JP3281364B1 - Method for producing blood purification membrane - Google Patents

Abstract

An object of the present invention is to provide a high-performance blood purification membrane having an extremely small amount of elution from the membrane and having excellent dialysis performance with little adhesion of blood proteins and platelets, and a production method. SOLUTION: The membrane does not contain a pore retaining agent, the permeability of pure water is 100 mL / (m ² · hr · mmHg) or more, the transmittance of polyvinylpyrrolidone having a weight average molecular weight of 40,000 exceeds 75%, and A method for producing a hollow fiber-shaped blood purification membrane, comprising drying a wet membrane having an albumin permeability of 0.3% or more in a bovine plasma system at a temperature of 120 ° C or less.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a high-performance blood purification membrane having an extremely small amount of elution from the membrane and an excellent dialysis performance with little adhesion of blood proteins and platelets.

[0002]

2. Description of the Related Art In recent years, the technology utilizing a selectively permeable membrane has been remarkably advanced, and thus far, gas and liquid separation filters, hemodialyzers, hemofilters, and blood component selective separation filters in the medical field have been used. Practical application in a wide range of fields such as

[0003] Materials for the membrane include polymers of cellulose type (regenerated cellulose type, cellulose acetate type, chemically modified cellulose type, etc.), polyacrylonitrile type, polymethyl methacrylate type, polysulfone type, polyethylene vinyl alcohol type, polyamide type etc. Has been used.

[0004] Among them, polysulfone-based polymers are semi-permeable because their blood compatibility is improved by adding a hydrophilizing agent to a stock solution for film formation in addition to its thermal stability, acid resistance and alkali resistance. Attention has been focused on membrane materials and research has been promoted.

On the other hand, it is necessary to dry the membrane in order to fabricate the module by bonding the membrane. However, a porous membrane made of an organic polymer, in particular, a dialysis membrane made of a hydrophobic polymer such as polysulfone-based membrane, It is known that when a filtration membrane is dried after film formation, the amount of water permeation is significantly reduced as compared to before the drying. Therefore, it was necessary to always handle the membrane in a wet state or in a state of being immersed in water.

[0006] As a countermeasure against this, a conventional method has been to fill a void portion in the porous film with a low-volatile organic liquid such as glycerin after the film is formed and before drying. However, low-volatile organic liquids are generally of high viscosity,
It takes time for cleaning and removal, and even after the membrane is formed into a module, a small amount of eluates derived from low-volatile organic liquids (various derivatives formed by chemical reaction with low-volatile organic liquid) are encapsulated in the module even after cleaning. There was a problem of being seen in the liquid.

As a method for drying without using a low-volatile organic liquid, Japanese Patent Application Laid-Open No. Hei 6-277470 discloses a method using an inorganic salt such as calcium chloride instead of the low-volatile organic liquid. The need for cleaning and removal remains the same. In addition, even if the amount is very small, there is a concern that the remaining inorganic salts may adversely affect dialysis patients.

[0008] JP-A-8-52331 and Japanese Patent Publication No.
No. 9668 discloses a hydrophilic film containing polyvinylpyrrolidone which has been dried without using a low volatile organic liquid. Although the performance of separating plasma components from blood is described, it can be seen that dialysis performance is not exhibited because plasma proteins are permeated. Furthermore, the film forming conditions are not described, and the film structure itself is unknown. In addition, since the polyvinylpyrrolidone is dried at a temperature at which the polyvinylpyrrolidone is decomposed and denatured, the production method is extremely unfavorable for the purpose of reducing the eluate from the membrane.

Japanese Patent Application Laid-Open No. 6-296686 discloses a hollow fiber membrane in which the abundance of polyvinylpyrrolidone on the inner surface of the membrane in direct contact with blood is about 20 to 50%. This mainly indicates a wet membrane for reducing the amount of deposits such as blood proteins and platelets. Accordingly, although it is shown that the blood protein is less likely to adhere and the filtrate speed is less likely to change with time, there is no description about dialysis performance such as low albumin permeability.

[0010]

An object of the present invention is to provide a method for producing a high-performance blood purification membrane having an excellent dialysis performance with an extremely small amount of elution from the membrane and little adhesion of blood proteins and platelets. It is in.

