JP2006075609A - Blood purification apparatus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood purification apparatus easily manufactured and capable of imparting hydrophilic property to blood contact side faces while leaving hydrophobic property to dialysis fluid contact side faces of hollow fiber membranes. <P>SOLUTION: In the blood purification apparatus 1 using the hollow fiber membranes formed of a hydrophobic polymer, an aqueous solution of a hydrophilic polymer is allowed to flow through a blood contact part of a module formed by charging a bundle of hollow fiber membranes in a casing 2. The hydrophilic polymer is thereby stuck and held only on the surface of the blood contact part, and the extra hydrophilic polymer out of the stuck and held hydrophilic polymer is washed away with water to selectively stick and hold the hydrophilic polymer stuck and held with predetermined adsorption force. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a blood purifier for blood purification, particularly hemodialysis therapy, hemofiltration dialysis therapy, or hemofiltration therapy for the purpose of treating kidney diseases or drug addiction.

Conventionally, semipermeable membranes and ultrafiltration membranes are used for hemodialysis therapy, hemofiltration dialysis therapy, hemofiltration therapy and the like (hereinafter referred to as blood purification therapy).
Membranes (semipermeable membranes and ultrafiltration membranes) used for blood purification therapy include cellulose, cellulose ester, polyacrylonitrile, polymethyl methacrylate, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyamide, polysulfone, polyester, etc. Is used.

In the blood purification therapy, a hollow fiber bundle obtained by spinning the above-described membrane into a hollow fiber shape (hereinafter referred to as a hollow fiber membrane) is loaded into a casing and bundled with about 5000 to 10,000 hollow fibers. A blood purifier is used.
In blood filtration therapy, uremic substances are 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. In hemofiltration dialysis therapy, uremic substances and excess water in the body are removed by the characteristics of both hemofiltration therapy and hemodialysis therapy, that is, filtration and diffusion.

  Such hollow fiber membranes are roughly classified into hydrophilic membranes typified by cellulose and hydrophobic membranes typified by polysulfone and polyester.

  This hydrophobic membrane material was originally developed as an engineering plastic, but its mechanical strength, heat resistance, chemical resistance, and good biocompatibility make it a blood purification therapy. It is used as a hollow fiber membrane.

  In this hydrophobic membrane, since it is hydrophobic, it cannot immediately exhibit its original permeability, so a treatment for imparting hydrophilicity to the hydrophobic membrane is performed in order to immediately demonstrate its original permeability. .

  As a treatment for imparting hydrophilicity, for example, there is a method disclosed in Japanese Patent Publication No. 5-54373 or Japanese Patent Laid-Open No. 7-289863. These publications disclose a method in which polyvinylpyrrolidone, which is a hydrophilic polymer, is mixed into a polysulfone-based resin stock solution, which is a hydrophobic polymer, and this solution is spun as a film-forming stock solution.

  In the method disclosed in the above publication, since spinning is performed from a film-forming stock solution mixed with a hydrophilic polymer, hydrophilicity is imparted over the entire inner and outer surfaces and thickness direction of the produced hollow fiber membrane. Yes.

  Further, in this method, mixing the hydrophilic polymer into the spinning dope also has the purpose of forming a membrane structure, so that the hydrophilic polymer must be mixed in a certain amount or more. For this reason, elution of the mixed hydrophilic polymer occurs from the hollow fiber membrane after spinning. Therefore, if this hollow fiber membrane is used in a blood purifier as it is, there is a high possibility that the hydrophilic polymer eluted into the patient's body will enter.

  As a method for preventing the elution of the hydrophilic polymer, for example, there is a method disclosed in Japanese Patent Publication No. 8-9668. In this method, a hollow fiber membrane spun from a membrane-forming stock solution in which polyvinylpyrrolidone, which is a hydrophilic polymer, is mixed with a stock solution of a polysulfone-based resin, which is a hydrophobic polymer, is subjected to insolubilization treatment such as irradiation and heat treatment. Polyvinylpyrrolidone is crosslinked and insolubilized to prevent elution from the hollow fiber membrane.

By the way, it is said that the hydrophobic surface generally adsorbs exothermic substances such as endotoxin contained in the dialysate, thereby preventing heat generation and the like caused by dialysis. However, in the method disclosed in the above publication, the entire hollow fiber membrane in the film thickness direction is hydrophilized, so that the ability to adsorb exothermic substances such as endotoxin is impaired.
In addition, since the hydrophobic surface also has the property of adsorbing proteins and the like in the blood, if the surface of the blood contact portion is hydrophobic, the proteins and the like in the blood will adhere to the surface of the blood contact portion, Blood components tend to remain in the blood purifier.

