JP4061798B2 - Semipermeable membrane for blood treatment and dialyzer for blood treatment using the same - Google Patents
Semipermeable membrane for blood treatment and dialyzer for blood treatment using the same Download PDFInfo
- Publication number
- JP4061798B2 JP4061798B2 JP36296199A JP36296199A JP4061798B2 JP 4061798 B2 JP4061798 B2 JP 4061798B2 JP 36296199 A JP36296199 A JP 36296199A JP 36296199 A JP36296199 A JP 36296199A JP 4061798 B2 JP4061798 B2 JP 4061798B2
- Authority
- JP
- Japan
- Prior art keywords
- hollow fiber
- water
- semipermeable membrane
- blood treatment
- membrane
- 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
- 0 CC*(C)*c1ccc(C(C)(CC)C(CC2)CC=C2OC(CC2)=CCC2S(C2=CCC(C(C)(C)C)C=C2)(O)=O)cc1 Chemical compound CC*(C)*c1ccc(C(C)(CC)C(CC2)CC=C2OC(CC2)=CCC2S(C2=CCC(C(C)(C)C)C=C2)(O)=O)cc1 0.000 description 1
Landscapes
- External Artificial Organs (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は膜性能が乾燥によっても変化が少なく、かつ親水性高分子の溶出が少ない血液処理用半透膜、および、それを用いた血液処理用透析器に関するものである。
【０００２】
【従来の技術】
人工腎臓を含む血液処理用の半透膜は、天然素材セルロース、また、その誘導体であるセルロースジアセテート、セルローストリアセテート、時代の変化とともに、合成高分子が登場し、ポリスルホン、ＰＭＭＡ、ポリアクリロニトリルなどが幅広く使用され、近年ではセルロースをＰＥＧなどで処理し、血液適合性を改良した改質膜も使用されるようになってきた。慢性腎不全患者の血液処理法についてはアルブミンの漏れは最小限に抑えつつ、その他の低分子蛋白を積極的に除去する試みがなされている。膜の改良だけでなく、血液透析濾過法（ＨＤＦ）や、プッシュ＆プル法が透析効率の向上や低分子蛋白の積極除去のため開発された。現在、膜素材の中で透水性能が高いポリスルホンが、このような透析手法の進歩に合致したものとして、幅広く使用されるに至っている。ポリスルホンは熱可塑性の耐熱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が、ポリスルホンのみで透析膜を作った場合、分子間凝集力が強く、ポアサイズのコントロールができないだけでなく、疎水性のために血液との親和性に乏しく、血小板などの血液成分が付着しやすく、残血の原因となるだけでなく、膜性能の低下も激しく起こる。さらに、エアーロック現象を起しやすいため、このままでは血液処理用に用いることはできない。
従って、孔形成材として無機塩などを混入し、脱離することで孔を形作り、後で親水化処理する方法や、予め、親水性高分子を造孔剤として混入し、脱離させてポアを形成後、残った親水性成分で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た。例示すると（１）金属塩を入れて製膜する方法 （２）親水性高分子を入れて製膜する方法（３）多価アルコールを入れて製膜する方法などがすでに開示されている。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、膜に残存するポリエチレングリコール等の溶出によって、透析時に患者の目に異常が起こる場合もある。金属塩類の場合はポアサイズが大きすぎて透析膜には不適である。また、特公平５−５４３７３ではドライタイプの透析膜が記載されているが、親水性高分子の溶出が少なく、かつ透水性能が高いドライタイプの膜は開示されていない。
【０００３】
【発明が解決しようとする課題】
長期透析による副作用、合併症が数多く報告され、ポリスルホン血液透析膜に多く含まれる親水性高分子は人体から見れば異物である。この溶出を抑えることは長期透析時の体内蓄積を防ぎ、副作用を防止する観点から重要な技術である。すでに水充填のγ線滅菌品（ウェットタイプ）は高透水性能と架橋による親水性高分子の溶出が押さえられているが、水充填のため重く、取扱性に欠けるという問題があった。
【０００４】
本発明は、この技術とは異なり、軽い・凍結しないなどの利点があるドライタイプの半透膜において、従来欠点とされていた透水性・透析性能をウェットタイプ並に向上させ、かつドライタイプにおけるエチレンオキサイドガス（以下ＥＯＧと略す。）滅菌、高圧蒸気滅菌品では従来困難であるとされた、膜の親水性高分子の溶出を押さえた血液処理用半透膜ならびに、それを利用した透析器を提供することである。
【０００５】
【課題を解決するための手段】
本発明は上記課題を達成するため、次の構成を有する。
（１）疎水性高分子、親水性高分子を構成成分として含んでなる半透膜において、疎水性高分子がポリスルホン系樹脂、親水性高分子がポリビニルピロリドンであり、保湿剤が付着されていない状態で測定された該半透膜の乾燥前透水性能に対する乾燥後透水性能が１／２以上であり、かつ、該親水性高分子の半透膜中からの溶出量が１０ｐｐｍ以下であり、前記透水性能は下記（Ａ）〜（Ｂ）の方法にて測定され、さらに、前記溶出量は下記（Ｃ）の方法にて測定される血液処理用半透膜。
（Ａ）透水性能の測定
中空糸両端部を封止したガラス管ミニモジュール（本数３６本：有効長１０ｃｍ）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、透水性能を下記の式で算出する。
【数１】
（Ｂ）乾燥による性能変化の確認
湿潤剤が付着していない場合、そのまま１００℃で２４時間乾燥し、付着している場合、中空糸１０ｇを１５０ｍｌの純水に浸漬し、２４時間放置する操作を２回繰り返した後、糸束の状態で、１００℃で２４時間乾燥し、その前後での透水性能を測定する。
（Ｃ）強制溶出試験における水層に移動した親水性高分子ポリビニルピロリドン濃度の測定
透析モジュールを血液側から透析液側へ純水１リットルで洗浄し、モジュールから取り出した中空糸１ｇを塩化メチレン１０ｍｌに入れ、３時間攪拌して溶解し（仕込量１０ｗｔ／ｖｏｌ％）、０．１Ｎ−塩化アンモニウム溶液（ｐＨ９．５）１０ｍｌで抽出を行い、そのまま、得られた塩化メチレン−水溶液を超遠心機（２００００ｒｐｍ×１５ｍｉｎ）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する。
この溶液を温度２３℃で東ソーＴＳＫ−ｇｅｌ−ＧＭＰＷＸＬ ２本直列につないだ理論段数（８９００段×２）のカラムを用い、移動相として０．１Ｎ−塩化アンモニウム溶液（ｐＨ９．５）、流量 １．０ｍｌ／ｍｉｎ、サンプル打ち込み量 ０．２ｍｌで分析を行う。９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較正を行い、標品のＰＶＰのピーク面積−濃度検量線を作成し、サンプルのＰＶＰピーク面積から水層（５ｍｌ）に移動したＰＶＰ濃度を求める。ＰＶＰが検出されたサンプルは、回収率（水相への移動量）を標品から求め、その回収率を元に水相のＰＶＰ濃度から中空糸当たりの溶出量を換算して求める。
（２）上記（１）項の記載の血液処理用半透膜を用いた血液処理用透析器。
【０００６】
【発明の実施の形態】
半透膜を構成する疎水性高分子として、例えば、ポリスルホン、ポリアミド、ポリイミド、ポリフェニルエーテル、ポリフェニレンスルフィドなどほとんどのエンジニアリングプラスチックを用いることができるが、下記示性式で表されるポリスルホンが特に好ましい。ポリスルホンは下記基本骨格からなるが、ベンゼン環部分を修飾したものも用いることができる。
【０００７】
【化１】
親水性高分子としては、例えばポリエチレングリコール、ポリビニルアルコール、カルボキシメチルセルロース、ポリビニルピロリドンなどが用いられ、単独で用いてもよいし、混合して用いてもよい。工業的にも比較的入手しやすいポリビニルピロリドンが好ましい。また、親水性高分子は分子量が異なる２種類以上を用いることも好ましい。その場合、重量平均分子量で５倍以上異なるものを用いることが好ましい。本発明において半透膜を形成するために用いられる原液としては疎水性高分子、親水性高分子、溶媒、および添加剤からなることが好ましい。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。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。添加剤はポリスルホンの貧溶媒で親水性高分子と相溶性を持つもので、アルコール、グリセリン、水、エステル類等であるが、プロセス適性の面から特に水が好ましい。
【０００９】
また、製膜原液の粘度は市販されている疎水性高分子の分子量が低いことから、親水性高分子の分子量に依存する。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。そのためＰＶＰは高分子量のものを用いることが好ましく、ＰＶＰを混合して用いる場合には平均分子量を２０万以上に上げることが好ましい。
