JP2003175321A - Method for manufacturing hollow fiber membrane - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for obtaining a hollow fiber membrane especially reduced in the irregularity of capacity such as water penetration quantity, water permeability or the like in a method for manufacturing a dry membrane extremely reduced in the elution quantity from the membrane and having excellent dialyzing capacity reduced in the adhesion of blood protein or a platelet. <P>SOLUTION: A method for manufacturing the dry hollow fiber membrane reduced in the amount of an eluted substance includes a process wherein a wet membrane comprising a polysulfone polymer and polyvinylpyrrolidone and containing no membrane pore holding material high in water penetration quantity and having a large pore size is preliminarily manufactured and dried after desolvation to contract the pore size of the wet membrane and a part of polyvinylpyrrolidone in the membrane is further made insoluble in water. In this manufacturing method, the wet membrane is heated and dried at 40-120°C in the wet membrane drying process while irradiated with microwaves. The hollow fiber membrane is suitably used in the dialysis of blood. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an excellent hollow fiber membrane which has an extremely small amount of elution from the membrane and little adhesion of blood proteins and platelets, and in particular, the variation in performance such as water permeability and permeability. The present invention relates to a method for producing a small hollow fiber membrane.

[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 the material of 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 or the like is used. Came. Of these, polysulfone-based polymers are heat-stable, acid-resistant, and alkali-resistant, and by adding a hydrophilizing agent to the membrane-forming stock solution to form a membrane, the blood compatibility is improved. Attention has been paid to research.

On the other hand, it is necessary to dry the membrane in order to manufacture the module by adhering the membrane, 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.

As a conventional measure against this, a low volatility organic liquid such as glycerin is filled in 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 of drying without using a low-volatile organic liquid, Patent Document 1 discloses a method of using an inorganic salt such as calcium chloride in place of the low-volatile organic liquid. The need remains the same. Moreover, even if the amount is very small, there is concern that the residual inorganic salts may adversely affect the dialysis patient.

Further, as a method for drying the membrane, Patent Document 2 discloses a method for producing a hollow fiber membrane in which the hollow fiber membrane is irradiated with microwaves while being subjected to wet heat treatment with steam. However, there is a drawback that the drying time is lengthened because it is subjected to steam treatment to prevent deformation of the film even though it is dried, and further, since it is the drying after the low volatile organic liquid such as glycerin is attached, The goal of reducing elution from the membrane is not achieved.

[0007] Patent Documents 3 and 4 disclose a hydrophilizing film containing polyvinylpyrrolidone which has been dried without using a low-volatile organic liquid. These documents describe the ability to separate plasma components from blood, but it is clear that they are not effective as dialysis membranes because they permeate plasma proteins. 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, in Patent Document 5, the existence ratio of polyvinylpyrrolidone on the inner surface of the membrane which is in direct contact with blood is 20 to 50%.
A sized hollow fiber membrane is disclosed. 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.

The present inventor has proposed a method for producing a high-performance blood purification membrane by drying a wet membrane having specific performance without impregnating it with a low-volatile organic liquid such as glycerin (Patent Document 6). . However, as a result of subsequent studies, it became clear that when this method was used to form a yarn bundle and the yarn was dried, there was a slight difference in performance between the film at the center of the yarn bundle and the film at the outer periphery.

[0010]

[Patent Document 1] Japanese Unexamined Patent Publication No. 6-277470

[Patent Document 2] Japanese Patent Laid-Open No. 11-332980

[Patent Document 3] Japanese Unexamined Patent Publication No. 8-52331

[Patent Document 4] Japanese Patent Publication No. 8-9668

[Patent Document 5] JP-A-6-296686

[Patent Document 6] Japanese Patent No. 3281364

[0011]

The object of the present invention is to provide an excellent method for producing a hollow fiber membrane, in which the amount of elution from the membrane is extremely small and blood proteins and platelets are less likely to adhere. The object is to provide a hollow fiber membrane having a small variation in performance.

