JPH10243999A - Polysulfone-base blood dialysis membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To suppress the elution of a hydrophilic polymer and to embody the removal of unnecessary materials and the recovery of a useful material with good efficiency by specifying selective sepn. layers having a thickness of a specific numerical value and the hydrophilic polymer to be extracted with hot water to specific values per unit weight of hollow fiber membranes or below. SOLUTION: Polyvinyl pyrrolidone which is the hydrophilic polymer and a polysulfone polymer are, dissolved in a common solvent to obtain a uniform spinning stock soln. and thereafter, the stock soln. is made into the hollow fibers by dry and wet process spinning. The thickness of the selective sepn. layers having substantially a sepn. function of the hollow fiber membranes is required to be 2 to 15μm, further preferably 3 to 12μm, more preferably 5 to 10μm. The measures quantity of the hydrophilic polymer extracted by the hot water is required to be <=0.5mg per 1g hollow fiber membrane. The weight ratio of the hydrophilic polymer is required to be 1 to 5%, further preferably 2 to 4.5. Further, the sieving coefft. of albumin is <=0.02, more preferably <=0.01.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a polysulfone-based hollow fiber membrane containing a hydrophilic polymer. More specifically, the present invention relates to a polysulfone-based hemodialysis membrane having an appropriate thickness of a selective separation layer and improved fractionation characteristics.

[0002]

2. Description of the Related Art Since a polysulfone-based polymer is a hydrophobic material, a permselective separation membrane using this material is
It has poor water wettability as compared with a permselective separation membrane using a hydrophilic material such as cellulose, polyacrylonitrile, and polyamide. Therefore, a permselective separation membrane in which a hydrophilic polymer is contained in a permselective separation membrane made of a polysulfone-based polymer and a method for producing the same have been proposed. For example, Japanese Patent Publication No. 5-54373 discloses that a low-viscosity undiluted solution composed of a hydrophobic polymer and a common solvent thereof is spun to contain a hydrophilic polymer in an amount of 1 to 10% by weight.
A hollow fiber membrane for blood treatment having a water absorption capacity of 3 to 10% and a method for producing the same are disclosed. JP-A-4-3006
No. 36 discloses a polysulfone-based selectively permeable hollow fiber membrane containing a hydrophilic polymer which is crosslinked and insoluble in water and present in a hydrogel state in the membrane, and a method for producing the same. JP-A-6-165926 discloses a polysulfone-based hollow fiber membrane having a dense layer on the inner surface side, wherein the hollow fiber membrane contains at least 1% by weight of a polyglycol and 1 to 8% by weight of a vinylpyrrolidone-based polymer. The weight ratio of the polysulfone-based polymer to the vinylpyrrolidone-based polymer present in the dense layer on the inner surface is 90:10 to 60:40, and the weight of the vinylpyrrolidone-based polymer present in the dense layer on the inner surface of the hollow fiber membrane The ratio is at least 1.1 of the weight ratio of the vinylpyrrolidone-based polymer present in the outer surface layer.
A polysulfone-based hollow fiber membrane characterized by a factor of two and a method for producing the same are disclosed. In recent years, low molecular proteins such as β2-microglobulin have been cited as a cause of dialysis complications, and a high-performance dialysis membrane capable of efficiently removing these from blood has been desired. In the above-mentioned conventional techniques, sufficient studies have not been made on the fractionation properties, and they are not always satisfactory. That is, if the permeation performance of the membrane is increased in order to improve the removal of the low molecular weight protein, leakage of useful proteins such as albumin becomes a problem.

