Hollow fiber membrane, method for producing hollow fiber membrane, and hollow fiber membrane module

Abstract

The purpose of the present invention is to provide: a hollow fiber membrane containing polymethylpentene as a main component, the hollow fiber membrane having biocompatibility that is stable for a long period of time and excellent gas permeability; and a method for producing the hollow fiber membrane. The hollow fiber membrane contains polymethylpentene as a main component, a hydrophilic polymer is fixed on a dense surface, and the thickness of a layer containing the hydrophilic polymer is 1.0 nm or more and 25.0 nm or less.

Description

TECHNICAL FIELD

[0001] The present application relates to a hollow fiber membrane, a method for producing a hollow fiber membrane, and a hollow fiber membrane module. BACKGROUND

[0002] A membrane-type artificial lung using a porous membrane is widely used as an extracorporeal circulation device at the time of open heart surgery for heart disease, a circulatory assist artificial heart-lung device, an extracorporeal membrane-type artificial lung (Extracorporeal membrane oxygenation, hereinafter referred to as ECMO) for respiratory system function substitution device. The membrane-type artificial lung mainly uses a hollow fiber membrane, and gas exchange in blood is performed via the hollow fiber membrane. As a method of perfusing blood to the artificial lung, there are an internal perfusion method in which blood flows on the inside of the hollow fiber membrane and gas flows on the outside of the hollow fiber membrane, and an external perfusion method in which blood flows on the outside of the hollow fiber membrane and gas flows on the inside of the hollow fiber membrane.

[0003] The hollow fiber membrane-type artificial lung has an inner surface or an outer surface of the hollow fiber membrane in contact with blood, and therefore the inner surface or the outer surface of the hollow fiber membrane in contact with blood has an influence on the adhesion and activation of platelets. In particular, in the external perfusion method in which the outer surface of the hollow fiber membrane is in contact with blood, since the flow of blood is turbulent flow, the adhesion and activation of platelets are easily influenced.

[0004] In a separation membrane for medical use in contact with body fluid, blood, the adhesion of proteins, platelets becomes a cause of a decrease in the performance of the separation membrane, a biological reaction, and becomes a serious problem. In particular, in an artificial lung, due to the adhesion of proteins, platelets on the surface of the hollow fiber membrane, or the adhesion of proteins inside the membrane hole and the surface of the hollow fiber membrane, hydrophilization occurs due to the loss of hydrophobicity of the surface and the inside of the hollow fiber membrane, and therefore when leakage (plasma leakage) of plasma components in the cross-sectional direction of the hollow fiber membrane occurs, a decrease in gas exchange capacity occurs with a decrease in the membrane area in which gas exchange can be performed, and therefore it is required to impart biological fitness for suppressing the adhesion of proteins, platelets on the hollow fiber membrane, and various studies have been conducted.

[0005] As a hollow fiber membrane for an artificial lung, a polyolefin hollow fiber membrane having gas permeability and hydrophobicity is preferably used, and a hollow fiber membrane in which polymethylpentene is a main component is widely used for the purpose of preventing plasma leakage because it has a dense structure on the outer surface side as a blood contact surface.

[0006] In order to impart biocompatibility to these polyolefins, a coating method is disclosed in which a polymer having an alkoxylalkyl (meth) acrylamide as a main constituent component is provided on the surface (Patent Document 1). In addition, a method of coating polymethoxyethyl acrylate (Patent Document 2) and a method of coating a copolymer of an alkoxylalkyl methacrylate and a hydroxyalkyl methacrylate (Patent Document 3) are also disclosed. In addition, as a coating method for improving the antithrombogenicity on an artificial lung, a method using heparin is also disclosed (Patent Document 4).

[0007] In addition, a method of safely and simply inhibiting the adhesion of platelets and proteins by imparting a hydrophilic polymer such as vinylpyrrolidone is utilized not only for hollow fiber membranes for artificial lungs.

[0008] For example, a method of imparting polyvinylpyrrolidone (Patent Document 5) or a copolymer of polyvinylpyrrolidone and vinyl acetate (Patent Document 6) to a film by radiation graft polymerization is disclosed.

[0009] Prior Art Documents Patent Documents Patent Document 1: Japanese Patent Application Laid-Open (JP-A) No. 2004-357826 Patent Document 2: Japanese Patent Application Laid-Open (JP-A) No. Hei 11-114056 Patent Document 3: Japanese Patent Application Laid-Open (JP-A) No. 2020-141901 Patent Document 4: Japanese Patent Application Laid-Open (JP-A) No. 2020-127705 Patent Document 5: Japanese Patent Application Laid-Open (JP-A) No. Hei 3-16626 Patent Document 6: Japanese Patent Application Laid-Open (JP-A) No. 2011-78974 Non-Patent Documents Non-Patent Document 1: M. Niinomi, “Metals for Biomedical Devices”, 2nd Edition, Elsevier, 2019, p. 405. SUMMARY

[0010] PROBLEMS TO BE SOLVED BY THE INVENTION The method described in Patent Document 1 is not preferable because the coating layer is 0.1 pm to 1 mm thick, which reduces the inherent substance permeability of the film. In addition, because of the thickness of the coating layer, the hydrophilicity of the film increases, and plasma leakage can occur when the film is in contact with blood for a long period of time. In addition, although the polymethoxyethyl acrylate described in Patent Document 2 exhibits excellent biocompatibility, an organic solvent such as methanol, which is a toxic substance, needs to be used as a solvent at the time of coating, and because of contact with the organic solvent, the fine film structure can be deformed. These coating methods can require structure control to maintain the performance of the film each time the conditions change.

[0011] Patent Literature 3 discloses a method of dissolving a copolymer in a mixed solvent of water and alcohol and coating on a polypropylene substrate (hereinafter referred to as "a casting method"). However, generally in coating of a polymer on a substrate by a casting method, the adhesion and durability of the coating composition vary depending on the presence or absence of fine structures such as unevenness on the surface of the substrate, and the hydrophilic or hydrophobic property of the surface of the substrate, and thus are not suitable for polymethylpentene having a dense surface with less unevenness and a strong hydrophobic property. In addition, in the casting method, the adhesion of a polymer having a small molecular weight to the substrate is low, and there is a tendency that the polymer cannot be coated, and thus the molecular weight of the polymer that can be coated is limited.

[0012] The method described in Patent Literature 4 has a problem of causing an allergy because heparin is a biological material, and further has a problem that it is difficult to maintain the blood coagulation inhibitory effect when used for a long time because heparin itself is consumed along with the inhibition of blood coagulation.

[0013] The method described in Patent Literature 5 or Patent Literature 6 has a problem that when a hollow fiber membrane is used as a gas exchange membrane, the hydrophilic polymer contributes to the penetration of plasma components into the fine pores inside the membrane, and thus it is likely to accelerate the occurrence of plasma leakage. These effects are confirmed only in a membrane for protein permeation in which the hydrophilic polymer is present in the entire membrane, and are not confirmed in an artificial lung hollow fiber membrane in which gas exchange is intended and the hydrophobicity of the membrane needs to be maintained.

[0014] Further, it is known that polyolefins, particularly polymethylpentene, generally have low radiation resistance (Non-Patent Literature 1). Thus, it is likely that the separation performance and mechanical properties of the membrane change due to radiation irradiation, and thus the use in a gas exchange membrane or a separation membrane for an artificial lung or the like has not been studied.

[0015] Thus, the method of imparting a hydrophilic polymer containing vinylpyrrolidone is simple and has high effects, but on the other hand, the hydrophilization is caused to the cross-sectional direction of the membrane due to the amount of the hydrophilic polymer to be imparted and the method of imparting, and thus the use in an artificial lung hollow fiber membrane has not been achieved.

[0016] Therefore, an object of the present application is to provide a hollow fiber membrane containing polymethylpentene as a main component, which has long-term stable biological compatibility and excellent gas permeability of the membrane, and a method for producing the same.

[0017] Means for solving the problem The present inventors and others have made intensive studies in order to solve the above problem. As a result, the present application for solving the above problem is configured as described below.

[0018] (1) A hollow fiber membrane comprising polymethylpentene as a main component, and having a hydrophilic polymer fixed on a dense surface, a thickness of a layer containing the hydrophilic polymer being 1.0 nm or more and 25.0 nm or less.

[0019] (2) The hollow fiber membrane according to (1), wherein a hydration energy density of the hydrophilic polymer is 167 kJ・mol -1 nm -3 or more and 213 kJ・mol-1・nm -3 or less.

[0020] (3) The hollow fiber membrane according to (1) or (2), wherein a nitrogen atom content is 0.0010 mass% or more and 0.0100 mass% or less.

[0021] (4) The hollow fiber membrane according to any one of (1) to (3), wherein the hydrophilic polymer has a hydrophilic unit selected from the group consisting of a vinylpyrrolidone unit, an acrylamide derivative unit, a methacrylamide derivative unit, an N-vinylacetamide derivative unit, and a vinylcaprolactam unit, a content of the hydrophilic unit being 0.010 mass% or more and 0.080 mass% or less.

[0022] (5) The hollow fiber membrane according to any one of (1) to (4), wherein a water contact angle of the dense surface is 70° or more and 95° or less.

