JPH0239537B2 - FUKINSHITSUTAKOMAKUNOSEIZOHO - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a polyvinyl alcohol (hereinafter referred to as PVA) polymer heterogeneous porous membrane having high water permeability and excellent fractionability. Many membranes such as cellulose-based membranes and synthetic membranes have been developed as microfilters such as dialysis membranes, ultrafiltration membranes, and ultra-precision membranes for medical and industrial use. The present inventors have discovered that it has extremely unique hydrophilic properties, excellent mechanical properties, durability, and chemical stability, as well as biocompatibility and anti-hemolytic properties, which are essential elements for medical materials. It can also be expected to have excellent antithrombotic properties.
We have been conducting intensive research on PVA-based polymer membranes. For example, an EVA dialysis membrane with a homogeneous porous structure using an ethylene-vinyl alcohol copolymer (hereinafter referred to as EVA) has already been published in
No. 1122, and its EVA hollow fiber membrane has already been successfully developed and is being used extensively for artificial kidneys. This type of dialysis membrane for artificial kidneys requires moderate water permeability and high permeability to uremic toxins, and while strictly controlling the many factors that develop the coagulation membrane to ensure an appropriate membrane structure, various factors that are extremely complex must be carefully controlled. As a result of successive efforts, the above-mentioned homogeneous structure type obtained by wet film formation under relatively slow conditions was found to be effective. On the other hand, membranes for general use, including medical applications, and ultrafiltration membranes in particular, require as high a water permeability as possible and a clear fractionation property, and therefore the appropriate membrane structure is naturally different. . This kind of membrane structure generally has an extremely thin active dense layer on the membrane epidermis,
It is well known that a membrane with a heterogeneous porous structure having a sparse internal pore structure is effective. By the way, the PVA-based polymer referred to in the present invention has not yet been sufficiently studied as a material for membranes with this type of heterogeneous structure.
With the method of 35969, it is difficult to form a stable and uniform active dense layer, and the water permeability achieved for a given fractionation performance is low. The problem was that the imageability itself was poor, and when conditions were changed to improve the fractionation, the water permeability had to drop significantly. Therefore, the present inventors conducted a detailed investigation into the effect on membrane structure development by adding second and third components to the membrane-forming stock solution or the entire coagulation system, and found We conducted extensive research on a method for manufacturing a heterogeneous porous membrane that forms a dense layer and has a sparse interior. As a result, by dissolving a substantially water-insoluble PVA polymer in dimethyl sulfoxide and forming a film from this polymer solution in a coagulation medium consisting of an aqueous solution containing a salt represented by M-X, high water permeability was achieved. At the same time, we discovered that a heterogeneous porous membrane with sharp fractionation properties could be obtained.
We have arrived at the present invention. As the membrane constituent raw material in the present invention, a PVA-based polymer that is substantially water-insoluble and soluble in dimethyl sulfoxide is suitably used. Specifically, the substantially water-insoluble PVA polymer mentioned here has an ethylene content of 10 to 70 mol%, preferably 15 to 60 mol%, and a saponification degree of 80% or more.
EVA, α-olefin with 3 to 20 carbon atoms (α-olefin
Olefin content is 10 to 70 mol%, preferably 15 to 60 mol% in terms of ethylene units) - hydrophobic monomers other than vinyl alcohol copolymers, ethylene, and α-olefins (e.g., vinyl chloride, "Veova")

[Formula] Here, R ₁ , R ₂ , and R ₃ are C ₁ to C ₂₀ alkyl groups}-vinyl alcohol copolymer, formaldehyde, acetaldehyde,
It means acetalized modified PVA (e.g. polyvinyl formal, formalized EVA) with various mono- or polyvalent aldehydes such as glutaraldehyde, various etherified and esterified modified PVA using polymer reactions, and mixtures thereof. is also available. Among these, EVA is preferred as shown in the examples described later. The EVA used in the present invention is random,
Either block or graft copolymers may be used, but if the ethylene content is less than 10 mol%, the mechanical properties when wet will be insufficient.
