JP6456034B2 - Hollow fiber membrane for blood treatment - Google Patents

Description

  The present invention relates to a hollow fiber membrane for blood processing.

  Conventionally, in blood purification treatments such as renal failure treatment, cellulose, cellulose diacetate, cellulose triacetate, polysulfone, polyethersulfone, polymethylmethacrylate, polyacrylonitrile, etc. Hollow fiber membrane blood purifiers such as hemodialyzers, hemofilters or hemodialyzers that have a hollow fiber membrane using molecules as a separator are widely used.

These hollow-fiber membrane blood purifiers have β2 microglobulin (causative agent of dialysis amyloidosis derived from prolonged dialysis treatment) in addition to low-molecular-weight uremic toxins represented by urea, which is the removal target in the early stage of dialysis treatment. Improvements aimed at improving permeability have been added using β2MG, molecular weight: 11,800) as a removal target. At this time, in order to avoid loss suppression of albumin (molecular weight: 66,000), which is a useful protein, the conventional research goal was to improve the fractionation property of β2MG and albumin.
Recently, it has been pointed out that albumin is oxidized by oxidative stress, or that albumin itself becomes uremic toxin by adsorbing uremic toxin (see, for example, Non-Patent Document 1). According to this theory, like a living kidney, it is considered that a certain amount of albumin should be actively removed to promote the metabolism of albumin. In addition, in addition to the improvement in the amount of β2MG removal, a further highly permeable hollow fiber membrane is required.

  In addition, there is an imbalance syndrome that presents symptoms such as headache, nausea, or vomiting due to osmotic pressure difference between blood whose uremic toxin concentration has been drastically decreased due to blood purification treatment and body tissue where uremic toxin concentration is easily maintained. Are known. Although these do not immediately induce life-threatening or serious sequelae, they are painful for the patient, and measures taken to relieve symptoms, such as changing to a blood purifier with a small membrane area, are therapeutic effects The symptomatic treatment at the time of symptom onset causes a burden on the medical staff.

Tokyo Medical Co., Ltd. Kidney and Dialysis Vol.73 Separate Volume High Performance Membrane '12 Clinical Usefulness and Limitations of Protein Leakage Treatment Kenji Tsuchida et al

However, as described above, the conventional high-performance blood purifier that also removes albumin also has an excessively low molecular removal performance, and there is a concern that the imbalance syndrome becomes more apparent. Therefore, there is a need for a new blood purifier that improves the polymer removal performance while keeping the low molecule removal performance mild while reversing the design concept of the conventional high-performance blood purification device.
In the prior art, there has been no blood purifier that has high solute permeation performance that can realize albumin leakage and can simultaneously suppress dialysis complications such as dialysis amyloidosis and dialysis imbalance syndrome.

  Therefore, the problem to be solved by the present invention is to provide a hollow fiber membrane for blood treatment having high solute permeation performance capable of realizing albumin leakage while keeping low molecular clearance moderately low.

As a result of intensive studies to solve the above problems, the present inventors have included a hydrophobic resin, a hydrophilic resin and an oil and fat, and the ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane is 32% or less. It contains 10 mg / m ^{2 to} 300 mg / m ² of oil and fat in terms of membrane area, 1.5 m ² converted urea clearance is 100 mL / min to 185 mL / min and albumin sieving coefficient is 0.001 or more The present inventors have found that the above problems can be solved by using a hollow fiber membrane of 0.008 or less, and completed the present invention.

That is, the present invention is as follows.
(1)
A hollow fiber membrane for blood treatment comprising a hydrophobic resin, a hydrophilic resin and an oil and fat,
The ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane is 32% or less,
Containing 10 mg / m ² or more and 300 mg / m ² or less of oil and fat in terms of membrane area,
The urea clearance converted to 1.5 m ² is 100 mL / min or more and 185 mL / min or less,
A hollow fiber membrane for blood treatment having an albumin sieving coefficient of 0.001 or more and 0.008 or less.
(2)
The ratio (Ii / Io) of the amount of fat (Ii) present on the inner surface of the hollow fiber membrane to the amount of fat (Io) present on the outer surface of the hollow fiber membrane is 1.0 or more and 1.5 or less. The hollow fiber membrane for blood processing according to (1).
(3)
The hollow fiber membrane for blood treatment according to (1) or (2), wherein the hydrophobic resin is a polysulfone resin.
(4)
The hollow fiber membrane for blood treatment according to any one of (1) to (3), wherein the hydrophilic resin is polyvinylpyrrolidone.
(5)
The hollow fiber membrane for blood treatment according to any one of (1) to (4), wherein the fat is a fat-soluble antioxidant.
(6)
The hollow fiber membrane for blood treatment according to any one of (1) to (5), further comprising a ketone and / or alcohol having 2 to 3000 μg of carbon atoms of 4 or less per 1 g of the hollow fiber membrane.

  ADVANTAGE OF THE INVENTION According to this invention, the hollow fiber membrane for blood processing which has the high solute permeation | transmission performance which can implement | achieve albumin leakage can be provided, keeping low molecular clearance moderately low.

1 shows a typical hollow fiber membrane blood purifier. It is a figure which shows the test circuit at the time of the clearance measurement of urea. It is a figure which shows the test circuit at the time of the sieve coefficient measurement of albumin.

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

<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”)
Including hydrophobic resins, hydrophilic resins and fats and oils,
The hydrophilic resin present on the inner surface of the hollow fiber membrane is 32% or less,
Containing 10 mg / m ² or more and 300 mg / m ² or less of oil and fat in terms of membrane area,
The urea clearance converted to 1.5 m ² is 100 mL / min or more and 185 mL / min or less,
The albumin sieving coefficient is 0.001 or more and 0.008 or less.
The hollow fiber membrane for blood treatment of this embodiment is a hollow fiber membrane used for hemodialyzers, hemofiltration dialysers, hemofilters, continuous hemofilters, continuous hemodialyzers, plasma separators, and the like. .
In the present embodiment, the inner diameter, membrane pressure, length, etc. of the hollow fiber membrane may be appropriately set according to the use of the hollow fiber membrane blood purifier.

  Considering that the oxidative stress received by a patient is accumulated by repeated or prolonged extracorporeal circulation treatment, it is used for blood treatment of this embodiment in hemodialysis or hemofiltration dialysis performed frequently and over a long period of time. A blood purifier comprising a hollow fiber membrane is preferred. A typical hollow fiber membrane blood purifier is shown in FIG. 1, but the design may be changed as appropriate within the range of the purpose.