[0023] (6) The hollow fiber membrane according to any one of (1) to (5), wherein the hydrophilic polymer has a hydrophobic unit selected from the group consisting of a carboxylic acid vinyl ester unit, an alkyl acrylate unit, and an alkyl methacrylate unit.

[0024] (7) The hollow fiber membrane according to (6), wherein a number of carbon atoms at a side chain end of the hydrophobic unit is 1 or more and 9 or less.

[0025] (8) A production method of the hollow fiber membrane according to any one of (1) to (7), having the following step 1, Step 1: a step of irradiating a hollow fiber membrane which has contacted a hydrophilic solution with a radiation.

[0026] (9) The production method of the hollow fiber membrane according to (8), wherein the hydrophilic solution is brought into contact with only one surface of the hollow fiber membrane.

[0027] (10) A hollow fiber membrane module filled with the hollow fiber membrane according to any one of (1) to (6).

[0028] (11) The hollow fiber membrane module according to (10), which is an artificial lung.

[0029] Further, the present application for solving the above problem is configured as described below.

[0030] (12) A hollow fiber membrane comprising polymethylpentene as a main component, and a hydrophilic polymer is fixed to a dense surface, and a thickness of a layer containing the hydrophilic polymer is 1.0 nm or more and 25.0 nm or less.

[0031] (13) The hollow fiber membrane according to (12), wherein a hydration energy density of the hydrophilic polymer is 167 kJ・mol -1 ・nm -3 or more and 213 kJ・mol-1・nm -3 or less.

[0032] (14) The hollow fiber membrane according to (12) or (13), wherein a nitrogen atom content is 0.0015 mass% or more and 0.0100 mass% or less.

[0033] (15) The hollow fiber membrane according to any one of (12) to (14), wherein the hydrophilic polymer has a vinylpyrrolidone unit, and a content of the vinylpyrrolidone unit is 0.010 mass% or more and 0.080 mass% or less.

[0034] (16) The hollow fiber membrane according to any one of (12) to (15), wherein a water contact angle of the dense surface is 80° or more and 95° or less.

[0035] (17) The hollow fiber membrane according to any one of (12) to (16), wherein the hydrophilic polymer has a carboxylic acid vinyl ester unit.

[0036] (18) The hollow fiber membrane according to (17), wherein a number of carbon atoms at a side chain end of the carboxylic acid vinyl ester unit is 1 to 9.

[0037] (19) A production method of a hollow fiber membrane according to any one of (12) to (18), which has the following step 1, Step 1: a step of irradiating a hollow fiber membrane with a hydrophilic solution with a radiation.

[0038] (20) The production method of a hollow fiber membrane according to (19), wherein the hydrophilic solution is brought into contact with only one surface of the hollow fiber membrane.

[0039] (21) A hollow fiber membrane module filled with the hollow fiber membrane described in any one of (12) to (18).

[0040] (22) The hollow fiber membrane module described in the above (21), which is an artificial lung.

[0041] Effects of the Invention The hollow fiber membrane and the hollow fiber membrane module according to the present application can inhibit the adhesion of biological components such as proteins and platelets. In addition, since the gas permeability is also excellent, it can be used as an artificial lung. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 : is a photograph showing the adhesion state of platelets of Examples 1 to 10.

[0043] Figure 2 : is a photograph showing the adhesion state of platelets of Comparative Examples 1 to 7.

[0044] Figure 3 : is a photograph showing the adhesion state of platelets of Examples 11 to 23. DETAILED DESCRIPTION

[0045] The present application is a hollow fiber membrane which contains polymethylpentene (hereinafter referred to as "PMP") as a main component, and has a hydrophilic polymer fixed to a dense surface, and the thickness of the layer containing the hydrophilic polymer is 1.0 nm or more and 25.0 nm or less.

[0046] The "main component" means a material constituting 50% by mass or more of the whole in the material constituting the hollow fiber membrane. From the viewpoint of forming a dense surface structure and maintaining mechanical strength, PMP is preferably 90% by mass or more, more preferably 95% by mass or more, of the whole of the hollow fiber membrane.

[0047] The hollow fiber membrane of the present application is preferably an asymmetric structure in which the fine pores in the hollow fiber membrane are present unevenly in the cross-sectional direction of the membrane, and the inner and outer surfaces are different in structure. By setting the contact surface of the blood component to the dense surface of the hollow fiber membrane, both the gas permeability and the inhibition of plasma leakage can be taken into account.

[0048] The "dense surface" means the surface of the side with a small pore diameter in the hollow fiber membrane having an asymmetric structure. For example, when the pore diameter of the outer surface is smaller than that of the inner surface, the outer surface becomes the dense surface.

[0049] The hollow fiber membrane of the present application has a hydrophobic PMP as a main component, and therefore the inner and outer surfaces of the hollow fiber membrane are hydrophobic, and biological components such as proteins and platelets easily adhere in this state. Therefore, it is necessary to fix a hydrophilic polymer to the dense surface which comes into contact with blood.

[0050] "Fixed" means a state that cannot be easily removed even when cleaned with solvents that can dissolve hydrophilic polymers. Examples of a fixed state include, for example, a state that is miscible with PMP, where the molecular chains are intertwined, or a state that is bonded by covalent or ionic bonds. Among these, a state that is bonded by covalent bonds is preferred from the viewpoint of minimizing the risk of leaching upon contact with blood.

[0051] By immobilizing hydrophilic polymers onto hollow fiber membranes, the adhesion of biological components can be inhibited. On the other hand, when a large amount of hydrophilic polymer is immobilized, the membrane as a whole becomes hydrophilic, potentially leading to plasma leakage. Furthermore, the reduced gas permeability of the hollow fiber membrane may compromise its performance as an artificial lung.

[0052] "Bioadaptability" refers to the property of inhibiting platelet and / or protein adhesion, making thrombus formation difficult. By imparting bioadaptability to the surface of the hollow fiber membrane in contact with blood, thrombus formation is prevented on the membrane surface, and the membrane area conducive to gas exchange is not reduced, thus maintaining gas permeability. Furthermore, it inhibits protein adhesion to the interior of the pores, preventing plasma leakage associated with the hydrophilicization of the hollow fiber membrane.

[0053] Therefore, the inventors conducted in-depth research and found that by setting the thickness of the hydrophilic polymer layer on the dense surface of the hollow fiber membrane to be more than 1.0 nm and less than 25.0 nm, both biocompatibility and gas permeability can be taken into account.

[0054] "Hydrophilic polymer-containing layer" refers to the etching depth at which the peak of secondary ions from the hydrophilic polymer is detected when the membrane surface is etched along the thickness direction using time-of-flight secondary ion mass spectrometry (hereinafter referred to as "GCIB-TOF-SIMS") equipped with a gas cluster ion gun. That is, unlike the thickness of a hydrophilic polymer layer existing on the surface of a hollow fiber membrane as a coating, it refers to a layer containing and immobilizing hydrophilic polymer that has permeated the interior of the hollow fiber membrane from the pores of the dense surface. Specifically, it can be measured using the method described later in "Thickness of Hydrophilic Polymer-Containing Layer".

[0055] Typically, the adhesion of proteins or platelets to material surfaces is considered to be due to changes in the higher-order structure of proteins, exposing hydrophobic sites that interact hydrophobically with the material surface, thus leading to adhesion. Furthermore, bound water (hydrogen-bonded water) exists around cells such as platelets, proteins, and on the material surface. Therefore, it is believed that if the material surface is highly hydrophilic, the bound water around the proteins will also be bound, failing to adequately inhibit protein adhesion. In other words, it can be inferred that to inhibit the adhesion of cells such as platelets and proteins, it is important to appropriately adjust the balance between the hydrophobicity and hydrophilicity of the material surface.

[0056] From the above, by providing a hydrophilic polymer-containing layer of a certain thickness on the surface of the hollow fiber membrane that contacts a biological component such as blood, a balance of moderate hydrophilicity and hydrophobicity is formed, whereby impartation of biological compatibility and gas permeation performance can be maintained.

[0057] From the viewpoint of imparting biological compatibility, the thickness of the hydrophilic polymer-containing layer is 1.0 nm or more, preferably 3.0 nm or more. On the other hand, when the hydrophilic polymer exists inside the fine pores of the hollow fiber membrane, the biological component easily penetrates inside the fine pores, the amount of protein adhered inside the fine pores increases, and plasma leakage becomes likely to occur. Furthermore, if the hydrophilic polymer-containing layer becomes thick, the permeation resistance becomes large, and the gas permeation performance decreases. Therefore, from the viewpoint of maintaining plasma leakage resistance and gas permeation performance of the hollow fiber membrane, the thickness of the hydrophilic polymer-containing layer is 25.0 nm or less, preferably 15.0 nm or less, more preferably 5.0 nm or less.

[0058] The "hydrophilic polymer" means a polymer having a solubility of 0.00001% by mass or more in water at room temperature (20°C) and having a hydrophilic unit.

[0059] The "hydrophilic unit" means a repeating unit having a solubility of 1% by mass or more in water at room temperature (20°C) in a polymer that contains only a hydrophilic unit.

[0060] The thickness of the hydrophilic polymer-containing layer can be controlled by adjusting the hydrophilic-hydrophobic property of the hydrophilic polymer or the concentration of the hydrophilic polymer in a hydrophilic solution used at the time of irradiation with a radiation.

