JP2703266B2 - Polysulfone hollow fiber membrane and method for producing the same - Google Patents

Description

The present invention relates to a polysulfone hollow fiber membrane and a method for producing the same. More particularly, it relates to a polysulfone hollow fiber membrane having a structure in which the inner surface has a skin layer, the inside of the membrane has a microporous structure, and the outer surface has micropores having an average pore diameter of 500 to 5000 ° at an opening ratio of 5 to 50%, and a method for producing the same.

[Conventional technology]

In recent years, in the medical field, a technique using a membrane having a selective transmittance has been remarkably advanced, and various filters and artificial organs are being put into practical use one after another. In particular, when the shape of the membrane is a hollow fiber, the membrane area per occupied volume is large, which is advantageous, and practical examples are increasing. In addition, various types of polymers have been researched and developed as membrane materials for the selective permeation separation membrane for medical use. Cellulose, cellulose acetate, polyamide, polyacrylonitrile, polymethyl methacrylate, polyvinyl alcohol, polysulfone, and polyolefin Polymers such as systems have been used.

Polysulfone-based polymers have excellent physical and chemical properties such as heat resistance, acid resistance, alkali resistance, and oxidation resistance. Therefore, in the industrial field, ultra-permeable membranes, composite membranes for reverse osmosis and gas separation, including ultra-permeable membranes Attention has been paid to and studied as a support for the compound. For example, Japanese Patent Application Laid-Open No. 54-145379 discloses a sloped double-sided skin type polysulfone hollow having fine pores of 10 to 100 mm on the inner surface and the outer surface, and the pores gradually increase toward the inside of the membrane. Fibers are described.

JP-A-56-105704 and JP-A-56-115602 disclose a double-sided skin type having no small holes or openings on both sides of a membrane, which can be observed microscopically, and a tube bundle-like structure, so-called finger-like. A polysulfone hollow fiber structure is described.

Also, JP-A-58-114702 discloses that an average width of 500
有 し Has the following slit-shaped fine gaps and an average pore diameter of 10 on the outer surface
A sponge-structured membrane with micropores of 00-5000 ° is shown.

Further, JP-A-56-152704 discloses a polysulfone hollow fiber membrane having a dense layer on an inner surface and / or an outer surface and having a sponge layer in contact with the dense layer. A polysulfone hollow fiber membrane having a dense layer on the inner surface and having a sponge layer containing a cavity in contact with the dense layer is disclosed in Japanese Patent Application Laid-Open No. 56-155401, an asymmetric polymer membrane comprising a skin and a porous support. Is disclosed.

As a medical hollow fiber membrane made of a polysulfone-based polymer, a hemofilter of Amicon and a hemoflow of Freginias are known.

[Problem to be Solved by the Invention] However, the membrane disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 54-145379 has a skin layer on both sides or a low continuity of the bore of the internal structure. There is a problem that the overspeed is low as an over film. Also, JP-A-56-105704
Also, the membranes disclosed in U.S. Pat. Further, JP-A-58-1147
Although the membrane disclosed in No. 02 is sufficient in terms of overspeed, the permeability of serum albumin, which is an important component of body fluids, is too large, and serum albumin is washed away.

The membrane having a dense layer on both sides described in JP-A-56-152704 has a small transmittance of albumin and is good, but has a low transmittance of inulin and is inferior in the effect of removing medium molecular weight substances.

Also, the film described in JP-A-57-82515 and JP-A-56-154
The asymmetric membrane described in No. 051 has a problem that the pressure resistance is poor.

Meanwhile, Amicon's hemofilter membrane (DIAFILTER)
Has a dense skin layer on the inner surface and 10 μm on the outer surface
Since a large number of the above macropores are present, and the inside of the membrane has a finger-like structure and a high porosity, some of them have considerably high water permeability, but have low pressure resistance.

In addition, Kanafuchi Chemical Industry Co., Ltd.
LUX) is a sponge-structured membrane with 1000-3000mm pores on the inner and outer surfaces, but has a low permeability for proteins such as albumin.
90% or more, which is different from the film of the present invention.

Accordingly, an object of the present invention is to provide a polysulfone hollow fiber membrane excellent in overspeed, pressure resistance and heat resistance.

Another object of the present invention is excellent in body fluid overspeed, beta ₂ with passing inulin efficiently - and fractionation property to Shiyapu such blocking microglobulin (β ₂ -MG) and Pairojien substances, such as urea low An object of the present invention is to provide a polysulfone hollow fiber membrane having high dialysis properties of a molecular weight substance.

Still another object of the present invention is to provide a method for producing the above polysulfone hollow fiber membrane.

Another object of the present invention is to provide a body fluid treatment method using the above-mentioned polysulfone hollow fiber membrane.

Still another object of the present invention is to provide a bodily fluid treatment device containing the polysulfone hollow fiber membrane.

