JP6682568B2 - Blood purifier and its manufacturing method - Google Patents

Description

  The present invention relates to a blood purifier having a hollow fiber membrane containing an inorganic ion adsorbent and a method for producing the same. More specifically, the present invention relates to a blood purifier having a porous hollow fiber membrane containing an inorganic ion adsorbent, which has a high phosphorus adsorption capacity and can be used safely, and a method for producing the same.

Hemodialysis has been performed as a maintenance therapy for patients with chronic renal failure. Further, in recent years, examples of therapy such as continuous hemofiltration, continuous hemofiltration dialysis, continuous hemodialysis, etc. are increasing as acute blood purification therapy for patients with serious pathological conditions such as acute renal failure and sepsis. . Materials for blood purification membranes used in these therapies include naturally-derived materials such as cellulose and cellulose derivatives, and synthetic polymer materials such as polysulfone-based resins, polymethylmethacrylate, polyacrylonitrile, and ethylene vinyl alcohol copolymers. Is used. Among them, a film made of a polysulfone-based resin has attracted particular attention in recent years because it has advantages such as good mechanical properties, heat resistance, and biocompatibility.
Since the polysulfone resin is relatively hydrophobic, it tends to adsorb plasma proteins when it comes into contact with blood. For this reason, when a blood purification membrane is manufactured with a polysulfone resin, a hydrophilic polymer (hereinafter, also referred to as a hydrophilic polymer) is generally added in order to impart hydrophilicity and improve blood compatibility. Target.

In addition, as described above, materials with strong hydrophobicity easily adsorb plasma proteins, so when used in contact with blood for a long period of time, the plasma proteins adsorbed on the surface will reduce the membrane performance over time. Will end up. Since plasma protein adsorption is reduced by imparting hydrophilicity, addition of hydrophilic polymer is effective not only for improving blood compatibility (biocompatibility) but also for exhibiting stable solute removal performance as a membrane. is there.
Polyvinylpyrrolidone (hereinafter, also referred to as PVP) is generally used as the hydrophilic polymer used in this way. However, when a hydrophilic polymer is used, it tends to swell in an aqueous solution and block the pores of the membrane, resulting in a decrease in the permeation performance.

  The following Patent Document 1 describes a method for producing a membrane in which only a polysulfone-based polymer, which is a base polymer of the membrane, is allowed to remain and a part of PVP is decomposed and removed with an aqueous sodium hypochlorite solution. However, this method has a problem that the hydrophilicity of the film is lowered because PVP, which is the hydrophilizing agent, is removed.

  In blood purification hollow fiber membranes, many studies have been conducted to improve the permeability of specific substances by mainly examining the membrane structure, membrane composition, and physical properties of the hollow fiber membranes. Specifically, while increasing the pore size of the membrane for removing uremic protein (also called low molecular weight protein), and suppressing permeation or loss of albumin, which is useful to the living body, Improvement of fractionation property that allows small low-molecular weight proteins to permeate, or improvement of membrane surface properties for more selective permeation of charged low-molecular weight non-protein uremic substances not limited to low-molecular weight proteins Etc. can be illustrated.

Dialysis amyloidosis is well known as a typical example of a complication caused by a long-term dialysis treatment and caused by a low molecular weight protein having urinary toxicity. On the other hand, in order to improve the removal performance of β2-microglobulin, which is a causative substance of dialysis amyloidosis, while suppressing permeation of albumin, which is useful to the living body, in order to sharpen the fractionation property of the hollow fiber membrane. Various improvements have been investigated.
For example, in Patent Document 2 below, a hydrophilic polymer is concentrated in a dense layer in the vicinity of the inner surface of the membrane to improve the balance of membrane permeation, and a membrane that has high water permeability but little protein leakage. Is disclosed.
Further, the following Patent Document 3 specifically discloses albumin permeability and phosphorus clearance performance, but the clearance performance of vitamin B ₁₂ is unknown.
Further, Patent Document 4 and Patent Document 5 below disclose a dialyzer comprising a hollow fiber membrane obtained from a 4-component membrane-forming stock solution comprising a polysulfone-based polymer, PVP, a solvent, and water. Addition of water to the stock solution for film formation facilitates precipitation of cyclic dimer, which is an impurity in the polysulfone-based polymer. Therefore, the amount of impurities in the stock solution for film formation increases, which is not suitable for stable production for a long period of time. Although the clearance performance of phosphorus and the clearance performance of vitamin B ₁₂ of these dialyzer are disclosed, it is a membrane having only an abnormally high water permeability.
Further, the following Patent Document 6 discloses the clearance performance of urea and the clearance performance of vitamin B ₁₂ , but the clearance performance of phosphorus is unknown.

Thus, to date, no blood purifier having high clearance performance, high water permeability, and safe use for phosphorus, urea, and vitamin B ₁₂ has been provided.

Japanese Patent Laid-Open No. 05-161833 JP-A-4-300636 Japanese Patent No. 4126062 JP 2001-170172 A JP 2001-170167 A International Publication No. 2004/094047

  In view of the above-mentioned problems of the prior art, the problem to be solved by the present invention is to provide a blood purifier having a porous hollow fiber membrane which has a high phosphorus adsorption capacity and can be used safely.

  The present inventor has conducted extensive studies and experiments in order to solve the above problems, and while containing an inorganic ion adsorbent having a high phosphorus adsorption capacity in the hollow fiber membrane, the hollow fiber membrane is washed with a supercritical fluid or a subcritical fluid By completely removing fine particles generated from a blood purifier having a thread membrane, it was found that a clearance value of phosphorus is high, and a blood purifier that can be used safely can be obtained, and the present invention is completed. It has come.

That is, the present invention is as follows.
[1] A blood purifier having a hollow fiber membrane containing an inorganic ion adsorbent, wherein a stock solution prepared by adding physiological saline to bovine serum to adjust the total protein concentration to 6.5 g / dL is applied to the hollow fiber membrane. When the filtrate is collected under a pressure of 25 mmHg of transmembrane pressure for 60 minutes and the albumin concentration is measured by the BCG method, the following formula (1):
Albumin permeability (%) = Albumin concentration of filtrate / Albumin concentration of stock solution × 100 (1)
In transmittance of the albumin expressed is 5% or less, the blood purifier in the enclosed injectable saline or 10μm of the injectable physiological saline 1mL after and 6 months after March from the and the number of particles below 25, and state, and are more number of particles 3 or less 25 [mu] m, the hollow fiber membrane is composed of a film forming polymer and a hydrophilic polymer and an inorganic ion adsorbent, membrane formation The polymer is a polymer capable of forming a porous hollow fiber membrane by wet membrane formation, the hydrophilic polymer is polyvinylpyrrolidone (PVP) -based polymer, and the inorganic ion adsorbent is a metal oxide or a polymer. The hollow fiber membrane is a salt of a valent metal or an insoluble hydrous oxide, and the hollow fiber membrane is a polyvinylpyrrolidone (PVP) polymer and polymethoxyethyl acrylate (PMEA) which are biocompatible polymers. The blood purifier characterized that you have been coated with.
[2] pore size before Symbol in hollow fiber membrane is larger toward the outer surface from the inner surface, blood purifier according to [1].
[3] The blood purifier according to [1] or [2] , wherein the degree of crosslinking of the PVP-based polymer is 80% or more and less than 100%.
[4] The blood purifier according to any one of [1] to [3] , wherein the clearance value of phosphorus is 190 ml / min or more per membrane area of 1.5 m ² .
[5] The blood purifier according to any one of [1] to [4] , wherein the urea clearance value is 195 ml / min or more per membrane area of 1.5 m ² .
[6] The blood purifier according to any one of [1] to [5] , wherein the creatinine clearance value is 186 ml / min or more per membrane area of 1.5 m ² .
[7] The blood purifier according to any one of [1] to [6] , wherein the clearance value of vitamin B ₁₂ is 142 ml / min or more per 1.5 m ^{2 of} membrane area.
[8] The method described in [1] to [1] , including a step of washing the hollow fiber membrane containing the inorganic ion adsorbent with a supercritical fluid or a subcritical fluid, and then coating the surface of the hollow fiber membrane with a biocompatible polymer . [7] The method for manufacturing a blood purifier according to any one of [ 7] .
[9] A PVP-based polymer and a crosslinking degree adjusting agent solution are sequentially injected from the inner surface side of the hollow fiber membrane, then the crosslinking degree adjusting agent solution is removed, and then the hollow fiber membrane is irradiated with radiation to produce PVP. The method for producing a blood purifier according to any one of [3] to [7] above, which comprises a step of setting the crosslinking degree of the base polymer to 80% or more and less than 100%.
[10] The method according to [9] , wherein the oxygen concentration in the blood purifier is adjusted to 0.01% by volume or more and 0.1% by volume or less when the radiation is applied.

The blood purifier according to the present invention has a high phosphorus adsorption capacity and can be used safely. The blood purifier according to the present invention also has high clearance performance for urea, creatinine, and vitamin B ₁₂ .
Specifically, the blood purifier of the present invention has excellent selectivity and adsorptivity for phosphorus in blood even when the blood flow rate is high during extracorporeal circulation treatment, and it is possible to remove other components in blood. Without affecting, it is possible to eliminate the required amount of phosphorus in the blood, and since it is possible to effectively remove the phosphorus in the blood by extracorporeal circulation, without taking a phosphorus adsorbent oral drug etc. with side effects, The phosphorus concentration in blood can be appropriately controlled.
Therefore, by using the blood purifier of the present invention, the dialysis patient does not take the phosphorus adsorbent oral drug, or even if it is kept in a small amount (auxiliary use), without causing a side effect of the dialysis patient, The phosphorus concentration in the blood of the body can be appropriately controlled.