[0011]

As described above, there has been no method for producing a dried blood purification membrane having dialysis performance without using a membrane pore retaining agent that causes elution from the module. The cause was that when dried without using a pore retaining agent, a low-performance membrane completely different from the wet state was obtained.

Therefore, the present inventors have previously prepared a wet membrane having a specific performance having a higher water permeability and a larger pore diameter than the target performance, and then drying and shrinking the wet membrane to achieve the target dialysis performance. As a result of intensive research based on an unprecedented idea of producing a membrane with a high degree of dialysis, it has been found that dialysis performance with extremely low eluate, low adhesion of blood proteins and platelets, and excellent selectivity. The present invention was able to obtain a film having the present invention.

That is, the present invention provides: (1) a membrane containing no pore retaining agent and having a pure water permeability of 100 mL;
/ (M ² · hr · mmHg) or more and a weight average molecular weight of 4
The permeability of polyvinylpyrrolidone of 000 exceeds 75% and the permeability of albumin in bovine plasma system is 0.
3% or more of polysulfone-based polymer and polyvinyl
A wet membrane comprising pyrrolidone is dried at a temperature of 120 ° C. or lower. (A) The pore diameter is continuous from the outer surface of the membrane to the inner surface dense layer.
It consists-sustaining small sponge structure, water permeability (b) pure water ^{10mL / (m 2 · hr ·} mmH
g) or more; (c) polyvinylpyrroli having a weight average molecular weight of 40,000
Don transmittance of 75% or less, (d) transmission of albumin in bovine blood plasma system is 0.3%
Less than a and, (e) absorbance der less than 0.04 of the eluate test liquid film
And the eluate test solution does not contain a pore retaining agent, and (f) a polysulfone-based polymer and polyvinylpyrrolidone
Of polyvinylpyrrolidone on the inner surface of the membrane.
A method for producing a hollow-fiber-shaped blood purification membrane having a degree of 30 to 45% by weight , (2) discharging a membrane-forming stock solution and an internal solution from a double annular nozzle, passing through an air gap, and coagulating in a coagulation bath. In the method for producing a hollow fiber membrane, the ratio of the air gap to the spinning speed is 0.01 to 0.1 m / (m / min), the method for producing a wet membrane according to the above (1), (3). The film forming stock solution comprises a polysulfone-based polymer, polyvinylpyrrolidone, and a solvent, and the ratio of polyvinylpyrrolidone to the polysulfone-based polymer is 18 to 27.
(1) or (2) above,
(4) The method according to any one of the above (1) to (3), wherein irradiation is performed after drying, and (5) the polyvinylpyrrolidone in which the hollow fiber blood purification membrane is insoluble in water. (1) to (1),
(4) The method for producing a blood purification membrane according to any of (4).

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a hollow fiber-shaped blood purification membrane of the present invention (hereinafter, also simply referred to as "membrane" or "hollow fiber membrane").
A method of manufacturing the device will be described. The production method of the present invention is characterized in that a wet membrane having a high water permeability and a large pore diameter is prepared in advance, and then dried without removing the membrane pore retaining agent after desolvation.

[0015] Usually, membrane pore-holding agents used when producing a hollow fiber-shaped blood purification membrane are classified into viscous organic substances and inorganic substances which may be toxic to the human body. Since the pore retaining agent composed of a viscous organic substance is difficult to completely remove by washing due to its high viscosity, it remains in the membrane to increase the amount of elution from the membrane, and furthermore, the remaining pores It can cause harmful substances by chemically reacting with the holding agent. On the other hand, even in the case of a pore retaining agent made of an inorganic substance, a trace amount thereof remains, so that there is a concern that it may adversely affect a dialysis patient.

The pore retaining agent referred to in the present invention is a substance that is filled in pores in the membrane during the manufacturing process before drying in order to prevent performance degradation during drying. By immersing the wet membrane in a solution containing the pore retaining agent, the pores in the membrane can be filled with the retaining agent. As long as the pore retaining agent is washed and removed even after drying, it is possible to maintain the same performance as a wet membrane, such as water permeability and rejection, by the effect of the pore retaining agent.