In the method disclosed in Japanese Patent Application Laid-Open No. 6-228887, in order to improve the biological reaction occurring between the surface of the hollow fiber membrane and the blood component, the inner surface (blood contact) in the hollow fiber membrane produced only with the polysulfone resin. After the polyvinyl pyrrolidone, which is a hydrophilic polymer, is attached only to the side), the attached polyvinyl pyrrolidone is subjected to insolubilization treatment such as irradiation and heat treatment to crosslink and insolubilize it. Elution of polyvinylpyrrolidone is prevented.
Japanese Patent Publication No. 5-54373 JP-A-7-289863 Japanese Patent Publication No.8-9668 Japanese Patent Laid-Open No. 6-228887

However, in the method of insolubilizing hollow fiber membranes spun with a membrane-forming stock solution in which a hydrophilic polymer is mixed with a hydrophobic polymer stock solution, the inner and outer surfaces of the hollow fiber membrane are hydrophilized, and heat-generating substances are adsorbed. Not only is the performance impaired, but also there is a large amount of hydrophilic polymer mixed in, so there is a risk that the hydrophilic polymer that could not be insolubilized even by the insolubilization process will be eluted.
On the other hand, in the method of attaching the hydrophilic polymer only to the blood contact side surface in the hollow fiber membrane and insolubilizing the adhered hydrophilic polymer, the manufacturing process becomes complicated by the insolubilization treatment and the subsequent water filling treatment, There is a risk of increasing the cost of the product.

  The present invention has been proposed in view of such circumstances, while leaving the hydrophobicity of one surface of the hollow fiber membrane (the surface on the dialysate contact side) on the other surface (the surface on the blood contact side). It is possible to prevent the adhering and remaining blood components while imparting hydrophilicity to prevent pyrogenic substances from mixing in the body, and it is easy without requiring separate insolubilization treatment such as radiation irradiation and heat treatment. It aims at providing the blood purifier which can be manufactured.

  As a result of intensive research to achieve this object, the inventors have made the hydrophilic polymer adhere to the blood contact portion of the blood purifier and then wash away the excess hydrophilic polymer with a washing solution. And a blood purifier capable of surprisingly reducing the residual blood components in the blood contact portion of the blood purifier while retaining the ability to adsorb pyrogens on the surface of the hollow fiber on the dialysate contact side, such as irradiation and heat treatment. The present invention has been achieved that it can be obtained without the need for a separate insolubilization treatment.

  That is, in the blood purifier using a hollow fiber membrane made of a hydrophobic polymer, the invention according to claim 1 has a molecular weight of 100,000 or more in a blood contact portion of a module in which a bundle of hollow fiber membranes is loaded in a casing. After adhering and holding the hydrophilic polymer, the excess hydrophilic polymer is washed and removed with a washing liquid, so that it does not pass through the hole formed on the surface of the hollow fiber membrane on the blood contact portion side, and The blood purifier is characterized in that only a hydrophilic polymer adsorbed with an adsorbing force of a predetermined strength is adhered and held only on the surface of the blood contact portion.

Here, the adsorbing force having a predetermined strength is an adsorbing force that can maintain the adhering and holding state with the blood contact portion against the blood flow during blood purification therapy performed using a blood purifier.
The surplus hydrophilic polymer refers to a hydrophilic polymer that is not adhered and held with a predetermined strength of adsorption force.

  In addition to the constitution of claim 1, the invention of claim 2 is characterized in that the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polyglycol monoester, polypropylene glycol copolymer, and polyacrylamide. A blood purifier characterized by being selected.

  The invention described in claim 3 is characterized in that, in addition to the structure described in claim 1 or 2, the hydrophobic polymer comprises a polyester resin and a polysulfone resin as main membrane materials. It is a purifier.

  The invention according to claim 4 is the blood purifier according to any one of claims 1 to 3, wherein the lower limit of the molecular weight of the hydrophilic polymer is set to 1200000.