[0061] The hydration energy density of the hydrophilic polymer fixed to the hollow fiber membrane of the present application is preferably 167 kJ・mol -1 nm -3 or more and 213 kJ・mol -1 nm -3 or more and 213 kJ・mol -1 nm -3 or more and 213 kJ・mol -1 nm -3 or more and 213 kJ・mol, preferably 170 kJ・mol -1 nm -3 or more and 190 kJ・mol -1 nm -3 or more and 190 kJ・mol, more preferably 175 kJ・mol -1 nm -30.0010 to 0.0100 mass% and more preferably 0.0015 to 0.0100 mass%. -1 nm -3 The following.

[0062] Further, when hydrophilic polymers are imparted by radiation graft polymerization of a hydrophobic polymethylpentene, the polymers themselves also have a certain degree of hydrophobicity, which makes the polymer adsorption equilibrium constant on the hollow fiber membrane high, and the hydrophilic polymers are easily imparted to the hollow fiber membrane, and thus the hydration energy density of the hydrophilic polymers is preferably 167 kJ・mol -1 nm -3 0.0010 to 0.0100 mass% and more preferably 0.0015 to 0.0100 mass%. -1 nm -3 The following.

[0063] The hydration energy density of the hydrophilic polymer is calculated based on the following formula (1).

[0064] [Numeral 1] In formula (1), the hydration energy of monomer unit i is the absolute value of the value obtained by subtracting the energy in vacuum of monomer unit i from the energy in water of monomer unit i, N represents the total number of monomer types constituting the copolymer, and i represents an integer of 1 or more and N or less.

[0065] The "hydration energy" means the energy change obtained by the system when a solute is added to an aqueous solution. As the unit of the hydration energy, for example, J・mol -1 or the like can be used.

[0066] The "hydration energy of monomer unit" means the absolute value of the value obtained by subtracting the energy in vacuum of the monomer unit from the energy in water of the monomer unit.

[0067] The "hydration energy density" means the hydration energy per unit volume. The unit of the hydration energy density uses kJ・mol -1 nm -3 .

[0068] The energy in vacuum and the energy in water of the monomer unit can be calculated by the method described in the "hydration energy density of the hydrophilic polymer" described later.

[0069] The hydration energy density of the hydrophilic polymer can be controlled by the combination of the hydrophilic units and the like monomers constituting the hydrophilic polymer.

[0070] The nitrogen atom content in the hollow fiber membrane of the present application is preferably 0.0010 to 0.0100 mass% and more preferably 0.0015 to 0.0100 mass%.

[0071] The "nitrogen atom content" means the content (mass %) of nitrogen atoms in 100 mass % of the hollow fiber membrane 100. The nitrogen atoms are preferably derived from the hydrophilic polymer.

[0072] The nitrogen atom content derived from the hydrophilic polymer is preferably 0.0010 mass % or more to obtain sufficient biological fitness, and more preferably 0.0015 mass % or more to obtain further preferable biological fitness. On the other hand, from the viewpoint of maintaining the hydrophobicity of the hollow fiber membrane and inhibiting the formation of a gel due to cross-linking of the hydrophilic polymer itself, maintaining the gas permeability of the hollow fiber membrane, the nitrogen atom content is preferably 0.0100 mass % or less, more preferably 0.0070 mass % or less, further preferably 0.0060 mass % or less, and still further preferably 0.0050 mass % or less.

[0073] The nitrogen atom content of the hollow fiber membrane can be determined by the oxidative decomposition-chemiluminescence method using a micro nitrogen analyzer (ND-100 type, Mitsubishi Chemical Corporation), for example.

[0074] The nitrogen content of the hollow fiber membrane can be controlled by adjusting the hydrophilic-hydrophobic property of the hydrophilic polymer or by adjusting the concentration of the hydrophilic polymer in the hydrophilic solution used when performing the irradiation with a radioactive ray.

[0075] When the hollow fiber membrane of the present application contains nitrogen atoms derived from the hydrophilic polymer, the nitrogen atoms are preferably derived from an amide bond other than a secondary amide bond, and more preferably from a polymer having an amine, a primary or secondary amide bond, or a heterocyclic compound containing a nitrogen atom.

[0076] As specific examples of the hydrophilic unit contained in the hydrophilic polymer satisfying the above, there can be mentioned a unit having a vinyl amine, an allyl amine, a lysine, or an amine such as diallyl methyl ammonium chloride, a methacrylamide, an urethane, an N, N-dimethyl methacrylamide, an N-vinyl acetamide, an N-isopropyl acrylamide, or a vinyl pyrrolidone, or a heterocyclic compound containing a nitrogen atom such as 2-vinyl pyridine.

[0077] The nitrogen atoms derived from which functional group can be identified by the secondary ion species containing a nitrogen atom by time-of-flight secondary ion mass spectrometry (hereinafter referred to as "TOF-SIMS measurement"), or by confirming the hydrophilic polymer extracted with an organic solvent such as ethanol, butanol, or hexanone, and measuring proton nuclear magnetic resonance spectroscopy (hereinafter referred to as "H-NMR measurement"). 1 Further, when the hydrophilic polymer contains an amide group, the ratio of the amide bond can be calculated from the ratio of the peak area derived from the amide bond by H-NMR measurement. 1 Further, when the hydrophilic polymer contains an amide group, the ratio of the amide bond can be calculated from the ratio of the peak area derived from the amide bond by H-NMR measurement.

[0078] Further, in the hydrophilic polymer, the functional group containing a nitrogen atom is present in the side chain, and from the viewpoint of being able to impart biological fitness in a state in which the thickness of the hydrophilic polymer-containing layer is thin and easily maintaining gas permeability, the molecular weight of the side chain is preferably small.

[0079] The hydrophilic polymer fixed to the hollow fiber membrane of the present application preferably has a hydrophilic unit selected from the group consisting of a vinylpyrrolidone unit, an acrylamide derivative unit, a methacrylamide derivative unit, an N-vinylacetamide derivative unit, and a vinylcaprolactam unit, and the content of the hydrophilic unit is preferably 0.0100 mass% or more and 0.0800 mass% or less.

[0080] From the viewpoint of less modification and activation of biological components, more preferably, the hydrophilic unit is a vinylpyrrolidone unit, an acrylamide derivative unit, or an N-vinylacetamide derivative carboxylic acid vinyl ester unit, and further more preferably, the hydrophilic unit is a vinylpyrrolidone unit.

[0081] The acrylamide derivative unit is a unit having an acrylamide structure (CH2=CH-CO-NH-). As the acrylamide derivative unit, for example, an acrylamide unit, an N-methylacrylamide unit, an N-isopropylacrylamide unit, an N-tert-butylacrylamide unit, or an N-phenylacrylamide unit can be given.

[0082] The methacrylamide derivative unit is a unit having a methacrylamide structure (CH2=C(CH3)-CO-NH-). As the methacrylamide derivative unit, for example, a methacrylamide unit, an N-isopropylmethacrylamide unit, or an N-phenylmethacrylamide unit can be given.

[0083] The N-vinylacetamide derivative unit is a unit having a vinylacetamide structure (CH2=CH-NH-CO-). As the N-vinylacetamide derivative unit, for example, an N-vinylacetamide unit or an N-methyl-N-vinylacetamide unit can be given.

[0084] The "content of the hydrophilic unit" means the content (mass%) of the hydrophilic unit in 100 mass% of the hollow fiber membrane. For example, in the case where the hydrophilic unit is a vinylpyrrolidone unit, it means the content (mass%) of the vinylpyrrolidone unit in 100 mass% of the hollow fiber membrane.

[0085] From the viewpoint of obtaining sufficient biocompatibility, the content of the hydrophilic unit is more preferably 0.010% by mass or more. On the other hand, from the viewpoint of maintaining the hydrophobicity of the hollow fiber membrane, inhibiting leakage of plasma, or inhibiting a decrease in the gas permeability of the hollow fiber membrane due to crosslinking of the hydrophilic polymer itself, the content of the hydrophilic unit is more preferably 0.050% by mass or less, and further preferably 0.035% by mass or less.

[0086] The content of the hydrophilic unit, for example, the content of the vinylpyrrolidone unit can be calculated by the method described in "Content of the vinylpyrrolidone unit" described later.

[0087] The static contact angle of water with respect to the dense surface of the hollow fiber membrane of the present application is preferably 70° or more and 95° or less. By making the static contact angle of water with respect to the dense surface of the hollow fiber membrane 70° or more, more preferably 75° or more, and further more preferably 80° or more, the hydrophobicity of the hollow fiber membrane can be maintained, and the occurrence of plasma leakage can be inhibited. On the other hand, from the viewpoint of obtaining sufficient biocompatibility, the static contact angle of water is preferably 95° or less, and more preferably 90° or less.

[0088] The static contact angle of water with respect to the dense surface of the hollow fiber membrane can be measured, for example, by the drop method using an automatic minimum contact angle meter (MCA-4, Kyowa Interface Science).

[0089] Further, the hydrophilic polymer in the hollow fiber membrane of the present application is not particularly limited, and preferably has a hydrophobic unit selected from a carboxylic acid vinyl ester unit, an alkyl acrylate unit, and an alkyl methacrylate unit. The hydrophilic polymer has an optimal biocompatibility imparting effect when the hydrophobic unit is present in the hydrophilic polymer. Among them, from the viewpoint of having less stimulating and activating effects on biological components such as blood cells, the carboxylic acid vinyl ester unit is more preferable.

