, the value obtained by subtracting MWRO from MWCO may be between 25,000 and less than 50,000, or between 25,000 and 48,000. In this case, since the porous membrane exhibits values ​​where MWCO and MWRO are close together, it is possible to achieve a higher level of both water permeability that removes not only water but also components with relatively small molecular weights, and performance that prevents leakage of components with relatively large molecular weights.

[0037] FIG. 2 is a logarithmic graph for explaining the narrow difference between MWRO and MWCO, which is a characteristic of the porous membrane (hollow fiber membrane) according to the present embodiment. In the sieving coefficient curve 1a of the hollow fiber membrane shown in FIG. 2, the first molecular weight 2 indicated by the broken line representing MWRO is about 12000, and the second molecular weight 3 indicated by the broken line representing MWCO is about 60000. In this case, the value obtained by subtracting the first molecular weight 2 from the second molecular weight 3 on the sieving coefficient curve 1a of the hollow fiber membrane is about 48000, and the second molecular weight 3 and the first molecular weight 2 are close values. From this, it is understood that the hollow fiber membrane shown in FIG. 2 can achieve both water permeability performance and performance of preventing components having a relatively large molecular weight from leaking out at a higher level. The sieving coefficient curve indicated by the fine broken line in FIG. 2 represents that of a conventional hollow fiber membrane applied to a blood concentrator.

[0038] The sieving coefficient for defining the above MWCO and the above MWRO is determined based on the following formula by using a sieving coefficient measurement solution (fractionation characteristic measurement solution) having a composition described later. Sieving coefficient S=(2C Ｆ ) / (C Ｂｉｎ +C Ｂｏｕｔ ) When the porous membrane is a hollow fiber membrane, the above C Ｆ is the concentration of the solute in the filtrate obtained by the fractionation characteristic measurement solution leaking to the outside after passing through the second surface from the first surface of the inner hollow portion of the hollow fiber membrane. The above C Ｂｉｎ is the concentration of the solute in the fractionation characteristic measurement solution. The above C Ｂｏｕｔ is the concentration of the solute in the fractionation characteristic measurement solution after passing through the inner hollow portion of the hollow fiber membrane.

[0039] A sieving coefficient S of 1 means that the solute in the fractionation characteristic measurement solution passes through the hollow fiber membrane without restriction, so that the entire amount leaks into the filtrate. A sieving coefficient S of 0 means that the solute in the fractionation characteristic measurement solution does not pass through the hollow fiber membrane from the first surface to the second surface at all.

[0040] The above-mentioned solution for measuring fractionation characteristics has the following composition. Specifically, the above-mentioned solution for measuring fractionation characteristics is obtained by dissolving 1.5 g of inulin and 9 g each of dextran (three types: T70, T40S, and T10S) in 3 L of RO water obtained by filtration with a reverse osmosis membrane. The molecular weight of inulin is 3000 to 5000, the molecular weight of dextran T70 is 60000 to 76000, the molecular weight of dextran T40S is 35000 to 45000, and the molecular weight of dextran T10S is 9000 to 11000.

[0041] In the case of the hollow fiber membrane described above, when the MWCO and MWRO values ​​are to be determined, the fractionation characteristic measurement solution is introduced into the hollow part of the hollow fiber membrane at a pressure of 7.7 kPa. Furthermore, the filtrate and the fractionation characteristic measurement solution after passing through the hollow part of the hollow fiber membrane described above are sampled, and the MWCO and MWRO values ​​are determined using the formula described above.

[0042] [Applications and Blood Concentrators] The porous membrane (hollow fiber membrane) according to this embodiment may be used for blood concentration. Figure 3 is an explanatory diagram illustrating extracorporeal circulation during open-heart surgery using a cardiopulmonary bypass machine, including a blood concentrator to which the porous membrane according to this embodiment is applied. As shown in Figure 3, the hollow fiber membrane may be applied to a blood concentrator 100 for concentrating blood A diluted by the injection of myocardial protective solution, etc., and returning it to the body B in cardiac surgery (open-heart surgery) where extracorporeal circulation is required and a cardiopulmonary bypass machine is used. Therefore, the blood concentrator 100 may include the porous membrane (hollow fiber membrane). Due to the characteristics of the porous membrane (hollow fiber membrane) described above, the blood concentrator 100 has high water permeability and can concentrate blood without leaking necessary proteins such as albumin, and return the blood to the body. In Figure 3, the body B includes a blood reservoir, a cardiopulmonary bypass machine, etc., to which the blood concentrated by the blood concentrator 100 is headed. Excess water, electrolytes, etc., removed from the blood concentrate device 100 are discharged from the system as filtrate 4.

