JPH10108907A - Membrane for hemocatharsis, its preparation and module for hemocatharsis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a membrane for hemocatharsis which can be used for not only ordinary hemodialysis but also a medical treatment for removing a large amt. of water such as hemodialysis filtration and hemofiltration in medical treatment of chronic renal failure and can perform stable removal of water with time when a large amt. of water is removed and can efficiently remove uremic substances, and also provide a method for preparing the membrane for hemocatharsis and a module for hemocatharsis using the membrane for hemocatharsis. SOLUTION: This membrane for hemocatharsis has a film thickness of 10-50μm, an inner diameter of 100-300μm, a pore factor of 50-85%, a water permeability of 100-500ml/m<2> .Hr.mmHg at 37 deg.C, and a screening factor to albumin of 0.04-0.5 when 5wt.% albumin soln. prepd. by dissolving albumin with a buffer soln. of pH7.4 is used. A module for hemocatharsis is obtd. by using this membrane for hemocatharsis. This can effectively and stably be used for medical treatment of chronic renal failure, etc., wherein the removal of a large amt. of water is required and can exhibit an enormous therapeutic effect.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a blood purification membrane used for hemodialysis and the like, a method for producing the blood purification membrane, and
The present invention relates to a blood purification module using the blood purification membrane.
More specifically, when used for the treatment of chronic renal failure, not only normal hemodialysis, but also hemodiafiltration and hemofiltration, a large amount of water can be stably removed over time. -A blood purification membrane suitable for mass dehydration therapy, capable of dialyzing / filtering out uremic substances such as microglobulin, a method for producing the blood purification membrane, and a blood purification membrane using the blood purification membrane About the module.

[0002]

2. Description of the Related Art Conventionally, hemodialysis has been mainly used as a maintenance treatment for patients with chronic renal failure. However, hemodialysis removes causative substances of uremia by diffusion alone, and thus is excellent in removing small molecular weight substances such as urea. However, it is not sufficient to remove low molecular weight proteins having a molecular weight of 10,000 or more. Therefore, complications such as dialysis amyloidosis and pain cannot be avoided, and the pain of the patient has increased. Under these circumstances, recently, in order to positively remove low-molecular-weight proteins having a molecular weight of 10,000 or more, which are considered to be the causative substances of the complications, filtration flow rates such as blood filtration (hereinafter, HF) and hemodiafiltration (hereinafter, HDF) have been proposed. He is interested in the blood purification method.

[0003] High ultrafiltration rates are required to enable high filtration flow rates. Factors that affect the ultrafiltration rate include the protein concentration in blood and the value of hematocrit, as well as blood flow as a controllable factor. Since the ultrafiltration rate can be increased by increasing the blood flow rate, the blood flow rate is often increased in HF and HDF more than usual (250 to 400 ml / min, usually 200 ml / min). However, the elderly and small-sized patients generally have small blood vessels, and the blood flow obtained is limited to 200 ml / min.
It is about 0 ml / min. In these patients, when performing HF or HDF, which filters a large amount of blood, it is necessary to extend the treatment time because the obtained ultrafiltration rate is small.
Alternatively, the required amount of filtration had to be abandoned. Therefore, depending on the treatment, the restraint time may be prolonged or a sufficient therapeutic effect may not be obtained, which has been a problem.

When blood is filtered, blood contains blood cell components and proteins, which may cause clogging of the membrane, adsorption of proteins on the membrane surface, and formation of a gel layer of the blood. A polarized protein layer at the lateral membrane, a so-called secondary layer, is formed. As described above, when the filtration flow rate at the time of blood filtration is increased, clogging occurs, conversely, solute removal performance is reduced, and since a secondary layer is formed, the filtration flow rate cannot be increased. There are also problems.

Various proposals have been made to solve the above problems. For example, JP-A-7-8767 and JP-A-7-24275 describe a cellulose triacetate hollow fiber membrane having a high water permeation rate and an excellent fractionation molecular weight characteristic. These hollow fiber membranes have a molecular weight of 10,000.
The fractionation properties of 00 and 70,000 dextran are indeed excellent. However, as described above, when blood is actually flowed, protein adsorption onto the membrane surface or a gel layer thereof is formed, and the fractionation characteristics of the blood system are generally different from those of the aqueous system. Know that it will be. That is,
Although these membranes have excellent dextran fractionation properties in aqueous systems, their clinical fractionation properties in blood are unknown, and these membranes are clinically effective against uremic substances such as β2-microglobulin. It is unclear whether it will exhibit excellent removal performance or removal stability over time.