[0090] The carboxylic acid vinyl ester unit means a repeating unit represented by "-CH(OCO-R)-CH2-" (R is a hydrocarbon group). As the carboxylic acid vinyl ester unit, a vinyl propionate unit, a vinyl butyrate unit, a vinyl pivalate unit, a vinyl valerate unit, a vinyl octanoate unit, a vinyl 2-ethylhexanoate unit, or a vinyl stearate unit, or the like can be given.

[0091] As the alkyl acrylate unit, an ethyl acrylate unit, a propyl acrylate unit, a butyl acrylate unit, an isobutyl acrylate unit, a tert-butyl acrylate unit, an octyl acrylate unit, or a hexadecyl acrylate unit, or the like can be given.

[0092] As the alkyl methacrylate unit, there can be mentioned an ethyl methacrylate unit, a propyl methacrylate unit, a butyl methacrylate unit, an isobutyl methacrylate unit, a tert-butyl methacrylate unit, a tridecyl methacrylate unit, a 1-butene unit, or a 1-nonene unit, and the like.

[0093] Generally, the more the number of carbon atoms of the side chain terminal R of the hydrophobic unit, the higher the hydrophobicity, and therefore, in order to maintain the hydrophobicity of the hollow fiber membrane after the hydrophilic polymer is imparted, the number of carbon atoms of the side chain terminal R of the hydrophobic unit is preferably 1 or more.

[0094] Further, the number of carbon atoms of the side chain terminal of the above hydrophobic unit is preferably 1 or more and 9 or less. When the hydrophilic polymer itself is highly hydrophobic, the water solubility of the hydrophilic polymer decreases, and therefore, it is preferable that the number of carbon atoms of the side chain terminal R of the hydrophobic unit be small, and more preferably 9 or less.

[0095] As the carboxylic acid vinyl ester unit having a number of carbon atoms of the side chain terminal R of the hydrophobic unit of 1 or more and 9 or less, there can be mentioned, for example, vinyl acetate (1 carbon atom), vinyl propionate (2 carbon atoms), vinyl butyrate (3 carbon atoms), vinyl valerate (4 carbon atoms), vinyl hexanoate (5 carbon atoms), vinyl heptanoate (6 carbon atoms), vinyl nonanoate (8 carbon atoms), or vinyl decanoate (9 carbon atoms), and the like.

[0096] Further, the side chain terminal R of the hydrophobic unit can include a branched structure such as an isopropyl group or a tert-butyl group, and there can be mentioned, for example, vinyl pivalate (4 carbon atoms) or vinyl 2-ethylhexanoate (7 carbon atoms), and the like. Further, the smaller the molecular weight of the hydrophobic unit of the side chain of the hydrophilic polymer, the more the biological fitness can be imparted in a state in which the thickness of the hydrophilic polymer-containing layer is thin, and the more the gas permeability can be easily maintained, and therefore, in the case where the hydrophobic unit is a carboxylic acid vinyl ester unit, the number of carbon atoms of the side chain terminal R is more preferably 1 or more and 7 or less, and further preferably 1 or more and 5 or less, and for example, in the case of a carboxylic acid vinyl ester unit, a vinyl acetate unit having 1 carbon atom, a vinyl propionate unit having 2 carbon atoms are particularly preferable.

[0097] The hydrophilic polymer in the present application preferably has a hydrophilic unit selected from a vinylpyrrolidone unit, an acrylamide derivative unit, or an N-N-vinylacetamide derivative carboxylic acid vinyl ester unit, and has a hydrophobic unit selected from a carboxylic acid vinyl ester unit, an alkyl acrylate unit, and an alkyl methacrylate unit. Further, the mole fraction of each unit in the copolymer of the hydrophilic unit and the hydrophobic unit differs depending on the structure of the hydrophobic unit, and is generally preferably 0.1 or more and 0.8 or less, and the hydration energy density calculated based on the above formula (1) is preferably 167 kJ・mol-1 or more.-1 nm -3 213 kJ · mol -1 nm -3 The following.

[0098] In the case where the hydrophobic unit is a carboxylic acid vinyl ester unit, the more the number of carbon atoms, the stronger the hydrophobicity, and therefore, in the case where the carboxylic acid vinyl ester has a large number of carbon atoms, the mole fraction of the carboxylic acid vinyl ester unit in the hydrophilic polymer is preferably low. In particular, in the case where the carboxylic acid vinyl ester unit is an acetic acid vinyl ester unit, a propionic acid vinyl ester unit, a butyric acid vinyl ester unit, or a pivalic acid vinyl ester unit, the mole fraction in the hydrophilic polymer is preferably 0.2 or more and 0.8 or less, and more preferably 0.35 or more and 0.65 or less. Furthermore, from the viewpoint of water solubility, the carboxylic acid vinyl ester unit is further preferably 0.35 or more and 0.60 or less, and particularly preferably 0.35 or more and 0.50 or less, further taking into consideration the handling properties.

[0099] In the case where the hydrophobic unit is an alkyl acrylate unit, the more the number of carbon atoms, the stronger the hydrophobicity, and therefore, in the case where the alkyl acrylate has a large number of carbon atoms, the mole fraction of the alkyl acrylate unit in the hydrophilic polymer is preferably low. In particular, in the case where the alkyl acrylate unit is an ethyl acrylate unit, the mole fraction in the hydrophilic polymer is preferably 0.2 or more and 0.8 or less, and more preferably 0.35 or more and 0.65 or less. Furthermore, from the viewpoint of water solubility, the alkyl acrylate unit is further preferably 0.40 or more and 0.60 or less, and particularly preferably 0.45 or more and 0.55 or less, further taking into consideration the handling properties.

[0100] As the hydrophilic polymer, a copolymer having a hydrophilic unit selected from a vinyl pyrrolidone unit, an acrylamide derivative unit, and an N-N-vinyl acetamide derivative carboxylic acid vinyl ester unit, and having a hydrophobic unit selected from a carboxylic acid vinyl ester unit and an alkyl acrylate unit can be used. In these cases, since the vinyl pyrrolidone unit is adjacent to the carboxylic acid vinyl ester unit, the biocompatibility is high, and the copolymer can be suitably used.

[0101] As the method of fixing the hydrophilic polymer to the hollow fiber membrane, for example, a method of fixing by crosslinking the hollow fiber membrane and the hydrophilic polymer by irradiation of a radioactive ray, heat treatment, or a crosslinking agent, or the like after coating the dense surface of the hollow fiber membrane with a hydrophilic solution can be given. Furthermore, the fixing can be performed by a crosslinking reaction by irradiation of a radioactive ray or heat treatment in a state where the hollow fiber membrane is in contact with a hydrophilic solution. The method of producing the hollow fiber membrane in the present application is not particularly limited, and a production method including a step of irradiating a radioactive ray in a state where the hydrophilic solution is in contact with the hollow fiber membrane (referred to as Step 1) is preferable.

[0102] "Hydrophilic solution" means a solution containing a hydrophilic polymer.

[0103] Generally, as the radiation dose in Step 1, it is preferable to be 5 kGy or more and 50 kGy or less.

[0104] Instead of Step 1, a cross-linking reaction using heat treatment can also be performed, and as the heating conditions at this time, it is appropriate to be 120°C or more and 300°C or less.

[0105] The step of fixing the hydrophilic polymer to the hollow fiber membrane can be performed before the hollow fiber membrane is assembled into the module housing, or after the hollow fiber membrane is assembled into the module housing or after the hollow fiber membrane is fixed to the module housing. Among these, since modification using heat or a cross-linking agent is difficult to occur in the hydrophilic solution and the module materials other than the hollow fiber membrane, a method of performing cross-linking and fixing by irradiation with a radiation in a state in which the hydrophilic solution is in contact with the hollow fiber membrane before the hollow fiber membrane is assembled into the module housing, that is, the production method including Step 1 is preferable.

[0106] In the present application, the radiation used in Step 1 can be α-rays, β-rays, γ-rays, X-rays, ultraviolet rays, or electron rays, and the like. In addition, since the blood contact material needs to be sterilized, a radiation sterilization method using γ-rays or electron rays is often used. That is, cross-linking using radiation irradiation can be performed while sterilizing the hollow fiber membrane and the hydrophilic polymer. When sterilization and cross-linking are performed at the same time, it is preferable to be an irradiation dose of 15 kGy or more. On the other hand, when the irradiation dose is 50 kGy or more, there is a risk that cross-linking or decomposition of the hydrophilic polymer or deterioration of the hollow fiber membrane or the module materials other than the hollow fiber membrane occurs, and thus it is more preferable to be 15 kGy or more and 50 kGy or less.

[0107] In addition, when the radiation is irradiated, by using an antioxidant, cross-linking reactions in the hydrophilic polymer, and modification of the polyolefin as the hollow fiber membrane material can also be suppressed.