[Means for solving the problem]

Means for Solving the Problems The present inventors diligently studied to achieve the above object, and reached the present invention. That is, the present invention has a dense skin layer in which no pores are recognized even by a scanning electron microscope (SEM) at a magnification of 10,000 on the inner surface, and a fine pore having an average pore diameter of 500 to 5000 mm on the outer surface. 5-50%, the inside of the membrane has a microporous structure, and the serum albumin permeability is 10% or less, the inulin permeability is 50% or more, and the water permeability is 60 ml / mmHg · m ² · H
r, a polysulfone hollow fiber membrane showing at least 80% by weight of polystyrene based on polysulfone, and a stock solution added in an amount that does not cause phase separation even when the stock solution is heated to 100 ° C. The above is a method for producing a polysulfone hollow fiber membrane which is extruded into a heated and humidified gas atmosphere and spin-dry-spun.

The polysulfone hollow fiber membrane of the present invention is excellent in overspeed,
It is extremely excellent in pressure resistance and heat resistance with a consolidation index of 0.2 or less.

In particular, the polysulfone hollow fiber membrane of the present invention not only has an excellent body fluid passage rate as is clear from the examples described later, but also allows efficient permeation of inulin and β ₂
-It has a sharp fractionation property such as blocking MG and pyrodiene substances and a high dialysis property of low molecular weight substances such as urea.

The hollow fiber membrane of the present invention has a dense skin layer in which no pores are recognized even by SEM of 10,000 times on its inner surface, and has fine pores having an average pore diameter of 500 to 5000 mm on the outer surface and an aperture ratio of 5 to 5 mm. It is a sponge structure film having a ratio of 50% and the inside of the film being microporous. The hemoflow of Fresinius has a sponge structure similarly to the present invention, but differs from the present invention in this point because the inner surface is made up of pores which are clearly recognized by 10,000 times SEM. It is presumed that the reason why the membrane of the present invention shows a smaller decrease in the body fluid treatment rate over time as compared with the membrane of Fregenius is partly due to the difference in the inner surface structure. 10,000 times SEM
Does not mean that no pores larger than at least 100 ° are present.

The polysulfone hollow fiber membrane of the present invention needs to have micropores with an average pore diameter of 500 to 5000 ° on the outer surface at an opening ratio of 5 to 50%. This is because when the outer surface is formed into a dense skin layer in which no pores are recognized, the overspeed is reduced, and when the polysulfone hollow fiber membrane is used for bodily fluid treatment, the overspeed of bodily fluid is reduced, and Therefore, the ability to remove β ₂ -MG, which is the substance to be removed, and the permeability of so-called medium molecular weight substances having a molecular weight of several thousand to about 10,000 are reduced, and the diffusion permeability of low molecular weight substances such as urea is also significantly reduced. To do that. Here, the average pore diameter of the micropores on the outer surface is Where: average pore diameter D _i ; actual measurement diameter of _i- th micropore D _n ; actual measurement diameter of _n- th micropore Note that the actual measurement diameter of D _i , D _n When the pore is not circular, the diameter of a circle having the same area as the pore is shown.

It is shown by. If the average pore diameter on the outer surface is less than 500 mm, the water permeability is too low. Average pore size 5000
When the value exceeds Å, not only the permeation of serum albumin becomes too high, but also the pressure resistance tends to decrease, which is not preferable.
In the case of an external pressure, a large molecular weight substance having a molecular weight of 100,000 or more penetrates into the inside of the membrane, so that not only the overspeed decreases rapidly, but also the membrane is regenerated by back washing or chemical washing. This tends to be insufficient and is not preferred. More preferably, the average pore size is 1500-3500 °.
In the case of the present invention, micropores of 100 ° or less are not included in the calculation of the average pore diameter. However, micropores of 100 ° or less may be present to such an extent that the object and effects of the present invention are not impaired. The fine pores on the outer surface preferably have a uniform pore size, but need not be uniform, and may be non-uniform. The aperture ratio according to the present invention is a percentage of the total pore area of the micropores opened on the outer surface to the outer surface area. An aperture ratio of less than 5% is not preferable because water permeability and permeability of a medium molecular weight substance are low. 50% aperture ratio
Exceeding the surface strength is not preferred because the surface strength is reduced and the film is easily damaged during handling. An aperture ratio of 10 to 40% is more preferable in terms of a balance between the permeability and the mechanical performance of the membrane.

In the present invention, the inside of the membrane has a microporous structure. Here, the microporous structure is a sponge structure such as a mesh structure, a honeycomb structure, and a fine gap structure. Since the polysulfone hollow fiber membrane of the present invention has a sponge structure substantially free of huge cavities, it can have a stable permeation performance over time, and also has excellent pressure resistance, especially excellent anti-consolidation property during long-term use, and further strength. Is also excellent.

Next, the polysulfone hollow fiber membrane of the present invention has a consolidation index of 0.
Another major feature is that it is less than 2. Here, the consolidation index α is represented by the following equation.

