JP5351394B2 - Polysulfone blood treatment membrane and method for producing the same - Google Patents
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本発明は、ポリスルホン系血液処理膜、およびその製造方法に関する。特に、脂溶性抗酸化剤を含んで抗酸化性に優れ、且つ処理血液へのエンドトキシン侵入の危険性の少ないポリスルホン系血液処理膜、およびその製造方法に関するものである。 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.
従来より、体外血液循環の分野、血液透析、開心手術中の血液への酸素付与あるいは血漿分離等には選択透過膜を用いた中空糸型血液処理器が広く使用され、近年、特に透析膜、ガス交換膜、血液成分分離膜等の血液処理膜分野においては、ポリスルホン製血液処理膜が広く利用されているが、単に分離膜としての役割だけでなく、長期透析患者で顕在化する酸化ストレスを緩和する試みもなされている。この試みの一つのアプローチとして酸化ストレス原因物質である過酸化物の消去や生体の抗酸化効果を回復することが挙げられ、例えば特許文献1には、生体内抗酸化作用、生体膜安定化作用、血小板凝集抑制作用などの種々の生理作用を有するビタミンEを、予め形成した膜の表面に被覆することにより得られた、抗酸化性に優れた血液処理膜が開示されている。 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.
酸化ストレスを緩和する別のアプローチとして、透析中に惹起される酸化反応を予防する考えもあるが、その中でも、生体に対する毒性の強いエンドトキシンの透析液からの侵入を阻止することも有用であると考えられる。エンドトキシンが血液・体内に侵入すると、生体防御反応の一環として貪食細胞から酸素ラジカルが産生・放出されるためである。 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.
この問題を解決するためには、エンドトキシンを吸着しやすい疎水性膜を用いるのが効果的ではあるが、単なる疎水性膜では血液適合性が悪く利用できない。そこで、例えば、ポリスルホンとポリアリレートのポリマーアロイからなる中空糸膜の内表面のみに親水性高分子を付着保持させることにより、疎水性の高い外表面でエンドトキシンを吸着除去しつつも内表面の抗血栓性を有する中空糸膜が開示されている(特許文献2)。しかしながら、この中空糸膜ではポリマーアロイの疎水性が高いため、透析液側からのエンドトキシンの侵入阻止に対しては効果的であるが、多孔部および外表面の疎水性が高すぎるためエアー抜けが悪く、膜を介した拡散透過性に影響を与えるものであった。また、エンドトキシン以外の酸化ストレス因に対しては全く効果がないものであった。さらに、湿式製膜時に開孔剤の役割を果たす親水性高分子が無いため、孔径の制御が困難であり、透過性の制御が困難であった。 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.
ポリスルホンと親水性高分子からなる膜においては、製膜時から膜全体の親水性高分子の含有量を下げることにより、膜外表面の疎水性を確保してエンドトキシン吸着性を高め、血液適合性を付与するために膜内表面のみに抗血栓性を有するビタミンEなどを付与する中空糸膜の製造技術が開示されている(特許文献3)。しかしながら、この方法では膜外表面には親水性高分子が存在するため、エンドトキシンの透過率を一時的に低くできても吸着***が起こりやい欠点があるばかりか、膜外表面の親水性高分子が少ないので依然としてエアー抜けは不十分であった。また、本発明者らの知見によれば、膜外表面の親水性高分子濃度が低くなるように製膜すると膜内表面の濃度も必然的に下がってしまい、抗血栓性の点で全く不十分なものであった。そのためか、より好ましい態様として、膜内表面にビタミンEを付与して血小板吸着性を改善することは記載されているが、付与したビタミンEの膜内分布や、それを利用してエンドトキシン吸着性を改善することについては何ら考慮されていなかった。 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.
一方、製膜原液にビタミンEを添加することにより膜基材内部を含む膜全体にビタミンEを付与する血液処理膜、およびその製造方法が開示されている(特許文献4)。このような膜では、膜の全体にビタミンEを存在させることができるため、従来のポリスルホンと親水性高分子からなるポリマー同士のブレンド膜とは違った表面状態が得られ、うまく制御すればエンドトキシン吸着性を高くできることも期待できる。しかしながら、本発明者らの知見によれば、十分な疎水性を膜外表面に付与するために多量のビタミンEを含有させると、得られた血液処理膜は機械的強度が低くて実用に供しうるものにならず、逆に、実用強度を維持できるビタミンE含有量に留めると、十分な疎水性を膜外表面に付与できなかった。これは、基材ポリマーのミクロドメイン界面にビタミンEが偏析する結果、基材ポリマーの分子間相互作用に影響を与えるからであろうと思われる。なお、特許文献1のように、膜表面全体にビタミンEが被覆された膜では強度低下の問題は回避できるが、既に構造形成された膜に被覆等の後処理を加えると、被覆物による細孔径の低下や、表面堆積による表面状態の顕著な変化をもたらすことがあり、決して採用しやすいものではなかった。 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.
このように、ポリスルホン系樹脂を基材ポリマーとする血液処理膜を脂溶性抗酸化剤で改質する際、得られた膜が、優れた抗酸化性と膜外表面からのエンドトキシン侵入の阻止に加えて、実用強度を具備することはきわめて困難であった。しかしながら、血液処理膜分野の中でも、ポリスルホン系樹脂を膜基材ポリマーとした血液処理膜の需要は高まる一方であり、したがって、前記特性を具備しつつ、なおかつ生産合理性の高いポリスルホン系の血液処理膜、およびその製造方法が強く望まれていた。
本発明は、優れた抗酸化性と膜外表面からのエンドトキシン侵入の阻止に加えて実用強度を有し、なおかつ生産合理性の高いポリスルホン系血液処理膜、およびその製造方法を提供することを目的とする。 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
前述のとおり、中空糸膜内外表面の親水性/疎水性分布を極端にしたり、親水性高分子を中途半端に減量したところで、エンドトキシンの吸着性に問題があったり、その他の問題の併発を免れなかった。また、脂溶性抗酸化剤の被覆やブレンドでも種々の問題があるなど、いずれの分布構造でも目的を達するには不十分と思われた。 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.