Examples of the membrane pore retaining agent include ethylene glycol, propylene glycol, trimethylene glycol,
1,2-butylene glycol, 1,3-butylene glycol, 2-butyne-1,4-diol, 2-methyl-
2,4-pentadiol, 2-ethyl-1,3-hexanediol, glycerin, tetraethylene glycol,
Organic compounds such as glycol-based or glycerol-based compounds such as polyethylene glycol 200, polyethylene glycol 300, and polyethylene glycol 400 and sucrose fatty acid esters, and inorganic salts such as calcium chloride, sodium carbonate, sodium acetate, magnesium sulfate, sodium sulfate, and zinc chloride. Can be mentioned.

In the present invention, a wet membrane having a high water permeability and a large pore diameter means that the water permeability is 100 mL / (m ² · hr
MmHg) or more and a weight average molecular weight of 40,00
Polyvinylpyrrolidone with a permeability of more than 75% and a permeability of albumin in bovine plasma systems of 0.3% or more.

The permeability of bovine plasma albumin can be measured by the following method. First, length 20c
A small module is manufactured by bundling 100 hollow fiber membranes of m. Heparin-added bovine plasma (5000 IU / I heparin, protein concentration 6.
0 g / dL (deciliter)) at a linear velocity of 1.
The solution is passed at 0 cm / sec, and ultrafiltration is performed for 60 minutes at an average pressure of 50 mmHg of the input pressure and the output pressure of the module. The concentrations of the obtained filtrate and the original solution are measured at a wavelength of 280 nm using an ultraviolet spectrophotometer, and the transmittance is calculated by substituting into the following equation (4). Transmittance (%) = (absorbance of filtrate) × 100 / (absorbance of original solution) (1)

The transmittance of polyvinylpyrrolidone can be determined by adding 3% by weight of polyvinylpyrrolidone (BASF) to the aqueous solution to be filtered.
K30, weight average molecular weight 40,000) phosphate buffer (0.15 mol / L, pH 7.4)
It is obtained by performing the same operation as in the measurement of the transmissivity of bovine plasma albumin except that the aqueous solution is used and the average pressure of the input pressure and the output pressure of the module is set to 200 mmHg.

The wet membrane having a high water permeability and a large pore size includes a polysulfone-based polymer (hereinafter, also simply referred to as “polymer”),
Polyvinylpyrrolidone, and a film-forming stock solution comprising a solvent,
In a production method in which the liquid is discharged from a double annular nozzle together with the internal liquid, passes through an air gap, and then coagulates in a coagulation bath, the liquid can be produced by using an aqueous solution of a polymer solvent as the internal liquid.

The internal liquid forms the hollow portion and the inner surface of the membrane, and it has been found that the pore size of the inner surface increases in proportion to the solvent concentration in the internal liquid. In the present invention,
Since the dialysis membrane having the target performance can be obtained by drying and shrinking the wet membrane, it is necessary to make the solvent concentration in the internal solution a higher concentration than when manufacturing a wet membrane having the target dialysis performance. is there.

Examples of the polysulfone polymer used in the present invention include those having a repeating unit represented by the following formula (2) or (3). Note that 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- (2) -O-Ar-SO 2 -Ar- (3)

In the present invention, polyvinylpyrrolidone having a weight average molecular weight of 900,000 or more has a sufficient effect because the higher the molecular weight, the higher the effect of hydrophilizing the film. Is used. A large amount of polyvinylpyrrolidone needs to remain in the membrane in order to impart a hydrophilizing effect to the membrane using polyvinylpyrrolidone having a weight average molecular weight of less than 900,000. Will increase. Conversely, if the residual amount of polyvinylpyrrolidone having a weight-average molecular weight of less than 900,000 in the membrane is reduced in order to reduce the eluate, the hydrophilizing effect becomes insufficient. The filtration rate decreases over time, and a sufficient effect cannot be exhibited.

The solvent used for dissolving the polysulfone-based polymer and polyvinylpyrrolidone is one that dissolves both of them, such as N-methyl-2-pyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide. And so on.

The concentration of the polymer in the film-forming stock solution is not particularly limited as long as it can be formed into a film and the obtained film has a performance as a film, and is 5 to 35% by weight, preferably 5 to 35% by weight. It is 10 to 30% by weight. In order to achieve high water permeability, the lower the polymer concentration, the better.
5% by weight is preferred.

