JP2010233991A - High performance blood purifier - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood purifier showing a high level of performance for removing impurities in blood, and especially phosphorus and vitamin B<SB>12</SB>. <P>SOLUTION: In the blood purifier having a hollow fiber membrane containing polyvinylpyrrolidone, the mode diameter of a peak on a side of the greatest particle size in a particle size distribution of the polyvinylpyrrolidone in the hollow fiber membrane measured under a dynamic light scattering method is 300 nm or less. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a blood purifier having a hollow fiber membrane containing polyvinylpyrrolidone and having a high ability to remove impurities in blood.

  Hemodialysis has been performed as maintenance therapy for patients with chronic renal failure. Also, 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 serious pathological conditions such as acute renal failure and sepsis. . Blood purification membrane materials used in these therapies include naturally occurring 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 a blood purification membrane is produced from 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.

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 Document 3 specifically discloses albumin permeability and phosphorus clearance performance. However, clearance performance of the vitamin B ₁₂ is unknown.
Furthermore, Patent Literature 4 and Patent Literature 5 disclose a dialyzer comprising a hollow fiber membrane obtained from a four-component membrane 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 phosphorus clearance and vitamin B ₁₂ of the dialyzer is disclosed, only water permeability is abnormally high film.
Patent Document 6 discloses the clearance performance of urea and the clearance performance of vitamin B ₁₂ , but the clearance performance of phosphorus is unknown.
Patent Documents 7 and 8 disclose clearance performance of vitamin B ₁₂ only.

JP 05-161833 A Japanese Patent Laid-Open No. 4-300636 Japanese Patent No. 4126062 JP 2001-170172 A JP 2001-170167 A International Publication No. 2004/094047 Pamphlet Japanese Patent Laid-Open No. 11-178919 JP 11-347117 A

Until now, the clearance of vitamin B ₁₂ of blood purifiers for dialysis has a limit of about 135 ml / min with respect to the clearance of vitamin B ₁₂ even though the removal performance of impurities in blood is considerably high.

An object of the present invention is to provide a blood purifier having high removal performance of impurities in blood, particularly phosphorus and vitamin B ₁₂ .

The present inventor has phosphorus of the hollow fiber membrane containing polyvinylpyrrolidone was intensively studied rejection of vitamin B _12, the impurity removal performance of the hollow fiber membrane is largely dependent on the particle size distribution of polyvinyl pyrrolidone in the hollow fiber membrane and, by adjusting the particle size distribution of polyvinyl pyrrolidone in the hollow fiber membrane was found to be able to achieve a clearance value of vitamin B ₁₂ which could not be achieved by the hollow fiber membranes so far as 150ml / min or more.

That is, the present invention
A blood purifier having a hollow fiber membrane containing polyvinylpyrrolidone,
A blood purifier having a mode diameter of a peak on the largest particle size side in a particle size distribution measured by a dynamic light scattering method of polyvinylpyrrolidone in the hollow fiber membrane of 300 nm or less.
Another aspect of the present invention is as follows:
A method for producing a blood purifier having a hollow fiber membrane containing polyvinylpyrrolidone,
Preparing a solution containing polyvinylpyrrolidone having a mode diameter of a peak on the largest particle size side in a particle size distribution measured by a dynamic light scattering method of 300 nm or less;
Producing a hollow fiber membrane using a solution containing the polyvinylpyrrolidone;
A method for producing a hollow fiber membrane comprising:

According to the present invention, blood impurities, in particular, it is possible to provide phosphorus, vitamin B _12, the removal performance of high blood purifier. Moreover, since the blood purifier of the present invention has a low albumin permeability, it can be used for medical purposes.

