JP2020110638A - Separation membrane for blood treatment, and blood treatment device incorporating the membrane - Google Patents

Abstract

To provide a separation membrane for blood treatment, excellent in blood compatibility even when performing radiation sterilization under atmosphere and in a dry state.SOLUTION: The separation membrane for blood treatment comprises: a separation membrane having a polysulfone-based polymer and polyvinyl pyrrolidone; and a coat disposed on a surface of the separation membrane, and including polymethoxy ethyl acrylate (PMEA).SELECTED DRAWING: Figure 1

Description

TECHNICAL FIELD The present invention relates to a separation membrane for blood treatment used for separating a specific substance in blood and a blood treatment device incorporating the membrane.

In the extracorporeal circulation therapy, a hollow fiber membrane blood treatment device using a selective separation membrane is widely used. For example, in hemodialysis as maintenance therapy for patients with chronic renal failure, in continuous hemofiltration, continuous hemofiltration dialysis, continuous hemodialysis, etc. as acute blood purification therapy for patients with serious disease states such as acute renal failure and sepsis, BACKGROUND ART A hollow fiber membrane-type blood processing device is used for oxygenation of blood or plasma separation during open heart surgery.
In these applications, the hollow fiber membrane has excellent mechanical strength and chemical stability.
Not only is it easy to control the permeation performance, there are few eluates, and there is little interaction with biological components,
It is required to be safe for the living body.

In recent years, from the viewpoint of mechanical strength, chemical stability, and controllability of permeation performance, selective separation membranes made of polysulfone-based resin have rapidly become popular. Since the polysulfone-based resin is a hydrophobic polymer, the hydrophilicity of the membrane surface is remarkably insufficient as it is, the blood compatibility is poor, interaction with blood components is caused, and blood coagulation easily occurs. The permeation performance is likely to deteriorate due to adsorption of protein components and the like.
Therefore, in order to make up for this drawback, studies have been made to impart blood compatibility by incorporating hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyvinyl alcohol, and polyethylene glycol in addition to hydrophobic polymers such as polysulfone-based resins. Has been done. For example, by forming a film using a spinning dope prepared by blending a hydrophobic polymer and a hydrophilic polymer, and drying the film, or by contacting the produced film with a solution containing a hydrophilic polymer and then drying the film. , A method of coating a hydrophilic polymer to impart blood compatibility is known.

By the way, in the extracorporeal circulation therapy, blood is used by bringing blood into direct contact with the selective separation membrane in the blood treatment device. Therefore, the selective separation membrane needs to be sterilized before use.
Ethylene oxide gas, high-pressure steam, radiation, etc. were used in the sterilization process, but there are problems with ethylene oxide gas sterilization and high-pressure steam sterilization such as allergies due to residual gas, the processing capacity of the sterilizer, and thermal deformation of materials. Currently, radiation sterilization using γ-rays and electron beams is becoming the mainstream.
On the other hand, dry products are becoming mainstream as blood processors due to handling and freezing problems in cold climates.In the sterilization process in the presence of oxygen by radiation sterilization, the generated radicals cause crosslinking of hydrophilic polymers. Reaction and decomposition, and eventually oxidative deterioration, etc. occur, which causes denaturation of the membrane material and causes deterioration of blood compatibility.

As a method to prevent such deterioration of the membrane material, for non-dry products,
A method of preventing oxidative deterioration of the membrane by filling the membrane module with an antioxidant solution and sterilizing by γ-ray, and a method of filling the membrane module with a PH buffer solution or an alkaline aqueous solution to sterilize and suppressing the oxidation of the filling solution It is disclosed.

On the other hand, regarding dry products, a method of suppressing the oxygen concentration during sterilization to 0.001% or more and 0.1% or less is disclosed (Patent Document 1). However, in the technique of Patent Document 1, it is necessary to replace the inside of the packaging bag with an inert gas for sterilization, or to seal the oxygen scavenger in the packaging bag and sterilize after a certain period of time. In addition, the technology to develop sufficient blood compatibility by radiation sterilization under air has not been established.

Patent Document 2 discloses coating the outer surface of a porous hollow fiber membrane for gas exchange with polymethoxyethyl acrylate (PMEA). However, there is no study on sterilization.

International Publication No. 2006/016575 Japanese Patent No. 3908839

It is an object of the present invention to provide a separation membrane for blood treatment, which has excellent blood compatibility and has little deterioration in blood compatibility even when radiation sterilized in a dry state in the atmosphere, and a blood treatment device incorporating the membrane. ..

As a result of intensive studies conducted by the present inventors to solve the above problems, polymethoxyethyl acrylate (PME) was added to a separation membrane containing at least a polysulfone-based polymer and polyvinylpyrrolidone.
The separation membrane for blood treatment coated with a film containing A) has very good blood compatibility, and it is also possible to maintain the very good blood compatibility even when sterilized in the atmosphere. Heading, the present invention was completed.

That is, the present invention is as follows.
A separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
A coating provided on the surface of the separation membrane and containing polymethoxyethyl acrylate (PMEA);
A separation membrane for treating blood, which comprises:
Further, another aspect of the present invention is as follows.
A step of forming a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
Coating the surface of the separation membrane with a coating liquid containing polymethoxyethyl acrylate (PMEA), water and an organic solvent;
A method for producing a separation membrane for blood treatment, comprising:

The separation membrane for blood treatment of the present invention and the blood treatment device incorporating the membrane can exhibit extremely excellent blood compatibility even when radiation-sterilized in a dry state in the atmosphere.