<Hydrophobic resin>
In the present embodiment, the hydrophobic resin is a synthetic polymer or a natural polymer that does not dissolve in water or does not show affinity for water.
Examples of the hydrophobic resin include polysulfone resins such as polysulfone, polyethersulfone, polyethersulfone-polyarylate polymer alloy, methacrylate resins such as polymethyl methacrylate, polyhydroxyethyl methacrylate and copolymers thereof, and cellulose triacetate. And cellulose acetate such as cellulose diacetate, polyacrylonitrile, polyamide, polyarylate, polycarbonate, polyether ether ketone, polyallyl ether ketone and the like. These may be used alone or in combination of two or more as the hydrophobic resin.
Among them, a synthetic polymer is preferable because of its uniform composition as a polymer, and polysulfone (hereinafter sometimes referred to as “PSf”) has many favorable clinical results in blood purification applications, and is stable as a raw material. Since it is excellent in supply property, it is more preferable.
In the present embodiment, “polysulfone” includes polyphenylsulfone, polyallyl ether sulfone, and the like in addition to those obtained by chemically modifying a part of the aromatic ring of aromatic polysulfone.
Examples of the polysulfone include polysulfone polymers whose repeating units are represented by the following chemical formulas (1) to (5). n is the degree of polymerization and may be any value.

PSf of the chemical formula (1) is commercially available from Solvay Advanced Polymers (Solvay) under the trade name “Udel” and from BASF Corporation under the trade name “Ultrazone”. Although there are a plurality of types depending on the degree of polymerization, there is no particular limitation.
PSf of the chemical formula (2) is commercially available from Sumitomo Chemical Co., Ltd. under the trade name “Sumika Excel PES”, and from BASF Corporation under the trade name “Ultra Zone”. The reduced viscosity measured with a 1 (W / V)% dimethylformamide solution is preferably 0.30 to 0.60 from the viewpoint that it is easy to obtain and preferably easy to handle and easy to obtain. Preferably it is 0.36-0.50.

<Hydrophilic resin>
In this embodiment, examples of the hydrophilic resin include polyvinyl pyrrolidone (hereinafter sometimes referred to as “PVP”), polyethylene glycol, polyvinyl alcohol, polypropylene glycol, and the like. From the viewpoint of affinity with PSf, PVP is preferably used. As hydrophilic resin, you may use these individually or in combination of 2 or more types.
There are several types of PVP depending on the degree of polymerization. For example, PFS has a trade name of “Prasdon” from BASF, with different molecular weights such as K-15, 30, 90, etc. Any exist, but any can be used.

<Oil and fat>
In the present embodiment, fats and oils are substances that are generally hardly soluble in water and are soluble in alcohol, petroleum, animal and vegetable oils, and other organic solvents, and natural or synthetic substances having low toxicity can be used.
Examples of oils and fats include vegetable oils such as cholesterol, castor oil, lemon oil and shea butter, animal oils such as fish oil, fatty acid esters such as sucrose fatty acid ester and polyglycerin fatty acid ester, vitamin A, vitamin D, vitamin E, vitamin K And fat-soluble vitamins such as ubiquinone, polyphenols, isoprenoids, hydrocarbons having a large carbon number, and the like. As fats and oils, you may use these individually or in combination of 2 or more types. Moreover, as fats and oils, those obtained by appropriately chemically modifying the exemplified compounds may be used for the purpose of adjusting the antioxidant capacity and affinity with the membrane substrate.
Among these, fat-soluble antioxidants such as fat-soluble vitamins and polyphenols are preferable in order to reduce oxidative stress associated with extracorporeal blood circulation. preferable.
Examples of vitamin E include α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, β-tocopherol, γ-tocopherol, and δ-tocopherol.
Examples of polyphenols include flavonoids such as catechin, anthocyanin, tannin, rutin, and isoflavone, phenolic acids such as chlorogenic acid, ellagic acid, lignan, curcumin, and coumarin.
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.

<Ratio of hydrophilic resin present on inner surface of hollow fiber membrane for blood treatment>
In this embodiment, the ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane is 32% or less, preferably 25 to 30%.
In the present embodiment, “the ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane” refers to the hydrophobicity at the outermost layer portion inside the hollow fiber membrane (that is, the surface where blood contacts the hollow fiber membrane). It is a ratio of the mass of the hydrophilic resin to the total mass of the hydrophilic resin and the hydrophilic resin.
The ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane can be measured, for example, by X-ray photoelectron spectroscopy (XPS).
The inner surface of the hollow fiber membrane is measured by XPS, and the ratio of the number of each atom on the surface is determined from the peak intensity of atoms peculiar to the hydrophobic resin and the hydrophilic resin, and the obtained hydrophobic resin and hydrophilic It can be measured by calculating the abundance of the hydrophilic resin from the mass ratio of the hydrophilic resin.
Specifically, it can be measured by the method described in the examples.
Explaining the case where PSf is used as the hydrophobic resin and PVP is used as the hydrophilic resin, it will be described from the number of nitrogen atoms (derived from PVP) and the number of sulfur atoms (derived from PSf) on the inner surface of the hollow fiber membrane. .
For example, when PSf consists of a repeating unit represented by the above general formula (1), the proportion of PVP present on the inner surface of the hollow fiber membrane can be determined by the following formula (1).
Here, in the following formula (1), 111 is the formula weight of the repeating unit of PVP, and 232 is the formula weight of the repeating unit of PSf. S is the element concentration of S2p, and N means the element concentration of N1s.

The mechanism of developing high-level polymer removal (albumin sieving coefficient) while moderately suppressing low-molecular removal (urea clearance) in this embodiment is still under study. According to the experiments by the present inventors, when the oil fixed on the hollow fiber membrane was removed with a surfactant, the albumin sieving coefficient was kept as it was and the urea clearance was remarkably increased. From this fact, it is clear that the fats and oils fixed to the hollow fiber membrane express the unique properties in this embodiment. When the amount of hydrophilic resin in the hollow fiber membrane is large, or when the permeation performance of the hollow fiber membrane is low, such a large change in performance due to the presence or absence of oil or fat is not recognized in the hollow fiber membrane in which the oil or fat is fixed by the conventional technology. .
On the other hand, the present inventors pay attention to the distribution of fats and oils in the hollow fiber membrane of the present embodiment, and even when the amount of fats and oils on the entire surface of the membrane is equalized, the hollow fiber membranes are compared with the hollow fiber membranes of the prior art. It has been found that the amount of oil and fat is large on the inner surface.
In the present embodiment, the surface of the entire membrane refers to the sum of all the pore surfaces of the outer surface and the porous layer in addition to the inner surface of the hollow fiber membrane. That is, in the hollow fiber membrane of the present embodiment, more oil and fat are present on the inner surface than on the outer surface of the hollow fiber membrane, and the ratio thereof is higher than that of the membrane of the prior art.
Consider from a more microscopic viewpoint. When a large amount of oil or fat is present on the membrane surface, the hydrophilic resin expands, ie, swells, opposite to the inner surface of the membrane due to hydrophobic-hydrophilic repulsion with the hydrophilic resin. When this occurs on the surface inside the pores, the substantial pore size is reduced, causing a decrease in solute diffusion efficiency, that is, a decrease in low molecular clearance.
In the hollow fiber membrane of the present embodiment, a large amount of oil and fat is present on the inner surface, which suggests that a large amount of oil and fat is present on the surface of the fine pores of the separation layer in contact with the inner surface. On the other hand, the swollen hydrophilic resin layer is flexible, and the resistance to the permeation of proteins and the like using the pressure difference as a driving force can be ignored. For this reason, the sieving coefficient of polymers such as albumin is kept high. When considered in this way, it can be explained that the unique properties of the present embodiment and that fats and oils are essential for it.
According to the experiments by the present inventors, the effect of the present embodiment is exhibited when the ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane is 32% or less. Considering the above hypothesis, if the ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane exceeds 32%, the density of PVP will increase excessively and the effect of repulsion with oil will be ignored. I can do it.