[0043] [Blood Concentration Method] The blood concentration method according to the present embodiment includes a blood concentration step using the porous membrane described above. The blood concentration method having such features, based on the above-described properties of the porous membrane, has high water permeability performance, and can concentrate blood without causing leakage of necessary proteins such as albumin, and return the blood into the body. Thereby, the blood concentration method can be applied to cardiac surgery (open-heart surgery) that requires extracorporeal circulation and uses a heart-lung machine.

[0044] [Method for Producing Porous Membrane] As for the method for producing a porous membrane according to the present embodiment, any appropriate production method may be used as long as the porous membrane having the above-described features can be obtained. However, according to the following method for producing a porous membrane, the porous membrane having the above-described features may be obtained with good yield. Hereinafter, the method for producing the porous membrane will be described by exemplifying a method for producing a hollow fiber membrane, which is one aspect of the porous membrane.

[0045] The method for producing the hollow fiber membrane includes a spinning step of discharging a spinning stock solution and an inner liquid from a double-pipe nozzle through an air running section into a coagulating liquid, coagulating the spinning stock solution in the coagulating liquid, and drawing a coagulated product of the spinning stock solution out of the coagulating liquid. The method for producing the hollow fiber membrane may include, in addition to the spinning step, a step of obtaining the hollow fiber membrane by washing and drying the coagulated product. The spinning stock solution contains a resin raw material including a hydrophobic polymer and a hydrophilic polymer, a solvent, and a non-solvent. The inner liquid contains water. The total concentration of components other than water in the inner liquid (inner liquid concentration) may be 30 to 70 mass%. The temperature of the coagulating liquid is 50 to 80°C, and the total concentration of components other than water in the coagulating liquid (coagulating liquid concentration) may be 15 to 45 mass%.

[0046] In the method for producing the hollow fiber membrane, first, the hydrophobic polymer and the hydrophilic polymer are prepared, for example, by being obtained from the market. The spinning stock solution is prepared by mixing the hydrophobic polymer and the hydrophilic polymer at a predetermined ratio by a known method. For example, the mixing ratio (mass ratio) of hydrophobic polymer / hydrophilic polymer may be 85 to 97 / 3 to 15. Predetermined amounts of a solvent and a non-solvent are also mixed into the spinning stock solution by a known method.

[0047] <Spinning Process> Figure 4 is a schematic diagram illustrating an example of a method for manufacturing a porous membrane according to this embodiment. As shown in Figure 4, the spinning process may include the following first to third steps, which proceed in that order. First, in the first step, the spinning dope 10a and the internal liquid 10b are discharged from a double-tube nozzle 20 through an air gap 20a into a first coagulation bath 21 filled with a coagulation liquid, which will be described later. In the second step, the spinning dope 10a coagulates in the first coagulation bath 21, thereby obtaining a solidified product. In the third step, the solidified product is pulled out of the first coagulation bath 21. Pulling out the solidified product is performed, for example, by a liquid guide 31 and a roller 32. The solidified product pulled out of the first coagulation bath 21 is further coagulated in a second coagulation bath 22 to become a hollow fiber membrane, which is then washed in a washing bath 23 and may be wound up by a winding machine 24. The composition of the coagulation solution filling the second coagulation bath 22 may be the same as the coagulation solution filling the first coagulation bath 21.

[0048] The nozzle 20 is double-tubular and comprises an outer tube and an inner tube provided inside the outer tube. The spinning solution 10a is discharged from the gap (slit) between the outer tube and the inner tube, and the inner solution 10b is discharged from inside the inner tube. The inner diameter of the outer tube may be 200 to 1500 μm, or 250 to 1200 μm. The outer diameter of the inner tube may be 100 to 700 μm, or 150 to 600 μm. The outer diameter of the inner tube may be about the same as the inner diameter of the hollow fiber membrane.

