JP2003033632A - Method for producing blood purifying membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a high performance blood purifying membrane which is extremely little in elution from the membrane, hardly causes sticking of blood protein and blood platelets thereto and has excellent dialysis performance and a producing method thereof. SOLUTION: This method for producing hollow fiber type blood purifying membrane features that the wet membrane where a pore retaining agent is not incorporated, water permeability of pure water is >=100 mL/m<2> .hr.mmHg, permeability of polyvinyl pyrrolidone of weight average molecular weight 40,000 is >75% and permeability of albumin in bovine blood plasma is >=0.3% is dried at a temperature of <=120 deg.C.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a high-performance blood purification membrane which has an extremely small amount of elution from the membrane and has a small amount of blood proteins and platelets attached, and has excellent dialysis performance.

[0002]

2. Description of the Related Art In recent years, the technology of utilizing a membrane having selective permeability has been remarkably advanced, and gas / liquid separation filters, hemodialyzers, blood filters, and blood component selective separation filters in the medical field have been developed so far. Practical application is progressing in a wide range of fields.

As a material for the membrane, a polymer such as cellulose type (regenerated cellulose type, cellulose acetate type, chemically modified cellulose type), polyacrylonitrile type, polymethylmethacrylate type, polysulfone type, polyethylene vinyl alcohol type, polyamide type, etc. Has been used.

Among these, the polysulfone-based polymer is improved in blood compatibility by adding a hydrophilizing agent to the stock solution for film formation, in addition to its thermal stability, acid resistance and alkali resistance, so that it is semipermeable. As a membrane material, attention has been paid to the research.

On the other hand, it is necessary to dry the membrane in order to adhere the membrane to form a module, but a porous membrane made of an organic polymer, especially a dialysis membrane made of a hydrophobic polymer such as polysulfone is used. It is known that when the filtration membrane is dried after the membrane formation, the water permeation amount is remarkably reduced as compared with before drying. Therefore, the membrane must always be handled in a wet state or immersed in water.

[0006] As a countermeasure against this, a conventional method has been to fill a low volatility organic liquid such as glycerin into the pores in the porous film after film formation and before drying. However, low-volatile organic liquids generally have high viscosity,
It takes a long time to wash and remove, and even after the membrane is molded into a module and washed, a small amount of eluate derived from a low-volatile organic liquid (various derivatives produced by a chemical reaction with the low-volatile organic liquid) is enclosed in the module. There was a problem with what was seen in the liquid.

As a method for drying without using a low-volatile organic liquid, JP-A-6-277470 discloses a method using an inorganic salt such as calcium chloride instead of the low-volatile organic liquid. There is no change in the need for cleaning and removal. Moreover, even if the amount is very small, there is concern that the residual inorganic salts may adversely affect the dialysis patient.

Japanese Unexamined Patent Publication No. 8-52331 and Japanese Patent Publication No. 8
No. 9668 discloses a hydrophilizing film containing polyvinylpyrrolidone that has been dried without using a low-volatile organic liquid. Although the ability to separate plasma components from blood has been described, it is clear that dialysis performance is not shown because plasma proteins permeate. Furthermore, the film forming conditions are not described, and the film structure itself is unknown. Further, since it is dried at a temperature at which polyvinylpyrrolidone is decomposed / denatured, it is an extremely unfavorable production method for the purpose of reducing the eluate from the membrane.

Further, Japanese Unexamined Patent Publication (Kokai) No. 6-296686 discloses a hollow fiber membrane in which the abundance of polyvinylpyrrolidone on the inner surface of the membrane, which is in direct contact with blood, is about 20 to 50%. This mainly indicates a wet film for reducing adhered substances such as blood proteins and platelets. Therefore, although it has been shown that blood proteins do not easily adhere to the filtrate, it is difficult for the filtrate velocity to change with time, but 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 extremely small amount of elution from the membrane and having excellent dialysis performance with little adhesion of blood proteins and platelets. It is in.