[0012]

Means for Solving the Problems As described above, a dry blood purification membrane having a dialysis performance, which is dried without using a membrane pore-holding agent that causes eluate from a module, is an invention filed by the present inventors (patented). There was no reference 6). The cause was that when dried without using a pore-holding agent, a low-performance membrane completely different from the wet state was obtained. 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 size than the target performance by the above application, and drying and shrinking the wet membrane to obtain the target dialysis. As a result of intensive research based on an unprecedented idea of producing a membrane with high performance, the amount of eluate was extremely small and the adhesion of blood proteins and platelets was low. A method for obtaining a membrane having However, after further research, the inventors of the present invention found that when the blood purification membrane was manufactured by the method of Patent Document 6, when the wet membrane was formed into a yarn bundle and dried, the central portion and the outer peripheral portion of the yarn bundle were formed. It was discovered that the water permeability and the permeation performance of the membrane differ. Then, as a result of earnest research for eliminating the variation, the inventors have found that the variation can be suppressed by devising a drying process, and thus the present invention has been achieved.

That is, according to the present invention, (1) a wet membrane composed of a polysulfone-based polymer and polyvinylpyrrolidone and having a high water permeability and a large pore diameter, which does not include a pore-holding material, is prepared in advance, and the solvent is removed and then dried. A method for producing a dry hollow fiber membrane with less elution, which comprises a step of insolubilizing a part of polyvinylpyrrolidone in the membrane into water after shrinking the pore diameter of the wet membrane, comprising the step of drying the wet membrane. A method for producing a hollow fiber membrane, which comprises performing heating and drying at a temperature of 40 ° C. or higher and 120 ° C. or lower and at the same time irradiating with microwaves. (2) The hollow fiber membrane during drying is bundled into a yarn bundle. And a dehumidifying body is ventilated in the yarn bundle, (3)
The difference in the water content of the membrane between the central portion and the outer peripheral portion of the yarn bundle at the start of drying is 10% or less, (4) the water content of the yarn bundle after the start of drying Is reduced to 20 to 70%, the output of the microwave irradiation is reduced, and (5) the water content of the yarn bundle after the start of drying is 20 to 70. The difference in the water content of the membrane between the central portion and the outer peripheral portion of the yarn bundle at the time of becoming 5% is within 5%, the production method according to the above (4),
And (6) the membrane-forming stock solution comprises a polysulfone-based polymer, polyvinylpyrrolidone, and a solvent, and the ratio of polyvinylpyrrolidone to the polysulfone-based polymer is 18 to 27.
The manufacturing method according to any one of the above (1) to (5), characterized in that the manufacturing method is wt%. The hollow fiber membrane obtained by the method of the present invention has excellent permeability and is used as a high performance blood purification membrane. Further, it is also useful as a membrane for other extracorporeal circulation treatment.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The constitution of the hollow fiber membrane of the present invention (hereinafter also simply referred to as "membrane") will be described in detail below. 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 when producing the hollow fiber 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.

Further, in the present invention, a wet membrane having a high water permeability and a large pore diameter means a water permeability of 100 mL / (m ² · hr ·
mmHg) or more, and the permeation rate of polyvinylpyrrolidone having a weight average molecular weight of 40,000 is more than 75%, and the permeation rate of albumin in bovine plasma system is 0.3% or more.

The permeability of bovine plasma albumin can be measured by the following method. First, the length is 20 cm
A small module is manufactured by bundling 100 hollow fiber membranes. Heparin-added bovine plasma heated to 37 ° C in this module (heparin 5000 IU / L (liter), protein concentration
6.0g / dL (deciliter)) on the inner surface of the membrane at a linear velocity of 1.0
It is passed through at a rate of cm / sec, and ultrafiltration is performed for 30 minutes at an average pressure of 50 mmHg of inlet pressure and outlet pressure of the module. The concentration of the obtained filtrate and the original solution was measured with an ultraviolet spectrophotometer at 280 n.
The transmittance is calculated by substituting in the following formula (1) by measuring at the wavelength of m. 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) aqueous solution, the average pressure of the module inlet and outlet is 200 mmH
It can be determined by performing the same operation as in the measurement of the transmittance of bovine plasma albumin, except that the value was changed to g.