Infrared absorption curve when total reflection infrared absorption measurement (ATR-IR) was performed on the surface of the separation membrane for blood treatment of Example 1. Chromatogram of pyrolysis gas chromatograph mass spectrometry for PMEA Chromatogram of the pyrolysis gas chromatograph mass spectrum of the separation membrane before PMEA coating in Example 1. Chromatogram when pyrolysis gas chromatograph mass spectrometry was performed on the blood treatment separation membrane of Example 1. 3 is a mass spectrum of a peak near a chromatogram RT 1.7 (minute) of the blood treatment separation membrane of Example 1. FIG. When analyzed, it was identified as having the chemical structural formula (2-methoxyethyl alcohol) shown below.

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

The separation membrane for blood treatment of the present embodiment includes a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone, and has a coating film containing polymethoxyethyl acrylate for imparting blood compatibility to the surface of the separation membrane.

First, a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone will be described.
<Polysulfone-based polymer>
In the present embodiment, the polysulfone-based polymer is a polymer containing a sulfone (—SO ₂ —) group in its structure. Specific examples of the polysulfone-based resin include polyphenylene sulfone, polysulfone, polyallyl ether sulfone, polyether sulfone, and copolymers thereof.
As the polysulfone-based polymer, one kind may be used alone, or a mixture of two or more kinds may be used.

Among them, the polysulfone-based polymer represented by the following formula (1) or the following formula (2) is preferable from the viewpoint of controlling the fractionation property.
_{(-Ar-SO 2 -Ar-O} -Ar-C (CH 3) 2 -Ar-O-) n (1)
_{(-Ar-SO 2 -Ar-O-} ) n (2)
In the formulas (1) and (2), Ar represents a benzene ring and n represents a repeating polymer, and is an integer of 1 or more.

Examples of the polysulfone-based polymer represented by the formula (1) include those commercially available under the name "Udel (trademark)" from Solvay and under the name "Ultrazone (trademark)" from BASF. To be Examples of the polyether sulfone represented by the formula (2) include those commercially available from Sumitomo Chemical Co., Ltd. under the name of "Sumika Excel (trademark)", and there are several types depending on the degree of polymerization and the like. Since they exist, these can be appropriately used.

<Polyvinylpyrrolidone>
Polyvinylpyrrolidone is a water-soluble hydrophilic polymer obtained by vinyl polymerization of N-vinylpyrrolidone, and is widely used as a material for hollow fiber membranes as a hydrophilizing agent and a pore forming agent.
As polyvinylpyrrolidone, for example, several commercially available polyvinylpyrrolidones having a molecular weight of "Lubitec (trademark)" are commercially available from BSF Corporation, and these can be appropriately used.
As the polyvinylpyrrolidone, one kind may be used alone, or a mixture of two or more kinds may be used.

The separation membrane may include a constituent component other than the polysulfone-based polymer and polyvinylpyrrolidone as the constituent component. Examples of other components include polyhydroxyethyl methacrylate, polyhydroxypropyl methacrylate, polyhydroxyalkyl methacrylate such as polyhydroxybutyl methacrylate, and polyethylene glycol. There is no limitation on the content of the other components, and the content may be 20% by mass or less,
The amount may be less than or equal to 5% by mass, or less than or equal to 5% by mass. Further, the other constituent components may not be contained at all.
Further, in the separation membrane of the present embodiment, it is preferable that the ratio of polyvinylpyrrolidone to the polysulfone-based polymer is 27% by mass or less because the elution amount of polyvinylpyrrolidone can be suppressed. More preferably, by setting the content to 18% by mass or more, the concentration of polyvinylpyrrolidone on the surface of the separation membrane can be controlled within a suitable range, the effect of suppressing protein adsorption can be enhanced, and the separation membrane for blood treatment is excellent in blood compatibility. Can be

The shape of the separation membrane is not limited, but the separation membrane preferably has a hollow fiber shape. Further, from the viewpoint of the transmission performance, it is more preferable that crimp is provided.

Next, a coating containing polymethoxyethyl acrylate (PMEA) will be described.
Regarding blood compatibility of PMEA, Ken Tanaka, Material for biocompatible surface of artificial organ, BIO INDUSTRY, Vol 20, No. 12, 59-70 2003.
Among them, PMEA and (meth)acrylate polymers having different side chain structures were prepared for comparison, and various markers of platelets, leukocytes, complement and coagulation system when blood was circulated were evaluated. "The activation of blood components on PMEA surface was less than that of other macromolecules. In addition, PMEA surface has excellent blood compatibility because adhesion number of human platelets is significantly less and morphological change of adhesion platelets is small. It is described as ".
As described above, it is considered that PMEA is not simply good in blood compatibility because it has an ester group in its structure, but that the state of water molecules adsorbed on the surface of PMEA greatly affects blood compatibility.

As described above, PMEA is a known substance as a biocompatible polymer, but in order to further improve the blood compatibility of the separation membrane applied to the surface thereof, it is particularly important to increase its abundance in the surface layer. It turned out that

Since the separation membrane containing the polysulfone-based polymer and polyvinylpyrrolidone is a porous body, when the coating solution is applied onto it, the coating solution may permeate into the separation membrane through the pores. In particular, the pore size of the separation membrane may be increased depending on the type of solvent of the coating liquid, and in that case, permeation is more likely to occur.
In addition, depending on the type of solvent of the coating liquid, when the coating liquid is applied onto the separation membrane, it may flow out from the surface and may not be able to stay on the surface.
Thus, it is considered that the amount and the composition of the solvent of the coating liquid containing PMEA used at the time of coating influences the amount of PMEA applied on the separation membrane that remains on the surface layer of the separation membrane after coating.
That is, it is important that the coating solution in which PMEA is dissolved is such that when it is applied on the surface of the porous separation membrane, it remains on the surface as it is and PMEA remains on the surface.

