JP3617194B2 - Permselective separation membrane and method for producing the same - Google Patents
Permselective separation membrane and method for producing the same Download PDFInfo
- Publication number
- JP3617194B2 JP3617194B2 JP17100796A JP17100796A JP3617194B2 JP 3617194 B2 JP3617194 B2 JP 3617194B2 JP 17100796 A JP17100796 A JP 17100796A JP 17100796 A JP17100796 A JP 17100796A JP 3617194 B2 JP3617194 B2 JP 3617194B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- less
- separation membrane
- polyvinylpyrrolidone
- molecular weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Images
Landscapes
- Separation Using Semi-Permeable Membranes (AREA)
- External Artificial Organs (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は選択透過性分離膜およびその製造方法に関するものである。さらに詳しくは膜中に存在する親水性高分子の分子量分布をコントロールすることによって血液処理に用いた場合、高い血液濾過流量、低アルブミン透過性を長時間にわたって維持し、中高分子蛋白からなる尿毒物質に対して高い選択透過性を有する膜ならびに、これらの膜を製造する方法に関する。
【０００２】
【従来の技術】
血液処理用の半透膜としては天然素材であるセルロース、合成高分子膜素材であるポリスルホン、ＰＭＭＡ、ポリアクリロニトリルなどが今日まで幅広く使用され、慢性腎不全患者の血液処理法については人腎に近づけるべく様々な技術開発がなされてきた。近年、これらの膜素材の中で透析技術の進歩に合致したものとして透水性能が高いポリスルホンが注目を浴びている。ポリスルホンは元来、熱可塑性の耐熱性エンジニアリングプラスチックとして自動車、電気、医療用具の分野で幅広く用いられているものであるが、ポリスルホン単体で半透膜を作った場合、分子間凝集力が強く、また、疎水性のために血液との親和性に乏しく、このまま血液処理用に用いることはできない。従って、孔形成材として親水性高分子、無機塩などを混入し、溶脱する事によって孔を形作り、同時にポリマー表面を親水化し、これを半透膜、逆浸透膜として用いる方法が考案され、出願されている。
【０００３】
血液処理用の半透膜の製造方法としては、金属塩を入れて製膜する方法、親水性高分子を入れて製膜する方法、多価アルコールを入れて製膜する方法などが公開されている。しかし、特開昭６１−２３２８６０、特開昭５８−１１４７０２のようにポリエチレングリコール等の多価アルコールを入れて製膜を行う場合、洗浄が不十分の場合、膜に残存するアルコールによって、透析時に患者の目に異常が起こる。特公平６−７５６６７ではポリビニルピロリドンを用いる製膜方法も開示されているが透水性能は高いものの、血液処理用（透析用）としては、アルブミン透過率が高いという問題がある。特開 昭６２−１２１６０８に示される金属塩を用いる方法も同様である。特開平６−２３３９２１では高分子量の親水性高分子を入れ、粘度を増加させて原液の良溶媒を１００％芯液として用いることができるようにする中空糸膜の製造方法が提案されているが、この方法では膜のアルブミン透過性をコントロールできない。また、膜中の親水性高分子の分子量分布についての知見はない。特公平２−１８６９５ではポリスルホンに対し高分子量ポリビニルピロリドンの含有率を高く規定し、ポリビニルピロリドンを膜中に大量に残存させることによって膜の耐汚染性、洗浄性を高めた膜が開示されているが、本発明が目的としている高い拡散性能は得られていない。さらに特公平５−５４３７３ではポリスルホンと比較的低分子量のポリビニルピロリドンからなる低粘度原液を用いて、大部分のポリビニルピロリドンを洗浄除去した膜が開示されているが本発明のような膜内に残る親水性高分子の分子量分布が高い拡散性能を発揮することは明記されていない。特に近年透析が始まって２０数年経たことから、長期透析による合併症が数多く報告され、手根管症候群、その他透析シンドロームの原因物質として分子量２万から４万の蛋白質が注目を浴びているが、いずれの方法においても前述の蛋白質を積極的に除去できる高い人腎機能を代替・模倣する選択分離膜は開示されていない。
【０００４】
【発明が解決しようとする課題】
本発明者らは、上記欠点を克服すべく鋭意検討を重ねた結果、本発明を達成することができた。すなわち、有用蛋白であるアルブミンの透過性を抑え、中高分子量尿毒蛋白の除去性能を高めた選択透過性分離膜、および、その製造方法を提供することを目的とする。
【０００５】
【課題を解決するための手段】
上記目的を達成するために、本願発明は下記の構成を有する。
【０００６】
ポリスルホン系樹脂、ポリビニルピロリドンを主成分としてなる選択透過性分離膜において、分子量10万未満のポリビニルピロリドンがポリビニルピロリドン全重量に対して１０重量％以上、５０重量％以下含まれ、１０万以上のポリビニルピロリドンがポリビニルピロリドン全重量に対し、５０重量％以上、９０重量％以下含まれていることを特徴とする選択透過性分離膜。
【０００７】
ポリスルホン系樹脂、ポリビニルピロリドンを主成分としてなる選択透過性分離膜において、分子量10万未満のポリビニルピロリドンがポリビニルピロリドン全重量に対して１０重量％以上、５０重量％以下含まれ、１０万以上のポリビニルピロリドンがポリビニルピロリドン全重量に対し、５０重量％以上、９０重量％以下含まれた膜を不溶化処理してなることを特徴とする選択透過性分離膜。
【０００８】
ポリスルホン系樹脂とポリビニルピロリドン、溶媒、添加剤を少なくとも含む製膜原液を用い、分子量の異なるポリビニルピロリドンを２種類以上含有し、かつ、分子量１０万以上のポリビニルピロリドンの含有比率が該製膜原液全体に対して１．８重量％以上、２０重量％以下であることを特徴とする選択透過性分離膜の製造方法。
【００１０】
【発明の実施の態様】
本発明において、選択分離膜を形成するために用いられる原液は疎水性高分子、親水性高分子、溶媒、および添加剤を少なくとも含有する。
【００１１】
この中で疎水性高分子としては、下記基本骨格を有するポリスルホンが用いられる。下記基本骨格中、ベンゼン環部分を修飾したものも好ましく用いることができる。
【００１２】
【化１】
【００１３】
溶媒については、疎水性高分子、親水性高分子、添加剤の３者を良く溶かす両性溶媒が用いられる。具体的にはジメチルアセトアミド、ジメチルホルムアミド、ジメチルスルホキシド、アセトン、アセトアルデヒド、２ーメチルピロリドンなどであるが、危険性、安定性、毒性の面からジメチルアセトアミドが好ましい。 添加剤としては、疎水性高分子の貧溶媒で親水性高分子と相溶性を持つものが用いられ、具体的には、アルコール、グリセリン、水、エステル類等が挙げられ、プロセス適性の面から特に水が好ましい。
【００１４】