More importantly, the amount of polyvinylpyrrolidone added is such that the mixing ratio of polyvinylpyrrolidone to the polymer is 27% by weight or less, preferably 10 to 27%.
%, More preferably 20 to 27% by weight. The mixing ratio of polyvinylpyrrolidone to polymer is 27
If the amount exceeds 10% by weight, the amount of elution tends to increase.
When the amount is less than% by weight, it is difficult to obtain a sponge-structured film because the viscosity of the stock solution is low. For the purpose of controlling the viscosity of the stock solution and the dissolution state, it is also possible to add a fourth component such as water or a poor solvent, and the type and amount of the fourth component may be determined as needed depending on the combination.

The air gap means a gap between the nozzle and the coagulation bath. The ratio of the air gap (m) to the spin speed (m / min) is very important for obtaining the membrane of the present invention. Because, in the membrane structure of the present invention, the non-solvent in the internal solution comes into contact with the stock solution to induce phase separation with time from the inner surface portion side to the outer surface portion side of the stock solution. If the phase separation from the membrane inner surface part to the outer surface part is not completed before the film forming stock solution enters the coagulation bath,
Because it cannot be obtained.

The ratio of the air gap to the spinning speed is 0.1.
It is preferably from 0.10 to 0.1 m / (m / min),
More preferably, 0.010 to 0.05 m / (m / min)
It is. The ratio of the air gap to the spinning speed is 0.010
When the ratio is less than m / (m / min), it is difficult to obtain a film having the structure and performance of the present invention. This is not preferred because the film tends to be cut and the production tends to be difficult.

Here, the spinning speed refers to a process in a series of steps of manufacturing a hollow fiber membrane in which a stock solution discharged together with an internal solution from a nozzle passes through an air gap and a film solidified in a coagulation bath is wound up. It means the winding speed when there is no stretching operation inside. Further, when the air gap is surrounded by a cylindrical tube and a gas having a constant temperature and humidity is flowed through the air gap at a constant flow rate, a hollow fiber membrane can be manufactured in a more stable state.

As the coagulation bath, for example, water; methanol,
Liquids that do not dissolve polymers, such as alcohols such as ethanol; ethers; aliphatic hydrocarbons such as n-hexane and n-heptane, are used, but water is preferred. Also,
It is also possible to control the coagulation rate by adding a small amount of a solvent that dissolves the polymer to the coagulation bath.

The temperature of the coagulation bath is -30 to 90 ° C, preferably 0 to 90 ° C, more preferably 0 to 80 ° C.
If the temperature of the coagulation bath exceeds 90 ° C. or is lower than −30 ° C., the surface state of the hollow fiber membrane in the coagulation bath is difficult to stabilize.

The drying after the solvent removal washing is not particularly limited as long as it does not modify or decompose polyvinylpyrrolidone. However, the drying temperature is preferably 120 ° C. or lower, more preferably 100 ° C. or lower. If the temperature exceeds 120 ° C., polyvinylpyrrolidone is denatured and decomposed, so that the amount of elution from the obtained dried membrane increases even without using a pore retaining agent.

Further, by irradiating the dried film with radiation such as electron beam and γ-ray, a part of PVP in the film can be insolubilized in water, so that the amount of elution from the film can be further reduced. It is. Irradiation with radiation may be performed before or after modularization. Further, if all PVP in the membrane is insolubilized, the amount of elution can be reduced, but it is not preferable because leukopenia symptoms are observed during dialysis.

The water-insoluble PVP referred to in the present invention is:
It is obtained by subtracting the amount of PVP soluble in water from the total amount of PVP in the membrane. The total amount of PVP in the film can be easily calculated by elemental analysis of nitrogen and sulfur. Also,
The amount of PVP soluble in water can be determined by the following method. After completely dissolving the membrane with N-methyl-2-pyrrolidone, water is added to the obtained polymer solution to completely precipitate the polysulfone-based polymer. Further, after allowing the polymer solution to stand, PVP soluble in water can be determined by determining the amount of PVP in the supernatant by liquid chromatography.