_{α = 1-Kv 4 / Kv} 1 Kv 1: Permeability rate when had a 100 ° C. hot water by an external pressure type with overpressure ^{1Kg / cm 2 (m 3 /} m 2 · hr · Kg / cm 2) Kv 4 : Permeation rate when hot water of 100 ° C is passed at an overpressure of 4 kg / cm ² by an external pressure method (m ³ / m ² · hr · Kg / cm ² ) The consolidation index α is 0.2 or less, that is, 0 to 0.2 That the pressure resistance is excellent, especially at high temperatures.
Furthermore, it means that there is little decrease in overspeed with time. If α is larger than 0.2, over-treatment is not preferable because over-treatment for a long time tends to cause consolidation due to an increase in pressure due to clogging of the film and the over-treatment speed tends to sharply decrease.

The inner diameter of the polysulfone membrane of the present invention is 50 μm to 500 μm.
m, preferably 100-350 μm, more preferably 150-3
00 μm, the film thickness is 5 to 250 μm, preferably 10 to 100 μm,
More preferably, it is 20 to 70 μm. If the inner diameter is less than 50 μm, the hollow fibers are too densely packed with each other, making it difficult to form a liquid-tight module. If the inner diameter is more than 500 μm, the module becomes too large and handling is inconvenient. The film thickness is 5μ.
If it is less than 250 m, spinning is difficult and leakage is likely to occur.
Above, the water permeability and the diffusive permeability of the low molecular substance are significantly reduced.

The polysulfone hollow fiber membrane of the present invention has the above-described structural performance and has a serum albumin permeability.
10% or less, preferably 5% or less, more preferably 1.5%
%, Inulin permeability is 50% or more, preferably 70% or more, more preferably 80% or more, and water permeation rate is 60 ml at 37 ° C.
/ mmHg · m ² · Hr or more, preferably 200ml / mmHg · m ² · Hr or more, more preferably 500ml / mmHg · m ² · Hr or more, it further preferably 1000ml / mmHg · m ² · Hr or more is necessary.

Serum albumin is an important component of body fluids, so if its permeability is higher than 10%, it will be necessary to replenish fresh serum albumin with body fluid treatment in order to adjust the oncotic pressure of patients. It is not preferable because the cost increases. If the permeability of inulin, which is a marker for a substance having a molecular weight of about 5,000, is less than 50%, the effect of removing a so-called medium molecular weight substance having a molecular weight of several thousands to about 10,000, which is one of the objectives of body fluid treatment, is insufficient. On the other hand, if the water permeability is less than 60 ml / mmHg · m ² · Hr, the permeation rate of the bodily fluid is low, and it takes a long time to process the bodily fluid, which is disadvantageous.

The use of the polysulfone membrane of the present invention that satisfies such performance not only completely prevents bacteria, bacteria, and viruses, but also lipopolysatsuka, which is known as a pyrogen (pyrrodiene) in bacterial secretions. Ride can be completely stopped. Another characteristic of the film of the present invention is a transmission behavior specific for beta ₂ -MG have accumulated in long term hemodialysis in patients. That is, when dialysis or excess of blood containing β ₂ -MG is performed using the membrane of the present invention, the β ₂ -MG concentration on the membrane permeate side (perfusate side) is practically close to zero. regardless, beta ₂ -MG in blood decreases with time. The reason for this is not clear, but due to the film structure and film material, β ₂
Probably because -MG is maintained, it is estimated that because of the specific affinity between polysulfone and beta ₂ -MG. Such β
By using the specific behavior of the ₂ -MG, it is also one of Meritsuto of the present invention is beta ₂ -MG without so much the excess can easily be removed.

 In addition, the transmittance | permeability in this invention is measured by the following method.

(1) After fixing both ends of a hollow fiber membrane bundle of a number calculated to have a surface area of 1 m ^{2 based on} the inner diameter to a cylindrical housing with urethane by a conventional method, open both ends of the hollow fiber bundle. At a minimum, an artificial kidney-like module with an effective length of 24.5 cm is manufactured. This module was immersed in a 70% aqueous ethanol solution for 60 minutes while oscillating at room temperature to sufficiently wet the polysulfone membrane, replacing the air in the membrane with the aqueous ethanol solution, and then replacing the aqueous ethanol solution with physiological saline. And store it tightly.

(2) The water permeability is measured by flowing a physiological saline solution at 37 ° C. through the hollow part of the hollow fiber membrane of the above module by a blood pump (internal perfusion). That is, the outlet side of the module is closed, and TMP (transmembrane pressure) when physiological saline is permeated by the total internal pressure method is measured under at least four different flow rates, and TMP and the liquid flow rate are measured. Is graphed, and the permeability rate is determined from the gradient.

(3) Permeability of serum albumin, inulin and β ₂ -MG was determined by measuring hematocrit 30%, total protein 6.0 ± 0.2 g / dl,
The test is carried out using ACD cow blood adjusted to serum albumin 4 ± 0.5 g / dl, β ₂ -MG 20 ± 5 mg / inulin 20 ± 5 mg / dl. That is, the adjusted bovine blood at 37 ° C. was internally perfused at 200 ml / min into the module replaced with the physiological saline as described above, and circulated under TMP100 mmHg for 30 minutes. The side blood, the outlet side blood and the liquid are collected, the concentration of each substance is analyzed, and the transmittance (%) is calculated according to the following equation.

The analysis of each substance is performed by the following method.

