JPH0427891B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a hydrophilic composite porous membrane for blood treatment and a method for producing the same. (Conventional technology) In recent years, porous membranes made of polymer compounds have been developed.
It is widely used for filtration of aqueous solutions or suspensions.In the industrial field, it is used to produce pure water for the electronic industry, sterilize raw water for pharmaceutical manufacturing, and as a battery separator, and in the medical field, it is used to filter blood components. It is used for separation, removal of malignant particles in ascites, removal of foreign substances in various infusions, and various sterilization filters. These porous membranes are broadly classified into hydrophilic membranes and hydroplastic membranes depending on the characteristics of their materials. Known examples of hydrophilic porous membranes include cellulose, cellulose derivatives, polyvinyl alcohol, and ethylene-vinyl alcohol copolymers. Hydrophilic porous membranes are characterized by the fact that the pore surfaces of the membrane are hydrophilic, so they are easily wetted by water and can filter aqueous solutions without special pretreatment. However, hydrophilic membranes have drawbacks such as a decrease in mechanical strength when wet and large swelling due to water, and a drawback that membrane performance tends to deteriorate when dried from a wet state. Examples of hydrophobic porous membranes include polyethylene,
Porous membranes such as polypropylene, polysulfone, and polytetrafluoroethylene are known. Hydrophobic membranes are characterized by less swelling by water and less decrease in mechanical strength due to wetting, and are widely used for filtration of aqueous liquids. However, a disadvantage of hydrophobic porous membranes is that since aqueous liquids do not wet the hydrophobic surface, it is difficult for them to penetrate into the pores of the porous membrane, and the aqueous liquid cannot be filtered as is. Therefore, it has been proposed that a hydrophobic porous membrane be hydrophilized in advance, and the method for making it hydrophilic is to infiltrate a low surface tension organic solvent that is miscible with water into the pores and then replace it with water. There are several methods, including a method of treating a hydrophobic porous membrane with a surfactant. However, in the former method, once the membrane is dried, its hydrophilic effect is lost and the same operation is required again. Furthermore, the latter method has disadvantages in that the surfactant is eluted into the treatment liquid during filtration and contaminates the treatment liquid, and the hydrophilic effect decreases over time. In order to improve the drawbacks of such hydrophobic porous membranes, hydrophilic porous composite structures have been proposed (JP-A-53-21270, JP-A-53-134871, JP-A-54-
8669, Japanese Patent Publication No. 117978). These structures are obtained by impregnating a water-soluble polymer into the porous spaces of a hydrophobic porous structure, and then insolubilizing the water-soluble polymer by a post-crosslinking treatment such as irradiation with ionizing radiation. Originally, water-soluble polymers have a high solubility parameter, so they have no affinity with hydrophobic polymers that have a low solubility parameter, and do not show any adhesion to hydrophobic polymers. However, by post-treatment, water-soluble polymers This is a three-dimensional structure in which the polymer is immobilized. Since these structures use water-soluble polymers, they have the disadvantage that if the crosslinking treatment is insufficient, the water-soluble polymers will be eluted into the aqueous treatment liquid, and if the degree of crosslinking is increased, the fineness of the membrane will increase. It has the disadvantage that the pore size decreases and the water permeation ability decreases. Further, from a practical standpoint, the post-crosslinking treatment is a complicated process, and in particular, ionizing radiation irradiation requires large-scale equipment and is expensive. (Problems to be Solved by the Invention) The present invention allows for easy handling of aqueous liquids without any special pretreatment, and also improves properties such as wet strength, swelling, and eluates. This provides porous membranes with excellent safety in the medical field. (Means for Solving the Problems) The gist of the present invention is to provide polyolefins with an average pore diameter of 0.02 to 4.0 μm, which are made of polyolefin and manufactured by a stretching pore method.
m of porous structured matrix and an ethylene content of 20 m, substantially covering the pore surfaces of the matrix.