Hereinafter, embodiments of the present invention will be described in detail.
The blood purifier of the present embodiment is a blood purifier having a hollow fiber membrane containing an inorganic ion adsorbent, and a stock solution prepared by adding physiological saline to bovine serum to adjust the total protein concentration to 6.5 g / dL. When passing through the hollow fiber membrane for 60 minutes, collecting the filtrate under a pressure of 25 mmHg between the membranes, and measuring the albumin concentration by the BCG method, the following formula (1):
Albumin permeability (%) = Albumin concentration of filtrate / Albumin concentration of stock solution × 100 (1)
Of albumin having a transmittance of 5% or less, and in 1 mL of the physiological saline solution for injection 3 months and 6 months after the physiological saline solution for injection is enclosed in the blood purifier. The number of fine particles of 10 μm or more is 25 or less, and the number of fine particles of 25 μm or more is 3 or less.

[Inorganic ion adsorbent]
The hollow fiber membrane of the present embodiment contains an inorganic ion adsorbent, and is preferably composed of a film-forming polymer, a hydrophilic polymer and an inorganic ion adsorbent.
The inorganic ion adsorbent contained in or constituting the hollow fiber membrane of the present embodiment means an inorganic substance exhibiting an ion adsorption phenomenon or an ion exchange phenomenon.
Examples of the natural product-based inorganic ion adsorbent include various mineral substances such as zeolite and montmorillonite.
Specific examples of various mineral substances include kaolin minerals having a single-layer lattice of aluminosilicate, muscovite with two-layer lattice structure, glauconite, Kanuma soil, pyrophyllite, talc, and feldspar with three-dimensional framework structure. , Zeolite, montmorillonite, and the like.
Examples of the synthetic inorganic ion adsorbents include metal oxides, salts of polyvalent metals, insoluble hydrous oxides, and the like. The metal oxide includes composite metal oxides, composite metal hydroxides, metal hydrous oxides, and the like.

The inorganic ion adsorbent has the following formula (2):
MN _x O _n · mH ₂ O (2)
Where, x is 0-3, n is 1-4, m is 0-6, and M and N are Ti, Zr, Sn, Sc, Y, La, Ce. , Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga, Fe, Mn, Ni, V, Ge, Nb, and Ta Metal elements selected from the group consisting of } It is preferable to contain at least 1 sort (s) of metal oxide represented by these.
The metal oxide may be a non-hydrated (unhydrated) metal oxide in which m in formula (2) is 0, or a metal hydrate (water) in which m is a value other than 0. A metal oxide).
When x in the formula (2) is a value other than 0, each metal element contained in the metal oxide has regularity and is uniformly distributed throughout the oxide, It is a composite metal oxide represented by a chemical formula in which the composition ratio of metal elements is fixed.
Specifically, a perovskite structure, a spinel structure, or the like is formed, and nickel ferrite (NiFe ₂ O ₄ ), zirconium hydrous ferrite (Zr · Fe ₂ O ₄ · mH ₂ O, where m is 0. 5 to 6) and the like.
The inorganic ion adsorbent may contain a plurality of types of metal oxides represented by formula (2).

The metal oxide as an inorganic ion adsorbent has the following (a) to (c) groups from the viewpoint of being excellent in adsorption performance of an object to be adsorbed, especially phosphorus:
(A) hydrated titanium oxide, hydrated zirconium oxide, hydrated tin oxide, hydrated cerium oxide, hydrated lanthanum oxide, and hydrated yttrium oxide;
(B) Composite metal oxidation of at least one metal element selected from the group consisting of titanium, zirconium, tin, cerium, lanthanum, and yttrium and at least one metal element selected from the group consisting of aluminum, silicon, and iron. Stuff;
(C) More preferably selected from activated alumina.
A material selected from any of the groups (a) to (c) may be used, or a material selected from any of the groups (a) to (c) may be used in combination, The materials in each of the groups (a) to (c) may be used in combination. When used in combination, it may be a mixture of two or more kinds of materials selected from any of the groups (a) to (c), and two or more groups of the groups (a) to (c). It may be a mixture of two or more materials selected from.

The inorganic ion adsorbent may contain aluminum sulfate-impregnated activated alumina from the viewpoint of being inexpensive and having high adsorbability.
As the inorganic ion adsorbent, in addition to the metal oxide represented by the formula (2), a solid solution of a metal element other than M and N described above is more preferable from the viewpoint of adsorbability of inorganic ions and manufacturing cost. preferable.
For example, hydrated zirconium oxide represented by ZrO ₂ · mH ₂ O (m is a value other than 0) in which iron is solid-dissolved can be mentioned.
Examples of the salt of polyvalent metal include the following formula (3):
M ²⁺ _(1-p) M ³⁺ _p (OH ⁻ ) _{(2 + p−q)} (A ⁿ⁻ ) _{q / r} (3)
{In the formula, M ²⁺ is at least one divalent metal ion selected from the group consisting of Mg ²⁺ , Ni ²⁺ , Zn ²⁺ , Fe ²⁺ , Ca ²⁺ , and Cu ²⁺ , and M ³⁺ is Al ³⁺ and At least one trivalent metal ion selected from the group consisting of Fe ³⁺ , A ⁿ⁻ is an n-valent anion, 0.1 ≦ p ≦ 0.5, and 0.1 ≦ q ≦ 0. .5 and r is 1 or 2. } The hydrotalcite type compound represented by these is mentioned.
The hydrotalcite-based compound represented by the formula (3) is preferable as the inorganic ion adsorbent because the raw material is inexpensive and the adsorptivity is high.
Examples of the insoluble hydrous oxide include insoluble heteropolyacid salt and insoluble hexacyanoferrate.
The inorganic ion adsorbent constituting the hollow fiber membrane in the present embodiment may contain an impurity element mixed in due to the manufacturing method or the like within a range that does not impair the function of the hollow fiber membrane. Examples of impurity elements that may be mixed include nitrogen (nitrate, nitrite, ammonium), sodium, magnesium, sulfur, chlorine, potassium, calcium, copper, zinc, bromine, barium, hafnium, and the like. To be

[Particle removal]
The blood purifier of the present embodiment is characterized in that it satisfies the artificial kidney device approval standard set forth by the Ministry of Health, Labor and Welfare, which will be described below, even though the hollow fiber contains the inorganic ion adsorbent described above. . Specifically, in the blood purifier of the present embodiment, fine particles of 10 μm or more in 1 mL of the physiological saline for injection 3 months and 6 months after the physiological saline for injection is sealed in the blood purifier. The number of particles is 25 or less, the number of fine particles of 25 μm or more is 3 or less, the absorbance of the eluate test solution is 0.1 or less, and the membrane pore retainer is contained in the test solution. Not included.
In the production of the blood purifier according to the present embodiment, the inventors of the present invention purify blood by cleaning the hollow fiber with a supercritical fluid or a subcritical fluid, even though the hollow fiber contains the inorganic ion adsorbent. It was found that the fine particles generated from the vessel can be completely removed.
The supercritical fluid means a fluid under the conditions of a critical pressure (hereinafter also referred to as Pc) or higher and a critical temperature (hereinafter also referred to as Tc) or higher. The subcritical fluid is a state other than the supercritical state, and when the pressure and temperature during the reaction are P and T, respectively, 0.5 <P / Pc <1.0 and 0.5 <P It means a fluid under the conditions of T / Tc or 0.5 <P / Pc and 0.5 <T / Tc <1.0. The preferable pressure and temperature ranges of the subcritical fluid are 0.6 <P / Pc <1.0 and 0.6 <T / Tc, or 0.6 <P / Pc and 0.6 <T. /Tc<1.0. However, when the fluid is water, the temperature and pressure ranges of the subcritical fluid are 0.5 <P / Pc <1.0 and 0.5 <T / Tc, or 0.5 < P / Pc and 0.5 <T / Tc <1.0 may be satisfied. Here, the temperature represents Celsius, but when either Tc or T is negative, the formula representing the subcritical state is not limited to this.
As the supercritical fluid or subcritical fluid, an organic medium such as water or alcohol, a gas such as carbon dioxide, nitrogen, oxygen, helium, argon or air, or a mixed fluid thereof is used. Carbon dioxide is most preferable because it can be brought into a supercritical state even at a temperature around room temperature and dissolves various substances well.

[Film forming polymer]
The film-forming polymer that constitutes the hollow fiber used in the blood purifier of the present embodiment may be any polymer that can form a porous hollow fiber membrane by wet film formation, and examples thereof include polysulfone-based polymers and polyvinylidene fluoride-based polymers. Examples include polymers, polyacrylonitrile-based polymers, polymethacrylic acid-based polymers, polyamide-based polymers, polyimide-based polymers, polyetherimide-based polymers, cellulose acetate-based polymers and the like. Among them, aromatic polysulfones are preferable because they are excellent in thermal stability, acid resistance, alkali resistance and mechanical strength.
As the aromatic polysulfone, the following formula (4):
_{-O-Ar-C (CH 3} ) 2 -Ar-O-Ar-SO 2 -Ar- ··· (4)
{In the formula, Ar is a 2-substituted phenyl group at the para position. } Or the following formula (5):
_{-O-Ar-SO 2 -Ar- ···} (5)
{In the formula, Ar is a 2-substituted phenyl group at the para position. } Which have the repeating unit represented by these. The degree of polymerization and the molecular weight of the aromatic polysulfone are not particularly limited.

[Hydrophilic polymer]
The hydrophilic polymer that can form the hollow fiber membrane is a biocompatible polymer that swells in water but does not dissolve in water, and is not particularly limited, but includes a sulfonic acid group, a carboxyl group, a carbonyl group, and an ester. Groups, amino groups, amide groups, cyano groups, hydroxyl groups, methoxy groups, phosphoric acid groups, oxyethylene groups, imino groups, imide groups, imino ether groups, pyridine groups, pyrrolidone groups, imidazole groups, quaternary ammonium groups, etc. Polymers having one kind or a plurality of kinds can be exemplified.
When the film-forming polymer is aromatic polysulfone, polyvinylpyrrolidone (hereinafter, also referred to as PVP) -based polymer is most preferable as the hydrophilic polymer.
Examples of the polyvinylpyrrolidone-based polymer include vinylpyrrolidone / vinyl acetate copolymer, vinylpyrrolidone / vinylcaprolactam copolymer, vinylpyrrolidone / vinyl alcohol copolymer, and the like, and at least one of them may be contained. preferable. Among them, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, and vinylpyrrolidone / vinylcaprolactam copolymer are preferably used from the viewpoint of compatibility with the polysulfone-based polymer.

