JPH07289863A - Polysulfone hollow fiber membrane and its production - Google Patents

Abstract

PURPOSE:To prepare a membrane excellent in anti-thrombus property and adaptability for blood with which blood protein of high mol.wt. can be removed by constituting the hollow fiber membrane of a polysulfone resin and a hydrophilic polymer and forming a dense active layer in the inner surface side of the membrane and forming pores having specified properties in the outer surface side. CONSTITUTION:This hollow fiber membrane consists of a polysulfone resin and a hydrophilic polymer such as polyvinylpyrolidone. The hollow fiber membrane has a dense active layer in the inner surface side and has pores of 0.3-20mum average pore diameter in the outer surface side. The membrane has such properties that the porosity on the outer surface is 20-50%, the inside of the membrane contains no microvoid of >=5mum size, the screening coefft. for albumen albumin is >=0.2, and water permeability is 100 to 500ml/ hr.m<2>.mmHg. This hollow fiber membrane has low permeability for albumin although protein in 20000-40000mol.wt. range can be removed with this membrane.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a polysulfone-based hollow fiber membrane, and more particularly to a hemodialysis hollow fiber membrane preferably used for medical purposes and a method for producing the same.

[0002]

2. Description of the Related Art Various artificial kidneys are currently used for the treatment of renal failure. These are used for hemodialysis and hemofiltration using a hollow fiber membrane to remove urea and other waste products in the blood. Is intended. Therefore, since blood must come into contact with the membrane, it is necessary to use a material that is safe for the living body. For example, until now, cellulose and cellulose have been used.
Suacetate, polyacrylonitrile, polymethylmethacrylate, methylene-vinyl alcohol copolymer and the like have been widely used. Further, recently, a hollow fiber membrane mainly made of polysulfone has attracted attention, and Japanese Patent Publication Nos. 2-18695 and 5-54373,
The technical disclosure is disclosed in Japanese Examined Patent Publication No. 3-267128.

However, the membrane disclosed in the above publication is not sufficient as a membrane for hemodialysis. For example, Japanese Patent Publication No. 2-1
In the case of the hollow fiber membranes disclosed in Japanese Patent No. 8695, the hollow fiber membranes are firmly fixed to each other and a module cannot be molded, or the membrane disclosed in Japanese Patent Publication No. 5-54373 has a molecular weight cutoff of 300.
Since it is only 0 to 40,000, 20,000 to 4
At present, the dialysis treatment technology required to remove proteins in the molecular weight range of 10,000 is only an unsatisfactory membrane. Further, the membrane disclosed in Japanese Patent Publication No. 3-267128 cannot be used as a membrane for hemodialysis because it has a high water permeability and a too large pore size.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a polysulfone-based hollow fiber membrane for an artificial kidney, which is excellent in antithrombogenicity and blood compatibility, and is capable of removing high-molecular weight blood proteins. It contributes to the improvement.

[0005]

[Means for Solving the Problems] Having antithrombotic properties and blood compatibility,
The present inventors have completed the present invention as a result of intensive studies to provide a polysulfone-based hollow fiber membrane having a large molecular weight cutoff. That is, a hollow fiber membrane composed of a polysulfone-based resin and a hydrophilic polymer, wherein a dense active layer is formed on the inner surface side of the hollow fiber membrane and an average pore diameter of 0.
The pores on the outer surface have a porosity of 20 to 50%, the inside of the membrane does not have macrovoids of 5 μ or more, and the sieving coefficient of ovalbumin is 0.
2 or more and water permeability of 100-500 ml / hr · m ²
It is a polysulfone-based hollow fiber membrane characterized by having mmHg, and the present invention will be described in detail below.

The polysulfone-based resin is a general term for polymer compounds having a sulfone bond and is not particularly defined. However, for example, the polysulfone resin represented by the following formula (1) or (2) is widely commercially available. The polysulfone resin having the chemical structure represented by the formula (1) is preferable because it is easily available. The polysulfone resin having this structure is commercially available from Amoco Performance Products under the trade name of "Uder", and there are several kinds depending on the degree of polymerization, but there is no particular restriction.