[0011]

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

[0012] Therefore, the inventors of the present invention previously prepared a wet membrane having a specific performance of having a higher water permeability and a larger pore diameter than the target performance, and drying and shrinking the wet membrane to obtain the target dialysis performance. As a result of intensive research based on an idea that no one could ever think of producing a membrane having a high dialysis performance with extremely low eluate and low adherence of blood proteins and platelets It is possible to obtain a film having the present invention, and the present invention has been achieved.

That is, the present invention (1) does not contain a membrane pore-holding agent, and has a pure water permeability of 100 mL / (m ² · hr · mm).
Hg) or more, the permeability of polyvinylpyrrolidone having a weight average molecular weight of 40,000 exceeds 75%, and the permeability of albumin in bovine plasma system is 0.3% or more, and dried at a temperature of 120 ° C or less. A method for producing a hollow fiber blood purification membrane, comprising: (2) a hollow fiber membrane in which a stock solution for membrane formation 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. In the manufacturing method, the ratio of the air gap to the spinning speed is 0.01 to
The method for producing a wet membrane according to the above (1), characterized in that it is 0.1 m / (m / min), and (3) the membrane-forming stock solution comprises a polysulfone-based polymer, polyvinylpyrrolidone, and a solvent. The ratio of polyvinylpyrrolidone to 18 to 27% by weight is (18) to (27)% by weight, and (4) the method of producing (4) radiation after drying. )
(5) the hollow fiber blood purification membrane,
A dry membrane containing no pore-holding agent, which has a sponge structure in which the pore size continuously decreases from the outer surface of the membrane toward the inner surface dense layer, and has a pure water permeability of 10 mL / (m ² ·
(hr · mmHg) or more, and 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%. (6) The method for producing a blood purification membrane according to any one of (4) to (6), wherein the hollow fiber blood purification membrane has a membrane eluate test solution having an absorbance of less than 0.04 and a membrane in the eluate test solution. The method for producing a blood purification membrane according to (5) above, which does not contain a pore-retaining agent, and (7) the hollow fiber blood purification membrane comprises a polysulfone-based polymer and polyvinylpyrrolidone, and the concentration of polyvinylpyrrolidone on the inner surface of the membrane. Is 30 to 45% by weight, and the method for producing a blood purification membrane according to the above (5) or (6), and (8) the hollow fiber blood purification membrane contains polyvinylpyrrolidone that is insoluble in water. Above, characterized in bets (5) -
(7) The method for producing a blood purification membrane according to any one of (7).

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The hollow fiber blood purification membrane of the present invention (hereinafter, also simply referred to as “membrane” or “hollow fiber membrane”)
The manufacturing method of 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 size is produced in advance and, after removing the solvent, the wet membrane is dried without impregnating the membrane pore retaining agent.

Usually, the membrane pore retaining agent used in the production of the hollow fiber blood purification membrane is classified into a viscous organic substance and an inorganic substance which may be toxic to the human body. Membrane pore retainers made of viscous organic substances are difficult to completely wash and remove due to their high viscosity, so they remain in the membrane and increase the amount of elution from the membrane. It may cause chemical reaction with the retentive agent to produce harmful substances. On the other hand, even a membrane pore-holding agent made of an inorganic substance remains in a very small amount, which may adversely affect dialysis patients.

The term "membrane pore-holding agent" as used in the present invention is a substance that is filled in the pores in the membrane during the production process before drying in order to prevent performance deterioration during drying. It is possible to fill the pores in the membrane with the retaining agent by immersing the wet membrane in a solution containing the membrane pore retaining agent. Even after drying, if the membrane pore retaining agent is only washed and removed, it is possible to maintain the same performance as the wet membrane such as water permeability and blocking rate due to the effect of the membrane pore retaining agent.