The hollow fiber membrane used in the blood purifier of the present embodiment is preferably coated with a biocompatible polymer, and the biocompatible polymer is preferably polymethoxyethyl acrylate (PMEA) and polyvinylpyrrolidone (PVP). It is selected from the group consisting of polymers.
[Polymethoxyethyl acrylate (PMEA)]
Regarding the biocompatibility (blood compatibility) of PMEA, Ken Tanaka, Material for biocompatible the surface of artificial organs, BIO INDUSTRY, Vol 20, No. 12, 59-70 2003.
Among them, acrylate polymers having different side chain structures were prepared for comparison with PMEA, and various markers of platelet, leukocyte, complement and coagulation system when circulating blood were evaluated. Activation of blood components was less than that of other macromolecules. In addition, the number of adherent human platelets on the PMEA surface was significantly less and the morphological change of adherent platelets was smaller, which is excellent in blood compatibility. " Has been done.
As described above, PMEA is not simply good in blood compatibility because it has an ester group in its structure and is hydrophilic, and it is considered that the state of water molecules adsorbed on the surface has a great influence on blood compatibility. Has been.
In the ATR-IR method, since the wave incident on the sample slightly digs into the sample and is reflected, it is known that the infrared absorption in the digging depth region can be measured. It was also found that the measurement area of the ATR-IR method is almost equal to the depth of the "surface layer" corresponding to the surface of the hollow fiber membrane. That is, the blood compatibility in the depth region almost equal to the measurement region of the ATR-IR method controls the blood compatibility of the hollow fiber membrane, and the presence of PMEA in the region allows blood having a certain blood compatibility. It has been found that a purifier can be provided. By coating PMEA on the surface of the hollow fiber membrane, generation of fine particles from the blood purifier after long-term storage can be suppressed.

The measurement region by the ATR-IR method depends on the wavelength of infrared light in air, the incident angle, the refractive index of the prism, the refractive index of the sample, and the like, and is usually a region within 1 μm from the surface.
The presence of PMEA on the surface of the hollow fiber membrane can be confirmed by thermal decomposition gas chromatography mass spectrometry of the hollow fiber membrane. The presence of PMEA is estimated by a total reflection infrared absorption (ATR-IR) measurement on the surface of the hollow fiber membrane if a peak is seen near 1735 cm ⁻¹ in the infrared absorption curve, but other peaks near this are estimated. It may also come from a substance. Therefore, the presence of PMEA can be confirmed by performing pyrolysis gas chromatography mass spectrometry and confirming 2-methoxyethanol derived from PMEA.
There is a unique solubility of PMEA in a solvent. For example, PMEA does not dissolve in 100% ethanol solvent, but the water / ethanol mixed solvent has a region in which it dissolves depending on the mixing ratio. Then, in the mixing ratio in the dissolving region, the peak intensity of the peak derived from PMEA (around 1735 cm ⁻¹ ) becomes stronger as the amount of water increases.
In the hollow fiber membrane containing PMEA on the surface, since the change in the pore size on the surface is small, the water permeability does not change so much and the product design is simple. In this embodiment, PMEA is provided on the surface of the hollow fiber membrane. For example, when PMEA is coated on the hollow fiber membrane, the PMEA adheres to the ultrathin film and the hollow fiber membrane does not substantially close the pores. It is thought that the surface is coated. In particular, PMEA is preferable because it has a small molecular weight and a short molecular chain, so that the coating structure is unlikely to become thick and the hollow fiber membrane structure is unlikely to change. Further, PMEA is preferable because it has high compatibility with other substances, can be uniformly applied to the surface of the hollow fiber membrane, and can improve blood compatibility.
The weight average molecular weight of PMEA can be measured, for example, by gel permeation chromatography (GPC).
As a method of forming the PMEA coating on the inner surface of the hollow fiber membrane, for example, a method of flowing a PMEA solution from the upper portion of the blood purifier filled with the hollow fiber membrane to perform coating is preferably used.

[Polyvinylpyrrolidone (PVP) polymer]
The polyvinylpyrrolidone (PVP) polymer is not particularly limited, but polyvinylpyrrolidone (PVP) is preferably used.
The degree of crosslinking of the PVP-based polymer is preferably 80% or more and less than 100%, more preferably 80% or more and 99% or less, and further preferably 85% or more and 95% or less.
If the degree of crosslinking of the PVP-based polymer in the hollow fiber membrane is less than 80%, the PVP-based polymer that contributes to making the hollow fiber membrane hydrophilic may be eluted from the membrane. On the other hand, if the degree of crosslinking of the PVP-based polymer is 100%, the elution amount can be reduced, but leukopenia symptoms may be observed during dialysis.
The degree of cross-linking of the PVP-based polymer is represented by the following formula (6):
Crosslinking degree (%) of PVP-based polymer = amount of PVP-based polymer insoluble in water / total amount of PVP-based polymer x 100 (6)
Is defined by
Here, the amount of the PVP-based polymer that is insoluble in water is the amount of the total PVP-based polymer minus the amount of the PVP-based polymer that is soluble in water. For example, the degree of crosslinking of polyvinylpyrrolidone PVP in the hollow fiber membrane can be determined from the total amount of PVP contained in the unit weight of the hollow fiber membrane and the amount of PVP that is insoluble in water (among them). The total amount of PVP in a unit weight of hollow fiber membrane is the chemiluminescence of the concentration of nitric oxide produced by vaporizing and oxidizing 0.2 to 0.5 mg of the dried hollow fiber membrane in a horizontal reactor (800 to 950 ° C). Method (the TN-10 manufactured by Mitsubishi Kagaku Co., Ltd. is used) is measured, and the obtained concentration is converted into the amount of PVP contained in the hollow fiber membrane per unit weight. For the quantification, a calibration curve prepared in advance using a standard sample of a nitrogen-containing polymer is prepared, and the concentration is determined using this.

The amount of PVP soluble in water can be determined by the following method.
That is, a unit mass of the hollow fiber membrane is dried to a water content of 0.3% by weight or less, and this is dissolved in N-methyl-2-pyrrolidone to a concentration of 2.5% by weight, Make a solution. To the solution, 1.7 times the volume of water was added and stirred for 10 minutes to sufficiently precipitate the polysulfone-based polymer in the hollow fiber membrane. The water-soluble PVP is contained in the solution together with the precipitated polysulfone fine particles. Then, the polysulfone fine particles in the solution are removed by filtering with a non-aqueous filter (manufactured by Tosoh, pore size: 2.5 μm) for HPLC (high performance liquid chromatography), and polyvinylpyrrolidone contained in the filtrate is quantified by HPLC. (Apparatus: Waters, GPC-244, column: TSKgelGMPWXL2, solvent: 0.1 M ammonium chloride (0.1 N ammonia), pH 9.5 ammonium chloride aqueous solution, flow rate: 1.0 ml / min, temperature: 23 ° C.). The amount of polyvinylpyrrolidone contained in the filtrate determined as described above is the amount of water-soluble PVP contained per unit weight of the hollow fiber membrane. As the amount of PVP soluble in water when calculating the degree of crosslinking of PVP, the above measurement is performed 10 times, and the average value of 8 points excluding the maximum and minimum values is used.

  The degree of crosslinking of PVP can be determined, for example, by sequentially injecting a PVP-based polymer and a crosslinking degree adjusting agent solution from the inner surface side of the hollow fiber membrane, then removing the crosslinking degree adjusting agent solution, and then irradiating the hollow fiber membrane with radiation. By doing so, it can be adjusted by going through a step of 80% or more and less than 100%. Further, it is preferable that the oxygen concentration in the blood purifier is 0.01% by volume or more and 10% by volume or less when the radiation is applied.

The form of the hollow fiber membrane is not particularly limited, and may be so-called straight yarn, but from the viewpoint of diffusion efficiency when used for hemodialysis, a crimped one is preferable.
In the blood purifier according to the present embodiment, by adjusting the degree of crosslinking of PVP as described above, PVP is insolubilized, the elution from the PVP in the solution enclosed in the blood purifier is suppressed, and the PVP is dissolved in the blood purifier. It is possible to reduce the PVP concentration in the solution to 10 ppm or less 6 months after the solution is sealed. As a blood purifier for dialysis, a non-rinse type (a blood purifier that is connected to a human body without performing priming cleaning with physiological saline or the like) is being widely used. Therefore, there is a demand for reduction of impurities present in the blood purifier, and not only PVP but also the solvent remaining in the membrane (eg, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, etc.) is removed as much as possible. Purifiers are needed. In the blood purifier of the present embodiment, the concentration of the solvent in the solution is 10 ppm or less 3 months and 6 months after the solution is enclosed in the blood purifier. Nearly 70% of blood purifiers for dialysis are used for 3 months to 6 months after being manufactured and shipped.

The method for measuring the PVP concentration and the solvent concentration in the solution enclosed in the blood purifier is as follows.
(1) Method of measurement in wet type blood purifier A wet type blood purifier is shipped as it is by encapsulating a solution (for example, UF filtration membrane water) immediately before shipping, performing radiation sterilization in the solution. . In such a wet type blood purifier, the PVP concentration and the solvent concentration in the solution (filling liquid) are measured. In the case of the wet type, the time from 3 months to 6 months after the solution is filled in the blood purifier is from the manufacturing month (manufacturing year / month that can be read from the manufacturing number) described in the manufacturing number to the end of the following month. It is calculated as one month later. The blood purifier is kept at 25 ° C ± 1 ° C and stored in a static state after being obtained. The solution (filling solution) is sampled after all the solution (filling solution) is taken out from the blood purifier as much as possible and then uniformly mixed. For example, after sampling for measurement at 3 months, the remaining whole solution (filling solution) is put into the original blood purifier, sealed, and stored for another 3 months, and used for measurement at 6 months.
(2) Measuring method in dry type blood purifier In a dry type blood purifier, radiation sterilization is often not performed in a solution, and the product is often shipped in a dry state. Therefore, the time when 3 months or more and 6 months or less have elapsed from the time when the pure water was enclosed in the blood purifier is calculated. When enclosing pure water in the blood purifier, pure water is also injected into the hollow part of the hollow fiber membrane, and the inner and outer surfaces of all hollow fiber membranes are always immersed in pure water at 25 ° C ± 1 ° C. And store it in a static state. However, use the blood purifier within 1 year from the manufacturing month (manufacturing year / month that can be read from the manufacturing number) described in the manufacturing number. The solution (filling solution) is sampled after all the solution (filling solution) is taken out from the blood purifier as much as possible and then uniformly mixed. For example, after sampling for measurement at 3 months, the remaining whole solution (filling solution) is put into the original blood purifier, sealed, and stored for another 3 months, and used for measurement at 6 months.

