JP3684676B2 - Method for producing polysulfone-based hollow fiber artificial kidney and artificial kidney - Google Patents

Description

ただし、式中、ｎは正の整数を表わす。
【００２１】
特に、この中で式（Ｉ）で示される構造を有するアモコ社のＰ−３５００、またはその同等品が好ましい。しかし、原液粘度調整のため、Ｐ−１７００などを混合できることはいうまでもない。
【００２２】
また、親水性高分子とは、ポリビニルピロリドンもしくはポリエチレングリコールなどの親水性に優れた高分子であるが、特にポリビニルピロリドンが好ましい。ポリビニルピロリドンはＢＡＳＦ社、ＧＡＦ社等から市販されている、例えばＫ−３０やＫ−９０等の重量平均分子量３０，０００以上のものが好ましく使用される。
【００２３】
本発明の中空糸型人工腎臓を構成する中空糸膜は上述のポリスルホン樹脂と親水性高分子とを溶媒に溶解して得られる紡糸原液を中心部に注入液を吐出できる環状スリット口金から吐出し、いわゆる乾湿式紡糸法により紡糸される。
【００２４】
溶媒としては、ジメチルアセトアミド、ジメチルスルホキシド、Ｎ−メチルピロリドン、ジメチルホルムアミド等を単独もしくは混合して使用できる。その中でも、ジメチルアセトアミドは素材ポリマの分子量や孔径調節剤として少量添加する水との組合せにより、人工腎臓用として良好な特性の中空糸膜を得ることができ、好ましい溶媒である。
【００２５】
本発明の製造方法の紡糸原液におけるポリスルホン系樹脂の濃度は、好ましくは１４〜２２重量％の範囲、より好ましくは１７〜１９重量％の範囲である。
【００２６】
親水性高分子の濃度は、好ましくは５〜１２重量％の範囲、より好ましくは７〜１０重量％の範囲である。
【００２７】
特に人工腎臓として良好な特性の中空糸膜を、経済性を考慮し高速で紡糸して得るためには、紡糸原液の粘度が重要である。粘度が低い場合、乾式部における糸切れや中空糸の直径のばらつきが大きくなると共に、アルブミンの透過率の制御が困難となり好ましくない。また粘度が高い場合、中空糸の膜厚のばらつきが大きくなると共に尿毒素物質の除去能が低下し好ましくない。
【００２８】
本発明の製造方法の紡糸原液においては、溶媒としてジメチルアセトアミドを用いる場合、３０℃における粘度は２５〜１３０ポイズの範囲（２０℃においては約３５〜１７０ポイズ）が好ましく、４０〜１１０ポイズの範囲がより好ましい。
【００２９】
この粘度の調節は紡糸原液中のポリスルホン樹脂の濃度、分子量、親水性高分子の濃度、分子量で行なうことができるが、最も好ましい方法は親水性高分子の分子量を変えることである。すなわち、例えば、重量平均分子量約４０，０００のポリビニルピロリドン（Ｋ−３０）と分子量約１，１００，０００のポリビニルピロリドン（Ｋ−９０）とを混合し、その混合比を変えることにより所望の粘度とする方法である。
【００３０】
具体的に好ましい例を示すと、ジメチルアセトアミドを溶媒として、アモコ社のポリスルホンＰ−３５００を濃度１８重量％とし、ポリビニルピロリドンの濃度を９重量％とする場合、Ｋ−３０とＫ−９０の混合比は、約９／０〜５／４の範囲、より好ましくは約８／１〜５．５／３．５の範囲となる。
【００３１】
また、本発明の紡糸原液においては、中空糸膜の孔径調節剤として少量の水を添加することが好ましい。最も好ましい溶媒であるジメチルアセトアミドを用いる場合、原液中に含まれる好ましい水の量ｙ（重量％）は、原液の粘度により規定され、次式
−０．０１ｘ＋１．４５≦ｙ≦−０．０１ｘ＋２．２５
を満足する範囲にある場合に良好な特性の中空糸膜を得ることができる。原液中に含まれる水の量ｙ（重量％）が次式
−０．０１ｘ＋１．６５≦ｙ≦−０．０１ｘ＋２．０５
を満足する範囲にある場合、より好ましい。ただし、ｘは紡糸原液の３０℃における粘度（ポイズ）であり、ｘは２５〜１３０ポイズの範囲、好ましくは４０〜１１０ポイズの範囲である。
【００３２】
水の添加が少ない場合は、紡糸原液の長期保管による白濁の生成（ポリスルホンオリゴマーが結晶化し白濁するとみられ、白濁が進むと紡糸中の糸切れの発生がみられるようになり好ましくない。）は押えられるが、細孔径が小さくなり、β_２−ミクログロブリン等の分子量が１０，０００以上の物質の除去能が低下し好ましくない。逆に水の添加が多い場合は、紡糸原液の安定性が不良となり、白濁化が起り、さらに、アルブミンの透過率が高くなりすぎ好ましくない。
【００３３】
さらに本発明の製造方法においては、口金の中心部から注入液を吐出し、中空糸の内表面をその凝固性により制御し、人工腎臓としての良好な特性を有する膜を得る。注入液としては、一般的に、中空糸の内表面から紡糸原液を緩慢に凝固させ、分離膜の緻密な活性層を形成させる目的で使用するため、凝固性が低いものが好ましく、アルコール等の有機溶剤単独、または水との混合液が使用可能である。
【００３４】
特に、本発明では、その回収のし易さや、高い性能を得るため、紡糸原液に使用する溶媒と水との混合溶液が好ましく、最も好ましい溶媒であるジメチルアセトアミドと水との混合溶媒がより好ましい。
【００３５】
このジメチルアセトアミドと水との混合溶媒を用いる場合、本発明の人工腎臓として良好な特性を有する膜を得るためには、注入液に含まれる水の量ｚ（重量％）が原液の粘度により規定され、次式
０．１４ｘ＋２５．５≦ｚ≦０．１４ｘ＋３７．５
を満足する範囲にあることが好ましい。注入液に含まれる水の量ｚ（重量％）が次式
０．１４ｘ＋２８．５≦ｚ≦０．１４ｘ＋３４．５
を満足する範囲にある場合、より好ましい。ただし、ｘは紡糸原液の３０℃における粘度（ポイズ）であり、ｘは２５〜１３０ポイズの範囲、好ましくは４０〜１１０ポイズの範囲である。
【００３６】
さらに、人工腎臓用の中空糸膜として、より良好な特性を有する膜は、原液中の水の量ｙ（重量％）と注入液中の水の量ｚ（重量％）との両者が上記のそれぞれの式を満足することによって得られる。
【００３７】
水の量が少ない場合には、紡糸原液の凝固が遅く内表面からの凝固が遅いため、乾式部での糸切れが起りやすく、また、アルブミン等の蛋白質の透過性が高くなりすぎる傾向もみられる。逆に水の量が多い場合には、β_２−ミクログロブリン等の分子量が大きい物質の除去性能が低下し、さらに水の量が多くなると低分子物質の除去性能も低下し好ましくない。
【００３８】
本発明の中空糸膜は上述のように設定された紡糸原液と注入液を用い、環状スリット型口金から直接凝固浴に導く湿式紡糸法、または口金からの中空糸を一旦気相中にさらした後、凝固浴中に導く乾湿式紡糸法で紡糸される。この際、良好な性能を得るためには、気相中（乾式部）に好ましくは０．１〜１．０秒、より好ましくは０．２〜０．８秒の範囲で走糸させる乾湿式紡糸法が好ましい。
【００３９】
