JP4055634B2 - Hemodialysis membrane and method for producing the same - Google Patents
Hemodialysis membrane and method for producing the same Download PDFInfo
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Description
【０００１】
【発明の属する技術分野】
本発明は、血液透析膜、血液濾過膜および血液濾過透析膜に用いられる血液浄化膜およびその製造方法に関するものである。さらに詳しくは慢性腎不全の血液透析等に用いられた際、膜性能の経時安定性に優れ、且つ不要な低分子タンパク質等の除去を効率よく行いうる血液透析用の中空糸膜に関する。
【０００２】
【従来の技術】
腎不全患者に対する最も一般的な治療方法として血液透析療法があるが、これに使用する血液透析器に関する。
【０００３】
従来、血液透析に用いられる中空糸膜の経時安定性を改善して膜表面へのたんぱく質等の吸着による膜の目詰まりを抑制する方法として、中空糸膜の内径を小さくすることで血液の流速を向上させ、さらに中空形成剤として気体を用いる乾湿式紡糸法に製造することで膜内表面を滑らかにする方法がある（例えば、特許文献１参照）。しかし、この方法では中空形成剤として気体を用いるため中空糸膜をボビン状に巻き取る際に、一般的に用いられる流動パラフィンおよびイソプロピルアルコール等の内液が入っていないために糸の真円度が低下したりする潰れが生じ、臨床使用時に残血が発生する可能性が高くなる。さらに、中空糸膜の内径を小さくすると血液側の圧力損失が上昇してしまうという問題があった。
【０００４】
【特許文献１】
特開平０８−０００９７０（第２頁）
【０００５】
【発明が解決しようとする課題】
本発明は上記の欠点を解決しようとするものであり、その目的は膜の孔径が大きく、不要なタンパク質等の除去を行いうる中空糸膜の血液透析時の経時安定性を改善するために、中空糸膜の膜構造および膜の湿潤状態での挙動を鋭意検討した結果、血液透析膜の湿潤状態の膜構造変化を大きくすることで経時変化が少なくなることを見出した。
【０００６】
また、中空糸膜の凝固が完了して膜構造が安定した後に張力が掛かった状態で７５℃超、９０℃以下の水溶液で加熱処理する事により、血液透析中に膜の微細構造が変化して、孔径が徐々に大きくなる事で、血液透析中の目詰まりを打ち消す方向に働く。さらに、上記の血液透析膜は血液濾過や血液透析濾過にも好適に用いることが可能なことを見出した。
【０００７】
【課題を解決するための手段】
本発明者らは、上記課題を解決すべく鋭意検討した結果、次のような血液透析膜およびその製法を見出したものである。
（１）内径が１００〜３００μｍ、純水の限外濾過係数が１５０〜５００ｍｌ／（ｍ２・ｍｍＨｇ・ｈｒ）の中空糸膜であって、生理食塩水または透析液でプライミングし、湿潤状態のまま３７℃、２４時間放置した後に１重量％牛血清アルブミン水溶液（ｐＨ７．５）を用いて測定したアルブミンの篩い係数（ＳＣＡｌｂ（２４ｈ））が０．３≧ＳＣＡｌｂ（２４ｈ）≧０．００５であって、プライミング直後に１重量％牛血清アルブミン水溶液を用いて測定したアルブミンの篩い係数（ＳＣＡｌｂ（０ｈ））との比が１．８０≧ＳＣＡｌｂ（２４ｈ）／ＳＣＡｌｂ（０ｈ）≧１．２、β２−ミクログロブリンの篩い係数が０．３５以上であることを特徴とする血液透析膜。
（２）中空糸膜がセルロース系ポリマーから成ることを特徴とする（１）に記載の血液透析膜。
（３）セルロース系ポリマーがセルローストリアセテートであることを特徴とする（２）に記載の血液透析膜。
（４）実質的に膜構造の固定された中空糸膜を張力のかかった状態で７５℃超、９０℃以下の水および／またはグリセリン液中で加熱処置することによって膜の微細構造を調整したものであることを特徴とする（１）〜（３）のいずれか記載の血液透析膜。
（５）製膜原液を凝固させた後の、実質的に膜構造が固定された中空糸膜を張力のかかった状態で７５℃超、９０℃以下の水および／またはグリセリン液中で加熱処理することを特徴とする血液透析膜の製造方法。
（６）中空糸膜がセルロース系ポリマーから成ることを特徴とする（５）に記載の血液透析膜の製造方法。
（７）セルロース系ポリマーがセルローストリアセテートであることを特徴とする（６）記載の血液透析膜の製造方法。
【０００８】
本発明の上記（１）〜（５）で示す性能を有する血液透析膜は、具体的には、（６）該血液透析膜が実質的に膜構造の固定された中空糸膜を張力のかかった状態で７５℃超、９０℃以下の高温の液体で加熱処理することによって膜の微細構造を調整した手法により収得されたものである。この加熱処理により膜の微細構造が微妙に変化するということは突き止めているが、実際に定量的にどのような質的な変化、或いは構造的な変化があったかは詳細には解明できていない。しかし、このような手法により入手された血液透析膜は本件明細書の特に実施例などにも詳細に示すとおり、その性能においては卓越したものであることは明白である。
【０００９】
本発明の上記（１）〜（５）で示す性能を有する血液透析膜である中空糸膜の経時変化の安定性、および性能を持続するための最適な膜の状態および性能を定量的に解析した結果、ＳＣＡｌｂの比がＳＣＡｌｂ（24ｈ））／（ＳＣＡｌｂ（0ｈ））≧１．２であるということを知見したものである。
もちろん、（ＳＣＡｌｂ（24ｈ））／（ＳＣＡｌｂ（0ｈ））≧１．２ということは、最適には１．５０、１．７５、１．８０、２．００などの適正な範囲があるが、技術的に可能な高度の手法によるなら、２．００、３．００のような非常に高い比を有することもあり得る。