The production method of the present invention is characterized in that a wet membrane containing no pore-holding agent is dried at a temperature of 120 ° C. or less, and the membrane obtained by the present production method is characterized in that A dry membrane containing no sponge having a sponge structure in which the pore size decreases continuously from the outer surface of the membrane to the dense inner surface layer, and the pure water permeability is 10 mL / (m ² · hr · mmH).
g) a hollow fiber blood purification membrane characterized in that the transmittance of polyvinylpyrrolidone having a weight average molecular weight of 40,000 is 75% or less and the transmittance of albumin in bovine plasma system is less than 0.3%. is there.

In recent hemodialysis treatment, β2-microglobulin (molecular weight: 11,800), which is a causative substance for improvement of dialysis amyloid pathology, is sufficiently transmitted, but albumin (molecular weight: 67,000) is used. The membrane of the present invention is required to have a permeability of albumin of 0.1 in bovine plasma system.
3% or less. An albumin permeability of more than 0.3% is not preferable as a hemodialysis membrane because it means that the effective albumin is largely lost in the body.

Further, the permeability of pure water is 10 mL / (m ² ···
In a film of not less than hr.mmHg), the transmittance (A (%)) of polyvinylpyrrolidone and the clearance (B (mL / min)) of β2-microglobulin are linear functions represented by the following equation (4). There is a strong correlation. For clearance evaluation, it is necessary to mold and process into a module of dialysis specification having an effective membrane area of 1.5 m ² ,
In this evaluation method, measurement can be performed simply, and the clearance can be easily estimated. B (mL / min) = 0.636A + 29.99 (4)

Here, the clearance of β2-microglobulin was set to a module having an effective membrane area of 1.5 m ² with a blood flow rate of 200 mL / min (on the inner surface of the membrane) and a dialysate flow rate of 50 mL.
Dialysis was measured under the condition of 0 mL / min (outer membrane surface side) according to the performance evaluation standard of the Japanese Society for Artificial Organs.

Various clearances are required for the clearance of β2-microglobulin according to the physical strength and disease state of the dialysis patient and the degree of progress of the disease state. If the transmittance of polyvinylpyrrolidone exceeds 75%, the transmittance of albumin exceeds 75%. Is 0.
Since it exceeds 3%, the transmittance of polyvinylpyrrolidone needs to be 75% or less.

Further, in the membrane produced by the production method of the present invention, since no pore retaining agent is used in the production process, there is no eluate derived from the pore retaining agent. Therefore, the absorbance of the eluate test solution of the membrane of the present invention is less than 0.04, and the test solution does not contain a pore retention agent. Here, the eluate test solution was prepared based on the approval criteria of the artificial kidney apparatus, and 1.5 g of the dry hollow fiber membrane cut into 2 cm and 150 mL of distilled water for injection were tested for glass containers for injection by the Japanese Pharmacopoeia. Put in a glass container compatible with the alkali dissolution test of
Heating at 70 ± 5 ° C. for 1 hour, removing the film after cooling, and adding distilled water to make 150 mL. The absorbance is measured by an ultraviolet absorption spectrum at a wavelength showing the maximum absorption wavelength at 220 to 350 nm. Although the approval standard of the artificial kidney apparatus stipulates that the absorbance be 0.1 or less, the membrane of the present invention does not hold a pore-holding agent, so that the absorbance is not more than 0.1.
It is possible to achieve less than 04. Further, regarding the presence or absence of a pore holding agent, the test solution obtained by concentrating or removing water was subjected to gas chromatography, liquid chromatography, a differential refraction system, an ultraviolet spectrophotometer, an infrared absorption spectrophotometer,
It can be detected by measurement by a known method such as nuclear magnetic resonance spectroscopy and elemental analysis. Further, whether or not the membrane contains a pore holding agent can be detected by these measuring methods.

The membrane produced by the production method of the present invention comprises a polysulfone-based polymer and polyvinylpyrrolidone, and the concentration of polyvinylpyrrolidone on the inner surface of the membrane is 3%.
0 to 45% by weight. An important factor for the blood compatibility of the membrane is the hydrophilicity of the inner surface of the membrane that comes into contact with blood. In a polysulfone-based membrane containing polyvinylpyrrolidone (hereinafter, also simply referred to as “PVP”), the PVP concentration on the inner surface of the membrane is important. It is. If the PVP concentration on the inner surface of the membrane is too low, the inner surface of the membrane becomes hydrophobic, plasma proteins are easily adsorbed, and blood coagulation tends to occur. That is, the blood compatibility of the membrane becomes poor. Conversely, if the PVP concentration on the inner surface of the membrane is too high, the amount of PVP eluted into the blood system will increase, giving undesired results for the purposes and applications of the present invention. Therefore, the concentration of PVP on the inner surface of the film in the present invention is in the range of 30 to 40%, preferably 33 to 40%.

