JP2015116212A - Hollow fiber membrane for blood treatment and blood treatment device in which membrane is embedded - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a hollow fiber membrane for blood treatment which has excellent blood compatibility, stable antioxidative performance, and a less amount of nitrate ion elution.SOLUTION: A hollow fiber membrane for blood treatment comprises at least a polysulfone resin and polyvinyl pyrrolidone and includes fat soluble vitamins on the surface of the hollow fiber membrane within a range of 10 mg/mor more and 300 mg/mor less calculated in terms of a membrane area. In the hollow fiber membrane for blood treatment, an abundance ratio of intermediate water in water existing on a separation function surface at the saturated point with retained moisture in soaking a hollow fiber membrane in a dried state in water is 20% or more, a water content rate is 10% or less, and the hollow fiber membrane is sterilized with radiation.

Description

  The present invention relates to a blood treatment hollow fiber membrane and a blood treatment device incorporating the membrane.

In extracorporeal circulation therapy, a hollow fiber membrane blood treatment device using a hollow fiber membrane as a selective separation membrane is widely used. For example, in hemodialysis as maintenance therapy for patients with chronic renal failure, in continuous hemofiltration, continuous hemofiltration dialysis, continuous hemodialysis, etc. as acute blood purification therapy for patients with serious pathological conditions such as acute renal failure and sepsis, In addition, a hollow fiber membrane blood processor is used for oxygenation or plasma separation during blood opening surgery.
In these applications, the hollow fiber membrane is excellent in mechanical strength and chemical stability, is easy to control the permeation performance, has less eluate, has less interaction with biological components, Are required to be safe.

  In recent years, from the viewpoint of mechanical strength, chemical stability, and controllability of permeation performance, a selective separation membrane made of a polysulfone resin has been rapidly spread. Since the polysulfone resin is a hydrophobic polymer, as it is, the hydrophilicity of the membrane surface is remarkably insufficient, blood compatibility is poor, interaction with blood components is caused, blood coagulation is likely to occur, Furthermore, permeation performance tends to deteriorate due to adsorption of protein components.

  Therefore, in order to compensate for these disadvantages, blood compatibility is selected by adding hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyvinyl alcohol, and polyethylene glycol in addition to hydrophobic polymers such as polysulfone resins. It has been studied to apply to an artificial separation membrane. For example, by forming a film using a membrane-spinning stock solution in which a hydrophobic polymer and a hydrophilic polymer are blended, the method increases the hydrophilicity of the membrane and improves blood compatibility, By forming a film using a hollow internal liquid containing a hydrophilic polymer and drying it, or by bringing the produced film into contact with a solution containing a hydrophilic polymer and then drying it, the hydrophilic polymer is obtained. A method of coating and imparting blood compatibility is known.

  Patent Documents 1 to 3 disclose the abundance of the hydrophilic polymer on the film surface, but do not mention the existence state of the hydrophilic polymer.

By the way, in extracorporeal circulation therapy, since the blood is directly brought into contact with the selective separation membrane in the blood treatment device, the selective separation membrane needs to be sterilized before use.
In sterilization treatment, ethylene oxide gas, high-pressure steam, radiation, etc. are used. However, ethylene oxide gas sterilization and high-pressure steam sterilization have problems such as allergies due to residual gas, treatment capacity of the sterilizer, and thermal deformation of materials. Yes, radiation sterilization such as gamma rays and electron beams has become the mainstream.
On the other hand, dry products are becoming mainstream as blood treatment devices due to handling problems, freezing problems during cold storage, etc., but in the sterilization process by radiation, the generated radicals cause cross-linking and decomposition of hydrophilic polymers, Eventually, oxidative degradation or the like occurs, which causes denaturation of the membrane material, leading to a decrease in blood compatibility and an increase in eluate.

  As a method for preventing such deterioration of the membrane material, when the blood processing device is not a dry product, Patent Document 4 describes that the membrane module is filled with an antioxidant solution and sterilized by γ-ray to oxidize the membrane In addition, Patent Document 5 discloses a method for suppressing acidification of a filling liquid by filling with a pH buffer solution or an alkaline aqueous solution and sterilizing.

  Regarding dry products, Patent Document 6 discloses a method of controlling the oxygen concentration during sterilization to 0.001% or more and 0.1% or less. However, in the technique of Patent Document 6, it is necessary to sterilize by replacing the inside of the packaging bag with an inert gas, or to sterilize after a certain period of time by enclosing an oxygen scavenger in the packaging bag. Even if the concentration exceeds only 0.1%, sufficient blood compatibility cannot be achieved by radiation sterilization.

“Intermediate water” has attracted attention as a method for improving the blood compatibility of a sterilized blood treatment device. Non-Patent Document 1 describes “the function of water molecules organized in a biointerface” regarding the state and biocompatibility of water contained in a polymer material such as poly (2-methoxyethyl acrylate) (PMEA). It has been reported.
According to Non-Patent Document 1, when water is contained in a general polymer material, the water in the polymer is (1) “non-freezing water” that does not freeze even at −100 ° C. due to strong interaction with the polymer. (2) Although it is dissolved at 0 ° C., it is divided into “free water” that weakly interacts with the polymer or antifreeze water. In the polymer with excellent biocompatibility, (3) There is “intermediate water” that is frozen at a temperature lower than 0 ° C. in the temperature process and has an intermediate interaction with polymer or antifreeze water. In addition, there is no “intermediate water” for polymers with poor biocompatibility.

Further, Non-Patent Document 1 has a result that suggests that there is a close relationship between the presence of “intermediate water” in the water in the polymer and the development of excellent biocompatibility of the polymer. It is disclosed.
The following is considered as a mechanism in which “intermediate water” affects the biocompatibility of the polymer.
Since “free water” is freely exchanged with bulk water, which is general water that does not interact with the polymer, it does not play the role of covering the surface of the polymer material. It exists to cover the surface of the polymer material by strong interaction. However, “antifreeze water” destroys the structure of the hydration shell by interacting with the hydration shell itself of biological components such as proteins that are stabilized by forming a hydration shell in the blood. Due to the destruction of the hydration shell, the biological component is adsorbed on the surface of the polymer material. Therefore, when a general polymer material having only “free water” and “non-freezing water” is used, the biological component recognizes the surface of the polymer material as a foreign substance and triggers an immune reaction.
“Intermediate water” interacts with “antifreeze water” to bind to the polymer material, covers the surface of “antifreeze water”, and has a unique hydrogen bond structure that destroys the hydration shell of biological components. As a result, the biological component cannot recognize the foreign material on the surface of the polymer material. Therefore, it is speculated that the polymer material having “intermediate water” is excellent in blood compatibility.

  In addition, regarding the intake of nitrate, the causal relationship with health hazards is not necessarily clear, but Non-Patent Document 2 reports that nitrate administration and effects on laboratory animals, etc., and that most nitrate is excreted from urine. ing. In view of the disclosure of Non-Patent Document 2, the intake of nitrate should be reduced even more in patients with renal failure, and the elution of nitrate ions is also reduced in blood treatment hollow fiber membranes and blood treatment devices. Seems to be preferable.

By the way, in recent years, for the purpose of alleviating not only blood compatibility of hollow fiber membranes but also oxidative stress that manifests in long-term dialysis patients, for example, peroxidation that is a causative substance of oxidative stress using hollow fiber membranes. Attempts have been made to erase things and restore the antioxidant effect of living bodies.
Patent Documents 7 and 8 propose a blood treatment device into which a fat-soluble vitamin such as vitamin E having various physiological functions such as in vivo antioxidant action, biological membrane stabilizing action, and platelet aggregation inhibiting action is introduced. . Polysulfone-based hollow fiber membranes and polyethersulfone-based hollow fiber membranes have a high affinity with fat-soluble vitamins that are effective in suppressing oxidative stress caused by extracorporeal circulation of blood. It is known that immobilization of fat-soluble vitamins is easy.

Japanese Patent No. 3551971 JP 2002-212333 A JP-A-6-296686 JP-A-4-338223 Japanese Patent Laid-Open No. 7-194949 International Publication No. 2006/016575 JP 2013-9761 A JP2013-94525A

PRESTO Study 21 of the Japan Science and Technology Agency: Ken Tanaka “Functions of Water Molecules Organized in Biointerfaces” (2001-2004) Report Evaluation report for soft drinks Nitrate nitrogen and Nitrite nitrogen: May 2012 Food Safety Committee

  On the other hand, since fat-soluble vitamins are hydrophobic substances, it is clear that immobilization of fat-soluble vitamins in a hollow fiber membrane of a blood treatment device above a certain amount reduces the above-mentioned intermediate water and lowers blood compatibility. It has become.