そして、そのＳＣＡｌｂ（24ｈ）／ＳＣＡｌｂ（0ｈ）≧１．２という性能を有する中空糸膜は、具体的には、上記（６）〜（７）で示す、即ち、製膜原液を凝固させた後の、実質的に膜構造が固定された中空糸膜を張力のかかった状態で７５℃超、９０℃以下の高温の液体で加熱処理することによる製造法によって製造することができる。
【００１０】
本発明の血液透析膜の製造方法を詳細に説明すると、まず、その加熱処理は、通常は、製膜原液を凝固した後に、一旦水洗などをしてから膜構造を安定化した状態にある中空糸膜を張力のかかった状態で６５〜１００℃、好ましくは７５〜９０℃の範囲内の高温の液体で加熱処理をすることにより膜構造を改変する。その処理温度７５〜９０℃の範囲内である、例えば８０℃、８５℃などの任意の温度で、本発明の特性を備えた血液透析膜が製造可能である。その高温液体による処理時間は、実用的には、中空糸膜を張力下、高温液体を走行させることにより行うことからすると、中空糸膜が高温液体中を走行する速度および距離により決まる。通常は、高温液体と接触する時間は、１分以内程度で済むが、実用的には３〜３０秒程度で高温液体中を通過させ、その後に常温に放置することによりその効果が発揮される。
【００１１】
走行する中空糸膜に加える張力とは、その膜を構成する材料が、例えば、再生セルロースであるか、或いはセルローストリアセテートであるかというように、材料の違いにより張力も微妙に変わるような性格のものであって、高温液体の温度が、例えば７５℃である、９０℃程度であるかというような、温度条件の違いも微妙に影響するために、一概に決めることが出来ないが、材料、温度などの違いの条件を考慮しなければならない。その張力の適正な範囲とは、中空糸膜が高温液体中で弛まずに単に真っ直ぐに張ることによる糸の形状を保つ程度の張力条件から、過度に張力をかけ過ぎないために、糸が伸張して形状が著しく変わることや、切断することが無いような張力条件までの、比較的緩和された状況に応じた広範囲の張力下で実施することを言う。実際には、血液透析膜の最適な性能を発現させるための要素である、中空糸膜の材料、走行速度、高温液体温度などの諸条件を考慮して全体のバランスに配慮して、試行錯誤により適正な張力条件を決めることが多い。セルローストリアセテート中空糸膜の場合、製膜条件によっても異なるが、およそ１〜１０％程度の長さ方向の収縮が起こる。ここで、加熱処理槽の入口ローラー速度と出口ローラー速度は等速で回転させているため、加熱槽を走行する中空糸膜は実質的に１〜１０％程度引っ張られた状態で加熱処理が行われることになる。
【００１２】
加熱処理に用いる高温液体とは、本発明の実施例では、実用的には６５％程度のグリセリン水溶液を用いているが、実際には７５〜９０℃程度の温度において比較的安定で、しかも作業上の健康や中空糸膜に残留して中空糸膜自体および治療に際して悪い影響を与えない液体ならば任意に選択可能である。
【００１３】
【発明の実施の形態】
以下、本発明を詳細に説明する。
本発明の中空糸膜の内径は１００〜３００μｍである。内径が１００μｍ未満の場合には中空糸膜の圧力損失が大きくなるため溶血のおそれが生じ、３００μmより大きい場合には中空糸膜内面の剪断速度が小さく、濾過に伴いタンパク質等が膜の内面に堆積し易くなる可能性がある。
【００１４】
純水の限外濾過係数は１５０〜５００ml／(ｍ2・mmHg・ｈｒ)である。限外濾過係数が１５０ml／(ｍ2・mmHg・ｈｒ)未満では、透析器の膜面積によらずアルブミン漏出量を２g以下に低く抑えることは可能であるが、β2−ミクログロブリンのクリアランスを臨床症状の改善効果が見られる５０以上に到達させるために膜面積をかなり大きくする必要が生ずる。また、限外濾過係数が５００ml／(ｍ2・mmHg・ｈｒ)を越えると高いβ2−ミクログロブリンクリアランスは発現するものの、膜面積によらずアルブミン漏出量が多くなり低タンパク血症をおこさない５g／（1透析）以下に抑えることができず、全ての患者に対して安全に使用できる透析器が得られない可能性がある。
【００１５】
生理食塩水または透析液プライミング後湿潤状態で３７℃、２４時間放置後に測定した１重量％牛血清アルブミン水溶液の篩い係数（ＳＣＡｌｂ（２４ｈ））とプライミング直後に測定した１重量％牛血清アルブミン水溶液の篩い係数（ＳＣＡｌｂ（０ｈ））で、ＳＣＡｌｂ（２４ｈ）／ＳＣＡｌｂ（０ｈ）≧１．２であることが必要である。ＳＣＡｌｂ（２４ｈ）／ＳＣＡｌｂ（０ｈ）が１．２未満である場合、膜の目詰まりにより血液透析中の血液濾過係数の変動が大きく、経時安定性に欠け、性能低下が大きくなり初期性能を維持することができず安定した血液透析を行うことができない。より安定した血液透析のためには、好ましくは１．５以上が必要である。
【００１６】
生理食塩水または透析液プライミング後湿潤状態で３７℃、２４時間放置後に測定した１重量％牛血清アルブミン水溶液の篩い係数（ＳＣＡｌｂ（２４ｈ））は、０．３≧ＳＣＡｌｂ（２４ｈ）≧０．００５である。０．３より大きい場合には、血液透析中のタンパク質漏出量が５ｇ／（1透析）以上となり低アルブミン血症を発症する可能性が生じ、栄養状態の良好な患者にしか使用できなくなってしまう。患者の栄養状態に拘わらず使用できるような汎用性の広い血液透析膜としては、好ましくはＳＣＡｌｂ（２４ｈ）は０．２以下であることが望ましい。一方、０．００５未満ではβ２−ミクログロブリンのクリアランスが低くなり、十分な治療効果が期待できない。治療効果を高めるためには、より好ましくはＳＣＡｌｂ（２４ｈ）≧０．０１であることが望ましい。