The present invention has the following effects.
That is, in a blood purifier using a hollow fiber membrane made of a hydrophobic polymer, a hydrophilic polymer having a molecular weight of 100,000 or more is adhered and held on a blood contact portion of a module in which a bundle of hollow fiber membranes is loaded in a casing. After that, the excess hydrophilic polymer is washed away with a washing solution, so that it does not pass through the hole formed on the surface of the hollow fiber membrane on the blood contact portion side, and has a predetermined strength of adsorption force. Since only the hydrophilic polymer to be adsorbed is attached and held only on the surface of the blood contact portion, the hydrophilic polymer is once attached and held on the blood contact portion, and the excess hydrophilic polymer is washed away with a washing solution. Thus, it is possible to selectively adhere and hold the hydrophilic polymer capable of maintaining the adhesion holding state against the flow of blood or the like at the blood contact portion.
Therefore, hydrophilicity is imparted to the other surface while leaving the hydrophobicity of one surface of the hollow fiber membrane easily without requiring separate insolubilization treatment (crosslinking treatment etc.) such as irradiation and heating. A blood purifier capable of achieving both contradictory functions of preventing contamination due to adhesion of blood components and preventing contamination of endotoxin in the body can be manufactured.
Moreover, since the molecular weight of the hydrophilic polymer is 100,000 or more, the hydrophilic polymer adheres to the blood contact portion without impairing the original function of the blood purifier in combination with the pore diameter of the dense layer in the hollow fiber membrane. The maintenance of the state can be made more reliable.

  Further, since the hydrophilic polymer is selected from the group consisting of polyvinyl pyrrolidone, polyethylene glycol, polyglycol monoester, polypropylene glycol copolymer, and polyacrylamide, the hydrophilic polymer is adhered and retained. The treatment can be performed with a solution, and the operation related to the treatment can be facilitated.

  Since the hydrophobic polymer is mainly composed of a polyester resin and a polysulfone resin, the hydrophilic polymer is adsorbed on the blood contact portion side surface, but the blood non-contact surface side has an adverse effect on the human body. It is possible to leave the adsorptive power with respect to substances (such as endotoxin) that exert a high level. Therefore, the contradictory functions of preventing the adhesion of blood components to the membrane surface and the invasion of substances having an adverse effect in the body can be made compatible at a higher level.

Embodiments of the present invention will be described below with reference to the drawings.
FIG. 1 is a flowchart showing an outline of a manufacturing process of a blood purifier according to the present invention. Hereinafter, description will be given with reference to this flowchart.

In this manufacturing process, the hollow fiber is first spun (spinning process, step S1).
In this spinning step, a film forming stock solution is first prepared. Here, the mixing weight ratio (A / B) of the polyester resin (A) and the polysulfone resin (B) is determined in the range of 0.1 to 10, and the total amount (A + B) of both resins is 10% by weight. A film forming stock solution is prepared by dissolving in an organic solvent so that the ratio is ˜25 wt%.

  In addition, the said polyester-type resin in this embodiment is polyarylate resin which has a repeating unit represented by following formula (1).

  The polysulfone resin is a polysulfone resin having at least one of the repeating unit represented by the formula (2) and the repeating unit represented by the formula (3).

  Further, the organic solvent is not particularly limited as long as it is a good solvent for the polyester resin and the polysulfone resin, and for example, N-methylpyrrolidone, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, and the like can be used. . Of these, N-methylpyrrolidone can be most preferably used.

A hollow fiber membrane can be produced by discharging this membrane-forming stock solution into the coagulation solution together with the core solution using a double tube spinneret.
Here, the core solution and the coagulation solution are for forming the membrane-forming stock solution into a hollow fiber membrane, but a mixed solvent obtained by mixing an organic solvent used for resin dissolution with water is preferable to water alone. . This is because it is easier to form a uniform fibril structure when a mixed solvent is used. As the organic solvent to be mixed, a good solvent for the resin, for example, N-methylpyrrolidone, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide and the like can be used. Of these, N-methylpyrrolidone can be most preferably used.

  The hollow fiber membrane thus spun has a dense layer formed on its inner surface and a porous layer so as to cover the outside of the dense layer. In the hollow fiber membrane, the dense layer is a portion that defines the selective permeability and permeation rate of the substance, and pores having an average pore diameter of less than 500 angstroms, specifically, pores having a pore radius of 30 to 100 angstroms are formed. ing. Further, the porous layer functions as a support layer that supports the dense layer and maintains the strength of the film, and pores that are considerably coarser than the dense layer are formed.

