JP6149125B2 - Separation membrane for blood treatment and blood treatment device comprising the same - Google Patents

Description

  The present invention relates to a separation membrane for blood processing and a blood processing device including the same.

  In 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. In addition, a hollow fiber membrane blood processor is used for oxygenation or plasma separation during blood opening surgery.

  In these applications, the hollow fiber membrane is excellent in mechanical strength and chemical stability, is easy to control the permeation performance, has less eluate, has less interaction with biological components, There is a need for products that are safe against sterility and that are guaranteed to be sterile.

  In recent years, from the viewpoint of mechanical strength, chemical stability, and controllability of permeation performance, a selective separation membrane made of a polysulfone resin has been rapidly spread. Since the polysulfone resin is a hydrophobic polymer, as it is, the hydrophilicity of the membrane surface is remarkably insufficient and the blood compatibility is low. For this reason, interaction with blood components is caused, blood coagulation is likely to occur, and permeation performance is likely to deteriorate due to adsorption of protein components.

  Therefore, in order to compensate for this drawback, blood compatibility is imparted by adding hydrophilic polymers such as polyvinyl pyrrolidone (PVP), polyvinyl alcohol, and polyethylene glycol in addition to hydrophobic polymers such as polysulfone resin. Consideration has been made. For example, by forming a film using a spinning stock solution blended with a hydrophobic polymer and a hydrophilic polymer, the hydrophilicity of the film is increased in the process of increasing the hydrophilicity of the film and improving blood compatibility, and the process of dry and wet film formation. Film formation using a hollow internal liquid containing molecules and drying, and contact with a solution containing a hydrophilic polymer, and then drying the produced film to coat the hydrophilic polymer A method for imparting blood compatibility is known.

  By the way, in extracorporeal circulation therapy, since the blood is directly brought into contact with the selective separation membrane in the blood treatment device, the selective separation membrane needs to be sterilized before use.

  In sterilization treatment, ethylene oxide gas, high-pressure steam, radiation, etc. are used. However, ethylene oxide gas sterilization and high-pressure steam sterilization have problems such as allergies due to residual gas, treatment capacity of the sterilizer, and thermal deformation of materials. Yes, radiation sterilization such as gamma rays and electron beams has become the mainstream.

  On the other hand, dry products are becoming mainstream as blood treatment devices due to handling problems, freezing problems during cold storage, etc., but in the sterilization process in the presence of oxygen by radiation sterilization, the generated radicals cause Cross-linking reaction and decomposition, as well as oxidative degradation, etc. occur, thereby causing denaturation of the membrane material, which may cause a decrease in blood compatibility.

  As a method for preventing such deterioration of the membrane material, if it is not a dry product, the membrane module is filled with an antioxidant solution and γ-ray sterilized to prevent oxidative deterioration of the membrane (Patent Document 1). And the method (patent document 2) which suppresses the oxidation of a filling liquid by filling with a pH buffer solution and alkaline aqueous solution and sterilizing is disclosed.

  On the other hand, for dry products, a method for controlling the oxygen concentration during sterilization to 0.001% or more and 0.1% or less is disclosed (Patent Document 3). However, in the technique of Patent Document 3, it is necessary to sterilize by replacing the inside of the packaging bag with an inert gas, or to sterilize after a certain period of time by enclosing an oxygen scavenger in the packaging bag. However, a technique for expressing sufficient blood compatibility by radiation sterilization in the atmosphere has not been established.

  Regarding the state of water and biocompatibility contained in polymer materials such as poly (2-methoxyethyl acrylate) (PMEA), “functions of water molecules organized in a biointerface” have been reported (non-patent) Reference 1).

  According to Non-Patent Document 1, when water is contained in a general polymer material, the water in the polymer is (1) “non-freezing water” that does not freeze even at −100 ° C. due to strong interaction with the polymer. (2) Although it dissolves at 0 ° C., it is divided into “free water” having weak interaction with polymer or antifreeze water. In the polymer material having excellent biocompatibility, (3) “intermediate water that is frozen at a temperature lower than 0 ° C. during the temperature rising process and has an intermediate interaction with the polymer or antifreeze water. Is present. In general, “intermediate water” does not exist in polymer materials having poor biocompatibility.

  Non-Patent Document 1 suggests that there is a close relationship between the presence of “intermediate water” in the water in the polymer material and the development of excellent biocompatibility of the polymer material. Results are disclosed.

  The following is considered as a mechanism in which “intermediate water” affects the biocompatibility of the polymer material.

  Since “free water” is freely exchanged with bulk water, which is general water that does not interact with the polymer, it does not play the role of covering the surface of the polymer material. It exists to cover the surface of the polymer material by strong interaction. However, “antifreeze water” destroys the structure of the hydration shell by interacting with the hydration shell itself of biological components such as proteins that are stabilized by forming a hydration shell in the blood. Due to the destruction of the hydration shell, the biological component is adsorbed on the surface of the polymer material. Therefore, when using a general polymer material that contains only "free water" and "antifreeze water", the biological component recognizes the surface of the polymer material as a foreign substance, which triggers an immune reaction. .

  On the other hand, “intermediate water” binds to a polymer material by interaction with “antifreeze water”, covers the surface of “antifreeze water”, and has a unique hydrogen bond that destroys the hydration shell of biological components. Since it does not have a structure, the biological component cannot recognize the foreign material on the surface of the polymer material. Therefore, it is speculated that the polymer material having “intermediate water” is excellent in blood compatibility.

JP-A-4-338223 Japanese Patent Laid-Open No. 7-194949 International Publication No. 2006/016575 JP-A-2-218374

PRESTO Study 21 of the Japan Science and Technology Agency: Ken Tanaka “Functions of Water Molecules Organized in Biointerfaces” (2001-2004) Report

  By the way, when preparing blood purification treatment in a medical institution, it becomes a serious problem if bacteria are mixed in the module and they grow. The sterilized module is taken out of the bag, the plugged module is opened and connected to the circuit to prepare for treatment. However, there is a risk of contamination by bacteria. In particular, a film having a property of including intermediate water and free water in a water-containing process from a dry state absorbs moisture in the air and retains moisture on the film surface. Therefore, there is an increased risk of bacteria growing using the moisture retained on the membrane surface. Usually, since the treatment is started immediately after priming, the growth of bacteria does not become a problem. However, when a circuit is connected and prepared on the day before the treatment, the contamination / growth of the bacteria cannot be ignored. In fact, there are very few facilities that implement the previous day's circuit connections so that such problems do not occur.

  However, for example, when performing multi-person dialysis in a facility, it is a burden on the treatment facility that preparation for treatment cannot be performed on the previous day. In particular, the burden will become even greater if dialysis is performed in the early morning. Since early morning dialysis greatly contributes to the rehabilitation of dialysis patients, it is very important in terms of increasing the degree of freedom of dialysis treatment to prepare for treatment the day before for the spread of dialysis patients.

  In addition, in the manufacturing process, if the product has a low risk of bacterial growth, the sterilization dose during radiation sterilization can be reduced, and the damage to the separation membrane due to radiation can be reduced, making it more blood compatible. It is possible to create a high separation membrane. Furthermore, a product with a low risk of bacterial growth can provide a safer product regardless of the storage environment.