【００１７】
（１重量％アルブミン篩い係数測定方法）
アルブミン・ウシ血清製（和光 一級 コード０１９−０７４９４）をｐＨ７．５の５０ｍＭリン酸緩衝液に溶かし１重量％のアルブミン水溶液を調整し、再度ｐＨ７．５に調整したものを測定に用いた。本発明の中空糸膜を用いて作製した１．５ｍ2の血液透析器の血液側に生理食塩水１，０００ｍｌ流し、次に透析液側に生理食塩水１，０００ｍｌを流し、血液側および透析液側に生理食塩水を充填したまま栓をしてプライミングを終了する。その後、３７℃の恒温槽に２４時間浸漬したモジュールとプライミング直後のモジュールを準備し、アルブミン篩い係数の測定に使用した。
モジュールは篩い係数を測定する直前にｐＨ７．５の５０ｍＭリン酸緩衝液で置換し、３７℃の１重量％アルブミン水溶液を２００ｍｌ／ｍｉｎで血液側に流し、３０ｍｌ／ｍｉｎで濾過をかけて、濾過を開始してから３０分後に１重量％アルブミン溶液（ＣI）、血液側出口の溶液（ＣO）および濾過側の溶液（ＣＦ）を採取し、分光光度計で波長UV280nmの吸光度を測定する。その測定値から下記の様にアルブミン篩い係数を求めた。各溶液は適宜希釈して測定した。
アルブミン篩い係数＝２×ＣＦ÷（ＣI＋ＣO）
【００１８】
（純水の限外濾過係数の測定方法）
中空糸膜モジュールを使用し、膜の内外両側に純水を満たし、37℃に恒温した。膜の内側に通じるモジュール入口から圧力をかけて37℃の純水を流し、膜の内側と外側の圧力差、すなわち膜間圧力差を生じせしめ、１分間に膜を通じて膜外側に出てくる純水の量を測定した。膜間圧力差（TMP）はTMP=（Pi+Po）／2とする。ここでPiはモジュール入口圧力、Poはモジュール出口圧力である。）４点の異なった膜間圧力差において、１分間の透水量を測定し、膜間圧力差と透水量の２次元座標にプロットして、それらの近似直線の傾きを求めた。この数値に６０をかけ、中空糸膜モジュールの膜面積で割って中空糸膜の純水の限外濾過係数を求めた（以下ＵＦＲと略記する。単位はｍｌ／(ｍ２・ｈｒ・ｍｍＨｇ)）。
【００１９】
（β２−ミクログロブリン篩い係数の測定方法）
濾過速度１０ｍｌ／分で血液濾過開始後１５分時点のモジュールの入口と出口の血液及び濾過液をサンプリングして、酵素免疫測定法（例えば、グラザイムβ2-Microglobulin-EIA Test 和光純薬工業）等によりβ2-ミクログロブリン（以下、β2-MGと略記する。）の濃度を測定する。なお、当該測定でモジュールに流す牛血液には適量のヒト由来β2-MGを添加して行い、サンプリングした血液は必要に応じて遠心分離してβ2-MGの測定に供する。これらのβ2-MGの濃度の値から下記式に従ってβ2-MGのＳＣを求める。
ＳＣ＝Ｃfil ／（（ＣI ＋ＣO ）／２）
Ｃfil ：濾過液のβ2-MG濃度
ＣI ：モジュール血液側入口の血液のβ2-ＭＧ濃度
ＣO ：モジュール血液側出口の血液のβ2-ＭＧ濃度
【００２０】
（中空糸内径の測定方法）
中空糸断面のサンプルは以下のようにして得ることができる。測定には中空形成材を洗浄、除去した後、中空糸膜を乾燥させた状態で観察することが好ましい。乾燥方法は特に問わないが乾燥により著しく形態が変化する場合には中空形成材を洗浄、除去した後、純水で完全に置換し、湿潤状態で形態を観察することが好ましい。乾燥後の中空糸膜を厚さ2mmのスライドグラスの中央に開けられたφ1mmの孔に適当数通し、スライドグラスの上下面でカミソリによりカットし、中空部を露出させた断面サンプルを得る。得られたサンプルは投影機（Nikon-12A）を用いて、視野内の任意の5サンプルを無作為に抽出し、各中空糸膜断面内側の短径と長径をそれぞれ測定し、その算術平均値を中空糸膜1個の内径とした。さらに5サンプルの平均値をもって中空糸膜内径とした。
【００２１】
実質的に膜構造が安定し中空糸膜に張力のかかった状態で７５℃超、９０℃以下の水溶液で加熱処置することが必要である。実質的に膜構造が安定し中空糸膜に張力のかかった状態とは、例えば紡糸原液を二重環状紡糸孔の外側から押しだし、中央からは流動パラフィンを送り込み、凝固性液体中で凝固され、水洗後の中空糸膜は既に膜構造が固定化され安定した状態のことを指しており、さらに中空糸膜の走行中は張力のかかった状態のことを示している。また、７５℃超、９０℃以下の水溶液とは水単独、またはグリセリン等の水溶液で中空糸膜の素材を溶解しないものであれば何でも良い。中空糸膜の凝固が完了して膜構造が安定した後に張力が掛かった状態で７５℃超、９０℃以下の水溶液で加熱処理する事により、原因はわからないが血液透析中に膜の微細構造が変化して、孔径が徐々に大きくなり、一方、血液透析中に時間とともに膜の細孔が目詰まり起こすが、それを孔径が拡大することで打ち消す方向に働く。さらに、上記の血液透析膜は血液濾過や血液透析濾過にも好適に用いることが可能なことを見出した。より血液濾過性能を安定させるために８０℃以上であることが好ましい。
【００２２】
β２−MGの篩い係数は０．３５以上あることが好ましい。β2−ＭＧの篩い係数が０．３５未満の場合にはβ２−MGのクリアランスが低くなり十分な治療効果が期待できない。好ましくは、０．５以上である。より好ましくは０．６５以上、さらに好ましくは０．７５以上である。
【００２３】
本発明における中空糸膜の材質としては、再生セルロース、改質セルロース、酢酸セルロース、ポリメタクリル酸メチル、ビニルアルコール−エチレン共重合体、ポリアクリロニトリル、ポリスルホン等が挙げられるが、タンパク吸着量が少なく、透水性、溶質透過性、生体適合性に優れる酢酸セルロースが好ましい。より高透水量で、溶質分離特性に優れる点でセルローストリアセテートがより好ましい。