In addition, the inventors' research has found that the water permeation performance may deteriorate over time in a severe environment such as a high temperature.
Accordingly, an object of the present invention is to provide a hollow fiber membrane for blood treatment that has good blood compatibility and stable antioxidant performance, and further has little nitrate ion elution.

  As a result of intensive studies by the present inventors to solve the above-mentioned problems, in order to impart excellent blood compatibility and stable antioxidant performance to the hollow fiber membrane for blood treatment, and to further reduce the elution of nitrate ions The present inventors have found that it is important to maintain the fat-soluble vitamin amount, water content, and intermediate water in the blood treatment hollow fiber membrane in an appropriate state.

That is, the present invention is as follows.
[1]
A hollow fiber membrane for blood treatment comprising at least a polysulfone resin and polyvinylpyrrolidone,
Containing 10 mg / m ² or more and 300 mg / m ² or less of fat-soluble vitamin on the surface of the hollow fiber membrane,
When the dry hollow fiber membrane is hydrated, the abundance of intermediate water in the water present on the surface of the separation function at the time of reaching the water saturation is 20% or more,
The moisture content is 10% or less,
A hollow fiber membrane for blood treatment, wherein the hollow fiber membrane is radiation sterilized.
[2]
The hollow fiber membrane for blood treatment according to [1], comprising a hydrophilic polymer at least on the separation functional surface.
[3]
The hollow fiber membrane for blood treatment according to [2], wherein the hydrophilic polymer is at least one selected from the group consisting of polyhydroxyalkyl methacrylates and sodium salts of polysaccharides.
[4]
The hollow fiber membrane for blood treatment according to any one of [1] to [3], wherein the hollow fiber membrane comprises a ketone having a carbon number of 4 or less and 2 or less and 3000 μg or less and / or alcohol.
[5]
The hollow fiber membrane for blood treatment according to any one of [1] to [4], which is radiation sterilized with an irradiation dose of 15 kGy or more and 50 kGy or less.
[6]
A blood processing device incorporating the hollow fiber membrane for blood processing according to any one of [1] to [5].

  The blood treatment hollow fiber membrane of the present invention and the blood treatment device incorporating the membrane exhibit the effects of exhibiting good blood compatibility and stable antioxidant performance, and little elution of nitrate ions.

The sample setting method of IR measurement at the time of calculating the abundance ratio of the intermediate water in the water existing on the surface of the separation function at the time when the water content saturation is reached when the dry hollow fiber membrane is water-containing is shown. An example of the experimental spectrum matrix A is shown.

  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.

<Hollow fiber membrane for blood treatment>
The hollow fiber membrane for blood treatment of the present embodiment (hereinafter sometimes simply referred to as “hollow fiber membrane”) is composed of a polysulfone resin and polyvinylpyrrolidone, and 10 mg / m in terms of membrane area on the surface of the hollow fiber membrane. ^{2 to} 300 mg / m ² or less of fat-soluble vitamins, and the water content in the separation function surface at the time of reaching water saturation when the dried hollow fiber membrane is hydrated is 20% or more. Yes, the moisture content is 10% or less, and the hollow fiber membrane is radiation sterilized.

  The hollow fiber membrane of this embodiment contains a polysulfone-based resin as a main component, and contains polyvinyl pyrrolidone in order to impart blood compatibility to the hollow fiber membrane. In order to impart antioxidant performance to the hollow fiber membrane, a fat-soluble vitamin is included on the surface of the hollow fiber membrane.

<Polysulfone resin>
The polysulfone resin is a sulfone (—SO ₂ —) group-containing synthetic polymer, and is excellent in heat resistance and chemical resistance. Examples of the polysulfone resin include polyphenylene sulfone, polysulfone, polyaryl ether sulfone, polyether sulfone, and copolymers thereof. As a polysulfone-type resin, you may use by 1 type and may use 2 or more types of mixtures.

Among these, from the viewpoint of controlling the fractionation property, a polysulfone-based polymer represented by the following formula (1) or the following formula (2) is preferable.
(—Ar—SO ₂ —Ar—O—Ar—C (CH ₃ ) ₂ —Ar—O—) _n (1)
(—Ar—SO ₂ —Ar—O—) _n (2)
In formula (1) and formula (2), Ar represents a benzene ring, and n represents repeating monomer units. The polysulfone represented by the formula (1) is commercially available, for example, under the name “Udel ™” from Solvay, and under the name “Ultrazone ™” from BSF, The polyethersulfone represented by the formula (2) is commercially available from Sumitomo Chemical Co., Ltd. under the name of “Sumika Excel (trademark)”, and there are several types depending on the degree of polymerization. Can do.

<Polyvinylpyrrolidone>
Polyvinylpyrrolidone is a water-soluble hydrophilic polymer 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.
Polyvinyl pyrrolidone is commercially available from BASF with several molecular weights under the name “Rubitec (trademark)”, and these can be used as appropriate.
As polyvinyl pyrrolidone, you may use by 1 type and may use 2 or more types of mixtures.

<Fat-soluble vitamin>
In the present embodiment, examples of the fat-soluble vitamin include vitamin A, vitamin D, vitamin E, vitamin K, and the like. Among these, from the viewpoint of not inducing a disorder even if overdose is taken, E is preferred. 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.

<Amount of fat-soluble vitamin present on the surface of the hollow fiber membrane>
In this embodiment, “the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane” refers to the amount of fat-soluble vitamin attached, adsorbed or coated on the surface of the hollow fiber membrane, and the fat-soluble vitamin present on the surface of the hollow fiber membrane. The amount can be quantified by, for example, the amount of fat-soluble vitamin extracted by the solvent without breaking or dissolving the hollow fiber membrane as described later.
The “membrane area” in terms of membrane area is the inner surface area of the hollow fiber membrane, and is calculated from the product of the average inner diameter (diameter), the circumference ratio, the number, and the effective length of the hollow fiber membrane.

In the present embodiment, the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane is 10 mg / m ² or more and 300 mg / m ² or less, preferably 50 mg / m ² or more and 250 mg / m ² or less, more preferably in terms of membrane area. Is 100 mg / m ² or more and 200 mg / m ² or less.
By including not less than 10 mg / m ² of fat-soluble vitamin in terms of membrane area on the surface of the hollow fiber membrane, sufficient antioxidant performance can be obtained, and by including not more than 300 mg / m ² , blood compatibility is excellent.

An example of a method for measuring the amount of fat-soluble vitamin present on the surface of the hollow fiber membrane will be described.
First, a blood treatment device incorporating a hollow fiber membrane is disassembled, the hollow fiber membrane is collected, washed with water, and then dried. Subsequently, a surfactant that dissolves the fat-soluble vitamin, for example, 1% by mass of a polyethylene glycol-t-octylphenyl ether aqueous solution, is added to the hollow fiber membrane that has been precisely weighed and dried, followed by stirring and extraction. The membrane area of the extracted hollow fiber membrane is calculated from the product of the average inner diameter (diameter), the circumference, the number, and the effective length of the hollow fiber membrane.
The quantitative operation is performed, for example, by liquid chromatography, and the concentration of the fat-soluble vitamin in the extract is calculated using a calibration curve obtained from the peak area of the fat-soluble vitamin standard solution.
The amount of fat-soluble vitamin (mg / m ² ) present on the surface of the hollow fiber membrane can be determined from the concentration of the obtained fat-soluble vitamin and the membrane area of the extracted hollow fiber membrane, with the extraction efficiency being 100%.
The liquid chromatographic method is described as an example, but can be performed as follows. A high-performance liquid chromatograph (pump: JASCO PU-1580, detector: Shimadzu RID-6A, autoinjector: Shimadzu SIL-6B, data processing: Tosoh GPC-8020, column oven: GL Sciences 556), column (Shodex Asahipak) ODP-506E packed column for HPLC (manufactured by Co., Ltd.) is attached, methanol for high performance liquid chromatography, which is a mobile phase, is passed at a column temperature of 40 ° C., for example, at a flow rate of 1 mL / min, and an absorption peak at a wavelength of 295 nm with a UV detector The fat-soluble vitamin concentration is determined from the area of the area.