  On the other hand, there is a method in which an aqueous sodium chloride solution is passed through a module and sodium chloride is adhered to a separation membrane (Patent Document 4). This makes it possible to protect the separation membrane during the sterilization process. However, in the method in which the sodium chloride aqueous solution is passed through and dried, a large amount of salt is attached, and a large amount of priming solution is required to sufficiently wash away the salt. I need. When treatment is started without sufficient sodium chloride being washed away, not only is the effect of the high-concentration sodium chloride aqueous solution entering the patient's body, but in the early stage of blood introduction, the salt mass is lost to the blood flow in the hollow fiber. Can cause clot formation and residual blood. In addition, due to the high salt concentration on the membrane surface, bound water is present on the membrane surface, and in a highly biocompatible membrane that would normally have intermediate water on the membrane surface, sufficient function cannot be expressed from the start of treatment. Furthermore, in the production process, it is necessary to go through a drying process to make a dry product after passing salt water, and a large-scale drying facility and energy are required to dry the module.

  If the surface of the separation membrane contains water, it has good blood compatibility, but if an inorganic salt is added to give an antibacterial action to the surface of the separation membrane, the inorganic salt and the intermediate water on the surface of the separation membrane Because of the interaction, if the inorganic salt is not sufficiently washed away, the amount of intermediate water is reduced, and blood compatibility at the initial stage of blood contact is lowered. Even if the inorganic salt is finely divided, if the inorganic salt is present on the surface of the separation membrane having intermediate water, even if the inorganic salt is washed away after radiation sterilization, good blood compatibility may not be exhibited. This was a challenge. The cause of this is not necessarily clear, but the influence of inorganic salts on the interaction between the slight moisture on the surface of the separation membrane and the hydrophilic groups of the separation membrane substrate causes intermediate crosslinking and modification during radiation sterilization. It is guessed that it works in the direction of reducing water. Therefore, even when the inorganic salt is adhered on the surface of the separation membrane, it has been a problem to improve the abundance ratio of intermediate water in order to develop good blood compatibility.

  Accordingly, the present invention provides a separation membrane for blood treatment that has excellent blood compatibility even when the amount of physiological saline used during priming is small and suppresses the growth of bacteria, and a blood treatment device incorporating the same. Objective.

  As a result of intensive investigations by the present inventors to solve the above problems, in order to impart excellent blood compatibility to the separation membrane for blood treatment, the ratio of intermediate water in the separation membrane is increased, and an inorganic salt It has become clear that it is effective to have fine particles present.

  Specifically, from the viewpoint of blood compatibility, the separation of the practical separation membrane on the surface of the separation functional membrane that comes into contact with the blood was separated as a result of water absorption from the dry state and the water content reaching saturation. When the ratio of the intermediate water in the functional membrane is 20% or more and the separation membrane contains 100 μg or more and 0.1 g or less of inorganic salt particles having a particle size of 3 μm or less, the amount of physiological saline used during priming is small. Found that the blood compatibility was excellent, and completed the present invention.

  When the blood treatment separation membrane is equally divided into five in the direction from the blood inlet side end to the outlet side end, the amount of the inorganic salt contained in the central separation membrane is 1/5. Because it is the smallest compared to the / 5 part of the separation membrane, it minimizes the amount of inorganic salts adhering to the separation membrane, and exhibits remarkable antibacterial action on the blood inlet side and outlet side where bacteria are likely to be mixed. It becomes possible to do.

  By making the inorganic salt into fine particles with a particle size of 3 μm or less, the inorganic salt instantly dissolves in the priming solution at the time of priming before the start of treatment. When the particle size of the inorganic salt exceeds 3 μm, if treatment is started without sufficiently washing away the inorganic salt (for example, sodium chloride), not only the effects of the high concentration of aqueous inorganic salt solution entering the patient's body In the early stage of blood introduction, a lump of inorganic salt may obstruct blood flow in the hollow fiber, and may cause thrombus formation and residual blood. In addition, coloring of inorganic salt particles after radiation sterilization may cause a problem in appearance.

  By making the inorganic salt into fine particles, it is possible to minimize the amount of the inorganic salt adhering to the separation membrane, and it is possible to wash the salt on the membrane surface with a smaller amount of priming solution. Further, by making fine particles and localizing them on the inner surface, the appearance problem is improved particularly when the inorganic salt particles are colored.

That is, the present invention is as follows.
[1] A blood treatment separation membrane having a blood inlet side end, a blood outlet side end, and a separation functional surface that contacts blood to be treated,
Distilled water permeates the dry separation membrane, and when the water content reaches saturation, when the water present on the separation function surface is divided into antifreeze water, intermediate water and free water, the intermediate water The abundance ratio is 20% or more based on the total amount of the antifreeze water, the intermediate water and the free water,
The water content of the separation membrane is 10% by mass or less with respect to the total mass of the separation membrane,
The separation membrane includes a separation membrane substrate and inorganic salt particles having a particle size of 3 μm or less attached to the surface of the separation membrane substrate, and the amount of the inorganic salt particles is from 100 μg to 0.1 g, In addition, among the 1/5 portions obtained by equally dividing the separation membrane into 5 portions between the blood inlet side end portion and the blood outlet side end portion, it is included in the central 1/5 portion. A separation membrane for blood treatment in which the amount of the inorganic salt particles is the smallest.
[2] The separation membrane for blood treatment according to [1], wherein the separation membrane substrate contains a hydrophobic polymer and a hydrophilic polymer.
[3] The separation membrane for blood treatment according to [2], comprising a polysulfone-based resin as the hydrophobic polymer and polyvinyl pyrrolidone as the hydrophilic polymer.
[4] The separation membrane for blood treatment according to [1], wherein the separation membrane substrate contains an ethylene vinyl alcohol copolymer.
[5] The separation membrane for blood treatment according to [3], wherein the separation function surface has a polymer having an action of suppressing radiation degradation of polyvinylpyrrolidone, and the polymer is polyhydroxyalkyl methacrylate.
[6] The separation membrane substrate contains a hydrophilic polymer and a polysulfone resin,
The hydrophilic polymer content A, which is the ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone-based resin in the entire separation membrane substrate, is 3% by mass or more and 10% by mass. % Or less,
The abundance ratio B of the hydrophilic polymer, which is a ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone-based resin on the separation function surface, is 35% by mass or more and 50% by mass or less. The separation membrane for blood treatment according to [1].
[7] The separation membrane for blood treatment according to any one of [1] to [6], wherein the membrane is sterilized with radiation or electron beam at an oxygen concentration of 3% or less during sterilization.
[8] A blood treatment device comprising the separation membrane for blood treatment according to any one of [1] to [7].

  The blood treatment separation membrane of the present invention and the blood treatment device incorporating the membrane have the effect of being excellent in blood compatibility and suppressing the growth of bacteria even if the amount of physiological saline used during priming is small.

