JP2004305561A - Hollow yarn type blood purification membrane - Google Patents
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【０００１】
【発明の属する技術分野】
本発明は、血液透析、血液濾過、血液透析濾過などの血液浄化に用いられる血液浄化膜に関する。
【０００２】
【従来の技術】
従来より、慢性腎不全患者に対する維持療法として血液透析が行われてきている。また、近年、急性腎不全や敗血症などの重篤な病態の患者に対して、急性血液浄化療法として、持続血液濾過、持続血液濾過透析、持続血液透析などの療法の実施例が増大しつつある。これらの療法に使用される血液浄化膜の素材としては、セルロース、セルロース誘導体などの天然由来の素材と、ポリスルホン系樹脂、ポリメチルメタクリレート、ポリアクリロニトリル、エチレンビニルアルコール共重合体などの合成高分子素材が利用されている。中でも、ポリスルホン系樹脂からなる膜は、良好な機械的特性、耐熱性、生体適合性などの長所を持つことから、近年特に注目されている。
【０００３】
ポリスルホン系樹脂は比較的疎水性が強いため、血液と接触した際に、血漿タンパク質を吸着しやすい傾向がある。このためポリスルホン系樹脂で血液浄化膜を製造する場合には、親水性を付与して血液適合性を向上させるため、親水性高分子を添加するのが一般的である。
【０００４】
また、前述のとおり疎水性の強い材料は血漿タンパクを吸着しやすいので、長時間にわたって血液と接触して使用した場合には、表面に吸着した血漿タンパクの影響で膜性能が経時的に低下してしまう。親水性の付与によって血漿タンパクの吸着が低減されるので、親水性高分子添加は血液適合性向上のほか、膜として安定した溶質除去性能を発揮するためにも有効である。
【０００５】
こういった目的で使用される親水性高分子としては、ポリビニルピロリドン（ＰＶＰ）が最も一般的である。しかしながら、ＰＶＰは膜の使用時、血液との接触によって溶出する可能性があり、場合によってはこの溶出したＰＶＰによって患者にアナフィラキシー様の症状を呈する可能性も否定できない。膜の高性能化には有効なＰＶＰであるが、このような副作用を招く可能性から、その溶出量は最小限に抑制するのが好ましい。
【０００６】
ＰＶＰの溶出を抑制するために、これまで多くの方法が提案されている。ＰＶＰの溶出を低減させる方法としては、化学的な処理によってＰＶＰを固定化する技術が開示されている（例えば、特許文献１参照）。このような方法ではＰＶＰを強固に固定化しているので溶出を抑制するのには有効であると考えられるが、操作が煩雑であり実施が容易とは言えない。また、反応性の強い試薬を使用する必要があるので、処理によって膜の特性が変化してしまう可能性がある。
【０００７】
また、ＰＶＰを含むポリスルホン系材料を熱および／または放射線照射することによってＰＶＰを架橋し、不溶化することで溶出を抑える技術も開示されている（例えば、特許文献２、３、４、５、６、７参照）。しかしながら、これらの方法では操作が煩雑である上、加熱部位や放射線照射部位が局在化してしまう可能性があり、処理の不十分な部位でのＰＶＰ架橋が十分に進行せず、溶出してしまうことが考えられる。
【０００８】
さらに、これらの方法で水あるいは熱水への溶出が抑制されたとしても、抽出力の高い血液または血漿との接触によって溶出してくる可能性は否定できない。事実、ＰＶＰ溶出量を抑制したと言われている透析膜でも、未だアナフィラキシーショックを招いたとの報告がある（例えば、非特許文献１参照）。
【０００９】
本発明者らは、化学改質、架橋による改質を施さなくても親水性高分子の溶出が見られない膜についても既に特許出願を行っている（例えば、特許文献８参照）。この技術においては、膜構造を均一微細構造とすることで親水性高分子の溶出を抑制しているが、水よりも抽出力の高い血液と接触した場合の親水性高分子溶出についての考慮が十分とは言えなかった。
【００１０】
本発明者らは、血液または血漿との接触時にもＰＶＰ溶出量が少ない膜について既に特許出願を行っている（例えば、特許文献９参照）。この技術においては、擬似血漿として水よりも抽出力高い４０％エタノール水溶液を使用して抽出した場合のＰＶＰ溶出量が血液接触側膜面積１ｍ２あたり１０ｍｇ以下である選択分離膜が開示されており、具体的には、特定の処置を施したＰＶＰを使用することが目的を達成するのに好適な手段として開示されている。しかしながら、このようにＰＶＰ溶出量に注力した場合には、安全性は向上するものの、血液を処理した際の膜性能の保持が困難であった。
【００１１】
【特許文献１】
特開平７−３０３４号公報（３頁）
【特許文献２】
特開平６−３３９６２０号公報（１頁〜２頁）
【特許文献３】
特開平９−２４２６１号公報（１頁〜４頁）
【特許文献４】
特開平９−１０３６６４号公報（１頁〜４頁）
【特許文献５】
特開平１０−６６８４６号公報（１頁〜３頁）
【特許文献６】
特開平１０−２３０１４８号公報（１頁〜３頁）
【特許文献７】
特開２０００−３５０９２６号公報（１頁〜５頁）
【特許文献８】
特開２０００−４２３８３号公報
【特許文献９】
特開２０００−３００６６３号公報
【非特許文献１】
中山ら、第４３回日本透析医学会予稿集、ｐ６２０、１９９８年
【００１２】
【発明が解決しようとする課題】
本発明は、上記課題を解決することを目的とし、親水性付与に不可欠の成分でありながら溶出による安全性に問題のある親水性高分子が溶出しにくく、かつ、血液と接触して使用した際の性能保持性に優れた中空糸型血液浄化膜、すなわち、血液適合性、安全性、性能保持性を同時に満足した中空糸型血液浄化膜を提供することを目的とする。
【００１３】
【課題を解決するための手段】
本発明者らは、上記課題を解決するため鋭意検討した結果、本発明に到達した。すなわち、本発明の中空糸型血液浄化膜は、
１．疎水性高分子と親水性高分子を含んでなり、該中空糸型血液浄化膜における該親水性高分子の含有量が５重量％以上、該中空糸型血液浄化膜を４０％エタノール水溶液で抽出した際に抽出される該親水性高分子の量が、該中空糸型血液浄化膜の血液接触側表面積１ｍ２あたり２０ｍｇ以下であり、牛血を使用し、血液流量２００ｍＬ／ｍｉｎ、濾過流量２０ｍＬ／ｍｉｎで灌流を行った際、灌流開始１５分時点での透水性を（Ａ）ｍＬ／（ｍ２・ｈｒ・ｍｍＨｇ）、灌流開始１２０分時点での透水性を（Ｂ）ｍＬ／（ｍ２・ｈｒ・ｍｍＨｇ）とした時、１００％×（Ｂ）／（Ａ）の値（以下Ｃ特性値と略記する）が６５％以上であることを特徴とする。
２．不溶成分の含有率が、膜全体に対して２重量％未満であることを特徴とする。
３．膜内部が実質的に均一構造、膜表面が平滑構造であることを特徴とする。
４．疎水性高分子がポリスルホン系高分子であることを特徴とする。
５．該ポリスルホン系高分子がポリエーテルスルホンであることを特徴とする。
６．親水性高分子がポリビニルピロリドンであることを特徴とする。
７．膜厚が１０〜４０μｍ、内径が１００〜３００μｍであって、３７℃での水の透水性が１〜３０ｍＬ／（ｍ２・ｈｒ・ｍｍＨｇ）、ミオグロビンのふるい係数が０〜０．４であることを特徴とする。
【００１４】
疎水性高分子と親水性高分子からなる中空糸型血液浄化膜において、該親水性高分子の溶出を皆無にするのは実質的に不可能なので、安全性の観点から上限値を設定する必要がある。また、親水性高分子の溶出量を徹底して低減することは、膜表面の親水性高分子を減少させることとなり、血液接触使用時の性能保持性を低下させる結果となることも考えられる。本件出願人らは鋭意検討の結果、中空糸型血液浄化膜における親水性高分子の含有量が５重量％以上、該中空糸型血液浄化膜を４０％エタノールで抽出した際に抽出される親水性高分子の量が、該中空糸型血液浄化膜の血液接触側表面積１ｍ２あたり２０ｍｇ以下、Ｃ特性値が６５％以上である膜が血液浄化性能、血液接触使用時の性能保持性、安全性を高レベルで両立できること見出し、本発明に到った。
【００１５】