Serum Albumin: BCG method beta ₂ -MG: Gurazaimu EIA-TEST (Wako Pure Chemical) inulin: 3-indole acetic acid method (4) Pairojien permeability measurements are modules, Yotsute all circuits or the like in a predetermined manner Pairojien After freeing, it is performed in the same manner as in (3) above, using a 10 ng / ml aqueous solution of lipopolysaccharide instead of bovine blood. In addition,
The analysis of the pyridiene is performed using a Wako Limulus single test (manufactured by Wako Pure Chemical Industries, Ltd.).

As described above, the polysulfone hollow fiber membrane of the present invention has excellent performance as a body fluid treatment membrane, particularly, a hemodialysis supermembrane of a long-term hemodialysis patient in which accumulation of β ₂ -MG is remarkable.

Next, a method for producing the polysulfone hollow fiber membrane of the present invention will be described.

Conventionally, a method of adding a denaturing agent to a membrane-forming stock solution has been carried out to improve the permeation performance of a membrane, and various types of polymers and solvents have been reported. For example, as a so-called swelling agent that increases the solvation effect of the stock solution,
There are inorganic salts such as ZnCl ₂ and organic substances such as alcohol. Other swelling agents include polyethylene glycol (PEG).

PEG as a denaturing agent is water-soluble and has good handleability because it can be easily extracted and removed after film formation.Because it has various molecular weights, it is possible to control the permeation performance by selecting the type. PEG for solvent
It has many advantages, such as high solubility, which allows it to be added in a relatively large amount despite being a high molecular weight substance, and has the property of increasing the viscosity of a stock solution because it is a high molecular weight substance. have.

Of these, increasing the amount added to the stock solution is effective because it can increase the permeation performance, particularly the water permeability. Regarding the viscosity of the stock solution, the water permeability is generally higher when the polymer concentration is lower, which is advantageous. However, when the polymer concentration is lower, the viscosity of the stock solution tends to be lower, and the film-forming stability tends to deteriorate. For example, in the case of hollow fibers, spinning becomes difficult if the viscosity is not higher than a certain viscosity. Therefore, the thickening effect by adding PEG is advantageous.

A method for producing a polysulfone membrane using PEG is disclosed in
No. 0-89475 and No. 54-26283 are already known, but each is a manufacturing method relating to a batch type flat membrane, and the resulting membrane has a fine pores (fine particles, etc.) having pores of about 0.03 μm to 10 μm on the surface. Used for the purpose of the present invention, having a substance permeability extremely specified as a body fluid treatment membrane, and having an inner surface formed of a dense skin layer and an outer surface having an average pore diameter of 500. There is no disclosure of a microporous (sponge) structure film having micropores of Å5000 ° at an opening ratio of 5 to 50%.

JP-A-58-114702 discloses polysulfone,
A technique for producing a hollow fiber membrane using a stock solution in which PEG is added until phase separation is disclosed.However, the membrane obtained by this method has too high a permeability for serum albumin, and the object of the present invention is not satisfied. It cannot be used as a body fluid treatment membrane.

The present inventors have found from many spinning experiments that in order to produce a polysulfone hollow fiber membrane having a structure and permeation performance suitable for body fluid treatment as described above, polysulfone and polyethylene glycol are mixed with N- A spinning stock solution dissolved in a solvent containing at least one of methylpyrrolidone, dimethylacetamide and dimethylsulfoxide is prepared and then extruded from an annular nozzle to produce polyethylene glycol (PEG). The addition rate of 80% or more of the polysulfone based on polysulfone and the stock solution added in an amount that does not cause phase separation even when the stock solution is heated to 100 ° C. is placed in a gas atmosphere whose temperature and humidity have been adjusted with a nozzle draft of 1.6 or more. It has been found that it is important to extrude and dry-wet spin. Hereinafter, the production method of the present invention will be described in more detail.

In the method for producing a polysulfone hollow fiber membrane of the present invention, the polysulfone concentration in the spinning dope is 12 to 30% by weight, preferably 15 to 22% by weight. If the amount is less than 12% by weight, the strength of the obtained membrane is not sufficient. On the other hand, if the amount exceeds 30% by weight, the polymer concentration is high, and the amount of PEG cannot be increased, so that the film has a sufficient permeability. It is not preferable because a film cannot be obtained.

A common solvent for polysulfone and PEG is a solvent that dissolves polysulfone and PEG and is compatible with a coagulating solution having a coagulating ability for polysulfone, such as dimethyl sulfoxide, dimethylacetamide, and a polar organic solvent such as N-methylpyrrolidone. can give. Among them, dimethylacetamide and N-methylpyrrolidone are most suitable in terms of affinity with polysulfone.

The amount of PEG added in the present invention was 8 to polysulfone.
The amount is 0% by weight or more and does not cause phase separation even when the stock solution is heated to 100 ° C. Usually, the preferable addition amount is 120 to 250% by weight, more preferably 160 to 200% by weight.