本発明の選択透過性分離膜は、分子量１０万未満の親水性高分子が親水性高分子全重量に対して１０重量％以上、５０重量％以下含まれ、かつ１０万以上の親水性高分子が親水性高分子全重量に対し、５０重量％以上、９０重量％以下含まれてなる。すなわち本願発明においては、親水性高分子中、高分子量親水性高分子に、低分子量親水性高分子が存在することで有用蛋白であるアルブミンの透過を抑えつつも中分子領域以上の拡散性能が特に向上することを見出した。これは、恐らく、大きな高分子量ポリマーに低分子のポリマーが入り込むことによって中分子量蛋白を透過させるべく適当な網目構造を形成することができるためではないかと考えられる。これが、高分子量親水性高分子単独の場合、高透水性能を保ったまま、人工腎臓などに必要な低アルブミン透過性は達成できない。また、低分子量親水性高分子単独の場合は適当な製膜条件によるポアサイズのコントロールが難しく、製膜条件の変更により工程が不安定となり膜の品位を悪化させるばかりでなく、透水性能を高くした場合、あるポイントで突然アルブミンのリークが起こり、透析用血液処理膜などとして使用することは不可能となる。
【００１５】
さらに、選択分離膜中、親水性高分子含有率が、疎水性高分子に対して、３重量％以上、１５重量％以下であることが好ましい。３重量％未満の場合は水濡れ性が不十分となる傾向があり、血液と接触した際に凝固を引き起こす場合があるからである。また、１５重量％を越えると、膜内にある多量の親水性高分子によって、透過性能の低下やアルブミンリークのコントロールが不十分となる傾向がある。
【００１６】
また、本発明においては、上記の分子量１０万未満の親水性高分子が親水性高分子全重量に対して１０重量％以上、５０重量％以下含まれ、１０万以上の親水性高分子が親水性高分子全重量に対し、５０重量％以上、９０重量％以下含まれている選択分離膜について、例えば、人工腎臓などに用いる場合には、その親水性高分子の溶出をできるだけ低減するためには、不溶化処理することが好ましい。不溶化とは、架橋により、架橋前のそれぞれのポリマの良溶媒に溶解しなくなることを意味する。また、不溶化処理後の膜においては、膜全重量に対し、２重量％以上、１５重量％以下の不溶化物を含むことが好ましい。２重量％未満では、膜内表面近傍の活性層が薄くなり、例えば、血液処理などに用いた場合、血液成分の凝集を招く傾向がある。又、１５重量％を越えると、活性層が厚くなりすぎて、透水性能の低下が起こる場合がある。
【００１７】
さらに、不溶化物中の由来高分子の比率は、疎水性高分子が１５重量％以上、４０重量％以下、親水性高分子が６０重量以上、８５重量％以下であることが好ましい。疎水性高分子が、１５重量％未満では、疎水性基の割合が小さくなり、膜全体の構造が外圧により容易に変化する傾向がある。また、４０重量％を越えると、逆にしなやかさが少なくなり、膜の糸形状加工（クリンプ付与など）を行う際に不利な場合がある。
【００１８】
不溶化方法としては、限定されるものではないが、例えばγ線、電子線、熱、化学的方法などにより、架橋を行うことが好ましい。特に、水の存在下でのγ線照射が好ましく、照射量は１０〜５０ＫＧｙ、さらには２０〜４０ＫＧｙであることが好ましい。不溶化橋処理により、疎水性高分子と親水性高分子が結合し、親水性高分子の溶出が減少する。また、このような処理を行うと性能、構造に変化が生じると考えられるが中高分子量蛋白を積極的に透過させる網目構造は架橋処理によって構造が保持、補強されるため若干の性能低下は見られるもののほとんど変化しない。
【００１９】
本発明において、選択分離膜中、疎水性高分子、親水性高分子が含まれていることは、固体１３Ｃ−ＮＭＲスペクトル分析により分析可能である。又、疎水性高分子、親水性高分子の含有量は、元素分析により分析可能である。
【００２０】
本発明においては、疎水性高分子、親水性高分子、溶媒、添加剤を少なくとも含む製膜原液を用い、分子量の異なる親水性高分子を２種類以上含有し、かつ、分子量１０万以上の親水性高分子の含有比率を該製膜原液全体に対して１．８重量％以上、２０重量％以下とすることにより、本願発明の選択分離膜を得ることができる。２０重量％を越えると、原液粘度が上昇し、製膜困難となり、又、透水性、拡散性能が低下する。一方、１．８重量％未満であると、中高分子尿毒蛋白を透過させるための適当な網目構造を構築できない。
【００２１】
高分子量の親水性高分子を添加することによる原液安定性については次の様に説明できる。添加剤は、共存する親水性高分子との分子間力により包接され、疎水性高分子と直接接触することはない。しかし、溶解中の高温のために、一部が離脱を起こし、そのために、疎水性高分子の２量体などのオリゴマーの再結晶化を促し、原液が白濁を起こす要因となる。親水性高分子の分子量が高くなるほど包接効果が増大するため、原液の安定性が改善される効果を生む。また、原液粘度は、親水性高分子の分子量に依存するが、当然ながら原液粘度の低下はその中空糸製膜時に糸切れ、糸揺れなどを起こし安定性を悪化させる。この点でも、親水性高分子の混合系において平均分子量を上げることは重要である。
【００２２】
次に製膜原液のポリマー濃度について述べる。前述の点からポリマー濃度は上げるに従って製膜性は良くなるが逆に空孔率が減少し、透水性能が低下するため最適範囲が存在する。ゆえに、疎水性高分子の濃度は１０〜３０重量％、好ましくは１５〜２５重量％、親水性高分子の濃度は２〜２０重量％、好ましくは３〜１５重量％である。
【００２３】
本願発明の選択分離膜の製造方法として、一例を以下に説明する。
【００２４】
上記のような製膜原液を、芯液と同時に２重スリット管構造の口金から同時に吐出させ、中空糸膜を成形する。その後、所定の水洗、保湿工程を経た後、巻き取られる。更に、例えば、人工腎臓などに用いられる場合には、モジュール化され、水充填し、架橋されることが好ましい。
【００２５】
更に、本願発明の選択透過性分離膜は、デキストランによる実施例において述べる拡散性能試験において、少なくとも３ｎｍの総括物質移動係数が０．００２５ｃｍ／ｍｉｎ以上で、かつアルブミン透過率が４％以下となる。アルブミン透過率は、更に、３％以下、２％以下であることが好ましい。
【００２６】
本発明において、選択透過性分離膜の形態としては、平膜、中空糸膜等、特に限定されるものではない。
【００２７】
本発明により得られた選択透過性分離膜は、人工腎臓、人工肝臓、エンドトキシンフィルター、バイオリアクター等の医療用途、水処理等、各種用途に用いることができる。
【００２８】
【実施例】
次に実施例に基づきに本発明を説明する。
【００２９】
用いた測定法は以下の通りである。
【００３０】
（１）透水性能の測定中空糸両端部を封止したモジュール（面積 １．６ｍ２ ）の中空糸内側に水圧１００ｍｍＨｇをかけ、外側へ流出してくる単位時間当たりの濾過量を測定した。透水性能は下記の式で算出した。
【００３１】
ＵＦＲ（ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ ）＝ＱＷ ／（Ｐ×Ｔ×Ａ）
ここでＱＷ ：濾過量（ｍｌ）、Ｔ：流出時間（ｈｒ）、 Ｐ：圧力（ｍｍＨｇ）、Ａ：膜面積（ｍ２ ）（中空糸内表面面積換算）を示す。
【００３２】
（２）デキストランによる拡散性能測定
基本的には透析性能測定法と同様に行った。その概要を示す。分子量分布の異なるデキストラン（ＦＵＬＫＡ社製 平均分子量〜１２００，〜６０００，１５０００〜２００００，４００００，５６０００，２２２０００）を０．５ｍｇ／ｍｌになるように限外濾過水に溶解した。この溶液を３７℃に加熱、保温し、血液側（中空糸内側）にポンプで流量２００ｍｌ／ｍｉｎで送り、透析液側は血液側と向流となるように限外濾過水を３７℃に保ったものを５００ｍｌ／ｍｉｎで送った。ここで、注意することは濾過圧力がゼロになるように調整することである。すなわち、限外濾過が生じない条件で膜の拡散性能を測定することである。平衡状態になるまで２０分送り続け、その後、血液側入り口、出口、透析側をサンプリングした。サンプリングした溶液を細孔径０．５ミクロンのフィルターで濾過を行った。その溶液をゲル透過クロマトグラフィー用カラム（東ソー ＴＳＫｇｅｌ Ｇ３０００ＰＷ）、カラム温度４０℃、移動相を液クロ用純水、１ｍｌ／ｍｉｎ、サンプル打ち込み量５０μｌで分析を行い、血液側の入り口、出口の濃度変化によってモジュールの総括物質移動係数を求めた。なお、測定前に、単分散の５種類のデキストランを用いてカラムのキャリブレーションを行った。総括物質移動係数は以下の式を用いて算出した。
【００３３】
