Hollow fiber membrane blood purifier

Abstract

A hollow fiber membrane-type blood purifier that comprises a hollow fiber membrane and a container in which the hollow fiber membrane is filled, wherein: the hollow fiber membrane contains a fat-soluble substance; the acetic acid content per hollow fiber membrane area contained in the blood purifier is 1-40 mg / m2; the water permeability is 163 mL / Hr / mmHg / m2 or more; and the hollow fiber elongation is 55% or more.

Description

[Technical Field]

[0001] The present invention relates to a hollow fiber membrane type blood purifier. [Background technology]

[0002] BACKGROUND ART Hollow fiber membrane blood processing devices using selectively permeable membranes have been widely used in the field of extracorporeal blood circulation, for example, in hemodialysis, oxygenation of blood during open-heart surgery, and plasma separation.

[0003] BACKGROUND ART In recent years, blood treatment membranes made of polysulfone resins have been widely used, particularly in the field of blood treatment membranes such as dialysis membranes, gas exchange membranes, and blood component separation membranes.

[0004] If only highly hydrophobic polysulfone resins are used as the constituent material of the blood treatment membrane, sufficient blood compatibility cannot be obtained, so complexes with hydrophilic polymers such as polyvinylpyrrolidone are generally used.

[0005] Furthermore, attempts are being made to develop blood processing membranes that not only function as separation membranes but also serve to alleviate the oxidative stress that manifests in long-term dialysis patients.

[0006] For example, it is conceivable to use separation membranes to eliminate peroxides, which are substances that cause oxidative stress, or to restore the antioxidant effect of the body.Specifically, a hollow fiber membrane-type blood purification device has been proposed in which the surface of the dialysis membrane is coated with vitamin E, which has various physiological effects such as antioxidant activity in the body, stabilizing biomembranes, and inhibiting platelet aggregation.

[0007] Considering the intended use of the hollow fiber membrane blood purification device, it is necessary to completely sterilize the device while it is still in its sealed package before use.

[0008] Conventionally, known methods for sterilizing hollow fiber membrane blood purification devices include gas sterilization using ethylene oxide gas or the like, autoclave sterilization using high-pressure steam, and radiation sterilization using gamma rays, electron beams, or the like.

[0009] Among these, gas sterilization using ethylene oxide gas raises concerns about the harmful effects of residual ethylene oxide gas on the human body, while autoclave sterilization using high-pressure steam may significantly reduce the performance of hollow fiber membrane blood purification devices during sterilization, depending on the material used.

[0010] It has also been pointed out that when a vitamin E-immobilized polysulfone membrane is sterilized using the autoclave method with high-pressure steam, the fat-soluble vitamins undergo local aggregation, causing cracks in the hollow fiber membrane and increasing the possibility of blood leakage (see, for example, Patent Document 1).

[0011] On the other hand, radiation sterilization is a preferred sterilization method because it does not cause the problems of residual ethylene oxide gas or leakage from hollow fiber membranes.

[0012] The hollow fiber membrane blood purification devices described above are broadly classified into a wet type, in which the hollow interior of the hollow fiber membrane and the gap between the hollow fiber membrane and the container are filled with an aqueous medium, and a dry type, in which the hollow interior of the hollow fiber membrane and the gap between the hollow fiber membrane and the container are not filled with an aqueous medium.

[0013] The dry type can be further divided into a type in which the moisture content of the membrane is low, at a few percent or less (narrowly defined dry type), and a type in which the membrane is moderately moistened with water, a moisturizer, etc. The latter is sometimes called a semi-dry type to distinguish it from the narrowly defined dry type, but since the characteristics are almost the same, in this specification both types will be collectively referred to as the dry type.

[0014] The dry type described above is characterized by being lighter in weight than the wet type and being less likely to freeze at low temperatures, and is therefore an excellent product form in terms of distribution, such as transportation and storage.

[0015] However, it is known that when dry-type polysulfone-based blood processing membranes are subjected to radiation sterilization, the hydrophilic polymers that make up the hollow fiber membranes are deteriorated and eluted, resulting in a decrease in blood compatibility.

[0016] In view of these problems, methods have been proposed to prevent a decrease in blood compatibility by sterilizing the hollow fiber membrane with radiation while protecting it with a specific amount of a moistening protective agent (see, for example, Patent Document 1), or by protecting it with a specific amount of a moistening protective agent and then controlling the oxygen concentration around the membrane before sterilizing it with electron beams (see, for example, Patent Document 2).

[0017] However, the above-mentioned methods may cause deterioration of various properties, particularly deterioration of antioxidant performance, when exposed to harsh environments. Furthermore, there is a growing demand for medical devices equipped with blood processing membranes that have an even higher level of blood compatibility.

[0018] In light of this situation, hollow fiber membrane-type blood purification devices with even better antioxidant properties and blood compatibility have been proposed in recent years. For example, Patent Document 3 proposes a hollow fiber membrane-type blood purification device equipped with a hollow fiber membrane containing a polysulfone resin, a hydrophilic polymer, and a fat-soluble vitamin, in which the amount of the fat-soluble vitamin present on the surface of the hollow fiber membrane is 0.5 mg to 25 mg per gram of the hollow fiber membrane, and the hollow fiber membrane has a hydrophilic compound attached to it in an amount of 5% to 50% by mass, including water, based on the dry weight of the hollow fiber membrane, and the device is a dry-type hollow fiber membrane-type blood purification device that has been subjected to radiation sterilization. Furthermore, Patent Document 4 proposes a dry-type hollow fiber membrane-type blood purification device in which the amount of the fat-soluble substance present on the surface of the membrane is 1 m / g. 2 The content of the lipid-soluble substance present on the surface of the membrane is 10 to 300 mg per 1.5 m of the blood purifier assembled using the membrane, and the content of the lipid-soluble substance present on the surface of the membrane is 40 to 95 mass % when the content of the lipid-soluble substance present on the entire membrane is 100 mass %. 2 A polysulfone-based hollow fiber membrane for blood processing has been proposed, which has a calculated β2MG clearance value of 65 mL / min or more. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] Japanese Patent Application Laid-Open No. 2006-296931 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-93228 [Patent Document 3] Japanese Patent Application Laid-Open No. 2013-009761 [Patent Document 4] International Publication No. 2014 / 171172 Summary of the Invention [Problem to be solved by the invention]

[0020] However, conventional hollow fiber membrane blood purifiers have the problem that the immobilization of lipid-soluble substances onto hollow fiber membranes changes hollow fiber performance, particularly the amount of albumin (Alb) leakage, compared to hollow fiber membranes without lipid-soluble substances immobilized thereon, making it difficult to control the amount of leakage. This problem is particularly problematic in clinical hemodiafiltration treatment.

[0021] Hemodiafiltration (HDF) is an effective treatment for dialysis complications, accounting for approximately half of the dialysis treatments used in recent years. To improve and treat dialysis complications, particularly itching, fingertip pinch strength, joint pain, finger numbness, and restless legs syndrome (RLS), it is recommended in clinical treatments to actively remove several grams of Alb. This recommended amount of Alb removal in clinical treatment corresponds to a removal of 1–3 g / h under specified predilution HDF conditions, calculated using the bovine blood test used in designing hollow fiber membranes (hereafter referred to as bovine blood Alb leakage).

[0022] Under the pre-dilution HDF conditions commonly used in Japan (blood flow rate (QB) = 250 mL / min, dialysate flow rate (QD) = 600 mL / min, replacement fluid flow rate (Qs) = 12 L / h), conventional coating technology has not yet been able to produce hemodiafilters with immobilized lipid-soluble substances that are clinically acceptable while achieving a bovine blood Alb leakage rate of 1.5 g or more. This is because the pressure-resistance strength of hollow fiber membranes decreases as water permeability increases. Therefore, hemodiafilters with immobilized lipid-soluble substances that achieve a bovine blood Alb leakage rate of 1.5 g or more are highly susceptible to hollow fiber leakage during clinical use due to the high transmembrane pressure (TMP) applied during HDF. More specifically, hemodiafilters that achieve a bovine blood Alb leakage rate of 1.5 g or more under pre-dilution HDF conditions may have reduced pressure-resistance strength.