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 of the present invention has a hollow fiber membrane containing polyvinylpyrrolidone. Furthermore, the present invention uses polyvinyl pyrrolidone whose mode diameter of the peak on the largest particle size side is 300 nm or less in the particle size distribution as measured by a dynamic light scattering apparatus. By using this polyvinylpyrrolidone, it is possible to obtain a membrane with high removal performance of impurities in blood and low permeability of albumin.
Polyvinylpyrrolidone contributes to making the hydrophobic polymer compound constituting the skeleton of the hollow fiber membrane such as polysulfone polymer hydrophilic. However, according to the research of the present inventors, it has been found that polyvinylpyrrolidone does not always cover the skeleton of the hydrophobic polymer compound uniformly, and some of them exist as a lump. And it is estimated that this block-like polyvinylpyrrolidone raises the filtration resistance of the membrane and lowers the permeation performance of the membrane. In the present invention, in order to identify the cause of the formation of massive polyvinyl pyrrolidone, polyvinyl pyrrolidone was investigated in detail. It was conceived that it may be a cause of generating massive polyvinylpyrrolidone. The polyvinyl pyrrolidone present in the hollow fiber membrane has a low content of such aggregating components, specifically, the largest particle size in the particle size distribution measured by the dynamic light scattering method. It has been found that the removal performance of impurities in blood can be improved by using a peak mode diameter of 300 nm or less.
The blood purifier of the present invention has a high clearance of vitamin B ₁₂ and phosphorus, and therefore has a high ability to remove impurities in blood. Clearance of the blood purifier of vitamin B ₁₂ of the present invention is preferably 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. Under such circumstances, the present invention pays attention to the existence state of polyvinylpyrrolidone at the molecular level, and as a result of analyzing the relationship between this and the removal performance of impurities in blood, the removal performance of phosphorus and vitamin B ₁₂ is particularly high. Succeeded in developing a blood purifier. In addition, the phosphorus clearance of the blood purifier of the present invention is preferably 185 ml / min or more per membrane area of 1.5 m ² / or in terms of the membrane area of 1.5 m ² . More preferably, it is 190 ml / min or more. When the particle size distribution exceeds 300 nm, it tends to be difficult to achieve 185 ml / min or more. Here, the membrane area refers to the area on the inner diameter side of the hollow fiber membrane.

In the present invention, the phosphorus clearance of the blood purifier is measured 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. Follow the Japanese Society for Artificial Organs). The product is measured as it is.
A 5mEq / L physiological saline solution of inorganic phosphorus (pH 7.4 aqueous solution in which 5mEq / L of monosodium phosphate and disodium phosphate were mixed at a ratio of 1: 4) on the blood side at a blood flow rate of 200 mL / min. Circulate, physiological saline is flowed to the dialysate side at a dialysate side flow rate of 500 mL / min, and dialysis is performed under conditions without filtration, and the circulating fluid is sampled from the blood inlet side and outlet side. The phosphorus concentration in the sampled liquid is measured by the molybdenum blue coloring method, 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)} : Phosphorus concentration on the blood purifier inlet side C _{B (out)} : Phosphorus concentration on the blood purifier outlet side Q _B : Blood side flow rate (mL / min) = 200

Similarly, in the present invention, the clearance of vitamin B ₁₂ in the blood purifier is measured by circulating a solution of 1.2 g vitamin B ₁₂ dissolved in 60 liters of physiological saline on the blood side at a blood side flow rate of 200 mL / min. The procedure is the same as the phosphorus clearance measurement except that physiological saline is flowed to the liquid side at a dialysate side flow rate of 500 mL / min and dialysis is performed under conditions without filtration. The concentration of vitamin B ₁₂ in the sampled liquid is measured at 360nm absorbance.

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 side flow rate of blood purifier used for clearance measurement (mL / min)
Q _B ': Blood 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)

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, in the present invention, the distance between the two open ends of the hollow fiber membrane obtained by loading the yarn bundle into a container, adhesively fixing both ends thereof with urethane resin, and cutting the both end surfaces, and the 2 It is preferable that the relationship between the average diameter of the two open ends (circular shape) is the relationship of the following formula (3).
Distance between two open ends / average diameter of two open ends = 4.5 to 6.5 (3)

