JP5062773B2 - Blood purifier - Google Patents

Description

  The present invention relates to a blood purifier having a hollow fiber membrane containing polyvinylpyrrolidone, which has high blood impurity removal performance and low albumin permeability.

  Hemodialysis has been performed as maintenance therapy for patients with chronic renal failure. In recent years, there have been an increasing number of examples of continuous hemofiltration, continuous hemofiltration dialysis, continuous hemodialysis, etc. as acute blood purification therapy for patients with severe pathological conditions such as acute renal failure and sepsis. . Blood purification membrane materials used in these therapies include naturally derived materials such as cellulose and cellulose derivatives, and synthetic polymer materials such as polysulfone resins, polymethyl methacrylate, polyacrylonitrile, and ethylene vinyl alcohol copolymers. Is being used. Among these, a membrane made of a polysulfone resin has attracted particular attention in recent years because it has advantages such as good mechanical properties, heat resistance, and biocompatibility.

  Since polysulfone-based resins are relatively hydrophobic, they tend to adsorb plasma proteins when they come into contact with blood. For this reason, when manufacturing a blood purification membrane with a polysulfone resin, it is common to add a hydrophilic polymer in order to impart hydrophilicity and improve blood compatibility.

  In addition, as described above, materials with strong hydrophobicity tend to adsorb plasma proteins, so when used in contact with blood for a long time, the membrane performance deteriorates over time due to the effects of plasma proteins adsorbed on the surface. End up. Since plasma protein adsorption is reduced by imparting hydrophilicity, the addition of a hydrophilic polymer is effective for improving blood compatibility and also exhibiting stable solute removal performance as a membrane.

  Polyvinylpyrrolidone is generally used as the hydrophilic polymer used for such purposes. However, when a hydrophilic polymer is used, it swells in an aqueous solution and closes the pores of the membrane, so that the permeation performance tends to decrease.

  Patent Document 1 describes a method for producing a membrane in which only a polysulfone-based polymer that is a base polymer is left and a part of polyvinylpyrrolidone is decomposed and removed with an aqueous sodium hypochlorite solution. However, this method has a problem that the hydrophilicity of the film is lowered because polyvinylpyrrolidone as a hydrophilizing agent is removed.

  In hollow fiber membranes for blood purification, many studies have been made to improve the permeability of specific substances by mainly studying the membrane structure, membrane composition and membrane properties of the hollow fiber membranes. Specifically, the membrane for removing uremic protein (also called low molecular weight protein) has a large pore size, and further, the molecular weight is smaller than that while suppressing the permeation or loss of albumin useful for the living body. Improvement of fractionation property that allows low-molecular-weight proteins to permeate, improvement of membrane surface characteristics for more selective permeation of charged low-molecular non-protein uremic substances, not limited to low-molecular-weight proteins, etc. Can be illustrated.

Dialysis amyloidosis is well known as a typical example of complications caused by prolonged dialysis treatment and caused by low molecular weight proteins with urine toxicity. In order to improve the removal performance of β ₂ -microglobulin which is a causative substance of dialysis amyloidosis while suppressing permeation of albumin useful for the living body, in order to sharpen the fractionation of the hollow fiber membrane Various improvements have been studied. In addition, in order to improve dialysis amyloidosis more effectively, studies have also been made to remove α ₁ -microglobulin, which is a low molecular weight protein having urine toxicity as well as β ₂ -microglobulin.

  For example, Patent Document 2 discloses a membrane in which hydrophilic polymer is concentrated in a dense layer near the inner surface of the membrane, improving the balance of permeation of the membrane, and having high water permeability and low protein leakage. Has been.

Patent Literature 3 and Patent Literature 4 disclose a dialyzer comprising a hollow fiber membrane obtained from a four-component membrane-forming stock solution comprising a polysulfone polymer, polyvinylpyrrolidone, a solvent and water. Addition of water to the film-forming stock solution facilitates precipitation of cyclic dimers that are impurities in the polysulfone-based polymer. Therefore, since the impurities in the film forming stock solution increase, it is unsuitable for stable production over a long period of time. Although clearance performance of vitamin B ₁₂ as an index of the performance of removing impurities in the blood are disclosed, only water permeability is abnormally high film.

Patent Document 5 and Patent Document 6, the clearance performance of only vitamin B ₁₂ is disclosed.

Patent Document 7 discloses a technique for coating polyvinylpyrrolidone on the inner surface of a film. Although clearance performance of vitamin B ₁₂ is disclosed, no description about the amount of adsorption of the adsorption amount and myoglobin of vitamin B _12.

JP 05-161833 A Japanese Patent Laid-Open No. 4-300636 JP 2001-170172 A JP 2001-170167 A Japanese Patent Laid-Open No. 11-178919 JP 11-347117 A JP-A-6-238139

Previously blood purifier of the vitamin B ₁₂ clearance for dialysis, the terms considerably even those high removal performance of impurities in the blood of vitamin B ₁₂ clearance was limited degree 135 ml / min.

The present invention relates to a blood purifier having a hollow fiber membrane composed of a polysulfone-based polymer and polyvinyl pyrrolidone, which has high blood impurity removal performance, low albumin permeability, and low molecular protein adsorption amount. Its purpose is to provide. In particular, the breaking strength and high elongation at break, a blood purifier comprising a small thickness hollow fiber membrane, high clearance value of vitamin B _12, particularly good blood in that low adsorbability of vitamin B ₁₂ Provide a purifier.

The present invention is as follows.
(1) A blood purifier having a hollow fiber membrane comprising a polysulfone-based polymer and polyvinylpyrrolidone, wherein the hollow fiber membrane has a structure in which the pore diameter continuously increases from the inner surface to the outer surface. , and a clearance value of blood purifier of vitamin B ₁₂ following irradiation is 152 ml / min or more membrane area 1.5 m ² per / or membrane area 1.5 m ² in terms of value, the adsorption rate of the vitamin B ₁₂ is 25 %, And the myoglobin adsorption rate is 20% or less, and the average thickness Y of the fibrils, which are mesh-like skeleton portions outside the film thickness direction of the hollow fiber membrane, and the fibrils inside the film thickness direction The blood purifier is characterized in that the albumin permeability is set to 0.35% or less by setting the ratio (Y / X) to the mean thickness X of 1.2 to 2.0 to 2.0.
(2) The blood purifier according to (1), wherein an average thickness of all fibrils present in the hollow fiber membrane is 100 nm or more and 200 nm or less.
(3) The blood purifier according to (1) or (2), wherein the container of the blood purifier is made of a polypropylene polymer.
(4) The blood purifier according to any one of (1) to (3), wherein the degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is 80% or more and less than 100%.
(5) By injecting the crosslinking degree adjusting agent solution into the hollow fiber membrane from the open end of the blood purifier, then removing the crosslinking degree adjusting agent solution from the hollow fiber membrane, and then irradiating the hollow fiber membrane with radiation. The blood purifier according to (4), wherein the degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is 80% or more and less than 100%.
(6) The blood purifier according to (5), wherein the oxygen concentration in the blood purifier is set to 0.01 vol% or more and 10 vol% or less during the radiation irradiation.
(7) The blood purifier according to any one of (1) to (6), wherein the thickness of the hollow fiber membrane is 25 μm or more and 40 μm or less.
(8) The hollow fiber membrane has a film thickness of 35 μm or less and a breaking strength of 7 MPa or more and a breaking elongation of 65% or more, or a film thickness of 30 μm or less and a breaking strength. The blood purifier according to (7), wherein the blood purifier is 7.5 MPa or more and the breaking elongation is 70% or more.

  The blood purifier of the present invention can be used for medical applications because of its high ability to remove impurities in blood and low albumin permeability.

It is an example of the particle size distribution which measured the polyvinylpyrrolidone solution with the dynamic light-scattering apparatus. It is a schematic diagram which shows the crimp shape of the hollow fiber membrane used for the blood purifier of this invention.

Below, the structure of the blood purifier of this invention is demonstrated in detail. The blood purifier according to the present invention has a hollow fiber membrane made of a polysulfone polymer and polyvinylpyrrolidone. The hollow fiber membrane has a structure in which continuous pore size towards the membrane surface membrane outer surface increases, blood purifier clearance values membrane area 1.5 m ² per vitamin B ₁₂ following irradiation The membrane area is 152 ml / min or more in terms of a membrane area of 1.5 m ^2, the adsorption rate of vitamin B ₁₂ is 25% or less, and the adsorption rate of myoglobin is 25% or less.

