JP4937767B2 - Blood purifier and manufacturing method thereof - Google Patents

Description

  The present invention relates to a blood purifier used for hemodialysis therapy, hemodiafiltration (HDF) therapy, and the like, and a manufacturing method thereof.

  In blood purification therapy, a hollow fiber bundle in which about 5000 to 10,000 hollow fibers are bundled in a casing is obtained by spinning a semipermeable membrane or an ultrafiltration membrane into a hollow fiber shape (hereinafter referred to as a hollow fiber membrane). A blood purifier constructed by loading is used. Then, the uremic substance is removed by filtration by flowing blood to the inner surface side of the hollow fiber membrane in the blood purifier. In hemodialysis therapy, blood is allowed to flow on the inner surface side of the hollow fiber membrane in the blood purifier and dialysate is allowed to flow on the outer surface side. Removes toxic substances and removes excess water from the body. Also, hemodiafiltration treatment removes uremic substances and excess water in the body by the characteristics of both hemofiltration therapy and hemodialysis therapy, that is, filtration and diffusion.

  Such blood purifiers include those in which filling water is sealed in advance in the blood purifier and those in which filling water is not sealed in the blood purifier (so-called dry type). Compared to the former type, the latter type is lighter and easier to handle because it does not contain filled water, and has the advantage that it is less likely to break due to freezing expansion even at low temperatures. A dry type blood purifier is preferably used.

  Examples of the hollow fiber membrane used in the blood purifier include various types. For example, a polyester-based polymer alloy membrane (hereinafter referred to as “polyarylate resin (PAR)” and “polyethersulfone resin (PES)”). PEPA (registered trademark) film) has been put into practical use (see, for example, Patent Document 1). This PEPA membrane has not only mechanical strength, heat resistance, chemical resistance, and good biocompatibility, but also has a high ability to inhibit pyrogens such as endotoxin in the dialysate. Therefore, there was a strong need for the development of a dry type blood purifier using this PEPA membrane.

Japanese Patent No. 2739903

  Since the PEPA membrane is a hydrophobic material, it is difficult to immediately exhibit its original permeability as it is. For this reason, the hollow fiber membrane is hydrophilized using polyvinyl pyrrolidone (PVP), which is a hydrophilic polymer, as a hydrophilizing agent, and in actual use, a physiological saline solution is placed in the blood purifier in order to exhibit its original permeability. The activation process (priming) is performed.

By the way, if it hydrophilizes with PVP, it will become easy to exhibit a permeability, but on the other hand, the hydrophobicity of a PEPA film | membrane will fall, and, thereby, the endotoxin blocking ability of a corner will fall.
Also, in the blood purification device manufacturing process, sterilization is performed, for example, by irradiating γ rays. At this time, if the amount of water contained in the hollow fiber membrane is small, the hollow fiber membrane becomes hydrophilic. As a result, the PVP applied as an agent is decomposed by γ rays, and as a result, there is a problem that PVP is eluted when the activation treatment is performed. On the other hand, from the viewpoint of suppressing the decomposition of PVP at the time of γ-ray irradiation, if the hollow fiber membrane contains excessive moisture, there has been a problem that air bubbles in the blood purifier deteriorated during the activation process.

  Moreover, regarding the amount of the hydrophilizing agent (PVP) applied to the hollow fiber membrane, if it is too small, the activation is insufficient and the permeability of the hollow fiber membrane cannot be sufficiently exhibited. There is a possibility that the hydrophilizing agent may be eluted from the thread membrane into the blood.

  The present invention has been proposed in view of the above, and a blood purifier capable of effectively demonstrating the permeability of a hollow fiber membrane, which is safe and easy to handle while ensuring endotoxin blocking ability, and its An object is to provide a manufacturing method.

The present invention has been proposed in order to achieve the above-mentioned object, and what is described in claim 1 is a hollow fiber membrane whose main membrane material is a polymer alloy membrane comprising a polyarylate resin and a polyethersulfone resin. A hollow fiber bundle is formed by bundling hollow fiber membranes having a dense layer on the inner surface side and outer surface side, and this hollow fiber bundle is loaded into a casing. Polyvinylpyrrolidone is used as a hydrophilic polymer. In the blood purifier using the blood contact portion of the hollow fiber membrane to make it hydrophilic,
The hollow fiber bundle is
The pore size on the inner surface side of the hollow fiber membrane is set to 9.2 to 15.3 nm, the pore size on the outer surface side of the hollow fiber membrane is set to a coarser pore diameter than the inner surface side in the range of 24.3 to 53.4 nm,
The mass ratio Mr of the hydrophilic polymer to the mass of the hollow fiber membrane is set in the range of 5 × 10 ⁻³ <Mr <15 × 10 ⁻³ ,
When the endotoxin solution of 1000 EU / L is filtered from the outside to the inside of the hollow fiber membrane having a converted membrane area of 0.15 m ² at a flow rate of 50 ml / min for 2 hours, the endotoxin concentration of the filtrate is 1.0 EU / L or less. A blood purifier characterized by being manufactured.

