JP6502111B2 - Hollow fiber type blood purifier and method of manufacturing the same - Google Patents

Description

  The present invention relates to a hollow fiber type blood purifier and a method of manufacturing the hollow fiber type blood purifier.

Cellulose, cellulose acetate, ethylene vinyl alcohol copolymer, polysulfone, polyether sulfone, polymethyl methacrylate and the like as dialysis membranes and plasma component separation membranes etc. conventionally used for blood purifiers such as artificial kidneys and plasma separators Synthetic polymer membranes such as polyacrylonitrile have been utilized. Synthetic polymer membranes are widely used as general-purpose membranes in response to the aim of improving the performance of blood purifiers.
On the other hand, in the gradual removal of urinary toxins and wastes from blood in aging dialysis patients and early adopters of hemodialysis treatment, it is also hydrophilic in patients showing allergic reactions to polysulfone-based polymer membranes. Polymer membranes are used.

However, in hydrophilic polymer membrane blood purifiers, it is known that adverse events such as platelet activation occur infrequently.
In recent years, in addition to the removal of urine toxins and waste products in blood, it is a causative agent of oxidative stress using dialysis membranes and plasma component separation membranes for the purpose of alleviating oxidative stress that is manifested in dialysis patients. Attempts have been made to eliminate peroxides and to restore the antioxidant effects of living organisms.

Patent Document 1 proposes a hollow fiber membrane for blood purification that contains a fat-soluble vitamin as a method for eliminating the harmful event of the hydrophilic polymer membrane and eliminating active oxygen produced during hemodialysis. There is.
Patent Literatures 2 and 3 disclose spinning techniques that maintain the pores of the hydrophilic polymer membrane and do not reduce the performance.

JP, 2013-94525, A JP 2001-286740 A JP 2011-41830 A

However, the hollow fiber membrane for blood purification disclosed in Patent Document 1 is a hollow fiber membrane in which a fat-soluble vitamin is kneaded and mixed in the hollow fiber membrane, and a large amount of fat-soluble vitamin is present in the membrane. As a result, it has been found that the plasticity of the hollow fiber membrane is enhanced and the strength of the hollow fiber membrane is lowered, which may cause a leak when the hollow fiber type blood purifier is used.
In addition, hollow fiber type blood purifiers using hydrophilic polymer membranes disclosed in Patent Documents 1 to 3 simultaneously achieve suppression of platelet activation, sufficient removal of medium molecular weight substances, and elimination of oxidative stress. Has not been reached.

  The problem to be solved by the present invention is to provide a hollow fiber type blood purifier with a hydrophilic polymer membrane capable of simultaneously achieving suppression of platelet activation, sufficient removal performance of medium molecular weight substances and elimination of oxidative stress. It is to be.

  The inventors of the present invention conducted intensive studies to solve the above problems, and as a result, a hollow fiber membrane containing a specific amount of a fat-soluble vitamin and incorporating a hollow fiber membrane exhibiting a specific amount of β2-microglobulin clearance By making it into a type blood purifier, it finds out that the above-mentioned subject can be solved and completed the present invention.

That is, the present invention is as follows.
(1) A hollow fiber membrane type blood purifier incorporating a hollow fiber membrane containing a hydrophilic polymer, comprising:
The hollow fiber membrane contains a fat-soluble vitamin of 10 mg or more and 300 mg or less per 1 m ^{2 of the} inner surface of the hollow fiber membrane,
The hollow fiber membrane type blood purifier, wherein the β2-microglobulin clearance converted to 1.5 m ^{2 of the} hollow fiber membrane is 5 mL / min or more and 90 mL / min or less.
(2) The hollow fiber type blood purifier according to (1), wherein the hydrophilic polymer is an ethylene-vinyl alcohol copolymer.
(3) The hollow fiber type blood purifier according to (1), wherein the hydrophilic polymer is cellulose triacetate.
(4) A step of adhering a fat-soluble vitamin to the hollow fiber membrane by passing an acetone solution of the fat-soluble vitamin in a hollow fiber membrane containing a hydrophilic polymer, (1) to (3) The manufacturing method of the hollow fiber membrane type blood purifier in any one.

  In the present invention, it is possible to provide a hollow fiber membrane type blood purifier with a hydrophilic polymer membrane capable of simultaneously achieving suppression of platelet activation, sufficient removal performance of medium molecular weight substances and elimination of oxidative stress.

1 shows a typical hollow fiber type blood purifier.

  Hereinafter, a mode for carrying out the present invention (hereinafter, referred to as “the present embodiment”) will be described in detail. The present invention is not limited to the present embodiment described below, and various modifications can be made within the scope of the present invention.

Hollow fiber type blood purifier
The hollow fiber type blood purifier of the present embodiment is a hollow fiber type blood purifier incorporating a hollow fiber membrane containing a hydrophilic polymer.
In the present embodiment, the “blood purifier” purifies the blood used for extracorporeal blood circulation treatment such as a hemodialyzer, a hemofiltration dialyzer, a hemofilter and a continuous hemodiafiltration (dialysis) device. Means the device to
The blood purifier incorporates a hollow fiber membrane in a container constituting the blood purifier, and the hollow fiber membrane contains a hydrophilic polymer.

<Hollow fiber membrane>
The inner diameter of the hollow fiber membrane is preferably 100 μm to 300 μm.
When the inner diameter of the hollow fiber membrane is 100 μm or more, the pressure loss of the liquid to be treated such as blood flowing through the hollow fiber hollow portion can be kept relatively small, for example, to prevent hemolysis when the blood flows. it can. The inner diameter of the hollow fiber membrane is more preferably 130 μm or more, further preferably 150 μm or more.
By setting the inner diameter of the hollow fiber membrane to 300 μm or less, it is possible to increase the shear rate of blood flowing through the hollow fiber membrane hollow part to some extent and prevent protein and the like from being deposited on the inner surface of the membrane during filtration. The inner diameter of the hollow fiber membrane is more preferably 280 μm or less, and still more preferably 260 μm or less.
The film thickness of the hollow fiber membrane is preferably 10 μm or more and 100 μm or less, and more preferably 10 μm or more and 50 μm or less from the viewpoint of improving spinnability and assemblability of the blood purifier.
The membrane structure of the hollow fiber membrane is preferably a homogeneous structure. The fact that the film structure is a homogeneous structure means that when the cross section of the film is observed at about 1000 times with a SEM (scanning electron microscope), nonuniformity is not observed in the film structure such as the support layer, skin layer and pore size distribution. Specifically, this means that non-uniformities such as voids and pinholes are not observed.
In the present embodiment, the inner diameter and the film thickness can be determined by the method described in the examples.

<Hydrophilic polymer>
In the present embodiment, “hydrophilic polymer” means a synthetic or natural polymer that is soluble in water or exhibits affinity to water.
The hydrophilic polymer is preferably a synthetic polymer, and examples of the synthetic polymer include regenerated cellulose, cellulose diacetate, cellulose triacetate, ethylene vinyl alcohol copolymer, polyacrylonitrile and polymethyl methacrylate.

In the present embodiment, the hollow fiber membrane contains a fat-soluble vitamin, but the instability of the fat-soluble vitamin to light may be a problem. When a product is shipped to a country where storage management is not thoroughly conducted, fat-soluble vitamins cause photodegradation, and various physiological effects such as in vivo antioxidant action, biological membrane stabilization action and platelet aggregation inhibition action There is a possibility that it is reducing it a little. One possible solution is to improve the storage environment, but it is not easy to improve all facilities. Moreover, although it is possible to avoid photodegradation of the fat-soluble vitamin by putting the blood purification device in a light-shielding sterile bag, the cost of the product member is increased.
In the present embodiment, when the hollow fiber membrane contains a hydrophilic polymer having an absorption wavelength in the same region as the fat-soluble vitamin, photodegradation of the fat-soluble vitamin can be suppressed.
Among them, from the viewpoint of productivity, regenerated cellulose, cellulose diacetate, cellulose triacetate and ethylene vinyl alcohol copolymer are preferable, and from the viewpoint of stability of spinning, cellulose triacetate and ethylene are high. Vinyl alcohol copolymers are more preferred.