Membrane pore retaining agents 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,
Glycol- or glycerol-based compounds such as polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 and organic compounds such as sucrose fatty acid ester 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 size means a water permeability of 100 mL / (m ² · hr).
-MmHg) or more and a weight average molecular weight of 40,000
0 means a polyvinylpyrrolidone permeability of more than 75% and an albumin permeability of 0.3% or more in bovine plasma system.

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 (heparin 5000 IU / I, protein concentration 6.
0 g / dL (deciliter)) at a linear velocity of 1.
It is passed through at 0 cm / sec, and ultrafiltration is performed for 60 minutes at an average pressure of 50 mmHg of inlet pressure and outlet pressure of the module. The concentrations of the obtained filtrate and the original solution are measured by an ultraviolet spectrophotometer at a wavelength of 280 nm, and the transmittance is calculated by substituting it in the following formula (4). Transmittance (%) = (absorbance of filtrate) × 100 / (absorbance of original solution) (1)

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

A wet membrane having a high water permeability and a large pore size is formed of a polysulfone-based polymer (hereinafter also simply referred to as "polymer"),
Polyvinylpyrrolidone, a film-forming stock solution consisting of a solvent,
It can be produced by using an aqueous solution of a polymer solvent as the internal liquid in a production method in which the internal liquid is discharged from a double annular nozzle, passed through an air gap, and then solidified in a coagulation bath.

The internal liquid forms the hollow portion and the inner surface of the membrane, and it has been known that the pore size of the inner surface increases in proportion to the concentration of the solvent in the internal liquid. In the present invention,
Since the dialysis membrane with the target performance can be obtained by drying and shrinking the wet membrane, it is necessary to increase the concentration of the solvent in the internal solution to a higher concentration than when producing the wet membrane with 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 formula (3). In the formula, Ar represents a 2-substituted phenyl group at the para position, and the degree of polymerization and the 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)

The higher the molecular weight of polyvinylpyrrolidone, the higher the hydrophilic effect on the membrane. Therefore, the higher the molecular weight of polyvinylpyrrolidone, the smaller the amount of polyvinylpyrrolidone. Is used. A large amount of polyvinylpyrrolidone must be left in the membrane in order to impart a hydrophilic effect to the membrane by using polyvinylpyrrolidone having a weight average molecular weight of less than 900,000. Will increase. On the contrary, 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 hydrophilic effect becomes insufficient, and as a result, when hemodialysis is performed. The filtration rate is lowered with time and the sufficient effect cannot be exhibited.

The solvent used for dissolving the polysulfone-based polymer and polyvinylpyrrolidone dissolves both of them, and includes N-methyl-2-pyrrolidone, N, N-dimethylformamide and N, N-dimethylacetamide. Etc.

The concentration of the polymer in the stock solution for film formation is not particularly limited as long as it is within the concentration range in which the film can be formed and the obtained film has the performance as a film, and is preferably 5 to 35% by weight, preferably It is 10 to 30% by weight. In order to achieve high water permeability, the polymer concentration should be low,
5% by weight is preferred.

What is more important is the amount of polyvinylpyrrolidone added, and the mixing ratio of polyvinylpyrrolidone to the polymer is 27% by weight or less, preferably 10 to 27.
%, And 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.
If it is less than 10% by weight, it is difficult to obtain a sponge-structured film because the viscosity of the stock solution is low. Further, a fourth component such as water or a poor solvent may be added for the purpose of controlling the viscosity of the stock solution and the dissolved state, and the kind and the addition amount thereof may be optionally changed depending on the combination.

The air gap means the gap between the nozzle and the coagulation bath. The ratio of the air gap (m) to the spinning speed (m / min) is extremely important for obtaining the membrane of the present invention. Because the membrane structure of the present invention, the non-solvent in the inner solution is contacted with the membrane-forming stock solution to induce phase separation over time from the inner surface site side to the outer surface site side of the membrane-forming stock solution. If the phase separation from the inner surface portion of the membrane to the outer surface portion is not completed before the stock solution for film formation enters the coagulation bath,
Because you cannot get it.