  The material of the container (housing) of the blood purifier of the present invention is not limited. For example, a mixture such as polystyrene polymer, polysulfone polymer, polyethylene polymer, polypropylene polymer, polycarbonate polymer, and styrene / butadiene block copolymer is used. Resin or the like 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 contains polyvinylpyrrolidone (hereinafter also simply referred to as “PVP”). In a preferred embodiment, the hollow fiber membrane is mainly composed of polyvinylpyrrolidone and a hydrophobic polymer compound. Here, “mainly comprising polyvinylpyrrolidone and a hydrophobic polymer compound” means that the total of polyvinylpyrrolidone and the hydrophobic polymer compound occupies 80% by mass or more of the material constituting the hollow fiber membrane, preferably Is 90% by mass or more, more preferably 95% by mass or more, and further preferably 100% by mass.
Examples of the hydrophobic polymer compound include polysulfone polymers, polyamides, polyimides, polyphenylene ethers, polyphenylene sulfides, and the like. Here, the polysulfone-based polymer refers to a polymer compound having a repeating structure containing a sulfonyl group (—SO ₂ —), and known ones conventionally used in hollow fiber membranes can be used.

  In the present invention, 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 ethanol-soluble polyvinylpyrrolidone in the vinyl hollow fiber membrane is 300 nm (nanometer) or less, preferably It is 200 nm or less, more preferably 60 nm or less.

According to the research of the present inventor, as the polyvinyl pyrrolidone in the hollow fiber membrane, the one having the largest mode particle diameter side of the particle diameter distribution measured by the dynamic light scattering method is 300 nm or less is used. It was found that the removal performance of impurities in the blood (especially vitamin B ₁₂ removal performance) was improved. The reason is estimated as follows (but not limited to this).
That is, ordinary polyvinyl pyrrolidone used in conventional hollow fiber membranes contains an agglomerated component entangled with a plurality of molecules produced in the production process, and these are present in the hollow fiber membrane in a lump shape. This massive polyvinylpyrrolidone is considered to increase the filtration resistance of the membrane and lower the permeation performance of the membrane. When polyvinyl pyrrolidone having a small aggregation component, specifically, one having a mode diameter of a peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method of 300 nm or less is used. Since the pyrrolidone does not exist in the form of a lump, it uniformly covers the periphery of the hollow fiber membrane skeleton (for example, a skeleton made of a hydrophobic polymer compound such as a polysulfone polymer). It is estimated that the permeation performance of the membrane is improved.

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 in the present invention 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 polyvinylpyrrolidone is two (typical example) has been described as an example. Polyvinylpyrrolidone in the inside is not limited to having two peaks in the particle size distribution measured by the dynamic light scattering method, and the mode diameter of the peak on the largest particle size side is 300 nm or less. As long as the conditions are satisfied, three or more peaks may exist.

  In the present invention, the peak mode diameter on the largest particle size side in the particle size distribution measured by the dynamic light scattering method of polyvinyl pyrrolidone is dimethyl adjusted to have a concentration of 5.0% by weight of polyvinyl pyrrolidone. It is determined by measuring an acetamide solution (polyvinylpyrrolidone solution) at a temperature of 25 ° C. using a dynamic light scattering apparatus (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.

In the present invention, 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 is the solubility of ethanol extracted from the hollow fiber membrane using ethanol 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 polyvinyldon.
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.

In the present invention, 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.

In the present invention, the degree of crosslinking of polyvinylpyrrolidone is defined by the following formula (4).
Crosslinking degree of PVP (%)
= PVP amount insoluble in water / Total PVP amount × 100 (4)
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.

  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.

  In the present invention, the thickness of the hollow fiber membrane 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. According to the inventor's research, it has been found that the hollow fiber membrane having a thin film thickness tends to have high impurity removal performance. However, when the film thickness is less than 25 μm, the hollow fiber membrane is frequently crushed at the time of bonding, and the performance of the dialysis blood purifier tends to be lowered as a result because the crushed yarn causes poor performance. If the film thickness exceeds 40 μm, it tends to be difficult to improve the impurity removal performance of the blood purifier for dialysis, which is not preferable. The film thickness referred to in the present invention is an average value of 100 hollow fiber membranes.