<Abundance ratio of intermediate water in water existing on the surface of the separation function when water content saturation is reached when water is contained in the dry hollow fiber membrane>
The hollow fiber membrane of the present embodiment is an abundance ratio of intermediate water in water existing on the separation functional surface at the time of reaching the water saturation when the dried hollow fiber membrane is hydrated (hereinafter simply referred to as “intermediate water abundance ratio”). Is a film with 20% or more.
In the hollow fiber membrane of the present embodiment, from the viewpoint of blood compatibility, in addition to polysulfone resin, polyvinyl pyrrolidone and a fat-soluble vitamin are added, and further, a hollow fiber membrane that can be practically used is in contact with blood. By making the abundance ratio of the intermediate water on the separation function surface near the inner surface of the thread membrane within a specific range, even if it is radiation sterilized in a dry state, it expresses good blood compatibility and antioxidant performance, This has the effect of reducing the elution amount of nitrate ions from the hollow fiber membrane.

In the present embodiment, the intermediate water abundance ratio is determined by measuring the total reflection infrared absorption (ATR-IR) of the separation function surface of the hollow fiber membrane in the process of water-containing the dry hollow fiber membrane, Calculated by analysis.
In the present embodiment, the “separation function surface” means a region corresponding to the film thickness of the blood contact surface detected by ATR-IR. Specifically, the separation functional surface is a detectable region when measured by ATR-IR, and is usually a region corresponding to a film thickness of 1 μm or less from the inner surface.
In the present embodiment, “the point of time when water saturation is reached when water is added to the dried hollow fiber membrane” refers to the peak intensity of the benzene ring (near 1485 cm ⁻¹ ) of the polysulfone resin measured by ATR-IR. In the process of hydrating the hollow fiber membrane in the dry state, it means the point at which the increase in peak intensity derived from the hydroxyl group (3000 to 3700 cm ⁻¹ ) is no longer observed. In the present embodiment, the “dry state” means a state where the equilibrium moisture content has been reached, as exemplified in the examples, and the “process of containing water in the dry state hollow fiber membrane” As illustrated, it means a process of allowing water to penetrate into a dry hollow fiber membrane.

In the present embodiment, when the hollow fiber membrane is hydrated from the dry state, the intermediate water is retained so that the ratio of the intermediate water to the water existing on the separation functional surface at the time when the water content saturation is reached is 20% or more. It must retain the qualities it can do.
Further, in the present embodiment, in order to impart biocompatibility to the hollow fiber membrane and reduce elution of nitrate ions from the hollow fiber membrane, polyvinylpyrrolidone is dried even in a state after radiation sterilization. When water is contained from the state, it must have the property of holding the intermediate water so that the existing ratio of the intermediate water in the water existing on the surface of the separation function at the time when the water saturation is reached is 20% or more.
For example, when a polymer is irradiated with radiation, radicals are generated on the polymer or attacked by oxygen radicals. Therefore, depending on the generation site and attack site, the main chain of the polymer is broken or cross-linked, Cleavage can occur.

When the main chain is cleaved with polyvinyl pyrrolidone in the hollow fiber membrane, the polyvinyl pyrrolidone is easily eluted due to the low molecular weight. In addition, when crosslinking or side chain cleavage occurs, the hydrophilicity of the hollow fiber membrane by polyvinylpyrrolidone decreases.
As a result, the effect of imparting biocompatibility to the hollow fiber membrane cannot be sufficiently exhibited, and the elution amount of nitrate ions from the inner surface increases.

Although the radical reaction is complex and the final product can take various forms, the blood compatibility of the hollow fiber membrane is associated with a slight change in the state of the material comprising the inner surface of the hollow fiber membrane. Conceivable. However, according to the conventional spectroscopic method, it has not been possible to directly detect a state change correlated with the blood compatibility of polyvinylpyrrolidone with respect to the radiation sterilization intensity (50 kGy or less) generally applied to medical devices. .
In this embodiment, the state change correlated with the blood compatibility of polyvinylpyrrolidone present on the separation function surface is analyzed by analyzing the time-resolved ATR-IR in the water-containing process and analyzing the change in the water present on the separation function surface. It became clear that it could be detected as a change in the ratio of the intermediate water. That is, the present inventors have found that as the abundance ratio of the intermediate water decreases, the polyvinyl pyrrolidone is changed to a state that does not exhibit blood compatibility, and at the same time, the amount of nitrate ions eluted from the inner surface increases.
Furthermore, as a result of the study by the present inventors, the hollow fiber membrane containing a polysulfone resin, polyvinylpyrrolidone and a fat-soluble vitamin is imparted with excellent biocompatibility, and the amount of nitrate ions eluted from the inner surface is reduced. In order to impart blood compatibility, it is necessary that the ratio of the intermediate water to the water existing on the separation function surface at the time when the water content saturation is reached is 20% or more in the process of water content in the dry hollow fiber membrane. It became clear that there was.

In this embodiment, the hollow fiber membrane used for radiation sterilization is, for example, in a wet state after spinning in order to make the existing ratio of intermediate water 20% or more in the hollow fiber membrane in which a certain amount or more of fat-soluble vitamins are fixed. When the membrane is dried for the first time, that is, when a never-dry membrane is dried, the membrane is dried using heated steam, or the separation functional surface is coated with a hydrophilic polymer described later. Although the reason why the ratio of intermediate water can be increased to 20% or more by these methods has not been clarified, the following reason is presumed. By drying and fixing the structure as if water is present around it, such as heated steam and polymer hydroxyl groups, the orientation and three-dimensional structure of the polyvinylpyrrolidone are maintained in a state close to the water environment. It is considered that the intermediate water can be easily retained, and the side chain decomposition due to radical transfer after radical generation is suppressed. Furthermore, although it does not go out of speculation, it is considered that the orientation and three-dimensional structure of polyvinylpyrrolidone in an aqueous environment can be reproduced even by drying in an atmosphere of a ketone having 4 or less carbon atoms and / or alcohol. As a result, the excessive decomposition reaction of polyvinyl pyrrolidone existing on the separation function surface is suppressed, and the effect of imparting biocompatibility is not reduced, and protein adsorption to the hollow fiber membrane and activation by the membrane surface are suppressed. It is considered that the hollow fiber membrane with high blood compatibility could be obtained, and at the same time, the elution of nitrate ions from the inner surface could be reduced.
In this embodiment, the method of drying with heated steam is to wind the hollow fiber membrane in a wet state, wrap it in a film such as PE in the form of a bundle, place it in a drying chamber, and introduce heated steam. And dry. At this time, normal pressure or reduced pressure may be used, but from the viewpoint of shortening the drying time and suppressing thermal decomposition, the temperature of the heated steam is equal to or higher than the reverse temperature (the point at which the evaporation rate becomes equal regardless of humidity). 200 ° C. or less is preferable.

<Moisture content>
The hollow fiber membrane of this embodiment has a moisture content of 10% or less, preferably 8% or less, and more preferably 5% or less. When the moisture content is 10% or less, condensation during storage can be prevented, and a preferable appearance is given. In addition, the mass can be set in an appropriate range, which is suitable for transportation in a facility.
In the present embodiment, the moisture content can be measured by the method described in the following examples.
In the present embodiment, the moisture content can be reduced to 10% or less by drying with heated steam on the hollow fiber membrane obtained by spinning. The hollow fiber membrane coated with a hydrophilic polymer can be dried at a moisture content of 10% or less by drying by a normal method using hot air or the like.

<Hydrophilic polymer>
The hollow fiber membrane of this embodiment preferably contains a hydrophilic polymer at least on the separation functional surface.
By including the hydrophilic polymer, deterioration of the hollow fiber membrane due to radiation irradiation can be suppressed.
The hydrophilic polymer is not particularly limited as long as it is a polymer that is easily compatible with water, and examples thereof include a polymer having a solubility parameter δ (cal / cm ³ ) ^1/2 of 10 or more and a polymer having a hydroxyl group.
The solubility parameter δ is an index described in, for example, “Polymer Data Handbook Fundamentals” edited by The Society of Polymer Science, Bafukan Co., Ltd., published on January 30, 1986, pages 591-593. When the parameter is high, the hydrophilicity is strong, and when the parameter is low, the hydrophobicity is strong.
Polymers having a solubility parameter δ (cal / cm ³ ) ^1/2 of 10 or more include polyhydroxyethyl methacrylate (δ = 10.00), cellulose diacetate (δ = 11.35), polyacrylonitrile (δ = 12.35). The value described as δ is described as an example.
Examples of the polymer having a hydroxyl group include polyhydroxyalkyl methacrylates such as polyhydroxyethyl methacrylate, polyhydroxypropyl methacrylate, and polyhydroxybutyl methacrylate, and sodium salts of polysaccharides such as sodium alginate, sodium hyaluronate, and sodium heparin. Polyhydroxyalkyl methacrylate is a synthetic polymer obtained by (co) polymerizing hydroxyalkyl methacrylate as a monomer unit, and is a compound having a hydroxyl group in a side chain.
As the hydrophilic polymer, one kind may be used, or a mixture of two or more kinds may be used. The method for imparting the hydrophilic polymer to the separation function surface will be described later.