Japanese Patent Application Laid-Open No. 1-94902 describes a polysulfone asymmetric hollow fiber membrane having excellent dialysis performance and little deterioration with time of filtration speed during long-term use. However, since the membrane removes β2-microglobulin (hereinafter, β2-MG) in blood by adsorption to the membrane (claim 1 on page 1, claim 2 on page 1, lower left column on page 5, line 3) To eleventh
Line), there is a limit value of the amount of β2-MG that can be removed by the membrane, namely, the amount of adsorption saturation. Further, even if β2-MG can be removed, the performance of removing toxic substances (uremic substances) having a molecular weight of thousands to tens of thousands other than β2-MG is unknown, and it is said that such harmful substances are sufficiently removed. I can't say.

Japanese Patent Publication No. 54373/1993 describes an asymmetric hollow fiber membrane for blood treatment having excellent solute permeability. Although the membrane has excellent dialysis removal performance and clearance even at a high filtration flow rate, it has been shown that the clearance of even low molecular substances such as urea is lower at the end of dialysis than at the start of dialysis ( First
It is not considered that harmful substances of low molecular weight proteins such as β2-MG can be stably removed.

[0008] As described above, a blood purification membrane capable of effectively removing uremic substances such as β2-MG with a stable filtration rate over time during large-volume water removal therapy such as hemodiafiltration has not yet been obtained. At present, the effect has not been satisfactory even if treated with HF or HDF.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above problems. That is, an object of the present invention is to obtain a high ultrafiltration rate without increasing the blood flow rate, and to exhibit a stable and excellent solute removal performance even at a high ultrafiltration rate, and to remove a large amount of HDF or HF. An object of the present invention is to provide a blood purification membrane capable of efficiently removing harmful low molecular proteins such as β2-MG during hydrotherapy, a method for producing the blood purification membrane, and a blood purification module using the blood purification membrane.

In order to solve the above-mentioned problems, the present inventors have conducted intensive studies on the relationship between the membrane structure of the blood purification membrane, clogging of the membrane during blood processing, and the so-called secondary layer. By setting the water permeability of the membrane and the sieving coefficient of the 5% aqueous albumin solution to an appropriate size within a certain range, clogging of the membrane and generation of a polarized protein layer at the blood lateral membrane can be achieved. It was found that the ultrafiltration rate and the solute separation performance became stable over time.

With respect to the above, the physical structure of the film should be originally specified, but observation with an electron microscope is also limited, and at present the exact structure cannot be grasped. However, the present inventors set the pore size of the membrane to a certain size by setting the water permeability of the membrane to a certain size, and then set the sieving coefficient of the 5% aqueous albumin solution to a certain size on the basis of the above-mentioned pore size. It is assumed that the distribution will be set more uniformly.

Furthermore, it has been found that by improving the smoothness of the membrane surface, the fractionation performance in blood and its stability over time are further improved.

It is extremely difficult to accurately and objectively quantify the degree of smoothness of the film surface as described above at the current level of science and technology. Therefore, in the present invention, the fact that the film surface is smooth means that there are no pores clearly observed on the film surface when observing the film surface with a 5000 × electron microscope. Here, the magnification of the electron microscope is set to 5000 times because if the magnification is higher than this, the polymer constituting the film may be melted by the heat generated by the electron microscope.

Further, as described above, it is extremely difficult to quantitatively grasp such membrane structures in the current science and technology. Therefore, in the present invention, these are inevitably used as characteristic values, β2-microglobulin retention rate, It was expressed by the retention rate of the filtration rate.

Further, the present inventors have proposed that when the above-mentioned blood purification membrane is a hollow fiber membrane, in a dry-wet spinning method using a gas as a hollow-forming agent, the temperature of the gas is made higher than the temperature of the coagulable liquid. By doing so, it has been found that a hollow fiber membrane having high smoothness on the inner surface of the hollow fiber membrane can be obtained. Although the cause of this is also not clear, by increasing the temperature of the gas supplied to the center of the hollow fiber membrane and performing dry-wet spinning, the solvent in the spinning solution near the inner surface of the hollow fiber membrane evaporates to some extent, Coagulation of the film will proceed, and the difference between the temperature of the coagulating liquid and the temperature of the gas will cause a more rapid coagulation, so that the pores formed in the film will be smaller within the above-mentioned smooth range. Further, it is considered that the hole is uniform and the irregularity of the shape of the hole is reduced.

In the process of spinning the hollow fiber membrane,
It is considered that by adding glycerin as a non-solvent to the spinning dope, the distribution of the dissolved polymer becomes more uniform, and the pore size of the formed membrane becomes more uniform.