乾式部の条件としては、相対湿度４０％以上が必要であり、好ましくは加湿した相対湿度７０％以上の湿潤気流中に接触させ、より好ましくは相対湿度８０％以上の湿潤気流中に接触させることにより良好な性能を得ることができる。
【００４０】
次に、このようにして口金から紡出された中空糸状の原液は凝固浴に導かれる。凝固浴では、溶媒とは混和するが、ポリスルホン樹脂に対しては凝固能を有する非溶媒である凝固液と接触し、外表面側からの支持層としての粗大孔スポンジ状構造の膜形成を行なう。
【００４１】
凝固液としては、非溶媒単独または２種以上を混合して用いることができるが、溶媒の回収の面から、紡糸原液の溶媒と水との混合溶液が好ましい。
【００４２】
凝固浴を出た中空糸は、水によって洗浄し、大部分の溶媒成分を除去した後、湿潤保持材溶液中に浸漬し、所定の長さに切断、所定の糸本数に集束して、中空糸内部の注入液が上記浸漬時に置換された湿潤保持材溶液を脱液し中空糸束を作成する。
【００４３】
湿潤保持剤としては、グリセリン、エチレングリコール、ポリプロピレングリコール、ポリエチレングリコール等の中空糸束を空気中に放置した場合にも、乾燥を防止できるアルコール類や無機塩の水溶液が使用できるが、特にグリセリンが好ましい。
【００４４】
グリセリンの場合には、乾燥による透過性の劣化を防止するためには、好ましくは５０重量％以上、より好ましくは６０〜７５重量％、さらに好ましくは６５〜７２重量％のグリセリン水溶液が用いられる。
【００４５】
湿潤保持剤水溶液の付着量は、中空糸膜の細孔中に該水溶液が存在する量を測定して抱液率として示す。この抱液率は膜の細孔容積率（空孔率）に容易に換算でき、膜の透析性能は一般に抱液率が高いものほど高くなる。本発明においては、製造工程中において乾燥による空孔率の低下を抑制するため、高い抱液率を保持した状態で製造して、中空糸膜の抱液率が従来のポリスルホン膜に比べ非常に高い、すなわち尿素やビタミンＢ₁₂等のダイアリザンスが高い人工腎臓を提供するものである。
【００４６】
すなわち、中空糸束を人工腎臓用モジュールケースに挿入する工程途中、あるいは製品の中空糸膜の抱液率が３５０〜５００％の範囲、好ましくは３７０〜４６０％の範囲、さらに好ましくは３９０〜４４０％の範囲である。
【００４７】
なお、この抱液率は、製品の場合、水が充填されている場合が多いが、測定途中の乾燥による誤差をなくすため、６８重量％のグリセリン水溶液（比重１．１８）に置換して測定され、抱液率もその重量から算出される。すなわち、中空糸の内側に封入されているグリセリン水溶液を遠心分離器中で１５００ｒｐｍの回転で２０分間脱液し、６０〜９０ｇ程の中空糸束を切出し、６８重量％のグリセリン水溶液が付着した中空糸束の重量Ａと、その中空糸束を水で洗浄してグリセリンを除去した後、１１０℃で乾燥した中空糸のみの重量Ｂを測定し、次式で算出された値である。
抱液率＝（Ａ−Ｂ）／Ｂ×１００（％）
なお、中空糸の周りにスペーサーを導入している場合は、そのスペーサーの重量を除いて、重量Ａ，重量Ｂの測定を行う。
【００４８】
これら湿潤保持材を付与することにより、人工腎臓として組立て加工する際の膜性能の低下を防止できるが、逆に、中空糸同志の密着が起こり、ポリウレタン等のポッティング材による管板形成の際、中空糸の間隙に浸透することが非常に困難となり、シール洩れを起こし、血液側と透析液側との管板による分離ができないという問題が生じる。この解決法としては、中空糸束を人工腎臓用ケースに挿入した後、低湿度の雰囲気中に長期間保管する方法（例えば、相対湿度４０％の室内に３日間程度以上保管）、非常に低湿度の気流をケースの両端部付近に当てた後さらに中空糸束の両端面に垂直方向の強い気流を当てて、糸束端部をばらけるようにする方法（例えば、相対湿度１０％以下の４０〜６０℃の空気を約２時間、ケースの両端部付近に当てた後、垂直方向から空気を強く吹き付けて両端部の中空糸をばらけさせる）などを行なった後、管板形成を行なう方法などがあるが、より好ましい方法は湿潤保持材を付与した後、中空糸束を作成する以前の過程で中空糸同志の密着を防止するためのスペーサーを導入する方法である。
【００４９】
このスペーサーの導入法は人工腎臓として使用する際、透析液が中空糸束の中央（中心）部にまでよく流れ込み、透析性能を高める効果もある一石二鳥の効果がある。このスペーサーの導入は、中空糸１本又は２本の周囲にポリエステル、ポリアミド、ポリアクリロニトリル、セルロースアセテート、絹、綿などの線状物を中空糸に沿うように付加したり、螺旋状に巻回する方法で行なうことができる。
【００５０】
ただし、この方法でシール洩れを完全に防止するためには、直径が中空糸外径の約２分の１程度以上（約１２０ミクロン以上）の太い線状物を使う必要があり、人工腎臓のケースの径が大きくなりあまり好ましい方法ではない。より好ましい方法は次に述べる２段階にスペーサーを導入する方法である。すなわち、１段階目に中空糸１本又は２本の周囲にポリエステル等の線状物を中空糸に沿うように付加する方法、線状物を螺旋状に巻回する方法のいずれかにより単位中空繊維素子を作り、さらに該単位中空繊維素子４本以上を集合させた周囲に２段階目のスペーサーとしての線状物を螺旋状に巻回して中空繊維束を作り、該中空繊維束５束以上を集合して、人工腎臓用の所定の中空糸本数となる中空糸束とする方法である。なお、この場合、単位中空繊維素子の作成は螺旋状に巻回する方法がより好ましい方法である。
【００５１】
この第１、第２段階に導入する線状物は、比較的嵩高性があり、かつ伸縮性がある捲縮繊維、加工糸、紡績糸などが好ましく用いられる。また、その太さはポリスルホン中空糸より細く、中空糸外径の２０分の１程度までであり、中空糸外径の２分の１から１０分の１程度が好ましい。
【００５２】
このスペーサーの導入を行なうことによって、膜の性能の乾燥による劣化を防止できる濃度（量）の湿潤保持材を付与した状態で管板形成が容易となり、これにより本発明の高い水透過性、高い尿毒素物質の除去能を有し、アルブミンの透過率が３％以下に制御された人工腎臓が高い工程収率で得られる。
【００５３】
このようにして得られた中空糸束の人工腎臓への組立て（モジュール化）は通常の方法で行なう。
【００５４】
すなわち、ポリスチレン樹脂等のケースに糸束を挿入し、ポリウレタン等のポッティング材を用い、遠心力を応用してケースの両端部に管板形成を行ない、リークテストを行なって人工腎臓用の形状とする。
【００５５】
次に、中空糸膜内部に残存する微量の溶媒や湿潤保持材などを水洗して除去し、水を充填した状態で滅菌し、製品である人工腎臓とする。この水洗は室温付近の水で行なうこともできるが、５５℃で２時間程度、８０℃で１５分程度の時間を要するため、５５℃以上の加熱水による洗浄が好ましい。また、短時間の洗浄を行なった後、５０℃以上の保温を行ない、その後短時間の洗浄を行なうなどの繰り返し洗浄も可能である。
【００５６】