【００１０】
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。本発明のように膜を乾燥させても高い選択透過性と低アルブミン透過性を兼ね備えた膜を得るためには疎水性高分子の濃度は１０〜２０重量％が好ましく、さらに好ましくは１２〜１８重量％、親水性高分子の濃度は２〜２０ 重量％が好ましく、さらに好ましくは３〜１５ 重量％である。さらに、分子量の異なる２種以上の親水性ポリマーを用いる場合には、原液中の分子量１０万以上のポリマーの混和比率は１〜１０重量％が好ましい。高すぎると原液粘度が上昇し、製膜困難となるだけでなく、透水性、拡散性能が低下する傾向がある。逆に低すぎる場合、中高分子尿毒蛋白を透過させるための適当なネットワークを構築できない傾向がある。
【００１１】
次いで、製膜方法の一態様を以下に説明する。上述したような構成の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、乾燥工程、クリンプ工程を経た後、巻き取られ、適当な長さにカットした後、ケースに挿入され、ポッティング材によって端部を封止し、モジュール化される。
【００１２】
特に本発明の場合、モジュール化までの工程において、膜を保湿剤で保持し、乾燥工程を一切入れないという方法を用いず、膜の収縮を考慮した原液設計を行って、保湿剤を用いずに乾燥する操作を行うことにより、本発明の乾燥前透水性能に対する乾燥後透水性能が１／２以上の膜を得ることができる。
【００１３】
さらに、特に人工腎臓に用いる場合など、このままでは半透膜から親水性高分子の溶出が多いため、溶出物低減のためにγ線、電子線、熱、化学的に架橋を行うことが好ましい。空気存在下（酸素存在下）でのγ線照射は励起した酸素ラジカルによって高分子の主鎖が切れ、分解が起こるため、好ましくは膜の自重に対して１００以上１０００％未満さらに好ましくは１００〜６００％の水を抱液させて、不活性ガスで空気を置換した後、γ線照射を行うと親水性高分子の溶出が好適に抑えられる。不活性ガスは窒素、アルゴン、ヘリウム、炭酸ガスなどが好適に用いられるが、特に、安価な窒素が好ましい。γ線照射量は１０〜５０Ｋｇｙが好ましく、さらに好ましくは１０〜３０ＫＧｙである。架橋処理により、疎水性高分子と親水性高分子が結合することで親水性高分子の溶出が減少し、後述する強制溶出試験における親水性高分子の溶出確認でもピークが確認されず、半透膜中からの溶出量が１０ｐｐｍ以下の膜とすることができる。ここでいう溶出量とは疎水性高分子と親水性高分子の良溶媒で、溶解度が０．５ｇ／１ｍｌ以上であり、かつ水と混合しない溶媒に一定量の中空糸を分散・溶解させ、次に一定量の水相（０．１Ｎ−塩化アンモニウム溶液（ｐＨ９．５））へ親水性高分子を抽出し、その抽出液中の親水性高分子の濃度を意味する。かかる良溶媒としては、例えばポリスルホンとポリビニルピロリドンの場合、塩化メチレンが好適に用いられる。
【００１４】
これらの方法で作成された半透膜は疎水性高分子と親水性高分子のネットワークによって、その尿毒物質の拡散、有用蛋白であるアルブミンの阻止などの血液処理膜としての性能を発揮し、親水性高分子の溶出が少ないという特徴を有する。アルブミン透過率が３％を越えるような場合は低アルブミン血症や、高齢者の場合はその栄養状態に影響を及ぼす傾向があり、アルブミン透過率は３％以下であることが好ましい。尿毒物質としては尿素、クレアチニン、尿酸などがあるが、それぞれ、１８８、１７５、１６５ｍｌ／ｍｉｎ以上のクリアランスを有することが実用上、好ましい。また、以上のような特性を得るためには、架橋後の膜中の親水性高分子の含有率が２〜６重量％であることが好ましい。極端に低い場合は水濡れ性が低下し、血液と接触した際に凝固を引き起こす。また、架橋後の膜は５〜１５重量％の不溶化物を含んでいることが好ましい。
【００１５】
以上の通り、本発明により得られた血液処理用半透膜は、湿潤保持剤の付着されていない状態で乾燥させる製造工程と、さらに製膜後架橋するという製造工程を採用することにより半透膜の乾燥前透水性能に対する乾燥後の透水性能が１／２以上であるという構造を形成することができる。その結果、ドライの状態で使用しても、透水性能の低下が少なく、かつ溶出物の漏れも少ないという優れた効果を有する透析器とすることができる。ドライ状態で使用できるため、軽く、凍結の心配がなく、取り扱いが容易で高性能な半透膜を提供することが出来、透析コストの削減にも寄与できる。また、乾燥による透析性能低下が少ないため、各種の温度・滅菌条件でも高い透析性能を実現する。同時に人体から見れば異物である親水性高分子の溶出を抑えることができ、医療用具の安全性を高めることができる。本発明の透析器は人工腎臓、血漿分離膜、体外循環吸着用担体などの血液処理用途に適用可能である。
【００１６】
【実施例】
次に実施例に基づき本発明を説明する。
【００１７】
用いた測定法は以下の通りである。
（１）透水性能の測定
中空糸両端部を封止したガラス管ミニモジュール（本数３６本：有効長１０ｃｍ）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。
【００１８】
【数１】
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）
（２）乾燥による性能変化の確認
湿潤剤が付着していなければ、そのまま下記条件で、乾燥しても良いが、付着している場合、湿潤剤を除くために、中空糸１０ｇを１５０ｍｌの純水に浸漬し、２４時間放置する。この操作を２回繰り返した後、糸束の状態で、１００℃で２４時間乾燥し、その前後での透水性能を測定する。
（３）溶質のクリアランス測定
昭和５７年９月発行日本人工臓器学会編ダイアライザー性能評価基準に基づいて行った。この中で測定方法が２種類あるが、本実験はＴＭＰ０ｍｍＨｇを基準とした。各溶質の内、特にＶＢ１２は光による分解が起こるため、サンプリング後、測定当日のうちに測定することが望ましい。クリアランスは以下の式を用いて計算した。膜面積が異なるものについては、クリアランスから総括物質移動係数を計算し、そこから面積換算を行うことができる。
クリアランス
【００２０】
【数２】
ここでＣＢｉ：モジュール入口側濃度、 ＣＢｏ：モジュール出口側濃度
ＱＢ：モジュール供給液量（ｍｌ／ｍｉｎ）
（４）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、血液は遠心分離により血清に分離した後、商品名Ａ／Ｇ Ｂ−テストワコー（和光純薬）のＢＣＧ（ブロムクレゾールグリーン）法キットによって分析し、その濃度からアルブミン透過率（％）を算出した。また、濾液の濃度算出に当たって、アルブミンの検量線については、良好な感度を得るため、低濃度での検量線を作成する目的で、キット付属の血清アルブミンを適宜、希釈して作成した。
【００２２】
【数３】
ここでＣＦ：濾液中、ＣＢｉ：モジュール入り口、 ＣＢｉ：モジュール出口のアルブミン濃度
（５）強制溶出試験における水層に移動した親水性高分子ポリビニルピロリドン濃度の測定
透析モジュールを血液側から透析液側へ純水１リットルで洗浄し、モジュールから取り出した中空糸１ｇを塩化メチレン１０ｍｌに入れ、３時間攪拌して溶解し（仕込量１０ｗｔ／ｖｏｌ％）、０．１Ｎ−塩化アンモニウム溶液（ｐＨ９．５）１０ｍｌで抽出を行い、そのまま、得られた塩化メチレン−水溶液を超遠心機（２００００ｒｐｍ×１５ｍｉｎ）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。
【００２４】
この溶液を温度２３℃で東ソーＴＳＫ−ｇｅｌ−ＧＭＰＷＸＬ ２本直列につないだ理論段数（８９００段×２）のカラムを用い、移動相として０．１Ｎ−塩化アンモニウム溶液（ｐＨ９．５）、流量 １．０ｍｌ／ｍｉｎ、サンプル打ち込み量 ０．２ｍｌで分析を行った。９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較正を行い、標品のＰＶＰのピーク面積−濃度検量線を作成し、サンプルのＰＶＰピーク面積から水層（５ｍｌ）に移動したＰＶＰ濃度を求めた。ＰＶＰが検出されたサンプルは、回収率（水相への移動量）を標品から求め、その回収率を元に水相のＰＶＰ濃度から中空糸当たりの溶出量を換算して求めた。
（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）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、さらに純水１００ｍｌで洗浄、同様に遠心分離操作を３回繰り返し、残った固形物を蒸発乾固し、最後に真空ポンプで乾燥した。その重量から不溶物の含有率を求めた。
実施例１
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）４部、（アモコ社 Ｕｄｅｌ−Ｐ１７００）１２部、ポリビニルピロリドン（インターナショナルスペシャルプロダクツ社；以下ＩＳＰ社と略す） Ｋ３０ ４部、ポリビニルピロリドン（ＩＳＰ社Ｋ９０）２部をジメチルアセトアミド７７部、水１部を加熱溶解し、製膜原液とした。原液粘度は５０℃で１３．４Ｐａ・ｓであった。この原液を温度５０℃の紡糸口金部へ送り、外径０．３５ｍｍ、内径０．２５ｍｍ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℃で調湿し、１０ミクロン以下のドライミストを加えた２５０ｍｍのドライゾーン雰囲気を経て、ジメチルアセトアミド２０重量％、水８０重量％からなる温度４０℃の凝固浴を通過させ、８０℃６０秒の水洗工程、１３５℃の乾燥工程を２分通過させ、１６０℃のクリンプ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、端部を両面開口させて、透析モジュールとした。