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 (5) is defined as the albumin transmittance.
Alb. Transmittance (%)
= Alb. Of filtrate Concentration / Alb. Concentration x 100 (5)
Here, the transmittance is the value after passing through for 60 minutes.

  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.

  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.

  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.

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. In other words, 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 the blood vessel and the remaining 60% is distributed outside the blood vessel. Keeps the state. 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 cleaved perpendicularly to the longitudinal direction in a frozen state at −30 ° C. to obtain a transverse section cleaved 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 from the inner surface to 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 by 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 in the present invention is the thickness of the thinnest part near the center of each fibril observed in the photograph, that is, the joint between the fibrils and the joint. The thickness of the narrowest part is read at an angle perpendicular to the longitudinal direction of the fibril.
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.

In the present invention, as a specific example of the method for 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, hollow fiber The polyvinyl pyrrolidone solution for use in producing the 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.

Next, the specific example of the manufacturing method of the hollow fiber membrane in this invention is demonstrated.
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 (6) or formula (7). 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— (6)
—O—Ar—SO ₂ —Ar— (7)
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 fibril to the average thickness of the fibrils on the inner side in 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.

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.

  As a method of irradiating radiation with the cross-linking degree adjusting agent attached to the hollow fiber membrane, for example, the hollow fiber membrane is immersed in a solution containing the cross-linking degree adjusting agent, and the hollow fiber membrane is applied to the hollow fiber membrane in the solution containing the cross-linking degree adjusting agent. The method of irradiating radiation is mentioned. In this case, it is effective to remove the oxygen in the solution containing the crosslinking degree adjusting agent to control the desired degree of crosslinking with good reproducibility. The solution can be deoxygenated by bubbling an inert gas such as nitrogen or argon. It is also possible to deoxygenate by using a commercially available degasser or by heating and reducing the pressure. The oxygen concentration in the solution is preferably 0.1 mg / L or more and 1 mg / L or less under 1 atm. If the oxygen concentration is less than 0.1 mg / L, it tends to be difficult to obtain a crosslinking degree of less than 90%. On the other hand, when it exceeds 1 mg / L, it tends to be difficult to obtain a crosslinking degree of 90% or more with good reproducibility.

In order to crosslink polyvinylpyrrolidone in a dry type hollow fiber membrane in a gas, a crosslinking degree adjusting agent solution is once injected into the hollow fiber membrane from the open end of the blood purifier, and then the crosslinking in the hollow fiber membrane is performed. It is preferable to remove the degree-adjusting agent solution, and then irradiate the blood purifier with an oxygen concentration of 0.01% by volume to 10% by volume. 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.

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. Here, as the mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinyl pyrrolidone when measured with a dynamic light scattering device, it is measured 10 times and 8 points excluding the maximum value and the minimum value The average value of was 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 55% by weight of dimethylacetamide and 45% by weight of water, a spinning nozzle (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.

(Manufacture of blood purifiers)
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 (length between the two open ends / average diameter of the two open ends = 5.6). In addition, header caps were attached to both ends.
A solution prepared by dissolving 15 g of glycerin (manufactured by Wako Pure Chemical Industries, special grade) and 5 g of glucose (manufactured by Wako Pure Chemical Industries, special grade) in 80 g of 0.1% by weight sodium thiosulfate (manufactured by Wako Pure Chemical Industries, special grade) is prepared. (This is called a (glycerin + glucose) solution having a concentration of 20% by weight). A solution obtained by diluting this solution 40 times with a 0.1% by weight aqueous sodium thiosulfate solution (0.5% by weight of (glycerin + glucose) concentration) was injected into the blood purifier, and the inside / outside of the hollow fiber membrane was So that the solution was fully immersed. At this time, the oxygen concentration in the solution was adjusted to be in the range of 0.3 to 0.8 mg / L. Thereafter, the blood purifier was irradiated with 20 kGy of an electron beam.

(Measurement of the mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method)
When the particle size distribution of soluble polyvinylpyrrolidone extracted from the blood purifier with ethanol was measured with a dynamic light scattering device, the peak mode diameter on the largest particle size side in the particle size distribution was 130 nm, and the hollow fiber membrane It was confirmed that the value was not different from the value of polyvinylpyrrolidone used in the production.