(About the sponge structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the membrane)
In dialysis applications, the mainstream is to flow blood through the hollow part (on the membrane inner surface side). Structure of hollow fiber membrane to keep high concentration of polyvinylpyrrolidone on the inner surface of the membrane and smooth mass transfer during filtration by dialysis so that proteins in the blood do not easily block the pores of the membrane It is preferable to have a structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the membrane. Furthermore, the structure of the hollow fiber membrane is preferably a sponge structure. Here, the sponge structure refers to the pore diameter (biaxial average diameter, that is, the average value of the short diameter and the long diameter) in the cross section of the membrane. Here, the short diameter and the long diameter respectively minimize the area circumscribing the void. (Short side and long side of circumscribed rectangle) refers to a structure having no voids of 5 μm or more.

(For clearance of vitamin B ₁₂₎
Blood purifier of the present invention due to its high clearance and phosphorus clearance of vitamin B _12, a high removal performance of impurities in the blood. Blood purifier of the vitamin B ₁₂ clearance of the present invention is 152 ml / min or more membrane area 1.5 m ² per / or membrane area 1.5 m ² equivalent. More preferably, it is 155 ml / min or more. When the particle size distribution exceeds 300 nm, it tends to be difficult to adjust to 152 ml / min or more. Previously blood purifier of the vitamin B ₁₂ clearance for dialysis, the terms considerably even those high removal performance of impurities in the blood of vitamin B ₁₂ clearance was limited degree 135 ml / min. In this embodiment, paying attention to the existence state of polyvinylpyrrolidone at the molecular level and analyzing the relationship between this and the removal performance of impurities in blood, a blood purifier with particularly high vitamin B ₁₂ removal performance is obtained. Realized. Here, the membrane area refers to the area on the inner diameter side of the hollow fiber membrane.

(About clearance measurement and conversion method)
The measurement of the clearance of the blood purifier of the present invention is carried out by converting the hollow fiber membrane into a blood purifier so as to have a predetermined membrane area, and using it as a blood purifier. (Institute of academic societies) The product is measured as it is.

Clearance measurement of vitamin B ₁₂ in the blood purifier of the present invention, a solution of vitamin B ₁₂ 1.2 g of physiological saline 60 l blood side circulating in the blood side flow rate 200 mL / min, the dialysate side Dialysis is performed under conditions where there is no filtration by flowing physiological saline at a dialysate side flow rate of 500 mL / min, the circulating fluid is sampled from the blood inlet side and the outlet side, and the clearance is calculated by the following equation (1). In addition, about the blood processing device in a dry state, it wets according to the above-mentioned dialyzer performance evaluation criteria, and uses it for measurement, after 60 minutes pass.
Clearance (mL / min) = [(C _{B (in)} −C _{B (out)} ) / C _{B (in)} ] × Q _B (1)
C _{B (in)} : Vitamin B ₁₂ concentration on the blood purifier inlet side C _{B (out)} : Vitamin B ₁₂ concentration on the blood purifier outlet side Q _B : Blood side flow rate (mL / min) = 200

Clearance conversion (film area conversion) is performed using the following equation (2).
C _L '= (1-Z) / (1 / Q _D ' -Z / Q _B ') (2)
Here, Z = exp [K × A ′ × (1 / Q _B '−1 / Q _D ′)]
(Exp means an exponential function)
K = Ln [(1-C _L / Q _D ) / (1-C _L / Q _B )] / [A × (1 / Q _B -1 / Q _D )]
(Ln means natural logarithm)
C _L : Clearance value obtained by measurement (mL / min)
C _L ': Clearance value to be calculated (mL / min)
A: Effective membrane area (cm ² ) of blood purifier used for clearance measurement
A ′: The effective membrane area of the blood purifier to be converted (cm ² )
(In the present invention, 1.5 m ² )
Q _B : Blood flow rate of blood purifier used for clearance measurement (mL / min)
Q _B ': Blood side flow rate of blood purifier to be converted (mL / min)
(In the present invention, it is converted at 200 mL / min)
Q _D : Dialysate side flow rate of blood purifier used for clearance measurement (mL / min)
Q _D ': Dialysate side flow rate of blood purifier to be converted (mL / min)
(In the present invention, it is converted at 500 mL / min)

(About myoglobin adsorption rate)
The blood purifier of the present invention has a myoglobin adsorption rate of 25% or less. It is known that myoglobin cannot be processed in the blood, and when it enters the kidney, it produces a substance that destroys the kidney. Therefore, if it is not treated immediately, it causes kidney failure and destroys the kidney. As exemplified by the crash syndrome, a large amount of myoglobin constituting the muscle may be released to clog the renal tubules and cause acute renal failure. Artificial dialysis using a blood purifier is most preferable for treating severe tubular disorders, and a membrane that can efficiently remove myoglobin (molecular weight 17,500 daltons) in blood is essential. However, low molecular weight proteins such as myoglobin are likely to be adsorbed to the blood purifier and have a function of reducing the removal performance of the blood purifier. Therefore, the myoglobin adsorption rate is preferably 25% or less in order to treat severe tubular disorders. More preferably, it is 20% or less, More preferably, it is 10% or less. If the adsorption rate of myoglobin exceeds 25%, the removal performance of the blood purifier tends to decrease rapidly, which is not preferable.

(Adsorption ratio of vitamin B ₁₂₎
In the blood purifier of the present invention, the adsorption rate of vitamin B ₁₂ is 25% or less. To clearance performance of the blood purifier to 152 mL / min or more even for vitamin B _12, the adsorption ratio of vitamin B ₁₂ is preferably 25% or less. More preferably, it is 20% or less, More preferably, it is 10% or less. If the adsorption rate of vitamin B ₁₂ exceeds 25%, the vitamin B ₁₂ clearance performance of the blood purifier tends to decrease rapidly with time after the start of dialysis.

(Measurement method of adsorption rate)
Bovine serum (frozen product: Valley Biomedical, Inc) is heated and dissolved at 37 ° C., and then diluted with physiological saline so that the total protein amount becomes 6.5 g / dL.
Vitamin B ₁₂ in the serum by dissolving 20ppm and myoglobin 100 ppm, and the test solution. Measurement is performed with a module having a membrane area of 1.5 m2. The blood flow rate was 200 ± 1 mL / min, the dialysate side flow rate was 500 ± 10 mL / min, and the solution was allowed to flow at 37 ° C. One minute after starting to flow, the dialysis fluid side was sampled for 3 minutes, while the blood side (out) fluid was sampled twice for 1 minute. The concentration of vitamin B12 in each solution was 360 nm and the concentration of myoglobin was Measured by absorbance at a wavelength of 408 nm.

Adsorption rate to hollow fiber membrane (%) = (1-Qf / (Qbi-Qbo)) × 100 (3)
The adsorption rate to the hollow fiber membrane is calculated by the above equation (3). Here, Qf is the concentration on the dialysate side, Qbi is the initial concentration of the circulating fluid, and Qbo is the concentration of the fluid on the blood side (out).
The performance of the blood purifier (for example, the performance of removing impurities in the case of a blood purifier for dialysis) varies greatly depending on the shape of the blood purifier. For example, the same membrane is used for the type in which the distance between both ends of the blood purifier is extremely short and the number of hollow fiber membranes is large, and the type in which the distance between both ends of the blood purifier is extremely long and the number of hollow fiber membranes is small. Even with the area, the blood purifier performance is completely different. This is because the shape of the blood purifier affects the fluid pressure distribution during filtration. Therefore, the distance between the two open ends of the hollow fiber membrane obtained by loading the yarn bundle into the container, adhesively fixing both ends thereof with urethane resin, and cutting both end surfaces, and the two open ends ( It is preferable that the relationship with the average diameter of (circular shape) is the relationship of the following formula (4).
Distance between two open ends / average diameter of two open ends = 4.5 to 6.5 (4)

  As the material of the blood purifier container (housing), for example, a mixed resin such as polystyrene polymer, polysulfone polymer, polyethylene polymer, polypropylene polymer, polycarbonate polymer, and styrene / butadiene block copolymer can be used. . From the viewpoint of raw material costs, polyethylene-based polymers and polypropylene-based polymers are preferably used. Polypropylene polymers are particularly preferred because of compatibility with polyurethane adhesives and strength of containers. When a polypropylene polymer is used as a container material, in the present invention, the container is preferably subjected to corona discharge treatment in order to improve adhesiveness with a polyurethane adhesive. In order to further improve the adhesion, it is more preferable to perform corona discharge treatment not only on the container but also on the yarn bundle. Corona discharge to the yarn bundle only occurs at the bonding site.

  The hollow fiber membrane of the present invention consists essentially of polyvinylpyrrolidone (hereinafter also simply referred to as “PVP”) and polysulfone.