【００２５】
モジュール化後、脱気工程を経た、温水（３７℃）で、血液側を毎分２００ｍｌ／ｍｉｎで１分充填した後、血液側を止め、不活性ガス（窒素）：圧力０．１ＭＰａ、１５秒で充填水を押し出した。この時の中空糸膜の抱液率は３２０％であった。透析液側も不活性ガスで置換後、最後に不活性ガス封入状態で湿潤状態のまま、γ線照射（２５ＫＧｙ）を行った。 透水性能、各溶質におけるクリアランス、アルブミン透過率を測定したところ、尿素、クレアチニン、尿酸、リン酸、ＶＢ１２のクリアランスはそれぞれ１９５ｍｌ／ｍｉｎ、１８５ｍｌ／ｍｉｎ、１８０ｍｌ／ｍｉｎ、１８６ｍｌ／ｍｉｎ、１４５ｍｌ／ｍｉｎ、透水性能７５６ｍｌ／ｈｒ／ｍ2／ｍｍＨｇ、アルブミン透過率１．５％であった。 また、乾燥後の中空糸の透水性能は７７２ ｍｌ／ｈｒ／ｍ2／ｍｍＨｇであり、性能低下は観測されなかった。
【００２６】
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３．５％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７．２％であった。強制溶出試験における中空糸膜から水層に移動したＰＶＰの濃度を調べた結果、ピークが現れず検出されなかった。
実施例２
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）４部、（アモコ社 Ｕｄｅｌ−Ｐ１７００）１２部、ポリビニルピロリドン（ＩＳＰ社 Ｋ３０）３部、ポリビニルピロリドン（ＩＳＰ社Ｋ９０）３部をジメチルアセトアミド７７部、水１部を加熱溶解し、製膜原液とした。原液粘度は５０℃で１８Ｐａ・ｓであった。実施例１と同様な工程を経てモジュールを作成した。
【００２７】
水押し出し後の中空糸膜の抱液率は３３０％であった。γ線照射（２５ＫＧｙ）後、透水性能、各溶質におけるクリアランス、アルブミン透過率を測定したところ、尿素、クレアチニン、尿酸、リン酸、ＶＢ１２のクリアランスはそれぞれ１９３ｍｌ／ｍｉｎ、１８２ｍｌ／ｍｉｎ、１７８ｍｌ／ｍｉｎ、１８４ｍｌ／ｍｉｎ、１４２ｍｌ／ｍｉｎ、透水性能 ７２０ｍｌ／ｈｒ／ｍ2／ｍｍＨｇ、アルブミン透過率１．８％であった。乾燥後の中空糸の透水性能は７３４ ｍｌ／ｈｒ／ｍ2／ｍｍＨｇであり、性能低下は観測されなかった。
【００２８】
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４．０％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７．８％となった。強制溶出試験における中空糸膜から水層に移動したＰＶＰの濃度を調べた結果、実施例１と同様に検出されなかった。
実施例３
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）４部、（アモコ社 Ｕｄｅｌ−Ｐ１７００）１２部、ポリビニルピロリドン（ＩＳＰ社 Ｋ３０）２部、ポリビニルピロリドン（ＩＳＰ社Ｋ９０）４部をジメチルアセトアミド７７部、水１部を加熱溶解し、製膜原液とした。原液粘度は５０℃で２３Ｐａ・ｓ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。
【００２９】
水押し出し後の中空糸膜の抱液率は４００％であった。γ線照射（２５ＫＧｙ）後、透水性能、各溶質におけるクリアランス、アルブミン透過率を測定したところ透水性能 ７０２ｍｌ／ｈｒ／ｍ2／ｍｍＨｇ、尿素、クレアチニン、尿酸、リン酸、ＶＢ１２のクリアランスはそれぞれ１９１ｍｌ／ｍｉｎ、１８０ｍｌ／ｍｉｎ、１７５ｍｌ／ｍｉｎ、１８１ｍｌ／ｍｉｎ、１４０ｍｌ／ｍｉｎ、アルブミン透過率１．０％であった。乾燥後の中空糸の透水性能は７２７ ｍｌ／ｈｒ／ｍ2／ｍｍＨｇであり、性能低下は観測されなかった。
【００３０】
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４．７％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８．３％となった。強制溶出試験における中空糸膜から水層に移動したＰＶＰの濃度を調べた結果、実施例１と同様に検出されなかった。
【００３１】
実施例４
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）４部、（アモコ社 Ｕｄｅｌ−Ｐ１７００）１２部、ポリビニルピロリドン（ＩＳＰ社 Ｋ３０）１部、ポリビニルピロリドン（ＩＳＰ社Ｋ９０）５部をジメチルアセトアミド７７部、水１部を加熱溶解し、製膜原液とした。原液粘度は５０℃で２９Ｐａ・ｓ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。
【００３２】
水押し出し後の中空糸膜の抱液率は３８０％であった。γ線照射（２５ＫＧｙ）後、透水性能、各溶質におけるクリアランス、アルブミン透過率を測定したところ透水性能 ６７５ｍｌ／ｈｒ／ｍ2／ｍｍＨｇ、尿素、クレアチニン、尿酸、リン酸、ＶＢ１２のクリアランスはそれぞれ１９０ｍｌ／ｍｉｎ、１７９ｍｌ／ｍｉｎ、１７３ｍｌ／ｍｉｎ、１７９ｍｌ／ｍｉｎ、１３８ｍｌ／ｍｉｎ、アルブミン透過率０．９％であった。乾燥後の中空糸の透水性能は６６８ ｍｌ／ｈｒ／ｍ2／ｍｍＨｇであり、性能低下は観測されなかった。
【００３３】
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５．１％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８．９％となった。強制溶出試験における中空糸膜から水層に移動したＰＶＰの濃度を調べた結果、実施例１と同様に検出されなかった。
実施例５
ポリスルホン（アモコ社 Ｕｄｅｌ−Ｐ３５００）４部、（アモコ社 Ｕｄｅｌ−Ｐ１７００）１２部、ポリビニルピロリドン（ＩＳＰ社Ｋ９０）６部をジメチルアセトアミド７７部、水１部を加熱溶解し、製膜原液とした。原液粘度は５０℃で３８Ｐａ・ｓ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。
【００３４】
水押し出し後の中空糸膜の抱液率は３５０％であった。γ線照射（２５ＫＧｙ）後、透水性能、各溶質におけるクリアランス、アルブミン透過率を測定したところ透水性能 ６２０ｍｌ／ｈｒ／ｍ2／ｍｍＨｇ、尿素、クレアチニン、尿酸、リン酸、ＶＢ１２のクリアランスはそれぞれ１８９ｍｌ／ｍｉｎ、１７７ｍｌ／ｍｉｎ、１６９ｍｌ／ｍｉｎ、１７８ｍｌ／ｍｉｎ、１３７ｍｌ／ｍｉｎ、アルブミン透過率０．８％であった。乾燥後の中空糸の透水性能は６５６ ｍｌ／ｈｒ／ｍ2／ｍｍＨｇであり、性能低下は観測されなかった。
【００３５】
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５．５％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９．２％となった。強制溶出試験における中空糸膜から水層に移動したＰＶＰの濃度を調べた結果、実施例１と同様に検出されなかった。
比較例１
実施例１の条件で製膜された中空糸を用い、同様にモジュール化し、水充填せずＥＯＧ滅菌を行った。透水性能、各溶質におけるクリアランス、アルブミン透過率を測定したところ、尿素、クレアチニン、尿酸、リン酸、ＶＢ１２のクリアランスはそれぞれ１９５ｍｌ／ｍｉｎ、１８３ｍｌ／ｍｉｎ、１８０ｍｌ／ｍｉｎ、１８５ｍｌ／ｍｉｎ、１４３ｍｌ／ｍｉｎ、透水性能 ７２１ｍｌ／ｈｒ／ｍ2／ｍｍＨｇ、アルブミン透過率１．２％であった。 また、乾燥後の中空糸の透水性能は７７０ ｍｌ／ｈｒ／ｍ２／ｍｍＨｇであり、性能変化は観測されなかった。
【００３６】
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３．８％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７．６％であった。強制溶出試験における中空糸膜から水層に移動したＰＶＰの濃度を調べた結果、中空糸当たり１４７８ｐｐｍ検出された。
比較例２
実施例１の条件で製膜された中空糸を用い、同様にモジュール化し、水充填せず高圧蒸気滅菌を行った。透水性能、各溶質におけるクリアランス、アルブミン透過率を測定したところ、尿素、クレアチニン、尿酸、リン酸、ＶＢ１２のクリアランスはそれぞれ１９４ｍｌ／ｍｉｎ、１８３ｍｌ／ｍｉｎ、１７９ｍｌ／ｍｉｎ、１８４ｍｌ／ｍｉｎ、１４０ｍｌ／ｍｉｎ、透水性能 ７１８ｍｌ／ｈｒ／ｍ２／ｍｍＨｇ、アルブミン透過率１．１％であった。乾燥後の中空糸の透水性能は７５８ ｍｌ／ｈｒ／ｍ2／ｍｍＨｇであり、性能低下は観測されなかった。
【００３７】
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３．２％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７．３％であった。強制溶出試験における中空糸膜から水層に移動したＰＶＰの濃度を調べた結果、中空糸当たり８９８ｐｐｍ検出された。
【００３８】
【発明の効果】
本発明により、軽い・凍結しないなどの利点があるドライタイプの半透膜であって、かつ、透水性、透析性能にも優れた半透膜を内蔵した血液処理用透析器を提供することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a semipermeable membrane for blood treatment with little change in membrane performance even when dried and with little elution of hydrophilic polymer, and a blood treatment dialyzer using the same.