The present inventors have conducted further studies based on such findings, and as a result, have completed the present invention.

[0018]

That is, the present invention relates to a blood purification membrane having a thickness of 10 to 50 μm, an inner diameter of 100 to 300 μm, and a porosity of 50 to 85%. Water permeability of 100 to 500 ml / m ² · Hr · mmHg
And 5% by weight dissolved in a buffer of pH 7.4
A blood purification membrane characterized by having a sieving coefficient for albumin of 0.04 to 0.5 when the albumin solution of (1) is used.

In a preferred embodiment, when the membrane surface of the blood purification membrane is observed with an electron microscope at 5000 times,
There are no apparent holes.

In a preferred embodiment, the module filled with the blood purification membrane has a hematocrit of 25 to 30.
%, Bovine blood with a protein concentration of 6-7 g / dl and a flow rate of 200 m
The ratio of the ultrafiltration rate at 5 hours after the start of filtration to the ultrafiltration rate at 10 minutes after the start of filtration when blood was filtered at a flow rate of 20 ml / min at a flow rate of 1 / min was 80. % Or more.

In a preferred embodiment, the module filled with the blood purification membrane has a hematocrit of 25 to 30.
%, Bovine blood with a protein concentration of 6-7 g / dl and a flow rate of 200 m
1 / min, and blood filtration at a filtration flow rate of 20 ml / min, with respect to the sieving coefficient of β2-microglobulin at 10 minutes after the start of filtration, relative to the sieving coefficient of β2-microglobulin at 5 hours after the start of filtration. The ratio of the sieving coefficients is 80% or more.

In a preferred embodiment, the module filled with the blood purification membrane has a hematocrit of 25 to 30.
%, Bovine blood with a protein concentration of 6-7 g / dl and a flow rate of 200 m
The sieving coefficient of β2-microglobulin is 0.4 or more when blood is filtered at a flow rate of 20 ml / min at a flow rate of 1 / min.

In a preferred embodiment, the blood purification membrane contains a cellulosic polymer.

In the present invention, the spinning dope is extruded from the outside of the double tube cap, and a gas is fed from the center of the double pipe cap as a hollow part forming agent. A method for producing a blood purification membrane by a dry-wet spinning method, which coagulates through a coagulable liquid, wherein the temperature of the gas is higher than the temperature of the coagulable liquid by 20 ° C. or more. Is provided.

In a preferred embodiment, the spinning solution contains glycerin as a non-solvent.

Further, the present invention provides a blood purification module characterized in that the blood purification membrane is filled so as to have a filling rate of 40 to 80% and a membrane area of 0.9 to ^2.5 m ^2. It is.

Hereinafter, the present invention will be described in detail.

The thickness of the blood purification membrane of the present invention is 10 to 50 μm.
m. When the film thickness is less than 10 μm, the strength of the blood purification film is reduced, and it is difficult to keep the film thickness constant, so that productivity is significantly reduced. On the other hand, if the film thickness exceeds 50 μm, the phase separation state at the time of film formation is not uniform, so that the smoothness of the inner surface of the film cannot be maintained. It causes the resistance to rise. This is because, in particular, in the case of a large amount of water removal therapy, the degree of reduction of the ultrafiltration rate over time increases, and it becomes difficult to maintain high dialysis and filtration performance. The preferred film thickness is 1
5 to 40 μm.

The porosity of the blood purification membrane of the present invention is 50% to 8%.
5%. If the porosity is less than 50%, sufficient solute removal performance cannot be obtained, and the film is not suitable for blood purification. If the porosity exceeds 85%, the strength of the blood purification membrane decreases. This is because productivity decreases. In addition, the porosity is determined by washing the blood purification membrane with water for 1 to 2 hours, and then water attached to the surface of the blood purification membrane (however, in the case of a hollow fiber type blood purification membrane, the water attached to the outer surface and the core) After removing the remaining water), the weight is measured (weight A), and after absolute drying at 105 ° C., the weight is measured (weight B) and calculated by the following equation. Porosity = (weight A−weight B) / ｛(weight A−weight B) +
(Weight B / ρ)｝ 100% where ρ is the specific gravity of the polymer

The inner diameter of the hollow fiber type blood purification membrane of the present invention is 10
It is 0 μm to 300 μm. When the inner diameter is less than 100 μm, the pressure loss when flowing the blood becomes large, which may damage the blood and cause hemolysis, and may cause the blood to coagulate and form a thrombus in the hollow portion, which is preferable. Absent. When the inner diameter exceeds 300 μm, the hollow portion becomes too large, it is difficult to maintain the hollow shape, and the productivity is reduced. In addition, the shear rate on the inner surface of the hollow fiber membrane decreases, and proteins and the like are more likely to be deposited on the inner surface of the membrane during filtration. The preferred inner diameter is between 120 and 250 μm.