本発明者らは、脂溶性抗酸化剤の理想的な分布構造について検討するにあたり、ポリスルホン膜表面、特に外表面側に疎水性の高い脂溶性抗酸化剤を油膜のごとく高率にカバーさせ、その上方には、該疎水層を突き抜け、水和した親水性高分子鎖が膜全体を覆うように存在することができれば、親水性高分子の量を減らすことなくしかも表面の疎水性は高くできる、すなわち親水性と疎水性の相反する性質が一つの膜表面で具備することが可能であろうと着想した。そして、この様な表面は、既に構造形成されたポリスルホンと親水性高分子からなる膜の上から脂溶性抗酸化剤を被覆するのでなく、膜の形成時に、凝固しつつあるポリマー相の内側から染み出すように脂溶性抗酸化剤を配置することにより得られるのではないかと考えた。これが実現すれば、酸化ストレス低減に対する2つのアプローチを同時に実現する、臨床上効果が高い中空糸膜が得られると考えられる。 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.
そこで、そのような血液処理膜と実用的な機械的強度を両立させるため、製膜原液に脂溶性抗酸化剤を添加して血液処理膜を製造するに際し、強度低下を生じない程度の脂溶性抗酸化剤を含有した血液処理膜、すなわち抗酸化性や膜外表面からのエンドトキシン侵入の阻止効果が不足気味の膜であっても、乾燥工程で特定の熱履歴を付与することによって脂溶性抗酸化剤を膜基材から滲み出させる、つまりマイグレーションさせることにより、膜表面に十分な量の脂溶性抗酸化剤を発現できることを見出した。そして、これにより得られる血液処理膜が上記の課題を解決できることを見いだし、本発明に到達した。 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.
即ち、本発明は以下のとおりである。
(1)ポリスルホン系樹脂、親水性高分子および脂溶性抗酸化剤からなる中空糸型多孔質膜であって、該膜は1g当たり脂溶性抗酸化剤を22〜76mg含有し、脂溶性抗酸化剤の膜表面濃度を示す指標であるTOF−SIMS規格化ピーク強度が、膜内表面で1.4×10−4以上、膜外表面で1.8×10−4以上であることを特徴とするポリスルホン系血液処理膜。
(2)脂溶性抗酸化剤が脂溶性ビタミンである請求項1記載のポリスルホン系血液処理膜。
(3)ポリスルホン系樹脂と親水性高分子と脂溶性抗酸化剤からなる多孔質血液処理膜の製造方法であって、1g当たり脂溶性抗酸化剤を22〜76mg含有する膜中間体を得た後、該膜中間体を乾燥状態で140〜180℃、0.1〜1分間加熱処理することを特徴とするポリスルホン系血液処理膜の製造方法。
(4)ポリスルホン系樹脂、親水性高分子、脂溶性抗酸化剤および溶剤を含む製膜原液から膜中間体を得る請求項3記載のポリスルホン系血液処理膜の製造方法。
(5)膜中間体を束状態に巻き取った後、加熱処理することを特徴とする、(3)または(4)記載のポリスルホン系血液処理膜の製造方法。
(6)膜中間体を加熱処理した後、束状態に巻き取ることを特徴とする、(3)または(4)記載のポリスルホン系血液処理膜の製造方法。
(7)脂溶性抗酸化剤が脂溶性ビタミンである(3)〜(6)のいずれかに記載のポリスルホン系血液処理膜の製造方法。
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.
本発明によれば、脂溶性抗酸化剤を含むポリスルホン系血液処理膜において、従来は両立が困難であった優れた抗酸化性と膜外表面からのエンドトキシン侵入の阻止に加えて実用強度を具備するポリスルホン系血液処理膜が得られる。また、本発明のポリスルホン系血液処理膜は脂溶性抗酸化剤を含む製膜原液から得られるので、コーティング設備等の後処理工程を必要としないため、生産合理性にも優れている。 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.
本発明におけるポリスルホン系樹脂(以下、PSf)とは、スルホン結合を有する高分子結合物の総称であり特に規定するものでないが、例を挙げると、下記式(1)〜(3)
(−Φ−SO2−Φ−O−Φ−C(CH3)2−Φ−O−)n (1)
(−Φ−SO2−Φ−O−)n (2)
(−Φ−SO2−Φ−O−Φ−Φ−O−)n (3)
(−Φ−C(CH3)2−Φ−O−CO−Φ−CO−O−)n (4)
に示される繰り返し単位をもつPSfが広く市販されており、入手も容易なため好ましく用いられる。ここでΦは芳香環を、nはポリマーの繰り返し数を表す。前者の構造を持つPSfはソルベイ社より「ユーデル」の商標名で、またビー・エー・エス・エフ社より「ウルトラゾーン」の商標名で市販されており、重合度等によっていくつかの種類が存在する。なお、本発明では、式(2)に式(4)をブレンドしたポリマーアロイもポリスルホン系樹脂の範疇とする。
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.
本発明の親水性高分子は、ポリビニルピロリドン(以下、PVP)、ポリエチレングリコール、ポリグリコールモノエステル、デンプン及びその誘導体、カルボキシメチルセルロース、酢酸セルロースなどの水溶性セルロース誘導体が使用できる。これらを組み合わせて使用することも可能だが、紡糸の安定性やPSfとの親和性の観点から、PVPかポリエチレングリコールが好ましく用いられ、なかでもPVPの使用が最も好ましい。PVPは、N−ビニルピロリドンをビニル重合させた水溶性の高分子化合物であり、アイ・エス・ピー社より「プラスドン」の商標名で、また、ビー・エー・エス・エフ社より「コリドン」の商標名で市販されており、それぞれいくつかの分子量のものがある。 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.
本発明における脂溶性抗酸化剤とは還元性を有し、且つ以下に例示する製膜原液の溶媒に可溶なものであれば特に限定されないが、生体に対する安全性、適用実績が豊富な点から脂溶性ビタミン類であることが好ましい。かかる脂溶性ビタミンとしては、ビタミンA、ビタミンD、ビタミンE、ビタミンKおよびユビキノン等が挙げられるが、これらの中では、ビタミンEが好適である。ビタミンEとしては、α−トコフェロール、α−酢酸トコフェロール、α−ニコチン酸トコフェロール、β−トコフェロール、γ−トコフェロール、δ−トコフェロール等が挙げられる。これらは単独で用いても良いが、混合物で用いてもよく、例えば市販のα−トコフェロールは上記ビタミンEの混合物である。さらに将来、天然物、人工物を問わず、生体に対する安全性の高い脂溶性抗酸化剤が出現すればそれを用いるのも本発明の範囲に属する。 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.