According to the second aspect of the present invention, the moisture content of the hollow fiber membrane is reduced to 1 m by applying a drying treatment by microwave irradiation. ² It is set to 5.8-6.7g per, It is a blood purifier of Claim 1 characterized by the above-mentioned.

What is described in claim 3 is a hollow fiber membrane mainly comprising a polymer alloy membrane comprising a polyarylate resin and a polyethersulfone resin, and having a dense layer on the inner surface side and the outer surface side. A hollow fiber bundle is formed by bundling and the blood contact part of the hollow fiber membrane is hydrophilized using polyvinylpyrrolidone as a hydrophilic polymer for a blood purifier formed by loading the hollow fiber bundle into a casing. In the method for producing a blood purifier for performing at least hydrophilic treatment, washing treatment of washing excess hydrophilic polymer with water, and drying treatment,
The hollow fiber bundle is
The pore size on the inner surface side of the hollow fiber membrane is set to 9.2 to 15.3 nm, the pore size on the outer surface side of the hollow fiber membrane is set to a coarser pore diameter than the inner surface side in the range of 24.3 to 53.4 nm,
The mass ratio Mr of the hydrophilic polymer to the mass of the hollow fiber membrane is set in the range of 5 × 10 ⁻³ <Mr <15 × 10 ⁻³ ,
In the hydrophilization treatment, the hollow fiber bundle was measured by filtering a 1000 EU / L endotoxin solution from the outside to the inside of a hollow fiber membrane with a converted membrane area of 0.15 m ² at a flow rate of 50 ml / min for 2 hours. A method for producing a blood purifier, wherein the filtrate is produced so that the endotoxin concentration is 1.0 EU / L or less.

According to a fourth aspect of the present invention, the drying treatment is performed by microwave irradiation, and the moisture content of the hollow fiber membrane is set to 1 m of the hollow fiber membrane. ² It is set as 5.8-6.7g per, It is a manufacturing method of the blood purifier of Claim 3 characterized by the above-mentioned.

According to the present invention, the following excellent effects can be obtained.
That is, a hollow fiber bundle comprising a polymer alloy film composed of a polyarylate resin and a polyethersulfone resin as a main membrane material, and a bundle of hollow fiber membranes having dense layers on the inner surface side and the outer surface side. In which a hollow fiber bundle is loaded into a casing, and the blood contact portion of the hollow fiber membrane is hydrophilized using polyvinylpyrrolidone as a hydrophilic polymer. Produced so that the endotoxin concentration of the filtrate is 1.0 EU / L or less when the / L endotoxin solution is filtered from the outside to the inside of the hollow fiber membrane with a converted membrane area of 0.15 m ² at a flow rate of 50 ml / min for 2 hours. Therefore, the permeability due to hydrophilicity can be exhibited while ensuring a high endotoxin blocking ability. Therefore, not only the activation treatment can be easily performed at the medical site, but also the permeation of pyrogens such as endotoxin can be prevented when hemodialysis treatment is performed, thereby reliably preventing the onset of fever symptoms.

And by adjusting the water content of the hollow fiber membrane to 5.8 to 6.7 g per 1 m ² of the hollow fiber membrane, it is adhered and held as a hydrophilic polymer to the hollow fiber membrane during sterilization treatment by γ-ray irradiation. While suppressing the decomposition of the polyvinyl pyrrolidone, it is possible to improve the escape of bubbles during the activation process .

Moreover, since the mass ratio Mr of the hydrophilic polymer with respect to the mass of the hollow fiber membrane was set in the range of 5 × 10 ⁻³ <Mr < 15 × 10 ⁻³ , the hydrophilic polymer was ensured while ensuring the activation. It becomes possible to suppress the outflow.

