JP2011212233A - Hollow fiber membrane module and method for manufacturing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hollow fiber membrane module having excellent biocompatibility.SOLUTION: The hollow fiber membrane module includes a hollow fiber membrane in a casing. The hollow fiber membrane includes a hydrophobic polymer and polyvinyl pyrrolidone, and the enzyme activity of a lactate dehydrogenase in an extract of components sticking to the hollow fiber membrane is less than 0.6 IU/mL/cm.

Description

  The present invention relates to a hollow fiber membrane module and a method for producing the same.

  In recent years, the progress of technology using a hollow fiber membrane having selective permeability in a separation operation has been remarkable and has been put into practical use for various applications. For example, polysulfone-based, cellulose-based, polyimide-based, polyvinyl alcohol-based, and polyacrylonitrile-based resins are used as the material for such hollow fiber membranes. In particular, polysulfone-based resins have heat resistance and acid resistance. It is said to be excellent in physical and chemical properties such as alkali resistance and oxidation resistance, and easy to form a film.

  However, for example, in a hollow fiber membrane made of a hydrophobic polymer such as a polysulfone-based resin, the permeation performance is remarkably reduced when the membrane is dried, and it must be wetted before it can be used again. In addition, protein and the like are easily adsorbed and the membrane is easily contaminated and clogged.

  As a method for solving these problems, a method of imparting a hydrophilic effect by leaving a hydrophilic polymer in the hollow fiber membrane has been proposed.

  For example, Patent Literature 1 and Patent Literature 2 describe a hydrophilized polysulfone membrane in which hydrophilic polyvinyl pyrrolidone is contained in a hollow fiber membrane.

  On the other hand, Patent Document 3 and Patent Document 4 disclose a method for producing polyvinylpyrrolidone in which residual monomers are reduced. Patent Document 5, Patent Document 6 and Patent Document 7 disclose a method for producing polyvinylpyrrolidone which suppresses the formation of by-products.

JP 58-104940 A JP 61-93801 A Japanese Patent Publication No. 58-50604 JP 2002-155108 A Japanese Patent Laid-Open No. 62-62804 Japanese Patent Publication No. 8-19174 JP 2001-354723 A

  However, in the hollow fiber membrane module using polyvinylpyrrolidone, a disease such as leucopenia due to the adhesion of blood cells in blood to the hollow fiber membrane module may occur at a frequency of 1 per million.

  Accordingly, an object of the present invention is to provide a hollow fiber membrane module having excellent biocompatibility, such as the adhesion of blood cells such as white blood cells and platelets, and a method for producing the same.

  The present inventors have found a novel finding that adhesion of blood cells to a module having a hollow fiber membrane containing polyvinyl pyrrolidone is caused by polyvinyl pyrrolidone itself, and that oxidative degradation of polyvinyl pyrrolidone is responsible for blood cell adhesion. The invention has been completed.

［式中、Ｃは前記ポリビニルピロリドンの水溶液におけるポリビニルピロリドン濃度（ｇ／Ｌ）であり、Ｃは１０（ｇ／Ｌ）である。Ｚは、２３℃にて毛細管粘度計にて測定された、濃度Ｃにおける前記ポリビニルピロリドンの水溶液の相対粘度である。］
［３］ 前記中空糸膜は、クリンプ形状を有する［１］又は［２］に記載の中空糸膜モジュール
［４］ 前記中空糸膜の膜厚は、２５μｍ以上４０μｍ以下である［１］〜［３］の何れかに記載の中空糸膜モジュール。
［５］前記中空糸膜は、膜厚が３０μｍ以下の場合には、破断強度が７．５ＭＰａ以上、破断伸度が７０％以上であり、膜厚が３０μｍを超え３５μｍ以下の場合には、破断強度が７ＭＰａ以上、破断伸度が６５％以上であり、膜厚が３５μｍを超える場合には、破断強度が６ＭＰａ以上、破断伸度が６０％以上である、［１］〜［４］の何れかに記載の中空糸膜モジュール。
［６］ 前記中空糸膜は、孔径が外表面から内表面に向かって連続的に減少した中空糸膜であり、且つスポンジ構造を有する、［１］〜［５］の何れかに記載の中空糸膜モジュール。
［７］ 血液浄化用である、［１］〜［６］の何れかに記載の中空糸膜モジュール。
［８］ アルブミンの透過率が０．３５％以下である、［１］〜［７］の何れか記載の中空糸膜モジュール。
［９］ 前記中空糸膜中のポリビニルピロリドンの架橋度が８０％以上１００％未満である、［１］〜［８］の何れかに記載の中空糸膜モジュール。
［１０］ 前記中空糸膜中のポリビニルピロリドンは、架橋度調整剤を中空糸膜内に注入し、前記中空糸膜に放射線照射することにより、架橋度を８０％以上１００％未満にされたものである、［９］の中空糸膜モジュール。 That is, the present invention relates to the following [1] to [24].
[1] A hollow fiber membrane module including a hollow fiber membrane in a casing,
The hollow fiber membrane is a hollow fiber membrane containing a hydrophobic polymer and polyvinylpyrrolidone,
Hollow, in which the enzyme activity of lactate dehydrogenase in the extract of the component adhering to the hollow fiber membrane is less than 0.6 IU / mL / cm ² when human blood added with an anticoagulant is passed through Yarn membrane module.
[2] The hollow fiber membrane according to [1], wherein the polyvinylpyrrolidone has a K value defined by the following formula of 75 or more and a value obtained by dividing the weight average molecular weight by the number average molecular weight is 2.95 or less. module.

[Wherein, C is the polyvinylpyrrolidone concentration (g / L) in the aqueous solution of polyvinylpyrrolidone, and C is 10 (g / L). Z is the relative viscosity of the aqueous solution of polyvinyl pyrrolidone at a concentration C measured at 23 ° C. with a capillary viscometer. ]
[3] The hollow fiber membrane has a crimp shape. [1] The hollow fiber membrane module according to [2] [4] The film thickness of the hollow fiber membrane is 25 μm or more and 40 μm or less. 3] The hollow fiber membrane module according to any one of [3].
[5] The hollow fiber membrane has a breaking strength of 7.5 MPa or more and a breaking elongation of 70% or more when the film thickness is 30 μm or less, and when the film thickness exceeds 30 μm and 35 μm or less, When the breaking strength is 7 MPa or more, the breaking elongation is 65% or more, and the film thickness exceeds 35 μm, the breaking strength is 6 MPa or more and the breaking elongation is 60% or more. The hollow fiber membrane module in any one.
[6] The hollow fiber membrane according to any one of [1] to [5], wherein the hollow fiber membrane is a hollow fiber membrane having a pore diameter continuously decreased from the outer surface toward the inner surface and has a sponge structure. Yarn membrane module.
[7] The hollow fiber membrane module according to any one of [1] to [6], which is for blood purification.
[8] The hollow fiber membrane module according to any one of [1] to [7], wherein the albumin permeability is 0.35% or less.
[9] The hollow fiber membrane module according to any one of [1] to [8], wherein the degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is 80% or more and less than 100%.
[10] Polyvinylpyrrolidone in the hollow fiber membrane has a degree of crosslinking of 80% or more and less than 100% by injecting a crosslinking degree adjusting agent into the hollow fiber membrane and irradiating the hollow fiber membrane with radiation. The hollow fiber membrane module according to [9].

［式中、Ｃは前記ポリビニルピロリドンの水溶液におけるポリビニルピロリドン濃度（ｇ／Ｌ）であり、Ｃは１０（ｇ／Ｌ）である。Ｚは、２３℃にて毛細管粘度計にて測定された、濃度Ｃにおける前記ポリビニルピロリドンの水溶液の相対粘度である。］
［１６］ 前記ポリビニルピロリドンは、酸化防止剤を含有するポリビニルピロリドンである、［１１］〜［１５］の何れか記載の製造方法。
［１７］ 前記酸化防止剤は、サリチル酸ナトリウムである、［１６］記載の製造方法。
［１８］ 前記ポリビニルピロリドンは、第２級アミン又はその塩を含有するポリビニルピロリドンである、［１１］〜［１７］の何れかに記載の製造方法。
［１９］ 前記第２級アミンは、ジエタノールアミンである、［１８］記載の製造方法。
［２０］ 前記ポリビニルピロリドンは、以下の式で定義されるＫ値が７５以上であり、重量平均分子量を数平均分子量で除した値が２．９５以下である、［１１］〜［１９］の何れかに記載の製造方法。

［式中、Ｃは前記ポリビニルピロリドンの水溶液におけるポリビニルピロリドン濃度（ｇ／Ｌ）であり、Ｃは１０（ｇ／Ｌ）である。Ｚは、２３℃にて毛細管粘度計にて測定された、濃度Ｃにおける前記ポリビニルピロリドンの水溶液の相対粘度である。］
［２１］ 前記ポリビニルピロリドンは、γ−ブチロラクトンとモノエタノールアミンから得たＮ−（２−ヒドロキシエチル）ピロリドンを気相脱水反応させて製造したＮ−ビニル−２−ピロリドンを重合したポリビニルピロリドンである、［１１］〜［２０］の何れかに記載の製造方法。
［２２］ 前記Ｎ−ビニル−２−ピロリドンは、Ｎ−ビニル−２−ピロリドンの純度が９９．９８％以上、有機不純物量が８０ｐｐｍ以下である、［２１］記載の製造方法。
［２３］ 前記中空糸膜は、前記ポリビニルピロリドンを含む溶液を孔径３μｍ以下の焼結フィルターで超音波振動を加えながら濾過し、これに前記疎水性ポリマーを添加した原液から製造される、［１１］〜［２２］の何れかに記載の製造方法。 [11] A method for producing a hollow fiber membrane module comprising a hollow fiber membrane containing a hydrophobic polymer and polyvinylpyrrolidone in a casing,
A production method wherein the production is carried out in a state where the polyvinylpyrrolidone is not substantially oxidized.
[12] The production method according to [11], wherein all steps from the preparation of the hollow fiber membrane forming solution to the packaging of the hollow fiber membrane module are performed in an oxygen-free state.
[13] The production method according to [12], wherein the oxygen-free state is achieved by an inert gas (a state in an inert gas atmosphere or a state where the oxygen-free state is replaced with an inert gas).
[14] The production method according to [13], wherein the inert gas is nitrogen.
[15] The polyvinyl pyrrolidone according to any one of [11] to [14], wherein the amount of decrease in K value defined by the following formula after storage for 40 days in a nitrogen atmosphere at 40 ° C. is less than 1. The manufacturing method as described.