[0002]
[Prior art]
Semi-permeable membranes for blood treatment including artificial kidneys are natural materials such as cellulose, and its derivatives cellulose diacetate, cellulose triacetate, and with the changing times, synthetic polymers have appeared, such as polysulfone, PMMA, polyacrylonitrile, etc. In recent years, modified membranes in which cellulose is treated with PEG or the like to improve blood compatibility have been used. With regard to blood treatment methods for patients with chronic renal failure, attempts have been made to actively remove other low molecular weight proteins while minimizing albumin leakage. In addition to improving membranes, hemodiafiltration (HDF) and push-pull methods have been developed to improve dialysis efficiency and actively remove low molecular weight proteins. At present, polysulfone, which has high water permeability among membrane materials, has been widely used as one that matches the progress of such dialysis techniques. Polysulfone is widely used as a thermoplastic heat-resistant engineering plastic in the fields of automobiles, electricity, and medical devices, but when a dialysis membrane is made of polysulfone alone, the intermolecular cohesion is strong and the pore size cannot be controlled. Because of its hydrophobicity, it has poor affinity with blood, and blood components such as platelets tend to adhere, causing not only residual blood but also severe deterioration of membrane performance. Furthermore, since an air lock phenomenon is likely to occur, it cannot be used for blood treatment as it is.
Therefore, it is possible to form pores by mixing and removing inorganic salts as pore-forming materials and then hydrophilizing them, or by previously mixing hydrophilic polymers as pore-forming agents and removing them to remove pores. After forming the film, a method has been devised in which the remaining hydrophilic component is used to simultaneously hydrophilize the polymer surface and use it as a semipermeable membrane or a reverse osmosis membrane. Illustratively, (1) a method for forming a film with a metal salt (2) a method for forming a film with a hydrophilic polymer (3) a method for forming a film with a polyhydric alcohol has already been disclosed. However, when a film is formed by adding a polyhydric alcohol such as polyethylene glycol as disclosed in JP-A-61-232860 and JP-A-58-114702, when washing is insufficient, elution of polyethylene glycol remaining on the film Depending on the condition, abnormalities may occur in the patient's eyes during dialysis. In the case of metal salts, the pore size is too large to be suitable for a dialysis membrane. Japanese Patent Publication No. 5-54373 describes a dry-type dialysis membrane, but does not disclose a dry-type membrane with little elution of hydrophilic polymer and high water permeability.
[0003]
[Problems to be solved by the invention]
Many side effects and complications due to long-term dialysis have been reported, and the hydrophilic polymer contained in a large amount of polysulfone hemodialysis membrane is a foreign body from the viewpoint of the human body. Suppressing this elution is an important technique from the viewpoint of preventing accumulation in the body during long-term dialysis and preventing side effects. Already water-filled γ-ray sterilized products (wet type) have high water permeability and elution of hydrophilic polymers due to cross-linking, but they are heavy due to water filling and have a problem of lack of handling.
[0004]
The present invention is different from this technology in that the dry type semipermeable membrane has advantages such as lightness and freezing, and has improved water permeability and dialysis performance, which has been regarded as a conventional defect, as well as the wet type. A semipermeable membrane for blood treatment that suppresses the elution of hydrophilic polymer in the membrane, which has been difficult in the past by sterilization with oxide gas (hereinafter abbreviated as EOG) and high-pressure steam sterilization products, and a dialyzer using the same Is to provide.
[0005]
[Means for Solving the Problems]
In order to achieve the above object, the present invention has the following configuration.
(1) In a semipermeable membrane comprising a hydrophobic polymer or a hydrophilic polymer as a constituent component,The hydrophobic polymer is a polysulfone resin, the hydrophilic polymer is polyvinylpyrrolidone,MoisturizerMeasured with no adhesionThe water permeation performance after drying with respect to the water permeation performance before drying of the semipermeable membrane is ½ or more, and the elution amount of the hydrophilic polymer from the semipermeable membrane is 10 ppm or less.The water permeability is measured by the following methods (A) to (B), and the elution amount is measured by the following method (C).Semipermeable membrane for blood treatment.
(A) Measurement of water permeability
Applying water pressure of 100 mmHg to the inside of the hollow fiber of the glass tube mini module (36 pipes: effective length 10 cm) sealed at both ends of the hollow fiber, measuring the filtration amount per unit time flowing out to the outside, Calculate with the following formula.
[Expression 1]
(B) Confirmation of performance change due to drying
When the wetting agent is not attached, it is dried as it is at 100 ° C. for 24 hours, and when it is attached, the operation of dipping the hollow fiber 10 g in 150 ml of pure water and leaving it for 24 hours is repeated twice, and then the yarn bundle In this state, it is dried at 100 ° C. for 24 hours, and the water permeability before and after that is measured.
(C) Measurement of the concentration of the hydrophilic polymer polyvinyl pyrrolidone moved to the water layer in the forced dissolution test
The dialysis module was washed from the blood side to the dialysate side with 1 liter of pure water, 1 g of hollow fiber taken out from the module was placed in 10 ml of methylene chloride and dissolved by stirring for 3 hours (feed amount: 10 wt / vol%). Extraction was performed with 10 ml of 1N-ammonium chloride solution (pH 9.5), and the resulting methylene chloride-water solution was separated as it was with an ultracentrifuge (20000 rpm × 15 min), and the aqueous layer was filtered with a filter having a pore size of 0.5 μm. Filter to make the sample solution.
Using a column with the theoretical plate number (8900 plates × 2) in which two Tosoh TSK-gel-GMPWXLs were connected in series at a temperature of 23 ° C., a 0.1N ammonium chloride solution (pH 9.5) as a mobile phase, a flow rate of 1 Analysis is performed at 0.0 ml / min and a sample injection amount of 0.2 ml. Nine types of monodisperse polyethylene glycols are used as the reference substance, molecular weight calibration is performed, a standard PVP peak area-concentration calibration curve is created, and the PVP concentration transferred from the sample PVP peak area to the aqueous layer (5 ml) is determined. . For the sample in which PVP is detected, the recovery rate (transfer amount to the aqueous phase) is determined from the preparation, and the elution amount per hollow fiber is calculated from the PVP concentration of the aqueous phase based on the recovery rate.