Then, as a result of intensive studies by the present inventors, it was found that when the solvent of the coating liquid is a mixture of water and an organic solvent, the amount of PMEA remaining on the surface largely changes depending on the mixing ratio of water and the organic solvent.
Specifically, the smaller the mixing ratio of the organic solvent, the easier the PMEA tends to stay on the surface of the separation membrane. Although the reason for this is not clear, when the mixing ratio of the organic solvent in the solvent of the coating liquid is large, PMEA is well dissolved in the coating liquid, so that when the coating liquid is coated on the separation membrane, PEMA also remains in the membrane. Although it does not easily permeate and stay on the surface, if the mixing ratio of the organic solvent is small, the solubility of PMEA in the coating solution is small, so when the coating solution is coated on the separation membrane, the organic solvent may first permeate into the membrane. If the balance of the organic solvent/water in the solvent is lost, PMEA is presumed to be deposited from the coating liquid and remain on the surface of the separation membrane.

In addition, in the ATR-IR method, since the wave incident on the sample slightly digs into the sample and is reflected, it is known that the infrared absorption in the digging depth region can be measured. It was also found that the measurement area of this ATR-IR method is almost equal to the depth of the above-mentioned "surface layer". That is, the blood compatibility in the depth region almost equal to the measurement region of the ATR-IR method governs the blood compatibility of the sample (separation membrane for blood treatment), and PMEA is added to the region.
Is present in a specific amount or more (in other words, by defining the amount of PMEA using the peak intensity derived from PMEA in the infrared absorption curve by ATR-IR), the separation for blood treatment having a certain blood compatibility. With the idea that a membrane can be provided, a more preferred embodiment of the present invention has been completed.
The measurement region by the ATR-IR method depends on the wavelength of infrared light in the air, the incident angle, the refractive index of the prism, the refractive index of the sample, and the like, and is usually a region within 1 μm from the film surface.

The presence of polymethoxyethyl methacrylate (PMEA) on the surface of the separation membrane can be confirmed by thermal decomposition gas chromatography mass spectrometry of the separation membrane. The presence of PMEA is estimated by a total reflection infrared absorption (ATR-IR) measurement on the surface of the separation membrane, if a peak is seen near 1735 cm ⁻¹ in the infrared absorption curve. May also be derived from. Therefore, pyrolysis gas chromatograph mass spectrometry is performed, and 2-methoxyethanol derived from PMEA is confirmed, so that it is determined to be PMEA.

In order for the separation membrane for blood treatment in the present embodiment to exhibit practically sufficient blood compatibility, ATR-
Ester group-O derived from polymethoxyethyl methacrylate (PMEA) measured by IR
-Peak intensity of infrared absorption peak of C=O (near 1735 cm ^-1 ) Peak of infrared absorption peak of C=C (C=C in Ar) derived from polysulfone polymer having P1 (near 1595 cm ^-1 ) The ratio (P1/P2) to the strength P2 is preferably 0.05 or more, more preferably 0.07 or more, and further preferably 0.09 or more.

It is not clear why the separation membrane for blood treatment of the present embodiment is very excellent in blood compatibility, but there is something between the polyvinylpyrrolidone (PVP) and the polymethoxyethylmethacrylate (PMEA) contained in the separation membrane. It is presumed that the anchor effect is caused by the interaction (for example, the entanglement of molecules between PVP and PMEA).

The peak intensity ratio (P1/P2) between the peak derived from PMEA (around 1735 cm ⁻¹ ) and the peak derived from a polysulfone-based polymer (around 1595 cm ⁻¹ ) is the composition of the solvent of the coating solution used during coating (specifically Can be adjusted by changing the mixing ratio of the organic solvent and water). Specifically, the larger the amount of organic solvent, the weaker the peak intensity P1 of the polymethoxyethyl methacrylate (PMEA)-derived peak (around 1735 cm ⁻¹ ) when ATR-IR is performed, and the smaller the amount of organic solvent. Peaks derived from PMEA (173
The peak intensity P2 around 5 cm ^-1 ) becomes stronger.

The solubility of polymethoxyethyl methacrylate (PMEA) in a solvent has a unique one. For example, PMEA does not dissolve in 100% ethanol solvent, but the water/ethanol mixed solvent has a region in which it dissolves depending on the mixing ratio. Then, in the mixing ratio in the dissolving region, the peak intensity P1 of the peak derived from PMEA (around 1735 cm ⁻¹ ) becomes stronger as the amount of water increases.

When the coating film containing PMEA is coated on the surface of the separation membrane containing the polysulfone-based polymer and polyvinylpyrrolidone, the UFR, which is one index of water permeability, is measured for the presence state of the PMEA-containing coating on the separation membrane. It can be evaluated by that.
When the separation membrane is coated with a coating containing PMEA, the change in pore diameter of the porous membrane surface is small, so that the water permeability does not change so much and product design is simple. It is considered that this is because the coating film containing PMEA adheres to the surface of the separation membrane in an extremely thin film state and coats the separation membrane in a state in which the holes are not blocked so much.