[Wherein, C is the polyvinylpyrrolidone concentration (g / L) in the aqueous solution of polyvinylpyrrolidone, and C is 10 (g / L). Z is the relative viscosity of the aqueous solution of polyvinyl pyrrolidone at a concentration C measured at 23 ° C. with a capillary viscometer. ]
[16] The method according to any one of [11] to [15], wherein the polyvinyl pyrrolidone is polyvinyl pyrrolidone containing an antioxidant.
[17] The production method according to [16], wherein the antioxidant is sodium salicylate.
[18] The production method according to any one of [11] to [17], wherein the polyvinylpyrrolidone is a polyvinylpyrrolidone containing a secondary amine or a salt thereof.
[19] The production method according to [18], wherein the secondary amine is diethanolamine.
[20] The polyvinyl pyrrolidone has a K value defined by the following formula of 75 or more, and a value obtained by dividing the weight average molecular weight by the number average molecular weight is 2.95 or less; [11] to [19] The manufacturing method in any one.

[Wherein, C is the polyvinylpyrrolidone concentration (g / L) in the aqueous solution of polyvinylpyrrolidone, and C is 10 (g / L). Z is the relative viscosity of the aqueous solution of polyvinyl pyrrolidone at a concentration C measured at 23 ° C. with a capillary viscometer. ]
[21] The polyvinylpyrrolidone is a polyvinylpyrrolidone obtained by polymerizing N-vinyl-2-pyrrolidone produced by subjecting N- (2-hydroxyethyl) pyrrolidone obtained from γ-butyrolactone and monoethanolamine to a gas phase dehydration reaction. , [11] to [20].
[22] The method according to [21], wherein the N-vinyl-2-pyrrolidone has a purity of N-vinyl-2-pyrrolidone of 99.98% or more and an organic impurity amount of 80 ppm or less.
[23] The hollow fiber membrane is manufactured from a stock solution in which the solution containing the polyvinyl pyrrolidone is filtered through a sintered filter having a pore size of 3 μm or less while applying ultrasonic vibration, and the hydrophobic polymer is added thereto. ] The manufacturing method in any one of [22].

  ADVANTAGE OF THE INVENTION According to this invention, the hollow fiber membrane module which has the outstanding biocompatibility, such as it becomes possible to reduce the adhesion of blood cells, such as leukocytes and platelets, and its manufacturing method are provided.

It is a figure of the particle size distribution which measured the polyvinylpyrrolidone solution with the dynamic light scattering method. It is a figure for demonstrating the crimp shape of a hollow fiber membrane.

  Hereinafter, embodiments of the present invention will be described in detail. In addition, the following is the illustration for demonstrating this invention, and is not the meaning which limits this invention to the following content. The present invention can be appropriately modified within the scope of the gist.

  First, the hollow fiber membrane used for the hollow fiber membrane module will be described.

  The hollow fiber membrane according to the embodiment includes polyvinyl pyrrolidone (hereinafter, also simply referred to as “PVP”), polyvinyl pyrrolidone, and a hydrophobic polymer as main components. Here, “based on polyvinyl pyrrolidone and a hydrophobic polymer” means that the total of polyvinyl pyrrolidone and the hydrophobic polymer occupies 80% by mass or more of the material constituting the hollow fiber membrane, preferably 90% by mass. % Or more, more preferably 95% by mass or more, and still more preferably 100% by mass.

Examples of the hydrophobic polymer include polysulfone polymers, polyamides, polyimides, polyphenylene ethers, polyphenylene sulfides, and among them, aromatic polysulfone polymers are preferable. Examples of the aromatic polysulfone-based polymer used in the present invention include those having a repeating unit represented by the following general formula (1) or general formula (2). In the formula, Ar represents a disubstituted phenyl group at the para position. The polymerization degree and molecular weight of the hydrophobic polymer are not particularly limited.
—O—Ar—C (CH ₃ ) ₂ —Ar—O—Ar—SO ₂ —Ar— (1)
—O—Ar—SO ₂ —Ar— (2)

  For polyvinylpyrrolidone used for hollow fiber membranes, the mode diameter of the peak on the largest particle size side (hereinafter referred to simply as “particle size”) in the particle size distribution of soluble polyvinylpyrrolidone extracted from the hollow fiber membrane measured by dynamic light scattering method. The mode diameter of the peak on the largest particle size side in the distribution ”is preferably 300 nm (nanometer) or less, more preferably 200 nm or less, still more preferably 60 nm or less. According to the study of the present inventor, by setting the mode diameter of the peak on the largest particle size side in the particle size distribution of the soluble polyvinylpyrrolidone within the above numerical range, there are few defects such as pinholes and film breakage, and the film thickness Can be a thin hollow fiber membrane. In addition, when polyvinylpyrrolidone having a peak mode diameter on the largest particle size side exceeding 300 nm in the above particle size distribution is used, there are many sites in the film where the polyvinylpyrrolidone concentration is locally high. Etc. are likely to occur.

Further, when polyvinyl pyrrolidone having a mode diameter on the largest particle size side in the above range in the particle size distribution is used, the impurity removal performance is enhanced. Especially, an excellent removal performance of vitamin B ₁₂ in the case of using the hollow fiber membranes for the blood purification dialysis. The reason is presumed as follows (but not limited to this).

  That is, the usual polyvinyl pyrrolidone used in the conventional hollow fiber membrane contains an agglomerated component in which a plurality of molecules generated in the production process are intertwined, and this is present in a lump in the hollow fiber membrane. This massive polyvinylpyrrolidone is considered to increase the filtration resistance of the membrane and lower the permeation performance of the membrane. When polyvinyl pyrrolidone having a small aggregation component, specifically, one having a mode diameter of a peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method of 300 nm or less is used. Pyrrolidone is rarely present in the form of a lump and uniformly covers the periphery of the hollow fiber membrane skeleton (for example, a skeleton composed of a hydrophobic polymer such as a polysulfone-based polymer), thereby reducing the filtration resistance of the membrane. It is estimated that the permeation performance of the membrane is improved.

  In general, when the particle size distribution of polyvinyl pyrrolidone present in a polyvinyl pyrrolidone solution is measured with a dynamic light scattering device, two peaks are observed in the range of particle size values of 1 to 5,000 nm (see FIG. 1). Here, in the particle size distribution, the secondary peak (B) and the primary peak (A) are set in order from the large particle size side. That is, in FIG. 1, the peak on the largest particle size side in the particle size distribution is the secondary peak (A).

  The primary peak is a co-diffusion mode and is a peak observed in ordinary concentrated polymer solutions (for example, “Physics of Dojang Polymer”, supervised by Ryogo Kubo, Hiroshi Takano, Shu Nakanishi, Yoshioka Shoten) Publishing, 1997, p208-p210.) The peak of the cooperative diffusion mode does not change even when the polyvinylpyrrolidone solution is filtered.

  On the other hand, the secondary peak is a unique peak seen in the polyvinylpyrrolidone solution. According to the study of the present inventor, the smaller the maximum value of the particle size distribution of the secondary peak (corresponding to the largest particle size peak in the particle size distribution in FIG. 1), the smaller the number of pinholes or film breakage. In order to prevent pinholes and film breakage, the mode diameter of the secondary peak may be set to 300 nm or less, and it is preferable to use polyvinyl pyrrolidone having no secondary peak.

  In FIG. 1, the case where the number of peaks in the particle size distribution measured by the dynamic light scattering method of polyvinyl pyrrolidone is two has been described as an example (typical example). Polyvinyl pyrrolidone in the film is not limited to the number of peaks in the particle size distribution measured by the dynamic light scattering method is two, for example, there may be three or more peaks, In this case, the mode diameter of the peak on the largest particle diameter side may be 300 nm or less.

  The mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method of polyvinyl pyrrolidone is a dimethylacetamide solution adjusted so that the concentration of polyvinyl pyrrolidone is 5.0% by mass ( The polyvinyl pyrrolidone solution) is determined by measuring at a temperature of 25 ° C. using a dynamic light scattering apparatus (FPAR-1000 or equivalent machine manufactured by Otsuka Electronics Co., Ltd.). The analysis condition is NNLS (non-negative constraint least square method), and the histogram range is set automatically. However, only the peak obtained when the particle size value is in the range of 1 to 5,000 nm is analyzed. Further, as the values of the viscosity and refractive index of the polyvinylpyrrolidone solution, the physical property values of dimethylacetamide at 25 ° C. are used.

  In addition, as the polyvinyl pyrrolidone dissolved in dimethylacetamide by the above-mentioned method, ethanol-soluble polyvinyl pyrrolidone extracted from a hollow fiber membrane using ethanol can be used. That is, ethanol-soluble polyvinyl pyrrolidone is extracted from the hollow fiber membrane using ethanol, and the ethanol-soluble polyvinyl pyrrolidone solution (ethanol solution) is deethanolated using, for example, an evaporator, and then made into a dimethylacetamide solution according to the above method.

  In addition, the method of extracting ethanol soluble polyvinylpyrrolidone from a hollow fiber membrane using ethanol can be performed as follows.

The hollow fiber membrane module (blood purifier or the like) is washed with pure water and dried until the water content in the hollow fiber membrane module is 0.3% by mass or less with respect to the hollow fiber membrane. The cleaning with pure water is performed until the crosslinking degree adjusting agent or the like is not extracted from the blood purifier. Specifically, the operation of injecting pure water from the open end of the hollow fiber membrane module, filling the hollow fiber membrane module with pure water, shaking for 3 minutes, and then discharging the pure water 10 times. repeat. Next, it is immersed in 50 ° C. ethanol in a hollow fiber membrane module, and the ethanol is filtered and circulated from the outer surface side to the inner surface side of the hollow fiber membrane for 3 hours. For the circulation of ethanol, tubes and joints and air pumps with no contamination in the circulation circuit are used. The filtration circulation rate is 30 mL / min. At this time, it is confirmed that the entire hollow fiber membrane module is immersed in ethanol. After 3 hours, ethanol circulated through the hollow fiber membrane was filtered with a 5 μm filter (Fuji Filter Co., Ltd., FD-5, effective filtration area 40 cm ² ), and then only ethanol was evaporated by using an evaporator. Soluble polyvinylpyrrolidone is obtained. Heating with an evaporator is performed at 50 ° C. or lower. The above procedure is repeated using different hollow fiber membrane modules having the same type (production lot) of hollow fiber membranes until an amount of soluble polyvinylpyrrolidone that can be measured with a dynamic light scattering device is obtained.

  The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is preferably 80% or more and less than 100%, more preferably 80% or more and 99% or less, and further preferably 85% or more and 95% or less.

  If the degree of crosslinking of PVP in the hollow fiber membrane is less than 80%, polyvinyl pyrrolidone present on the inner surface of the hollow fiber membrane and substantially contributing to hydrophilicity may be eluted from the membrane. On the other hand, if the degree of crosslinking is 100%, the amount of elution can be reduced. On the other hand, when the hollow fiber membrane according to the present invention is used for dialysis, leucopenia symptoms may be observed during dialysis.