以下、本発明のポリスルホン系血液処理膜について、製造方法も含めて説明する。
中空糸膜の製造方法は、ポリスルホン系樹脂(PSf)と親水性高分子と脂溶性抗酸化剤及び溶剤を含む製膜原液を中空内液とともに紡糸口金から吐出する工程、吐出した原液を凝固させる工程、凝固した中空糸膜を乾燥する工程を少なくとも含む。つまり、従来一般的に知られている技術である乾湿式製膜技術を応用する。
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.
まず、PSfと親水性高分子と脂溶性抗酸化剤を共通溶媒に溶解し、製膜原液を調整する。特に、親水性高分子がPVPであり、脂溶性抗酸化剤がα−トコフェロールである場合、共通溶媒としては、例えば、ジメチルアセトアミド(以下、DMAc)、ジメチルスルホキシド(DMSO)、N−メチル−2−ピロリドン、ジメチルホルムアミド、スルホラン、ジオキサン等の溶媒、あるいは上記2種以上の混合液からなる溶媒が挙げられる。なお、孔径制御のため、製膜原液には水などの添加物を加えても良い。 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.
製膜原液中のPSf濃度は、製膜可能で、かつ得られた膜が透過膜としての性能を有するような濃度の範囲であれば特に制限されず、5〜35重量%、好ましくは10〜30重量%である。高い透水性能を達成するためには、ポリマー濃度は低い方がよく、10〜25重量%が好ましい。PVP濃度は、PSfに対するPVPの混和比率が27重量%以下、好ましくは18〜27重量%、さらに好ましくは20〜27重量%となるように調整する。PSfに対するPVPの混和比率が27重量%を超えると溶出量が増える傾向にあり、また18重量%未満では膜内表面のPVP濃度が低下し、患者の血液中の白血球濃度が急激に低下するロイコペニア症状が観察されるため好ましくない。このようにして得られた中空糸膜は膜内表面のPVP濃度が20%以上、50%以下、膜外表面のPVP濃度が30%以上、70%以下、好ましくは膜内表面のPVP濃度が30%以上、45%以下、膜外表面のPVP濃度が40%以上、65%以下、となっており、抗血栓性、生体適合性に優れ、蛋白、血小板等の膜面付着も軽微である。この膜は安定した除水能力を有しており血液透析、血液ろ過等の治療を安定に実施するために大きな効果を発揮するものである。 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.
ところで、膜表面でのPVP濃度を20%以上とすることでなぜ安定した除水能力が得られるのかについての詳細は不明であるが、疎水性で蛋白等を吸着しやすいポリスルホンの表面部を親水性の高分子であるPVPが覆い隠すのに必要な存在率が20%以上であり、その結果として膜表面は充分に親水化されているので、膜表面への蛋白等の吸着性が弱められ安定した除水能力が得られるものと予想される。また、膜表面でのPVP濃度が50%より大きいと膜表面はより一層親水化されているので性能は安定しているのであるが、その反面、血液透析時等においてPVPが血液中に溶出してくる危険性を伴ない、安全性の上で問題がでてくる可能性があるので、PVP濃度は50%以下であることが好ましい。 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.
なお本発明でいう膜表面でのPVP濃度とは血液が膜と接触する極表層部での存在率であり、実施例にて詳述するようにエックス線光量子スペクトル(X−ray photoelectron spectroscopy,以下XPS)により測定した値から計算することができる。 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.
製膜原液における脂溶性抗酸化剤の濃度は、得られる血液処理膜中の脂溶性抗酸化剤の含有が一定の範囲となるように適宜調整する必要がある。後述するように、十分な抗酸化性や外表面からのエンドトキシン侵入の阻止能力を発現させる為に含量は膜1gあたり22mg以上必要であり、一方で、過剰に存在すると膜の機械的強度を激減させるので、76mg以下であることが必要である。 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.
次に、チューブインオリフィス型の紡糸口金を用い、該紡糸口金のオリフィスから製膜原液を、チューブから該製膜原液を凝固させる為の中空内液とを同時に空中に吐出させる。中空内液は水、または水を主体とした凝固液が使用でき、一般的には製膜原液に使った溶剤と水との混合溶液が好適に使用される。例えば、0〜60重量%のDMAc水溶液などが用いられる。紡糸口金から中空内液とともに吐出された製膜原液は、空走部を走行させ、紡糸口金下部に設置した水を主体とする凝固浴中へ導入、浸漬して凝固を完了させる。 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.
こうして得られた膜構造は中空糸内表面に緻密なスキン層を有し、スキン層から外表面の間に多孔質構造を有する。多孔質構造を有することは外表面から侵入するエンドトキシンを吸着除去する際に、吸着のための有効面積を拡大する上で好ましい。次いで水などによる洗浄を経て中空糸膜中間体を得る。さらに膜中間体を乾燥機に導入して乾燥し、中空糸膜を得る。ここで膜中間体は湿潤状態で切断し、束状とした後に乾燥しても良いし、連続走行させたままで乾燥を行っても構わない。この時、中空糸膜にクリンプを付与すると、血液透析に用いる時、拡散性能発現を効率的に行うことができて好ましい。 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.
血液処理膜に対する脂溶性抗酸化剤の含有量は高いほど膜としての抗酸化性や膜外表面からのエンドトキシン侵入の阻止能は高まるが、一方で含有量の増加は機械的強度の漸減を伴い、ある程度以上の含有量を境に膜の機械的強度を激減させる。この理由は定かではないが、機械的強度の減少は主に破断伸度の低下により生じる。ここから導かれる仮説としては、膜基材ポリマーのミクロドメインの界面に脂溶性抗酸化剤(例えば、ビタミンE)が偏析して界面接着力を徐々に低下させていたものが、ある含有量でほぼ全ての界面を脂溶性抗酸化剤が占めるようになり、界面接着力が急激に消失した可能性が考えられる。 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.
血液処理膜は使用に際し、容器に収納されてモジュール形態で用いられることが多いが、機械的強度が十分でないとモジュール製造、あるいは取り扱いの際に膜の破壊が生じる危険性がある。機械的強度は引っ張り試験から得られるタフネスで表すことが出来、血液処理膜が中空糸膜である場合、中空糸膜1本あたり1000gf・%のタフネスがあれば実用上十分である。なお、本発明でいうタフネスとは破断強力(gf)と伸度(%)を掛け合わせたものであり、測定方法については実施例の分析方法にて詳しく説明する。 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.
本発明者らは鋭意研究した結果、ポリスルホン系樹脂を基材ポリマーとする膜の場合は、血液処理膜1g当たりの脂溶性抗酸化剤含有量が76mg以下であればタフネスが1000gf・%を上回ることを見出した。このため、血液処理膜1g当たりの脂溶性抗酸化剤は76mg以下であることが必要である。 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.