<Amount of oil in terms of membrane area>
In this embodiment, the hollow fiber membrane contains 10 mg / m ² or more and 300 mg / m ² or less of fats and oils in terms of membrane area, preferably 20 mg / m ² or more and 250 mg / m ² or less, more preferably 40 mg / m ² or more and 200 mg. / M ² or less.
In the present embodiment, the membrane area is the area of the blood contact surface of the hollow fiber membrane, the inner surface area of the hollow fiber membrane, the average inner diameter (diameter) of the hollow fiber membrane, the circumferential ratio, the number, and the effective Calculated from the product of the lengths. The average inner diameter is measured by observing the cross section of the hollow fiber with an optical microscope or a scanning electron microscope (SEM).
When the amount of oil in terms of membrane area is 10 mg / m ² or more, uneven coating of the oil can be prevented, and control of albumin permeability can be obtained with good reproducibility. In addition, it can exhibit excellent antioxidant ability. When the amount of the oil / fat in terms of membrane area is 300 mg / m ² or less, the active separation layer in the hollow fiber membrane is appropriately coated with the oil / fat and excellent in high permeability such as albumin.
The amount of oil or fat in terms of membrane area can be measured, for example, as follows.
If necessary, the hollow fiber membrane blood purifier is disassembled, the hollow fiber membrane is collected, washed with water, and then dried. For example, an aqueous solution of polyethylene glycol-t-octylphenyl ether, which is a surfactant that dissolves oil and fat, is added to the hollow fiber membrane after drying precisely weighed so as to correspond to a membrane area of 0.2 m ² and stirred to extract the oil and fat. I do.
The quantitative operation is performed, for example, by a liquid chromatograph method, and the concentration of the fat in the extract is calculated using a calibration curve obtained from the peak area of the fat standard solution. Based on the obtained concentration and the membrane area of the extracted hollow fiber membrane, the extraction efficiency can be taken as 100%, and the amount of oil / fat in terms of membrane area (mg / m ² ) can be determined.
Specifically, it can be measured by the method described in the examples.

<Urea clearance>
The hollow fiber membrane for blood treatment of the present embodiment has a urea clearance of 100 mL / min or more and 185 mL / min or less, preferably 110 mL / min or more and 185 mL / min or less, more preferably when used as a blood purifier. 110 mL / min or more and 180 mL / min or less.
Urea clearance is superior to blood purification performance when it is 100 mL / min or more, and it indicates that blood purification device performance is high when it is 185 mL / min or less, and prevents the nutrients necessary for patients from flowing out excessively. can do.

The urea clearance can be measured according to a measurement method specified by JIS T 3250.
Specifically, it can be measured by the method described in the examples. When the film area is 1.5 m ² , the measurement is performed as follows.
As the test solution used on the blood side, an aqueous urea solution adjusted to 1 g / L (17 mmol / L) is used. Use pure water as the test solution on the dialysate side. The blood purifier is set in the test circuit shown in FIG. 2, the blood inlet flow rate (QBi) of the blood purifier is 200 mL / min, the dialysate inlet flow rate (QDi) is 500 mL / min, and the dialysate outlet flow rate (QDo). Are adjusted to 500 mL / min. After a steady waiting until the blood side outlet solute concentration CBo is stabilized, the liquid is sampled from the blood side test solution, the blood side test solution outlet and the dialysate side test solution outlet, and the respective urea concentrations CBi, CBo and CDo are sampled. Measure. The urea concentration may be measured using a commercially available device, or a measurement can be requested from a clinical laboratory.
The urea clearance (CL) can be obtained by calculation from the following equation (2).
CL = (CBi−CBo) / CBi × QBi (2)
For blood purifiers with membrane areas other than 1.5 m ² , refer to the method described in Mineshima Michio, “Blood Purifiers-Performance Evaluation Basics, Issued by Japan Medical Center, 2002, 1st Edition”. The measured value is converted into a clearance value of 1.5 m ² .
When the film area is other than 1.5 m ² , the measurement is performed as follows.
First, urea clearance is measured by the above method except that QBi is reset by the following formula (3).
QBi = 200−10 × A (A: membrane area, m ² ) (3)
Next, the overall mass transfer coefficient (K0) is calculated by the following equation (4).
Further, the urea clearance in terms of the membrane area of 1.5 m ² is calculated by the following formula (5).

<Albumin sieve coefficient>
The hollow fiber membrane for blood treatment of the present embodiment has an albumin sieving coefficient of 0.001 or more and 0.008 or less, preferably 0.001 to 0.007, more preferably when used as a blood purifier. 0.002 to 0.007.
When the albumin sieving coefficient is 0.001 or more, the blood purification performance is excellent, and when it is 0.08 or less, it is possible to prevent excessive nutrients necessary for the patient from flowing out.