In the present embodiment, the weight average molecular weight of the polymethoxyethyl methacrylate (PMEA) polymer can be measured, for example, by gel permeation chromatography (GPC) as described in Examples.
In the present embodiment, as a method of providing a coating film containing PMEA on the surface of the separation membrane, for example, a method of mixing and dissolving PMEA in a stock solution for spinning (spinning) at the time of forming the separation membrane and spinning, PMEA
A method of mixing and dissolving the above-mentioned in a hollow liquid during membrane formation and spinning, and a method of coating a coating solution in which PMEA is dissolved on the separation membrane are preferably used.
Among these methods, the coating method of coating the separation membrane with the coating solution seems to be most suitable in view of the solubility of PMEA in the membrane-forming stock solution and the hollow internal solution.

As a method of coating the separation membrane with the coating solution in which PMEA is dissolved, the separation membrane is preferably formed on the separation membrane, preferably after the separation membrane is formed into a blood processor and molded.
The coating can be performed by passing the coating liquid through contact with the coating liquid.

The separation membrane for blood treatment of the present embodiment can be sterilized by radiation sterilization even in an atmosphere having an oxygen concentration of 15% or more. That is, when the blood treatment separation membrane is subjected to radiation sterilization, it is not necessary to use a deoxidizer or replace it with an inert gas such as nitrogen to reduce the oxygen concentration, and the radiation sterilization is performed in the atmosphere. Can be given.

Next, the blood processor will be described.
The blood processor of the present embodiment is a blood processor in which the separation membrane for blood processing of the present embodiment is incorporated, and is hemodialysis, hemofiltration, hemodiafiltration, blood component fractionation, oxygenation, and plasma. It can be used for extracorporeal blood purification therapy such as separation. In the blood treatment apparatus of the present embodiment, even if the separation membrane for blood treatment is subjected to radiation sterilization in the atmosphere, some interaction (molecules) between polyvinylpyrrolidone and PMEA contained in the separation membrane is Since a strong bond is formed due to the anchor effect due to the entanglement of each other), the PMEA-containing coating is not peeled off and the blood compatibility is very good.

The blood processor is preferably used in a hemodialyzer, a hemofilter, a hemodialyzer, etc., and is a continuous use of these, as a continuous hemodialyzer, a continuous hemofilter, a continuous hemofilter dialyzer. It is more preferable to use. Detailed specifications such as the size and fractionation of the separation membrane are determined according to each application.

Next, a method for manufacturing the blood processing device of this embodiment will be described.
The method for producing a separation membrane for blood treatment of the present embodiment includes a step of forming a separation membrane containing at least a polysulfone-based polymer and polyvinylpyrrolidone, and polymethoxyethyl acrylate (PMEA), water, and water on the surface of the separation membrane. Coating with a coating liquid containing an organic solvent.
Furthermore, it is possible to include a step of drying the separation membrane so that the water content is 10% by mass or less, and a step of sterilizing the blood treatment separation membrane by radiation sterilization in an atmosphere having an oxygen concentration of 15% or more.

The separation membrane can be prepared by forming a membrane by a usual method using a membrane-forming stock solution containing at least a polysulfone-based polymer and polyvinylpyrrolidone.
The stock solution for film formation can be prepared by dissolving a polysulfone polymer and polyvinylpyrrolidone in a solvent.
Examples of such a solvent include dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, and dioxane.
As the solvent, one type may be used alone, or a mixed solvent of two or more types may be used.

The concentration of the polysulfone-based polymer in the membrane-forming undiluted solution is not particularly limited as long as it is a concentration range in which the membrane can be formed and the obtained membrane has performance as a permeable membrane, but is 5 to 35% by mass. It is preferably present, and more preferably 10 to 30% by mass. In order to achieve high water permeability, the polysulfone resin concentration is preferably low, and more preferably 10 to 25% by mass.

The concentration of polyvinylpyrrolidone in the film-forming stock solution is not limited, but for example, the ratio of polyvinylpyrrolidone to polysulfone-based polymer (mass of polyvinylpyrrolidone/mass of polystyrene-based polymer) is preferably 27% by mass or less, more preferably 18 It is preferable to adjust the content to be ~27% by mass, more preferably 20 to 27% by mass.
When the ratio of polyvinylpyrrolidone to the polysulfone-based polymer is 27% by mass or less, the elution amount of polyvinylpyrrolidone can be suppressed. Also preferably 1
By setting the content to 8% by mass or more, the concentration of polyvinylpyrrolidone on the surface of the separation membrane can be controlled within a suitable range, the effect of suppressing protein adsorption can be enhanced, and a separation membrane for blood treatment having excellent blood compatibility can be obtained. ..

A separation membrane such as a flat membrane or a hollow fiber membrane can be formed by a commonly used method using the above membrane-forming stock solution.
An example of the method for manufacturing the hollow fiber membrane will be described.
A tube-in-orifice type spinneret is used. From the orifice of the spinneret, a film-forming spinning solution is discharged from the tube, and a hollow liquid for coagulating the film-forming spinning solution is simultaneously discharged into the air. As the hollow internal liquid, water or a liquid containing water as a main component can be used, and generally, a mixed solution of the solvent used for the membrane-forming spinning solution and water is preferably used. For example, a 20 to 70 mass% dimethylacetamide aqueous solution or the like is used.
The inner diameter and the film thickness of the hollow fiber membrane can be adjusted to desired values by adjusting the discharge rate of the stock solution for membrane spinning and the discharge rate of the liquid inside the hollow fiber.