FIG. 5 is a diagram showing an outline of an IR measurement method for calculating the abundance ratio of intermediate water in water existing on the separation function surface when distilled water is infiltrated into a separation membrane from a dry state and the water content reaches saturation. is there. An example of the experimental spectrum matrix A is shown.

  Hereinafter, modes for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail below. In addition, this invention is not limited to the following embodiment, In the range of the summary, various deformation | transformation can be implemented.

  The separation membrane according to the present embodiment has an intermediate water content ratio (hereinafter simply referred to as an “intermediate water content ratio”) in the water existing on the surface of the separation function when the water content reaches saturation by infiltrating distilled water from the dry state. ] May be 20% or more.

  In this embodiment, the intermediate water abundance ratio is analyzed by measuring total reflection infrared absorption (ATR-IR) on the separation function surface of the separation membrane in the process of water permeating into the dry membrane, and analyzing the change over time. It is calculated by doing.

  The separation membrane according to the present embodiment has a blood inlet side end, a blood outlet side end, and a separation function surface that contacts blood to be treated. In the present embodiment, the “separation function surface” means a region corresponding to the film thickness of the blood contact surface detected by ATR-IR. Specifically, the separation functional surface is a detectable region when measured by ATR-IR, and is usually a region from the membrane surface to a depth of 1 μm or less.

In this embodiment, “when the distilled water penetrates from the dry state and the water content reaches saturation” refers to a process in which water penetrates the dry separation membrane as measured by ATR-IR. It means the point at which the increase in peak intensity derived from the hydroxyl group (3000 to 3700 cm ⁻¹ ) is no longer observed. When the separation membrane contains a polysulfone-based resin, the saturation of moisture can be determined by comparing the peak intensity derived from a hydroxyl group with the peak intensity of the benzene ring (near 1485 cm ⁻¹ ) of the polysulfone-based resin. In the present embodiment, the “dry state” means a state where the equilibrium moisture content has been reached, as exemplified in the examples.

  In this embodiment, in order to impart better biocompatibility to the separation membrane, even if the separation functional surface is in a state after radiation sterilization, the water content is saturated by infiltrating distilled water from the dry state. At the point of time, the intermediate water may be retained so that the ratio of the intermediate water to the water existing on the separation function surface is 20% or more.

  From the viewpoint of blood compatibility, distilled water is infiltrated into the separation membrane in a dry state, and the existing ratio of intermediate water when the water content reaches saturation is preferably 20% or more, and more preferably 40% or more.

The separation membrane according to the present embodiment includes a separation membrane substrate that forms a membrane, and inorganic salt particles attached to the surface of the separation membrane substrate. The separation membrane substrate includes, for example, a hydrophobic polymer and a hydrophilic polymer. The hydrophobic polymer and the hydrophilic polymer may be the same polymer having a hydrophobic portion and a hydrophilic portion. Examples of the hydrophobic polymer include a polysulfone resin. The polysulfone-based resin is a sulfone (—SO ₂ —) group-containing synthetic polymer, and examples thereof include polyphenylene sulfone, polysulfone, polyaryl ether sulfone, polyether sulfone, and copolymers thereof. As a polysulfone-type resin, you may use by 1 type and may use 2 or more types of mixtures. Examples of the hydrophilic polymer include polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol. Examples of the same polymer having a hydrophobic portion and a hydrophilic portion include an ethylene vinyl alcohol copolymer.

  In one embodiment, the separation membrane substrate may include a polysulfone-based resin as a hydrophobic polymer and polyvinyl pyrrolidone as a hydrophilic polymer, or may be configured from a polysulfone-based resin and polyvinyl pyrrolidone. May be.

  In other embodiments, the separation membrane substrate may include an ethylene vinyl alcohol copolymer, or may include an ethylene vinyl alcohol copolymer.

  In one embodiment, the separation membrane substrate may contain a hydrophilic polymer such as polyvinyl pyrrolidone and a polysulfone resin. In this case, the hydrophilic polymer content A, which is the ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone resin in the entire separation membrane substrate, is 3% by mass or more and 10% by mass or less. It may be. In order to immobilize the hydrophilic polymer in a practically sufficient amount on the separation membrane substrate, the hydrophilic polymer content A is preferably 3% by mass or more. When the content A is 10% by mass or less, it becomes easier to obtain a practically sufficient tensile strength, and at the same time, it becomes easier to obtain the stability of the permeation performance in a harsh environment. From the same viewpoint, the content A of the hydrophilic polymer is preferably 4% by mass or more and 9% by mass or less, and more preferably 5% by mass or more and 8% by mass or less.

As a measuring method of content rate A of a hydrophilic polymer, the method using the measurement result by < ¹ > H-NMR is mentioned, for example. That is, in the method using ¹ H-NMR, the peak intensity derived from the proton of the group unique to the polysulfone resin and the intensity of the peak derived from the proton of the group unique to the hydrophilic polymer are determined. The molar ratio is obtained, and the content of the hydrophilic polymer in the entire separation membrane substrate can be calculated based on the molar ratio.

  Further, the abundance ratio B of the hydrophilic polymer, which is the ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone resin on the separation function surface, is 35% by mass or more and 50% by mass or less. Also good. The separation functional surface is a region corresponding to the film thickness of the blood contact surface detected by ATR-IR. For example, when the separation membrane is a hollow fiber, the separation functional surface is the outermost layer portion inside the hollow fiber membrane. That is, the surface where blood contacts the hollow fiber membrane. If the abundance ratio B of the hydrophilic polymer is 35% by mass or more, sufficient blood compatibility can be obtained. Moreover, the air remaining amount after priming can be reduced more as it is 50 mass% or less. The abundance B of the hydrophilic polymer is preferably 39% by mass or more and 50% by mass or less, and more preferably 40% by mass or more and 50% by mass or less.

  As a measuring method of the abundance ratio B of the hydrophilic polymer, for example, a method using a measurement result by an X-ray photoelectron spectrum (XPS) is used. That is, the separation function surface is measured by XPS, and the ratio of the number of each atom on the surface is obtained from the peak intensity of atoms peculiar to the polysulfone resin and the hydrophilic polymer, and the mass ratio of both compounds obtained based on the ratio. From the above, the abundance ratio can be calculated.

  When the separation membrane substrate contains polyvinylpyrrolidone, in order to make the existing ratio of intermediate water 20% or more, for example, a polymer having a function of suppressing the radiation degradation of polyvinylpyrrolidone during radiation sterilization is used. Can be coated. In the separation functional surface having the above-mentioned polymer that coats the separation membrane, the polymer is coated with polyvinyl pyrrolidone present on the separation functional surface, so that direct contact between polyvinyl pyrrolidone and oxygen is avoided. It is presumed that the attack on polyvinylpyrrolidone from oxygen radicals during sterilization is prevented. As a result, excessive degradation and crosslinking reactions of polyvinyl pyrrolidone present on the surface of the separation function are suppressed, the effect of imparting biocompatibility is unlikely to occur, protein adsorption to the separation membrane can be suppressed, and blood compatibility can be suppressed. A high separation membrane can be obtained. It is also effective to reduce the oxygen concentration during radiation sterilization in order to prevent the attack of oxygen radicals so that the intermediate water content is 20% or more. By setting the oxygen concentration at the time of radiation sterilization to 3% or less, the existence ratio of intermediate water becomes 20% or more, and a separation membrane with high blood compatibility can be obtained. Electron beam sterilization can be performed instead of radiation sterilization.