A hydrophilic composite porous membrane for blood component separation consisting of an ethylene-vinyl alcohol copolymer coating layer with ~70 mol% and saponification degree of 80% or more, and the pore surface of a porous structure matrix consisting of polyolefin. Ethylene content of 20 to 70 mol% dissolved in a water-miscible organic solvent alone or a mixed solvent of the solvent and water,
The method for producing the hydrophilic composite porous membrane is characterized in that it is treated with an ethylene-vinyl alcohol copolymer solution having a saponification degree of 80% or more. (Functions and Embodiments) The hydrophilic composite porous membrane for blood treatment of the present invention comprises a porous structured matrix made of hydrophobic polyolefin and an ethylene-vinyl alcohol-based copolymer that substantially covers the pore surface of the matrix. Because it is a composite porous membrane consisting of a polymer coating layer, it hardly swells with water or loses strength due to water when it comes in contact with an aqueous solution, similar to hydrophobic porous membranes, and the surface is made of a hydrophilic coating layer. Because of this, it has good water wettability and can be used as a filtration membrane without any pretreatment to make it hydrophilic. In addition, the composite porous membrane of the present invention shows almost no dimensional change or change in performance even after repeated drying and wetting. Since there is no need for a surfactant for oxidation, the porous membrane is clean and substantially free of eluates that contaminate the processing liquid. The composite porous membrane referred to in the present invention is a membrane having a large number of pores penetrating from one side of the membrane to the other, and the membrane has a porous structure matrix and a pore surface of the matrix. Refers to something that is substantially covered by a covering layer. Note that the pore surface of the porous structure matrix refers to the sum of the inner wall surfaces of the pores that penetrate through the pores and both surfaces of the porous structure matrix body, which can contribute to the permeation of the target substance. This is essentially different from an asymmetric composite membrane that has reverse osmosis ability by forming an ultra-thin membrane on one side of a support membrane with a porous structure. The composite porous membrane of the present invention may be in the form of a flat membrane, a tube, a hollow fiber, etc.
Hollow fibers are preferred because they are small and can filter efficiently. Further, the preferable average pore diameter and porosity of the pores of the composite porous membrane are 0.02 to 4.0 μm and 30 to 90% by volume. Examples of the polyolefin used in the present invention include polyethylene, polypropylene, poly-3-
Methylbutene-1, poly-4-methylpentene-
1 and copolymers of these constituent monomers, among which polyethylene and polypropylene are preferred since they provide a porous structure with a sufficiently large pore size. The ethylene-vinyl alcohol copolymer used in the present invention may be any type of copolymer, such as random, block, or graft, but the ethylene content of the copolymer is in the range of 20 to 70 mol%. It is necessary. If the ethylene content is less than 20 mol%, the adhesion of the polymer to polyolefin will be low and peeling of the coating layer from the matrix of the composite porous membrane will occur, which is undesirable. Moreover, if it exceeds 70 mol%, the hydrophilicity of the coating layer will be lost, which is not preferable. In particular, 25 to 50 mol% is preferable since it has a good balance between adhesiveness and hydrophilicity. It is believed that the ethylene-vinyl alcohol copolymer provides good adhesive properties because it contains ethylene, which has a structure common to that of the polyolefin serving as the matrix. The porous structural matrix used in the present invention is obtained by stretching and opening a hydrophobic crystalline polyolefin. The stretching pore method is a method in which a crystalline polymer is formed into a hollow fiber or film, and then the crystal lamellae are cleaved by cold stretching, and the pore diameter is expanded by hot stretching to create a porous structure. Porous structures are manufactured by physical means of stretching without adding solvents or other additives to molecular materials.
This is a preferred method for producing membranes for blood component separation because there are no problems such as residual solvent. The coating layer of the composite porous membrane only needs to substantially cover the pore surface of the porous structure matrix,
The thickness of the coating layer is preferably about a monolayer.