<C4 or less ketone and / or alcohol>
The hollow fiber membrane of the present embodiment preferably contains a ketone and / or alcohol having 4 or less carbon atoms.
By including a ketone and / or alcohol having 4 or less carbon atoms, the hollow fiber membrane of this embodiment can stably exhibit antioxidant performance.
Examples of the ketone having 4 or less carbon atoms include acetone and methyl ethyl ketone, and examples of the alcohol having 4 or less carbon atoms include methanol, ethanol, propyl alcohol, isopropyl alcohol, ethylene glycol, glycerin, and butyl alcohol. Of these, acetone, ethanol, and isopropyl alcohol are preferably used.
When ethers such as tetrahydrofuran are used, the polysulfone resin swells or dissolves to change the structure, and the performance of the hollow fiber membrane (decrease in water permeability performance and increase in water permeability performance variation) may be reduced. The following ketones and / or alcohols are preferred.

Conventionally, in a hollow fiber membrane to which a fat-soluble vitamin is added, the stability of the fat-soluble vitamin particularly in a harsh environment such as high-temperature storage is lowered, that is, the performance of the hollow fiber membrane may be lowered. Although the cause of this is not clear, the present inventors presume that the performance decrease is due to a decrease in structure retention in the fat-soluble vitamin and the base resin of the hollow fiber membrane. The present inventors have added a ketone and / or alcohol having a carbon number of 4 or less to a fat-soluble vitamin to suppress a decrease in structure retention between the fat-soluble vitamin and the polysulfone resin in a harsh environment such as a high temperature. Successful.
A method of including a ketone and / or alcohol having 4 or less carbon atoms in the hollow fiber membrane will be described later.

The amount of ketone and / or alcohol having 4 or less carbon atoms contained in the hollow fiber membrane is preferably 2 μg or more and 3000 μg or less, more preferably 10 μg or more and 2000 μg or less, and further preferably 25 μg per 1 g of the hollow fiber membrane. The amount is 1500 μg or less.
When the abundance is 2 μg / g or more, sufficient structure retention between the fat-soluble vitamin and the polysulfone resin can be obtained, and when it is 3000 μg / g or less, a ketone having 4 or less carbon atoms and / or Alcohol can be prevented from eluting into the blood.

The content of ketone and / or alcohol having 4 or less carbon atoms per 1 g of the hollow fiber membrane can be measured, for example, by the following method.
Disassemble the blood processor and vacuum dry until constant weight is achieved. Thereafter, the hollow fiber membrane is taken out. After this mass was precisely weighed (Wg), N-methyl-2-pyrrolidone was added, stirred, dissolved, dissolved, and then the concentration of ketones and / or alcohols having 4 or less carbon atoms by gas chromatography (GC). x (%) is calculated. Subsequently, the mass (μg / g) of a ketone and / or alcohol having 4 or less carbon atoms per 1 g of the hollow fiber membrane is calculated from W and x.

<Blood processor>
The blood treatment device of the present embodiment is a blood treatment device in which the hollow fiber membrane of the present embodiment is incorporated, such as hemodialysis, blood filtration, blood filtration dialysis, blood component fractionation, oxygenation, and plasma separation. Used for extracorporeal circulation type blood purification therapy.
As a blood treatment device, it is preferably used in hemodialyzers, blood filter devices, blood filter dialyzers, etc., and these are continuous applications, continuous hemodialyzers, continuous blood filter devices, continuous blood filter dialyzer devices It is more preferable to use as. Detailed specifications such as dimensions and fractionation of the hollow fiber membrane are determined according to each application.
It is preferable that a crimp is imparted to the hollow fiber membrane incorporated in the blood treatment device from the viewpoint of permeation performance.

<Method for producing hollow fiber membrane for blood treatment and blood treatment device>
The method for producing a hollow fiber membrane for blood treatment according to this embodiment includes a step of forming a hollow fiber membrane comprising at least a polysulfone resin and polyvinylpyrrolidone, and a step of immobilizing fat-soluble vitamins on the surface of the hollow fiber membrane.

<Process for forming hollow fiber membrane>
In the method for producing a hollow fiber membrane of the present embodiment, a normal membrane forming process is performed using a membrane-spinning stock solution containing at least a polysulfone resin and polyvinylpyrrolidone.
The membrane-spinning stock solution can be prepared by dissolving a polysulfone resin and polyvinylpyrrolidone in a solvent.
Examples of such solvents include dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, and dioxane.
As a solvent, you may use by 1 type and may use 2 or more types of mixed solvents.

The concentration of the polysulfone resin in the membrane-spinning stock solution is not particularly limited as long as the membrane can be formed and the obtained membrane has a performance as a permeable membrane, but is preferably 5% by mass or more. It is 35 mass% or less, More preferably, it is 10 mass% or more and 30 mass% or less. In order to achieve high water permeability, the polysulfone resin concentration should be low, and more preferably 10% by mass to 25% by mass.
The concentration of polyvinyl pyrrolidone in the membrane spinning solution is such that the mixing ratio of polyvinyl pyrrolidone to the polysulfone resin is preferably 27% by mass or less, more preferably 18% by mass or more and 27% by mass or less, and further preferably 20% by mass or more and 27% by mass. Adjust so that it is below%.
By adjusting the mixing ratio of polyvinyl pyrrolidone to the polysulfone resin to 27% by mass or less, the elution amount of polyvinyl pyrrolidone can be suppressed. In addition, preferably, by setting the content to 18% by mass or more, the polyvinylpyrrolidone concentration on the separation function surface can be controlled within a suitable range, the effect of suppressing protein adsorption can be enhanced, and blood compatibility is excellent.

  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 20% by mass or more and 70% by mass or less dimethylacetamide aqueous solution or the like 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 inner diameter of the hollow fiber membrane may generally be 170 μm or more and 250 μm or less, preferably 180 μm or more and 220 μm or less in blood treatment applications. From the viewpoint of the efficiency of diffusion removal of low molecular weight substances by mass transfer resistance as a permeable membrane, the thickness of the hollow fiber membrane is preferably 50 μm or less. Moreover, it is preferable that it is 10 micrometers or more from a viewpoint of intensity | strength.

The film-forming spinning solution discharged from the spinneret together with the hollow inner liquid travels through the air gap and is introduced into a coagulation bath mainly composed of water installed at the lower part of the spinneret. Complete. At this time, it is preferable that the draft represented by the ratio between the film-spinning stock solution discharge linear velocity and the take-up velocity is 1 or less.
The air gap means a space between the spinneret and the coagulation bath, and the film-forming spinning solution is solidified from the inner surface side by a poor solvent component such as water in the hollow inner liquid discharged simultaneously from the spinneret. Starts. Since the smooth hollow fiber membrane surface is formed at the start of solidification and the hollow fiber membrane structure is stabilized, the draft is preferably 1 or less, more preferably 0.95 or less.

Next, after removing the solvent remaining in the hollow fiber membrane by washing with hot water, etc., after winding the hollow fiber membrane in a wet state, the length and number are adjusted so that the desired membrane area is obtained. The bundle is wrapped in a film such as PE, the hollow fiber membrane bundle is placed in a drying chamber, and heated steam is introduced into the drying chamber and dried.
In order to remove unnecessary polyvinyl pyrrolidone, the washing is preferably performed with hot water at 60 ° C. or higher for 120 seconds or more, and more preferably washed with hot water at 70 ° C. or higher for 150 seconds or longer.
The heated water vapor may be introduced at normal pressure or reduced pressure, but from the viewpoint of shortening the drying time and suppressing thermal decomposition, the reverse temperature (the point at which the evaporation rate becomes equal regardless of humidity) or more, 200 C. or lower is preferable.

<Assembly process>
A blood treatment device is assembled based on the hollow fiber membrane obtained through the above steps. 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 urethane resin. Next, the cured urethane portion is cut so as to form an end 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 loaded and assembled into the shape of a blood processor.

<Step of fixing fat-soluble vitamins>
For the process of immobilizing fat-soluble vitamins on the surface of hollow fiber membranes, basically known methods can be used. Among them, the coating method is a fat having various permeation performances using existing equipment and product lineup. It is excellent in that it can realize soluble substance-immobilized membrane production.