[0023] Therefore, the present invention aims to provide a hollow fiber membrane blood purifier containing a lipid-soluble substance, which has a pressure resistance strength of 55% or more in hollow fiber elongation and a bovine blood Alb leakage of 1 to 3 g per hour under pre-dilution HDF conditions, thereby achieving both high pressure resistance and excellent substance permeability suitable for HDF clinical treatment. [Means for solving the problem]

[0024] As a result of intensive research conducted by the present inventors to solve the above problems, they discovered that in a hollow fiber membrane blood purifier containing a lipid-soluble substance, by controlling the amount of acetic acid contained in the blood purifier per area of ​​the hollow fiber membrane within a specific range, the lipid-soluble substance-immobilized hollow fiber membrane combines high pressure resistance with high water permeability, which is the basis for excellent substance permeability suitable for HDF clinical treatment, and that the amount of bovine blood Alb leakage under pre-dilution HDF conditions can be controlled to 1 to 3 g per hour, leading to the completion of the present invention.

[0025] That is, the present invention is as follows. [1] A hollow fiber blood purifier comprising a hollow fiber membrane and a container in which the hollow fiber membrane is packed, the hollow fiber membrane contains a fat-soluble substance, The amount of acetic acid per area of ​​the hollow fiber membrane contained in the blood purifier is 1 to 40 mg / m 2 and Water permeability is 163mL / Hr / mmHg / m 2 or more, and the hollow fiber elongation is 55% or more. [2] The hollow fiber membrane blood purifier according to [1], wherein the fat-soluble substance comprises at least one selected from the group consisting of vitamin A, vitamin D, vitamin E, and vitamin K. [3] The hollow fiber membrane type blood purifier according to [1] or [2], wherein the hollow fiber membrane is a hollow fiber membrane to which a fat-soluble substance is immobilized. [4] The hollow fiber membrane type blood purifier according to [1] or [2], wherein the hollow fiber membrane is a hollow fiber membrane to which a fat-soluble vitamin is immobilized. [5] The amount of acetic acid contained in the blood purifier per area of ​​the hollow fiber membrane is 1 to 30 mg / m 2 The hollow fiber membrane blood purifier according to any one of [1] to [4], [6] Permeability is 163 to 350 mL / Hr / mmHg / m 2 The hollow fiber membrane blood purifier according to any one of [1] to [5], [7] The hollow fiber membrane blood purifier according to any one of [1] to [6], wherein the hollow fiber elongation is 61 to 80%. [8] The amount of fat-soluble substance immobilized in the hollow fiber membrane is 1 to 500 mg / m 2 The hollow fiber membrane blood purifier according to any one of [1] to [7], [9] The hollow fiber membrane type blood purifier according to any one of [1] to [8], wherein the material constituting the hollow fiber membrane includes at least one selected from the group consisting of hydrophilic polymers and hydrophobic polymers.

[10] The hollow fiber membrane type blood purifier according to any one of [1] to [9], wherein the inner diameter of the hollow fiber membrane is 170 μm or more and 250 μm or less.

[11] The hollow fiber membrane type blood purifier according to any one of [1] to

[10] , wherein the membrane thickness of the hollow fiber membrane is 10 μm or more and 50 μm or less.

[12] The method includes a step of immobilizing a fat-soluble substance on a hollow fiber membrane, The method for producing a hollow fiber membrane blood purifier according to any one of [1] to

[11] , wherein in the fixing step, a coating liquid in which a fat-soluble substance is dissolved in an organic solvent is sent to the inside of the hollow fiber, and when the coating liquid is removed by compressed air, the pressure difference between the inside and outside of the hollow fiber (inside - outside) is -0.1 MPa or more.

[13] The method for producing a hollow fiber membrane blood purifier according to

[12] , wherein in the fixing step, after the coating liquid is removed, the hollow fiber membrane is dried with oxygen-containing air at 40 to 60°C.

[14] The method for producing a hollow fiber membrane blood purifier according to

[12] or

[13] , further comprising a step of wetting the hollow fiber membrane.

[15] The method for producing a hollow fiber membrane blood purifier according to any one of

[12] to

[14] , further comprising a step of sterilizing the hollow fiber membrane blood purifier. [Effects of the Invention]

[0026] The hollow fiber membrane blood purifier of the present invention uses a lipid-soluble substance-immobilized hollow fiber membrane that combines high pressure resistance with high water permeability, which is the basis for excellent substance permeability suitable for HDF clinical treatment.The lipid-soluble substance-immobilized hollow fiber membrane can control the amount of bovine blood Alb leakage to 1 to 3 g per hour under pre-dilution HDF conditions, and can provide a hollow fiber membrane blood purifier with immobilized lipid-soluble substances, which has long been desired in HDF clinical treatment. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 is a conceptual diagram of an example of a device used to measure the amount of acetic acid contained in a dry-type hollow fiber membrane blood purifier. [Figure 2] FIG. 1 is a conceptual diagram of an example of a circuit through which water is passed as priming when measuring the water permeability of a hollow fiber membrane blood purifier. [Figure 3]FIG. 1 is a conceptual diagram of an example of a circuit used when measuring the water permeability of a hollow fiber membrane blood purifier. DETAILED DESCRIPTION OF THE INVENTION

[0028] Hereinafter, a mode for carrying out the present invention (hereinafter referred to as "the present embodiment") will be described in detail. Note that the present invention is not limited to the following embodiment, and various modifications can be made within the scope of the gist thereof.

[0029] <Hollow fiber membrane type blood purifier> The hollow fiber membrane blood purifier of this embodiment is A hollow fiber blood purifier comprising a hollow fiber membrane and a container in which the hollow fiber membrane is packed, the hollow fiber membrane contains a fat-soluble substance, The amount of acetic acid per area of ​​the hollow fiber membrane contained in the blood purifier is 1 to 40 mg / m 2 and Water permeability is 163mL / Hr / mmHg / m 2 That's all, The hollow fiber elongation is 55% or more. By adopting such a configuration, the hollow fiber membrane blood purifier of this embodiment, even if it contains a lipid-soluble substance, can maintain a pressure resistance strength with a hollow fiber elongation of 55% or more, and can reduce the bovine blood Alb leakage amount to 1 to 3 g per hour under pre-dilution HDF conditions.

[0030] <Amount of acetic acid> The hollow fiber membrane blood purifier of this embodiment has an acetic acid content of 1 to 40 mg / m per hollow fiber membrane area. 2 and 1 to 30 mg / m 2 and more preferably 1 to 20 mg / m 2 It is more preferable that: In the hollow fiber membrane blood purifier of this embodiment, when the amount of acetic acid per hollow fiber membrane area is within the above range, the bovine blood Alb leakage amount under pre-dilution HDF conditions can be reduced to 1 to 3 g per hour.

[0031] The method for controlling the amount of acetic acid per area of ​​the hollow fiber membrane within the above range is not particularly limited, but may include, for example, a method of carrying out the step of immobilizing a fat-soluble substance described below. In this embodiment, the amount of acetic acid per area of ​​the hollow fiber membrane can be measured by the method described in the Examples below.

[0032] <Water permeability> The hollow fiber membrane blood purifier of this embodiment has a water permeability of 163 mL / Hr / mmHg / m 2 or more, 163 to 350 mL / Hr / mmHg / m 2 Preferably, the blood pressure is 163 to 300 mL / Hr / mmHg / m 2 It is more preferable that: When the hollow fiber membrane blood purifier of this embodiment has water permeability within the above range, the bovine blood Alb leakage under pre-dilution HDF conditions can be reduced to 1 to 3 g per hour.

[0033] The method for controlling the water permeability within the above range is not particularly limited, but examples include a method of carrying out the fat-soluble substance immobilization process described below and a method of appropriately adjusting the type and content of the material constituting the hollow fiber membrane. In this embodiment, the water permeability can be measured by the method described in the examples below.

[0034] The hollow fiber membrane blood purifier of this embodiment is not particularly limited, but can be used for extracorporeal circulation blood purification therapies such as hemodialysis, hemofiltration, hemodiafiltration, blood component fractionation, oxygenation, and plasma separation. The hollow fiber membrane blood purifier of this embodiment is preferably used as a hemodialyzer, a hemofilter, a hemodiafiltration device, etc., and is more preferably used for continuous applications such as a continuous hemodialyzer, a continuous hemofilter, or a continuous hemodiafiltration device. Detailed specifications such as the dimensions and fractionation of the hollow fiber membrane are determined depending on the application. The hollow fiber membrane blood purifier of this embodiment has a pressure resistance strength with a hollow fiber elongation of 55% or more, and can reduce the bovine blood Alb leakage amount under pre-dilution HDF conditions to 1 to 3 g per hour. Therefore, it can be suitably used for improving and treating dialysis complications, particularly itching, finger pinch strength, joint pain, finger numbness, and RLS.