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) polyvinylpyrrolidone in the membrane as of high molecular weight Since the higher the hydrophilicity is, the smaller the molecular weight, the more the sufficient effect can be exhibited. Therefore, polyvinylpyrrolidone having a weight average molecular weight of 900,000 or more is used in the present invention. It is necessary to leave a large amount of polyvinylpyrrolidone in the membrane in order to impart the hydrophilic effect to the membrane by using polyvinylpyrrolidone having a weight average molecular weight of less than 900,000, but this increases the eluate from the membrane. Will be done. On the other hand, if the residual amount of polyvinylpyrrolidone having a weight average molecular weight of less than 900,000 in the membrane is decreased in order to reduce the eluate, the hydrophilic effect becomes insufficient, and as a result, the filtration rate when hemodialysis is performed. And the effect cannot be fully exerted.

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, preferably 10 to 25% by weight.

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% by weight, more preferably 20 to 27% by weight. If the mixing ratio of polyvinylpyrrolidone to the polymer exceeds 27% by weight, the elution amount tends to increase, and if it is less than 10% by weight, it is difficult to obtain a sponge structure film because the viscosity of the stock solution for forming the film 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.

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 condition of the hollow fiber membrane in the coagulation bath.

Drying after washing with a solvent is carried out in the form of a bundle of bundles of a large number of hollow fiber membranes (hereinafter simply referred to as a "bundle"), when the bundle of sufficiently moistened particles is 40 ° C. or higher. It is carried out by blast drying at a temperature of ℃ or less and at the same time irradiating with microwaves.

By performing the heating and drying and the microwave irradiation at the same time, it is possible not only to suppress the variation in the performance within the yarn bundle, but also to shorten the drying time as compared with the case of the microwave irradiation alone. Further, in order to eliminate the difference in drying speed between the central portion and the outer peripheral portion of the yarn bundle, it is preferable to ventilate the dehumidifying body at a temperature of less than 40 ° C. Ventilation in the yarn bundle means flowing air between the hollow fiber membranes. In the present invention, 40 ° C
Ventilation of the dehumidifier having a temperature of 120 ° C. or higher into the yarn bundle means that the yarn bundle is heated and dried at the same time as being ventilated in the yarn bundle.

Since the microwave irradiation is suitable for drying the yarn bundle having a low water content more uniformly, the average water content of the yarn bundle is 20 to 70 in order to prevent deformation and melting of the film due to overheating.
%, Preferably 50 to 70%, it is preferable to reduce the output of microwave irradiation. Furthermore, when the average water content of the yarn bundle becomes 20 to 70%, preferably 50 to 70%, the difference in water content of the membrane between the central portion and the outer peripheral portion of the yarn bundle is 5%.
It is preferably within the range in order to suppress variations in performance. At the time of drying, the moisture content of the membrane in the central portion and the outer peripheral portion of the yarn bundle at the time when the average moisture content of the yarn bundle becomes 20 to 70%, preferably 50 to 70% by performing ventilation in the yarn bundle. It is possible to keep the rate difference within 5%. Here, the central portion of the yarn bundle is the diameter 1 / diameter from the center point in the circular cross section of the yarn bundle.
Refers to the range of 6. Further, the outer peripheral portion of the yarn bundle refers to a range of 1/6 of the diameter from the outer periphery in the circular cross section of the yarn bundle.

For the same reason, it is preferable that the difference in water content of the membrane between the central portion and the outer peripheral portion of the yarn bundle at the start of drying is within 10%. If the yarn bundle is left unsolved after solvent removal, there will be a difference in water content between the central portion and the outer peripheral portion of the yarn bundle.Therefore, immersing the yarn bundle in water immediately before entering the drying process It is possible to keep the difference in water content between the outer and outer parts within 10%. Here, the water content is the weight (A (g)) of the yarn bundle (or film) before drying.
And the weight (B (g)) of the dried yarn bundle (or film), which is calculated by the equation (4). Moisture content (%) = (A−B) × 100 / B (4)

The drying temperature is preferably 40 ° C. or higher and 120 ° C. or lower, more preferably 100 ° C. or lower. 120
If the temperature exceeds ℃, the polyvinylpyrrolidone is modified and decomposed, so that the amount eluted from the dried film obtained without using the pore-holding agent increases, which is not preferable. If the temperature is lower than 40 ° C, the drying time becomes too long, which is not preferable. The microwave output is preferably high, but the optimum value varies depending on the amount of the film to be dried.