The ratio of air gap to spinning speed is 0.
010 to 0.1 m / (m / min) is preferable,
More preferably 0.010 to 0.05 m / (m / min)
Is. The ratio of air gap to spinning speed is 0.010
If it is less than m / (m / min), it is difficult to obtain a film having the structure and performance of the present invention, and if it exceeds 0.1 m / (m / min), the tension to the film is high, so the air gap part is high. This is not preferable because it often causes film breakage and tends to be difficult to manufacture.

Here, the spinning speed is a series of manufacturing steps of a hollow fiber membrane in which a membrane-forming raw solution discharged from a nozzle together with an internal solution passes through an air gap and is wound up in a coagulating bath. It means the winding speed when there is no stretching operation inside. Also, by enclosing the air gap with a cylindrical tube or the like and flowing a gas having a constant temperature and humidity at a constant flow rate into the air gap, the hollow fiber membrane can be manufactured in a more stable state.

As the coagulation bath, for example, water; methanol,
Liquids such as alcohols such as ethanol; ethers; aliphatic hydrocarbons such as n-hexane and n-heptane that do not dissolve the polymer are used, and water is preferable. 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.
When the temperature of the coagulation bath is higher than 90 ° C or lower than -30 ° C, it is difficult to stabilize the surface state of the hollow fiber membrane in the coagulation bath.

Further, the drying after washing with a solvent is not particularly limited as long as it is a method which does not modify or decompose polyvinylpyrrolidone. However, the drying temperature is preferably 120 ° C. or lower, and more preferably 100 ° C. or lower. If it exceeds 120 ° C., polyvinylpyrrolidone is denatured and decomposed, and the amount eluted from the dried film obtained without using a pore-holding agent increases, which is not preferable.

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 elution amount from the film can be further reduced. Is. Irradiation may be performed before or after modularization. Further, if all the PVP in the membrane is insolubilized, the elution amount can be reduced, but leukopenia symptoms are observed during dialysis, which is not preferable.

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. After allowing the polymer solution to stand still, the amount of PVP in the supernatant can be quantified by liquid chromatography to quantify the PVP soluble in water.

The manufacturing 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 lower, and the membrane obtained by this manufacturing method contains the pore-holding agent. It is a dry film that does not contain a sponge structure in which the pore size continuously decreases from the outer surface of the film to the inner surface dense layer, and the pure water permeability is 10 mL / (m ² · hr · mmH
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 the recent hemodialysis therapy, β2-microglobulin (molecular weight: 11,800), which is a causative substance for improving dialysis amyloid pathology, is sufficiently permeated, but albumin (molecular weight: 67,000) is used. There is a demand for a membrane having a fractional property that almost does not allow permeation, and the membrane of the present invention has an albumin permeability of 0.
It is 3% or less. An albumin permeability of more than 0.3% means a large loss of effective albumin in the body, and is not preferable as a hemodialysis membrane.

Further, the amount of pure water permeated is 10 mL / (m ² ·
In the case of a membrane having a thickness of hr · mmHg) or more, the permeability (A (%)) of polyvinylpyrrolidone and the clearance (B (mL / min)) of β2-microglobulin are expressed by the following linear function (4). There is a strong correlation. For clearance evaluation, it is necessary to mold and process into a dialysis-specification module with an effective membrane area of 1.5 m ² .
With this evaluation method, it is possible to easily measure, and it is possible to easily estimate the clearance. B (mL / min) = 0.636A + 29.99 (4)

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

Various β2-microglobulin clearances are required depending on the physical strength of the dialysis patient, the medical condition, and the progress of the medical condition. When the polyvinylpyrrolidone permeability exceeds 75%, the albumin permeability is higher than 75%. Is 0.
Since it exceeds 3%, it is necessary that the transmittance of polyvinylpyrrolidone is 75% or less.