[0108] "Antioxidant" means a molecule having a property of easily donating an electron to other molecules. Examples include water-soluble vitamins such as vitamin C, polyphenols, alcohols such as ethanol, propanol, ethylene glycol, propylene glycol, or glycerol, sugars such as glucose, galactose, mannose, or trehalose, inorganic salts such as sodium hyposulfite, sodium pyrosulfite, or sodium dithionite, uric acid, cysteine, or glutathione, and the like. These antioxidants can be used alone or in combination with two or more. In the case of a blood contact material for medical use, as a substance having low toxicity to living organisms, it is preferable to use ethanol, n-propanol, 2-propanol, ethylene glycol, propylene glycol, or glycerol, and the like.

[0109] The amount of the antioxidant added to the hydrophilic solution varies depending on the kind of the antioxidant, and in the case of ethanol, n-propanol or 2-propanol, it is preferably 0.01% by mass or more and 30.0% by mass or less, more preferably 0.05% by mass or more and 20.0% by mass or less, from the viewpoint of properly crosslinking the hollow fiber membrane with the hydrophilic polymer and the viewpoint of preventing deterioration of the material or the like caused by radiation.

[0110] In the case where the adsorption equilibrium constant of the hydrophilic polymer to the hollow fiber membrane is high, the amount of adsorption on the hollow fiber membrane is large, the hydrophilization of the hollow fiber membrane progresses, and the plasma leakage resistance is likely to decrease. At this time, by reducing the concentration of the hydrophilic polymer contained in the hydrophilic solution or reducing the amount of the hydrophilic solution with respect to the hollow fiber membrane, it is possible to adjust the amount of the hydrophilic polymer fixed to the surface of the hollow fiber membrane. Further, by the antioxidant having polarity, it is also possible to adjust the thickness of the hydrophilic polymer. For example, when the antioxidant is ethanol, by the polarity of ethanol, it is possible to increase the affinity of the hydrophilic polymer to the hydrophobic base material. Therefore, by adjusting the concentration of ethanol in the hydrophilic polymer solution, it is possible to adjust the thickness of the hydrophilic polymer.

[0111] In the case where the hollow fiber membrane is PMP and the hydrophilic polymer is a copolymer of vinylpyrrolidone and vinyl propionate, a copolymer of polyvinylpyrrolidone and vinyl acetate, a copolymer of polyvinylpyrrolidone and vinyl butyrate, a copolymer of polyvinylpyrrolidone and vinyl pivalate, a copolymer of polyvinylpyrrolidone and vinyl nonanoate, a copolymer of polyvinylpyrrolidone and vinyl decanoate, a copolymer of N-isopropyl acrylamide units and ethyl acrylate units, a copolymer of vinyl acetamide units and vinyl pivalate units, or polyvinylpyrrolidone, the concentration of the hydrophilic polymer in the hydrophilic solution is preferably 10 ppm or more and 5000 ppm or less, more preferably 100 ppm or more and 5000 ppm or less, from the viewpoint of maintaining the hydrophobicity of the hollow fiber membrane, inhibiting plasma leakage, or inhibiting the decrease in gas permeability caused by crosslinking of the hydrophilic polymer itself. Further, the concentration of ethanol is preferably 0.01% by mass or more and 20.0% by mass or less, more preferably 0.1% by mass or more and 20.0% by mass or less.

[0112] The method for producing the hollow fiber membrane of the present application preferably irradiates the radiation in step 1 in a state where the hydrophilic solution contacts only one surface of the hollow fiber membrane, i.e., only the dense surface that becomes the blood contact surface. As a method for contacting the hydrophilic solution with the outer surface of the hollow fiber membrane, there can be mentioned, for example, a method of irradiating the radiation while preventing the hydrophilic solution from permeating into the inside of the hollow fiber membrane in a state where the end portion of the hollow fiber membrane is embedded in a resin or the like, and crosslinking and fixing. Then, by cutting the portion of the hollow fiber membrane embedded in the resin, a hollow fiber membrane in which the hydrophilic polymer is crosslinked and fixed to the outer surface can be obtained.

[0113] Further, when crosslinking and fixing is performed in a state where the hollow fiber membrane is assembled into the module case, the end portion of the hollow fiber membrane is held by a holding plate or holding resin of the module case, and the space of the outer surface and the inner surface of the hollow fiber membrane can be divided, so the hydrophilic solution can be caused to stay only in the space that contacts the outer surface of the hollow fiber membrane, and by irradiating the radiation in this state, a hollow fiber membrane module in which the hollow fiber membrane in which the hydrophilic polymer is crosslinked and fixed to the outer surface is built-in can be obtained.

[0114] Further, as a method for causing the hydrophilic solution to contact only the inner surface, there can be mentioned, for example, a method of supplying the hydrophilic solution to the inside of the hollow fiber membrane, and crosslinking the hydrophilic polymer by irradiating the radiation in a sealed state. In the case of supplying the hydrophilic solution to the inside, it is preferable to perform the supply under pressure, and thus it is preferable to perform in a state where the hollow fiber membrane is inserted into the module case and held. As a sealing material for the end portion of the hollow fiber membrane, there can be mentioned a urethane resin, an epoxy resin, an acrylic resin, or the like. From the viewpoint of resistance to radiation irradiation and biological compatibility, it is preferable to be a urethane resin. Further, as the module case into which the hollow fiber membrane is inserted, from the viewpoint of radiation resistance, it is preferable to use polystyrene or polycarbonate, or the like.

[0115] The hollow fiber membrane module of the present application is filled with the hollow fiber membrane of the present application. The method for filling the hollow fiber membrane in the hollow fiber membrane module of the present application is not particularly limited, and a bundle of hollow fiber membranes that is provided in a bundle shape, a layer shape, a coil shape, or a fabric shape can be filled.

[0116] The hollow fiber membrane module of the present application is particularly suitable for a hollow fiber membrane-type artificial lung that is used for removing carbonic acid gas such as carbon dioxide from blood and adding oxygen to blood in extracorporeal blood circulation. When used as a hollow fiber membrane-type artificial lung, it is used in combination with a circuit and a catheter for extracorporeal blood withdrawal and blood return, a pump, a blood reservoir, a heat retaining device, a gas line, a gas cylinder, a gas regulator, a living body monitor, and a device monitor.

[0117] The hollow fiber membrane of the present application preferably has a nitrogen gas permeability of 0.02 mL / [min cm 2or more bar, the hollow fiber membrane has sufficient gas permeation performance as an artificial lung. From the viewpoint of improving the gas exchange performance as an artificial lung, the nitrogen permeability of the hollow fiber membrane is more preferably 0.20 mL / [min-cm 2 or more bar, the hollow fiber membrane has sufficient gas permeation performance as an artificial lung. From the viewpoint of improving the gas exchange performance as an artificial lung, the nitrogen permeability of the hollow fiber membrane is more preferably 0.20 mL / [min-cm 2 or more bar, the hollow fiber membrane has sufficient gas permeation performance as an artificial lung. From the viewpoint of improving the gas exchange performance as an artificial lung, the nitrogen permeability of the hollow fiber membrane is more preferably 0.20 mL / [min-cm 2 or more bar, the hollow fiber membrane has sufficient gas permeation performance as an artificial lung. From the viewpoint of improving the gas exchange performance as an artificial lung, the nitrogen permeability of the hollow fiber membrane is more preferably 0.20 mL / [min-cm 2 or less bar. Examples

[0118] Hereinafter, examples and comparative examples are listed to explain the present application, but the present application is not limited by these examples.

[0119] Thickness of the Hydrophilic Polymer-Containing Layer As an example, an embodiment using a hydrophilic polymer containing a nitrogen atom is described. Even in the case of using a hydrophilic polymer not containing a nitrogen atom, the measurement can be similarly performed by detecting peaks from atoms or chemical structures specific to the hydrophilic polymer.

[0120] A hollow fiber membrane having a hydrophilic polymer containing a nitrogen atom fixed on the outer surface as a dense surface is dried, and using GCIB-TOF-SIMS, the peak intensity of secondary ions from the detected hydrophilic polymer and the peak intensity of secondary ions from the main component of the hollow fiber membrane are measured along the film thickness direction from the outer surface of the hollow fiber membrane. The thickness of the hydrophilic polymer-containing layer is the etching distance in the film thickness direction until the sum of the peak intensities of CNO - and C4HNO - reaches 0.5 or less of the peak intensity of C2H - of the main component of the hollow fiber membrane, namely, PMP.

[0121] More specifically, using TOF-SIMS 5 (manufactured by ION-TOF), the sum of the peak intensities of negative secondary ions detected as CNO - (m / z = 42.00) and C4HNO - (m / z = 84.04) of the hydrophilic polymer is divided by the peak intensity of the chain hydrocarbon C2H -The etching distance in the film thickness direction until the value of the peak intensity of the negative secondary ions (m / z = 25.01) reaches 0.5 was set as the hydrophilic polymer-containing layer.

[0122] Note that the intensity of the secondary ion peak was set to the average intensity of the secondary ion peak of 200 μm2, which was measured each time etching was performed. Further, the etching depth was measured by a stylus-type surface roughness meter after GCIB-TOF-SIMS measurement, and the value obtained by dividing the total etching number (120 times) was set as the etching depth per 1 time (6.16 nm). The secondary ion peak intensity of each measurement interval was calculated by linear approximation from the measurement values of the two points before and after. Note that the measurement conditions of GCIB-TOF-SIMS were as described below.