In the present invention, the amount showing the phase separation phenomenon is the amount of polysulfone and / or PEG that undergoes phase separation to form a non-uniform cloudy slurry when PEG is added to a mixture of polysulfone and a solvent at 100 ° C. 80% by weight of PEG added
If the amount is less than the above range, sufficient water permeability cannot be obtained. If the amount exceeds the amount causing phase separation, the spinning condition becomes unstable, and the serum albumin permeability becomes too large, which is inconvenient as a body fluid treatment membrane.

The PEG used in the present invention has a molecular weight of 400 to 20,000, preferably 600 to 2,000. If it is less than 400, it is difficult to improve the permeability of the membrane to the extent that the amount of addition increases, while if it exceeds 20,000, the amount of addition cannot be increased, and sufficient permeability cannot be obtained.

In preparing the stock solution, polysulfone, PEG and a mixture of these common solvents are usually heated and stirred at 80 ° C. to 130 ° C., or even 100 ° C. to 130 ° C. in consideration of the dissolution rate of the polysulfone and PEG in the solvent, to obtain a homogeneous solution. Since a solution is obtained, it is cooled to 0 to 60 ° C, preferably 10 to 40 ° C, to obtain a spinning dope.

When wet spinning is performed using this stock solution, a dense skin layer is easily formed on the outer surface, and the average pore size required in the present invention is obtained.
In order to obtain an outer surface structure in which pores having a large pore diameter of 500 to 5000 ° exist at an opening ratio of 5 to 50%, dry-wet spinning is suitable.

Here, the dry-wet spinning refers to a method in which a spinning solution is once extruded into a gas (in most cases, air) and then introduced into a coagulation solution, that is, a method in which a nozzle is not immersed in the coagulation solution. If the distance between the nozzle discharge surface and the surface of the coagulating liquid, that is, the traveling distance in the air is defined as the dry zone length, the dry zone length is preferably 0.1 to 200 cm. If it is shorter than 0.1 cm, the nozzle is immersed in the coagulation liquid even with a slight undulation of the coagulation liquid, so that dry-wet spinning cannot be performed substantially. If it exceeds 200 cm, the yarn sways greatly and normal spinning cannot be performed. A more preferred dry zone length is 0.5 to 50 cm, and 1 to 30 cm is the best in terms of balance between spinnability and membrane performance. Conventionally, dry-wet spinning is often performed for the purpose of reducing the diameter of the hollow fiber membrane and improving the spinning speed, or dry-wet spinning for the purpose of evaporating the solvent in the dry zone to obtain a skin layer on the surface. In the case of (1), a skin layer is not formed on the outer surface, but rather micropores are formed on the contrary, and a slight amount of water present in the dry zone causes slow coagulation. Therefore, the purpose and effect of the conventional dry-wet spinning are clearly different. The effect of the dry-wet spinning of the present invention is that the dry zone length is 0.
It is also distinctive in that it shows a clear difference from wet spinning with a dry zone length of 0 cm even though it is very short at 1 cm. The pore diameter on the outer surface can be controlled by the dry zone length and the atmosphere in the dry zone. Heating and humidifying the dry zone is an important factor in forming pores having an average pore diameter of 500 to 5000 mm on the outer surface, and is preferably 30 ° C x 70% RH or more or the equivalent water vapor pressure or more, More preferably, heating and humidification at 40 ° C. × 90% RH or higher or a corresponding water vapor pressure or higher can provide a hollow fiber membrane having a large surface aperture ratio.

The nozzle draft between the first roller and the undiluted solution, that is, the value of “the rotation speed of the first roller / the undiluted solution linear velocity” is also a factor that greatly affects the membrane structure and permeability,
Spinning with a nozzle draft of 1.6 or more, preferably 2.4 or more, more preferably 2.8 or more is important for obtaining the body fluid treatment membrane of the present invention. If the nozzle draft is smaller than 1.6, the membrane structure becomes too dense, and the permeability of inulin tends to decrease.

The coagulation bath is not particularly limited as long as it is miscible with the common solvent of polysulfone and PEG and is a non-solvent of polysulfone. In general, water or a mixture of water and a solvent (preferably dimethylacetamide or N-methylpyrrolidone) and water is used. Further, it may be convenient to add a surfactant or the like. The internal coagulating fluid flowing through the needle of the annular nozzle is not particularly limited, such as a coagulating liquid, an immiscible liquid, and a gas (air, nitrogen), but is preferably a coagulating liquid such as water or a mixture of a solvent and water. Among them, a mixture of water and a common solvent of polysulfone and polyethylene glycol is used to form a dense skin layer on the inner surface of the hollow fiber membrane where no pores are observed even when observed with a 10,000 times SEM. Is good.
A coagulable liquid having a weight ratio of the solvent / water of 0/100 to 85/15 is preferable. If the weight ratio of the solvent / water is 0/100 to 70/30, a balance between spinnability and membrane performance is required. Optimal.

After coagulation, 60 ° C or higher to remove the solvent and PEG,
Washing is preferably performed in warm water at 90 ° C. or higher.

If necessary, moist heat treatment can be performed in a bath containing water as a main component for removing PEG and improving pressure resistance.
Usually, when the wet membrane is dried, the water permeability decreases, but the moisture heat treatment is effective because the water permeability can be maintained even after the drying.