The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is defined by the following formula (3).
Degree of crosslinking of PVP (%) = PVP amount (mass) insoluble in water / Total PVP amount (mass) in membrane × 100 (3)

  Here, the amount of PVP insoluble in water is obtained by subtracting the amount of PVP soluble in water from the amount of total polyvinylpyrrolidone (total amount of PVP in the membrane).

  The total amount of PVP in the hollow fiber membrane of unit mass is the concentration of nitric oxide produced by vaporizing or oxidizing 0.2 to 0.5 mg of the dried hollow fiber membrane in a horizontal reactor (800 to 950 ° C.). It can be determined by measuring with a chemiluminescence method (apparatus can be manufactured by Mitsubishi Chemical, TN-10), and converted from the obtained concentration to the amount of PVP contained in the hollow fiber membrane of unit mass. For quantification, a calibration curve prepared with a nitrogen-containing polymer standard is prepared in advance, and the concentration is determined using this calibration curve.

  The amount of PVP soluble in water can be determined by the following method.

  That is, the unit mass of the hollow fiber membrane was dried so that the water content was 0.3% by mass or less, and this was dissolved in N-methyl-2-pyrrolidone to a concentration of 2.5% by mass, Make a solution. By adding 1.7 times the volume of water to the solution and stirring for 10 minutes, the hydrophobic polymer (polysulfone polymer, etc.) in the hollow fiber membrane is sufficiently precipitated. PVP which is soluble in water is contained in the solution together with the precipitated hydrophobic polymer fine particles. Next, the hydrophobic polymer fine particles in the solution are removed by filtration with a non-aqueous filter (manufactured by Tosoh, pore size: 2.5 μm) for HPLC (high performance liquid chromatography), and the polyvinylpyrrolidone contained in the filtrate is converted to HPLC. (Equipment: Waters, GPC-244, column: TSKgel GMPWXL, solvent: 0.1M ammonium chloride (0.1N ammonia), pH 9.5 aqueous ammonium chloride solution, flow rate: 1.0 mL / min, temperature: 23) ° C). The amount of polyvinylpyrrolidone contained in the filtrate quantified as described above is the amount of PVP soluble in water contained per unit mass of the hollow fiber membrane. In addition, as the amount of PVP soluble in water when calculating the degree of crosslinking of PVP, the above measurement is performed 10 times, and an average value of 8 points excluding the maximum value and the minimum value is used.

ここで、Ｃは前記ポリビニルピロリドンの水溶液におけるポリビニルピロリドン濃度（ｇ／Ｌ）であり、Ｃは１０（ｇ／Ｌ）である。Ｚは、２３℃にて毛細管粘度計にて測定された、濃度Ｃにおける前記ポリビニルピロリドンの水溶液の相対粘度である。 It is preferable that K value calculated | required by the following formula | equation with PVP used by this invention is 75 or more. PVP tends to flow out of the membrane at the time of film formation (phase separation) and at the time of post-treatment washing, but if the K value is 75 or more, the amount of PVP remaining in the membrane is large. Therefore, it is preferable. In this invention, it is preferable that it is PVP whose K value defined by following Formula is 75-100. When the K value exceeds 100, it tends to be difficult to dissolve in a solvent.

Here, C is the polyvinyl pyrrolidone concentration (g / L) in the aqueous solution of polyvinyl pyrrolidone, and C is 10 (g / L). Z is the relative viscosity of the aqueous solution of polyvinyl pyrrolidone at a concentration C measured at 23 ° C. with a capillary viscometer.

  Furthermore, the value (Mw / Mn) obtained by dividing the weight average molecular weight (Mw) of PVP by the number average molecular weight (Mn) is preferably 2.00 or more and 2.95 or less. By using PVP having such a sharp molecular weight distribution, it is possible to sharpen the pore size distribution of the obtained membrane. By using PVP having this molecular weight distribution, it is possible to reduce the albumin permeability to 0.15% or less. In addition, it is difficult to obtain PVP with Mw / Mn less than 2.00.

Mw and Mn of PVP are obtained, for example, by preparing a sample solution in which PVP is dissolved in DMF at a concentration of 1.0 mg / mL and performing gel permeation chromatography (GPC) measurement under the following conditions ( It is converted to PMMA as described below). Mw / Mn is determined from the result of the measurement.
Equipment: HLC-8220GPC (Tosoh Corporation)
Column: Shodex KF-606M, KF-601
Oven: 40 ° C
Mobile phase: 0.6 mL / min DMF
Detector: Differential refractive index detector

  Here, a calibration curve (tertiary equation) was created using polymethyl methacrylate resin (PMMA), which is a GPC standard substance with known Mw and Mn, and PMMA was calculated from the flow time of polyvinylpyrrolidone based on the calibration curve. Converted Mw and Mn are obtained.

  As PVP, it is preferable to use PVP containing an antioxidant. PVP having a K value of 75 or more always undergoes oxidative decomposition due to oxygen in the air. Therefore, the K value tends to decrease with time. By having an antioxidant, the same lot of PVP can be used for a long period of time, so there is an advantage that a product (film) with stable performance can be supplied for a long period of time.

  Examples of the antioxidant include sodium salicylate, methylbenzotriazole potassium salt, 2-mercaptobenzimidazole, 2,4-dihydroxybenzophenone, 2,6-di-t-butyl-p-cresol, butylated hydroxyanisole, 2 , 6-Di-tert-butyl-4-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, stearyl-β- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate , 3,4,5-trihydroxybenzoic acid propyl ester, hydroquinone, catechol, and other phenolic antioxidants; 2,2′-methylenebis (4-methyl-6-tert-butylphenol), 2,2′-methylenebis ( 4-ethyl-6-tert-butylphenol), 4,4′-thiobis (3-methyl- -T-butylphenol), 4,4'-butylidenebis (3-methyl-6-t-butylphenol), 3,9-bis [1,1-dimethyl-2- [β- (3-t-butyl-4-) Hydroxy-5-methylphenyl) propionyloxy] ethyl] -2,4,8,10-tetraoxaspiro [5,5] undecane, 4,4 ′-(2,3-dimethyltetramethylene) dipyrocatechol, etc. Bisphenol antioxidants; 1,1,3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, 1,3,5-trimethyl-2,4,6-tris (3,5 -Di-t-butyl-4-hydroxybenzyl) benzene, tetrakis [methylene-3- (3 ', 5'-di-t-butyl-4'-hydroxyphenyl) propionate] methane, bis [3 3′-bis (4′-hydroxy-3′-t-butylphenyl) butyric acid] glycol ester, 1,3,5-tris (3 ′, 5′-di-t-butyl-4′-hydroxybenzyl)- Polymeric phenolic antioxidants such as s-triazine-2,4,6- (1H, 3H, 5H) trione, tocopherols; dilauryl-3,3′-thiodipropionate, dimyristyl-3,3 ′ -Sulfur-based antioxidants such as thiodipropionate, distearyl-3,3'-thiodipropionate, 2-mercaptobenzimidazole, tetrakismethylene-3- (laurylthio) propionate methane, stearylthiopropylamide; Triphenyl phosphite, diphenyl isodecyl phosphite, phenyl diisodecyl phosphite, 4,4'-butylene -Bis (3-methyl-6-tert-butylphenylditridecyl) phosphite, cyclic neopentanetetraylbis (octadecyl) phosphite, tris (nonylphenyl) phosphite, tris (mono and / or dinonylphenyl) ) Phosphite, diisodecylpentaerythritol diphosphite, 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide, 10- (3,5-di-t-butyl-4-hydroxybenzyl)- 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide, 10-decyloxy-9,10-dihydro-9-oxa-10-phosphaphenanthrene, tris (2,4-di-t- Butylphenyl) phosphite, cyclic neopentanetetra Irbis (2,6-di-t-butyl-4-methylphenyl) phosphite, 2,2-methylenebis (4,6-di-t-butylphenyl) octyl phosphite, distearyl pentaerythritol diphosphite, di Phosphorous antioxidants such as (2,4-di-t-butylphenyl) phosphite and tetrakis (2,4-di-t-butylphenyl) -4,4-biphenylene phosphite; erythorbic acid, sodium erythorbate Alcohol-based antioxidants such as isopropyl citrate; methylated diphenylamine, ethylated diphenylamine, butylated diphenylamine, octylated diphenylamine, laurylated diphenylamine, N, N′-di-sec-butyl-p-phenylenediamine, N, N'-diphenyl-p-phenylenediam Amine-based antioxidants such as 4-benzoyloxy-2,2,6,6-tetramethylpiperidine, bis (2,2,6,6-tetramethyl-4-piperidinyl) sebacate, bis (1-octyloxy- 2,2,6,6-tetramethyl-4-piperidinyl) sebacate, bis (1,2,2,6,6-pentamethyl-4-piperidinyl) sebacate, dimethyl-1- (2-hydroxyethyl) -succinate 4-hydroxy-2,2,6,6-tetramethylpiperidine and its condensate, 8-acetyl-3-dodecyl-7,7,9,9-tetramethyl-1,3,8-triazaspiro [4,5 Hindered amine antioxidants such as decane-2,4-dione; and the like. These antioxidants may be used alone or in combination of two or more. Of these antioxidants, phenolic antioxidants are preferred, and sodium salicylate is particularly preferred.

  The amount of the antioxidant used is preferably 0.0001% by mass or more and 10% by mass or less, more preferably 0.001% by mass or more and 5% by mass or less with respect to PVP. When the amount of the antioxidant is less than 0.0001% by mass, it may be difficult to stabilize the K value of PVP. On the contrary, when the usage-amount of antioxidant exceeds 10 mass%, the original characteristics of PVP, such as a property and an external appearance, may be impaired.

  The PVP is also preferably a PVP containing a secondary amine or a salt thereof. Since PVP containing a secondary amine or a salt thereof has high solubility in a solvent, it is possible to produce a membrane efficiently. Examples of the secondary amine include dimethylamine, diethylamine, dipropylamine, diisopropylamine, N-methylethylamine, N-methylpropylamine, N-methylisopropylamine, N-methylbutylamine, N-methylisobutylamine, N Aliphatic secondary compounds such as -methylcyclohexylamine, N-ethylpropylamine, N-ethylisopropylamine, N-ethylbutylamine, N-ethylisobutylamine, N-ethylcyclohexylamine, N-methylvinylamine, N-methylallylamine N-methylethylenediamine, N-ethylethylenediamine, N, N′-dimethylethylenediamine, N, N′-diethylethylenediamine, N-methyltrimethylenediamine, N-ethyltrimethylenediamine N, N′-dimethyltrimethylenediamine, N, N′-diethyltrimethylenediamine, diethylenetriamine, dipropylenetriamine and other aliphatic diamines and triamines; N-methylbenzylamine, N-ethylbenzylamine, N-methylpheny Aromatic amines such as tilamine and N-ethylphenethylamine; N-methylethanolamine, N-ethylethanolamine, N-propylethanolamine, N-isopropylethanolamine, N-butylethanolamine, N-isobutylethanolamine and the like Monoalkanolamines; dialkanolamines such as diethanolamine, dipropanolamine, diisopropanolamine, dibutanolamine; pyrrolidine, piperidine, piperazine, N-methylpipera Emissions, N- ethylpiperazine, morpholine, cyclic amines, such as thiomorpholine; and the like. These secondary amines may be used alone or in combination of two or more. Of these secondary amines, dialkanolamines and dialkylamines are preferred, dialkanolamines are more preferred, and diethanolamines are particularly preferred.