And this hollow fiber membrane has the molecular weight fractionation characteristic shown in FIG.
As shown in the figure, for example, for a material with a molecular weight of 35000, the sieve coefficient (SC) is about 0.5, that is, about 50% of the total amount permeates this hollow fiber membrane, and for a material with a molecular weight of 70000 It can be seen that the sieve coefficient is about 0.05, that is, about 5% of the total amount permeates the hollow fiber membrane and the remaining about 95% cannot permeate. Similarly, it is considered that almost the entire amount (100%) cannot be transmitted for a substance having a molecular weight of 100,000 or more.

Next, the hollow fiber membranes thus spun are bundled (bundling process step, step S2).
In this bundling process, a bundle is formed in which about 10,000 hollow fiber membranes are formed into one bundle. The bundle of hollow fiber membranes (hereinafter referred to as hollow fiber bundle) is adjusted to an outer diameter corresponding to the inner diameter of the cylindrical casing.

Next, the hollow fiber bundle is loaded into the casing (loading step, step S3).
As shown in the sectional view of FIG. 3, the blood purifier 1 according to the present invention includes a casing 2, an injection-side blood port 3 that functions as a closing lid member that is detachably screwed to the casing 2, and a discharge side. And blood port 4.
The casing 2 is a cylindrical member formed of polycarbonate. A dialysate inlet 5 is formed on the side of the casing 2 on the discharge side blood port 4 side, and a dialysate discharge port 6 is formed on the end of the injection side blood port 3. Has been.
The injection-side blood port 3 and the discharge-side blood port 4 are screwed together so as to close the openings at both ends of the casing 2, and are formed of polycarbonate as in the casing 2. The injection side blood port 3 is provided with an injection port 7 for injecting blood, and the discharge side blood port 4 is provided with a discharge port 8 for discharging blood. In addition, O-rings 9 are disposed at the contact portions of the injection-side blood port 3 and the discharge-side blood port 4 and the casing 2 as sealing materials for maintaining watertightness.

  In this loading step, the above-described hollow fiber bundle 10 is loaded into the casing 2 in a state where the injection-side blood port 3 and the discharge-side blood port 4 are disconnected. At this time, in order to prevent the hollow fiber bundle 10 from being contaminated and to facilitate loading, the outer periphery of the hollow fiber bundle 10 is previously covered with a sheet, and the entire sheet is loaded into the casing 2. Then, after loading, the sheet is extracted. In addition, in a state where the hollow fiber bundle 10 is loaded, both end portions of the hollow fiber bundle 10 are in a state of protruding outside the casing 2.

Next, potting is performed (potting process, step S4).
In this potting step, the opening of the casing 2 indicated by reference numeral 11 in FIG. 3 is sealed (sealed) with a urethane resin 12 as a sealing material, and the portion of the hollow fiber bundle 10 that protrudes outside the casing is Cut so that it is flush with the two openings 11. Thereby, a module in which the hollow fiber bundle 10 is loaded in the casing 2 is created.
As shown in FIG. 4, the cut surface of the hollow fiber bundle 10 is in a state where a large number of hollow fiber membranes 13 whose ends are open are densely packed, and the urethane resin 12 is a gap between the hollow fiber membranes 13. Since the urethane resin 12 does not block the inflow port 5 and the outflow port 6 of the dialysate, the blood flow channel is used in this module. (The inner surface 13 ′ side of the hollow fiber membrane 13) and the dialysate flow path (the outer surface side of the hollow fiber membrane 13) are separated by the hollow fiber membrane 13.

Next, a hydrophilic treatment is performed (hydrophilic treatment step, step S5).
This hydrophilic treatment process is a hydrophilic polymer adhesion holding process in the present embodiment. In this process, the injection side blood port 3 is provided at both ends of the module (that is, the casing 2 loaded with the hollow fiber bundle 10). In the state where the discharge side blood port 4 is mounted, the hydrophilic polymer aqueous solution prepared at a predetermined concentration is injected from the injection port 7 of the injection side blood port 3, and the hydrophilicity that has passed through the blood contact part side in the module. The aqueous polymer solution is discharged from the discharge port of the discharge side blood port 4. Then, by performing this treatment for several tens of seconds to several tens of minutes, the hydrophilic polymer is brought into contact with blood such as the inner surface 13 ′ of the hollow fiber membrane 13, the inner surfaces of both blood ports 3 and 4, or the surface of the urethane resin 12. Adhere to the part.
That is, in this hydrophilization treatment step, the hydrophilic polymer is adhered and held only on the surface of the blood contact portion in the module or both blood ports 3 and 4 by flowing an aqueous solution of the hydrophilic polymer toward the blood contact portion side. To selectively hydrophilize only this surface.