The inner diameter of the hollow fiber membrane is not particularly limited, but is generally 170 to 250 in blood processing applications.
It may be μm, and is preferably 180 to 220 μm. The thickness of the hollow fiber membrane is preferably 50 μm or less from the viewpoint of the efficiency of diffusion and removal of low molecular weight substances due to the mass transfer resistance of the permeable membrane.
From the viewpoint of strength, it is more preferably 10 μm or more.

The film-forming spinning solution discharged from the spinneret together with the hollow inner solution is run through the air gap part, then introduced into a water-based coagulation bath installed under the spinneret, and immersed for a certain period of time. , Its solidification is complete. At this time, it is preferable that the draft represented by the ratio of the linear velocity of the film-forming spinning solution discharge and the take-up velocity is 1 or less.
The air gap means the space between the spinneret and the coagulation bath, and the film-forming spinning solution is a poor solvent component such as water in the hollow internal liquid discharged simultaneously from the spinneret (polysulfone-based polymer and Due to the poor solvent component for polyvinylpyrrolidone), coagulation starts from the inner surface side. In order to form a smooth separation membrane surface at the start of solidification and stabilize the separation membrane structure, the draft is preferably 1 or less, more preferably 0.95 or less.

Then, the solvent remaining in the hollow fiber membrane is removed by washing with hot water or the like, and then the hollow fiber membrane can be continuously introduced into a drier to obtain a dried hollow fiber membrane. In order to remove unnecessary polyvinylpyrrolidone, the washing is preferably performed with hot water at 60° C. or higher for 120 seconds or more, and more preferably with hot water at 70° C. or higher for 150 seconds or more.

In order to embed in a urethane resin in a subsequent step, and in this embodiment, to perform radiation sterilization in a dry state, it is preferable to set the water content of the separation membrane to 10% by mass or less by drying.

The hollow fiber membrane obtained through the above steps can be subjected to the module manufacturing step as a bundle of which the length and the number are adjusted so that the desired membrane area is obtained. In this step, the hollow fiber membrane is filled in a tubular container having two nozzles near both ends of the side surface, and both ends are embedded with urethane resin.
Next, the cured urethane portions on both ends are cut to form the ends where the hollow fiber membrane is opened (exposed). A header cap having a nozzle for introducing (outleting) a liquid is loaded on both ends thereof to be assembled into a blood processing device.
After assembling the module as described above, it is also possible to form a coating film containing polyvinylpyrrolidone on the surface of the separation membrane by injecting a coating solution containing PMEA into the hollow fiber membrane.

Next, a method for forming a film containing PMEA on the surface of the separation film will be described in detail.
In this embodiment, for example, a coating film can be formed by applying a coating solution containing PMEA to the surface of the separation membrane.

The coating liquid is not particularly limited as long as it is a solvent that does not dissolve the polysulfone-based polymer and can dissolve or disperse PMEA. However, the safety of the process and the subsequent drying process From the viewpoint of easy handling, water or an aqueous alcohol solution is preferable. From the viewpoint of boiling point and toxicity, water, ethanol aqueous solution, methanol aqueous solution, isopropyl alcohol aqueous solution and the like are preferably used.
In addition, it is necessary to consider the type of solvent of the coating liquid and the composition of the solvent, including the relationship with the separation membrane that is the substrate to be coated, as described above.

The concentration of PMEA in the coating liquid is not limited, but, for example, 0.001% by mass to 1% by mass of the coating liquid.
It can be made into mass %, and it is more preferable that it is 0.005 mass%-0.2 mass %.
The method of applying the coating liquid is not limited, but, for example, a method of injecting the coating liquid onto the separation membrane from a header cap having a nozzle and then removing the excess solution using compressed air can be adopted.
Drying is preferably performed after coating, and the drying method is not limited, but may be dried under reduced pressure until it reaches a constant weight, or may be dried by heating. The temperature for heating and drying may be set as appropriate as long as it is a temperature at which the members of the module are not deteriorated, since it only depends on the process time.

The blood treatment separation membrane having the PMEA thus obtained on the surface of the separation membrane can be subjected to radiation sterilization treatment. There is no limitation on the atmosphere in which radiation sterilization is performed, and the oxygen concentration is 1
Radiation sterilization can be performed in an atmosphere of 5% or more and even in the air without causing denaturation of the separation membrane.

Electron beams, gamma rays, X-rays and the like can be used in the radiation sterilization method, and any of them may be used. The irradiation dose of radiation is usually 15 to 50 Kgy in the case of electron beam or gamma ray, and it is preferable to irradiate in the dose range of 20 to 40 Kgy. Through such a sterilization process such as radiation sterilization, a blood processor is completed.

The present invention will be specifically described below with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.
(1) Infrared ATR (total reflection method) measurement The sample procedure was as follows.
Priming was performed by washing the inner surface of the hollow fiber shape separation membrane with distilled water at 100 ml/min for 5 minutes per 1.5 m ² . After priming, the blood processor was disassembled and the hollow fibers sampled were opened with a razor, the surface of the hollow fiber separation membrane was faced upward, and a prism was pressed against that portion for infrared ATR measurement. (650 cm ^{-1 to} 4000 cm ^-1 )
The peak intensity area (peak area with 1715 cm ⁻¹ and 1755 cm ⁻¹ as a baseline) of the infrared absorption peak of ester group —O—C═O near 1735 cm ⁻¹ derived from PMEA was P1.
, The peak intensity area of the C=C infrared absorption peak near 1595 cm ⁻¹ derived from polysulfone (
Let P2 be the peak area with 1555 cm ^-1 and 1620 cm ^-1 as the baseline, and P1/
The amount of PMEA present on the surface of the separation membrane was measured from the ratio of P2.