  In the present embodiment, the separation membrane used for radiation sterilization is, for example, a method of drying using superheated steam when a separation membrane in a wet state (that is, a never dry separation membrane) is dried for the first time after spinning, or polyvinylpyrrolidone. By the method of coating the separation function surface with a polymer having an action of suppressing radiation degradation of the intermediate water, the abundance ratio of intermediate water can be increased to 20% or more. The reason why the existence ratio of intermediate water can be increased to 20% or more by these methods is not clarified, but the following reason is presumed. By drying and fixing the structure as if water is present in the surroundings, such as water and hydroxyl groups of the polymer, the orientation and three-dimensional structure of polyvinylpyrrolidone are maintained in a state close to the water environment. It is considered that the intermediate water can be easily retained, and that the side chain decomposition due to radical transfer after radical generation is suppressed. As a result, the excessive decomposition reaction of polyvinyl pyrrolidone present on the surface of the separation function is suppressed, and the effect of imparting biocompatibility is not reduced, and protein adsorption to the separation membrane and activation by the membrane surface can be suppressed. It is considered that a separation membrane with high blood compatibility can be obtained.

  In this embodiment, the method of drying with superheated steam is to wind up the separation membrane in a wet state, wrap it in a bundle form in a film such as PE, and then put it in a drying chamber and introduce superheated steam to dry it. . At this time, it may be normal pressure or reduced pressure, but from the viewpoint of shortening the drying time and suppressing thermal decomposition, the temperature of the superheated steam is equal to or higher than the reverse temperature (the point at which the evaporation rate becomes equal regardless of humidity). 180 ° C. or less is preferable, and the drying time is preferably 30 seconds or less.

<Polymer with action to suppress degradation of polyvinylpyrrolidone by irradiation>
In the present embodiment, as a polymer having an action of suppressing deterioration of polyvinyl pyrrolidone due to irradiation (hereinafter sometimes simply referred to as “polymer”), the surface of polyvinyl pyrrolidone is subjected to radiation sterilization. The polymer is not particularly limited as long as it is a polymer that can be coated to suppress the decomposition and crosslinking of polyvinylpyrrolidone by radiation. In order to coat and protect polyvinylpyrrolidone on the separation function surface, The polymer is soluble in the hollow inner liquid or the coating liquid, and the cause is unknown, but the polymer is required to have a hydroxyl group.

  Examples of the polymer include polyhydroxyalkyl methacrylates such as polyhydroxyethyl methacrylate, polyhydroxypropyl methacrylate, and polyhydroxybutyl methacrylate. Polyhydroxyalkyl methacrylate is a synthetic polymer obtained by (co) polymerizing hydroxyalkyl methacrylate as a monomer unit, and is a compound having a hydroxyl group in a side chain. As a polymer, you may use by 1 type and may use 2 or more types of mixtures.

  In consideration of elution into the priming solution, the polymer is preferably insoluble or hardly soluble in water, and polyhydroxyalkyl methacrylate is preferably used.

  From the viewpoint of the coating forming ability, the weight average molecular weight of the polymer is preferably 10,000 or more, more preferably 100,000 or more, and further preferably 300,000 or more. The solubility of such a polymer in 100 g of water at 20 ° C. is preferably less than 1 g, more preferably 0.8 g or less, and even more preferably 0.5 g or less.

  In the present embodiment, the weight average molecular weight of the polymer can be measured by, for example, gel permeation chromatography (GPC).

  In the present embodiment, as a method for imparting the polymer to the separation membrane, the polymer is mixed and dissolved in a spinning stock solution at the time of membrane formation, and the polymer is turned into a hollow inner solution at the time of membrane formation. A method of spinning by mixing and dissolving, a method of coating a separation membrane with a coating solution in which a polymer is dissolved, and the like are preferably used.

  Among these methods, from the viewpoint of the mechanical properties of the separation membrane, the method of mixing and dissolving in the hollow inner liquid at the time of membrane formation and spinning or coating is simple, and the amount of polymer used is small. it can.

  For example, as a method of spinning by mixing and dissolving a polymer in a hollow inner liquid during separation membrane formation, a membrane-forming spinning stock solution containing a hollow inner liquid in which a polymer is dissolved, a polysulfone resin, polyvinylpyrrolidone and a solvent are used. Are simultaneously discharged from the tube-in-orifice type spinneret, the polymer can be coated with polyvinylpyrrolidone present on the separation function surface.

  As a method of coating the separation membrane on the separation membrane, preferably, the separation membrane is formed into a membrane, incorporated into a blood treatment device and molded, and then the polymer is dissolved on the separation functional surface. A coating method can be adopted by passing the coating solution through and bringing it into contact.

  The above embodiments relating to the polymer are the same when a hydrophilic polymer other than polyvinylpyrrolidone is used.

<Moisture content>
In the present embodiment, a blood treatment separation membrane having excellent blood compatibility even after radiation sterilization in a dry state and a blood treatment device incorporating the membrane are provided. Specifically, the moisture content of the separation membrane according to this embodiment is 10% or less by mass based on the total mass of the separation membrane containing water. The moisture content of the dry separation membrane may be 10% by mass or less. When the moisture content of the separation membrane is 10% by mass or less, condensation during storage can be further suppressed, which is more preferable in terms of appearance. In addition, the mass does not increase, and it is easy to carry it together in a facility.

  In this embodiment, the moisture content can be reduced to 10% by mass or less by drying the separation membrane obtained by spinning using superheated steam. In addition, for a separation membrane coated with a polymer having an action of suppressing deterioration of polyvinyl pyrrolidone by irradiation, the moisture content is 10% by mass or less by drying by a usual method using hot air or the like. can do. In the present embodiment, the moisture content can be measured by the method described in the following examples.

<Blood processor>
The blood treatment device of the present embodiment is a blood treatment device incorporating the separation membrane of the present embodiment, such as hemodialysis, blood filtration, blood filtration dialysis, blood component fractionation, oxygenation, and plasma separation. Used for extracorporeal circulation blood purification therapy. The area of the separation membrane to be incorporated (area of the separation function surface) is not particularly limited, but may be, for example, 0.3 to 3.0 m ² .

  As a blood treatment device, it is preferably used in hemodialyzers, blood filter devices, blood filter dialyzers, etc., and these are continuous applications, continuous hemodialyzers, continuous blood filter devices, continuous blood filter dialyzer devices It is more preferable to use as. Depending on each application, detailed specifications such as separation membrane dimensions and fractionation are determined.

<Method for producing separation membrane for blood treatment>
The method for producing a separation membrane for blood treatment according to the present embodiment includes a step of forming the separation membrane described above, and a step of drying a never dry separation membrane to a moisture content of 10% or less using superheated steam. And sterilizing the separation membrane with radiation.