In this embodiment, polyvinyl pyrrolidone having a peak mode diameter of 300 nm or less on the largest particle size side in the particle size distribution measured by the dynamic light scattering method is used. By using this polyvinyl pyrrolidone, it is possible to obtain a membrane with high removal performance of impurities in blood and low albumin permeability. Polyvinylpyrrolidone contributes to making the hydrophobic polymer constituting the skeleton of the hollow fiber membrane such as a polysulfone polymer hydrophilic. However, polyvinylpyrrolidone does not necessarily cover the skeleton of the hydrophobic polymer compound uniformly and exists in a lump shape. And since this blocky polyvinylpyrrolidone increases the filtration resistance of the membrane, the permeation performance of the membrane may be lowered. In the present embodiment, for example, the particle size distribution of polyvinylpyrrolidone is set to 300 nm or less, and the removal performance of impurities in blood is improved while imparting hydrophilicity of the film.
Polyvinylpyrrolidone may have a mode diameter of a peak on the largest particle size side in a particle size distribution measured by a dynamic light scattering method, preferably 200 nm or less, more preferably 60 nm or less.

In general, when the particle size distribution of polyvinyl pyrrolidone present in a polyvinyl pyrrolidone solution is measured with a dynamic light scattering device, two peaks are observed in the particle size range of 1 to 5,000 nm (see FIG. 1). ). Here, the secondary peak (B) and the primary peak (A) are set in order from the large particle diameter side.
The primary peak is a cooperative diffusion mode, which is a peak observed in a normal concentrated polymer solution (supervised by Ryogo Kubo, “Dojin Polymer Physics”, Hiroshi Takano, Shu Nakanishi, Yoshioka Shoten, 1997) Pp 208-210). The peak of the co-diffusion mode does not change even when the polyvinyl pyrrolidone solution is filtered.
On the other hand, the secondary peak is a unique peak seen in the polyvinylpyrrolidone solution. According to the study of the present inventor, the smaller the mode diameter (particle diameter at the peak) (mode diameter) of the secondary peak, the better the impurity removal performance. In particular, when the mode diameter of the secondary peak is 300 nm or less, vitamin B12 It was found that an extremely excellent impurity removal performance with a clearance value of 150 ml / min or more can be obtained. The mode diameter of the secondary peak is preferably as small as possible, and it is more preferable to use polyvinylpyrrolidone that does not have a secondary peak (in this case, “the largest particle size side in the particle size distribution measured by the dynamic light scattering method”). “A certain peak” is the primary peak).
Therefore, the ideal particle size distribution of polyvinylpyrrolidone is 60 nm or less.
In the above description, the case where the number of peaks in the particle size distribution measured by the dynamic light scattering method of polyvinyl pyrrolidone is two has been described as an example (typical example), but polyvinyl pyrrolidone in the hollow fiber membrane is described as an example. Is not limited to the number of peaks in the particle size distribution measured by the dynamic light scattering method, but satisfies the condition that the mode diameter of the peak on the largest particle size side is 300 nm or less. As long as it exists, three or more peaks may exist.

  In the present embodiment, the mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method of polyvinyl pyrrolidone is adjusted so that the concentration of polyvinyl pyrrolidone is 5.0% by weight. The measured dimethylacetamide solution (polyvinylpyrrolidone solution) is measured at a temperature of 25 ° C. using a dynamic light scattering device (FPAR-1000 or equivalent machine manufactured by Otsuka Electronics Co., Ltd.). The analysis condition is NNLS (non-negative constraint least square method), and the histogram range is set automatically. However, only the peak obtained when the particle size value is in the range of 1 to 5,000 nm is analyzed. Further, as the values of the viscosity and refractive index of the polyvinylpyrrolidone solution, the physical property values of dimethylacetamide at 25 ° C. are used.

  Here, in the particle size distribution measured by the dynamic light scattering method of polyvinylpyrrolidone in the hollow fiber membrane, the peak mode diameter on the largest particle size side is ethanol-soluble polyvinyl extracted from the hollow fiber membrane with ethanol. It means the mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method of pyrrolidone.

Extraction of ethanol-soluble polyvinylpyrrolidone from a hollow fiber membrane using ethanol is performed by the following method.
The blood purifier is washed with pure water and dried until the amount of water in the blood purifier is 0.3% by weight or less with respect to the hollow fiber membrane. The cleaning with pure water is performed until the crosslinking degree adjusting agent or the like is not extracted from the blood purifier. Specifically, the operation of injecting pure water from the open end of the blood purifier, filling the blood purifier with pure water, shaking for 3 minutes, and then discharging the pure water is repeated 10 times. Next, the blood purifier is immersed in ethanol at 50 ° C., and the ethanol is filtered and circulated from the outer surface side to the inner surface side of the hollow fiber membrane for 3 hours. For the circulation of ethanol, tubes and joints and air pumps with no contamination in the circulation circuit are used. The filtration circulation rate is 30 ml / min. At this time, it is confirmed that the entire blood purifier is immersed in ethanol. After 3 hours, ethanol circulated in the hollow fiber membrane was filtered with a 5 μm filter (Fuji Filter Co., Ltd., FD-5, effective filtration area 40 cm ² ), and only the ethanol in the filtrate was evaporated using an evaporator. To obtain ethanol-soluble polyvinylpyrrolidone. Heating with an evaporator is performed at 50 ° C. or lower. The above operation is repeated using a plurality of blood purifiers having the same type (manufacturing lot) of hollow fiber membranes until an amount of soluble polyvinylpyrrolidone that can be measured with a dynamic light scattering device is obtained.

(About the degree of crosslinking of polyvinylpyrrolidone)
In the present embodiment, the degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is preferably 80% or more and less than 100%, preferably 80% or more and 99% or less, more preferably 85% or more and 95% or less. .
If the degree of crosslinking of PVP in the hollow fiber membrane is less than 80%, polyvinyl pyrrolidone that exists in the hollow fiber membrane and contributes to hydrophilicity of the hollow fiber membrane may be eluted from the membrane. On the other hand, if the degree of crosslinking is 100%, the amount of elution can be reduced, while leucopenia symptoms may be observed during dialysis.

The degree of crosslinking of polyvinylpyrrolidone is defined by the following formula (5).
Crosslinking degree of PVP (%)
= PVP amount insoluble in water / Total PVP amount × 100 (5)
Here, the amount of PVP insoluble in water is obtained by subtracting the amount of PVP soluble in water from the amount of total polyvinylpyrrolidone (total PVP amount).
And the crosslinking degree of polyvinylpyrrolidone in a hollow fiber membrane can be calculated | required from the total PVP amount contained in the hollow fiber membrane of unit weight, and the amount of PVP insoluble in water (of which). The total amount of PVP in the hollow fiber membrane of unit weight is the chemiluminescence concentration of the nitric oxide produced by vaporizing and oxidizing 0.2 to 0.5 mg of the dried hollow fiber membrane in a horizontal reactor (800 to 950 ° C). (The apparatus uses TN-10 manufactured by Mitsubishi Chemical Corporation) and is converted from the obtained concentration to the amount of PVP contained in the hollow fiber membrane of unit weight. In quantification, a calibration curve prepared in advance using a standard sample of nitrogen-containing polymer is prepared, and the concentration is determined using this calibration curve. The amount of PVP soluble in water can be determined by the following method.
That is, the hollow fiber membrane having a unit mass is dried so that the water content is 0.3% by weight or less, and this is dissolved in N-methyl-2-pyrrolidone so as to have a concentration of 2.5% by weight. Make a solution. By adding 1.7 times the volume of water to the solution and stirring for 10 minutes, the polysulfone polymer in the hollow fiber membrane is sufficiently precipitated. PVP that is soluble in water is contained in the solution together with the precipitated polysulfone fine particles. Next, the polysulfone fine particles in the solution are removed by filtration through a non-aqueous filter (manufactured by Tosoh, pore size: 2.5 μm) for HPLC (high performance liquid chromatography), and the polyvinylpyrrolidone contained in the filtrate is quantified by HPLC. (Apparatus: Waters, GPC-244, column: 2 TSKgel GMPWXL, solvent: 0.1 M ammonium chloride (0.1 N ammonia), pH 9.5 aqueous ammonium chloride solution, flow rate: 1.0 ml / min, temperature: 23 ° C.). The amount of polyvinylpyrrolidone contained in the filtrate quantified as described above is the amount of PVP soluble in water contained per unit weight of the hollow fiber membrane. In addition, as the amount of PVP soluble in water when calculating the degree of crosslinking of PVP, the above measurement is performed 10 times, and an average value of 8 points excluding the maximum value and the minimum value is used.