The water permeability of the blood purification membrane of the present invention at 37 ° C. is 100 to 500 ml / m ² · mmHg · hr. When the water permeability is less than 100 ml / m ² · mmHg · hr, the water permeability at the time of flowing blood is not sufficient, it is difficult to remove a large amount of water, and the pore diameter of the membrane is small. -Insufficient removal rate of uremic substances such as microglobulin. Water permeability is 500ml / m ² · mmHg · hr
If it exceeds, the pore size of the membrane becomes too large and albumin is lost during blood purification. Preferred water permeability of pure water is 200 to 500 ml / m ² · mmHg · hr. Within this range, the pore size of the membrane is also appropriate,
This is because better spinning of the hollow fiber membrane is possible. The method for measuring the water permeability of this pure water is as follows.
Water at 37 ° C. is passed through the module filled with the hollow fiber membrane at a differential pressure of 100 mmHg for 1 minute, and the filtration flow rate is measured. Water permeability = Q (ml / min) × 60 (min / hr) ÷ (A (m ² ) × 100
(mmHg)) Q: Filtration flow rate (ml / min) A: Total membrane surface area (m ² )

The sieving coefficient for albumin when using a 5% by weight albumin solution of the blood purification membrane of the present invention dissolved in a pH 7.4 buffer is 0.04 to 0.5.
When the sieving coefficient of albumin is less than 0.04, β2-microglobulin (hereinafter, referred to as “blood-purifying”) is used for actual blood purification.
The removal amount of uremic substances such as β2-MG) is insufficient. If the sieving coefficient for albumin exceeds 0.5,
Albumin necessary for the human body will be lost during blood purification. In the present application, the sieving coefficient for albumin relates to a 5% by weight aqueous solution of albumin, and the sieving coefficient for albumin when blood purification is actually performed is affected by the protein secondary layer formed during blood purification. , Of course, very low. That is, in the module using the blood purification membrane of the present invention, for example, the amount of protein leaked in a single blood purification process of removing about 10 l of water is 5 g or less. The preferred sieving coefficient for albumin is 0.05-0.4.

When the membrane surface of the blood purification membrane of the present invention is observed with an electron microscope at 5,000 times, there are no clearly recognized pores, and the membrane surface of the blood purification membrane of the present invention has a substantially smooth structure. is there. It is particularly important that the surface on the side that comes into contact with blood be smooth without causing clogging of proteins and the like at the time of blood filtration, and to obtain high filtration performance that is stable over time. In the case where the surface of the membrane has a curved structure such as a hollow fiber membrane, observation using an atomic force microscope is substantially difficult, and it is practical to observe with a SEM at the blood purification membrane level. Evaluation method. Therefore, in this case, the fact that the film surface has a smooth structure is clearly recognized on the surface when the film is washed with water, freeze-dried to maintain the film structure, and observed with a 5000 × electron microscope. No holes are present. Furthermore, the fact that there are no pores that are clearly observed when observed with an electron microscope at 5000 times
It means that there is no hole having a diameter of 0.2 mm or more, that is, a hole having a diameter of 400 Å or more on the inner surface in a double magnification photograph.

It is preferable that the inside of the blood purification membrane of the present invention has a substantially uniform structure. When the inside of the film has a non-uniform structure, the separation by the film is performed only on the film surface.If a partial defect or fluctuation at the time of separation occurs on the film surface, the film Clogging is likely to progress at the center, and particularly when filtering blood containing a large amount of blood cells or proteins, the influence of these components on clogging becomes very large. On the other hand, since a uniform membrane supports filtration in the entire membrane, even when there is a defect as described above in a part of the membrane surface, the entire membrane can cover such a defect and suppress the clogging as described above. . That is, when the membrane has a uniform structure, the entire internal structure of the membrane can support filtration and exhibit stable diafiltration performance. Here, the expression that the inside of the membrane has a substantially uniform structure means that the hollow fiber membrane does not have asymmetry in its radial direction and cross-sectional direction, and is not only radially symmetric but also substantially This means that a homogeneous porous structure is formed in the thickness portion of the film. Therefore, in the case of the blood purification membrane of the present invention, when washed with water, freeze-dried so as to maintain the membrane structure, and observed with a microscope, the cross-sectional structure of the membrane is a uniform structure in which a tissue such as a finger-like structure or a network structure is not observed. Means to be observed.