クリアランス
【化２】
【００３４】
【化３】
【００３５】
ストークス半径は文献｛Ｊ．Ｂｒａｎｄｒｕｐ，Ｅ．Ｈ．Ｉｍｍｅｒｇｕｔ ”Ｐｏｌｙｍｅｒ Ｈａｎｄｂｏｏｋ” （１９８９）、〓１１２〜１１３頁 Ｊｏｈｎ Ｗｉｌｅｙ＆Ｓｏｎｓ，ｉｎｃ｝、｛人工臓器１３巻６号（１９８４）２３〜３０頁｝に基づいて下記式にて計算した。ストークス半径（ｎｍ）＝０．０４４５６×（デキストラン分子量）０．４３８２１
（３）アルブミン透過率の測定
血液槽に温度３７℃で保温したヘマトクリット３０％、総蛋白量６．５ｇ／ｄｌの牛血（ヘパリン処理血）を用いて、中空糸内側にポンプで２００ｍｌ／ｍｉｎで送った。その際、モジュール出口側の圧力を調整して、濾過量がモジュール面積１ｍ２ 当たり２０ｍｌ／ｍｉｎ（すなわち１．６ｍ２ では３２ｍｌ／ｍｉｎ）かかるようにし、濾液、出口血液は血液槽に戻した。環流開始後１時間後に中空糸側入り口、出口の血液、濾液をサンプリングし、血液側をＢＣＧ法、濾液側をＣＢＢ法キット（和光純薬）によって分析し、その濃度からアルブミン透過率（％）を算出した。
【００３６】
【化４】
【００３７】
（４）ゲル透過クロマトグラフィーによるポリビニルピロリドン分子量分布の測定
所定の凝固水洗工程を経た中空糸１００ｍｇをγ線照射前に塩化メチレン５ｍｇに溶解し、塩存在下で水抽出を行い、得られた水溶液を超遠心機（２００００ｒｐｍ×１０ｍｉｎ）で分離し、水層を細孔径０．５ミクロンのフィルターで濾過を行いサンプル液とした。この溶液を温度２３℃で東ソーＴＳＫ−ｇｅｌ−ＧＭＰＷｘ１ ２本直列につないだ理論段数（８９００段）のカラムを用い、移動相として０．０８Ｍ−トリス緩衝液（ｐＨ７．９）、流量 １．０ｍｌ／ｍｉｎ、サンプル打ち込み量 ０．３ｍｌで分析を行った。５種の単分散ポリエチレングリコールを基準物質にして分子量分布を求めた。
【００３８】
（５）紡糸原液中のポリビニルピロリドンの重量平均分子量
紡糸原液中のポリビニルピロリドンの重量平均分子量はＫ値と光散乱法によって求めた重量平均分子量の相関曲線から換算した。ＢＡＳＦ社の技術情報文献”Ｋｏｌｌｉｄｏｎ ：Ｐｏｌｙｖｉｎｙｌｐｙｒｒｏｌｉｄｏｎｅ ｆｏｒ Ｐｈａｒｍａｃｅｕｔｉｃａｌ ｉｎｄｕｓｔｒｙ” のＦｉｇ．１５から重量平均分子量とＫ値との関係において下記の式を用いて計算した。重量平均分子量（Ｍｗ）＝ ｅｘｐ１．０５５４９５×Ｋ２．８７１６８２
（６）元素分析法によるポリビニルピロリドンの含有率の測定
γ線照射後のサンプルを常温、真空ポンプで乾固させ、その１０ｍｇをＣＨＮコーダーで分析し、窒素含有量からポリビニルピロリドンの含有率を計算した。（７）項で得られた不溶化物も同様に測定し、ポリビニルピロリドン、ポリスルホン由来の組成含有率を計算した。
【００３９】
（７）不溶物量の測定
γ線照射後の中空糸膜１０ｇを取り、１００ｍｌのジメチルホルムアミドに溶解した。遠心分離機で１５００ｒｐｍ １０分で不溶物を分離し、上澄み液を捨てる。この操作を３回繰り返し、残った固形物を蒸発乾固し、その重量から不溶物の含有率を求めた。
【００４０】
実施例１
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）１８部、ポリビニルピロリドン（ＢＡＳＦ Ｋ９０）３部、ポリビニルピロリドン（ＢＡＳＦ Ｋ３０）６部をジメチルアセトアミド７２部、水１部に加え、加熱溶解し、製膜原液とした。原液粘度は３０℃で７０ポイズであった。この原液を温度５０℃の紡糸口金部へ送り、外径０．３ｍｍ、内径０．２ｍｍの２重スリット管から芯液としてジメチルアセトアミド６５部、水３５部からなる溶液を吐出させ中空糸膜を形成させた後、温度３０℃、露点２８℃の調湿２５０ｍｍのドライゾーン雰囲気を経て、ジメチルアセトアミド２０ｗｔ％、水８０ｗｔ％からなる温度４０℃の凝固浴を通過させ、８０℃２０秒の水洗工程、グリセリンによる保湿工程を経て得られた中空糸膜を巻き取り束とした。この中空糸膜を１．６ｍ２ になるように、ケースに充填し、ポッティングしてモジュールとした。次に、γ線照射前にゲル透過クロマトグラフィー法による中空糸残存ポリビニルピロリドンの分子量分布を調べた結果、分子量１０万未満が２７％、１０万以上が７３％であった。また、γ線照射前のモジュールについて総括物質移動係数（Ｋｏ）を測定した結果、ストークス半径４．５ｎｍで０．００２５ｃｍ／ｍｉｎ、透水性能 ９８０ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ、アルブミン透過率１．４％であった。γ線照射後、同様に総括物質移動係数（Ｋｏ）及び水濾過性能、アルブミン透過率を測定したところＫｏはストークス半径４ｎｍで０．００２５ｃｍ／ｍｉｎ、透水性能 １０００ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ、アルブミン透過率１．５％であった。 さらに、中空糸膜中のポリビニルピロリドン量を元素分析法により測定したところ８％であった。また、γ線照射後の中空糸の不溶物量を測定したところ１１％であった。不溶化物の組成を調べたところポリスルホン由来２６％、ポリビニルピロリドン由来７４％であった。
【００４１】
実施例２
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）１８部、ポリビニルピロリドン（ＢＡＳＦ Ｋ９０）４部、ポリビニルピロリドン（ＢＡＳＦ Ｋ３０）５部をジメチルアセトアミド７２部、水１部に加え、加熱溶解し製膜原液とした。原液粘度は３０℃で１２０ポイズであった。実施例１と同様な工程を経てモジュール化した。次に、γ線照射前にゲル透過クロマトグラフィー法による中空糸残存ポリビニルピロリドンの分子量分布を調べた結果、分子量１０万未満が３５％、１０万以上が６５％であった。
【００４２】
γ線照射後、総括物質移動係数（Ｋｏ）及び水濾過性能、アルブミン透過率を測定したところＫｏはストークス半径３．３ｎｍで０．００２５ｃｍ／ｍｉｎ、透水性能 ８００ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ、アルブミン透過率２．０％であった。さらに、中空糸膜中のポリビニルピロリドン量を元素分析法により測定したところ９％であった。また、γ線照射後の中空糸の不溶物量を測定したところ１２％となった。不溶化物の組成を調べたところポリスルホン由来２０％、ポリビニルピロリドン由来８０％であった。
【００４３】
実施例３
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）１８部、ポリビニルピロリドン（ＢＡＳＦ Ｋ６０）９部をジメチルアセトアミド７２部、水１部に加え、加熱溶解し製膜原液とした。原液粘度は３０℃で１００ポイズであった。実施例１と同様な工程を経てモジュール化した。次に、γ線照射前にゲル透過クロマトグラフィー法による中空糸残存ポリビニルピロリドンの分子量分布を調べた結果、分子量１０万未満が４０％、１０万以上が６０％であった。
【００４４】
γ線照射後、総括物質移動係数（Ｋｏ）及び水濾過性能、アルブミン透過率を測定したところＫｏはストークス半径３．５ｎｍで０．００２５ｃｍ／ｍｉｎ、透水性能 ５００ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ、アルブミン透過率１．８％であった。さらに、中空糸膜中のポリビニルピロリドン量を元素分析法により測定したところ５％であった。また、γ線照射後の中空糸の不溶物量を測定したところ１０％となった。不溶化物の組成を調べたところポリスルホン由来１５％、ポリビニルピロリドン由来８５％であった。
【００４５】
比較例１
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）１８部、ポリビニルピロリドン（ＢＡＳＦ Ｋ９０）１．５部、ポリビニルピロリドン（ＢＡＳＦ Ｋ３０）７．５部をジメチルアセトアミド７２部、水１部に加え、加熱溶解し、製膜原液とした。原液粘度は３０℃で６０ポイズであった。実施例１に従って製膜し、モジュール化した。次に、γ線照射前にゲル透過クロマトグラフィー法による中空糸残存ポリビニルピロリドンの分子量分布を調べた結果、分子量１０万未満が６０％、１０万以上が４０％であった。