Fat-soluble vitamins
In the present embodiment, the hollow fiber membrane contains 10 mg or more and 300 mg or less of the fat-soluble vitamin per 1 m ^{2 of the} inner surface of the hollow fiber membrane.
In the present embodiment, examples of fat-soluble vitamins include vitamin A, vitamin D, vitamin E, and vitamin K.
Among them, vitamin E is preferred from the viewpoint of not inducing any disorder even if it is ingested excessively.
Examples of vitamin E include α-tocopherol, α-tocopherol acetate, α-tocopherol tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and tocotrienol.
Among them, α-tocopherol is preferable because it is excellent in various physiological actions such as in vivo antioxidant action, biological membrane stabilizing action, and platelet aggregation inhibiting action, and has a high effect of suppressing oxidative stress.
It may be a lipid-soluble vitamin derivative such as lipoyl vitamin E or DHL-VE-Zn, which is improved for the purpose of improving the antioxidant property, the affinity of the membrane area, and the like.
The fat-soluble vitamin may be used alone or as a mixture of two or more.

<Amount of fat-soluble vitamin present in hollow fiber membrane>
In the present embodiment, the amount of the fat-soluble vitamin present in the hollow fiber membrane is equivalent to the membrane area, that is, 10 mg or more and 300 mg or less per 1 m ^{2 of the} hollow fiber inner surface, preferably 10 mg or more and 250 mg or less. It is more preferable that it is 200 mg or less.
When the amount of the fat-soluble vitamin present in the hollow fiber membrane is 10 mg or more per 1 m ^{2 of the} inner surface of the hollow fiber membrane, it is possible to exert the effect of reducing activation of platelets by the fat-soluble vitamin. By being 300 mg or less per 1 m ² , a hollow fiber membrane excellent in blood compatibility and water permeability can be obtained.
In the present embodiment, “the amount of fat-soluble vitamin present in the hollow fiber membrane” refers to the content of the fat-soluble vitamin attached, adsorbed or coated on the inside and / or the surface of the hollow fiber membrane, “hollow fiber the content of fat-soluble vitamins present in the membrane ", the content of ² per inner surface 1m hollow fiber membrane, for example, the content of fat-soluble vitamins that are extracted by the solvent without destroying and dissolving hollow fiber membrane It can be quantified by

An example of the method of measuring the content of the fat-soluble vitamin present in the hollow fiber membrane will be described.
The hollow fiber type blood purifier is disassembled, the hollow fiber membrane is collected, washed with water, and then subjected to a drying treatment. Subsequently, a surfactant solution which dissolves a fat-soluble vitamin, for example, a 1% by mass aqueous solution of polyethylene glycol-t-octylphenyl ether, is added to the hollow fiber membrane which has been precisely weighed and dried, and the mixture is stirred and extracted. The membrane area of the hollow fiber membrane is calculated from the weight. The quantitative operation can be performed, for example, by liquid chromatography. Using a calibration curve obtained from the peak area of the fat-soluble vitamin standard solution, measure the concentration of fat-soluble vitamin in the extract, and then, as the content per 1 m ^{2 of the} inner surface of the hollow fiber membrane, in the hollow fiber membrane Calculate the content of fat-soluble vitamin present.
Liquid chromatography can be performed, for example, by the method described in the examples.

<Β2-microglobulin clearance>
In the present embodiment, the β 2 -microglobulin clearance converted to 1.5 m ² of the hollow fiber membrane is 5 mL / min or more and 90 mL / min or less.
The β2-microglobulin clearance functions as a hollow fiber type blood purifier by being 5 mL / min or more, and indicates that the performance of the blood purifier is high by being 90 mL / min or less, and it is necessary for the patient to have nutrients Can be prevented from flowing out excessively.
The β2-microglobulin clearance is preferably 5 mL / min or more and 75 mL / min or less, and is 5 mL / min or more and 50 ml / min or less when mild dialysis is considered for elderly people and patients who are initially introduced. Is more preferred.

In the present embodiment, β 2 -microglobulin clearance is a dialyzer performance evaluation criteria (Sato, et al .: functions and applications of various blood purification methods-performance evaluation method and functional classification of blood purifiers, "Dialyser Journal", Nippon Dialysis Corporation Medical Association, 29 (8), 1231-1245 (1996)).
The blood-side inlet flow rate (QB) of the hollow fiber membrane type blood purifier is adjusted to 200 mL / min, and the dialysate-side inlet flow rate (QD) to 500 mL / min. After waiting for steady state until the solute concentration in the blood side outlet becomes stable, the test solution is sampled from the blood side inlet, the blood side outlet and the dialysate side outlet respectively, and the blood side inlet concentration of each β2-microglobulin (CBi And blood side outlet concentration (CBo). The β 2 -microglobulin concentration may be measured using a commercially available device, or it may be possible to request a measurement from a clinical testing company.
The β2 microglobulin clearance (CL) can be calculated by the following formula (1).
CL = (CBi-CBo) / CBi x QB (1)

In the present embodiment, for a hollow fiber type blood purifier having a membrane area other than 1.5 m ² as β 2 -microglobulin clearance, “Measuru Mineshima,” “Blood purifier-basic of performance evaluation, published by Japan Medical Center. The measured value is converted into a clearance value of 1.5 m ² as follows by referring to the method described in “1st edition, 2002”. Specifically, it is as follows.
The β2-microglobulin concentration is measured by the above method except that the QB is reset by the following formula (2).
QB = 200-10 × A (2)
In Formula (2), A represents a membrane area (m ² ).
The overall mass transfer coefficient (K0) is calculated by the following equation (3).
K0 = (QB / A (1-QB / QD)) * ln ((1-CL measured value / QD) / (1-CL measured value / QB)) (3)
The β2-microglobulin clearance is calculated by converting the membrane area to 1.5 m ^{2 according} to the following formula (4).
CL converted value = QB × ((1−exp [K0 × A (1 / QB−1 / QD)]) / (QB / QD−exp [K0 × A (1 / QB−1 / QD)]) ···・ (4)

In the present embodiment, the “membrane area” is the inner surface area of the hollow fiber membrane, and is calculated from the product of the inner diameter of the hollow fiber membrane (diameter of hollow fiber membrane hollow portion), the ratio, the number, and the effective length. Be done.
The effective length means the length excluding the potting portion of the hollow fiber membrane in the blood purifier.

<Method of producing hollow fiber membrane>
In the present embodiment, the hollow fiber membrane can be manufactured by using a known technique and adding a step of immobilizing a fat-soluble vitamin. The hollow fiber membrane may be a single porous membrane or a composite porous membrane.
As a hydrophilic polymer, although the ethylene vinyl alcohol copolymer and a cellulose triacetate are made into an example, although the manufacturing method of a hollow fiber membrane is demonstrated hereafter, it is not limited to these.
Immobilization of the fat-soluble vitamin may be carried out in the process of producing the hollow fiber membrane, or may be carried out after assembling into a hollow fiber type blood purifier.

<Production Method of Single Porous Membrane Containing Ethylene-Vinyl Alcohol Copolymer>
A single porous membrane is a membrane having a large number of pores penetrating from one side of the membrane to the other side, and the membrane has a porous structure.
Hereinafter, a single porous membrane containing an ethylene vinyl alcohol copolymer will be described.
The ethylene-vinyl alcohol copolymer may be any of random, block and graft copolymers, but from the viewpoint of sufficient mechanical strength at the time of film formation, the degree of polymerization of ethylene and vinyl alcohol is at least 800. Is preferable, and 1000 or more is more preferable.
The ethylene-vinyl alcohol copolymer may be a copolymer containing an olefin other than ethylene. Examples of the olefin other than ethylene include propylene, 3-methylbutene-1 and 4-methylpentene-1.
When it is a copolymer containing olefins other than ethylene, it is preferable that it is a copolymer containing propylene from which a porous structure with a sufficiently large pore diameter can be obtained.
The olefin may be used alone or in combination of two or more.
The olefin (including ethylene) content is preferably 10 mol% or more in view of the wet mechanical properties of the hollow fiber membrane and the suppression of the eluate, and in view of increasing the permeability of the medium molecular weight substance 10 mol% or more and 60 mol% or less is more preferable. The ethylene content is preferably 10 mol% or more, and more preferably 10 mol% or more and 60 mol% or less.
The degree of saponification of the ethylene-vinyl alcohol copolymer is preferably 95% by mole or more from the viewpoint of the wet mechanical strength of the hollow fiber membrane, and is substantially completely saponified with a degree of saponification of 99% by mole or more It is more preferable to use one of