[0035] Removal of substances in the α1-microglobulin (α1-MG) region (molecular weight 30,000–40,000) is believed to be effective in preventing and improving complications associated with dialysis treatment. To prevent and improve symptoms such as itching, finger pinch strength, joint pain, finger numbness, and RLS, an α1-MG removal rate of 10% or more throughout treatment is required. Meanwhile, Alb is a substance whose leakage during dialysis treatment is desired to be suppressed due to its role in osmotic pressure regulation and as a nutrient. However, no blood purifier has been developed to date that removes 10% or more of the α1-MG region alone and completely prevents Alb leakage, based on the molecular weight fraction. Therefore, current dialysis treatments often involve removal of the α1-MG region while allowing a certain amount of Alb leakage (1–3 g).

[0036] On the other hand, it has been pointed out that Alb can be oxidized by oxidative stress and bind to uremic toxins, potentially turning into uremic toxins. Therefore, some believe that a certain amount of Alb should be actively removed to promote Alb metabolism. For these reasons, filtration is the dominant method of substance removal. In recent years, hemodiafiltration equipment capable of maximizing bovine blood Alb leakage of 1 g or more has become mainstream in HDF treatment (pre-dilution HDF conditions), which can efficiently remove uremic toxin proteins. Furthermore, hemodialysis equipment with immobilized lipid-soluble substances (e.g., vitamin E) is widely used in Japan and Europe due to its high biocompatibility and the expected clinical benefits of the antioxidant properties of lipid-soluble substances.

[0037] However, as mentioned above, it is extremely difficult to create a hemodiafilter that can achieve a bovine blood Alb leakage of 1 to 3 g under pre-dilution HDF conditions while immobilizing a lipid-soluble substance using conventional techniques. The present invention makes it possible to provide a hollow fiber membrane blood purifier containing a lipid-soluble substance (e.g., vitamin E) while achieving a bovine blood Alb leakage of 1 to 3 g, which is said to be effective in preventing and improving dialysis complications. Furthermore, by controlling the amount of acetic acid per hollow fiber membrane area contained in the blood purifier within a specific range, it is possible to provide, for example, a vitamin E-immobilized hemodiafilter that can achieve any bovine blood Alb leakage of 1 to 3 g using a hollow fiber membrane with a single performance. In other words, the present invention makes it possible to provide a hollow fiber membrane blood purifier that can, for example, immobilize vitamin E and contribute to the prevention and improvement of a wider range of dialysis complications.

[0038] The hollow fiber membrane used in the hollow fiber membrane blood purifier of this embodiment is preferably crimped from the viewpoint of permeability. The method for crimping is not particularly limited, and known methods can be used.

[0039] <Fat-soluble substances> In the hollow fiber membrane type blood purifier of this embodiment, the hollow fiber membrane contains a fat-soluble substance. In this embodiment, the term "fat-soluble substance" generally refers to a substance that is poorly soluble in water but soluble in alcohol or fats and oils, and low-toxicity natural or synthetic substances can be used. Specific examples of fat-soluble substances include, but are not limited to, cholesterol, vegetable oils such as castor oil, lemon oil, and shea butter, animal oils such as fish oil, fatty acids such as sucrose fatty acid esters and polyglycerin fatty acid esters, isoprenoids, hydrocarbons with a large carbon number, and silicone oil. Fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, vitamin K, and ubiquinone are also preferably used.

[0040] Among these, the fat-soluble substance preferably contains at least one selected from the group consisting of vitamin A, vitamin D, vitamin E, and vitamin K. Among these, vitamin E is preferred from the viewpoint that excessive intake does not induce disorders. The fat-soluble substance may be used alone or in a mixture of two or more.

[0041] Examples of vitamin E include α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, β-tocopherol, γ-tocopherol, δ-tocopherol, and mixtures thereof. Among these, α-tocopherol is preferred because it has excellent physiological effects such as antioxidant activity in the body, stabilizing biomembranes, and inhibiting platelet aggregation, and is highly effective in suppressing oxidative stress.

[0042] The hollow fiber membrane used in this embodiment is preferably a hollow fiber membrane on which a fat-soluble substance is immobilized, and more preferably a hollow fiber membrane on which a fat-soluble vitamin is immobilized.

[0043] The amount of fat-soluble substance immobilized in the hollow fiber membrane is 1 to 500 mg / m 2 and the amount of fat-soluble substance immobilized in the hollow fiber membrane is preferably 1 mg / m 2 By exceeding this limit, sufficient antioxidant performance can be obtained, and the maximum concentration is 500 mg / m 2 Furthermore, the blood compatibility is excellent when the concentration is 10 to 300 mg / m or less. 2 It is more preferable that:

[0044] In this embodiment, the "amount of fat-soluble substance immobilized in the hollow fiber membrane" refers to the amount of fat-soluble substance bound to, attached to, adsorbed to, or coated on the entire hollow fiber membrane, and the amount of fat-soluble substance present in the entire hollow fiber membrane can be quantified, for example, by the amount of fat-soluble substance extracted by a solvent without destroying or dissolving the hollow fiber membrane, as described below.

[0045] An example of a method for measuring the amount of fat-soluble substances in a hollow fiber membrane will be described. First, a hollow fiber membrane-type blood purifier incorporating hollow fiber membranes is disassembled, and the hollow fiber membranes are collected, washed with water, and then dried. Next, a surfactant or organic solvent capable of dissolving lipid-soluble substances, such as a 1% by weight aqueous solution of polyethylene glycol-t-octylphenyl ether or ethanol, is added to the precisely weighed, dried hollow fiber membranes, and the mixture is stirred and extracted. The membrane area of ​​the extracted hollow fiber membrane is either the hollow fiber membrane area stated by the manufacturer (the hollow fiber membrane area listed on the label, etc.) or the internal surface area calculated from the product of the average inner diameter (diameter), pi, number of hollow fiber membranes, and effective length. The effective length is the length of the hollow fiber membrane that is permeable, excluding urethane sealing sections, etc., within the total length of the hollow fiber membrane.

[0046] The quantitative analysis is carried out, for example, by liquid chromatography, and the concentration of the fat-soluble substance in the extract is calculated using a calibration curve obtained from the peak area of ​​a standard solution of the fat-soluble substance.

[0047] The amount of fat-soluble substance in the hollow fiber membrane (mg / m) was calculated based on the concentration of fat-soluble substance obtained and the membrane area of ​​the extracted hollow fiber membrane, assuming the extraction efficiency to be 100%. 2 ) can be obtained.

[0048] Liquid chromatography is described as an example and can be performed as follows: A column (Shodex Asahipak ODP-506E packed column for HPLC) is attached to 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), and methanol for high-performance liquid chromatography (the mobile phase) is passed through the column at a flow rate of, for example, 1 mL / min at a column temperature of 40°C. The concentration of the fat-soluble substance is determined from the area of ​​the absorption peak at a wavelength of 295 nm using a UV detector.

[0049] <Hydrophilic and hydrophobic polymers> The material constituting the hollow fiber membrane preferably contains at least one selected from the group consisting of hydrophilic polymers and hydrophobic polymers, which tends to result in a membrane with high physical strength and excellent biocompatibility.

[0050] In particular, it is preferable that the hollow fiber membrane contains a hydrophilic polymer at least on the separation function surface, since the hollow fiber membrane containing a hydrophilic polymer tends to have improved biocompatibility.

[0051] The hydrophilic polymer is not particularly limited as long as it is a polymer that is easily compatible with water, but it is also preferable that the solubility parameter δ (cal / cm 3 ) 1 / 2 Examples of such polymers include polymers having a molecular weight of 10 or more and polymers having hydroxyl groups.

[0052] The solubility parameter δ is an index described, for example, in "Polymer Data Handbook Basics," edited by the Society of Polymer Science, Baifukan Co., Ltd., first edition published on January 30, 1986, pages 591-593, where a high solubility parameter indicates strong hydrophilicity, and a low solubility parameter indicates strong hydrophobicity.

[0053] Solubility parameter δ(cal / cm 3 ) 1 / 2 The polymer having a δ of 10 or more is not particularly limited, but examples thereof include polyhydroxyethyl methacrylate (δ=10.00), cellulose diacetate (δ=11.35), polyacrylonitrile (δ=12.35), etc. The values ​​given for δ are given as examples.

[0054] The polymer having a hydroxyl group is not particularly limited, but examples thereof 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 the side chain.

[0055] The hydrophilic polymer is not particularly limited, but examples thereof include polyvinylpyrrolidone (hereinafter also referred to as "PVP"), polyethylene glycol (hereinafter also referred to as "PEG"), polyvinyl alcohol (hereinafter also referred to as "PVA"), polypropylene glycol, etc. These hydrophilic polymers may be used alone or in combination of two or more.