血液適合性、血液接触使用時の性能保持性の観点からは膜に含有される親水性高分子の量は多い方が好ましいが、一方で、親水性高分子含量を多くするとその溶出量も増加する傾向にあり、安全性の観点から見た場合には好ましくない。前者の観点から、中空糸型血液浄化膜における親水性高分子の含量は５重量％以上であることが好ましく、さらに、６重量％以上であることがより好ましい。後者の観点から、中空糸型血液浄化膜を４０％エタノール水溶液で抽出した際の親水性高分子抽出量は２０ｍｇ／（ｍ２−中空糸型血液浄化膜血液接触表面積）であることが好ましく、１５ｍｇ／（ｍ２−中空糸型血液浄化膜血液接触表面積）であることがより好ましい。１０ｍｇ／（ｍ２−中空糸型血液浄化膜血液接触表面積）であることがさらに好ましい。また、血液接触使用時、時間経過に伴って透水性が低下することは、膜への血液成分の吸着により膜の目詰まりが進行することを意味する。Ｃ特性値が高いことはこのような好ましくない血液成分吸着が抑制されていることを示唆しており、血液接触使用時の性能保持性の観点から、Ｃ特性値は６５％以上であることが好ましく、より好ましくは７５％以上、さらに好ましくは８０％以上、最も好ましくは８５％以上である。
【００１６】
これらの値は、どれかひとつが上記の範囲から外れても、膜のトータル性能を低下させることとなる。全てが同時に満たされることにより、本発明の意図する血液適合性、安全性、性能保持性を同時に満足した中空糸型血液浄化膜が得られる。
【００１７】
架橋などの処理によって構造の一部を改変した親水性高分子は、本来その親水性高分子が持つ特性と微妙に異なる挙動を示すことが考えられる。血液接触使用時の性能保持性を確保するために、本発明の中空糸型血液浄化膜に含まれる親水性高分子は実質的に不溶化されていないことが好ましく、具体的には不溶成分の含有率が膜全体に対して２重量％未満であることが好ましい。より好ましくは１．５重量％未満、さらに好ましくは１重量％未満である。
【００１８】
本発明の中空糸型血液浄化膜は、血液浄化性能、血液接触使用時の性能保持性、安全性を高レベルで両立するための構造的な特徴として、膜内部が実質的に均一構造、膜表面が平滑構造であることが好ましい。このような膜構造となった場合、膜全体としての親水性高分子含有量は高いながら、表面からの溶出は比較的低く抑えられる。詳細な機構は不明であるが、内外面いずれにも粗い構造の散漫層が存在せず、含有された親水性高分子が逃げにくい構造であるためであると推定される。ここで言う「実質的に均一構造」とは、膜断面を電子顕微鏡で観察した際、膜表面から膜中心にかけての構造的な不均一性が目視で認められないことを意味する。
【００１９】
このような中空糸型血液浄化膜を得る具体的な手段としては、例えば、中空糸製造の際に使用される内腔形成剤（内液）として、疎水性高分子溶液を凝固させにくいものを使用する方法がある。
【００２０】
中空糸膜を製造する際には、素材となる高分子の溶液（ドープ）と、内腔の形成剤を二重管型のノズルから吐出し、空走部分を経て凝固浴に導き凝固させ、洗浄の工程を経て巻取る乾湿式紡糸法をとるのが一般的である。従来、ポリスルホン系の疎水性高分子とＰＶＰを主構成成分として成る中空糸型血液浄化膜では、内腔形成剤（内液）として疎水性高分子を凝固させる水系の液体を使用するのが一般的である。このような技術によって製造された中空糸膜は、まず内腔側の表面でドープが凝固し、その状態で凝固浴に浸漬して成形されているので、必然的に内腔側表面が緻密で、外表面が粗い不均質構造となる。このような構造では洗浄工程で外表面の散漫層から親水性高分子が溶出しやすいため、ドープ中の親水性高分子濃度を高くしても、得られる中空糸膜中の親水性高分子含量は低下してしまう可能性が高い。
【００２１】
これに対し、内液としてドープ低凝固性の液体を使用した場合には、空走部分での凝固が穏やかであり、内腔側表面でのドープ凝固が急速には進行せず、均質の構造となりやすい。このため、外表面が凝固系内液を使用した場合ほどには粗くならないので、洗浄工程での親水性高分子脱離が軽微である。すなわち、このような方法で調製した場合、中空糸膜中の親水性高分子含量は相対的に高くなる。
【００２２】
しかしながら、このように内液をドープ低凝固性の液体とした場合には、逆に外表面の構造が相対的に緻密になる可能性もある。そこで、均一の膜構造を得るには、凝固浴での凝固を制御し、外表面の緻密構造形成をある程度抑制することが好ましい。具体的には、凝固液をドープ凝固性液体と、ドープ非凝固性あるいはドープ低凝固性の混合液とすること、凝固液の温度を比較的低温にすることが好ましい。より好ましくは、凝固液をドープ溶媒と水との混合液とし、溶媒濃度が５〜７０重量％、さらには、溶媒濃度が７〜６５重量％であることが好ましい。凝固液の温度は、より好ましくは０〜３５℃、さらに好ましくは０〜３０℃、さらに好ましくは５〜２５℃であるのが好適である。
【００２３】
本発明における疎水性高分子とは、例えば、ポリエステル、ポリカーボネート、ポリウレタン、ポリアミド、ポリスルホン、ポリエーテルスルホン、ポリメチルメタクリレートなどの合成高分子やセルローストリアセテート、セルロースナイトレートなどのセルロース系高分子が例示される。中でも、ポリスルホン、ポリエーテルスルホン等のポリスルホン系高分子は、生体適合性に優れ、尿毒症関連物質の高い除去性能が得られるので、好ましい。ここで言うポリスルホン系高分子は、官能基やアルキル基などの置換基を含んでいてもよく、炭化水素骨格の水素原子はハロゲンなど他の原子や置換基で置換されていてもよい。また、これらは単独で使用しても、２種以上を混合して使用してもよい。
【００２４】
本発明における親水性高分子とは、例えば、ポリエチレングリコール、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロース、デンプンおよびその誘導体、酢酸セルロースなどの高分子が例示される。中でも、ポリスルホン系高分子との相溶性、血液浄化膜素材としての使用実績から、ポリビニルピロリドンが好ましい。これらは単独で使用しても、２種以上を混合して使用してもよい。
【００２５】
本発明の中空糸型血液浄化膜は血液適合性、安全性、性能保持性を同時に満足するという観点から、膜厚が１０〜４０μｍ、内径が１００〜３００μｍであることが好ましい。膜厚が上記の範囲よりも小さい場合には、十分な強度を確保するのが困難となり、上記の範囲よりも大きい場合には物質透過性能が低下してしまう。膜厚のより好ましい範囲は１０〜３５μｍ、さらに好ましい範囲は１０〜３０μｍである。内径が上記の範囲から外れると、血液灌流時の血液流速が過小または過大となり、膜表面との相互作用による血液成分の吸着などによる血液適合性低下や性能保持性低下を招く可能性がある。また、本発明の中空糸型血液浄化膜は３７℃での水の透水性が１〜３０ｍＬ／（ｍ２・ｈｒ・ｍｍＨｇ）、ミオグロビンのふるい係数が０〜０．４であることが好ましい。この範囲を下回る場合は血液浄化膜としての性能が不十分であり、この範囲を上回る場合、性能保持性が低下してしまう可能性がある。
【００２６】
また、前述のような中空糸型血液浄化膜を得る他の具体的な手段としては、例えば、中空糸製造の際に調製するドープ中の疎水性高分子濃度を高めに設定する方法がある。詳細な機構は不明であるが、疎水性高分子濃度を高めにすることで、親水性高分子を強固に包接した状態でドープの凝固が進行しやすく、結果として親水性高分子の溶出が抑制可能になるものと推定される。さらに、使用する疎水性高分子の還元粘度は好ましくは０．２〜０．６であることが好ましい。詳細な機構は不明であるが、このような還元粘度の疎水性高分子を使用することで凝固浴内での凝固が適度に制御され、前述のような中空糸型血液浄化膜を得るのに好適となると考えられる。
【００２７】
疎水性高分子および親水性高分子を溶解する溶媒としては、例えば、ジメチルアセトアミド（ＤＭＡｃ）、ジメチルスルホキシド（ＤＭＳＯ）、Ｎ−メチル−２−ピロリドン（ＮＭＰ）などが例示される。中でも、ＤＭＡｃまたはＮＭＰが好ましい。中空糸製造に使用するドープに添加する非溶媒としては、例えば、エチレングリコール、ジエチレングリコール、トリエチレングリコール、ポリエチレングリコール、水などが例示される。
【００２８】
紡糸用ドープにおける疎水性高分子の濃度は好ましくは、２０重量％〜５０重量％、より好ましくは２５重量％〜４５重量％、さらに好ましくは３０重量％〜４５重量％、最も好ましくは３５〜４５重量％である。これよりも濃度が低いと膜の強度を確保するのが困難になり、また、本発明が意図する親水性高分子の含量、４０％エタノールで抽出される親水性高分子の量を実現するのが困難となる可能性が高くなり、これよりも濃度が高いと操業性が悪化する恐れがある。
【００２９】