In addition, since there is an increase in eluate, it is preferable that 70
If the amount exceeds mol%, biocompatibility and permeability decrease, which is not preferable. Therefore, 10-70 mol%
Among these, 15 to 60 mol% is preferable. like this
Unlike PVA, EVA is characterized by very little eluate, making it suitable as a hemodialysis membrane material in the medical field. If the degree of saponification of EVA is not 80 mol% or more, the mechanical properties when wet will be insufficient, and a degree of saponification of EVA of 95 mol% or more is more preferable. Generally, a material that is substantially completely saponified with a degree of saponification of 99 mol% or more is used. For example, EVA may be copolymerized with a copolymerizable monomer such as methacrylic acid, vinyl chloride, methyl methacrylate, acrylonitrile, or vinylpyrrolidone in a range of 15 mol% or less, or before film formation or After film formation, EVA is treated with an inorganic cross-linking agent such as a boron compound or an organic cross-linking agent such as diisocyanate or dialdehyde, resulting in cross-linking or 30 mol% of functional hydroxyl groups in vinyl alcohol units. Within this range, those acetalized with aldehydes such as formaldehyde, acetaldehyde, butyraldehyde, and benzaldehyde are also included. The EVA used in the present invention was measured by viscosity measurement [the viscosity of a dimethyl sulfoxide solution (temperature 30° C.) with a concentration of 3% by weight was measured using a B-type viscometer. ] is 1.0
It is preferable to use one in the range of ~50 centipoise. As a result, if the viscosity is low, that is, if the degree of polymerization is low, the necessary mechanical performance as a membrane cannot be obtained, and if the viscosity is higher than this, it becomes difficult to form a membrane. As a solvent for these PVA-based polymers, especially EVA, dimethyl sulfoxide is suitable and used. Dimethyl sulfoxide can be partially mixed with other solvents such as acetone, methanol, ethanol, propanol, isopropanol, water, methylpyrrolidone, dimethylacetamide, dimethylformamide, etc., but the mixing ratio is used in the present invention. The effect of the coagulation aid consisting of the salt represented by M--X should be maintained at a level that does not impair the effect. The PVA polymer concentration in the stock solution is 10 to 30% by weight, preferably 15 to 30% by weight.
It is 25%. If the concentration is higher than this range, the membrane performance will be extremely low in water permeability, making it unusable, and if the concentration is lower than this range, the membrane forming property will be poor. The temperature of the stock solution during film formation is usually 10 to 100°C, preferably 20 to 100°C.
It is in the range of 80℃. Outside this range, it is difficult to develop the desired heterogeneous structure, and the transmission properties are impaired. The coagulation medium in the present invention refers to an aqueous solution containing one or more salts represented by MX as coagulation aids. Here, MX means M is a group element of the periodic table, preferably calcium, magnesium, zinc, aluminum, etc., and X is a Bronsted acid residue, preferably a halogen, and The solubility of MX in water at 20°C is at least 0.5 g/dl, preferably 1.0 g/dl or more. If the salt has a low solubility below this level, it is difficult to express the effect and it is not suitable for use. Furthermore, among Group 1 elements, highly toxic elements such as mercury and cadmium cannot be put to practical use. Specific examples of M-X include calcium chloride (CaCl ₂ ), calcium bromide (CaBr 2 ), calcium iodide (CaI ₂ ), magnesium chloride (MgCl ₂ ), magnesium bromide (MgBr ₂ ), and magnesium iodide _. (MgI ₂ ), zinc chloride (ZnCl ₂ ), zinc bromide (ZnBr ₂ ), zinc iodide (ZnI ₂ ), copper chloride (CuCl 2 ), copper bromide ( _{CuBr 2 )} , aluminum chloride (AlCl ₃ ), Aluminum bromide (AlBr ₃ ), zinc sulfate (ZnSO ₄ ), aluminum sulfate (Al ₂ (SO ₄ ) ₃ ),
Examples include magnesium sulfate (MgSO ₄ ). Among these, calcium chloride is most suitable. The appropriate concentration range for use of M-X cannot be unambiguously defined;
The desired fraction size is determined in correlation with other factors such as the concentration of the stock solution, the temperature of the stock solution, and the temperature of the coagulation medium, but the general idea is that the concentration of MX in the coagulation medium is 5 to 30% by weight, preferably or 5 to 20% by weight.