滅菌は通常の方法、すなわち、９０℃以上の熱水を用いての滅菌や、ガンマー線（γ線）や電子線を用いる放射線による水を充填した状態での滅菌が適用できる。γ線や電子線を用いる放射線による滅菌は、膜中の親水性高分子の架橋による不溶化が起こる場合もあり好ましい方法である。本発明において親水性高分子として最も好ましいポリビニルピロリドンを使用した場合には、約２０ＫＧｙ〜３５ＫＧｙの範囲の線量でγ線を照射すると、ポリビニルピロリドンの架橋による不溶化と同時に、医療器具としての滅菌も同時に行なうことができ、最も実用的な滅菌方法である。
【００５７】
この放射線滅菌によりポリビニルピロリドンの架橋による不溶化を同時に行なうことは、その溶出を押えることができ製品の安全性を高める。また、この方法により、ポリビニルピロリドンを製品の中空糸中に多く含有させることができ、そのため水との親和性が良好な膜となり、本願の高い性能を発現させることができる。なお、ポリビニルピロリドンの架橋による不溶化を行うために、滅菌に先立って別個に放射線照射する方法も可能であることはいうまでもないが、一度の放射線照射で架橋と滅菌を同時に行う方が、高性能の膜を得るために好ましい。
【００５８】
【実施例】
以下、実施例によって具体的に説明するが、本発明がこれによって限定されるものではない。また、本発明の特性の評価は次の方法により行なった。
【００５９】
［水透過性］
γ線滅菌を行なって完成した製品人工腎臓のケースを切断して得られる長さ約１５ｃｍの中空糸３０本を用いて、小型ガラス管モジュールを作成し、膜の外と内の圧力差、すなわち膜間圧力差を約１００ｍｍＨｇで水の透過量を測定し、ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２で表わした。
【００６０】
［尿素およびビタミンＢ₁₂のダイアリザンス］
尿素６０ｇとビタミンＢ₁₂１．２ｇを水６０リットルに溶解し、血液側流量２００ｍｌ／ｍｉｎ、透析液側流量５００ｍｌ／ｍｉｎ、濾過速度を１０ｍｌ／ｍｉｎとして、透析器の血液側入口と出口、透析液側の入口と出口の濃度を測定し、血液側基準と透析液側基準のダイアリザンスをそれぞれ算出し、その平均値を用い、ｍｌ／ｍｉｎで表示した。
【００６１】
［アルブミンの透過率］
ヘマトクリット３０％、蛋白質濃度６ｇ／ｄｌ、３７℃の牛血２ｌをビーカーに入れ、血液側流量２００ｍｌ／ｍｉｎ、膜間圧力差を約１００ｍｍＨｇで１時間循環し、その間に得られる濾液はビーカーに戻す。その後、膜間圧力差を約６０ｍｍＨｇとして、１５分間隔に濾液３本を採取した。牛血を遠心分離して得られた血漿中のアルブミン濃度をＢＣＧ法（和光純薬）で、濾液中のアルブミン濃度をＣＢＢ法（東京化成）で測定し、３本の濾液の平均値からアルブミン透過率を算出した。
【００６２】
［β_２−ミクログロブリンの除去率］
体重５０ｋｇ〜６０ｋｇで、かつ、透析前のβ_２−ミクログロブリンが２５〜３５ｍｇ／ｌの６名の患者さんで、ヘパリンを抗凝固剤として、血液側流量２００ｍｌ／ｍｉｎ、透析液側流量５００ｍｌ／ｍｉｎ、４時間で除水量２．５〜３．５ｌの血液透析を行ない、透析前後のβ_２−ミクログロブリン濃度をラテックス凝集免疫法で測定し、蛋白質濃度の補正を行ない算出し、平均値を用いる。
【００６３】
［紡糸原液粘度］Ｂ型粘度計（トキメック（株）ＤＶ−ＢII形ディジタル粘度計）を用い、容器内径の影響を受けないよう３００ｍｌ以上の紡糸原液を採取して測定した。
【００６４】
実施例１
ポリスルホン（アモコ社製“Ｐ−３５００”）１８部（以下単に「部」という場合は「重量部」を意味する）とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−３０”；分子量約４０，０００）６部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−９０”；分子量約１，１００，０００）３部とを、ジメチルアセトアミド７１．９５部と水１．０５部との混合溶液に加えて、８０℃に保温しながら１２時間撹拌して溶解し、紡糸原液を調製した。この紡糸原液は３０℃で７６．９ポイズ（２０℃で１１３．１ポイズ）の均一で、わずかに乳白色を帯びた澄明液であった。
【００６５】
この紡糸原液を３０℃で環状スリット口金から吐出し、口金の中心部からジメチルアセトアミド６０部と水４０部とを混合して調製した注入液を注入した。乾式部分の長さを２５０ｍｍとし、その部分に相対湿度８８％の湿潤空気を流しながら紡糸速度４０ｍ／ｍｉｎで紡糸し、４０℃の凝固浴（ジメチルアセトアミド／水（重量比）＝２０／８０）に導き、凝固浴出の中空糸を洗浄後、６８重量％のグリセリンを含む水溶液に浸漬した。表面に付着した過剰のグリセリンを取り除いた後、中空糸２本の回りに５０デニール５フイラメント（約８８ミクロン）のポリエステル仮撚り加工糸を、中空糸１０ｍｍに対し０．５回の巻数でＺ方向に螺旋巻回して単位中空繊維素子とし、この単位中空繊維素子を２４単位集合し、その回りに同じポリエステル加工糸をほぼ同じピッチでＳ方向に螺旋巻回して２層にスペーサーを入れ、中空繊維束を作った。該中空繊維束を２２１束集合し、中空糸束を作成した。この中空糸束を遠心分離器中で回転させ中空糸内部の注入液と置換されて封入されているグリセリン水溶液を脱液し、人工腎臓用ケースに挿入するための中空糸束とした。この中空糸の内径は２００ミクロン、外径２８０ミクロンであり、この中空糸束は中空糸１０，６０８本を集合したものであった。この中空糸束の抱液率は４２０％であった。
【００６６】
この中空糸束を内径４０ｍｍの人工腎臓用ケースに挿入し、両端部に仮のキャップをつけて、回転遠心力の場で、透析液側流入口からポリウレタンを流し込み、しかるのちポリウレタンを固化させた。次いで仮のキャップをはずし、ケースの両端部からはみだしているポリウレタンおよび中空糸束の端部近傍を切断し、ヘッダーキャップを取付け、０．８ｋｇ／ｃｍ^２の加圧空気を用いて漏洩試験を行なった。
【００６７】
１０００本のサンプルを用いて漏洩試験を行なった結果、１２本の不良品が発生していた。その原因を調査したところ、ケースに中空糸束を充填する際にケースの端部や内壁に接触したことによる単純作業ミスによる折れ糸、切れ糸に起因するものであり、ポリウレタン管板部のシール洩れは全くみられなかった。
【００６８】
次に、漏洩試験に合格したモジュールを８０℃で３０分間逆浸透膜を通した純水で洗浄し、包装した後、３２ＫＧｙのγ線を照射し滅菌し、有効長１９５ｍｍ、有効面積１．３ｍ^２の人工腎臓透析器を作成した。この透析器は透析型人工腎臓装置承認基準に全ての項目で合格するものであった。このモジュールから切出した中空糸の水透過性は８１５ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２、モジュールのアルブミンの透過率は１．２％、尿素のダイアリザンスは１９５ｍｌ／ｍｉｎ、ビタミンＢ₁₂のダイアリザンスは１４３ｍｌ／ｍｉｎであった。
【００６９】
また、このモジュールを使用して臨床評価した際のβ_２−ミクログロブリンの除去率は７３％と非常に高い結果であり、残血等の使用上特に問題となる点はみられなかった。なお、このモジュールから切出した中空糸束の抱液率は４２０％であった。