  The PVP concentration and the solvent concentration in the sampled solution (or filling liquid) were separated by using an apparatus in which a column (ASAHIPAK GS-620H manufactured by Asahi Kasei Co., Ltd. or an equivalent performance column) was connected to a liquid chromatograph and an ultraviolet spectrometer ( It can be determined by measuring with Tosoh UV8010 or equivalent performance machine). With respect to the use conditions, for example, in the case of PVP, mobile phase: pure water, column temperature: 38 ° C., measurement wavelength: 208 nm can be used.

Generally, a blood purifier is used for removing unnecessary substances such as urea and water in blood, and for removing disease-causing substances from blood and plasma. For example, in a hyperlipidemic patient, it is possible to remove only the plasma from the blood and remove the lipid from the plasma. The blood purifier of this embodiment is particularly preferably used for dialysis applications.
In order for the blood purifier for dialysis to obtain the manufacturing (import) approval of the dialysis type artificial kidney device, it is necessary to meet the artificial kidney device approval standard set by the Ministry of Health, Labor and Welfare. Therefore, it is necessary that the blood purifier of the present embodiment satisfies the criteria of the eluate test described in the artificial kidney device approval criteria, and that the eluate test solution in the test does not contain a membrane pore retaining agent. . Specifically, in the blood purifier of the present embodiment, fine particles of 10 μm or more in 1 mL of the physiological saline for injection 3 months and 6 months after the physiological saline for injection is sealed in the blood purifier. The number of particles is 25 or less, the number of fine particles of 25 μm or more is 3 or less, the absorbance of the eluate test solution is 0.1 or less, and the membrane pore retainer is contained in the test solution. Not included.

The method for measuring the number of fine particles in the physiological saline solution for injection enclosed in the blood purifier is as follows.
(1) Method of measurement in wet type blood purifier A wet type blood purifier is shipped as it is by encapsulating a solution (for example, UF filtration membrane water) immediately before shipping, performing radiation sterilization in the solution. . In such a wet type blood purifier, after completely removing the solution, after filtering with 10 L of physiological saline for injection from the inner surface side to the outer surface side of the hollow fiber membrane in the blood purifier, After enclosing a new physiological saline solution for injection, it is kept warm at 25 ° C ± 1 ° C and stored in a static state for 3 months. The sampling of the saline solution from the blood purifier is performed after all the solutions (filling liquids) have been taken out from the blood purifier as much as possible and then uniformly mixed. For example, after sampling for measurement at 3 months, the remaining saline is put into the original blood purifier, sealed, and stored for another 3 months, and used for measurement at 6 months.
(2) Measuring method in dry type blood purifier In a dry type blood purifier, radiation sterilization is often not performed in a solution, and the product is often shipped in a dry state. After filtering with 10 L of physiological saline for injection from the inner surface side to the outer surface side of the hollow fiber membrane in the blood purifier, a new physiological saline solution for injection is sealed and kept at 25 ° C ± 1 ° C. And store in a static state for 3 months. The sampling of the saline solution from the blood purifier is performed after all the solutions (filling liquids) have been taken out from the blood purifier as much as possible and then uniformly mixed. For example, after sampling for measurement at 3 months, the remaining saline is put into the original blood purifier, sealed, and stored for another 3 months, and used for measurement at 6 months.
The number of fine particles in the sampled solution (or filling liquid) can be measured with a particle counter.

The membrane pore retaining agent is a substance that is filled in the pores in the membrane during the manufacturing process before drying in order to prevent performance deterioration in the drying step when manufacturing the blood purifier. Examples of the membrane pore retaining agent include ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, 2-butyne-1,4-diol, 2-methyl-2,4. -Organic compounds such as pentadiol, 2-ethyl-1,3-hexanediol, glycerin, tetraethylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and other glycol-based or glycerol-based compounds and sucrose fatty acid ester; Inorganic salts such as calcium, sodium carbonate, sodium acetate, magnesium sulfate, sodium sulfate and zinc chloride can be mentioned.
By immersing the wet membrane in the solution containing the membrane pore retaining agent, it is possible to fill the pore portion in the membrane with the membrane pore retaining agent. If the membrane pore retaining agent is only washed and removed after drying, it is possible to maintain the same performance as the wet membrane such as the amount of water permeation and blocking rate due to the effect of the membrane pore retaining agent. However, it has been reported that various derivatives are generated as a result of chemical reaction with the pore-holding agent when the pore-holding agent is present in a trace amount in the membrane and / or in the blood purifier enclosed liquid. . The blood purifier of this embodiment does not use the membrane pore retaining agent in the manufacturing process. More specifically, in the blood purifier of the present embodiment, first, a membrane having a pore diameter larger than the final pore diameter is finally produced, and in the subsequent drying step, the final pore diameter is finally obtained. Since the film is dried and shrunk as described above, it is not necessary to use the membrane hole holding material in the manufacturing process. Therefore, the blood purifier of the present embodiment does not contain a membrane pore retaining agent in the eluate test solution in the eluate test described in the artificial kidney device approval standard.

  The eluate test solution in the above-mentioned eluate test was prepared based on the approval criteria of the artificial kidney device. 1.5 g of the dry hollow fiber membrane cut into 2 cm and 150 mL of distilled water for injection were used for injection in the Japanese Pharmacopoeia. The sample was placed in a glass container compatible with the alkali elution test of the glass container test, heated at 70 ± 5 ° C. for 1 hour, and after cooling, the membrane was removed and distilled water was added to make 150 mL. The absorbance of the eluate test solution is measured by an ultraviolet absorption spectrum at a wavelength showing a maximum absorption wavelength at 220 to 350 nm. Although the artificial kidney device approval standard stipulates that the absorbance should be 0.1 or less, the blood purifier of the present embodiment does not contain a membrane pore retaining agent and can achieve an absorbance of less than 0.04. Is. Further, regarding the presence or absence of a membrane pore retaining agent in the eluate test solution, after concentrating or removing water from the eluate test solution, gas chromatography, liquid chromatography, differential refractometer, ultraviolet spectrophotometer, infrared absorption spectrophotometry , Nuclear magnetic resonance spectroscopy, and elemental analysis. Whether or not the hollow fiber membrane of the blood purifier contains a membrane pore retaining agent can also be detected by these measuring methods.

  The material of the container (housing) of the blood purifier of the present embodiment is not limited, and examples thereof include polystyrene-based polymers, polysulfone-based polymers, polyethylene-based polymers, polypropylene-based polymers, polycarbonate-based polymers, and mixtures such as styrene-butadiene block copolymers. Resin or the like can be used. From the viewpoint of the cost of raw materials, polyethylene-based polymers and polypropylene-based polymers are preferably used. From the viewpoint of compatibility with polyurethane adhesives and strength of containers, polypropylene polymers are particularly preferable. When a polypropylene-based polymer is used as the material of the container, it is preferable to subject the container to corona discharge treatment in order to improve the adhesiveness with the polyurethane-based adhesive. In order to further improve the adhesiveness, it is more preferable to subject the yarn bundle to the corona discharge treatment as well as the container. Corona discharge to the yarn bundle is carried out only at the adhesion site.

The blood purifier of the present embodiment has an albumin transmittance of 5% or less, preferably 3% or less, more preferably 2% or less, still more preferably 1% or less, particularly preferably 0.35% or less. . 0.35% or less is preferable as a dialyzer for removing unnecessary substances such as urea and water in blood. In a blood purifier used for removing disease-causing substances from blood and plasma, albumin may have a transmittance of 5% or less. For example, in a hyperlipidemic patient, it is possible to remove only the plasma from the blood and remove the lipid from the plasma. In this embodiment, a blood purifier having an albumin transmittance of more than 5% is not preferable in the generation of fine particles. The blood purifier of this embodiment is particularly preferably used for dialysis applications.
The transmittance of albumin (hereinafter, also simply referred to as “Alb.”) Can be measured by the following method. 100 hollow fiber membranes taken out from the blood purifier are bundled to produce a mini module having an effective length of 18 cm. A bovine serum prepared by adding physiological saline to adjust the total protein concentration to 6.5 g / dL is used as a stock solution, and the concentration of albumin is determined in advance by the BCG method. This is passed through a mini-module at a linear velocity of 0.4 cm / sec, and a filtrate having a transmembrane pressure difference of 25 mmHg is applied to collect the filtrate. The temperature of the stock solution and the measurement environment is 25 ° C. In addition, the hollow fiber membranes constituting the mini module may be in a wet state or a dry state. Subsequently, the concentration of albumin in the filtrate was obtained by the BCG method, and the following formula (1):
Alb. Transmittance (%) = Alb. Concentration / stock solution Alb. Density x 100 (1)
The value obtained by is defined as the albumin transmittance. Here, as the transmittance, a value after passing through the liquid for 60 minutes is used.

The clearance of phosphorus of the blood purifier of the present embodiment is 190 ml / min or more per membrane area of 1.5 m ² , or in terms of membrane area of 1.5 m ² equivalent, preferably 195 ml / min or more. By including an inorganic ion adsorbent in the hollow fiber membrane, the clearance of phosphorus in the blood purifier can be increased to more than 190 ml / min per membrane area of 1.5 m ² , or in terms of membrane area of 1.5 m ^2. is there.
The amount of phosphorus removed by the blood purifier of the present embodiment is 900 mg or more per membrane area of 1.5 m ² , and preferably 1,000 mg or more per 1.5 m ² . The amount of phosphorus removed by the blood purifier is influenced by the concentration of phosphorus in the blood, but it is possible to make it 900 mg or more per 1.5 m ^{2 of} membrane area by including an inorganic ion adsorbent in the membrane.