The albumin sieving coefficient can be measured according to the measurement method specified by JIS T 3250.
Specifically, it can be measured by the method described in the examples.
The test solution used on the blood side is bovine plasma obtained by separating anticoagulated bovine whole blood into plasma. The anticoagulant may be a citric acid type or heparin. Adjust plasma total protein concentration to 6.0 ± 0.5 g / dL. The blood purifier is set in the test circuit shown in FIG. 3, the blood inlet flow rate (QBi) of the blood purifier is 200 mL / min, the blood outlet flow rate (QBo) is 185 mL / min, and the filtrate flow rate (QF) is 15 mL / min. Adjust to each min and measure. After stabilizing the flow of blood and filtrate, the fluid is sampled from the blood supply solution, the blood test solution outlet and the filtration outlet, and the respective albumin concentrations CBi, CBo and CF are measured. The albumin concentration may be measured using a commercially available device, or a measurement can be requested from a clinical laboratory.
The albumin sieving coefficient (SC) can be calculated by the following formula (6).
SC = 2 × CF / (CBi + CBo) (6)

<Ratio of the amount of fats and oils present on the inner and outer surfaces of the hollow fiber membrane (Ii / Io)>
In this embodiment, it is preferable that the amount of fats and oils (Ii / Io) present on the inner and outer surfaces of the hollow fiber membrane is 1.0 or more and 1.5 or less.
When Ii / Io is 1.0 or more, low molecular clearance can be effectively suppressed. When Ii / Io is 1.5 or less, the risk of a decrease in blood compatibility due to the hydrophobicity of component C can be avoided.
In the present embodiment, the amount of fats and oils present on the surface of the hollow fiber membrane can use the normalized peak intensity of the parent mass peak obtained by TOF-SIMS (time-of-flight secondary ion mass spectrometry) measurement as an index. . The amount of fat (Ii) present on the inner surface of the hollow fiber membrane can be determined as the normalized peak strength of the inner surface of the hollow fiber membrane, and the amount of fat present on the outer surface of the hollow fiber membrane It can be determined as the normalized peak intensity of the outer surface of the film.
Specifically, it can be measured by the method described in the examples.
The amount of fats and oils measured by this method can be considered to detect only the fats and oils exposed on the surface because the measurement depth is as shallow as several to several tens of angstroms. On the other hand, in this method, it measures independently as the quantity of the fats and oils exposed to the film inner surface and the film outer surface.

<C4 or less ketone and / or alcohol>
It is preferable that the hollow fiber membrane of this embodiment further contains a ketone and / or alcohol having 4 or less carbon atoms.
By including a ketone having 4 or less carbon atoms and / or alcohol, a more reliable effect can be obtained in suppressing deterioration of the performance of the hollow fiber membrane, that is, suppressing variation in urea clearance.
Examples of the ketone having 4 or less carbon atoms include acetone and methyl ethyl ketone. Examples of the alcohol having 4 or less carbon atoms include methanol, ethanol, propyl alcohol, isopropyl alcohol, ethylene glycol, glycerin, and butyl alcohol. Is mentioned. Of these, acetone, ethanol, and isopropyl alcohol are preferably used.
When other than the above, for example, ether type or tetrahydrofuran is used, the hydrophobic resin may swell or dissolve to change the structure, and the performance may be significantly lowered.

Conventionally, in the step of adding fats and oils, the performance of the hollow fiber membrane may be reduced. However, the performance degradation is low in the fats and oils and the hydrophobic resin that is the membrane substrate of the hollow fiber membrane. This is because they have compatibility and the structure retention of the hydrophobic resin is reduced.
If there is no compatibility between the hydrophobic resin of the hollow fiber membrane and the oil or fat, the oil or fat will only adhere to the surface of the hydrophobic resin as an oil layer and will not enter the hydrophobic resin.
The present inventors succeeded in further reducing the compatibility between fats and oils and hydrophobic resins by adding ketones and / or alcohols having 4 or less carbon atoms, to the hydrophobic resin as a membrane substrate. As a result, the decrease in the structure holding force was suppressed.

<Abundance of ketones and / or alcohols having 4 or less carbon atoms>
The amount of ketone and / or alcohol having 4 or less carbon atoms is not particularly limited, but is preferably 2 to 3000 μg, more preferably 10 to 2000 μg, and even more preferably per 1 g of the hollow fiber membrane. Is 25 to 1500 μg.
When the amount of ketone and / or alcohol having 4 or less carbon atoms is 2 μg or more, the compatibility between the fat and the hydrophobic resin can be sufficiently lowered, and the structure retention of the hollow fiber membrane can be secured. It is possible to prevent the film performance from being deteriorated. Since one of the objects of this embodiment is to suppress excessive removal of low molecules, it is preferable that the performance variation is small.
When the abundance of ketones and / or alcohols having 4 or less carbon atoms is 3000 μg or less, peeling of fats and oils can be prevented at the time of clinical practice, and elution into blood and fats and oils are fat-soluble antioxidants. In this case, it is possible to prevent deterioration of antioxidant performance and performance change.
The abundance of ketones and / or alcohols having 4 or less carbon atoms can be determined in the case of a blood purifier filled with water (wet blood purifier) or a dry blood purifier by the method described in the following examples. Can be measured.

<Method for producing hollow fiber membrane>
In the present embodiment, the hollow fiber membrane can be produced by utilizing a known dry / wet film forming technique.
Hydrophobic resin and hydrophilic resin are dissolved in a common solvent to prepare a spinning dope. Examples of the common solvent include N, N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, dioxane and the like. A mixed solvent obtained by mixing two or more of these common solvents may be used.
The spinning dope is continuously extruded into a hollow fiber shape and simultaneously brought into contact with a coagulant to obtain a solidified continuous hollow fiber membrane. The coagulant is composed of a mixture of a hydrophobic resin solvent and a non-solvent, and the concentration of the solvent is preferably 0% or more and 60% or less. In order to control the pore diameter of the target hollow fiber membrane, an additive such as water may be added to the spinning dope.
The hydrophobic resin concentration in the spinning dope 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 to 35% by mass. It is below, More preferably, it is 10 to 30 mass%. In order to achieve high water permeability, the content is more preferably 10% by mass or more and 25% by mass or less.

The concentration of the hydrophilic resin in the spinning dope with respect to the hydrophobic resin is such that the mixing ratio of the hydrophilic resin to 100% by mass of the hydrophobic resin is preferably 27% by mass or less, more preferably 10% by mass to 25% by mass. More preferably, it is 15 mass% or more and 25 mass% or less.
It is preferable that the mixing ratio of the hydrophilic resin to the hydrophobic resin is 27% by mass or less because the elution amount of the hydrophilic resin tends to be reduced. Further, by being 10% by mass or more, it is more preferable that the hydrophilic resin can be distributed without gaps on the surface of the hollow fiber membrane, and the occurrence of leucopenia symptoms in which the leukocyte concentration in the patient's blood rapidly decreases can be reduced. .