[0056] Among these, the hydrophilic polymer preferably contains at least one selected from the group consisting of polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG).When the hollow fiber membrane contains such a hydrophilic polymer, biocompatibility tends to be improved.

[0057] The hydrophobic polymer is not particularly limited, but examples thereof include polysulfone-based resins such as polysulfone (PS), polyethersulfone (PES), and polyarylethersulfone (PAES); cellulose-based resins such as regenerated cellulose, cellulose acetate, and cellulose triacetate (CTA); and other examples include polyacrylonitrile (PAN), polyvinylidene fluoride (PVDF), polymethyl methacrylate, and ethylene-vinyl alcohol copolymer. Among these, polysulfone-based resins are preferred.

[0058] Polysulfone-based resins are synthetic polymers containing sulfonyl (-SO2-) groups and have excellent heat resistance and chemical resistance. Examples of polysulfone-based resins include, but are not limited to, polyphenylene sulfone, polysulfone, polyaryl ether sulfone, polyether sulfone, and copolymers thereof. Polysulfone-based resins may be used singly or in combination of two or more.

[0059] Among these, polysulfone polymers represented by the following formula (1) or (2) are preferred from the viewpoint of controlling fractionation. (-Ar-SO2-Ar-O-Ar-C(CH3)2-Ar-O-) n (1) (-Ar-SO2-Ar-O-) n (2) In formulas (1) and (2), Ar represents a benzene ring, and n represents a repeating monomer unit. Polysulfone represented by formula (1) is commercially available, for example, from Solvay under the name "Udel (trademark)" and from BASF under the name "Ultrason (trademark)." Polyethersulfone represented by formula (2) is commercially available from Sumitomo Chemical Co., Ltd. under the name "Sumikaexcel (trademark)." Several types exist depending on the degree of polymerization, and these can be used as appropriate.

[0060] <Antioxidants> In this embodiment, the hollow fiber membrane is preferably sterilized in an aqueous antioxidant solution from the viewpoint of blood compatibility and also because it prevents lipid-soluble substances in the hollow fiber membrane from being oxidized during the sterilization process.

[0061] The antioxidant is not particularly limited as long as it is an atom, molecule, or ion that has the property of easily donating electrons to other molecules, etc., and examples thereof include ultraviolet absorbers and light stabilizers, metal deactivators, antiozonants, amine-based antioxidants, phenol-based antioxidants, sulfur-based antioxidants, and phosphorus-based antioxidants.

[0062] Examples of ultraviolet absorbers and light stabilizers include, but are not limited to, phenyl salicylate, monoglycol salicylate, p-tert-butylphenyl salicylate, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-octoxybenzophenone, and 2(2'-hydroxy-5'-methylphenyl)benzotriazole.

[0063] The metal deactivator is not particularly limited, but examples thereof include N-salicyloyl-N'-aldehyde hydrazine, N-salicyloyl-N'-acetylhydrazine, and N,N'-diphenyloxamide.

[0064] The antiozonant is not particularly limited, but examples thereof include 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline, N-phenyl-N'-isopropyl-p-phenylenediamine, and the like.

[0065] The amine-based antioxidant is not particularly limited, but examples thereof include phenyl-β-naphthylamine, α-naphthylamine, and phenothiazine.

[0066] The phenol-based antioxidant is not particularly limited, but examples thereof include 2,6-di-tert-butyl-p-cresol, 2,6-di-tert-butylphenol, and 2,4-di-methyl-6-tert-butylphenol.

[0067] The sulfur-based antioxidant is not particularly limited, but examples thereof include dilauryl thiodipropionate, lauryl stearyl thiodipropionate, dilauryl sulfide, sodium hydrogen sulfite, sodium pyrosulfite, sodium sulfite, sodium pyrosulfite, sodium hydrosulfite, and acetone sodium bisulfite.

[0068] The phosphorus-based antioxidant is not particularly limited, but examples thereof include triphenyl phosphite and tridodecyl phosphite.

[0069] The antioxidant is not particularly limited, but other antioxidants such as L-ascorbic acid, cysteine, thioglycerol, and isopropyl citrate may also be used.

[0070] The antioxidant may be used alone or in combination of two or more.

[0071] Among these, sodium hydrogen sulfite, sodium pyrosulfite, sodium sulfite, and sodium pyrosulfite are preferred from the viewpoint of ease of handling.

[0072] When sterilization is carried out in an aqueous solution of an antioxidant, it is preferable to dissolve the antioxidant in water and then irradiate the hollow fiber membrane with radiation while the membrane is wetted with the aqueous solution.

[0073] The concentration of the antioxidant in the aqueous antioxidant solution is preferably 50 ppm or more and 2000 ppm or less. In addition to the antioxidant, the aqueous antioxidant solution may also contain a pH adjuster such as sodium carbonate, sodium chloride, glycerin, etc.

[0074] In the hollow fiber membrane blood purifier of this embodiment, the hollow fiber elongation is 55% or more, preferably 55 to 100%, more preferably 61 to 80%, and even more preferably 61 to 70%. When the hollow fiber elongation is within this range, the pressure resistance strength of the hollow fiber membrane is improved, and the occurrence of leaks tends to be suppressed.

[0075] The method for controlling the elongation of the hollow fiber within the above range is not particularly limited, but examples thereof include a method of carrying out the immobilization step of a fat-soluble substance described below and a method of appropriately adjusting the type and content of the material constituting the hollow fiber membrane. In this embodiment, the elongation of the hollow fiber can be measured by the method described in the examples below.

[0076] <Hollow fiber membrane manufacturing method> The hollow fiber membrane used in this embodiment can be produced by utilizing a known dry-wet membrane-forming technique. The method is not particularly limited, but examples thereof include a method having a spinning step of obtaining a membrane intermediate material containing a hydrophilic polymer and a hydrophobic polymer by a dry-wet spinning method, and an immobilization step of immobilizing a fat-soluble substance on the membrane intermediate material. It should be noted that the hollow fiber membrane used in this embodiment does not need to use both a hydrophilic polymer and a hydrophobic polymer, and may be a membrane made of a single material.

[0077] In the process for producing a hollow fiber membrane, for example, a method is mentioned, but is not limited to, in which a tube-in-orifice type spinneret is used, and a spinning dope is discharged from the orifice of the spinneret into the air from a tube together with a hollow inner liquid for solidifying the spinning dope.

[0078] The hollow fiber inner liquid may be water or a coagulation liquid mainly composed of water, and the composition thereof may be determined depending on the desired permeability of the hollow fiber membrane. In general, a mixed solution of the solvent used in the spinning dope and water is preferably used.

[0079] The spinning dope discharged from the spinneret together with the hollow inner liquid is allowed to travel through the free-running section, introduced into a coagulation bath mainly composed of water placed below the spinneret, and immersed therein to complete coagulation. After undergoing a washing step, the dope is wound up by a hollow fiber membrane winder in a wet state to obtain a bundle of hollow fiber membranes, which are then dried. Alternatively, after the washing step, the dope may be dried in a dryer to obtain a bundle of hollow fiber membranes.

[0080] Specific examples of the method for producing the hollow fiber membrane used in this embodiment include, but are not limited to, a method in which a normal membrane production process is carried out using a membrane-forming spinning dope containing a polysulfone-based resin and polyvinylpyrrolidone.

[0081] The membrane-forming spinning dope can be prepared, for example, by dissolving a polysulfone-based resin and polyvinylpyrrolidone in a solvent.

[0082] Such solvents are not particularly limited, but examples thereof include dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, and dioxane. The solvent may be used alone or in combination of two or more solvents.

[0083] The concentration of the polysulfone resin in the membrane-forming spinning dope is not particularly limited as long as it is within a concentration range that allows membrane formation and the resulting membrane has permeable membrane properties, but is preferably 5% by mass or more and 35% by mass or less, and more preferably 10% by mass or more and 30% by mass or less, when the resin composition is taken as 100% by mass. To achieve high water permeability, the polysulfone resin concentration should be low, and even more preferably 10% by mass or more and 25% by mass or less.

[0084] The polyvinylpyrrolidone concentration in the membrane-forming spinning dope is adjusted so that the mixing ratio of polyvinylpyrrolidone to polysulfone-based resin is preferably 27% by mass or less, more preferably 18% by mass or more and 27% by mass or less, and even more preferably 20% by mass or more and 27% by mass or less.