The coagulation medium containing the coagulation aid is preferably an aqueous one, but some include various alcohols such as methyl alcohol, ethyl alcohol, propanol, and isopropanol, dimethyl sulfoxide, methyl pyrrolidone, dimethyl acetamide, dimethyl formamide, acetone, methyl ethyl ketone, and acetic acid ester. It is also possible to use some organic solvents such as . The membrane forming method of the present invention can be applied to any membrane shape such as a flat membrane, a tube-shaped membrane, a hollow fiber membrane, a composite membrane with a support, etc., but the method of the present invention is particularly suitable for producing hollow fiber membranes. Useful in manufacturing. The film thickness is approximately 3 to 2000μ for a flat membrane, and the outer diameter for a hollow fiber membrane.
The film thickness is about 40 to 3000μ, more preferably 100 to 2000μ, and the film thickness is about 3 to 1000μ, more preferably about 10 to 500μ. In the spinning of hollow fiber membranes, the coagulation medium is used only as an injection liquid in hollow fiber membranes for forming hollow fibers,
Spinning can be performed using a common coagulation bath (such as water or a mixture of water and dimethyl sulfoxide). In this case, an active dense layer is formed on the inner surface of the hollow fiber membrane. Further, if the coagulation medium is used not only for the solution injected into the hollow fiber membrane but also for the coagulation bath solution, a hollow fiber membrane having active dense layers on the surfaces of the inner and outer layers can be obtained. Furthermore, by introducing an inert gas such as nitrogen into the hollow fiber membrane and using the coagulation medium in the coagulation bath, a hollow fiber membrane having an active dense layer on the surface of the outer layer can be obtained. As the film forming method of the present invention, in addition to the wet method in which the stock solution exits the die or nozzle that is the stock solution discharge port is immediately immersed in a coagulation bath, a so-called wet-dry method in which the stock solution is immersed in a coagulation bath after passing through the air is also applied. be able to. Solidification temperature is usually 0~40℃, preferably 10~35℃
A range of is appropriate. At temperatures lower than this range, sufficient membrane properties, especially water permeability, cannot be obtained, and at higher temperatures, spinning stability is poor and performance is poor. As a result of observation using a scanning electron microscope, the membrane thus obtained was found to have an extremely thin and uniform active dense layer on the side that came into contact with the coagulation medium, as is clear from Figures 1 and 2. However, it was confirmed that the inside of the membrane on the opposite side had a good so-called ultrafiltration membrane type inhomogeneous porous structure consisting of a sparse void layer (finger-like void layer). Further, the obtained membrane has a molecular weight cut-off of 10,000 to 600,000, preferably 40,000 to 400,000, and has sharp fractionation within this range. Further, by subjecting the membrane thus obtained to post-treatments such as stretching and heat treatment, the membrane structure can be further stabilized. In addition, as explained in the explanation of EVA above, the obtained PVA-based film may be treated with an inorganic cross-linking agent such as a boron compound or an organic cross-linking agent having a functional group such as isocyanate or aldehyde, if necessary, and further treated with radiation. Modification can be carried out by introducing crosslinking by means such as irradiation, and improvement in mechanical properties can be expected in particular. The membrane obtained by the present invention can be used not only for general ultrafiltration purposes, but also for biological fluid filtration, such as hypermorphic artificial kidneys, abdominal and pleural effusion protein concentration, and membranes for fractionating protein components in living organisms (for example, membranes for plasma processing fractionation). Can be used. The present invention will be further explained below with reference to Examples. Example 1 Saponified ethylene-vinyl acetate copolymer (ethylene content 31 mol%, degree of saponification 99.9 mol%) 220 g
After dissolving in 780g of dimethyl sulfoxide at 90℃,
The mixture was left to stand at 60°C for degassing. This stock solution was casted onto a glass plate placed on a hot plate, and a 10% aqueous solution of CaCl ₂ (CaCl ₂
A white film was obtained by immersing the entire glass plate in a solution (solubility in water at 20°C: 83 g/dl) and wet coagulating it. When the cross section of the obtained film was observed using a scanning electron microscope, a clear active dense layer was observed on the free surface side. This membrane has a bovine serum albumin rejection rate of 98%, a sharp fractionation, and a water permeability of 112ml/
^m2 ． It showed a high level of hr.mmHg. Example 2 250 g of saponified ethylene-vinyl acetate copolymer (ethylene content: 40 mol%, saponification degree: 98 mol%) was dissolved in a mixed solvent of 720 g of dimethyl sulfoxide and 30 g of water, and this was used as a stock solution for the following hollow fiber spinning. I did it. The nozzle used was a single-hole type made by Kasei Nozzle Co., Ltd., with an inner diameter of 600μ and an outer diameter of the part that extruded the stock solution.