(2) A blood processing dialyzer using the blood processing semipermeable membrane according to item (1).
[0006]
DETAILED DESCRIPTION OF THE INVENTION
As the hydrophobic polymer constituting the semipermeable membrane, for example, most engineering plastics such as polysulfone, polyamide, polyimide, polyphenyl ether and polyphenylene sulfide can be used, but polysulfone represented by the following formula is particularly preferable. . Polysulfone is composed of the following basic skeleton, but those having a modified benzene ring portion can also be used.
[0007]
[Chemical 1]
As the hydrophilic polymer, for example, polyethylene glycol, polyvinyl alcohol, carboxymethyl cellulose, polyvinyl pyrrolidone and the like may be used, which may be used alone or in combination. Polyvinylpyrrolidone which is relatively easily available industrially is preferable. It is also preferable to use two or more hydrophilic polymers having different molecular weights. In that case, it is preferable to use those having a weight average molecular weight different by 5 times or more. The stock solution used for forming the semipermeable membrane in the present invention preferably comprises a hydrophobic polymer, a hydrophilic polymer, a solvent, and an additive. As for the solvent, an amphoteric solvent which dissolves the three of the hydrophobic polymer, the hydrophilic polymer and the additive well is used. Examples thereof include dimethylacetamide, dimethylformamide, dimethylsulfoxide, acetone, acetaldehyde, 2-methylpyrrolidone, and dimethylacetamide is preferable from the viewpoint of danger, stability, and toxicity. The additive is a poor solvent for polysulfone and is compatible with a hydrophilic polymer. Examples of the additive include alcohol, glycerin, water, and esters. Water is particularly preferable from the viewpoint of process suitability.
[0009]
Moreover, since the molecular weight of the hydrophobic polymer marketed is low, the viscosity of the film-forming stock solution depends on the molecular weight of the hydrophilic polymer. The decrease in the viscosity of the undiluted solution causes yarn breakage and yarn shaking during the hollow fiber film formation, thereby deteriorating the stability. Therefore, it is preferable to use high molecular weight PVP, and when mixing PVP, it is preferable to increase the average molecular weight to 200,000 or more.
[0010]
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. In order to obtain a membrane having both high selective permeability and low albumin permeability even when the membrane is dried as in the present invention, the concentration of the hydrophobic polymer is preferably 10 to 20% by weight, more preferably 12 to 18%. The concentration by weight and the hydrophilic polymer concentration is preferably 2 to 20% by weight, more preferably 3 to 15% by weight. Further, when two or more hydrophilic polymers having different molecular weights are used, the mixing ratio of the polymer having a molecular weight of 100,000 or more in the stock solution is preferably 1 to 10% by weight. If the viscosity is too high, the viscosity of the undiluted solution increases and not only film formation becomes difficult, but also water permeability and diffusion performance tend to decrease. On the other hand, if it is too low, there is a tendency that an appropriate network for permeating medium high molecular weight uremic protein cannot be constructed.
[0011]
Next, one aspect of the film forming method will be described below. A membrane-forming stock solution having the above-described configuration is simultaneously discharged from a die having a double slit tube structure simultaneously with the core solution, thereby forming a hollow fiber membrane. Then, after passing through a predetermined water washing, drying process, and crimping process, it is wound up, cut into an appropriate length, inserted into a case, and the end is sealed with a potting material to be modularized.
[0012]
Especially in the case of the present invention, in the process up to modularization, without using a method of holding the film with a moisturizing agent and not including a drying process at all, designing the stock solution considering the contraction of the film, without using the moisturizing agent By performing the drying operation, it is possible to obtain a membrane having a water permeability after drying of ½ or more of the water permeability before drying of the present invention.
[0013]
Furthermore, especially when used in an artificial kidney, since the hydrophilic polymer is often eluted from the semipermeable membrane as it is, it is preferable to carry out γ-ray, electron beam, heat, and chemical crosslinking in order to reduce the eluate. In the presence of air (in the presence of oxygen), irradiation with γ-rays causes the main chain of the polymer to be broken by the excited oxygen radicals, causing decomposition. When γ-ray irradiation is performed after immersing 600% water and replacing the air with an inert gas, the elution of the hydrophilic polymer is suitably suppressed. As the inert gas, nitrogen, argon, helium, carbon dioxide, or the like is preferably used, but particularly inexpensive nitrogen is preferable. The amount of γ-ray irradiation is preferably 10 to 50 Kgy, more preferably 10 to 30 KGy. The cross-linking treatment reduces the elution of the hydrophilic polymer by bonding the hydrophobic polymer and the hydrophilic polymer, and no peak is confirmed even in the elution confirmation of the hydrophilic polymer in the forced elution test described later. The amount of elution from the membrane can be 10 ppm or less. The elution amount here is a good solvent for hydrophobic polymer and hydrophilic polymer, the solubility is 0.5 g / 1 ml or more, and a certain amount of hollow fiber is dispersed and dissolved in a solvent that is not mixed with water, Next, the hydrophilic polymer is extracted into a certain amount of aqueous phase (0.1N ammonium chloride solution (pH 9.5)), and the concentration of the hydrophilic polymer in the extract is meant. As such a good solvent, for example, in the case of polysulfone and polyvinylpyrrolidone, methylene chloride is preferably used.
[0014]
The semipermeable membranes created by these methods show the performance of blood treatment membranes, such as diffusion of uremic substances and prevention of albumin, a useful protein, by the network of hydrophobic and hydrophilic polymers. It has the characteristic that there is little elution of a conductive polymer. If the albumin permeability exceeds 3%, hypoalbuminemia tends to affect the nutritional status of the elderly, and the albumin permeability is preferably 3% or less. Uremic substances include urea, creatinine, uric acid and the like, but it is practically preferable to have clearances of 188, 175 and 165 ml / min or more, respectively. In order to obtain the above characteristics, the content of the hydrophilic polymer in the film after crosslinking is preferably 2 to 6% by weight. If it is extremely low, water wettability is reduced, causing clotting when in contact with blood. Moreover, it is preferable that the film | membrane after bridge | crosslinking contains 5 to 15weight% of the insolubilization thing.
[0015]
As described above, the semipermeable membrane for blood treatment obtained by the present invention adopts a production process in which a wet retention agent is not attached and a production process in which crosslinking is performed after film formation, and a semipermeable membrane is obtained. It is possible to form a structure in which the water permeability after drying with respect to the water permeability before drying of the membrane is 1/2 or more. As a result, even when used in a dry state, it is possible to provide a dialyzer having an excellent effect that there is little decrease in water permeability and little leakage of eluate. Since it can be used in a dry state, it is light, free from fear of freezing, easy to handle, and capable of providing a high-performance semipermeable membrane, which can contribute to reduction of dialysis costs. In addition, since dialysis performance is not degraded by drying, high dialysis performance is achieved even under various temperature and sterilization conditions. At the same time, when viewed from the human body, the elution of the hydrophilic polymer, which is a foreign substance, can be suppressed, and the safety of the medical device can be improved. The dialyzer of the present invention can be applied to blood treatment applications such as artificial kidneys, plasma separation membranes, and extracorporeal circulation adsorption carriers.
[0016]
【Example】
Next, this invention is demonstrated based on an Example.
[0017]
The measurement method used is as follows.
(1) Measurement of water permeability
A water pressure of 100 mmHg was applied to the inside of the hollow fiber of a glass tube mini-module (36 pieces: effective length: 10 cm) sealed at both ends 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.
[0018]
[Expression 1]
Where QW: Filtration volume (ml) T: Outflow time (hr) P: Pressure (mmHg)
A: Membrane area (m2) (in terms of hollow fiber inner surface area)
(2) Confirmation of changes in performance due to drying
If the wetting agent is not attached, it may be dried as it is under the following conditions. However, in order to remove the wetting agent, 10 g of hollow fiber is immersed in 150 ml of pure water and left for 24 hours. . After repeating this operation twice, the yarn is dried in a bundle of yarns at 100 ° C. for 24 hours, and the water permeability before and after the measurement is measured.