本発明の血液処理膜において、その使用に際し抗酸化性を発揮するのは被処理液が接触する部分、即ち膜表面に存在する脂溶性抗酸化剤のみであり、膜基材に埋もれて被処理液と接触しない脂溶性抗酸化剤は血液成分への直接的な抗酸化効果には関与しない。ここで「膜表面」とは血液と直接接する中空糸内表面のみを指すものではなく、外表面や膜厚部の多孔質部分の表面も含む。血液成分のうち血球は内表面のみとしか接しないが、蛋白などの液性成分や活性酸素などの過酸化物質は拡散により膜厚部を行き来するため、多孔部や外表面に至る全ての膜表面が抗酸化作用に寄与するのである。このため、抗酸化能力においては全ての膜表面に存在する脂溶性抗酸化剤の総量が問題となる。 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.
膜表面に存在する脂溶性抗酸化剤の量は、TOF−SIMS(飛行時間型2次イオン質量分析法)測定で得られる親マスピークの規格化ピーク強度を指標とすることができる。測定方法は実施例において詳細に説明するが、この方法での測定深さは極めて浅く(数〜数十オングストローム)、表面に露出している脂溶性抗酸化剤のみを検出していると考えて良い。一方で、この方法では膜内表面、膜外表面を独立して測定することができるが、多孔質部分の脂溶性抗酸化剤の存在量を測定するのは困難である。しかしながら、少なくとも内表面近傍の多孔質部分の測定値は内表面の測定値とほぼ同等であると見なし得ると考えられるので、これで代表させる。 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.
本発明者らが行った人新鮮血と血液処理膜との接触実験によれば、通常の血液処理膜に対して本発明の血液処理膜が抗酸化作用において優位性を示すには、規格化ピーク強度の測定値として1.4×10−4以上が必要である。本発明における抗酸化性能の試験は実施例の分析方法にて詳しく説明する。 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.
さらに本発明の血液処理膜において、その使用に際し、膜外表面からのエンドトキシン侵入の阻止能を発揮させるためには、膜外表面ならびに多孔質部分に一定以上の脂溶性抗酸化剤が存在することが必要である。膜外表面の脂溶性抗酸化剤もTOF−SIMS測定の規格化ピーク強度を指標とすることができる。膜外表面からのエンドトキシン侵入の阻止は膜外表面、および多孔質部分の表面が担う。このうち、多孔質部分の脂溶性抗酸化剤の存在量を測定するのは困難であるが、少なくとも外表面近傍の存在量は外表面の測定値とほぼ同等と見なし得ると考えられる。つまり、膜外表面からのエンドトキシン侵入の阻止能を発揮させるために必要なパラメータとしては、前述の膜外表面の規格化ピーク強度で代表させることができ、目的の機能を発揮するためには測定値として2.8×10−4以上が必要である。 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.
一方で、膜表面における過剰の脂溶性抗酸化剤の存在は膜表面の過度の疎水化を招き、混入したエアーの除去や血液適合性の観点から望ましくない。しかしながら、本発明の血液処理膜における脂溶性抗酸化剤の含有量は、膜1gあたり22〜76mgに限定しているために、後に述べる加熱処理条件の範囲内であれば好ましくないほどの疎水化は生じない。例えば膜1gあたり76mgの脂溶性抗酸化剤を含む膜を乾燥状態で180℃、1分間過熱した場合、得られた膜の外表面における脂溶性抗酸化剤の規格化ピーク強度は1.0×10−2であるが、この程度であれば好ましくないほどの疎水化は生じない。 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.
以上の点から、本発明の血液処理膜では脂溶性抗酸化剤の含有量が膜1gあたり22〜76mgであり、脂溶性抗酸化剤の規格化ピーク強度が膜内表面では1.4×10−4以上、膜外表面では1.8×10−4以上であることが必要である。 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.
本発明では、血液処理膜の全体および表面に上述した範囲で脂溶性抗酸化剤とPVPが存在すれば、本来相反するはずの良好なエアー抜けや血液適合性などの親水性表面としての特性とエンドトキシン吸着除去という疎水性表面としての特性が両立する。その理由は定かでないが、ポリスルホン膜表面に脂溶性抗酸化剤の疎水層が油膜のごとくカバーし、その上方には水和した親水性高分子鎖が膜全体を覆うことにより親水性と疎水性の相反する性質が一つの膜表面で具備しているものと推測する。なお、特許文献1、3、4記載の完成した膜表面に脂溶性抗酸化剤を被覆することにより得られた血液処理膜は、本発明の分布構造にはなりえない。PVPは親水性である反面、エタノール等の脂溶性抗酸化剤の有機溶媒にも可溶性を有しているので、被覆溶媒中で脂溶性抗酸化剤と相溶する結果、PVPの一部〜大部分が脂溶性抗酸化剤の被覆層に埋没してしまうからである。 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.
この様な表面特性は、動的接触角測定装置を用い、血液処理膜の端を封じて測定した外表面の後退接触角と前進接触角で確認することができる。測定方法は実施例にて説明するが、後退接触角は水中(親水性雰囲気)での接触角を、前進接触角は空気中(疎水性雰囲気)での接触角を表す。ポリウレタンの様な疎水性表面にポリエチレングリコールのような運動性の高い親水性高分子鎖が存在すると、親水性雰囲気では親水性高分子鎖が、疎水性雰囲気では疎水性表面が支配的となるため、「後退接触角<前進接触角」となることが知られている(A.Takahara,N.J.Jo,T.Kajima,J.Biometer.Sci.Polymer Edn,Vol.1,No.1,pp17−29(1989))。 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)).
PSfとPVPのみからなる通常のポリスルホン系血液処理膜も、疎水性表面であるPSfと運動性の高い親水性高分子鎖であるPVPの組み合わせであり、本発明者らの行った実験によれば、「後退接触角<前進接触角」なる状態が観察される。ここで本発明の血液処理膜と、PSfとPVPのみからなる通常のポリスルホン系血液処理膜を比較すると、後退接触角は両者の間に差が無い。これは、本発明の血液処理膜の外表面が、親水性雰囲気では通常のPSf−PVP血液処理膜と同様の性質を有することを意味している。すなわち、本発明の血液処理膜は、通常のPSf−PVP血液処理膜と同様、表面親水性を発揮する、即ち表面に露出可能な十分な量のPVPを膜外表面に、親水性雰囲気における膜表面ではPVP鎖の性質が支配的になると推定される。その結果、特許文献2、3記載の血液処理膜とは違って、プライミング時のエアー抜けが従来のPSf−PVP膜に遜色ない程度に良好となると考えられる。 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.