[0003]

DISCLOSURE OF THE INVENTION The present invention solves the problems of the prior art and contains a hydrophilic polymer, but its elution is suppressed, and the removal of unnecessary substances and the recovery of useful substances are carried out efficiently. It is an object of the present invention to provide a polysulfone-based hemodialysis membrane having a sharp molecular weight fractionation property.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to achieve the above object, and as a result, have appropriately controlled the thickness of a selective separation layer having an effect of substantially filtering solute molecules in a membrane. It has been found that the above problem can be solved by selectively removing a hydrophilic polymer which is easily eluted and suppressing the elution. That is, the present invention provides a polysulfone-based hollow fiber membrane containing a hydrophilic polymer, wherein the thickness of the selective separation layer is 2
A polysulfone-based hemodialysis membrane, characterized in that the hydrophilic polymer extracted with hot water is 0.5 mg or less per 1 g of the hollow fiber membrane. Sieving of solute molecules is determined by the size of the solute molecules and the size of the pores in the membrane. That is, solute molecules smaller than the pore size of the membrane can pass through the membrane, but solute molecules larger than the pore size of the membrane cannot. This principle causes solute molecules to be sieved, but in the case of a membrane with an uneven membrane structure,
When the pore diameter becomes smaller in the cross-sectional direction of the membrane, that is, sieving occurs in the selective separation layer according to the present invention. Generally, the pore diameter of the membrane is small at the dense structure of the polymer portion. Therefore, the selective separation layer in the present invention can be read from a transmission electron microscope image of the cross section of the membrane. That is, the transmission electron microscope image of the cross section of the film is sectioned at a fixed width, image analysis is performed, and the ratio (tissue ratio) occupied by the polymer portion is determined. When this operation is performed from the inside of the hollow fiber to the outside of the hollow fiber, the distribution of the tissue ratio in the cross-sectional direction of the hollow fiber membrane becomes clear. As will be described later, there is a pore size distribution in the membrane, and in consideration of this, in the present invention, when the selective separation layer is subjected to image analysis with an image analysis width of 0.5 to 1.0 μm, the tissue ratio is reduced. From the highest value, 30
%, And the thickness was measured. The fractionation properties of the membrane are described in a multilayer structure model. That is, a structure in which a number of layers obtained by slicing the film in parallel to the film surface (and therefore perpendicular to the film cross section) is stacked is assumed. It is considered that the solute molecules are sieved for each layer, and that the entire membrane is subjected to multi-stage filtration. The average pore size differs for each layer, but if one layer is taken up, there is a distribution of pore sizes in that layer, so only the layer with the smallest average pore size has the effect of sieving solutes. The layer having a slightly larger pore size can also capture large solute molecules that have passed through. In other words, a solute molecule that has passed through a large pore size in a layer with a small average pore size,
Although the average pore size was slightly larger, it was sufficiently captured by pores smaller in size than the solute molecules. Therefore, as the selective separation layer, a layer from the layer having the smallest average pore diameter to the layer having a slightly larger average pore diameter is effective. In the present invention, the average pore size of the selective separation layer,
It can also be calculated by reading the size of the gap from the image of the cross section of the membrane with a transmission electron microscope, but this is a complicated operation and the size itself is small and the error increases. For this reason, in the present invention, the evaluation is made by replacing the pore diameter itself with a relatively large solute permeability. That is, in the present invention, the pore size of the selective separation layer is evaluated using the sieving coefficient of α1-microglobulin (α1-MG) measured using human serum.