【００７０】
実施例２
ポリスルホン（アモコ社製“Ｐ−３５００”）１８部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−３０”）９部とを、ジメチルアセトアミド７１．６部と水１．４０部との混合溶液に加えて、９０℃に保温しながら１２時間撹拌して溶解し、紡糸原液を調製した。この紡糸原液は３０℃で２８．４ポイズ（２０℃で３８．８ポイズ）であった。
【００７１】
この紡糸原液を３０℃で環状スリット口金から吐出し、口金の中心部からジメチルアセトアミド６５部と水３５部とを混合して調製した注入液を注入した。乾式部分の長さを３５０ｍｍとし、その部分で相対湿度８４％の湿潤空気に当てながら紡糸速度４０ｍ／ｍｉｎで紡糸し、以下部分を除き実施例１と同様の方法で人工腎臓透析器を作成した。この途中で１０００本のサンプルを用いて漏洩試験を行なった結果、１７本の不良品が発生したが、その原因は実施例１と同じであった。なお、この中空糸束の抱液率は３８０％であった。
【００７２】
このようにして得られた有効面積１．３ｍ^２の透析器は透析型人工腎臓装置承認基準に全ての項目で合格した。この透析器から切出した中空糸の水透過性は７１０ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２であり、モジュールのアルブミン透過率は０．４％、尿素およびビタミンＢ₁₂のダイアリザンスはそれぞれ１９４ｍｌ／ｍｉｎ、１３９ｍｌ／ｍｉｎであった。また、このモジュールを使用して臨床評価を行なった際のβ_２−ミクログロブリンの除去率は６７％であり、残血等の使用上特に問題となる点はみられなかった。なお、このモジュールから切出した中空糸束の抱液率は３８０％であった。
【００７３】
実施例３
ポリスルホン（アモコ社製“Ｐ−３５００”）１８部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−３０”）９部とを，ジメチルアセトアミド７１．８部と水１．２部との混合溶液に加えて、８０℃に保温しながら１２時間撹拌して溶解し、紡糸原液を調製した。この紡糸原液は３０℃で２６．８ポイズであった。以下、注入液組成をジメチルアセトアミド６０部と水４０部と混合した注入液を用いた以外は実施例１と同様の方法で人工腎臓透析器を作成した。なお、ここで用いた中空糸束の抱液率は３５０％であった。
【００７４】
この透析器から切出した中空糸の水透過性は７４０ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２であり、モジュールのアルブミン透過率は０．１％、尿素およびビタミンＢ₁₂のダイアリザンスはそれぞれ１９２ｍｌ／ｍｉｎ、１３６ｍｌ／ｍｉｎであった。また、このモジュールを使用して臨床評価を行なった際のβ_２−ミクログロブリンの除去率は６２％であり、残血等の使用上特に問題となる点はみられなかった。なお、この透析器の中空糸の抱液率は３６０％であった。
【００７５】
実施例４
実施例１の途中段階の中空繊維束をそれぞれ１７０束および３０６束集合して中空糸束を作成し、そのそれぞれを内径３５．５ｍｍおよび４６．５ｍｍの人工腎臓用ケースに挿入し、実施例１と同じ方法で人工腎臓透析器を作製した。
【００７６】
それぞれの有効面積は１．０ｍ^２と１．８ｍ^２であり、ビタミンＢ₁₂のダイアリザンスを測定したところ１２７ｍｌ／ｍｉｎと１６５ｍｌ／ｍｉｎであった。
実施例５
実施例３の途中段階の中空糸束を用いて、集合本数を変えて中空糸束を作り、それぞれを内径３５．５ｍｍ、４４．０ｍｍおよび４６．５ｍｍの人工腎臓用ケースに挿入して、それぞれの有効面積が１．０ｍ^２、１．６ｍ^２および１．８ｍ^２の人工腎臓透析器を実施例３と同様の方法で作成した。
【００７７】
尿素およびビタミンＢ₁₂のダイアリザンスならびにアルブミンの透過率を測定したところ、尿素のダイアリザンスはそれぞれ１８７ｍｌ／ｍｉｎ、１９５ｍｌ／ｍｉｎおよび１９７ｍｌ／ｍｉｎ、ビタミンＢ₁₂のダイアリザンスはそれぞれ１２２ｍｌ／ｍｉｎ、１４７ｍｌ／ｍｉｎおよび１５６ｍｌ／ｍｉｎ、アルブミンの透過率はそれぞれ０．２％、０．１％および０．２％であった。
【００７８】
実施例６
ポリスルホン（アモコ社製“Ｐ−３５００”）１８部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−３０”）６部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−９０”）３部とを、ジメチルアセトアミド７１．８５部と水１．１５部との混合溶液に加えて、９０℃に保温しながら１２時間撹拌して溶解し、紡糸原液を調製した。この紡糸原液は３０℃で７１．４ポイズであった。
【００７９】
この紡糸原液を４０℃で環状スリット口金から吐出し、口金の中心部からジメチルアセトアミド５８部と水４２部とを混合して調製した注入液を注入した。乾式部分の長さを３５０ｍｍとし、その部分に相対湿度８５％の湿潤空気を流しながら紡糸速度４２ｍ／ｍｉｎで４５℃の凝固浴に導き、以下実施例１と同様の方法で人工腎臓透析器を作製した。なお、途中段階の人工腎臓用ケースに挿入する時点での中空糸束の抱液率は４１０％であった。
【００８０】
このようにして得られた有効面積１．３ｍ^２の透析器から切り出した中空糸の水透過性は８１０ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２であり、アルブミン透過率は０．６％、尿素およびビタミンＢ₁₂のダイアリザンスはそれぞれ１９５ｍｌ／ｍｉｎ、１４２ｍｌ／ｍｉｎであった。また、このモジュールを使用して臨床評価を行なった際のβ_２−ミクログロブリンの除去率は７４％であり、残血等の使用上特に問題となる点はみられなかった。なお、このモジュールの中空糸の抱液率は４２０％であった。
【００８１】
実施例７
実施例６の原液を用いて、ジメチルアセトアミド５６部と水４４部とを混合して調整した注入液を用いる以外は、実施例６と同様の方法で人工腎臓透析器を作製した。なお、途中段階の中空糸束の抱液率は４００％であった。
【００８２】
このようにして得られた有効面積１．３ｍ^２の透析器から切り出した中空糸の水透過性は７６０ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２であり、アルブミン透過率は０．２％、尿素およびビタミンＢ₁₂のダイアリザンスはそれぞれ１９４ｍｌ／ｍｉｎ、１４０ｍｌ／ｍｉｎであった。また、このモジュールを使用して臨床評価を行なった際のβ_２−ミクログロブリンの除去率は７１％であり、残血等の使用上特に問題となる点はみられなかった。なお、このモジュールの中空糸の抱液率は４１０％であった。
【００８３】
実施例８