A method for adding a fat-soluble vitamin to the surface of the hollow fiber membrane is a method in which a fat-soluble vitamin is added to the membrane-spinning stock solution during film formation so that the entire hollow fiber membrane contains the fat-soluble vitamin (for example, JP-A-9-66225). No. publication), a method of adding a fat-soluble vitamin to a hollow inner liquid and a surfactant if necessary, and allowing the hollow fiber membrane surface to contain a fat-soluble vitamin (for example, Patent No. 4038583), as a coating method, After assembling the blood treatment device, a fat-soluble vitamin solution is allowed to adhere to the hollow fiber membrane surface by flowing the fat-soluble vitamin solution into the hollow portion on the inner surface side of the hollow fiber membrane (for example, JP-A-2006-296931). Various methods have been disclosed, such as a publication, but any method including other methods may be used.
Among these, the method of adding a fat-soluble vitamin to the membrane-spinning stock solution and the hollow inner solution has the fat-soluble vitamin immobilized on the hollow fiber membrane at the stage of spinning the hollow fiber membrane, but in the coating method, The fat-soluble vitamin may be assembled after the fat-soluble vitamin is immobilized on the formed hollow fiber membrane, or the fat-soluble vitamin can be assembled by passing the coating solution after assembly as a blood processor or during the assembly process. May be fixed.

  In the present embodiment, it is preferable to impart a hydrophilic polymer to the separation functional surface of the hollow fiber membrane. The hydrophilic polymer can be applied to the hollow fiber membrane by the same method as the method of immobilizing the fat-soluble vitamin on the hollow fiber membrane. In this case, the fat-soluble vitamin and the hydrophilic polymer may be imparted to the hollow fiber membrane by different methods, or may be imparted to the hollow fiber membrane by the same method. For example, the same membrane-spinning spinning solution, hollow inner solution And the fat-soluble vitamin and the hydrophilic polymer may be mixed in the coating solution.

<Immobilization process of ketone and / or alcohol having 4 or less carbon atoms to hollow fiber membrane>
A ketone and / or alcohol having 4 or less carbon atoms can be contained in the hollow fiber membrane using the following method.
For example, after assembling a hollow fiber membrane blood treatment device, a method of drying in a steam atmosphere of a ketone having 4 or less carbon atoms and / or alcohol can be mentioned.

<Sterilization process of blood treatment device>
It is preferable to sterilize the blood treatment device. The sterilization method may be any method such as a radiation sterilization method or a steam sterilization method. Since the hollow fiber membrane containing a large amount of fat-soluble vitamins has a risk of causing damage to the hollow fiber membrane due to extreme heating, the radiation sterilization method is more preferable. In the radiation sterilization method, an electron beam, a gamma ray, an X-ray or the like can be used, and any of them may be used. In the case of γ rays or electron beams, the radiation dose is usually 15 kGy or more and 50 kGy or less, preferably 20 kGy or more and 40 kGy or less.

  EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples. The measurement method used in this example is as follows.

<Calculation of the abundance ratio of intermediate water in the water existing on the separation function surface at the time when water content saturation is reached when water is contained in the dry hollow fiber membrane>
The intermediate water abundance ratio was calculated by (1) IR measurement, (2) determination of when water saturation was reached, and (3) data analysis by chemometrics.

(1) IR measurement Time-resolved IR measurement was performed under the conditions described in Table 1. The sampling procedure was as follows. After washing the inner surface with distilled water at 1.5 m ² per 100 mL / min 5 min of the hollow fiber membranes, by the outer surface of the hollow fiber membrane is washed for 2 minutes with 500 mL / min, were primed. The hollow fiber membrane (sample) sampled by disassembling the blood processor after priming was freeze-dried in advance and left in a constant temperature and humidity chamber at a temperature of 23 ° C. and a humidity of 50% for at least 24 hours to reach an equilibrium moisture content. A thing (referred to as “dry state”) was subjected to measurement.
1) KIRIYAMA filter paper (No. 5C, 1 μm retained particles) having a diameter of 40 mmφ was cut into a 1/8 fan shape.
2) The sample was opened with a razor, and the inner surface of the hollow fiber membrane was faced up and placed on a filter paper as shown in FIG.
3) ATR crystal is brought into contact with the separation function surface, and 13-15 μL of distilled water is dropped on the end of the fan-shaped filter paper on the arc side using a microsyringe. Water penetrates into the hollow fiber membrane, and the OH peak is saturated. Time-resolved IR measurement was carried out until the time point.

In the measurement, in order to confirm the contact state between the ATR crystal and the sample, it was confirmed that the strength of the benzene ring (near 1485 cm ⁻¹ ) derived from the polysulfone resin was 0.1 or more.
The time when the OH peak is saturated is the time when the peak intensity derived from the hydroxyl group (3,000 to 3700 cm ⁻¹ ) is no longer observed relative to the peak intensity of the benzene ring (near 1485 cm ⁻¹ ) of the polysulfone resin. is there.

(2) Determination of the point of time when the water saturation was reached The obtained spectrum data was normalized by the strength of the benzene ring (near 1485 cm ⁻¹ ) derived from the polysulfone resin. Set baseline 2700 cm ^-1 and 3800 cm ^-1, was calculated peak area of the hydroxyl group.
Smoothing processing was performed as an average value of 9 points of data including 4 points before and after the time-series hydroxyl group area intensity data. With respect to the data point after the smoothing process, the point at which the average slope (increase rate) of the previous 10 data points including the data point became 0 or less was determined as the time when the water saturation was reached.
Note that if an area increase of 5% or more is recognized between 30 points (6 s) after the point where the slope becomes 0, it is determined that saturation has not been reached, and further data satisfy the above conditions. The point was determined as the point at which water saturation was reached.

(3) Data analysis by chemometrics The basics of the analysis method used the following software and computer using one of the chemometrics methods called altering least square (ALS) method.
Software used for calculation: Mathworks (Natick, MA) MATLAB. R2008a
Computer: Fujitsu FMV LIFEBOOK
A specific procedure will be described below.
Intensity for each wave number from the spectrum measured every 0.2 seconds until 1550～1800Cm ^-1 and 2700~3800cm ^-1 (3.858cm each ^-1, the total 351 points) is stored into the line, 0.2 seconds The experimental spectrum matrix A was created by arranging the measured spectra for each column in a column. An example is shown in FIG.
Next, the spectrum matrix A is divided into three types of antifreeze water (in the present embodiment, the hydrogen bond region is detected spectroscopically, so described as “bound water” below), intermediate water, and free water. Decomposition was performed into four components (pure spectrum matrix K) composed of chemical components and difference spectra, and a concentration matrix C corresponding to each. At that time, the matrix was limited so that the decomposition could be achieved uniquely. In the ALS method, spectral decomposition was performed by subjecting a non-negative condition that a pure spectrum and a concentration matrix had absolutely no negative elements. This is based on the basis that the absorption spectrum and concentration cannot be negative. When a negative value appears in the process of the compromise solution calculation, it is forcibly replaced with zero and the regression calculation is repeated, and the spectral solution, C and K are converged by converging so that all matrix elements satisfy the non-negative condition. Asked.
A = CK Formula (1)
The first measurement spectrum A _1, the second measurement spectrum A _2, the spectrum of the time t from ... measurement start represents a A _t, bound water, intermediate water, K ₁ free water and the difference spectrum, Set K ₂ , K ₃ , and K ₄ (it is unknown which component is K ₁ , K ₂ , K ₃ , or K ₄ at this point), and the concentration ratio of the four components at time t from the start of measurement. If C _1t , C _2t , C _3t , and C _4t are set, the calculation formula (1) can be expressed as the following calculation formula (2).

Random numbers are generated in the matrix C of Equation (2), and the spectra K ₁ , K ₂ , K ₃ , and K ₄ are obtained after substituting 0 for negative values based on the non-negative condition that the concentration does not become negative. It was. Next, since there is a non-negative condition that the spectrum does not become negative, a component having a negative value in the spectrum K is replaced with 0, and C is obtained. Furthermore, K was determined from this C under non-negative conditions. This operation was repeated until all the components of K and C became 0 or more, and a solution was obtained.
From the obtained K and C, the difference spectrum is the one where the concentration is almost zero, and among the other three spectra, it has a large peak at 1550 to 1800 cm ⁻¹ , and 3100 to 3500 cm ^−. binding those have little peak at ¹ water, 3400 cm ^-1 intermediate water one having a peak near, were assigned free water broad peak with a peak at 3200,3400cm ^-1.
Subtract the difference spectrum from C _1t , C _2t , C _3t , and C _4t for 6 seconds (30 measurement points) from the saturation arrival point, and calculate the concentration ratio again. The average value of the concentration was calculated, and the abundance ratio of the intermediate water was determined.