Examples of the solvent for dissolving the ethylene-vinyl alcohol copolymer used in the membrane-forming solution include dimethylsulfoxide (hereinafter referred to as DMSO), N, N-dimethylacetamide (hereinafter referred to as DMAc) and N-methylpyrrolidone (hereinafter referred to as , And NMP).
Among them, DMSO is preferable from the viewpoint of relatively low toxicity in addition to the viewpoint of productivity.
The solvent may be used alone or as a mixed solvent of two or more. A mixed solvent containing DMSO and other solvents such as water, methanol, propanol and dimethylformamide in the range of 80% or less may be used.
Although the density | concentration of the ethylene vinyl alcohol copolymer in a film forming undiluted | stock solution can be selected arbitrarily, it is preferable that it is 3 to 30 mass%, and it is more preferable that it is 5 to 20 mass%.
The temperature of the membrane-forming solution is preferably 0 ° C. or more and 120 ° C. or less, and is 5 ° C. or more and 80 ° C. or less, in order to make the viscosity suitable for spinning while preventing deterioration of the ethylene vinyl alcohol copolymer. Is more preferred.

In order to produce a hollow fiber membrane, the membrane-forming stock solution is extruded and coagulated in a coagulation bath while discharging a non-coagulable liquid from the central portion using a double annular nozzle.
In the coagulation bath, an aqueous medium is used as a coagulant.
The aqueous medium contains a mixed solvent of water and water-soluble organic solvents such as DMSO, DMAc, NMP, pyrrolidone and alcohol, and water-soluble inorganic salts such as NaCl, Na ₂ SO ₄ and NaOH. And the like.
Among them, a mixed solvent of water and DMSO is preferred.

By setting the temperature of the coagulation bath to -10 ° C. or more and 3 ° C. or less, it is possible to control the β2-microglobulin clearance of the hollow fiber type blood purifier to 5 ml / min or more and 90 ml / min or less By setting the temperature to 1 ° C. or higher, the β2-microglobulin clearance can be controlled to 5 ml / min to 50 ml / min.
When the membrane-forming solution is coagulated at the above-mentioned coagulation bath temperature, a homogeneous fine pore structure required as a hollow fiber membrane is formed. The coagulation can be carried out in one or more stages, but at least the first bath of the coagulation bath needs to satisfy the above-mentioned coagulation bath temperature.

In the present embodiment, the obtained hollow fiber membrane is preferably sequentially subjected to water washing, wetting treatment, drying and dry heat treatment.
The film after water washing is immersed in a water-miscible volatile organic solvent, subjected to a wet treatment to replace water on the surface or inside of the film, and then dried at normal pressure or reduced pressure.
Examples of the water-miscible volatile organic solvents include acetone, amyl alcohol, xylene, ethyl acetate, methyl acetate, cyclohexane, methyl ethyl ketone, diethyl ketone, styrene, tetrahydrofuran and toluene.
Among them, acetone is preferable from the viewpoint of good substitution efficiency in wetting treatment and dispersibility with a fat-soluble vitamin and suppressing the deterioration of performance due to drying.
In the wet treatment, the fat-soluble vitamin is added to a water-miscible volatile organic solvent at a concentration of preferably 0.01% by mass to 10% by mass, more preferably 0.1% by mass to 5% by mass. The filamentous membrane may contain a fat-soluble vitamin.

  In order to perform drying in a short time while maintaining the performance at the time of wet treatment, it is necessary to carry out under the following conditions. Drying conditions are a temperature of water content of 20% or less, a temperature of glass transition point (hereinafter Tg) of ethylene vinyl alcohol copolymer, under normal pressure or reduced pressure, and water vapor pressure needs to be 20 mmHg or more.

The dried hollow fiber membrane is subjected to dry heat treatment mainly for the purpose of improving the storage stability of the size and performance.
When the dry heat treatment temperature (HT ° C.) is performed at Tg + 20 ° C. or less, the hollow fiber membrane can be flattened and the performance can be maintained.
The dry heat treatment temperature is preferably Tg-40 ° C. or more and Tg + 20 ° C. or less, more preferably Tg-20 ° C. or more and Tg ° C. or less, from the viewpoint of suppressing formation of sufficient pores and shrinkage of the hollow fiber membrane. preferable.
Under the dry heat treatment atmosphere from the viewpoint of preventing the adsorption of water molecules to the ethylene vinyl alcohol copolymer and preventing the film structure from being changed along with the desorption of water molecules when released to the room temperature atmosphere after the dry heat treatment The water vapor pressure is preferably 60 mmHg or less.
The dry heat treatment time is preferably within 20 minutes.
After the dry heat treatment, the obtained dried hollow fiber membrane may be wound on a bobbin, a frame or the like, or may be cut into a predetermined length and then bundled in a predetermined number to form a hollow fiber bundle.
The thickness of the hollow fiber membrane containing ethylene vinyl alcohol copolymer is preferably 10 μm or more and 100 μm or less, and more preferably 10 μm or more, from the viewpoint of securing spinnability and mechanical strength and securing removal performance of medium molecular weight substances. The thickness is more preferably 50 μm or less, and still more preferably 15 μm to 50 μm. The outer diameter of the ethylene-vinyl alcohol copolymer hollow fiber membrane is usually 120 μm to 500 μm, preferably 120 μm to 480 μm, and more preferably 120 μm to 460 μm.

As a method of coating a fat-soluble vitamin, it may be carried out at the time of moist heat treatment, or after obtaining a hollow fiber membrane, impregnating the fat-soluble vitamin solution and thereafter drying it to coat the fat-soluble vitamin on the hollow fiber membrane. Good.
Examples of the solvent used for the fat-soluble vitamin solution include acetone, amyl alcohol, xylene, ethyl acetate, methyl acetate, cyclohexane, methyl ethyl ketone, diethyl ketone, styrene, tetrahydrofuran and toluene.
Among them, acetone, cyclohexane, methyl ethyl ketone and diethyl ketone are preferable because they disperse the fat-soluble vitamin well and suppress the deterioration of the membrane performance.
The fat-soluble vitamin concentration in the fat-soluble vitamin solution is preferably 0.01% by mass or more and 10% by mass or less.

<Production Method of Composite Porous Membrane Containing Ethylene-Vinyl Alcohol Copolymer>
The composite porous membrane is a membrane having a large number of pores penetrating from one side of the membrane to the other side, and the membrane substantially has a porous structure and the pore surface of the porous structure. It is what is comprised by a coating layer to coat | cover. The pore surface of the porous structure refers to a combination of the inner wall surface of the penetrated pore which can contribute to the permeation of the medium molecular weight substance and both surfaces of the porous structure.
Examples of the composite porous membrane include a composite porous membrane comprising a porous structure made of a hydrophobic polyolefin and a coating layer of an ethylene vinyl alcohol copolymer which is a hydrophilic polymer.
The ethylene content of the polyolefin is 20 mol% or more from the viewpoint of enhancing the adhesiveness with the ethylene-vinyl alcohol copolymer and preventing the peeling of the coating layer from the pores of the porous structure and the viewpoint of hydrophilicity Is more preferably 20 mol% or more and 70 mol% or less, and still more preferably 25 mol% or more and 50 mol% or less from the viewpoint of the balance between adhesiveness and hydrophilicity. Since the ethylene-vinyl alcohol copolymer contains ethylene having a structure common to that of the polyolefin as a component, good adhesion can be obtained.
As the ethylene-vinyl alcohol copolymer, the same ethylene-vinyl alcohol copolymer as described above for the method for producing a single porous membrane may be used.