The PVP concentration on the inner surface of the film was measured by an X-ray photon spectrum (X-ray Photoelectron).
n spectroscopy (hereinafter referred to as XPS). That is, the XPS of the inner surface of the film is measured by a normal method after arranging the samples on a double-sided tape, incising in the fiber axis direction with a cutter, and spreading the inside of the film so that the inside thereof is facing up. . That is, C1s, O1s, N1
It refers to the concentration obtained from the surface intensity of nitrogen (nitrogen atom concentration) and the surface concentration of sulfur (sulfur atom concentration) from the area intensity of the s and S2p spectra using the relative sensitivity coefficient attached to the device. Is the structure of the expression (2), it can be calculated by the expression (5). PVP concentration (% by weight) = C ₁ M ₁ × 100 / (C ₁ M ₁ + C ₂ M ₂ ) (5) where C ₁ : nitrogen atom concentration (%) C ₂ : sulfur atom concentration (%) M ₁ : Molecular weight of a repeating unit of PVP (111) M ₂ : molecular weight of a repeating unit of polysulfone polymer (442)

Examples of the present invention will be described below, but the present invention is not limited to these examples. (Measurement of platelet adhesion) Measurement of platelet adhesion to the membrane
The following operation procedure was used. A small module is prepared by bundling 10 hollow fiber membranes having a length of 15 cm, and heparin-added human fresh blood is applied to the module at a linear velocity of 1.0 cm / sec.
Minutes, followed by saline for 1 minute.
Next, the hollow fiber membrane is shredded at intervals of about 5 mm, and ultrasonically irradiated in a physiological saline solution containing 0.5% polyethylene glycol alkylphenyl ether (trade name: Triton X-100, manufactured by Wako Pure Chemical Industries, Ltd.) to the membrane surface. Lactate dehydrogenase (hereinafter referred to as “LDH”) released from the adhered platelets was quantified and calculated as LDH activity per membrane area (internal surface conversion). The enzyme activity was measured using an LDH monotest kit (Boehringer Mannheim, Yamanouchi). As a positive control, a film containing no PVP (the film of Example 1 before γ-ray irradiation was treated with an effective chlorine concentration of 1500
immersion in ethanol for 2 days, and then immersion in ethanol for 1 day), and compared with the test sample.

(Amount of adsorbed plasma protein) The amount of adsorbed plasma protein on the membrane was determined by performing the same operation as in the measurement of albumin transmittance except that the ultrafiltration time was set to 240 minutes, followed by washing with physiological saline for 1 minute. did. Next, the hollow fiber membrane was chopped at intervals of about 5 mm, stirred in a physiological saline solution containing 1.0% sodium laurate, and the extracted plasma protein was quantified to calculate the protein adsorption amount per membrane weight. As the protein concentration, a BCA protein assay (Pierce) was used. As a positive control, P
A film containing no VP (obtained by immersing the film of Example 1 before γ-ray irradiation in sodium hypochlorite having an effective chlorine concentration of 1500 ppm for 2 days and then immersing in ethanol for 1 day) It was compared with the test sample.

[0046]

Example 1 Polysulfone (Amoco Engine)
ering Polymers P-1700) 1
8.0% by weight, polyvinylpyrrolidone (manufactured by BASF)
K90, weight average molecular weight 1,200,000) 4.3% by weight, N, N-dimethylacetamide 77.7% by weight
Into a homogeneous solution. Here, the mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-forming stock solution was 23.9% by weight. This film forming stock solution was kept at 60 ° C., and N, N-dimethylacetamide (30% by weight) and water (70%) were added.
The mixture was discharged from a spinning nozzle (double annular nozzle 0.1 mm-0.2 mm-0.3 mm) together with an internal solution composed of a mixed solution of 0.1% by weight and passed through a 0.96 m air gap.
It was immersed in a coagulation bath consisting of 5 ° C. water. At this time, the space from the spinneret to the coagulation bath is surrounded by a cylindrical tube, and while flowing nitrogen gas containing water vapor into the tube, the humidity in the tube is 54.5%,
The temperature was controlled at 51 ° C. The spinning speed was fixed at 80 m / min. Here, the ratio of the air gap to the spinning speed was 0.012 m / (m / min). The water permeability, albumin transmittance and PVP transmittance of the obtained wet membrane were as shown in Table 1.