Clearance of urea blood purifier of the present embodiment is 195 ml / min or more membrane area 1.5 m ² per or membrane area 1.5 m ² in terms of value, because it is preferably 198 ml / min or more, the hollow fiber Despite having the inorganic ion adsorbent in the membrane, it has the same performance as the conventional IV type dialyzer.

Blood purifier creatinine clearance of this embodiment is 186 ml / min or more membrane area 1.5 m ² per or membrane area 1.5 m ² in terms of value, because it is preferably 190 ml / min or more, the hollow fiber Despite having the inorganic ion adsorbent in the membrane, it has the same performance as the conventional IV type dialyzer.

Because clearance of the blood purifier of vitamin B ₁₂ in this embodiment is 142 ml / min or more membrane area 1.5 m ² per or membrane area 1.5 m ² in terms of value, preferably 150ml / min or more, Despite having an inorganic ion adsorbent in the hollow fiber membrane, it has the same performance as the conventional IV type dialyzer.

The measurement of phosphorus clearance of the blood purifier is based on the dialyzer performance evaluation standard (September 1982, Japan Society for Artificial Organs) after using the hollow fiber membrane as a blood purifier having a predetermined membrane area. carry out. For products, measure as is.
A 5 mEq / L physiological saline solution of inorganic phosphorus (pH 7.4 aqueous solution obtained by mixing each 5 mEq / L solution of monosodium phosphate and disodium phosphate at a ratio of 1: 4) on the blood side at a blood side flow rate of 200 mL / min. Circulating, dialysis fluid side is made to flow physiological saline at a dialysate side flow rate of 500 mL / min to perform dialysis under the condition without filtration, and the circulating fluid is sampled from the blood inlet side and the outlet side. The phosphorus concentration in the sampled liquid is measured by the molybdenum blue coloring method, and the following formula (7):
Clearance (mL / _{min) = {(C B (in} ) -C B (out)) / C B (in)} × Q B ··· (7)
{In the formula, C _{B (in)} : phosphorus concentration at the blood purifier inlet side, C _{B (out)} : phosphorus concentration at the blood purifier outlet side, Q _B : blood side flow rate (mL / min) = 200. } To calculate the clearance. Incidentally, the blood processor in a dry state is subjected to a moisturizing treatment in accordance with the above-mentioned evaluation standard of the dialyzer performance and used for measurement after 60 minutes have elapsed.

The clearance of urea, creatinine, and vitamin B _{12 in} the blood purifier was measured by dissolving a solution of 60 g of urea, 12 g of creatinine, and 1.2 g of vitamin B _{12 in} 60 liters of physiological saline in the blood side, respectively. The clearance is the same as that for phosphorus except that the physiological saline is circulated at a flow rate of 500 ml / min on the dialysate side and the dialysate side flow rate is 500 mL / min to perform dialysis under the condition without filtration. The concentrations of urea, creatinine and vitamin B _{12 in} the sampled liquid are measured by the absorbance at 190 nm, 230 nm and 360 nm, respectively.

The clearance conversion (membrane area conversion) is performed by the following equations (8) to (10):
_{C L '= (1-Z} ) / (1 / Q D' -Z / Q B ') ··· (8)
Wherein, Z = exp [K × A '× (1 / Q B' -1 / Q D ')] ··· (9)
K = ln [(1-C L / Q D) / (1-C L / Q B)] / [A × (1 / Q B -1 / Q D)] ··· (10)
_CL : Clearance value obtained by measurement (mL / min)
C _L ': Clearance value you want to convert (mL / min)
A: Effective membrane area (cm ² ) of the blood purifier used for clearance measurement
A ′: Effective membrane area (cm ² ) of the blood purifier to be converted, 1.5 m ^{2 in} this embodiment.
Q _B : Blood flow rate of blood purifier used for clearance measurement (mL / min)
Q _B ': blood flow rate (mL / min) of the blood purifier to be converted, 200 mL / min in the present embodiment Q _D : dialysate flow rate (mL / min) of the blood purifier used for clearance measurement
Q _D ': dialysate side flow rate (mL / min) of the blood purifier to be converted, 500 mL / min in the present embodiment

The performance of the blood purifier (for example, the impurity removal performance in the case of a blood purifier for dialysis) largely changes depending on the shape of the blood purifier. For example, the type with the extremely short distance between both ends of the blood purifier and the large number of hollow fiber membranes and the type with the extremely long distance between both ends of the blood purifier and the small number of hollow fiber membranes are the same. Even if the membrane area is different, the blood purifier performance will be completely different. This is because the shape of the blood purifier affects the pressure distribution of the fluid during filtration. Therefore, in the present embodiment, the yarn bundle is loaded into a container, both ends thereof are adhesively fixed with urethane resin, and both end faces are cut, and the distance between two open ends of the hollow fiber membrane and The relationship between the average diameter of the two open ends (circular shape) is expressed by the following formula (11):
Distance between two open ends / average diameter of two open ends = 4.5 to 6.5 (11)
It is preferable that the following relationship is satisfied.

  In a blood purifier having a hollow fiber membrane containing PVP, when the degree of crosslinking of PVP is high, blood compatibility tends to be low. In a blood purifier, blood generally flows on the inner surface of the membrane. The blood purifier of the present embodiment preferably has, for example, a PVP coating layer inside the hollow fiber membrane. This coating layer tends to improve blood compatibility because the amount of PVP existing on the inner surface of the membrane is large even if the degree of crosslinking of PVP is high.

  The blood purifier of this embodiment can be used for dialysis applications. In dialysis applications, it is the mainstream to let blood flow through the hollow part (inner membrane surface side). In order to prevent the proteins in blood from blocking the pores of the membrane on the inner surface of the membrane, a high concentration of PVP is retained on the inner surface of the membrane, and at the same time, the structure of the hollow fiber membrane is designed to promote mass transfer during filtration by dialysis. It is preferable to have a structure in which the pore diameter continuously increases from the inner surface to the outer surface, and the hollow fiber membrane preferably has a sponge structure. Here, the sponge structure refers to the pore diameter (biaxial average diameter, that is, the average value of the short diameter and the long diameter in the cross section of the film. Here, the short diameter and the long diameter respectively mean that the area circumscribing the void is the minimum. The short side and the long side of the circumscribed rectangle are 5 μm or more and have no void. Here, the void means a defective portion of the polymer, which is described below, for example, a gap between fibrils, which is a network-like skeleton portion made of the polymer.

  The hollow fiber membrane used in the blood purifier has a sponge structure in which the pore diameter continuously increases from the inner surface to the outer surface, and most of the membrane portion has a network-like skeleton portion called “fibril”. The average thickness of all fibrils present in the hollow fiber membrane is preferably 100 nm or more and 200 nm or less. When the average thickness of all the fibrils is less than 100 nm, the breaking strength and the breaking elongation tend to decrease, which is not preferable. On the other hand, if the average thickness of all fibrils exceeds 200 nm, the albumin transmittance exceeds 0.35% during dialysis use, which is not preferable. Although a membrane having a fractionation property that hardly allows albumin (molecular weight: 67,000), which is useful for the human body, to be transmitted, the hollow fiber membrane of the present embodiment has a bovine plasma albumin permeability of 0.35%. The following can be realized. An albumin transmittance of more than 0.35% means a large loss of effective albumin in the body, and is not preferable as a dialysis membrane. The amount of albumin stored in vivo in an adult male is about 300 g (4.6 g / kg), about 40% of which is distributed inside the blood vessel, and the remaining about 60% is distributed outside the blood vessel. It is in equilibrium. Albumin is decomposed in muscle, skin, liver, kidney, etc., and the daily decomposition rate of albumin is about 4% (0.18 g / kg / day) of the stored amount in the body. The half-life of albumin in vivo is about 17 days. On the other hand, albumin is mainly produced in the liver (0.20 g / kg / day). Therefore, the balance of albumin in the living body is close to ± 0. Generally, dialysis patients undergo blood purification by artificial dialysis three times a week. Therefore, an artificial dialysis with a membrane having an albumin permeability of 0.35% results in an albumin loss of about 0.02 g / kg / week. Therefore, if the albumin permeability exceeds 0.35%, the equilibrium state of albumin in the living body is disrupted, which may cause other diseases, which is not preferable.

The thickness of the fibril (mesh skeleton) can be measured by the following method.
In addition, the pore diameter of the membrane, that is, the pore diameter of the above-mentioned void in the membrane cross section (biaxial average diameter, that is, the average value of the minor diameter and the major diameter. Here, the minor diameter and the major diameter are respectively circumscribed with the void. The short side and the long side of the circumscribed rectangle having the smallest area can be measured in the same manner as the thickness of the fibril.
After swelling the target hollow fiber membrane with water, it is frozen at −30 ° C. and then cut vertically to obtain a cross-section cut sample. A cross section of the obtained sample is photographed using a scanning electron microscope (SEM). The photographing is performed at an acceleration voltage of 10 kV and a photographing magnification of 10,000 times. Under this condition, a structure having a width of 15 μm at the cross section in the film thickness direction can be observed.
An SEM photograph is taken with the innermost side of the film thickness portion (inner film surface side) aligned with the edge of the field of view, and using this, the average thickness of the fibrils on the inner side in the film thickness direction is measured. Next, an SEM photograph is taken with the outermost side aligned with the edge of the visual field, and the SEM photograph is used to measure the average thickness of the fibrils on the outer side in the film thickness direction.
The average thickness of all fibrils is measured using the above two photographs when the hollow fiber membrane has a thickness of 30 μm or less. On the other hand, in the case of a hollow fiber membrane having a thickness of more than 30 μm, there is a portion that is not covered (cannot be photographed) in the above two photographs, so that the distance between the inner surface and the outer surface in the film thickness direction is After deciding the center points that are equal points, the center of the field of view is set to the center point and SEM photographs are taken to photograph the portions that cannot be photographed by the above two photographs, and use this to measure in the film thickness direction. Measure the average thickness of the fibrils in the center.
However, when determining the thickness of the fibrils in the central portion in the film thickness direction, the portions not included in the photograph of the inner surface and outer surface of the film are used.
The thickness of the fibril (mesh-like skeleton) defined here means the thickness of the thinnest part near the center of each fibril observed in the above photograph, that is, between the joints between fibrils. The thickness of the narrowest part is read at an angle perpendicular to the longitudinal direction of the fibril.
The area for measuring the thickness of the fibrils is an area band corresponding to a central width of 5 μm in the film thickness direction in a sectional SEM photograph of each area having a width of 15 μm, and 100 fibrils in the area band are arbitrarily selected. And measure the thickness. This is performed for each cross-sectional SEM photograph of each site. The average value of the values of each 100 pieces is set as the average thickness of the fibrils in each portion (outer side, inner side, and central portion (only when the film thickness exceeds 30 μm) in the film thickness direction). The value obtained by arithmetically averaging each average value is the average thickness of all fibrils.