In addition, since the membrane produced by the production method of the present invention does not use the membrane pore retaining agent in the production process, there is no eluate derived from the membrane pore retaining agent. Therefore, the absorbance of the eluate test solution for the membrane of the present invention is less than 0.04, and the test solution does not contain a membrane pore retaining agent. Here, the eluate test liquid was prepared based on the approval criteria of the artificial kidney device, and 1.5 g of the dry hollow fiber membrane cut into 2 cm and 150 mL of distilled water for injection were tested in a glass container for injection in the Japanese Pharmacopoeia. Put it in a glass container compatible with the alkaline elution test of
It means that the mixture was heated at 70 ± 5 ° C. for 1 hour, and after cooling, the membrane was removed and distilled water was added to make 150 mL. The absorbance is measured by an ultraviolet absorption spectrum at a wavelength showing a maximum absorption wavelength at 220 to 350 nm. The artificial kidney device approval standard stipulates that the absorbance should be 0.1 or less, but since the membrane of the present invention does not retain the membrane pore retaining agent, it is 0.
It is possible to achieve less than 04. Further, with respect to the presence or absence of a membrane pore-holding agent, gas chromatographic, liquid chromatography, differential refraction system, ultraviolet spectrophotometer, infrared absorption spectrophotometric method in which the test solution is concentrated or water is removed,
It can be detected by measuring by a known method such as nuclear magnetic resonance spectroscopy and elemental analysis. Further, it is possible to detect whether or not the membrane pore retaining agent is contained in the membrane 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
It is 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 is in 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. Is. When the PVP concentration on the inner surface of the membrane is too low, the inner surface of the membrane exhibits hydrophobicity, plasma proteins are easily adsorbed, and blood coagulation easily occurs. That is, the blood compatibility of the membrane is poor. On the other hand, if the PVP concentration on the inner surface of the membrane is too high, the amount of PVP eluted into the blood system increases, which is not desirable for the purpose and application of the present invention. Therefore, the concentration of PVP on the inner surface of the membrane in the present invention is in the range of 30-40%, preferably 33-40%.

The PVP concentration on the inner surface of the film was determined by X-ray photoelectron spectroscopy (X-ray Photoelectron spectroscopy).
n spectroscopy, hereinafter XPS). That is, the XPS of the inner surface of the film is measured by arranging the samples on the double-sided tape, incising in the fiber axis direction with a cutter, expanding the inside of the film so that it is on the front side, and then measuring by an ordinary method. . That is, C1s, O1s, N1
It means the concentration obtained from the surface intensity of s, S2p spectrum and the surface concentration of nitrogen (nitrogen atom concentration) and the surface concentration of sulfur (sulfur atom concentration) using the relative sensitivity coefficient attached to the device. When is the structure of equation (2), it can be calculated by equation (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 repeating unit of PVP (111) M ₂ : Molecular weight of repeating unit of polysulfone polymer (442)

Examples of the present invention will be shown below, but the present invention is not limited thereto. (Measurement of Platelet Adhesion Amount)
The procedure was as follows. A small module was prepared by bundling 10 hollow fiber membranes having a length of 15 cm, and heparin-added human fresh blood was added to the module at a linear velocity of 1.0 cm / sec.
It was passed for 1 minute, followed by saline for 1 minute.
Next, the hollow fiber membrane was shredded at intervals of about 5 mm, and the membrane surface was irradiated with ultrasonic waves in physiological saline containing 0.5% polyethylene glycol alkylphenyl ether (trade name Triton X-100 manufactured by Wako Pure Chemical Industries, Ltd.). The lactate dehydrogenase (hereinafter referred to as “LDH”) released from the adhered platelets was quantified to calculate the LDH activity per membrane area (inner surface conversion). The LDH monotest kit (Boehringer Mannheim, Yamanouchi) was used to measure the enzyme activity. As a positive control, a film containing no PVP (the film of Example 1 before γ-ray irradiation was used, the effective chlorine concentration was 1500 p
(A sample obtained by immersing in pm of sodium hypochlorite for 2 days and then in ethanol for 1 day) was used and compared with the test product.