一方、前進接触角を比較すると、本発明の血液処理膜の方がPSfとPVPのみからなる通常のポリスルホン系血液処理膜よりも高い。これは、本発明の血液処理膜の外表面が、疎水性雰囲気では通常のPSf−PVP血液処理膜よりもさらに疎水性であることを意味している。すなわち、本発明の血液処理膜は、通常のPSf−PVP血液処理膜と同等のPVPを膜外表面に露出可能であるにもかかわらず、疎水性雰囲気になると、PVPに代わって疎水面が支配的になりやすいと推定される。その結果、水中にあっても、例えばエンドトキシンのような巨大分子の疎水面が膜外表面に接近することにより疎水性が支配的になりやすく、通常のPSf表面よりもさらに疎水性が高くなるため、エンドトキシン吸着能が一層高くなると考えられる。これは、被覆ではなく予め製膜原液中に存在する疎水性の脂溶性抗酸化剤が、後述する熱処理を経て、特に膜外表面に高率に滲み出すことによると思われる。 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.
上記の動的接触角の知見に基づいて、本発明の血液処理膜の膜構造と作用効果のメカニズムをより概念的に説明すると以下のようになる。すなわち、特許文献2,3に記載のように、膜外表面の親水性高分子を減らすあるいは無くすことにより、ポリマー自身により疎水面が形成された場合はいわば硬い面となり、エンドトキシンは幾つかの点で接触して着地するかの如く結合する。それに対して、低分子の脂溶性抗酸化剤により疎水面が形成された場合は、いわば柔軟な油膜(油層)と考えられるから、エンドトキシンは生来グラム陰性菌の細胞膜(脂質二重膜)に埋め込まれていたのと同じように油膜(油層)埋め込まれる。結果として、本発明の血液処理膜はエンドトキシンの膜外表面への結合がより安定で、かつ強固になって、高いエンドトキシン保持能力を得ているものと考えられる。 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.
次に、上記の膜構造を得る上でポイントとなる処理条件について説明する。
本発明者らは、ポリスルホン系血液処理膜が優れた抗酸化性と実用強度を具備するように鋭意研究を進めた結果、脂溶性抗酸化剤を含有する従来のポリスルホン系血液処理膜であっても、特定の乾燥状態で加熱処理することにより、膜全体の脂溶性抗酸化剤の含有量を変化させずに、すなわち実用強度を確実に維持しつつ、膜表面の存在量のみを増加させうることを見出した。なお、この方法により膜内表面の脂溶性抗酸化剤規格化ピーク1.4×10−4以上の抗酸化剤を膜表面に発現させ、且つ膜外表面の脂溶性抗酸化剤規格化ピーク1.8×10−4以上にするためには、血液処理膜1g当たり脂溶性抗酸化剤を22mg以上含む必要がある。
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.
本発明で言う乾燥状態とは、少なくとも膜が飽和含水率以下、すなわち、膜の周囲が完全には水で満たされておらず、水分が滴らない状態にあることをいう。水分率は特に限定されるものではないが、好ましくは水分率0〜100%、より好ましくは水分率0〜50%の状態である。これよりも高い水分率では、外部から熱を加えても水の蒸発潜熱により血液処理膜自体の温度が上昇せず、水分が蒸散するまでの間、目的である脂溶性抗酸化剤の膜表面へのマイグレーションが遅延してしまう。 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.
本発明における乾燥状態にある血液処理膜の加熱処理は、血液処理膜の製造を終了した後に別途行っても良いし、モジュールに組み立てた状態で行っても良いが、製膜装置の乾燥工程において乾燥に引き続き加熱処理を連続して行うことが生産合理性の面で好ましい。 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.
加熱処理条件に関しては、処理温度が低温では脂溶性抗酸化剤の表面へのマイグレーションが進まず、高温では血液処理膜が軟化したり、抗酸化剤の酸化が進行してしまうため、140〜180℃の範囲が好ましく、140〜170℃の範囲がより好ましい。処理時間も同様に短時間ではマイグレーションが進まず、長時間では抗酸化剤の酸化が進行してしまうため、0.1〜1分間の範囲が好ましく、0.2〜0.8分間の範囲がより好ましい。 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.
なお、製膜装置の乾燥工程において乾燥に引き続き加熱処理を連続して行う場合、水分を除去する乾燥と、脂溶性抗酸化剤を膜表面にマイグレーションさせる加熱処理を明確に区分出来ない場合もある。本発明の真意は血液処理膜の加熱処理、即ち膜基材の温度を上げることにある。よって、乾燥から加熱処理を連続して行う場合、減率乾燥域までを水分を除去する乾燥工程、恒率乾燥域以降を脂溶性抗酸化剤を表面にマイグレーションさせる加熱処理工程として区別すればよい。 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. .
以上述べたとおり、本発明の血液処理膜は、脂溶性抗酸化剤を含むポリスルホン系血液処理膜において、従来は両立が困難であった優れた抗酸化性と膜外表面からのエンドトキシン侵入の阻止に加えて実用強度を具備するポリスルホン系血液処理膜となっている。のみならず、本発明の血液処理膜のように、膜全体に脂溶性抗酸化剤が存在することは、血液処理膜の長期保管に際して、膜を構成する高分子の酸化分解に由来する人体に望ましくない低分子量物の溶出などを抑制するのにも効果がある。血液処理膜に用いられる高分子素材は十分な安全性が確認されているが、それでも過剰な溶出に対して生体の防御機構が作動し、酸化ストレス状態に導かれるリスクがあり得るからである。この点、特許文献1,3のように、表面以外の内部には脂溶性抗酸化剤が含まれない被覆型の膜では酸化分解に対する耐性が低かったが、この点も改善される。 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.
以下に脂溶性抗酸化剤としてビタミンEを用いる実施例を示し、本発明を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。まず初めに、用いた原料と試薬ならびに測定方法について説明する。 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.