The performance of this blood purifier 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 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purification device consisting of a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.

[Example 2]
The same operation as in Example 1 was performed except that the internal liquid concentration was changed to 50% by weight. The film thickness was 40.0 μm. The performance of this blood purifier 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 152 ml / min and 185 ml / min, respectively. . Moreover, the transmittance of albumin was 0.20%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
[Example 3]
The same operation as in Example 1 was performed except that the internal liquid concentration was 52% by weight, 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 the values measured for vitamin B ₁₂ clearance and phosphorus clearance after irradiation were 152 ml / min and 186 ml / min, respectively. . The albumin transmittance was 0.35%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.

[Example 4]
The same operation as in Example 1 was performed except that the internal liquid concentration was 54 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 the values measured for vitamin B ₁₂ clearance and phosphorus clearance after irradiation were 152 ml / min and 185 ml / min, respectively. . The albumin permeability was 0.18%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
[Example 5]
The same operation as in Example 1 was performed except that the internal liquid concentration was 52% by weight, 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 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 161 ml / min and 194 ml / min, respectively. . Moreover, the transmittance of albumin was 0.33%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
In addition, since this example has a thin film thickness, the filtration resistance is low, and coupled with the fact that the mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinyl pororidone in the hollow fiber membrane is small, The removal performance of phosphorus and vitamin B ₁₂ was extremely high.

[Example 6]
The same operation as in Example 1 was performed except that the concentration of (glycerin + glucose) in the aqueous solution sealed in the blood purifier when irradiated with radiation was 0.02 wt%. The sodium thiosulfate concentration in the aqueous solution was 0.1% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 99.4%. 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 the values measured for vitamin B ₁₂ clearance and phosphorus clearance after irradiation were 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
[Example 7]
The same operation as in Example 1 was performed except that the concentration of (glycerin + glucose) in the aqueous solution sealed in the blood purifier at the time of irradiation was 0.1 wt%. The sodium thiosulfate concentration in the aqueous solution was 0.1% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 94.9%. 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 the values measured for vitamin B ₁₂ clearance and phosphorus clearance after irradiation were 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.

[Example 8]
The same operation as in Example 1 was performed except that the concentration of (glycerin + glucose) in the aqueous solution sealed in the blood purifier at the time of irradiation was changed to 10% by weight. The sodium thiosulfate concentration in the aqueous solution was 0.1% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 81.3%. The performance of this blood purifier 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 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
[Example 9]
The same operation as in Example 1 was performed except that the concentration of (glycerin + glucose) in the aqueous solution sealed in the blood purifier at the time of irradiation was changed to 7% by weight. The sodium thiosulfate concentration in the aqueous solution was 0.1% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 86.2%. The performance of this blood purifier 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 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.

[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 performance of this blood purifier 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 152 ml / min and 185 ml / min, respectively. . The albumin transmittance was 0.27%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
[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 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 the values measured for vitamin B ₁₂ clearance and phosphorus clearance after irradiation were 160 ml / min and 193 ml / min, respectively. . The albumin transmittance was 0.27%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
Further, in this example, since the mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinyl pororidone in the hollow fiber membrane was very small, the removal performance of phosphorus and vitamin B ₁₂ was extremely high. Thereby, it has confirmed that the removal performance of an impurity improved, so that the mode diameter of the peak in the largest particle size side is small in the particle size distribution of the polyvinyl pororidone in a hollow fiber membrane.

[Example 12]
A 12.1% (glycerin + glucose) aqueous solution (concentration of sodium thiosulfate in the aqueous solution is 0.1% by weight) is injected into the hollow fiber membrane for 2.3 seconds from the open end, and 10% with 0.3 MPa air is used. After flashing for 2 seconds, 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. Except for the above, the same operation as in Example 1 was performed. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 80.6%. The performance of this blood purifier 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 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
[Example 13]
The same operation as in Example 12 was performed except that a 2.2% (glycerin + glucose) aqueous solution (the concentration of sodium thiosulfate in the aqueous solution was 0.1% by weight) was used. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 94.5%. The performance of this blood purifier 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 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.