In the process of manufacturing the hollow fiber membrane, it is preferable to use a tube-in-orifice type spinneret and discharge the spinning stock solution from the spinneret orifice into the air simultaneously with the hollow inner liquid as a coagulant. .
As the hollow inner liquid, water or a solution mainly composed of water can be used. In general, a mixed solution of common solvent and water used for the spinning dope is preferably used. In order to satisfy the purpose of controlling the solute permeation performance of the membrane, it is preferable to adjust the concentration of the common solvent, and an aqueous solution of 0% by mass to 70% by mass is generally used. It is also possible to adjust the abundance of the hydrophilic resin on the inner surface of the hollow fiber membrane by adding a hydrophilic resin to the hollow inner liquid so as to be 0% by mass or more and 2% by mass or less.
The spinning dope discharged from the spinneret together with the hollow inner liquid travels through the idle running part and is introduced into the coagulation bath mainly composed of water installed at the bottom of the spinneret to complete the coagulation. Then, it winds up with the wet state hollow fiber membrane winder, obtains a hollow fiber membrane bundle, and performs a drying process after that. Or after passing through the above-mentioned washing process, it may dry in a drier and may obtain a hollow fiber membrane bundle.

<Method for producing hollow fiber membrane blood purifier>
As a preferable manufacturing method of the hollow fiber membrane blood purifier of the present embodiment, for example, a hollow fiber membrane bundle is manufactured as described above, and a cylindrical shape having a treatment liquid inlet / outlet contacting the hollow fiber membrane bundle with the outside of the membrane Insert a potting agent such as polyurethane into both bundle ends to form a potting layer and seal both ends, and then cut off and remove the excess potting agent after curing to open the end face. There is a method of immobilizing oils and fats after manufacturing a hollow fiber membrane blood purifier by attaching a header having an inlet / outlet. Moreover, you may implement a header after fixing fats and oils.
Subsequently, further sterilization treatment may be performed. Moreover, you may perform fixation of fats and oils in the state of the hollow fiber membrane bundle before setting it as a hollow fiber membrane type blood purifier.

<Fixing process of fats and oils to the hollow fiber membrane>
A known method can be basically used for the step of fixing fats and oils to the hollow fiber membrane. Above all, the coating method is excellent in that it can realize production of an oil-and-fat fixed membrane having various permeation performances using existing facilities and product lineup.
Specifically, the method for fixing fats and oils to the hollow fiber membrane includes a method in which fats and oils are added to the spinning stock solution during the production of the hollow fiber membranes, and the whole hollow fiber membranes contain fats and oils. And a method of adding oil and fat to the inner surface of the hollow fiber membrane (for example, Patent No. 4038583 and International Publication No. 98/52683), after assembling the hollow fiber membrane blood purifier, Various methods such as a method of attaching oil and fat to the inner surface of the hollow fiber membrane by flowing an oil and fat solution composed of a solvent of oil and fat into the inner cavity of the hollow fiber membrane (for example, JP 2006-296931 A) However, any method including other methods may be used.

<Wetting process of hollow fiber membrane>
The hollow fiber membrane blood purifier assembled with the oil and fat immobilized thereon may wet the hollow fiber membrane with an aqueous solution before sterilization. Wetting the hollow fiber membrane with an aqueous solution stabilizes the hollow fiber membrane and reduces changes in performance such as water permeability, dialysis performance, and filtration performance. Methods of wetting the hollow fiber membrane with the aqueous solution include a method of filling the container filled with the hollow fiber membrane bundle with the aqueous solution, a method of draining after filling the container with the aqueous solution, and the like. This wetting step of the hollow fiber membrane can also serve as a sterilization protective agent addition step.

<Immobilization process of ketone and / or alcohol having 4 or less carbon atoms to hollow fiber membrane>
The step of immobilizing ketones and / or alcohols having 4 or less carbon atoms to the hollow fiber membrane includes, for example, assembling a hollow fiber membrane-type blood purifier and passing oil and fat, and then ketones and / or carbon atoms having 4 or less carbon atoms. The method of drying in the vapor | steam atmosphere of alcohol is mentioned. By using a ketone and / or alcohol having 4 or less carbon atoms as a coating solvent and devising drying conditions, a vapor atmosphere of a ketone and / or alcohol having 4 or less carbon atoms can be maintained. When a drying gas to be introduced contains a ketone and / or alcohol having 4 or less carbon atoms, a vapor atmosphere of the ketone and / or alcohol having 4 or less carbon atoms can be stably realized, and the ketone and / or carbon atoms having 4 or less carbon atoms can be obtained. It is more preferable because immobilization of alcohol can be performed without variation.

<Sterilization protective agent addition process>
A sterilization protective agent may be further added to a blood purifier in which fats and oils are fixed, or a device that has undergone a further wetting process.
The sterilization protective agent is for protecting the hydrophilic resin of the hollow fiber membrane from being significantly modified by radiation energy irradiated in the sterilization process, and includes a plurality of hydroxyl groups and aromatic rings in one molecule. It is a radical scavenger having
Examples of the sterilization protective agent include (polyhydric) alcohols such as glycerin and propylene glycol, water-soluble saccharides such as oligosaccharides and polysaccharides, and inorganic salts having an antioxidant action such as sulfites.
The method for impregnating the hollow fiber membrane with the sterilizing protective agent is a method in which the sterilizing protective agent is dissolved in an appropriate solvent and introduced into the hollow fiber membrane blood purifier, for example, the sterilizing protective agent is dissolved in water or a physiological salt solution. A method of filling the space inside the hollow fiber membrane blood purifier or impregnating only the hollow fiber membrane is used. In the wetting step, the aqueous solution may be wetted with an aqueous solution containing a sterilization protective agent. Further, it may be applied in the spinning process, or may be applied simultaneously in the fixing process of fats and oils by being contained in the coating liquid of fats and oils.
When a sterilization protective agent is present in the hollow fiber membrane blood purifier, the hollow fiber membrane blood purifier, particularly the hollow fiber membrane, can be prevented from being changed by radiation sterilization described below.
When the sterilization protective agent is used in a solution state, the concentration of the sterilization protective agent may be determined optimally depending on the material of the hollow fiber membrane blood purifier, the type of the hydrophilic resin, and the sterilization conditions. It is 0.001% or more and 1% or less, and more preferably 0.005% or more and 0.5% or less.

<Sterilization process of hollow fiber membrane blood purifier>
It is preferable to sterilize the hollow fiber membrane blood purifier. Examples of the sterilization method include a radiation sterilization method and a steam sterilization method.
Since the hollow fiber membrane containing a large amount of oil and fat has a risk of causing breakage of the hollow fiber 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. In the case of γ rays or electron beams, the radiation dose is preferably 5 kGy or more and 50 kGy or less, more preferably 20 kGy or more and 40 kGy or less.
When the blood purifier is of a dry type, it is preferable to replace the inside of the module with an inert gas such as nitrogen before sterilization because it can prevent oxidation of the hydrophilic resin and fats and oils.