(Amount of adsorbed plasma protein) The amount of adsorbed plasma protein on the membrane was the same as that for measuring the transmittance of albumin except that the ultrafiltration time was 240 minutes, followed by washing with physiological saline for 1 minute. did. Next, the hollow fiber membrane was shredded at intervals of about 5 mm, and the plasma protein extracted by stirring in physiological saline containing 1.0% sodium laurate was quantified to calculate the protein adsorption amount per membrane weight. For the protein concentration, 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 in ethanol for 1 day) was used. A comparison was made at the same time as the test product.

[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
To form a uniform solution. Here, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 23.9% by weight. The film-forming stock solution was kept at 60 ° C., and 30% by weight of N, N-dimethylacetamide and 70% of water were added.
Along with an internal liquid consisting of a mixed solution of wt%, it was discharged from a spinneret (double annular nozzle 0.1 mm-0.2 mm-0.3 mm) and passed through an air gap of 0.96 m to obtain 7
It was immersed in a coagulation bath consisting of water at 5 ° C. At this time, the cylinder from the spinneret to the coagulation bath was surrounded by a cylindrical tube, and while the nitrogen gas containing water vapor was flown into the tube, the humidity in the tube was 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 permeability, and PVP permeability of the wet membrane obtained here are as shown in Table 1.

After cutting the wound yarn bundle, the residual solvent in the film was removed by washing from above the cut surface of the bundle with a hot water shower at 80 ° C. for 2 hours. This film is added to 87 ℃
By drying with hot air for 7 hours, a dry film having a water content of less than 1% was obtained. Furthermore, 2.5 Mra was added to the obtained dry film.
A part of PVP in the film was insolubilized by irradiating with γ ray of d. This membrane had a sponge structure which did not include a polymer defect site having a size of more than 10 μm inside the membrane and in which the pore diameter continuously decreased from the outer surface of the membrane toward the inner surface dense layer. The thickness of the inner surface dense layer was about 10 μm. The performance of this dry film is shown in Table 1.

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 that it was 32 mL / min.
It became clear that it was equivalent to the clearance of 32.5 mL / min calculated by substituting the transmittance of P into the equation (5).
Further, when permeation of urea and vitamin B12 was measured in the module, the clearance and permeation rate of urea were 185 mL / min and 83%, respectively. Similarly, for vitamin B12, it was 95 mL / min and 48%. The measurement is

The same procedure as described in the above was carried out. In addition, the total P in the film
62% of the VP amount was insoluble in water.

As a result of the eluate test of the membrane, the absorbance of the eluate test solution was 0.04 or less. Further, since the membrane pore retaining agent was not used, the eluate test solution did not contain the membrane pore retaining agent. In addition, this membrane had lower platelet adhesion than the positive control membrane (43.4 Unit positive control membrane).
/ M ² ), and the amount of plasma protein adhered was also low (positive control membrane 62.5 mg / g). From the performance mentioned above, it was revealed that this membrane has an extremely small amount of elution from the membrane and little adhesion of blood proteins and platelets. In addition, albumin has a low permeability and β2
-It was found that the membrane was also excellent in dialysis performance because it was also excellent in clearance of microglobulin.

[0050]

Example 2 The same operation as in Example 1 was performed except that polyvinylpyrrolidone was 4% by weight and N, N-dimethylacetamide was 78% by weight in the stock solution for film formation. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 22.2% by weight. The performance of this membrane is shown in Table 1 along with the performance of the wet membrane before drying. This membrane is
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 has a low albumin permeability and an excellent β2-microglobulin clearance, and thus it was found that the membrane has excellent dialysis performance.