Furthermore, the pore size on the inner surface side of the hollow fiber membrane was set to 9.2 to 15.3 nm, and the pore size on the outer surface side of the hollow fiber membrane was set to a coarser pore diameter than the inner surface side in the range of 24.3 to 53.4 nm . Therefore, the permeability of the hollow fiber membrane and the ability of blocking the exothermic substance can be exhibited more effectively .

Hereinafter, embodiments of the present invention will be described with reference to the drawings.
First, the configuration of the blood purifier 1 will be described with reference to FIGS. 1 and 2. The illustrated blood purifier 1 has a configuration in which a hollow fiber bundle 3 is provided inside a case 2.

  The case 2 includes a cylindrical casing 4 that can accommodate the hollow fiber bundle 3, a discharge-side cap member 5 that is screwed into an opening at one end of the casing 4, and an opening at the other end of the casing 4. And a cap member 6 on the injection side that is screwed onto the cap. The casing 4 is a cylindrical member provided with enlarged diameter portions 7 at both ends in the longitudinal direction of the cylinder, and is made of, for example, polycarbonate. The enlarged diameter portion 7 located on one end side in the longitudinal direction of the cylinder is provided with a dial 8 (purification liquid) injection port 8 communicating with the internal space of the casing 4 so as to project toward the side of the cylinder. The enlarged diameter portion 7 located on the end side is provided with a dial 9 discharge port 9 communicating with the internal space of the casing 4 so as to project toward the side of the cylinder.

  Sealing portions 10 are provided at both ends of the casing 4 in the longitudinal direction of the cylinder. The sealing part 10 is a part for adhering and fixing the end of the hollow fiber bundle 3 to the casing 4 and sealing it, and is made of, for example, a sealing material. As the sealing material, a resin composition, for example, a urethane-based adhesive is used. As shown in FIG. 2A, the sealing material is filled between the hollow fiber bundle 3 and the casing 4 and between the hollow fiber membranes 12 constituting the hollow fiber bundle 3. As a result, both end surfaces of the casing 4 are in a state in which a plurality of hollow fiber membranes 12 whose ends are open are in a dense state, and a sealing material is in a sealed state in which gaps between the hollow fiber membranes 12 are closed.

  And this sealing part 10 is provided in the edge part side of a cylinder longitudinal direction rather than the opening position of the dialysate injection | pouring port 8 or the dialysate discharge | emission port 9 (refer FIG. 1). For this reason, the hollow fiber membrane 12 and the sealing portion 10 divide the inner space of the casing 4 into an inner space and an outer space of the hollow fiber membrane 12. Further, the outer space of the hollow fiber membrane 12 communicates with the outside of the casing 4 through the dialysate injection port 8 and the dialysate discharge port 9. The inner space of the hollow fiber membrane 12 functions as a first fluid passage space for passing a solution to be purified such as blood, and the outer space of the hollow fiber membrane 12 is a first passage for passing a purification solution such as dialysis solution. Functions as a two-fluid space.

  The discharge-side cap member 5 is a substantially funnel-shaped cap member having a blood discharge port 13, and is screwed to the other end side in the longitudinal direction of the cylinder. The discharge-side cap member 5 is provided with an O-ring 14 that can be in close contact with the outer peripheral portion of the outer surface of the sealing portion. The O-ring 14 is in close contact with the outer surface of the sealing portion, thereby sealing the boundary between the casing 4 and the discharge-side cap member 5 in a liquid-tight manner. The injection-side cap member 6 has a structure similar to that of the discharge-side cap member 5 and is a substantially funnel-shaped cap member provided with a blood injection port 15. The injection-side cap member 6 is screwed and attached to one end of the casing 4 in the longitudinal direction of the cylinder, and in the attached state, the O-ring 14 is in close contact with the outer surface of the sealing portion, and the casing 4 and the injection-side cap member 6 Liquid tightly seal the boundary. In the mounted state of the cap members 5 and 6, the internal space of the discharge side cap member 5 and the internal space of the injection side cap member 6 constitute a blood flow path through which blood passes together with the inner space of each hollow fiber membrane 12. To do.

  As shown in FIG. 2 (b), the hollow fiber membrane 12 is a hollow fiber-like semipermeable membrane, and the membrane substrate has a very thin thickness of about 5 to 50 micrometers and an inner diameter of about 100 to 500 micrometers. It is. Moreover, the sealing part 10 is formed in the both ends fixed with the resin composition.

  The membrane substrate is a hydrophobic polymer semipermeable membrane made of a polymer alloy membrane made of polyarylate resin (PAR) and polyethersulfone resin (PES) as a main membrane material. Here, the polyarylate resin has a repeating unit represented by the following formula (1).