[0085] By adjusting the mixing ratio of polyvinylpyrrolidone to polysulfone resin to 27% by mass or less, the amount of polyvinylpyrrolidone eluted can be suppressed, and by adjusting the mixing ratio to 18% by mass or more, the polyvinylpyrrolidone concentration on the separating functional surface can be controlled within a suitable range, which enhances the effect of suppressing protein adsorption and improves blood compatibility.

[0086] The membrane-forming spinning dope is used to form a hollow fiber membrane by a commonly used method. For example, a tube-in-orifice type spinneret is used, and the membrane-forming spinning dope is discharged from the orifice of the spinneret into the air through the tube together with a hollow inner liquid for solidifying the membrane-forming spinning dope. The hollow inner liquid can be water or a liquid mainly composed of water. A mixed solution of the solvent used in the membrane-forming spinning dope and water is generally used as the hollow inner liquid. For example, a 20% by mass to 70% by mass aqueous solution of dimethylacetamide or the like is used.

[0087] By adjusting the discharge rate of the membrane-forming spinning dope and the discharge rate of the hollow fiber inner solution, the inner diameter and membrane thickness of the hollow fiber membrane can be adjusted to desired values.

[0088] For blood treatment applications, the inner diameter of the hollow fiber membrane is generally 170 μm to 250 μm, preferably 180 μm to 220 μm. From the viewpoint of the efficiency of diffusion removal of low-molecular-weight substances due to mass transfer resistance as a permeable membrane, the membrane thickness of the hollow fiber membrane is preferably 50 μm or less. Furthermore, from the viewpoint of strength, the membrane thickness is preferably 10 μm or more. In this embodiment, the inner diameter and membrane thickness of the hollow fiber membrane can be measured by the method described in the Examples below.

[0089] The membrane-forming spinning dope discharged from the spinneret together with the hollow inner liquid is made to travel through an air gap and introduced into a coagulation bath mainly composed of water installed below the spinneret, and is immersed for a certain period of time to complete coagulation. At this time, it is preferable that the draft, which is the ratio of the linear velocity of the membrane-forming spinning dope discharged to the take-up velocity, is 1 or less.

[0090] The air gap refers to the space between the spinneret and the coagulation bath, and the membrane-forming spinning dope starts coagulating from the inner surface side due to poor solvent components such as water in the hollow inner liquid simultaneously discharged from the spinneret. At the start of coagulation, a smooth hollow fiber membrane surface is formed and the hollow fiber membrane structure becomes stable, so the draft is preferably 1 or less, more preferably 0.95 or less.

[0091] Next, the solvent remaining in the hollow fiber membrane is removed by washing with hot water or the like, and then the hollow fiber membrane is placed in a drying chamber to remove moisture from the hollow fiber membrane.

[0092] <Manufacturing method of hollow fiber membrane type blood purifier> The hollow fiber membrane-type blood purifier is assembled using the hollow fiber membrane obtained through the above process. First, the hollow fiber membrane is filled into a cylindrical container with two nozzles near both ends of the side, and both ends are embedded in urethane resin. Next, the hardened urethane is cut to form open ends of the hollow fiber membrane. Header caps with nozzles for introducing (extracting) liquids such as blood and dialysis fluid are attached to both ends, and the hollow fiber membrane-type blood purifier is assembled.

[0093] <Step of immobilizing fat-soluble substances onto hollow fiber membranes> In this embodiment, the amount of acetic acid per unit area of ​​the hollow fiber membrane and the water permeability can be controlled within the above-mentioned ranges by carrying out the following coating method as a step of immobilizing the fat-soluble substance on the hollow fiber membrane. The coating method is a method in which a fat-soluble substance solution is poured into the hollow part on the inner surface side of the hollow fiber membrane, thereby attaching the fat-soluble substance to the surface of the hollow fiber membrane.

[0094] In the coating method, the fat-soluble substance may be immobilized on the produced hollow fiber membrane and then assembled into a hollow fiber membrane-type blood purifier, or the fat-soluble substance may be immobilized by passing a coating liquid through the hollow fiber membrane-type blood purifier after or during assembly.

[0095] The concentration of the fat-soluble substance in the coating liquid is preferably 0.1% by mass or more and 30% by mass or less, more preferably 0.1% by mass or more and 20% by mass or less, and even more preferably 0.1% by mass or more and 10% by mass or less, when the total amount of the coating liquid is 100% by mass.

[0096] The process of immobilizing a fat-soluble substance includes a liquid-feeding process and a liquid-removal process. The liquid-feeding process is a process in which a coating liquid, prepared by dissolving a fat-soluble substance (e.g., vitamin E) in an organic solvent (e.g., 2-propanol), is fed to the inside of the hollow fibers. At this time, the liquid may be fed to the inside of the hollow fibers with the dialysate port closed. The amount of the coating liquid may be appropriately set. Subsequently, in the liquid-removal process, the coating liquid is removed using compressed air. When removing the coating liquid with compressed air, compressed air is delivered from either the inside or the outside of the hollow fibers, or both. The pressure difference between the inside and outside of the hollow fibers (inside-outside) is -0.1 MPa or more, preferably greater than 0 MPa. In other words, the pressure inside the hollow fibers is higher than the pressure outside. The upper limit of this pressure difference (inside-outside) is not particularly limited, but is, for example, 0.1 MPa. Alternatively, compressed air of 0.1 MPa or more may be delivered only to the inside of the hollow fibers with the module dialysate port closed to remove the liquid. Alternatively, deliquoring may be performed by sending compressed air in pulses only to the inside of the hollow fibers. The pressure applied to the inside and outside of the hollow fibers during deliquoring may be set as appropriate, but it is preferable to increase the pressure inside the hollow fibers so that more of the coating liquid remains in the membrane thickness portion. Thereafter, in a drying step, the coating liquid remaining on the hollow fiber membrane is slowly dried and removed using oxygen-containing air. The temperature of the air used for drying is preferably 40 to 60°C.

[0097] In this embodiment, by carrying out the step of immobilizing a fat-soluble substance on the hollow fiber membrane as described above, the amount of acetic acid per area of ​​the hollow fiber membrane and the elongation of the hollow fiber can be easily controlled within the above-mentioned ranges.

[0098] By carrying out the above-mentioned process of immobilizing a fat-soluble substance on the hollow fiber membrane, the amount of acetic acid per unit area of ​​the hollow fiber membrane can be easily controlled within a specific range, and the amount of Alb leakage can also be controlled. Although the mechanism is not clear, the present inventors speculate that the mechanism of acetic acid generation is as follows. In the draining process, the pressure outside the hollow fiber is typically higher than the pressure inside the hollow fiber to efficiently drain the blood from the blood side. However, by intentionally lowering the draining efficiency by maintaining a pressure difference between the inside and outside of the hollow fiber (inside minus outside) of -0.1 MPa or higher, preferably greater than 0 MPa, i.e., by increasing the pressure inside the hollow fiber higher than the pressure outside, a large amount of coating liquid remains in the hollow fiber membrane after the draining process. Under these conditions, slow drying with oxygen-containing air at 40 to 60°C is thought to oxidize and decompose the organic solvent contained in the coating liquid into acetic acid. Surprisingly, we found that the amount of acetic acid contained in a blood purifier correlates with the amount of bovine blood Alb leakage within a certain range, and that controlling the amount of acetic acid can control the amount of bovine blood Alb leakage. The difficulty of controlling bovine blood Alb leakage is a major issue when using hollow fiber membranes with immobilized lipid-soluble substances. Several methods exist for immobilizing lipid-soluble substances on hollow fiber membranes. For example, a coating solution containing the lipid-soluble substance dissolved in an organic solvent is introduced into the hollow fiber membrane, causing the lipid-soluble substance to adhere to the membrane surface. As a result, the adhesion of lipid-soluble substances can cause changes in the pore size of the hollow fiber membrane and changes in the hydrophilicity and hydrophobicity of the membrane surface, particularly a decrease in pore size and hydrophilicity, resulting in a decrease in Alb leakage. Furthermore, during radiation sterilization, the radiation energy is thought to cause cross-linking between the molecules that make up the hollow fiber membrane, resulting in changes in the pore size of the hollow fiber.The inventors have succeeded for the first time in designing an optimal membrane for HDF clinical conditions by intentionally reducing the drainage efficiency, particularly in the drainage step, during the process of immobilizing lipid-soluble substances onto the hollow fiber membrane.In this state, the membrane is slowly dried with oxygen-containing air, generating a predetermined amount of acetic acid.Based on the correlation between the amount of acetic acid generated and the amount of bovine blood Alb leakage, the inventors have succeeded for the first time in designing an optimal membrane for HDF clinical conditions.