【００２４】
本発明に使用される中空糸膜は、例えば以下のように製造することができるが、本発明は何等以下に限定されるものでは無い。セルローストリアセテート１５〜２２重量％、溶媒４６．８〜６８重量％、非溶媒１０〜３８．２重量％を含む紡糸原液を１３０〜１９０℃に加熱して溶解し、二重環状紡糸孔の外側から押しだし、中央からは流動パラフィンを送り込み、押しだされた紡糸原液は空中を走行した後、５〜６０℃の凝固性液体中で凝固され、水洗し、実質的に膜構造が安定した状態にある中空糸膜を張力のかかった状態で７５℃〜９０℃の高温の液体で加熱処理することを特徴とする。
【００２５】
【実施例】
以下、実施例により本発明の効果ならびにより詳細な説明を加えるが、本発明は実施例によりなんら限定されるものではない。
【００２６】
（実施例１）
セルローストリアセテート１９．０重量％、N−メチルピロリドン５６．７重量％、トリエチレングリコール２４．３重量％を１５０℃で溶解して製膜溶液を得た。１２０℃に加温したチューブインオリフィスノズルから中空形成剤として流動パラフィンを用いて製膜原液を吐出、エアギャップを通過後、３０℃の水中で凝固させた。その後、水洗し膜構造を安定化させた後、７８℃、６５％のグリセリン水溶液中を通過させ、ドライヤーで乾燥しボビンに巻き上げた。得られた中空糸膜の内径は１９９μm、膜厚は１５μmであった。このように得られた中空糸膜を用いて、膜面積１．５m2の中空糸膜モジュールを作製し、限外濾過速度（ｍｌ／(ｈｒ・m2・mｍＨｇ)）、ＳＣＡｌｂ（０ｈ）、ＳＣＡｌｂ（２４ｈｒ）を測定した結果を表１に示す。
【００２７】
（実施例２）
セルローストリアセテート１７．５重量％、N−メチルピロリドン５７．８重量％、トリエチレングリコール２４．７重量％の製膜原液を用い、凝固させた。その後、水洗膜構造を安定化させた後、８５℃、６５％のグリセリン溶液で処理した以外は実施例１と同様に中空糸膜を作製した。その中空糸膜の性能を評価したところ、実施例１に示す程度の性能を有することが確認できた。結果を表1に示す。
【００２８】
（実施例３）
実施例２でグリセリン水溶液の温度を９０℃、５０％にした以外は実施例１と同じ条件で中空糸膜を作製した。得られた中空糸膜の内径は１９６μm、膜厚は１５μmであった。この様にして得られた中空糸膜から膜面積１．５m2の中空糸膜モジュールを作製して、実施例１と同様に中空糸膜の性能評価を行った結果を表１に示す。
【００２９】
（比較例１）
水洗し膜構造を安定化させた後、６０℃、６５％のグリセリン水溶液中を通過させた以外は実施例１と同じ条件で中空糸膜を製造した。
得られた中空糸膜の内径は２０１μm、膜厚は１５μmであった。
この様にして得られた中空糸膜から膜面積１．５m2の中空糸膜モジュールを作製して、実施例１と同様に中空糸膜の性能評価を行った。結果を表１に示す。
【００３０】
（比較例２）
水洗し膜構造を安定化させた後、９５℃、６５％のグリセリン水溶液中を通過させた実施例１と同じ条件で中空糸膜を製造した。
得られた中空糸膜の内径は２０１μm、膜厚は１５μmであった。
この様にして得られた中空糸膜から膜面積１．５m2の中空糸膜モジュールを作製して、実施例１と同様に中空糸膜の性能評価を行った。結果を表１に示す。
このように、本発明の優れた性能を有する中空糸膜を製造するためには、中空糸膜の内径が１００〜３００μｍという程度のことは定量的に把握できるが、一方で、中空糸膜の微妙な構造変化を定量的に特定することは技術的に相当の技量を要する。いずれにせよ、膜構造を安定化した状態にある中空糸膜を張力のかかった状態で、６５〜１００℃、好ましくは７５〜９０℃の範囲内の高温の液体で加熱処理することにより本発明特有の性能と構造を有する中空糸膜が製造され得るということは、本発明者の知見に基くものである。
【００３１】
【表１】
【発明の効果】
以上のように、血液透析膜の湿潤状態放置時の膜構造変化を惹起することで血液透析中の経時安定性が優れ、性能低下が少なく性能を維持することができる。また、中空糸膜の凝固が完了して膜構造が安定した後に張力が掛かった状態で７５℃超、９０℃以下の水溶液で加熱処理する事により、血液透析中に膜の微細構造が変化して、孔径が徐々に大きくなる事で、血液透析中の目詰まりを打ち消す方向に働く。さらに、上記の血液透析膜は血液濾過や血液透析濾過にも好適に用いることが可能なことを見出した。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a hemodialysis membrane, a blood filtration membrane, a blood purification membrane used for a blood filtration dialysis membrane, and a method for producing the same. More particularly, the present invention relates to a hollow fiber membrane for hemodialysis that is excellent in stability over time of membrane performance and can efficiently remove unnecessary low-molecular proteins and the like when used for hemodialysis of chronic renal failure.