[0007]

[Chemical 1]

As the hydrophilic polymer, polymers having hydrophilicity such as polyvinylpyrrolidone, polyethylene glycol, polyethyleneimine and polyacrylic acid can be used, but polyvinylpyrrolidone, which has a good affinity for polysulfone resin, Polyethylene glycol is preferably used, and polyvinylpyrrolidone is most preferably used.

In forming the hollow fiber membrane in the present invention, a dry-wet film forming technique which is a generally known technique can be used, and a polysulfone-based solution is used as a film forming stock solution for performing the dry-wet film forming. A uniformly dissolved polymer solution containing a resin, a hydrophilic polymer, a solvent and / or a non-solvent is used.

A solvent having a common solubility for both the polysulfone-based resin and the hydrophilic polymer is used for preparing the membrane-forming stock solution, and although not particularly specified, examples include N, N. Solvents such as -dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide have high solubility and are easily available, and thus are preferably used. Among them, N, N-dimethylacetamide and N-methylpyrrolidone are preferable because of their high solubility in polysulfone and safety against living organisms, and among them, N, N-dimethylacetamide is most preferably used. Further, these solvents do not have to be used alone, and two or more kinds of solvents may be mixed for the purpose of adjusting the solubility in the polymer and the viscosity of the film forming solution. it can. Furthermore, non-solvents such as water, alcohols such as isopropyl alcohol and ethanol, inorganic salts such as sodium chloride and calcium chloride, glycols such as propylene glycol and tetraethylene glycol are used. It is also possible to add, and by doing so, the film properties can be changed, which is an advantageous method for controlling the film performance. The amount and type of addition may be appropriately selected according to the intended properties of the hollow fiber membrane.

If the amount of the polysulfone-based resin added is too small, the formation of a film becomes difficult and the film strength becomes too weak, and if it is too large, the spinnability deteriorates and the pore size becomes too small. It is preferably 15 to 20% by weight, and more preferably 16 to 18% by weight. However, it is not absolutely in this range and can be made smaller or larger than this range depending on the properties of the target hollow fiber membrane, and since the membrane properties also change by changing other spinning conditions, The optimum combination may be selected as appropriate. As the hydrophilic polymer, hydrophilic polymer compounds such as polyvinylpyrrolidone, polyethylene glycol, polyethyleneimine and polyacrylic acid are used, but it is not always necessary to use them alone and several hydrophilic compounds are used. Polymers may be mixed and added.

The addition amount of the hydrophilic polymer to the stock solution for film formation cannot be unconditionally determined because the optimum addition region varies depending on the kind of the hydrophilic polymer and the molecular weight of the hydrophilic polymer. Generally, it is 3 to 30%, and when the hydrophilic polymer is polyvinylpyrrolidone, it is preferably 3 to 20% by weight, more preferably 3 to 15% by weight. Polyvinylpyrrolidone is a water-soluble polymer compound having a structure represented by the following formula (3), which is a trademark of "Plasdone" from IS-P and a trademark of "Kolidone" from BSF. There are several molecular weight polyvinylpyrrolidones, each of which is commercially available at.

[0013]

[Chemical 2]

Since the purpose of adding the hydrophilic polymer to the stock solution for membrane formation is to impart hydrophilicity to the membrane by leaving the hydrophilic polymer in the hollow fiber membrane, selection of its molecular weight is extremely important. Is. If the molecular weight of the hydrophilic polymer is too small, the hydrophilic polymer will easily come out of the membrane during coagulation of the membrane-forming stock solution and during washing of the obtained hollow fiber membrane. This is because a large amount of hydrophilic polymer must be added to the membrane-forming stock solution in order to leave sufficient hydrophilic polymer in the hollow fiber membrane to impart hydrophilicity thereto. Therefore, in order to increase the residual rate of the hydrophilic polymer in the hollow fiber membrane, it is preferable that the molecular weight is large, which allows the hydrophilic polymer added to the membrane forming stock solution to be effectively utilized and the addition amount to be reduced. It is preferable because it is possible.