Further, when the film has a non-uniform structure,
For example, when the membrane is formed of a hydrophobic polymer and a hydrophilic polymer, the hydrophilic polymer in the membrane flows out from the large pores of the membrane, and changes in membrane performance and elutions from the membrane cause many problems. In some cases, when the membrane has a uniform structure, the hydrophilic polymer in the membrane is trapped in the membrane tissue and is firmly fixed, and the above-described problem does not occur. In addition, in the case of a nonuniform membrane having a large pore diameter outside the membrane, there is a risk that foreign substances may contaminate from the dialysate side, but there is an advantage that a uniform membrane does not have such a risk.

It should be noted that the uniform film as described above is
A bovine blood containing an anticoagulant added to a module having a membrane area of 1.5 m 2 filled with a hollow fiber at a filling rate of 55% is allowed to flow at a flow rate of 200 ml / min inside or outside the hollow fiber membrane.
It can also be confirmed from the fact that the ultrafiltration rate (ml / min · mmHg) per module when performing hemofiltration does not substantially differ between the inner and outer surfaces of the membrane. In the blood purification membrane of the present invention, the membrane surface on the dialysate side during the blood purification treatment also has a smooth structure, so that contamination from the dialysate side can be prevented, and the filtrate can be smoothly transferred to the dialysate.

The module filled with the blood purification membrane of the present invention has a hematocrit of 25 to 30% and a protein concentration of 6 to 7 g /
dl of bovine blood at a flow rate of 200 ml / min to perform blood filtration.
Β2-MG (molecular weight: 11,60) 10 minutes after the start of filtration
Β2-M 5 hours after the start of filtration for the sieving coefficient of 0)
The ratio of the sieving coefficient of G is 80% or more. This ratio is 80%
If it is less than 3, the removal rate of uremic substances having a molecular weight of thousands to tens of thousands such as β2-MG becomes insufficient. The preferred ratio is 90
% Or more.

The effect of the present invention on the protein concentration of bovine blood and the ultrafiltration rate of hematocrit used in the above-mentioned provisions is large. In the present invention, the performance evaluation of the membrane summarized by the Working Group of the High Performance Membrane Research Society was conducted. Method, the hematocrit value was 25% to 30% and the protein concentration was 6 to 7 g / dl.
It was determined with reference to the description that the blood was bovine blood at ° C.

The module filled with the blood purification membrane of the present invention has a hematocrit of 25 to 30% and a protein concentration of 6 to 7 g /
dl of bovine blood at a flow rate of 200 ml / min to perform blood filtration, β at a filtration rate of 20 ml / min
The sieving coefficient of 2-MG is preferably 0.4 or more.
If the sieving coefficient of β2-MG is less than 0.4, HF or HDF
This is because the treatment has a low removal efficiency of uremic substances having molecular weights of several thousands to tens of thousands including β2-MG, and a sufficient therapeutic effect cannot be obtained. More preferably, the sieving coefficient of β2-MG is 0.5 or more.

The module filled with the blood purification membrane of the present invention has a hematocrit of 25 to 30% and a protein concentration of 6 to 7 g /
When dl bovine blood is flowed at a flow rate of 200 ml / min and the filtration rate is 20 ml / min, the ultrafiltration rate at 5 hours after the start of blood filtration is compared with the ultrafiltration rate at 10 minutes after the start of blood filtration. Is 80% or more. If the ratio is less than 80%, the filtration efficiency is largely reduced due to clogging, and the removal efficiency is reduced.

The material of the blood purification membrane of the present invention is not particularly limited, and examples thereof include cellulose polymers, polysulfone polymers, polyamide polymers, polymethyl methacrylate, polyacrylonitrile, and vinyl alcohol-ethylene copolymer. Although it can be used, from the suitability as an artificial blood purification membrane cellulosic polymer,
Polysulfone polymers are more preferred. Examples of these polymers include cellulose acetate-based polymers such as cellulose acetate, cellulose triacetate, and cellulose, and polysulfone-based polymers include, for example, polysulfone, polyether sulfone, and polyaryl sulfone. Among these, cellulose triacetate is particularly preferable in terms of biocompatibility, that is, a good balance between hydrophilicity and hydrophobicity of the polymer, and in terms of water permeability, solute permeability, and stain characteristics. The degree of polymerization of the polymer is related to the surface smoothness of the obtained film.
If the reduction viscosity is 0.55 or more as a factor that changes the degree of polymerization in the case of polyether sulfone, the surface smoothness of the obtained film becomes better. When a polysulfone-based polymer is used as the polymer, the hydrophobicity of the material is high, and in order to increase the hydrophilicity of the entire membrane, polyvinylpyrrolidone or polyethylene glycol is blended as a hydrophilic polymer. Is preferably increased.