[0123] Primary ion: Bi3 ＋＋ Secondary ion polarity: only negative ions Acceleration voltage: primary ion 30 kV Pulse width: 11.3 ns Beam mode: yes Detected mass range (m / z): 0 to 2500 Grating size: 200 μm Scanning number: 1 scan / cycle Pixel number: 128 pixels Measurement vacuum degree: (before sample introduction) 4 x 10 -7 Pa or less Charging neutralization: yes Post-acceleration: 9.5 kV Etching ion: Ar-GCIB Etching ion acceleration voltage: 5 kV Ar cluster size: 1500 (median) The same measurement was performed on different two positions, and the average value was calculated. Note that the thickness of the hydrophilic polymer-containing layer was rounded off to the second decimal place.

[0124] <Hydration Energy Density of Hydrophilic Polymer> The hydration energy of the monomer unit was defined by a molecular model of the monomer unit. The molecular model of the monomer unit was a structure in which the end of the repeating unit was set as a straight-chain alkane as a calculation object. The quantum chemical calculation used Gaussian 09, Revision D.01 (manufactured by Gaussian, Inc.), and the Connolly surface used Materials Studio (manufactured by BIOVIA, Inc.).

[0125] The hydration energy of the monomer unit described above was calculated by the following method. First, the monomer unit in vacuum was subjected to structure optimization, and then the energy in vacuum and the energy in water were calculated for the structure subjected to the structure optimization.

[0126] In the structure optimization step, density functional theory was used. As the functional, B3LYP was used, and as the basis function, 6-31G(d, p) was used. Further, as the keyword described in the input file, opt was set.

[0127] Next, the energy in vacuum and the energy in water were calculated for the structure subjected to the structure optimization described above. The energy in vacuum was calculated using density functional theory. As the functional, B3LYP was used, and as the basis function, 6-31G(d, p) was used. The energy in water was calculated using density functional theory. As the functional, B3LYP was used, and as the basis function, 6-31G(d, p) was used. Further, in order to calculate the energy in water, the continuum solvation model was used, and the following was used as the keyword.

[0128] SCRF = (PCM, G03Gefaults, Read, Solvent = Water) Radii = UAHF Alpha = 1.20 By calculating the SCF energies in vacuum and in water, the hydration energy of the monomer unit described above was determined. Here, the SCF energy means the value of E mentioned in the line described as "SCF Done:". The energy calculation described above was performed using the quantum chemistry calculation software Gaussian 09, Revision D.01 (manufactured by Gaussian, Inc.). The hydration energy density of the hydrophilic polymer described above was defined based on the following formula (1).

[0129] [Num 2] In the formula (1) described above, the hydration energy of the monomer unit i is the absolute value of the value obtained by subtracting the energy in vacuum of the monomer unit i from the energy in water of the monomer unit i, N represents the total number of monomer types constituting the copolymer, and i represents an integer of 1 or more and N or less.

[0130] The volume of the monomer unit described above was calculated using the Connolly surface method of Materials Studio (manufactured by BIOVIA).

[0131] At this time, the parameters were as follows.

[0132] Grid resolution = Coarse Grid interval = 0.075 nm vdW factor = 1.0 Connolly radius = 0.1 nm The hydration energy density of the above hydrophilic polymer is defined by the above formula (1) based on the above hydration energy and the volume calculated using the Connolly surface method. The volume of the above monomer unit in the above formula (1) is set to the structure optimized above. The hydration energy density uses the value obtained by rounding off the first digit after the decimal point. Note that the mole fraction of the above formula (1) can use the value calculated in "Mole fraction of monomer unit" described later. The mole fraction cannot be calculated by the above formula (1) due to reasons such as peaks overlapping each other. 1 When the above mole fraction is calculated by H-NMR measurement, the above mole fraction can also be calculated by elemental analysis.

[0133] "Mole fraction of monomer unit" A hydrophilic polymer 2 mg was dissolved in chloroform-D, 99.7% (containing 0.05% by volume of TMS, and manufactured by Wako Pure Chemical Industries, Ltd.) 2 mL, and 0.1 mL of deuterium oxide was added thereto. The sample was measured by H-NMR. 1 In the sample tube for H-NMR measurement, the following was performed 1 H-NMR (superconducting FTNMR EX-270, manufactured by JEOL Ltd.) measurement. The temperature was set to room temperature, and the number of accumulations was set to 32 times. From the peak of the proton (H) from the carbon atom adjacent to the nitrogen atom of vinylpyrrolidone confirmed to be 2.7 ppm or more and 4.3 ppm or less and the area A of the region surrounded by the baseline, and the peak of the proton (H) from the carbon bonded to the α-position of the carboxylic acid vinyl ester confirmed to be 4.3 ppm or more and 5.2 ppm or less and the area A of the region surrounded by the baseline, the value of A 3 / (A PVP + A 1 ) was calculated, and was set to the mole fraction of the vinylpyrrolidone unit. Note that the mole fraction was calculated by rounding off the second digit after the decimal point. VC PVP PVP VC

[0134] "Nitrogen atom content" The nitrogen atom content in 100 mass% of the hollow fiber membrane 100 was measured by the oxidative decomposition-reduced pressure chemiluminescence method using a trace nitrogen analysis device (ND-100 type, manufactured by Mitsubishi Chemical Corporation) by drying the hollow fiber membrane in which the nitrogen-containing hydrophilic polymer was fixed and cutting it into a certain mass. More specifically, the hollow fiber membrane was about 15 cm and was heat-decomposed and oxidized, and the generated nitric oxide was measured by the chemiluminescence method. The quantification was calculated from the standard curve prepared using a pyridine standard solution. The settings at the time of measurement are described below.

[0135] ​​​​Temperature of electric furnace: 800°C for thermal decomposition part, 900°C for catalyst part Main O2 flow rate: 300 mL / min Sub O2 flow rate: 300 mL / min Ar flow rate: 400 mL / min Sensing mode: High Note that the average value of the results of three measurements was used as the measurement value, and the value obtained by rounding off the fifth digit after the decimal point was used.

[0136] <Content of vinylpyrrolidone unit> For the content of the vinylpyrrolidone unit in 100 mass% of the hollow fiber membrane, since one atom of nitrogen (atomic weight: 14) is contained in the vinylpyrrolidone unit (molecular weight: 111) with respect to the nitrogen content calculated in the above-described "nitrogen content", the content of the nitrogen atom was converted into the content of the vinylpyrrolidone unit by the following formula (2) to be calculated.

[0137] Content of vinylpyrrolidone unit (mass%) = Nitrogen content (mass%) x (molecular weight of vinylpyrrolidone unit / atomic weight of nitrogen)... Formula (2) Note that the vinylpyrrolidone content was used as the value obtained by rounding off the fourth digit after the decimal point.

[0138] <Static contact angle of water> The static contact angle of water of the dense surface of the hollow fiber membrane was measured by the liquid drop method using an automatic minimum contact angle meter (MCA-4, manufactured by Kyowa Interface Science Co., Ltd.). The liquid used at the time of measurement was distilled water, and the measurement was performed at room temperature under a humidity of 30 ± 2%. The liquid amount of the liquid drop was set to 44.7 ± 3.4 pL, and was discharged from a capillary tube of φ 5 μm to the outer surface of the hollow fiber membrane as the dense surface at 115 kPa x 18 ms. The liquid drop was measured 250 times at intervals of 10 ms, and was analyzed by the θ / 2 method. In addition, the analysis used the first image in which the water drop was dropped on the sample. The measurement was repeated three times, and the average value was calculated. Note that the static contact angle of water was used as the value obtained by rounding off the second digit after the decimal point.

[0139] <Nitrogen gas permeability> The gas permeability of the hollow fiber membrane was measured by the pressure sensor method according to JIS K7126-1 (2006) at a measurement temperature of 37°C by measuring the pressure change on the permeation side per unit time of nitrogen gas by the outside pressure method to calculate the permeation gas volume. The measurement conditions were as follows.

[0140] Supply pressure of nitrogen gas: 0.04 MPa (gauge pressure) Volume on the permeation side: 475.9 cm 3 Measurement time: 4 minutes The gas permeability was calculated by the following equation (3) using an assembly in which a hollow fiber membrane having a length of 7 cm was sealed and fixed with an epoxy resin.

[0141] Nitrogen permeability (mL / [min cm 2 bar]) = volume of permeated gas (mL) / [time (min) x outer surface area of hollow fiber membrane (cm 2 x pressure difference (bar)]... Equation (3) Note that the nitrogen permeability was rounded off to the third decimal place.

[0142] <Protein attachment amount> A hollow fiber membrane having a length of 1.5 m and both ends sealed with an epoxy resin was washed with phosphate buffered saline (hereinafter referred to as "PBS"). Next, the hollow fiber membrane was immersed in 10 mL of an 80 g / L albumin / PBS solution and incubated at 37°C for 72 hours. After washing the immersed hollow fiber membrane with PBS, it was fixed with a 2.5% glutaraldehyde / physiological saline solution and dried. Next, the hollow fiber membrane was immersed in 1.8 mL of Working reagent of a BCA assay kit (Micro BCA Protein Assay Kit, product number: 23235, manufactured by Thermo Fisher Scientific). After incubation at 60°C for 60 minutes, the absorbance at 562 nm of the Working reagent after the reaction was measured, and the amount of protein attached to the hollow fiber membrane was calculated. Note that the protein attachment amount was rounded off to the second decimal place.