After the wound yarn bundle was cut, the remaining solvent in the film was removed by washing with a hot water shower at 80 ° C. for 2 hours from above the cut surface of the bundle. This film is further heated at 87 ° C.
For 7 hours to obtain a dried film having a water content of less than 1%. Further, 2.5 Mra was added to the obtained dried film.
By irradiating the gamma ray of d, a part of PVP in the film was insolubilized. This film had a sponge structure in which the pore size was continuously reduced from the outer surface of the film to the dense layer on the inner surface without containing a defect portion of the polymer having a size exceeding 10 μm inside the film. The thickness of the dense layer on the inner surface was about 10 μm. Table 1 shows the performance of the dried film.

When this membrane was used as a module having an effective filtration area of 1.5 m ² , the clearance of β2-microglobulin was measured and found to be 32 mL / min.
It became clear that the clearance was equivalent to 32.5 mL / min calculated by substituting the transmittance of P into the equation (5).
Further, when the permeation of urea and vitamin B12 was measured by the module, the clearance and permeation rate of urea were 185 mL / min and 83%, respectively. Similarly, vitamin B12 was 95 mL / min and 48%. The measurement is

The procedure was performed in the same manner as described above. Also, all P in the film
62% of the VP amount was insoluble in water.

As a result of an eluate test on the membrane, the absorbance of the eluate test solution was 0.04 or less. Further, since no pore retaining agent was used, the membrane pore retaining agent was not contained in the eluate test solution. Further, this membrane has a lower platelet adhesion amount than the positive control membrane (43.4 Unit of the positive control membrane).
/ M ² ), and the adhesion of plasma proteins was also low (positive control membrane 62.5 mg / g). From the performances described above, it was clarified that this membrane had a very small amount of elution from the membrane and little adhesion of blood proteins and platelets. In addition, the albumin transmittance is low and β2
-It was found that the membrane was excellent in dialysis performance because of excellent microglobulin clearance.

[0050]

Example 2 The same operation as in Example 1 was carried out except that polyvinylpyrrolidone was 4% by weight and N, N-dimethylacetamide was 78% by weight. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-forming stock solution was 22.2% by weight. Table 1 shows the performance of this membrane together with the performance of the wet membrane before drying. This membrane
It was revealed that the amount of elution from the membrane was extremely small, and the adhesion of blood proteins and platelets was small. Further, it was suggested that the membrane had a low albumin permeability and a good clearance of β2-microglobulin, and thus the membrane was excellent in dialysis performance.

[0051]

Example 3 Polyvinylpyrrolidone in a film forming solution was added to 4.
The same operation as in Example 1 was performed except that 8% by weight and N, N-dimethylacetamide were 77.2% by weight. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-forming stock solution was 26.7% by weight. Table 1 shows the performance of this membrane together with the performance of the wet membrane before drying. It was revealed that this membrane had a very small amount of elution from the membrane and little adhesion of blood proteins and platelets. Further, it was suggested that the membrane had a low albumin permeability and a good clearance of β2-microglobulin, and thus the membrane was excellent in dialysis performance.

[0052]

Example 4 N, N-dimethylacetamide 5
The same operation as in Example 3 was performed except that a mixed solution consisting of 2% by weight and 48% by weight of water was used. Table 1 shows the performance of this membrane together with the performance of the wet membrane before drying. It was revealed that this membrane had a very small amount of elution from the membrane and little adhesion of blood proteins and platelets. Further, it was suggested that the membrane had a low albumin permeability and a good clearance of β2-microglobulin, and thus the membrane was excellent in dialysis performance.

[0053]

Comparative Example 1 The same operation as in Example 1 was performed except that no γ-ray irradiation was performed. Table 2 shows the results. It became clear that the absorbance of the dissolution test solution exceeded 0.04 due to the dissolution of PVP.