(About the shape of the hollow fiber membrane)
The form of the hollow fiber membrane is not particularly limited and may be a so-called straight thread, but is preferably provided with a crimp from the viewpoint of diffusion efficiency when used for hemodialysis. As shown in FIG. 2, the shape of the crimp is defined by wavelength (1) and amplitude (2). The wavelength is preferably 2 mm or more and 20 mm, more preferably 4 mm or more and 8 mm or less. On the other hand, the amplitude is preferably 0.1 mm or more and 5 mm or less, more preferably 0.2 mm or more and 1 mm or less. The shorter the wavelength, the higher the filling rate of the blood purifier may be. However, it tends to be difficult to make the wavelength less than 2 mm. If the wavelength exceeds 20 mm, the effect of crimping tends to be difficult. Even if the amplitude is less than 0.1 mm, the effect of crimping tends to be difficult, and if it exceeds 5 mm, it tends to be difficult to make a blood purifier when bonding.

(About film thickness of hollow fiber membrane)
In the present invention, the thickness of the hollow fiber membrane used in the blood purifier is preferably 25 μm or more and 40 μm or less. More preferably, they are 25.5 micrometers or more and 35 micrometers or less. The thinner the film thickness, the lower the filtration resistance, so the dialysis blood purifier clearance performance tends to increase. However, a film thickness of less than 25 μm is not preferable because the hollow fiber membrane is frequently crushed during bonding. Since the performance failure is caused by the thread crushing, the clearance performance of the blood purifier for dialysis tends to be lowered as a result. If the film thickness exceeds 40 μm, the clearance performance of the dialysis blood purifier tends to be difficult to improve, which is not preferable. The film thickness (membrane inner diameter, membrane outer diameter) referred to in the present invention is an average value of the film thicknesses of 100 hollow fiber membranes.

  The hollow fiber membrane preferably has an inner diameter of 160 μm or more and 190 μm or less. More preferably, the inner diameter is 170 μm or more and 190 μm or less. An inner diameter of less than 160 μm is not preferable because blood tends to be hemolyzed due to an increase in shear rate and pressure loss when blood flows in the hollow portion of the hollow fiber membrane. On the other hand, if the inner diameter exceeds 190 μm, the overall mass transfer coefficient of the low-molecular protein tends to decrease, such being undesirable.

(About membrane hole retaining material)
The hollow fiber membrane of the present invention does not use a membrane hole holding material.
The membrane pore retainer is a substance that is packed in the pores in the membrane in the production process before drying in order to prevent performance degradation during drying. By dipping a wet membrane in a solution containing a membrane pore retention agent, the pore retention portion in the membrane can be filled with the retention agent. As long as the membrane pore retainer is washed and removed even after drying, it is possible to maintain performance such as water permeability and blocking rate equivalent to a wet membrane due to the effect of the membrane pore retainer. However, there is a report that considers various derivatives produced by chemical reaction with the membrane pore retention agent due to the presence of a minute amount of the membrane pore retention agent in the membrane and / or in the blood purifier filled liquid. Since this membrane pore retainer is not used in the production process, there is no eluate derived from the membrane pore retainer.
The absorbance of the eluate test solution of the hollow fiber membrane of the present embodiment is 0.1 or less, and the membrane solution is not included in the test solution. Here, the eluate test solution was prepared based on the approval criteria for an artificial kidney device, and 1.5 g of a dry hollow fiber membrane cut into 2 cm and 150 mL of distilled water for injection were tested in a glass container for injection by the Japanese Pharmacopoeia. It is placed in a glass container that complies with the alkali elution test, and heated at 70 ± 5 ° C. for 1 hour. After cooling, the membrane is removed, and distilled water is added to make 150 mL. Absorbance is measured with an ultraviolet absorption spectrum at a wavelength indicating the maximum absorption wavelength at 220 to 350 nm. Although the artificial kidney device approval standard stipulates that the absorbance be 0.1 or less, the membrane of the present invention does not retain a membrane pore-retaining agent, and can achieve less than 0.04. As for the presence or absence of a membrane pore-retaining agent, gas chromatography, liquid chromatography, differential refractometer, ultraviolet spectrophotometer, infrared absorptiometry, nuclear magnetic resonance spectroscopy, which is obtained by concentrating or removing water from the test solution, And it can detect by measuring by well-known methods, such as elemental analysis. Moreover, it can be detected by these measurement methods whether or not a membrane pore retainer is contained in the membrane.
As the membrane pore retainer, ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, 2-butyne-1,4-diol, 2-methyl-2,4-penta Organic compounds such as diol, 2-ethyl-1,3-hexanediol, glycerin, tetraethylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and the like, or organic compounds such as glycerol-based compounds and sucrose fatty acid esters, and calcium chloride; Examples thereof include inorganic salts such as sodium carbonate, sodium acetate, magnesium sulfate, sodium sulfate, and zinc chloride.

(About the measurement method of albumin)
The transmittance of albumin (hereinafter also simply referred to as “Alb.”) Can be measured by the following method. A mini module having an effective length of 18 cm is manufactured by bundling 100 hollow fiber membranes taken out from the blood purifier.
Bovine serum prepared by adding physiological saline and adjusting the total protein concentration to 6.5 g / dL is used as a base solution, and the concentration of albumin is obtained in advance by the BCG method. This is passed through the mini-module at a linear velocity of 0.4 cm / sec, and the filtrate is collected by applying a pressure of 25 mmHg between the membranes. The temperature of the original solution and the measurement environment is 25 ° C. In addition, the hollow fiber membrane which comprises a minimodule may be wet or dry. Subsequently, the concentration of albumin in the filtrate is obtained by the BCG method, and the value obtained by the following equation (6) is defined as the albumin transmittance.
Alb. Transmittance (%)
= Alb. Of filtrate Concentration / Alb. Concentration x 100 (6)
Here, the transmittance is the value after passing through for 60 minutes.

(About breaking strength / breaking elongation of hollow fiber membrane)
Since the thickness of the hollow fiber membrane of the present invention is as thin as 25 μm or more and 40 μm or less in a preferred embodiment, the breaking strength in the longitudinal direction of the yarn is preferably 6 MPa or more, and the breaking elongation in the longitudinal direction of the yarn is preferably 60% or more. Since the absolute strength of the membrane decreases as the film thickness decreases, the hollow fiber membrane may be crushed by the pressure of the adhesive during bonding. Therefore, it is necessary to increase the breaking strength as the film thickness decreases. If the film thickness is 35 μm or less, the breaking elongation is preferably 7 MPa or more, and if the film thickness is 30 μm or less, the breaking elongation is preferably 7.5 MPa or more. Further, if the film thickness is thin, there is a risk that the film may be cut at the adhesive interface. Therefore, if the film thickness is 35 μm or less, the breaking elongation is preferably 65% or more, and if the film thickness is 30 μm or less, the breaking elongation is preferably 70% or more.

(About uses of blood purifiers)
In general, a blood purifier is used for removing unnecessary substances such as urea and water in blood and removing disease-causing substances from blood and plasma. For example, in the case of a hyperlipidemic patient, it is possible to take out only plasma from blood and remove lipids from the plasma. The blood purifier of the present invention is particularly preferably used for dialysis.

(About fibrils)
When the hollow fiber membrane used in the blood purifier has a sponge structure in which the pore diameter is continuously reduced from the outer surface toward the inner surface, it has a network-like skeleton portion called “fibril” in the majority of the film thickness portion. The average thickness of all fibrils present in the hollow fiber membrane is preferably 100 nm or more and 200 nm or less. If the average thickness of all the fibrils is less than 100 nm, the breaking strength and breaking elongation tend to decrease, which is not preferable.
When the average thickness of all fibrils exceeds 200 nm, the albumin permeability exceeds 0.35% when the hollow fiber membrane of the present invention is used for dialysis. There is a need for a membrane having a fractionation property that hardly permeates albumin (molecular weight: 67,000) that is useful for the human body. The hollow fiber membrane of the present invention has a permeability of bovine plasma albumin of 0.35% or less. Can be realized. When the albumin permeability exceeds 0.35%, it means that effective albumin is largely lost in the body, which is not preferable as a membrane for dialysis. The amount of albumin stored in vivo is about 300 g (4.6 g / kg) for adult males. About 40% of the total is distributed in blood vessels and the remaining 60% is distributed outside the blood vessels. ing. Albumin is decomposed in muscle, skin, liver, kidney, etc., and the daily decomposition rate of albumin is approximately 4% (0.18 g / kg / day) of the amount stored in vivo. The half-life of albumin in vivo is about 17 days. On the other hand, albumin is produced mainly in the liver (0.20 g / kg / day). Therefore, the balance of albumin in the living body is in a state close to ± 0. In general, dialysis patients undergo blood purification by artificial dialysis three times a week. Therefore, when artificial dialysis is performed on a membrane having an albumin permeability of 0.35%, an albumin loss of about 0.02 g / kg / week results. Therefore, if the albumin permeability exceeds 0.35%, the equilibrium state of albumin in the living body may be lost, causing other diseases, which is not preferable.