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

<Ratio of hydrophilic resin present on inner surface of hollow fiber membrane for blood treatment>
The hollow fiber membrane blood purifier was disassembled and the hollow fiber membrane was taken out. The hollow fiber membrane was tied with a string to make a bundle of about 50 × 20 cm, and immersed in a vat filled with distilled water overnight. The vat distilled water was always replenished with fresh distilled water and overflowed.
The bundle of hollow fiber membranes was taken out, cut into 5 cm, and frozen in a −40 ° C. freezer. At this time, freeze-drying was performed overnight at a degree of vacuum of about 0.3 to 0.4 torr.
The dried hollow fiber membrane was cut open in the longitudinal direction to expose the inner surface, and several samples were arranged on a double-sided tape.
The ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane was measured under the following conditions using an X-ray photoelectron spectrometer (manufactured by Thermo Fisher Scientific Co., Ltd., ESCALAB250).
Measurement conditions Excitation source: mono. AlKα 15kV × 10mA
Capture area Survey scan: 0 to 1,100 eV
Narrow scan: C1s, O1s, N1s, S2p
PassEnergy: 100eV
The element concentration was determined from the area intensity of the obtained narrow scan spectrum using the library relative sensitivity coefficient of the apparatus, and quantitatively calculated. The relative sensitivity coefficients used are C1s: 0.296, O1s: 0.711, S2p: 0.666, and N1s: 0.477.
A method for calculating the proportion of PVP present on the inner surface of the hollow fiber membrane of the hollow fiber membrane using PSf represented by the above chemical formula (1) as the hydrophobic resin and PVP as the hydrophilic resin will be described below.
S2p obtained by the measurement is derived from PSf, and N1s is derived from PVP.
The formula weight of the repeating unit of PSf is 232, and the formula weight of the repeating unit of PVP is 111.
When the element concentration of S2p is S and the element concentration of N1s is N, the ratio of PVP present on the inner surface of the hollow fiber membrane was determined by the following formula (1).

<Amount of oil in terms of membrane area>
The hollow fiber membrane blood purifier was disassembled, the hollow fiber membrane was collected, washed with water, cut into 1 cm length, and vacuum dried at 40 ° C. until a constant weight was obtained. Weigh 0.2m ² of hollow fiber membrane after drying into a glass bottle, add 80% aqueous solution of 1% by weight Triton X-100 (Kishida Chemical, Chemical), and apply oil and fat while applying ultrasonic vibration for 60 minutes at room temperature. Was extracted.
Quantification was performed by a liquid chromatograph method, and the amount of fat and oil in the extract was determined using a calibration curve obtained from the peak area of the fat and oil standard solution.
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 Kogyo Co., Ltd.) was installed, methanol for high performance liquid chromatography as a mobile phase was passed at a flow rate of 1 mL / min at a column temperature of 40 ° C., and the area of the absorption peak at a wavelength of 295 nm was measured with a UV detector From this, the oil and fat concentration was determined. The extraction efficiency was set to 100%, and the amount of oil / fat in terms of membrane area (mg / m ² ) was determined.
In order to determine the amount of partially oxidized oils and fats in order to determine the amount of partially oxidized oils and fats, the oils and fats used for preparing the calibration curve are exposed to 50 kGy radiation in the air in advance, in order to determine the amount of oils and fats partially oxidized by sterilization treatment. Absorption peaks of partially oxidized fats and oils were determined in advance, included in a peak group used for area calculation, and added.

<Urea clearance>
1 g of urea was dissolved per liter of pure water to prepare a blood side test solution. The dialysate side test solution was pure water, and the blood side test solution and the dialysate side test solution were both kept at 37 ± 1 ° C. and subjected to the test. A blood purifier having a membrane area of 1.5 m ² is set in the test circuit shown in FIG. 2, the blood side inlet flow rate (QBi) is 200 mL / min, the dialysate inlet flow rate (QDi) is 500 mL / min, and the dialysate outlet flow rate ( QDo) was adjusted to 500 mL / min. After confirming that the air in the blood purifier was removed, QBo and QDo were measured for 1 minute using a graduated cylinder and confirmed to be the set flow rate. After flowing for 4 minutes or more to stabilize the flow rate, the blood was sampled from the blood side test solution, the blood side test solution outlet and the dialysate side test solution outlet, and the respective urea concentrations CBi, CBo and CDo were measured. Each urea concentration CBi, CBo, and CDo was quantified with an automatic analyzer Biolis24i (Tokyo Trading Medical System Co., Ltd.) using Iatro UN reagent (Mitsubishi Chemical Medience Co., Ltd.). The urea clearance (CL) was calculated by the following formula (2).
CL = (CBi−CBo) / CBi × QBi (2)
The measurement was performed with 10 blood purifiers, and the measured value (average value) and standard deviation were calculated.

<Measurement of albumin sieving coefficient>
Dissolve 30 g of trisodium citrate dihydrate, 23.2 g of glucose, 3.58 g of citric acid monohydrate and 2.51 g of sodium dihydrogen phosphate dihydrate in 1 L of water for injection to give an anticoagulant (CPD )created. Anticoagulated bovine blood was obtained by adding 614 mL of CPD to 5 L of fresh bovine blood. The obtained blood was centrifuged at 3500 rpm for 20 minutes to separate plasma. A blood side test solution was prepared by adjusting with plasma or physiological saline so that the total plasma protein concentration was 6.0 ± 0.5 g / dL. The blood side test solution was kept at 37 ± 1 ° C. and used for the test. A blood purifier having a membrane area of 1.5 m ² is set in the test circuit shown in FIG. 3, the blood side inlet flow rate (QBi) of the blood purifier is 200 mL / min, the blood outlet side flow rate (QBo) is 185 mL / min, and the filtrate. The flow rate (QF) was adjusted to 15 mL / min. After confirming that the air in the blood purifier was released, QBo and QF were measured for 1 minute using a graduated cylinder and confirmed to be the set flow rate. After flowing for 1 hour to stabilize the flow rate, the solution was sampled from the blood supply solution, the blood test solution outlet and the filtration outlet, and the respective albumin concentrations CBi, CBo and CF were measured. Each albumin concentration CBi, CBo, CF was quantified with an automatic analyzer Biolis 24i (Tokyo Trading Medical System Co., Ltd.) using Iatro U-ALB (TIA) reagent (manufactured by Mitsubishi Chemical Medience Corporation). The albumin sieving coefficient (SC) was calculated by the following formula (6).
SC = 2 × CF / (CBi + CBo) (6)