紡糸用ドープにおける親水性高分子の濃度は好ましくは、１〜１５重量％、さらに好ましくは１〜１０重量％である。これよりも濃度が低いと本発明が意図する親水性高分子の含量を実現するのが困難となる可能性が高くなり、これよりも濃度が高いと本発明が意図する、４０％エタノールで抽出される親水性高分子の量を実現するのが困難となる可能性が高くなる。また、親水性高分子の分子量は大きすぎると紡糸用ドープの溶解性に問題が生じ、小さすぎると膜から溶出しやすくなるため、重量平均分子量で好ましくは２〜１２０万、さらに好ましくは４万〜１１０万であることが好ましい。
【００３０】
中空糸膜を製造する際に使用されるのが好ましいドープ低凝固性の内液としては、例えば、流動パラフィン、ミリスチン酸イソプロピルなどが例示される。
【００３１】
また、前述のような中空糸型血液浄化膜を得る他の具体的な手段としては、例えば、中空糸膜製造の際に凝固浴中で延伸を加える方法がある。詳細な機構は不明であるが、中空糸膜の凝固途中に延伸をかけることによって膜孔の微細構造が最適化され、好ましい特性が発揮されるものと考えられる。延伸は好ましくは３〜３０％、より好ましくは３〜２５％、さらに好ましくは３〜２０％である。ここで言う延伸とは凝固浴入口ローラー速度と凝固浴出口ローラー速度との比である。ポリスルホンおよびポリエーテルスルホンのような結晶化しにくいポリマーを非凝固性の内液を用いて紡糸する場合は、凝固速度が緩やかであるため、凝固浴中において適度な延伸をかけることにより、血液接触部である内表面の状態は、細孔形状の変形が大きくなりすぎず、孔の整列性が高く、均一で平滑性のある状態となる。このような特徴をもつことにより、血小板の粘着が抑制され、また血中タンパクの吸着が単分子層に抑制されるため、本発明の特徴であるろ過をかけながら血液灌流を行った際にも透水性の経時的低下が少ない中空糸膜が得られると考えられる。また、延伸をすることにより膜表面の緻密化を抑制し、過剰な親水性高分子が除去され易く、使用時の溶出量を低減する効果もある。
【００３２】
【実施例】
以下、実施例によって本発明を具体的に説明するが、本発明はこれによって限定されるものではない。
【００３３】
［不溶成分含有量の測定・算出方法］
完成品としての中空糸型血液浄化膜１０ｇを製造の際に使用した溶媒１００ｍＬで溶解した。この液を遠心分離により１５００ｒｐｍ、１０分で不溶成分を分離し、上清を除去した。この操作を３回繰返し、残った不溶成分を蒸発乾固して重量を測定し、不溶成分の含有量を算出した。
【００３４】
［親水性高分子含有量の測定・算出方法］
中空糸型血液浄化膜を適当な溶媒に溶解し、１Ｈ−ＮＭＲの測定を行って、疎水性高分子に含まれる水素原子（Ｈ１とする）由来のピークと、親水性高分子に含まれる水素原子（Ｈ２とする）由来のピークの面積比を求めた（この面積比をａ１：ａ２とする）。疎水性高分子の繰返し単位の分子量をＭ１、繰返し単位中に含まれる上記ａ１の個数をｎ１、親水性高分子の繰返し単位の分子量をＭ２、繰返し単位中に含まれる上記ａ２の個数をｎ２として、次の式により親水性高分子の含有量を算出した。
親水性高分子の含有量（％）＝
（（ａ２／ｎ２）×Ｍ２×１００）／（（ａ１／ｎ１）×Ｍ１＋（ａ２／ｎ２）×Ｍ２）
【００３５】
［中空糸膜のＰＶＰ含有量の測定方法］
中空糸膜を重ＤＭＳＯで溶解し、１Ｈ−ＮＭＲの測定を行い、疎水性高分子由来のピークと、親水性高分子由来のピークの面積比から中空糸膜における親水性高分子の含有率を計算した。
【００３６】
［４０％エタノール水溶液での抽出方法］
４０％エタノール水溶液での抽出試験は以下の手順で行った。中空糸膜モジュールの中空糸内側に４００ｍＬの純水を流してフラッシングを行った後、モジュール内の純水を４０容量％のエタノール水溶液で置換した。中空糸外側のモジュールケース内部にも４０溶量％のエタノール水溶液で満たして封止した。続いて４０℃の条件下、２００ｍＬの４０容量％エタノールを１５０ｍＬ／ｍｉｎで１時間にわたって中空糸内側を循環させた後、循環した４０容量％エタノール水溶液を回収し、そのＰＶＰ濃度を測定した。モジュールの中空糸内側容積とモジュール出入り口のヘッダー部分の体積、すなわちプライミングボリュームに２００ｍＬを加えた、抽出液総体積と抽出液中のＰＶＰ濃度から、抽出されたＰＶＰ総重量を算出し、さらに、中空糸膜モジュールの膜面積（中空糸内径基準）から、被処理液接触側膜面積１ｍ２あたりのＰＶＰ抽出量を求めた。
【００３７】
［ＰＶＰ濃度の測定方法］
ＰＶＰの濃度測定は、Ｋ．Ｍｕｅｌｌｅｒの方法（Ｋ．Ｍｕｅｌｌｅｒ，Ｐｈａｒｍ．Ａｃｔａ．Ｈｅｌｖ．，４３，１０７（１９６８））によって行った。すなわち、検体にクエン酸とヨウ素溶液を加え、吸光度を測定し、濃度既知のＰＶＰから求めた検量線により濃度を求めた。ここで、濃度測定の際には、エタノールによる発色の阻害を避けるため２倍以上に希釈する必要がある。具体的には、例えば２倍希釈で濃度測定を行う場合、検体を１．２５ｍＬ、水１．２５ｍＬ、０．２ｍｏｌ／Ｌクエン酸水溶液１．２５ｍＬ、０．００６規定ヨウ素水溶液０．５ｍＬをよく混合し、１０分間静置した後、４７０ｎｍの吸光度を測定し、その測定値からＰＶＰ濃度を算出すればよい。
【００３８】
［中空糸膜の透水性の測定方法］
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た。膜の内側に通じるモジュール入り口から純水によって圧力をかけて、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。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数値として求めた。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透水性を求めた（以下ＵＦＲと略記する。単位はｍＬ／（ｍ２・ｈｒ・ｍｍＨｇ））。
【００３９】
［中空糸膜のＣ特性値の測定方法］
中空糸膜モジュールを使用し、ヘマトクリット３５％の牛血液を２００ｍＬ／ｍｉｎの流量で中空糸の内側に灌流した。同時に、中空糸外側から２０ｍＬ／ｍｉｎの流量で濾過を行った。灌流・濾過開始１５分後の膜間圧力と濾過液量から、牛血液系での透水性（以下ＭＦＲと略記する。）を算出した。この値を（Ａ）とし、灌流・濾過開始１２０分後、同様の操作により求めたＭＦＲの値（Ｂ）とから、１００（％）×（Ｂ）／（Ａ）の計算によりＣ特性値を算出した。
【００４０】
［クリアランスの測定方法］
ビタミンＢ１２が２０ｐｐｍ、尿素が１０００ｐｐｍ、塩化ナトリウムが１８０ｐｐｍ、リン酸一ナトリウム（無水）が４０ｐｐｍ、リン酸二ナトリウム（１２水和物）が４８０ｐｐｍになるよう調製したキンダリー希釈液（３５倍希釈）を使い、膜面積１．５ｍ２のモジュールで測定した。血液側の流速は２００±１ｍｌ／ｍｉｎ、透析液側の流速は５００±１０ｍｌ／ｍｉｎとし、３７℃で上記キンダリー溶液を流した。流し始めてから１分後に３分間にわたって透析液側の液をサンプリングし、その間血液側（ｏｕｔ）の液のサンプリングを１分間にわたって行った。それぞれの液について尿素の濃度を和光純薬工業株式会社製尿素窒素Ｂ−テストワコーを使用したウレアーゼ・インドフェノール法により測定した。また、ビタミンＢ１２の濃度を３６０ｎｍの吸光度から測定した。これらの測定値から中空糸膜の尿素クリアランス（ＣＬｕｎ）、ビタミンＢ１２クリアランス（ＣＬｖｂ）を算出した。
【００４１】
（実施例１）
ＤＭＦ中での還元粘度が０．４８であるポリエーテルスルホン（以下ＰＥＳと略記する。）およびＢＡＳＦ社製ＰＶＰ（Ｋ−９０）をＮＭＰとトリエチレングリコール（以下ＴＥＧと略記する。）の混合液（重量比でＮＭＰ：ＴＥＧ＝８：２）にそれぞれ３５重量％、７重量％になるよう混合・溶解し、均一な溶液とした。この溶液を紡糸原液として、二重環状スリット口金から吐出すると同時に、紡糸原液に対して非凝固性である流動パラフィンを内液として吐出した。口金から凝固層までの乾式部分を経て凝固層内に紡糸原液／内液を落とし込み、７％の延伸をかけながら凝固させて中空糸膜として成形して７５ｍ／ｍｉｎの速度で巻取った。この際に使用した凝固液の組成は１０重量％のＮＭＰ水溶液で温度は２５℃であった。中空糸膜巻き取りの過程において、水洗浴、３０重量％のグリセリン水溶液浴を経ることで洗浄、表面へのグリセリン塗布を行い、さらに乾燥を行った。この際、内液となる流動パラフィンの流量を調節することで中空糸の内径を２００μｍに制御した。
【００４２】