  Moreover, the said polyethersulfone resin has a repeating unit represented by following formula (2).

  Next, the manufacturing process of the blood purifier will be described based on the flowchart shown in FIG.

In this manufacturing process, the hollow fiber is first spun (spinning process, step S1).
In this spinning process, a film-forming stock solution is first prepared. The film forming stock solution for spinning the hydrophobic membrane base material determines the mixing weight ratio (A / B) of the polyarylate resin (A) and the polyethersulfone resin (B) in the range of 0.1 to 10. At the same time, it is prepared by dissolving in an organic solvent such that the total amount (A + B) of both resins is in the ratio of 10 wt% to 25 wt%.

  When the membrane-forming stock solution prepared as described above is discharged into the coagulation liquid together with the core liquid using a double-tube spinneret, a hollow fiber-like membrane substrate using a polyester polymer alloy as a membrane material, that is, a hollow fiber membrane 12 is obtained. The hollow fiber membrane 12 has dense layers on the inner surface side and the outer surface side, and a support layer composed of pores coarser than both dense layers is formed between the inner dense layer and the outer dense layer. ing. In this embodiment, as described later, the pore diameter distribution range of the inner dense layer is small and the pore diameter of the outer dense layer is formed larger. The inner dense layer is a part that defines the permeability, that is, the selective permeability and the permeation speed of the substance in this hollow fiber membrane (membrane base material). In this embodiment, the average pore diameter (pore size) is 2 to 80 nm. ) Are formed. Further, the outer dense layer has a range of 10 to 100 nm, and pores that are coarser than the inner dense layer are formed. The pore size in each layer can be adjusted by changing the mixing weight ratio of the polyarylate resin and the polyethersulfone resin when forming the PEPA film. The pore size in each layer is more preferably in the range of 5 to 50 nm for the inner dense layer and 15 to 70 nm for the outer dense layer, which is larger than the pore size in the inner dense layer. Thus, by defining the pore sizes of the inner dense layer and the outer dense layer, the permeability of the PEPA membrane, which is the hollow fiber membrane 12, and the ability to inhibit the exothermic substance can be more effectively exhibited.

  The hollow fiber membrane 12 has molecular weight fractionation characteristics shown in FIG. As shown in this figure, for example, for a material having a molecular weight of 35,000, the sieve coefficient (SC) is about 0.5, that is, about 50% of the total amount permeates the membrane substrate (specifically, In the case of a substance having a molecular weight of 70,000, the sieve coefficient is about 0.05, that is, about 5% of the total amount permeates the membrane substrate, and the rest It can be seen that about 95% cannot be transmitted. Furthermore, for substances having a molecular weight of 100,000 or more, almost the entire amount (100%) cannot penetrate the membrane substrate.

  Next, the hollow fiber membranes thus spun are bundled (bundling process, step S2). In this bundling process, about 3000 to 15000 hollow fiber membranes 12 are bundled as a unit and cut into a predetermined length to form a hollow fiber bundle 3. The hollow fiber bundle 3 is adjusted to an outer diameter corresponding to the inner diameter of the casing 4.

  Subsequently, the hollow fiber bundle 3 is loaded into the casing 4 (loading process, step S3). In this loading process, the above-described hollow fiber bundle 3 is loaded into the casing 4 with the blood injection port 15 and the blood discharge port 13 removed. At this time, in order to prevent the hollow fiber bundle 3 from being contaminated and to facilitate loading, the outer periphery of the hollow fiber bundle 3 is covered with a sheet in advance, and the entire sheet is loaded into the casing 4. Then, after loading, the sheet is extracted. In addition, in a state where the hollow fiber bundle 3 is loaded, both ends of the hollow fiber bundle 3 are in a state of protruding outside the casing 4.

  Next, potting is performed (step S4). In this potting process, the opening portion of the casing 4 is sealed (sealed) with a urethane-based resin as a sealing material to form the sealing portion 10, and the portion of the hollow fiber bundle 3 that protrudes outside the casing 4 is Cut so as to be flush with the opening of the casing 4. Thereby, a module in which the hollow fiber bundle 3 is loaded in the casing 4 is created.