Hereinafter, the method for manufacturing the hollow fiber membrane of the present embodiment will be described.
The hollow fiber membrane-forming stock solution is a hydrophilic polymer solution (for example, polyvinylpyrrolidone (PVP) -based polymer) and other materials (for example, a polyvinylpyrrolidone (PVP) -based polymer) in a temperature-controllable container while applying ultrasonic vibration as necessary. , A film-forming polymer, and a pulverized inorganic ion adsorbent), and the mixture is dissolved and mixed using a mixer such as a stirrer or a Hensyl mixer.
Since impurities may be mixed in the film-forming polymer, etc., it is also possible to filter with a filter with a pore size of 40 μm or less to remove impurities or undissolved substances after preparing the film-forming stock solution. Is.
The solvent for the solution of the hydrophilic polymer (for example, PVP-based polymer) or the solution for forming the membrane may be any solvent that dissolves the hydrophilic polymer (for example, PVP-based polymer) and other materials for the membrane. When (for example, polysulfone-based polymer) is used, N-methyl-2-pyrrolidone, dimethylacetamide, or the like is used as the solvent.
The weight average molecular weight of the hydrophilic polymer is preferably 1,000 to 2,000,000, more preferably 10,000 to 1,300,000.
The concentration of the film-forming polymer (for example, polysulfone-based polymer) in the stock solution for film formation should be within the range such that the film can be formed from the stock solution and the obtained film has the performance as a film. There is no particular limitation, and it is 1 to 50% by weight, preferably 10 to 35% by weight, more preferably 10 to 30% by weight. In order to achieve high water permeability or large molecular weight cutoff, the polymer concentration is preferably low, preferably 10 to 25% by weight. Further, to the film forming stock solution, it is possible to add a plurality of non-solvents such as water, salts, alcohols, ethers, ketones and glycols for the purpose of controlling the stock solution viscosity and dissolution state. The addition amount may be determined at any time depending on the combination.

The concentration of the pulverized inorganic ion adsorbent (for example, cerium oxide hydrate) in the stock solution for film formation is 1 to 20% by weight, preferably 1 to 15% by weight, more preferably 2 to 10% by weight. From the viewpoint of the balance between the clearance value of the blood purifier and the inorganic ion adsorption performance, the concentration of the inorganic ion adsorbent is preferably low, preferably 2 to 8% by weight.
The amount of the hydrophilic polymer in the membrane-forming stock solution is 1 to 30% by weight, preferably 1 to 20% by weight, but the optimum concentration is determined by the molecular weight of the hydrophilic polymer used.
The inorganic ion adsorbent can be pulverized by wet pulverizing and mixing the inorganic ion adsorbent in a solvent of the hydrophilic polymer and the film-forming polymer.
The pulverizing and mixing means is not particularly limited as long as it can pulverize and mix the inorganic ion adsorbent and the hydrophilic polymer and the solvent of the film-forming polymer together.
As the pulverizing / mixing means, for example, means used in physical crushing methods such as pressure breaking, mechanical grinding, ultrasonic treatment, etc. can be used.
Specific examples of the pulverizing and mixing means include a generator shaft type homogenizer, a blender such as a Waring blender, a media milling type mill such as a sand mill, a ball mill, an attritor and a bead mill, a jet mill, a mortar and pestle, a raker, an ultrasonic processor, etc. Is mentioned. Among them, the medium agitation mill is preferable because it has high pulverization efficiency and can pulverize to a high viscosity.
The diameter of the balls used in the medium stirring mill is not particularly limited, but is preferably 0.1 to 10 mm. If the ball diameter is 0.1 mm or more, the mass of the ball is sufficient, so that there is a crushing force and the crushing efficiency is high, and if the ball diameter is 10 mm or less, the fine crushing ability is excellent.
The material of the balls used in the medium agitation mill is not particularly limited, but various metals such as metals such as iron and stainless steel, oxides such as alumina and zirconia, and non-oxides such as silicon nitride and silicon carbide. Examples include ceramics. Among them, zirconia is excellent in that it has excellent wear resistance and little contamination (contamination of wear products) with the product.
After the pulverization, it is preferable that the inorganic ion adsorbent is sufficiently dispersed in the solvent of the hydrophilic polymer and the film-forming polymer, and then filtered and purified using a sintered filter or the like.

The particle size of the pulverized and purified inorganic ion adsorbent is 0.001 to 10 μm, preferably 0.001 to 2 μm, and more preferably 0.01 to 0.1 μm. In order to uniformly disperse the inorganic ion adsorbent in the stock solution for film formation, it is preferable that the particle size of the inorganic ion adsorbent is smaller, but it tends to be difficult to produce uniform fine particles of less than 0.001 μm. On the other hand, if the inorganic ion adsorbent exceeds 1 μm, it tends to be difficult to stably manufacture the hollow fiber membrane.
The hollow fiber membrane can be produced, for example, by simultaneously discharging the above-mentioned stock solution for film formation together with the internal solution from the double annular nozzle into the coagulation bath to coagulate.
The internal liquid used for producing the hollow fiber membrane is used for forming the hollow portion of the hollow fiber membrane. When forming a dense layer on the outer surface, a high-concentration aqueous solution of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and the like can be used as the internal liquid. In the case of forming a dense layer on the inner surface, the internal liquid may be the one described in the coagulation bath described later. It is also possible to add glycols such as tetraethylene glycol and polyethylene glycol, and non-solvents such as glycerin for the purpose of controlling the viscosity of the internal liquid.
The hollow fiber membrane can be formed by using a known tube-in-orifice type double annular nozzle, and more specifically, the above-mentioned stock solution for film formation and the internal solution are simultaneously discharged from this double annular nozzle. After passing through the air gap, it can be obtained by coagulating in a coagulating bath.
The air gap means the distance (gap) between the nozzle and the coagulation bath. The ratio of the air gap (m) to the spinning speed (Vs) (m / min) is extremely important for obtaining a film having a sponge structure in which the pore size continuously increases from the inner surface to the outer surface of the film. is there. Because the sponge structure in which the pore size increases continuously from the inner surface of the membrane to the outer surface, the non-solvent in the inner solution comes into contact with the undiluted solution for film formation from the inner surface portion of the undiluted solution for film formation to the outer surface. This is because phase separation is induced over time to the site side, and phase separation from the inner surface part to the outer surface part of the membrane is not completed before the stock solution for film formation enters the coagulation bath.

The ratio (Ga / Vs) of the air gap (Ga) to the spinning speed (Vs) may be 0.01 to 0.1 m / (m / min) when the thickness of the hollow fiber membrane is 34 μm or more. It is more preferably 0.01 to 0.05 m / (m / min). When the ratio of the air gap to the spinning speed is less than 0.01 m / (m / min), it is difficult to obtain a sponge-structured membrane in which the pore size continuously increases from the inner surface to the outer surface of the membrane, and it is 0.1 m. When the ratio exceeds / (m / min), the tension to the film is high, so that the film often breaks in the air gap portion, which tends to be difficult to manufacture. On the other hand, when the film thickness is less than 34 μm, the amount of good solvent in the film-forming stock solution is small, so that even if the Ga / Vs is low, the pore size increases continuously from the inner surface to the outer surface of the film. It is possible to obtain When the film thickness is less than 34 μm, Ga / Vs is preferably 0.001 to 0.01 m / (m / min).
Spinning speed (Vs) (m / min) refers to a series of manufacturing steps of a hollow fiber membrane in which a membrane-forming stock solution discharged together with an internal solution from a nozzle passes through an air gap to wind up a membrane coagulated in a coagulation bath. The moving speed of the membrane means the moving speed of the hollow fiber membrane before the stretching operation, if any.
Further, by enclosing the air gap with a cylindrical tube or the like and flowing a gas having a constant temperature and humidity at a constant flow rate into the air gap, the hollow fiber membrane can be manufactured in a more stable state.

Examples of the coagulation bath include water; alcohols such as methanol and ethanol; ethers; aliphatic hydrocarbons such as n-hexane and n-heptane, which do not dissolve polymers, and phase separation for a membrane-forming stock solution. A liquid (non-solvent) that induces is used, but it is preferable to use water. It is also possible to control the coagulation rate by adding a good solvent for the polymer to the coagulation bath.
The temperature of the coagulation bath is -30 to 100 ° C, preferably 0 to 98 ° C, more preferably 10 to 95 ° C. When the temperature of the coagulation bath is higher than 100 ° C and lower than -30 ° C, it is difficult to stabilize the surface condition of the film in the coagulation bath.