【００４６】
γ線照射後、総括物質移動係数（Ｋｏ）及び水濾過性能、アルブミン透過率を測定したところＫｏはストークス半径２．５ｎｍでＫｏが０．００２５ｃｍ／ｍｉｎ、透水性能 ６００ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ、アルブミン透過率０．５％であった。さらに、中空糸膜中のポリビニルピロリドン量を元素分析法により測定したところ４％であった。また、γ線照射後の中空糸の不溶物量を測定したところ０．１５％となった。不溶化物の組成を調べたところポリスルホン由来１０％、ポリビニルピロリドン由来９０％であった。
【００４７】
比較例２
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）１８部、ポリビニルピロリドン（ＢＡＳＦ Ｋ９０）７部をジメチルアセトアミド７４部、水１部に加え、加熱溶解し製膜原液とした。原液粘度は３０℃で２５０ポイズであった。実施例１に従って製膜し、モジュール化した。次に、γ線照射前にゲル透過クロマトグラフィー法による中空糸残存ポリビニルピロリドンの分子量分布を調べた結果、分子量１０万未満が８％、１０万以上が９２％であった。
【００４８】
γ線照射後、総括物質移動係数（Ｋｏ）及び水濾過性能、アルブミン透過率を測定したところＫｏはストークス半径２．８ｎｍで０．００２５ｃｍ／ｍｉｎ、透水性能１２０ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ、アルブミン透過率４．５％であった。さらに、中空糸膜中のポリビニルピロリドン量を元素分析法により測定したところ１６％であった。また、γ線照射後の中空糸の不溶物量を測定したところ２０％となった。不溶化物の組成を調べたところポリスルホン由来４％、ポリビニルピロリドン由来９６％であった。
【００４９】
比較例３
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）１８部、ポリビニルピロリドン（ＢＡＳＦ Ｋ３０）９部をジメチルアセトアミド７２部、水１部に加え、加熱溶解し、製膜原液とした。原液粘度は３０℃で３０ポイズであった。実施例１に従って製膜し、モジュール化した。次に、γ線照射前にゲル透過クロマトグラフィー法による中空糸残存ポリビニルピロリドンの分子量分布を調べた結果、分子量１０万未満が８０％、１０万以上が２０％であった。
【００５０】
γ線照射後、総括物質移動係数（Ｋｏ）及び水濾過性能、アルブミン透過率を測定したところＫｏはストークス半径２．８ｎｍで０．００２５ｃｍ／ｍｉｎ、透水性能７１０ｍｌ／ｈｒ／ｍ２ ／ｍｍＨｇ、アルブミン透過率０．０２％であった。さらに、中空糸膜中のポリビニルピロリドン量を元素分析法により測定したところ４％であった。また、γ線照射後の中空糸の不溶物量を測定したところ０．５％となった。不溶化物の組成を調べたところポリスルホン由来４２％、ポリビニルピロリドン由来５８％であった。
【００５１】
【発明の効果】
選択透過性分離膜に存在する親水性高分子の分子量分布をコントロールすることによって例えば医療分野に用いた場合、低分子から中高分子領域全般に優れた尿毒物質拡散性能を維持しつつ、アルブミン透過性を抑えることが出来るため、血液透析、血液濾過、血液透析濾過等に利用した場合、腎不全患者の病体改善に良い治療成績が期待できる。また、高透水性能を活かして透析液浄化のためのエンドトキシン除去フィルターなどに適用可能である。
【図面の簡単な説明】
【図１】γ線照射前の膜中の親水性高分子ポリビニルピロリドンの分子量分布を示す。
【図２】γ線照射後の膜の総括物質移動係数（Ｋｏ）とストークス半径の関係を表す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a selectively permeable separation membrane and a method for producing the same. More specifically, when used for blood treatment by controlling the molecular weight distribution of the hydrophilic polymer present in the membrane, it maintains a high blood filtration flow rate and low albumin permeability over a long period of time, and a uremic substance consisting of a medium polymer protein. The present invention relates to a membrane having high permselectivity and a method for producing these membranes.
[0002]
[Prior art]
As a semipermeable membrane for blood treatment, cellulose, which is a natural material, polysulfone, PMMA, polyacrylonitrile, etc., which are synthetic polymer membrane materials have been widely used to date, and the blood treatment method for patients with chronic renal failure is closer to that of the human kidney. Various technological developments have been made as much as possible. In recent years, among these membrane materials, polysulfone having high water permeability has been attracting attention as being consistent with the progress of dialysis technology. Polysulfone is originally widely used as a thermoplastic heat-resistant engineering plastic in the fields of automobiles, electricity, and medical devices, but when a semipermeable membrane is made of polysulfone alone, the intermolecular cohesion is strong, Moreover, since it is hydrophobic, it has poor affinity with blood and cannot be used for blood treatment as it is. Therefore, a method has been devised, in which a hydrophilic polymer, inorganic salt, etc. are mixed in as a pore-forming material to form pores by leaching, and at the same time the polymer surface is hydrophilized and used as a semipermeable membrane or reverse osmosis membrane Has been.