  The amount of secondary amine used may be appropriately adjusted according to the amount of monomer used, and is not particularly limited. For example, the pH of the aqueous monomer solution is preferably 7 or more, 10 or less, More preferably, it may be 7 or more and 9 or less. Specifically, the use amount of the secondary amine is preferably 10 ppm or more and 10,000 ppm or less, more preferably 50 ppm or more and 5,000 ppm or less with respect to the use amount of the monomer.

  PVP is preferably PVP obtained by polymerizing N-vinyl-2-pyrrolidone synthesized from γ-butyrolactone and monoethanolamine and produced by vapor-phase dehydration reaction of N- (2-hydroxyl) pyrrolidone. PVP produced by this method is preferable because it is characterized by few impurities such as by-products. The purity of N-vinyl-2-pyrrolidone obtained using this method is 99.98% or more and less than 100%, and the amount of organic impurities is 1 ppm or more and 80 ppm or less. Since it is PVP polymerized from a raw material (N-vinyl-2-pyrrolidone) with few impurities, the molecular weight distribution is sharp. Furthermore, it is possible to sharpen the pore size distribution of the obtained membrane. By using PVP having this molecular weight distribution, it is possible to reduce the albumin permeability to 0.15% or less.

  The purity of N-vinyl-2-pyrrolidone and the amount of organic impurities were measured by gas chromatography (column: manufactured by SPELCO; DB-1, carrier gas: He, flow rate: 17.2 mL / min, temperature: 60-250 ° C). Can be measured.

  The form of the hollow fiber membrane is not particularly limited and may be a so-called straight thread, but is preferably provided with a crimp from the viewpoint of diffusion efficiency when used for hemodialysis. FIG. 2 is a view for explaining the crimp shape of the hollow fiber membrane. As shown in FIG. 2, the crimp shape is the outer surface shape of the hollow fiber membrane, and the outer surface shape is represented by a predetermined wavelength (1) and amplitude (2) when viewed from the cross-sectional direction. Say. The wavelength is preferably 2 mm or more and 20 mm, more preferably 4 mm or more and 8 mm or less. On the other hand, the amplitude is preferably 0.1 mm or more and 5 mm or less, more preferably 0.2 mm or more and 1 mm or less. The shorter the wavelength, the higher the filling rate into the hollow fiber membrane module such as a blood purifier, but it is difficult to make the wavelength less than 2 mm. If the wavelength exceeds 20 mm, the effect of crimping tends to be difficult. Even if the amplitude is less than 0.1 mm, the effect of crimping tends to be difficult, and if it exceeds 5 mm, it tends to be difficult to make a blood purifier when bonding.

  The film thickness of the hollow fiber membrane is preferably 25 μm or more and 40 μm or less. More preferably, they are 25.5 micrometers or more and 35 micrometers or less. According to the inventor's research, it has been found that the hollow fiber membrane having a thin film thickness tends to have high impurity removal performance. However, if the film thickness is less than 25 μm, the hollow fiber membrane is frequently crushed at the time of bonding, and the performance of the hollow fiber membrane module such as a dialysis blood purifier is deteriorated as a result. There is a tendency. When the film thickness exceeds 40 μm, the impurity removal performance of a hollow fiber membrane module such as a blood purifier for dialysis tends to be difficult to improve. In addition, the film thickness as used in the field of this invention is an average value of 100 hollow fiber membranes.

  Since the thickness of the hollow fiber membrane is as thin as 25 μm or more and 40 μm or less in a preferred embodiment, it is preferable that the breaking strength in the longitudinal direction of the yarn is 6 MPa or more and the elongation at break is 60% or more. The thinner the film thickness, the lower the absolute strength of the film. Therefore, the hollow fiber film may be crushed by the pressure of the adhesive during bonding. Therefore, it is preferable to increase the breaking strength as the film thickness decreases. Specifically, if the film thickness of the hollow fiber membrane is 35 μm or less, the breaking elongation is preferably 7 MPa or more, and if the film thickness is 30 μm or less, the breaking elongation is preferably 7.5 MPa or more. Further, if the hollow fiber membrane is thin, the membrane may be cut at the adhesive interface. Therefore, if the film thickness of the hollow fiber membrane is 35 μm or less, the breaking elongation is preferably 65% or more, and if the film thickness is 30 μm or less, the breaking elongation is preferably 70% or more.

  The hollow fiber membrane preferably has a sponge structure in which the pore diameter continuously decreases from the outer surface toward the inner surface. For example, in dialysis applications, the mainstream is to flow blood through the hollow portion (inner membrane surface side) of the hollow fiber membrane. In order to make it difficult for protein in the blood to block the pores of the hollow fiber membrane on the inner surface of the membrane, a high concentration of polyvinyl pyrrolidone is retained on the inner surface of the membrane, and at the same time, in order to smooth the mass transfer during filtration by dialysis The structure of the thread membrane is preferably a structure in which the pore diameter continuously decreases from the outer surface to the inner surface of the membrane. Furthermore, the structure of the hollow fiber membrane is preferably a sponge structure. Here, the “sponge structure” refers to a structure having no voids having a pore diameter (biaxial average diameter, that is, an average value of a short diameter and a long diameter) of 5 μm or more in the membrane cross section. Note that “minor axis” and “major axis” refer to the short side and long side of a circumscribed rectangle that minimizes the area circumscribing the void, respectively.

  When the hollow fiber membrane has a sponge structure in which the pore diameter continuously decreases from the outer surface toward the inner surface, it has a skeleton portion called “fibril” that exists in a mesh shape in the majority of the film thickness portion. The average thickness of all fibrils present in the hollow fiber membrane is preferably 100 nm or more and 200 nm or less. When the average thickness of all the fibrils is less than 100 nm, the breaking strength and breaking elongation tend to decrease.

  When the average thickness of all the fibrils exceeds 200 nm, the albumin permeability may exceed 0.35% when the hollow fiber membrane is used for dialysis. When used for dialysis, etc., a membrane having a fractionation property that hardly permeates albumin (molecular weight: 67,000) useful for the human body is required, and the permeability of bovine plasma albumin is 0.35% or less. it can. When the albumin permeability exceeds 0.35%, it means that effective albumin is largely lost in the body, which is not preferable as a membrane for dialysis.

  The amount of albumin stored in vivo is about 300 g (4.6 g / kg) for adult males. About 40% of the total is distributed in the blood vessels and the remaining 60% is distributed outside the blood vessels. I keep it. Albumin is decomposed in muscle, skin, liver, kidney and the like, and the daily decomposition rate of albumin is approximately 4% (0.18 g / kg / day) of the amount stored in vivo. The half-life of albumin in vivo is about 17 days. On the other hand, albumin is produced mainly in the liver (0.20 g / kg / day). Therefore, the balance of albumin in the living body is in a state close to ± 0. In general, dialysis patients undergo blood purification by artificial dialysis three times a week. Therefore, when artificial dialysis is performed on a membrane having an albumin permeability of 0.35%, an albumin loss of about 0.02 g / kg / week results. Therefore, if the albumin permeability exceeds 0.35%, the equilibrium state of albumin in the living body is lost, which may cause other diseases.

  Furthermore, in the present invention, when the ratio (Y / X) of the average thickness Y of the fibrils on the outer side in the film thickness direction and the average thickness X of the fibrils on the inner side in the film thickness direction is large, the impurity removal performance may be improved. I understood. Specifically, it is preferable that Y / X is 1.2 or more and 2.0 or less. When the ratio of the average thickness of the fibrils on the outer side in the film thickness direction to the average thickness of the fibrils on the inner side in the film thickness direction is less than 1.2, the pore diameter continuously decreases from the outer surface to the inner surface of the film. Since the slope is small, the albumin permeability tends to exceed 0.35%.

  The larger the ratio of the average thickness of the fibrils on the outer side in the film thickness direction to the average thickness of the fibrils on the inner side in the film thickness direction, the more the filtration rate (for example, impurity removal performance in dialysis) is improved. This is preferable because the transmittance can be kept low. However, it is difficult to manufacture a film exceeding 2.0 in terms of (Ga / Vs ′ × Am / As), which has a relationship with (spinning speed and air gap) and (spinner discharge cross-sectional area and film area) described later. is there.

  The thickness of the fibril (network-like skeleton) is measured by the following method. After the target hollow fiber membrane is swollen with water, it is fractured perpendicularly to the longitudinal direction in a state of being frozen at −30 ° C. to obtain a transverse section fracture sample. A cross section of the sample obtained using a scanning electron microscope (SEM) is photographed. Photographing is performed at an acceleration voltage of 10 kV and a photographing magnification of 10,000 times. Under this condition, it is possible to observe a structure corresponding to a width of 15 μm at the cross section in the film thickness direction.

  For hollow fiber membranes with a film thickness of 30 μm or less, SEM photographs were taken with the innermost side (inner membrane surface side) of the film thickness part aligned with the edge of the field of view, and this was used to average the fibrils inside the film thickness direction Measure thickness.

  The average thickness of all fibrils is measured using the above two photographs in the case of a hollow fiber membrane having a thickness of 30 μm or less. On the other hand, in the hollow fiber membrane having a film thickness exceeding 30 μm, there is a portion that is not covered (not photographed) by the above two photographs, so that the distance from the inner surface to the outer surface is equal in the film thickness direction. After a certain center point is determined, the SEM photograph is taken with the center of the field of view aligned with the center point, and a portion that cannot be taken with the above two photographs is taken, and this is used to center the film thickness direction. Measure the average thickness of a fibril.

  However, when determining the thickness of the fibril at the center in the film thickness direction, the portion not included in the photograph on the inner and outer surfaces of the film is used.

  The thickness of the fibril (network-like skeleton) defined in the present invention is the thickness of the thinnest part near the center of each fibril observed in the above photograph, that is, the joint between the fibrils and the joint. The thickness of the narrowest part is read at an angle perpendicular to the longitudinal direction of the fibril.

  The part for measuring the thickness of the fibril is the area band corresponding to the width of the central part in the film thickness direction in the cross-sectional SEM photograph of each part taken corresponding to the width of 15 μm, and 100 fibrils in the area band are arbitrarily selected. And measure the thickness. This is performed for each cross-sectional SEM photograph of each part. The average value of the 100 values is the average thickness of fibrils at each site (outside, inside and center in the film thickness direction (only when the film thickness exceeds 30 μm)). Moreover, the value which carried out the arithmetic mean of each average value is made into the average thickness of all the fibrils.