It is 10 Å or more, and there is no particular upper limit to the thickness. The amount of the coating layer expressed as the weight per unit pore surface area of the porous structure matrix is approximately 1×10 ^-3 g/m ² or more 2×
It is preferably about 10 g/m ² or less. The hydrophilic composite porous membrane for blood treatment of the present invention is manufactured by the following manufacturing method. That is, the composite porous membrane is prepared by treating the pore surface of a porous matrix made of polyolefin with a solution of an ethylene-vinyl alcohol copolymer dissolved in a water-miscible organic solvent alone or in a mixed solvent of the solvent and water. It can be obtained by The treatment with an ethylene-vinyl alcohol copolymer solution includes a step of applying the copolymer solution to the pore surface of the porous structure matrix, and subsequent to the step, evaporating and removing the solvent of the copolymer solution. Includes a drying process. The organic solvent for dissolving the ethylene-vinyl alcohol copolymer of the present invention is a water-miscible organic solvent, exhibits a solubility in water of 20 wt% or more at a temperature below the boiling point of the solvent, and has a Hildebrand solubility parameter. An organic solvent of 9.5 (cal·cm ^-3 ) ^1/2 or more is preferable. Examples of preferred organic solvents include:
Alcohols such as methanol, ethanol, n-propanol, isopropanol, sec-butanol, t-butanol, cyclohexanol, polyhydric alcohols such as ethylene glycol, propylene glycol, glycerin, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, dimethyl Examples include acetamide, formamide, and ethylene chlorohydrin. Among these, ethanol and dimethyl sulfoxide are particularly preferred because they have good solubility in the ethylene-vinyl alcohol copolymer and have low toxicity. These organic solvents can be used alone or in a mixed solvent system, and a mixed solvent system with water is particularly preferred. Ethylene-vinyl alcohol copolymer is composed of a non-polar and hydrophobic ethylene part and a polar and hydrophilic vinyl alcohol part, but when it is dissolved in a highly polar solvent and coated on a non-polar polyolefin. It is thought that the non-polar ethylene moiety is likely to be localized on the polyolefin side, and the polar vinyl alcohol moiety is likely to be localized on the surface side. This phenomenon is a desirable phenomenon because it improves the adhesion between the coating layer and the matrix and also improves the hydrophilicity of the surface of the coating layer. Adding water to the above organic solvent to form a mixed solvent system makes the polarity of the solvent stronger, which promotes the above phenomenon, which is preferable. The proportion of water added is preferably as large as possible within a range that does not inhibit the solubility of the ethylene-vinyl alcohol copolymer, and the proportion varies depending on the ethylene content of the copolymer, the temperature of the solution, etc., but for example, 5 to 60% water. A preferred range is weight %. The concentration of the copolymer used can be selected to be any concentration suitable for coating, but a concentration of about 0.1 to 5% by weight is suitable, for example. The coating treatment may be completed in one treatment, but it is also possible to repeat the treatment several times at a relatively low concentration. The temperature of the copolymer solution is not particularly limited, but generally a high temperature is preferable because the solubility of the copolymer is better and the viscosity of the solution is lowered, and a range from room temperature to 100°C is preferable. . The coating treatment time is preferably in the range of several seconds to several tens of minutes. This process can also be carried out in batches by cutting the porous structure matrix into a certain shape.