(3) Solute clearance measurement
This was performed based on the criteria for evaluating dialyzer performance published in the Japanese Society for Artificial Organs published in September 1982. Among these, there are two types of measurement methods, but this experiment was based on TMP 0 mmHg. Among the solutes, particularly VB12 is decomposed by light, so that it is desirable to measure within the measurement day after sampling. The clearance was calculated using the following formula. For those with different membrane areas, the overall mass transfer coefficient can be calculated from the clearance and the area converted from there.
clearance
[0020]
[Expression 2]
Where CBi: Module inlet side concentration, CBo: Module outlet side concentration
QB: Module supply liquid volume (ml / min)
(4) 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 was adjusted so that the filtration amount was 20 ml / min per 1 m 2 of module area (that is, 32 ml / min at 1.6 m 2), 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, and the blood was separated into serum by centrifugation, and then BCG (Bromocresol) under the trade name A / GB B-Test Wako (Wako Pure Chemical Industries, Ltd.) Green) was analyzed by the method kit, and albumin permeability (%) was calculated from the concentration. In calculating the concentration of the filtrate, an albumin calibration curve was prepared by appropriately diluting the serum albumin attached to the kit for the purpose of creating a calibration curve at a low concentration in order to obtain good sensitivity.
[0022]
[Equation 3]
Where CF: filtrate, CBi: module inlet, CBi: module outlet albumin concentration
(5) Measurement of the concentration of the hydrophilic polymer polyvinylpyrrolidone transferred to the water layer in the forced dissolution testConstant
The dialysis module was washed from the blood side to the dialysate side with 1 liter of pure water, 1 g of hollow fiber taken out from the module was placed in 10 ml of methylene chloride and dissolved by stirring for 3 hours (feed amount: 10 wt / vol%). Extraction was performed with 10 ml of 1N-ammonium chloride solution (pH 9.5), and the resulting methylene chloride-water solution was separated as it was with an ultracentrifuge (20000 rpm × 15 min), and the aqueous layer was filtered with a filter having a pore size of 0.5 μm. Filtration was performed to obtain a sample solution.
[0024]
Using a column with the theoretical plate number (8900 plates × 2) in which two Tosoh TSK-gel-GMPWXLs were connected in series at a temperature of 23 ° C., a 0.1N ammonium chloride solution (pH 9.5) as a mobile phase, a flow rate of 1 The analysis was performed at 0.0 ml / min and a sample injection amount of 0.2 ml. Nine kinds of monodisperse polyethylene glycols are used as a reference substance for molecular weight calibration, a standard PVP peak area-concentration calibration curve is created, and the PVP concentration transferred from the sample PVP peak area to the aqueous layer (5 ml) is determined. It was. For the sample in which PVP was detected, the recovery rate (transfer amount to the aqueous phase) was determined from the sample, and the elution amount per hollow fiber was calculated from the PVP concentration of the aqueous phase based on the recovery rate.
(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 which was analyzed with a CHN coder, and the content of polyvinylpyrrolidone was calculated from the nitrogen content.
(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, and further washed with 100 ml of pure water. Similarly, the centrifugation operation was repeated three times, and the remaining solid was evaporated to dryness and finally dried with a vacuum pump. The content of insoluble matter was determined from the weight.
Example 1
Polysulfone (Amoco Corporation Udel-P3500) 4 parts, (Amoco Corporation Udel-P1700) 12 parts, Polyvinylpyrrolidone (International Special Products Inc .; hereinafter abbreviated as ISP) K30 4 parts, Polyvinylpyrrolidone (ISP K90) 2 parts dimethyl 77 parts of acetamide and 1 part of water were dissolved by heating to obtain a stock solution. The stock solution viscosity was 13.4 Pa · s at 50 ° C. This undiluted solution is sent to a spinneret at a temperature of 50 ° C., and a solution comprising 65 parts of dimethylacetamide and 35 parts of water is discharged as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm. Then, the humidity is adjusted at a temperature of 30 ° C. and a dew point of 28 ° C., and after passing through a 250 mm dry zone atmosphere to which a dry mist of 10 microns or less is added, a temperature of 40 ° C. comprising 20% by weight of dimethylacetamide and 80% by weight of water. The hollow fiber membrane obtained by passing through a coagulation bath of 80 ° C. and a water washing step at 60 ° C. for 60 seconds and a drying step at 135 ° C. for 2 minutes and undergoing a crimping step at 160 ° C. was used as a wound bundle. 1.6m of this hollow fiber membrane2The dialysis module was prepared by filling the case, potting, and opening both ends of the case.
[0025]
After modularization, after passing through a deaeration process, the blood side was filled with 200 ml / min for 1 minute with warm water (37 ° C.), then the blood side was stopped, and inert gas (nitrogen): pressure 0.1 MPa, 15 The filling water was pushed out in seconds. The liquid retention of the hollow fiber membrane at this time was 320%. The dialysate side was also replaced with an inert gas, and finally γ-ray irradiation (25 KGy) was performed with the inert gas sealed in a wet state. When the water permeability, clearance in each solute, and albumin permeability were measured, the clearances of urea, creatinine, uric acid, phosphoric acid, and VB12 were 195 ml / min, 185 ml / min, 180 ml / min, 186 ml / min, 145 ml / min, respectively. Water permeability 756ml / hr / m2/ MmHg, albumin permeability was 1.5%. The water permeability of the hollow fiber after drying is 772 ml / hr / m.2/ MmHg, and no performance degradation was observed.
[0026]
Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 3.5%. The amount of insoluble matter in the hollow fiber after γ-irradiation was measured and found to be 7.2%. As a result of examining the concentration of PVP moved from the hollow fiber membrane to the aqueous layer in the forced elution test, no peak appeared and was not detected.
Example 2
4 parts of polysulfone (Amoco Udel-P3500), 12 parts of (Amoco Udel-P1700), 3 parts of polyvinylpyrrolidone (ISP K30), 3 parts of polyvinylpyrrolidone (ISP K90), 77 parts of dimethylacetamide and 1 part of water This was dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 18 Pa · s at 50 ° C. A module was prepared through the same steps as in Example 1.
[0027]
The liquid retention of the hollow fiber membrane after water extrusion was 330%. After γ-ray irradiation (25 KGy), water permeability, clearance in each solute, and albumin permeability were measured. The clearances of urea, creatinine, uric acid, phosphoric acid, and VB12 were 193 ml / min, 182 ml / min, 178 ml / min, respectively. 184 ml / min, 142 ml / min, water permeability 720 ml / hr / m2/ MmHg, albumin permeability was 1.8%. The water permeability of the hollow fiber after drying is 734 ml / hr / m2/ MmHg, and no performance degradation was observed.
[0028]
Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 4.0%. Further, the amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured and found to be 7.8%. As a result of examining the concentration of PVP migrated from the hollow fiber membrane to the aqueous layer in the forced elution test, it was not detected as in Example 1.
Example 3
4 parts of polysulfone (Amoco Udel-P3500), 12 parts of (Amoco Udel-P1700), 2 parts of polyvinylpyrrolidone (ISP K30), 4 parts of polyvinylpyrrolidone (ISP K90), 77 parts of dimethylacetamide and 1 part of water This was dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 23 Pa · s at 50 ° C. A module was formed through the same steps as in Example 1.
[0029]
The liquid retention of the hollow fiber membrane after water extrusion was 400%. After γ-ray irradiation (25 KGy), water permeability, clearance in each solute, and albumin permeability were measured. Water permeability 702 ml / hr / m2The clearances of / mmHg, urea, creatinine, uric acid, phosphoric acid, and VB12 were 191 ml / min, 180 ml / min, 175 ml / min, 181 ml / min, 140 ml / min, and albumin permeability 1.0%, respectively. The water permeability of the hollow fiber after drying is 727 ml / hr / m2/ MmHg, and no performance degradation was observed.
[0030]
Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 4.7%. The amount of insoluble matter in the hollow fiber after γ-irradiation was measured and found to be 8.3%. As a result of examining the concentration of PVP migrated from the hollow fiber membrane to the aqueous layer in the forced elution test, it was not detected as in Example 1.
[0031]
Example 4
4 parts of polysulfone (Amoco Udel-P3500), 12 parts (Amoco Udel-P1700), 1 part of polyvinylpyrrolidone (ISP K30), 5 parts of polyvinylpyrrolidone (ISP K90), 77 parts of dimethylacetamide and 1 part of water This was dissolved by heating to obtain a film forming stock solution. The stock solution viscosity was 29 Pa · s at 50 ° C. A module was formed through the same steps as in Example 1.
[0032]
The liquid retention of the hollow fiber membrane after water extrusion was 380%. After γ-ray irradiation (25KGy), the water permeability, clearance in each solute, and albumin permeability were measured. Water permeability 675 ml / hr / m2The clearances of / mmHg, urea, creatinine, uric acid, phosphoric acid, and VB12 were 190 ml / min, 179 ml / min, 173 ml / min, 179 ml / min, 138 ml / min, and albumin permeability 0.9%, respectively. The water permeability of the hollow fiber after drying is 668 ml / hr / m2/ MmHg, and no performance degradation was observed.