  As shown in FIG. 2A, the cut surface of the hollow fiber bundle 3 is in a state where a large number of hollow fiber membranes 12 whose ends are open are densely packed, and the urethane resin as the sealing portion 10 However, the gap between the hollow fiber membranes 12 is closed in a state of ensuring liquid tightness, and the sealing portion 10 does not close the injection port 8 and the discharge port 9 for dialysate. In this module, the blood flow path (the inner surface side of the hollow fiber membrane 12) and the dialysate flow path (the outer surface side of the hollow fiber membrane 12) are separated by the hollow fiber membrane 12.

  When the potting process is completed, a hydrophilic process (hydrophilic polymer adhesion holding process) is performed (step S5). This hydrophilization treatment can be performed at the time of spinning the hollow fiber membrane 12 or after the hollow fiber membrane 12 is bundled and before being loaded into the casing 4. An example in which the bundle 3 is loaded in the casing 4 will be described.

  Here, polyvinylpyrrolidone (PVP) is used as the hydrophilic polymer (hydrophilizing agent) used for the hydrophilization treatment. This hydrophilization treatment is performed for the purpose of hydrophilizing only the blood contact portion side surface of the module and the blood ports 13 and 15 by flowing an aqueous solution of a hydrophilizing agent to the blood contact portion side in the module. The hydrophilic polymer is required to have a property of not passing through the hollow fiber membrane 12 and a property of having a strong adsorptive power to the blood contact portion. From this point of view, the PVP is blocked without penetrating the pore-sized holes formed on the inner surface side of the hollow fiber membrane 12 (that is, the inner dense layer), and the inner surface of the hollow fiber membrane 12 is blocked. In contrast, it has a molecular weight that exhibits an adsorption force of a predetermined strength. In particular, when PVP has an average molecular weight of 70,000 or more, sufficient adsorption power to the inner surface of the hollow fiber membrane 12 is obtained and no permeation from the inner surface side to the outer surface side of the hollow fiber membrane 12 is observed (that is, It was confirmed that it can be suitably used without passing through the holes formed in the dense layer.

In this hydrophilization treatment, elution of the hydrophilizing agent into the blood during use is prevented, and the activation treatment when the blood purifier 1 is used for blood purification therapy or the like is facilitated (that is, air bubbles are eliminated). From the viewpoint of improving the removal, the amount of hydrophilic agent applied to the hollow fiber membrane 12 is important. In view of this point, the present inventor optimized the mass ratio of PVP to be applied as a hydrophilizing agent to the mass of the PEPA membrane which is the hollow fiber membrane 12 (mass A of polyarylate resin + mass B of polyethersulfone resin). Turned into. Specifically, the applied amount is adjusted so that the ratio Mr of the mass (C) of the PVP to the mass (A + B) of the hollow fiber membrane 12 satisfies 2 × 10 ⁻³ <Mr <32 × 10 ⁻³ . Thus, by prescribing the mass ratio Mr of PVP with respect to the mass of the hollow fiber membrane 12, it is possible to suppress the outflow of PVP while securing the ease of activation during use. Further, in the present invention, in order to ensure appropriate endotoxin blocking ability, a hollow fiber bundle is flowed from the outside to the inside of a hollow fiber membrane having a converted membrane area of 0.15 m ² with a flow rate of 50 ml / min. The filtrate is prepared (adjusted) so that the endotoxin concentration of the filtrate is 1.0 EU / L or less as measured by filtration for 2 hours. “Equivalent membrane area 0.15 m ² ” means that even if the membrane area of the hollow fiber membrane that actually measures the endotoxin concentration by filtering the endotoxin solution is large or small, the membrane area is converted to 0.15 m ² The meaning of

  In this hydrophilization treatment, blood injection port 15 and blood discharge port 13 are attached to both ends of the module (that is, casing 4 loaded with hollow fiber bundle 3), dialysate injection port 8 and dialysate discharge port. In a state in which 9 is closed, an aqueous solution (treatment solution) of a hydrophilizing agent adjusted to a specified concentration is injected into the casing 4 through the blood injection port 15, and then the dialysate ports 8 and 9 are opened and the blood is injected. With the port 15 closed, the treatment liquid is moved from the inner surface side to the outer surface side of the hollow fiber membrane 12 by introducing a compressed gas (for example, air or nitrogen) from the blood discharge port 13, thereby hydrophilizing. The agent is adhered and held on the hollow fiber membrane 12.

  If the hydrophilization process is completed, a leak detection process is performed (step S6). In this leak detection process, for example, colored smoke is allowed to flow through the module, and the presence or absence of a leak due to a pinhole or the like generated in the hollow fiber membrane 12 is specified by coloring due to the passage of the smoke, and the leak location. In addition, there is a method of detecting a leak based on the presence or absence of bubbles when air is passed through the module while the module is immersed in water.

