JP5351394B2 - Polysulfone blood treatment membrane and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood treatment membrane which exhibits a high antioxidative property, has a small risk of invasion of endotoxin into a treatment liquid at the same time and further exhibits high practical strength and high rationality of production and to provide its manufacturing method. <P>SOLUTION: A porous membrane consists of a polysulfone-based resin, hydrophilic polymers and a liposoluble antioxidant. The membrane contains the liposoluble antioxidant at the rate of 22-76 mg per gram. The TOF-SIMS standardized peak intensity of the liposoluble antioxidant is 1.4&times;10<SP>-4</SP>or more on the intramembrane surface and is 1.8&times;10<SP>-4</SP>or more on the extramembrane surface. In the method for manufacturing the blood treatment membrane and the porous blood treatment membrane consisting of the polysulfone-based resin, the hydrophilic polymers and the liposoluble antioxidant, after obtaining a membrane intermediate containing the liposoluble antioxidant at the rate of 22-76 mg per gram, the membrane intermediate is heat-treated at 140-180&deg;C for 0.1-1 minute in the dry state. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a polysulfone blood treatment membrane and a method for producing the same. In particular, the present invention relates to a polysulfone blood treatment membrane that contains a fat-soluble antioxidant and is excellent in antioxidant properties and has a low risk of endotoxin intrusion into treated blood, and a method for producing the same.

  Conventionally, hollow fiber blood treatment devices using a permselective membrane have been widely used for the field of extracorporeal blood circulation, blood dialysis, oxygenation to blood during open heart surgery or plasma separation, etc. In the field of blood treatment membranes such as gas exchange membranes and blood component separation membranes, polysulfone blood treatment membranes are widely used, but not only as a separation membrane, but also due to oxidative stress manifested in long-term dialysis patients. Attempts have also been made to mitigate. One approach to this attempt is to eliminate peroxides that cause oxidative stress and to restore the antioxidant effect of the living body. For example, Patent Document 1 discloses an in vivo antioxidant action and a biological membrane stabilizing action. Further, a blood treatment membrane excellent in antioxidation property obtained by coating vitamin E having various physiological actions such as platelet aggregation inhibitory action on the surface of a previously formed membrane is disclosed.

  Another approach to relieve oxidative stress is to prevent the oxidative reaction induced during dialysis, but it is also useful to prevent endotoxin, which is highly toxic to the living body, from entering the dialysate. Conceivable. This is because, when endotoxin enters the blood or body, oxygen radicals are produced and released from phagocytic cells as part of the biological defense reaction.

  In order to solve this problem, it is effective to use a hydrophobic membrane that easily adsorbs endotoxin, but a simple hydrophobic membrane has poor blood compatibility and cannot be used. Therefore, for example, by adsorbing and retaining a hydrophilic polymer only on the inner surface of a hollow fiber membrane made of a polymer alloy of polysulfone and polyarylate, while adsorbing and removing endotoxin on the outer surface with high hydrophobicity, A hollow fiber membrane having thrombosis has been disclosed (Patent Document 2). However, in this hollow fiber membrane, since the polymer alloy is highly hydrophobic, it is effective in preventing the entry of endotoxin from the dialysate side. However, since the hydrophobicity of the porous portion and the outer surface is too high, air leakage is not possible. It was bad and affected the diffusion permeability through the membrane. Moreover, it was completely ineffective against oxidative stress causes other than endotoxin. Furthermore, since there is no hydrophilic polymer that plays the role of a pore-forming agent during wet film formation, it is difficult to control the pore diameter and it is difficult to control the permeability.

  In membranes composed of polysulfone and hydrophilic polymers, the hydrophilic polymer content of the entire membrane is reduced from the time of membrane formation, ensuring hydrophobicity on the outer surface of the membrane and increasing endotoxin adsorption, and blood compatibility. A technique for producing a hollow fiber membrane in which vitamin E having antithrombotic properties is imparted only to the inner surface of the membrane in order to impart the above (Patent Document 3). However, in this method, since a hydrophilic polymer is present on the outer membrane surface, there is a drawback that even if the permeability of endotoxin can be temporarily lowered, adsorption breakage easily occurs. Since there are few molecules, air escape was still insufficient. Further, according to the knowledge of the present inventors, when the film is formed so that the hydrophilic polymer concentration on the outer surface of the membrane is lowered, the concentration on the inner surface of the membrane is inevitably lowered, which is totally inferior in antithrombogenicity. It was enough. For this reason, as a more preferable embodiment, it is described that vitamin E is applied to the inner surface of the membrane to improve the platelet adsorptivity. However, the distribution of the applied vitamin E in the membrane and the endotoxin adsorptivity using the distribution are also described. There was no consideration for improving the quality.

  On the other hand, a blood treatment membrane that imparts vitamin E to the entire membrane including the inside of the membrane substrate by adding vitamin E to the membrane-forming stock solution and a method for producing the same are disclosed (Patent Document 4). In such a membrane, since vitamin E can be present in the entire membrane, a surface state different from a conventional blend membrane of polysulfone and a polymer composed of a hydrophilic polymer can be obtained, and if controlled well, endotoxin It can also be expected that the adsorptivity can be increased. However, according to the knowledge of the present inventors, when a large amount of vitamin E is contained in order to impart sufficient hydrophobicity to the outer surface of the membrane, the obtained blood treatment membrane has low mechanical strength and is practically used. On the contrary, if the vitamin E content is maintained so that the practical strength can be maintained, sufficient hydrophobicity cannot be imparted to the outer surface of the membrane. This seems to be because vitamin E segregates at the microdomain interface of the base polymer, thereby affecting the intermolecular interaction of the base polymer. Note that, as in Patent Document 1, the problem of strength reduction can be avoided with a film in which the entire surface of the film is coated with vitamin E. However, if post-treatment such as coating is applied to a film that has already been structured, fine coating by the coating is possible. This may cause a decrease in the pore diameter or a significant change in the surface condition due to surface deposition, and it was never easy to adopt.

Thus, when a blood treatment membrane using a polysulfone resin as a base polymer is modified with a fat-soluble antioxidant, the resulting membrane has excellent antioxidant properties and prevents endotoxin penetration from the outer surface of the membrane. In addition, it was very difficult to have practical strength. However, in the field of blood treatment membranes, there is an increasing demand for blood treatment membranes using polysulfone resins as membrane base polymers. Therefore, polysulfone blood treatments having the above-mentioned characteristics and high production rationality are provided. Membranes and methods for their production have been highly desired.
JP 7-178166 A JP-A-10-151196 JP 2000-254222 A JP-A-9-66225

  An object of the present invention is to provide a polysulfone-based blood treatment membrane having excellent antioxidant properties and practical strength in addition to preventing endotoxin invasion from the outer surface of the membrane, and a production rationality thereof, and a method for producing the same. And

  As described above, when the hydrophilic / hydrophobic distribution on the inner and outer surfaces of the hollow fiber membrane is made extreme, or when the hydrophilic polymer is reduced to halfway, there is a problem with endotoxin adsorption, and other problems can be avoided. There wasn't. In addition, it seems that any distribution structure is insufficient to achieve the purpose, such as coating and blending of fat-soluble antioxidants.