[原料と試薬]
1.PSf:ソルベイ社製、P−1700
2.PVP:アイ・エス・ピー社製、K−90
3.ビタミンE(dl−α−トコフェロール):DSMニュートリションジャパン、局方
4.α−酢酸トコフェロール:和光純薬、試薬特級
5.プルロニックF−68:ポリエチレングリコール−ポリプロピレングリコール共重合体、旭電化工業
6.DMAc:キシダ化学、試薬特級
7.DMSO:キシダ化学、試薬特級
8.N、N−ジメチルホルムアミド(以下、DMFと略す):キシダ化学、試薬特級
9.1−メチル−2−ピロリドン(以下、NMPと略す):東京化成、試薬特級
10.塩化第二鉄6水和物:和光純薬、試薬特級
11.エタノール:和光純薬、試薬特級
12.2,2’−ビピリジル:和光純薬、試薬特級
13.注射用水(純水):大塚製薬
14.抗酸化能測定キット:日研ザイル株式会社製、抗酸化能測定キットPAO
[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
[血液処理膜全体のビタミンE含有量(以下、バルクVE量と略す)]
乾燥した血液処理膜をNMPに溶解(約3重量%)して測定液を調製した。液体クロマトグラフィー(カラム:イナートシルC8−3μm(4.6φ×250mm)+ODP−50 6E(4.6φ×250mm)、溶離液:NMP、流量:0.5ml/分、カラム温度40℃、UV検出器波長295nm)にて測定したビタミンEに対応するピーク面積と、濃度既知の標準液で別途作成した検量線を用いて測定液のビタミンE濃度を求めた。得られた濃度と希釈倍率から膜1g当たりのビタミンE含有量(mg)=バルクVE(mg/g)を求めた。
[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.
[膜外表面のビタミンE規格化ピーク強度]
血液処理膜を純水に12時間浸漬した後、凍結乾燥させた。乾燥した中空糸の膜外表面、あるいは中空糸の縦方向に切れ目を入れて開いて露出させた膜内表面をTOF−SIMS装置(TRIFTIII,Physical Electronics社製)を用いて測定した。測定条件は、一次イオンGa+、加速電圧15kV、電流600pA(DCとして)、分析面積200μm×200μm、積算時間5minで行ない、検出器により、負イオン(Massとして、ビタミンEは163)を検出イオンとして検出した。本測定装置の特性上、測定深さは表面から5nmまでの深さに相当する。得られたビタミンEピークのイオン強度(IV)を、プロトンのイオン強度IH、総イオン強度ITを用い、以下の式(5)によりビタミンEの規格化ピーク強度を計算した。
規格化ピーク強度=IV/(IT−IH) (5)
[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)
[血液処理膜のタフネス]
室温20〜25℃、湿度55〜60RH%の室内で、島津製作所製の引っ張り試験機(EZ Test series)を用い、乾燥した20cmの中空糸膜1本をチャックを用いて固定し、30cm/分の速度で引っ張り、破断したときの応力(gf)を測定した。
また、中空糸膜が破断したときの伸びを、測定前の中空糸膜の長さである20cmで除して100を掛けた値を伸度(%)として求め、以下の式(6)によりタフネスを計算した。
タフネス(gf・%)=破断応力(gf)×伸度(%) (6)
[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)
[抗酸化能]
血液処理膜2gを2〜3mm長に切断し、生理食塩水でプライミングした後、ヘパリン加血人新鮮血2mlを加えて、振とう下で37℃×4時間インキュベートした。1つの膜に対して3名の人血を別個に用いた(n=3試験)。次いで遠心分離により血漿を回収した。回収した血漿の抗酸化能力(PAO)を抗酸化能測定キットPAO(日研ザイル株式会社)を用いて測定した。血液が膜と接触することにより生体反応が惹起し、PAOが低下するが、抗酸化能を有する膜ではこのPAO低下が抑制されることから、得られたPAO値が高いほど血液処理膜の血液に対する抗酸化能が高いと言える。
[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
[エンドトキシン侵入率(以下「ET透過率」と略す)]
血液処理膜9984本からなる糸束を、側面に上下2つのノズル(透析液側ノズル)を有する約280mm長の筒状容器に充填して両端部をウレタン樹脂で包埋後、硬化したウレタン部分を切断して中空糸膜が開口した端部に加工した。この両端部に液体導入(導出)用のノズル(血液側ノズル)を有するヘッダーキャップを装填し透析モジュールの形状に組み上げ、血液側ノズルが上下に向くように固定した。
[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.
汚染透析液の過酷モデル液として、エンドトキシン濃度97100EU/Lに調製した水道水をポンプを用いて500ml/minの流量で下側Dノズルから導入し、透析液側から血液側に逆ろ過を行うことにより上側Bノズルから20分間排出した。20分排出後のろ液をサンプリングしてエンドトキシン濃度を測定し、ろ過前の液のエンドトキシン濃度に対する割合として、ET透過率を小数点以下2桁まで百分率で求めた。エンドトキシン濃度の測定は、エンドトキシン測定機(和光純薬工業株式会社製、トキシノメーターET−2000)と同社の専用LAL試薬を用い、比色(時間分析)法にて行った。 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.
[血液処理膜からのエアー抜け性の評価]
血液処理膜9984本からなる糸束を、約280mm長の筒状容器に充填して両端部をウレタン樹脂で包埋後、硬化したウレタン部分を切断して中空糸膜が開口した端部に加工した。この両端部に液体導入(導出)用のノズルを有するヘッダーキャップを装填しモジュールの形状に組み上げ、ノズルが上下に向くように固定した。ポンプを用いて注射用水を100ml/minの流量で下側のノズルから導入し、上側のノズルから排出してモジュール内の空気を注射用水に置換した。置換が終了したら注射用水を流しながら注射器を用いて下側のノズルから空気を10ml注入した。注射用水とともに上側のノズルから出た空気を捕集し、10分間後の捕集量の注入量に対する割合から空気回収率を求めた。空気回収率が低いほどエアー抜け性が劣ること、ならびに膜厚部〜外表面でのエアーたまりによる透過性への悪影響の可能性があることを意味する。
[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.
[表面PVP濃度の測定]
中空糸膜の表面PVP濃度は、X線光電子分光法(XPS)によって決定される。すなわち、外表面測定の場合は中空糸膜の試料を両面テープ上に数本並べたものを試料とし、内表面測定の場合は縦方向に切り開いて内面を露出させた中空糸を両面テープ上に数本並べたものを試料として、通常の方法で表面の元素濃度を測定した。得られたC1s、O1s、N1s、S2pスペクトルの面積強度より、装置付属の相対感度係数を用いて窒素の表面濃度(A)とイオウの表面濃度(B)を求め、以下の式(7)より内表面PVP濃度を算出した。
内表面PVP濃度={A×111/(A×111+B×C)}×100 (%) (7)
ここでCはPSfの繰り返し単位の「式量÷イオウの元素数」であり、(1)式のPSfの場合は442である。また、(7)式中の111はPVPの繰り返し単位の「式量÷窒素の元素数」である。
[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.