<Measurement of moisture content>
About 1 g of the hollow fiber membrane (sample) sampled by disassembling the blood treatment device without pretreatment such as priming was sampled and accurately weighed. Then, after vacuum-drying at 60 degreeC x 12 hr, it measured, and the moisture content was computed by making a weight loss part into a water | moisture content. When the mass before drying is W ₁ and the mass after drying is W ₂ , the moisture content W (%) is expressed by the following calculation formula (5).

<Amount of fat-soluble vitamin present on the surface of the hollow fiber membrane>
The blood treatment device was disassembled, a hollow fiber membrane was collected, washed with water, and then vacuum dried at 40 ° C. The hollow fiber membrane is weighed in a glass bottle so that the area of the hollow fiber membrane surface after drying is 0.2 m ^2, and 80 mL of 1% by weight Triton X-100 (Kishida Chemical, Chemical) aqueous solution is added at room temperature. Extraction of fat-soluble vitamins 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. That is, the fat-soluble vitamin amount is a value that can be obtained as an average value of the hollow fiber membranes where the area of the hollow fiber membrane surface is 0.2 m ² .
A high-performance liquid chromatograph (pump: JASCO PU-1580, detector: Shimadzu RID-6A, autoinjector: Shimadzu SIL-6B, data processing: Tosoh GPC-8020, column oven: GL Sciences 556), column (Shodex Asahipak) ODP-506E packed column for HPLC) was attached, and at a column temperature of 40 ° C., high-performance liquid chromatography methanol as a mobile phase was passed at a flow rate of 1 mL / min, and the fat-soluble vitamin concentration was determined from the absorption peak area in the ultraviolet region. Asked. From this concentration, the amount of fat-soluble vitamin (mg / m ² ) present on the surface of the hollow fiber membrane was determined with an extraction efficiency of 100%.
The amount of fat-soluble vitamin partially oxidized by sterilization was also included in the amount of fat-soluble vitamin per 1 m ^{2 of the} hollow fiber membrane surface. In order to determine the amount of fat-soluble vitamin partially oxidized by sterilization treatment, the fat-soluble vitamin used for preparing the calibration curve is irradiated in advance with 50 kGy radiation in the air, the absorption peak of the partially oxidized fat-soluble vitamin is determined in advance, and the area is calculated It was included in the peak group used for and added.

<Measurement of hydrophilic polymer concentration>
A hollow fiber membrane was collected from the blood treatment device, cut open along the fiber axis to expose the separation function surface, and the concentration of the hydrophilic polymer on the separation function surface was measured by X-ray photoelectron spectroscopy under the following conditions.
Measuring device: Thermo Fisher ESCALAB250
Excitation source: Monochromatic AlKα 15 kV × 10 mA
Analysis size: Elliptical photoemission angle of major axis of about 1 mm: 0 ° (spectrometer axis is perpendicular to sample surface)
Capture area Survey scan: 0 to 1,100 eV
Narrow scan: C1s, O1s, N1s, S2p, Na1s
Pass Energy
Survey scan: 100 eV
Narrow scan: 20 eV
The concentration of the hydrophilic polymer on the separation function surface does not contain sulfur or nitrogen in the case of polyhydroxyalkyl methacrylate. Therefore, the amount of carbon and oxygen derived from the amount of polysulfone resin is calculated from the amount of sulfur, and the amount of polyvinyl pyrrolidone derived from the amount of nitrogen. The amounts of carbon and oxygen were calculated, and the difference carbon and oxygen amounts were derived from the polymer and converted to mass concentration. In the case of sodium salt of polysaccharide, the amount of polysaccharide was calculated from the amount of sodium, the amount of nitrogen and sulfur was calculated according to the structure, and the amount of polyvinylpyrrolidone and polysulfone resin was calculated from the difference nitrogen and sulfur. In X-ray photoelectron spectroscopy, hydrogen was not detected and was excluded from the calculation. The carbon amount, oxygen amount, nitrogen amount, sulfur amount, and sodium amount are the relative sensitivity coefficients of each element (C1s: 1.00, O1s: 2.72, N1s: C1s, O1s, N1s, S2p, Na1s). 1.68, S2p: 1.98, Na1s: 10.2) and measured as a relative amount (atomic%).
The abundance of the hydrophilic polymer on the separation functional surface was determined as (mass concentration of hydrophilic polymer on separation functional surface) / (mass concentration of polyvinylpyrrolidone on molecular functional surface).

<Measurement of ketones and / or alcohols having 4 or less carbon atoms>
The content of ketone and / or alcohol having 4 or less carbon atoms contained in the hollow fiber membrane per 1 g of the hollow fiber membrane was measured by the following method.
Disassemble the blood processor and vacuum dry until constant weight is achieved. Thereafter, the hollow fiber membrane is taken out. After this mass was precisely weighed (Wg), N-methyl-2-pyrrolidone was added, stirred and dissolved, and then the concentration y (%) of ketone and / or alcohol having 4 or less carbon atoms was measured by gas chromatography (GC). Was calculated.
Subsequently, the mass per 1 g of the hollow fiber membrane was calculated from W and y.

<Measurement of lactate dehydrogenase (LDH) activity>
The blood compatibility of the hollow fiber membrane was evaluated by the adhesion of platelets to the membrane surface, and quantified using the activity of lactate dehydrogenase contained in the platelets attached to the membrane as an index.
After washing the inner surface of the hollow fiber membrane with physiological saline (Otsuka raw food injection, Otsuka Pharmaceutical Co., Ltd.) for 5 minutes with distilled water at 100 mL / min per 1.5 m ² , the outer surface of the hollow fiber membrane is 2 at 500 mL / min. Priming was performed by washing for minutes. A hollow fiber membrane collected by disassembling the blood processor after priming was processed with an epoxy resin so that the effective length was 15 cm and the membrane area was 5 × 10 ⁻³ m ² to prepare a mini module. The mini-module was washed by flowing 10 mL of physiological saline to the inner surface side of the hollow fiber membrane. Thereafter, 15 mL of heparin-added blood (heparin 1000 IU / L) was circulated at 37 ° C. for 4 hours through the mini-module prepared above at a flow rate of 1.3 mL / min. The inside of the mini module was washed with 10 mL and the outside with 10 mL with physiological saline. Half of the entire hollow fiber membrane having a length of 7 cm was collected from the washed mini-module, and then cut into a Spitz tube for LDH measurement as a measurement sample.
Next, a 0.5% by volume Triton X-100 / PBS solution obtained by dissolving Triton X-100 (Nacalai Tesque Co., Ltd.) in a phosphate buffer solution (PBS) (Wako Pure Chemical Industries, Ltd.) was used as a Spitz tube for LDH measurement. After 0.5 mL was added, ultrasonic treatment was performed for 60 minutes to destroy cells (mainly platelets) adhering to the hollow fiber membrane, and LDH in the cells was extracted. 0.05 mL of this extract was collected, and further reacted with 2.7 mL of 0.6 mM sodium pyruvate solution and 0.3 mL of 1.277 mg / mL nicotinamide adenine dinucleotide (NADH) solution. 0.5 mL was fractionated and the absorbance at 340 nm was measured. The remaining solution was further reacted at 37 ° C. for 1 hour, and then the absorbance at 340 nm was measured, and the decrease in absorbance immediately after the reaction was measured. Similarly, the absorbance of a hollow fiber membrane (blank) not reacted with blood was also measured, and the difference in absorbance was calculated by the following formula (4). In this method, the larger the decrease, the higher the LDH activity, that is, the greater the amount of platelets attached to the membrane surface. In addition, the measurement was performed 3 times and described as an average value.
Δ340 nm = (absorbance immediately after sample reaction−absorbance after 60 minutes of sample) − (absorbance immediately after reaction of blank−absorbance after 60 minutes of blank) Formula (4)
As hollow fiber membranes with excellent blood compatibility, those with LDH activity of 40 (Δabs / hr · m ² ) or less are judged as having good blood compatibility, and exceed 40 (Δabs / hr · m ² ). The product was judged to be poor in blood compatibility and was evaluated as x.