[0049] The air gap length (AG length), which is the straight-line distance of the air-traveling section (air gap) 20a (the distance between the tip of the nozzle 20 and the liquid surface of the solidifying liquid), may be 100 to 500 mm, or 150 to 400 mm.

[0050] The hollow fiber membrane obtained by the spinning process described above may be subjected to a further washing process with pure water (washing process). In the washing process, the water flow may be in the opposite direction to the direction of movement of the hollow fiber membrane (countercurrent), or it may be in the same direction as the direction of movement of the hollow fiber membrane (parallel current). In the washing process, the hollow fiber membrane may be washed with reverse osmosis (RO) water at 50 to 90°C, for example. After the washing process, the hollow fiber membrane may be subjected to a drying process. In the drying process, the hollow fiber membrane may be dried at 50 to 90°C for 10 to 25 hours, for example.

[0051] (Spinning Solution) The spinning solution 10a contains the hydrophobic polymer and the hydrophilic polymer as described above. Specifically, the spinning solution 10a contains, for example, polyethersulfone as the hydrophobic polymer and polyvinylpyrrolidone as the hydrophilic polymer. The spinning solution 10a may further contain a solvent and may contain a non-solvent.

[0052] The temperature of the spinning solution 10a at the nozzle 20 (discharge temperature) may be 40 to 80°C, or 50 to 70°C.

[0053] The concentration of polyethersulfone in the spinning solution 10a may be 10 to 30% by mass, or 10 to 25% by mass. If the concentration of polyethersulfone is too low, the strength of the hollow fiber membrane may be reduced. On the other hand, if the concentration of polyethersulfone is too high, the viscosity of the spinning solution 10a may become too high, making spinning difficult.

[0054] The concentration of polyvinylpyrrolidone in the spinning solution 10a may be 0.1 to 10% by mass, or 0.5 to 5% by mass. If the concentration of polyvinylpyrrolidone is too low, it may adversely affect the water permeability performance of the hollow fiber membrane. On the other hand, if the concentration of polyvinylpyrrolidone is too high, the viscosity of the spinning solution 10a may become too high, making spinning difficult.

[0055] The solvent may be a liquid capable of dissolving the polyethersulfone. The solvent may be a polar solvent. The polar solvent may be an aprotic polar solvent. Examples of the aprotic polar solvent include N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), and acetonitrile.

[0056] The non-solvent is a liquid (excluding water) that does not dissolve the polyethersulfone. Examples of the non-solvent include glycol esters, glycerin, and alcohols. The non-solvent may be a glycol ester. Examples of glycol esters include ethylene glycol, triethylene glycol (TEG), polyethylene glycol (polyethylene glycol 200, polyethylene glycol 400, etc.), and propylene glycol.

[0057] In the spinning solution 10a, the ratio of the mass of solvent (S) to non-solvent (NS) (S / NS ratio) may be 30 / 70 to 70 / 30, or 40 / 60 to 60 / 40. If the S / NS ratio in the spinning solution becomes too small, the dissolution of the polyethersulfone becomes unstable, which may lead to decreased spinning stability or the failure to obtain a hollow fiber membrane with a non-uniform structure in the film thickness direction as described above. If the S / NS ratio becomes too large, spinning stability may decrease. In addition to the solvent and non-solvent, the spinning solution may also contain water.

[0058] The order of adding materials and the mixing method when mixing the resin raw materials, solvents, and non-solvents that constitute the hollow fiber membrane are not particularly limited, and known orders and methods may be used.

[0059] (Internal coagulation solution (internal liquid)) The internal liquid 10b contains water. The water content in the internal liquid 10b may be 30 to 70% by mass, or 40 to 60% by mass.

[0060] The internal liquid 10b may contain solvents, non-solvents, etc., in addition to water. Examples of non-solvents include ethylene glycol, triethylene glycol (TEG), polyethylene glycol 200 or 400, glycerin, and propylene glycol. Examples of solvents include N-methyl-2-pyrrolidone (NMP), dimethylacetamide, dimethylformamide, and dimethyl sulfoxide.