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. . 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 the wet membrane containing no pore-holding agent is heated and dried at a temperature of 40 ° C. or higher and 120 ° C. or lower, and simultaneously dried by microwave irradiation.
The membrane obtained by using this production method is a dry membrane containing no pore-holding agent, and has a pure water permeability of 10 to 1,000 mL /
(M ² · hr · mmHg), 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%, and the variation in each performance is small. Is a hollow fiber membrane.

In recent hemodialysis therapy, β ₂ -microglobulin (molecular weight: 11,800), which is a causative substance for improving dialysis amyloid pathology, is sufficiently permeated.
A membrane having a fractionation property that hardly allows albumin (molecular weight: 67,000) to permeate is required, and the membrane of the present invention has an albumin permeability of 0.3% or less in a bovine plasma system. An albumin transmittance of more than 0.3% means a large loss of effective albumin in the body and is not preferable as a dialysis membrane.

Further, the amount of pure water permeated is 10 mL / (m ² · h
For a membrane having a thickness of r · mmHg) or higher, the transmittance (A (%)) of polyvinylpyrrolidone and the clearance (B (mL / min)) of β ₂ -microglobulin are represented by the following formula (5).
There exists a linear functional correlation shown in. For clearance evaluation, it is necessary to mold and process into a dialysis module having an effective membrane area of 1.5 m ² , but with this evaluation method it is possible to easily measure and to easily estimate the clearance. Is. B (mL / min) = 0.636A + 29.99 (5) Here, the clearance of β ₂ -microglobulin is 1.
Blood flow rate of 200 mL / in a module with an effective membrane area of 5 m ^2.
Minutes (inner membrane surface side) and dialysis fluid flow rate of 500 mL / min (outer membrane surface side) according to the performance evaluation standard of the Japanese Society for Artificial Organs.

Various β ₂ -microglobulin clearances are required depending on the physical strength of the dialysis patient, the medical condition and the progress of the medical condition, but when the permeability of polyvinylpyrrolidone exceeds 75%, the permeation of albumin is increased. Rate is 0.3%
Therefore, the transmittance of polyvinylpyrrolidone must be 75% or less.

Further, 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 solution was prepared based on the approval criteria of the artificial kidney device, and 1.5 g of the dry hollow fiber membrane cut to 2 cm and 150 mL of distilled water for injection were tested in the glass container for injection of Japanese Pharmacopoeia. Put in a glass container compatible with the alkaline elution test, heat at 70 ± 5 ° C for 1 hour, remove the membrane after cooling, add distilled water
It means 150 mL. Absorbance 220 ~ 350nm
The ultraviolet absorption spectrum is used for measurement at the wavelength showing the maximum absorption wavelength in. 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 pore-retaining agent, it can achieve less than 0.04. Further, with respect to the presence or absence of a membrane pore retaining agent, gas chromatography, liquid chromatography, differential refraction system, ultraviolet spectrophotometer, infrared absorptiometry, nuclear magnetic resonance spectroscopy, obtained by concentrating or removing water from the test solution. Also, it can be detected by measuring by a known method such as 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 polymer and polyvinylpyrrolidone, and the concentration of polyvinylpyrrolidone on the inner surface of the membrane is 30.
~ 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 to 40%, preferably 33%.
~ 40%. The PVP concentration on the inner surface of the film is determined by X-ray photoelectron spectroscopy,
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, C
1s, O1s, N1s, S2p It is the concentration obtained from 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 from the area intensity of the spectrum. When the polysulfone-based polymer has the structure of the formula (2), it can be calculated by the formula (6). PVP concentration (% by weight) = C ₁ M ₁ × 100 / (C ₁ M ₁ + C ₂ M ₂ ) (6) Here, C ₁ : nitrogen atom concentration (%) C ₂ : sulfur atom concentration (%) M ₁ : Molecular weight of PVP repeating unit (111) M ₂ : Molecular weight of repeating unit of polysulfone polymer (442)

[0041]