  If the leak detection process is completed, a cleaning process is subsequently performed (step S7). This washing process removes excess hydrophilizing agent for the module that has been hydrophilized. Specifically, purified water for washing (washing water) is introduced into the module in place of the aqueous solution of the hydrophilizing agent in the above-described hydrophilization treatment. That is, purified water is passed through the blood contact portion side of the blood purifier 1. By this washing treatment, of the hydrophilicizing agent adhering to the blood contact portion in the blood purifier 1, excess hydrophilicizing agent adsorbed with an adsorption force lower than a predetermined adsorption force is washed away.

  Next, the module that has been washed with water is dried (step S8). This drying process is performed in order to make the blood purifier 1 a module having a specification that is not filled with water (so-called dry type). This dry type module is advantageous in that it is difficult to freeze in a cold region or the like, and is lightweight and easy to handle. As a drying method, there are a method of irradiating the module with microwaves and a method of flowing warm air into the module. In the drying process in this embodiment, the former method is performed by using microwaves. Specifically, after removing the cleaning liquid remaining in the module to some extent by pushing it out with compressed air, etc., the module is irradiated with microwaves of a predetermined output while removing the vapor inside the module using a vacuum pump. Dry.

The treatment conditions in this drying treatment (microwave parameters or hot air temperature, drying time, etc.) are related to the water content in the hollow fiber membrane 12 after drying. The water content of the hollow fiber membrane 12 is important from the viewpoint of suppressing the decomposition of the hydrophilizing agent during the sterilization process described below and improving the bubble removal during the activation process. For this reason, in this drying process, the water content of the hollow fiber membrane 12 is adjusted within a range of 2.0 to 15.0 g per 1 m ² of the hollow fiber membrane. Moreover, it is more preferable that it is in the range of 3.0-10.0g regarding this moisture content. By regulating the moisture content of the hollow fiber membrane 12 in this way, while suppressing the decomposition of PVP adhered and held on the hollow fiber membrane 23 as a hydrophilizing agent during the drying treatment described below, It is possible to improve the escape of bubbles during the activation process.

Next, a sterilization process is performed on the blood purifier 1 after the drying process (step S9). Sterilization methods include EOG (ethylene oxide gas) sterilization, steam sterilization, and γ-ray sterilization, but EOG sterilization has a problem of residual gas after sterilization, and steam sterilization has a high temperature and damages the module. In the present embodiment, sterilization by γ-ray irradiation is performed because of the large size. In this sterilization treatment, degradation of PVP imparted to the hollow fiber membrane 12 as a hydrophilizing agent in the hydrophilization treatment becomes a problem. However, in the blood purifier 1 according to the present invention, as described above, the hollow fiber of PVP is used. Since the amount applied to the membrane 12 and the moisture content of the hollow fiber membrane 12 are optimized, the decomposition of the PVP adhered and held on the hollow fiber membrane 12 can also be suppressed by irradiating γ rays. This makes it possible to prevent PVP from eluting into the blood when the blood purifier 1 is used.

  As described above, for the dry type blood purifier 1 using the hollow fiber membrane 12 whose main membrane material is a PEPA membrane, using PVP as a hydrophilizing agent, and not prefilled with water, the hollow fiber membrane 12 by setting the pore size of the inner dense layer and the outer dense layer of 12, the mass ratio Mr of PVP to the mass of the hollow fiber membrane 12, and the water content of the hollow fiber membrane 12 within the specified ranges, respectively. Can be ensured and elution of the hydrophilizing agent can be suppressed. As a result, this type of blood purifier 1 can more effectively exhibit the inherent permeability and pyrogen blocking ability.

  In order to confirm the effectiveness of the present invention, a comparative experiment was performed under the following conditions. The experimental results are shown in Table 1 below. Examples 1 to 3 in Table 1 are conditions for the mass ratio Mr of PVP to the mass of the hollow fiber membrane 12, the pore size of the inner dense layer and the outer dense layer of the hollow fiber membrane 12, and the moisture content of the hollow fiber membrane 12. Are the experimental results for the module set within the specified range, and Comparative Examples 1 to 7 are the experimental results for the module in which at least one of the conditions falls outside the specified range. In Examples 1 to 3 and Comparative Examples 1 to 6, a PEPA film is used as a film material, and only Comparative Example 7 uses polystyrene (PS) as a film material for comparison. Moreover, PVP is used as a hydrophilizing agent in any experiment. Further, except for Comparative Example 5, drying treatment was performed by microwave irradiation, and Comparative Example 5 was dried by blowing warm air.