  The hollow fiber membrane includes a step of filtering a solution containing polyvinylpyrrolidone as a raw material, and a step of obtaining a hollow fiber membrane containing polyvinylpyrrolidone and a hydrophobic polymer by adding a hydrophobic polymer to the filtered solution and discharging the solution. And a step of coating the inner surface of the hollow fiber membrane with a solution substantially free of polyvinyl pyrrolidone and a step of crosslinking the polyvinyl pyrrolidone contained in the hollow fiber membrane by at least a production method Can do. By this production method, it is possible to produce a hollow fiber membrane in which soluble polyvinylpyrrolidone extracted from the hollow fiber membrane has a peak mode diameter of 300 nm or less on the largest particle size side in a particle size distribution measured by a dynamic light scattering method.

  The raw materials for solid materials such as polyvinylpyrrolidone and hydrophobic polymers used in the manufacturing process of the hollow fiber membrane should be made oxygen-free by repeating decompression, substitution of inert gas such as nitrogen and carbon dioxide, and decompression several times. Is preferred. Polyvinylpyrrolidone is preferably managed from the production to the use in an inert gas atmosphere or under reduced pressure so that oxygen never enters, and all solutions such as solvent and water used in the production and production process are removed. An oxygen state is preferred. A deoxygenated state can be obtained by deaeration or bubbling with an inert gas. Among these, substitution of an inert gas such as nitrogen or carbon dioxide is preferable because the manufacturing cost can be reduced. It is preferable to circulate nitrogen and carbon dioxide while removing oxygen using a gas separation membrane, an adsorbent, or the like because it can be used at a lower cost.

  In the present invention, a hollow fiber membrane is produced as a method for setting the mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic scattering method of polyvinylpyrrolidone in the hollow fiber membrane to 300 nm or less. The polyvinyl pyrrolidone solution used as a raw material at this time may be filtered in advance using a filter. In that case, it is also possible to filter the polyvinyl pyrrolidone solution while applying ultrasonic vibration. More specifically, in a film forming method for forming a film forming stock solution obtained by mixing and dissolving a polysulfone-based polymer, polyvinyl pyrrolidone and a solvent into a predetermined shape, a polyvinyl pyrrolidone solution in which polyvinyl pyrrolidone and a solvent are dissolved in advance. After filtering with a filter having a pore size of 3 μm or less while applying ultrasonic vibration, other materials (for example, a hydrophobic polymer such as polysulfone polymer (or solvent and polysulfone polymer)) were dissolved in the solution. It can manufacture by using a film-forming stock solution.

  Predetermined concentration, temperature, and filtration flow range using a filter having a pore size of 3 μm or less while applying ultrasonic vibration to a solution in which polyvinylpyrrolidone and a solvent are dissolved in advance (hereinafter also simply referred to as “polyvinylpyrrolidone solution”). The secondary peak component and the like shown in FIG. 1 can be removed by filtering with.

  The polyvinyl pyrrolidone concentration in the polyvinyl pyrrolidone solution varies depending on the molecular weight of the polyvinyl pyrrolidone used, but it is preferably 0.1 to 15% by mass for polyvinyl pyrrolidone having a weight average molecular weight of 1,200,000. If it is less than 0.1% by mass, it is not practical, and if it exceeds 15% by mass, the particle size of polyvinylpyrrolidone after filter filtration exceeds 300 nm, which is not preferable.

  The temperature of the polyvinylpyrrolidone solution varies depending on the solvent used and the material of the filter, but is preferably 35 to 120 ° C. When the temperature is lower than 35 ° C., the particle size of the polyvinyl pyrrolidone after filtration exceeds 300 nm, and when the temperature is kept at 120 ° C. or higher for a long time, the polyvinyl pyrrolidone may be crosslinked or modified even in a deoxygenated state.

The filtration flow rate of the polyvinylpyrrolidone solution is preferably 0.01 to 3 mL (milliliter) / (minute (unit time) · cm ² (per filter unit effective filtration area)). If it is less than 0.01 mL / (min · cm ² ), the filtration flow rate is slow, which is not practical. If it exceeds 3 mL / (min · cm ² ), the particle size of polyvinylpyrrolidone after filtration exceeds 300 nm, which is not preferable.

  The filter that can be used in the present invention has a minimum pore diameter (hereinafter, simply referred to as “pore diameter”) of 0.01 to 3 μm, preferably 0.1 to 2 μm. When the pore size of the filter is larger than 3 μm, it is difficult to make the mode diameter of the peak closest to the subject particle size in the particle size distribution measured by the dynamic light scattering method to 300 nm or less, and when the pore size is less than 0.01 μm, filtration is performed. The speed is low and impractical.

  The ultrasonic vibration applied to the polyvinyl pyrrolidone solution at the time of filter filtration is necessary to reduce the particle size of the polyvinyl pyrrolidone after filter filtration to 300 nm or less. The frequency of the ultrasonic vibration is preferably 20 kHz or more and 1000 kHz or less, more preferably 40 kHz or more and 100 kHz or less. Less than 20 kHz is not preferable because the effect tends to be low. If the frequency exceeds 1000 kHz, the filter and the filter housing may be damaged when ultrasonic vibration is repeatedly applied for a long time.

  The stock solution for membrane formation is placed in a temperature-controllable container with ultrasonic vibration and filtered polyvinylpyrrolidone solution after filtration and a hydrophobic polymer (for example, polysulfone polymer (or polysulfone polymer and solvent)). It is manufactured by dissolving using a mixer such as a sill mixer. This is preferably performed in a deoxygenated atmosphere.

  Since there is a possibility that impurities are also mixed in a hydrophobic polymer such as a polysulfone-based polymer, after preparing the film forming stock solution by the above method, the pore diameter is about 40 μm or less again to remove impurities or undissolved materials. It is preferable to filter with this filter.

Examples of the polysulfone-based polymer that can be used in the present invention include those having a repeating unit represented by the following formula (4) or formula (5). Ar in the formula represents a disubstituted phenyl group at the para position, and the degree of polymerization and molecular weight are not particularly limited.
—O—Ar—C (CH ₃ ) ₂ —Ar—O—Ar—SO ₂ —Ar— (4)
—O—Ar—SO ₂ —Ar— (5)

  The solvent for the polyvinyl pyrrolidone solution or the film forming stock solution may be any solvent that dissolves both the polysulfone polymer and the polyvinyl pyrrolidone. For example, if the polysulfone polymer is a polysulfone polymer, the solvent is N-methyl-2. -Pyrrolidone, dimethylacetamide, etc. are used. In addition, it is preferable to use what deoxygenated all the solvents.

  The weight average molecular weight of the polyvinylpyrrolidone used in the present invention is preferably in the range of 1,000 to 2,000,000, and more preferably in the range of 10,000 to 1,300,000. The present invention is particularly effective when a hollow fiber membrane using a high molecular weight polyvinylpyrrolidone having a weight average molecular weight of 800,000 or more is used. Even if a high molecular weight polyvinylpyrrolidone having a weight average molecular weight of 800,000 or more is used, the pin is used. A hollow fiber membrane free from defects such as holes and membrane breakage can be obtained.

  The concentration of the hydrophobic polymer (polysulfone polymer, etc.) in the membrane forming stock solution is particularly limited as long as the membrane can be formed from the stock solution and the obtained membrane has the performance as a membrane. It is 1-50 mass%, Preferably it is 10-35 mass%, More preferably, it is 10-30 mass%. In order to achieve high water permeability or a large molecular weight cut off, the polymer concentration should be low, and preferably 10 to 25% by mass. In addition, a plurality of non-solvents such as water, salts, alcohols, ethers, ketones, glycols, etc. can be added to the film-forming stock solution for the purpose of controlling the viscosity and dissolution state of the stock solution. The addition amount may be determined as needed depending on the combination.

  The amount of polyvinylpyrrolidone in the film-forming stock solution is 1 to 30% by mass, preferably 1 to 20% by mass, and the optimum concentration is determined by the molecular weight of the polyvinylpyrrolidone used.

  The hollow fiber membrane can be produced, for example, by simultaneously discharging the above-mentioned membrane-forming stock solution together with the internal solution from a double annular nozzle into a coagulation bath and coagulating it.

  The internal liquid used for the production of the hollow fiber membrane is used for forming the hollow part of the hollow fiber membrane. When a dense layer is formed on the outer surface, a high-concentration aqueous solution of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and the like can be used as the internal liquid. When a dense layer is formed on the inner surface, the internal liquid described in the coagulation bath described later can be used. Further, for the purpose of controlling the viscosity of the internal liquid, it is also possible to add glycols such as tetraethylene glycol and polyethylene glycol and non-solvents such as glycerin.

  The hollow fiber membrane can be formed using a known tube-in-orifice type double annular nozzle. More specifically, a hollow fiber membrane can be obtained by simultaneously discharging the above-described membrane-forming stock solution and internal solution from the double annular nozzle, passing through the air gap, and then solidifying in a coagulation bath.

  Here, the “air gap” means a distance (gap) between the nozzle and the coagulation bath. In order to obtain a membrane having a sponge structure in which the pore diameter continuously decreases from the outer surface to the inner surface, the ratio of the air gap (m) to the spinning speed (m / min) is extremely important. This is because the sponge structure in which the pore diameter continuously decreases from the outer surface of the membrane toward the inner surface, the non-solvent in the inner solution comes into contact with the film-forming stock solution, and the outer surface from the inner surface portion of the film-forming stock solution. This is because phase separation is induced over time toward the site side, and further, phase separation from the inner surface portion of the membrane to the outer surface portion is not completed before the membrane-forming stock solution enters the coagulation bath.

  The ratio (Ga / Vs) of the air gap (Ga) to the spinning speed (Vs) is 0.01 to 0.1 m / (m / min) when the thickness of the hollow fiber membrane is 34 μm or more. It is preferably 0.01 to 0.05 m / (m / min). When the ratio of the air gap to the spinning speed is less than 0.01 m / (m / min), it is difficult to obtain a sponge-structured membrane in which the pore diameter continuously decreases from the outer surface to the inner surface. If the ratio exceeds / (m / min), the tension on the film is high, and therefore there is a tendency that film breakage frequently occurs in the air gap part, which is not preferable.

  On the other hand, when the film thickness of the hollow fiber membrane is less than 34 μm, the pore size continuously increases from the outer surface to the inner surface of the membrane even when Ga / Vs is low because the amount of good solvent in the membrane forming stock solution is small. A small sponge structure can be obtained. When the film thickness is less than 34 μm, Ga / Vs is preferably 0.001 to 0.01 m / (m / min).