  In examining the ideal distribution structure of the fat-soluble antioxidant, the present inventors have a highly hydrophobic fat-soluble antioxidant on the surface of the polysulfone membrane, particularly on the outer surface side, so as to cover a high rate like an oil film, Above that, if the hydrated hydrophilic polymer chain can penetrate the hydrophobic layer and cover the entire membrane, the hydrophobicity of the surface can be increased without reducing the amount of the hydrophilic polymer. In other words, it was conceived that it would be possible to have the opposite properties of hydrophilicity and hydrophobicity on one membrane surface. Such a surface is not coated with a fat-soluble antioxidant on the already-structured polysulfone and hydrophilic polymer film, but from the inside of the polymer phase that is solidifying when the film is formed. We thought that it might be obtained by placing a fat-soluble antioxidant so that it would ooze out. If this is realized, it is considered that a hollow fiber membrane having a high clinical effect that simultaneously realizes two approaches for reducing oxidative stress can be obtained.

  Therefore, in order to make such a blood treatment membrane compatible with practical mechanical strength, the fat solubility is such that strength reduction does not occur when a blood treatment membrane is produced by adding a fat-soluble antioxidant to the membrane forming stock solution. Blood treatment membranes containing antioxidants, that is, membranes that are poor in antioxidant properties and endotoxin invasion from the outer surface of the membrane, are given a fat-soluble resistance by giving a specific heat history during the drying process. It has been found that a sufficient amount of a fat-soluble antioxidant can be expressed on the film surface by causing the oxidant to ooze out from the film substrate, that is, to migrate. And it discovered that the blood processing film | membrane obtained by this can solve said subject, and reached | attained this invention.

That is, the present invention is as follows.
(1) A hollow fiber type porous membrane comprising a polysulfone resin, a hydrophilic polymer, and a fat-soluble antioxidant, the membrane containing 22 to 76 mg of a fat-soluble antioxidant per gram, and a fat-soluble antioxidant The TOF-SIMS normalized peak intensity, which is an index indicating the film surface concentration of the agent, is 1.4 × 10 ⁻⁴ or more on the inner surface and 1.8 × 10 ⁻⁴ or more on the outer surface. Polysulfone blood treatment membrane.
(2) The polysulfone blood treatment membrane according to claim 1, wherein the fat-soluble antioxidant is a fat-soluble vitamin.
(3) A method for producing a porous blood treatment membrane comprising a polysulfone resin, a hydrophilic polymer, and a fat-soluble antioxidant, and a membrane intermediate containing 22 to 76 mg of a fat-soluble antioxidant per gram was obtained. Then, the membrane intermediate is heat-treated at 140 to 180 ° C. for 0.1 to 1 minute in a dry state.
(4) The method for producing a polysulfone-based blood treatment membrane according to claim 3, wherein a membrane intermediate is obtained from a membrane-forming stock solution containing a polysulfone-based resin, a hydrophilic polymer, a fat-soluble antioxidant and a solvent.
(5) The method for producing a polysulfone blood treatment membrane according to (3) or (4), wherein the membrane intermediate is wound into a bundle and then heat-treated.
(6) The method for producing a polysulfone-based blood treatment membrane according to (3) or (4), wherein the membrane intermediate is heated and then wound into a bundle.
(7) The method for producing a polysulfone blood treatment membrane according to any one of (3) to (6), wherein the fat-soluble antioxidant is a fat-soluble vitamin.

  According to the present invention, in a polysulfone blood treatment membrane containing a fat-soluble antioxidant, it has practical strength in addition to excellent antioxidant properties that have been difficult to achieve in the past and prevention of endotoxin penetration from the outer surface of the membrane. A polysulfone blood treatment membrane is obtained. In addition, since the polysulfone blood treatment membrane of the present invention is obtained from a membrane-forming stock solution containing a fat-soluble antioxidant, it does not require a post-treatment step such as a coating facility, and is excellent in production rationality.

The polysulfone-based resin (hereinafter referred to as PSf) in the present invention is a general term for polymer conjugates having a sulfone bond, and is not particularly defined, but examples include the following formulas (1) to (3).
(-Φ-SO ₂ -Φ-O-Φ-C (CH ₃ ) ₂ -Φ-O-) _n (1)
(-Φ-SO ₂ -Φ-O-) _n (2)
(-Φ-SO ₂ -Φ-O-Φ-Φ-O-) _n (3)
(-Φ-C (CH ₃ ) ₂ -Φ-O-CO-Φ-CO-O-) _n (4)
PSf having a repeating unit represented by is widely available on the market and is preferably used because it is easily available. Here, Φ represents an aromatic ring, and n represents the number of polymer repetitions. PSf having the former structure is commercially available from Solvay under the “Udel” trade name and from BSF Corporation under the “Ultrazone” trade name. Exists. In the present invention, a polymer alloy obtained by blending the formula (2) with the formula (4) is also included in the category of the polysulfone resin.

  As the hydrophilic polymer of the present invention, water-soluble cellulose derivatives such as polyvinyl pyrrolidone (hereinafter referred to as PVP), polyethylene glycol, polyglycol monoester, starch and derivatives thereof, carboxymethyl cellulose, and cellulose acetate can be used. Although these can be used in combination, PVP or polyethylene glycol is preferably used from the viewpoint of spinning stability and affinity with PSf, and PVP is most preferable. PVP is a water-soluble polymer compound obtained by vinyl polymerization of N-vinylpyrrolidone. It is a trade name of “Prasdon” from ISP, and “Collidon” from BSF. There are several molecular weights of each.

  The fat-soluble antioxidant in the present invention is not particularly limited as long as it has reducibility and is soluble in the solvent of the film-forming stock solution exemplified below, but it has abundant safety and application results for living bodies. To fat-soluble vitamins. Examples of such fat-soluble vitamins include vitamin A, vitamin D, vitamin E, vitamin K, and ubiquinone. Among these, vitamin E is preferred. Examples of vitamin E include α-tocopherol, α-tocopherol acetate, α-tocopherol nicotinate, β-tocopherol, γ-tocopherol, and δ-tocopherol. These may be used alone or in a mixture. For example, commercially available α-tocopherol is a mixture of the above vitamin E. Further, in the future, if a fat-soluble antioxidant that is highly safe for living organisms appears regardless of whether it is a natural product or an artificial product, it is also within the scope of the present invention to use it.

Hereinafter, the polysulfone blood treatment membrane of the present invention will be described including the production method.
The method for producing a hollow fiber membrane includes a step of discharging a membrane forming stock solution containing polysulfone resin (PSf), a hydrophilic polymer, a fat-soluble antioxidant and a solvent from a spinneret together with a hollow inner solution, and solidifying the discharged stock solution. At least a step of drying the solidified hollow fiber membrane. That is, a dry and wet film forming technique that is a conventionally known technique is applied.