[0033]
Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 5.1%. Moreover, when the amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured, it was 8.9%. As a result of examining the concentration of PVP migrated from the hollow fiber membrane to the aqueous layer in the forced elution test, it was not detected as in Example 1.
Example 5
4 parts of polysulfone (Amoco Udel-P3500), 12 parts of (Amoco Udel-P1700), 6 parts of polyvinylpyrrolidone (ISP K90) were dissolved in 77 parts of dimethylacetamide and 1 part of water to prepare a film forming stock solution. The stock solution viscosity was 38 Pa · s at 50 ° C. A module was formed through the same steps as in Example 1.
[0034]
The liquid retention of the hollow fiber membrane after water extrusion was 350%. After γ-ray irradiation (25 KGy), water permeability, clearance in each solute, and albumin permeability were measured. Water permeability 620 ml / hr / m2The clearances of / mmHg, urea, creatinine, uric acid, phosphoric acid, and VB12 were 189 ml / min, 177 ml / min, 169 ml / min, 178 ml / min, 137 ml / min, and albumin permeability 0.8%, respectively. The water permeability of the hollow fiber after drying is 656 ml / hr / m2/ MmHg, and no performance degradation was observed.
[0035]
Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 5.5%. The amount of insoluble matter in the hollow fiber after γ-irradiation was measured and found to be 9.2%. As a result of examining the concentration of PVP migrated from the hollow fiber membrane to the aqueous layer in the forced elution test, it was not detected as in Example 1.
Comparative Example 1
Using the hollow fiber formed under the conditions of Example 1, it was modularized in the same manner, and EOG sterilization was performed without filling with water. When the water permeability, clearance in each solute, and albumin permeability were measured, the clearance of urea, creatinine, uric acid, phosphoric acid, and VB12 was 195 ml / min, 183 ml / min, 180 ml / min, 185 ml / min, 143 ml / min, respectively. Water permeability 721ml / hr / m2/ MmHg, albumin permeability was 1.2%. Moreover, the water permeability of the hollow fiber after drying was 770 ml / hr / m2 / mmHg, and no change in performance was observed.
[0036]
Furthermore, when the amount of polyvinylpyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 3.8%. The amount of insoluble matter in the hollow fiber after γ-irradiation was measured and found to be 7.6%. As a result of examining the concentration of PVP moved from the hollow fiber membrane to the aqueous layer in the forced elution test, 1478 ppm was detected per hollow fiber.
Comparative Example 2
Using the hollow fiber formed under the conditions of Example 1, it was modularized in the same manner, and high-pressure steam sterilization was performed without filling with water. The water permeability, clearance in each solute, and albumin permeability were measured. The clearances of urea, creatinine, uric acid, phosphoric acid, and VB12 were 194 ml / min, 183 ml / min, 179 ml / min, 184 ml / min, 140 ml / min, respectively. Water permeability: 718 ml / hr / m2 / mmHg, albumin permeability 1.1%. The water permeability of the hollow fiber after drying is 758 ml / hr / m2/ MmHg, and no performance degradation was observed.
[0037]
Furthermore, when the amount of polyvinyl pyrrolidone in the hollow fiber membrane was measured by elemental analysis, it was 3.2%. The amount of insoluble matter in the hollow fiber after γ-ray irradiation was measured and found to be 7.3%. As a result of examining the concentration of PVP moved from the hollow fiber membrane to the aqueous layer in the forced elution test, 898 ppm was detected per hollow fiber.
[0038]
【The invention's effect】
According to the present invention, it is possible to provide a blood processing dialyzer which is a dry type semipermeable membrane having advantages such as lightness and freezing, and which has a semipermeable membrane with excellent water permeability and dialysis performance. it can.
Claims (6)
（Ａ）透水性能の測定
中空糸両端部を封止したガラス管ミニモジュール（本数３６本：有効長１０ｃｍ）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、透水性能を下記の式で算出する。
（Ｂ）乾燥による性能変化の確認
湿潤剤が付着していない場合、そのまま１００℃で２４時間乾燥し、付着している場合、中空糸１０ｇを１５０ｍｌの純水に浸漬し、２４時間放置する操作を２回繰り返した後、糸束の状態で、１００℃で２４時間乾燥し、その前後での透水性能を測定する。
（Ｃ）強制溶出試験における水層に移動した親水性高分子ポリビニルピロリドン濃度の測定
透析モジュールを血液側から透析液側へ純水１リットルで洗浄し、モジュールから取り出した中空糸１ｇを塩化メチレン１０ｍｌに入れ、３時間攪拌して溶解し（仕込量１０ｗｔ／ｖｏｌ％）、０．１Ｎ−塩化アンモニウム溶液（ｐＨ９．５）１０ｍｌで抽出を行い、そのまま、得られた塩化メチレン−水溶液を超遠心機（２００００ｒｐｍ×１５ｍｉｎ）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する。
この溶液を温度２３℃で東ソーＴＳＫ−ｇｅｌ−ＧＭＰＷＸＬ ２本直列につないだ理論段数（８９００段×２）のカラムを用い、移動相として０．１Ｎ−塩化アンモニウム溶液（ｐＨ９．５）、流量 １．０ｍｌ／ｍｉｎ、サンプル打ち込み量 ０．２ｍｌで分析を行う。９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較正を行い、標品のＰＶＰのピーク面積−濃度検量線を作成し、サンプルのＰＶＰピーク面積から水層（５ｍｌ）に移動したＰＶＰ濃度を求める。ＰＶＰが検出されたサンプルは、回収率（水相への移動量）を標品から求め、その回収率を元に水相のＰＶＰ濃度から中空糸当たりの溶出量を換算して求める。 Measured in a semipermeable membrane comprising hydrophobic polymer and hydrophilic polymer as constituents, where the hydrophobic polymer is polysulfone resin, the hydrophilic polymer is polyvinylpyrrolidone, and no humectant is attached. after drying the water permeability to dry before the water permeability of been semi-permeable membrane is not less 1/2 or more, and state, and are amounts elution 10ppm or less from in the semipermeable membrane of the hydrophilic polymer, the water permeability Is a semipermeable membrane for blood treatment, measured by the following methods (A) to (B), and further, the elution amount is measured by the following method (C) .
(A) Measurement of water permeability
Applying water pressure of 100 mmHg to the inside of the hollow fiber of the glass tube mini module (36 pipes: effective length 10 cm) sealed at both ends of the hollow fiber, measuring the filtration amount per unit time flowing out to the outside, Calculate with the following formula.
(B) Confirmation of performance change due to drying
When the wetting agent is not attached, it is dried as it is at 100 ° C. for 24 hours, and when it is attached, the operation of dipping the hollow fiber 10 g in 150 ml of pure water and leaving it for 24 hours is repeated twice, and then the yarn bundle In this state, it is dried at 100 ° C. for 24 hours, and the water permeability before and after that is measured.
(C) Measurement of the concentration of the hydrophilic polymer polyvinyl pyrrolidone moved to the water layer in the forced dissolution test
The dialysis module was washed from the blood side to the dialysate side with 1 liter of pure water, 1 g of hollow fiber taken out from the module was placed in 10 ml of methylene chloride and dissolved by stirring for 3 hours (feed amount: 10 wt / vol%). Extraction was performed with 10 ml of 1N-ammonium chloride solution (pH 9.5), and the resulting methylene chloride-water solution was separated as it was with an ultracentrifuge (20000 rpm × 15 min), and the aqueous layer was filtered with a filter having a pore size of 0.5 μm. Filter to make the sample solution.