[0099] In hemodiafiltration, the pressure drop and membrane resistance are reduced by increasing the inner diameter of the hollow fiber membrane and decreasing the membrane thickness to prevent an increase in transmembrane pressure (hereinafter also referred to as "TMP"). From this perspective, for example, it is preferable for the hollow fiber membrane to have an inner diameter of 200 μm or more and a membrane thickness of less than 45 μm. Furthermore, the higher the permeability of the raw fiber, the better. However, hollow fiber membranes with an inner diameter of 200 μm or more and a membrane thickness of less than 45 μm and high permeability that have been coated with lipid-soluble substances by known methods have low pressure resistance and are unsuitable for HDF. Therefore, developing a high-flux membrane for HDF (bovine blood Alb leakage of 1 g or more) is extremely difficult. However, the present inventors have found that by carrying out the above-mentioned process of immobilizing a lipid-soluble substance on a hollow fiber membrane, the amount of acetic acid per hollow fiber membrane area and hollow fiber elongation can be easily controlled within the above-mentioned ranges, and as a result, the amount of bovine blood Alb leakage when used in pre-dilution HDF can be controlled within the range of 1 to 3 g. Furthermore, the relationship between the amount of acetic acid and the amount of bovine blood Alb leakage does not depend on the inner diameter, membrane thickness, or water permeability of the hollow fiber membrane. Therefore, by using this technology, the amount of acetic acid per hollow fiber membrane area contained in a blood purifier after sterilization can be controlled to 1 to 40 mg / m 2 If the amount of acetic acid per hollow fiber membrane area contained in the blood purifier is controlled to 1-30 mg / m, it is possible to arbitrarily control the amount of Alb leakage to 1-3 g when using pre-dilution HDF, regardless of the inner diameter and membrane thickness of the hollow fiber membrane. Furthermore, considering the balance between the amount of Alb leakage and the dialysis complications that can be improved, the amount of acetic acid per hollow fiber membrane area contained in the blood purifier should be 1-30 mg / m. 2 is preferable, and more preferably 1 to 20 mg / m 2 It is more preferable that:

[0100] Furthermore, when a hemodialyzer with the highest Alb leakage rate among those immobilized with lipid-soluble substances using conventional coating technology is used under pre-dilution HDF conditions, the bovine blood Alb leakage rate is 1.5 g. However, the hollow fiber elongation, a parameter for pressure resistance, is 53%, making the hollow fiber membrane unsuitable for HDF use in the first place. Therefore, it is impossible to manufacture a blood purifier using conventional coating technology that can guarantee a bovine blood Alb leakage rate of 1.5 g or more and a hollow fiber elongation of 55% or more. However, by carrying out the above-described process of immobilizing fat-soluble substances on hollow fiber membranes, it is possible to achieve pressure resistance sufficient for use in hemodiafiltration devices, i.e., hollow fiber elongation of 55% or more, while immobilizing fat-soluble substances and further controlling Alb leakage to a desired level of 1 to 3 g.

[0101] <Hollow fiber membrane wetting process> In the assembled hollow fiber membrane blood purifier, it is preferable to wet the hollow fiber membrane with an aqueous solution before sterilization from the viewpoint of protecting the hollow fiber membrane, and it is more preferable to sterilize it in an aqueous antioxidant solution. Methods for wetting the hollow fiber membrane with an aqueous solution include filling a container filled with hollow fiber membranes with the aqueous solution, and filling a container with the aqueous solution and then draining the solution by air flushing or the like. Among these, filling the module with an aqueous solution of sodium pyrosulfite and / or sodium carbonate is preferred.

[0102] <Blood processing equipment sterilization process> It is preferable to sterilize the hollow fiber membrane blood purifier. Examples of sterilization methods include radiation sterilization, electron beam sterilization, high-pressure steam sterilization, and ethylene oxide gas (EOG) sterilization. Radiation sterilization is preferred for hollow fiber membranes containing fat-soluble substances because extreme heating poses a risk of hollow fiber breakage. Electron beams, gamma rays (γ rays), X-rays, etc. can be used for radiation sterilization. γ-ray sterilization is preferred for precisely controlling the amount of acetic acid in the hollow fiber membrane blood purifier after sterilization. For γ rays or electron beams, the radiation exposure dose is preferably 15 kGy or more and 50 kGy or less, more preferably 20 kGy or more and 40 kGy or less. [Example]

[0103] 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 methods used in these examples are as follows.

[0104] <Inner diameter and membrane thickness of hollow fiber membrane> The inner diameter and membrane thickness of the hollow fiber membrane were measured as follows. First, the dried hollow fiber membrane was cut perpendicular to the axial direction using a razor. Care was taken not to crush or deform the hollow fiber membrane during cutting. The inner diameter and membrane thickness were measured at three random points on the cross section of the cut hollow fiber membrane using a microscope, and the average values ​​were used as the inner diameter and membrane thickness of the hollow fiber membrane.

[0105] <Amount of acetic acid contained in hollow fiber membrane blood purifiers> ◇ For wet type The filling fluids on the blood side and the dialysate side of the hollow fiber membrane blood purifier were extracted and mixed. The acetic acid concentration (μg / mL) in the resulting filling fluid was measured by ion chromatography. The measured acetic acid concentration was multiplied by the volume of the filling fluid to calculate the amount of acetic acid contained in the blood purifier. Next, the calculated amount of acetic acid was divided by the hollow fiber membrane area, and the obtained value was used as the amount of acetic acid (mg / m) per hollow fiber membrane area contained in the blood purifier. 2 ) was decided. ◇For dry type As shown in Figure 1, 1 L of water was circulated through the hollow fiber membrane blood purifier at 250 mL / min for 3 hours. The circulating water was passed through the blood inlet, blood outlet, dialysate inlet, and dialysate outlet in parallel. After circulation, the fluid inside the blood purifier and the circulating fluid were pooled, and the acetic acid concentration (μg / mL) was measured by ion chromatography. The acetic acid concentration was multiplied by the volume of water (1 L) to calculate the amount of acetic acid. The calculated amount of acetic acid was then divided by the hollow fiber membrane area, and the resulting value was used to calculate the amount of acetic acid (mg / m ) per hollow fiber membrane area contained in the blood purifier. 2 ) was decided. The hollow fiber membrane area used to calculate the amount of acetic acid is either the hollow fiber membrane area stated by the manufacturer (the hollow fiber membrane area printed on the label, etc.) or the inner surface area calculated from the product of the average inner diameter (diameter) of the hollow fiber membrane, pi, the number of fibers, and the effective length. The effective length is the length of the permeable hollow fiber within the entire length of the hollow fiber membrane, excluding urethane sealing portions, etc.

[0106] <Measurement of water permeability> The hollow fiber membrane blood purifier was thoroughly primed and immersed in water. Priming was performed by passing water through the circuit shown in Figure 2. The blood flow rate was 5 L / min and the dialysate flow rate was 4 L / min, and priming was performed for more than 5 minutes. Next, the hollow fiber membrane blood purifier was attached to the circuit for evaluating water permeability, as shown in Figure 3. Water heated to 37-38°C was introduced into the blood inlet at a flow rate of 300 mL / min into the blood inlet and 500 mL / min into the dialysate inlet, and the pressures were measured between 56 and 115 seconds after the start of circulation. Based on the pressure reading, the water permeability (UFR) of the hollow fiber membrane blood purifier was calculated using the following formula. UFR [mL / Hr / mmHg / m 2 ]=300[mL / min]×60[min]÷TMP[mmHg]÷membrane area[m 2 ] TMP[mmHg]=(PBin+PBout) / 2-(PDin+PDout) / 2 (In the formula, PBin [mmHg] is the blood side inlet pressure, PBout [mmHg] is the blood side outlet pressure, PDin [mmHg] is the dialysate side inlet pressure, and PDout [mmHg] is the dialysate side inlet pressure.) The water permeability was measured for the hollow fiber membrane type blood purifier before and after immobilization of the fat-soluble substance.