[0143] <Platelet attachment number> A hollow fiber membrane in a state where the outer surface was exposed was attached and arranged on the bottom surface of a sample cup, and after being brought into contact with human fresh blood, the washed and fixed hollow fiber membrane was observed by a scanning electron microscope (hereinafter referred to as "SEM"). More specifically, human fresh blood was collected by 10% ACD-A blood collection, and centrifuged at 160G for 25 minutes, thereby obtaining platelet-rich plasma (hereinafter referred to as "PRP") containing a large amount of platelets. The hollow fiber membrane fixed on the bottom surface of the sample cup was previously washed with PBS.

[0144] After aliquoting 1 mL of PRP into the sample cup, adenosine-2-phosphate, acting as a platelet-activating stimulant, was added at a concentration of 100 μmol / L, followed by shaking for 15 minutes. After 15 minutes, the PRP in the sample cup was discarded, and 1 mL of physiological saline was added. This shaking and discarding process was repeated approximately 10 times to remove platelets from the sample cup through washing. Next, a 2.5% glutaraldehyde / physiological saline solution was added to the sample cup, and the mixture was allowed to stand for at least 1 hour to fix the platelets attached to the hollow fiber membrane.

[0145] After fixation, the samples were washed with water for injection after the fixative was discarded, and then dried in a vacuum dryer (FD-1, manufactured by Tokyo Riko Machinery Co., Ltd.) for at least 1 hour. For SEM observation, Pt sputtering (E-1045, manufactured by Hitachi High-Tech Fielding Co., Ltd.) was performed at a discharge current of 15mA for 40 seconds. Platelets adhered to the outer surface of the hollow fiber membrane were observed using a SEM (SEMEDX Type-HS-3000, manufactured by Hitachi High-Tech Fielding Co., Ltd.). The observation settings were 1500x magnification and a field of view of 4.35×10⁻⁶. 4 μm 2 The average value of 20 fields of view was used as the platelet attachment number.

[0146] It should be noted that the count for each field of view is set to up to 50, and more than 50 is set to >50. The average value is calculated, and the value is rounded to the first decimal place as the platelet attachment count. In addition, if multiple platelets are extended or deformed and cannot be counted individually, but platelet attachment is confirmed in most cases, thrombosis is assumed to have occurred.

[0147] <Platelet attachment state> Similar to the platelet count determination, the sputtered hollow fiber membrane was observed using a SEM (SEMEDX Type-HS-3000, Hitachi High-Tech Fielding) at 250x magnification to examine the thrombi adhering to the hollow fiber membrane. Figure 1 and Figure 3 As shown, almost no platelet adhesion was observed in the examples, such as Figure 2 As shown, platelet adhesion was observed in the comparative example. It should be noted that thrombus formation is considered to occur when the hollow fiber membrane as a whole is completely thrombus-laden.

[0148] [Example 1] A hollow fiber membrane was made of PMP, using those having an outer diameter of 380 μm, an inner diameter of 200 μm, a membrane thickness of 90 μm, and a dense surface on the outer surface. The end portion of the hollow fiber membrane was sealed, and set in a state where only the outer surface was in contact with a liquid. The hollow fiber membrane was immersed in a hydrophilic solution of a random copolymer of a vinylpyrrolidone unit and a vinyl propionate unit (weight average molecular weight: 58,000, molar fraction of vinylpyrrolidone unit: 0.6, hydration energy density: 182 kJ・mol -1 nm -3 ) 10 ppm, ethanol 0.1 mass%, and subjected to γ-ray irradiation of 25 kGy. The hollow fiber membrane after the γ-ray irradiation was washed with PBS to obtain a hollow fiber membrane 1.

[0149] [Example 2] A random copolymer of a vinylpyrrolidone unit and a vinyl propionate unit of the hydrophilic solution was set to a concentration of 100 ppm, and the same operation as in Example 1 was performed except for this to obtain a hollow fiber membrane 2.

[0150] [Example 3] A random copolymer of a vinylpyrrolidone unit and a vinyl propionate unit of the hydrophilic solution was set to a concentration of 200 ppm, and the same operation as in Example 1 was performed except for this to obtain a hollow fiber membrane 3.

[0151] [Example 4] A random copolymer of a vinylpyrrolidone unit and a vinyl propionate unit of the hydrophilic solution was set to a concentration of 500 ppm, and ethanol was set to a concentration of 1.0 mass%, and the same operation as in Example 1 was performed except for this to obtain a hollow fiber membrane 4.

[0152] [Example 5] Ethanol of the hydrophilic solution was set to a concentration of 10.0 mass%, and the same operation as in Example 4 was performed except for this to obtain a hollow fiber membrane 5.

[0153] [Example 6] Ethanol of the hydrophilic solution was set to a concentration of 20.0 mass%, and the same operation as in Example 4 was performed except for this to obtain a hollow fiber membrane 6.

[0154] [Example 7] A random copolymer of a vinylpyrrolidone unit and a vinyl propionate unit of the hydrophilic solution was set to a concentration of 1000 ppm, and ethanol was set to a concentration of 10.0 mass%, and the same operation as in Example 1 was performed except for this to obtain a hollow fiber membrane 7.

[0155] [Example 8] The ethanol concentration of the hydrophilic solution was set to 20.0 mass%, and the same operation as in Example 7 was performed except for this, to obtain a hollow fiber membrane 8.

[0156] [Example 9] The random copolymer concentration of the vinylpyrrolidone unit and the vinyl propionate unit of the hydrophilic solution was set to 5000 ppm, and the ethanol concentration was set to 10.0 mass%, and the same operation as in Example 1 was performed except for this, to obtain a hollow fiber membrane 9.

[0157] [Example 10] The ethanol concentration of the hydrophilic solution was set to 20.0 mass%, and the same operation as in Example 9 was performed except for this, to obtain a hollow fiber membrane 10.

[0158] [Comparative Example 1] The ethanol concentration of the hydrophilic solution was set to 10.0 mass%, and the same operation as in Example 1 was performed except for this, to obtain a hollow fiber membrane 11.

[0159] [Comparative Example 2] The random copolymer concentration of the vinylpyrrolidone unit and the vinyl propionate unit of the hydrophilic solution was set to 1 ppm, and the ethanol concentration was set to 0.1 mass%, and the same operation as in Example 1 was performed except for this, to obtain a hollow fiber membrane 12.

[0160] [Comparative Example 3] The random copolymer concentration of the vinylpyrrolidone unit and the vinyl propionate unit of the hydrophilic solution was set to 15000 ppm, and the ethanol concentration was set to 20.0 mass%, and the same operation as in Example 1 was performed except for this, to obtain a hollow fiber membrane 13.

[0161] The results obtained by measuring the thickness of the hydrophilic polymer-containing layer, the hydration energy density of the hydrophilic polymer, the kind of the hydrophilic unit, the kind of the hydrophobic unit, the nitrogen atom content of the hollow fiber membrane, the vinylpyrrolidone unit content, the static contact angle of water of the dense surface, and the nitrogen permeability of the obtained hollow fiber membranes 1 to 13 are shown in Table 1, and the results obtained by measuring the protein adhesion amount and the platelet adhesion number are shown in Table 2.

[0162] [Table 1]

[0163] [Table 2]

[0164] [Example 11] The concentration of polyvinylpyrrolidone (weight average molecular weight: 40,000, molar fraction of vinylpyrrolidone units: 1.0, hydration energy density: 213 kJ・mol -1 ・nm -3 ) was set to 200 ppm, and the concentration of ethanol was set to 0.1 mass%, and the same operation as in Example 1 was performed, except for the above, to obtain a hollow fiber membrane 14.

[0165] [Example 12] The concentration of polyvinylpyrrolidone of the hydrophilic solution was set to 1000 ppm, and the concentration of ethanol was set to 20 mass%, and the same operation as in Example 11 was performed, except for the above, to obtain a hollow fiber membrane 15.

[0166] [Example 13] The concentration of a random copolymer of vinylpyrrolidone units and vinyl acetate units (weight average molecular weight: 58,000, molar fraction of vinylpyrrolidone units: 0.6, hydration energy density: 187 kJ・mol -1 ・nm -3 ) was set to 200 ppm, and the concentration of ethanol was set to 0.1 mass%, and the same operation as in Example 1 was performed, except for the above, to obtain a hollow fiber membrane 16.

[0167] [Example 14] The concentration of a random copolymer of vinylpyrrolidone units and vinyl acetate units was set to 1000 ppm, and the concentration of ethanol was set to 10 mass%, and the same operation as in Example 13 was performed, except for the above, to obtain a hollow fiber membrane 17.

[0168] [Example 15] The concentration of a random copolymer of vinylpyrrolidone units and vinyl acetate units was set to 7500 ppm, and the concentration of ethanol was set to 0.1 mass%, and the same operation as in Example 13 was performed, except for the above, to obtain a hollow fiber membrane 18.

[0169] [Example 16] The concentration of a random copolymer of vinylpyrrolidone units and vinyl butyrate units (weight average molecular weight: 21000, molar fraction of vinylpyrrolidone units: 0.7, hydration energy density: 193 kJ・mol -1 ・nm -3 ) was set to 500 ppm, and the concentration of ethanol was set to 20 mass%, and the same operation as in Example 1 was performed, except for the above, to obtain a hollow fiber membrane 19.