The manufacturing method of the porous structure in a composite porous membrane can utilize the manufacturing method of a normal porous membrane, and can adopt well-known methods, such as a wet phase inversion method, a melt phase separation method, an extending | stretching open hole method. In the drawing and stretching method, a crystalline polymer is formed into a hollow fiber or a film, and then cold drawing is performed to cleave between crystal lamellas, and further, heat drawing is performed to enlarge the pore diameter to form a porous structure. In the stretching / opening method, a porous structure is produced by physical means of stretching without adding a solvent or other additives to a crystalline polymer, and it is a preferred method because there is no problem of residual solvent and the like.
Polyolefin is spun at a spinning temperature of 145 ° C. or more and 155 ° C. or less using a double annular nozzle, and the obtained hollow fiber is annealed at 115 ° C. or more and 120 ° C. or less for 1 hour or more and 3 hours or less, and then room temperature or more 100 10% or more and 30% or less stretching is performed, and then 30% or more and 350% or less heat stretching is performed at 100 ° C. or more and 120 ° C. or less to obtain a hollow fiber membrane having a porous structure.

A composite porous membrane containing an ethylene-vinyl alcohol copolymer is obtained by treating the surface of pores of a porous structure comprising a polyolefin with an ethylene-vinyl alcohol copolymer solution dissolved in a mixed solvent of the solvent and water. Can.
The hollow fiber membrane in the present embodiment can be obtained by treating the pore surface of the porous structure with a mixed solution of an ethylene-vinyl alcohol copolymer and a fat-soluble vitamin.
The treatment with the solution containing the ethylene-vinyl alcohol copolymer includes a step of applying the solution to the surface of the pores of the porous structure, and a drying step of evaporating the solvent of the solution after the step.

The ethylene-vinyl alcohol copolymer or the solvent for dissolving the ethylene-vinyl alcohol copolymer and the fat-soluble vitamin is a water-miscible organic solvent, and examples of the organic solvent include acetone, amyl alcohol, xylene, ethyl acetate, acetic acid Examples thereof include methyl, cyclohexane, methyl ethyl ketone, diethyl ketone, styrene, tetrahydrofuran and toluene.
Among them, acetone is preferable from the viewpoint of dispersibility of the fat-soluble vitamin and from the viewpoint of suppressing the performance decrease due to drying.
When a solution containing a fat-soluble vitamin is used, the concentration of the fat-soluble vitamin is preferably 0.01% by mass or more and 10% by mass or less, and more preferably 0.1% by mass or more and 5% by mass or less .

The organic solvent may be used alone, but can also be used as a mixed solvent, and it is preferable to use it as a mixed solvent of water and an organic solvent.
The ethylene-vinyl alcohol copolymer is composed of a nonpolar and hydrophobic ethylene moiety and a polar and hydrophilic vinyl alcohol moiety, but when it is dissolved in a highly polar solvent system and coated on a nonpolar polyolefin, it is nonpolar. It is considered that the polar ethylene portion is localized on the polyolefin side, and the polar vinyl alcohol portion is likely to be localized on the surface side. The phenomenon is a preferable phenomenon because the adhesion between the coating layer and the pore surface of the porous structure is improved and the hydrophilicity of the surface of the coating layer is improved.
Using a mixed solvent obtained by adding water to the organic solvent makes the polarity of the solution containing the ethylene-vinyl alcohol copolymer stronger, and the above phenomenon is promoted, which is preferable. The proportion of water in the mixed solvent is preferably as large as not to inhibit the solubility of the ethylene-vinyl alcohol copolymer, but the proportion varies depending on the ethylene content of the ethylene-vinyl alcohol copolymer, the temperature of the solution, etc. For example, it is preferable that they are 5 mass% or more and 60 mass% or less.
The concentration of the ethylene-vinyl alcohol copolymer can be selected from any concentration suitable for coating, and is, for example, about 0.1% by mass or more and 5% by mass or less.
In this treatment, the porous membrane can be cut into a predetermined shape and treated batchwise, but the hollow fiber porous membrane can be run in the longitudinal direction to be treated continuously, which is preferable because of excellent productivity. It is a method.

<Production Method of Hollow Fiber Membrane Containing Cellulose Triacetate>
In the present embodiment, cellulose acetate may be used as the hydrophilic polymer that is the material of the hollow fiber membrane.
Cellulose acetate has a hydroxyl group capped to some extent and is excellent in blood compatibility such as suppression of complement activity and good blood return without blood clotting, and is suitable for use in blood purification, for example, cellulose diacetate And cellulose triacetate and the like. The hollow fiber membrane containing cellulose triacetate is preferably a single porous membrane.

As a solvent which melt | dissolves cellulose triacetate used for film forming undiluted | stock solution, DMSO, DMAc, NMP, a dimethylformamide etc. are mentioned, for example.
The solvent may be used alone or as a mixed solvent of two or more.
A mixed solvent containing non-solvent such as glycerin, ethylene glycol, triethylene glycol and polyethylene glycol may be used for the membrane forming solution.
The preferred ratio of cellulose triacetate, solvent, non-solvent and water contained in the membrane-forming solution in the membrane-forming solution composition is 15% by mass to 28% by mass of cellulose acetate, 50% by mass to 60% by mass of solvent, non-solvent 20 It is the mass% or more and 25 mass% or less, and the water 0 mass% or more and 2 mass% or less.

In order to produce a hollow fiber membrane, the membrane-forming solution is discharged from the outer peripheral pipe into the air while discharging the hollow forming material from the central portion using a double tubular nozzle.
As a hollow forming material, a liquid, an inert liquid and a gas active to cellulose triacetate can be used.
Active liquids include mixtures of solvents and non-solvents of cellulose triacetate with water, and examples of inert liquids include liquid paraffin and isopropyl myristate, and examples of inert gases include nitrogen. And argon.
When an active liquid is used as the hollow forming material, the resulting hollow fiber membrane tends to have a nonuniform structure, and when an inert liquid and gas are used, the resulting hollow fiber membrane tends to have a uniform structure.
In the case of a hollow fiber membrane containing a pore diameter retention agent such as glycerin, it is preferable to use a hollow fiber membrane having a uniform structure from the viewpoint of preventing the pore diameter retention agent from falling out of the pores. Is preferred.

The membrane-forming solution discharged together with the hollow forming material from the double tubular nozzle is allowed to travel through the free running part, introduced into a coagulation bath installed at the lower part of the double tubular nozzle, and immersed to complete coagulation.
Since the structure and characteristics of the hollow fiber membrane obtained by the coagulation liquid composition change in the coagulation bath, the mixing ratio of solvent, non-solvent and water is included in the membrane forming solution according to the target membrane structure and membrane characteristics. A mixture of solvent, non-solvent and water is preferably used.
It is preferable to set the temperature of the membrane forming solution to 70 ° C. or more and 110 ° C. or less, and to set the temperature of the inner liquid as a hollow forming material to 0 ° C. or more and 40 ° C. or less. It is preferable to provide a temperature difference of 50 ° C. or more and 100 ° C. or less between the membrane forming solution and the inner solution. Even if the setting of the temperature difference is too large, heat conduction can not actually be suppressed, and if the temperature difference is too small, solidification can not be promoted, so the temperature difference is more preferably 40 ° C. or more and 90 ° C. or less, More preferably, the temperature is 50 ° C. or more and 85 ° C. or less.

  The coagulated hollow fiber membrane is preferably subjected to a washing step and impregnated with a hollow fiber membrane pore diameter retention agent such as a glycerol solution of 15% by mass to 90% by mass before reaching the drying step. Water may be used as a solvent of the solution containing the pore diameter retention agent.

A hollow fiber in which a fat-soluble vitamin is immobilized by adding a fat-soluble vitamin at 0.01% to 10% by mass to a glycerin solution, simultaneously applying the glycerin and the fat-soluble vitamin to the hollow fiber membrane and drying it. Membranes can also be obtained.
Examples of the organic solvent to be contained in the glycerol solution for improving the dispersion of the fat-soluble vitamin include acetone, amyl alcohol, xylene, ethyl acetate, methyl acetate, cyclohexane, methyl ethyl ketone, diethyl ketone, styrene, tetrahydrofuran and toluene. It can be mentioned.

It is also possible to obtain a hollow fiber membrane in which a fat-soluble vitamin is solidified by impregnating with a pore-diameter-retaining agent and then obtaining a dried hollow fiber membrane, and thereafter impregnating with a fat-soluble vitamin solution and drying again.
Examples of the solvent of the fat-soluble vitamin solution include acetone, amyl alcohol, xylene, ethyl acetate, methyl acetate, cyclohexane, methyl ethyl ketone, diethyl ketone, styrene, tetrahydrofuran and toluene. The solvent may be used alone or as a mixed solvent of two or more.
Among them, acetone is preferable from the viewpoint of good dispersion of the fat-soluble vitamin and suppression of the decrease in performance of the membrane.

<Method of manufacturing hollow fiber type blood purifier>
In the hollow fiber membrane type blood purifier of this embodiment, the hollow fiber membrane bundle is inserted into a cylindrical container having an inlet / outlet for treatment liquid in contact with the outside of the membrane, and a potting agent such as polyurethane is injected into both bundle ends. The potting layer can be formed to seal both ends, and then the excess potting agent after curing can be cut off to open the end face, and a header having a fluid port can be attached.
A typical hollow fiber membrane type blood purification apparatus is shown in FIG. 1, but the design may be modified as appropriate within the scope of the present invention.

Immobilization of the fat-soluble vitamin may be carried out at the production stage of the hollow fiber membrane as described above, or may be carried out in the state where the hollow fiber membrane is incorporated in the blood purifier.
When immobilizing a fat-soluble vitamin after assembly into a hollow fiber type blood purifier, the fat-soluble vitamin is attached to the inner surface of the hollow fiber membrane by injecting the fat-soluble vitamin solution into the hollow part of the hollow fiber membrane. It is preferable to Since the amount of fat-soluble vitamin adhering to the hollow fiber membrane can be controlled by the concentration of fat-soluble vitamin, the fat-soluble vitamin concentration of the fat-soluble vitamin solution is preferably in the range of 0.01 to 10% by mass.
Examples of the solvent of the fat-soluble vitamin solution include acetone, amyl alcohol, xylene, ethyl acetate, methyl acetate, cyclohexane, methyl ethyl ketone, diethyl ketone, styrene, tetrahydrofuran and toluene. The solvent may be used alone or as a mixed solvent of two or more.

The hollow fiber type blood purifier in which the fat-soluble vitamin is immobilized and assembled may wet the hollow fiber membrane with an aqueous solution before sterilization (wetting step). By wetting the hollow fiber membrane with an aqueous solution, the hollow fiber membrane is stabilized, and changes in performance such as water permeability, dialysis performance, filtration performance, etc. are less likely to occur.
The wetting step can be carried out by a method of filling a container containing a hollow fiber membrane with an aqueous solution.
In the wetting step, after the container is filled with the aqueous solution, the aqueous solution may be drained.
The wetting step may be combined with the addition step of the sterilizing agent.

The sterilizing agent is for protecting the hydrophilic polymer of the hollow fiber membrane from being significantly denatured by the radiation energy irradiated in the sterilization process.
Examples of the sterilizing agent include (polyhydric) alcohols such as glycerin and propylene glycol, water-soluble saccharides such as oligosaccharides and polysaccharides, and inorganic salts such as sulfites.
The method of impregnating the hollow fiber membrane with the sterilizing agent is a method of dissolving the sterilizing agent in a suitable solvent and introducing it into a hollow fiber type blood purifier, for example, dissolving the sterilizing agent in water or physiological salt solution And then filling the space inside the hollow fiber type blood purifier or impregnating only the hollow fiber membrane.
In the wetting step, the wetting step and the addition step of the sterilizing agent can be simultaneously performed by wetting with the aqueous solution containing the sterilizing agent as the aqueous solution.
When a sterilizing agent is present in the hollow fiber type blood purifier, the hollow fiber type blood purifier, in particular, the hollow fiber membrane can be prevented from being changed by the sterilization process.
When a sterilizing agent is used in solution, the concentration of the sterilizing agent may be determined according to the material of the hollow fiber membrane blood purifier, the type of hydrophilic polymer and the conditions of sterilization, but 0 It is preferable that it is .001% or more and 1% or less, and it is more preferable that it is 0.005% or more and 0.5% or less.

The hollow fiber type blood purifier may be subjected to sterilization treatment (sterilization treatment step). Examples of the sterilization treatment include radiation sterilization and steam sterilization.
The hollow fiber membrane containing a large amount of fat-soluble vitamin has a risk of being damaged by extreme heating, so radiation sterilization is preferred. For the radiation sterilization method, electron beam, gamma ray, X-ray or the like can be used. The irradiation dose of radiation is preferably 5 kGy or more and 50 kGy or less, and more preferably 20 kGy or more and 40 kGy or less in the case of a γ ray or an electron beam.

  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples. The evaluation method and the measurement method used in this example are as follows.

<Internal diameter and film thickness>
The potting portion of the hollow fiber type blood purifier was cut off, and the hollow fiber membrane left in the container was collected. An appropriate number of hollow fiber membranes were obtained so that the hollow fiber membranes did not fall through the φ3 mm holes opened at the center of the slide glass, and the upper and lower surfaces of the slide glass were cut with a razor to obtain hollow fiber membrane cross-section samples .
The short diameter and the long diameter of the hollow fiber membrane cross section were measured using a projector Nikon-V-12A. The minor axis and major axis in two directions are measured for each hollow fiber membrane cross section, the arithmetic mean value of each is taken as the inner diameter and outer diameter of one hollow fiber membrane cross section, and the film thickness is calculated by (outside diameter-inner diameter) / 2 did. The measurement was similarly performed on the 5 cross sections, and the average value was defined as the inner diameter and the film thickness.

<Measurement of the amount of fat-soluble vitamin present in hollow fiber membranes>
The potting portion of the hollow fiber type blood purifier was separated, and the hollow fiber membrane remaining in the container was collected, washed with water and vacuum dried at 40 ° C. The hollow fiber membrane is weighed in a glass bottle so that the inner surface area of the hollow fiber membrane after drying is 0.2 m ² , 80 mL of 1% by mass aqueous solution of Triton X-100 (for Kishida Chemical, Chemical) is added, and at room temperature Extraction of a fat-soluble vitamin was performed while applying ultrasonic vibration for 60 minutes.
The quantitative operation was performed by liquid chromatography, and the amount of fat-soluble vitamin in the extract was determined using a calibration curve obtained from the peak area of the fat-soluble vitamin standard solution.
High-performance liquid chromatograph (pump: JASCO PU-1580, detector: Shimadzu RID-6A, auto injector: Shimadzu SIL-6B, data processing: Tosoh GPC-8020, column oven: GL Sciences 556), column (Shodex Asahipak) Attach ODP-506E packed column for HPLC), pass methanol for high-performance liquid chromatography as a mobile phase at a flow rate of 1 mL / min at a column temperature of 40 ° C, and select fat-soluble vitamin concentration from the area of ultraviolet absorption peak I asked. From this concentration, the extraction efficiency was 100%, and the amount of fat-soluble vitamin (mg / m ² ) present in the hollow fiber membrane was determined.

<Measurement of Permeability Reduction Rate of Hollow Fiber Membrane Blood Purifier>
Under constant pressure (200 mmHg) and temperature (37 ° C.) conditions, the inside of the hollow fiber membrane type blood purifier was totally filtered with pure water, and the time required for filtration was measured. From this result, the water permeability (UFR (mL / hr · mmHg)) was calculated.
Subsequently, the water permeation performance reduction rate was calculated from the following equation.

The decrease in water permeability is caused by the fact that the pores of the hollow fiber membrane are coated with a fat-soluble vitamin. By increasing the size of the pores of the hollow fiber membrane, the range in which the performance of the hollow fiber membrane can be controlled even if it is coated with a fat-soluble vitamin is judged to be a water permeation performance reduction rate of 50% or less.

<Measurement of β2-microglobulin clearance>
β2-microglobulin clearance is the dialyzer performance evaluation criteria (Sato, et al .: Functions and applications of various blood purification methods-Performance evaluation method and functional classification of blood purifiers, "Dialyser Journal", published by The Japan Society for Dialysis Therapy, 29 (8), 1231-1245, 1996).
Using anti-coagulated bovine whole blood plasma-separated bovine plasma (total protein concentration TP = 6.5 ± 0.5 g / dL), the following flow conditions were made according to standard treatment.
The flow conditions were as follows: QB = 200 ± 4 mL / min, QD = 500 ± 15 mL / min.

<Measurement of photodegradation rate of fat-soluble vitamin contained in hollow fiber membrane>
In order to evaluate the decomposition of the fat-soluble vitamin immobilized on the hollow fiber membrane by light, the hollow fiber type blood purifier was disassembled to remove the wetting liquid, and then completely dried using a vacuum dryer. The dried hollow fiber membrane bundle is divided into two parts, one at a temperature of 25 ° C. and 50% RH, one from a fluorescent lamp (FLR40S-N / M-X. 3.6 manufactured by Panasonic Corporation, illuminance 3000 lx, sample from fluorescent lamp A distance of 1 m was applied directly (A), and the other was covered with aluminum foil on the bundle and shielded from light, and then the light of the fluorescent lamp was applied (B). After 5 days of exposure to finely cut the respective hollow fiber bundle, placed in a sample bottle lid, followed by the addition of ethanol membrane area 1 m ² per 380.95mL hollow fiber. The sample bottle was covered, and extraction operation was performed for 1 hour using an ultrasonic cleaner (manufactured by Kamimei Kogyo Co., Ltd., UA100) to obtain an extract of a fat-soluble vitamin.
By the following method, the concentration (CA) of the fat-soluble vitamin in the extract of Experiment (A) and the concentration (CB) of the fat-soluble vitamin in the extract of Experiment (B) were quantified.
・ High-performance liquid chromatograph (pump: JASCO PU-1580, detector: Shimadzu RID-6A, auto injector: Shimadzu SIL-6B, data processing: Tosoh GPC-8020, column oven: GL Sciences 556)
・ Column (Shodex Asahipak ODP-506E packed column for HPLC), column temperature 40 ° C
Mobile phase: Methanol for high performance liquid chromatography, flow through at a flow rate of 1 mL / min. The concentration of a fat-soluble vitamin was determined from the area of the absorption peak at a wavelength of 295 nm with a UV detector.
The decomposition rate of the fat-soluble vitamin was evaluated by the value obtained by the following formula.
Photodegradation rate of fat-soluble vitamin (%) = CA / CB x 100 (5)
In this method, the smaller the rate of change, the less the decomposition of vitamin by light. In other words, it means that the photodegradation of vitamin was suppressed by the membrane. Therefore, if this photodegradation rate was 20% or less, it was judged that it was favorable.

<Measurement of blood compatibility of blood purification apparatus: Measurement of lactate dehydrogenase (LDH) activity>
The blood compatibility of the hollow fiber membrane was evaluated by the adhesion of platelets to the surface of the hollow fiber membrane, and quantified using the activity of lactate dehydrogenase (LDH) contained in platelets attached to the hollow fiber membrane as an index.
The hollow fiber membrane collected by disassembling the hollow fiber type blood purifier was bonded with epoxy adhesive at both ends so that the effective length of 10 cm and the area of the inner surface of the membrane were 0.01 m ² to produce a mini module . With respect to this mini-module, 100 mL of physiological saline (Otsuka Pharmaceutical Co., Ltd., Otsuka Dietary Supplement) was flowed and washed in the hollow fiber hollow part at a flow rate of 10 mL / min.
Thereafter, 30 mL of heparinized human blood was adjusted to 37 ° C. and circulated for 2 hours in the mini module at a flow rate of 10.7 mL / min. After circulation, the inner surface (hollow portion) of the hollow fiber membrane of the mini module was washed with 10 mL and the outer surface with 10 mL with physiological saline. After the hollow fiber membrane was collected from the washed mini module, it was shredded and placed in a Spitz tube for LDH measurement to obtain a measurement sample.
Next, a 0.5 volume% Triton X-100 / PBS solution obtained by dissolving Triton X-100 (manufactured by Nacalai Tesque) in a phosphate buffer solution (PBS) (manufactured by Wako Pure Chemical Industries, Ltd.) was subjected to LDH measurement. After adding 1.79 mL to a Spitz tube for centrifugation, centrifuge (2700 rpm × 5 min) to sink the hollow fiber membrane in the solution, shake extraction is performed for 60 minutes to destroy cells (mainly platelets) attached to the hollow fiber membrane. And extracted the LDH in the cells. 0.05 mL of this extract is taken, and 2.7 mL of a 0.6 mM sodium pyruvate solution and 0.3 mL of a 1.277 mg / mL nicotinamide adenine dinucleotide (NADH) solution are further added and reacted, After reacting for 1 hour at ° C, the absorbance at 340 nm was measured. Similarly, the absorbance was also measured for a membrane (blank) which was not reacted with blood, and the difference in absorbance was calculated by the following formula (6). Furthermore, LDH was evaluated by the value obtained by following formula (7) which divided the value obtained by following formula (6) by effective membrane area.
Δ340 nm = absorbance after 60 minutes of the sample−absorbance after 60 minutes of the blank (6)
LDH = Δ340 nm / effective film area ... (7)
In this method, the larger the reduction width, the higher the LDH activity, that is, it is evaluated that it means that the adhesion amount of platelets to the hollow fiber membrane surface is large, and the LDH activity is 50 or less and the blood compatibility is good. It was judged.

Example 1
15% by mass ethylene vinyl alcohol copolymer (EVAL EC-F100A manufactured by Kuraray Co., Ltd., EVAL EC-F 100A) having an ethylene content of 60% by mole and a degree of saponification of 99% 90% by mass DMSO, 10% by mass water and 2% by mass lithium chloride It heat-melted at ° C and obtained the film forming undiluted | stock solution. The temperature of the obtained membrane-forming solution was 28 ° C. The film-forming stock solution at 40 ° C. was extruded while injecting water into the inside of the double annular nozzle, passed through air at 15 ° C., and introduced into a water bath having a coagulation bath temperature of 2 ° C.
Subsequently, according to a conventional method, washing with water, wetting treatment, drying and dry heat treatment were performed to obtain a dried hollow fiber membrane.
The resulting dried hollow fiber membrane is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the cured urethane portion is cut to form a hollow fiber membrane Processed at the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² . The internal diameter of the obtained hollow fiber membrane was 175 μm, and the film thickness was 25 μm.
Next, a coating solution prepared by dissolving 0.1% by mass of α-tocopherol (Wako Pure Chemical Industries, Ltd. special grade) in 99.9% by mass of acetone is added to the hollow fiber membrane from the blood introduction nozzle of the blood processing apparatus at a temperature of 24 ° C. The solution was passed through for 1 minute on the inner surface side to make contact with α-tocopherol. Thereafter, the residual solution in the hollow portion was removed by air flushing, and then the solvent was removed by drying by passing dry air at 24 ° C. for 30 minutes, thereby immobilizing α-tocopherol.
As a wetting step before sterilization, an aqueous solution (wet solution) containing 0.06% sodium bisulfite and 0.03% sodium carbonate for pH adjustment is used as the blood-side flow path (inner surface side) of the blood processor And a filtrate side flow path (outer surface side), and the blood processing device is obtained by sterilizing 25 kGy of γ rays while the nozzles are tightly sealed.

Example 2
15% by mass ethylene vinyl alcohol copolymer (EVAL EC-F100A manufactured by Kuraray Co., Ltd., EVAL EC-F 100A) having an ethylene content of 60% by mole and a degree of saponification of 99% 90% by mass DMSO, 10% by mass water and 2% by mass lithium chloride It heat-melted at ° C and obtained the film forming undiluted | stock solution. The temperature of the obtained membrane-forming solution was 28 ° C. The film-forming stock solution at 40 ° C. was extruded while injecting water into the inside of the double annular nozzle, passed through air at 15 ° C., and introduced into a water bath having a coagulation bath temperature of 1 ° C.
Subsequently, according to a conventional method, water washing, moist heat treatment, drying and dry heat treatment were performed to obtain a dried hollow fiber membrane. The internal diameter of the obtained hollow fiber membrane was 175 μm, and the film thickness was 25 μm.
The resulting dried hollow fiber membrane is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the cured urethane portion is cut to form a hollow fiber membrane Processed at the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
Next, a coating solution prepared by dissolving 0.1% by mass of α-tocopherol (Wako Pure Chemical Industries, Ltd. special grade) in 99.9% by mass of cyclohexane is added to a hollow fiber membrane from a blood introduction nozzle of a blood processing apparatus at a temperature of 24 ° C. The solution was passed through for 1 minute on the inner surface side to make contact with α-tocopherol. Thereafter, the residual solution in the hollow portion was removed by air flushing, and then the solvent was removed by drying by passing dry air at 24 ° C. for 30 minutes, thereby immobilizing α-tocopherol.
As a wetting step before sterilization, an aqueous solution (wet solution) containing 0.06% sodium bisulfite and 0.03% sodium carbonate for pH adjustment is used as the blood-side flow path (inner surface side) of the blood processor And a filtrate side flow path (outer surface side), and the blood processing device is obtained by sterilizing 25 kGy of γ rays while the nozzles are tightly sealed.

Example 3
15% by mass ethylene vinyl alcohol copolymer (EVAL EC-F100A manufactured by Kuraray Co., Ltd., EVAL EC-F 100A) having an ethylene content of 10% by mole, 99% by mass DMSO, 10% by mass water, and 2% by mass lithium chloride It heat-melted at ° C and obtained the film forming undiluted | stock solution. The temperature of the obtained membrane-forming solution was 28 ° C. The film-forming stock solution at 40 ° C. was extruded while injecting water into the inside of the double annular nozzle, passed through air at 15 ° C., and introduced into a water bath having a coagulation bath temperature of 3 ° C.
Subsequently, water washing and wetting treatment were carried out according to a conventional method.
The wet hollow fiber membrane was immersed in 96.8% by mass of methyl ethyl ketone in which 3.2% by mass of α-tocopherol (Wako Pure Chemical Industries, Ltd. Special Grade) was dissolved to replace water present on the surface or inside of the membrane.
Subsequently, drying and heat treatment were performed according to a conventional method to obtain a dried hollow fiber membrane. The internal diameter of the obtained hollow fiber membrane was 175 μm, and the film thickness was 25 μm.
The resulting dried hollow fiber membrane is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the cured urethane portion is cut to form a hollow fiber membrane Processed at the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
As a wetting step before sterilization, an aqueous solution (wet solution) containing 75 ppm of hydrogen peroxide is filled in the blood side flow passage (inner surface side) and the filtrate side flow passage (outer surface side) of the blood processor, and each nozzle is The blood processor was obtained by sterilizing 25 kGy of γ-rays in a sealed state.

Example 4
15% by mass ethylene vinyl alcohol copolymer (EVAL EC-F100A manufactured by Kuraray Co., Ltd., EVAL EC-F 100A) having an ethylene content of 10% by mole, 99% by mass DMSO, 10% by mass water, and 2% by mass lithium chloride It heat-melted at ° C and obtained the film forming undiluted | stock solution. The temperature of the obtained membrane-forming solution was 28 ° C. The film-forming stock solution at 40 ° C. was extruded while injecting water into the inside of the double annular nozzle, passed through air at 15 ° C., and introduced into a water bath having a coagulation bath temperature of 3 ° C.
Subsequently, water washing and wet heat treatment were performed according to a conventional method.
The wet hollow fiber membrane was immersed in 96.8% by mass of acetone in which 3.2% by mass of α-tocopherol (Wako Pure Chemical Industries, Ltd. Special Grade) was dissolved to replace water present on the surface or inside of the membrane.
Subsequently, drying and heat treatment were performed according to a conventional method to obtain a dried hollow fiber membrane. The internal diameter of the obtained hollow fiber membrane was 175 μm, and the film thickness was 25 μm.
The resulting dried hollow fiber membrane is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the cured urethane portion is cut to form a hollow fiber membrane Processed at the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
As a wetting step before sterilization, an aqueous solution (wet solution) containing 75 ppm of hydrogen peroxide is filled in the blood side flow passage (inner surface side) and the filtrate side flow passage (outer surface side) of the blood processor, and each nozzle is The blood processor was obtained by sterilizing 25 kGy of γ-rays in a sealed state.

Example 5
C. 19.0 mass% of cellulose triacetate (manufactured by Daicel Chemical Industries, Ltd.), 56.7 mass% of N-methyl-2-pyrrolidone (manufactured by Mitsubishi Chemical Corporation), 24.3 mass% of triethylene glycol (manufactured by Mitsui Chemicals, Inc.) at 145 ° C. The solution was dissolved to obtain a membrane-forming solution. A film forming solution was discharged from a tube-in-orifice nozzle heated to 120 ° C. using liquid paraffin as a hollow forming material, passed through an air gap, solidified in water at 30 ° C., and a hollow fiber membrane was spun. Then, after washing with water to stabilize the membrane structure, 30% of 65% by mass of glycerin, 34.25% by mass of acetone and α-tocopherol (special grade Wako Pure Chemical Industries) are passed through a 0.75% by mass solution. After drying with a dryer, it was wound up on a bobbin with an angle of 4 ° and a thickness of 12 cm. The internal diameter of the obtained hollow fiber membrane was 200 μm, and the film thickness was 15 μm.
The hollow fiber membrane thus obtained is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the hardened urethane portion is cut to form a hollow fiber membrane. It processed to the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
Physiological saline (wet solution) is filled in the blood side channel (inner surface side) and the filtrate side channel (outer surface side) of the blood processor as a wetting step before sterilization, and the nozzles are sealed The blood processor was obtained by sterilizing the γ rays with 25 kGy.

Example 6
The hollow fiber membrane was spun under the same conditions as in Example 5. Then, after washing with water to stabilize the membrane structure, it was passed through an aqueous solution of glycerin at 60 ° C. and 65% by mass, dried by a drier, and wound up on a bobbin with a winding angle of 4 ° and a winding thickness of 12 cm. The internal diameter of the obtained hollow fiber membrane was 200 μm, and the film thickness was 15 μm.
The hollow fiber membrane thus obtained is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the hardened urethane portion is cut to form a hollow fiber membrane. It processed to the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
Next, a coating solution prepared by dissolving 0.75% by mass of α-tocopherol (Wako Pure Chemical Industries, Ltd. special grade) in 99.25% by mass of diethyl ketone is hollow fiber membrane from the blood introduction nozzle of the blood processing apparatus at a temperature of 24 ° C. The solution was passed through for 1 minute on the inner surface side of to make contact with α-tocopherol. Thereafter, the residual solution in the hollow portion was removed by air flushing, and then the solvent was removed by drying by passing dry air at 24 ° C. for 30 minutes, thereby immobilizing α-tocopherol.
As a wetting step before sterilization, an aqueous solution (wet solution) containing 0.06% sodium bisulfite and 0.03% sodium carbonate for pH adjustment is used as the blood-side flow path (inner surface side) of the blood processor And a filtrate side flow path (outer surface side), and the blood processing device is obtained by sterilizing 25 kGy of γ rays while the nozzles are tightly sealed.

Example 7
High density polyethylene (density 0.988, Mu direct 5.5, trade name Hyzex 2208J) is spun at a spinning temperature of 150 ° C using a double annular nozzle, and the obtained hollow fiber is annealed at 120 ° C for 2 hours Then, the film was subjected to 5 times heating at room temperature and then 5.4 times heat drawing at 105 ° C. to obtain a hollow fiber membrane. The inner diameter of the hollow fiber membrane was 300 μm, and the film thickness was 45 μm.
An ethylene vinyl alcohol copolymer having an ethylene content of 38 mol% (Soanol E manufactured by Japan Synthetic Chemical Industry Co., Ltd.) was dissolved by heating in 98.4 mass% of a 75 vol% acetone aqueous solution (0.5 mass% as a final concentration). 1.1 mass% of alpha-tocopherol (Wako Pure Chemical Industries, Ltd. special grade) was melt | dissolved in this solution, and the coating liquid was created. The hollow fiber membrane was immersed in the solution and left for 10 minutes. Then, after removing an excess copolymer solution, it was dried with hot air at 40 ° C. for 3 hours.
The internal diameter of the obtained hollow fiber membrane was 300 μm, and the film thickness was 45 μm. Moreover, this film was good in water wettability, and was easily wetted when immersed in water.
The hollow fiber membrane thus obtained is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the hardened urethane portion is cut to form a hollow fiber membrane. It processed to the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
Physiological saline (wet solution) is filled in the blood side channel (inner surface side) and the filtrate side channel (outer surface side) of the blood processor as a wetting step before sterilization, and the nozzles are sealed The blood processor was obtained by sterilizing the γ rays with 25 kGy.

