JP3281363B1 - Blood purification membrane - Google Patents

Abstract

【wrap up】 PROBLEM TO BE SOLVED: To provide an extremely small amount of elution from a membrane,
Excellent dialysis performance with little adhesion of proteins and platelets
To provide a high performance blood purification membrane. SOLUTION: The membrane does not contain a pore retaining agent and has a permeability of pure water of 1
00mL / (m^Two・ Hr ・ mmHg) or more, weight average
The transmittance of polyvinylpyrrolidone with a molecular weight of 40,000
Albumin penetration above 75% and in bovine plasma system
A wet film having a rate of 0.3% or more at a temperature of 120 ° C. or less
Drying free of membrane pore retainer obtained by drying
A membrane having pores extending from the outer surface of the membrane to the inner surface dense layer.
Consisting of a sponge structure with a continuously decreasing diameter, pure water
Water permeability is 10 to 1000 mL / (m ^Two・ Hr ・ mmH
g), polyvinylpyrroli having a weight average molecular weight of 40,000
Don permeability is less than 75% and bovine plasma albumin
Hollow fiber shape having transmittance of 0.3% or less
Blood purification membrane.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a high-performance blood purification membrane having an extremely small amount of elution from the membrane and 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 hemodialysis performance is not shown 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 and the like are hardly attached to the filtrate, it is difficult for the filtrate speed to change with time, but there is no description about dialysis performance such as low albumin permeability.

[0010]

SUMMARY OF THE INVENTION 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 excellent dialysis performance with little adhesion of blood proteins and platelets.

[0011]

As described above, there has been no blood purification membrane having dialysis performance that has been dried without using a pore retaining agent that causes eluted substances 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. In other words, the membrane pore-preserving agent prevents the performance of the membrane from deteriorating due to drying, and if the membrane-pore retaining agent is not used, the water permeation performance is extremely reduced to such an extent that the water permeability cannot be obtained. It has not been possible to dry without using a pore-holding agent in a method for producing a membrane having the same. Therefore, the present inventors have previously prepared a wet membrane having a specific performance with a high water permeability and a large pore diameter than the target performance, and then drying and shrinking the wet membrane to obtain a membrane having the target performance. As a result of intensive research based on an unprecedented idea of manufacturing, a membrane with extremely low eluate, little adhesion of blood proteins and platelets, and excellent dialysis performance is obtained. This has led to 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 dried membrane not containing a pore holding agent obtained by drying a wet membrane made of pyrrolidone at a temperature of 120 ° C. or lower, wherein (a) the pore diameter increases from the outer surface of the membrane toward the inner surface dense layer. (B) pure water permeability is 10 to 1000 mL / (m ² ·
hr.mmHg), (c) the permeability of polyvinylpyrrolidone having a weight average molecular weight of 40,000 is 75% or less, and (d) the permeability of albumin in bovine plasma system is 0.3%.
(E) the absorbance of the eluate test solution of the membrane is less than 0.04.
And (f) a polysulfone-based polymer and polyvinylpyrrolid without a pore retention agent in the eluate test solution.
Of polyvinylpyrrolidone on the inner surface of the membrane
The present invention relates to a hollow fiber-shaped blood purification membrane characterized by having a concentration of 30 to 45% by weight , and (2) the blood purification membrane of the above (1), which comprises polyvinyl pyrrolidone which is insoluble in water. is there.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The structure of a hollow fiber blood purification membrane of the present invention (hereinafter, also simply referred to as “membrane” or “hollow fiber membrane”) will be described below. The membrane of the present invention is a dry membrane that does not contain a pore retaining agent, and has a sponge structure in which the pore size decreases continuously from the outer surface of the membrane toward the inner surface dense layer.

The hollow fiber membrane of the present invention has an integral and continuous structure from one surface to the other surface of the membrane, for example, from the inner surface to the outer surface. Between the outer surface of the membrane and the dense layer on the inner surface, that is, the inside of the membrane has a network structure having a mesh size (pores) of 10 μm or less, and a void having a size of more than 10 μm (a defective portion of the polymer). , Huge pores). This structure is called a sponge structure in the present invention. In the present invention, the dense layer is a layer having a small void portion, that is, a hole of a polymer constituting the film in a cross section in the film thickness direction, and contributing to the fractionation performance of the film.