The method for producing the blood purification membrane of the present invention is not particularly limited, and can be obtained by a usual production method. However, when the blood purification membrane of the present invention is a hollow fiber type blood purification membrane, in order to make the pore size of the inner surface of the hollow fiber membrane small and uniform and obtain a smooth surface state, dry and wet using a gas as a hollow forming agent. The film is preferably formed by a spinning method. Here, for example, nitrogen,
Helium, air and the like can be mentioned, but it is preferable to use nitrogen from the viewpoint of quality and supply stability. Further, in order to further improve the smoothness of the surface state above, and to further improve the water permeability in blood diafiltration and the like, and the retentivity thereof, the temperature of the gas used as the hollow forming agent is adjusted to the temperature of the coagulating liquid. It is particularly preferable to raise the temperature by 20 ° C. or more. Further, it is preferable that the hollow fiber is spun substantially without drawing, that is, it is wound up with only a force necessary for taking up the hollow fiber without forcibly drawing. This is for suppressing deformation of the holes formed in the film. Here, "substantially non-stretching" means that the film is not stretched by 10% or more in each step of spinning.

The hollow fiber type blood purification membrane of the present invention can be produced, for example, as follows, but the present invention is not limited to the following. The spinning dope comprises a polymer or a combination of a plurality of polymers and a solvent or a combination of a plurality of solvents, and a non-solvent or a combination of a plurality of non-solvents.

As the composition of the spinning dope, the weight fraction of the total polymer is suitably from 15 to 35% by weight. If it is 15% or less, the spinning solution has low viscosity due to low viscosity, and if it is 35% or more, phase separation occurs. Is too fast. Total solvent fraction is 30-70
% By weight, and the total non-solvent fraction is preferably 5 to 50% by weight. After the above spinning dope is heated to room temperature to 190 ° C. to uniformly dissolve it, and then degassed and filtered, it is extruded from the outside of the double-ring spinneret, and dried gas heated to 50 to 160 ° C. from the center. Supply at a constant rate. The extruded spinning solution is 1 ~
After traveling in the air for a certain distance of 20 mm, it is solidified through a solidifying liquid at 5 to 60 ° C. to form a membrane structure. After washing with water, it is passed through a 30 to 60% by weight aqueous glycerin solution to retain the membrane structure, impregnated with glycerin, dried in a drier and wound up.

The above-mentioned solvents include so-called aprotic polar solvents, N, N-dimethylformamide, N, N-
Dimethylacetamide, γ-butyrolactone, N-methylpyrrolidone and the like are used alone or in combination.

Examples of the non-solvent include inorganic salts and alcohols, such as glycerin, ethylene glycol,
It is preferable to use glycols such as triethylene glycol and polyethylene glycol alone or as a mixture. In particular, the non-solvent is important for controlling phase separation, for example, in the presence of glycerin. Preferably, phase separation is suppressed.

As the second polymer, for example, polyvinylpyrrolidone or the like may be added to the spinning dope.

As the coagulable liquid, water or a mixed aqueous solution of the solvent used in water and the stock solution for spinning and a non-solvent can be used.

The membrane performance of the hollow fiber membrane can be controlled by so-called phase separation conditions, such as the composition and temperature of the spinning solution, the composition and temperature of the coagulable liquid, and the concentration of glycerin to be impregnated. In order to make the shape of the hollow fiber membrane uniform and to make the membrane surface smooth, first, in the step of forming the hollow fiber membrane, the hollow forming agent is mixed with a non-coagulable gas, which is substantially inward. It must be performed by liquid spinning. Further, the spinning method is dry-wet spinning, and its aerial running portion is preferably as short as 1 to 20 mm. When there is no aerial running part, the film surface rapidly solidifies and wrinkles, and the smoothness of the film surface is reduced. When the film surface is 20 mm or more, thread breakage is apt to occur, and the pores on the inner surface of the film are small and easily asymmetric. . In the spinning process, after discharging the undiluted solution, a coagulation bath, a washing bath, a glycerin bath, etc., after the discharge of the undiluted spinning solution, no stretching of 10% or more is performed in each process bath.
It must be carried out substantially without stretching. The degree of polymerization of the polymer used is preferably a polymer having a high degree of polymerization suitable for spinning without inner liquid. Although the degree of polymerization of the polymer depends on the material, it cannot be specified unconditionally, but in the case of a low degree of polymerization, micropores are partially formed in the surface structure of the membrane, even if non-inner liquid spinning is possible
There are problems such as that the film surface is unlikely to have a uniform structure and a smooth structure.