[0005] The thickness of the selective separation layer is important for the sharpness of the fractionation characteristics. When the selective separation layer is thin, albumin, which is a useful plasma protein, is easily permeated if the average pore size is slightly increased to improve the molecular weight fractionability. This is because there is a distribution of pore sizes in the selective separation layer, and as the average pore size increases, the number of pores through which albumin can permeate increases. When the selective separation layer is thin, there is no other selective separation layer that traps albumin that has once leaked from a portion having a large pore diameter, so that the membrane permeates the membrane as it is. In addition, even when a structural defect occurs in the selective separation layer due to a slight change in spinning conditions or the like, leakage of a high molecular weight substance is particularly remarkable.
On the other hand, when the selective separation layer is thick, even if the membrane structure is relatively loose and the sieving coefficient of α1-MG is increased, the thicker the thickness, the smaller the leakage of albumin, that is, the sharper the molecular weight fractionation characteristics. become. This is because, because the selective separation layer of the membrane is thick, even if albumin permeates in one layer, it is trapped in any layer of the selective separation layer, and as a result, the probability of permeation through the membrane decreases. . However, if the selective separation layer is too thick, the permeation resistance becomes too large. Therefore, in the present invention, it is necessary to be 2 μm to 15 μm, more preferably 3 μm to 12 μm, and more preferably 5 μm to 10 μm. In order to remove unnecessary plasma proteins, it is desirable that the pore size of the selective separation layer is large. In the membrane of the present invention, the sieving coefficient of α1-MG is preferably 0.1 or more,
Further, it is preferably 0.2 or more. Furthermore, in the present invention, by making the thickness of the selective separation layer appropriate, such α1-
A hollow fiber membrane having an MG sieving coefficient and a sieving coefficient for albumin of 0.02 or less, preferably 0.01 or less, can be provided. The position of the selective separation layer in the cross section of the hollow fiber membrane may be inside the hollow fiber, in the center of the cross section, or both inside the hollow fiber and outside the hollow fiber, and the position is not particularly limited. In the present invention, it is preferable that the selective separation layer is located inside the hollow fiber because the protein infiltrates the membrane from the blood flowing inside the hollow fiber and the inside of the membrane is easily contaminated with the protein.

[0006] The polysulfone hemodialysis membrane of the present invention contains a hydrophilic polymer. When the content of the hydrophilic polymer is small, the hydrophilicity of the membrane surface is deteriorated, the plasma protein is adsorbed, the performance is deteriorated, and blood coagulation is liable to occur. Conversely, if the amount is too large, it does not contribute to imparting hydrophilicity to the membrane surface, and the viscosity increases with an increase in the amount charged in the spinning solution, making stable spinning difficult and increasing the production cost. Disadvantages such as come out. In addition, there is also a disadvantage that the amount of the hydrophilic polymer that is easily taken out without being strongly taken into the polysulfone-based polymer particles only increases. For this reason, in the present invention, the weight ratio of the hydrophilic polymer is preferably 1 to 5%, preferably 2 to 5%.
More preferably, it is 4.5%. Here, as a method of measuring the weight ratio of the hydrophilic polymer present in the polysulfone-based hemodialysis membrane, a method of calculating from the total nitrogen measured using elemental analysis, or a method such as pyrolysis gas chromatography A quantification method can be exemplified.

[0007] The polysulfone-based hemodialysis membrane of the present invention contains a hydrophilic polymer, but its elution from the membrane is suppressed. In the present invention, in order to improve the fractionation characteristics, the selective separation layer, that is, the dense layer having many polymer portions is set to the appropriate thickness as described above. The dense layer has few voids, and it is difficult to wash the hydrophilic polymer at this portion, and it is easily assumed that the elution of the hydrophilic polymer is further increased. In the present invention, it is found that such a hard-to-wash hydrophilic polymer can be washed as described later, and by reducing the elutable hydrophilic polymer as much as possible,
The amount of elution from the membrane was reduced. In the present invention,
Elution of the hydrophilic polymer from the membrane is evaluated as follows. That is, 0.1 g of the hollow fiber membrane was finely chopped, and 70 ° C.
Immersed in 5 cc of hot water and extracted for 1 hour. Using the extract as a test liquid, the amount of the hydrophilic polymer is determined by GPC (gel permeation chromatography). According to such a method, the amount of the hydrophilic polymer extracted with hot water can be measured. In the present invention, the amount needs to be 0.5 mg or less per 1 g of the hollow fiber membrane.
When the hollow fiber membrane of the present invention is used for hemodialysis, the amount of the hydrophilic polymer eluted into the blood can be suppressed to a substantially negligible level. In the present invention, the diameter of the film is 1 μm.
Although a film having a void-like structure having the above-mentioned voids may be used, air may remain in these voids to deteriorate blood coagulation. For this reason, in the present invention, it is preferable that the sponge-like film structure does not substantially include such a void.