Furthermore, in the present invention, when the ratio (Y / X) of the average thickness Y of the fibrils on the outer side in the film thickness direction of the hollow fiber membrane and the average thickness X of the fibrils on the inner side in the film thickness direction is large, impurities are removed. It was also found that the performance was improved. Specifically, it is preferable that Y / X is 1.2 or more and 2.0 or less. When the ratio of the average thickness of the fibrils on the outer side in the film thickness direction to the average thickness of the fibrils on the inner side in the film thickness direction is less than 1.2, the pore diameter continuously decreases from the outer surface to the inner surface of the film. tend to vitamin B ₁₂ and phosphorus clearance for inclination is small decreases further, since the transmittance of albumin tends to more than 0.35% is not preferable. The larger the ratio of the average thickness of the fibrils on the outside in the film thickness direction to the average thickness of the fibrils on the inside in the film thickness direction, not only improves the filtration rate (for example, dialysis impurity removal performance) but also permeates albumin. It is preferable because the rate can be kept low. However, a film exceeding 2.0 is difficult to manufacture in the following (Ga / Vs ′ × Am / As), which has a relationship with (spinning speed and air gap) and (spinner discharge cross-sectional area and film area) described later. This is not preferable.

The thickness of the fibril (network-like skeleton) is measured by the following method. After the target hollow fiber membrane is swollen with water, it is fractured perpendicularly to the longitudinal direction in a state of being frozen at −30 ° C. to obtain a transverse section fracture sample. A cross section of the sample obtained using a scanning electron microscope (SEM) is photographed. Photographing is performed at an acceleration voltage of 10 kV and a photographing magnification of 10,000 times. Under this condition, it is possible to observe a structure corresponding to a width of 15 μm at the cross section in the film thickness direction.
An SEM photograph is taken with the innermost side (inner film surface side) of the film thickness portion aligned with the edge of the field of view, and the average thickness of the fibrils on the inner side in the film thickness direction is measured using this. Next, an SEM photograph is taken with the outermost side aligned with the edge of the field of view, and the average thickness of the fibrils on the outer side in the film thickness direction is measured using this.
The average thickness of all fibrils is measured using the above two photographs in the case of a hollow fiber membrane having a thickness of 30 μm or less. On the other hand, in the case of a hollow fiber membrane having a film thickness exceeding 30 μm, there is a portion that is not covered (not photographed) in the above two photographs, so the distance between the inner surface and the outer surface in the film thickness direction is After determining the center point that is the same point, the SEM photograph is taken by aligning the center of the field of view with the center point, and a portion that cannot be photographed with the above two photographs is photographed. Measure the average thickness of the fibrils in the center.
However, when determining the thickness of the fibril at the center in the film thickness direction, the portion not included in the photograph on the inner and outer surfaces of the film is used.

The thickness of the fibril (network-like skeleton) defined here is the thickness of the thinnest part near the center of each fibril observed in the photograph, that is, between the joints between the fibrils. The thickness of the narrowest part is read at an angle perpendicular to the longitudinal direction of the fibrils.
The part for measuring the thickness of the fibril is the area band corresponding to the width of the central part in the film thickness direction in the cross-sectional SEM photograph of each part taken corresponding to the width of 15 μm, and 100 fibrils in the area band are arbitrarily selected. And measure the thickness. This is performed for each cross-sectional SEM photograph of each part. The average value of the 100 values is the average thickness of fibrils at each site (outside, inside and center in the film thickness direction (only when the film thickness exceeds 30 μm)). Moreover, the value which carried out the arithmetic mean of each average value is made into the average thickness of all the fibrils.

(About manufacturing method of hollow fiber membrane)
In the present embodiment, as a specific example of a method of setting the mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method of polyvinylpyrrolidone in the hollow fiber membrane to 300 nm or less, The polyvinyl pyrrolidone solution used for producing the hollow fiber membrane may be filtered in advance using a filter. At that time, it is also possible to filter the vinyl pyrrolidone solution while applying ultrasonic vibration.
The polyvinyl pyrrolidone concentration in the polyvinyl pyrrolidone solution varies depending on the molecular weight of the polyvinyl pyrrolidone used, but it is preferably 0.1 to 15% by weight for polyvinyl pyrrolidone having a weight average molecular weight of 1,200,000. If it is less than 0.1% by weight, it is not practical, and if it exceeds 15% by weight, the particle size of polyvinylpyrrolidone after filter filtration exceeds 300 nm, which is not preferable.
The temperature of the polyvinylpyrrolidone solution varies depending on the solvent used and the material of the filter, but is preferably 35 to 120 ° C. If it is less than 35 ° C., the particle size of polyvinyl pyrrolidone after filtration may exceed 300 nm, and if it is kept at a temperature of 120 ° C. or more for a long time, polyvinyl pyrrolidone may be crosslinked or modified.
The filtration flow rate of the polyvinylpyrrolidone solution is preferably 0.01 to 3 mL (milliliter) / (minute (unit time) · cm ² (per filter unit effective filtration area)). If it is less than 0.01 mL / (min · cm ² ), the filtration flow rate is slow, so it is not practical. If it exceeds 3 mL / (min · cm ² ), the particle size of the polyvinylpyrrolidone after filtration may exceed 300 nm. It is not preferable.
The minimum pore size of the filter (hereinafter simply referred to as “pore size”) is preferably 0.01 to 3 μm, more preferably 0.1 to 2.5 μm, and still more preferably 0.1 to 2 μm. When the pore size of the filter is larger than 3 μm, it is difficult to make the mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method less than 300 nm, and when the pore size is less than 0.01 μm, filtration is performed. The speed is low and impractical.
The frequency of ultrasonic vibration applied to the polyvinylpyrrolidone solution during filter filtration is preferably 20 kHz or more and 1000 kHz or less, more preferably 40 kHz or more and 100 kHz or less. Less than 20 kHz is not preferable because the effect tends to be low. If the frequency exceeds 1000 kHz, the filter and the filter housing may be damaged when ultrasonic vibration is repeatedly applied for a long time.

A hollow fiber membrane forming stock solution is prepared by adding a polyvinylpyrrolidone solution and other materials (for example, a polysulfone polymer (or a polysulfone polymer and a solvent) while applying ultrasonic vibration to a temperature-controllable container as necessary. ) And dissolved using a mixer such as a stirrer or a Hensyl mixer.
Since impurities etc. may be mixed in polysulfone-based polymers, etc., it is possible to filter with a filter with a pore diameter of about 40 μm or less in order to remove impurities or undissolved substances after preparing the film forming stock solution. It is.

Examples of the polysulfone-based polymer that can be used in the present invention include those having a repeating unit represented by the following formula (7) or formula (8). Ar in the formula represents a disubstituted phenyl group at the para position, and the degree of polymerization and molecular weight are not particularly limited.
—O—Ar—C (CH ₃ ) ₂ —Ar—O—Ar—SO ₂ —Ar— (7)
—O—Ar—SO ₂ —Ar— (8)
The solvent for the polyvinyl pyrrolidone solution or the film-forming stock solution may be any solvent that dissolves polyvinyl pyrrolidone and other membrane materials. For example, when a polysulfone polymer is used, the solvent is N-methyl-2- Pyrrolidone, dimethylacetamide, etc. are used.

  The weight average molecular weight of the polyvinylpyrrolidone used in the present invention is preferably in the range of 1,000 to 2,000,000, and more preferably in the range of 10,000 to 1,300,000. The present invention is particularly effective when a high molecular weight polyvinyl pyrrolidone having a weight average molecular weight of 800,000 or more is used. Even if a high molecular weight polyvinyl pyrrolidone having a weight average molecular weight of 800,000 or more is used, pinholes, film breakage, etc. There are few defective parts.

The concentration of the hydrophobic polymer compound (polysulfone-based polymer, etc.) in the membrane-forming stock solution is within the range where the membrane can be produced from the stock solution and the obtained membrane has performance as a membrane. It does not restrict | limit, It is 1 to 50 weight%, Preferably it is 10 to 35 weight%, More preferably, it is 10 to 30 weight%. In order to achieve high water permeability or a large molecular weight cut off, the polymer concentration should be low, preferably 10 to 25% by weight. In addition, a plurality of non-solvents such as water, salts, alcohols, ethers, ketones, glycols, etc. can be added to the film-forming stock solution for the purpose of controlling the viscosity and dissolution state of the stock solution. The addition amount may be determined as needed depending on the combination.
The amount of polyvinylpyrrolidone in the film-forming stock solution is 1 to 30% by weight, preferably 1 to 20% by weight. The optimum concentration is determined by the molecular weight of polyvinylpyrrolidone used.