Using a column with the theoretical plate number (8900 plates × 2) in which two Tosoh TSK-gel-GMPWXLs were connected in series at a temperature of 23 ° C., a 0.1N ammonium chloride solution (pH 9.5) as a mobile phase, a flow rate of 1 Analysis is performed at 0.0 ml / min and a sample injection amount of 0.2 ml. Nine types of monodisperse polyethylene glycols are used as the reference substance, molecular weight calibration is performed, a standard PVP peak area-concentration calibration curve is created, and the PVP concentration transferred from the sample PVP peak area to the aqueous layer (5 ml) is determined. . For the sample in which PVP is detected, the recovery rate (transfer amount to the aqueous phase) is determined from the preparation, and the elution amount per hollow fiber is calculated from the PVP concentration of the aqueous phase based on the recovery rate.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36296099A JP4211168B2 (en) | 1999-12-21 | 1999-12-21 | Dialyzer manufacturing method and sterilization method |
| JP36296199A JP4061798B2 (en) | 1999-12-21 | 1999-12-21 | Semipermeable membrane for blood treatment and dialyzer for blood treatment using the same |
| US09/736,373 US6605218B2 (en) | 1999-12-21 | 2000-12-15 | Dialyzers for blood treatment and processes for production thereof |
| TW089127070A TW467750B (en) | 1999-12-21 | 2000-12-18 | The dialyzater for blood treatment and the method of production thereof |
| KR1020000078501A KR100701115B1 (en) | 1999-12-21 | 2000-12-19 | Dialyzers for Blood Treatment and Processes for Production Thereof |
| CA002329103A CA2329103C (en) | 1999-12-21 | 2000-12-20 | Dialyzers for blood treatment and processes for production thereof |
| CNB2004100955019A CN100453126C (en) | 1999-12-21 | 2000-12-20 | Dialyzers for blood treatment and processes for production thereof |
| CNB001355821A CN1240446C (en) | 1999-12-21 | 2000-12-20 | Blood dialyser and manufacture thereof |
| DE60034416T DE60034416T2 (en) | 1999-12-21 | 2000-12-21 | Dialyzers for blood treatment and their manufacturing process |
| AT00311580T ATE359858T1 (en) | 1999-12-21 | 2000-12-21 | DIALYZERS FOR BLOOD TREATMENT AND THEIR PRODUCTION PROCESS |
| EP00311580A EP1110563B1 (en) | 1999-12-21 | 2000-12-21 | Dialyzers for blood treatment and processes for production thereof |
| ES00311580T ES2285998T3 (en) | 1999-12-21 | 2000-12-21 | DIALIZERS FOR THE TREATMENT OF BLOOD AND PROCESSES FOR THE PRODUCTION OF THE SAME. |
| US10/404,099 US6960297B2 (en) | 1999-12-21 | 2003-04-02 | Dialyzers for blood treatment and processes for production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36296199A JP4061798B2 (en) | 1999-12-21 | 1999-12-21 | Semipermeable membrane for blood treatment and dialyzer for blood treatment using the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2001170171A JP2001170171A (en) | 2001-06-26 |
| JP4061798B2 true JP4061798B2 (en) | 2008-03-19 |
Family
ID=18478173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP36296199A Expired - Lifetime JP4061798B2 (en) | 1999-12-21 | 1999-12-21 | Semipermeable membrane for blood treatment and dialyzer for blood treatment using the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4061798B2 (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4683402B2 (en) * | 2001-06-29 | 2011-05-18 | 旭化成クラレメディカル株式会社 | Hollow fiber membrane for blood purification, method for producing the same, and blood purifier |
| JP4678063B2 (en) * | 2001-12-19 | 2011-04-27 | 東レ株式会社 | Hollow fiber membrane module |
| JP4453248B2 (en) * | 2001-12-19 | 2010-04-21 | 東レ株式会社 | Method for producing hollow fiber membrane and hollow fiber membrane module |
| US20050273031A1 (en) * | 2002-08-21 | 2005-12-08 | Tory Industries, Inc. | Modified substrate and process for producing modified substrate |
| JP3594032B1 (en) * | 2003-08-29 | 2004-11-24 | 東洋紡績株式会社 | Highly permeable hollow fiber membrane blood purifier |
| JP3551971B1 (en) * | 2003-11-26 | 2004-08-11 | 東洋紡績株式会社 | Polysulfone permselective hollow fiber membrane |
| JP3580314B1 (en) | 2003-12-09 | 2004-10-20 | 東洋紡績株式会社 | Polysulfone-based selectively permeable hollow fiber membrane bundle and method for producing the same |
| 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 |
| JP4501530B2 (en) * | 2004-05-19 | 2010-07-14 | 東洋紡績株式会社 | Highly permeable hollow fiber membrane blood purifier |
| JP4587024B2 (en) * | 2004-05-20 | 2010-11-24 | 東洋紡績株式会社 | Polysulfone-based selectively permeable hollow fiber membrane with excellent blood compatibility |
| JP4587025B2 (en) * | 2004-06-01 | 2010-11-24 | 東洋紡績株式会社 | Polysulfone-based selectively permeable hollow fiber membrane with excellent blood compatibility |
| JP4288602B2 (en) * | 2004-06-09 | 2009-07-01 | 東洋紡績株式会社 | Polysulfone permselective hollow fiber membrane |
| JP4748350B2 (en) * | 2004-12-27 | 2011-08-17 | 東洋紡績株式会社 | Method for producing polysulfone-based hollow fiber membrane |
| JP4839630B2 (en) * | 2005-02-22 | 2011-12-21 | 東洋紡績株式会社 | Polysulfone-based permselective hollow fiber membrane bundle and blood purifier |
| JP4839631B2 (en) * | 2005-02-22 | 2011-12-21 | 東洋紡績株式会社 | Polysulfone-based permselective hollow fiber membrane bundle and blood purifier |
| JP5028745B2 (en) * | 2005-02-28 | 2012-09-19 | 東レ株式会社 | Method for producing hollow fiber membrane |
| JP4967242B2 (en) * | 2005-02-28 | 2012-07-04 | 東レ株式会社 | Method for producing hollow fiber membrane |
| JP3772909B1 (en) * | 2005-04-04 | 2006-05-10 | 東洋紡績株式会社 | Blood purifier |
| JP4843988B2 (en) * | 2005-04-05 | 2011-12-21 | 東洋紡績株式会社 | Polysulfone hollow fiber membrane blood purifier |
| EP1710011A1 (en) * | 2005-04-07 | 2006-10-11 | Gambro Lundia AB | Filtration membrane |
| JP4876704B2 (en) * | 2006-05-09 | 2012-02-15 | 東洋紡績株式会社 | Blood purifier |
-
1999
- 1999-12-21 JP JP36296199A patent/JP4061798B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001170171A (en) | 2001-06-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4211168B2 (en) | Dialyzer manufacturing method and sterilization method | |
| JP4061798B2 (en) | Semipermeable membrane for blood treatment and dialyzer for blood treatment using the same | |
| JP4453248B2 (en) | Method for producing hollow fiber membrane and hollow fiber membrane module | |
| JP4848663B2 (en) | Method for coating surface modification agent on hollow fiber blood purification membrane, surface modification agent coated hollow fiber blood purification membrane, and surface modification agent coated hollow fiber blood purification device | |
| JP4190079B2 (en) | Hollow fiber membrane for blood purification and hollow fiber membrane artificial kidney | |
| JP4992104B2 (en) | Module for hemofiltration or hemodiafiltration | |
| JP4211169B2 (en) | Dialysis machine for blood treatment | |
| JP3617194B2 (en) | Permselective separation membrane and method for producing the same | |
| EP0750936B1 (en) | Permselective membranes and methods for their production | |
| JP3966481B2 (en) | Semipermeable membrane | |
| JP2003175320A (en) | Method for manufacturing hollow fiber membrane | |
| JP3424810B2 (en) | High performance blood purification membrane | |
| JPH09308685A (en) | Hollow fiber membrane for blood purification and blood purifying device | |
| JP3651121B2 (en) | Permselective separation membrane | |
| JP4003982B2 (en) | Polysulfone-based selectively permeable separation membrane | |
| JP2007054470A (en) | Hollow fiber membrane for blood purification and its manufacturing method | |
| JP3334705B2 (en) | Polysulfone-based selectively permeable hollow fiber membrane | |
| JP2003175321A (en) | Method for manufacturing hollow fiber membrane | |
| JP4678063B2 (en) | Hollow fiber membrane module | |
| JP2894475B2 (en) | Hemodialysis machine using hollow fiber membrane | |
| JP2000210544A (en) | Production of semipermeable membrane | |
| Göhl et al. | PC-PE Hollow-Fiber Membrane: Structure, Performance Characteristics and Manufacturing | |
| JPH10248925A (en) | Selectively transmitting hollow yarn membrane | |
| JP2007260345A (en) | Permselective separation membrane module | |
| KR20010073727A (en) | A polysulfone-based hollow fiber membrance for hemodialysis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20061220 |
|
| A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20070420 |
|
| A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20070516 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070529 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070730 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070904 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20071102 |
|
| 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: 20071204 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20071217 |
|
| R151 | Written notification of patent or utility model registration |
Ref document number: 4061798 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R151 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110111 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120111 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130111 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130111 Year of fee payment: 5 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140111 Year of fee payment: 6 |
|
| EXPY | Cancellation because of completion of term |