The hydrophilic polymer constituting the membrane can be crosslinked by irradiating the thus obtained hollow fiber membrane with radiation such as electron beam and gamma ray. Irradiation may be performed either before the blood purifier is manufactured using the hollow fiber membrane or after the blood purifier is manufactured. That is, the blood purifier of the present embodiment is usually commercialized as a product that has been subjected to radiation sterilization treatment after manufacturing, but the hydrophilic polymer may be crosslinked by irradiation with radiation in such radiation sterilization treatment.
As described above, the degree of crosslinking of the hydrophilic polymer in the hollow fiber membrane can be appropriately adjusted by irradiating the hollow fiber membrane with the crosslinking degree adjusting agent attached thereto.
The crosslinking degree adjusting agent is not particularly limited as long as it inhibits the crosslinking reaction of the hydrophilic polymer with respect to radiation irradiation. However, when it is used for blood purification, it is necessary to consider its safety, and therefore it is preferable to use one that is easy to wash with a physiological aqueous solution and has low toxicity. Among them, water-soluble vitamins, glycerin, mannitol, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, glycols such as terra ethylene glycol, polyethylene glycol, polyglycols such as propylene glycol, alcohols such as ethanol, polyethyleneimine, Polysaccharides, saccharides such as trehalose and glucose, inorganic salts such as sodium pyrosulfite, sodium thiosulfate and sodium hydrogen carbonate, carbon dioxide and the like can be mentioned, and they are preferably used. These crosslinking degree regulators may be used alone or in combination of two or more.
The amount and type of the crosslinking degree adjusting agent attached to the hollow fiber membrane and the concentration of the crosslinking degree adjusting agent existing around the hollow fiber membrane in the aqueous solution are appropriately adjusted depending on the radiation irradiation dose, the irradiation time, and the desired crosslinking degree. It is possible to
As a method of irradiating the hollow fiber membrane with a crosslinking degree adjusting agent attached thereto, first, for example, the hollow fiber membrane is dipped in a solution containing the crosslinking degree adjusting agent, and the hollow fiber is immersed in the solution containing the crosslinking degree adjusting agent. There is a method of irradiating the film with radiation. In this case, removal of oxygen from the solution containing the crosslinking degree adjusting agent is effective for reproducibly controlling the desired crosslinking degree. Deoxidation of the solution is possible by bubbling an inert gas such as nitrogen or argon. It is also possible to deoxidize by using a commercially available degasser, or by heating and reducing the pressure. The oxygen concentration in the solution is preferably 0.1 mg / L or more and 1 mg / L or less (0.01 volume% or more and 0.1 volume% or less) under 1 atm. If the oxygen concentration is less than 0.1 mg / L, it tends to be difficult to obtain a crosslinking degree of less than 90%. On the other hand, if it exceeds 1 mg / L, it tends to be difficult to obtain a crosslinking degree of 90% or more with good reproducibility.

  Radiation irradiation means radiation irradiation using an electron beam, a gamma ray or the like, and the dose thereof is 5 kGy or more and 50 kGy or less, preferably 15 kGy or more and 30 kGy or less, and more preferably around 25 kGy.

  The blood purifier of this embodiment can be radiation-sterilized. The method of radiation sterilization is not particularly limited, and a method known to those skilled in the art can be used. For example, it can be performed by irradiating the blood purifier with radiation. For example, it is possible to easily sterilize radiation by irradiating with radiation upon crosslinking the hydrophilic polymer.

  In the blood purifier of the present embodiment, the blood purifier having a coating layer of a biocompatible polymer inside the hollow fiber membrane, for example, the hollow fiber membrane after contacting the biocompatible polymer to the inner surface of the hollow fiber membrane. It can be obtained by irradiation with radiation. It can be conveniently obtained by injecting a coating solution containing a biocompatible polymer into the hollow fiber membrane, removing the coating solution from the hollow fiber membrane, and then irradiating the hollow fiber membrane with radiation. The molecular weight of the biocompatible polymer in this coating solution is preferably similar to that of the hydrophilic polymer that can be used in the above-mentioned membrane-forming stock solution. The concentration of the biocompatible polymer in the coating solution is influenced by the molecular weight, but is preferably 0.01% by weight or more and 20% by weight or less, more preferably 0.05% by weight or more and 5% by weight or less, It is more preferably 0.1% by weight or more and 5% by weight or less. If the concentration of the biopolymer in the coating solution is less than 0.01% by weight, the effect of the coating layer tends not to be obtained. On the other hand, when the concentration of the biocompatible polymer in the coating solution exceeds 20% by weight, the permeation performance of the membrane tends to be significantly reduced. Further, in order to simultaneously perform the radiation irradiation when coating the inside of the hollow fiber membrane with the biocompatible polymer and the radiation irradiation during the crosslinking of the hydrophilic polymer used in the production of the above-mentioned hollow fiber membrane, a biocompatible polymer is used. The coating solution and the crosslinking degree adjusting agent containing solution may be injected into the hollow fiber membrane in this order, and the solution may be removed from the hollow fiber membrane before irradiation. Irradiation can also be performed after injecting a mixed solution of the coating solution and the crosslinking degree adjusting agent solution into the hollow fiber membrane and removing the mixed solution from the hollow fiber membrane.

Hereinafter, the present invention will be specifically described based on Examples, Production Examples, and Comparative Examples (also referred to simply as "Examples and the like" in the present specification), but the scope of the present invention is as follows. The present invention is not limited to this, and various modifications can be made within the scope of the gist.
The hollow fiber membranes used as measurement samples were all in the state of being sufficiently impregnated with water.

The following measuring method was used.
[Average particle size of inorganic ion adsorbent]
The average particle size of the inorganic ion adsorbent was measured with a laser diffraction / scattering particle size distribution analyzer (LA-950 (trade name) manufactured by HORIBA). Water was used as the dispersion medium. When measuring the sample using hydrated cerium oxide as the inorganic ion adsorbent, the value of cerium oxide was used as the refractive index. Similarly, when measuring a sample using hydrated zirconium oxide as the inorganic ion adsorbent, the value of zirconium oxide was used as the refractive index.

[Number of fine particles]
Each evaluation sample was measured using a particle counter (KL-04 manufactured by Rion Co., Ltd.). Regarding the measured values, the first measured value was discarded, the second and subsequent measurements were performed three times, and the average value was used as the official value.

[Example 1]
(Preparation of hydrated cerium oxide)
2000 g of cerium sulfate tetrahydrate (Wako Pure Chemical Industries, Ltd.) was put into 50 L of pure water, dissolved using a stirring blade, and then 3 L of 8M caustic soda (Wako Pure Chemical Industries, Ltd.) was added at 20 ml / min. Was added dropwise at a rate of to obtain a precipitate of hydrated cerium oxide. After filtering the obtained precipitate with a filter press, 500 L of pure water was passed through for washing, and further 80 L of ethanol (Wako Pure Chemical Industries, Ltd.) was passed through to remove water contained in hydrated cerium oxide. It was replaced with ethanol. At this time, 10 ml of the filtrate at the end of filtration was collected, and the water content was measured with a Karl Fischer water content meter (CA-200 (trade name) manufactured by Mitsubishi Chemical Analytech Co., Ltd.). Was 5% by mass, and the substitution rate of the organic liquid was 95% by mass. The hydrated cerium oxide containing the obtained organic liquid was air-dried to obtain dried hydrated cerium oxide.
The dry hydrated cerium oxide thus obtained was subjected to a pneumatic pressure of 0.8 MPa and a raw material feed rate of 100 g / hr using a jet mill device (SJ-100 (trade name) manufactured by Nisshin Engineering Co., Ltd.). The powder was pulverized to obtain a hydrated helium oxide powder having an average particle diameter of 0.08 μm.

(Preparation of Polyvinylpyrrolidone Solution and Filtration of the Solution)
N-methyl-2-pyrrolidone (NMP, 84 g) of polyvinylpyrrolidone (manufactured by BASF, K90, weight average molecular weight 1,200,000) having a water content of 0.3% by weight or less by drying at a temperature of 100 ° C. or less. It was dissolved in 1491 g of Mitsubishi Chemical Corporation to obtain a uniform solution (polyvinylpyrrolidone solution) (polyvinylpyrrolidone concentration 5.63% by weight).
This solution was kept warm at 70 ° C. and a filtration rate of 2 mL / (min · cm ² ) was obtained using a stainless sintered filter having a pore size of 2 μm (manufactured by Nippon Seisen Co., Ltd., NS-02S2, effective filtration area 20 cm ² ). ). During the filtration, the sintered filter was immersed in an ultrasonic cleaner to constantly apply ultrasonic vibrations of 59 kHz (output 3 kW) to the polyvinylpyrrolidone solution.

(Preparation of film forming solution and film formation)
787.5 g of the solution (polyvinylpyrrolidone solution) after the above filter filtration was mixed with 42.5 g of hydrated cerium oxide having an average particle size of 0.08 μm with a Hensyl mixer, and then an aromatic polysulfone (P-made by Amoco Engineering Polymers Co., Ltd.). 1700) 170 g was added and dissolved to prepare a uniform solution (stock solution for film formation). In order to remove undissolved polysulfone and the like, the membrane-forming stock solution was filtered using a filter having a pore size of 5 μm (Fuji Filter Co., Ltd., FD-5, effective filtration area 40 cm ² ). The weight ratio of hydrated cerium oxide to aromatic polysulfone was 25%.
This solution (stock solution for film formation) was degassed and kept at 60 ° C., and the spinneret (double annular nozzle, 0.2. 1 mm-0.2 mm-0.3 mm) (the inner liquid is discharged from an annular nozzle having an inner wall diameter of 0.1 mm, and the stock solution for film formation is discharged from an outer wall diameter of 0.2 mm and an inner wall diameter of 0.3 mm), 380 mm It was made to pass through the air gap of and was immersed in a coagulation bath made of water at 70 ° C. At this time, the area from the spinneret to the coagulation bath was surrounded by a cylindrical tube, and the humidity of the air gap in the tube was controlled to 100%, and the temperature was controlled to 45 ° C. The spinning speed was fixed at 27 m / min. Before the obtained hollow fiber membrane was wound, a crimp having a wavelength of 6 mm and an amplitude of 0.6 mm was provided by a crimper (a device for providing a crimp to the hollow fiber membrane). The drying temperature with the crimper was set to 155 ° C. and the drying time was set to 120 seconds. The film-forming stock solution was constantly stirred. It was always confirmed that the hydrated cerium oxide in the stock solution for film formation discharged from the spinneret was uniformly dispersed.

(Manufacture of blood purifier)
A bundle of 9600 wound hollow fiber membranes was loaded into a polypropylene cylindrical container designed so that the effective membrane area of the hollow fiber membrane was 1.5 m ^2, and both ends were adhesively fixed with urethane resin. Then, both end faces were cut to form an open end of the hollow fiber membrane. Further, header caps were attached to both ends to obtain a blood purifier.