[0054]

Comparative Example 2 Polyvinylpyrrolidone in a film forming stock solution was used
The same operation as in Example 1 was performed, except that 0% by weight and N, N-dimethylacetamide were 77.0% by weight. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-forming stock solution was 27.8% by weight. Table 2 shows the performance of this film. Since the mixing ratio of polyvinylpyrrolidone to polysulfone in the stock solution for film formation exceeds 27% by weight, the elution amount and the concentration of PVP on the inner surface of the film are increased.

[0055]

Comparative Example 3 Polyvinylpyrrolidone in a stock solution was used
The same operation as in Example 1 was performed except that 6% by weight and N, N-dimethylacetamide were 78.4% by weight. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-forming stock solution was 20.0% by weight. Table 2 shows the performance of this film. It became clear that the amount of PVP on the inner surface of the film was less than 30%.

[0056]

Comparative Example 4 N, N-dimethylacetamide 6
The same operation as in Example 3 was performed except that a mixed solution consisting of 0% by weight and 40% by weight of water was used. Table 2 shows the performance of this film. This membrane had a permeation rate of albumin exceeding 0.3% and a permeation rate of PVP exceeding 75%.

[0057]

Comparative Example 5 N, N-dimethylacetamide 1 in the internal solution
The same operation as in Example 1 was performed except that a mixed solution consisting of 0% by weight and 90% by weight of water was used. Table 2 shows the performance of this film. Pure water permeability is 10 mL / (m ² · hr · m
mHg).

[0058]

Comparative Example 6 The same operation as in Example 1 was performed except that the drying temperature was 170 ° C. Table 2 shows the performance of this film.
In this membrane, all PVP in the membrane was insoluble in water. This membrane is made into a module with an effective filtration area of 1.5 m ²

When clinical blood was evaluated by the method shown in
Leukopenia symptoms, in which the white blood cell count of dialysis patients temporarily decreased, were observed.

[0059]

[Table 1]

[0060]

[Table 2]

[0061]

EFFECTS OF THE INVENTION The membrane obtained by the production method of the present invention has an extremely small amount of elution from the membrane and has excellent dialysis performance with little adhesion of blood proteins and platelets. Can be used for industrial applications.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁷ , DB name) B01D 67/00-71/82

Claims (5)

(57) [Claims] 1. A membrane containing no pore retaining agent and having a water permeability of 1
In ^{00mL / (m 2 · hr ·} mmHg) or more, beyond the polyvinylpyrrolidone transmittance 75% of the weight-average molecular weight of 40,000, is and transmittance of albumin in bovine blood plasma system is 0.3% or more, polysulfone Polymer and po
Characterized in that the wet film made of vinyl pyrrolidone is dried at a temperature of 120 ° C. or less, (a) the pore size is continuous from the outer surface of the film to the inner surface dense layer.
It consists-sustaining small sponge structure, water permeability (b) pure water ^{10mL / (m 2 · hr ·} mmH
g) or more; (c) polyvinylpyrroli having a weight average molecular weight of 40,000
Don transmittance of 75% or less, (d) transmission of albumin in bovine blood plasma system is 0.3%
Less than a and, (e) absorbance der less than 0.04 of the eluate test liquid film
And the eluate test solution does not contain a pore retaining agent, and (f) a polysulfone-based polymer and polyvinylpyrrolidone
Of polyvinylpyrrolidone on the inner surface of the membrane.
A method for producing a hollow fiber blood purification membrane having a degree of 30 to 45% by weight . 2. A method for producing a hollow fiber membrane in which a stock solution and an internal solution are discharged from a double annular nozzle and then passed through an air gap and then coagulated in a coagulation bath. 0.01 to 0.1 m / (m /
2. The method for producing a wet film according to claim 1, wherein 3. The film forming stock solution is a polysulfone polymer,
It comprises polyvinylpyrrolidone and a solvent, and the ratio of polyvinylpyrrolidone to polysulfone-based polymer is 1
The method according to claim 1 or 2, wherein the content is 8 to 27% by weight. 4. The method according to claim 1, wherein irradiation is performed after drying. 5. The hollow fiber blood purification membrane according to claim 1, comprising polyvinyl pyrrolidone insoluble in water.
5. The method for producing a blood purification membrane according to any one of items 1 to 4.