[外表面接触角度の測定]
DataPhysics Instruments GmbH製の動的接触角測定装置DataPhysics DCAT11と付属ソフトウェアを用い、末端を焼いたナイフで封じた中空糸膜の前進接触角と後退接触角を測定した。測定条件は以下のとおり。
浸漬液体:注射用水、水温:25℃、浸漬速度:0.10mm/sec、浸漬深さ:10.00mm、測定繰り返し回数:6回(1回目のデータは除き、残りのデータを平均)
[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)
[長期保存安定性に対するモデル試験]
血液処理膜を以下の操作により、血液透析モジュールに成型・組み立てした。即ち、9984本からなる糸束を、約280mm長の筒状容器に充填して両端部をウレタン樹脂で包埋後、硬化したウレタン部分を切断して中空糸膜が開口した端部に加工した。この両端部に液体導入(導出)用のノズルを有するヘッダーキャップを装填しモジュールの形状に組み上げ、300ppmのピロ亜硫酸ナトリウム水溶液を封入し各ノズルを密栓した状態で25kGyのγ線を照射した。得られたモジュールを60℃の恒温庫の中で3週間加熱することにより、長期保管に相当する加速試験を実施した。加熱開始前と終了後のモジュールを解体して取り出した血液処理膜1.5gを70℃の純水150mlで1時間抽出した。抽出液の350nm〜220nmのUVスペクトルを測定し、最大吸収を示す吸光度をもって血液処理膜からの溶出物の量の代用指数とした。
[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.
[実施例1]
PSf17重量部、PVP4重量部、α−トコフェロール0.5重量部、DMAc79重量部からなる製膜原液を作成した。中空内液にはDMAC41重量%水溶液を用い、スリット幅50μmの紡糸口金から吐出させた。この際、吐出時の製膜原液の温度は60℃であった。吐出した原液をフードで覆った落下部を経て50cm下方に設けた水よりなる90℃の凝固浴に浸漬し、30m/分の速度で凝固、精錬を行った後、乾燥機に導入した。120℃で2分間減率乾燥後、さらに180℃で0.5分間の加熱処理を行った後、9984本の中空糸膜を巻き取った。なお、乾燥後の膜厚を45μm、内径を185μmに合わせるように製膜原液、中空内液の吐出量を調整した(以下の実施例、比較例も同様に膜厚、内径を調整)。
得られた中空糸膜束のバルクVE量は22mg/g、VE規格化ピーク強度は内表面で1.4×10−4、外表面で1.8×10−4であった。人血試験によるPAO値は平均924(人血A:1087、人血B:735、人血C:951)であった。タフネスは1610gf・%であった。ET透過率は0.02%であった。内表面PVP量は36%、外表面PVP量は48%であり、外表面の後退接触角は15°、前進接触角は44°であった。
得られた中空糸膜束を血液透析モジュールに組み立て、長期保存安定性のモデル試験を行った結果、溶出液のUV吸光度は加熱前0.07、加熱後0.06であった。
[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.
[実施例2]
PSf17重量部、PVP4重量部、α−トコフェロール2重量部、DMAc 77重量部からなる製膜原液を用い、実施例1と同様に凝固、精錬、乾燥した後、170℃で1分間加熱処理を行った後、9984本の中空糸膜を巻き取った。
得られた中空糸膜束のバルクVE量は76mg/g、VE規格化ピーク強度は内表面で4.3×10−3、外表面で8.5×10−3、空気回収率は97%であった。人血試験によるPAO値は平均2625(人血A:2482、人血B:2829、人血C:2564)であった。タフネスは1125gf・%であった。ET透過率は0.01%であった。
[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%.
[比較例1]
PSf17重量部、PVP4重量部、DMAc79重量部からなる製膜原液を用い、実施例1と同様に凝固、精錬、乾燥、加熱処理、巻き取りを行って中空糸膜束を得た。
得られた中空糸膜束のバルクVE量は0mg/g、VE規格化ピーク強度は内表面で0.0、外表面で0.0、空気回収率は99%であった。人血試験によるPAO値は平均841(人血A:894、人血B:747、人血C:881)であった。タフネスは1265gf・%であった。ET透過率は0.24%であった。内表面PVP量は35%、外表面PVP量は47%であり、外表面の後退接触角は14°、前進接触角は32°であった。
得られた中空糸膜束を血液透析モジュールに組み立て、長期保存安定性のモデル試験を行った結果、溶出液のUV吸光度は加熱前0.06、加熱後0.19であった。
[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.
[比較例2]
PSf15重量部、PVP9重量部、α−トコフェロール0.5重量部、DMAc30重量部、DMSO46重量部からなる製膜原液と、DMAc30重量%、DMSO30重量%、水40重量%からなる中空内液を用い、実施例1と同様に凝固、精錬した後、9984本の中空糸膜を湿潤状態で巻き取った。
得られた中空糸束を80℃で420分間減率乾燥を行い、さらに同じ温度で240分間加熱処理を行った。得られた中空糸膜束のバルクVE量は24mg/g、VE規格化ピーク強度は内表面で8.9×10−5、外表面で8.8×10−5であった。人血試験によるPAO値は平均850(人血A:852、人血B:772、人血C:926)であった。タフネスは1131gf・%であった。ET透過率は0.19%であった。
[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%.
[比較例3]
製膜原液としてPSf17重量部、PVP4重量部、α−トコフェロール0.4重量部、DMAc77重量部を用い、実施例1と同様に凝固、精錬、乾燥、加熱処理、巻き取り、を行って中空糸膜束を得た。
得られた中空糸膜束のバルクVE量は20mg/g、VE規格化ピーク強度は内表面で1.0×10−4、外表面で1.4×10−4であった。人血試験によるPAO値は平均887(人血A:938、人血B:853、人血C:870)であった。タフネスは1140gf・%であった。ET透過率は0.15%であった。
[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%.
[比較例4]
PSf17重量部、PVP4重量部、α−トコフェロール2.1重量部、DMAc76.9重量部からなる製膜原液を用い、実施例1と同様に凝固、精錬、乾燥、巻き取って中空糸膜束を得た。
得られた中空糸膜束のバルクVE量は80mg/gであった。タフネスは950gf・%であった。
[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 ·%.