<Measurement of antioxidant performance of blood treatment device>
Ferric chloride hexahydrate was dissolved in pure water to prepare an aqueous solution of 0.3 w / v% (amount of solute in 100 mL of solution (g)). Next, the blood treatment device was disassembled, a hollow fiber membrane was collected, washed with water, and then vacuum-dried at 40 ° C. 1 g of the hollow fiber membrane after drying and 20 mL of ferric chloride aqueous solution were weighed in a glass bottle, degassed for 10 minutes at 60 mmHg, and then incubated at 30 ° C. for 4 hours under shaking (exists on the surface of the hollow fiber membrane). Fat-soluble vitamins reduce iron (III) ions to produce iron (II).) The incubated aqueous solution was mixed with 2.6 mL of ethanol, 0.7 mL of ethanol, and 0.7 mL of a separately prepared 0.5 w / v% 2,2′-bipyridylethanol aqueous solution, and incubated at 30 ° C. for 30 minutes under shaking ( Iron (II) and bipyridyl form a complex and color). The absorbance at 520 nm of the colored liquid was measured using a spectrometer.
Using a fat-soluble vitamin ethanol solution with a known concentration instead of the hollow fiber membrane, the same incubation, color reaction, and absorbance measurement were performed to create a calibration curve, and the anti-fiber surface surface 1 m ² was expressed. Oxidation performance was determined as the mass equivalent value of fat-soluble vitamins (rounded to the first decimal place).
The case where the mass equivalent value of the fat-soluble vitamin per 1 m ^{2 of the} hollow fiber membrane is 10 (mg / m ² ) or more is judged to be good antioxidant performance, and ○ is less than 10 (mg / m ² ) The case was judged to be poor in antioxidation performance and was evaluated as x.

<Measurement of antioxidation performance stability of blood treatment device>
The following method evaluated the prevention effect of the fall of antioxidant performance when preserve | saved in a severe environment. The antioxidant performance of each of the blood treatment device immediately after production and the blood treatment device stored in a 60 ° C. constant temperature bath for 6 days was measured by the following method.
Moreover, the antioxidant performance stability by 60 degreeC heating was computed by the following formula (5) using the measured value of the antioxidant performance.
Antioxidant performance stability (%) = (Antioxidant performance of heat-treated product at 60 ° C.) / (Antioxidant performance of product immediately after production) × 100 Formula (5)
When the antioxidant performance stability calculated by the calculation formula (5) is 70 (%) or more, the stability is evaluated as good, and when it is less than 70 (%), the stability is evaluated as not good. X.

<Measurement of nitrate ion concentration eluted from the inner surface>
The hollow fiber membrane sampled by disassembling the blood treatment device without pretreatment such as priming is processed with epoxy resin so that the effective length is 15 cm and the membrane area is 12.2 × 10 ⁻³ m ^2. Created. To this mini module, 37 ° C. distilled water for injection (Otsuka Pharmaceutical) was set at a rate of 3 mL / min so that the flow direction was from top to bottom, and flowed to the inner surface side of the hollow fiber membrane, 5 ml of the liquid that emerged was sampled into PS transparent pitch (sterilized: ASONE Co., Ltd. code: 2-466-01). The nitrate ion concentration in this solution was quantified by ion chromatography under the conditions described in Table 2.

According to Non-patent Document 2, the NOAEL as nitrate nitrogen (NOAEL) is 1.5 mg / kg body weight / day, but this is ingestion, and the safety factor is 1000 times. Assuming that dialysis is performed three times a week, the allowable amount per dialysis is 0.21 mg / session. When a blood treatment device having a membrane area of 2.5 m ² is used, the allowable concentration of nitrate ion concentration in this measurement is calculated to be 0.21 ppm. In the case where the nitrate ion concentration was 0.21 ppm or less, it was rated as ◯, and in the case where it exceeded 0.21 ppm, it was marked as x.

<Measurement of water permeability of blood treatment device>
The hollow fiber membrane type blood treatment device produced in the examples and comparative examples was completely filtered with pure water in the blood treatment device under the conditions of constant pressure (200 mmHg) and temperature (37 ° C.), and the time required for filtration was reduced. It was measured. From this result, water permeation performance (UFR (mL / hr · mmHg)) was calculated.
Measure three or more hollow fiber membrane blood treatment devices, average the square of the difference (deviation) from the average value, and take the standard deviation (variation σ) (to show this in the same dimension as the variable) ) When the calculated water permeability is 60 (UFR (mL / hr · mmHg)) or more, the stability is evaluated as good, and ○, and when it is less than 60 (UFR (mL / hr · mmHg)), the stability Was evaluated as x when it was not good.
Further, regarding the water permeability performance variation, when it is 2.0 or more, it is evaluated that the performance variation within the same group is not large and good, and x is less than 2.0, and the performance variation within the same group is small and good. It evaluated and set as (circle).

[Example 1]
As a membrane-spinning stock solution, 17.5% by mass of polysulfone (Solvay P-1700 solubility parameter δ 9.90) and 3.5% by mass of polyvinylpyrrolidone (BASF K90) were mixed with N, N-dimethylacetamide. It dissolved in 79.0 mass% and it was set as the uniform solution. The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-spinning stock solution was 20% by mass. This membrane-spinning stock solution was kept at 60 ° C., and discharged from a double annular nozzle together with a hollow inner solution composed of a mixed solution of 58.1% by mass of N, N-dimethylacetamide and 41.9% by mass of water. It was passed through a 96 m air gap, immersed in a coagulation bath made of 75 ° C. water, and wound up at 80 m / min. After cutting the wound yarn bundle, the remaining solvent in the film is removed by washing with a hot water shower at 80 ° C. for 2 hours from above the cut surface of the bundle, and the film is further placed in a drying chamber. Was heated and dried to obtain a dry film having a water content of less than 1%.
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 35 μm and the inner diameter was 185 μm.
Next, the dried membrane is bundled so that the effective membrane area when assembled into a module is 1.5 m ² , and after packaging in PE film, it has two nozzles for introducing and discharging liquid. After filling the cylindrical container and embedding both ends with urethane resin, the cured urethane portion was cut and processed into the end where the hollow fiber membrane was opened. A header cap having a blood introduction (lead-out) nozzle was loaded at both ends, and assembled into a blood treatment device having an effective membrane area of 1.5 m ² .
Next, a coating solution in which 0.11% by mass of α-tocopherol (special grade of Wako Pure Chemical Industries, Ltd.) is dissolved in an aqueous solution of 57% by mass of isopropanol is applied to the hollow fiber membrane from the blood introduction nozzle of the blood treatment device at a temperature of 24 ° C. The liquid was passed through the inner surface side for 1 minute to contact α-tocopherol. Thereafter, the remaining liquid in the inner space was removed by air flushing, and then the α-tocopherol was immobilized by ventilating dry air at 24 ° C. in an isopropanol atmosphere for 30 minutes to remove the solvent by drying.
Gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.

[Example 2]
The membrane spinning solution is 79% by mass of dimethylacetamide (Kishida Chemical Co., Ltd., reagent grade), 17% by mass of polysulfone (Solvay, P-1700) and 4% by mass of polyvinylpyrrolidone (BASF, K-90). It was made by dissolving. The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-spinning stock solution was 24% by mass.
The hollow inner liquid was prepared by dissolving polyhydroxypropyl methacrylate (Aldrich, weight average molecular weight 330,000, solubility less than 0.1 g) in a dimethylacetamide 60 mass% aqueous solution so as to be 0.1 mass%.
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. The spinning speed was 30 m / min.
After coagulation, washing with water, bundling so that the effective membrane area when assembled into a module is 1.5 m ² , packaging in PE film, placing in a drying room, introducing 180 ° C heated steam and drying Thus, a hollow fiber membrane was obtained. The washing temperature was 90 ° C. and the washing time was 180 seconds.
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 35 μm and the inner diameter was 185 μm.
Next, a coating solution obtained by dissolving 0.64% by mass of α-tocopherol (special grade of Wako Pure Chemical Industries, Ltd.) in an aqueous solution of 57% by mass of acetone is applied to the hollow fiber membrane from the blood introduction nozzle of the blood treatment device at a temperature of 24 ° C. The liquid was passed through the inner surface side for 1 minute to contact α-tocopherol. Thereafter, air flushing was performed to remove the remaining liquid in the hollow portion, and then the α-tocopherol was immobilized by ventilating dry air at 24 ° C. in an acetone atmosphere for 30 minutes to dry remove the solvent.
A module having an effective membrane area of 1.5 m ² was assembled from the obtained hollow fiber membrane, and electron beam sterilization was performed at 20 kGy in an air atmosphere to obtain a blood treatment device.