  First, PSf, a hydrophilic polymer, and a fat-soluble antioxidant are dissolved in a common solvent to prepare a film-forming stock solution. In particular, when the hydrophilic polymer is PVP and the fat-soluble antioxidant is α-tocopherol, examples of common solvents include dimethylacetamide (hereinafter referred to as DMAc), dimethyl sulfoxide (DMSO), and N-methyl-2. -Solvents such as pyrrolidone, dimethylformamide, sulfolane, dioxane, etc., or a solvent composed of a mixture of two or more of the above. In order to control the pore size, additives such as water may be added to the film forming stock solution.

  The PSf concentration in the membrane-forming stock solution is not particularly limited as long as the membrane can be formed and the obtained membrane has a performance as a permeable membrane, and is 5 to 35% by weight, preferably 10 to 10%. 30% by weight. In order to achieve high water permeability, the polymer concentration should be low, preferably 10 to 25% by weight. The PVP concentration is adjusted so that the mixing ratio of PVP to PSf is 27 wt% or less, preferably 18 to 27 wt%, more preferably 20 to 27 wt%. When the mixing ratio of PVP with respect to PSf exceeds 27% by weight, the amount of elution tends to increase. Since symptoms are observed, it is not preferable. The hollow fiber membrane thus obtained has a PVP concentration of 20% or more and 50% or less on the inner surface of the membrane, a PVP concentration of 30% or more and 70% or less on the outer surface of the membrane, preferably a PVP concentration on the inner surface of the membrane. 30% or more and 45% or less, and PVP concentration on the outer membrane surface is 40% or more and 65% or less. Excellent antithrombogenicity and biocompatibility. . This membrane has a stable water removal capability and exhibits a great effect for stably performing treatment such as hemodialysis and blood filtration.

  By the way, although it is unclear why the stable water removal capability can be obtained by setting the PVP concentration on the membrane surface to 20% or more, the surface portion of polysulfone that is hydrophobic and easily adsorbs proteins and the like is hydrophilic. The existence rate necessary for covering PVP, which is a high molecular weight polymer, is 20% or more, and as a result, the membrane surface is sufficiently hydrophilic, so that the adsorptivity of proteins and the like to the membrane surface is weakened. Stable water removal capacity is expected to be obtained. Also, if the PVP concentration on the membrane surface is greater than 50%, the membrane surface is more hydrophilic and the performance is stable. On the other hand, PVP is eluted into the blood during hemodialysis. The PVP concentration is preferably 50% or less because there is a risk that it may come out and there may be a problem in safety.

  The PVP concentration on the membrane surface referred to in the present invention is the abundance ratio at the extreme surface layer where blood contacts the membrane, and as will be described in detail in Examples, X-ray photoelectron spectroscopy (hereinafter referred to as XPS). ) Can be calculated from the value measured.

  The concentration of the fat-soluble antioxidant in the film-forming stock solution needs to be adjusted as appropriate so that the content of the fat-soluble antioxidant in the obtained blood treatment membrane falls within a certain range. As will be described later, a content of 22 mg or more per gram of membrane is required to develop sufficient antioxidant properties and the ability to prevent endotoxin invasion from the outer surface. On the other hand, if it is present excessively, the mechanical strength of the membrane is drastically reduced. Therefore, it is necessary to be 76 mg or less.

  Next, using a tube-in-orifice type spinneret, a film-forming stock solution is simultaneously discharged from the orifice of the spinneret and a hollow inner solution for coagulating the film-forming stock solution from the tube into the air. As the hollow inner liquid, water or a coagulating liquid mainly composed of water can be used. In general, a mixed solution of a solvent and water used for the film-forming stock solution is preferably used. For example, a 0 to 60% by weight DMAc aqueous solution is used. The raw film-forming solution discharged from the spinneret together with the hollow inner liquid travels through the idle running part, and is introduced and immersed in a coagulation bath mainly composed of water installed at the lower part of the spinneret to complete coagulation.

  The membrane structure thus obtained has a dense skin layer on the inner surface of the hollow fiber, and has a porous structure between the skin layer and the outer surface. Having a porous structure is preferable in expanding the effective area for adsorption when adsorbing and removing endotoxin entering from the outer surface. Subsequently, the hollow fiber membrane intermediate is obtained through washing with water or the like. Further, the membrane intermediate is introduced into a dryer and dried to obtain a hollow fiber membrane. Here, the film intermediate may be cut in a wet state and dried after being bundled, or may be dried while continuously running. At this time, it is preferable to apply a crimp to the hollow fiber membrane because the diffusion performance can be efficiently expressed when used for hemodialysis.

  The higher the content of fat-soluble antioxidants in the blood treatment membrane, the higher the antioxidant properties as a membrane and the ability to prevent endotoxin invasion from the outer surface of the membrane, while the increase in content is accompanied by a gradual decrease in mechanical strength. When the content exceeds a certain level, the mechanical strength of the film is drastically reduced. The reason for this is not clear, but the decrease in mechanical strength is mainly caused by a decrease in elongation at break. The hypothesis derived from this is that a fat-soluble antioxidant (for example, vitamin E) segregates at the microdomain interface of the membrane base polymer and gradually decreases the interfacial adhesive strength. It is conceivable that almost all the interfaces are occupied by the fat-soluble antioxidants, and the interfacial adhesive force may be rapidly lost.

  In use, the blood treatment membrane is often stored in a container and used in the form of a module. However, if the mechanical strength is not sufficient, there is a risk that the membrane may be destroyed during module manufacture or handling. The mechanical strength can be expressed by toughness obtained from a tensile test. When the blood treatment membrane is a hollow fiber membrane, a toughness of 1000 gf ·% per hollow fiber membrane is sufficient for practical use. The toughness referred to in the present invention is a product of the breaking strength (gf) and the elongation (%), and the measuring method will be described in detail in the analysis method of the examples.

  As a result of intensive studies, the present inventors have found that in the case of a membrane using a polysulfone resin as a base polymer, the toughness exceeds 1000 gf ·% if the fat-soluble antioxidant content per gram of blood treatment membrane is 76 mg or less. I found out. For this reason, the fat-soluble antioxidant per gram of blood treatment membrane needs to be 76 mg or less.

  In the blood treatment membrane of the present invention, it is only the fat-soluble antioxidant present on the surface of the membrane that is in contact with the liquid to be treated, ie, the fat-soluble antioxidant, which is buried in the membrane substrate and exhibits the antioxidant properties. Fat-soluble antioxidants that do not come into contact with fluids are not involved in the direct antioxidant effect on blood components. Here, the “membrane surface” does not indicate only the inner surface of the hollow fiber that is in direct contact with blood, but also includes the outer surface and the surface of the porous portion of the film thickness portion. Among blood components, blood cells are in contact only with the inner surface, but liquid components such as proteins and peroxides such as active oxygen move back and forth through the film thickness part, so all films that reach the porous part and the outer surface The surface contributes to the antioxidant effect. For this reason, in the antioxidant capacity, the total amount of the fat-soluble antioxidant present on all film surfaces becomes a problem.