EXAMPLES 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. 10 hollow fiber membranes with a length of 15 cm
A small module was prepared by bundling 0 pieces of the same, and heparin-added human fresh blood was passed through the module for 15 minutes at a linear velocity of 1.0 cm / sec, and then physiological saline was passed for 1 minute. Next, the hollow fiber membrane was chopped into 5 mm intervals and 0.5% polyethylene glycol alkyl phenyl ether (manufactured by Wako Pure Chemical Industries, Ltd.
The membrane area (inner surface) was quantified by quantifying lactate dehydrogenase (hereinafter referred to as "LDH") released from platelets adhered to the membrane surface by ultrasonic irradiation in physiological saline containing Triton X-100). It was calculated as LDH activity per (converted). The LDH monotest kit (Boehringer Mannheim, Yamanouchi) was used to measure the enzyme activity. As a positive control, a membrane containing no PVP (obtained by immersing the membrane of Example 1 before γ-ray irradiation in sodium hypochlorite having an effective chlorine concentration of 1,500 ppm for 2 days and then in ethanol for 1 day) And the test product was compared at the same time.

(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, and then washed 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 lauryl sulfate 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, PVP
A film not containing (obtained by immersing the film of Example 1 before γ-ray irradiation in sodium hypochlorite having an effective chlorine concentration of 1,500 ppm for 2 days and then in ethanol for 1 day), A comparison was made at the same time as the test product.

[0043]

[Example 1] (Film formation and removal of residual solvent) Polysulfone (P-1700 manufactured by Amoco Engineering Polymers) 1
8.0% by weight, polyvinylpyrrolidone (BASF K
90, weight average molecular weight 1,200,000) 4.3 wt%, N, N
Dissolved in 77.7% by weight of dimethylacetamide to give a uniform solution. Here, the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution was 23.9% by weight. This film-forming stock solution was kept at 60 ° C., and an inner solution consisting of a mixed solution of 30% by weight of N, N-dimethylacetamide and 70% by weight of water together with a spinneret (double annular nozzle 0.1 mm-0.2 mm
(-0.3 mm), passed through an air gap of 0.96 m, and immersed in a coagulation bath made of water at 75 ° C. At this time,
The cylinder from the spinneret to the coagulation bath is surrounded by a cylindrical tube, and while the nitrogen gas containing water vapor is flown into the tube, the humidity in the tube is adjusted to 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). After cutting the wound yarn bundle, the residual 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 (length 300 mm, number of films 9200).

(Drying of wet film and insolubilization treatment of PVP)
Yarn bundle after removing the residual solvent (water content is 300%, water content of the membrane at the center of the yarn bundle is 300%, water content of the membrane at the outer periphery of the yarn bundle is 300%
%, The difference in the water content of the membrane between the center and the outer periphery of the yarn bundle is 0
30) Microwave irradiation (output 30 kW) for 30 minutes for 15 minutes and at the same time a dryer set to 87 ° C (wind speed in the dryer is 3 m /
Second) and dried by heating. At this point, the water content of the yarn bundle is 62% (the water content of the membrane at the center of the yarn bundle is 62%, the water content of the membrane at the outer periphery of the yarn bundle is 62%, and the moisture content of the membrane at the center and outer periphery of the yarn bundle is The difference in water content was 0%). Then,
A dry film (yarn bundle) having a water content of less than 1% was obtained by reducing only the microwave irradiation output from 30 kW to 21 kW. In addition, from the start of drying to the end of drying, dehumidified air (humidity 10
% Or less) was ventilated from the bottom to the top of the yarn bundle. At this time,
From the top of the yarn bundle, the average yarn bundle at the start of drying is 1 m /
The wind speed in seconds was measured. Furthermore, by irradiating the obtained dried film (yarn bundle) with 25 kGy of γ-ray, PV in the film
Part of P was insolubilized.