[0003]
As a method for producing a semipermeable membrane for blood treatment, a method for forming a film by adding a metal salt, a method for forming a film by adding a hydrophilic polymer, a method for forming a film by adding a polyhydric alcohol have been disclosed Yes. However, when a film is formed by adding a polyhydric alcohol such as polyethylene glycol as disclosed in JP-A-61-2232860 and JP-A-58-114702, when washing is insufficient, the alcohol remaining on the membrane may cause a problem during dialysis. Abnormalities occur in the patient's eyes. Japanese Patent Publication No. 6-75667 discloses a film forming method using polyvinylpyrrolidone. However, although water permeability is high, there is a problem that albumin permeability is high for blood treatment (dialysis). The method using a metal salt disclosed in JP-A-62-1121608 is also the same. Japanese Patent Laid-Open No. 6-233922 proposes a method for producing a hollow fiber membrane in which a high molecular weight hydrophilic polymer is added to increase the viscosity so that a good solvent of the stock solution can be used as a 100% core solution. This method cannot control the albumin permeability of the membrane. Moreover, there is no knowledge about the molecular weight distribution of the hydrophilic polymer in the film. Japanese Patent Publication No. 2-18695 discloses a membrane in which the content of the high molecular weight polyvinyl pyrrolidone is specified to be higher than that of polysulfone, and the membrane is made to have a large amount of polyvinyl pyrrolidone remaining in the membrane, thereby improving the contamination resistance and detergency of the membrane. However, the high diffusion performance intended by the present invention is not obtained. Further, Japanese Patent Publication No. 5-54373 discloses a membrane obtained by washing and removing most of polyvinylpyrrolidone using a low-viscosity stock solution comprising polysulfone and a relatively low molecular weight polyvinylpyrrolidone, but remains in the membrane as in the present invention. It is not specified that the molecular weight distribution of the hydrophilic polymer exhibits high diffusion performance. In particular, since 20 years have passed since the start of dialysis, many complications due to long-term dialysis have been reported, and proteins with a molecular weight of 20,000 to 40,000 are attracting attention as causative agents of carpal tunnel syndrome and other dialysis syndromes. In any of these methods, there is no disclosure of a selective separation membrane that substitutes or mimics the high human kidney function that can positively remove the aforementioned protein.
[0004]
[Problems to be solved by the invention]
As a result of intensive studies to overcome the above-mentioned drawbacks, the present inventors were able to achieve the present invention. That is, an object of the present invention is to provide a selectively permeable separation membrane in which the permeability of albumin, which is a useful protein, is suppressed and the removal performance of medium high molecular weight uremic protein is enhanced, and a method for producing the same.
[0005]
[Means for Solving the Problems]
In order to achieve the above object, the present invention has the following configuration.
[0006]
Polysulfone resin,PolyvinylpyrrolidoneIs a permselective separation membrane with a molecular weight of less than 100,000.PolyvinylpyrrolidoneButPolyvinylpyrrolidone10% or more and 50% or less by weight based on the total weightPolyvinylpyrrolidoneButPolyvinylpyrrolidoneA selectively permeable separation membrane comprising 50 wt% or more and 90 wt% or less with respect to the total weight.
[0007]
Polysulfone resin,PolyvinylpyrrolidoneIs a permselective separation membrane with a molecular weight of less than 100,000.PolyvinylpyrrolidoneButPolyvinylpyrrolidone10% or more and 50% or less by weight based on the total weightPolyvinylpyrrolidoneButPolyvinylpyrrolidoneA selectively permeable separation membrane obtained by insolubilizing a membrane containing 50 wt% or more and 90 wt% or less with respect to the total weight.
[0008]
Polysulfone resinWhenPolyvinylpyrrolidone, Solvents and additives are used, and the molecular weight is different.Polyvinylpyrrolidone2 or more, and has a molecular weight of 100,000 or morePolyvinylpyrrolidoneThe method for producing a selectively permeable separation membrane, characterized in that the content ratio of is 1.8% by weight or more and 20% by weight or less with respect to the whole membrane-forming stock solution.
[0010]
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, the stock solution used for forming the selective separation membrane contains at least a hydrophobic polymer, a hydrophilic polymer, a solvent, and an additive.
[0011]
Among these, as hydrophobic polymers,underPolysulfone having the basic skeletonUsed. In the following basic skeleton, those obtained by modifying the benzene ring moiety can also be preferably used.
[0012]
[Chemical 1]
[0013]
As the solvent, an amphoteric solvent that dissolves the three of the hydrophobic polymer, the hydrophilic polymer, and the additive well is used. Specific examples include dimethylacetamide, dimethylformamide, dimethylsulfoxide, acetone, acetaldehyde, 2-methylpyrrolidone and the like, and dimethylacetamide is preferable from the viewpoint of danger, stability and toxicity. As the additive, a poor solvent of a hydrophobic polymer that is compatible with a hydrophilic polymer is used, and specifically, alcohol, glycerin, water, esters and the like can be mentioned, from the viewpoint of process suitability. Water is particularly preferable.
[0014]
The permselective separation membrane of the present invention comprises a hydrophilic polymer having a molecular weight of less than 100,000 and containing 10 wt% or more and 50 wt% or less with respect to the total weight of the hydrophilic polymer, and 100,000 or more hydrophilic polymers. Is contained in an amount of 50% by weight to 90% by weight based on the total weight of the hydrophilic polymer. In other words, in the present invention, the presence of a low molecular weight hydrophilic polymer in the high molecular weight hydrophilic polymer in the hydrophilic polymer suppresses permeation of albumin, which is a useful protein, and has a diffusion performance in the middle molecular region or higher. It was found to improve in particular. This is probably due to the fact that a low molecular weight polymer can enter a large high molecular weight polymer to form an appropriate network structure that allows the medium molecular weight protein to permeate. When this is a high molecular weight hydrophilic polymer alone, the low albumin permeability required for an artificial kidney or the like cannot be achieved while maintaining high water permeability. In addition, in the case of a low molecular weight hydrophilic polymer alone, it is difficult to control the pore size under appropriate film forming conditions, and changing the film forming conditions makes the process unstable and deteriorates the quality of the film, and also increases the water permeability. In some cases, albumin leaks suddenly at a certain point, making it impossible to use as a blood treatment membrane for dialysis.
[0015]
Further, the hydrophilic polymer content in the selective separation membrane is preferably 3% by weight or more and 15% by weight or less with respect to the hydrophobic polymer. If it is less than 3% by weight, the water wettability tends to be insufficient, and coagulation may occur when it comes into contact with blood. On the other hand, if it exceeds 15% by weight, there is a tendency that the permeation performance is lowered and the control of albumin leakage is insufficient due to the large amount of hydrophilic polymer in the membrane.
[0016]
In the present invention, the hydrophilic polymer having a molecular weight of less than 100,000 is contained in an amount of 10% by weight to 50% by weight based on the total weight of the hydrophilic polymer, and 100,000 or more hydrophilic polymers are hydrophilic. In order to reduce the elution of the hydrophilic polymer as much as possible when the selective separation membrane contained in the total weight of the hydrophilic polymer is used in an artificial kidney or the like, for example, in the range of 50% to 90% by weight. Is preferably insolubilized. Insolubilization means that the polymer does not dissolve in the good solvent of each polymer before crosslinking due to crosslinking. Further, the film after insolubilization treatment preferably contains 2% by weight or more and 15% by weight or less of insolubilized material with respect to the total weight of the film. If it is less than 2% by weight, the active layer in the vicinity of the inner surface of the membrane becomes thin. For example, when used for blood treatment, there is a tendency to cause aggregation of blood components. On the other hand, if it exceeds 15% by weight, the active layer becomes too thick and the water permeability may be deteriorated.
[0017]
Further, the ratio of the derived polymer in the insolubilized material is preferably 15% by weight to 40% by weight for the hydrophobic polymer and 60% by weight to 85% by weight for the hydrophilic polymer. If the hydrophobic polymer is less than 15% by weight, the proportion of the hydrophobic group becomes small, and the structure of the entire membrane tends to easily change due to external pressure. On the other hand, if it exceeds 40% by weight, the flexibility is reduced, which may be disadvantageous when the film is processed into a yarn shape (such as crimping).