[0107] <Amount of fat-soluble substance immobilized in hollow fiber membrane> The hollow fiber membrane blood purifier was washed with water, dried, and then disassembled to collect the hollow fiber membrane, which was then cut into pieces of approximately 4 cm. The washing was performed at 5 L / min for 2 minutes. The drying was performed at 60 L / min or more in room temperature air for 6 hours or more. The membrane area (m 2 381 mL of ethanol per 100ml sample was added to the hollow fibers, and the fat-soluble substances were extracted at room temperature for 60 minutes while applying ultrasonic vibrations. Quantitative analysis was performed using liquid chromatography, and the amount of fat-soluble substances in the extract was determined using a calibration curve obtained from the peak areas of the fat-soluble substance standard solution. A column (Shodex Asahipak ODP-506E packed column for HPLC) was attached to 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). The column temperature was 40°C, and the mobile phase, methanol for high-performance liquid chromatography, was passed through at a flow rate of 1 mL / min. The concentration of the fat-soluble substance was determined from the area of ​​the ultraviolet absorption peak. From this concentration, the amount of fat-soluble substance immobilized on the hollow fiber membrane (mg / m) was calculated, assuming the extraction efficiency to be 100%. 2 ) was sought. The amount of fat-soluble substances partially oxidized by sterilization treatment was also measured within 1 m of the hollow fiber membrane surface. 2 In order to determine the amount of fat-soluble substance partially oxidized by sterilization, the fat-soluble substance used to prepare the calibration curve was exposed to 50 kGy of radiation in air, and the absorption peak of the partially oxidized fat-soluble substance was determined in advance and included in and added to the group of peaks used in area calculation.

[0108] <Measurement of hollow fiber elongation> The elongation of the hollow fiber in the hollow fiber membrane blood purifier was measured as follows. First, a sterilized hollow fiber membrane blood purifier was washed with water and disassembled, and hollow fibers (whole hollow fiber membrane modules) were cut out. The cut hollow fibers (whole hollow fiber membrane modules) were dried in a vacuum dryer. Drying was continued until there was no difference in the hollow fiber weight before and after drying (check interval: 12 hours) within ±0.05 g. The humidity in the hollow fiber elongation test room was set to 60%, and the temperature was room temperature (20-25°C). Next, one hollow fiber was clamped in a Tensilon tester with a chuck distance of 200 mm. One side of the Tensilon tester was fixed, and the hollow fiber was pulled at a test speed of 300 mm / min. The hollow fiber was pulled until it broke, and the hollow fiber length at break was divided by the hollow fiber length at zero load (200 mm) to calculate the hollow fiber elongation. Since the hollow fiber elongation measurement varies, measurements were made on n=20 or more samples, and the average value was taken as the hollow fiber elongation of the sample.

[0109] <Measurement of bovine blood Alb leakage> For the hollow fiber membrane blood purifier, the bovine blood Alb leakage was measured for 1 hour from the start of the test under pre-dilution HDF conditions (blood flow rate (QB) = 250 mL / min, dialysate flow rate (QD) = 600 mL / min, replacement fluid flow rate (Qs) = 12 L / h). The circulating bovine blood was adjusted to a total protein concentration of 6.0 ± 0.5 g / dL and a hematocrit of 32 ± 3%.

[0110] [Example 1] A membrane-forming solution was prepared from 17 parts by weight of polysulfone (PSf) (Solvay, P-1700), 4 parts by weight of polyvinylpyrrolidone (PVP) (BASF, K-90), and 79 parts by weight of dimethylacetamide (DMAc) (Kishida Chemical, special grade reagent). A 58% by weight aqueous solution of DMAc was used as the hollow inner liquid, and the solution was extruded from a spinneret with a 50 μm slit. The temperature of the membrane-forming solution at extrusion was 40°C. The extruded solution was passed through a drop section covered by a hood and immersed in a coagulation bath of water at 60°C for coagulation. The air gap length was 400 mm, and the spinning speed was 34 m / min. The blood treatment membrane was then obtained after a water-washing and drying process. The amounts of the membrane-forming solution and hollow inner solution dispensed were adjusted so that the membrane thickness after drying would be 43 μm and the inner diameter would be 200 μm. Next, the bundle of 13,000 hollow fiber membranes that had been dried and wound up was placed in a cylindrical container equipped with two nozzles for introducing and discharging liquid, and both ends were embedded in urethane resin. The hardened urethane resin was then cut off to form open ends of the hollow fiber membranes. Header caps equipped with nozzles for introducing (discharging) blood were placed on both ends, and the membrane area was reduced to 2.2 m. 2 The hollow fiber membrane blood purifier was assembled into a shape of 100 mmHg. The water permeability of the hollow fiber membrane blood purifier at this stage was measured by the above method and found to be 252 mL / Hr / mmHg / m 2 It was. Next, the following liquid transfer step, liquid removal step, and drying step were carried out to immobilize vitamin E as a fat-soluble substance on the hollow fiber membrane. (liquid transfer process) A coating solution (vitamin E coating solution) consisting of 0.05% by mass of vitamin E (α-tocopherol (Wako Pure Chemical Industries, special grade)) dissolved in a 57% by mass aqueous solution of 2-propanol (when the total amount of the coating solution was taken as 100% by mass) was delivered at 24°C from the inlet nozzle on the blood side (hereinafter also referred to as "side B") of the hollow fiber membrane blood purifier to the inner surface of the hollow fiber membrane to contact the vitamin E. At this time, the solution was delivered to the inside of the hollow fiber with the dialysate side (hereinafter also referred to as "side D") port of the hollow fiber membrane blood purifier closed. (Deliquoring process) Next, the pressure difference (side B - side D) was set to +0.05 MPa, and compressed air was sent from sides B and D to remove the liquid. (drying process) Thereafter, oxygen-containing air at 40 to 45°C was sent to side B:side D at a ratio (volume ratio) of 6:1 to dry and remove the solvent. Through the above-mentioned liquid transfer step, liquid removal step and drying step, vitamin E was immobilized on the hollow fiber membrane. Next, the wetting step was carried out as follows: First, the hollow fiber membrane blood purifier was washed with water. Then, an aqueous solution containing 0.06% by mass of sodium pyrosulfite as an antioxidant and 0.03% by mass of sodium carbonate for pH adjustment was filled into the blood flow channel (inner surface side) and the filtrate flow channel (outer surface side) of the hollow fiber membrane blood purifier. After the wetting step, the device was sterilized by gamma ray irradiation at 25 kGy with each nozzle tightly sealed, to obtain a hollow fiber membrane blood purifier. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method, and was found to be 14.3 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 223 mL / Hr / mmHg / m 2 Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane blood purifier was measured by the above-mentioned method and was found to be 61%. The amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 363 mg / m 2 It was.

[0111] [Example 2] As shown in Table 1, the hollow fiber membrane blood purifier of Example 2 was obtained in the same manner as in Example 1, except that in the fat-soluble substance immobilization process, the amount of coating liquid in the liquid supply process was changed to 800 mL, and the pressure difference (inside - outside) between the inside (side B) and outside (side D) of the hollow fiber in the liquid removal process was changed to +0.10 MPa. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method and found to be 17.4 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 239 mL / Hr / mmHg / m 2 Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane type blood purifier was measured by the above-mentioned method and was found to be 62%. The amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 378 mg / m 2 It was.

[0112] [Example 3] As shown in Table 1, the hollow fiber membrane blood purifier of Example 3 was obtained in the same manner as in Example 1, except that in the fat-soluble substance immobilization process, the amount of coating liquid in the liquid delivery process was changed to 700 mL and the pressure difference in the liquid removal process was changed to 0 MPa. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method, and was found to be 10.4 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 199 mL / Hr / mmHg / m 2 Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane type blood purifier was measured by the above-mentioned method and was found to be 62%. The amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 312 mg / m 2 It was.

[0113] [Example 4] As shown in Table 1, the hollow fiber membrane blood purifier of Example 4 was obtained in the same manner as in Example 1, except that in the fat-soluble substance immobilization process, the amount of coating liquid in the liquid delivery process was changed to 500 mL and the pressure difference in the liquid removal process was changed to -0.10 MPa. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method, and was found to be 1.3 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 163 mL / Hr / mmHg / m 2 Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane type blood purifier was measured by the above-mentioned method and was found to be 61%. The amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 265 mg / m 2 It was.

[0114] [Example 5] As shown in Table 1, the hollow fiber membrane blood purifier of Example 5 was obtained in the same manner as in Example 1, except that the pressure difference in the liquid removal step in the fat-soluble substance immobilization step was changed to -0.05 MPa. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method, and was found to be 1.5 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 172 mL / Hr / mmHg / m 2 Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane type blood purifier was measured by the above-mentioned method and was found to be 61%. The amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 287 mg / m 2 It was.