  Or the manufacturing method of the separation membrane for blood processing of this embodiment suppresses the radiation degradation of the process which forms the separation membrane mentioned above, the process which dries the moisture content of a separation membrane to 10 mass% or less, and polyvinylpyrrolidone And a step of radiation sterilizing a separation membrane having at least a separation functional surface having a polymer having the function of:

  As a shape of the separation membrane incorporated in the blood treatment device, it is preferable to have a hollow shape. The separation membrane may be a hollow fiber. Moreover, it is more preferable that the crimp is provided from the viewpoint of permeation performance.

<Inorganic salt particles>
The separation membrane according to this embodiment contains 100 μg or more and 0.1 g or less of inorganic salt particles having a particle size of 3 μm or less attached to the surface of the separation membrane substrate. The amount of inorganic salt particles having a particle size of 3 μm or less may be 100 μg or more and 0.1 g or less per 2.5 m ² of the separation functional surface area of the separation membrane substrate (or separation membrane). Substantially all of the inorganic salt particles adhering to the surface of the separation membrane substrate may have a particle size of 3 μm or less.

  By making the inorganic salt into fine particles with a particle size of 3 μm or less, the inorganic salt instantly dissolves in the priming solution at the time of priming before the start of treatment. The particle diameter of the inorganic salt particles is preferably 2 μm or less, and more preferably 1 μm or less. The particle diameter of the inorganic salt particles can be measured, for example, by the method described in the following examples.

The amount of inorganic salt particles adhering to the surface of the separation membrane substrate is preferably 100 μg or more from the viewpoint of suppressing the growth ability of bacteria. In addition, the amount of the inorganic salt in the separation membrane is preferably 0.1 g or less in order to be washed away with a small amount of priming solution. When inorganic salt does not dissolve instantly at the time of priming and treatment is started without being sufficiently washed away with the priming solution, not only is the effect of the high concentration of aqueous inorganic salt solution entering the patient's body, but at the initial stage of blood introduction, A lump of salt can obstruct blood flow in the hollow fiber, and can cause thrombus formation and residual blood. In addition, coloring of inorganic salt particles after radiation sterilization may cause a problem in appearance. By making the inorganic salt into fine particles, it is possible to minimize the amount of the inorganic salt adhering to the separation membrane, and it is possible to wash the salt on the membrane surface with a smaller amount of priming solution. Further, by making fine particles and localizing them on the inner surface, the appearance problem is improved particularly when the inorganic salt particles are colored.

  Further, among the 1/5 portions obtained by equally dividing the separation membrane into 5 portions between the blood inlet side end portion and the blood outlet side end portion, the inorganic contained in the central 1/5 portion. The amount of salt particles is the smallest. This makes it possible to exert a remarkable antibacterial action on the blood inlet side and outlet side where bacteria are likely to be mixed while minimizing the amount of inorganic salt adhering to the separation membrane.

  Although it does not specifically limit as inorganic salt in this embodiment, Inorganic salts, such as sodium chloride, calcium chloride, sodium carbonate, sodium acetate, magnesium chloride, potassium sulfate, ammonium chloride, sodium nitrate, can be used. Among these, sodium chloride is preferable from the viewpoint of safety to the human body.

  The method for generating the inorganic salt particles is not particularly limited, but a method of crushing and dispersing an inorganic salt aqueous solution with an atomizer (atomizer) with pressurized air, drying the generated mist, and forming an aerosol (Japanese Industrial Standard JIS B9928: 1998 Annex 3 Method 1) or a method of bubbling an aqueous solution of inorganic salt particles with pressurized air and drying fine droplets formed when the generated bubbles burst (Japanese Industrial Standards JIS) B9928: 1998 Annex 3 method 2) and the like.

  Aerosol containing inorganic salt particles is blown into the blood inlet side and outlet side of the blood purifier by piping, and the outer surface side of the separation membrane is decompressed, so that it is contained in the central 1/5 separation membrane. It is possible to make the amount of the inorganic salt particles to be the smallest as compared with the amount of the inorganic salt particles contained in the separation membrane of the other 1/5 portion.

  EXAMPLES 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. Evaluation Method The measurement method used in this example is as follows.
[Calculation of the ratio of intermediate water to water existing on the surface of the separation function when distilled water penetrates the dry separation membrane and the water content reaches saturation]
The intermediate water abundance ratio was calculated by (1) IR measurement, (2) determination of when the water content reached saturation, and (3) data analysis by chemometrics.

(1) IR measurement Time-resolved IR measurement was performed under the conditions described in Table 1. FIG. 1 is a schematic diagram showing a measurement method. The sampling procedure was as follows. Priming was performed by washing the inner surface (separation function surface) of the hollow fiber separation membrane with 100 mL / min distilled water per 1.5 m ² for 5 minutes. The blood processor after priming is disassembled and a hollow fiber separation membrane as a sample is sampled, lyophilized in advance, and left in a constant temperature and humidity chamber at a temperature of 23 ° C. and a humidity of 50% for 24 hours or more. Those that reached the rate (referred to as “dry state”) were subjected to measurement.
1) KIRIYAMA filter paper (No. 5C, 1 μm retained particles) having a diameter of 40 mmφ was cut into a 1/8 fan shape.
2) The sample (hollow fiber separation membrane 1) was opened with a razor, and the inner surface (separation function surface S) of the membrane was faced up and placed on the filter paper 2 as shown in FIG.
3) While bringing the ATR crystal 5 into contact with the separation function surface S, 13 to 15 μL of distilled water 4 was dropped onto the arc-side end of the fan-shaped filter paper 2 using the microsyringe 3. Time-resolved IR measurement was performed until the time when the dropped water permeated the hollow fiber separation membrane and the peak of the hydroxyl group was saturated.

In the measurement, in order to confirm the contact state between the ATR crystal and the sample, it was confirmed that the intensity of the peak derived from the polysulfone-based resin-derived benzene ring (near 1485 cm ⁻¹ ) was 0.1 or more. The point at which the peak of the hydroxyl group is saturated is the point at which an increase in the peak intensity derived from the hydroxyl group (3,000 to 3700 cm ⁻¹ ) is no longer observed with respect to the peak intensity of the benzene ring (near 1485 cm ⁻¹ ) of the polysulfone resin. .

(2) Determination of the point in time when the water content reaches saturation The obtained spectrum data was normalized based on the strength of the benzene ring (near 1485 cm ⁻¹ ) derived from the polysulfone resin. Set baseline 2700 cm ^-1 and 3800 cm ^-1, was calculated peak area of the hydroxyl group.
Regarding the intensity data at the measurement points every 0.2 seconds obtained from the peak area of the hydroxyl group, the average value of the intensity data of 9 points including 4 points before and after is calculated, and the previous average value data 10 including the average value is calculated. The point at which the average slope (increase rate) of the points became 0 or less was determined as the time when the water content reached saturation.
Note that if an area increase of 5% or more is recognized between 30 points (6 s) after the point where the slope becomes 0, it is determined that saturation has not been reached, and further data satisfy the above conditions. The point was determined as the time when the water content reached saturation.