The hollow fiber membrane can be produced, for example, by simultaneously discharging the above-mentioned membrane-forming stock solution together with the internal solution from a double annular nozzle into a coagulation bath and coagulating it.
The internal liquid used for the production of the hollow fiber membrane is used for forming the hollow part of the hollow fiber membrane. When a dense layer is formed on the outer surface, a high-concentration aqueous solution of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and the like can be used as the internal liquid. When a dense layer is formed on the inner surface, the internal liquid described in the coagulation bath described later can be used. Further, for the purpose of controlling the viscosity of the internal liquid, it is also possible to add glycols such as tetraethylene glycol and polyethylene glycol and non-solvents such as glycerin.

The hollow fiber membrane can be formed using a known tube-in-orifice type double annular nozzle. More specifically, the hollow fiber membrane of the present invention is obtained by simultaneously discharging the above-mentioned membrane-forming stock solution and internal solution from the double annular nozzle, passing through the air gap, and then coagulating in a coagulation bath. Can do.
Here, the air gap means the distance (gap) between the nozzle and the coagulation bath. In order to obtain a membrane having a sponge structure in which the pore diameter continuously decreases from the outer surface to the inner surface, the ratio of the air gap (m) to the spinning speed (m / min) is extremely important. This is because the sponge structure in which the pore diameter continuously decreases from the outer surface of the membrane toward the inner surface, the non-solvent in the inner solution comes into contact with the film-forming stock solution, and the outer surface from the inner surface portion of the film-forming stock solution. This is because phase separation is induced over time toward the site side, and further, phase separation from the inner surface portion of the membrane to the outer surface portion is not completed before the membrane-forming stock solution enters the coagulation bath.
The ratio (Ga / Vs) of the air gap (Ga) to the spinning speed (Vs) is 0.01 to 0.1 m / (m / min) when the thickness of the hollow fiber membrane is 34 μm or more. Is more preferable, and 0.01 to 0.05 m / (m / min) is more preferable. When the ratio of the air gap to the spinning speed is less than 0.01 m / (m / min), it is difficult to obtain a sponge-structured membrane in which the pore diameter continuously decreases from the outer surface to the inner surface. When the ratio exceeds / (m / min), since the tension on the film is high, film breakage frequently occurs in the air gap portion, and the production tends to be difficult. On the other hand, when the film thickness is less than 34 μm, since the amount of good solvent in the film forming stock solution is small, a sponge structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the film even when Ga / Vs is low. It is possible to obtain. When the film thickness is less than 34 μm, Ga / Vs is preferably 0.001 to 0.01 m / (m / min).
Here, the spinning speed (Vs) (m / min) is a series of production of hollow fiber membranes in which the membrane-forming stock solution discharged from the nozzle together with the internal solution passes through the air gap and the membrane coagulated in the coagulation bath is wound up. It refers to the moving speed of the membrane in the process, and when there is a stretching operation, it means the moving speed of the hollow fiber membrane before the stretching operation.
Further, when the air gap is surrounded by a cylindrical tube or the like and a gas having a constant temperature and humidity is caused to flow through the air gap at a constant flow rate, the hollow fiber membrane can be manufactured in a more stable state.

Furthermore, it has been found that the relationship between the cross-sectional area (As) of the spinning nozzle discharged from the film-forming stock solution and the cross-sectional area (Am) of the obtained film affects the fibril thickness. Am / As means the remaining rate of the film-forming polymer with respect to the discharge amount of the film-forming stock solution per unit time. Therefore, the larger Am / As, the thicker the fibril. In the present invention, Ga / Vs ′ (where Vs ′ (m / second) is a value obtained by converting the above-described spinning speed Vs (minute speed) into a second speed) and Am / As (unit: m / second). (M / sec)) is 0.15 or more and 0.75 or less, a fibril that has a sponge structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the membrane and is located outside in the film thickness direction. It is possible to make a film structure in which the ratio of the average thickness of the fibrils to the average thickness of the fibrils inside the film thickness direction is 1.2 or more and 2.0 or less. When the product of Ga / Vs ′ and Am / As is less than 0.15, the ratio of the average thickness of the fibrils on the outer side in the film thickness direction to the average thickness of the fibrils on the inner side in the film thickness direction is less than 1.2. When the product of Vs ′ and Am / As exceeds 0.75, the ratio of the average thickness of the fibrils outside the film thickness direction to the average thickness of the fibrils inside the film thickness direction tends to exceed less than 2.0. is there.
Furthermore, in the present invention, the average thickness of all fibrils can be adjusted to 100 nm or more and 200 nm or less by adjusting the relationship between the product of Ga / Vs ′ and Am / As and other film forming conditions.
Examples of the coagulation bath include water; alcohols such as methanol and ethanol; ethers; and aliphatic hydrocarbons such as n-hexane and n-heptane. The inducing liquid (non-solvent) is used, but it is preferable to use water. It is also possible to control the coagulation rate by adding a good solvent for the polymer to the coagulation bath.
The temperature of the coagulation bath is -30 to 100 ° C, preferably 0 to 98 ° C, more preferably 10 to 95 ° C. If the temperature of the coagulation bath exceeds 100 ° C. or is less than −30 ° C., the state of the film surface in the coagulation bath is difficult to stabilize.
By irradiating the hollow fiber membrane with radiation such as electron beam and gamma ray, it is possible to crosslink the PVP in the membrane. The irradiation with radiation may be performed either before or after the hollow fiber membrane is made into a blood purifier.

(Regarding the method for adjusting the degree of crosslinking of polyvinylpyrrolidone)
By irradiating the hollow fiber membrane with a crosslinking degree adjusting agent, the degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane can be appropriately adjusted.
The cross-linking degree adjusting agent is not particularly limited as long as it inhibits the cross-linking reaction of polyvinyl pyrrolidone with respect to radiation irradiation. However, when it is used for blood purification, it is necessary to consider the safety thereof, and those that are easily washed with a physiological aqueous solution and have low toxicity are preferably used. Among them, water-soluble vitamins, glycerin, mannitol, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, teraethylene glycol and other glycols, polyethylene glycol, propylene glycol and other polyglycols, ethanol and other alcohols, polyethyleneimine, Examples thereof include saccharides such as polyphenol, trehalose and glucose, inorganic salts such as sodium pyrosulfite, sodium thiosulfate and sodium hydrogen carbonate, carbon dioxide and the like, which are preferably used. These crosslinking degree adjusting agents may be used alone or in combination of two or more.
The amount and type of the cross-linking degree adjusting agent attached to the hollow fiber membrane and the concentration of the cross-linking degree adjusting agent present around the hollow fiber membrane in the aqueous solution are appropriately adjusted depending on the radiation exposure dose, irradiation time, and the desired degree of cross-linking. Is possible.

In order to crosslink polyvinylpyrrolidone, the crosslinking degree adjusting agent solution is once injected into the hollow fiber membrane from the open end of the blood purifier, then the crosslinking degree adjusting agent solution in the hollow fiber membrane is removed, and then blood purification is performed. It is preferable to irradiate the oxygen concentration in the chamber at 0.01 vol% or more and 10 vol% or less. More preferably, it is 0.1 volume% or less and 5 volume% or less. When the oxygen concentration in the blood purifier is less than 0.01% by volume, the container and header are colored, and the product appearance is deteriorated. On the other hand, when the oxygen concentration in the blood purifier exceeds 10% by volume, radicals are generated from oxygen in the air, and polyvinyl pyrrolidone in the hollow fiber membrane is considered to be decomposed, and the eluate tends to increase. is there.
The radiation irradiation in the present invention refers to radiation irradiation using an electron beam, a gamma ray or the like, and the dose is 5 kGy or more and 50 kGy or less, preferably 15 kGy or more and 30 kGy or less, more preferably around 25 kGy.

(About PVP inner coat)
A membrane having a high degree of crosslinking of polyvinylpyrrolidone tends to have poor blood compatibility. In blood purifiers, it is common to have blood flow on the inner surface of the membrane. In the present embodiment, for example, after a film containing polyvinylpyrrolidone is manufactured, the inner surface of the film is further coated with polyvinylpyrrolidone. By coating polyvinyl pyrrolidone on the inner surface of the membrane, even if the degree of crosslinking of polyvinyl pyrrolidone is high, the amount of polyvinyl pyrrolidone present on the inner surface of the membrane tends to be high, so that blood compatibility tends to be improved.