(Performance Evaluation Results) The performance of this film is shown in Table 1. The performance shows the average value of the results measured 10 times. When this membrane was used as a module with an effective filtration area of 1.5 m ² and the clearance of β ₂ -microglobulin was measured, it was 32 mL.
It was found that it was / min, and it was found that it was equivalent to the clearance of 32.5 mL / min calculated by substituting the transmittance of PVP into the equation (5). Further, when the permeation of urea and vitamin B ₁₂ was measured in the module, the clearance and the permeation rate of urea were 185 mL / min and 83%, respectively. Similarly, for vitamin B ₁₂ , 95 mL
/ Min, 48%. The measurement is

The same procedure as 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 an 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 has lower platelet adhesion than the positive control membrane (positive control membrane).
(43.4 Unit / m ² ) and the amount of plasma protein adhered was also low (positive control membrane 62.5 mg /
g).

From the above-mentioned performances, it became clear that this membrane has an extremely small amount of elution from the membrane and little adhesion of blood proteins and platelets. It was also found that the membrane has excellent dialysis performance because it has a low albumin permeability and an excellent β ₂ -microglobulin clearance. Furthermore, since the difference in the performance of the film between the central portion and the outer peripheral portion of the yarn bundle is smaller than that of the conventional drying method (Comparative Example 1), it is clear that there is little variation in performance.

[0047]

[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. 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. Furthermore, since the difference in the performance of the film between the central portion and the outer peripheral portion of the yarn bundle is smaller than that of the conventional drying method (Comparative Example 1), it is clear that there is little variation in performance.

[0048]

[Example 3] The polyvinylpyrrolidone in the stock solution for film formation was adjusted to 4.8.
The same operation as in Example 1 was performed except that the weight% and N, N-dimethylacetamide were changed to 77.2% by weight. 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. The amount of elution from this membrane is extremely small,
It became clear that blood proteins and platelets were less attached. In addition, albumin has low permeability and β2
-Since it was suggested that the clearance of microglobulin was also excellent, it was found that the membrane had excellent dialysis performance. Furthermore, since the difference in the performance of the film between the central portion and the outer peripheral portion of the yarn bundle is smaller than that of the conventional drying method (Comparative Example 1), it is clear that there is little variation in performance.

[0049]

Example 4 N, N-Dimethylacetamide 52 was added to the internal liquid.
Except that a mixed solution consisting of 48% by weight of water and 48% by weight of water was used,
The same operation as in Example 3 was performed. The performance of this membrane is shown in Table 2. 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. In addition, it was suggested that the membrane has a low albumin permeability and an excellent β ₂ -microglobulin clearance. Therefore, it was found that the membrane has excellent dialysis performance. Furthermore, since the difference in the performance of the film between the central portion and the outer peripheral portion of the yarn bundle is smaller than that of the conventional drying method (Comparative Example 1), it is clear that there is little variation in performance.

[0050]

[Comparative Example 1] Yarn bundle after removal of residual solvent (moisture content is 300%, moisture content of the membrane at the center of the yarn bundle is 300%, moisture content of the membrane at the outer periphery of the yarn bundle is 300%, center portion of the yarn bundle The difference between the water content of the membrane at the outer circumference and the water content of the outer periphery is 0%). 30 pieces are placed in a dryer set at 87 ° C (wind speed in the dryer is 3 m / sec) for 7 hours to heat-dry and the water content is less than 1%. The same operation as in Example 1 was performed except that the yarn bundle of No. 1 was obtained. The results are shown in Table 2. Permeability and PV
It was revealed that there is a difference in the film performance between the central portion and the outer peripheral portion of the yarn bundle in the transmittance of P, and as a result, there is a variation in the performance within the yarn bundle.

[0051]

[Comparative Example 2] The same operation as in Example 1 was carried out except that no γ-ray irradiation was performed. The results are shown in Table 3. It was revealed that the absorbance of the dissolution test solution exceeded 0.04 due to the dissolution of PVP.

[0052]

[Comparative Example 3] The polyvinylpyrrolidone in the stock solution for film formation was adjusted to 5.0.
The same operation as in Example 1 was performed except that the weight% and N, N-dimethylacetamide were 77.0% by weight. 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 3. Since the mixing ratio of polyvinylpyrrolidone to polysulfone in the film-forming stock solution exceeds 27% by weight,
The elution amount and the PVP concentration on the inner surface of the membrane are increasing.