[0018]
The insolubilizing method is not limited, but it is preferable to perform crosslinking by, for example, γ rays, electron beams, heat, chemical methods, or the like. In particular, γ-ray irradiation in the presence of water is preferable, and the irradiation amount is preferably 10 to 50 KGy, more preferably 20 to 40 KGy. By the insolubilizing bridge treatment, the hydrophobic polymer and the hydrophilic polymer are combined, and the elution of the hydrophilic polymer is reduced. In addition, it is thought that the performance and structure change when such treatment is performed, but the network structure that actively permeates medium high molecular weight proteins retains and reinforces the structure by the crosslinking treatment, so there is a slight decrease in performance. There is little change in things.
[0019]
In the present invention, it can be analyzed by solid state 13C-NMR spectrum analysis that the selective separation membrane contains a hydrophobic polymer and a hydrophilic polymer. The content of hydrophobic polymer and hydrophilic polymer can be analyzed by elemental analysis.
[0020]
In the present invention, a film-forming stock solution containing at least a hydrophobic polymer, a hydrophilic polymer, a solvent, and an additive is used, a hydrophilic polymer having two or more types of hydrophilic polymers having different molecular weights and having a molecular weight of 100,000 or more. The selective separation membrane of the present invention can be obtained by adjusting the content ratio of the conductive polymer to 1.8% by weight or more and 20% by weight or less with respect to the whole membrane-forming stock solution. If it exceeds 20% by weight, the viscosity of the undiluted solution will increase, making it difficult to form a film, and the water permeability and diffusion performance will decrease. On the other hand, if it is less than 1.8% by weight, an appropriate network structure for allowing the medium high molecular weight uremic protein to permeate cannot be constructed.
[0021]
The stability of the stock solution by adding a high molecular weight hydrophilic polymer can be explained as follows. The additive is included by the intermolecular force with the coexisting hydrophilic polymer and does not come into direct contact with the hydrophobic polymer. However, due to the high temperature during dissolution, a part of the polymer is detached, which promotes recrystallization of oligomers such as dimers of the hydrophobic polymer and causes the stock solution to become cloudy. Since the inclusion effect increases as the molecular weight of the hydrophilic polymer increases, the stability of the stock solution is improved. Further, the viscosity of the stock solution depends on the molecular weight of the hydrophilic polymer, but naturally, a decrease in the viscosity of the stock solution causes yarn breakage and yarn shaking during the formation of the hollow fiber, thereby deteriorating the stability. Also in this respect, it is important to increase the average molecular weight in the mixed system of hydrophilic polymers.
[0022]
Next, the polymer concentration of the film forming stock solution will be described. From the above points, the film-forming property improves as the polymer concentration increases, but conversely there is an optimum range because the porosity decreases and the water permeability performance decreases. Therefore, the concentration of the hydrophobic polymer is 10 to 30% by weight, preferably 15 to 25% by weight, and the concentration of the hydrophilic polymer is 2 to 20% by weight, preferably 3 to 15% by weight.
[0023]
An example of the method for producing the selective separation membrane of the present invention will be described below.
[0024]
The membrane-forming stock solution as described above is simultaneously discharged from the die having a double slit tube structure simultaneously with the core solution to form a hollow fiber membrane. Then, it winds up after passing through predetermined water washing and a moisturizing process. Furthermore, for example, when used for an artificial kidney or the like, it is preferably modularized, filled with water, and crosslinked.
[0025]
Furthermore, the permselective separation membrane of the present invention has a total mass transfer coefficient of at least 3 nm of 0.0025 cm / min or more and an albumin permeability of 4% or less in the diffusion performance test described in the examples using dextran. The albumin permeability is further preferably 3% or less and 2% or less.
[0026]
In the present invention, the form of the selectively permeable separation membrane is not particularly limited, such as a flat membrane and a hollow fiber membrane.
[0027]
The permselective separation membrane obtained by the present invention can be used for various uses such as artificial kidneys, artificial livers, endotoxin filters, bioreactors and other medical uses, and water treatment.
[0028]
【Example】
Next, the present invention will be described based on examples.
[0029]
The measurement method used is as follows.
[0030]
(1) Measurement of water permeation performance Module (both 1.6m in area) sealed at both ends of hollow fiber2The water pressure of 100 mmHg was applied to the inside of the hollow fiber, and the amount of filtration per unit time flowing out to the outside was measured. The water permeability was calculated by the following formula.
[0031]
UFR (ml / hr / m2/ MmHg) = QW/ (P × T × A)
Where QW: Filtration amount (ml), T: outflow time (hr), P: pressure (mmHg), A: membrane area (m2) (In terms of the surface area of the hollow fiber).
[0032]
(2) Diffusion performance measurement with dextran
Basically, it was performed in the same manner as the dialysis performance measurement method. The outline is shown. Dextran having a different molecular weight distribution (average molecular weight of 1200, 6000, 15000 to 20000, 40000, 56000, 222000, manufactured by FULKA) was dissolved in ultrafiltered water so as to be 0.5 mg / ml. This solution is heated to 37 ° C. and kept warm, pumped to the blood side (inside the hollow fiber) at a flow rate of 200 ml / min, and ultrafiltrated water is kept at 37 ° C. so that the dialysate side is countercurrent to the blood side. Was sent at 500 ml / min. Here, care should be taken to adjust the filtration pressure to zero. That is, the diffusion performance of the membrane is measured under the condition that no ultrafiltration occurs. Feeding was continued for 20 minutes until equilibrium was reached, and then the blood inlet / outlet and dialysis side were sampled. The sampled solution was filtered with a filter having a pore diameter of 0.5 microns. The solution was analyzed with a gel permeation chromatography column (Tosoh TSKgel G3000PW), the column temperature of 40 ° C., the mobile phase was pure water for liquid chromatography, 1 ml / min, and the sample injection amount was 50 μl. The overall mass transfer coefficient of the module was obtained from the change. Before the measurement, the column was calibrated using five monodispersed dextrans. The overall mass transfer coefficient was calculated using the following formula.
[0033]
clearance
[Chemical 2]
[0034]
[Chemical 3]
[0035]
The Stokes radius can be found in the literature {J. Brandrup, E .; H. Based on Immergut "Polymer Handbook" (1989), p. 112-113, John Wiley & Sons, Inc}, {Artificial Organ Vol. 13 No. 6 (1984) 23-30} Stokes radius (nm) = 0.04456 x (dextran molecular weight)0.43821
(3) Measurement of albumin permeability
A hematocrit of 30% kept at 37 ° C. in a blood tank and bovine blood (heparin-treated blood) having a total protein amount of 6.5 g / dl was sent to the inside of the hollow fiber at a rate of 200 ml / min. At that time, the pressure on the module outlet side is adjusted so that the filtration amount is 1 m of module area.2Per 20ml / min (ie 1.6m2(32 ml / min), and the filtrate and outlet blood were returned to the blood tank. One hour after the start of reflux, the blood and filtrate at the inlet and outlet of the hollow fiber were sampled, the blood side was analyzed by the BCG method, and the filtrate side was analyzed by the CBB method kit (Wako Pure Chemical Industries). Was calculated.
[0036]
[Formula 4]
[0037]
(4) Measurement of polyvinylpyrrolidone molecular weight distribution by gel permeation chromatography
100 mg of hollow fiber that has undergone a predetermined coagulation water washing step is dissolved in 5 mg of methylene chloride before γ-ray irradiation, water extraction is performed in the presence of salt, and the resulting aqueous solution is separated with an ultracentrifuge (20000 rpm × 10 min), The layer was filtered with a filter having a pore size of 0.5 micron to obtain a sample solution. This solution was used at a temperature of 23 ° C. and a Tosoh TSK-gel-GMPWx1 column connected in series with a theoretical plate number (8900 plates), 0.08 M Tris buffer (pH 7.9) as a mobile phase, flow rate 1.0 ml. / Min, analysis was performed at a sample injection amount of 0.3 ml. Molecular weight distribution was determined using five types of monodisperse polyethylene glycol as reference materials.