<Ratio of the amount of fats and oils present on the inner and outer surfaces of the hollow fiber membrane (Ii / Io)>
The hollow fiber membrane was removed from the hollow fiber blood purifier. The hollow fiber membrane was tied with a string to make a bundle of about 50 × 20 cm, and immersed in a vat filled with distilled water overnight. The distilled water in the vat was always replenished with fresh distilled water and overflowed.
The bundle of hollow fiber membranes was taken out, cut into 5 cm, and frozen in a −40 ° C. freezer. At this time, freeze-drying was performed overnight at a degree of vacuum of about 0.3 to 0.4 torr.
A dried hollow fiber membrane was cut in the longitudinal direction to expose the inner surface or outer surface of the membrane and fixed on a Si wafer as a sample.
The exposed inner surface and outer surface of the membrane were measured using a nano-TOF apparatus (manufactured by ULVAC-PHI). The measurement conditions were as follows: primary ion Bi ₃ ⁺⁺ , acceleration voltage 30 kV, current 0.2 nA (as DC), analysis area 200 μm × 200 μm, integration time 3 min, and negative ions (as mass, vitamin E 163) by the detector. Was detected as a detected ion. Due to the characteristics of this measuring apparatus, the measurement depth corresponds to a depth of 5 nm from the surface. Using the proton ionic strength (IH) and total ionic strength (IT) as the ionic strength (IV) of the obtained oil-and-fat peak, the normalized peak strength of vitamin E was calculated according to the following formula (7).
Normalized peak intensity = IV / (IT-IH) (7)
Of the normalized peak intensities calculated by the above formula (7), the normalized peak intensity of the inner surface of the hollow fiber membrane is defined as the amount of oil (Ii) present on the inner surface, The ratio (Ii / Io) of the amount of fats and oils present on the inner and outer surfaces of the hollow fiber membrane was determined with the normalized peak intensity of the surface as the amount of fats and oils (Io) present on the outer surface.

<Abundance of ketones and / or alcohols, diethyl ether, and tetrahydrofuran having 4 or less carbon atoms>
The amount of ketone and / or alcohol having 4 or less carbon atoms (hereinafter referred to as “ketone and the like” in this paragraph), diethyl ether, and tetrahydrofuran in 1 g of the hollow fiber membrane blood purifier. It measured by the following method.
[For blood purifiers filled with water]
The blood purifier was disassembled, the hollow fiber membrane was taken out, and water was removed by centrifugation at 3500 rpm for 10 minutes using a commercially available centrifuge. Of the hollow fiber membrane from which moisture was removed, 0.25 g was weighed (this mass was defined as (w1 g)). After 25 g of N-methyl-2-pyrrolidone (w2 g) was added and dissolved, ketones, diethyl ether, and tetrahydrofuran were quantified by gas chromatography (GC).
Using calibration curves obtained from the peak areas of ketone, etc., diethyl ether, and tetrahydrofuran, the concentrations x (%) of ketone, etc., diethyl ether, and tetrahydrofuran in the recovered solution were determined.
An autoinjector (AOC-20i / AOC-17) was connected to a gas chromatograph (Shimadzu Corporation GC-2014 / GC14B), and calculation was performed from an absorption peak obtained by an FID detector (hydrogen flame ionization detector).
The amounts (Dg) of ketone, diethyl ether, and tetrahydrofuran per gram of hollow fiber membrane were calculated by substituting numerical values w1, w2, and x into the following formula (8).
D = (x × (w1 + w2)) ÷ w1 (8)
[Dry blood purifier]
The hollow fiber membrane blood purifier was disassembled and the hollow fiber membrane was taken out. After drying to a constant weight in a desiccator as a calcium chloride desiccant, this mass was precisely weighed (w3g), then added with N-methyl-2-pyrrolidone (w4g), stirred and dissolved, The concentrations y (w / w%) of ketones, diethyl ether, and tetrahydrofuran were determined by the above method. The amounts (Dg) of ketone, diethyl ether, and tetrahydrofuran per gram of hollow fiber membrane were calculated by substituting w3, w4, and y into the following formula (9).
D = (y × (w3 + w4)) ÷ w3 (9)
In Table 1, “content” of each component is shown.

[Example 1]
16.5% by mass of polysulfone (P-1700 manufactured by Solvay) and 3.3% by mass of polyvinylpyrrolidone (K90 manufactured by PVP BASF) were dissolved in 80.2% by mass of N, N-dimethylacetamide (Mitsui Chemicals). To obtain a homogeneous solution. The mixing ratio of PVP to polysulfone in the spinning dope was 20% by mass. The stock solution for spinning is kept at 45 ° C. and discharged from a spinneret having a slit width of 50 μm together with a hollow inner liquid composed of a mixed solution of 52.5% by mass of N, N-dimethylacetamide and 47.5% by mass of water and covered with a hood. After passing through the falling part, it was immersed in a 54 ° C. coagulation bath made of water and coagulated. The air gap length was 400 mm and the spinning speed was 32 m / min. Washing with water and drying were performed to obtain a hollow fiber membrane. The drying temperature was 160 ° C., the drying time was 100 seconds, and the discharge rate of the spinning solution and the hollow inner solution was adjusted so that the film thickness after drying was 35 μm and the inner diameter was 185 μm.
The dried hollow fiber membrane is filled into a cylindrical container having two nozzles for introducing and discharging liquid, and both ends are embedded with urethane resin, and then the cured urethane portion is cut to open the hollow fiber membrane. Processed to the end. A header cap having a blood introduction (lead-out) nozzle was loaded at both ends, and assembled into a blood purifier shape having a membrane area of 1.5 m ² .
Next, a coating solution in which α-tocopherol (special grade manufactured by Wako Pure Chemical Industries, Ltd.) as an oil / fat was dissolved in an isopropanol 57% by mass aqueous solution was dissolved from the blood introduction nozzle of the blood purifier through the lumen of the hollow fiber membrane. The oil and fat were brought into contact with each other for 52 seconds. The remaining liquid in the lumen was removed by air flushing, and then the solvent was dried and removed by aeration with dry air at 24 ° C. in an isopropanol atmosphere for 30 minutes, and the oil was fixed by coating.
As a wetting step, an aqueous solution containing 0.06% sodium pyrosulfite, which is a sterilization protective agent, and 0.03% sodium carbonate for pH adjustment is added to the blood side flow path and the filtrate side flow path of the blood purifier. A blood purifier was obtained by filling and sterilizing γ rays with 25 kGy with each nozzle sealed.

[Example 2]
A blood purifier was obtained in the same manner as in Example 1 except that 0.40% by mass of α-tocopherol was dissolved in a 57% by mass aqueous solution of isopropanol as a coating solution.

Example 3
As the spinning dope, 3.5% by mass of PVP and 81.9% by mass of N, N-dimethylacetamide (the mixing ratio of PVP to polysulfone was 19% by mass), and as a coating solution, an α- A blood purifier was obtained in the same manner as in Example 1 except that 0.45% by mass of tocopherol was dissolved and dry air at 24 ° C. in an ethanol atmosphere was aerated for 15 minutes.