[Example 3]
The membrane spinning solution is 79% by mass of dimethylacetamide (Kishida Chemical Co., Ltd., reagent grade), 17% by mass of polysulfone (Solvay, P-1700) and 4% by mass of polyvinylpyrrolidone (BASF, K-90). It was made by dissolving. The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-spinning stock solution was 24% by mass.
As the hollow inner liquid, a 60% by mass 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. The spinning speed was 30 m / min.
After solidification, it is washed with water, bundled so that the effective membrane area when assembled in a module is 1.5 m ² , wrapped in PE film, put into a drying room, heated steam at 180 ° C. is introduced and dried To obtain a hollow fiber membrane. The washing temperature was 90 ° C. and the washing time was 180 seconds.
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 35 μm and the inner diameter was 185 μm.
Next, a coating solution in which 3.2% by mass of α-tocopherol (special grade of Wako Pure Chemical Industries) was dissolved in an aqueous solution of 57% by mass of isopropanol was applied to the hollow fiber membrane from the blood introduction nozzle of the blood treatment device at a temperature of 24 ° C. The liquid was passed through the inner surface side for 1 minute to contact α-tocopherol. Thereafter, air flushing was performed to remove the remaining liquid in the hollow portion, and then the α-tocopherol was immobilized by ventilating dry air at 24 ° C. in an isopropanol atmosphere for 30 minutes to remove the solvent by drying.
A module having an effective membrane area of 1.5 m ² was assembled from the obtained hollow fiber membrane, and γ-ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.

[Example 4]
As a membrane-spinning stock solution, 17% by mass of polysulfone (Solvay P-1700 solubility parameter δ 9.90), 4% by mass of polyvinylpyrrolidone (BASF, K-90), α-tocopherol (Wako Pure Chemical Industries, Ltd.) (Special grade) 0.6% by mass was dissolved in 78.4% by mass of N, N-dimethylacetamide. The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-spinning stock solution was 24% by mass.
The hollow inner liquid was prepared by dissolving polyhydroxypropyl methacrylate (Aldrich, weight average molecular weight 330,000, solubility less than 0.1 g) in a 60% by mass aqueous solution of dimethylacetamide to 0.1% by mass.
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. The spinning speed was 30 m / min.
After coagulation, it was washed with water, introduced into a dryer, dried at 120 ° C. for 2 minutes, and further subjected to heat treatment at 160 ° C. for 0.5 minutes, and then wound with a polysulfone-based hollow fiber membrane to which crimps were applied. . They were bundled so that the effective membrane area when assembled into a module was 1.5 m ² and packaged in PE film.
In addition, the discharge amount of the spinning solution and the hollow inner solution was adjusted so that the film thickness after drying was 45 μm and the inner diameter was 185 μm.
A module having an effective membrane area of 1.5 m ² was assembled from the obtained hollow fiber membrane, and γ-ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.

[Example 5]
As a membrane spinning solution, 79% by mass of dimethylacetamide (Kishida Chemical Co., Ltd., reagent grade), 17% by mass of polysulfone (Solvay, P-1700), 4% by mass of polyvinyl pyrrolidone (BASF, K-90) It was made by dissolving. The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-spinning stock solution was 24% by mass.
The hollow inner liquid was prepared by dissolving polyhydroxypropyl methacrylate (Aldrich, weight average molecular weight 330,000, solubility less than 0.1 g) in a dimethylacetamide 60 mass% aqueous solution so as to be 0.1 mass%.
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. The spinning speed was 30 m / min.
After coagulation, washing with water, bundling so that the effective membrane area when assembled into a module is 1.5 m ² , packaging in PE film, placing in a drying room, introducing 180 ° C heated steam and drying Thus, a hollow fiber membrane was obtained. The washing temperature was 90 ° C. and the washing time was 180 seconds.
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 35 μm and the inner diameter was 185 μm.
Next, a coating solution obtained by dissolving 0.64% by mass of α-tocopherol (special grade of Wako Pure Chemical Industries, Ltd.) in an aqueous solution of 57% by mass of tetrahydrofuran is subjected to a hollow fiber membrane from a blood introduction nozzle of a blood treatment device at a temperature of 24 ° C. The liquid was passed through the inner surface side for 1 minute to contact α-tocopherol. Thereafter, the remaining liquid in the hollow portion was removed by air flushing, and then the α-tocopherol was immobilized by ventilating dry air at 24 ° C. in a tetrahydrofuran atmosphere for 30 minutes to dryly remove the solvent.
A module having an effective membrane area of 1.5 m ² was assembled from the obtained hollow fiber membrane, and electron beam sterilization was performed at 20 kGy in an air atmosphere to obtain a blood treatment device.

[Comparative Example 1]
The membrane spinning solution is 79% by mass of dimethylacetamide (Kishida Chemical Co., Ltd., reagent grade), 17% by mass of polysulfone (Solvay, P-1700) and 4% by mass of polyvinylpyrrolidone (BASF, K-90). It was made by dissolving. The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-spinning stock solution was 24% by mass.
As the hollow inner liquid, a 60% by mass 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. The spinning speed was 30 m / min.
After coagulation, followed by washing with water, and the flux so that the effective membrane area is 1.5 m ² when assembled into modules, after packaged in PE film, placed in a drying chamber, introducing a 180 ° C. heating steam drying To obtain a hollow fiber membrane. The washing temperature was 90 ° C. and the washing time was 180 seconds.
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 35 μm and the inner diameter was 185 μm.
A module having an effective membrane area of 1.5 m ² was assembled from the obtained hollow fiber membrane, and γ-ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.

[Comparative Example 2]
As the spinning dope, 17% by mass of polysulfone (Solvay P-1700 solubility parameter δ 9.90) and 4% by mass of polyvinylpyrrolidone (BASF, K-90), α-tocopherol (special grade of Wako Pure Chemical Industries) It was prepared by dissolving 1.9% by mass in 77.1% by mass of N, N-dimethylacetamide. The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane-spinning stock solution was 24% by mass.
A 42% by mass aqueous solution of dimethylacetamide was used as the hollow inner liquid.
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. The spinning speed was 30 m / min.
After coagulation, it was washed with water, introduced into a dryer, dried at 120 ° C. for 2 minutes, and further subjected to heat treatment at 160 ° C. for 0.5 minutes, and then wound with a polysulfone-based hollow fiber membrane to which crimps were applied. . They were bundled so that the effective membrane area when assembled into a module was 1.5 m ² and packaged in PE film.
In addition, the discharge amount of the spinning solution and the hollow inner solution was adjusted so that the film thickness after drying was 45 μm and the inner diameter was 185 μm.
A module having an effective membrane area of 1.5 m ² was assembled from the obtained hollow fiber membrane, and γ-ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.

Table 3 shows the measurement results of the blood processing devices obtained in Examples and Comparative Examples.

  According to the present invention, it is possible to provide a hollow fiber membrane for blood treatment that has good blood compatibility and stable antioxidant performance, and has a small nitrate ion elution amount. The blood processing apparatus of the present invention has industrial applicability in blood purification therapy.

Claims (6)

A hollow fiber membrane for blood treatment comprising at least a polysulfone resin and polyvinylpyrrolidone,
Containing 10 mg / m ² or more and 300 mg / m ² or less of fat-soluble vitamin on the surface of the hollow fiber membrane,
When the dry hollow fiber membrane is hydrated, the abundance of intermediate water in the water present on the surface of the separation function at the time of reaching the water saturation is 20% or more,
The moisture content is 10% or less,
A hollow fiber membrane for blood treatment, wherein the hollow fiber membrane is radiation sterilized.   The hollow fiber membrane for blood treatment according to claim 1, comprising a hydrophilic polymer on at least a separation function surface.   The hollow fiber membrane for blood treatment according to claim 2, wherein the hydrophilic polymer is at least one selected from the group consisting of polyhydroxyalkyl methacrylates and sodium salts of polysaccharides.   The hollow fiber membrane for blood treatment according to any one of claims 1 to 3, wherein the hollow fiber membrane comprises a ketone and / or alcohol having 2 to 3000 µg and having 4 or less carbon atoms.   The hollow fiber membrane for blood treatment according to any one of claims 1 to 4, which has been radiation sterilized with an irradiation dose of 15 kGy or more and 50 kGy or less.   The blood processing device incorporating the hollow fiber membrane for blood processing according to any one of claims 1 to 5.