ポリスルホン（アモコ社製“Ｐ−３５００”）１８部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−３０”）７部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−９０”）２部とを、ジメチルアセトアミド７１．８５部と水１．１５部との混合溶液に加えて、９０℃に保温しながら１２時間撹拌して溶解し、紡糸原液を調製した。この紡糸原液は３０℃で５３．０ポイズであった。
【００８４】
この紡糸原液を４０℃で環状スリット口金から吐出し、口金の中心部からジメチルアセトアミド６０部と水４０部とを混合して調製した注入液を注入し、以下実施例６と同様の方法で人工腎臓透析器を作製した。なお、途中段階の中空糸束の抱液率は３９０％であった。
【００８５】
このようにして得られた有効面積１．３ｍ^２の透析器から切り出した中空糸の水透過性は６８０ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２であり、アルブミン透過率は０．３％、尿素およびビタミンＢ₁₂のダイアリザンスはそれぞれ１９３ｍｌ／ｍｉｎ、１４０ｍｌ／ｍｉｎであった。
【００８６】
比較例１
ポリスルホン（アモコ社製“Ｐ−３５００”）１８部とポリビニルピロリドン（ＢＡＳＦ社製“Ｋ−３０”）９部とを、ジメチルアセトアミド４４部とジメチルスルホキシド２８部と水１．０部との混合溶液に加えて、８０℃に保温しながら１５時間撹拌して溶解し、紡糸原液を調製した。この紡糸原液は３０℃で３２．９ポイズであった。この紡糸原液を３０℃で環状スリット口金から吐出し、口金の中心部からジメチルアセトアミド６０部と水４０部とを混合した注入液を注入した。以下、実施例１と同様の方法で人工腎臓透析器を作成した。
【００８７】
この透析器から切出した中空糸の水透過性は８３０ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２であり、モジュールのアルブミン透過率は０．２％、ビタミンＢ₁₂のダイアリザンスは１３２ｍｌ／ｍｉｎであった。また、このモジュールを使用して臨床評価を行なった際のβ_２−ミクログロブリンの除去率は４９％と低い値であった。なお、この透析器の中空糸の抱液率は３４０％であった。
【００８８】
比較例２
実施例１の凝固浴出の中空糸を洗浄後、４５重量％のグリセリンを含む水溶液に浸漬した。表面に付着した過剰のグリセリンを取り除いた後、一辺が３０ｃｍの６角形のかせに巻取り、室温で通風乾燥した後、かせから切出して中空糸束を作製した。この中空糸束の抱液率は２７０％であった。この中空糸束は中空糸１０，６０８本を集合したものである。中空糸束を内径４０ｍｍの人工腎臓用ケースに挿入し、中空糸束の両端面に垂直方向の乾燥空気を当てて糸束端部をばらけさせた後、実施例１と同様の方法で管板形成を行ない、透析液側から加圧空気を入れ、血液側に水を満たしてのバブルポイント法による漏洩試験を行なった後、実施例１と同様の方法でγ線滅菌を行なって人工腎臓透析器を作製した。
【００８９】
このモジュールから切出した中空糸の水透過性は４１０ｍｌ／ｈｒ・ｍｍＨｇ・ｍ^２、アルブミン透過率は０．３％、尿素のダイアリザンスは１９０ｍｌ／ｍｉｎ、ビタミンＢ₁₂のダイアリザンスは１２５ｍｌ／ｍｉｎと低い値となった。すなわち、低濃度のグリセリン付加の場合にはスペーサーなしでの管板形成が容易であるが、乾燥による中空糸の透過性の劣化が起り、本発明のような高い性能の人工腎臓の製造は困難であった。なお、この透析器の中空糸の抱液率は３００％であった。
【００９０】
【発明の効果】
本発明によれば、水透過性が高く、尿毒物質の除去性能が高く、かつ適度のアルブミン透過性がある人工腎臓を、中空糸紡糸時に得られた膜の良好な特性を保持して安定に、かつ容易に製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an artificial kidney used for hemodialysis and hemofiltration therapy for prolonging the life of patients such as renal failure and a method for producing the same.
[0002]
[Prior art]
Separation membranes made of polysulfone resins are widely used due to their good mechanical properties and heat resistance.
[0003]
In the field of artificial kidneys, it is described in Japanese Patent Publication No. 5-54373, Japanese Patent Application Laid-Open No. 6-238139, and Japanese Patent Application Laid-Open No. 4-300636 that it has an excellent ability to remove uremic substances.
[0004]
However, as the number of long-term dialysis patients increases, dialysis techniques are diversified and higher performance is required for artificial kidneys. That is, extremely high water permeability is required in online filtration dialysis and push-pull filtration dialysis, and in normal hemodialysis, β₂-High removal ability of substances having a molecular weight of 10,000 or more such as microglobulin is required. In the past, albumin, which is a useful protein in blood, has been permeated as much as possible. However, it has been found that harmful substances accumulated in dialysis patients are strongly bound to albumin. Membranes that permeate the body are also required, and many improvements in symptoms by artificial kidneys using such membranes have been reported.