The polysulfone hollow fiber membrane of the present invention is bundled, and both ends thereof are fixed to the housing with a thermosetting resin such as a polyurethane resin, and are modularized. The module is sterilized by a known method such as EOG sterilization, γ-ray sterilization, or high-pressure steam sterilization, if necessary, and then subjected to excess or concentration as a treatment device for bodily fluids or the like. To use such a bodily fluid treatment apparatus, the arterial pressure may be used as a driving force for blood treatment, or may be used for bodily fluid treatment using a pump as necessary.

When body fluid treatment is performed using the polysulfone hollow fiber membrane of the present invention, for example, when concentrating various components in ascites, the concentration time is greatly reduced as compared with the case of using a conventional cellulose-based hollow fiber. it can. In the case of concentrating various blood components in the diluted blood, it is possible to perform treatment without losing plasma proteins in the same required time as compared with the conventional centrifugation method.

〔Example〕

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 Polysulfone (manufactured by Union Carbide, Udel P1
700) 20 parts by weight, 36 parts by weight of polyethylene glycol (manufactured by Sanyo Chemical Industries, Ltd., PEG # 600, molecular weight 600) and N, N-
44 parts by weight of dimethylacetamide (DMA) were mixed and heated and stirred to prepare a uniform and transparent stock solution. The viscosity of the stock solution is 25 ° C
It was 121 poise. After leaving still at 25 ° C. for 16 hours and defoaming, 0.88 cc / min while introducing 1.0 cc / min of a DMA 55 wt% aqueous solution as an internal coagulating liquid from an annular nozzle having an outer diameter of 0.70 mm and an inner diameter of 0.28 mm. At a rate of 95% relative humidity and adjusted to 40 ° C. After traveling in the air for 10 cm, the mixture was guided into water at 30 ° C. for coagulation, and the hollow fiber was wound up at a speed of 10.5 m / min. The nozzle draft at this time was 2.9. The hollow fiber is wound into a mold, and the remaining solvent and PE
G was removed by washing to obtain a hollow fiber having an outer diameter of 380 μm and an inner diameter of 240 μm. When the consolidation index of the hollow fiber was measured according to the method described above, it was 0.14, which was good.

When the hollow fiber was observed by SEM, a dense skin layer in which no holes were observed even at a magnification of 10,000 times was present on the inner surface of the hollow fiber, and holes having an average pore diameter of 2000 mm were present on the outer surface at an opening ratio of 20%. However, it was confirmed that the inside of the membrane had a sponge structure.

When the membrane performance of the obtained hollow fiber membrane was evaluated according to the method described above, the water permeation rate was 1100 ml / mmHg · m ² · hr, the transmittance of albumin was 0%, the transmittance of inulin was 95%, β
The transmittance of _2- MG was 0%. The concentration of β ₂ -MG at the entrance of the module was reduced to about 60% of the initial value after 30 minutes. Also, no permeation of pyridiene was observed.

Example 2 Example 1 except that the solvent was changed to N-methylpyrrolidone (NMP) and the internal coagulation liquid was a 50% by weight aqueous solution of NMP.
In the same manner as above, an average of 1000 mm holes on the outer surface have an aperture ratio of 15%
A hollow fiber having an outer diameter of 380 μm and an inner diameter of 240 μm was obtained. The consolidation index of the citrus yarn was 0.10. The membrane performance of the hollow fiber was the same as that of Example 1 except that the water permeation rate was 560 ml / mmHg · m ² · hr and the inulin transmittance was 62%.

Comparative Example 1 Spinning was performed under the same conditions as in Example 1 except that the stock solution discharge rate was 1.20 cc / min and the nozzle draft was 1.3, and a hollow fiber (an outer diameter of 385 μm and an inner diameter of 240 μm) which was almost the same as that of Example 1 in appearance was used. Obtained.

The hollow fiber has a consolidation index of 0.12 and a water permeability of 656 ml / mmHg.
M ² · hr, the transmittance of albumin was 0%, the transmittance of β ₂ -MG was 0%, and the permeability of pyrodiene was not recognized, but the transmittance of inulin was as low as 48%. or,
Since the nozzle draft was small, the tension of the hollow fiber in the coagulation bath was reduced, and the hollow fiber was liable to come off the winding roller, and the spinning was unstable.

Example 3 0.94 from an annular nozzle having a nozzle outer diameter of 0.65 mm and an inner diameter of 0.28 mm
Spinning was performed under the same conditions as in Example 1 except that the jetting was performed at a rate of cc / min and the nozzle draft was performed at 2.0, to obtain a hollow fiber having an outer diameter of 380 μm and an inner diameter of 250 μm.

The consolidation index of the hollow fiber is 0.15, and the water permeability is 600 ml / mmHg.
・ M ²・ hr, transmittance of albumin 0%, transmittance of inulin
The transmittance was 80% and the transmittance of β ₂ -MG was 0%. Note that β ₂ -MG
The decrease in concentration at the inlet of the module was the same as in Example 1. Also, no permeation of pyridiene was observed.