1200μ was used. The temperature of the stock solution was maintained at 50°C, and a 10% aqueous solution of CaCl ₂ at 15°C was used as the solution injected into the cavity, and water adjusted to 20°C was used as the coagulation bath. The raw solution transfer speed is a gear pump discharge rate of 5ml/min.
Wet spinning was performed at a bath separation yarn speed of 8 m/min.
The obtained hollow fiber membrane had an outer diameter of 950 μm and an inner diameter of 500 μm, and had an almost perfectly circular cross-sectional shape. The cross-sectional structure of the obtained hollow fiber membrane was examined using scanning electron micrographs. The first electron micrograph
Shown in Figure 2. Figure 1: A cross-sectional view at 450 magnification, showing that the inner layer has a sparse structure with finger-like void layers, a dense active layer on the inner surface, and a porous layer on the outer surface. . Figure 2: A cross-sectional view of the inner surface at a magnification of 9000.
It is clearly seen that there is a dense layer on the inner surface. This hollow fiber membrane was incorporated into a small module, and performance measurements showed that the water permeability was 105 ml/m ² hrmmHg, the serum albumin rejection rate was 98%, and the fractionation was sharp. Comparative Example 1 Bovine serum albumin rejection rate of membrane obtained when using only distilled water in the coagulation bath under the same conditions as Example 1
65%, water separation 120ml/ ^m2 . hr.mmHg, and protein fractionation was significantly inferior for a given water permeability. Example 3 Under the same conditions as Example 2, the inner diameter of the nozzle was
400μ and outer diameter 800μ, and also for coagulation bath.
The same 10% CaCl ₂ aqueous solution as the hollow injection solution was used.
When the obtained hollow fiber membrane was observed using a scanning electron microscope, dense layers were observed in the inner and outer epidermal layers. The permeation characteristics are good with a protein rejection rate of 98-99%, but the water permeability is 95ml/
^m2 ． hr.mmHg was slightly low.

[Brief explanation of drawings]

FIG. 1 is a scanning electron micrograph at a magnification of 450 showing a cross-sectional view of the hollow fiber membrane obtained by the present invention, and FIG. 2 is a scanning electron micrograph at a magnification of 9000 showing a cross-sectional view of the inner surface side of the hollow fiber membrane. This is an electron micrograph.

Claims (1)

[Scope of Claims] 1. A method for producing a heterogeneous porous membrane made of a polyvinyl alcohol polymer, which comprises dissolving a substantially water-insoluble polyvinyl alcohol polymer in dimethyl sulfoxide; 1. A method for producing a heterogeneous porous membrane, comprising forming a polymer solution into a coagulation medium consisting of an aqueous solution containing 5 to 30% by weight of a salt represented by MX. However, in M-X, M is a group element or group element of the periodic table, X is a Brønsted acid residue, and
Solubility in water at 20℃ is at least 0.5g/dl
It is a salt that shows