  The amount of the fat-soluble antioxidant present on the film surface can be determined by using the normalized peak intensity of the parent mass peak obtained by TOF-SIMS (time-of-flight secondary ion mass spectrometry) measurement as an index. The measurement method will be described in detail in Examples, but the measurement depth by this method is extremely shallow (several to several tens of angstroms), and it is considered that only the fat-soluble antioxidants exposed on the surface are detected. good. On the other hand, in this method, the inner surface and the outer surface can be measured independently, but it is difficult to measure the amount of the fat-soluble antioxidant in the porous portion. However, it is considered that at least the measured value of the porous portion in the vicinity of the inner surface can be regarded as almost equivalent to the measured value of the inner surface, and this is represented.

According to a contact experiment between human fresh blood and a blood treatment membrane conducted by the present inventors, the blood treatment membrane of the present invention shows superiority in antioxidant action over a normal blood treatment membrane. The measured value of the peak intensity needs to be 1.4 × 10 ⁻⁴ or more. The antioxidant performance test in the present invention will be described in detail in the analysis method of the examples.

Furthermore, in the blood treatment membrane of the present invention, in order to exhibit the ability to prevent endotoxin entry from the outer membrane surface during use, a certain amount or more of a fat-soluble antioxidant exists on the outer membrane surface and the porous portion. is necessary. The fat-soluble antioxidant on the outer surface of the membrane can also use the normalized peak intensity of TOF-SIMS measurement as an index. Prevention of endotoxin invasion from the outer membrane surface is borne by the outer membrane surface and the surface of the porous portion. Among these, it is difficult to measure the abundance of the fat-soluble antioxidant in the porous portion, but it is considered that the abundance near at least the outer surface can be regarded as almost equivalent to the measured value of the outer surface. In other words, the parameters required to demonstrate the ability to prevent endotoxin invasion from the outer membrane surface can be represented by the normalized peak intensity of the outer membrane surface described above. A value of 2.8 × 10 ⁻⁴ or more is necessary.

On the other hand, the presence of an excessive fat-soluble antioxidant on the membrane surface leads to excessive hydrophobicity of the membrane surface, which is undesirable from the viewpoint of removal of mixed air and blood compatibility. However, since the content of the fat-soluble antioxidant in the blood treatment membrane of the present invention is limited to 22 to 76 mg per gram of membrane, it is undesirably hydrophobized within the range of the heat treatment conditions described later. Does not occur. For example, when a film containing 76 mg of fat-soluble antioxidant per 1 g of film is heated in a dry state at 180 ° C. for 1 minute, the normalized peak intensity of the fat-soluble antioxidant on the outer surface of the obtained film is 1.0 × Although it is 10 ⁻² , if it is this level, the undesired hydrophobicity does not occur.

From the above points, in the blood treatment membrane of the present invention, the content of the fat-soluble antioxidant is 22 to 76 mg per 1 g of the membrane, and the normalized peak intensity of the fat-soluble antioxidant is 1.4 × 10 on the inner surface of the membrane. ⁻⁴ or more and 1.8 × 10 ⁻⁴ or more on the outer surface of the film.

  In the present invention, if the fat-soluble antioxidant and PVP are present in the above-described range on the entire blood treatment membrane and on the surface, the characteristics as a hydrophilic surface such as good air escape and blood compatibility, which should be contrary to each other, The hydrophobic surface property of endotoxin adsorption removal is compatible. The reason is not clear, but the hydrophobic layer of fat-soluble antioxidants covers the surface of the polysulfone membrane like an oil membrane, and the hydrated hydrophilic polymer chain covers the entire membrane above it, making it hydrophilic and hydrophobic. It is presumed that these contradictory properties are provided on one film surface. Note that the blood treatment membrane obtained by coating the completed membrane surface described in Patent Literatures 1, 3, and 4 with a fat-soluble antioxidant cannot have the distribution structure of the present invention. While PVP is hydrophilic, it is also soluble in organic solvents such as ethanol and other fat-soluble antioxidants. As a result, it is compatible with fat-soluble antioxidants in the coating solvent. This is because the portion is buried in the coating layer of the fat-soluble antioxidant.

  Such surface characteristics can be confirmed by the receding contact angle and the advancing contact angle of the outer surface measured by sealing the end of the blood treatment film using a dynamic contact angle measuring device. The measuring method will be described in Examples. The receding contact angle represents the contact angle in water (hydrophilic atmosphere), and the advancing contact angle represents the contact angle in air (hydrophobic atmosphere). If a hydrophilic polymer chain with high mobility such as polyethylene glycol is present on a hydrophobic surface such as polyurethane, the hydrophilic polymer chain is dominant in the hydrophilic atmosphere, and the hydrophobic surface is dominant in the hydrophobic atmosphere. It is known that “backward contact angle <forward contact angle” (A. Takahara, NJJo, T. Kajima, J. Biometer. Sci. Polymer Edn, Vol. 1, No. 1, pp 17-29 (1989)).

  An ordinary polysulfone-based blood treatment membrane composed only of PSf and PVP is also a combination of PSf which is a hydrophobic surface and PVP which is a hydrophilic polymer chain having high mobility, and according to experiments conducted by the present inventors. A state of “retreating contact angle <advancing contact angle” is observed. Here, when comparing the blood treatment membrane of the present invention with a normal polysulfone-based blood treatment membrane comprising only PSf and PVP, there is no difference in the receding contact angle between the two. This means that the outer surface of the blood treatment membrane of the present invention has the same properties as a normal PSf-PVP blood treatment membrane in a hydrophilic atmosphere. That is, the blood treatment membrane of the present invention exhibits surface hydrophilicity as in the case of a normal PSf-PVP blood treatment membrane, that is, a sufficient amount of PVP that can be exposed on the surface is provided on the outer surface of the membrane and in a hydrophilic atmosphere. It is presumed that the properties of the PVP chain become dominant on the surface. As a result, unlike the blood treatment membranes described in Patent Documents 2 and 3, it is considered that the air removal during priming is as good as the conventional PSf-PVP membrane.

  On the other hand, when comparing the advancing contact angles, the blood treatment membrane of the present invention is higher than the normal polysulfone blood treatment membrane consisting only of PSf and PVP. This means that the outer surface of the blood treatment membrane of the present invention is more hydrophobic in a hydrophobic atmosphere than a normal PSf-PVP blood treatment membrane. That is, in the blood treatment membrane of the present invention, the PVP equivalent to the normal PSf-PVP blood treatment membrane can be exposed to the outer surface of the membrane. It is estimated that it is easy to become. As a result, even in water, the hydrophobicity of macromolecules such as endotoxin tends to dominate by approaching the outer surface of the membrane, and the hydrophobicity becomes higher than the normal PSf surface. It is considered that the endotoxin adsorption ability is further enhanced. This is presumably because the hydrophobic fat-soluble antioxidant existing in the film-forming stock solution in advance, rather than the coating, exudes at a high rate especially on the outer surface of the film through the heat treatment described later.

  Based on the above knowledge of the dynamic contact angle, the membrane structure of the blood treatment membrane of the present invention and the mechanism of action and effect will be explained more conceptually as follows. That is, as described in Patent Documents 2 and 3, by reducing or eliminating the hydrophilic polymer on the outer surface of the membrane, when the hydrophobic surface is formed by the polymer itself, it becomes a hard surface, and endotoxin has several points. Connect as if touching and landing. In contrast, when a hydrophobic surface is formed by a low-molecular-weight, fat-soluble antioxidant, it can be thought of as a flexible oil film (oil layer), so endotoxin is inherently embedded in the cell membrane (lipid bilayer) of Gram-negative bacteria. The oil film (oil layer) is embedded in the same way as it was. As a result, the blood treatment membrane of the present invention is considered to have a high endotoxin retention ability because the endotoxin binding to the outer membrane surface is more stable and strong.