Example 4 6,500 hollow fiber membranes of the present invention were bundled, and both ends were fixed to a cylindrical housing with a polyurethane resin to prepare a module (effective membrane area: 1.3 m ² ). Ascites collected from a patient with cirrhosis was circulated by a circuit incorporating this module, and various components in the ascites were concentrated. The inlet pressure of the module is 2 at a constant ascites flow rate = 200 ml / min.
The filtrate flow rate was adjusted by a clamp installed in the module outlet side circuit so that the pressure became 00 mmHg. Table 1 shows changes in the liquid volume and concentration at this time.

As described above, by using the hollow fiber membrane of the present invention, the time required for concentration can be reduced to half that of the conventional method using a cellulose hollow fiber membrane. In addition, there is almost no protein cloth due to protein adhesion to the inner wall of the hollow fiber membrane, and albumin and the like are concentrated and recovered at a high rate.On the other hand, small molecular weight components are filtered and discharged at an equal concentration, so uremic substances are not concentrated, and electrolytes are not concentrated. It can be seen that the balance of E. coli is kept constant, and extremely physiological protein concentration is possible.

Example 5 6,500 hollow fiber membranes of the present invention were bundled, and both ends were fixed to a cylindrical housing with a polyurethane resin to produce a module (effective area: 1.3 m ² ). The diluted blood remaining in the heart-lung machine circuit used at the time of open heart surgery was circulated by the circuit incorporating this module to concentrate various blood components. It was adjusted by a clamp installed in the circuit on the module outlet side so that the filtration pressure of the module was 200 mmHg under a constant blood circulation flow rate of 250 ml / min.

Table 2 shows the changes in the liquid volume and concentration at this time.

As described above, by using the hollow fiber membrane of the present invention, the treatment can be performed in the same required concentration time as in the conventional method using a centrifugal separator. Furthermore, it is possible to effectively recover various plasma components, especially proteins, which had to be discarded in the past.
Further, since the small molecular weight components are filtered and discharged at the same concentration, the balance of the electrolyte is kept constant, and it is found that extremely physiological protein concentration is possible.

Example 6 Modules of 1.3 m ² and 0.4 m ² were prepared using hollow fiber polysulfone membrane, and overtested with bovine blood. The results were as follows.

The UFR of bovine blood was 15 to 45 ml / m ² · hr · mmHg. Inulin transmission ranged from 82% to 95%. At the same time, the transmittances of β ₂ -MG and albumin were measured and found to be 0 at all points.

The 1.3 m ² module was used clinically for the treatment of patients with chronic renal failure. Especially for patients at high concentrations in the blood of beta ₂ -MG, of 20 liters over Oyobi, 18 liters was replacement fluid underwent excessive blood performs the concentration before treatment of beta ₂ -MG is, 69 mg / in In contrast, the post-treatment value was reduced to 36 mg /. The concentration of β ₂ -MG in the solution was outside the detection limit.

 The following table shows other examples.

As described above, the modules, as over-the test results for bovine blood, despite the transmittance of the beta ₂ -MG is 0, to enforce over blood Yotsute beta ₂ -MG of It has been found that removal is possible.

Example 7 A 0.4 m ² module was clinically used as a CAVH (continuous blood method) in patients with renal failure and heart failure. CA
VH is a system for obtaining and passing blood flow using arterial pressure as a driving force, so that it was possible to sufficiently exhibit the characteristics of a module having a high UFR even at a low pressure. The following table shows some examples.

In 10 cases, this module showed less thrombus formation and stable overperformance.

Example 8 A 1.3 m ² module was used for hemodialysis. In the nine cases, the clearance and removal rates of various solutes are shown in the following table.

The 1.3 m ² module also has excellent dialyzability for small molecular weight substances and has sufficient performance as a hemodialyzer. It has been found that β ₂ -MG can be removed at the same time.

Example 9 and Comparative Examples 2 to 5 The permeation performance of β ₂ -MG and albumin was evaluated for the hollow fiber membranes of the present invention.

100 hollow fiber membranes of the present invention were bundled, and both ends were fixed to a cylindrical housing with epoxy resin, to produce a module having an effective membrane area of 100 cm ² . The peritoneal dialysis waste solution containing β ₂ -MG is concentrated, and the concentrated solution and bovine plasma are mixed to obtain a total protein concentration of 7 g / dl, an albumin concentration of 3 g / dl and β
Plasma with a concentration of 20 mg / mg of _2- MG was used for the experiment.

Using the apparatus shown in FIG. 3, circulating filtration was performed at a circulation flow rate (Q _B ) of 4 ml / min and a filtration flow rate (Q _F ) of 0.4 ml / min, and the plasma in the beaker and the filtered plasma were collected over time. The analysis of plasma components was performed (Example 9).

For comparison, a module having an effective membrane area of 100 cm ² was prepared for each of the polysulfone membrane [Hemoflow (F-80)] and three kinds of prototype polysulfone membranes A, B and C by the same method as in Example 9. To perform a filtration experiment (Comparative Examples 2 to 5, respectively).