  In order to contact polyvinyl pyrrolidone with the inner surface of the hollow fiber membrane after the hollow fiber membrane is molded into a blood purifier, an aqueous solution in which polyvinyl pyrrolidone is dissolved in the above-described crosslinking degree adjusting agent solution is injected into the hollow fiber membrane. Then, after removing the aqueous solution in the hollow fiber membrane, irradiation is performed. The molecular weight of the polyvinyl pyrrolidone used is the same as that of the polyvinyl pyrrolidone used for the film-forming stock solution described above. The concentration of polyvinylpyrrolidone in the solution is affected by the molecular weight of polyvinylpyrrolidone, but is preferably 0.01% by weight or more and 20% by weight or less, more preferably 0.05% by weight or more and 5% by weight or less, and still more preferably. Is 0.1% by weight or more and 5% by weight or less. When the concentration of polyvinyl pyrrolidone in the solution is less than 0.01% by weight, there is a tendency that the effect of the coating does not exist. On the other hand, if the concentration of polyvinylpyrrolidone in the solution exceeds 20% by weight, the membrane permeation performance tends to be greatly reduced, which is not preferable. Also, in order to simultaneously perform the irradiation of the polyvinyl pyrrolidone coating inside the hollow fiber membrane and the irradiation of the polyvinyl pyrrolidone crosslinking described above, a coating solution containing polyvinyl pyrrolidone and a cross-linking degree adjusting agent solution in this order. After injecting into the hollow fiber membrane and removing these solutions from the hollow fiber membrane, radiation irradiation can also be performed. Radiation irradiation can also be performed after injecting a mixed solution of the coating solution and the crosslinking degree adjusting agent solution into the hollow fiber membrane and removing the mixed solution from the hollow fiber membrane.

Examples of the present invention are shown below, but the present invention is not limited thereto. Each measuring method is as follows.
The hollow fiber membranes used as measurement samples were all in a state sufficiently impregnated with water.
The breaking strength of the membrane was measured using an autograph AGS-5D manufactured by Shimadzu Corporation at a sample length of 30 mm, 25 ° C., and a tensile speed of 50 mm / min.
The breaking strength is represented by the calculation (kgf / cm ² ) per membrane cross-sectional area before drawing the breaking load per hollow fiber membrane, and the breaking elongation (elongation) is determined by the breaking of the original length. Expressed in stretched length (%).

Example 1
(Preparation of polyvinylpyrrolidone solution and filtration of the solution)
A uniform solution in which 84 g of polyvinylpyrrolidone (BASF, K90, weight average molecular weight 1,200,000) having a water content of 0.3 wt% or less by drying at a temperature of 100 ° C. or less is dissolved in 1576 g of dimethylacetamide. (Polyvinylpyrrolidone solution) (Polyvinylpyrrolidone concentration 5.06% by weight).
The stainless steel sintered filter of the solution was kept at 70 ° C. The pore size 2 [mu] m (Nippon Seisen Co., Ltd., NS-02S2, effective filtration area 20 cm ²⁾ filtration with a flow rate 2 mL / (min · cm ² ). During filtration, the sintered filter was immersed in an ultrasonic cleaning machine, and ultrasonic vibration of 59 kHz (output 3 kW) was constantly applied to the polyvinylpyrrolidone solution. The polyvinylpyrrolidone solution after filtration is adjusted to a concentration of 5.0% by weight, and the peak on the largest particle size side in the particle size distribution of polyvinylpyrrolidone when measured with a dynamic light scattering device The mode diameter of was 130 nm. As the mode diameter, an average value measured 10 times was used. In calculating the average value, eight values excluding the maximum value and the minimum value were used.
(Preparation of film forming stock solution and film forming)
A uniform solution (film forming stock solution) was prepared by adding 170 g of aromatic polysulfone (Amoco Engineering Polymers P-1700) to 830 g of the above filtered solution (polyvinylpyrrolidone solution) and dissolving it. In order to remove undissolved polysulfone and the like, this membrane-forming stock solution was filtered using a filter having a pore diameter of 5 μm (manufactured by Fuji Filter Co., Ltd., FD-5, effective filtration area 40 cm ² ).
This solution (film forming stock solution) was kept at 60 ° C. after defoaming, and with an internal solution composed of a mixed solution of 54% by weight of dimethylacetamide and 46% by weight of water, a spinneret (double annular nozzle 0.1 mm-0.2 mm) -0.3 mm) (inner liquid is discharged from an annular nozzle with an inner wall diameter of 0.1 mm, and a film-forming solution is discharged from between an outer wall diameter of 0.2 mm and an inner wall diameter of 0.3 mm) and passes through an air gap of 380 mm. And immersed in a coagulation bath made of 70 ° C. water. At this time, the nozzle to the coagulation bath were surrounded by a cylindrical tube, and the humidity of the air gap in the tube was controlled to 100% and the temperature to 45 ° C. The spinning speed was fixed at 27 m / min. Before winding the obtained hollow fiber membrane, a crimper having a wavelength of 6 mm and an amplitude of 0.6 mm was applied by a crimper (a device for applying a crimp to the hollow fiber membrane). The drying temperature in the crimper was set to 155 ° C., and the drying time was set to 120 seconds. A bundle of 9600 wound hollow fiber membranes is loaded into a polypropylene cylindrical container designed so that the effective membrane area of the hollow fiber membrane is 1.5 m ^2, and both ends thereof are bonded and fixed with urethane resin. Then, both end surfaces were cut to form an open end of the hollow fiber membrane. In addition, header caps were attached to both ends.
A solution (PVP coating solution) in which 2 g of polyvinylpyrrolidone K90 (manufactured by BASF, K90, weight average molecular weight 1,200,000) was dissolved in 1,998 g of pure water at 70 ° C. was prepared. The stainless steel sintered filter of the solution was kept at 70 ° C. The pore size 2 [mu] m (Nippon Seisen Co., Ltd., NS-02S2, effective filtration area 20 cm ²⁾ filtration with a flow rate 2 mL / (min · cm ² ). During filtration, the sintered filter was immersed in an ultrasonic cleaning machine, and an ultrasonic vibration of 59 kHz (output 3 kW) was constantly applied to the polyvinylpyrrolidone solution. This solution was injected from the open end into the hollow part of the hollow fiber membrane for 2.3 seconds and flushed with 0.3 MPa air for 10 seconds.
Furthermore, a crosslinking degree adjusting agent solution in which 360 g of glucose (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was dissolved in 1,640 g of pure water at 70 ° C. was prepared.
This solution was injected into the hollow portion of the hollow fiber membrane from the open end for 2.3 seconds, flushed with 0.3 MPa air for 10 seconds, and then header caps were attached to both ends. After plugging the blood inflow / outflow nozzle, it was placed in a sterilization bag together with an oxygen scavenger (Ageless (registered trademark) manufactured by Mitsubishi Gas Chemical Company), adjusted to an oxygen concentration of 3.5%, and then irradiated with 20 kGy of electron beam. . The overall mass transfer coefficient and adsorption amount of α ₁ microglobulin of this blood purifier were 0.0046 [cm / min] and 0.49 [mg / m ² ], respectively.
The mode diameter of the peak on the largest particle size side in the particle size distribution measured with a dynamic light scattering device of soluble polyvinylpyrrolidone extracted from the blood purifier after irradiation was 130 nm. The performance of this hollow fiber membrane is shown in Table 1. The hollow fiber membranes were prepared in a 1.5 m ² blood purifier, and the values measured for vitamin B ₁₂ clearance and phosphorus clearance after irradiation were 158 ml / min and 188 ml / min, respectively. . The albumin permeability was 0.25%. Furthermore, adsorption rate of vitamin B ₁₂ and myoglobin, 23%, was 20%. Further, it is a hollow fiber membrane that does not have a membrane-hole holding material, and does not dissolve in the eluate test solution based on the approval criteria for an artificial kidney device, and the membrane-hole holding material in the eluate test solution in the eluate test solution Was not included.
It was revealed that the hollow fiber membrane had a high breaking strength, a high breaking elongation, a small amount of elution, a high overall mass transfer coefficient of α ₁ microglobulin, and a low albumin permeability.