上記の方法でこの中空糸膜のＰＶＰ含量、中空糸膜の血液接触側表面積１ｍ２あたりの４０％エタノール水溶液によるＰＶＰ抽出量、Ｃ特性値を測定した。結果は表１に示した。
【００４３】
【表１】
また、上記の方法でこの中空糸膜のＵＦＲ、さらに、Ｃ特性値測定前後でのＣＬｕｎ、ＣＬｖｂを測定した。結果は表２に示した。なお、Ｃ特性値測定前後とは、すなわち１２０分間の血液接触前後ということを意味する。Ｃ特性値測定後のモジュールは水洗により内部の血液を十分に除去してクリアランス測定を行った。
【００４５】
【表２】
（実施例２）
ＰＥＳの濃度が４２重量％、ＰＶＰの濃度が５重量％、紡糸の際の延伸が１５％である以外は実施例１と同様の条件、手法で中空糸膜を得た。実施例１と同様の方法で、この中空糸膜のＰＶＰ含量、中空糸膜の血液接触側表面積１ｍ２あたりの４０％エタノール水溶液によるＰＶＰ抽出量、Ｃ特性値、ＵＦＲ、さらに、Ｃ特性値測定前後でのＣＬｕｎ、ＣＬｖｂを測定した。結果は表１または表２に示した。
【００４７】
（比較例１）
ＤＭＦ中での還元粘度が０．７５であるＰＥＳが２５重量％、ＰＶＰが３重量％、凝固浴中で実質的に延伸がかからないようにした以外は実施例１と同様の条件、手法で中空糸膜を得た。実施例１と同様の方法で、この中空糸膜のＰＶＰ含量、中空糸膜の血液接触側表面積１ｍ２あたりの４０％エタノール水溶液によるＰＶＰ抽出量、Ｃ特性値、ＵＦＲ、さらに、Ｃ特性値測定前後でのＣＬｕｎ、ＣＬｖｂを測定した。結果は表１または表２に示した。
【００４８】
（比較例２）
ＤＭＦ中での還元粘度が０．７５であるＰＥＳが２５重量％、ＰＶＰが３重量％、凝固浴中での延伸を３５％にした以外は実施例１と同様の条件、手法で中空糸膜を得た。実施例１と同様の方法で、この中空糸膜のＰＶＰ含量、中空糸膜の血液接触側表面積１ｍ２あたりの４０％エタノール水溶液によるＰＶＰ抽出量、Ｃ特性値、ＵＦＲ、さらに、Ｃ特性値測定前後でのＣＬｕｎ、ＣＬｖｂを測定した。結果は表１または表２に示した。
【００４９】
（比較例３）
ＤＭＦ中での還元粘度が０．７５であるＰＥＳが２８重量％、ＰＶＰが３重量％、凝固浴を４０重量％ＮＭＰ水溶液で温度５℃、凝固浴中での延伸を５％にした以外は実施例１と同様の条件、手法で中空糸膜を得た。実施例１と同様の方法で、この中空糸膜のＰＶＰ含量、中空糸膜の血液接触側表面積１ｍ２あたりの４０％エタノール水溶液によるＰＶＰ抽出量、Ｃ特性値、ＵＦＲ、さらに、Ｃ特性値測定前後でのＣＬｕｎ、ＣＬｖｂを測定した。結果は表１または表２に示した。
【００５０】
（比較例４）
ＤＭＦ中での還元粘度が０．４８であるＰＥＳおよびＢＡＳＦ社製ＰＶＰ（Ｋ−９０）をＤＭＡｃと水の混合液（重量比でＤＭＡｃ：水＝１５：１）にそれぞれ２０重量％、５重量％になるよう混合・溶解し、均一な溶液とした。この溶液を紡糸原液として、二重環状スリット口金から吐出すると同時に、紡糸原液に対して凝固性である５０重量％ＤＭＡｃ水溶液を内液として吐出した。口金から凝固層までの乾式部分を経て凝固層内に紡糸原液／内液を落とし込み、凝固浴内で２％の延伸をかけながら凝固させて中空糸膜として成形して５０ｍ／ｍｉｎの速度で巻取った。中空糸膜巻き取りの過程において、水洗浴を経ることで洗浄を行った。この際、内液の流量を調節することで中空糸の内径を２００μｍに制御した。
【００５１】
実施例１と同様の方法で、この中空糸膜のＰＶＰ含量、中空糸膜の血液接触側表面積１ｍ２あたりの４０％エタノール水溶液によるＰＶＰ抽出量、Ｃ特性値、ＵＦＲ、さらに、Ｃ特性値測定前後でのＣＬｕｎ、ＣＬｖｂを測定した。結果は表１または表２に示した。
【００５２】
（安全性試験例）
実施例１で得た中空糸膜モジュールを、上記［４０％エタノール水溶液での抽出方法］に示した方法で抽出し、中空糸膜モジュール５本分の抽出液をあわせて濃縮して４０％エタノール水溶液を完全に留去した。この濃縮残渣を生理食塩水で再溶解し、全量で１０ｍＬになるように調製した。この液を濾過滅菌し、体重約１０ｋｇのイヌの静脈に投与し、アナフィラキシー様症状の観察という観点から状態の変化を観察した。結果は表３に示した。
【００５３】
比較例１で得た中空糸膜モジュールを使用し、上記と同様の方法で濃縮抽出液のイヌへの投与試験を行った。結果は表３に示した。
【００５４】
【表３】
−：症状発現なし
±：軽度な色調変化（耳介、眼周囲、腹部から鼠脣部にかけての部位など）
軽度な口唇腫脹
体こすり
頭部の振り
＋：色調変化
口唇腫脹
頻繁な体こすり
頻繁な頭部の振り
＋＋：振戦
丘疹
呼吸頻回
チアノーゼ
粗大呼吸
脱力
【００５５】
【発明の効果】
本発明の中空糸型血液浄化膜は、血液接触前後での溶質クリアランスの測定値の差異が小さく、血液接触使用時の性能保持性に優れていることが示された。また、安全性試験例の結果から、本発明の中空糸型血液浄化膜は、抽出物投与によっても実験動物の状態変化が見られず、安全性にも優れていることが示された。すなわち、本発明の中空糸型血液浄化膜は、疎水性高分子と親水性高分子を含んでなり、中空糸型血液浄化膜中における親水性高分子の含量、中空糸型血液浄化膜を４０％エタノール水溶液で抽出した際に抽出される親水性高分子の量が所定範囲にあり、Ｃ特性値が所定範囲の数値をとることによって血液接触使用時の性能保持性、安全性が高レベルで実現されていることがわかる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a blood purification membrane used for blood purification such as hemodialysis, hemofiltration, and hemodiafiltration.
[0002]
[Prior art]
Conventionally, hemodialysis has been performed as maintenance therapy for patients with chronic renal failure. Also, in recent years, examples of acute blood purification therapy, such as continuous hemofiltration, continuous hemofiltration dialysis, and continuous hemodialysis, have been increasing for patients with serious conditions such as acute renal failure and sepsis. . Blood purification membrane materials used in these therapies include naturally occurring materials such as cellulose and cellulose derivatives, and synthetic polymer materials such as polysulfone resins, polymethyl methacrylate, polyacrylonitrile, and ethylene vinyl alcohol copolymer. Is used. Above all, a membrane made of a polysulfone-based resin has been receiving particular attention in recent years because of its advantages such as good mechanical properties, heat resistance, and biocompatibility.
[0003]
Polysulfone resins have relatively strong hydrophobicity and tend to adsorb plasma proteins when in contact with blood. For this reason, when producing a blood purification membrane with a polysulfone-based resin, a hydrophilic polymer is generally added to impart hydrophilicity and improve blood compatibility.