[0002]
[Prior art]
The most common treatment method for patients with renal failure is hemodialysis, which relates to a hemodialyzer used for this.
[0003]
Conventionally, as a method of improving the temporal stability of hollow fiber membranes used for hemodialysis and suppressing clogging of the membrane due to adsorption of proteins etc. to the membrane surface, the flow rate of blood is reduced by reducing the inner diameter of the hollow fiber membrane. In addition, there is a method of smoothing the inner surface of the membrane by producing a dry and wet spinning method using a gas as a hollow forming agent (see, for example, Patent Document 1). However, since this method uses a gas as a hollow forming agent, when winding the hollow fiber membrane into a bobbin shape, it does not contain commonly used liquids such as liquid paraffin and isopropyl alcohol. As a result, there is a high possibility that residual blood will be generated during clinical use. Furthermore, when the inner diameter of the hollow fiber membrane is reduced, there is a problem that the pressure loss on the blood side increases.
[0004]
[Patent Document 1]
JP 08-000970 (2nd page)
[0005]
[Problems to be solved by the invention]
The present invention is intended to solve the above-mentioned drawbacks, the purpose of which is to improve the aging stability during hemodialysis of the hollow fiber membrane, which has a large membrane pore size and can remove unwanted proteins, etc. As a result of intensive studies on the membrane structure of the hollow fiber membrane and the behavior of the membrane in the wet state, it was found that the change over time is reduced by increasing the membrane structure change of the hemodialysis membrane in the wet state.
[0006]
In addition, after the coagulation of the hollow fiber membrane is completed and the membrane structure is stabilized, the membrane microstructure is changed during hemodialysis by heat treatment with an aqueous solution of 75 ° C. or higher and 90 ° C. or lower in a tensioned state. Thus, the pore diameter gradually increases, which works in the direction of canceling clogging during hemodialysis. Furthermore, it has been found that the above hemodialysis membrane can be suitably used for hemofiltration and hemodiafiltration.
[0007]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors have found the following hemodialysis membrane and its production method.
(1) A hollow fiber membrane having an inner diameter of 100 to 300 μm and an ultrafiltration coefficient of pure water of 150 to 500 ml / (m 2 · mmHg · hr), primed with physiological saline or dialysate, and in a wet state The sieving coefficient of albumin (SCAlb (24h)) measured using a 1% by weight bovine serum albumin aqueous solution (pH 7.5) after standing at 37 ° C. for 24 hours was 0.3 ≧ SCAlb (24h) ≧ 0.005 there are, sieving coefficient of albumin was measured using a 1% by weight bovine serum albumin aqueous solution immediately after priming (sCAlb (0h)) ratio of the 1.80 ≧ sCAlb (24h) / sCAlb (0h) ≧ 1.2, A hemodialysis membrane, wherein the sieving coefficient of β 2 -microglobulin is 0.35 or more.
(2) The hemodialysis membrane according to (1) , wherein the hollow fiber membrane is made of a cellulose polymer.
(3) The hemodialysis membrane according to (2) , wherein the cellulose polymer is cellulose triacetate.
(4) The fine structure of the membrane was adjusted by heat-treating the hollow fiber membrane having a substantially fixed membrane structure in water and / or glycerin liquid at a temperature above 75 ° C. and below 90 ° C. under tension. The hemodialysis membrane according to any one of (1) to (3) , wherein the hemodialysis membrane is one.
(5) Heat treatment in a water and / or glycerin solution at a temperature higher than 75 ° C. and lower than 90 ° C. in a state where tension is applied to the hollow fiber membrane in which the membrane structure is substantially fixed after the membrane-forming stock solution is solidified A method for producing a hemodialysis membrane.
(6) The method for producing a hemodialysis membrane according to (5) , wherein the hollow fiber membrane comprises a cellulose polymer.
(7) The method for producing a hemodialysis membrane according to (6) , wherein the cellulose polymer is cellulose triacetate.
[0008]
Specifically, the hemodialysis membrane having the performance shown in the above (1) to (5) of the present invention is (6) a tension applied to the hollow fiber membrane to which the hemodialysis membrane is substantially fixed in membrane structure. In this state, the film was obtained by a technique in which the fine structure of the film was adjusted by heat treatment with a liquid having a high temperature of 75 ° C. or more and 90 ° C. or less. Although it has been found that the fine structure of the film is slightly changed by this heat treatment, it has not been clarified in detail what kind of qualitative change or structural change has actually occurred. However, it is obvious that the hemodialysis membrane obtained by such a technique is excellent in performance as shown in detail in the examples of the present specification.
[0009]
Quantitative analysis of the stability of the hollow fiber membrane, which is the hemodialysis membrane having the performance shown in the above (1) to (5) of the present invention, and the optimum membrane state and performance for maintaining the performance As a result, it was found that the ratio of SCAlb is SCAlb (24h)) / (SCAlb (0h)) ≧ 1.2.
Of course, (SCAlb (24h)) / (SCAlb (0h)) ≧ 1.2 has an appropriate range such as 1.50, 1.75, 1.80, 2.00, etc. Depending on the technically possible advanced approach, it can have very high ratios such as 2.00, 3.00.
And the hollow fiber membrane which has the performance of the SCAlb (24h) / SCAlb (0h) ≧ 1.2 is specifically shown in the above (6) to (7), that is, the membrane forming stock solution is solidified. The hollow fiber membrane having a substantially fixed membrane structure can be manufactured by a subsequent heating method with a liquid having a high temperature of 75 ° C. or higher and 90 ° C. or lower in a tensioned state.