The hydrophilic polymer used in this hydrophilization treatment step can be selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polyglycol monoester, polypropylene glycol copolymer, and polyacrylamide.
However, this hydrophilization treatment is performed for the purpose of hydrophilizing only the blood contact surface side surface of the module and both blood ports 3 and 4 by flowing an aqueous solution of a hydrophilic polymer to the blood contact region side in the module. Therefore, the hydrophilic polymer is required to have a property of not permeating the hollow fiber membrane 13 and a property of having a strong adsorptive power to the blood contact portion.

These properties are defined by the molecular weight. In general, it is known that a water-soluble polymer (that is, a hydrophilic polymer) adsorbs one molecule at a number of adsorption points, and the higher the molecular weight, the stronger the adsorbing power and the higher the molecular weight. As the size of the molecule increases, it becomes difficult to penetrate the hollow fiber membrane 13.
Therefore, as the hydrophilic polymer used in this hydrophilization treatment step, pores having an average pore diameter of less than 500 angstroms formed on the inner surface 13 ′ side (that is, the dense layer) of the hollow fiber membrane 13 are blocked without being transmitted. Moreover, those having a molecular weight that has an adsorbing force of a predetermined strength with respect to the inner surface 13 ′ of the hollow fiber membrane 13 are suitable.
Then, if a polymer having a non-permeability of 95% or more of the hollow fiber membrane 13 is suitable (that is, a polymer having a molecular weight of 70,000 or more) Although considered, a polymer having a molecular weight of 100,000 or more is preferable for the purpose of making only the surface of the blood contact portion hydrophilic (see FIG. 2).

  As a result of research by the present inventors, it has been found that polyvinylpyrrolidone is most suitable as a hydrophilic polymer that satisfies the above-described conditions. However, this polyvinyl pyrrolidone also has a plurality of types depending on the molecular weight. Experimentally, with K30 having an average molecular weight of about 40,000, the adsorbing power is weak and the adhering material peels off and permeation from the inner surface side to the outer surface side of the hollow fiber membrane is recognized and is difficult to use. In addition, with K90 having an average molecular weight of 1200,000, a strong adsorbing force is obtained and no permeation from the inner surface 13 ′ side to the outer surface side of the hollow fiber membrane 13 is observed (that is, it does not pass through the holes formed in the dense layer) It was confirmed that it can be suitably used.

  From the above, it is predicted that the lower limit value of the molecular weight of polyvinylpyrrolidone that can be suitably used is in the range of K30 and K90, that is, the average molecular weight of 40000 to the average molecular weight of 1200000, but at present, Polyvinyl pyrrolidone that has an average molecular weight between K30 and K90 and can be used for medical purposes is difficult to obtain, so it has not been confirmed.

However, as described above, the passage in the thickness direction of the hollow fiber membrane 13 is blocked by the holes formed on the inner surface side 13 ′ of the hollow fiber membrane 13, and the inner surface side 13 ′ of the hollow fiber membrane 13 is blocked. On the other hand, it is considered that any polyvinyl pyrrolidone having a molecular weight having a predetermined strength of adsorption can be suitably used. Therefore, any polyvinyl pyrrolidone having an average molecular weight of 100,000 or more can be suitably used. It should be noted that polypinylpyrrolidone having an average molecular weight higher than K90 can be suitably used as long as it is not affected by other factors such as viscosity.
When this K90 is used, it has been confirmed at this time that it can be suitably used if the concentration of K90 in the aqueous solution is at least 0.01% or more.

Next, water washing is performed (cleaning process, step S6).
This washing process is a water washing process (excess polymer removal process) in the present embodiment. In this process, excess hydrophilic polymer is removed from the blood purifier 1 that has been hydrophilized. Specifically, purified water for washing (wash water) is introduced into the blood purifier 1 instead of the hydrophilic polymer aqueous solution in the above-described hydrophilic treatment step. That is, purified water is flowed to the blood contact portion side in the blood purifier 1. By this washing step, of the hydrophilic polymer adhering to the blood contact portion in the blood purifier 1, excess hydrophilic polymer adsorbed with an adsorption force lower than a predetermined adsorption force is washed away. The