[0038]
(5) Weight average molecular weight of polyvinylpyrrolidone in the spinning dope
The weight average molecular weight of polyvinylpyrrolidone in the spinning dope was converted from a correlation curve between the K value and the weight average molecular weight determined by the light scattering method. FIG. Of the technical information document “Kollidon: Polyvinylpyrrolidone for Pharmaceutical Industry” of BASF Corporation. 15 was calculated using the following formula in relation to the weight average molecular weight and the K value. Weight average molecular weight (Mw) = exp1.055495× K2.871682
(6) Measurement of polyvinylpyrrolidone content by elemental analysis
The sample after γ-ray irradiation was dried at room temperature with a vacuum pump, 10 mg of the sample was analyzed with a CHN coder, and the content of polyvinylpyrrolidone was calculated from the nitrogen content. The insolubilized material obtained in the item (7) was measured in the same manner, and the composition content rate derived from polyvinylpyrrolidone and polysulfone was calculated.
[0039]
(7) Measurement of insoluble matter
10 g of the hollow fiber membrane after γ-irradiation was taken and dissolved in 100 ml of dimethylformamide. The insoluble matter is separated at 1500 rpm for 10 minutes using a centrifuge, and the supernatant is discarded. This operation was repeated three times, the remaining solid was evaporated to dryness, and the content of insoluble matter was determined from its weight.
[0040]
Example 1
18 parts of polysulfone (Amoco Udel-P3500), 3 parts of polyvinylpyrrolidone (BASF K90) and 6 parts of polyvinylpyrrolidone (BASF K30) were added to 72 parts of dimethylacetamide and 1 part of water and dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 70 poise at 30 ° C. This undiluted solution is sent to a spinneret at a temperature of 50 ° C., and a hollow fiber membrane is formed by discharging 65 parts of dimethylacetamide and 35 parts of water as a core liquid from a double slit tube having an outer diameter of 0.3 mm and an inner diameter of 0.2 mm. After forming, after passing through a dry zone atmosphere with a temperature of 30 ° C. and a dew point of 28 ° C. and a humidity of 250 mm, it is passed through a coagulation bath at a temperature of 40 ° C. consisting of 20 wt% of dimethylacetamide and 80 wt% of water. The hollow fiber membrane obtained through the moisturizing step with glycerin was used as a wound bundle. 1.6m of this hollow fiber membrane2Then, the case was filled and potted to make a module. Next, as a result of examining the molecular weight distribution of hollow fiber residual polyvinylpyrrolidone by gel permeation chromatography before γ-ray irradiation, the molecular weight was less than 100,000, 27%, and 100,000 or more was 73%. Moreover, as a result of measuring the overall mass transfer coefficient (Ko) for the module before γ-ray irradiation, 0.0025 cm / min at a Stokes radius of 4.5 nm, water permeability of 980 ml / hr / m2/ MmHg, albumin permeability 1.4%. After γ-ray irradiation, the overall mass transfer coefficient (Ko), water filtration performance, and albumin permeability were measured, and Ko was 0.0025 cm / min at a Stokes radius of 4 nm, and water permeability was 1000 ml / hr / m.2/ MmHg, albumin permeability was 1.5%. Furthermore, when the amount of polyvinyl pyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 8%. The amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured and found to be 11%. The composition of the insolubilized material was examined and found to be 26% derived from polysulfone and 74% derived from polyvinylpyrrolidone.
[0041]
Example 2
18 parts of polysulfone (Amoco Udel-P3500), 4 parts of polyvinylpyrrolidone (BASF K90) and 5 parts of polyvinylpyrrolidone (BASF K30) were added to 72 parts of dimethylacetamide and 1 part of water and dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 120 poise at 30 ° C. A module was formed through the same steps as in Example 1. Next, as a result of examining the molecular weight distribution of hollow fiber residual polyvinylpyrrolidone by gel permeation chromatography before γ-ray irradiation, the molecular weight was less than 100,000 and 35% was 100,000 and 65 or more was 65%.
[0042]
After γ-irradiation, the overall mass transfer coefficient (Ko), water filtration performance, and albumin permeability were measured. Ko was 0.0025 cm / min at a Stokes radius of 3.3 nm, and water permeability was 800 ml / hr / m.2/ MmHg, albumin permeability was 2.0%. Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 9%. Further, the amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured and found to be 12%. When the composition of the insolubilized material was examined, it was 20% derived from polysulfone and 80% derived from polyvinylpyrrolidone.
[0043]
Example 3
18 parts of polysulfone (Amoco Udel-P3500) and 9 parts of polyvinylpyrrolidone (BASF K60) were added to 72 parts of dimethylacetamide and 1 part of water, and dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 100 poise at 30 ° C. A module was formed through the same steps as in Example 1. Next, as a result of examining the molecular weight distribution of the hollow fiber remaining polyvinylpyrrolidone by gel permeation chromatography before γ-ray irradiation, the molecular weight was less than 100,000 and 40% and 100,000 or more were 60%.
[0044]
After γ-irradiation, the overall mass transfer coefficient (Ko), water filtration performance, and albumin permeability were measured. Ko was 0.0025 cm / min at a Stokes radius of 3.5 nm, and water permeability was 500 ml / hr / m.2/ MmHg, albumin permeability was 1.8%. Furthermore, when the amount of polyvinyl pyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 5%. Further, when the amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured, it was 10%. When the composition of the insolubilized material was examined, it was 15% derived from polysulfone and 85% derived from polyvinylpyrrolidone.
[0045]
Comparative Example 1
Polysulfone (Amoco Udel-P3500) 18 parts, polyvinylpyrrolidone (BASF K90) 1.5 parts, polyvinylpyrrolidone (BASF K30) 7.5 parts is added to 72 parts of dimethylacetamide and 1 part of water, and dissolved by heating to form a film. The stock solution was used. The stock solution viscosity was 60 poise at 30 ° C. A film was formed and modularized according to Example 1. Next, as a result of examining the molecular weight distribution of the hollow fiber remaining polyvinylpyrrolidone by gel permeation chromatography before γ-ray irradiation, the molecular weight was less than 100,000 and 60% and 100,000 or more were 40%.
[0046]
After γ-irradiation, the overall mass transfer coefficient (Ko), water filtration performance, and albumin permeability were measured. Ko was a Stokes radius of 2.5 nm, Ko was 0.0025 cm / min, and water permeability was 600 ml / hr / m.2/ MmHg, albumin permeability was 0.5%. Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 4%. Moreover, the amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured and found to be 0.15%. When the composition of the insolubilized material was examined, it was 10% derived from polysulfone and 90% derived from polyvinylpyrrolidone.
[0047]
Comparative Example 2
18 parts of polysulfone (Amoco Udel-P3500) and 7 parts of polyvinylpyrrolidone (BASF K90) were added to 74 parts of dimethylacetamide and 1 part of water, and dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 250 poise at 30 ° C. A film was formed and modularized according to Example 1. Next, as a result of examining the molecular weight distribution of hollow fiber residual polyvinylpyrrolidone by gel permeation chromatography before γ-ray irradiation, the molecular weight was less than 100,000 and 8%, and 100,000 or more was 92%.