(2) Pyrolysis gas chromatograph mass spectrometry Pyrolysis gas chromatograph mass spectrometry was performed using the following apparatus under the following conditions.
Device name Agilent 5973N-MSD (manufactured by Agilent)
Pyrolysis device name Double shot pyrolyzer Py-2020iD (manufactured by Frontier Lab)
Column name HP-5MS
Column overview Length 30m, inner diameter 0.25mm, film thickness 0.25μm, phenylmethylsiloxane membrane Pyrolysis temperature/hour 600°C 0 seconds Pyrolysis device interface temperature 320°C
GC injection temperature 320°C
GC oven initial temperature/holding time 40°C/3 minutes GC oven temperature raising rate 10°C/minute GC oven temperature reached/holding time 300°C/0 minutes MS transfer line temperature 300°C
MS ionization source temperature 230°C
MS quadrupole temperature 150°C
MS ionization voltage/current 70 eV/35 μA
MS scan range 29-550

(3) Measurement of UFR (ml/Hr·mmHg) From the blood side inlet (bin) to the blood side outlet (bout) of the blood processor, the original solution (Urea=
1000 ppm, VB-12 (vitamin B12)=10 ppm/pure water) 100 ml/m
Then, pure water was flown from the dialysate side inlet (din) to the dialysate side outlet (dout) at a rate of 500 ml/min in a direction intersecting with the original solution.
UFR is represented by the following formula.
UFR (ml/Hr·mmHg)
={bin flow rate (ml/min)×60 (min/Hr)×UFR coefficient}/TMP
={100×60×UFR coefficient}/TMP
Here, the UFR coefficient is a reference pressure when calculating the UFR measurement value. In addition, TMP(m
mHg) is a pressure applied to the blood treatment separation membrane when the blood side outlet part is stopped, and is expressed by the following equation.
TMP={(Pbin+Pbout)-(Pdin+Pdout)}/2

(4) Measurement of contact angle Priming was carried out by washing the inner surface of the hollow fiber shape separation membrane with distilled water for 5 minutes at 100 ml/min per 1.5 m ² . The blood processing device after priming was disassembled and the hollow fiber sampled was opened with a razor, and the contact angle was measured with the surface of the hollow fiber separation membrane facing upward.
Then, priming of washing at 100 ml/min for 5 minutes per 1.5 m ² was repeated 5 times to confirm whether or not the contact angle on the surface of the hollow fiber separation membrane changed.

(5) Preparation of PMEA (polymethoxyethyl acrylate) 15 g of 2-methoxyethyl acrylate was used in 60 g of 1,4-dioxane with azobisisobutyronitrile (0.1% by weight) as an initiator while bubbling nitrogen to 75. 10 at ℃
Polymerization was carried out for a period of time. After the completion of the polymerization reaction, the obtained polymerization solution was added dropwise to n-hexane to precipitate the product and isolate it. The product obtained is dissolved in tetrahydrofuran and n-
Purification was performed using hexane. The purified product was dried under reduced pressure overnight. A colorless and transparent starch syrup-like polymer was obtained. The amount (yield) was 12.3 g (82.0%).
The obtained polymer structure was confirmed by 1H-NMR.
Moreover, the number average molecular weight (Mn) was 20,000 and the molecular weight distribution (Mw/Mn) was 2.4 from the result of the molecular weight analysis of GPC.

(6) Confirmation of Solubility of PMEA with Solvent To prepare a coating liquid, the solubility of PMEA with a solvent was confirmed. The results are shown in the table below. It was found that there is a difference in the solubility of PMEA between the ethanol/water system and the methanol/water system.