[0051]

[Example 3] The polyvinylpyrrolidone in the stock solution for film formation was changed to 4.
The same operation as in Example 1 was performed except that 8% by weight and 77.2% by weight of N, N-dimethylacetamide were used. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 26.7% by weight. The performance of this membrane is shown in Table 1 along with the performance of the wet membrane before drying. It was revealed that the amount of elution from the membrane was extremely small and that blood proteins and platelets were not attached to this membrane. Further, it was suggested that the membrane has a low albumin permeability and an excellent β2-microglobulin clearance, and thus it was found that the membrane has excellent dialysis performance.

[0052]

[Example 4] N, N-dimethylacetamide 5 was added to the internal liquid.
The same operation as in Example 3 was performed except that a mixed solution containing 2% by weight and 48% by weight of water was used. The performance of this membrane is shown in Table 1 along with the performance of the wet membrane before drying. It was revealed that the amount of elution from the membrane was extremely small and that blood proteins and platelets were not attached to this membrane. Further, it was suggested that the membrane has a low albumin permeability and an excellent β2-microglobulin clearance, and thus it was found that the membrane has excellent dialysis performance.

[0053]

[Comparative Example 1] The same operation as in Example 1 was carried out except that no γ-ray irradiation was performed. The results are shown in Table 2. It was revealed that the absorbance of the dissolution test liquid exceeded 0.04 due to the dissolution of PVP.

[0054]

[Comparative Example 2] The polyvinylpyrrolidone in the stock solution for film formation was changed to 5.
The same operation as in Example 1 was performed except that 0% by weight and 77.0% by weight of N, N-dimethylacetamide were used. At this time, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 27.8% by weight. The performance of this membrane is shown in Table 2. Since the mixing ratio of polyvinylpyrrolidone to polysulfone in the stock solution for film formation exceeds 27% by weight, the amount of elution and the concentration of PVP on the inner surface of the film are increased.

[0055]

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

[0056]

[Comparative Example 4] N, N-dimethylacetamide 6 was added to the inner liquid.
The same operation as in Example 3 was performed except that a mixed solution of 0% by weight and 40% by weight of water was used. The performance of this membrane is shown in Table 2. This membrane had an albumin transmittance of more than 0.3% and a PVP transmittance of more than 75%.

[0057]

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

[0058]

Comparative Example 6 The same operation as in Example 1 was performed except that the drying temperature was 170 ° C. The performance of this membrane is shown in Table 2.
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 were observed in which the white blood cell count in dialysis patients was temporarily reduced.

[0059]

[Table 1]

[0060]

[Table 2]

[0061]

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. It can be used for industrial purposes.

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[Procedure amendment]

[Submission date] January 10, 2002 (2002.1.1
0)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0013

[Correction method] Change

[Correction content]