This washing step is the most important step in the present invention. That is, only by flowing purified water for washing to the blood contact portion side, the hydrophilic polymer adhering and holding on the blood contact portion in the previous hydrophilization treatment step is adsorbed with a predetermined strength of adsorption force. It is possible to wash away the hydrophilic polymer that is not sufficiently adhered and retained while only adhered and retained. And even after this washing process, the hydrophilic polymer adhered and held on the inner surface 13 ′ of the hollow fiber membrane 13 is not separated by the blood flowing through the blood contact portion in the blood purifier 1.
Therefore, it is not necessary to separately perform a treatment for cross-linking / insolubilizing the hydrophilic polymer such as irradiation, and when the blood purifier 1 is used, the effect of reducing blood adhesion is exhibited. be able to.

By the way, in the cleaning process in the present embodiment, purified water is used as the cleaning liquid for reasons such as no influence on the living body and ease of handling, but the cleaning liquid is not limited to this.
That is, as the cleaning liquid used in this cleaning step, “the surplus of adhering and holding with an adsorbing force less than a predetermined strength while leaving the hydrophilic polymer adhering and holding with an adsorbing force of a predetermined strength on the surface of the blood contact portion” Any liquid may be used as long as it satisfies the requirement that the hydrophilic polymer is removed and the cleaning liquid itself and the residue of the cleaning liquid do not adversely affect the living body.
Therefore, if this requirement is satisfied, liquid other than purified water, purified water to which additives are added, and the like can also be used.

Then, the blood purifier 1 that has been washed with water is filled with water (step S7). This water filling process is a treatment for facilitating replacement with physiological saline when the blood purifier 1 is used for blood purification therapy, and purifies both the blood contact portion side and the dialysate contact portion side. In addition to filling the water and preventing the filled purified water from leaking, the injection port 7 of the injection-side blood port 3, the discharge port 8 of the discharge-side blood port 4, the inflow port 5 and the discharge port 6 of the casing 2. Plug it.
The above is a process with water filling specifications, but after removing excess hydrophilic polymer (step S6), it may be a module with specifications not filling with water through a drying process (step S7 '). This specification of the module not filled with water has the advantage that it does not freeze in cold regions.
Next, a sterilization process is performed on the blood purifier 1 filled with the purified water (step S8). In this sterilization process, γ-ray sterilization and steam sterilization can be used for the blood purifier 1. Furthermore, the module of the specification not filled with water may use ethylene oxide sterilization in addition to γ ray sterilization and steam sterilization.

In the processing steps described above, the hydrophilic blood solution is passed through the assembled blood purifier 1 (hydrophilic polymer adhesion retention treatment), and then the excess hydrophilic polymer is washed away with water. (Excess polymer removal treatment), a process of passing an aqueous solution of hydrophilic polymer or purified water for washing to the blood purifier 1 may be added. The spinning process and modularization process are the existing processes. It is the same process.
Therefore, it is only necessary to add an equipment for passing an aqueous solution of hydrophilic polymer or purified water for washing to the blood purifier 1 to the existing production equipment, and the existing production equipment can be used effectively. .

Moreover, although the above description demonstrated the example which performed the hydrophilic treatment and the water washing process in the state which connected both the blood ports 3 and 4, the hydrophilic treatment and the water washing of both the blood ports 3 and 4 are performed as needed. Therefore, only the casing 2 (that is, the module) in the state in which the middle yarn bundle 9 is loaded may be hydrophilized and washed with water.
However, by performing hydrophilic treatment and water washing with both blood ports 3 and 4 connected, all blood contact portions in the blood purifier 1 are hydrophilized at a time, so that the treatment is easy. Since the gaps between the respective parts are also made hydrophilic, the adhesion / remaining of blood components can be further reduced.

  Next, the present invention will be described more specifically with reference to examples of the present invention.

Example 1
Polyarylate resin represented by the above formula (1) [trade name; U polymer manufactured by Unitika Ltd.] and polyethersulfone resin represented by the above formula (3) [manufactured by Sumitomo Chemical Co., Ltd. Name: Sumika Excel PES] and N-methylpyrrolidone were prepared. The weight mixing ratio of the polyarylate resin and the polyethersulfone resin was 1: 1. Further, an N-methylpyrrolidone aqueous solution was used as a coagulating liquid and a core liquid.
Then, the membrane-forming stock solution is discharged into the coagulation solution together with the core solution using a double tube spinneret to produce a hollow fiber membrane 13, and about 10,000 hollow fiber membranes 13 are bundled to form a hollow fiber bundle 10. Got.
Furthermore, after this hollow fiber bundle 10 is loaded into a cylindrical polycarbonate casing 2, the end portion is bonded with a polyurethane resin (a type of urethane resin 12), which is a type of urethane resin, to form a module, Blood ports 3 and 4 were connected to both ends of this module, and a blood purifier 1 having a membrane area of 1.5 square meters was prototyped.