[0061] When the water content of the internal liquid 10b is low and the content of each solvent is high, the solidification rate on the first surface side of the hollow fiber membrane slows down, the phase separation time is extended, and a structure with high porosity (a structure with low density) tends to be constructed on the first surface side. When the water content of the internal liquid 10b is high and the content of each solvent is low, the solidification rate on the first surface side of the hollow fiber membrane speeds up, the phase separation time is shortened, and a structure with low porosity (a structure with high density) tends to be constructed on the first surface. For this reason, the total concentration of solvents and non-solvents in the internal liquid 10b may be 30 to 70% by mass, or 40 to 60% by mass. The ratio of the mass of solvents to non-solvents in the internal liquid (solvent / non-solvent) is, for example, 40 / 60 to 70 / 30.

[0062] When the spinning solution 10a and the internal liquid 10b are discharged from the double-tube nozzle 20, a temperature difference may be provided between the spinning solution 10a and the internal liquid 10b.

[0063] (External Coagulation Solution) The coagulation solution may contain a solvent and a non-solvent. The solvent and non-solvent may each be one type or a mixture of multiple types. If the content of each solvent in the coagulation solution is too high, the coagulation rate of the second surface side of the hollow fiber membrane will slow down, the phase separation time will be extended, and a structure with high porosity (low density) may be constructed on the second surface side. If the water content in the coagulation solution is too high and the content of each solvent is too low, the coagulation rate of the second surface side of the hollow fiber membrane will be too fast, the phase separation time will be shortened, and a structure with low porosity (high density) may be constructed on the second surface side. From the viewpoint of obtaining the hollow fiber membrane having a structure with high porosity (low density) on the second surface side, the ratio of the total amount of the solvent and non-solvent in the coagulation solution (concentration of the coagulation solution: CB concentration) may be 15 to 45% by mass, or 25 to 35% by mass. The ratio of the mass of the solvent to the non-solvent in the coagulation solution (solvent / non-solvent) is, for example, 40 / 60 to 70 / 30.

[0064] The temperature of the coagulation solution greatly affects the coagulation time of the hollow fiber membrane. If the temperature of the coagulation solution is too high, the coagulation rate on the second surface side of the hollow fiber membrane will slow down, the phase separation time will be prolonged, and a structure with high porosity (low density) may be formed on the second surface side. If the temperature of the coagulation solution is too low, the coagulation rate on the second surface side of the hollow fiber membrane will be fast, the phase separation time will be shortened, and a structure with low porosity (high density) may be formed on the second surface side. From the viewpoint of obtaining a hollow fiber membrane having a structure with high porosity (low density) on the second surface side, the temperature of the coagulation solution may be 50 to 90°C or 60 to 80°C.

[0065] In order to obtain a hollow fiber membrane having a non-uniform structure in the film thickness direction as described above, the balance between the concentration of the internal liquid and the concentration of the coagulation solution, as well as their temperatures, may be adjusted as appropriate.

[0066] <Effects> The above-described manufacturing method yields a porous membrane that is excellent in both water permeability and the ability to prevent leakage of necessary proteins such as albumin.

[0067] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these. Below, the manufacturing method and characteristics of porous membranes (hollow fiber membranes) of Samples 1 to 6 and Samples 11 to 15 will be described. Samples 1 to 6 are examples, and Samples 11 to 15 are comparative examples.

[0068] [Production of Porous Membrane (Hollow Fiber Membrane)] <Sample 1> (Preparation of Spinning Solution) A spinning solution was prepared by mixing 17.0% by mass of polyethersulfone (PES, Ultrason® E6020P manufactured by BASF), 1.0% by mass of polyvinylpyrrolidone (PVP K90, manufactured by Nippon Shokubai), 45.1% by mass of N-methyl-2-pyrrolidone (NMP, manufactured by Mitsubishi Chemical Corporation), and 36.9% by mass of triethylene glycol (TEG, manufactured by Mitsubishi Chemical Corporation), heating them, and dissolving them uniformly.