SC and U of β2-MG of the blood purification membrane of the present invention
FR (B) is measured by the following method. 5000 to 20,000 hollow fiber membranes of the blood purification membrane of the present invention are placed in a plastic molded product to produce a module. After washing this module with physiological saline, the above-mentioned bovine blood is flowed at 200 ml / min on the blood side. Module membrane area
The pressure at the inlet and outlet on the module blood side or the pressure on the dialysate side is adjusted so that the filtration flow rate per 5 m ² becomes 20 ml / min, and blood filtration is performed to measure the following.

1. β2-MG SC At a filtration rate of 20 ml / min, blood and filtrate at the inlet and outlet of the module at 10 minutes and 5 hours after the start of blood filtration were sampled and subjected to enzyme immunoassay (eg, Glazyme β2-Microglobulin- The concentration of β2-MG is measured by EIA Test (Wako Pure Chemical Industries) or the like. In this measurement, a suitable amount of human-derived β2-MG is added to bovine blood flowing to the module in the measurement, and the sampled blood is centrifuged, if necessary, for measurement of β2-MG. From these β2-MG concentration values, the SC of β2-MG is determined according to the following equation 1. SC = Cfil / ((CI + Co) / 2) (Equation 1) Cfil: β2-MG concentration of filtrate CI: β2-MG concentration of blood at inlet of module blood side CO: β2-MG of blood at outlet of module blood side concentration

2. UFR (B) retention The pressures at the inlet and outlet on the blood side and the filtrate side of the module at 10 minutes and 5 hours after the start of blood filtration at a filtration rate of 20 ml / min are measured. UFR (B) was determined from these pressure values according to the following equation 2, and the ratio of UFR (B) at 5 hours to UFR (B) at 10 minutes after the start of hemodialysis (retention rate of UFR (B)) Ask for. UFR (B) = Qf / (A × ((PI + PO) / 2-Pfil)) (Equation 2) Qf: Ultrafiltration speed (ml / hour) A: Surface area of the membrane (m ² ) PI: Module blood side Inlet pressure (mmHg) PO: pressure at module blood side outlet (mmHg) Pfil: pressure at module filtrate side (mmHg)

3. Albumin sieving coefficient Albumin is dissolved in physiological saline to which a phosphate buffer solution has been added so as to be 5% by weight, and a solution adjusted to pH 7.4 (5% by weight albumin solution) is passed through the module at 200 ml / min. . With a filtration flow rate of 10 ml / min per 1.5 m ² ,
The albumin concentration of the module inlet and outlet and the filtrate is BC
Measure by G method. The sieving coefficient of albumin is measured by the following equation. From these albumin concentration values, the SC of albumin is determined according to the following formula 3. SC = Dfil / ((DI + DO) / 2) (Equation 3) Dfil: albumin concentration of filtrate DI: albumin concentration at module inlet DO: albumin concentration at module outlet

[0054]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 A raw material comprising 17% by weight of cellulose triacetate, 57% by weight of N-methylpyrrolidone as a solvent, and 13% by weight of glycerin and 13% by weight of ethylene glycol as non-solvents was heated to 180 ° C. to dissolve. Extruded solution from the outside of the double circular spinning hole,
Nitrogen is fed from the center as an inert gas to form a hollow fiber, which is coagulated by passing through a coagulating liquid composed of four components, water, N-methylpyrrolidone, glycerin and ethylene glycol, washed with water, and washed with a 60% by weight glycerin aqueous solution. After passing through and impregnating with glycerin, it was dried with a dryer to obtain a hollow fiber membrane having an inner diameter of 200 μm. The obtained hollow fiber membrane 84
00 modules were housed in a plastic molded product, and both ends were hardened with an epoxy-based adhesive to be fixed to form a module. In order to evaluate the hollow fiber membrane, bovine blood (hematocrit 30%, protein concentration 7 g / dl) at 37 ° C. was introduced from the inlet of the module at a blood flow rate of 200 ml / min, and blood was passed through the hollow part of the hollow fiber membrane. Ultrafiltration flow rate of 20
Hemofiltration was performed at ml / min. The ultrafiltration coefficient and the sieving coefficient of β2-MG at 10 minutes and 5 hours after blood filtration were measured, and the respective retention rates were calculated. The results were as shown in Table 1.

Example 2 A hollow fiber membrane having an inner diameter of 145 μm was obtained under the same conditions as in Example 1 except that the amount of nitrogen supplied was reduced. The hollow fiber membrane performance was measured in the same manner as in Example 1. The results were as shown in Table 1.