For the mass ratio Mr, the hollow fiber membrane is taken out from the module, washed with ethanol, dried in a 68 ° atmosphere, and dried using a trace total nitrogen analyzer (TN-110, ND-100 manufactured by Dia Instruments). The nitrogen content in 1 mg of the hollow fiber membrane was measured and converted from the obtained nitrogen content. Regarding the water content, a value obtained by subtracting the weight of the reference module not containing water from the module weight after washing and drying was converted into the weight per membrane area, and this was used as the water content. With regard to the ease of activation (priming property), the module was activated at a flow rate of 100 mL / min, and the case where the time from the start of activation until the bubbles no longer emerged from the module was 4 minutes or less. About the amount of PVP elution, 1000 mL of physiological saline was used to circulate the inside (blood contact portion) of the hollow fiber membrane for 4 hours at a flow rate of 200 mL / min. Then, the physiological saline solution after circulation was sampled, and the concentration of PVP was measured using the Muller method. From this measured value, the elution amount of PVP was converted. Regarding the endotoxin efflux concentration of the filtrate, a 0.15 m ² minimodule was prepared for the experiment, and a 1000 EU / L endotoxin solution was completely filtered from the outside to the inside of the hollow fiber membrane at a flow rate of 50 mL / min for 2 hours. Thereafter, the filtrate was sampled and the endotoxin concentration was measured using a well reader (SK603) manufactured by Seikagaku Corporation. And in this invention, it adjusts so that the endotoxin density | concentration of the filtrate at the time of measuring on the said measurement conditions may be a level of 1.0 EU / L or less. Note that “ND” in the table indicates that endotoxin was not detected. The pore size of the inner surface (inner dense layer) and outer surface (outer dense layer) of the hollow fiber membrane was measured using an AFM (atomic force microscope).

（表１中、緻密層ポアサイズは内側緻密層ポアサイズ、多孔層ポアサイズは外側緻密層ポアサイズを意味する。）

(In Table 1, the dense layer pore size means the inner dense layer pore size, and the porous layer pore size means the outer dense layer pore size.)

For Examples 1 to 3 that fall within the specified range for all conditions, it was found that good results were obtained with all of the ease of activation, the PVP elution amount, and the endotoxin efflux concentration. In Comparative Example 1, the water content was larger than the specified range (2.0 to 15.0 g), but in this case, it was found that bubbles were not easily removed during the activation process. Although the comparative example 2 is a case where water content is less than a regulation range, it turned out that there is much PVP elution amount compared with Examples 1-3 in this case. Comparative Example 3 is a case where the mass ratio Mr is below the specified range (2 × 10 ⁻³ <Mr <32 × 10 ⁻³ ). In Comparative Example 3, the activation process was difficult. In Comparative Example 4, the mass ratio Mr is larger than the specified range (2 × 10 ⁻³ <Mr <32 × 10 ⁻³ ), and in this case, the PVP elution amount is larger than those in Examples 1 to 3. understood. Comparative Example 5 is a case where the pore size of the outer dense layer (porous layer) of the hollow fiber membrane exceeds the specified range (10 to 100 nm). In Comparative Example 5, the module is dried by blowing warm air. In this case, endotoxin efflux into the filtrate was observed. Comparative Example 6 is an example in which the drying time by microwave irradiation was set longer (8 minutes) than in the case of Examples 1 to 3 (3 minutes), and in this case, deformation of the module was observed. Comparative Example 7 is a case using polystyrene as the membrane material of the hollow fiber membrane. In Comparative Example 7, the mass ratio Mr of PVP with respect to the mass of the membrane material is larger than the specified range, and the pore size of the outer dense layer is also larger than the specified range. And in this comparative example 7, it became a result that the elution of PVP and the outflow of endotoxin were seen.
The blood purifier is required to have not only endotoxin blocking ability and permeation blocking function, but also other solute removal performance such as small molecular substances such as urea and creatinine. Thus, Table 1 shows the results of measuring urea clearance based on the measurement method in accordance with the guidelines of the Japanese Society for Dialysis Therapy. As shown in Table 1, Examples 1, 2, and 3 were found to have sufficient solute removal performance with respect to urea.