[0069] (Preparation of the internal solution) A mixture was obtained by mixing NMP (solvent) and TEG (non-solvent) in a mass ratio (S / NS ratio) of NMP / TEG = 55 / 45. The internal solution was prepared by mixing the above mixture with reverse osmosis (RO) water. The total concentration of the solvent and non-solvent in the above internal solution (internal solution concentration) was 50% by mass, and the RO water was 50% by mass.

[0070] (Preparation of Coagulation Solution) A coagulation solution was prepared by mixing NMP (solvent) and TEG (non-solvent) in a mass ratio (S / NS ratio) of NMP / TEG = 55 / 45. The total concentration of the solvent and non-solvent in the above coagulation solution (CB concentration) was 30% by mass, and RO water was 70% by mass. The temperature of the above coagulation solution (CB temperature) was set to 72°C.

[0071] (Spinning Process) The porous membrane (hollow fiber membrane) of Sample 1 was manufactured using basically the same method as described in the above section [Method for Manufacturing Porous Membrane]. In the spinning process, the spinning solution was discharged together with the internal liquid from a heated tube-in-orifice nozzle, passed through a dry section (air-running section: air gap) isolated from the outside air by a spinning tube, and then solidified in the first and second solidification baths filled with the solidification solution to obtain the hollow fiber membrane. After that, the hollow fiber membrane went through a washing bath and was wound up at a predetermined spinning speed using a skein winder. Bundles of the obtained hollow fiber membranes (approximately 8200 strands) were cut to a certain length and dried in a hot air dryer. The specific conditions were as follows: The CB concentration and CB temperature of the solidification solution in the first and second solidification baths were the same. Thus, the hollow fiber membrane of Sample 1 was obtained.

[0072] 1) Spinning process conditions Discharge temperature of spinning solution (set temperature): 60°C Distance of air travel section (air gap length: AG length): 310 mm Drawing speed (spinning speed): 31 m / min 2) Washing (water washing) conditions RO water at 70°C or higher 3) Drying conditions 15 hours at 60°C

[0073] (Samples 2 to 6) Using the spinning solution prepared in Sample 1, the spinning process was carried out at the discharge temperature and AG length, as well as the CB concentration and CB temperature of the coagulation solution, as shown in Table 1 below, to produce hollow fiber membranes for Samples 2 to 6. In the production of the porous membranes for Samples 2 to 6, the spinning speed, washing conditions, and drying conditions in the spinning process were the same as those for Sample 1.

[0074]

[0075] (Samples 11 to 13) Membrane A disclosed in Japanese Patent Publication No. 7326403 (Patent Document 1) is the hollow fiber membrane of Sample 11, Membrane B is the hollow fiber membrane of Sample 12, and Membrane C is the hollow fiber membrane of Sample 13. For data regarding the properties of the hollow fiber membranes of Samples 11 to 13, data disclosed in the corresponding Japanese Patent Publication No. 7326403 (Patent Document 1) was cited.

[0076] (Sample 14) The FX-220 filter (manufactured by Fresenius Medical Care Japan Co., Ltd.), which is membrane 4 disclosed in Japanese Patent Publication No. 7326403 (Patent Document 1), was used as the hollow fiber membrane for Sample 14. For data regarding the properties of the hollow fiber membrane for Sample 14, data disclosed in the corresponding Japanese Patent Publication No. 7326403 (Patent Document 1) and prior art information were cited.

[0077] (Sample 15) The hollow fiber membrane of Example 1 disclosed in Japanese Patent Publication No. 7305712 was used as the hollow fiber membrane for Sample 15. For the data regarding the properties of the hollow fiber membrane of Sample 15, the data disclosed in the corresponding Japanese Patent Publication No. 7305712 was cited.

[0078] [Evaluation of Porous Membranes (Hollow Fiber Membranes)] The shape (outer diameter, inner diameter, and film thickness) and characteristics (MWRO, MRCO, ultrafiltration coefficient (UFR) of pure water, albumin sieving coefficient (SCalb), and intermembrane pressure difference (TMP(6hr)) after 6 hours of water permeation) of the hollow fiber membranes of Samples 1 to 6 were evaluated. MWRO and MRCO were determined by the methods described above.