Next, processing conditions that are points in obtaining the above-described film structure will be described.
As a result of diligent research to ensure that the polysulfone blood treatment membrane has excellent antioxidant properties and practical strength, the present inventors have obtained a conventional polysulfone blood treatment membrane containing a fat-soluble antioxidant. However, by heat-treating in a specific dry state, it is possible to increase only the abundance of the film surface without changing the content of the fat-soluble antioxidant in the entire film, that is, while maintaining the practical strength. I found out. In addition, the fat-soluble antioxidant normalization peak of 1.4 × 10 ⁻⁴ or more of the inner surface of the membrane is expressed on the membrane surface by this method, and the fat-soluble antioxidant normalization peak 1 of the outer surface of the membrane is observed. In order to make it 8 × 10 ⁻⁴ or more, it is necessary to contain 22 mg or more of fat-soluble antioxidant per 1 g of blood treatment membrane.

  The dry state referred to in the present invention means that at least the film has a saturated water content or less, that is, the periphery of the film is not completely filled with water and water does not drip. The moisture content is not particularly limited, but is preferably in a state where the moisture content is 0 to 100%, more preferably 0 to 50%. If the moisture content is higher than this, even if heat is applied from the outside, the surface of the blood treatment membrane itself does not rise due to the latent heat of vaporization of the water, and until the moisture evaporates, the membrane surface of the target fat-soluble antioxidant Migration to is delayed.

  The heat treatment of the blood treatment membrane in a dry state in the present invention may be performed separately after the production of the blood treatment membrane is completed, or may be performed in a state assembled in a module. It is preferable from the viewpoint of production rationality to perform the heat treatment continuously after drying.

  Regarding the heat treatment conditions, the migration to the surface of the fat-soluble antioxidant does not proceed at a low treatment temperature, and the blood treatment film softens or the oxidation of the antioxidant proceeds at a high temperature. The range of ° C is preferred, and the range of 140 to 170 ° C is more preferred. Similarly, since the migration does not proceed in a short time and oxidation of the antioxidant proceeds in a long time, the range of 0.1 to 1 minute is preferable, and the range of 0.2 to 0.8 minute is preferable. More preferred.

  In addition, in the drying process of the film forming apparatus, when the heat treatment is continuously performed after the drying, it may not be possible to clearly distinguish between the drying for removing moisture and the heat treatment for migrating the fat-soluble antioxidant to the film surface. . The true meaning of the present invention is to heat-treat the blood treatment membrane, that is, increase the temperature of the membrane substrate. Therefore, when the heat treatment is continuously performed from the drying, it is only necessary to distinguish the drying step for removing moisture up to the reduced rate drying region and the heat treatment step for migrating the fat-soluble antioxidant to the surface after the constant rate drying region. .

  As described above, the blood treatment membrane of the present invention is a polysulfone-based blood treatment membrane containing a fat-soluble antioxidant, which has been difficult to achieve at the same time and prevents endotoxin penetration from the outer surface of the membrane. In addition, it is a polysulfone blood treatment membrane having practical strength. Not only that, as in the blood treatment membrane of the present invention, the presence of a fat-soluble antioxidant throughout the membrane means that the human body derived from the oxidative degradation of the polymer constituting the membrane during long-term storage of the blood treatment membrane. It is also effective in suppressing the elution of undesirable low molecular weight substances. This is because the polymer material used for the blood treatment membrane has been confirmed to be sufficiently safe, but there is still a risk that the defense mechanism of the living body operates against excessive elution, leading to an oxidative stress state. In this regard, as in Patent Documents 1 and 3, the coating type film in which the fat-soluble antioxidant is not contained in the interior other than the surface has low resistance to oxidative degradation, but this point is also improved.

  Examples of using vitamin E as a fat-soluble antioxidant are shown below, and the present invention will be specifically described. However, the present invention is not limited to these examples. First, the raw materials and reagents used and the measurement method will be described.

[Raw materials and reagents]
1. PSf: P-1700, manufactured by Solvay
2. PVP: manufactured by ISP, K-90
3. Vitamin E (dl-α-tocopherol): DSM Nutrition Japan, Pharmacopeia α-tocopherol acetate: Wako Pure Chemical Industries, reagent special grade Pluronic F-68: polyethylene glycol-polypropylene glycol copolymer, Asahi Denka Kogyo DMAc: Kishida chemistry, reagent special grade7. DMSO: Kishida chemistry, reagent special grade8. N, N-dimethylformamide (hereinafter abbreviated as DMF): Kishida Chemical, reagent grade 9.1-methyl-2-pyrrolidone (hereinafter abbreviated as NMP): Tokyo Kasei, reagent grade 10. Ferric chloride hexahydrate: Wako Pure Chemical Industries, reagent special grade11. Ethanol: Wako Pure Chemical, reagent grade 12.2, 2'-bipyridyl: Wako Pure Chemical, reagent grade 13. Water for injection (pure water): Otsuka Pharmaceutical 14. Antioxidant activity measurement kit: manufactured by Nikken Zeil Co., Ltd., antioxidant activity measurement kit PAO

[Vitamin E content of whole blood treatment membrane (hereinafter abbreviated as bulk VE amount)]
The dried blood treatment membrane was dissolved in NMP (about 3% by weight) to prepare a measurement solution. Liquid chromatography (column: inert sill C8-3 μm (4.6 φ × 250 mm) + ODP-50 6E (4.6 φ × 250 mm), eluent: NMP, flow rate: 0.5 ml / min, column temperature 40 ° C., UV detector The vitamin E concentration of the measurement solution was determined using a peak area corresponding to vitamin E measured at a wavelength of 295 nm and a calibration curve separately prepared with a standard solution with a known concentration. Vitamin E content per 1 g of membrane (mg) = bulk VE (mg / g) was determined from the obtained concentration and dilution ratio.