  Hydrophilic treatment was performed by flowing a 3.0% aqueous solution of polyvinyl pyrrolidone (manufactured by BASF, trade name: Kollidon K-90) at a flow rate of 100 mL / min for about 5 minutes on the blood contact portion side of the blood purifier 1. . After this blood purifier 1 was washed with 1 L of purified water, bovine blood (hematocrit 30%, total protein 6.5 g / dL) was circulated at a flow rate of 200 mL / min and the filtration flow rate was adjusted to 90 mL / min. A test was conducted to examine the change over time in the amount of external filtration (UFR, mL / hr · mmHg). Furthermore, the blood inlet / outlet and the residual blood state of the hollow fiber membrane after the test were observed. The test results are shown in Table 1, and the observation results are shown in Table 2.

Moreover, the test which investigates the elution amount of the polyvinyl pyrrolidone in the blood purifier 1 which performed the said hydrophilic treatment was done.
Specifically, after the blood purifier 1 is washed with 1 L of purified water, the purified water is filled into the blood purifier, heated at 70 ° C. for 3 hours, and then filled (liquid on the blood contact portion side). Was extracted, and the concentration of polyvinylpyrrolidone was measured to obtain the concentration of polyvinylpyrrolidone in the filling liquid. In addition, 500 mL of purified water was circulated at 70 ° C. at a flow rate of 200 mL / min for 4 hours with respect to the blood purifier 1 after the filling solution was extracted in the above test, and the polyvinyl extracted by this circulation to the purified water side The concentration of pyrrolidone was measured to obtain a polyvinylpyrrolidone concentration in the extract. The test results are shown in Table 3.

Moreover, the test which investigates the adhesion holding | maintenance state of polyvinylpyrrolidone in the hollow fiber membrane 13 of the blood purifier 1 which performed the said hydrophilic treatment was done.
Specifically, after the blood purifier 1 is washed with 1 L of purified water, the hollow fiber membrane 13 is cut out and cut into a flat shape, and the dry hollow fiber membrane 13 is used as a measurement sample to determine the contact angle with water. It was measured. The test results are shown in Table 4.

(Comparative Example 1)
Tests and observations were performed under the same conditions as in Example 1 using the blood purifier 1 that had not been hydrophilized. The test results are shown in Table 1, and the observation results are shown in Table 2.

In Example 1, almost no change with time in the ultrafiltration amount was observed. Further, blood adhesion to the hollow fiber membrane 13 was hardly observed at about 0 to 5, and blood adhesion to the blood ports 3 and 4 was not recognized.
In Comparative Example 1, the amount of ultrafiltration decreased with time, and blood adhesion to the hollow fiber membrane 13 was observed in 2% to 5% (200 to 500) of the whole. Furthermore, with regard to blood ports 3 and 4, a small amount of residual blood was observed on both the inlet and outlet urethane surfaces.

(Comparative Example 2)
For the blood purifier 1 that has not been subjected to hydrophilization treatment, a 3.0% aqueous solution of polyvinylpyrrolidone (manufactured by BASF, trade name: Kollidon K-30) is added to the blood contact portion side of the blood purifier 1 at 100 mL / min. Hydrophilic treatment was performed by flowing at a flow rate of about 5 minutes. And the test (The content of a test is the same as Example 1) which investigates the elution amount of the polyvinyl pyrrolidone in the blood purifier 1 was done. The test results are shown in Table 3.
Further, the hollow fiber membrane 13 of the blood purifier 1 is washed with 1 L of purified water, cut out and cut into a flat shape, and a dried sample is used as a sample to examine the state of polyvinylpyrrolidone adhering and holding on the hollow fiber membrane 13 (the test content is Same as Example 1). The test results are shown in Table 4.

(Comparative Example 3)
The spun hollow fiber membrane is washed with purified water, cut out, cut into a flat shape, and dried (that is, a hollow fiber membrane that has not been hydrophilized) as a sample. A test was conducted (test contents are the same as in Example 1). The test results are shown in Table 4.