The polysulfone polymer used in the present invention is a polymer comprising a repeating unit of the formula (1) or (2), but may be a polymer containing a functional group or an alkyl group, and is not particularly limited. Not something.

[0009]

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[0010]

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Examples of the hydrophilic polymer used in the present invention include water-soluble cellulose such as polyvinylpyrrolidone (hereinafter referred to as PVP), polyethylene glycol, polyglycol monoester, starch and derivatives thereof, carboxymethylcellulose and cellulose acetate. Derivatives can be mentioned. These hydrophilic polymers can be used alone or in combination. The water-soluble polymer and the polysulfone-based polymer are dissolved in a common solvent to obtain a uniform spinning solution, and then formed into a hollow fiber by dry-wet spinning. An additive such as water may be added to the spinning dope for controlling the pore size. Here, as a solvent for dissolving both the polysulfone-based polymer and the hydrophilic polymer, for example, dimethylacetamide (hereinafter referred to as DMAC), dimethylsulfoxide (hereinafter referred to as DMSO), N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, Dioxane and the like can be mentioned. These solvents can be used alone or in combination.

When forming a hollow fiber membrane, a tube-in-orifice-type double spinneret is used, and the spinning stock solution and a hollow inner solution for coagulating the spinning stock solution are simultaneously extruded from the spinneret into the air. After running in the idle running section, it is immersed and coagulated in a coagulation bath mainly composed of water installed under the spinneret and then wound up. Excessive hydrophilic polymer and solvent are removed from the wound hollow fiber membrane by washing, and glycerin is applied as necessary, and then dried by dry heat or the like. Examples of the cleaning solution for cleaning and removing excess hydrophilic polymer include a mixed solvent of a good solvent and a poor solvent of an alcohol solvent or a polysulfone polymer. More specifically, high temperature glycerin at 130 to 160 ° C. and aqueous DMAC and / or DMSO at 50 to 98 ° C. are exemplified. Examples of the washing method include a method of dipping hollow fibers in these washing liquids, a method of showering these washing liquids on hollow fibers, and a method of running hollow fibers in these washing liquids, but are not limited thereto. Any method may be used as long as the method makes contact with the hollow fiber.

In order to achieve the object of the present invention, the average pore size (in other words, the density of the membrane) and the thickness of the selective separation layer are important. . First, the type and concentration of the liquid in the hollow are important, and a mixed solvent of a good solvent and a poor solvent for the polysulfone-based polymer, for example, a dimethylacetamide aqueous solution is preferably used. If the concentration of the solvent in the hollow internal solution is increased, the coagulation force is weakened, so that the coagulation proceeds slowly. As a result, a dense coagulated structure cannot be obtained, and the selective separation layer has a sparse structure. Next, the viscosity of the spinning solution is important. If the viscosity is high, the movement of the polysulfone polymer during coagulation is suppressed, and the selective separation layer becomes thicker than when the viscosity is low under the same conditions. The viscosity of the spinning dope depends on the molecular weight of the hydrophilic polymer, the concentration of the polysulfone polymer and the hydrophilic polymer in the spinning dope, the temperature of the spinning dope, and all factors have a significant effect on the formation of the selective separation layer. Exert. The spinning draft is also an important factor, and it is necessary to increase the spinning draft to have a thick selective separation layer. Other factors affecting the formation of the selective separation layer include the distance between the spinneret and the coagulation bath, the spinneret size, the temperature and composition of the coagulation bath, the spinning speed, and the solvent used for the spinning solution. There is a balance with solute permeation performance,
It is necessary to set in consideration of the purpose.

Examples of the present invention will be described below together with comparative examples, but the present invention is not limited to these examples.