上記表1の実施例1と比較例1、2を比較することにより、非ビタミンE含有血液処理膜である比較例1に対して有意に抗酸化性を示し、且つエンドトキシン侵入の阻止効果を示す為には、膜内表面のVE規格化ピーク強度が1.4×10−4以上、且つ膜外表面のVE規格化ピーク強度が2.8×10−4以上必要であることが分かる。さらに実施例1と比較例3を比較することにより、膜内表面のVE規格化ピーク強度を1.4×10−4以上とするためには、バルクVE量が20mg/g以上が必要であることが分かる。一方、実施例2と比較例4を比較することにより、タフネス1000gf・%以上を確保するためにはバルクVE量が76mg/g以下であることが必要であることが分かる。
また、比較例2は、従来技術である特許文献4の実施例2に記載の膜を追試したものであるが、この場合には機械的強度は十分であるものの、膜表面VE量が十分でなく、非ビタミンE含有膜である比較例1に対して抗酸化性に優位性は認められず、さらにエンドトキシン侵入の阻止効果も不十分であった。
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.
[比較例5]
製膜原液としてPSf17重量部、PVP4重量部、α−トコフェロール1重量部、DMAc78重量部からなる製膜原液を用い、比較例2と同様に凝固、精錬を行った湿潤状態の中空糸束を100本巻き取ることにより得た湿潤状態の中空糸束を80℃で3時間乾燥を行った。
得られた中空糸膜束のバルクVE量は40mg/g、表面VE量は0.7mg/g、VE規格化ピーク強度は内表面で9.1×10−5、外表面で9.6×10−5、ET透過率は0.20%であった。以下同様に、主な処理条件と測定値を表2に示した。
[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.
[比較例6]
比較例6の中空糸束を130℃で1分間加熱処理を行った。
得られた中空糸膜束のバルクVE量は40mg/g、表面VE量は2.6mg/g、VE規格化ピーク強度は内表面で9.8×10−5、外表面で1.1×10−4、ET透過率は0.18%であった。
[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%.
[実施例3]
比較例6の中空糸束を140℃で1分間加熱処理を行った。
得られた中空糸膜束のバルクVE量は40mg/g、表面VE量は3.6mg/g、VE規格化ピーク強度は内表面で1.8×10−4、外表面で2.3×10−4、ET透過率は0.01%であった。
[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%.
[実施例4]
比較例6の中空糸束を180℃で0.1分間加熱処理を行った。
得られた中空糸膜束のバルクVE量は40mg/g、表面VE量は4.5mg/g、VE規格化ピーク強度は内表面で2.3×10−4、外表面で3.2×10−4、ET透過率は0.01%であった。
[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%.
[比較例7]
比較例6と同じ製膜原液を実施例6と同様に凝固、精錬、乾燥した後、190℃で0.1分間加熱処理を行って巻き取ろうと試みたが中空糸が軟化し、巻き取ることが出来なかった。
[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.
上記表2の実施例3と比較例6を比較することにより、表面へのビタミンEの十分なマイグレーションには140℃以上の温度が必要であることが分かる。さらに実施例4と比較例7を比較することにより、最低限の加熱時間0.5分間でも血液処理膜を安定的に製造するためには加熱温度180℃以下が必要であることが分かる。 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.
[比較例8]
比較例4の中空糸束を110℃で1080分間加熱処理を行った。
得られた中空糸膜束のバルクVE量は80mg/g、VE規格化ピーク強度は内表面で6.2×10−3、空気回収率は79%であった。
[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%.
上記表3の実施例2と比較例8を比較することにより、内表面VE規格化ピーク強度が4.3×10−3を超えると空気回収率が顕著に低下することが分かる。 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.
表4に示すとおり、実施例1と比較例1の血液処理膜はいずれも膜外表面の後退接触角が同等でありながら、前進接触角は実施例1の膜の方が高くなった。後退接触角の同等性については、実施例1の膜は、外表面にビタミンEが存在するにも関わらず、ビタミンEを含まない膜と同等の親水性をPVP鎖により発揮していることになる。つまり、実施例1の膜では、外表面のPVPの殆どが機能を損なうことなく、親水性に寄与できている。一方、前進接触角の差異については、実施例1の膜の方が高値であることから、実施例1の膜は、疎水的雰囲気下ではPVP鎖ではなく、疎水面が支配的になることを示している。これは、外表面に高率に析出したVEの層によるものである。
それゆえ、実施例1の如き本発明の血液処理膜は、きわめて高濃度のエンドトキシン溶液を負荷しても、エンドトキシンの透過率はごくわずかである。このような高濃度のエンドトキシン溶液を用いた過酷試験においてさえエンドトキシンの透過がほとんど認められないということは、本発明の血液処理膜にはエンドトキシンへの吸着座が多数存在することと、しかも安定な吸着座であることを示唆している。
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.
[比較例9]
PSf19重量部、PVP9重量部、DMF72重量部からなる製膜原液と、DMF60重量部、水40重量部の混合液に対して0.1重量部のα−酢酸トコフェロールと0.1重量部のプルロニックF−68を添加した中空内液を用い、実施例1と同様に凝固した後、60℃の温水を1L/分で1時間シャワー洗浄して9984本の中空糸膜を湿潤状態で巻き取った。さらに110℃の温水中1時間処理し、洗浄した。
得られた中空糸膜束のVE規格化ピーク強度は外表面で0.0であった。
得られた中空糸膜束を血液透析モジュールに組み立て、長期保存安定性のモデル試験を行った結果、溶出液のUV吸光度は加熱前0.06、加熱後0.17であった。
[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.
比較例9は特許文献3の実施例2に相当する。上記表5の実施例1と比較例1、9を比較することにより、長期保存に相当する60℃、3週間の加熱によっても本発明の血液処理膜の溶出量は透析型人工腎臓装置承認基準(昭和58年6月20日薬発第494号薬 務局長通知)の範囲内である吸光度0.1以下であるが、脂溶性抗酸化剤を含まない比較例1や外表面〜膜厚部にかけて脂溶性抗酸化剤を含まない比較例9では基準を大幅に超過しており、本発明の血液処理膜の良好な長期保存安定性が分かる。 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.
本発明の血液処理膜は血液と接触した時の生体内抗酸化作用に優れると同時に処理液へのエンドトキシン侵入の危険性が少なく、且つ製造過程あるいは使用時の膜破断など不意の事故を予防する実用強度を有し、さらに生産合理性の高いので、効果的で安全な血液透析など血液の体外循環処理に用いられる。 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)
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.
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