[0010]
The method for producing the hemodialysis membrane of the present invention will be described in detail. First, the heat treatment is usually a hollow state in which the membrane structure is stabilized after the membrane-forming stock solution is solidified and then washed with water once. The membrane structure is modified by heat-treating the yarn membrane with a high-temperature liquid in the range of 65 to 100 ° C., preferably 75 to 90 ° C. in a tensioned state. A hemodialysis membrane having the characteristics of the present invention can be produced at an arbitrary temperature such as 80 ° C. or 85 ° C. within the processing temperature range of 75 to 90 ° C. The treatment time with the high-temperature liquid is practically determined by the speed and distance at which the hollow fiber membrane travels in the high-temperature liquid, when the hollow fiber membrane is run by running the high-temperature liquid under tension. Usually, the contact time with the high-temperature liquid is about 1 minute or less, but practically, the effect is exhibited by allowing the liquid to pass through the high-temperature liquid in about 3 to 30 seconds and then leaving it at room temperature. .
[0011]
The tension applied to the traveling hollow fiber membrane is such that the tension changes slightly depending on the material, such as whether the material constituting the membrane is regenerated cellulose or cellulose triacetate. The temperature of the high-temperature liquid is, for example, about 75 ° C. or about 90 ° C., because the difference in temperature conditions also has a subtle effect. Difference conditions such as temperature must be taken into account. The proper range of tension means that the yarn does not stretch too much because tension is not excessively applied from the tension condition that the hollow fiber membrane maintains the shape of the yarn simply by stretching straight without slackening in a high-temperature liquid. In this case, the process is carried out under a wide range of tension according to a relatively relaxed situation up to a tension condition in which the shape is remarkably changed or is not cut. Actually, trial and error, taking into account the overall balance, taking into account various conditions such as the material of the hollow fiber membrane, the running speed, and the high-temperature liquid temperature, which are the factors for expressing the optimal performance of the hemodialysis membrane. In many cases, the proper tension condition is determined by. In the case of a cellulose triacetate hollow fiber membrane, the contraction in the length direction of about 1 to 10% occurs depending on the film forming conditions. Here, since the inlet roller speed and the outlet roller speed of the heat treatment tank are rotated at a constant speed, the hollow fiber membrane running through the heat tank is subjected to the heat treatment in a state of being substantially pulled about 1 to 10%. It will be.
[0012]
In the examples of the present invention, the high-temperature liquid used for the heat treatment is practically about 65% glycerin aqueous solution, but actually it is relatively stable at a temperature of about 75 to 90 ° C. Any liquid can be selected as long as it remains in the above health or hollow fiber membrane and does not adversely affect the hollow fiber membrane itself and treatment.
[0013]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
The inner diameter of the hollow fiber membrane of the present invention is 100 to 300 μm. If the inner diameter is less than 100 μm, the pressure loss of the hollow fiber membrane increases, so that hemolysis may occur. It may be easy to deposit.
[0014]
The ultrafiltration coefficient of pure water is 150 to 500 ml / (m 2 · mmHg · hr). If the ultrafiltration coefficient is less than 150 ml / (m 2 · mmHg · hr), it is possible to keep the albumin leakage to 2 g or less regardless of the membrane area of the dialyzer, but the clearance of β 2 -microglobulin is reduced. In order to reach 50 or more where an effect of improving clinical symptoms is observed, it is necessary to considerably increase the membrane area. In addition, when the ultrafiltration coefficient exceeds 500 ml / (m 2 · mmHg · hr), high β 2 -microglobulin clearance is manifested, but albumin leakage increases regardless of the membrane area and does not cause hypoproteinemia. It cannot be reduced to 5 g / (1 dialysis) or less, and a dialyzer that can be used safely for all patients may not be obtained.
[0015]
The sieving coefficient (SCAlb (24h)) of a 1 wt% bovine serum albumin aqueous solution measured after standing for 24 hours at 37 ° C in a moist state after priming with physiological saline or dialysate, and the 1 wt% bovine serum albumin aqueous solution measured immediately after priming It is necessary that SCAlb (24h) / SCAlb (0h) ≧ 1.2 in terms of the sieving coefficient (SCAlb (0h)). When SCAlb (24h) / SCAlb (0h) is less than 1.2, blood filtration coefficient during hemodialysis is greatly fluctuated due to clogging of the membrane, the stability over time is lacking, performance deterioration is large, and initial performance is maintained. It is not possible to perform stable hemodialysis. For more stable hemodialysis, 1.5 or more is necessary.
[0016]
The sieving coefficient (SCAlb (24h)) of a 1% by weight bovine serum albumin aqueous solution measured after standing for 24 hours at 37 ° C. in the wet state after priming with physiological saline or dialysate is 0.3 ≧ SCAlb (24h) ≧ 0.005 It is. If it is greater than 0.3, the amount of protein leakage during hemodialysis is 5 g / (1 dialysis) or more, which may cause hypoalbuminemia and can only be used for patients with good nutrition. . As a versatile hemodialysis membrane that can be used regardless of the nutritional state of the patient, SCAlb (24h) is preferably 0.2 or less. On the other hand, if it is less than 0.005, the clearance of β 2 -microglobulin becomes low, and a sufficient therapeutic effect cannot be expected. In order to enhance the therapeutic effect, SCAlb (24h) ≧ 0.01 is more preferable.
[0017]
(Method for measuring 1% by weight albumin sieving coefficient)
Albumin / bovine serum (Wako primary code 019-07494) was dissolved in 50 mM phosphate buffer at pH 7.5 to prepare a 1% by weight albumin aqueous solution, and the pH adjusted to 7.5 again was used for the measurement. 1,000 ml of physiological saline is flowed to the blood side of a 1.5 m 2 hemodialyzer prepared using the hollow fiber membrane of the present invention, and then 1,000 ml of physiological saline is flowed to the dialysate side. The priming is completed by closing the stopper while filling the liquid side with physiological saline. Thereafter, a module immersed in a constant temperature bath at 37 ° C. for 24 hours and a module immediately after priming were prepared and used for measurement of the albumin sieving coefficient.