[0048]
After γ-irradiation, the overall mass transfer coefficient (Ko), water filtration performance, and albumin permeability were measured. Ko was 0.0025 cm / min at a Stokes radius of 2.8 nm, and water permeability was 120 ml / hr / m.2/ MmHg, albumin permeability was 4.5%. Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 16%. Further, when the amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured, it was 20%. The composition of the insolubilized material was examined and found to be 4% derived from polysulfone and 96% derived from polyvinylpyrrolidone.
[0049]
Comparative Example 3
18 parts of polysulfone (Amoco Udel-P3500) and 9 parts of polyvinylpyrrolidone (BASF K30) were added to 72 parts of dimethylacetamide and 1 part of water and dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 30 poise at 30 ° C. A film was formed and modularized according to Example 1. Next, as a result of examining the molecular weight distribution of the hollow fiber residual polyvinylpyrrolidone by gel permeation chromatography before γ-ray irradiation, the molecular weight of less than 100,000 was 80% and 100,000 or more was 20%.
[0050]
After γ-irradiation, the overall mass transfer coefficient (Ko), water filtration performance, and albumin permeability were measured. Ko was 0.0025 cm / min at a Stokes radius of 2.8 nm, and water permeability was 710 ml / hr / m.2/ MmHg, albumin permeability was 0.02%. Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 4%. Further, the amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured and found to be 0.5%. When the composition of the insolubilized material was examined, it was 42% derived from polysulfone and 58% derived from polyvinylpyrrolidone.
[0051]
【The invention's effect】
By controlling the molecular weight distribution of the hydrophilic polymer present in the selectively permeable separation membrane, for example, when used in the medical field, the albumin permeability is maintained while maintaining excellent uremic substance diffusion performance from low to medium molecules. Therefore, when used for hemodialysis, hemofiltration, hemodiafiltration, etc., good therapeutic results can be expected for improving the pathology of renal failure patients. Moreover, it can be applied to an endotoxin removal filter for purification of dialysate by utilizing its high water permeability.
[Brief description of the drawings]
FIG. 1 shows a molecular weight distribution of a hydrophilic polymer polyvinylpyrrolidone in a film before γ-ray irradiation.
FIG. 2 shows the relationship between the overall mass transfer coefficient (Ko) of the film after γ-ray irradiation and the Stokes radius.
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17100796A JP3617194B2 (en) | 1995-06-30 | 1996-07-01 | Permselective separation membrane and method for producing the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7-166461 | 1995-06-30 | ||
| JP16646195 | 1995-06-30 | ||
| JP17100796A JP3617194B2 (en) | 1995-06-30 | 1996-07-01 | Permselective separation membrane and method for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0970524A JPH0970524A (en) | 1997-03-18 |
| JP3617194B2 true JP3617194B2 (en) | 2005-02-02 |
Family
ID=26490827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17100796A Expired - Lifetime JP3617194B2 (en) | 1995-06-30 | 1996-07-01 | Permselective separation membrane and method for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3617194B2 (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100351886B1 (en) * | 1997-05-19 | 2002-09-12 | 아사히 메디칼 가부시키가이샤 | Polysulfone-Base Hollow-Fiber Hemocathartic Membrane And Processes For The Production Thereof |
| AUPQ319199A0 (en) * | 1999-09-30 | 1999-10-28 | Unisearch Limited | Method and apparatus for culturing cells |
| JP2004231650A (en) * | 2003-01-09 | 2004-08-19 | Toray Ind Inc | Mastocyte stimulatory factor-containing composition and blood depurator for removing the same |
| TWI406703B (en) | 2003-11-17 | 2013-09-01 | Asahi Kasei Medical Co Ltd | Purify blood with hollow fiber membrane and use its blood purifier |
| JP3642065B1 (en) | 2004-03-22 | 2005-04-27 | 東洋紡績株式会社 | Permselective separation membrane and method for producing a selectively permeable separation membrane |
| EP1790364B1 (en) | 2004-08-06 | 2012-09-12 | Asahi Kasei Medical Co., Ltd. | Polysulfone hemodialyzer |
| EP1710011A1 (en) * | 2005-04-07 | 2006-10-11 | Gambro Lundia AB | Filtration membrane |
| JP5113178B2 (en) * | 2006-10-18 | 2013-01-09 | ガンブロ・ルンディア・エービー | Hollow fiber membrane and method for producing hollow fiber membrane |
| JP5473215B2 (en) * | 2007-12-28 | 2014-04-16 | 三菱レイヨン株式会社 | Method for producing porous membrane for water treatment |
| KR101342187B1 (en) * | 2009-07-22 | 2013-12-16 | 미쯔비시 레이온 가부시끼가이샤 | Process for producing porous film |
| JP5633277B2 (en) * | 2009-09-30 | 2014-12-03 | 東レ株式会社 | Separation membrane module |
| JP5952159B2 (en) * | 2012-10-16 | 2016-07-13 | 旭化成株式会社 | Separation membrane and manufacturing method thereof |
| KR102422691B1 (en) | 2014-02-06 | 2022-07-18 | 감브로 룬디아 아베 | Hemodialyzer for blood purification |
| PL3102314T3 (en) | 2014-02-06 | 2019-02-28 | Gambro Lundia Ab | Membrane for blood purification |
-
1996
- 1996-07-01 JP JP17100796A patent/JP3617194B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0970524A (en) | 1997-03-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100432464B1 (en) | Polysulfone Hollow Fiber Semipermeable Membrane | |
| CN100457242C (en) | Dialysis membrane having improved average molecular distance | |
| US4874522A (en) | Polysulfone hollow fiber membrane and process for making the same | |
| JP4211168B2 (en) | Dialyzer manufacturing method and sterilization method | |
| JP5129962B2 (en) | Integral asymmetric membrane, method for producing the same and use thereof | |
| EP1388364A1 (en) | Asymmetric porous films and process for producing the same | |
| JP3617194B2 (en) | Permselective separation membrane and method for producing the same | |
| JP4061798B2 (en) | Semipermeable membrane for blood treatment and dialyzer for blood treatment using the same | |
| EP0842694A1 (en) | Hollow yarn membrane used for blood purification and blood purifier | |
| KR102230435B1 (en) | Porous membrane, blood purifying module incorporating porous membrane, and method for producing porous membrane | |
| US6355730B1 (en) | Permselective membranes and methods for their production | |
| EP0750936B1 (en) | Permselective membranes and methods for their production | |
| JPH10108907A (en) | Membrane for hemocatharsis, its preparation and module for hemocatharsis | |
| JP3366040B2 (en) | Polysulfone-based semipermeable membrane and method for producing the same | |
| JP3966481B2 (en) | Semipermeable membrane | |
| JP4211169B2 (en) | Dialysis machine for blood treatment | |
| JPH0317532B2 (en) | ||
| JP4352709B2 (en) | Polysulfone-based semipermeable membrane and artificial kidney using the same | |
| JP3651121B2 (en) | Permselective separation membrane | |
| JP4003982B2 (en) | Polysulfone-based selectively permeable separation membrane | |
| JPH09308685A (en) | Hollow fiber membrane for blood purification and blood purifying device | |
| JPH0970431A (en) | Production of polysulfone hollow fiber type artificial kidney and artificial kidney | |
| JP3770145B2 (en) | Method for producing semipermeable membrane and dialyzer using the semipermeable membrane | |
| JP2000325763A (en) | Production of hollow-fiber membrane for hemocatheresis, and hollow-fiber membrane thereof | |
| JP2000153134A (en) | High performance blood purifying membrane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20041019 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20041101 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20071119 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20081119 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20081119 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20091119 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20091119 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101119 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20101119 Year of fee payment: 6 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20111119 Year of fee payment: 7 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121119 Year of fee payment: 8 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121119 Year of fee payment: 8 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131119 Year of fee payment: 9 |
|
| EXPY | Cancellation because of completion of term |