Polysulfone membrane A: Homogeneous porous membrane having an average pore diameter of 0.2 μm and albumin transmittance of 100% Polysulfone membrane B: Supporting a dense skin layer having slit-like pores having an average pore diameter of 0.02 μm and a sponge structure having pores of 0.5 to 3 μm Asymmetric membrane consisting of layers, with 95% transmittance of albumin and 100% transmittance of inulin Polysulfone membrane C: Dense skin layer with no pores recognized even by 10,000 times SEM and 5-10 μm finger-like An asymmetric membrane having a support layer in which a void having a structure is present and having a transmittance of 0% for albumin and a transmittance of 30% for inulin. FIG. 4 shows the time-dependent change in the residual rate of β ₂ -MG in plasma in a beaker. In the polysulfone membrane manufactured by Fresinius and three kinds of prototype polysulfone membranes, the β ₂ -MG residual ratio slightly decreased one hour after the start of filtration, but showed a substantially constant concentration for 5 hours thereafter. Typically ₂ -
MG residual rate decreased, and after 5 hours, β _{2 in} plasma in beaker
The -MG concentration was almost zero.

Table 3 shows the SC of albumin and β ₂ -MG, the water permeation rate, and the remaining rate of β ₂ -MG for Example 9 and Comparative Examples 2 to 5.

From the above results, the effect of the hollow fiber membrane of the present invention is clear.

〔The invention's effect〕

The polysulfone hollow fiber membrane obtained by the present invention can inhibit bacteria, bacteria, viruses and the like, and is therefore useful as an industrial membrane for water purification and the like, and a membrane for bodily fluids and concentration. Further, since it is particularly excellent in removing β ₂ -MG, it is extremely useful as a body fluid treatment membrane for hemodialysis or hemofiltration.

[Brief description of the drawings]

FIG. 1 is an electron micrograph (magnification: 10,000) of the inner surface of the polysulfone hollow fiber membrane of the present invention. FIG. 2 is an electron micrograph (magnification: 5000) of the outer surface of the polysulfone hollow fiber membrane of the present invention. FIG. 3 is a schematic view of an apparatus used in the filtration experiments of Example 9 and Comparative Examples 2 to 5. FIG. 4 is a graph showing the change over time in the β ₂ -MG residual ratio in plasma obtained in the filtration experiments of Example 9 and Comparative Examples 2 to 5. DESCRIPTION OF SYMBOLS 1 ... Module 2 ... Roller pump 3 ... Beaker 4 ... Plasma 5 ... Stirrer 6 ... Stirrer 7 ... Constant temperature water tank 8 ... Polysulfone membrane of Example 9 9 ... Comparative example 2 Polysulfone membrane 10 Polysulfone membrane of Comparative Example 3 11 Polysulfone membrane of Comparative Example 4 12 Polysulfone membrane of Comparative Example 5

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Hiroyuki Akasu 1621 Sazu, Kurashiki City, Okayama Prefecture Kuraray Co., Ltd. Examiner Koichi Nakano (56) References JP-A-58-114702 (JP, A)

Claims (8)

(57) [Claims] An inner surface has a dense skin layer in which no holes are observed even by 10,000 times electron microscopic observation (SEM), and fine holes having an average pore diameter of 500 to 5000 mm are formed on the outer surface with an aperture ratio of 5 to 50. %, The inside of the membrane has a microporous structure, and the serum albumin permeability is 10% or less, the inulin permeability is 50% or more,
A polysulfone hollow fiber membrane having a water permeation rate of 60 ml / mmHg · m ² · Hr or more. 2. The polysulfone hollow fiber membrane according to claim 1, wherein the transmittance of β2-microglobulin is zero. 3. The polysulfone hollow fiber membrane according to claim 1, wherein the transmittance of the pyrogen is zero. 4. The method according to claim 1, wherein the consolidation index is 0.2 or less.
The polysulfone hollow fiber membrane according to any one of the above. 5. A hollow fiber obtained by extruding a spinning stock solution obtained by dissolving polysulfone and polyethylene glycol in a solvent containing at least one of N-methylpyrrolidone, dimethylacetamide and dimethylsulfoxide, which are common solvents thereof, is extruded from an annular nozzle. In the production of polyethylene glycol, a stock solution obtained by adding 80% by weight or more of polyethylene glycol to polysulfone and an amount that does not cause phase separation even when the stock solution is heated to 100 ° C. is heated and humidified by a nozzle draft 1.6 or more. A method for producing a polysulfone hollow fiber membrane, wherein the membrane is extruded into a wet gas atmosphere and spin-dried. 6. The method according to claim 5, wherein the internal coagulation liquid is water or a mixture of water and a common solvent of polysulfone and polyethylene glycol. 7. The method for producing a polysulfone hollow fiber membrane according to claim 5, wherein the external coagulation liquid has an affinity for a common solvent of polysulfone and polyethylene glycol and is a non-solvent for polysulfone. 8. The method for producing a polysulfone hollow fiber membrane according to claim 5, wherein the external coagulating liquid is water.