It is also possible to carry out continuous treatment by running a continuous flat film-like or hollow fiber-like porous structural matrix in the longitudinal direction, which is a preferred method with excellent productivity. During continuous processing, when the porous structural matrix is in the form of a flat membrane, the copolymer solution can be supplied from one or both sides of the matrix. When the matrix is in the form of hollow fibers, the copolymer solution can be supplied from the outer surface of the hollow fibers. Even if the shape of the matrix is hollow fiber,
Since the structure is porous, the copolymer solution can easily penetrate into the interior of the matrix and the main coating treatment can be performed. The solution used in this treatment can be dried by conventional drying methods such as vacuum drying, hot air drying, etc. A continuous composite porous membrane can also be dried continuously in a running state. The degree of drying may be at a temperature at which the composite porous membrane is not deformed by heat, and is preferably 130° C. or lower. The hydrophilic composite porous membrane of the present invention has strong wet strength,
It has excellent dimensional stability, good water wettability, and does not use leachable substances such as surfactants, so it has excellent medical safety, and is especially suitable for blood processing such as plasma separation membranes and plasma component fractionation membranes. It is valid. Next, the present invention will be explained with examples. The various physical properties were measured using the following methods. [Average pore diameter (μm)] A pore diameter that indicates a pore area that is 1/2 of the total pore volume on a pore diameter-pore area integral curve determined by a mercury polysimeter. [Water permeation rate (l/hr・m ²・mmHg)] Directly immersed in pure water without pretreatment such as hydrophilization with ethanol. Measured at 25℃ and differential pressure of 50mmHg. [Tensile strength at break (Kgf/cm ² ) Tensile elongation at break (%)] Strain rate 200 using an Instron tensile tester
Measured in %/min. [Pore surface area of porous structure matrix (m ² /
g)] Measured by nitrogen adsorption amount using a BET surface measuring device. [Plasma flow rate (ml/hr・^m2・mmHg)] Using bovine ACD (citric acid-sodium citrate-glucose) blood (hematocrit 35%), 37
Measure the plasma filtration rate when a differential pressure of 30 mmHg is applied to the membrane at ℃. [Hot water extraction test] Extract the composite porous membrane in hot water at 80±5°C for 3 hours, and measure the weight change before and after extraction. [Polymer latex transmittance] Using styrene-butadiene latex [SBR636 manufactured by Dow Chemical Co., Ltd.] with an average particle size of 0.2 μm, an aqueous suspension having a concentration of 0.033% by weight was prepared. Differential pressure 50mm
The liquid is filtered within Hg and the concentration is determined by nephelometric method at a wavelength of 500 nm, and the concentration is determined by transmittance (SC) = (Cf/Co) x 100 (%) (Cf is the concentration of the permeated liquid, and Co is the concentration of the stock solution). Ta. Example 1 High-density polyethylene (density 0.968, MI value 5.5, trade name Hi-Zex 2208J) was made using a circular double spinneret.
Spin at a spinneret concentration of 150°C, and spin the resulting hollow fiber at 120°C.
After annealing for 2 hours at room temperature, the material was hot-stretched by 30% at room temperature and then by 350% at 105°C to obtain a hollow fiber polyethylene porous structure matrix. The inner diameter of the matrix is 320 μm, the film thickness is 45 μm, and the pore surface area is
It was 21m ² /g. An ethylene-vinyl alcohol copolymer (Soarnol E manufactured by Nippon Gosei Kagaku Kogyo) having an ethylene content of 38 mol % was heated and dissolved in a 75 volume % ethanol aqueous solution to form a 0.5 weight % solution. The temperature of the solution is maintained at 50°C, and the hollow fiber polyethylene porous structure matrix is immersed in the solution.
It was left for 10 minutes. Then, after removing the excess copolymer solution, it was dried with hot air at 50°C for 3 hours. The resulting composite porous membrane had an inner diameter of 320 μm, a film thickness of 45 μm, a coating amount of 3.2×10 ^-3 g/m ² , and an average pore diameter of
It was 0.70 μm. This film also has good water wettability,
It easily gets wet when immersed in water, exhibits water permeability without special treatment, and has a water permeability rate of 7.9/hr・m ²・
It was mmHg. In addition, the plasma flow rate was 85ml/hr・
It showed sufficient performance with m ² · mmHg. The result of the hot water extraction test was that the extraction amount was 0.0%.