[0005]
However, an artificial kidney that satisfies all these requirements has not yet been obtained. For example, although the polysulfone membrane disclosed in Japanese Patent Publication No. 5-54373 is good as an artificial kidney, the water permeability required for the filtration dialysis described above and the ability to remove low-molecular substances in hemodialysis are just one step away. is there. The polysulfone membrane disclosed in JP-A-4-300366 has sufficient water permeability, but it is a urea substance, especially β₂-The ability to remove substances with large molecular weight such as microglobulin is just one step away. Further, when the obtained hollow fiber membrane is produced as an artificial kidney, when potting is performed in the presence of a wet retaining material (eg glycerin) that is imparted in order to maintain water permeability, due to the close contact between the hollow fibers, polyurethane or the like There is a major problem in production such that the potting material is difficult to penetrate into the gap between the hollow fibers and causes seal leakage.
[0006]
[Problems to be solved by the invention]
The present invention eliminates the problems of the prior art, has a high water permeability, a high uremic substance removal performance, and an artificial kidney having an appropriate albumin permeability. The present invention provides a method for stably and easily producing while maintaining the characteristics.
[0007]
[Means for Solving the Problems]
  The method for producing a polysulfone-based hollow fiber artificial kidney of the present invention comprises a spinning dope containing a polysulfone-based resin and a hydrophilic polymer.In addition,A hollow fiber spun using an organic solvent or a mixed liquid of an organic solvent and water as an injection solution is impregnated with a wet retaining material, and a hollow fiber bundle is prepared in a state where a wet retaining material aqueous solution is adhered. Insert the thread bundle into the module case for the artificial kidney, create the tube sheet, create an intermediate product, wash the wet retaining material with water, and then sterilize itInsideManufacturing method of empty fiber type artificial kidneyIn order to remove the wet retaining material, after heating with heated water at 55 ° C. or higher, gamma rays are irradiated at a dose in the range of 20 KGy or more and 35 KGy or less in a state filled with water, and the hydrophilic polymer is applied. The present invention relates to a method for producing a polysulfone-based hollow fiber artificial kidney, which is crosslinked and insolubilized..
[0008]
  The albumin permeability is 0.3% or more and 2.0% or less, and the membrane area is 1.3 m. ² Vitamin B in the module of ¹² A polysulfone-based hollow fiber artificial kidney characterized by having a dialysance of 140 or more.
[0009]
  Also,Membrane area 1.3m ² Β in clinical use in hemodialysis mode in the module ₂ The microglobulin removal rate is 60% or more (1) Or (2) To the polysulfone-based hollow fiber artificial kidney described in 1..
[0010]
  Also,Membrane area 1.3m ² Β in clinical use in hemodialysis mode in the module ₂ -The microglobulin removal rate is 70% or more. (1) Or (2) To the polysulfone-based hollow fiber artificial kidney described in 1..
[0011]
DETAILED DESCRIPTION OF THE INVENTION
For details, use a hollow fiber having good characteristics for an artificial kidney obtained by spinning under the conditions of a specific dry section using a specific spinning solution and injection solution described later, and without deteriorating the characteristics. Hold it to make an artificial kidney module. For this purpose, a sufficient amount of wet retaining material is applied to the hollow fiber to assemble the module, and after removing the wet retaining material, the product is filled with water. At this time, if a hollow fiber bundle is created with a wet retaining material applied to the hollow fiber, the hollow fibers are in close contact with each other, making it difficult to form a tube plate with a potting material. This is a more preferable method.
[0012]
That is, a hollow fiber bundle is prepared with a sufficient amount of wet retaining material applied to the hollow fiber, tube tube formation is performed, the wet retaining material is washed with water, and then sterilized. The polysulfone-based hollow fiber artificial kidney produced and obtained by the above method has an albumin permeability of 3.0% or less and a membrane area of 1.3 m.²Vitamin B in the module of₁₂The dialysance is 135 or more.
[0013]
Furthermore, in this production method, by adopting the preferable conditions described in the present application, the albumin permeability is 0.1% or more and 2.4% or less, and vitamin B₁₂The artificial kidney is characterized by having a dialysance of 137 or more, and under a more preferable combination of conditions, the albumin permeability is 0.3% or more and 2.0% or less, and vitamin B₁₂An artificial kidney characterized by having a dialysance of 140 or more can be obtained.
[0014]
In the production method of the present invention, an artificial kidney having a urea dialysance of 191 or more can be obtained by adopting preferred production conditions. By adopting a more preferred production condition, the urea dialysance is 192. The above artificial kidney can be obtained, and by adopting more preferable production conditions, an artificial kidney having urea dialysance of 193 or more can be obtained.
[0015]
According to the method of the present invention, the water permeability of the hollow fiber is 500 ml / hr · mmHg · m.²The above artificial kidney can be obtained, and by adopting more preferable production conditions, the water permeability of the hollow fiber is 600 ml / hr · mmHg · m.²The above artificial kidney can also be obtained. The water permeability of the hollow fiber membrane obtained with the best clinical evaluation result obtained by the method of the present invention is 800 ml / hr · mmHg · m.²That was all.
[0016]
In order to obtain good symptom improvement by hemodialysis, the albumin permeability (screening coefficient expressed in%) is preferably 0.6% or more, and the upper limit is the limit of protein loss (4-6 grams / time) From about 2.0 to 3.0%. That is, in a preferred embodiment of the present invention, the albumin permeability is 0.6% or more and 2.0% or less, and low molecular weight uremic toxin components such as urea and creatine, and β₂-Providing an artificial kidney with higher removal performance of high-molecular-weight uremic toxin components such as microglobulin compared to conventional products.
[0017]
Furthermore, blood filtration and hemofiltration dialysis have high water permeability and uremic toxin component removal performance, and the albumin permeability is preferably 0.1% or more and 1.0% or less, although it varies depending on the treatment method. The present invention also provides an artificial kidney having albumin permeability of 1.0% or less and higher uremic toxin component removal performance and water permeability than conventional products.
[0018]
In addition, β in clinical evaluation₂-Microglobulin removal rate and vitamin B₁₂There is a positive correlation with the dialysance of vitamin B₁₂The dialyzance is the best indicator of membrane performance.
[0019]
The polysulfone-based hollow fiber artificial kidney of the present invention is composed of a hollow fiber membrane made of a polysulfone resin containing a hydrophilic polymer.
[0020]
Examples of the polysulfone resin include those represented by the formula (I) or the formula (II) commercially available from Amoco, BASF or ICI.
[Chemical 1]

In the formula, n represents a positive integer.
[0021]
In particular, Amoco P-3500 having the structure represented by the formula (I) or an equivalent thereof is preferred. However, it goes without saying that P-1700 and the like can be mixed for adjusting the viscosity of the stock solution.
[0022]
The hydrophilic polymer is a polymer having excellent hydrophilicity such as polyvinyl pyrrolidone or polyethylene glycol, and polyvinyl pyrrolidone is particularly preferable. As the polyvinyl pyrrolidone, those having a weight average molecular weight of 30,000 or more, such as K-30 and K-90, which are commercially available from BASF and GAF are preferably used.