[0079] <Measurement of Average Outer Diameter, Average Inner Diameter, and Average Film Thickness of Hollow Fiber Membranes> The average outer diameter, average inner diameter, and average film thickness of the hollow fiber membranes were measured by the following method. Specifically, multiple hollow fiber membranes were passed through a 3 mm diameter hole in the center of a microscope slide, ensuring that they did not fall out. The hollow fiber membranes were then cut along the top and bottom surfaces of the slide using a razor blade to obtain cross-sectional samples of the hollow fiber membranes. A projector (Nikon PROFILE PROJECTOR V-12) was used to measure the inner and outer diameters of these hollow fiber membrane cross-sectional samples. Specifically, the inner and outer diameters of the hollow fiber membranes were obtained by measuring their minor and major axes within the cross-sectional samples. For each hollow fiber membrane cross-section, the outer diameter and inner diameter were measured in the minor and major axis directions, and their arithmetic mean values ​​were taken as the inner and outer diameters of a single hollow fiber membrane. Similar measurements were performed on five hollow fiber membrane cross-sectional samples, and their average values ​​were taken as the average inner diameter and average outer diameter. The average film thickness was obtained by subtracting the average inner diameter from the average outer diameter of the hollow fiber membranes and dividing the result by 2.

[0080] <Measurement of Ultrafiltration Coefficient (UFR) of Pure Water> The above UFR was measured by the following method. Specifically, a hollow fiber membrane module applicable to a hemoconcentrator was fabricated from the hollow fiber membranes of each of the above samples. The blood outlet circuit of the hollow fiber membrane module was sealed, and dead-end filtration was performed. Specifically, a pressurized tank was filled with pure water kept at 37°C, and while the pressure was controlled by a regulator, pure water was sent to the inside of the hollow fiber membrane of the hollow fiber membrane module in a constant temperature bath kept at 37°C, and the amount of filtrate that flowed out from the outside of the hollow fiber membrane was measured with a graduated cylinder. In this case, the intermembrane pressure difference (TMP) was given as TMP = (Pi + Po) / 2, where Pi is the pressure at the module inlet and Po is the pressure at the module outlet. By changing TMP, the filtration flow rates at four points were measured, and the ultrafiltration coefficient (UFR, in units of mL / min / m) of the module was determined from the slope of the lines between them. ２ The TMP (TMP / mmHg) was calculated. At this time, the correlation coefficient between TMP and filtration flow rate must be 0.999 or higher. Furthermore, to minimize pressure loss errors due to the circuit, TMP was measured within a range of 100 mmHg or less.

[0081] <Measurement of Intermembrane Pressure Difference (TMP(6hr)) after 6 Hours of Water Permeation> The above TMP(6hr) was determined by the following measurement method. Specifically, hollow fiber membrane modules applicable to a blood concentrator were prepared from the hollow fiber membranes of each of the above samples. Meanwhile, bovine blood, which had been prepared to have a hematocrit of 32±3% and a protein concentration of 6±0.5 g / dL by adding citrate to suppress coagulation, was used. The above bovine blood was circulated through the above hollow fiber membrane module for 6 hours under the conditions of a blood flow rate (Qb) of 500 mL and a filtration flow rate (Qf) of 80 mL / min. The pressure at the module inlet, module outlet, and filtrate side were measured 6 hours after the start of circulation, and the intermembrane pressure difference (TMP(6hr)) was determined from these using the following formula: TMP(6hr) = ([Inlet pressure] + [Outlet pressure]) / 2 - [Filtrate pressure]

[0082] <Measurement of Albumin Sieving Coefficient (SCalb)> The SCalb was determined by the following measurement method. Specifically, the blood flow rate (Qb) was stabilized at 50 ± 5 mL / min, and after circulating for 30 minutes, the liquid was sampled from the module inlet side, the module outlet side, and the filtrate side when the blood flow rate (Qb) was 300 ± 6 mL / min and the intermembrane pressure difference (TMP) was 26.7 ± 2.7 kPa (200 mmHg). The albumin concentration in each of these sampled liquids was measured using the A / G B Test Wako (manufactured by Fujifilm Wako Pure Chemical Industries), and the SCalb was determined from these values ​​using the following formula: SCalb = 2 × [filtrate concentration] / ([inlet side concentration] + [outlet side concentration]) The results are shown in Table 2.