[0115] [Comparative Example 1] The DMAc concentration of the hollow fiber solution used to manufacture the hollow fiber membrane was changed to 56% by mass, the spinning speed was changed to 32 m / min, and as shown in Table 2, the inner diameter of the hollow fiber membrane was changed to 185 μm, the membrane thickness was changed to 45 μm, the number of hollow fiber membranes was changed to 13,500, and the membrane area of ​​the hollow fiber membrane was changed to 2.1 m 2 The hollow fiber membrane blood purifier of Comparative Example 1 was obtained in the same manner as in Example 1, except that the amount of coating liquid in the liquid feeding step in the fat-soluble substance immobilization step was changed to 750 mL, and the pressure difference (inside - outside) between the inside (side B) and outside (side D) of the hollow fiber in the liquid removal step was changed to -0.25 MPa. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method, and was found to be 2.5 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 155 mL / Hr / mmHg / m 2 The water permeability of the hollow fiber membrane blood purifier before the fat-soluble substance immobilization process was 246 mL / Hr / mmHg / m 2 Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane type blood purifier was measured by the above-mentioned method and was found to be 65%. The amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 152 mg / m 2 It was.

[0116] Comparative Example 2 A hollow fiber membrane blood purifier of Comparative Example 2 was obtained in the same manner as in Comparative Example 1, except that the DMAc concentration in the hollow inner liquid during production of the hollow fiber membrane was changed to 58 mass %. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method and found to be 2.1 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 184 mL / Hr / mmHg / m 2 The water permeability of the hollow fiber membrane blood purifier before the fat-soluble substance immobilization process was 287 mL / Hr / mmHg / m 2 Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane blood purifier was measured by the above-mentioned method and was found to be 53%, which was inferior in terms of pressure resistance strength compared to Example 1. In addition, the amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 141 mg / m 2 It was.

[0117] Comparative Example 3 A hollow fiber membrane blood purifier of Comparative Example 3 was obtained in the same manner as in Comparative Example 1, except that the DMAc concentration in the hollow inner liquid during production of the hollow fiber membrane was changed to 64 mass %. The amount of acetic acid per area of ​​the hollow fiber membrane in the obtained hollow fiber membrane blood purifier was measured by the above method and found to be 2.1 mg / m 2 The water permeability of the obtained hollow fiber membrane blood purifier was measured by the above method and was found to be 344 mL / Hr / mmHg / m 2 The water permeability of the hollow fiber membrane blood purifier before the fat-soluble substance immobilization process was 411 mL / Hr / mmHg / m 2 Furthermore, when the elongation of the hollow fiber in the obtained hollow fiber membrane type blood purifier was measured by the above-mentioned method, it was 45%, which was inferior in terms of pressure resistance strength compared to Example 1. In addition, the amount of fat-soluble substance (vitamin E) immobilized in the hollow fiber membrane was 144 mg / m 2 It was.

[0118] Comparative Example 4 A membrane-forming solution was prepared containing 16 parts by mass of PSf (P-1700, manufactured by Solvay), 3.5 parts by mass of PVP (K-90, manufactured by BASF), and 81.5 parts by mass of DMAc (special grade, Kishida Chemical). A 46% by mass aqueous solution of DMAc was used as the hollow fiber inner solution, and the hollow fiber membrane blood purifier of Comparative Example 4 was obtained in the same manner as Comparative Example 1, except that it was extruded from a spinneret with a slit width of 50 μm. The amounts of the membrane-forming solution and hollow inner solution dispensed were adjusted so that the membrane thickness after drying would be 43 μm and the inner diameter would be 200 μm. Next, the bundle of 13,000 hollow fiber membranes that had been dried and wound up was placed in a cylindrical container equipped with two nozzles for introducing and discharging liquid, and both ends were embedded in urethane resin. The hardened urethane resin was then cut off to form open ends of the hollow fiber membranes. Header caps equipped with nozzles for introducing (discharging) blood were placed on both ends, and the membrane area was reduced to 2.2 m. 2 The hollow fiber membrane blood purifier was assembled into a shape of 260 mL / Hr / mmHg / m. The water permeability of the hollow fiber membrane blood purifier at this stage was measured by the above method. 2 It was. Furthermore, the elongation of the hollow fiber in the obtained hollow fiber membrane blood purifier was measured by the above-mentioned method and was found to be 64%. However, the hollow fiber membrane blood purifier of Comparative Example 4 does not have antioxidant properties because no fat-soluble substance is immobilized on the hollow fiber membrane.

[0119] [Table 1]

[0120] [Table 2]

[0121] Comparing Examples 1 to 5 with Comparative Examples 1 to 4, the amount of acetic acid per area of ​​the hollow fiber membrane contained in the blood purifier was 1 to 40 mg / m 2 and the water permeability is 163mL / Hr / mmHg / m 2 By doing the above, it was possible to fix the lipid-soluble substance while ensuring elongation of 55% or more, making it possible to use HDF, and it was found that the amount of bovine blood Alb leakage under pre-dilution HDF conditions could be controlled within the range of 1 to 3 g per hour.

[0122] This application is based on a Japanese patent application (Patent Application No. 2021-181728) filed on November 8, 2021, the contents of which are incorporated herein by reference. [Industrial Applicability]

[0123] According to the present invention, in a hollow fiber membrane blood purifier containing a lipid-soluble substance, the Alb leakage amount of bovine blood under pre-dilution HDF conditions can be controlled to the range of 1 to 3 g per hour. The hollow fiber membrane blood purifier of the present invention has industrial applicability, for example, in blood purification therapy.

Claims

1. A hollow fiber membrane type blood purifier including a hollow fiber membrane and a container in which the hollow fiber membrane is packed, the hollow fiber membrane contains a fat-soluble substance, The amount of acetic acid contained in the blood purifier per area of ​​the hollow fiber membrane is 1 to 40 mg / m 2 and Water permeability is 163 mL / Hr / mmHg / m 2 That's all, A hollow fiber membrane type blood purifier, wherein the hollow fiber elongation is 55% or more.

2. 2. The hollow fiber membrane type blood purifier according to claim 1, wherein the fat-soluble substance comprises at least one selected from the group consisting of vitamin A, vitamin D, vitamin E, and vitamin K.

3. 3. The hollow fiber membrane type blood purifier according to claim 1, wherein the hollow fiber membrane is a hollow fiber membrane on which a fat-soluble substance is immobilized.

4. 3. The hollow fiber membrane type blood purifier according to claim 1, wherein the hollow fiber membrane is a hollow fiber membrane to which a fat-soluble vitamin is immobilized.

5. The amount of acetic acid contained in the blood purifier per area of ​​the hollow fiber membrane is 1 to 30 mg / m 2 3. The hollow fiber membrane blood purifier according to claim 1 or 2, wherein:

6. Water permeability of 163 to 350 mL / Hr / mmHg / m 2 3. The hollow fiber membrane blood purifier according to claim 1 or 2, wherein:

7. 3. The hollow fiber membrane blood purifier according to claim 1, wherein the hollow fiber has an elongation of 61 to 80%.

8. The amount of fat-soluble substance immobilized in the hollow fiber membrane is 1 to 500 mg / m 2 3. The hollow fiber membrane blood purifier according to claim 1 or 2, wherein:

9. 3. The hollow fiber membrane type blood purifier according to claim 1, wherein the material constituting the hollow fiber membrane comprises at least one selected from the group consisting of hydrophilic polymers and hydrophobic polymers.

10. 3. The hollow fiber membrane type blood purifier according to claim 1, wherein the inner diameter of the hollow fiber membrane is 170 μm or more and 250 μm or less.

11. 3. The hollow fiber membrane type blood purifier according to claim 1, wherein the membrane thickness of the hollow fiber membrane is 10 μm or more and 50 μm or less.

12. The method includes a step of immobilizing a fat-soluble substance on a hollow fiber membrane, The method for producing a hollow fiber membrane blood purifier according to claim 1, wherein in the fixing step, a coating liquid prepared by dissolving a fat-soluble substance in an organic solvent is sent to the inside of the hollow fiber, and the pressure difference between the inside and outside of the hollow fiber (inside - outside) when the coating liquid is removed by compressed air is set to -0.1 MPa or more.

13. 13. The method for producing a hollow fiber membrane blood purifier according to claim 12, wherein in the fixing step, after the coating liquid is removed, the hollow fiber membrane is dried with oxygen-containing air at 40 to 60°C.

14. The method for producing a hollow fiber membrane blood purifier according to claim 12 or 13, further comprising a step of wetting the hollow fiber membrane.

15. The method for producing a hollow fiber membrane blood purifier according to claim 12 or 13, further comprising a step of sterilizing the hollow fiber membrane blood purifier.

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