(3) Data analysis by chemometrics The basics of the analysis method used the following software and computer using one of the chemometrics methods called altering least square (ALS) method.
Software used for calculation: Mathworks (Natick, MA) MATLAB. R2008a
Computer: Fujitsu FMV LIFEBOOK

A specific procedure will be described below.
Storing intensity for each wave number (becomes total 351 points per 3.858cm ^-1) to the line from the spectrum measured every 0.2 seconds until 1550～1800Cm ^-1 and 2700~3800cm ^-1, 0.2 sec The experimental spectrum matrix A was created by arranging the measured spectra for each column in a column. An example of the experimental spectrum matrix A is shown in FIG.

Next, the spectrum matrix A is divided into three types of antifreeze water (in the present embodiment, the hydrogen bond region is detected spectroscopically, so described as “bound water” below), intermediate water, and free water. Decomposition was performed into four components (pure spectrum matrix K) composed of chemical components and difference spectra, and a concentration matrix C corresponding to each (Equation (1)). At that time, the matrix was limited so that the decomposition could be achieved uniquely. In the ALS method, spectral decomposition was performed by subjecting a non-negative condition that a pure spectrum and a concentration matrix had absolutely no negative elements. This is based on the basis that the absorption spectrum and concentration cannot be negative. When a negative value appears in the process of the compromise solution calculation, it is forcibly replaced with zero and the regression calculation is repeated, and the spectral solution, C and K are converged by converging so that all matrix elements satisfy the non-negative condition. Asked.
A = CK Formula (1)

The first measurement spectrum A _1, the second measurement spectrum A _2, the spectrum of the time t from ... measurement start represents a A _t, bound water, intermediate water, K ₁ free water and the difference spectrum, K ₂ , K ₃ , K ₄ are set (it is unknown which component is K ₁ , K ₂ , K ₃ , K ₄ at this point), and the concentration ratio of the four components at the time t from the start of measurement is If C _1t , C _2t , C _3t , and C _4t are set, equation (1) can be expressed as equation (2) below.

Spectra K ₁ , K ₂ , K ₃ , and K ₄ were obtained by generating random numbers in the matrix C of Equation (2) and substituting the negative values with 0 for the non-negative condition that the concentration should not be negative. . Next, since there is a non-negative condition that the spectrum does not become negative, a component having a negative value in the spectrum K is replaced with 0, and C is obtained. Furthermore, K was determined from this C under non-negative conditions. This operation was repeated until all the components of K and C became 0 or more, and a solution was obtained.

From the obtained K and C, the difference spectrum is the one where the concentration is almost zero, and among the other three spectra, it has a large peak at 1550 to 1800 cm ⁻¹ , and 3100 to 3500 cm ⁻ binding those have little peak at ¹ water, 3400 cm ^-1 intermediate water one having a peak near, were assigned free water broad peak with a peak at 3200,3400cm ^-1.

Subtract the difference spectrum from C _1t , C _2t , C _3t , and C _4t for 6 seconds (30 measurement points) from the saturation arrival point, and calculate the concentration ratio again, and each of the bound water, intermediate water, and free water The average value of the concentration was calculated, and the abundance ratio of the intermediate water was determined based on the bound water, intermediate water and free water. In the data analysis, the molar extinction coefficient of νOH was assumed to be equal.

[Measurement of amount of inorganic salt particles in separation membrane]
The blood treatment device was disassembled without pretreatment such as priming, and the taken out hollow fiber separation membrane for blood treatment was equally divided into five in the length direction from the blood inlet side end to the outlet side end. About 1 g of a hollow fiber separation membrane (sample) sampled from each fragment after division was accurately weighed. Distilled water (046-16971 for high-performance liquid chromatograph; Wako Pure Chemical Industries, Ltd.) was added to this 50 times the mass of the separation membrane, and the mixture was extracted by shaking at 37 ° C. for 24 hours. The sodium ions were quantified by ion chromatography. What performed the same operation without a sample was made into the blank.

  The value obtained by subtracting the sodium concentration of the blank from the sodium concentration of the extract is multiplied by the volume of distilled water, divided by the sampled hollow fiber separation membrane mass to obtain the amount of sodium per 1 g of hollow fiber, and further the chloride per 1 g of hollow fiber. The amount of sodium was calculated. The amount of sodium chloride per gram of hollow fiber in each sample divided equally into 5 was calculated. Moreover, the amount of sodium chloride of the whole hollow fiber separation membrane was computed by multiplying each 1/5 mass of the whole hollow fiber separation membrane, and totaling.

[Measurement of particle size of inorganic salt particles]
In order to measure the particle size of the inorganic salt particles on the surface of the separation membrane, a sample in which the hollow fiber separation membrane was opened was prepared, and the surface was analyzed with a time-of-flight secondary ion mass spectrometer (TOF-SIMS). Since sodium chloride was used as the inorganic salt, secondary ion images were imaged under the conditions of Table 3 for the strength of sodium (m / z = 23). Whether or not the particle diameter is 3 μm or less can be determined by measuring the particle diameter of the bright spot from the obtained image.

[Measurement of moisture content]
About 1 g was sampled from the hollow fiber separation membrane (sample) taken out by disassembling the blood processing device without pretreatment such as priming, and accurately weighed. Thereafter, after vacuum drying at 60 ° C. × 12 hr, the sample was weighed, and the moisture content was calculated by regarding the mass reduced by drying as the amount of moisture contained in the separation membrane.

[Measurement of Lactate Dehydrogenase (LDH) Activity]
The blood compatibility of the separation membrane was evaluated by the adhesion of platelets to the membrane surface. Platelet adhesion was quantified using the activity of lactate dehydrogenase contained in platelets attached to the membrane as an index.

Priming was performed by washing the blood treatment device with physiological saline (Otsuka raw food injection, Otsuka Pharmaceutical Co., Ltd.). The separation membrane collected by disassembling the blood processor after priming was processed with silicon so that the effective length was 15 cm, and the area of the inner surface of the membrane was 5 × 10 ⁻³ m ² , thereby producing a mini module. The mini-module was washed by flowing 10 mL of physiological saline inside the hollow fiber. Thereafter, 15 mL of heparin-added blood (heparin 1000 IU / L) was circulated at 37 ° C. for 4 hours through the mini-module prepared above at a flow rate of 1.3 mL / min. The inside of the mini module was washed with 10 mL and the outside with 10 mL with physiological saline. Half of the entire hollow fiber membrane having a length of 7 cm was collected from the washed mini-module, and then cut into a Spitz tube for LDH measurement as a measurement sample.