Even when the hydrophilic polymer is polyvinylpyrrolidone, it is preferable that the molecular weight is large, for example, 500,
When polyvinylpyrrolidone having a viscosity average molecular weight of 000 or more is used, it is preferably 3 to 6% by weight. When forming a hollow fiber membrane, a tube-in-orifice double spinneret is used, and a film-forming stock solution and a hollow liquid for coagulating the film-forming stock solution are simultaneously extruded into the air, and After running in an idle section of up to 50 cm, it may be dipped in a coagulation bath mainly composed of water installed in the lower part of the spinneret to coagulate and then wound.

At this time, it is important to adjust the viscosity of the stock solution for film formation to 1,500 to 6,000 centipoise, especially 3,5.
It is to carry out film formation in a state of being 00 to 5,000 centipoise. It is well known that the viscosity of the polymer solution changes depending on its composition, temperature, etc., but heating or cooling may be carried out in order to keep the viscosity of the stock solution for film formation within this range. That is, the term "viscosity" as used herein is not a viscosity under uniformly defined conditions, but it is important to control the viscosity of the undiluted solution under film forming conditions. It suffices to set the condition range so as to obtain 1,000 centipoise.

Although the reason for this is not clear, when a hollow fiber membrane is formed from a stock solution having a low viscosity, macrovoids larger than 5μ will appear in the membrane, but In the case of a hollow fiber membrane for dialysis, the presence of a large number of such macrovoids makes the activation of platelets in the blood so strong that a stable hemodialysis treatment cannot be performed when an artificial kidney is used. Therefore, it is preferable that the hollow fiber membrane used for hemodialysis does not have macrovoids, and for that purpose, it is preferable to form the membrane in a state where the stock solution viscosity is 1,500 centipoise or more. The term "macrovoid" as used herein refers to a hole portion having no polymer inside the film and having a maximum diameter of 5 µm or more. On the other hand, if the viscosity of the stock solution becomes too high, the spinnability deteriorates and thread breakage and the like frequently occur. Therefore, it is preferable to use a stock solution in a viscosity state not exceeding 6,000 centipoise.

More important is the atmosphere of the empty running section,
The absolute humidity of the atmosphere in which the hollow fiber membrane extruded from the double spinneret and started to coagulate runs from 0.02 to 0.3 kg · H ₂ O
/ Kg · dry air, and by setting the humidity atmosphere in the idle section to a humidity condition within this range, the open area ratio of the outer surface of the hollow fiber membrane can be increased. It becomes possible to prevent sticking, and exerts a great effect on improving moldability into a module.

Although the reason for this is not known in detail, the water vapor in the idle portion comes into contact with the outer surface of the hollow fiber membrane-forming raw material solution discharged from the double spinneret to induce coagulation of the membrane-forming raw material solution and to cause coagulation. The coagulation proceeds slowly even before the coagulation is completely completed in the bath. As a result, on the outer surface of the hollow fiber membrane-forming stock solution discharged from the spinneret, a state in which phase separation has progressed, that is, the polymer high-concentration phase and the polymer
It is considered that the polymer-low-concentration phase becomes voids because the polymer-low-concentration phase is immersed in the coagulation bath in a state where it is separated into the low-concentration phase and the coagulation is completed. More preferably 0.04 to 0.20 kg · H ₂ O
/ Kg · dry air is preferable, but in order to increase the humidity, the idle part is shielded from the outside by a hood, etc., and saturated steam is blown into the shielded hood, or a coagulation bath is used. This can be achieved by filling the hood with water vapor generated by raising the temperature.

Water or a coagulating liquid mainly composed of water can be used as the hollow liquid, and the composition and the like may be appropriately determined depending on the desired membrane performance of the hollow fiber membrane, but cannot be determined unconditionally. Generally, a mixed solution of the solvent and water used for preparing the film-forming stock solution is preferably used. For example, an aqueous solution of 20 to 60% by weight of N, N-dimethylacetamide is used, but 35 to 50% by weight is particularly preferable. Further, a hydrophilic polymer aqueous solution can be used as the hollow liquid. The hollow fiber membrane formed is washed and wound up, and if necessary, glycerin,
A pore size-retaining agent such as polyethylene glycol may be applied and then dried to obtain a dry film.