  Here, the spinning speed (Vs, unit: m / min) is a series of hollow fiber membranes in which the membrane-forming stock solution discharged from the nozzle together with the internal solution passes through the air gap and the membrane coagulated in the coagulation bath is wound up. It refers to the moving speed of the membrane in the production process, and when there is a stretching operation, it means the moving speed of the hollow fiber membrane before the stretching operation. Further, when the air gap is surrounded by a cylindrical tube or the like, and an inert gas having a constant temperature and humidity is allowed to flow through the air gap at a constant flow rate, the hollow fiber membrane can be manufactured in a more stable state. In addition, when extending | stretching, it means the moving speed of the hollow fiber membrane before extending | stretching operation.

  Furthermore, it has been found that the relationship between the cross-sectional area (As) of the spinning nozzle discharged from the film-forming stock solution and the cross-sectional area (Am) of the obtained film affects the fibril thickness. Am / As means the remaining rate of the film-forming polymer with respect to the discharge amount of the film-forming stock solution per unit time. Therefore, the larger Am / As, the thicker the fibril. Ga / Vs ′ (where Vs ′ (m / second) is a value obtained by converting the above-described spinning speed Vs (minute speed) into a second speed) and Am / As (unit: m / (m / Second)) is 0.15 or more and 0.75 or less, the sponge structure has a pore diameter continuously decreasing from the outer surface to the inner surface of the membrane, and the average thickness of the fibrils on the outer side in the film thickness direction. And the ratio of the average thickness of fibrils on the inner side in the film thickness direction can be a film structure of 1.2 or more and 2.0 or less. When the product of Ga / Vs ′ and Am / As is less than 0.15, the ratio of the average thickness of the fibrils on the outer side in the film thickness direction to the average thickness of the fibrils on the inner side in the film thickness direction is less than 1.2. When the product of Vs ′ and Am / As exceeds 0.75, the ratio of the average thickness of the fibrils outside the film thickness direction to the average thickness of the fibrils inside the film thickness direction tends to exceed less than 2.0. is there.

  Furthermore, the average thickness of all fibrils can be adjusted to 100 nm or more and 200 nm or less by adjusting the relationship between the product of Ga / Vs ′ and Am / As and other film forming conditions.

  Examples of the coagulation bath include water; alcohols such as methanol and ethanol; ethers; and aliphatic hydrocarbons such as n-hexane and n-heptane. The inducing liquid (non-solvent) is used, but it is preferable to use water. It is also possible to control the coagulation rate by adding a good solvent for the polymer to the coagulation bath.

  The temperature of the coagulation bath is -30 to 100 ° C, preferably 0 to 98 ° C, more preferably 10 to 95 ° C. If the temperature of the coagulation bath exceeds 100 ° C. or is less than −30 ° C., the state of the film surface in the coagulation bath is difficult to stabilize.

  By irradiating the hollow fiber membrane with radiation such as electron beam and gamma ray, it is possible to crosslink the PVP in the membrane. Irradiation may be performed either before or after manufacturing the hollow fiber membrane module using the hollow fiber membrane.

  It is preferable to appropriately adjust the degree of crosslinking of the polyvinylpyrrolidone in the hollow fiber membrane by irradiating the hollow fiber membrane with a crosslinking degree adjusting agent.

  As a method of irradiating radiation with the degree of cross-linking attached to the hollow fiber membrane, for example, the hollow fiber membrane is immersed in a solution containing a cross-linking degree adjusting agent, and the hollow fiber membrane is irradiated with radiation in a solution containing the cross-linking degree adjusting agent. The method of irradiating is mentioned.

  The cross-linking degree adjusting agent is not particularly limited as long as it inhibits the cross-linking reaction of polyvinyl pyrrolidone with respect to radiation irradiation. However, when it is used for blood purification, it is necessary to consider the safety thereof, and those that are easily washed with a physiological aqueous solution and have low toxicity are preferably used. Among them, water-soluble vitamins, glycerin, mannitol, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, teraethylene glycol and other glycols, polyethylene glycol, propylene glycol and other polyglycols, ethanol and other alcohols, polyethyleneimine, Examples thereof include saccharides such as polyphenol, trehalose and glucose, inorganic salts such as sodium pyrosulfite, sodium thiosulfate and sodium hydrogen carbonate, carbon dioxide and the like, which are preferably used. These crosslinking degree adjusting agents may be used alone or in combination of two or more. The solvent for dissolving the crosslinking degree adjusting agent is preferably an aqueous solution, for example, since it is necessary to consider its safety when used for blood purification.

  Before the polyvinyl pyrrolidone is subjected to a crosslinking treatment, it is possible to prevent the polyvinyl pyrrolidone from being crosslinked more than necessary by coating the inner surface of the hollow fiber membrane with a solution containing the crosslinking degree adjusting agent. The content of polyvinyl pyrrolidone in the solution of the crosslinking degree adjusting agent is preferably small, and more preferably substantially free of polyvinyl pyrrolidone. Normally, coating with a polyvinylpyrrolidone is performed on a hollow fiber membrane made of a hydrophilic resin such as a polysulfone-based polymer, but surprisingly, by coating with a solution that does not contain polyvinylpyrrolidone. The degree of crosslinking of polyvinylpyrrolidone contained in the hollow fiber membrane can be controlled effectively.

  In particular, when the hollow fiber membrane of the present invention is used for medical purposes, sterilization is performed by radiation irradiation or the like from the viewpoint of hygiene, and it is possible to prevent gelation from proceeding more than necessary by this radiation treatment.

  The amount and type of the cross-linking degree adjusting agent imparted to the hollow fiber membrane and the concentration of the cross-linking degree adjusting agent present around the hollow fiber membrane in the solution are appropriately adjusted according to the radiation exposure dose, irradiation time, and the desired degree of cross-linking. Is possible.

  In order to crosslink polyvinylpyrrolidone in the hollow fiber membrane in a solution such as an aqueous solution, it is effective to control the target degree of crosslinking with good reproducibility by removing oxygen in the solution containing a crosslinking degree adjusting agent.

  Here, “radiation irradiation” refers to radiation irradiation using electron beams, gamma rays, etc., and the dose is preferably 5 kGy or more and 50 kGy or less, more preferably 15 kGy or more and 30 kGy or less, and around 25 kGy. More preferably.

  Next, the hollow fiber membrane module will be described.

  The hollow fiber membrane module which concerns on embodiment of this invention is a hollow fiber membrane module provided with a hollow fiber membrane in a casing, and the hollow fiber membrane bundle which consists of a plurality of things is normally used as a hollow fiber membrane. here

  The hollow fiber membrane module can be used for blood purification. Blood purification refers to removal of unnecessary substances such as urea and water in blood of humans and animals, and removal of disease-causing substances from blood and plasma. For example, in the case of a hyperlipidemic patient, it is possible to take out only plasma from blood and remove lipids from the plasma. The hollow fiber membrane module is particularly preferably used for dialysis.

  When the hollow fiber membrane module is applied as a blood purifier, the hollow fiber membrane module has a configuration in which a hollow fiber membrane bundle is built in a container having a blood inlet and outlet and a treatment liquid inlet and outlet. Are preferred.

  As such a hollow fiber membrane module, for example, a hollow fiber membrane bundle is accommodated in a cylindrical casing, both ends of the hollow fiber membrane bundle are fixed by a sealing portion, and the opening portions at both ends of the casing are formed by the sealing portion. A first chamber on the inner surface side of the hollow fiber membrane and a second chamber on the outer surface side of the hollow fiber membrane are formed in the casing and communicated with the second chamber on the outer peripheral surface in the vicinity of both ends of the casing. A hollow fiber membrane module having a supply port and a discharge port for a purification treatment liquid, and having a closure lid provided with a supply port and a discharge port for a liquid to be processed (blood, etc.) communicating with the first chamber at both ends of the cylindrical casing Is applicable.

The hollow fiber membrane module is an enzyme activity of lactate dehydrogenase (hereinafter simply referred to as “enzyme activity”) in the extract of components adhering to the hollow fiber membrane when human blood to which an anticoagulant is added is passed. Is sometimes less than 0.6 IU / mL / cm ² . Enzyme activity is preferably less than 0.3IU / mL / cm ^2, more preferably not more than 0.1IU / mL / cm ^2.

  The enzyme activity is a numerical value that serves as an index of blood compatibility when the hollow fiber membrane module is applied as a blood purifier. This blood compatibility is obtained when blood flows through the hollow fiber membrane mini-module. It can be evaluated by the enzymatic activity of lactate dehydrogenase (hereinafter also referred to as “LDH”) contained in leukocytes, platelets and the like attached to the membrane.

  The “enzyme activity” in the present invention is measured by the following method. That is, a mini-module of a hemofilter with an effective length of 7 cm and 112 hollow fiber membranes filled in a container was prepared, and heparin (HeparinSodium Injection, Yoshitomi Pharmaceutical Co., Ltd.) was added as an anticoagulant at 1,000 IU / L. 30 ml of the prepared human blood is passed through the mini module at 37 ° C. for 18 hours at a flow rate of 1.8 ml / min. Thereafter, the mini-module is thoroughly washed with physiological saline to wash away blood cells such as erythrocytes that are loosely attached to the hollow fiber membrane. After washing, the polysulfone-based hollow fiber membrane in the mini-module is taken out, immersed in 1 ml of 0.5 wt% Triton solution (Triton X-100, Polysciences, Inc.), and shaken at 750 rpm for 60 minutes at room temperature. The extract is obtained by dissolving white blood cells and platelets that adhere strongly to the membrane.

  The enzyme activity of LDH derived from blood cells contained in this extract is measured as follows.

  First, 0.6 mM sodium pyruvate (Wako Pure Chemical Industries, Ltd.) / Phosphate buffer (Wako Pure Chemical Industries, Ltd.): 0.18 mM reduced nicotinamide adenine dinucleotide (SIGMA) / phosphate buffer (Wako Pure Chemical) Prepare a reaction solution at 9: 1), add the above extract at a ratio of 50 μl to 3 ml of this reaction solution, and heat at 37 ° C. for 60 minutes. Thereafter, the absorbance is promptly measured at 340 nm, and the enzyme activity value of LDH is calculated by comparison with an untreated membrane. The enzyme activity of LDH per unit membrane area is expressed by IU which is an international unit showing enzyme activity. 1 IU means the amount of enzyme that acts on 1 micromole of substrate per minute at 37 ° C.

  The lower the LDH enzyme activity per unit membrane area measured in this way, the less blood cells are attached to the hollow fiber membrane, and the blood filter filled with the hollow fiber membrane is more biocompatible. It is judged.

  The production of the hollow fiber membrane module includes (1) a process for producing a membrane-forming stock solution for producing a hollow fiber membrane, (2) a membrane-forming step for coagulating the membrane-forming stock solution in a coagulation solution, and (3) adjusting the degree of crosslinking. A post-processing step to be performed, (4) a bundling step for bundling a plurality of hollow fiber membranes into a hollow fiber membrane bundle, (5) a modularization step for bonding the hollow fiber membrane bundle to the casing, and (6) packing the hollow fiber membrane module The process of the packing process to include may be included. Thereafter, (7) the user uses the hollow fiber membrane module.