(7) Blood compatibility Measurement of lactate dehydrogenase (LDH) activity and residual blood count The blood compatibility of the separation membrane was evaluated by the adhesion of platelets to the membrane surface, and lactate dehydrogenation contained in the platelets attached to the membrane. The activity of the enzyme (LDH) was quantified as an index.
By washing the blood processor with physiological saline (Otsuka raw food injection, Otsuka Pharmaceutical Co., Ltd.),
Primed. The separation membrane collected by disassembling the blood processing device after priming was processed with silicon at both ends so that the effective length was 15 cm and the area of the inner surface of the membrane was 5×10 ⁻³ m ² , to produce a mini module. The mini module was washed by pouring 10 ml of physiological saline into the hollow fiber.
After that, heparin-added blood 15 ml (heparin 1000 IU/L) was added at 1.3 ml/min.
The mini module prepared above was circulated at 37° C. for 4 hours at a flow rate of The inside of the mini module was washed with 10 ml and the outside was washed with 10 ml with physiological saline. A 7 cm-long hollow fiber membrane was collected from the washed mini-module, half of the whole was cut into small pieces, and the pieces were placed in a Spitz tube for LDH measurement to obtain a measurement sample. In addition, it was visually determined how many residual blood (blood coagulated in the hollow fiber) was generated in the hollow fiber in the mini-module.
Next, Triton X-100 (in Wako Pure Chemical Industries, Ltd.) was added to a phosphate buffer solution (PBS).
0.5% by volume of Triton X-100/PB obtained by dissolving Nacalai Tesque, Inc.)
After adding 0.5 ml of the S solution to a Spitz tube for LDH measurement, shaking treatment was performed for 60 minutes to destroy cells (mainly platelets) attached to the separation membrane and extract LDH in the cells. 0 this extract
． 05 ml fractionation, and 2.7 ml of 0.6 mM sodium pyruvate solution, 1.27
0.3 mg of a 7 mg/ml nicotinamide adenine dinucleotide (NADH) solution was added, and the mixture was reacted at 37° C. for 1 hour, and then the absorbance at 340 nm was measured.
Similarly, for the separation membrane (blank) not reacted with blood, the absorbance is similarly measured,
The difference in absorbance ΔAbs (340 nm)/Hr was calculated by the following formula.
ΔAbs (340 nm)/Hr
= [Abs (340 nm) after 1 Hr of blank (blood non-contact membrane)]-[Abs (340 nm) after 1 Hr of sample (blood contact membrane)]
The separation membrane containing polysulfone-based polymer and polyvinylpyrrolidone (Comparative Example 1 this time) was also used as a control sample in the same manner as ΔAbs (340 nm)/Hr.
Was measured and a proportional value was calculated when the value was set to 100.
In this method, this proportional value was used as the LDH activity of each sample. A high LDH activity means that the amount of platelets attached to the membrane surface is large and the blood compatibility is low. In addition, the measurement is performed 3 times,
The average value is shown.
As the separation membrane having excellent blood compatibility, those having LDH activity of 5 or less are preferable, and those having LDH activity of 2 or less can be judged to have very excellent blood compatibility.

(Example 1)
The film-forming spinning solution is composed of 79 parts by mass of dimethylacetamide (manufactured by Kishida Chemical Co., Ltd., special grade reagent), 17 parts by mass of polysulfone (P-1700 manufactured by Solvay Co.) and 4 parts by mass of polyvinylpyrrolidone (K-90 manufactured by BSF). Was prepared by dissolving.
A 60% by mass dimethylacetamide aqueous solution was used as the hollow internal liquid.
From the tube-in-orifice type spinneret, the stock solution for film formation and the hollow internal solution were discharged.
The temperature of the stock solution for film formation during discharge was 40°C. The discharged film-forming spinning solution was immersed in a coagulation bath of water at 60° C. through a dropping part covered with a hood to coagulate it. The spinning speed was 30 m/min.
After coagulation, washing with water and drying were performed to obtain a hollow separation membrane. Washing temperature is 90 ℃, washing time is 1
It was set to 80 seconds. The amounts of the stock solution for membrane spinning and the liquid in the hollow space were adjusted so that the film thickness after drying was 35 μm and the inner diameter was 185 μm.
The obtained hollow fiber separation membrane was incorporated into a blood treatment device and molded, and a module having an effective area of 1.5 m ² was assembled. Next, 0.1 g of PMEA (Mn 20,000, Mw/Mn 2.4) was dissolved in an aqueous solution (100 g) of 40 g of ethanol/60 g of water to prepare a coating liquid.
The assembled module was vertically held, and the coating liquid was caused to flow from the upper portion at a flow rate of 100 ml/min to bring the coating liquid into contact with the surface of the separation membrane.
After contact with the coating liquid, the coating liquid in the module is blown off with air of 0.1 KMpa, the module is put in a vacuum dryer and vacuum dried at 35° C. for 15 hours.
Gamma-ray sterilization was performed at y to obtain a blood processor.
As a result of performing a blood compatibility test on the obtained blood treatment device, LDH activity was 1.3 and residual blood count was 0.

Infrared ATR measurement was performed on this sample. The infrared absorption curve is shown in FIG.
An ester group (—O—C═O) peak of infrared absorption (around 1735 cm ⁻¹ ) derived from PMEA was confirmed.
In addition, the infrared absorption (around 1735 cm ^-1 ) peak intensity area P1 and the infrared absorption (1595 cm ^-1 )
The ratio P1 / P2 ^-1 vicinity) peak intensity area P2 was 0.115.

This sample was subjected to pyrolysis gas chromatograph mass spectrometry.
The result is shown in FIG. In addition, as a control, the result of the thermal decomposition gas chromatograph mass spectrometry of PMEA is shown in FIG.
The peak of the chromatogram of the thermal decomposition product of PMEA is at RT 1.7 min (Fig. 2
), a similar trace was also seen in this sample (Fig. 4). And the mass spectrum search result (
From FIG. 5), it was found that this peak belongs to 2-methoxyethanol. Since 2-methoxyethanol is considered to be a hydrolyzate of the thermal decomposition product (of the side chain portion) of PMEA, it was confirmed from this that PMEA was present on the surface of the separation membrane of Example 1. did it. As will be described later (Comparative Example 1), when a separation membrane not coated with PMEA was also subjected to the same pyrolysis gas chromatograph mass spectrometry (FIG. 3), no trace of a peak was observed at RT 1.7 min.

The contact angle of this sample was measured.
The results are shown in the table below.
The contact angle was about 60°, and the contact angle did not change even after repeated priming.

UFR (ml/Hr·mmHg) of this sample was measured and found to be UFR=477.
(Ml/Hr·mmHg).