The hollow fiber membrane obtained by the present invention has a dense layer on the inner surface of the membrane, but has a density of 0.
It had pores with a size of 3 to 2.0 μ and a porosity of 20 to 50%. A hollow fiber membrane having a dense layer on the outer surface side, or a hollow fiber membrane with small pores even if there are pores, or a hollow fiber membrane with a low porosity, the fixation between the hollow fiber membranes is severe and the artificial kidney Although the reason for this is not well understood because the encapsulation by the potting material when molding the module was insufficient, the structure of the outer surface is in terms of preventing the hollow fiber membrane from sticking and facilitating the encapsulation by the potting material. It has a big meaning.

On the other hand, when the membrane pore diameter is larger than 2.0 μ and the open area ratio is larger than 50%, not only the hollow fiber membrane becomes weak and the hollow fiber becomes difficult to handle, but also the protein permeability becomes too high. It is not preferable because it becomes unsuitable as a hollow fiber membrane for hemodialysis. The hole size here is the diameter calculated by calculating the open area of each hole by image processing and then considering this area as a circle, and the average hole diameter is calculated from the size of each hole and its number. The average pore size. That is, the diameters of the N holes are D1, D2, and
The average pore size is calculated by the following equation (4), where DN is set. The open area ratio is expressed as the sum of the open area of each hole existing in a unit area. Average pore size = (D1 + D2 + ... + DN) / N (4) Further, since the hollow fiber membrane obtained by the present invention has a large molecular weight cutoff of about 50,000, it is a normal hemodialysis membrane. With this, it is possible to remove even large molecular weight unwanted proteins that are difficult to remove.

In the hollow fiber membrane according to the present invention, the outer surface has large pores of 0.3 to 2.0 μ, but the inner surface has a dense active layer. In addition, the permeability of blood albumin to the total protein in blood is less than 5%, and by controlling the coagulation conditions appropriately, it became possible to permeate a relatively large molecular weight substance such as ovalbumin. 20,000 to 40 in blood,
Unnecessary protein having a molecular weight of 000 can be removed, and a great effect can be exerted in preventing various complications associated with long-term dialysis, which greatly contributes to improvement of dialysis medical technology. The present invention may be used not only as a membrane material for medical use such as hemodialysis but also as a membrane for various industrial uses.

[0024]

EXAMPLES The present invention will be described in detail below with reference to examples and reference examples. (Example 1) 18 parts of polysulfone resin (Amoco Performance Products, P-1700), 5 parts of polyvinylpyrrolidone (IPS, K-90), N, N
A uniform film-forming stock solution was prepared, which consisted of 77 parts of dimethylacetamide. A 40% by weight aqueous solution of N, N-dimethylacetamide was used as a hollow liquid inside, and the stock solution for film formation was simultaneously extruded from a double spinneret in a state of 45 ° C. (3,800 centipoise) and attached to shut off from the outside. It was dipped in water at 50 ° C., which was provided 30 cm downward through the inside of the container, and was wound at a speed of 50 m / min. At this time, the hood had high humidity due to water vapor from the coagulation bath, and the absolute humidity was measured and found to be 0.05 kg · H ₂ O / kg · dry air. The obtained hollow fiber membrane was treated with a 20 wt% glycerin aqueous solution and then dried at 75 ° C. for evaluation. The average pore diameter of the outer surface of this membrane was 1.1 μ, and the open area ratio was 35%.

Reference Example 1 Spinning was carried out under the same conditions as in Example 1 except that the hood of the idle running portion was removed. At this time, the absolute humidity of the idle portion was 0.016 kg · H ₂ O / kg · dry air. The hollow fiber membrane was treated in the same manner as in Example 1 and dried. It was a hollow fiber membrane having an average pore diameter of 0.2 μm on the outer surface and an opening ratio of 16%.