The pores having a network structure inside the membrane have an inclined structure in which the pore diameter decreases continuously from the outer surface of the membrane toward the dense inner surface layer in a cross section perpendicular to the longitudinal direction of the membrane. In other words, when considering several cylindrical surfaces concentric with the central axis extending in the length direction of the hollow fiber membrane, the average pore diameter of the pores on each surface increases from the outer surface of the membrane to the inner surface dense layer. It is getting smaller continuously. When blood is brought into contact with the inner surface side of the membrane, it is impossible to have a sharp fractionation performance unless the membrane has an inclined structure in which the pore diameter decreases continuously from the outer surface of the membrane toward the dense inner surface layer.

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 a 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. However, it has been reported that various derivatives formed by a chemical reaction with the pore holding agent are problematic due to the presence of a small amount of the pore holding agent in the membrane and / or the module filling solution. Does not use this membrane pore preservative in the production process, so there is no eluate derived from the membrane pore preservative.

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 alkaline dissolution test described above, heat at 70 ± 5 ° C for 1 hour, remove the film after cooling, add distilled water, and add 150 mL
Means that 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 specifies that the absorbance be 0.1 or less, the membrane of the present invention can achieve a value of less than 0.04 because it does not hold a pore-holding agent. Further, regarding the presence or absence of a pore retaining agent, the test solution obtained by concentrating or removing water is subjected to gas chromatography, liquid chromatography, a differential refractometer, an ultraviolet spectrophotometer, an infrared absorption spectrophotometer, a nuclear magnetic resonance spectroscopy, And by a known method such as elemental analysis. Further, whether or not the membrane contains a pore holding agent can be detected by these measuring methods.

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.

The membrane of the present invention comprises a polysulfone polymer and polyvinylpyrrolidone, and the concentration of polyvinylpyrrolidone on the inner surface of the membrane is 30 to 45% by weight. An important factor for the blood compatibility of a membrane is the hydrophilicity of the inner surface of the membrane with which blood comes into contact, and polyvinylpyrrolidone (hereinafter simply referred to as “PV”).
P), the PVP concentration on the inner surface of the film is important. 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, PVP on the inner surface of the membrane
If the concentration is too high, the amount of PVP eluted into the blood system increases, 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 3
It is in the range of 0 to 45%, preferably 33 to 40%.

Examples of the polysulfone polymer used in the present invention include those having a repeating unit represented by the following formula (1) or (2). 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- (1) -O-Ar-SO 2 -Ar- (2)

The PVP concentration on the inner surface of the film is determined by an X-ray photoelectron 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. Can be obtained by calculation according to equation (3). PVP concentration (% by weight) = C ₁ M ₁ × 100 / (C ₁ M ₁ + C ₂ M ₂ ) (3) where C ₁ : nitrogen atom concentration (%) C ₂ : sulfur atom concentration (%) M ₁ : Molecular weight of repeating unit of PVP (111) M ₂ : molecular weight of repeating unit of polysulfone polymer (442)

The membrane of the present invention has a water permeability of pure water of 10
~ 1000mL / (m^Two・ Hr ・ mmHg)
15-1000 mL / (m^Two・ Hr ・ mmH
g). 10 mL / (m^Two・ Hr ・ mmHg)
In this case, the water removal capacity during dialysis is inferior, which is not preferable. This
This means that even if the membrane of the present invention is a dry membrane, it has good water permeability.
It shows that it has. In addition, pure water permeability is 1
0 to 1000 mL / (m ^Two・ Hr ・ mmHg)
It is difficult to reduce the transmittance of albumin to less than 0.3%.
This tends to be difficult and is not preferred.

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 has a permeability of bovine plasma albumin of 0.3% 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.

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) (4)

The pure water permeation amount 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 represented by a linear function represented by the following equation (5). 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 (5)

Here, the clearance of β2-microglobulin is determined by setting the module having an effective membrane area of 1.5 m ² to a blood flow rate of 200 mL / min (inside of the membrane surface) and a dialysate flow rate of 50 mL / min.
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. β2-
Various clearances of microglobulin are required according to the physical strength and disease state of the dialysis patient and the degree of progression of the disease state. When the permeability of polyvinylpyrrolidone exceeds 75%, the permeability of albumin becomes 0.3%. Therefore, the transmittance of polyvinylpyrrolidone needs to be 75% or less.

The permeation rate of polyvinylpyrrolidone was determined by adding 3% by weight of polyvinyl pyrrolidone (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.