[Example 14]
The same operation as in Example 12 was performed except that a 0.4% (glycerin + glucose) aqueous solution (the concentration of sodium thiosulfate in the aqueous solution was 0.1% by weight) was used. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 99.0%. The performance of this blood purifier 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 156 ml / min and 190 ml / min, respectively. . The albumin permeability was 0.25%. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.
[Example 15]
The hollow fiber membrane is loaded into a cylindrical container made of Asaflex (styrene / butadiene block copolymer) designed so that the effective membrane area of the hollow fiber membrane is 2.1 m ^2, and both ends thereof are bonded and fixed with urethane resin, Both ends were cut to form an open end of the hollow fiber membrane (length between the two open ends / average diameter of the two open ends = 5.6). Further, the same operation as in Example 1 was performed except that header caps were attached to both ends. In addition, 13,400 hollow fiber membranes were loaded in the Asaflex cylindrical container. The performance of this blood purifier is shown in Table 1. The values obtained by measuring the clearance value of vitamin B _{12 and} the clearance value of phosphorus (a value of membrane area 2.1 m ² ) of the obtained blood purifier were 174 ml / min and 196 ml / min, respectively. The values converted to an area of 1.5 m ² were 157 (mL / min) and 189 (mL / min) for vitamin B ₁₂ and phosphorus, respectively. It was revealed that the performance of removing impurities in blood was high and the albumin permeability was low. In particular, the breaking strength and breaking elongation is high, a blood purifier comprising a small thickness hollow fiber membrane, the clearance value of vitamin B ₁₂ was particularly excellent blood purifier.

[Example 16]
The same operation as in Example 1 was performed except that the internal liquid concentration was changed to 50% by weight. The film thickness was 40.8 μm. The performance of this blood purifier is shown in Table 2.
This example had high impurity removal performance, but had a breaking strength of less than 6.0 MPa and a breaking elongation of less than 60.
[Example 17]
The same operation as in Example 1 was performed except that the internal liquid concentration was 50% by weight, 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.
Since the ratio of the average thickness of the fibrils on the outer side and the inner side is small, the impurity removal performance should be considerably low if it is originally, but in the particle size distribution of polyvinyl pyrrolidone in the hollow fiber membrane, Since the mode diameter of a certain peak is small, a suitable impurity removal performance was obtained. Moreover, since the ratio of the average thickness of the fibrils on the outer side and the inner side was small, the albumin permeability was a performance exceeding 0.35%.

[Example 18]
The same operation as in Example 1 was performed except that the internal liquid concentration was 52% by weight and the air gap was 210 mm. The performance of this blood purifier is shown in Table 2.
Since the film thickness is too thin at less than 25 μm, the impurity removal performance should be considerably reduced by yarn crushing, but the peak on the largest particle size side in the particle size distribution of polyvinylpyrrolidone in the hollow fiber membrane Since the mode diameter is small, some impurity removal performance was obtained.
[Example 19]
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. In the particle size distribution of polyvinyl pyrrolidone used as a raw material during film formation, the peak mode diameter on the largest particle size side is small, so that good impurity removal performance was obtained.
However, when this blood purifier was evaluated for clinical blood, a leucopenia symptom in which the white blood cell count of a dialysis patient temporarily decreased was observed.
[Example 20]
The same operation as in Example 1 was performed except that the concentration of (glycerin + glucose) in the aqueous solution sealed in the blood purifier at the time of irradiation was changed to 7% by weight. The sodium thiosulfate concentration in the aqueous solution was 0.1% 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. In the particle size distribution of polyvinyl pyrrolidone in the hollow fiber membrane, since the mode diameter of the peak on the largest particle size side is small, good impurity removal performance was obtained.
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.