The average value of Example 3 was 0.4%, which was lower than the maximum value of 1.6%. The tensile breaking strength of this membrane when dry is
510Kgf/cm ² , tensile elongation at break is 30%, tensile strength at break when wet is 517Kgf/cm ² , tensile elongation at break is 31%
There was no difference between dry and wet conditions, and both showed excellent mechanical properties. Further, no swelling in the longitudinal direction of the yarn was observed during wetting. Further, although drying and wetting were repeated ten times, no decrease in water permeability or change in mechanical properties was observed. Comparative Example 1 Regarding the hollow fiber polyethylene porous structure matrix obtained in Example 1, the average pore diameter and water permeation rate were measured in the same manner as in Example 1, and they were 0.56 μm and 3.8/hr・m ²・mmHg, respectively. . Example 2 Polypropylene (trade name Noblen D-501)
After mixing and pelletizing 23% by weight of differential silicic acid, 23.5% by weight of dibutyl phthalate, and 53.5% by weight of dibutyl phthalate, the pellets were spun using an extruder equipped with a circular double spinneret to obtain hollow fibers. This hollow fiber was extracted with 1,1,1-trichloroethane to remove dibutyl phthalate, and then
Fine powder silicic acid was extracted with a 40% caustic soda aqueous solution, washed with water, and dried to obtain a hollow fiber polypropylene porous structure matrix with an inner diameter of 550 μm and a film thickness of 160 μm.
Example 1 except that various ethylene-vinyl alcohols with different ethylene contents (manufactured by Nippon Gosei Kagaku Kogyo Co., Ltd., trade name: Soarnol, and Kuraray Co., Ltd., trade name: EVAL) were used, and the temperature of the ethylene-vinyl alcohol solution was maintained at 75°C. An ethylene-vinyl alcohol coating layer was formed in the same manner as above to obtain a composite porous membrane shown in Table 1. The pore diameters of these composite porous membranes were all 0.25 μm. Furthermore, as shown in Table 1, it exhibited high water permeability.

[Table] Example 3 A flat membrane-shaped polyethylene porous structural matrix was obtained by a known method disclosed in JP-A-57-117951. Ethylene-vinyl alcohol (trade name EVAL EP-G) having an ethylene content of 47 mol% was dissolved in dimethyl sulfoxide (DMSO) or a mixture of DMSO and water to form a 0.5% by weight solution. The solution was impregnated into the matrix at room temperature and then dried to obtain a flat composite porous membrane. The thickness of the film is
30μm, and the pore diameter was 0.60μm. The water permeation rate showed a high value as shown in Table 2.

[Table] Example 4 The same hollow fiber polyethylene porous structure matrix used in Example 1 was added to a 0.5% by weight solution of ethylene-vinyl alcohol (ethylene content 29 mol%, trade name Soarnol Z) maintained at 60°C. Inside,
Run continuously so that the residence time is 5 minutes,
The matrix is impregnated with the solution, the ethylene-vinyl alcohol solution is applied to the surface of the pores of the matrix, and the solvent is completely evaporated by blowing hot air at 55°C while the matrix is running, drying the hollow fibers to form hollow fiber composite pores. A membrane was obtained. The solvent used for the ethylene-vinyl alcohol solution was a mixed solvent of ethanol and water shown in Table 3. As shown in Table 3, all exhibited high water permeability.

[Table] Example 5 High-density polyethylene (density 0.968, MI value 5.5, trade name Hi-Zex 2208J) was made using a circular double spinneret.
Spun at a spinneret temperature of 150°C, the resulting hollow fiber was
After annealing at ℃ for 2 hours, hot stretching was carried out at room temperature for 30%, then at 98℃ for 200%, and then at 110℃ for a second step of hot stretching for a total of 330% to create a hollow fiber polyethylene porous structure. I got the matrix.
The inner diameter of the matrix was 340 μm, and the film thickness was 50 μm. 840 such matrices are bundled and the length is 30cm.