[Vitamin E normalized peak intensity on outer surface]
The blood treatment membrane was immersed in pure water for 12 hours and then freeze-dried. The outer surface of the dried hollow fiber or the inner surface of the hollow fiber exposed by opening a slit in the longitudinal direction was measured using a TOF-SIMS device (TRIFT III, manufactured by Physical Electronics). Measurement conditions are as follows: primary ion Ga +, acceleration voltage 15 kV, current 600 pA (as DC), analysis area 200 μm × 200 μm, integration time 5 min, detector detects negative ions (Mass, vitamin E 163) as detected ions Detected. Due to the characteristics of this measuring apparatus, the measurement depth corresponds to a depth of 5 nm from the surface. Using the ionic strength (IV) of the obtained vitamin E peak, the ionic strength IH of protons and the total ionic strength IT, the normalized peak strength of vitamin E was calculated by the following equation (5).
Normalized peak intensity = IV / (IT-IH) (5)

[Toughness of blood treatment membrane]
Using a tensile tester (EZ Test series) manufactured by Shimadzu Corporation in a room with a room temperature of 20 to 25 ° C. and a humidity of 55 to 60 RH%, one dry 20 cm hollow fiber membrane is fixed using a chuck, and 30 cm / min. The stress (gf) at the time of pulling and breaking at a speed of was measured.
Further, the elongation when the hollow fiber membrane broke was divided by 20 cm, which is the length of the hollow fiber membrane before measurement, and multiplied by 100 to obtain the elongation (%), and the following formula (6) Toughness was calculated.
Toughness (gf ·%) = breaking stress (gf) × elongation (%) (6)

[Antioxidant capacity]
After 2 g of the blood treatment membrane was cut into a length of 2 to 3 mm and primed with physiological saline, 2 ml of heparinized blood was added and incubated at 37 ° C. for 4 hours under shaking. Three human bloods were used separately for one membrane (n = 3 test). Plasma was then collected by centrifugation. Antioxidant ability (PAO) of the collected plasma was measured using an antioxidant ability measuring kit PAO (Nikken Zile Co., Ltd.). When the blood comes into contact with the membrane, a biological reaction is caused and PAO is reduced. However, in the membrane having antioxidant ability, this decrease in PAO is suppressed. Therefore, the higher the obtained PAO value, the more blood in the blood treatment membrane It can be said that the antioxidant capacity against

[Endotoxin penetration rate (hereinafter abbreviated as “ET permeability”)]
A urethane part filled with 9984 blood treatment membranes in an approximately 280 mm long cylindrical container having two upper and lower nozzles (dialysate side nozzles) on the side, embedded in both ends with urethane resin, and hardened urethane part Was cut into a hollow fiber membrane and processed into an open end. A header cap having a liquid introduction (lead-out) nozzle (blood side nozzle) was loaded at both ends, assembled into a dialysis module shape, and fixed so that the blood side nozzle faced up and down.

  As a severe model solution of contaminated dialysate, tap water prepared at an endotoxin concentration of 97100 EU / L is introduced from the lower D nozzle at a flow rate of 500 ml / min using a pump, and reverse filtration is performed from the dialysate side to the blood side. For 20 minutes from the upper B nozzle. The filtrate after discharging for 20 minutes was sampled to measure the endotoxin concentration, and the ET permeability was obtained as a percentage up to two digits after the decimal point as a ratio to the endotoxin concentration of the solution before filtration. The endotoxin concentration was measured by a colorimetric (time analysis) method using an endotoxin measuring machine (Wako Pure Chemical Industries, Ltd., Toxinometer ET-2000) and its exclusive LAL reagent.

[Evaluation of air release from blood treatment membrane]
A thread bundle consisting of 9984 blood treatment membranes is filled into a cylindrical container of about 280 mm length, both ends are embedded with urethane resin, the cured urethane portion is cut, and the hollow fiber membrane is processed into the open end did. A header cap having a nozzle for introducing (leading out) a liquid was loaded at both ends, assembled into a module shape, and fixed so that the nozzle faced up and down. Water for injection was introduced from the lower nozzle at a flow rate of 100 ml / min using a pump and discharged from the upper nozzle to replace the air in the module with water for injection. When the replacement was completed, 10 ml of air was injected from the lower nozzle using a syringe while flowing water for injection. Air from the upper nozzle was collected together with water for injection, and the air recovery rate was determined from the ratio of the collected amount to the injected amount after 10 minutes. This means that the lower the air recovery rate, the poorer the air release property, and the possibility of an adverse effect on the permeability due to the accumulation of air from the film thickness portion to the outer surface.

[Measurement of surface PVP concentration]
The surface PVP concentration of the hollow fiber membrane is determined by X-ray photoelectron spectroscopy (XPS). In other words, in the case of measuring the outer surface, several hollow fiber membrane samples arranged on a double-sided tape are used as samples, and in the case of measuring the inner surface, a hollow fiber that has been cut open in the vertical direction to expose the inner surface is placed on the double-sided tape. Using several samples as a sample, the surface element concentration was measured by a normal method. From the area intensities of the obtained C1s, O1s, N1s, and S2p spectra, the surface concentration of nitrogen (A) and the surface concentration of sulfur (B) are obtained using the relative sensitivity coefficient attached to the apparatus, and from the following equation (7) The inner surface PVP concentration was calculated.
Inner surface PVP concentration = {A × 111 / (A × 111 + B × C)} × 100 (%) (7)
Here, C is “formula amount / number of elements of sulfur” of the PSf repeating unit, and is 442 in the case of PSf of the formula (1). Further, 111 in the formula (7) is “formula amount ÷ number of nitrogen elements” of the repeating unit of PVP.

[Measurement of outer surface contact angle]
Using a dynamic contact angle measuring device DataPhysics DCAT11 manufactured by DataPhysics Instruments GmbH and the attached software, the advancing contact angle and the receding contact angle of the hollow fiber membrane sealed with a knife whose end was baked were measured. The measurement conditions are as follows.
Immersion liquid: Water for injection, Water temperature: 25 ° C., Immersion speed: 0.10 mm / sec, Immersion depth: 10.00 mm, Measurement repeat count: 6 times (except for the first data, the remaining data is averaged)

[Model test for long-term storage stability]
The blood treatment membrane was molded and assembled into a hemodialysis module by the following operation. That is, a bundle of 9984 yarns was filled into a cylindrical container of about 280 mm length, both ends were embedded with urethane resin, the cured urethane portion was cut, and the hollow fiber membrane was processed into the open end. . A header cap having a liquid introduction (lead-out) nozzle was loaded at both ends, assembled into a module shape, sealed with 300 ppm sodium pyrosulfite aqueous solution, and each nozzle was sealed and irradiated with 25 kGy of γ rays. The obtained module was heated in a 60 ° C. thermostatic chamber for 3 weeks to perform an accelerated test corresponding to long-term storage. The blood treatment membrane 1.5 g taken out by dismantling the module before and after the start of heating was extracted with 150 ml of pure water at 70 ° C. for 1 hour. The UV spectrum of the extract from 350 nm to 220 nm was measured, and the absorbance indicating the maximum absorption was used as a surrogate index for the amount of eluate from the blood treatment membrane.