[0170] [Example 17] The concentration of the random copolymer of vinylpyrrolidone units and vinyl butyrate units in the hydrophilic solution was set to 1000 ppm and ethanol to 20% by mass. Otherwise, the same operation as in Example 16 was performed to obtain hollow fiber membrane 20.

[0171] [Example 18] For hydrophilic solutions, a random copolymer of vinylpyrrolidone units and vinyl neopentanoate units (weight average molecular weight: 39000, mole fraction of vinylpyrrolidone units: 0.7, hydration energy density: 172 kJ·mol⁻¹) was formed. -1 ・nm -3 The concentration of ) was set to 200 ppm and the ethanol was set to 10% by mass. Otherwise, the same operation as in Example 1 was performed to obtain hollow fiber membrane 21.

[0172] [Example 19] The concentration of the random copolymer of vinylpyrrolidone units and vinyl pentanoate units in the hydrophilic solution was set to 500 ppm and ethanol to 20% by mass. Otherwise, the same operation as in Example 18 was performed to obtain hollow fiber membrane 22.

[0173] [Example 20] Random copolymers of vinylpyrrolidone units and vinyl nonanoate units in hydrophilic solutions (weight average molecular weight: 44000, mole fraction of vinylpyrrolidone units: 0.8, hydration energy density: 167 kJ·mol⁻¹) -1 ・nm -3 The concentration of ) was set to 500 ppm and the ethanol was set to 10% by mass. Otherwise, the same operation as in Example 1 was performed to obtain hollow fiber membrane 23.

[0174] [Example 21] Random copolymers of vinylpyrrolidone units and vinyl decanoate units in hydrophilic solutions (weight average molecular weight: 19000, mole fraction of vinylpyrrolidone units: 0.8, hydration energy density: 171 kJ·mol⁻¹) -1 ・nm -3 The concentration of ) was set to 500 ppm and the ethanol was set to 10% by mass. Otherwise, the same operation as in Example 1 was performed to obtain hollow fiber membrane 24.

[0175] [Example 22] Random copolymers of N-isopropylacrylamide units and ethyl acrylate units in hydrophilic solutions (weight average molecular weight: 3000, mole fraction of N-isopropylacrylamide: 0.5, hydration energy density: 181 kJ·mol⁻¹) -1 ・nm -3The concentration of the random copolymer of vinyl acetoamide units and vinyl pivalate units (weight average molecular weight: 76000, molar fraction of vinyl acetoamide units: 0.5, hydration energy density: 178 kJ・mol -1 ・nm -3 ) was set to 500 ppm, and the concentration of ethanol was set to 15 mass%, and the same operation as in Example 1 was performed, except for the above, to obtain a hollow fiber membrane 25.

[0176] [Example 23] The concentration of the random copolymer of vinyl acetoamide units and vinyl pivalate units (weight average molecular weight: 76000, molar fraction of vinyl acetoamide units: 0.5, hydration energy density: 178 kJ・mol -1 ・nm -3 ) was set to 500 ppm, and the concentration of ethanol was set to 15 mass%, and the same operation as in Example 1 was performed, except for the above, to obtain a hollow fiber membrane 25.

[0177] Comparative Example 4 The concentration of polyvinylpyrrolidone was set to 20 ppm, and the concentration of ethanol was set to 0.1 mass%, and the same operation as in Example 11 was performed, except for the above, to obtain a hollow fiber membrane 27.

[0178] Comparative Example 5 The concentration of the random copolymer of vinyl pyrrolidone units and vinyl acetate units was set to 20 ppm, and the concentration of ethanol was set to 0.1 mass%, and the same operation as in Example 13 was performed, except for the above, to obtain a hollow fiber membrane 28.

[0179] Comparative Example 6 The concentration of the random copolymer of vinyl pyrrolidone units and vinyl pivalate units was set to 50 ppm, and the concentration of ethanol was set to 20 mass%, and the same operation as in Example 18 was performed, except for the above, to obtain a hollow fiber membrane 29.

[0180] Comparative Example 7 The concentration of polyvinyl alcohol (weight average molecular weight: 95000, hydration energy density: 1531 kJ・mol -1 ・nm -3 ) was set to 1000 ppm, and the concentration of ethanol was set to 0.1 mass%, and the same operation as in Example 1 was performed, except for the above, to obtain a hollow fiber membrane 30.

[0181] The results of the measurement of the thickness of the hydrophilic polymer-containing layer, the hydration energy density of the hydrophilic polymer, the kind of the hydrophilic unit, the kind of the hydrophobic unit, the nitrogen atom content of the hollow fiber membrane, the vinyl pyrrolidone unit content, and the static contact angle of water of the dense surface of the obtained hollow fiber membranes 14 to 30 are shown in Tables 3 and 4, and the results of the measurement of the nitrogen gas permeability, the protein adhesion amount, and the platelet adhesion number are shown in Table 5.

[0182] [Table 3]

[0183] [Table 4]

[0184] [Table 5]

[0185] The hollow fiber membranes 1 to 10 and 14 to 26 had low amounts of protein and platelet adhesion, and no thrombus formation on the entire hollow fiber membrane, and had a gas permeability of 0.2 mL / [min-cm 2 bar] or more, and were membranes having both biological adaptability and gas permeability. This can be considered to be due to the fact that the thickness of the hydrophilic polymer-containing layer was sufficient to inhibit the adhesion of biological components, and was a thickness that did not reduce the gas permeability. Further, the static contact angle of water was 70° or more, and it was considered to be a membrane having a hydrophobicity that inhibited plasma leakage.

[0186] On the other hand, the hollow fiber membranes 11 and 12, and 27 to 30 had a large amount of protein and platelet adhesion due to the fact that the thickness of the hydrophilic polymer-containing layer was insufficient, and further, the hollow fiber membranes 11 and 27 to 30 had thrombus formation on the entire hollow fiber membrane, and were membranes having low biological adaptability. The hollow fiber membrane 13 was a membrane having low gas permeability due to the fact that the thickness of the hydrophilic polymer-containing layer was thick. Further, since the static contact angle of water was 80° or less, the hydrophilicity was strong, and it was considered to be a membrane in which plasma leakage easily occurred. The hollow fiber membrane 30 was a membrane in which plasma leakage easily occurred due to the fact that the density of the hydration energy of the hydrophilic polymer was small, and protein and platelet adhesion occurred.

[0187] Industrial applicability Although blood components are exemplified as the contact liquid in the present application, the contact liquid is not limited to blood components. For example, it can be applied to a cell suspension liquid composed of cells, microorganisms, plant cultured cells, or somatic cells, reproductive cells, somatic stem cells, artificial pluripotent stem cells, or embryonic liver cells, a blood preparation such as a platelet preparation or a red blood cell preparation, or a fine particle dispersion liquid such as a synthetic fine particle, an inorganic fine particle, or a vesicle. Further, it can also be applied to rainwater, seawater, slurry, or a synthetic polymer solution in the environment, or the like. These solutions can also be used as an oxidation membrane or a degassing membrane.

Claims

1. A hollow fiber membrane comprising polymethylpentene as a main component, and a hydrophilic polymer is fixed to a dense surface, a layer containing the hydrophilic polymer has a thickness of 1.0 nm or more and 25.0 nm or less.

2. The hollow fiber membrane according to claim 1, wherein, The hydrophilic polymer has a hydration energy density of 167 kJ・mol -1 nm -3 213 kJ・mol -1 nm -3 kJ・mol 3. The hollow fiber membrane according to claim 1 or 2, wherein, The nitrogen atom content is 0.0010 mass% or more and 0.0100 mass% or less.

4. The hollow fiber membrane according to any one of claims 1 to 3, wherein, The hydrophilic polymer has a hydrophilic unit selected from the group consisting of a vinylpyrrolidone unit, an acrylamide derivative unit, a methacrylamide derivative unit, an N-vinylacetamide derivative unit, and a vinylcaprolactam unit, and the content of the hydrophilic unit is 0.010 mass% or more and 0.080 mass% or less.

5. The hollow fiber membrane according to any one of claims 1 to 4, wherein, The dense surface has a water contact angle of 70° or more and 95° or less.

6. The hollow fiber membrane according to any one of claims 1 to 5, wherein, The hydrophilic polymer has a hydrophobic unit selected from the group consisting of a carboxylic acid vinyl ester unit, an alkyl acrylate unit, and an alkyl methacrylate unit.

7. The hollow fiber membrane according to claim 6, wherein, The number of carbon atoms at the side chain end of the hydrophobic unit is 1 or more and 9 or less.

8. A method for producing the hollow fiber membrane according to any one of claims 1 to 7, having the following step 1, Step 1: a step of irradiating a hollow fiber membrane that has contacted a hydrophilic solution with a radiation.

9. The method for producing a hollow fiber membrane according to claim 8, wherein, The hydrophilic solution is caused to contact only one surface of the hollow fiber membrane.

10. A hollow fiber membrane module filled with the hollow fiber membrane according to any one of claims 1 to 7.

11. The hollow fiber membrane module according to claim 10, which is an artificial lung.

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