[0023]
The hollow fiber membrane constituting the hollow fiber type artificial kidney of the present invention is discharged from an annular slit base capable of discharging an injection solution at the center of a spinning stock solution obtained by dissolving the above-mentioned polysulfone resin and hydrophilic polymer in a solvent. The fiber is spun by a so-called dry and wet spinning method.
[0024]
As the solvent, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide and the like can be used alone or in combination. Among them, dimethylacetamide is a preferable solvent because it can obtain a hollow fiber membrane having good characteristics for an artificial kidney by combining with water added in a small amount as a molecular weight or pore size regulator of the raw material polymer.
[0025]
The concentration of the polysulfone resin in the spinning dope of the production method of the present invention is preferably in the range of 14 to 22% by weight, more preferably in the range of 17 to 19% by weight.
[0026]
The concentration of the hydrophilic polymer is preferably in the range of 5 to 12% by weight, more preferably in the range of 7 to 10% by weight.
[0027]
In particular, in order to obtain a hollow fiber membrane having good characteristics as an artificial kidney by spinning at high speed in consideration of economy, the viscosity of the spinning dope is important. When the viscosity is low, the yarn breakage in the dry part and the variation in the diameter of the hollow fiber become large, and it becomes difficult to control the albumin permeability, which is not preferable. On the other hand, when the viscosity is high, the variation in the film thickness of the hollow fiber is increased, and the ability to remove the uremic toxin is lowered, which is not preferable.
[0028]
In the spinning dope for the production method of the present invention, when dimethylacetamide is used as the solvent, the viscosity at 30 ° C is preferably in the range of 25 to 130 poise (about 35 to 170 poise at 20 ° C), and in the range of 40 to 110 poise. Is more preferable.
[0029]
The viscosity can be adjusted by adjusting the polysulfone resin concentration, molecular weight, hydrophilic polymer concentration and molecular weight in the spinning dope. The most preferable method is to change the molecular weight of the hydrophilic polymer. That is, for example, polyvinyl pyrrolidone (K-30) having a weight average molecular weight of about 40,000 and polyvinyl pyrrolidone (K-90) having a molecular weight of about 1,100,000 are mixed, and a desired viscosity is changed by changing the mixing ratio. It is a method.
[0030]
Specifically, when dimethylacetamide is used as a solvent, Amoco's polysulfone P-3500 has a concentration of 18% by weight, and polyvinylpyrrolidone has a concentration of 9% by weight, a mixture of K-30 and K-90. The ratio will be in the range of about 9/0 to 5/4, more preferably in the range of about 8/1 to 5.5 / 3.5.
[0031]
Moreover, in the spinning dope of the present invention, it is preferable to add a small amount of water as a pore size regulator of the hollow fiber membrane. When dimethylacetamide, which is the most preferred solvent, is used, the preferred amount y (% by weight) of water contained in the stock solution is defined by the viscosity of the stock solution,
−0.01x + 1.45 ≦ y ≦ −0.01x + 2.25
In the range satisfying the above, a hollow fiber membrane having good characteristics can be obtained. The amount y (wt%) of water contained in the stock solution is
−0.01x + 1.65 ≦ y ≦ −0.01x + 2.05
Is more preferable. Where x is the viscosity (poise) of the spinning dope at 30 ° C., and x is in the range of 25 to 130 poise, preferably in the range of 40 to 110 poise.
[0032]
When the amount of water added is small, the formation of white turbidity due to long-term storage of the spinning stock solution (polysulfone oligomers are crystallized and become white turbid, and when white turbidity progresses, yarn breakage during spinning is observed, which is not preferable). Although it is held down, the pore diameter becomes smaller and β₂-It is not preferable because the ability to remove substances having a molecular weight of 10,000 or more such as microglobulin is reduced. On the other hand, when the amount of water added is large, the stability of the spinning dope becomes poor, white turbidity occurs, and the albumin permeability becomes too high, which is not preferable.
[0033]
Furthermore, in the production method of the present invention, the injection solution is discharged from the center of the die, and the inner surface of the hollow fiber is controlled by its coagulation property to obtain a membrane having good characteristics as an artificial kidney. In general, the injection solution is preferably used for the purpose of slowly solidifying the spinning solution from the inner surface of the hollow fiber to form a dense active layer of the separation membrane. An organic solvent alone or a mixed solution with water can be used.
[0034]
In particular, in the present invention, a mixed solution of a solvent and water used for the spinning stock solution is preferable, and a mixed solvent of dimethylacetamide and water, which is the most preferable solvent, is more preferable in order to easily collect and obtain high performance. .
[0035]
When this mixed solvent of dimethylacetamide and water is used, in order to obtain a membrane having good characteristics as the artificial kidney of the present invention, the amount z (% by weight) of water contained in the injection solution is defined by the viscosity of the stock solution. And the following formula
0.14x + 25.5 ≦ z ≦ 0.14x + 37.5
It is preferable that it is in a range satisfying. The amount of water (% by weight) contained in the injection solution is
0.14x + 28.5 ≦ z ≦ 0.14x + 34.5
Is more preferable. Where x is the viscosity (poise) of the spinning dope at 30 ° C., and x is in the range of 25 to 130 poise, preferably in the range of 40 to 110 poise.
[0036]
Furthermore, as a hollow fiber membrane for an artificial kidney, a membrane having better characteristics is obtained when both the amount y (wt%) of water in the stock solution and the amount z (wt%) of water in the infusion solution are as described above. It is obtained by satisfying each formula.
[0037]
When the amount of water is small, solidification of the spinning stock solution is slow and solidification from the inner surface is slow, so yarn breakage tends to occur in the dry part, and there is also a tendency that the permeability of proteins such as albumin becomes too high. . Conversely, if the amount of water is large, β₂-The removal performance of a substance having a large molecular weight such as microglobulin is lowered, and if the amount of water is increased, the removal performance of a low molecular weight substance is also lowered.
[0038]
The hollow fiber membrane of the present invention uses the spinning stock solution and the injection solution set as described above, and wet spinning method that directly leads to the coagulation bath from the annular slit die or the hollow fiber from the die is once exposed to the gas phase. Thereafter, spinning is performed by a dry and wet spinning method that leads to a coagulation bath. In this case, in order to obtain good performance, the wet and dry running is preferably performed in the gas phase (dry part) for 0.1 to 1.0 seconds, more preferably 0.2 to 0.8 seconds. A spinning method is preferred.
[0039]
The dry part must have a relative humidity of 40% or higher, preferably in a humidified airflow with a relative humidity of 70% or higher, and more preferably in a wet airflow with a relative humidity of 80% or higher. Better performance can be obtained.
[0040]
Next, the hollow fiber stock solution spun from the die in this way is guided to a coagulation bath. In the coagulation bath, it is miscible with the solvent, but the polysulfone resin is contacted with a coagulation liquid which is a non-solvent having coagulation ability, and a film having a coarse pore sponge structure is formed as a support layer from the outer surface side. .