[Example 1]
A film-forming stock solution comprising 17 parts by weight of PSf, 4 parts by weight of PVP, 0.5 parts by weight of α-tocopherol, and 79 parts by weight of DMAc was prepared. As the hollow inner liquid, a 41% by weight aqueous solution of DMAC was used and discharged from a spinneret having a slit width of 50 μm. At this time, the temperature of the film forming stock solution at the time of discharge was 60 ° C. The discharged stock solution was immersed in a 90 ° C. coagulation bath made of water provided 50 cm below through a dropping part covered with a hood, solidified and refined at a rate of 30 m / min, and then introduced into a dryer. After drying at a reduced rate of 2 minutes at 120 ° C. and further heat treatment at 180 ° C. for 0.5 minutes, 9984 hollow fiber membranes were wound up. The film forming stock solution and the discharge amount of the liquid in the hollow were adjusted so that the thickness after drying was 45 μm and the inner diameter was 185 μm (the film thickness and inner diameter were also adjusted in the following Examples and Comparative Examples).
The obtained hollow fiber membrane bundle had a bulk VE amount of 22 mg / g, and a VE normalized peak intensity of 1.4 × 10 ^{−4 on} the inner surface and 1.8 × 10 ⁻⁴ on the outer surface. The average PAO value in the human blood test was 924 (human blood A: 1087, human blood B: 735, human blood C: 951). The toughness was 1610 gf ·%. The ET transmittance was 0.02%. The inner surface PVP amount was 36%, the outer surface PVP amount was 48%, the receding contact angle of the outer surface was 15 °, and the advancing contact angle was 44 °.
As a result of assembling the obtained hollow fiber membrane bundle into a hemodialysis module and conducting a model test of long-term storage stability, the UV absorbance of the eluate was 0.07 before heating and 0.06 after heating.

[Example 2]
A film-forming stock solution consisting of 17 parts by weight of PSf, 4 parts by weight of PVP, 2 parts by weight of α-tocopherol, and 77 parts by weight of DMAc was coagulated, refined and dried in the same manner as in Example 1, followed by heat treatment at 170 ° C. for 1 minute. After that, 9984 hollow fiber membranes were wound up.
The obtained hollow fiber membrane bundle has a bulk VE amount of 76 mg / g, a VE normalized peak intensity of 4.3 × 10 ^{−3 on} the inner surface, 8.5 × 10 ^{−3 on} the outer surface, and an air recovery rate of 97%. Met. The average PAO value in the human blood test was 2625 (human blood A: 2482, human blood B: 2829, human blood C: 2564). The toughness was 1125 gf ·%. The ET transmittance was 0.01%.

[Comparative Example 1]
A hollow fiber membrane bundle was obtained by performing coagulation, refining, drying, heat treatment and winding in the same manner as in Example 1 using a membrane forming stock solution comprising 17 parts by weight of PSf, 4 parts by weight of PVP, and 79 parts by weight of DMAc.
The obtained hollow fiber membrane bundle had a bulk VE amount of 0 mg / g, a VE normalized peak intensity of 0.0 on the inner surface, 0.0 on the outer surface, and an air recovery rate of 99%. The average PAO value by human blood test was 841 (human blood A: 894, human blood B: 747, human blood C: 881). The toughness was 1265 gf ·%. The ET transmittance was 0.24%. The inner surface PVP amount was 35%, the outer surface PVP amount was 47%, the receding contact angle of the outer surface was 14 °, and the advancing contact angle was 32 °.
As a result of assembling the obtained hollow fiber membrane bundle into a hemodialysis module and conducting a model test for long-term storage stability, the UV absorbance of the eluate was 0.06 before heating and 0.19 after heating.

[Comparative Example 2]
Using a film-forming stock solution consisting of 15 parts by weight of PSf, 9 parts by weight of PVP, 0.5 parts by weight of α-tocopherol, 30 parts by weight of DMAc and 46 parts by weight of DMSO, and a hollow internal liquid consisting of 30% by weight of DMAc, 30% by weight of DMSO and 40% by weight of water After solidifying and refining in the same manner as in Example 1, 9984 hollow fiber membranes were wound in a wet state.
The obtained hollow fiber bundle was dried at 80 ° C. for 420 minutes and further subjected to heat treatment at the same temperature for 240 minutes. The resulting hollow fiber membrane bundle had a bulk VE amount of 24 mg / g, and a VE normalized peak intensity of 8.9 × 10 ^{−5 on} the inner surface and 8.8 × 10 ⁻⁵ on the outer surface. The average PAO value in the human blood test was 850 (human blood A: 852, human blood B: 772, human blood C: 926). The toughness was 1131 gf ·%. The ET transmittance was 0.19%.

[Comparative Example 3]
As a film forming stock solution, PSf 17 parts by weight, PVP 4 parts by weight, α-tocopherol 0.4 parts by weight, DMAc 77 parts by weight were subjected to coagulation, refining, drying, heat treatment and winding in the same manner as in Example 1 to obtain a hollow fiber A membrane bundle was obtained.
The resulting hollow fiber membrane bundle had a bulk VE amount of 20 mg / g, and a VE normalized peak intensity of 1.0 × 10 ^{−4 on} the inner surface and 1.4 × 10 ⁻⁴ on the outer surface. The average PAO value in the human blood test was 887 (human blood A: 938, human blood B: 853, human blood C: 870). The toughness was 1140 gf ·%. The ET transmittance was 0.15%.

[Comparative Example 4]
Using a membrane-forming stock solution consisting of 17 parts by weight of PSf, 4 parts by weight of PVP, 2.1 parts by weight of α-tocopherol, and 76.9 parts by weight of DMAc, the hollow fiber membrane bundle was obtained by coagulation, refining, drying and winding in the same manner as in Example 1. Obtained.
The bulk VE amount of the obtained hollow fiber membrane bundle was 80 mg / g. The toughness was 950 gf ·%.

By comparing Example 1 and Comparative Examples 1 and 2 in Table 1 above, it shows significant antioxidative properties against Comparative Example 1, which is a non-vitamin E-containing blood treatment membrane, and shows an effect of preventing endotoxin invasion. Therefore, it can be seen that the VE normalized peak intensity on the inner surface of the film needs to be 1.4 × 10 ⁻⁴ or more and the VE normalized peak intensity of the outer surface of the film needs to be 2.8 × 10 ⁻⁴ or more. Further, by comparing Example 1 and Comparative Example 3, the bulk VE amount needs to be 20 mg / g or more in order to make the VE normalized peak intensity on the inner surface of the film be 1.4 × 10 ⁻⁴ or more. I understand that. On the other hand, comparing Example 2 with Comparative Example 4, it can be seen that the bulk VE amount needs to be 76 mg / g or less in order to ensure a toughness of 1000 gf ·% or more.
Comparative Example 2 is a trial of the film described in Example 2 of Patent Document 4 as a conventional technique. In this case, although the mechanical strength is sufficient, the film surface VE amount is sufficient. Furthermore, no superiority was observed in the antioxidant property over Comparative Example 1 which is a non-vitamin E-containing film, and the effect of preventing endotoxin invasion was insufficient.

[Comparative Example 5]
Using a membrane-forming stock solution consisting of 17 parts by weight of PSf, 4 parts by weight of PVP, 1 part by weight of α-tocopherol, and 78 parts by weight of DMAc as a membrane-forming stock solution, 100 wet wet fiber bundles coagulated and refined as in Comparative Example 2 were prepared. The wet hollow fiber bundle obtained by this winding was dried at 80 ° C. for 3 hours.
The resulting hollow fiber membrane bundle has a bulk VE amount of 40 mg / g, a surface VE amount of 0.7 mg / g, and a VE normalized peak intensity of 9.1 × 10 ^{−5 on} the inner surface and 9.6 × on the outer surface. 10 ⁻⁵ and ET transmittance was 0.20%. Similarly, the main processing conditions and measured values are shown in Table 2 below.