A hollow fiber bundle was obtained. An ethylene-vinyl alcohol copolymer (Soarnol Z manufactured by Nippon Gosei Kagaku Kogyo Co., Ltd.) with an ethylene content of 29 mol% was dissolved by heating in a 60 volume% ethanol aqueous solution.
A 0.5% by weight solution was prepared. The temperature of the solution was maintained at 50° C., and the hollow fiber bundle was immersed in the solution and left for 5 minutes. Then after removing excess copolymer solution 55
It was dried with hot air at ℃ for 2 hours. The treatment with the ethylene-vinyl alcohol copolymer solution and drying were repeated again to obtain a composite porous membrane bundle. The resulting composite porous membrane had an inner diameter of 340 μm and a film thickness of 50 μm. The water permeation rate of this membrane is 9.5/hr・m ²・
The transmittance of the polymer latex with mmHg and average particle size of 0.2 μm was 29%. This composite porous membrane bundle has an inner diameter of 18 mm and a length of 220 mm.
The membrane bundle was placed in a polycarbonate cylindrical container, both ends were fixed with urethane adhesive, the end faces of both ends of the membrane bundle were cut out, and nozzles were attached to both ends to produce a composite porous membrane module. The effective length of the module was 20 cm, and the effective membrane area was 0.18 m ² . Then, fill the space of the module with sterile distilled water,
High-pressure steam sterilization was performed at 121°C for 30 minutes.
In order to measure the performance of the module as a plasma separator, first, the distilled water filled in the module was replaced with physiological saline, and then as an anticoagulant.
Bovine blood with a hematocrit of 35% to which ACD solution (citric acid-sodium citrate-glucose solution) was added was passed at a blood flow rate of 60 m ³ /min, and the transmembrane pressure was 40 mm.
Plasma was collected by applying Hg. The plasma collection rate and protein permeability are shown in Table 4, indicating excellent performance as a plasma separator.

[Table] (Effects of the invention) The hydrophilic composite porous membrane for blood treatment of the present invention has good water wettability and exhibits water permeability without any special pretreatment, and there is no decrease in mechanical strength or swelling due to wetting. It is also an excellent porous membrane that does not contain water-soluble eluates.

Claims (1)

[Scope of Claims] 1. A porous structured matrix made of polyolefin and manufactured by a stretch pore method and having an average pore diameter of 0.02 to 4.0 μm, and an ethylene content of 20 μm that substantially covers the pore surface of the matrix. A hydrophilic composite porous membrane for blood treatment comprising a coating layer of an ethylene-vinyl alcohol copolymer with a saponification degree of ~70 mol% and a saponification degree of 80% or more. 2. The hydrophilic composite porous membrane according to claim 1, wherein the polyolefin constituting the porous structure matrix is polyethylene or polypropylene. 3. The hydrophilic composite porous membrane according to claim 1 or 2, wherein the membrane is a hollow fiber membrane. 4. The pore surface of a porous structure matrix made of polyolefin and having an average pore diameter of 0.02 to 4.0 μm manufactured by a stretch pore method was dissolved in a water-miscible organic solvent alone or in a mixed solvent of the solvent and water. A method for producing a hydrophilic porous membrane for blood treatment, which comprises treating with an ethylene-vinyl alcohol copolymer solution having an ethylene content of 20 to 70 mol% and a degree of saponification of 80% or more. 5. The manufacturing method according to claim 4, wherein the water-miscible organic solvent is dimethyl sulfoxide or ethanol. 6. The manufacturing method according to claim 4 or 5, wherein the treatment with the ethylene-vinyl alcohol copolymer solution is a continuous treatment of the following (a) and (b). (a) A step of supplying an ethylene-vinyl alcohol copolymer solution to one or both sides of the porous structure matrix in a running state. (b) A drying process in which the solvent is evaporated and removed while the vehicle is running. 7 Claim 6, wherein the porous structural matrix made of polyolefin has a hollow fiber shape.
Manufacturing method described in section.