Example 1 Polysulfone (P-1700: AMOCO
18 parts by weight and PVP (K-90: ISP) 5
Parts by weight were dissolved in 77 parts by weight of DMAC and stirred for 10 hours to obtain a spinning stock solution. A 40% by weight aqueous solution of DMAC is used as a hollow inner solution, and the above spinning stock solution is simultaneously extruded at a draft rate of 3.2 times from a double spinneret at a temperature of 45 ° C. After being led to the coagulation bath, it was wound into a scallop. After washing with a 45% aqueous solution of DMAC at 85 ° C. for 50 minutes, it was washed with hot water at 90 ° C. for 20 hours to give glycerin, and further dried with dry heat. After glycerin was removed from the obtained hollow fiber membrane, it was stained with an osmium tetroxide aqueous solution, dehydrated, embedded in an epoxy resin, and after curing, an ultra-thin section of about 60 nm was prepared using an ultramicrotome to obtain a TEM.
(JEM2000FX) was observed. Obtained TEM
Using the image, the tissue ratio was measured at 0.7 μm intervals from the inner surface side of the hollow fiber toward the outer surface side using an image analyzer (IP-1000: manufactured by Asahi Kasei Corporation). The obtained data was plotted against the distance from the inner surface of the membrane to determine the thickness of the selective separation layer. Table 1 shows the results.

[0015]

Example 2 Polysulfone (P-1700: AMOCO
16 parts by weight and PVP (K-90: ISP) 4
Parts by weight were dissolved in 80 parts by weight of DMAC and stirred for 10 hours to obtain a spinning stock solution. A 30% by weight aqueous solution of DMAC is made into a hollow inner solution, and the above spinning stock solution is simultaneously extruded at a draft rate of 1.4 times from a double spinneret at a temperature of 55 ° C. After being led to the coagulation bath, it was wound into a scallop. After washing with a 45% aqueous solution of DMAC at 85 ° C. for 50 minutes, it was washed with hot water at 90 ° C. for 20 hours to give glycerin, and further dried with dry heat. After glycerin was removed from the obtained hollow fiber membrane, it was stained with an osmium tetroxide aqueous solution, dehydrated, embedded in an epoxy resin, and after curing, an ultra-thin section of about 60 nm was prepared using an ultramicrotome to obtain a TEM.
(JEM2000FX) was observed. Obtained TEM
Using the image, the tissue ratio was measured at 0.7 μm intervals from the inner surface side of the hollow fiber toward the outer surface side using an image analyzer (IP-1000: manufactured by Asahi Kasei Corporation). The obtained data was plotted against the distance from the inner surface of the membrane to determine the thickness of the selective separation layer. Table 1 shows the results.

[0016]

Comparative Example 1 Polysulfone (P-1700: AMOCO)
20 parts) and 6 parts by weight of PVP (K-90: made by ISP) were dissolved in 74 parts by weight of DMAC and stirred for 10 hours to prepare a spinning dope. A 45 wt% DMAC aqueous solution is used as a hollow inner solution, and the above spinning stock solution is simultaneously extruded at a draft rate of 3.4 times from a double spinneret at a temperature of 45 ° C., and passes through a 70 cm idle running section and is made of water at 50 ° C. After being led to the coagulation bath, it was wound into a scallop. After washing with a 45% aqueous solution of DMAC at 85 ° C. for 50 minutes, it was washed with hot water at 90 ° C. for 20 hours to give glycerin, and further dried with dry heat. After glycerin was removed from the obtained hollow fiber membrane, it was stained with an osmium tetroxide aqueous solution, dehydrated, embedded in an epoxy resin, cured, and then formed into an ultrathin section of about 60 nm using an ultramicrotome.
EM2000FX) was observed. Using the obtained TEM image, the tissue ratio was measured at an interval of 0.7 μm from the inner surface side of the hollow fiber toward the outer surface side using an image analyzer (IP-1000: manufactured by Asahi Kasei Corporation). The obtained data was plotted against the distance from the inner surface of the membrane to determine the thickness of the selective separation layer. Table 1 shows the results.