(Example 2) 9,500 hollow fiber membranes obtained in Example 1 were inserted into a cylindrical resin case, and polyurethane was potted at 750 rpm by a centrifugal molding method. Polyurethane was enclosed between the hollow fiber membranes and could be molded without problems, and the yield was satisfactory. Reference Example 2 Centrifugal molding was performed under the same conditions as in Example 2 except that the hollow fiber membrane obtained in Reference Example 1 was used, but polyurethane was not enclosed between the hollow fiber membranes and the yield was It was extremely low. The molding yield is shown in Table 1.

[0027]

[Table 1]

(Example 3) A mini-module (effective length 25 cm) consisting of 100 hollow fiber membranes obtained in Example 1 was prepared, and the water permeation amount was measured by the stop method under a pressure condition of 200 mmHg. . Then 250 of ovalbumin
The ppm aqueous solution was passed through a mini module to measure the sieving coefficient of ovalbumin. The ovalbumin sieving coefficient is a value calculated from the ovalbumin concentration in the original solution measured at 280 nm and the ovalbumin concentration in the filtrate using the following formula (5). Sieving coefficient = Ovalbumin concentration of filtrate / Ovalbumin concentration of original solution (5) The measurement results are shown in Table 2.

Reference Example 3 A mini-module was prepared in the same manner as in Example 3 except that the hollow fiber membrane obtained in Reference Example 1 was used, and the water permeability and the ovalbumin sieving coefficient were measured. The measurement results are shown in Table 2.

[0030]

[Table 2]

Example 4 Using the hollow fiber membrane of Example 1, a mini module similar to that of Example 3 was prepared. 200m
Filtration was performed while passing bovine plasma (total protein concentration 5.5 g) under the pressure of mHg, and the transmittance of albumin to the total protein was 0.9%, which was very small, which is a level with no practical problems. Met.

[0032]

The hollow fiber membrane of the present invention has a molecular weight of 2
Although it is possible to remove proteins in the molecular weight range of 50,000 to 40,000, it is clear that albumin can be used without any practical problems because of its low permeability.
It is possible to provide an artificial kidney that is very significant in the future dialysis treatments in which removal of high molecular weight proteins is required.

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Claims (7)

[Claims] 1. A hollow fiber membrane comprising a polysulfone-based resin and a hydrophilic polymer, wherein a dense active layer is provided on the inner surface side of the hollow fiber membrane and an average pore diameter of 0.3-about. 2.0
The pore ratio of the pores on the outer surface is 20 to 5
It is 0% and does not have macrovoids of 5μ or more inside the membrane, the sieving coefficient of ovalbumin is 0.2 or more, and the water permeability is 100 to 500 ml / hr · m ² · mmHg.
And a polysulfone-based hollow fiber membrane. 2. The polysulfone-based hollow fiber membrane according to claim 1, wherein the hydrophilic polymer is polyvinylpyrrolidone and / or polyethylene glycol. 3. The polysulfone hollow fiber membrane according to claim 1 or 2, wherein the content of the hydrophilic polymer present in the polysulfone hollow fiber membrane is 3 to 20%. 4. A method for producing a hollow fiber membrane by dry-wet spinning, using a uniformly dissolved membrane-forming stock solution comprising a polysulfone-based resin, a hydrophilic polymer, and a solvent in which these are commonly dissolved. Absolute humidity of 0.02
A method for producing a polysulfone-based hollow fiber membrane, which comprises 0.3 kg water / kg dry air. 5. The method for producing a polysulfone-based hollow fiber membrane according to claim 4, wherein the hydrophilic polymer is polyvinylpyrrolidone and / or polyethylene glycol. 6. The method for producing a polysulfone-based hollow fiber membrane according to claim 4, wherein the temperature in the air running portion is 25 to 60 ° C. 7. The polysulfone-based hollow fiber membrane according to claim 1, wherein the polysulfone-based hollow fiber membrane is formed by the method according to any one of claims 4, 5, and 6.