[0083]

[0084] <Discussion> According to Table 2 above, the porous membranes of Samples 1 to 6 have an MWRO of 12,000 to 20,000 and an MWCO of 30,000 to 80,000. Furthermore, the porous membranes of Samples 1 to 6 have a small value obtained by subtracting MWRO from MWCO. The porous membranes of Samples 1 to 6 have a large UFR, a small SCalb, and maintain a low TMP (6hr). Thus, it is suggested that the porous membranes of Samples 1 to 6 are superior in both water permeability and the ability to prevent leakage of proteins with relatively large molecular weights such as albumin. Furthermore, it is suggested that the porous membranes of Samples 1 to 6 are superior in both of the above-mentioned performances compared to the porous membranes of Samples 11 to 15.

[0085] Although embodiments of the present invention have been described above, it is also intended from the outset that the configurations of each of the above embodiments may be combined as appropriate.

[0086] The embodiments disclosed herein should be considered in all respects to be illustrative and not restrictive. The scope of the invention is indicated by the claims rather than by the foregoing description, and all modifications within the meaning and scope of equivalents of the claims are intended to be included.

[0087] 1 Hollow fiber membrane, 1a Sieving coefficient curve of hollow fiber membrane, 11 First surface, 12 Second surface, 2 First molecular weight, 3 Second molecular weight, 4 Filtrate, A Diluted blood, B Body, 10a Spinning solution, 10b Internal fluid (internal coagulation solution), 20 Nozzle, 20a Air-running section (air gap), 21 First coagulation bath, 22 Second coagulation bath, 23 Washing bath, 24 Winding machine, 31 Guide in liquid, 32 Roller.

Claims

1. A porous membrane comprising a hydrophobic polymer and a hydrophilic polymer, wherein the molecular weight at which the sieving coefficient measured by a dextran sieve is 0.9 is between 12,000 and 20,000, and the molecular weight at which the sieving coefficient is 0.1 is between 30,000 and 80,000.

2. The porous membrane according to claim 1, wherein the molecular weight at which the sieving coefficient is 0.9 is greater than 14,000 and less than or equal to 20,000.

3. The porous membrane according to claim 1 or claim 2, wherein the value obtained by subtracting the molecular weight for which the sieving coefficient is 0.9 from the molecular weight for which the sieving coefficient is 0.1 is between 24,000 and 50,000.

4. The porous membrane according to any one of claims 1 to 3, wherein the porous membrane is a hollow fiber membrane.

5. The porous membrane according to claim 4, wherein the hollow fiber membrane has an inner first surface and an outer second surface, the hollow fiber membrane has a structure in which both or either the porosity and pore diameter are non-uniform in the direction from the first surface to the second surface, and the first surface has both or either the porosity and pore diameter smaller than the second surface.

6. The porous membrane according to claim 4 or claim 5, wherein the hollow fiber membrane has an average film thickness of 15 μm or more and 45 μm or less.

7. The porous membrane according to any one of claims 4 to 6, wherein the hollow fiber membrane has an average inner diameter of 180 μm or more and 220 μm or less.

8. The porous membrane according to any one of claims 1 to 7, wherein the hydrophobic polymer is both or either polysulfone and polyethersulfone.

9. The porous membrane according to any one of claims 1 to 8, wherein the hydrophilic polymer is both or either polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate.

10. The porous membrane according to any one of claims 1 to 9, wherein the hydrophobic polymer is both or either polysulfone and polyethersulfone, the hydrophilic polymer is both or either polyvinylpyrrolidone and a copolymer of vinylpyrrolidone and vinyl acetate, and the ratio of the mass of the hydrophilic polymer to the mass of the hydrophobic polymer is 0.01 or more and 0.05 or less.

11. A porous membrane according to any one of claims 1 to 10, for use in blood concentration.

12. A blood concentrator comprising a porous membrane according to any one of claims 1 to 11.

13. A blood concentration method comprising a blood concentration step using a porous membrane according to any one of claims 1 to 11.

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