[0004]
Also, as mentioned above, materials with strong hydrophobicity tend to adsorb plasma proteins, and when used in contact with blood for a long period of time, the membrane performance decreases over time due to the effects of plasma proteins adsorbed on the surface. Would. Since the addition of hydrophilicity reduces the adsorption of plasma proteins, the addition of a hydrophilic polymer is effective not only for improving blood compatibility but also for exhibiting stable solute removal performance as a membrane.
[0005]
As a hydrophilic polymer used for such a purpose, polyvinylpyrrolidone (PVP) is the most common. However, PVP may be eluted by contact with blood when the membrane is used, and in some cases, the eluted PVP may cause anaphylaxis-like symptoms in patients. Although PVP is effective for improving the performance of the membrane, it is preferable to minimize the elution amount because of the possibility of causing such side effects.
[0006]
Many methods have been proposed to suppress the elution of PVP. As a method of reducing the elution of PVP, a technique of immobilizing PVP by a chemical treatment has been disclosed (for example, see Patent Document 1). Such a method is considered to be effective in suppressing elution since PVP is firmly immobilized, but the operation is complicated and implementation is not easy. In addition, since it is necessary to use a highly reactive reagent, there is a possibility that the characteristics of the film may be changed by the treatment.
[0007]
In addition, a technique has been disclosed in which a polysulfone-based material containing PVP is irradiated with heat and / or radiation to crosslink PVP and insolubilize the PVP to suppress elution (for example, Patent Documents 2, 3, 4, 5, and 6). , 7). However, in these methods, the operation is complicated, and there is a possibility that a heating site or a radiation irradiation site may be localized, and PVP cross-linking at a site where treatment is insufficient does not sufficiently proceed, and elution occurs. It is possible that
[0008]
Furthermore, even if the elution to water or hot water is suppressed by these methods, the possibility of elution due to contact with blood or plasma having high extraction power cannot be denied. In fact, there is a report that even a dialysis membrane that is said to suppress the amount of PVP eluted still caused anaphylactic shock (for example, see Non-Patent Document 1).
[0009]
The present inventors have already filed a patent application for a membrane in which elution of a hydrophilic polymer is not observed even without modification by chemical modification or crosslinking (for example, see Patent Document 8). In this technology, the elution of the hydrophilic polymer is suppressed by making the membrane structure a uniform fine structure, but consideration must be given to the elution of the hydrophilic polymer when it comes into contact with blood that has a higher extraction power than water. Not enough.
[0010]
The present inventors have already filed a patent application for a membrane with a small amount of PVP eluted even when it comes into contact with blood or plasma (for example, see Patent Document 9). In this technique, the amount of PVP eluted when a 40% ethanol aqueous solution having a higher extraction power than water is extracted as a simulated plasma has a blood contact side membrane area of 1 m. 2 A selective separation membrane weighing 10 mg or less is disclosed, and specifically, the use of PVP subjected to a specific treatment is disclosed as a suitable means for achieving the purpose. However, when focusing on the amount of PVP eluted as described above, although the safety is improved, it is difficult to maintain the membrane performance when treating blood.
[0011]
[Patent Document 1]
JP-A-7-3034 (p. 3)
[Patent Document 2]
JP-A-6-339620 (pages 1 to 2)
[Patent Document 3]
JP-A-9-24261 (pages 1 to 4)
[Patent Document 4]
JP-A-9-103664 (pages 1 to 4)
[Patent Document 5]
JP-A-10-68646 (pages 1 to 3)
[Patent Document 6]
JP-A-10-230148 (pages 1 to 3)
[Patent Document 7]
JP-A-2000-350926 (pages 1 to 5)
[Patent Document 8]
JP-A-2000-42383
[Patent Document 9]
JP 2000-300663 A
[Non-patent document 1]
Nakayama et al., Proceedings of the 43rd Annual Meeting of the Japanese Society for Dialysis Therapy, p620, 1998
[0012]
[Problems to be solved by the invention]
The present invention aims to solve the above-mentioned problems, and is difficult to elute a hydrophilic polymer having a problem in safety due to elution while being an essential component for imparting hydrophilicity, and used in contact with blood. An object of the present invention is to provide a hollow fiber type blood purification membrane excellent in performance retention at the time, that is, a hollow fiber type blood purification membrane which simultaneously satisfies blood compatibility, safety, and performance retention.
[0013]
[Means for Solving the Problems]
Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have reached the present invention. That is, the hollow fiber blood purification membrane of the present invention,
1. A hydrophobic polymer and a hydrophilic polymer, wherein the content of the hydrophilic polymer in the hollow fiber blood purification membrane is 5% by weight or more, and the hollow fiber blood purification membrane is extracted with a 40% aqueous ethanol solution. When the amount of the hydrophilic polymer extracted at the time of the removal is 1 m on the blood contact side surface of the hollow fiber type blood purification membrane, 2 When perfusion was performed using bovine blood at a blood flow rate of 200 mL / min and a filtration flow rate of 20 mL / min, the water permeability at the start of perfusion at 15 minutes was (A) mL / (m 2 · Hr · mmHg) and the water permeability at the start of perfusion 120 minutes (B) mL / (m 2 (Hr · mmHg), a value of 100% × (B) / (A) (hereinafter abbreviated as C characteristic value) is 65% or more.
2. The content of the insoluble component is less than 2% by weight based on the whole film.
3. It is characterized in that the inside of the film has a substantially uniform structure and the film surface has a smooth structure.
4. The hydrophobic polymer is a polysulfone polymer.
5. The polysulfone polymer is a polyether sulfone.
6. It is characterized in that the hydrophilic polymer is polyvinylpyrrolidone.
7. The film thickness is 10 to 40 μm, the inner diameter is 100 to 300 μm, and the water permeability at 37 ° C. is 1 to 30 mL / (m 2 · Hr · mmHg), and the sieving coefficient of myoglobin is 0 to 0.4.
[0014]
In a hollow fiber type blood purification membrane composed of a hydrophobic polymer and a hydrophilic polymer, it is practically impossible to completely eliminate the elution of the hydrophilic polymer, so it is necessary to set an upper limit from the viewpoint of safety. There is. Further, it is considered that the thorough reduction of the elution amount of the hydrophilic polymer results in a decrease in the amount of the hydrophilic polymer on the membrane surface, which may result in a decrease in performance retention when used in contact with blood. As a result of intensive studies, the present applicant has found that the content of the hydrophilic polymer in the hollow fiber blood purification membrane is 5% by weight or more, and the hydrophilic fiber extracted when the hollow fiber blood purification membrane is extracted with 40% ethanol. The amount of the hydrophilic polymer is 1 m on the blood contact side of the hollow fiber type blood purification membrane. 2 The inventors have found that a membrane having a C characteristic value of not more than 20 mg per day and a C characteristic value of not less than 65% can achieve both blood purification performance, performance retention during blood contact use, and safety at a high level.
[0015]
From the viewpoint of blood compatibility and retention of performance when used in contact with blood, it is preferable that the amount of hydrophilic polymer contained in the membrane is large, but if the content of hydrophilic polymer is increased, the amount of elution increases This is not preferable from the viewpoint of safety. From the viewpoint of the former, the content of the hydrophilic polymer in the hollow fiber type blood purification membrane is preferably 5% by weight or more, and more preferably 6% by weight or more. From the viewpoint of the latter, the extraction amount of the hydrophilic polymer when the hollow fiber type blood purification membrane is extracted with a 40% aqueous ethanol solution is 20 mg / (m 2 -Hollow fiber type blood purification membrane blood contact surface area), preferably 15 mg / (m 2 -Hollow fiber blood purification membrane blood contact surface area). 10 mg / (m 2 -Hollow fiber blood purification membrane blood contact surface area). Further, when blood contact is used, a decrease in water permeability over time means that clogging of the membrane progresses due to adsorption of blood components to the membrane. A high C characteristic value suggests that such undesired adsorption of blood components is suppressed, and from the viewpoint of performance retention when used in contact with blood, the C characteristic value should be 65% or more. It is preferably at least 75%, more preferably at least 80%, most preferably at least 85%.
[0016]
Even if any one of these values is out of the above range, the total performance of the film will be reduced. When all are satisfied at the same time, a hollow fiber type blood purification membrane which simultaneously satisfies the blood compatibility, safety, and performance retention intended by the present invention can be obtained.
[0017]
It is conceivable that a hydrophilic polymer whose structure has been partially modified by a treatment such as cross-linking behaves slightly different from the characteristics originally possessed by the hydrophilic polymer. In order to ensure performance retention during blood contact use, it is preferable that the hydrophilic polymer contained in the hollow fiber type blood purification membrane of the present invention is not substantially insolubilized, and specifically contains an insoluble component. Preferably, the percentage is less than 2% by weight, based on the entire membrane. More preferably less than 1.5% by weight, even more preferably less than 1% by weight.