[0017]

Comparative Example 2 Polysulfone (P-1700: AMOCO
18 parts), 9 parts by weight of PVP (K-30: manufactured by ISP), 43 parts by weight of DMAC, 29 parts by weight of DMSO, and 1 part of water.
The resulting solution was added to parts by weight, dissolved, and stirred for 10 hours to obtain a spinning stock solution. A 30% by weight aqueous solution of DMAC was used as a hollow inner solution, and the above spinning stock solution was simultaneously extruded at a draft rate of 1.3 times from a double spinneret at 60 ° C., and passed through a 30 cm idle running portion to obtain a spinning solution of 50%.
After being led to a coagulation bath consisting of water at a temperature of ° C., it was wound into a scab.
After washing with a 45% aqueous solution of DMAC at 85 ° C. for 50 minutes, 9
The resultant was washed with hot water of 0 ° C. for 20 hours to give glycerin, and further dried by dry heat. After glycerin was removed from the obtained hollow fiber membrane, it was stained with an osmium tetroxide aqueous solution, dehydrated, embedded in an epoxy resin, cured, and then formed into an ultrathin section of about 60 nm using an ultramicrotome.
00FX) Observations were made. Using the obtained TEM image, the tissue ratio was measured at an interval of 0.7 μm from the inner surface side of the hollow fiber toward the outer surface side using an image analyzer (IP-1000: manufactured by Asahi Kasei Corporation). The obtained data was plotted against the distance from the inner surface of the membrane to determine the thickness of the selective separation layer. Table 1 shows the results.

[0018]

[Table 1]

[0019]

Example 3 Using the hollow fibers obtained in Examples 1 and 2 and Comparative Examples 1 and 2, a mini-module (effective length 25 cm) consisting of 100 fibers was prepared, and a human serum having a protein concentration of 6.5 g / dL was prepared. At a linear velocity of 0.4 cm / sec. Α1 in the filtrate and the original solution collected at a transmembrane pressure difference of 25 mmHg
-The concentrations of MG and albumin were measured, and the sieving coefficient was calculated from the ratio. Table 2 shows the results.

[0020]

[Table 2]

[0021]

EXAMPLE 4 The weight ratio of the hydrophilic polymer present in the membranes of the hollow fibers obtained in Examples 1 and 2 and Comparative Examples 1 and 2 was determined by elemental analysis, and the heat ratio of the hydrophilic polymer was determined. Table 1 shows the extraction amount in water.

[0022]

The polysulfone hemodialysis membrane of the present invention is
As shown in Tables 1 and 2, as compared with known homogenous dialysis membranes, they contain a hydrophilic polymer but its elution is suppressed, and it is possible to efficiently remove unnecessary substances and collect useful substances. The membrane has a sharp molecular weight fractionation property, and its usefulness is great.

Claims (5)

[Claims] 1. In a polysulfone-based hollow fiber membrane containing a hydrophilic polymer, a selective separation layer having a substantial separation function has a thickness of 2 to 15 μm, and a hydrophilic polymer extracted with hot water is used. A polysulfone-based hemodialysis membrane characterized by being 0.5 mg or less per 1 g of a hollow fiber membrane. 2. The polysulfone-based hemodialysis membrane according to claim 1, wherein the selective separation layer exists on the inner surface side of the hollow fiber. 3. The polysulfone hemodialysis membrane according to claim 1, wherein the hydrophilic polymer is polyvinylpyrrolidone. 4. The weight ratio of the hydrophilic polymer present in the polysulfone-based hemodialysis membrane is 1 to 5% by weight.
The polysulfone-based hemodialysis membrane according to the above. 5. The polysulfone-based hemodialysis membrane according to claim 1, wherein the sieving coefficient of albumin is 0.02 or less, and the sieving coefficient of α1-microglobulin is 0.1 or more.