Hereinafter, representative examples of the method for producing the film of the present invention will be described. The membrane of the present invention is prepared in advance by preparing a wet membrane having a high water permeability and a large pore diameter, desolvating, and then drying to reduce the pore diameter of the wet membrane, and furthermore, PVP in the membrane.
Is made insoluble in water to reduce the pore size from the wet membrane. The wet membrane is formed by discharging a stock solution comprising a polysulfone-based polymer (hereinafter simply referred to as “polymer”), polyvinylpyrrolidone, and a solvent from a double annular nozzle together with an internal solution, passing through an air gap, and then coagulating a bath. In the production method of coagulation, the aqueous solution of the polymer solvent can be used 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 of the target performance is obtained by drying and shrinking the wet membrane, the solvent concentration in the internal solution is set to a higher concentration than when the wet membrane having the target dialysis performance is manufactured. Need to be

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 · m
mHg) or more, meaning a wet membrane having a permeability of polyvinyl porolidone having a weight average molecular weight of 40,000 exceeding 75% and a permeability of albumin in bovine plasma system of 0.3% or more. . Since the higher the molecular weight of polyvinylpyrrolidone, the higher the effect of hydrophilizing the film, the smaller the molecular weight of polyvinylpyrrolidone, the more sufficient effect can be exhibited. Therefore,
In the present invention, it is preferable to use polyvinylpyrrolidone having a weight average molecular weight of 900,000 or more. 90
A large amount of polyvinylpyrrolidone needs to be left in the membrane in order to impart a hydrophilicity effect to the membrane using polyvinylpyrrolidone having a weight average molecular weight smaller than 0000. Will increase. Conversely, 900,00 to reduce the eluate
If the residual amount of polyvinylpyrrolidone having a weight average molecular weight smaller than 0 in the membrane is reduced, the hydrophilizing effect becomes insufficient, and as a result, the filtration rate decreases with time when hemodialysis is performed. I can't show it.

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 membrane-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.

What is more important is the amount of polyvinylpyrrolidone to be added. The mixing ratio of polyvinylpyrrolidone to the polymer is 27% by weight or less, preferably 18 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 elution amount tends to increase.
If the amount is less than 10% by weight, the PVP concentration on the inner surface of the membrane decreases, and the leukopenia symptom in which the leukocyte concentration in the blood of the patient rapidly decreases is not preferable. For the purpose of controlling the viscosity of the stock solution and the dissolution state, a fourth component such as water or a poor solvent can be added, and the type and amount of addition may be determined as needed depending on the combination.

[0033] 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 is a series of processes for 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.
° C, more preferably 0-80 ° 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 the PVP in the membrane is insolubilized, the amount of elution can be further reduced, but it is not preferable since leukopenia symptoms are observed during dialysis.

In the present invention, PVP which is insoluble in water 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.

The amount of PVP soluble in water can be determined by the following method. The membrane was N-methyl-2-
After complete dissolution with pyrrolidone, water is added to the resulting 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.

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.

[0043]

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 cutting the wound yarn bundle, 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 and the clearance of β2-microglobulin was measured, it was 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.

[0047]

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.

[0048]

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.

[0049]

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.

[0050]

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.

[0051]

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.

[0052]

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%.

[0053]

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%.

[0054]

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).

[0055]

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.

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

EFFECT OF THE INVENTION The membrane 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, so that it can be used for pharmaceutical, medical and general industrial applications. it can.

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

Claims (2)

(57) [Claims] 1. A membrane containing no pore retaining agent and having a water permeability of 1
A polysulfone having a permeability of at least 00 mL / (m ² · hr · mmHg), polyvinyl pyrrolidone having a weight average molecular weight of 40,000 exceeding 75%, and a bovine plasma system having a permeability of albumin of 0.3% or more ; Polymer and po
A dry film containing no pore-holding agent obtained by drying a wet film made of ribyl pyrrolidone at a temperature of 120 ° C. or less, wherein (a) from the outer surface of the film to the inner surface dense layer It has a sponge structure in which the pore diameter is continuously reduced, and (b) the permeability of pure water is 10 to 1000 mL / (m ² ·
hr.mmHg), (c) the permeability of polyvinylpyrrolidone having a weight average molecular weight of 40,000 is 75% or less, and (d) the permeability of albumin in bovine plasma system is 0.3%.
(E) the absorbance of the eluate test solution of the membrane is less than 0.04.
And (f) a polysulfone-based polymer and polyvinylpyrrolid without a pore retention agent in the eluate test solution.
Of polyvinylpyrrolidone on the inner surface of the membrane
A hollow fiber-shaped blood purification membrane having a concentration of 30 to 45% by weight . 2. The blood purification membrane according to claim 1, further comprising polyvinylpyrrolidone which is insoluble in water.