[0018]
The hollow fiber type blood purification membrane of the present invention has a substantially uniform structure inside the membrane as a structural feature for achieving a high level of blood purification performance, performance retention during blood contact use, and safety at a high level. Preferably, the surface has a smooth structure. In the case of such a film structure, the elution from the surface can be suppressed relatively low while the content of the hydrophilic polymer as the whole film is high. Although the detailed mechanism is unknown, it is presumed that this is because there is no diffuse layer having a rough structure on any of the inner and outer surfaces, and the contained hydrophilic polymer is difficult to escape. Here, the “substantially uniform structure” means that when the cross section of the film is observed with an electron microscope, structural nonuniformity from the film surface to the center of the film is not visually recognized.
[0019]
As a specific means for obtaining such a hollow fiber type blood purification membrane, for example, as a lumen forming agent (inner solution) used in the production of a hollow fiber, a material which does not easily solidify a hydrophobic polymer solution is used. There are ways to use it.
[0020]
When manufacturing a hollow fiber membrane, a polymer solution (dope) as a raw material and a forming agent for the lumen are discharged from a double-tube type nozzle, guided into a coagulation bath through an idle portion, and solidified. In general, a dry-wet spinning method of winding up after a washing step is employed. Conventionally, in a hollow fiber type blood purification membrane composed mainly of a polysulfone-based hydrophobic polymer and PVP, an aqueous liquid that solidifies the hydrophobic polymer is generally used as a lumen forming agent (inner solution). It is a target. In the hollow fiber membrane produced by such a technique, first, the dope solidifies on the surface on the lumen side, and is immersed in a coagulation bath in that state, so that the surface on the lumen side is necessarily dense. As a result, the outer surface has a rough heterogeneous structure. In such a structure, the hydrophilic polymer is easily eluted from the diffused layer on the outer surface in the washing step. Therefore, even if the concentration of the hydrophilic polymer in the dope is increased, the content of the hydrophilic polymer in the obtained hollow fiber membrane is increased. Is likely to decrease.
[0021]
On the other hand, when a liquid with low coagulation is used as the internal liquid, coagulation in the free running portion is gentle, coagulation of the dope does not progress rapidly on the surface on the lumen side, and a homogeneous structure is obtained. It is easy to be. For this reason, since the outer surface is not as rough as when the coagulation-based internal solution is used, desorption of the hydrophilic polymer in the washing step is slight. That is, when prepared by such a method, the content of the hydrophilic polymer in the hollow fiber membrane becomes relatively high.
[0022]
However, when the internal liquid is a liquid with low coagulability as described above, the structure of the outer surface may be relatively dense. Therefore, in order to obtain a uniform film structure, it is preferable to control the coagulation in the coagulation bath and suppress the formation of a dense structure on the outer surface to some extent. Specifically, it is preferable that the coagulating liquid is a mixed liquid of the dope coagulating liquid and the dope non-coagulating or dope low coagulating liquid, and the temperature of the coagulating liquid is relatively low. More preferably, the coagulation liquid is a mixed liquid of a dope solvent and water, and the solvent concentration is preferably 5 to 70% by weight, and more preferably the solvent concentration is 7 to 65% by weight. The temperature of the coagulating liquid is more preferably 0 to 35 ° C, further preferably 0 to 30 ° C, and still more preferably 5 to 25 ° C.
[0023]
Examples of the hydrophobic polymer in the present invention include synthetic polymers such as polyester, polycarbonate, polyurethane, polyamide, polysulfone, polyethersulfone, and polymethyl methacrylate, and cellulose-based polymers such as cellulose triacetate and cellulose nitrate. You. Among them, polysulfone-based polymers such as polysulfone and polyethersulfone are preferable since they are excellent in biocompatibility and can obtain high removal performance of uremic substances. The polysulfone-based polymer mentioned here may contain a substituent such as a functional group or an alkyl group, and the hydrogen atom of the hydrocarbon skeleton may be substituted with another atom or a substituent such as halogen. These may be used alone or as a mixture of two or more.
[0024]
Examples of the hydrophilic polymer in the present invention include polymers such as polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, starch and derivatives thereof, and cellulose acetate. Above all, polyvinylpyrrolidone is preferable from the viewpoint of compatibility with the polysulfone-based polymer and use results as a blood purification membrane material. These may be used alone or as a mixture of two or more.
[0025]
The hollow fiber blood purification membrane of the present invention preferably has a thickness of 10 to 40 μm and an inner diameter of 100 to 300 μm from the viewpoint of simultaneously satisfying blood compatibility, safety, and performance retention. When the film thickness is smaller than the above range, it is difficult to secure sufficient strength, and when the film thickness is larger than the above range, the material permeation performance is reduced. A more preferable range of the film thickness is 10 to 35 μm, and a further preferable range is 10 to 30 μm. If the inner diameter is out of the above range, the blood flow rate during blood perfusion becomes too small or too large, which may cause a decrease in blood compatibility and a decrease in performance retention due to adsorption of blood components due to interaction with the membrane surface. The hollow fiber blood purification membrane of the present invention has a water permeability of 1 to 30 mL / (m 2 Hr.mmHg), and the sieving coefficient of myoglobin is preferably 0 to 0.4. When the ratio is below this range, the performance as a blood purification membrane is insufficient. When the ratio exceeds this range, the performance retention may be reduced.
[0026]
Further, as another specific means for obtaining the hollow fiber type blood purification membrane as described above, for example, there is a method of setting a high concentration of a hydrophobic polymer in a dope prepared at the time of manufacturing a hollow fiber. Although the detailed mechanism is unknown, increasing the concentration of the hydrophobic polymer makes it easier for the dope to coagulate in a state in which the hydrophilic polymer is firmly included, resulting in elution of the hydrophilic polymer. It is estimated that it can be suppressed. Furthermore, the reduced viscosity of the hydrophobic polymer used is preferably 0.2 to 0.6. Although the detailed mechanism is unknown, coagulation in the coagulation bath is appropriately controlled by using such a hydrophobic polymer having a reduced viscosity, and it is necessary to obtain the hollow fiber blood purification membrane as described above. It is considered suitable.
[0027]
Examples of the solvent that dissolves the hydrophobic polymer and the hydrophilic polymer include dimethylacetamide (DMAc), dimethylsulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP). Among them, DMAc or NMP is preferable. Examples of the non-solvent added to the dope used in the production of the hollow fiber include ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, water, and the like.
[0028]
The concentration of the hydrophobic polymer in the spinning dope is preferably 20% to 50% by weight, more preferably 25% to 45% by weight, still more preferably 30% to 45% by weight, and most preferably 35 to 45% by weight. % By weight. If the concentration is lower than this, it is difficult to secure the strength of the membrane, and the content of the hydrophilic polymer intended by the present invention and the amount of the hydrophilic polymer extracted with 40% ethanol are realized. Is likely to be difficult, and if the concentration is higher than this, operability may be deteriorated.
[0029]
The concentration of the hydrophilic polymer in the spinning dope is preferably 1 to 15% by weight, more preferably 1 to 10% by weight. If the concentration is lower than this, it is more likely that it is difficult to realize the content of the hydrophilic polymer intended by the present invention. If the concentration is higher than this, extraction with 40% ethanol intended by the present invention is performed. It is more likely that it will be difficult to achieve the amount of hydrophilic polymer to be achieved. If the molecular weight of the hydrophilic polymer is too large, there is a problem in the solubility of the spinning dope. If the molecular weight is too small, the polymer is easily eluted from the membrane. Preferably, it is ~ 1.1 million.
[0030]
Examples of the dope-low coagulating internal solution that is preferably used when producing the hollow fiber membrane include liquid paraffin and isopropyl myristate.
[0031]
Further, as another specific means for obtaining the above-mentioned hollow fiber type blood purification membrane, for example, there is a method in which drawing is performed in a coagulation bath during production of the hollow fiber membrane. Although the detailed mechanism is unknown, it is considered that by stretching the hollow fiber membrane during coagulation, the fine structure of the membrane pores is optimized and preferable characteristics are exhibited. Stretching is preferably 3 to 30%, more preferably 3 to 25%, and still more preferably 3 to 20%. The term “stretching” as used herein refers to the ratio of the speed of the coagulation bath inlet roller to the speed of the coagulation bath outlet roller. When spinning a hardly crystallizable polymer such as polysulfone and polyethersulfone using a non-coagulable internal solution, the coagulation speed is slow. In the state of the inner surface, the deformation of the pore shape does not become too large, the alignment of the pores is high, and the state is uniform and smooth. By having such a characteristic, adhesion of platelets is suppressed, and adsorption of blood protein is suppressed to a monolayer, so that even when performing blood perfusion while performing filtration which is a feature of the present invention. It is considered that a hollow fiber membrane having a small decrease in water permeability over time can be obtained. Further, by stretching, densification of the membrane surface is suppressed, excess hydrophilic polymer is easily removed, and there is also an effect of reducing the elution amount during use.
[0032]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
[0033]
[Method of measuring and calculating insoluble component content]
10 g of a hollow fiber type blood purification membrane as a finished product was dissolved in 100 mL of the solvent used in the production. This solution was centrifuged to remove insoluble components at 1500 rpm for 10 minutes, and the supernatant was removed. This operation was repeated three times, the remaining insoluble components were evaporated to dryness, the weight was measured, and the content of the insoluble components was calculated.
[0034]
[Method for measuring and calculating hydrophilic polymer content]
Dissolve the hollow fiber type blood purification membrane in a suitable solvent, 1 By performing H-NMR measurement, the area ratio between a peak derived from a hydrogen atom (H1) contained in the hydrophobic polymer and a peak derived from a hydrogen atom (H2) contained in the hydrophilic polymer is determined. (This area ratio is a1: a2). The molecular weight of the repeating unit of the hydrophobic polymer is M1, the number of a1 contained in the repeating unit is n1, the molecular weight of the repeating unit of the hydrophilic polymer is M2, and the number of a2 contained in the repeating unit is n2. The content of the hydrophilic polymer was calculated by the following equation.
Content of hydrophilic polymer (%) =
((A2 / n2) × M2 × 100) / ((a1 / n1) × M1 + (a2 / n2) × M2)
[0035]
[Method for measuring PVP content of hollow fiber membrane]
Dissolving the hollow fiber membrane with heavy DMSO, 1 H-NMR was measured, and the content of the hydrophilic polymer in the hollow fiber membrane was calculated from the area ratio of the peak derived from the hydrophobic polymer to the peak derived from the hydrophilic polymer.
[0036]
[Extraction method with 40% ethanol aqueous solution]
The extraction test with a 40% aqueous ethanol solution was performed according to the following procedure. After flushing was performed by flowing 400 mL of pure water inside the hollow fiber of the hollow fiber membrane module, the pure water in the module was replaced with a 40% by volume aqueous ethanol solution. The inside of the module case outside the hollow fiber was also filled with a 40% by volume aqueous ethanol solution and sealed. Subsequently, 200 mL of 40% by volume ethanol was circulated inside the hollow fiber at 150 mL / min for 1 hour under the condition of 40 ° C., and the circulated 40% by volume aqueous ethanol solution was recovered, and the PVP concentration was measured. The total weight of the extracted PVP was calculated from the total volume of the extract and the PVP concentration in the extract obtained by adding 200 mL to the inner volume of the hollow fiber of the module and the header portion at the module entrance / exit, that is, the priming volume. From the membrane area (based on the inner diameter of the hollow fiber) of the fiber membrane module, the membrane area on the contact side of the liquid to be treated is 1 m 2 The amount of PVP extracted per unit was determined.
[0037]
[Method of measuring PVP concentration]
The measurement of PVP concentration is described in K. This was performed according to the method of Mueller (K. Mueller, Pharm. Acta. Helv., 43, 107 (1968)). That is, citric acid and an iodine solution were added to the sample, the absorbance was measured, and the concentration was determined by a calibration curve obtained from PVP with a known concentration. Here, at the time of concentration measurement, it is necessary to dilute at least twice in order to avoid inhibition of color development by ethanol. Specifically, for example, when performing a concentration measurement by 2-fold dilution, 1.25 mL of a sample, 1.25 mL of water, 1.25 mL of a 0.2 mol / L citric acid aqueous solution, and 0.5 mL of a 0.006 N iodine aqueous solution are often used. After mixing and standing for 10 minutes, the absorbance at 470 nm is measured, and the PVP concentration may be calculated from the measured value.
[0038]
[Method of measuring water permeability of hollow fiber membrane]
Using a hollow fiber membrane module, both sides of the inside and outside of the membrane were filled with pure water. A pressure is applied by pure water from the module entrance leading to the inside of the membrane to generate a pressure difference between the inside and outside of the membrane, that is, a transmembrane pressure difference. It was measured. At four different transmembrane pressure differences, the water permeation amount for one minute was measured, plotted on the two-dimensional coordinates of the transmembrane pressure difference and the water permeation amount, and the slopes of the approximate straight lines were obtained as numerical values. This value was multiplied by 60 and divided by the membrane area of the hollow fiber membrane module to determine the water permeability of the hollow fiber membrane (hereinafter abbreviated as UFR. The unit is mL / (m 2 · Hr · mmHg)).
[0039]
[Method of measuring C characteristic value of hollow fiber membrane]
Using a hollow fiber membrane module, bovine blood with a hematocrit of 35% was perfused inside the hollow fiber at a flow rate of 200 mL / min. At the same time, filtration was performed from the outside of the hollow fiber at a flow rate of 20 mL / min. Water permeability (hereinafter abbreviated as MFR) in the bovine blood system was calculated from the transmembrane pressure and the filtrate volume 15 minutes after the start of perfusion / filtration. This value is defined as (A), and after 120 minutes from the start of perfusion / filtration, the C characteristic value is calculated from the MFR value (B) obtained by the same operation as 100 (%) × (B) / (A). Calculated.
[0040]
[Measuring method of clearance]
Kindary diluent (35-fold dilution) prepared so that vitamin B12 is 20 ppm, urea is 1000 ppm, sodium chloride is 180 ppm, monosodium phosphate (anhydrous) is 40 ppm, and disodium phosphate (decahydrate) is 480 ppm. Use, membrane area 1.5m 2 The module was measured. The flow rate on the blood side was 200 ± 1 ml / min, and the flow rate on the dialysate side was 500 ± 10 ml / min. One minute after the start of the flow, the fluid on the dialysate side was sampled for 3 minutes, and the fluid on the blood side (out) was sampled for 1 minute. The urea concentration of each solution was measured by the urease-indophenol method using urea nitrogen B-test Wako manufactured by Wako Pure Chemical Industries, Ltd. In addition, the concentration of vitamin B12 was measured from the absorbance at 360 nm. Urea clearance (CLun) and vitamin B12 clearance (CLvb) of the hollow fiber membrane were calculated from these measured values.
[0041]
(Example 1)
A mixed solution of NMP and triethylene glycol (hereinafter abbreviated as TEG) of polyethersulfone (hereinafter abbreviated as PES) having a reduced viscosity of 0.48 in DMF and PVP (K-90) manufactured by BASF. (NMP: TEG = 8: 2 in weight ratio) was mixed and dissolved to be 35% by weight and 7% by weight, respectively, to obtain a uniform solution. This solution was discharged as a spinning dope from a double annular slit die, and at the same time, liquid paraffin which was non-coagulable with respect to the spinning dope was discharged as an inner liquid. The spinning solution / inner solution was dropped into the solidified layer through a dry portion from the die to the solidified layer, solidified while being stretched by 7%, formed into a hollow fiber membrane, and wound at a speed of 75 m / min. The composition of the coagulating liquid used at this time was a 10% by weight NMP aqueous solution and the temperature was 25 ° C. In the process of winding the hollow fiber membrane, washing was performed by passing through a water washing bath and a 30% by weight glycerin aqueous solution bath, glycerin was applied to the surface, and further dried. At this time, the inner diameter of the hollow fiber was controlled to 200 μm by adjusting the flow rate of the liquid paraffin as the internal liquid.
[0042]
According to the above method, the PVP content of the hollow fiber membrane, the blood contact side surface area of the hollow fiber membrane 1 m 2 The amount of PVP extracted by a 40% aqueous ethanol solution and the C characteristic value were measured. The results are shown in Table 1.
[0043]
[Table 1]
Further, UFR of this hollow fiber membrane, and CLun and CLvb before and after the C characteristic value measurement were measured by the above method. The results are shown in Table 2. In addition, before and after the C characteristic value measurement means that before and after the blood contact for 120 minutes. After measuring the C characteristic value, the module was washed with water to sufficiently remove the internal blood, and the clearance was measured.
[0045]
[Table 2]
(Example 2)
A hollow fiber membrane was obtained under the same conditions and procedures as in Example 1 except that the concentration of PES was 42% by weight, the concentration of PVP was 5% by weight, and the stretching during spinning was 15%. In the same manner as in Example 1, the PVP content of the hollow fiber membrane, the blood contact side surface area of the hollow fiber membrane 1 m 2 The amount of PVP extracted by a 40% aqueous ethanol solution per unit, C characteristic value, UFR, and CLun and CLvb before and after the C characteristic value measurement were measured. The results are shown in Table 1 or Table 2.
[0047]
(Comparative Example 1)
Except that PES having a reduced viscosity in DMF of 0.75 was 25% by weight, PVP was 3% by weight, and stretching was substantially not performed in a coagulation bath, and hollowed out under the same conditions and method as in Example 1. A fibrous membrane was obtained. In the same manner as in Example 1, the PVP content of the hollow fiber membrane, the blood contact side surface area of the hollow fiber membrane 1 m 2 The amount of PVP extracted by a 40% aqueous ethanol solution per unit, C characteristic value, UFR, and CLun and CLvb before and after the C characteristic value measurement were measured. The results are shown in Table 1 or Table 2.
[0048]
(Comparative Example 2)
Hollow fiber membrane under the same conditions and procedures as in Example 1 except that PES having a reduced viscosity in DMF of 0.75 was 25% by weight, PVP was 3% by weight, and stretching in a coagulation bath was 35%. Got. In the same manner as in Example 1, the PVP content of the hollow fiber membrane, the blood contact side surface area of the hollow fiber membrane 1 m 2 The amount of PVP extracted by a 40% aqueous ethanol solution per unit, C characteristic value, UFR, and CLun and CLvb before and after the C characteristic value measurement were measured. The results are shown in Table 1 or Table 2.
[0049]
(Comparative Example 3)
Except that PES having a reduced viscosity in DMF of 0.75 is 28% by weight, PVP is 3% by weight, the coagulation bath is a 40% by weight NMP aqueous solution at a temperature of 5 ° C., and the stretching in the coagulation bath is 5%. A hollow fiber membrane was obtained under the same conditions and in the same manner as in Example 1. In the same manner as in Example 1, the PVP content of the hollow fiber membrane, the blood contact side surface area of the hollow fiber membrane 1 m 2 The amount of PVP extracted by a 40% aqueous ethanol solution per unit, C characteristic value, UFR, and CLun and CLvb before and after the C characteristic value measurement were measured. The results are shown in Table 1 or Table 2.
[0050]
(Comparative Example 4)
PES having a reduced viscosity of 0.48 in DMF and PVP (K-90) manufactured by BASF were added to a mixed solution of DMAc and water (weight ratio of DMAc: water = 15: 1) at 20% by weight and 5% by weight, respectively. % To obtain a uniform solution. This solution was discharged as a spinning solution from a double annular slit die, and at the same time, a 50% by weight aqueous solution of DMAc which was coagulable with the spinning solution was discharged as an inner solution. The spinning solution / inner solution is dropped into the coagulation layer through the dry portion from the die to the coagulation layer, solidified while being stretched by 2% in a coagulation bath, formed into a hollow fiber membrane, and wound at a speed of 50 m / min. I took it. In the process of winding the hollow fiber membrane, washing was performed by passing through a washing bath. At this time, the inner diameter of the hollow fiber was controlled to 200 μm by adjusting the flow rate of the internal solution.
[0051]
In the same manner as in Example 1, the PVP content of the hollow fiber membrane, the blood contact side surface area of the hollow fiber membrane 1 m 2 The amount of PVP extracted by a 40% aqueous ethanol solution per unit, C characteristic value, UFR, and CLun and CLvb before and after the C characteristic value measurement were measured. The results are shown in Table 1 or Table 2.
[0052]
(Example of safety test)
The hollow fiber membrane module obtained in Example 1 was extracted by the method described in the above [Extraction method with 40% ethanol aqueous solution], and the extracts of five hollow fiber membrane modules were combined and concentrated to obtain 40% ethanol. The aqueous solution was completely distilled off. This concentrated residue was redissolved in physiological saline, and adjusted to a total volume of 10 mL. This solution was sterilized by filtration, and administered to a vein of a dog weighing about 10 kg, and a change in the condition was observed from the viewpoint of observing anaphylactic symptoms. The results are shown in Table 3.
[0053]
Using the hollow fiber membrane module obtained in Comparative Example 1, a test of administering the concentrated extract to dogs was performed in the same manner as described above. The results are shown in Table 3.
[0054]
[Table 3]
-: No symptoms occurred
±: Mild color change (auricle, peri-ocular, part from abdomen to rat stalk)
Mild lip swelling
Body rub
Swinging the head
+: Color tone change
Lip swelling
Frequent rubbing
Frequent head shaking
++: Tremor
Papules
Frequent breathing
Cyanosis
Gross breathing
Weakness
[0055]
【The invention's effect】
The hollow fiber blood purification membrane of the present invention showed a small difference in the measured value of solute clearance before and after blood contact, indicating that the membrane had excellent performance retention during blood contact use. In addition, the results of the safety test examples showed that the hollow fiber-type blood purification membrane of the present invention did not show any change in the state of the experimental animal even after administration of the extract, and was excellent in safety. That is, the hollow fiber type blood purification membrane of the present invention comprises a hydrophobic polymer and a hydrophilic polymer, the content of the hydrophilic polymer in the hollow fiber type blood purification membrane, the hollow fiber type blood purification membrane is 40%. %, The amount of the hydrophilic polymer extracted when extracted with an aqueous ethanol solution is within a predetermined range, and the C characteristic value is within the predetermined range. It can be seen that it has been realized.
Claims (7)
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| JP2003105397A JP4381022B2 (en) | 2003-04-09 | 2003-04-09 | Hollow fiber blood purification membrane |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006187768A (en) * | 2004-12-09 | 2006-07-20 | Toray Ind Inc | Production method of polysulfone type hollow fiber membrane and production method of module for medical care using it |
| WO2010090174A1 (en) | 2009-02-04 | 2010-08-12 | 東洋紡績株式会社 | Hollow-fiber membrane, process for producing same, and blood purification module |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06296686A (en) * | 1993-04-19 | 1994-10-25 | Asahi Chem Ind Co Ltd | Polysulfone hollow yarn membrane for medical purpose |
| JPH09154936A (en) * | 1994-12-16 | 1997-06-17 | Toyobo Co Ltd | Blood purifying module, blood purifying membrane and production thereof |
| JPH09220455A (en) * | 1996-10-04 | 1997-08-26 | Toyobo Co Ltd | Hollow yarn type selective separation membrane |
| JPH10108907A (en) * | 1996-10-08 | 1998-04-28 | Toyobo Co Ltd | Membrane for hemocatharsis, its preparation and module for hemocatharsis |
| JP2000042383A (en) * | 1998-07-31 | 2000-02-15 | Toyobo Co Ltd | Hydrophilic selective transmitting membrane |
| JP2000300663A (en) * | 1999-04-19 | 2000-10-31 | Toyobo Co Ltd | Selective separation membrane |
| JP2001205057A (en) * | 2000-01-27 | 2001-07-31 | Toyobo Co Ltd | Hollow fiber membrane |
| JP3253861B2 (en) * | 1996-08-28 | 2002-02-04 | 帝人株式会社 | Permselective hollow fiber membrane |
| WO2002009857A1 (en) * | 2000-07-27 | 2002-02-07 | Asahi Medical Co., Ltd. | Modified hollow-fiber membrane |
-
2003
- 2003-04-09 JP JP2003105397A patent/JP4381022B2/en not_active Expired - Lifetime
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06296686A (en) * | 1993-04-19 | 1994-10-25 | Asahi Chem Ind Co Ltd | Polysulfone hollow yarn membrane for medical purpose |
| JPH09154936A (en) * | 1994-12-16 | 1997-06-17 | Toyobo Co Ltd | Blood purifying module, blood purifying membrane and production thereof |
| JP3253861B2 (en) * | 1996-08-28 | 2002-02-04 | 帝人株式会社 | Permselective hollow fiber membrane |
| JPH09220455A (en) * | 1996-10-04 | 1997-08-26 | Toyobo Co Ltd | Hollow yarn type selective separation membrane |
| JPH10108907A (en) * | 1996-10-08 | 1998-04-28 | Toyobo Co Ltd | Membrane for hemocatharsis, its preparation and module for hemocatharsis |
| JP2000042383A (en) * | 1998-07-31 | 2000-02-15 | Toyobo Co Ltd | Hydrophilic selective transmitting membrane |
| JP2000300663A (en) * | 1999-04-19 | 2000-10-31 | Toyobo Co Ltd | Selective separation membrane |
| JP2001205057A (en) * | 2000-01-27 | 2001-07-31 | Toyobo Co Ltd | Hollow fiber membrane |
| WO2002009857A1 (en) * | 2000-07-27 | 2002-02-07 | Asahi Medical Co., Ltd. | Modified hollow-fiber membrane |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006187768A (en) * | 2004-12-09 | 2006-07-20 | Toray Ind Inc | Production method of polysulfone type hollow fiber membrane and production method of module for medical care using it |
| WO2010090174A1 (en) | 2009-02-04 | 2010-08-12 | 東洋紡績株式会社 | Hollow-fiber membrane, process for producing same, and blood purification module |
| US8840788B2 (en) | 2009-02-04 | 2014-09-23 | Toyo Boseki Kabushiki Kaisha | Hollow fiber membrane, method for manufacturing the same, and blood purification module |
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| JP4381022B2 (en) | 2009-12-09 |
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