[Example 21]
The same operation as in Example 12 was performed, except that a 16.3% (glycerin + glucose) aqueous solution (sodium thiosulfate concentration in the aqueous solution was 0.1% by weight) was used. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 78.7%. The performance of this blood purifier is shown in Table 2. In the particle size distribution of polyvinyl pyrrolidone in the hollow fiber membrane, since the mode diameter of the peak on the largest particle size side is small, good impurity removal performance was obtained.
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.
[Example 22]
The same operation as in Example 12 was performed except that the aqueous solution was not injected from the open end and deoxidation in the blood purifier was not performed. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 100%. The performance of this blood purifier is shown in Table 2. In the particle size distribution of polyvinyl pyrrolidone used as a raw material during film formation, the peak mode diameter on the largest particle size side is small, so that good impurity removal performance was obtained.
However, when this blood purifier was evaluated for clinical blood, a leucopenia symptom in which the white blood cell count of a dialysis patient temporarily decreased was observed.

[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.
In Comparative Example 1, since the ratio of the average thickness of the fibrils on the outside and the inside is large, the impurity removal performance should be improved, but the largest particle size in the particle size distribution of polyvinylpyrrolidone in the hollow fiber membrane As a result, the mode diameter of the peak on the side was very large, and as a result, the performance of removing impurities in blood was low.

[Comparative Example 2]
The same operation as in Example 1 was performed except that the internal liquid concentration was 52% by weight, 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 3]
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. In the particle size distribution of polyvinyl pyrrolidone in the hollow fiber membrane, the mode diameter of the peak on the largest particle size side is larger than 300 nm, so the performance of removing impurities in blood was low.

A Primary peak B Secondary peak 1 Wavelength 2 Amplitude

Claims (12)

A blood purifier having a hollow fiber membrane containing polyvinylpyrrolidone,
A blood purifier having a mode diameter of a peak on the largest particle size side in a particle size distribution measured by a dynamic light scattering method of polyvinylpyrrolidone in the hollow fiber membrane of 300 nm or less.   The blood purifier according to claim 1, wherein the hollow fiber membrane is composed of polyvinylpyrrolidone and a polysulfone-based polymer.   The blood purifier according to claim 1 or 2, wherein the hollow fiber membrane has a structure in which the pore diameter continuously increases from the inner surface to the outer surface. Clearance value of vitamin B ₁₂ is not less 152 ml / min or more membrane area 1.5 m ² per / or membrane area 1.5 m ² conversion value,
Clearance values of phosphorus is membrane area 1.5 m ² per / or membrane area 1.5 m ² in terms of value 185 ml / min or more, blood purifier according to any one of claims 1 to 3.   The blood purifier according to any one of claims 1 to 4, wherein the albumin permeability is 0.35% or less.   The blood purifier according to any one of claims 1 to 5, wherein a container of the blood purifier is made of a polypropylene polymer.   The blood purifier according to any one of claims 1 to 6, wherein the degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is 80% or more and less than 100%. Polyvinylpyrrolidone in the hollow fiber membrane is
The crosslinking degree adjusting agent solution is injected into the hollow fiber membrane from the open end of the blood purifier, then the crosslinking degree adjusting agent solution is removed from the hollow fiber membrane, and then the hollow fiber membrane is irradiated with radiation to adjust the degree of crosslinking. The blood purifier according to claim 7, wherein the blood purifier is 80% or more and less than 100%.   The blood purifier according to claim 8, wherein the degree of crosslinking of polyvinylpyrrolidone is 80% or more and less than 100% by setting the oxygen concentration in the blood purifier to 0.01 vol% or more and 10 vol% or less at the time of irradiation.   The blood purifier according to any one of claims 1 to 9, 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. The blood purifier according to claim 10, which has the breaking elongation of 70% or more. A method for producing a blood purifier having a hollow fiber membrane containing polyvinylpyrrolidone,
Preparing a solution containing polyvinylpyrrolidone having a mode diameter of a peak on the largest particle size side in a particle size distribution measured by a dynamic light scattering method of 300 nm or less;
Producing a hollow fiber membrane using a solution containing the polyvinylpyrrolidone;
A method for manufacturing a blood purifier comprising: