JP2018171430A - Hollow fiber membrane and hollow fiber membrane blood purifier - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hollow fiber membrane having an antioxidative property similar to that of a prior art in a blood circulation line, and in addition to this, having an effect for suppressing the aggravation of oxidation stress from a dialysate solution side, and a plasticizer adsorption effect.SOLUTION: In a hollow fiber membrane containing an oil-soluble antioxidant, an amount of the oil-soluble antioxidant per effective membrane area 1 mis not smaller than 50 mg/m, and not larger than 600 mg/m, and when removing cut faces of the hollow fiber membrane from both ends by 5 μm, trisecting a remaining membrane thickness, setting the trisected membrane thicknesses as an inside region, an intermediate region and an outside region, and setting TOF-SIMS standardized peak intensities of the respective regions as li, lc and lo, li is not smaller than 0.18, lc/li is not smaller than 0.80 and not larger than 1.0, and lo/li is not smaller than 0.70 and not larger than 1.0.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a hollow fiber membrane and a hollow fiber membrane blood purifier.

  So far, blood purification methods using membrane separation techniques such as hemodialysis, blood filtration, and hemofiltration dialysis have been devised. These blood purification therapies are widely applied not only to patients with chronic renal failure but also to patients with acute renal failure, and in recent years, they have been widely used in lifesaving and ICU.

  Acute renal failure patients often have multiple organ failure or circulatory instability, which is a more serious condition than patients with chronic renal failure. Therefore, when blood purification treatment by membrane separation is performed for patients with acute renal failure, a continuous kidney that slowly adjusts the body fluid over a long time with a lower circulatory flow rate than the treatment conditions of normal hemodialysis and hemofiltration A treatment mode called functional replacement therapy (CRRT) is mainly employed. CRRT is applied not only to replace renal function such as water removal, waste removal, and electrolyte balance correction, but also to removal of pathological substances related to sepsis, multiple organ failure, etc. In each case, blood flow is 50 to 150 mL / It is carried out for 8 to 24 hours or more under the conditions of min and filtration rate of 5 to 50 mL / min. Cases that last 20 hours to several days are not uncommon.

  A hollow fiber membrane blood purifier for performing blood purification therapy is generally filled with a cylindrical container and a longitudinal direction of the cylindrical container, and both ends are fixed to both ends of the cylindrical container. A hollow fiber membrane bundle. Moreover, it has the potting resin part which embeds and fixes the said hollow fiber membrane bundle by the both ends of the said cylindrical container. Further, both end portions of the cylindrical container are provided opposite to both end surfaces of the hollow fiber membrane, and each is provided on a header having a nozzle serving as a fluid inlet / outlet, and on a side portion of the cylindrical container. And a port serving as a fluid inlet / outlet port.

Concerns regarding blood purification therapy involving extracorporeal circulation of blood include biocompatibility of the material of the blood circulation line (blood purifier, circuit, etc.) and dialysate, or oxidative stress due to extracorporeal circulation.
Of these, taking hemodialysis as an example of oxidative stress, in dialysis patients, the production of free radicals by leukocytes activated by contact between blood and the dialysis membrane is increased, and vitamin C, vitamin E, etc. A state in which oxidative stress is enhanced by reduction of antioxidants, induction of oxidative stress by glucose degradation products (Glucose degradation products (GDP)) such as glyoxal and methylglyoxal produced by degradation of glucose contained in the dialysate It is known to be. Considering that CRRT is performed for a long time, oxidative stress cannot be ignored in patients undergoing CRRT, even if it is not a long-term treatment.

  It is considered that the oxidation of glucose in the dialysate proceeds by the following mechanism. That is, in an environment where blood extracorporeal circulation treatment is performed, when the dialysate is exposed to ultraviolet light, decomposition of water molecules occurs, decomposition species such as hydroxy radicals are generated, and oxygen in which the water decomposition species is dissolved. By reacting, active oxygen species such as superoxide, hydroperoxyl, and hydrogen peroxide are generated. When these reactive oxygen species react with glucose, a glucose degradation product containing aldehydes harmful to the human body such as glyoxal and methylglyoxal is produced.

From such a background, in the blood circulation line, a method of immobilizing vitamin E having various physiological activities such as in vivo antioxidant action, biological membrane stabilization action, and platelet aggregation inhibition on the inner wall of the blood flow path of the dialyzer (Patent Documents 1 and 2) are methods for lowering the redox potential of dialysate by increasing dissolved hydrogen in dialysate preparation water or decreasing dissolved oxygen in dialysate (Patent Documents 3 and 4). ) Has been proposed.
The techniques of Patent Documents 1 and 2 mainly cover vitamin E on the inner surface of the hollow fiber membrane, but the effect is not sufficient.

  As for the dialysate, as in Patent Document 3, the method for reducing the oxidation-reduction potential of dialysate preparation water requires electrolysis of raw water and a special operation for purifying the cathode water obtained thereby. In order to obtain a high hydrogen concentration, the pH inevitably becomes alkaline (preferably pH 8.5 to 9.5 in the literature). Although dialysate has a buffering power to correct this by buffering with bicarbonate or acetate, the use of dialysate with a pH of 8.0 or higher is intended to correct the acid-base balance of dialysis patients. It is not preferable.

  Patent Document 4 discloses a method of increasing the dissolved hydrogen concentration by bubbling hydrogen after degassing raw water or dialysate to lower the dissolved oxygen concentration. This method also requires a dedicated device for producing hydrogen water, such as a deaeration device or a bubbling device. It is easy to introduce in a facility that continuously prepares dialysate for frequent artificial dialysis, but in facilities that use dialysis fluid or replacement fluid such as ICU or CCU, where CRRT is mainly performed, It is economically undesirable to introduce such a device.

In addition, regarding the extracorporeal blood circulation, the elution of the plasticizer from the blood circuit made of vinyl chloride is also a problem. As a typical plasticizer, diethylhexyl phthalate (hereinafter referred to as DEHP) is known to have an endocrine disrupting action and the like. Since DEHP is lipophilic, it is said to elute by binding to albumin or the like contained in blood, and there is a concern that the amount of DEHP elution increases in CRRT where the circuit and blood are in contact with each other for a long time.
In response to this problem, it has been reported that a high performance film (HPM) is effective in removing DEHP (Non-patent Document 1). In this document, a CTA film having increased hydrophobicity as a result of substitution of a hydroxyl group with an acetyl group, or a PMMA or PS film having both a hydrophobic part and a hydrophilic part as compared with a cellulose film having a hydrophilic hydroxy group in the molecular structure. It has been clarified that the amount of DEHP removed is large, and the mechanism is presumed to be due to the adsorption of DEHP onto the membrane surface by hydrophobic bonds. However, since the removal of DEHP is due to adsorption to the membrane surface, there is a possibility that adsorption saturation may be reached with a relatively small amount of adsorption, and considering that it is used for CRRT with contact with blood for a long time, the membrane module described above The performance of was not enough.

Japanese Patent No. 4845417 Japanese Unexamined Patent Publication No. 2015-198708 Japanese Patent No. 4004523 Japanese Patent No. 5872321

Atsushi Ohashi, Shin Hibiya, Nei Nakagami, Masao Kato, Hiroto Yoshikawa, Takako Toba, Hiroko Kushimoto, Hideki Katsumata, Kazutaka Murakami, Midori Hasegawa, Ryo Tomita, Hiroshi Hasegawa, Masahiko Shikano, Shirou Kawashima Of Elution of Endocrine Disrupting Substance Di- (2-ethylhexyl) phthalate and Examination of Removal by High Performance Membrane ”, Dialysis Society Vol. 32, No. 10 (1999), p. 1291-1297.

  As described above, in the long-term extracorporeal circulation treatment such as CRRT, the effect of suppressing the increase of oxidative stress from both the blood circulation line (inside the hollow fiber membrane surface) and the dialysate (outside the hollow fiber membrane surface) No hollow fiber membrane or blood purifier has been known which has a high removal efficiency of the plasticizer eluted from the circuit.

  In view of the problems of the prior art, the present invention has the same antioxidant property as the conventional one in the blood circulation line, in addition to the effect of suppressing the increase of oxidative stress from the dialysate side, Another object of the present invention is to provide a hollow fiber membrane and a blood purifier that also have a plasticizer adsorption effect.

  As a result of intensive studies in view of the above circumstances, the present inventors have retained a sufficient amount of a fat-soluble antioxidant in the surface region of the film thickness portion in a film in which the film surface is coated with a fat-soluble antioxidant. In addition, by immobilizing the necessary amount of fat-soluble antioxidants in the middle and outer areas, the blood compatibility and antioxidant action of the blood circulation line is maintained, and the oxidants that enter from the dialysate side are suppressed. It has been found that the adsorption amount of the plasticizer eluted from the circuit can be increased by increasing the hydrophobicity of the membrane itself, and the present invention has been achieved.

That is, the present invention is as follows.
[1] A hollow fiber membrane containing a fat-soluble antioxidant,
The amount of fat-soluble antioxidant per 1 m ^{2 of} effective membrane area is 50 mg / m ² or more and 600 mg / m ² or less,
5 μm is removed from both ends of the cut surface of the hollow fiber membrane, and the remaining film thickness is divided into three equal parts, and the TOF-SIMS normalized peak intensity in each region when the inner region, the intermediate region, and the outer region are obtained, As Ii, Ic and Io,
Ii is 0.18 or more,
A hollow fiber membrane having an Ic / Ii of 0.80 to 1.0 and an Io / Ii of 0.70 to 1.0.
[2] A hollow fiber membrane according to [1] containing a polysulfone resin and a hydrophilic polymer, [3] A bundle of hollow fiber membranes according to [1] or [2], and a container containing the bundle. Blood purifier.
[4] The hollow fiber membrane blood purifier according to any one of [1] to [3], wherein Ii is 0.2 or more.
[5] The hollow fiber membrane blood purifier according to any one of [1] to [4], wherein Ic / Ii is 0.85 or more and 1.0 or less.
[6] The hollow fiber membrane blood purifier according to any one of [1] to [5], wherein Io / Ii is 0.75 or more and 1.0 or less.
[7] The hollow fiber membrane according to any one of [1] to [6], wherein the container has an oxygen permeability coefficient of 1.8 × 10 ⁻¹⁰ cm ³ · cm / (cm ² · S · cmHg) or less. Type blood purifier.
[8] The hollow fiber membrane mold according to any one of [1] to [7], wherein the container has a cylindrical shape, and the absorbance at a wavelength of 350 nm of the body portion is 0.35 or more and 2.00 or less. Blood purifier.
[9] The hollow fiber membrane blood purifier according to any one of [1] to [8], wherein the fat-soluble antioxidant is a fat-soluble vitamin.
[10] A continuous slow blood filter (CRRT filter) including the hollow fiber membrane blood purifier according to any one of [1] to [9].

  According to the present invention, in a hollow fiber membrane in which a hollow fiber membrane is coated with a fat-soluble antioxidant, an effect of removing an oxidizing substance entering from the dialysate side while maintaining the antioxidant action of the blood circulation line is achieved. It is possible to obtain a hollow fiber membrane that has an effect of sufficiently adsorbing a plasticizer that is held and that is sufficiently adsorbed from the circuit.

It is explanatory drawing about the inner side area | region of a hollow fiber membrane cut surface, an intermediate | middle area | region, and an outer side area | region. In an Example, it is the schematic of the circuit used in order to evaluate the oxidation inhibitory effect of a dialysate. In an Example, it is the schematic of the circuit used in order to evaluate the DEHP removal effect.

  Hereinafter, modes for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail below. In addition, this invention is not limited to the following embodiment, In the range of the summary, various deformation | transformation can be implemented.

  The hollow fiber membrane blood purifier of the present embodiment is a blood purifier incorporating the hollow fiber membrane of the present embodiment, hemodialysis, blood filtration, blood filtration dialysis, blood component fractionation, oxygenation, It can also be used for extracorporeal circulation type blood purification therapy such as plasma separation. The blood purifier is preferably used in hemodialysis, blood filtration, hemofiltration dialysis, etc., and can be used as a continuous hemodialysis machine, continuous hemofiltration machine, continuous hemofiltration dialyzer, which are these continuous uses. More preferred. Detailed specifications such as dimensions and fractionation of the hollow fiber membrane are determined according to each application.

<Hollow fiber membrane>
The shape, dimensions, and fractionation characteristics of the hollow fiber membrane of the present embodiment are not particularly limited, and can be appropriately selected in light of the purpose of use. For example, the inner diameter may be from 10 μm to 300 μm, the film thickness may be from 10 μm to 100 μm, and the length may be from 8 cm to 40 cm.
The hollow fiber membrane is preferably provided with a crimp from the viewpoint of permeation performance. In order to achieve both high molecular weight fractionation and high water permeability, a so-called asymmetric membrane having a thin dense layer (active separation layer) and a porous layer (support layer) that bears the strength of the hollow fiber membrane is desirable. In addition, when used for CRRT, it is desirable to have the ability to actively remove not only low molecular weight solutes but also large molecules of low molecular weight proteins.
<Container>
In the blood purifier of the present embodiment, the hollow fiber membrane is preferably filled in a container as a hollow fiber membrane bundle in which a plurality of hollow fiber membranes are bundled.
Although there is no limitation in the shape of a container, a cylindrical container is mentioned as a specific example. Moreover, in this embodiment, it is preferable that the oxygen permeability coefficient of the trunk | drum of a cylindrical container is 1.8 * 10 < ^-10 > cm < ³ > * cm / (cm < ² > * S * cmHg) or less.

The material of the hollow fiber membrane is not particularly limited, but a polysulfone resin such as polysulfone (hereinafter sometimes referred to as “PSf”) or polyethersulfone contains a hydrophilizing agent such as polyvinylpyrrolidone. The porous hollow fiber membrane is widely used as a hollow fiber membrane for blood purification because it is suitable for controlling the fractionation property according to the application and can easily optimize blood compatibility.
The hollow fiber membrane may further contain a second hydrophilizing agent such as glycerin or polyethylene glycol, other additives, a surface modifier, and the like.

<Polysulfone resin>
Polysulfone-based resin is a general term for bisphenol-type polysulfone, which is a polymer having a repeating unit represented by formula (1), and polyethersulfone, which is a polymer having a repeating unit represented by formula (2). Widely used as a material for membranes.
(-Φ-SO ₂ -Φ-O-C (CH ₃ ) ₂ -Φ-O-) n (1)
(-Φ-SO ₂ -Φ-O-) n (2)
Here, Φ represents a benzene ring, and n represents a repetition of the polymer.

<Hydrophilic polymer>
The hydrophilic polymer is a synthetic polymer or a natural polymer that dissolves in water or has an affinity for water.
In the present embodiment, a hydrophilic polymer can be used as the aforementioned hydrophilizing agent. As such a hydrophilic polymer, for example, polyvinylpyrrolidone (hereinafter sometimes referred to as “PVP”) may be used. , Polyethylene glycol, polyvinyl alcohol, polypropylene glycol, ethylene-vinyl alcohol copolymer and the like. From the viewpoint of spinning stability and affinity with polysulfone resin, PVP is particularly preferably used. These may be used alone or in combination of two or more as the hydrophilic polymer.
PVP is a water-soluble polymer compound obtained by vinyl polymerization of N-vinylpyrrolidone, and is widely used as a material for hollow fiber membranes as a hydrophilizing agent or a pore-forming agent.

<Fat-soluble antioxidant>
The fat-soluble antioxidant means a substance having reducibility and soluble in alcohol and fats and oils, and generally not easily soluble in water.
The fat-soluble antioxidant is not particularly limited, but fat-soluble vitamins, polyphenols, and the like are preferable, and fat-soluble vitamins are preferable from the viewpoint of rich safety and application results for living bodies.

Examples of the fat-soluble vitamin include vitamin A, vitamin D, vitamin E, vitamin K, and the like. Among these, vitamin E is preferable from the viewpoint of not inducing a disorder even if it is excessively consumed. As fat-soluble vitamins, one kind may be used, or a mixture of two or more kinds may be used.
Examples of vitamin E include α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, β-tocopherol, γ-tocopherol, δ-tocopherol and mixtures thereof. 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 inhibitory action, and is highly effective in suppressing oxidative stress.

  Examples of polyphenols include flavonoids such as catechin, anthocyanin, tannin, rutin, and isoflavone, phenolic acids such as chlorogenic acid, ellagic acid, lignan, curcumin, and coumarin.

<Amount of fat-soluble antioxidant in hollow fiber membrane>
In the present embodiment, the “amount of fat-soluble antioxidant” means that the surface of the hollow fiber membrane (the inner surface, the outer surface, and the surface of the pores present in the film thickness portion) is attached, adsorbed, or the like. The amount of the fat-soluble antioxidant can be quantified by the amount of the fat-soluble antioxidant extracted with a solvent without destroying or dissolving the hollow fiber membrane as described later in Examples.
In this embodiment, the amount of the fat-soluble antioxidant is defined as an amount per 1 m ^{2 of} the effective membrane area, and the “effective membrane area” is the area of the inner surface of the hollow fiber membrane, Can be calculated from the product of the average inner diameter (diameter), the circumference ratio, the number, and effective length.

In the present embodiment, the amount of the fat-soluble antioxidant in the hollow fiber membrane is 50 mg / m ² or more and 600 mg / m ² or less.
When the amount of the fat-soluble antioxidant is 50 mg / m ² or more, a hollow fiber membrane having stable antioxidant performance can be obtained, and when it is 600 mg / m ² or less, a high DEHP adsorption amount is maintained. On the other hand, a hollow fiber membrane having good blood compatibility can be obtained, and the manufacturing cost is excellent.
The amount of the fat-soluble antioxidant in the hollow fiber membrane is more preferably 50 mg / m ² or more and 550 mg / m ² or less.

DEHP adsorption performance is improved by the presence of a fat-soluble antioxidant in the hollow fiber membrane, but if the amount is too large, the DEHP adsorption performance decreases.
The reason is that if an excessive amount of the fat-soluble antioxidant is coated, the pores of the porous portion are blocked by the fat-soluble antioxidant, and the effective area that the DEHP can contact is reduced. I guess. However, the mechanism does not depend on this.

<Amount of fat-soluble antioxidant present in the hollow fiber film thickness part>
The amount of the fat-soluble antioxidant present on the material surface of the pores present in the hollow fiber film thickness part is the normalized peak intensity of the parent mass peak obtained by TOF-SIMS (time-of-flight secondary ion mass spectrometry) measurement ( I) can be used as an index.
In this embodiment, on the cut surface perpendicular to the length direction of the hollow fiber membrane, remove 5 μm from both ends (outer surface side and inner surface side), and divide the remaining film thickness into three equal parts, When the intermediate region and the outer region are used, the TOF-SIMS normalized peak intensity (Ii) is 0.18 or more for the inner region of the cut surface of the hollow fiber membrane, and the TOF-SIMS for each of the inner region and the intermediate region. Ratio of normalized peak intensity (Ii and Ic) (Ic / Ii) is 0.80 or more and 1.0 or less, and ratio of TOF-SIMS normalized peak intensity (Ii and Io) for each of the inner region and outer region (Io / Ii) is 0.70 or more and 1.0 or less.
More preferably, Ii is 0.19 or more, Ic / Ii is 0.83 or more and 1.0 or less, and Io / Ii is 0.73 or more and 1.0 or less, Ii is 0.20 or more, More preferably, Ic / Ii is 0.85 to 1.0 and Io / Ii is 0.75 to 1.0.

Here, the inner region, the intermediate region, and the outer region will be described in detail. The radius of the outer peripheral portion of the hollow fiber membrane (the circle of the cross section perpendicular to the length direction) is R (μm), and the hollow portion of the hollow fiber membrane. The following region is defined when the radius of the (circle of the hollow portion in the cross section perpendicular to the length direction) is r (μm) (see FIG. 1).
Inner region: outside the circle with radius (r + 5) μm, and
Inside the circle with radius (r + 5 + (R−r−10) / 3) μm Middle region: outside the circle with radius (r + 5 + (R−r−10) / 3) μm, and
Inside the circle with radius (r + 5 + 2 × (R−r−10) / 3) μm Outside region: outside the circle with radius (r + 5 + 2 × (R−r−10) / 3) μm, and
Inside the circle with radius (R-5) μm

The optimal fat-soluble antioxidant distribution in the hollow fiber film thickness portion will be described in more detail below in order to effectively use the minimum necessary amount of the fat-soluble antioxidant to exert the intended function.
First, what is important when the hollow fiber membrane is used in a blood purifier is antioxidation to the blood circulation line. In this regard, it was found that blood cells contact only with the inner surface of the membrane among blood components, but liquid components such as proteins move back and forth through the film thickness near the inner surface by diffusion. Therefore, from the viewpoint of antioxidant properties and biocompatibility with respect to the blood circulation line, it is necessary that a certain amount of fat-soluble antioxidant is present not only on the inner surface but also on the inner region of the film thickness portion.

  Second, in order to achieve the object of the present invention, it is necessary to have an effect of adsorbing a plasticizer eluted from a circuit or the like. In this regard, in general, the plasticizer contained in the circuit elutes into blood containing mainly fat-soluble substances such as albumin and enters the blood purifier via the blood circulation pathway, but it is a molecule compared to other biomolecules. Since the size is small, it can be considered that the film moves from the inner surface of the hollow fiber membrane to the film thickness portion by diffusion. Therefore, the penetration amount of the plasticizer in the film thickness portion when using the blood purifier is the largest in the inner region of the film thickness portion, followed by the intermediate region and the outer region. Therefore, it is desirable that a fat-soluble antioxidant is present in the film thickness portion in accordance with this distribution. With such a distribution, the plasticizer is adsorbed even in the film thickness portion, so that the number of adsorption sites increases and the adsorption saturation value can be increased compared to the case of adsorbing only on the inner surface. But it is advantageous.

  Thirdly, it is necessary to suppress not only the blood circulation line but also the oxidizing substances that enter from the dialysate side. For example, oxygen-active species such as hydroxy radicals are considered to enter the blood circulation line from the outer membrane surface side through the film thickness portion. Therefore, it is effective to make the fat-soluble antioxidant exist also in the outer region and intermediate region of the film thickness portion.

  Based on the above consideration, according to the study conducted by the present inventors, the TOF-SIMS normalized peak intensity (Ii) indicating the amount of the fat-soluble antioxidant present in the inner region of the cut surface of the hollow fiber membrane is 0. 18 or more are required, and in order to improve both the effect of suppressing the invasion of the oxidizing substance from the dialysate and the effect of adsorbing the plasticizer, TOF- indicating the amount of the fat-soluble antioxidant present in the inner region and the intermediate region The SIMS normalized peak intensity Ic and Ii ratio (Ic / Ii) is 0.80 or more and 1.0 or less, and the TOF-SIMS normalized peak indicating the amount of the fat-soluble antioxidant present in the inner region and the outer region. It was found that when the ratio of the intensity Io to Ii (Io / Ii) is 0.70 or more and 1.0 or less, the antioxidant property on both the blood circulation line and the dialysate side is enhanced, and the plasticizer removal rate can be improved. .

<Method for producing hollow fiber membrane>
The method for producing the hollow fiber membrane is not limited to the following. For example, a tube-in-orifice type spinneret is used, and a membrane-forming stock solution is formed from the orifice of the spinneret, and a hollow inner solution for coagulating the membrane-forming stock solution is used. At the same time, the hollow fiber membrane can be produced by discharging the tube into the air.

  The film-forming stock solution can be prepared by dissolving polysulfone resin and PVP in a common solvent. Examples of the common solvent include solvents such as dimethylacetamide (hereinafter referred to as DMAc), dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, and dioxane, or a solvent composed of a mixture of two or more of the above. .

  Using a membrane-spinning stock solution, a hollow fiber membrane is formed by a commonly used method. For example, a tube-in-orifice type spinneret is used, and the membrane-spun stock solution is discharged from the spinneret orifice into the air simultaneously with the hollow inner solution for coagulating the membrane-spun stock solution from the tube. As the hollow inner liquid, water or a liquid mainly composed of water can be used. In general, a mixed solution of the solvent and water used in the membrane spinning solution is preferably used. For example, a dimethylacetamide aqueous solution of 20 wt% to 60 wt% is used.

  The inner diameter and film thickness of the hollow fiber membrane can be adjusted to desired values by adjusting the membrane spinning raw solution discharge amount and the hollow inner solution discharge amount.

The film-forming spinning solution discharged from the spinneret together with the hollow inner liquid is introduced into a coagulation bath mainly composed of water installed in the lower part of the spinneret as it travels through the air gap as necessary, and is immersed for a certain period of time. Coagulation is completed.
The air gap means a space between the spinneret and the coagulation bath, and the film-forming spinning solution during the air gap traveling is due to a poor solvent component such as water in the hollow inner liquid discharged simultaneously from the spinneret. Solidification starts from the inner surface side.

  The hollow fiber membrane that has been immersed in the coagulation bath is then washed with hot water to remove the solvent remaining in the hollow fiber membrane, and then continuously guided into a dryer and dried with hot air or the like. Can be obtained.

<Manufacturing method of blood purifier>
There is no limitation in the method of manufacturing a blood purifier using the hollow fiber membrane of this embodiment, It can manufacture by a well-known method.
Specifically, first, a hollow fiber membrane is filled in a cylindrical container having two nozzles in the vicinity of both end portions of the side surface, and both end portions are embedded with a potting resin such as urethane resin. Next, the hardened potting resin portion is cut so as to form an end portion where the hollow fiber membrane is opened. At both ends, header caps having nozzles for introducing (leading out) liquid such as blood and dialysate are attached and assembled into a blood purifier shape.

<Method for making fat-soluble antioxidant present in hollow fiber membrane>
In the present embodiment, there is no limitation on the method of allowing the fat-soluble antioxidant to exist in the hollow fiber membrane with a predetermined concentration distribution. For example, as in the conventional method, the fat-soluble antioxidant is immobilized on the surface of the hollow fiber membrane. Can be realized.
At this time, as a method for immobilizing the fat-soluble antioxidant on the surface of the hollow fiber membrane, basically known methods can be used. Above all, the coating method is excellent in that the fat-soluble antioxidant can be immobilized under various conditions using existing equipment and product lineup.

  When the hollow fiber membrane is incorporated into the blood purifier, the fat-soluble antioxidant may be immobilized on the surface of the hollow fiber membrane after (partial) assembly of the blood purifier.

As the coating method, a fat-soluble antioxidant solution is allowed to flow onto the hollow surface on the inner surface side of the hollow fiber membrane, thereby allowing the fat-soluble antioxidant to adhere to the hollow fiber membrane surface (for example, JP 2006-2006 A). No. 296931) is known, but is not limited to this.
The concentration of the fat-soluble antioxidant in the coating solution is preferably 0.1 wt% or more and 30 wt% or less, more preferably 0.1 wt% or more and 20 wt% or less, and further preferably 0.1 wt% or more and 10 wt% or less. It is as follows.

  The amounts of fat-soluble antioxidants (Ii, Ic and Io, respectively) present in the inner region, intermediate region and outer region of the cut surface of the hollow fiber membrane were 0.18 ≦ Ii, 0.8 ≦ Ic / Ii ≦ 1. The conditions for satisfying 0, 0.7 ≦ Io / Ii ≦ 1.0 are not limited, and for example, the liquid flow rate and the composition of the coating liquid (solvent, fat-soluble antioxidant concentration) are appropriately adjusted. However, particularly preferable conditions and methods will be described below.

A coating solution containing a fat-soluble antioxidant can be prepared, for example, by dissolving 0.25 to 2 wt% of a fat-soluble antioxidant in an aqueous alcohol solution such as 50 to 80 wt% of propanol.
The coating liquid is passed through the hollow fiber membrane at a flow rate of 825 to 1875 mL / min. At this time, the liquid passing direction is not limited, but when the hollow fiber membrane is set vertically and the coating liquid is flowed upward from the lower direction of the hollow fiber membrane, a coating liquid having a general composition is used. It has been found that the coating liquid can be sufficiently exuded to the film thickness portion even when the liquid is passed at a normal liquid passing speed.
In addition, when coating is performed after (partial) assembly of the blood purifier, the hollow fiber membrane bundle in which both ends are embedded with potting resin and excess potting resin is cut (both ends are opened) is contained in the container. The hollow fiber membrane blood purifier filled in is placed vertically in a fat-soluble antioxidant solution coating apparatus to allow fluid passage.

After passing, the coating solution is blown off by air blow.
At this time, when the coating liquid is blown off by air blow in a state where air or an inert gas is pressurized from 0.1 to 0.35 MPa from the opposite side of the coated surface of the hollow fiber membrane (outside the hollow fiber membrane), the hollow fiber It is possible to prevent the coating liquid adhering to the inner surface side from moving to the outer surface side. From this viewpoint, it is preferable to continue to pressurize air or the like at 0.1 to 0.35 MPa from the opposite side of the coated surface of the hollow fiber membrane for 30 seconds to 60 minutes after the air blow is stopped. In this case, the pressurization duration may be 30 seconds to 30 minutes, or 30 seconds to 10 minutes.
The pressure at the time of pressurization with air or the like at the time of air blow and / or after the air blow is stopped may be 0.1 to 0.32 MPa, or may be 0.1 to 0.30 MPa. .

Next, the solvent is removed by drying to immobilize the fat-soluble antioxidant. Drying is usually performed by flowing dry air into the blood flow channel region and the dialysate flow channel region.
At this time, drying starts from the inner surface and the outer surface of the hollow fiber membrane, and it has been found that the setting of the drying temperature and drying time also affects Ii, Ic, and Io.
This is because the liquid (coating liquid) moves along the gradient of moisture content from a point where moisture content is high (inside the hollow fiber membrane) to a point where the moisture content is low (inside and outside surfaces of the hollow fiber membrane). As a result, the fat-soluble antioxidant gradually moves to the inner surface and the outer surface, and the immobilized amount (Ic) at the center portion decreases. Therefore, in order to make the distribution of the fat-soluble antioxidants Ii (inner region) ≧ Ic (intermediate region) ≧ Io (outer region), it is considered that drying conditions need to be set appropriately.
However, it was found that the higher the drying temperature, the higher the transfer rate of the fat-soluble antioxidant from the inside of the film to the inner and outer surfaces, and the longer the drying time, the greater the amount of movement. Therefore, a person skilled in the art will consider Ii, Ic, and Io as a result of several trials of drying with different drying temperatures and drying times. The drying temperature and drying time that satisfy the conditions of the embodiment can be easily set.
For example, when the solvent of the coating liquid is a 57 wt% alcohol aqueous solution, when the drying air temperature is 30 ° C., the drying time is 5 to 10 min. When the drying air temperature is 40 ° C., the drying time is 3 to 7 min. When the drying air temperature is 50 ° C., the drying time is preferably 1 to 3 minutes, and when the drying air temperature is 60 ° C., the drying time is preferably 0.5 to 1.5 minutes. By doing this, the solvent can be distilled off before the fat-soluble antioxidant inside the hollow fiber membrane moves to the inner and outer surfaces of the hollow fiber membrane, and the necessary amount of fat-soluble antioxidant is maintained inside the hollow fiber membrane. Can be made.
From the viewpoint of oxidation of the fat-soluble antioxidant by dry air, the higher the drying temperature, the shorter the drying time and the shorter the contact time between the fat-soluble antioxidant and air, and the oxidation of the fat-soluble antioxidant. Therefore, the drying temperature is preferably 30 ° C. or higher. On the other hand, from the viewpoint of the fluidity of the fat-soluble oxidizer, the lower the drying temperature can suppress the change in the distribution of the fat-soluble antioxidant in the film thickness portion due to the pressure of the dry air, gravity, etc. The drying temperature is preferably 60 ° C. or lower.

  When coating is performed after partial assembly of the blood purifier, by installing header caps with nozzles for introducing (leading out) blood or dialysate at both ends, the blood purifier is assembled into a shape. Complete the hollow fiber membrane blood purifier.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to a following example. The evaluation method and measurement method used in this example are as follows.

<Amount of fat-soluble antioxidant in hollow fiber membrane (total amount of fat-soluble antioxidant (vitamin E) present in hollow fiber membrane)>
After draining the filling liquid on the blood flow path side and dialysate flow path side of the hollow fiber membrane blood purifier having an effective membrane area of 1.3 m ² , normal temperature pure water was poured and washing was performed for 5 minutes. Moisture was removed with 0.05 MPa pressure for 10 seconds, and drying was further performed with 0.1 MPa pressure for 6 hours.
The hollow fiber membrane blood purifier was disassembled to collect a hollow fiber membrane bundle, the hollow fiber membrane bundle was cut into a length of 5 cm, and placed in a metal mug having a volume that can sufficiently accommodate the entire amount. Subsequently, 99.5% ethanol (manufactured by Wako Pure Chemical Industries, Ltd.) was poured in an amount so that the total amount of the hollow fiber membrane bundle cut into a mug was soaked in the sea (in this case, 400 mL), and vitamin E was applied for 60 minutes at room temperature while applying ultrasonic vibration Was extracted. Quantification was performed by liquid chromatography, and the amount of vitamin E in the extract was determined using a calibration curve obtained from the peak area of the vitamin E standard solution. That is, a high performance liquid chromatograph apparatus (JA-20 Co., Ltd. UV-2075 plus intelligent UV / VIS Detector, PU-2080 plus intelligent HPLC pump, CO-2065 plus intelligent column 19: AS-2057 plus int. A column (ODP-50 6E packed column for HPLC manufactured by Shodex Asahipak) was attached to the column, and methanol for high performance liquid chromatography as a mobile phase was passed at a flow rate of 1 ml / min at a column temperature of 40 ° C. Vitamin E concentration was determined from the peak area. From this concentration and an effective membrane area of 1.3 m ² , the amount of vitamin E (mg / m ² ) present in the hollow fiber membrane was determined with an extraction efficiency of 100%.

<Vitamin E normalized peak intensity of hollow fiber film thickness part>
After discharging the filling liquid of the hollow fiber membrane blood purifier having an effective membrane area of 1.3 m ² , normal temperature pure water was poured into the blood flow path side and the dialysate flow path side, and washing was performed for 5 minutes. Moisture was removed under a pressure of 0.05 MPa over 10 seconds.
The blood purifier was disassembled and a hollow fiber membrane was collected and lyophilized. The dried hollow fiber membrane was frozen and cut perpendicularly to the length direction, and the cross section was measured using a TOF-SIMS device (nano-TOF, ULVAC-PHI).
The measurement conditions are: primary ion Bi ₃ ⁺⁺ , acceleration voltage 30 kV, current 0.1 nA (as DC), analysis area 70 μm × 70 μm, integration time approximately 60 min, image of sum of all detected ions up to mass number 2000 , Total ion detection image).
Next, in the film cross section in the total ion detection image, the remaining film thickness part from which 5 μm is removed from both ends (inner surface side and outer surface side) of the film is divided into three equal parts in order to avoid the influence of the edge effect. A spectrum of each region was extracted with an inner region, an intermediate region, and an outer region (see FIG. 1).
Specifically, the spectrum of each region was detected by a detector using positive ions (molecular ions of m / z = 430) as detection ions. The ionic strength (IV) of the vitamin E peak obtained from the spectrum is calculated using the ionic strength IH of proton, the ionic strength INa of sodium, and the ionic strength obtained for a mass range of m / z = 0.5 to 2000. Using the total ionic strength IT which is the sum, it was converted into a normalized peak strength by the following formula 1.
Formula 1:
(Normalized peak intensity of vitamin E) = IV / (IT-IH-INa) × 1000

<Oxidation suppression effect of dialysate>
A redox potential is known as one index for knowing the redox equilibrium state in a solution. In this evaluation system, the same batch of test solution was used for each evaluation sample, and the oxidation-reduction potential was compared under the condition that the temperature and pH of each test solution after the test were the same.

  The oxidation-reduction potential is an index for knowing whether electrons tend to be accepted or supplied in an aqueous solution. The difference between the oxidation power and the reduction power is measured, and the voltage (mV) is measured. expressed. The redox potential is determined by the amount of oxidizing agent (electron acceptor) and reducing agent (electron donor) present in the solution. Therefore, when the redox potential is high, substances in the system are oxidative. It means a state. In an aqueous solution, the oxidation / reduction reaction of the solute proceeds via water. Therefore, in a state where the oxidation-reduction potential in the aqueous solution is high, glucose is easily oxidized and a glucose degradation product (GDP) is easily produced. Easy to provoke.

  Test compositions were prepared by dissolving the compositions in Table 1 in distilled water for injection and degassed for 4 hours for testing.

Subsequently, after discharging the filling liquid of the hollow fiber membrane blood purifier having an effective membrane area of 1.3 m ² , the blood flow path area and the dialysate flow path area were sufficiently washed with sprayed distilled water (flow rate 100 mL / min), set to the circuit shown in FIG. 1000 mL of the test solution was placed in a metal mug, and the blood channel area was replaced with 100 mL of the test solution, and then the distilled water for injection in the dialysate channel area was discarded. The flow rate was adjusted to 50 mL / min, and 24 hours after the start of circulation, the oxidation-reduction potential of the pooled test solution was measured using an ORP meter (Mother Tool, YK-23RP).
The case where the oxidation-reduction potential of the test solution for 24 hours was 210 mV or less was rated as good when the oxidation inhibitory effect was good, and the case where it was 215 mV or higher was marked as x when the oxidation inhibitory effect was not good.

<DeHP reduction rate in DEHP solution>
After 15 mg of DEHP was placed in 3.5 L of distilled water for injection and stirred at room temperature for 2 hours or more, DEHP remaining on the surface was removed to prepare a saturated aqueous solution of DEHP.
Subsequently, after discharging the filling liquid of the hollow fiber membrane blood purifier having an effective membrane area of 1.3 m ² , the blood flow path area and the dialysate flow path area are sufficiently washed with distilled water for injection (flow rate: 100 mL). / Min), set to the circuit shown in FIG. After 700 mL of DEHP saturated aqueous solution was put in a metal mug and the blood flow path area was replaced with 100 mL of DEHP saturated aqueous solution, distilled water for injection in the dialysate flow path area was discarded. The blood side flow rate (Qb) was adjusted to 100 mL / min, and the dialysate side flow rate (Qf) was adjusted to 10 mL / min. The DEHP concentration in the DEHP aqueous solution 24 hours after the start of circulation was analyzed according to JIS standard K0450-30-10. That is, 500 mL of DEHP aqueous solution was measured with a graduated cylinder, concentrated to 1 mL by hexane extraction, and quantified by GC-MS (Shimadzu Corporation, QP-2010).
The DEHP reduction rate (%) was calculated using Equation 2.
Formula 2:
(DEHP decrease rate) = (1−post-circulation DEHP concentration / pre-circulation DEHP concentration) × 100

[Example 1]
The membrane-spinning stock solution is prepared by dissolving 17 wt% of polysulfone (Solvay, P-1700) and 4 wt% of polyvinylpyrrolidone (BSF, K-90) in 79 wt% of dimethylacetamide (Kishida Chemical Co., Ltd., special grade reagent). Made. As the hollow inner liquid, a 60 wt% aqueous solution of dimethylacetamide was used.
From the tube-in-orifice type spinneret, the membrane-spun stock solution and the hollow inner solution were discharged. The temperature of the film-forming spinning solution at the time of discharge was 40 ° C. The discharged film-forming spinning solution was immersed in a 60 ° C. coagulation bath made of water through a dropping part covered with a hood and coagulated. At that time, the air gap length was 400 mm, and the spinning speed was 30 m / min. After coagulation, washing with water and drying were performed to obtain a blood purification membrane. Here, the drying temperature was 160 ° C. and the drying time was 100 seconds. In addition, the discharge amounts of the membrane-spinning stock solution and the hollow inner solution were adjusted so that the film thickness after drying was 43 μm and the inner diameter was 200 μm.
Next, the dried membrane bundle is filled into a cylindrical container having two nozzles for introducing and discharging liquid, embedded at both ends with urethane resin, and then the cured urethane resin portion is cut and hollowed The end of the thread membrane was processed into an opening, and the blood purifier body was assembled.
Next, the body part of this blood purifier is set vertically, and a coating solution in which 0.5 wt% of α-tocopherol (special grade of Wako Pure Chemical Industries, Ltd.) is dissolved in an aqueous solution of 57 wt% isopropyl alcohol at a temperature of 24 ° C. From the blood introduction nozzle of the processor body to the body fluid flow path surface side (inner surface of the hollow fiber membrane), liquid is passed from the lower side to the upper side at a flow rate of 1250 mL / min, and α- Tocopherol was contacted. Thereafter, the coating liquid was blown off by air blow while air was pressurized at 0.30 MPa from the outside of the hollow fiber membrane (opposite to the surface to be coated). After pressurizing with the above-mentioned pressure from the opposite side of the surface to be coated, α-tocopherol was fixed by aeration of dry air at 40 ° C. for 6 minutes to dry remove the solvent.
A header cap having a blood introduction (lead-out) nozzle was loaded at both ends, and assembled into a blood purifier shape.
As the wetting step, an aqueous solution containing 0.06 wt% of sodium hydrogen sulfite as an antioxidant and 0.03 wt% of sodium carbonate for pH adjustment is added to the blood side flow path and the filtrate side flow path of the blood purifier. The blood purifier was completed by filling and sterilizing γ rays with 25 kGy with each nozzle sealed.

[Example 2]
A blood purifier of Example 2 was obtained by the same method as Example 1 except that the concentration of α-tocopherol (special grade of Wako Pure Chemical Industries) in the coating solution was changed to 0.25 wt%.

[Example 3]
A blood purifier of Example 3 was obtained by the same method as Example 1 except that the concentration of α-tocopherol (special grade of Wako Pure Chemical Industries) in the coating solution was changed to 2.0 wt%.

[Example 4]
A blood purifier of Example 4 was obtained by the same method as Example 1 except that the pressure at the time of pressurization from the outside of the hollow fiber membrane was changed to 0.35 MPa.

[Comparative Example 1]
Blood was passed through the hollow fiber membrane in the same manner as in Example 1 except that the coating liquid containing α-tocopherol was not passed, and the subsequent steps (air blow, pressurization and solvent removal) were not performed. I got a purifier.

[Comparative Example 2]
A blood purifier of Comparative Example 2 was obtained in the same manner as in Example 1 except that the concentration of α-tocopherol (special grade of Wako Pure Chemical Industries) in the coating solution was changed to 0.02 wt%.

[Comparative Example 3]
A blood purifier of Comparative Example 3 was obtained in the same manner as in Example 1 except that the concentration of α-tocopherol (special grade of Wako Pure Chemical Industries) in the coating solution was changed to 4.0 wt%.

[Comparative Example 4]
Example except that the coating liquid was passed through the hollow fiber membrane in the reverse direction (from the top to the bottom) and no air pressure was applied during air blow or after air blow was stopped. In the same manner as in Example 1, a blood purifier was obtained.

[Comparative Example 5]
The membrane-spinning stock solution dissolves 17 wt% of polysulfone (Solvay, P-1700) and 4 wt% of polyvinylpyrrolidone (BSF, K-90) in 79 wt% of dimethylacetamide (manufactured by Kishida Chemical Co., Ltd., special grade reagent). It was prepared by adding 0.5 parts by weight of α-tocopherol (special grade of Wako Pure Chemical Industries) to 100 parts by weight of the solution thus obtained. A dimethylacetamide 41 wt% aqueous solution was used as the hollow inner liquid.
A film-forming spinning solution and a hollow inner solution were discharged from a spinneret having a slit width of 50 μm. At this time, the temperature of the membrane spinning solution at the time of discharge was set to 60 ° C. The discharged film-forming spinning solution was immersed in a 90 ° C. coagulation bath made of water through a dropping part covered with a hood, and coagulated. At that time, the air gap length was 500 mm, and the spinning speed was 30 m / min. After coagulation, washing with water and drying were performed. Here, as drying, after heat-reducing at 120 ° C. for 2 minutes, heat treatment was further performed at 180 ° C. for 0.5 minutes. Thereafter, 9984 hollow fiber membranes were wound up. In addition, the discharge amounts of the film-forming spinning solution and the hollow inner solution were adjusted so that the film thickness after drying was 45 μm and the inner diameter was 185 μm.
Next, the dried membrane bundle is filled into a cylindrical container having two nozzles for introducing and discharging liquid, embedded at both ends with urethane resin, and then the cured urethane resin portion is cut and hollowed The end of the thread membrane was processed into an opening, and the blood purifier body was assembled.
A header cap having a blood introduction (lead-out) nozzle was loaded at both ends, and assembled into a blood purifier shape.
As the wetting step, an aqueous solution containing 0.06 wt% of sodium hydrogen sulfite as an antioxidant and 0.03 wt% of sodium carbonate for pH adjustment is added to the blood side flow path and the filtrate side flow path of the blood purifier. The blood purifier was completed by filling and sterilizing γ rays with 25 kGy with each nozzle sealed.

The results are shown below.
In addition, the blood purifier of Comparative Example 5 in which a hollow fiber membrane was produced by adding a fat-soluble oxidant to the membrane-spun stock solution had a good dialysis solution oxidation-suppressing effect, but a plasticizer adsorption effect (DEHP reduction) Rate) was small. This is because the amount of the fat-soluble antioxidant on the hollow fiber membrane surface is large, so the oxidation-reduction potential showed a low value. On the side, it is considered that the plasticizer adsorption effect (DEHP reduction rate) was small because the pores were reduced by the fat-soluble antioxidant and the effective area that DEHP could contact was reduced.

According to the hollow fiber membrane of the present invention, it is possible to efficiently suppress the oxidizing substances entering from both the inside and the outside (blood circulation line and dialysate side), and at the same time, the plasticizer eluted from the circuit can be removed.
Therefore, the hollow fiber membrane blood purifier of the present invention can be used for purifying various blood, and particularly preferably used as a blood purifier such as a hemodialyzer, a blood filter or a blood filter dialyzer. it can. In particular, it can be suitably used for blood purification therapy that extracorporeally circulates blood for a long time, such as CRRT.

Claims (10)

A hollow fiber membrane containing a fat-soluble antioxidant,
The amount of fat-soluble antioxidant per 1 m ^{2 of} effective membrane area is 50 mg / m ² or more and 600 mg / m ² or less,
5 μm is removed from both ends of the cut surface of the hollow fiber membrane, and the remaining film thickness is divided into three equal parts, and the TOF-SIMS normalized peak intensity in each region when the inner region, the intermediate region, and the outer region are obtained, As Ii, Ic and Io,
Ii is 0.18 or more,
A hollow fiber membrane having an Ic / Ii of 0.80 to 1.0 and an Io / Ii of 0.70 to 1.0.   The hollow fiber membrane according to claim 1, comprising a polysulfone-based resin and a hydrophilic polymer.   A blood purifier comprising a bundle of hollow fiber membranes according to claim 1 or 2 and a container containing the bundle.   The hollow fiber membrane blood purifier according to any one of claims 1 to 3, wherein Ii is 0.2 or more.   The hollow fiber membrane blood purifier according to any one of claims 1 to 4, wherein Ic / Ii is 0.85 or more and 1.0 or less. The hollow fiber membrane blood purifier according to any one of claims 1 to 5, wherein Io / Ii is 0.75 or more and 1.0 or less. The hollow fiber membrane blood purifier according to any one of claims 1 to 6, wherein the container has an oxygen permeability coefficient of 1.8 × 10 ^-10 cm ³ · cm / (cm ² · S · cmHg) or less.   The hollow fiber membrane-type blood purifier according to any one of claims 1 to 7, wherein the container has a cylindrical shape, and the absorbance of the trunk at a wavelength of 350 nm is 0.35 or more and 2.00 or less.   The hollow fiber membrane blood purifier according to any one of claims 1 to 8, wherein the fat-soluble antioxidant is a fat-soluble vitamin.   A continuous slow blood filter (CRRT filter) comprising the hollow fiber membrane blood purifier according to any one of claims 1 to 9.