[0053]

[Comparative Example 4] The polyvinylpyrrolidone in the stock solution for film formation was adjusted to 3.6.
The same operation as in Example 1 was performed except that the weight% and N, N-dimethylacetamide were 78.4% by weight. 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 3. It was revealed that the PVP amount on the inner surface of the film was less than 30%.

[0054]

[Comparative Example 5] N, N-dimethylacetamide 60 was added to the internal liquid.
Except that a mixed solution consisting of 40% by weight of water and 40% by weight of water was used,
The same operation as in Example 3 was performed. The performance of this membrane is shown in Table 3. This membrane had an albumin transmittance of more than 0.3% and a PVP transmittance of more than 75%.

[0055]

[Comparative Example 6] N, N-dimethylacetamide 10 was used as the internal liquid.
Except that a mixed solution consisting of 90% by weight of water and 90% by weight of water was used,
The same operation as in Example 1 was performed. The performance of this membrane is shown in Table 3. Pure water permeability is 10mL / (m ² · hr · mmH
The performance was lower than g).

[0056]

[Comparative Example 7] Example 1 except that the drying temperature was changed to 170 ° C.
The same operation was performed. The performance of this membrane is shown in Table 3. In this membrane, all PVP in the membrane was insoluble in water. This membrane is used as a module with an effective filtration area of 1.5 m ² and a blood flow rate of 2
When clinical blood was evaluated according to the performance evaluation criteria of the Japan Society for Artificial Organs under the conditions of 00 mL / min (inner membrane surface side) and dialysate flow rate 500 mL / min (outer membrane surface side), the white blood cell count of the dialysis patient was temporarily Decreasing leukopenia symptoms were observed.

[0057]

[Table 1]

[0058]

[Table 2]

[0059]

[Table 3]

[0060]

INDUSTRIAL APPLICABILITY The membrane of the present invention has an extremely small amount of elution from the membrane and has excellent dialysis performance with little adherence of blood proteins and platelets, and therefore can be used for pharmaceutical applications, medical applications, and general industrial applications. it can.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) // A61M 1/02 540 A61M 1/02 540 D01F 6/76 D01F 6/76 DF term (reference) 4C077 AA05 AA12 BB01 BB02 EE01 KK03 KK11 KK13 LL05 PP09 PP15 4D006 GA06 GA07 GA13 HA01 JA02A LA01 MA01 MA21 MB01 MB02 MC40 MC40X MC62 MC62X MC88 NA04 NA10 NA17 NA18 NA32 NA64 PA01 PB09 PB46 PB52 PC04 CC20FF0720

Claims (6)

[Claims] 1. A wet membrane composed of a polysulfone-based polymer and polyvinylpyrrolidone, which does not contain a membrane pore-holding material having a high water permeability and a large pore diameter, is prepared in advance, and the pore diameter of the wet membrane is reduced by drying after removing the solvent. After shrinking, a method for producing a dry hollow fiber membrane with little elution including a step of insolubilizing a part of polyvinylpyrrolidone in the membrane in water, wherein the drying step of the wet membrane is 40 ° C or more and 120 ° C or less. A method for producing a hollow fiber membrane, which comprises performing heating and drying at the temperature of 1 and irradiating with microwaves at the same time. 2. The manufacturing method according to claim 1, wherein the hollow fiber membranes during drying are bundled into a yarn bundle, and a dehumidifying body is passed through the yarn bundle. 3. The method according to claim 2, wherein the difference in water content of the film between the central portion and the outer peripheral portion of the yarn bundle at the start of drying is within 10%. 4. The average water content of the yarn bundle after the start of drying is 20 to 70.
The manufacturing method according to claim 2 or 3, wherein the output of microwave irradiation is reduced at the time when the ratio becomes%. 5. The difference in the water content of the membrane between the central portion and the outer peripheral portion of the yarn bundle when the water content of the yarn bundle after the start of drying reaches 20 to 70% is within 5%. The manufacturing method according to claim 4. 6. The membrane-forming stock solution is a polysulfone-based polymer,
Consisting of polyvinylpyrrolidone and solvent, the ratio of polyvinylpyrrolidone to polysulfone-based polymer is 18
~ 27% by weight, the manufacturing method according to any one of claims 1 to 5.