That is, the present invention (1) does not contain a membrane pore-holding agent, and has a pure water permeability of 100 mL / (m ² · hr · mm).
In Hg) or higher, a weight average polyvinylpyrrolidone transmittance of molecular weight 40,000 is more than 75%, and the transmittance of albumin in bovine blood plasma system is 0.3% or more, poly
A pore size from the outer surface of the membrane (a) to the inner surface dense layer, which is characterized in that a wet membrane composed of a sulfone polymer and polyvinylpyrrolidone is dried at a temperature of 120 ° C. or lower.
Has a sponge structure in which
Water permeability of 10mL / (m ² · hr · mmHg) or less
Above, (c) Polyvinylpyrrole having a weight average molecular weight of 40,000.
The transmittance of loridone is 75% or less, and (d) bovine plasma system
The albumin has a transmittance of less than 0.3%, (e)
The absorbance of the membrane eluate test solution is less than 0.04, and the elution
(F) Polysulfone containing no pore-holding agent in the test liquid
Made of phon polymer and polyvinylpyrrolidone
The concentration of polyvinylpyrrolidone on the surface is 30 to 45
A method for producing a hollow fiber blood purification membrane in which the weight percentage is (2) A hollow fiber membrane which is produced by discharging a membrane-forming stock solution and an internal solution from a double annular nozzle, passing through an air gap, and then coagulating in a coagulation bath. In the method, 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 (1) above, and (3) a membrane-forming stock solution, The production method according to (1) or (2) above, which comprises a polysulfone-based polymer, polyvinylpyrrolidone, and a solvent, and the ratio of polyvinylpyrrolidone to the polysulfone-based polymer is 18 to 27% by weight. (4) After drying Irradiation is performed, and the production method according to any one of (1) to (3) above, and (5) the hollow fiber blood purification membrane contains polyvinylpyrrolidone that is insoluble in water. Method for producing any of the blood purification membrane of (1) to (4) which relates.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI theme code (reference) C08J 7/00 CEZ C08J 7/00 CEZ C08L 81/06 C08L 81/06 D01F 6/76 D01F 6/76 D // (C08L 81/06 C08L 39:06 39:06) F term (reference) 4C077 AA05 BB01 KK11 KK23 LL05 LL17 LL22 LL23 NN05 PP09 PP15 4D006 GA06 GA07 GA13 MA01 MA25 MA28 MB02 MB06 MB09 MB20 MC40X MC62X NA05 NA54 NA40 NA40 NA40 NA40 NA40 NA40 NA40 NA63 NA64 NA75 PA01 PB09 PB52 PC47 4F073 AA05 BA32 BA34 BB01 BB03 CA41 4J002 BJ002 CN031 GB00 GB01 4L035 BB04 DD03 EE20 GG08 MF01

Claims (8)

[Claims] 1. A pure water permeation amount of 1 which does not include a membrane pore holding agent.
A wet membrane having a permeability of polyvinylpyrrolidone having a weight average molecular weight of 40,000 of more than 75% and an albumin permeability of bovine plasma system of 0.3% or more at 00 mL / (m ² · hr · mmHg) or more. Is dried at a temperature of 120 ° C. or lower, and a method for producing a hollow fiber blood purification membrane. 2. A method for producing a hollow fiber membrane in which a membrane-forming raw 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. 0.01-0.1 m / (m /
The method for producing a wet film according to claim 1, wherein 3. The membrane-forming stock solution is a polysulfone-based polymer,
Consisting of polyvinylpyrrolidone and solvent, the ratio of polyvinylpyrrolidone to polysulfone-based polymer is 1
It is 8 to 27% by weight, and the manufacturing method according to claim 1 or 2. 4. The method according to any one of claims 1 to 3, which comprises irradiating with radiation after drying. 5. The hollow fiber blood purification membrane is a dry membrane that does not contain a membrane pore retaining agent, and has a sponge structure in which the pore size continuously decreases from the outer surface of the membrane toward the inner surface dense layer. Water permeability is 10mL / (m ² · hr · mmH
g) or more, the transmittance of polyvinylpyrrolidone having a weight average molecular weight of 40,000 is 75% or less, and the transmittance of albumin in the bovine plasma system is less than 0.3%. The method for producing a blood purification membrane according to any one of claims. 6. The hollow fiber blood purification membrane is characterized in that the absorbance of the eluate test solution of the membrane is less than 0.04, and the eluate test solution does not contain a membrane pore retaining agent. 5. The method for producing the blood purification membrane according to 5. 7. The hollow fiber blood purification membrane is composed of a polysulfone-based polymer and polyvinylpyrrolidone, and the concentration of polyvinylpyrrolidone on the inner surface of the membrane is 30 to 45% by weight.
The method for producing a blood purification membrane according to claim 5 or 6, wherein 8. The hollow fiber blood purification membrane contains polyvinylpyrrolidone which is insoluble in water.
8. The method for producing a blood purification membrane according to any one of 7 to 7.