Next, 0.5 vol% Triton X-100 / PBS solution obtained by dissolving Triton X-100 (Nacalai Tesque) in phosphate buffer solution (PBS) (Wako Pure Chemical Industries, Ltd.) was used for LDH measurement. After adding 0.5 mL to the Spitz tube, sonication was performed for 60 minutes to destroy cells (mainly platelets) adhering to the separation membrane, and LDH in the cells was extracted. 0.05 mL of this extract was collected, and further reacted with 2.7 mL of 0.6 mM sodium pyruvate solution and 0.3 mL of 1.277 mg / mL nicotinamide adenine dinucleotide (NADH) solution. 0.5 mL was fractionated and the absorbance at 340 nm was measured. The remaining solution was further reacted at 37 ° C. for 1 hour, and then the absorbance at 340 nm was measured, and the decrease in absorbance immediately after the reaction was measured. Similarly, the absorbance of a separation membrane (blank) not reacted with blood was also measured, and the difference in absorbance (Δ340 nm) was calculated according to the following formula. In this method, the larger the decrease, the higher the LDH activity, that is, the greater the amount of platelets attached to the membrane surface. In addition, the measurement was performed 3 times and described as an average value.
Δ340 nm = (absorbance immediately after sample reaction−absorbance after 60 minutes of sample) − (absorbance immediately after reaction of blank−absorbance after 60 minutes of blank)
As the separation membrane having excellent blood compatibility, those having an LDH activity of 40 or less are preferable.

[Measurement of bacterial growth ability (ability to inhibit bacterial growth)]
Pseudomonas arginosa was injected into the blood treatment device after radiation sterilization from the blood inlet side. The concentration of the bacteria was 1 × 10 ⁷ cells / mL, and 88 mL of the bacterial solution was injected. Then, after culturing at 37 ° C. for 18 hours in a plugged state, a physiological saline containing a surfactant was injected, and 500 mL of a discharge liquid was collected. The collected discharged liquid was subjected to suction filtration with a membrane filter, and the number of viable bacteria of the bacteria collected on the filter was measured by the same method as in JIS L1902.

[Priming property (suppressing salt concentration)]
From the blood inlet side of the module, 500 mL of physiological saline was passed at 100 mL / min, the initial 110 mL of the liquid discharged from the blood outlet side was sampled, and the salinity concentration was measured. Salinity was measured using an Atago ES-421 digital salinity meter. Since the initial salt concentration of physiological saline was 0.90%, it was assumed that the residual sodium chloride was not sufficiently washed when the sampling solution was increased to 0.95% or more.

2. Preparation and evaluation of separation membrane [Example 1]
The membrane spinning solution is 79 parts by mass of dimethylacetamide (manufactured by Kishida Chemical Co., Ltd., reagent grade), 17 parts by mass of polysulfone (manufactured by Solvay, P-1700) and 4 parts by mass of polyvinylpyrrolidone (manufactured by BASF, K-90). The part was dissolved. As the hollow inner liquid, a 60% by mass aqueous solution of dimethylacetamide was used.
From the tube-in-orifice type spinneret, the membrane-spun stock solution and the hollow inner solution were discharged. The temperature of the film-forming spinning solution at the time of discharge was 40 ° C. The discharged film-forming spinning solution was immersed in a 60 ° C. coagulation bath made of water through a dropping part covered with a hood and coagulated. The spinning speed was 30 m / min. After solidification, it is washed with water, bundled so that the effective membrane area when assembled in a module is 1.5 m ² , packed in PE film, put into a drying room, introduced 180 ° C superheated steam, dried To obtain a hollow separation membrane. The washing temperature was 90 ° C. and the washing time was 180 seconds. In addition, the discharge amounts of the film-forming spinning solution and the hollow inner solution were adjusted so that the film thickness after drying was 35 μm and the inner diameter was 185 μm.
After assembling a module having an effective membrane area of 2.5 m ² from the obtained separation membrane, fine particles of sodium chloride were introduced into the surface of the separation membrane. The method for generating inorganic salt fine particles is a method of bubbling with pressurized air using a 5% by weight aqueous sodium chloride solution and drying fine droplets formed when the generated bubbles burst to form an aerosol (Japan). The industry standard JIS B9928: 1998 Annex 3 method 2) was used. The aerosol was introduced into the blood inlet side and outlet side at 100 L / min for 4 seconds each, and at the same time, the inlet and outlet ports of the dialysate were depressurized with a vacuum pump via piping.
Thereafter, gamma ray sterilization was performed at 25 kGy in an atmosphere with an oxygen concentration of 0.5% to obtain a blood treatment device.
The sodium chloride particle size in the separation membrane was 3 μg or less, and the amount of adhesion was 103 μg in total for each 1/5 portion. Further, when the length from the blood inlet side end portion to the outlet side end portion of the blood treatment separation membrane is divided into five, the amount of inorganic salt contained in the separation membrane of the central 1/5 portion is 2.2% by mass, which is the smallest compared to the other 1/5 portion of the separation membrane.
The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 3.7 × 10 ⁷ . The presence ratio of the intermediate water was 48%, the water content was 0.8% by mass, and the LDH activity was 6.5 [Δabs / hr / m ² ].

[Example 2]
The hollow inner solution is 0.03% by mass of 60% by mass aqueous solution of dimethylacetamide and polyhydroxyethyl methacrylate (pHEMA, Scientific Polymer Products, Inc., weight average molecular weight 350,000, solubility less than 0.1 g). A hollow fiber separation membrane was obtained in the same manner as in Example 1 except that the membrane was dissolved in After assembling a module having an effective membrane area of 2.5 m ² from the obtained separation membrane, fine particles of sodium chloride were introduced into the surface of the separation membrane. The same method as in Example 1 was used as the method for generating the inorganic salt fine particles. The aerosol was introduced at 100 L / min to the blood inlet side and the outlet side for 100 seconds, respectively, and at the same time, the inlet and outlet ports of the dialysate were decompressed with a vacuum pump via piping. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
The sodium chloride particle size in the separation membrane was 3 μm or less, and the adhesion amount was 2700 μg in total for each 1/5 portion. Further, when the length from the blood inlet side end portion to the outlet side end portion of the blood treatment separation membrane is divided into five, the amount of inorganic salt contained in the separation membrane of the central 1/5 portion is It was 2.4% by mass, which was the smallest compared with the other 1/5 portion of the separation membrane.
The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 3.5 × 10 ⁷ . The intermediate water content was 60%, the water content was 1% by mass, and the LDH activity was 5.5 [Δabs / hr / m ² ], which was a good result.

[Comparative Example 1]
In the same manner as in Example 2, a hollow fiber separation membrane was obtained. After assembling a module having an effective membrane area of 2.5 m ² from the obtained separation membrane, 0.45 mass% sodium chloride aqueous solution was passed from the blood inlet side to the outlet side, and the sodium chloride aqueous solution was infiltrated into the module. After that, compressed air was aerated and dried until there was no weight change. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
The sodium chloride particle diameter in the separation membrane was 3 μm or more, and the adhesion amount was 0.3 g (1.6% by mass with respect to the mass of the hollow fiber separation membrane). In addition, since the sodium chloride aqueous solution exuded on the outer surface of the hollow fiber is dried and crystallized, the particles have a size of about several mm that can be visually confirmed, and coloring due to gamma ray sterilization is seen, which is not preferable in appearance. Met.
The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 2.0 × 10 ⁷ . The water content was 1% by mass. As for the abundance ratio of the intermediate water, a slight peak change was observed with the constrained water, but accurate quantification was impossible due to the influence of excessive sodium chloride adhesion. In addition, an increase in salt concentration is observed in the sampling solution after passing the surface of the hollow fiber separation membrane through 500 mL of physiological saline at 100 mL / min. Saline was required. The LDH activity was 17.1 [Δabs / hr / m ² ].