In Example 1, with polyvinylpyrrolidone (K-90) having a large molecular weight, elution of polyvinylpyrrolidone (K-90) was not observed in both the filling liquid and the extract.
On the other hand, in Comparative Example 2, the polyvinyl pyrrolidone (K-30) having a low molecular weight was eluted in both the filling liquid and the extraction liquid, and the concentration was extracted when the filling liquid was 1. The liquid was about 0.38. That is, it can be seen that polyvinyl pyrrolidone having a small molecular weight is gradually detached from the surface even if it adheres to the surface.

Further, in Example 1, polyvinyl pyrrolidone (K-90) having a large molecular weight has a contact angle with water of 10 ° or less on the inner surface 13 ′ side (blood contact portion side), and is given hydrophilicity. It was recognized that On the outer surface side (dialysate contact portion side), the contact angle was 68 °, and it was recognized that hydrophobicity remained. As a result of comparison between Example 1 and Comparative Example 3, the hydrophobicity on the outer surface side was almost the same level as the hydrophobicity of the hollow fiber membrane (contact angle 69 °) not subjected to the hydrophilic treatment. Therefore, it can be seen that polyvinylpyrrolidone having a large molecular weight is adhered and held on the inner surface 13 ′ without passing through the holes formed on the inner surface 13 ′ (dense layer) of the hollow fiber membrane 13.
On the other hand, in Comparative Example 2, polyvinyl pyrrolidone (K-30) having a small molecular weight has a contact angle of 10 ° or less for both the inner surface 13 ′ side and the outer surface side, and is imparted with hydrophilicity. It was recognized that That is, polyvinylpyrrolidone having a small molecular weight permeates through the hole formed on the inner surface 13 ′ of the hollow fiber membrane 13 and permeates to the outer surface side which is the opposite surface.

  From the above, once the polyvinyl pyrrolidone having a high molecular weight adheres to the surface of the blood contact portion such as the hollow fiber membrane 13 or the blood ports 3 and 4, it does not detach from the surface and penetrates in the film thickness direction of the hollow fiber membrane 13. The polyvinyl pyrrolidone having a small molecular weight is gradually detached from the surface even if it adheres to the surface of the blood contact portion, and when it adheres to the surface of the hollow fiber membrane 13, the inside of the hollow fiber membrane 13 It was found that it has the property of penetrating in the film thickness direction and eluting from the opposite surface.

  Therefore, when polyvinyl pyrrolidone (K-90) having a large molecular weight is used, it is selectively hydrophilic with respect to the surface 13 'on the blood contact side while leaving the hydrophobicity of the dialysate side surface in the hollow fiber membrane 13. Can be granted.

It is a flowchart which shows the outline of the manufacturing process of a blood purifier. It is the figure which showed the molecular weight fractionation characteristic of the hollow fiber membrane. It is explanatory drawing which made the blood purifier the cross section. It is the figure which showed the cut surface of the hollow fiber bundle in the edge part of a casing, (a) is the figure which showed the whole cut surface, (b) is the figure which expanded and showed a part.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Blood purifier 2 Casing 3 Inlet side blood port 4 Outlet side blood port 5 Dialysate inlet 6 Dialysate outlet 7 Blood inlet 8 Blood outlet 9 O-ring 10 Hollow fiber bundle 11 Opening of casing 12 Urethane resin 13 Hollow fiber membrane

Claims (4)

In a blood purifier using a hollow fiber membrane made of a hydrophobic polymer,
By adhering and holding a hydrophilic polymer having a molecular weight of 100,000 or more to a blood contact portion of a module in which a bundle of hollow fiber membranes is loaded in a casing, the excess hydrophilic polymer is washed and removed with a washing liquid. Only the hydrophilic polymer that does not pass through the holes formed on the surface of the hollow fiber membrane on the blood contact portion side and adsorbs with a predetermined strength of adsorption force is adhered and held only on the surface of the blood contact portion. A blood purifier characterized by that.   The blood purification according to claim 1, wherein the hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polyglycol monoester, polypropylene glycol copolymer, and polyacrylamide. vessel.   The blood purifier according to claim 1 or 2, wherein the hydrophobic polymer uses a polyester-based resin and a polysulfone-based resin as main membrane materials. The blood purifier according to any one of claims 1 to 3, wherein the lower limit of the molecular weight of the hydrophilic polymer is set to 1200000.

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