(Comparative Example 1) A solution prepared by heating a raw material composed of 24% by weight of cellulose triacetate, 53% by weight of N-methylpyrrolidone as a solvent, and 23% by weight of triethylene glycol as a non-solvent at 180 ° C. ,
Extruded from the outside of the double circular spinning hole, liquid paraffin is sent as an internal liquid from the center to form a hollow fiber, water,
It is coagulated by passing through a coagulating liquid composed of N-methylpyrrolidone and triethylene glycol, washed with water, passed through a 42% by weight aqueous glycerin solution, impregnated with glycerin, and then dried in a drier to form a hollow having an inner diameter of 200 μm. A fibrous membrane was obtained. Thereafter, the performance of the hollow fiber membrane was measured using the module in the same manner as in Example 1. The results were as shown in Table 1.

[0058]

[Table 1]

[0059]

As is clear from the above configuration and explanation, the present invention can be used for ordinary hemodialysis, and in particular, a large amount of water removal therapy such as hemodiafiltration or hemofiltration. It is intended to provide a blood purification membrane which can be suitably used for a blood purification membrane, a method for producing the blood purification membrane, and a blood purification module using the blood purification membrane. That is, when the blood purification module using the blood purification membrane of the present invention is used for a large volume of water removal therapy or the like, a large amount of water can be stably removed over time, and β2-MG or the like can be efficiently used even during a large amount of water removal. Of uremic substances can be dialyzed / filtered out. As described above, the blood purification module using the blood purification membrane of the present invention can be used stably and effectively in the treatment of chronic renal failure and the like that requires a large amount of water removal, and exhibits a tremendous therapeutic effect. Can be. Therefore, the effect of the present invention is great.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI B01D 71/68 B01D 71/68 D01F 1/08 D01F 1/08 2/00 2/00 A 6/00 6/00 B

Claims (9)

[Claims] 1. A film having a thickness of 10 to 50 μm and an inner diameter of 100 to 100 μm.
A blood purification membrane having a thickness of 300 μm and a porosity of 50 to 85%, and a water permeability at 37 ° C. of 100 to 500 ml / m ^2.
A blood purification membrane having a sieving coefficient for albumin of 0.04 to 0.5 when using a 5% by weight albumin solution which is Hr · mmHg and is dissolved in a buffer solution of pH 7.4; . 2. The blood purification membrane according to claim 1, wherein, when the membrane surface of the blood purification membrane is observed with an electron microscope at a magnification of 5,000, there are no holes that are clearly recognized. 3. The module filled with the blood purification membrane is provided with a hematocrit of 25 to 30% and a protein concentration of 6 to 7 g.
/ Dl of bovine blood at a flow rate of 200 ml / min and blood filtration at a filtration flow rate of 20 ml / min with respect to the ultrafiltration rate at 10 minutes after the start of filtration and the limit at 5 hours after the start of filtration. The blood purification membrane according to claim 1 or 2, wherein the ratio of the external filtration rate is 80% or more. 4. A module filled with the blood purification membrane is provided with a hematocrit of 25 to 30% and a protein concentration of 6 to 7 g.
/ Dl of bovine blood at a flow rate of 200 ml / min and blood filtration at a filtration flow rate of 20 ml / min, 5 hours after the start of filtration, relative to the sieving coefficient of β2-microglobulin at 10 minutes after the start of filtration 4. The blood purification membrane according to claim 1, wherein the ratio of the sieving coefficient of β2-microglobulin is 80% or more. 5. The module filled with the blood purification membrane is provided with a hematocrit of 25 to 30% and a protein concentration of 6 to 7 g.
/ Dl, wherein the sieving coefficient of β2-microglobulin is 0.4 or more when bovine blood is flowed at a flow rate of 200 ml / min and blood filtration is performed at a filtration flow rate of 20 ml / min. 5. The blood purification membrane according to 4. 6. The blood purification membrane according to claim 1, wherein the blood purification membrane contains a cellulose-based polymer or a polysulfone-based polymer. 7. A spinning dope is extruded from the outside of a double tube cap, a gas is fed as a hollow part forming agent from the center of the double pipe cap, and the extruded spinning solution travels in the air and then passes through a coagulating liquid. A method for producing a blood purification membrane by a dry-wet spinning method, wherein the temperature of the gas is higher than the temperature of the coagulable liquid by 20 ° C. or more. 8. The method according to claim 7, wherein the spinning solution contains glycerin as a non-solvent. 9. A blood purification module, wherein the blood purification membrane according to claim 1 is filled so as to have a filling rate of 40 to 80% and a membrane area of 0.9 to ^2.5 m ² .