The module is replaced with 50 mM phosphate buffer pH 7.5 immediately before measuring the sieving coefficient, 1% by weight albumin aqueous solution at 37 ° C. is flowed to the blood side at 200 ml / min, filtered at 30 ml / min, and filtered. Thirty minutes after starting, a 1% by weight albumin solution (CI), a blood outlet solution (CO), and a filtration solution (CF) are collected, and the absorbance at a wavelength of UV 280 nm is measured with a spectrophotometer. From the measured value, the albumin sieving coefficient was determined as follows. Each solution was appropriately diluted and measured.
Albumin sieve coefficient = 2 × CF ÷ (CI + C0)
[0018]
(Measurement method of ultrafiltration coefficient of pure water)
Using a hollow fiber membrane module, pure water was filled on both the inside and outside of the membrane, and the temperature was maintained at 37 ° C. Pure water at 37 ° C is flowed by applying pressure from the module inlet leading to the inside of the membrane, causing a pressure difference between the inside and outside of the membrane, that is, a pressure difference between the membranes. The amount of water was measured. The transmembrane pressure difference (TMP) is TMP = (Pi + Po) / 2. Here, Pi is the module inlet pressure, and Po is the module outlet pressure. ) At four different intermembrane pressure differences, the water permeation amount for 1 minute was measured and plotted on the two-dimensional coordinates of the transmembrane pressure difference and the water permeation amount, and the slopes of these approximate lines were obtained. The numerical value was multiplied by 60 and divided by the membrane area of the hollow fiber membrane module to obtain the ultrafiltration coefficient of pure water of the hollow fiber membrane (hereinafter abbreviated as UFR. The unit is ml / (m 2 · hr · mmHg). ).
[0019]
(Method for measuring β 2 -microglobulin sieving coefficient)
Sampling the blood and filtrate at the inlet and outlet of the module 15 minutes after the start of blood filtration at a filtration rate of 10 ml / min, and enzyme immunoassay (eg, Grazyme β 2 -Microglobulin-EIA Test Wako Pure Chemical Industries) the beta 2 - microglobulin (hereinafter, abbreviated as beta 2 -MG.) to measure the concentration of. In addition, an appropriate amount of human-derived β 2 -MG is added to the bovine blood to be flowed to the module in the measurement, and the sampled blood is centrifuged as necessary for measurement of β 2 -MG. From these β 2 -MG concentration values, the SC of β 2 -MG is determined according to the following formula.
SC = Cfil / ((CI + C0) / 2)
Cfil: filtrate beta 2 -MG concentration CI: Module blood side inlet of the blood beta 2 -MG concentration CO: Module beta 2 -MG concentration [0020] Blood on the blood side outlet
(Measurement method of hollow fiber inner diameter)
A sample having a hollow fiber cross section can be obtained as follows. For the measurement, it is preferable to observe the hollow fiber membrane after drying and removing the hollow forming material. The drying method is not particularly limited. However, when the shape is remarkably changed by drying, it is preferable to clean and remove the hollow forming material, completely replace with pure water, and observe the shape in a wet state. A suitable number of the hollow fiber membranes after drying are passed through a φ1 mm hole formed in the center of a 2 mm thick slide glass and cut with a razor on the upper and lower surfaces of the slide glass to obtain a cross-sectional sample in which the hollow portion is exposed. Using the projector (Nikon-12A), the sample obtained was randomly extracted from any 5 samples in the field of view, and the minor axis and major axis inside the cross section of each hollow fiber membrane were measured. Was the inner diameter of one hollow fiber membrane. Further, the average value of 5 samples was taken as the inner diameter of the hollow fiber membrane.
[0021]
It is necessary to heat-treat with an aqueous solution above 75 ° C. and below 90 ° C. while the membrane structure is substantially stable and the hollow fiber membrane is under tension. The state in which the membrane structure is substantially stable and the hollow fiber membrane is in tension is, for example, that the spinning stock solution is pushed out from the outside of the double annular spinning hole, liquid paraffin is fed from the center, and solidified in a coagulating liquid. The hollow fiber membrane after washing indicates that the membrane structure has already been fixed and is stable, and further shows that the hollow fiber membrane is in tension while the hollow fiber membrane is running. Further, the aqueous solution above 75 ° C. and below 90 ° C. may be anything as long as it does not dissolve the material of the hollow fiber membrane with an aqueous solution of water alone or glycerin. After the coagulation of the hollow fiber membrane is completed and the membrane structure is stabilized, heat treatment is performed with an aqueous solution above 75 ° C. and below 90 ° C. in a state where tension is applied. The pore diameter gradually changes and the pore diameter gradually increases. On the other hand, the pores of the membrane are clogged with time during hemodialysis, but this works in the direction of canceling out by increasing the pore diameter. Furthermore, it has been found that the above hemodialysis membrane can be suitably used for hemofiltration and hemodiafiltration. In order to further stabilize blood filtration performance, the temperature is preferably 80 ° C. or higher.
[0022]
The sieving coefficient of β 2 -MG is preferably 0.35 or more. β 2 sieving coefficient of -MG is in the case of less than 0.35 lower clearance of β 2 -MG sufficient therapeutic effect can not be expected. Preferably, it is 0.5 or more. More preferably, it is 0.65 or more, More preferably, it is 0.75 or more.
[0023]
Examples of the material of the hollow fiber membrane in the present invention include regenerated cellulose, modified cellulose, cellulose acetate, polymethyl methacrylate, vinyl alcohol-ethylene copolymer, polyacrylonitrile, polysulfone, etc. Cellulose acetate excellent in water permeability, solute permeability, and biocompatibility is preferred. Cellulose triacetate is more preferable in terms of higher water permeability and superior solute separation characteristics.