Example 4
As a coating solution, a blood purifier was prepared in the same manner as in Example 3 except that 0.03% by mass of α-tocopherol was dissolved in 57% by mass of acetone, and dry air at 24 ° C. in an acetone atmosphere was vented for 15 minutes. Obtained.

Example 5
A blood purifier was obtained in the same manner as in Example 1 except that 40 ° C. dry air in an isopropanol atmosphere was aerated for 80 minutes.

Example 6
As the spinning dope, 1.5% by mass of PVP and 86.0% by mass of N, N-dimethylacetamide (the mixing ratio of PVP with respect to polysulfone is 11% by mass), and as a coating solution, an α- A blood purifier was obtained in the same manner as in Example 1 except that 0.30% by mass of tocopherol was dissolved and 24 ° C. dry air in an isopropanol atmosphere was aerated for 45 minutes.

Example 7
As the spinning dope, 1.8% by mass of PVP and 86.2% by mass of N, N-dimethylacetamide (the mixing ratio of PVP with respect to polysulfone is 8% by mass), and the coating solution from the blood introduction nozzle of the blood purifier The solution was passed through the hollow portion of the hollow fiber membrane for 60 seconds, and dry solvent at 24 ° C. in an isopropanol atmosphere was passed through for 40 minutes to remove the solvent by drying. A blood purifier was obtained by the same method as in Example 1 under other conditions.

Example 8
A blood purifier was obtained in the same manner as in Example 1 except that 60 ° C. dry air in an isopropanol atmosphere was vented for 100 minutes.

Example 9
As a coating solution, 0.1% by mass of poly (2-hydroxyethyl methacrylate) (manufactured by SIGMA-ALDRICH, average molecular weight 20000) and 0.45% by mass of α-tocopherol are dissolved in an aqueous solution of 57% by mass of isopropanol. A blood purifier was obtained in the same manner as in Example 1, except that the moistening step was not performed, the inside of the module was replaced with nitrogen, and γ-rays were sterilized by irradiation with 25 kGy with each nozzle sealed. Poly (2-hydroxyethyl methacrylate) is a coating polymer introduced for the purpose of protecting hydrophobic and / or hydrophilic resins from sterilization degradation.

[Comparative Example 1]
The spinning dope is 3.9% by mass of PVP and 81.1% by mass of N, N-dimethylacetamide (the mixing ratio of PVP to polysulfone is 21% by mass), and the coating solution is α- A blood purifier was obtained in the same manner as in Example 1 except that 0.03% by mass of tocopherol was dissolved and dry air at 24 ° C. in an isopropanol atmosphere was aerated for 15 minutes.

[Comparative Example 2]
As a coating solution, 0.02% by mass of α-tocopherol was dissolved in an aqueous solution of 57% by mass of isopropanol, and dry air at 24 ° C. in an isopropanol atmosphere was aerated for 15 minutes. Obtained.

[Comparative Example 3]
A blood purifier was obtained in the same manner as in Example 7, except that the coating solution was passed through the lumen of the hollow fiber membrane from the blood introduction nozzle of the blood purifier for 45 seconds.

[Comparative Example 4]
As a coating solution, a blood purifier was obtained in the same manner as in Example 1 except that 0.45% by mass of α-tocopherol was dissolved in a solution of 57% by mass of diethyl ether and 43% by mass of isopropanol.
Urea clearance and albumin sieving coefficient could not be measured because the amount of liquid permeation through the membrane was too small.

[Comparative Example 5]
As a coating solution, a blood purifier was obtained in the same manner as in Example 1 except that 0.45% by mass of α-tocopherol was dissolved in 57% by mass of tetrahydrofuran.
Urea clearance and albumin sieving coefficient could not be measured because the amount of liquid permeation through the membrane was too small.

  Table 1 shows the results obtained based on the evaluation method for the blood purifiers obtained in Examples and Comparative Examples.

From the results of Example 3 and Comparative Example 2, it was found that the urea clearance is kept moderately low when the amount of oil and fat is 10 mg / m ² or more and 300 mg / m ² in terms of membrane area.
From the results of Example 4 and Comparative Example 1, it was found that when the hydrophilic resin present on the inner surface was 32% or less, a hollow fiber membrane having good urea clearance and albumin leakage was obtained.
From the results of Example 1 and Comparative Examples 4 and 5, it was found that good urea clearance was exhibited by selecting an alcohol or ketone having 4 or less carbon atoms.

ADVANTAGE OF THE INVENTION According to this invention, the hollow fiber membrane for blood processing which has the high solute permeation | permeability performance and antioxidant performance which can implement | achieve albumin leakage, and is excellent in biocompatibility by suppressing complications can be provided.
The hollow fiber membrane for blood treatment of the present invention has industrial applicability in blood purification treatment.

DESCRIPTION OF SYMBOLS 1 Blood processing hollow fiber membrane 1a 1st flow path 2 Cylindrical container 2a, 2b Port 3a, 3b Sealing resin 6a, 6b Nozzle 7a Header cap 8 Header inner space 10 Hollow fiber membrane type blood purifier 11 2nd Flow path Fa Flow direction of treatment liquid 1 (for example, dialysate) Fb Flow direction of treatment liquid 2 (for example, blood)

Claims (7)

A hollow fiber membrane for blood treatment comprising a hydrophobic resin, a hydrophilic resin and an oil and fat,
The ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane is 25% or more and 32% or less,
Containing 10 mg / m ² or more and 300 mg / m ² or less of oil and fat in terms of membrane area,
The urea clearance converted to 1.5 m ² is 100 mL / min or more and 185 mL / min or less,
A hollow fiber membrane for blood treatment having an albumin sieving coefficient of 0.001 or more and 0.008 or less.   The hollow fiber membrane for blood treatment according to claim 1, wherein the ratio of the hydrophilic resin present on the inner surface of the hollow fiber membrane is 25% or more and 30% or less.   The ratio (Ii / Io) of the amount of fat (Ii) present on the inner surface of the hollow fiber membrane to the amount of fat (Io) present on the outer surface of the hollow fiber membrane is 1.0 or more and 1.5 or less. The hollow fiber membrane for blood processing according to claim 1 or 2.   The hollow fiber membrane for blood treatment according to any one of claims 1 to 3, wherein the hydrophobic resin is a polysulfone resin.   The hollow fiber membrane for blood treatment according to any one of claims 1 to 4, wherein the hydrophilic resin is polyvinylpyrrolidone.   The hollow fiber membrane for blood treatment according to any one of claims 1 to 5, wherein the fat is a fat-soluble antioxidant. The hollow fiber membrane for blood treatment according to any one of claims 1 to 6 , further comprising a ketone and / or alcohol having 2 to 3000 µg of carbon atoms of 4 or less per 1 g of the hollow fiber membrane.