(Cleaning with supercritical fluid)
The obtained blood purifier was washed with a supercritical fluid consisting of carbon dioxide (critical temperature 304.1 K, critical pressure 7.38 MPa, equipment manufactured by Aitec Co., Ltd.) for 1 hour.

(PMEA coating)
A coating liquid was prepared by dissolving 2 g of PMEA (Mn 20,000, Mw / Mn 2.4) in 1,000 g of a solution of 40 g of ethanol / 60 g of water. This solution was kept warm at 70 ° C. and a filtration rate of 2 mL / (min · cm ² ) was obtained using a stainless sintered filter having a pore size of 2 μm (manufactured by Nippon Seisen Co., Ltd., NS-02S2, effective filtration area 20 cm ² ). ). This solution was injected into the hollow portion of the hollow fiber membrane of the blood purifier through the open end for 2.3 seconds and flushed with 0.3 MPa air for 10 seconds. Next, the coating liquid was flown on the outer surface of the hollow fiber membrane of the blood purifier at a flow rate of 100 mL / min for 5 minutes. After washing the outer surface of the hollow fiber membrane with pure water, a blood purifier was placed in a vacuum dryer and vacuum dried at 35 ° C. for 15 hours.

(PVP coating)
A solution (PVP coating solution) was prepared by dissolving 2 g of polyvinylpyrrolidone K90 (manufactured by BASF, K90, weight average molecular weight 1,200,000) in 1,998 g of pure water at 70 ° C. This solution was kept warm at 70 ° C. and a filtration rate of 2 mL / (min · cm ² ) was obtained using a stainless sintered filter having a pore size of 2 μm (manufactured by Nippon Seisen Co., Ltd., NS-02S2, effective filtration area 20 cm ² ). ). During the filtration, the sintered filter was immersed in an ultrasonic cleaning machine to constantly apply ultrasonic vibration of 59 kHz (output 3 kW) to the polyvinylpyrrolidone solution. This solution was injected from the open end into the hollow portion of the hollow fiber membrane of the blood purifier after PMEA coating for 2.3 seconds and flushed with 0.3 MPa air for 10 seconds.
Furthermore, 360 g of glucose (manufactured by Wako Pure Chemical Industries, Ltd., special grade) was dissolved in 1,640 g of pure water at 70 ° C. to prepare a crosslinking degree adjusting agent solution. This solution was injected into the hollow portion of the hollow fiber membrane of the blood purifier through the open end for 2.3 seconds, flushed with 0.3 MPa air for 10 seconds, and then header caps were attached to both ends. After plugging the blood inflow and outflow side nozzle, put it in a sterilization bag together with an oxygen absorber (Ageless (registered trademark) manufactured by Mitsubishi Gas Chemical Co., Inc.), adjust the oxygen concentration to 3.5%, and then irradiate the electron beam with 20 kGy. A radiation sterilized blood purifier was produced. Various characteristics of the obtained blood purifier are shown in Table 1 below.

[Example 2]
In the above (Preparation of polyvinylpyrrolidone solution and filtration of the solution), 1406 g of N-methyl-2-pyrrolidone, and in (Preparation of stock solution for membrane formation and film formation), 745 g of solution (polyvinylpyrrolidone solution) after filter filtration. Then, 85 g of hydrated cerium oxide having an average particle diameter of 0.08 μm was used to prepare a radiation-sterilized blood purifier in the same manner as in Example 1. The weight ratio of hydrated cerium oxide to aromatic polysulfone was 50%. Various characteristics of the obtained blood purifier are shown in Table 1 below.

[Example 3]
A radiation sterilized blood purifier was produced in the same manner as in Example 1 with the internal liquid concentration adjusted to 65.0% by weight. Various characteristics of the obtained blood purifier are shown in Table 1 below. The pore size increased and the albumin transmittance increased to 4.5%.

[Example 4]
A radiation sterilized blood purifier was produced in the same manner as in Example 1 except that the glucose concentration in the crosslinking degree adjusting agent solution was changed to 45% by weight. The degree of crosslinking of polyvinylpyrrolidone in the hollow fiber membrane was 77.9%. Various characteristics of the obtained blood purifier are shown in Table 1 below. Since the degree of cross-linking of polyvinylpyrrolidone in the hollow fiber membrane is as low as less than 80%, the solution at 3 months and 6 months after the solution was enclosed in the blood purifier using this hollow fiber membrane. When the polyvinylpyrrolidone concentration therein was measured, all were 10 ppm or more.

[Example 5]
A radiation sterilized blood purifier was produced in the same manner as in Example 1 except that the concentration of the internal liquid was changed to 52% by weight. Various characteristics of the obtained blood purifier are shown in Table 1 below. The pore size increased slightly and the albumin transmittance increased to 0.38%.

[ Reference Example 6]
A radiation sterilized blood purifier was produced in the same manner as in Example 1 except that PMEA coating was not performed. Various characteristics of the obtained blood purifier are shown in Table 1 below.

[ Reference Example 7]
A radiation sterilized blood purifier was produced in the same manner as in Example 1 except that PMEA coating and PVP coating were not performed. Various characteristics of the obtained blood purifier are shown in Table 1 below.

[Example 8]
Before washing with a supercritical fluid, 500 ppm sodium hypochlorite aqueous solution of blood purifier is filtered for 1 hour, filtered with pure water at 60 ° C for 1 hour, filtered with ethanol at 30 ° C for 1 hour, and purified with pure water at 60 ° C for 1 hour. Radiation-sterilized blood was treated in the same manner as in Example 1 except that the PVP coating was not performed using a blood purifier in which the amount of PVP in the hollow fiber membrane was less than 0.2 wt% by repeating the time filtration step 3 times. A purifier was made. Various characteristics of the obtained blood purifier are shown in Table 1 below.

[Comparative Example 1]
A blood purifier was produced in the same manner as in Example 1 except that cleaning with a supercritical fluid was not performed. Various characteristics of the obtained blood purifier are shown in Table 1 below.

[Comparative Example 2]
A radiation sterilized blood purifier was produced in the same manner as in Example 1 except that the concentration of the internal liquid was changed to 65.2% by weight. Various characteristics of the obtained blood purifier are shown in Table 1 below. It was found that the pore size increased and the number of fine particles increased.

[Comparative Example 3]
In (Preparation of polyvinylpyrrolidone solution and filtration of the solution), 1576 g of N-methyl-2-pyrrolidone and in (Preparation of stock solution for film formation and film formation), 830 g of solution (polyvinylpyrrolidone solution) after filter filtration (Preparation of Membrane Forming Solution and Membrane Formation) The hydrated cerium oxide was adjusted to 0 g to prepare a radiation sterilized blood purifier in the same manner as in Example 1. Various characteristics of the obtained blood purifier are shown in Table 1 below. Since there was no inorganic ion adsorbent, the clearance value for phosphoric acid was less than 190 ml / min.

  INDUSTRIAL APPLICABILITY The blood purifier according to the present invention has a high phosphorus adsorption capacity and can be used safely, and thus can be suitably used for acute blood purification therapy and the like.

Claims (10)

A blood purifier having a hollow fiber membrane containing an inorganic ion adsorbent, wherein a stock solution prepared by adding physiological saline to bovine serum to adjust the total protein concentration to 6.5 g / dL is passed through the hollow fiber membrane for 60 minutes. When the filtrate is sampled under a pressure of transmembrane pressure difference of 25 mmHg and the albumin concentration is measured by the BCG method, the following formula (1):
Albumin permeability (%) = Albumin concentration of filtrate / Albumin concentration of stock solution × 100 (1)
In transmittance of the albumin expressed is 5% or less, the blood purifier in the enclosed injectable saline or 10μm of the injectable physiological saline 1mL after and 6 months after March from the and the number of particles below 25, and state, and are more number of particles 3 or less 25 [mu] m, the hollow fiber membrane is composed of a film forming polymer and a hydrophilic polymer and an inorganic ion adsorbent, membrane formation The polymer is a polymer capable of forming a porous hollow fiber membrane by wet membrane formation, the hydrophilic polymer is polyvinylpyrrolidone (PVP) -based polymer, and the inorganic ion adsorbent is a metal oxide or a polymer. The hollow fiber membrane is a salt of a valent metal or an insoluble hydrous oxide, and the hollow fiber membrane is a polyvinylpyrrolidone (PVP) polymer and polymethoxyethyl acrylate (PMEA) which are biocompatible polymers. The blood purifier characterized that you have been coated with. Pore size before Symbol in hollow fiber membrane is larger toward the outer surface from the inner surface, blood purifier according to claim 1. The blood purifier according to claim 1 or 2 , wherein the degree of crosslinking of the PVP-based polymer is 80% or more and less than 100%. Clearance values of phosphorus is membrane area 1.5 m ² per 190 ml / min or more, blood purifier according to any one of claims 1-3. Is clearance value of urea membrane area 1.5 m ² per 195 ml / min or more, blood purifier according to any one of claims 1-4. Clearance values of creatinine is the membrane area 1.5 m ² per 186 ml / min or more, blood purifier according to any one of claims 1-5. Clearance value of vitamin _{B 12} is the membrane area 1.5 m ² per 142 ml / min or more, blood purifier according to any one of claims 1-6. The hollow fiber membrane comprising said inorganic ion adsorbent after washing with supercritical fluid or subcritical fluid, the surface of the hollow fiber membrane comprising the step of coating with a biocompatible polymer, any one of claims 1 to 7 1 A method of manufacturing a blood purifier according to item. A PVP-based polymer and a crosslinking degree adjusting agent solution are sequentially injected from the inner surface side of the hollow fiber membrane, then the crosslinking degree adjusting agent solution is removed, and then the hollow fiber membrane is irradiated with radiation to remove the PVP-based polymer. the degree of crosslinking comprising the step of less than 80% to 100% manufacturing method of a blood purifier according to any one of claims 3-7. The method according to claim 9 , wherein the oxygen concentration in the blood purifier is adjusted to 0.01% by volume or more and 0.1% by volume or less when the radiation is applied.