Comparative Example 1
15% by mass ethylene vinyl alcohol copolymer (EVAL EC-F100A manufactured by Kuraray Co., Ltd., EVAL EC-F 100A) having an ethylene content of 10% by mole, 99% by mass DMSO, 10% by mass water, and 2% by mass lithium chloride It heat-melted at ° C and obtained the film forming undiluted | stock solution. The temperature of the obtained membrane-forming solution was 28 ° C. The film-forming stock solution at 40 ° C. was extruded while injecting water into the interior of the double annular nozzle, passed through air at 15 ° C., and introduced into a water bath at a coagulation bath temperature of 1 ° C.
Thereafter, according to a conventional method, washing with water, moist heat treatment, drying and dry heat treatment were performed to obtain a dry hollow fiber membrane. The internal diameter of the obtained hollow fiber membrane was 175 μm, and the film thickness was 25 μm.
The resulting dried hollow fiber membrane is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the cured urethane portion is cut to form a hollow fiber membrane Processed at the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
Next, a coating solution prepared by dissolving 0.5% by mass of α-tocopherol (Wako Pure Chemical Industries, Ltd. special grade) in an aqueous solution of 57% by mass of isopropanol was added to a hollow fiber membrane from a blood introduction nozzle of a blood processing unit at a temperature of 24 ° C. The solution was passed through for 1 minute on the inner surface side to make contact with α-tocopherol. Thereafter, the residual solution in the hollow portion was removed by air flushing, and then the solvent was removed by drying by passing dry air at 24 ° C. for 30 minutes, thereby immobilizing α-tocopherol.
As a wetting step before sterilization, an aqueous solution (wet solution) containing 75 ppm of hydrogen peroxide is filled in the blood side flow passage (inner surface side) and the filtrate side flow passage (outer surface side) of the blood processor, and each nozzle is The blood processor was obtained by sterilizing 25 kGy of γ-rays in a sealed state.

Comparative Example 2
As a membrane forming solution, 17.5% by mass of polysulfone (Solvay P-1700, solubility parameter δ 9.90), 3.5% by mass of polyvinyl pyrrolidone (BASF K90), N, N-dimethylacetamide It was dissolved in 79.0% by mass to obtain a uniform solution. The mixing ratio of polyvinyl pyrrolidone to polysulfone in the membrane-forming solution was 20% by mass. The film-forming stock solution is maintained at 60 ° C. and discharged from a tube-in-orifice nozzle together with a hollow internal solution consisting of a mixed solution of 58.1 mass% of N, N-dimethylacetamide and 41.9 mass% of water, 0.96 m The resultant was immersed in a coagulation bath consisting of water at 75.degree. C. and wound up at 80 m / min. After cutting the wound fiber bundle, the residual solvent in the film is removed by washing the hot water shower at 80 ° C. for 2 hours from above the cut surface of the bundle, and the water content is further dried by further drying the film. A dry film of less than 1% was obtained. The internal diameter of the obtained hollow fiber membrane was 185 μm, and the film thickness was 45 μm.
Next, the dried membrane is filled in a cylindrical container having two nozzles for introduction and discharge of liquid and both ends are embedded with a urethane resin, and the cured urethane portion is cut to open the hollow fiber membrane. Processed to the end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
Next, a coating solution prepared by dissolving 1.1% by mass of α-tocopherol (Wako Pure Chemical Industries, Ltd. special grade) in an aqueous solution of 57% by mass of isopropanol was added to a hollow fiber membrane from a blood introduction nozzle of a blood processing apparatus at a temperature of 24 ° C. The solution was passed through for 1 minute on the inner surface side to make contact with α-tocopherol. Thereafter, the residual solution in the hollow portion was removed by air flushing, and then the solvent was dried and removed by bubbling dry air at 24 ° C. in an isopropanol atmosphere for 30 minutes to immobilize α-tocopherol.
As a wetting step prior to sterilization, the blood side flow path (inner surface side) and filtrate side of the blood processing unit contain an aqueous solution containing 0.06% sodium bisulfite and 0.03% sodium carbonate for pH adjustment The blood processing apparatus was obtained by filling in the flow path (outer surface side) and sterilizing the γ-rays with 25 kGy in a state where each nozzle is sealed.

Comparative Example 3
C. 19.0 mass% of cellulose triacetate (manufactured by Daicel Chemical Industries, Ltd.), 56.7 mass% of N-methyl-2-pyrrolidone (manufactured by Mitsubishi Chemical Corporation), 24.3 mass% of triethylene glycol (manufactured by Mitsui Chemicals, Inc.) at 145 ° C. The solution was dissolved to obtain a membrane-forming solution. A film forming solution was discharged from a tube-in-orifice nozzle heated to 120 ° C. using liquid paraffin as a hollow forming material, and after passing through an air gap, it was solidified in water at 30 ° C.
After washing with water to stabilize the membrane structure, 30.degree. C., 96.29% by mass of acetone and 3.71% by mass of .alpha.-tocopherol (special grade Wako Pure Chemical Industries) are passed through a solution and dried with a drier, It wound up on the bobbin by 4 degrees of winding angles, and 12 cm of rolling thickness. The internal diameter of the obtained hollow fiber membrane was 200 μm, and the film thickness was 15 μm.
The hollow fiber membrane thus obtained is filled in a cylindrical container having two nozzles for introduction and discharge of liquid, and both ends are embedded with a urethane resin, and then the hardened urethane portion is cut to form a hollow fiber membrane. It processed to the open end. A header cap having a nozzle for blood introduction (extraction) was loaded at the both ends, and assembled in the shape of a blood treatment device having a membrane area of 1.5 m ² .
As a wetting step prior to sterilization, the blood side flow path (inner surface side) and filtrate side of the blood processing unit contain an aqueous solution containing 0.06% sodium bisulfite and 0.03% sodium carbonate for pH adjustment The blood processing apparatus was obtained by filling in the flow path (outer surface side) and sterilizing the γ-rays with 25 kGy in a state where each nozzle is sealed.

  According to the present invention, it is possible to provide a hollow fiber type blood purifier with a hydrophilic polymer membrane capable of simultaneously achieving suppression of platelet activation, sufficient removal performance of medium molecular weight substances and elimination of oxidative stress. . The hollow fiber type blood purification apparatus of the present invention has industrial applicability in blood purification therapy.

DESCRIPTION OF SYMBOLS 1 hollow fiber membrane 1a 1st flow path 2 cylindrical container 2a, 2b port 3a, 3b sealing resin 6a, 6b nozzle 7a header cap 8 inner space of header 10 hollow fiber membrane type blood purifier 11 2nd flow path Fa Flow direction of treatment solution 1 (for example, dialysate) Fb Flow direction of treatment solution (for example, blood)

Claims (5)

A hollow fiber type blood purifier incorporating a hollow fiber membrane containing a hydrophilic polymer, comprising:
The hydrophilic polymer is selected from the group consisting of regenerated cellulose, cellulose diacetate, cellulose triacetate, ethylene vinyl alcohol copolymer, polyacrylonitrile and polymethyl methacrylate,
The hollow fiber membrane contains a fat-soluble vitamin of 10 mg or more and 300 mg or less per 1 m ^{2 of the} inner surface of the hollow fiber membrane,
The hollow fiber membrane type blood purifier, wherein the β2-microglobulin clearance converted to 1.5 m ^{2 of the} hollow fiber membrane is 5 mL / min or more and 90 mL / min or less. The hollow fiber membrane type blood purifier according to claim 1, wherein the hollow fiber membrane comprises only a hydrophilic polymer. The hollow fiber type blood purifier according to claim 1 or 2 , wherein the hydrophilic polymer is an ethylene-vinyl alcohol copolymer. The hollow fiber type blood purifier according to claim 1 or 2 , wherein the hydrophilic polymer is cellulose triacetate. The fat-soluble vitamin is made to adhere to the said hollow fiber membrane by passing the acetone solution of a fat-soluble vitamin in the hollow fiber membrane containing a hydrophilic polymer, The process in any one of Claims 1-4 is included. The manufacturing method of the hollow fiber membrane type blood purifier as described.