(Comparative Example 1)
A module having an effective area of 1.5 m ² was assembled in the same manner as in Example 1 except that the coating solution was not brought into contact with the separation membrane. As a result of blood compatibility test performed on this, LDH activity was 1
The number of residual blood was 6 and 6.
Infrared ATR measurement was performed on this sample.
m ^-1 vicinity) peak was observed.
The result of the pyrolysis gas chromatograph mass spectrometry performed on this sample is shown in FIG. PM
2-methoxyethanol derived from EA could not be confirmed.
The contact angle was measured in the same manner as in Example 1. The results are shown in the table below. The contact angle was about 70°, and the contact angle did not change even after repeated priming.

(Comparative example 2)
A separation membrane was formed in the same manner as in Example 1 except that polyvinylpyrrolidone was not added to the membrane-spinning stock solution of Example 1, and this was incorporated into a blood treatment device and molded in the same manner as in Example 1 to obtain PME.
When the blood compatibility test was carried out on the product coated with A, the LDH activity was 27 and the number of residual blood was 3.
Further, the contact angle of this sample was measured. The results are shown in the table below. The contact angle changed to hydrophobic by repeating priming. It is considered that the immobilization of PMEA on the surface of the separation membrane was unstable.

(Examples 2 to 5, Comparative Example 3)
A hollow fiber separation membrane was formed in the same manner as in Example 1, and the hollow fiber separation membrane was incorporated into a blood processor and molded.
A module with an effective area of 1.5 m ² was assembled.
Then, a blood processor was prepared in the same manner as in Example 1 except that the PMEA concentration of the coating liquid and the mixing ratio of water and the organic solvent (ethanol) were changed as shown in Table 1. LDH activity, residual blood count, The infrared absorption peak ratio was measured.
The results are shown in Table 1 below.
LDH activity was slightly improved with increasing PMEA concentration, but no significant difference was observed.
On the other hand, when the mixed solvent ratio (ETOH/H ₂ O) is changed, the peak ratio (P1/P2) decreases as the amount of organic solvent increases, that is, the amount of PMEA existing on the surface of the separation membrane tends to decrease. In addition, LDH activity tends to increase, that is, blood compatibility tends to decrease. However, the LDH activities are all within the range of values usually possessed by commercial products.

Similar to Example 1, the samples of Examples 2 to 5 and Comparative Example 3 were analyzed by pyrolysis gas chromatograph mass spectrometry. RT, which is the peak of PMEA pyrolyzate, for all samples
A peak at 1.7 min was confirmed, and it was found from the mass spectrum search results that this peak was 2-methoxyethanol. From this, it was confirmed that PMEA was present on the film surface in Examples 2 to 5 and Comparative Example 3 as well.

(Examples 6 to 7)
Regarding the membrane-forming spinning solution, the amount of polysulfone (P-1700 manufactured by Solvay Co., Ltd.) and the amount of polyvinylpyrrolidone (K-90 manufactured by BSF Corporation) with respect to 79 parts by mass of dimethylacetamide (Kesida Chemical Co., Ltd., special grade reagent) are as follows. Example 1 except that it was changed as shown in the table of
A hollow fiber separation membrane is formed in the same manner as above, and the hollow fiber separation membrane is incorporated into a blood processing unit and coated with PMEA to form an LD.
H activity was measured.
The results are shown in the table below. Even if the composition of the stock solution for film formation was changed, the LDH activity was small and the blood compatibility was good.

(Comparative Example 4)
When the blood compatibility test was similarly performed on the commercial product CX-21U (manufactured by Toray) and the LDH activity and the number of residual blood were measured, the LDH activity was 66.2 and the number of residual blood was 4, residual blood occurred. What is said is that blood compatibility is considered to be poor.
Here, as the HF used for measuring the LDH activity, one that does not contain residual blood thread is selected.

INDUSTRIAL APPLICABILITY The blood treatment separation membrane of the present invention and the blood treatment device incorporating the membrane are extremely good blood compatibility even though they are blood treatment separation membranes that are radiation-sterilized in the dry state under the atmosphere and provided in the dry state. It has the effect of exhibiting sex, and can be suitably used in extracorporeal circulation therapy such as hemodialysis, hemofiltration, hemodiafiltration, blood component fractionation, oxygenation, and plasma separation.

Claims (6)

A separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
A coating provided on the surface of the separation membrane and containing polymethoxyethyl acrylate (PMEA);
A separation membrane for treating blood, which comprises: In the infrared absorption curve when performing total reflection infrared absorption measurement (ATR-IR) to the surface, infrared absorption at around 1595cm ^-1 and the peak intensity of the infrared absorption peak (P1) near 1735 cm ^-1 The ratio (P1/P2) of the peak intensity (P2) of the peak is 0.05 or more,
The separation membrane for blood treatment according to claim 1. A blood processing apparatus comprising the separation membrane for blood processing according to claim 1 or 2. A step of forming a separation membrane containing a polysulfone-based polymer and polyvinylpyrrolidone,
Coating the surface of the separation membrane with a coating liquid containing polymethoxyethyl acrylate (PMEA), water and an organic solvent;
A method for producing a separation membrane for blood treatment, comprising: The method for producing a separation membrane for blood treatment according to claim 4, wherein the organic solvent is ethanol, methanol, or a mixture thereof. In the step of forming the separation membrane,
The separation membrane is formed using a membrane-forming stock solution containing a polysulfone-based polymer and polyvinylpyrrolidone,
The ratio of polyvinylpyrrolidone to polysulfone-based polymer in the stock solution for film formation (polyvinylpyrrolidone/polysulfone-based polymer) is 27 mass% or less.
The method for producing the separation membrane for blood treatment according to claim 4 or 5.