[Comparative Example 6]
The hollow fiber bundle of Comparative Example 6 was heat-treated at 130 ° C. for 1 minute.
The resulting hollow fiber membrane bundle has a bulk VE amount of 40 mg / g, a surface VE amount of 2.6 mg / g, a VE normalized peak intensity of 9.8 × 10 ^{−5 on} the inner surface, and 1.1 × on the outer surface. 10 ⁻⁴ , and ET transmittance was 0.18%.

[Example 3]
The hollow fiber bundle of Comparative Example 6 was heat-treated at 140 ° C. for 1 minute.
The obtained hollow fiber membrane bundle has a bulk VE amount of 40 mg / g, a surface VE amount of 3.6 mg / g, and a VE normalized peak intensity of 1.8 × 10 ^{−4 on} the inner surface and 2.3 × on the outer surface. 10 ⁻⁴ , ET transmittance was 0.01%.

[Example 4]
The hollow fiber bundle of Comparative Example 6 was heat-treated at 180 ° C. for 0.1 minute.
The obtained hollow fiber membrane bundle has a bulk VE amount of 40 mg / g, a surface VE amount of 4.5 mg / g, and a VE normalized peak intensity of 2.3 × 10 ^{−4 on} the inner surface and 3.2 × on the outer surface. 10 ⁻⁴ , ET transmittance was 0.01%.

[Comparative Example 7]
The same film forming stock solution as in Comparative Example 6 was coagulated, refined and dried in the same manner as in Example 6 and then subjected to heat treatment at 190 ° C. for 0.1 minutes to wind up, but the hollow fiber softened and wound up. I couldn't.

  By comparing Example 3 and Comparative Example 6 in Table 2 above, it can be seen that a temperature of 140 ° C. or higher is necessary for sufficient migration of vitamin E to the surface. Further, by comparing Example 4 and Comparative Example 7, it can be seen that a heating temperature of 180 ° C. or lower is necessary to stably produce a blood treatment membrane even with a minimum heating time of 0.5 minutes.

[Comparative Example 8]
The hollow fiber bundle of Comparative Example 4 was heat treated at 110 ° C. for 1080 minutes.
The obtained hollow fiber membrane bundle had a bulk VE amount of 80 mg / g, a VE normalized peak intensity of 6.2 × 10 ^{−3 on} the inner surface, and an air recovery rate of 79%.

By comparing Example 2 and Comparative Example 8 in Table 3 above, it can be seen that when the inner surface VE normalized peak intensity exceeds 4.3 × 10 ⁻³ , the air recovery rate is significantly reduced.

As shown in Table 4, the blood treatment membranes of Example 1 and Comparative Example 1 all had the same receding contact angle on the outer surface of the membrane, but the advancing contact angle of the membrane of Example 1 was higher. Regarding the equivalence of the receding contact angle, the membrane of Example 1 exhibits hydrophilicity equivalent to that of the membrane not containing vitamin E by the PVP chain even though vitamin E is present on the outer surface. Become. That is, in the film of Example 1, most of the PVP on the outer surface contributes to hydrophilicity without impairing the function. On the other hand, regarding the difference in advancing contact angle, since the membrane of Example 1 has a higher value, the membrane of Example 1 shows that the hydrophobic surface is dominant in the hydrophobic atmosphere, not the PVP chain. Show. This is due to the VE layer deposited at a high rate on the outer surface.
Therefore, even when the blood treatment membrane of the present invention as in Example 1 is loaded with an extremely high concentration of endotoxin solution, the permeability of endotoxin is negligible. The fact that almost no endotoxin permeation is observed even in a severe test using such a high concentration endotoxin solution means that the blood treatment membrane of the present invention has many adsorption sites for endotoxin and is stable. This suggests that it is an adsorption site.

[Comparative Example 9]
0.1 parts by weight of α-tocopherol acetate and 0.1 parts by weight of Pluronic with respect to a mixture of a film-forming stock solution comprising 19 parts by weight of PSf, 9 parts by weight of PVP and 72 parts by weight of DMF, 60 parts by weight of DMF, and 40 parts by weight of water After solidifying in the same manner as in Example 1 using the hollow internal solution to which F-68 was added, hot water at 60 ° C. was shower washed at 1 L / min for 1 hour to wind up 9984 hollow fiber membranes in a wet state. . Further, it was treated with 110 ° C. warm water for 1 hour and washed.
The VE normalized peak intensity of the obtained hollow fiber membrane bundle was 0.0 on the outer surface.
As a result of assembling the obtained hollow fiber membrane bundle into a hemodialysis module and conducting a model test for long-term storage stability, the UV absorbance of the eluate was 0.06 before heating and 0.17 after heating.

  Comparative Example 9 corresponds to Example 2 of Patent Document 3. By comparing Example 1 and Comparative Examples 1 and 9 in Table 5 above, the elution amount of the blood treatment membrane of the present invention is the dialysis-type artificial kidney device approval criteria even by heating at 60 ° C. for 3 weeks corresponding to long-term storage. Absorbance of 0.1 or less within the range of (December 20, 1984, Yakusei No. 494, General Affairs Bureau's notice), but does not contain a fat-soluble antioxidant, and outer surface to film thickness portion In Comparative Example 9 which does not contain a fat-soluble antioxidant, the standard is greatly exceeded, and the good long-term storage stability of the blood treatment membrane of the present invention can be seen.

  The blood treatment membrane of the present invention is excellent in in vivo antioxidant action when in contact with blood, and at the same time, has a low risk of endotoxin intrusion into the treatment solution, and prevents unexpected accidents such as membrane breakage during the production process or use. Since it has practical strength and has a high production rationality, it is used for extracorporeal blood treatment such as effective and safe hemodialysis.

Claims (4)

A hollow fiber type porous membrane comprising a polysulfone-based resin, a hydrophilic polymer and a fat-soluble antioxidant, the membrane containing 22 to 76 mg of a fat-soluble antioxidant per gram, and a membrane of a fat-soluble antioxidant TOF-SIMS normalized peak intensity is an index showing the surface concentration at membrane surface 1.4 × 10 ^-4 or more state, and are 1.8 × 10 ^-4 or more outer surface of the membrane, lipophilic antioxidant polysulfone-based blood treatment membrane but characterized by vitamin E der Rukoto. A method for producing a porous blood treatment membrane comprising a polysulfone-based resin, a hydrophilic polymer, and a fat-soluble antioxidant, from a film-forming stock solution containing a polysulfone-based resin, a hydrophilic polymer, a fat-soluble antioxidant, and a solvent after obtaining a membrane intermediate that 22~76mg containing vitamin E is a fat-soluble antioxidant per 1 g, 140 to 180 ° C. the membrane intermediate in the dry state, heat treatment 0.1 minutes, fat A method for producing a polysulfone-based blood treatment membrane, wherein vitamin E as a soluble antioxidant is migrated to the membrane surface . 3. The method for producing a polysulfone-based blood treatment membrane according to claim 2 , wherein the membrane intermediate is wound into a bundle and then heat-treated. The method for producing a polysulfone-based blood treatment membrane according to claim 2 or 3 , wherein the membrane intermediate is heated and then wound into a bundle.