[Comparative Example 2]
In the same manner as in Example 2, a hollow fiber separation membrane was obtained. After assembling a module having an effective membrane area of 2.5 m ² from the obtained separation membrane, 6.0 mass% sodium chloride aqueous solution was passed from the blood inlet side to the outlet side, and the sodium chloride aqueous solution was infiltrated into the module. After that, compressed air was aerated and dried until there was no weight change. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
The sodium chloride particle size in the separation membrane was 3 μm or more, and the adhesion amount was 7.2 g (35.8 mass% with respect to the weight of the hollow fiber separation membrane). In addition, since the sodium chloride aqueous solution exuded on the outer surface of the hollow fiber is dried and crystallized, the particles have a size of about several mm that can be visually confirmed, and coloring due to gamma ray sterilization is seen, which is not preferable in appearance. Met.
The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 2.0 × 10 ⁷ . The water content was 1% by mass. As for the abundance ratio of the intermediate water, a slight peak change was observed with the constrained water, but accurate quantification was impossible due to the influence of excessive sodium chloride adhesion. In addition, an increase in salt concentration is observed in the sampling solution after passing the surface of the hollow fiber separation membrane through 500 mL of physiological saline at 100 mL / min. Saline was required. The LDH activity was 62.7 [Δabs / hr / m ² ].

[Comparative Example 3]
In the same manner as in Example 2, a hollow fiber separation membrane was obtained. After assembling a module having an effective membrane area of 2.5 m ² from the obtained separation membrane, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
The number of viable bacteria in the measurement of the growth ability of the bacteria was 7.0 × 10 ⁷ , and the growth of the bacteria was not suppressed. The presence ratio of the intermediate water was 60%, the water content was 1.0% by mass, and the LDH activity was 5.5 [Δabs / hr / m ² ].

[Comparative Example 4]
A hollow fiber separation membrane was obtained in the same manner as in Example 1 except that the drying step using superheated steam was not performed. After assembling a module having an effective membrane area of 2.5 m ² from the obtained separation membrane, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
The number of viable bacteria in the measurement of the growth ability of the bacteria was 5.5 × 10 ⁷ , and the growth of the bacteria was not suppressed. The presence ratio of the intermediate water was 12%, the water content was 0.7% by mass, and the LDH activity was 395 [Δabs / hr / m ² ].

[Comparative Example 5]
A hollow fiber separation membrane was obtained in the same manner as in Example 1 except that the drying step using superheated steam was not performed. After assembling a module having an effective membrane area of 2.5 m ² from the obtained separation membrane, fine particles of sodium chloride were introduced into the surface of the separation membrane. The same method as in Example 1 was used as the method for generating the inorganic salt fine particles. The aerosol was introduced into the blood inlet side and outlet side at 100 L / min for 4 seconds each, and at the same time, the inlet and outlet ports of the dialysate were depressurized with a vacuum pump via piping. Thereafter, gamma ray sterilization was performed at 25 kGy in an air atmosphere to obtain a blood treatment device.
The sodium chloride particle size in the separation membrane was 3 μm or less, and the adhesion amount was 103 μg. Further, when the length from the blood inlet side end portion to the outlet side end portion of the blood treatment separation membrane is divided into five, the amount of inorganic salt contained in the separation membrane of the central 1/5 portion is 2.2% by mass, which is the smallest compared to the other 1/5 portion of the separation membrane.
The number of viable bacteria in the measurement of the growth ability of the bacteria was suppressed to 3.0 × 10 ⁷ . The presence ratio of the intermediate water was 12%, the water content was 0.7% by mass, and the LDH activity was 390 [Δabs / hr / m ² ].

  From the above experimental results, according to the present invention, it was confirmed that even if the amount of physiological saline used at the time of priming is small, it is possible to obtain a blood treatment device that has excellent blood compatibility and suppresses bacterial growth. .

  The separation membrane for blood treatment according to the present invention and the blood treatment device incorporating the membrane are excellent in blood compatibility even if the amount of physiological saline used during priming is small, and suppresses the growth of bacteria. It can be suitably used in extracorporeal circulation therapies such as filtration, hemofiltration dialysis, blood component fractionation, oxygenation, and plasma separation.

  DESCRIPTION OF SYMBOLS 1 ... Separation membrane, 2 ... Filter paper, 3 ... Micro syringe, 4 ... Water, 5 ... ATR crystal | crystallization, S ... Separation functional surface.

Claims (8)

A separation membrane for blood treatment having a blood inlet side end, a blood outlet side end, and a separation function surface that contacts blood to be treated,
Distilled water permeates the dry separation membrane, and when the water content reaches saturation, when the water present on the separation function surface is divided into antifreeze water, intermediate water and free water, the intermediate water The abundance ratio is 20% or more based on the total amount of the antifreeze water, the intermediate water and the free water,
The water content of the separation membrane is 10% by mass or less with respect to the total mass of the separation membrane,
The separation membrane includes a separation membrane substrate and inorganic salt particles having a particle size of 3 μm or less attached to the surface of the separation membrane substrate, and the amount of the inorganic salt particles is from 100 μg to 0.1 g, In addition, among the 1/5 portions obtained by equally dividing the separation membrane into 5 portions between the blood inlet side end portion and the blood outlet side end portion, it is included in the central 1/5 portion. A separation membrane for blood treatment in which the amount of the inorganic salt particles is the smallest.   The separation membrane for blood treatment according to claim 1, wherein the separation membrane substrate contains a hydrophobic polymer and a hydrophilic polymer.   The separation membrane for blood treatment according to claim 2, comprising a polysulfone resin as the hydrophobic polymer and polyvinylpyrrolidone as the hydrophilic polymer.   The separation membrane for blood treatment according to claim 1, wherein the separation membrane substrate contains an ethylene vinyl alcohol copolymer.   The separation membrane for blood treatment according to claim 3, wherein the separation function surface has a polymer having an action of suppressing radiation degradation of polyvinylpyrrolidone, and the polymer is polyhydroxyalkyl methacrylate. The separation membrane substrate contains a hydrophilic polymer and a polysulfone resin;
The hydrophilic polymer content A, which is the ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone-based resin in the entire separation membrane substrate, is 3% by mass or more and 10% by mass. % Or less,
The abundance ratio B of the hydrophilic polymer, which is a ratio of the mass of the hydrophilic polymer to the total mass of the hydrophilic polymer and the polysulfone-based resin on the separation function surface, is 35% by mass or more and 50% by mass or less. The separation membrane for blood processing according to claim 1, wherein   The separation membrane for blood treatment according to any one of claims 1 to 6, which is sterilized by radiation or electron beam in a state where the oxygen concentration during sterilization is 3% or less.   A blood treatment device comprising the separation membrane for blood treatment according to any one of claims 1 to 7.