  It is preferable that the steps from (1) to (6) (or just before (7)) are performed in a deoxygenated state. It is possible to ultimately reduce the oxidation of polyvinylpyrrolidone by deoxidizing.

  The solid raw materials such as polyvinylpyrrolidone and the hydrophobic polymer are preferably brought into an oxygen-free state by repeating decompression, inert gas replacement, decompression and the like several times. Polyvinylpyrrolidone is preferably managed from the production to the use in an inert gas atmosphere or under reduced pressure so that oxygen never enters, and all solutions such as solvent and water used in the production and production process are removed. An oxygen state is preferred. A deoxygenated state can be obtained by deaeration or bubbling with an inert gas. Among these, substitution of an inert gas such as nitrogen or carbon dioxide is preferable because the manufacturing cost can be reduced. It is preferable to circulate nitrogen and carbon dioxide while removing oxygen using a gas separation membrane, an adsorbent, or the like because it can be used at a lower cost.

  Further, by making the atmosphere in contact with the film in the manufacturing process or the like an inert gas, it is possible to avoid contact with oxygen. The steps (3) to (6) are preferably performed in an inert gas atmosphere. Furthermore, it is airtight or liquid-tight with a cap or the like so that oxygen never enters the module. It is also possible to use an oxygen scavenger as a countermeasure to rarely mix air into the module.

As described above, the hollow fiber membrane module can be manufactured in a deoxygenated state, and thus, the measured enzyme activity of LDH can be made less than 0.3 IU / mL / cm ² .

  The material of the casing (housing) when the hollow fiber membrane is modularized is a mixed resin such as polystyrene polymer, polysulfone polymer, polyethylene polymer, polypropylene polymer, polycarbonate polymer, and styrene / butadiene block copolymer. Is used. From the viewpoint of raw material costs, polyethylene-based polymers and polypropylene-based polymers are preferably used. Polypropylene polymers are particularly preferred because of compatibility with polyurethane adhesives and strength of containers. When a polypropylene polymer is used as a container material, in the present invention, the container is preferably subjected to corona discharge treatment in order to improve adhesiveness with a polyurethane adhesive. In order to further improve the adhesion, it is more preferable to perform corona discharge treatment not only on the container but also on the yarn bundle. Corona discharge to the yarn bundle is performed only at the bonding site.

  Examples are shown below, but the present invention is not limited to the following description.

  Each measuring method performed in the examples is as follows. The hollow fiber membranes used as measurement samples were all in a state sufficiently impregnated with water.

  The breaking strength of the hollow fiber membrane was measured using an autograph AGS-5D manufactured by Shimadzu Corporation at a sample length of 30 mm, 25 ° C., and a tensile speed of 50 mm / min.

The breaking strength represents the breaking load per hollow fiber membrane by calculation (kgf / cm ² ) per membrane cross-sectional area before pulling, and the breaking elongation (elongation) is determined by the breaking of the original length. Expressed in stretched length (%).

[Pinhole inspection method]
The hollow fiber membrane was tested as a blood purifier. The blood purifier was immersed in water, and a pinhole inspection of the hollow fiber membrane was performed by applying nitrogen gas from the inside of the hollow fiber membrane at a differential pressure of 1.5 kgf / cm ² for 30 seconds.

[Method for measuring albumin]
The transmittance of albumin (hereinafter also simply referred to as “Alb.”) Was measured by the following method. First, 100 hollow fiber membranes were bundled to produce a mini blood purifier having an effective length of 18 cm.
Bovine serum adjusted to a total protein concentration of 6.5 g / dL by adding physiological saline is used as the original solution, and this solution is passed through the minimodule at a linear speed of 0.4 cm / sec, and the pressure difference between the membranes is 25 mmHg. Over time, the filtrate was collected. The temperature of the original solution and the measurement environment was 25 ° C. Moreover, the hollow fiber membrane which comprises a minimodule may be in a wet state or a dry state. Subsequently, the concentration of albumin is obtained by the BCG method, and the value obtained by the following equation (4) is defined as the transmittance of albumin.
Alb. Permeability (%) = Alb. Concentration / Alb. Concentration x 100 (4)
Here, the transmittance is the value after passing through for 60 minutes.

[Biocompatibility test]
The following biocompatibility test was performed using a mini-module of a blood filter in which an effective length of 7 cm and 112 polysulfone-based hollow fiber membranes were filled in a container.

  30 ml of human blood previously washed with physiological saline and added with heparin (HeparinSodium Injection, Yoshitomi Pharmaceutical Co., Ltd.) as an anticoagulant at 1,000 IU / L is transferred to the mini-module produced at a flow rate of 1.8 ml / min. Circulation was carried out at 37 ° C. for 18 hours. Thereafter, the mini-module is washed with physiological saline, and the polysulfone-based hollow fiber membrane in the mini-module is taken out and immersed in 1 ml of 0.5% Triton solution (Triton X-100, Polysciences, Inc.) for 60 minutes at room temperature. By shaking at 750 rpm, leukocytes and platelets strongly adhering to the polysulfone-based hollow fiber membrane in the minimodule were dissolved to obtain an extract. The enzyme activity of LDH contained in this extract was measured. In addition, the measurement was performed 3 times and described as an average value.

<Example 1>
1) Production of N- (2-hydroxyethyl) -2-pyrrolidone γ-butyrolactone, 2-aminoethanol and water were charged into a reaction vessel to produce N- (2-hydroxyethyl) -2-pyrrolidone. . The molar ratio of 2-aminoethanol / γ-butyrolactone was 1.0, the molar ratio of γ-butyrolactone / water was 1.1, the reaction temperature was 250 ° C., and the reaction time was 2 hours. The reaction product obtained was 73.0% by weight of N- (2-hydroxyethyl) -2-pyrrolidone, 21.1% by weight of low-boiling components (0.1% by weight of 2-aminoethanol, γ-butyrolactone. 0% by weight and 20.0% by weight of water) and 5.9% by weight of a high-boiling component. Purified N- (2-hydroxyethyl) -2-pyrrolidone was recovered from this reaction product by distillation. According to the impurity measurement of this product, γ-butyrolactone, 2-aminoethanol (low boiling point component) and high boiling point component were not detected.

2) Production and purification of N-vinyl-2-pyrrolidone 3.45 g of lithium nitrate was dissolved in 50 g of water, heated and stirred at 90 ° C., added with 30 g of silicon oxide, heated and concentrated, and then in air at 120 ° C. for 20 hours. Dried. The obtained solid was crushed to 9 to 16 mesh, and calcined at 500 ° C. for 2 hours in the air to prepare a catalyst having a composition of Li 1 Si 10 (Li: Si = 1: 10) at an atomic ratio excluding oxygen. 5 mL of this catalyst was filled in a stainless steel reaction tube having an inner diameter of 10 mm, and the reaction tube was immersed in a 400 ° C. molten salt bath. A raw material gas diluted with nitrogen so that the partial pressure of N- (2-hydroxyethyl) -2-pyrrolidone was 1.01 × 10 4 Pa (76 mmHg) was added to the reaction tube with N- (2-hydroxyethyl) -2. -Pyrrolidone was supplied and reacted at a space velocity of 200 h-1, and the resulting reaction gas (N-vinyl-2-pyrrolidone) excluding nitrogen was collected by cooling. The obtained N-vinyl-2-pyrrolidone was distilled with a distillation apparatus to obtain N-vinyl-2-pyrrolidone having a purity of 99.99% and organic impurities of 65 ppm.

3) Production and purification of polyvinylpyrrolidone <Polymerization process>
A reactor equipped with a stirrer, a thermometer and a reflux tube was charged with 640 parts of ion-exchanged water and 160 parts of N-vinyl-2-pyrrolidone, and nitrogen gas was introduced into the reactor while stirring the aqueous monomer solution to dissolve dissolved oxygen. Then, while stirring, the reactor was heated so that the internal temperature of the reactor became 75 ° C. Polymerization was initiated by adding a polymerization initiator solution in which 0.44 part of 2,2′-azobis (2-methylbutyronitrile) was dissolved in 4.5 parts of isopropanol to this reactor. After the polymerization initiator solution was added, the reaction was carried out by raising the jacket hot water temperature to the internal temperature from the time when the increase in the internal temperature due to the polymerization reaction was observed.
<Acid treatment process>
The reaction is continued for about 3 hours after adding the polymerization initiator solution, and then an acid aqueous solution in which 0.14 part of malonic acid is dissolved in 1.8 parts of ion-exchanged water is added to adjust the reaction solution to pH 3.5. The internal temperature was maintained at 90 ° C. for 90 minutes.
<Alkali treatment process>
Next, an alkaline aqueous solution in which 0.4 part of guanidine carbonate was dissolved in 4.2 parts of ion-exchanged water was added to adjust the reaction solution to pH 6.7, and the internal temperature was maintained at 90 ° C. for 30 minutes. An aqueous polymer solution containing polyvinylpyrrolidone was obtained.
<Antioxidant addition process>
To the resulting aqueous polymer solution, 0.8 part of sodium salicylate was added as an antioxidant and dissolved with stirring.
<Filtering process>
The resulting aqueous polymer solution (containing sodium salicylate) was diluted to a concentration of 5 wt% with ion-exchanged water. A filter made of polycarbonate having a pore diameter of 8 μm (manufactured by Advantec, diameter 47 mm) was set in a filter, 50 g of isopropanol was filtered, and 50 g of ion-exchanged water was further filtered to hydrophilize the filter. Subsequently, using this filter, the aqueous polymer solution diluted to a concentration of 5 wt% was suction filtered.
<Drying and grinding process>
The filtered aqueous polymer solution was put into a drum dryer, dried at a drum surface temperature of 140 ° C. for 20 seconds (drum rotation speed 1.5 rpm), and then pulverized using a Victory Mill VP-1 (manufactured by Hosokawa Micron Corporation), A polyvinylpyrrolidone powder composition having a solid content of 97.2 wt%, an average particle diameter of 260 μm, and a K value of 90 was obtained. Moreover, the weight average molecular weight was 1,200,000, and the value obtained by dividing the weight average molecular weight by the number average molecular weight was 2.90.
<Evaluation>
The content of insoluble matter in the obtained polyvinyl pyrrolidone was 40 ppm. The obtained polyvinyl pyrrolidone was stored in dry air at 40 ° C. for 3 months. The K value was 90, and no decrease in the K value was observed.

(Preparation of polyvinylpyrrolidone solution and filtration of the solution)
All the steps were performed in a deoxygenated state or in an inert gas atmosphere. A uniform solution (polyvinylpyrrolidone solution) obtained by dissolving 84 g of the above polyvinylpyrrolidone having a water content of 0.3% by mass or less by drying in an inert gas atmosphere at a temperature of 100 ° C. or less in 1576 g of dimethylacetamide, (Polyvinylpyrrolidone concentration 5.06% by mass). Dimethylacetamide was sufficiently deaerated and contained no oxygen.