[0024]
Although the hollow fiber membrane used for this invention can be manufactured as follows, for example, this invention is not limited to any less. A spinning stock solution containing 15 to 22% by weight of cellulose triacetate, 46.8 to 68% by weight of solvent, and 10 to 38.2% by weight of non-solvent is dissolved by heating to 130 to 190 ° C. from the outside of the double annular spinning hole. Extruded, liquid paraffin is sent from the center, and the extruded spinning solution travels in the air, then solidifies in a coagulating liquid at 5-60 ° C, is washed with water, and the membrane structure is substantially stable. The hollow fiber membrane is heat-treated with a high-temperature liquid at 75 ° C. to 90 ° C. in a tensioned state.
[0025]
【Example】
Hereinafter, the effects of the present invention and more detailed description will be given by way of examples, but the present invention is not limited to the examples.
[0026]
Example 1
Cellulose triacetate (19.0% by weight), N-methylpyrrolidone (56.7% by weight) and triethylene glycol (24.3% by weight) were dissolved at 150 ° C. to obtain a film forming solution. A film-forming stock solution was discharged from a tube-in orifice nozzle heated to 120 ° C. using liquid paraffin as a hollow forming agent, passed through an air gap, and then coagulated in water at 30 ° C. After washing with water to stabilize the membrane structure, the membrane structure was passed through a glycerin aqueous solution at 78 ° C. and 65%, dried with a dryer and wound up on a bobbin. The resulting hollow fiber membrane had an inner diameter of 199 μm and a film thickness of 15 μm. Using the hollow fiber membrane thus obtained, a hollow fiber membrane module having a membrane area of 1.5 m 2 was prepared, ultrafiltration rate (ml / (hr · m 2 · mmHg)), SCAlb (0h), The results of measuring SCAlb (24 hr) are shown in Table 1.
[0027]
(Example 2)
Coagulation was performed using a film-forming stock solution of 17.5% by weight of cellulose triacetate, 57.8% by weight of N-methylpyrrolidone, and 24.7% by weight of triethylene glycol. Then, after stabilizing the washing membrane structure, a hollow fiber membrane was prepared in the same manner as in Example 1 except that the membrane was treated with a glycerin solution at 85 ° C. and 65%. When the performance of the hollow fiber membrane was evaluated, it was confirmed that the hollow fiber membrane had the performance shown in Example 1. The results are shown in Table 1.
[0028]
(Example 3)
A hollow fiber membrane was produced under the same conditions as in Example 1 except that the temperature of the glycerin aqueous solution was changed to 90 ° C. and 50% in Example 2. The resulting hollow fiber membrane had an inner diameter of 196 μm and a film thickness of 15 μm. A hollow fiber membrane module having a membrane area of 1.5 m 2 was produced from the hollow fiber membrane thus obtained, and the performance evaluation of the hollow fiber membrane was conducted in the same manner as in Example 1. Table 1 shows the results.
[0029]
(Comparative Example 1)
After washing with water and stabilizing the membrane structure, a hollow fiber membrane was produced under the same conditions as in Example 1 except that it was passed through a 65% aqueous glycerin solution at 60 ° C.
The resulting hollow fiber membrane had an inner diameter of 201 μm and a film thickness of 15 μm.
A hollow fiber membrane module having a membrane area of 1.5 m 2 was produced from the hollow fiber membrane thus obtained, and the performance of the hollow fiber membrane was evaluated in the same manner as in Example 1. The results are shown in Table 1.
[0030]
(Comparative Example 2)
After washing with water and stabilizing the membrane structure, a hollow fiber membrane was produced under the same conditions as in Example 1, which were passed through a 65% aqueous glycerin solution at 95 ° C.
The resulting hollow fiber membrane had an inner diameter of 201 μm and a film thickness of 15 μm.
A hollow fiber membrane module having a membrane area of 1.5 m 2 was produced from the hollow fiber membrane thus obtained, and the performance of the hollow fiber membrane was evaluated in the same manner as in Example 1. The results are shown in Table 1.
Thus, in order to produce a hollow fiber membrane having excellent performance of the present invention, it can be quantitatively grasped that the hollow fiber membrane has an inner diameter of 100 to 300 μm. Quantitatively identifying subtle structural changes requires considerable technical skill. In any case, the hollow fiber membrane having a stabilized membrane structure is subjected to heat treatment with a high-temperature liquid in a range of 65 to 100 ° C., preferably 75 to 90 ° C. in a tensioned state. It is based on the knowledge of the present inventor that a hollow fiber membrane having specific performance and structure can be manufactured.
[0031]
[Table 1]
【The invention's effect】
As described above, by inducing a membrane structure change when the hemodialysis membrane is left in a wet state, the stability over time during hemodialysis is excellent, and the performance can be maintained with little deterioration in performance. In addition, after the coagulation of the hollow fiber membrane is completed and the membrane structure is stabilized, the membrane microstructure is changed during hemodialysis by heat treatment with an aqueous solution of 75 ° C. or higher and 90 ° C. or lower in a tensioned state. Thus, the pore diameter gradually increases, which works in the direction of canceling clogging during hemodialysis. Furthermore, it has been found that the above hemodialysis membrane can be suitably used for hemofiltration and hemodiafiltration.
Claims (7)
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| US8114276B2 (en) * | 2007-10-24 | 2012-02-14 | Baxter International Inc. | Personal hemodialysis system |
| WO2012057701A1 (en) * | 2010-10-25 | 2012-05-03 | Agency For Science, Technology And Research | Tubular fiber membrane with nanoporous skin |
| JP2011041830A (en) * | 2010-11-01 | 2011-03-03 | Toyobo Co Ltd | Hollow fiber membrane for blood purification, and method of manufacturing the same |
| DE102011008222A1 (en) | 2011-01-10 | 2012-07-12 | Fresenius Medical Care Deutschland Gmbh | Process for producing a hollow fiber membrane |
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