(Example 2)
The same operation as in Example 1 was performed except that the internal liquid concentration was changed to 51% by weight. The film thickness was 40.0 μm. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 154 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.20%, 18%, and 15%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 3)
The same operation as in Example 1 was performed except that the internal liquid concentration was 53 wt%, the air gap was 180 mm, and the spinning speed was 39 m / min. The value of (Ga / Vs ′ × Am / As) was 0.159. The performance of this blood purifier is shown in Table 1. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 154 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.35%, 25%, and 25%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

Example 4
The same operation as in Example 1 was performed except that the internal liquid concentration was 53 wt%, the air gap was 615 mm, and the spinning speed was 36 m / min. The value of (Ga / Vs ′ × Am / As) was 0.728. The performance of this blood purifier is shown in Table 1. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 153 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.18%, 15%, and 12%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 5)
The same operation as in Example 1 was performed except that the internal liquid concentration was 53 wt%, the air gap was 210 mm, and the spinning speed was 33 m / min. The film thickness was 25.5 μm. The performance of this blood purifier is shown in Table 1. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 163 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.33%, 22%, and 19%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 6)
The same operation as in Example 1 was performed except that the glucose concentration in the crosslinking degree adjusting agent was changed to 2% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 99.2%. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 158 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.25%, 23%, and 20%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 7)
The same operation as in Example 1 was performed except that the glucose concentration in the crosslinking degree adjusting agent was changed to 5% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 94.3%. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 158 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.25%, 23%, and 20%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 8)
The same operation as in Example 1 was performed except that the glucose concentration in the cross-linking degree adjusting agent was 40% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 80.7%. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 158 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.25%, 23%, and 20%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

Example 9
The same operation as in Example 1 was performed except that the glucose concentration in the crosslinking degree adjusting agent was changed to 30% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 85.8%. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 158 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.25%, 23%, and 20%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 10)
The same operation as in Example 2, except that the filter used for filtration of the polyvinylpyrrolidone solution was a sintered filter made of stainless steel having a pore diameter of 3 μm (manufactured by Nippon Seisen Co., Ltd., NS-03S2, effective filtration area 20 cm ² ). Went. The mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinylpyrrolidone when diluted with the polyvinylpyrrolidone solution after filtration and measured with a dynamic light scattering apparatus was 290 nm. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 153 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.27%, 21%, and 24%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 11)
The same operation as in Example 2 was performed except that the temperature of the polyvinylpyrrolidone solution at the time of filter filtration was 90 ° C. The mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinylpyrrolidone when diluted with a polyvinylpyrrolidone solution after filtration and measured with a dynamic light scattering device was 40 nm. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 162 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.27%, 15%, and 13%, respectively. The performance of this blood purifier is shown in Table 1.
A blood purifier comprising a thin hollow fiber membrane with high breaking strength and breaking elongation, high blood impurity removal performance, low albumin permeability and low molecular protein adsorption, and vitamins It was found that the clearance value of B ₁₂ was high and the amount of vitamin B ₁₂ adsorbed was low.

(Example 12)
The same operation as in Example 1 was performed except that the polyvinylpyrrolidone concentration in the PVP coating solution was changed to 0.5% by weight. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 158 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.25%, 10%, and 9%, respectively. The performance of this blood purifier is shown in Table 1. The overall mass transfer coefficient and adsorption amount of α ₁ microglobulin of this hollow fiber membrane were 0.0056 [cm / min] and 0.39 [mg / m ² ], respectively. Further, it is a hollow fiber membrane that does not have a membrane-hole holding material, and does not dissolve in the eluate test solution based on the approval criteria for an artificial kidney device, and the membrane-hole holding material in the eluate test solution in the eluate test solution Was not included.
It was revealed that the hollow fiber membrane had a high breaking strength, a high breaking elongation, a small amount of elution, a high overall mass transfer coefficient of α ₁ microglobulin, and a low albumin permeability.

(Example 13)
The same operation as in Example 1 was performed except that the polyvinylpyrrolidone concentration in the PVP coating solution was changed to 1.0% by weight. The hollow fiber membrane was prepared in a 1.5 m ² blood purifier and after irradiation, the clearance value of vitamin B ₁₂ was 158 ml / min. The albumin permeability, vitamin B _{12 and} myoglobin adsorption rates were 0.25%, 5%, and 3%, respectively. The performance of this blood purifier is shown in Table 1. The overall mass transfer coefficient and adsorption amount of α ₁ microglobulin of this hollow fiber membrane were 0.0069 [cm / min] and 0.28 [mg / m ² ], respectively. Further, it is a hollow fiber membrane that does not have a membrane-hole holding material, and does not dissolve in the eluate test solution based on the approval criteria for an artificial kidney device, and the membrane-hole holding material in the eluate test solution in the eluate test solution Was not included.
It was revealed that the hollow fiber membrane had a high breaking strength, a high breaking elongation, a small amount of elution, a high overall mass transfer coefficient of α ₁ microglobulin, and a low albumin permeability.

(Comparative Example 1)
The filter used for filtration of the polyvinylpyrrolidone solution is a sintered filter made of stainless steel having a pore diameter of 5 μm (Fuji Filter Co., Ltd., FD-5, effective filtration area 40 cm ² ), and ultrasonic vibration is applied to the polyvinylpyrrolidone solution. The same operation as in Example 2 was performed except that there was no. The mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinylpyrrolidone when diluted with the polyvinylpyrrolidone solution after filtration and measured with a dynamic light scattering device was 550 nm. The performance of this blood purifier is shown in Table 2. It was revealed that the removal performance of impurities in blood was low.

(Comparative Example 2)
The same operation as in Example 1 was performed except that the internal liquid concentration was changed to 51% by weight. The film thickness was 40.8 μm. The performance of this blood purifier is shown in Table 2. The breaking strength was less than 6.0 MPa, and the breaking elongation was less than 60.

(Comparative Example 3)
The same operation as in Example 1 was performed except that the internal liquid concentration was 53 wt%, the air gap was 180 mm, and the spinning speed was 39 m / min. The value of (Ga / Vs ′ × Am / As) was 0.145. The performance of this blood purifier is shown in Table 2. The transmittance of albumin exceeded 0.35%.

(Comparative Example 4)
The same operation as in Example 1 was performed except that the internal liquid concentration was 53 wt%, the air gap was 585 mm, and the spinning speed was 24 m / min. The value of (Ga / Vs ′ × Am / As) was 0.755. The performance of this blood purifier is shown in Table 2. The film was broken frequently, and stable production for a long time was difficult.

(Comparative Example 5)
The same operation as in Example 1 was performed except that the internal liquid concentration was 53 wt% and the air gap was 210 mm. The performance of this blood purifier is shown in Table 2. The film thickness was less than 25 μm.

(Comparative Example 6)
The same operation as in Example 10 was performed except that ultrasonic vibration was not applied to the polyvinylpyrrolidone solution. The mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinyl pyrrolidone when diluted with the polyvinyl pyrrolidone solution after filtration and measured with a dynamic light scattering device was 320 nm. The performance of this blood purifier is shown in Table 2. It was revealed that the removal performance of impurities in blood was low.

(Production Example 1)
The same operation as in Example 1 was performed except that the aqueous solution sealed in the blood purifier when irradiated with radiation was made pure water and oxygen in the aqueous solution was not removed. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 100%. The performance of this blood purifier is shown in Table 2. When this blood purifier was evaluated for clinical blood, a leucopenia symptom in which the leukocyte count of the dialysis patient temporarily decreased was observed.

(Production Example 2)
The same operation as in Example 1 was performed except that the glucose concentration in the crosslinking degree adjusting agent was changed to 45% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 77.9%. The performance of this blood purifier is shown in Table 2. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was less than 80%. A hollow fiber membrane in which polyvinylpyrrolidone has a high degree of crosslinking could not be obtained.

A Primary peak B Secondary peak 1 Wavelength 2 Amplitude

Claims (8)

A blood purifier having a hollow fiber membrane comprising a polysulfone polymer and polyvinylpyrrolidone,
The hollow fiber membrane has a structure in which the pore diameter continuously increases from the inner surface to the outer surface of the membrane,
The clearance value of vitamin B ₁₂ of the blood purifier after irradiation is 152 ml / min or more per 1.5 m ^{2 of} membrane area / converted to 1.5 m ^{2 of} membrane area, and the adsorption rate of vitamin B ₁₂ is 25% And myoglobin adsorption rate is 20% or less,
The ratio (Y / X) of the average thickness Y of the fibrils that are the skeleton-like skeleton portions outside the film thickness direction of the hollow fiber membrane and the average thickness X of the fibrils inside the film thickness direction, A blood purifier having an albumin permeability of 0.35% or less by being 1.2 or more and 2.0 or less. The blood purifier according to claim 1, wherein the average thickness of all fibrils present in the hollow fiber membrane is 100 nm or more and 200 nm or less.   The blood purifier according to claim 1 or 2, wherein the container of the blood purifier is made of a polypropylene polymer.   The blood purifier according to any one of claims 1 to 3, wherein the degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is 80% or more and less than 100%.   By injecting a crosslinking degree adjusting agent solution into the hollow fiber membrane from the open end of the blood purifier, then removing the crosslinking degree adjusting agent solution from the hollow fiber membrane, and then irradiating the hollow fiber membrane with radiation, The blood purifier according to claim 4, wherein the degree of crosslinking of polyvinylpyrrolidone in the thread membrane is 80% or more and less than 100%.   The blood purifier according to claim 5, wherein the oxygen concentration in the blood purifier is set to 0.01 vol% or more and 10 vol% or less at the time of the radiation irradiation.   The blood purifier according to any one of claims 1 to 6, wherein the hollow fiber membrane has a thickness of 25 µm or more and 40 µm or less.   The hollow fiber membrane has a film thickness of 35 μm or less and a breaking strength of 7 MPa or more and a breaking elongation of 65% or more, or a film thickness of 30 μm or less and a breaking strength of 7.5 MPa. 8. The blood purifier according to claim 7, wherein the breaking elongation is 70% or more.