The stainless steel sintered filter of the solution was kept at 70 ° C. The pore size 2 [mu] m (Nippon Seisen Co., Ltd., NS-02S2, effective filtration area 20 cm ²⁾ filtration with a flow rate 2 mL / (min · cm ² ). During filtration, the sintered filter was immersed in an ultrasonic cleaning machine, and ultrasonic vibration of 59 kHz (output 3 kW) was constantly applied to the polyvinylpyrrolidone solution. The mode of the peak on the largest particle size side in the particle size distribution of polyvinyl pyrrolidone as measured with a dynamic light scattering device by adjusting the concentration of the polyvinyl pyrrolidone solution after filtration to 5.0% by mass The diameter was 130 nm. The average value measured 10 times was used as the mode diameter of the peak on the largest particle size side in the particle size distribution of polyvinylpyrrolidone by a dynamic light scattering apparatus. In calculating the average value, eight values excluding the maximum value and the minimum value were used.

(Preparation of film forming stock solution and film forming)
All the steps were performed in a deoxygenated state or in an inert gas atmosphere. Further, all the liquids such as solvent and water used were deoxygenated. A uniform solution (film forming stock solution) was prepared by adding 170 g of aromatic polysulfone (Amoco Engineering Polymers P-1700) to 830 g of the above filtered solution (polyvinylpyrrolidone solution) and dissolving it. In order to remove undissolved materials and the like of polysulfone, this membrane-forming stock solution was filtered using a filter having a pore size of 5 μm (manufactured by Fuji Filter Co., Ltd., FD-5, effective filtration area 40 cm ² ).

  This solution (film forming stock solution) was kept at 60 ° C. after defoaming, and with an internal solution composed of a mixed solution of 55% by mass of dimethylacetamide and 45% by mass of water, a spinning nozzle (double annular nozzle 0.1 mm-0.2 mm -0.3 mm) (inner liquid is discharged from an annular nozzle with an inner wall diameter of 0.1 mm, and a film-forming solution is discharged from between an outer wall diameter of 0.2 mm and an inner wall diameter of 0.3 mm) and passes through an air gap of 380 mm. And immersed in a coagulation bath made of 70 ° C. water. At this time, the nozzle to the coagulation bath were surrounded by a cylindrical tube, and the humidity of the air gap in the tube was controlled to 100% and the temperature to 45 ° C. The spinning speed was fixed at 27 m / min. Before winding the obtained hollow fiber membrane, a crimper having a wavelength of 6 mm and an amplitude of 0.6 mm was applied by a crimper (a device for applying a crimp to the hollow fiber membrane). The drying temperature in the crimper was set to 155 ° C., and the drying time was set to 120 seconds.

(Manufacture of blood purifiers)
All the steps were performed in a deoxygenated state or in an inert gas atmosphere. Further, all the liquids such as solvent and water used were deoxygenated. A bundle of 9600 wound hollow fiber membranes is loaded into a polypropylene cylindrical container designed so that the effective membrane area of the hollow fiber membrane is 1.5 m ^2, and both ends thereof are bonded and fixed with urethane resin. Then, both end surfaces were cut to form an open end of the hollow fiber membrane. In addition, header caps were attached to both ends.

  A solution prepared by dissolving 15 g of glycerin (manufactured by Wako Pure Chemical Industries, special grade) and 5 g of glucose (manufactured by Wako Pure Chemical Industries, special grade) in 80 g of an aqueous solution of 0.1% by weight sodium thiosulfate (manufactured by Wako Pure Chemical Industries, special grade) is prepared. (This is called a (glycerin + glucose) solution having a concentration of 20% by mass). A solution obtained by diluting this solution 40-fold with a 0.1% by mass aqueous sodium thiosulfate solution ((glycerin + glucose) concentration 0.5% by mass) was injected into the blood purifier to enter / exit the hollow fiber membrane. So that the solution was fully immersed. The solution was thoroughly bubbled with nitrogen. At this time, it was confirmed that there was no oxygen in the solution. Thereafter, the blood purifier was irradiated with 20 kGy of an electron beam.

(Measurement of the mode diameter of the peak on the largest particle size side in the particle size distribution measured by the dynamic light scattering method)
The mode diameter of the peak on the largest particle size side in the particle size distribution measured with a dynamic light scattering device of soluble polyvinylpyrrolidone extracted from the blood purifier after irradiation was 130 nm. A pinhole test was performed on the blood purifier, but no missing yarn was found. The performance of this membrane is shown in Table 1.

Value of this hollow fiber membrane was measured clearance value and the clearance values of phosphorus vitamin _{B 12} after irradiation to create the blood purifier of 1.5 m ^2, respectively 156 mL / min, was 190 mL / min. The albumin permeability was 0.25%. The enzyme activity of LDH was 0.1 IU / mL / cm ² .
It has been clarified that the present invention is a hollow fiber membrane module having excellent biocompatibility such as less adhesion of blood cells such as leukocytes and platelets.

<Comparative Example 1>
The same as in Example 1 except that polyvinylpyrrolidone (BASF, K value 90, weight average molecular weight 1,200,000) having a water content of 0.3% by mass or less by drying at a temperature of 100 ° C. or lower was used. The operation was performed.

<Comparative example 2>
The same operation as in Example 1 was performed except that the solvent and the production process were not deoxygenated.

Claims (23)

A hollow fiber membrane module comprising a hollow fiber membrane in a casing,
The hollow fiber membrane is a hollow fiber membrane containing a hydrophobic polymer and polyvinylpyrrolidone,
Hollow, in which the enzyme activity of lactate dehydrogenase in the extract of the component adhering to the hollow fiber membrane is less than 0.6 IU / mL / cm ² when human blood added with an anticoagulant is passed through Yarn membrane module. The hollow fiber membrane module according to claim 1, wherein the polyvinyl pyrrolidone has a K value defined by the following formula of 75 or more and a value obtained by dividing the weight average molecular weight by the number average molecular weight is 2.95 or less.

[Wherein, C is the polyvinylpyrrolidone concentration (g / L) in the aqueous solution of polyvinylpyrrolidone, and C is 10 (g / L). Z is the relative viscosity of the aqueous solution of polyvinyl pyrrolidone at a concentration C measured at 23 ° C. with a capillary viscometer. ]   The hollow fiber membrane module according to claim 1 or 2, wherein the hollow fiber membrane has a crimp shape.   The hollow fiber membrane module according to any one of claims 1 to 3, wherein a film thickness of the hollow fiber membrane is 25 µm or more and 40 µm or less. The hollow fiber membrane is
When the film thickness is 30 μm or less, the breaking strength is 7.5 MPa or more, the breaking elongation is 70% or more,
When the film thickness exceeds 30 μm and is 35 μm or less, the breaking strength is 7 MPa or more, the breaking elongation is 65% or more,
The hollow fiber membrane module according to any one of claims 1 to 4, wherein when the film thickness exceeds 35 µm, the breaking strength is 6 MPa or more and the breaking elongation is 60% or more.   The hollow fiber membrane module according to any one of claims 1 to 5, wherein the hollow fiber membrane is a hollow fiber membrane having a pore diameter continuously decreased from an outer surface toward an inner surface and has a sponge structure. .   The hollow fiber membrane module according to any one of claims 1 to 6, which is used for blood purification.   The hollow fiber membrane module according to any one of claims 1 to 7, wherein the albumin permeability is 0.35% or less.   The hollow fiber membrane module according to any one of claims 1 to 8, wherein a degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane is 80% or more and less than 100%. Polyvinylpyrrolidone in the hollow fiber membrane is
The hollow fiber membrane module according to claim 9, wherein the crosslinking degree is adjusted to 80% or more and less than 100% by injecting a crosslinking degree adjusting agent into the hollow fiber membrane and irradiating the hollow fiber membrane with radiation. A method for producing a hollow fiber membrane module comprising a hollow fiber membrane containing a hydrophobic polymer and polyvinylpyrrolidone in a casing,
A production method wherein the production is carried out in a state where the polyvinylpyrrolidone is not substantially oxidized.   The manufacturing method of Claim 11 which performs all the processes from the membrane-forming stock solution preparation of the said hollow fiber membrane to the packaging of a hollow fiber membrane module in an oxygen-free state.   The manufacturing method according to claim 12, wherein the oxygen-free state is achieved by an inert gas.   The manufacturing method of Claim 13 whose said inert gas is nitrogen. The production according to any one of claims 11 to 14, wherein the polyvinyl pyrrolidone has a decrease in K value defined by the following formula of less than 1 after storage for 40 days in a nitrogen atmosphere at 40 ° C. Method.

[Wherein, C is the polyvinylpyrrolidone concentration (g / L) in the aqueous solution of polyvinylpyrrolidone, and C is 10 (g / L). Z is the relative viscosity of the aqueous solution of polyvinyl pyrrolidone at a concentration C measured at 23 ° C. with a capillary viscometer. ]   The said polyvinyl pyrrolidone is a manufacturing method as described in any one of Claims 11-15 which is polyvinyl pyrrolidone containing antioxidant.   The manufacturing method according to claim 16, wherein the antioxidant is sodium salicylate.   The said polyvinyl pyrrolidone is a manufacturing method as described in any one of Claims 11-17 which is a polyvinyl pyrrolidone containing a secondary amine or its salt.   The production method according to claim 18, wherein the secondary amine is diethanolamine. The polyvinyl pyrrolidone has a K value defined by the following formula of 75 or more, and a value obtained by dividing a weight average molecular weight by a number average molecular weight is 2.95 or less. The manufacturing method as described.

[Wherein, C is the polyvinylpyrrolidone concentration (g / L) in the aqueous solution of polyvinylpyrrolidone, and C is 10 (g / L). Z is the relative viscosity of the aqueous solution of polyvinyl pyrrolidone at a concentration C measured at 23 ° C. with a capillary viscometer. ]   The polyvinyl pyrrolidone is a polyvinyl pyrrolidone obtained by polymerizing N-vinyl-2-pyrrolidone produced by subjecting N- (2-hydroxyethyl) pyrrolidone obtained from γ-butyrolactone and monoethanolamine to vapor phase dehydration reaction. The manufacturing method as described in any one of 11-20.   The method according to claim 21, wherein the N-vinyl-2-pyrrolidone has a purity of N-vinyl-2-pyrrolidone of 99.98% or more and an organic impurity amount of 80 ppm or less. The said hollow fiber membrane is manufactured from the stock solution which filtered the solution containing the said polyvinylpyrrolidone, applying a ultrasonic vibration with a sintered filter with a hole diameter of 3 micrometers or less, and added the said hydrophobic polymer to this. The manufacturing method as described in any one of these.

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