  Based on the above experimental results, a dry-type blood purifier that uses a hollow fiber membrane made mainly of a PEPA membrane, uses PVP as a hydrophilizing agent, and does not pre-fill water, By setting the pore size of the inner dense layer and the outer dense layer, the mass ratio Mr of PVP to the mass of the hollow fiber membrane, and the moisture content of the hollow fiber membrane 12 within the above specified range, while ensuring endotoxin blocking ability It was found that easiness of activation treatment can be secured and elution of the hydrophilizing agent can be suppressed. Therefore, it is possible to more effectively exhibit the permeation ability and the blocking ability of pyrogens that this type of blood purifier 1 originally has.

It is sectional drawing of the blood purifier which cut and showed the middle of the longitudinal direction partially. (A) is explanatory drawing of the cut surface of the hollow fiber bundle in the edge part of a casing, (b) is the elements on larger scale of (a). It is a flowchart explaining the manufacturing process of a blood purifier. It is a figure explaining the molecular weight fractionation characteristic of the membrane base material formed into a film.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Blood purifier 2 Case 3 Hollow fiber bundle 4 Casing 5 Cap member on the discharge side 6 Cap member on the injection side 7 Expanded portion 8 Dialysate injection port 9 Dialysate discharge port 10 Sealing portion 12 Hollow fiber membrane 13 Blood discharge port 14 O-ring 15 Blood injection port

Claims (4)

A hollow fiber bundle composed of a polymer fiber membrane composed of a polyarylate resin and a polyethersulfone resin as a main membrane material, and a hollow fiber bundle having a dense layer on the inner surface side and the outer surface side. In the blood purifier in which the hollow fiber bundle is loaded in the casing and the blood contact portion of the hollow fiber membrane is hydrophilized using polyvinylpyrrolidone as the hydrophilic polymer.
The hollow fiber bundle is
The pore size on the inner surface side of the hollow fiber membrane is set to 9.2 to 15.3 nm, the pore size on the outer surface side of the hollow fiber membrane is set to a coarser pore diameter than the inner surface side in the range of 24.3 to 53.4 nm,
The mass ratio Mr of the hydrophilic polymer to the mass of the hollow fiber membrane is set in the range of 5 × 10 ⁻³ <Mr <15 × 10 ⁻³ ,
When the endotoxin solution of 1000 EU / L is filtered from the outside to the inside of the hollow fiber membrane having a converted membrane area of 0.15 m ² at a flow rate of 50 ml / min for 2 hours, the endotoxin concentration of the filtrate is 1.0 EU / L or less. A blood purifier characterized by being manufactured. The hollow fiber bundle is subjected to a drying treatment by microwave irradiation, and the water content of the hollow fiber membrane is reduced to 1 m from the hollow fiber membrane. ² The blood purifier according to claim 1, wherein the blood purifier is set to 5.8 to 6.7 g per unit. A hollow fiber bundle composed of a polymer fiber membrane composed of a polyarylate resin and a polyethersulfone resin as a main membrane material, and a hollow fiber bundle having a dense layer on the inner surface side and the outer surface side. For the blood purifier formed by loading this hollow fiber bundle in the casing, the hydrophilic treatment for hydrophilizing the blood contact portion of the hollow fiber membrane using polyvinylpyrrolidone as the hydrophilic polymer and the excess hydrophilization In the method for producing a blood purifier for performing at least a washing treatment for washing a polymer with water and a drying treatment,
  The hollow fiber bundle is
  The pore size on the inner surface side of the hollow fiber membrane is set to 9.2 to 15.3 nm, the pore size on the outer surface side of the hollow fiber membrane is set to a coarser pore diameter than the inner surface side in the range of 24.3 to 53.4 nm,
  The mass ratio Mr of the hydrophilic polymer to the mass of the hollow fiber membrane is 5 × 10 5. ^-3 <Mr <15 × 10 ^-3 Set in the range of
  In the hydrophilization treatment, the hollow fiber bundle is converted into a 1000 EU / L endotoxin solution in an equivalent membrane area of 0.15 m. ² A blood purifier characterized by being manufactured so that the endotoxin concentration of the filtrate is 1.0 EU / L or less when measured by filtration from the outside to the inside of the hollow fiber membrane at a flow rate of 50 ml / min for 2 hours. Production method. The drying treatment is performed by microwave irradiation, and the moisture content of the hollow fiber membrane is reduced to 1 m from the hollow fiber membrane. ² The method for producing a blood purifier according to claim 3, wherein the amount is 5.8 to 6.7 g per unit.

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