[0041]
As the coagulation liquid, a non-solvent alone or a mixture of two or more kinds can be used. From the viewpoint of solvent recovery, a mixed solution of a solvent for spinning and water is preferable.
[0042]
The hollow fiber that has exited the coagulation bath is washed with water to remove most of the solvent components, then immersed in a wet holding material solution, cut into a predetermined length, converged to a predetermined number of yarns, and hollow. The wet holding material solution in which the injection solution inside the yarn is replaced during the dipping is drained to form a hollow fiber bundle.
[0043]
As the wet retention agent, an aqueous solution of alcohols or inorganic salts that can prevent drying even when a hollow fiber bundle such as glycerin, ethylene glycol, polypropylene glycol, polyethylene glycol or the like is left in the air can be used. preferable.
[0044]
In the case of glycerin, an aqueous glycerin solution of preferably 50% by weight or more, more preferably 60 to 75% by weight, and still more preferably 65 to 72% by weight is used in order to prevent deterioration of permeability due to drying.
[0045]
The adhesion amount of the wet retention agent aqueous solution is shown as a liquid retention rate by measuring the amount of the aqueous solution present in the pores of the hollow fiber membrane. This liquid retention rate can be easily converted into the pore volume ratio (porosity) of the membrane, and the dialysis performance of the membrane generally increases as the liquid retention rate increases. In the present invention, in order to suppress a decrease in porosity due to drying during the production process, it is produced while maintaining a high liquid retention rate, and the liquid fiber retention rate of the hollow fiber membrane is much higher than that of a conventional polysulfone membrane. High, ie urea or vitamin B₁₂It is intended to provide an artificial kidney with high dialysance.
[0046]
That is, during the process of inserting the hollow fiber bundle into the artificial kidney module case, or the liquid hollow fiber membrane of the product is in the range of 350 to 500%, preferably in the range of 370 to 460%, more preferably 390 to 440. % Range.
[0047]
This liquid retention rate is often filled with water in the case of products, but in order to eliminate errors due to drying during measurement, it is measured by substituting it with a 68 wt% glycerin aqueous solution (specific gravity 1.18). The liquid retention rate is also calculated from the weight. That is, the aqueous glycerin solution enclosed inside the hollow fiber was dehydrated in a centrifuge for 20 minutes at a rotation of 1500 rpm, a hollow fiber bundle of about 60 to 90 g was cut out, and a hollow with a 68% by weight aqueous glycerin solution attached thereto. The weight A of the yarn bundle and the weight B of only the hollow fiber dried at 110 ° C. after washing the hollow fiber bundle with water to remove glycerin, were calculated by the following formula.
Liquid retention rate = (A−B) / B × 100 (%)
In addition, when the spacer is introduce | transduced around the hollow fiber, the weight A and the weight B are measured except the weight of the spacer.
[0048]
By applying these wet retention materials, it is possible to prevent deterioration in membrane performance when assembling and processing as an artificial kidney, but conversely, close contact between hollow fibers occurs, and when forming a tube sheet with a potting material such as polyurethane, It becomes very difficult to penetrate into the gaps of the hollow fibers, causing seal leakage and causing a problem that the blood plate and the dialysate side cannot be separated by the tube plate. As this solution, after inserting the hollow fiber bundle into the artificial kidney case, it is stored for a long time in an atmosphere of low humidity (for example, stored in a room with a relative humidity of 40% for about 3 days or more). A method in which a strong airflow in the vertical direction is applied to both end surfaces of the hollow fiber bundle after the airflow of humidity is applied to both ends of the case so that the ends of the yarn bundle are separated (for example, a relative humidity of 10% or less After applying air at 40 to 60 ° C. to the vicinity of both ends of the case for about 2 hours, the air is strongly blown from the vertical direction to disperse the hollow fibers at both ends, and the tube sheet is formed. Although there is a method, a more preferable method is a method of introducing a spacer for preventing the close contact between the hollow fibers in the process before forming the hollow fiber bundle after applying the wet holding material.
[0049]
When this spacer is introduced as an artificial kidney, the dialysate flows well into the center (center) of the hollow fiber bundle, and has the effect of two birds with one stone, which has the effect of improving dialysis performance. This spacer can be introduced by adding a linear object such as polyester, polyamide, polyacrylonitrile, cellulose acetate, silk, cotton or the like around one or two hollow fibers along the hollow fiber, or winding it in a spiral shape. It can be done by the method.
[0050]
However, in order to completely prevent seal leakage by this method, it is necessary to use a thick linear object having a diameter of about one half or more (about 120 microns or more) of the outer diameter of the hollow fiber. This is not a preferable method because the case diameter increases. A more preferable method is a method of introducing a spacer in the following two steps. That is, in the first stage, the unit is hollow by either a method of adding a linear object such as polyester around one or two hollow fibers along the hollow fiber, or a method of spirally winding the linear object. A fiber element is made, and further, a linear fiber as a second stage spacer is spirally wound around the assembly of four or more unit hollow fiber elements to form a hollow fiber bundle. Is a hollow fiber bundle having a predetermined number of hollow fibers for an artificial kidney. In this case, the method of winding the unit hollow fiber element is more preferably a method of winding in a spiral.
[0051]
As the linear material introduced into the first and second stages, crimped fibers, processed yarns, spun yarns, and the like, which are relatively bulky and stretchable, are preferably used. Further, the thickness is thinner than that of the polysulfone hollow fiber and is up to about 1/20 of the outer diameter of the hollow fiber, and preferably about 1/2 to 1/10 of the outer diameter of the hollow fiber.
[0052]
By introducing this spacer, it becomes easy to form a tube sheet in a state in which a wet holding material having a concentration (amount) that can prevent deterioration due to drying of the performance of the membrane is provided. An artificial kidney having the ability to remove uremic toxins and having albumin permeability controlled to 3% or less can be obtained with a high process yield.
[0053]
The hollow fiber bundles thus obtained are assembled into an artificial kidney (modularized) by a normal method.
[0054]
That is, a yarn bundle is inserted into a case such as polystyrene resin, a potting material such as polyurethane is used, tube plates are formed at both ends of the case by applying centrifugal force, and a leak test is performed to determine the shape for an artificial kidney. To do.
[0055]
Next, a trace amount of solvent or wet retaining material remaining inside the hollow fiber membrane is removed by washing with water, and sterilized in a state filled with water to obtain a product artificial kidney. Although this water washing can be performed with water near room temperature, since it takes about 2 hours at 55 ° C. and about 15 minutes at 80 ° C., washing with heated water at 55 ° C. or higher is preferable. In addition, it is possible to repeatedly perform cleaning such as performing short-time cleaning, then keeping the temperature at 50 ° C. or higher, and then performing short-time cleaning.
[0056]
Sterilization can be performed by a normal method, that is, sterilization using hot water of 90 ° C. or higher, or sterilization in a state where water is filled with radiation using gamma rays (γ rays) or electron beams. Sterilization by radiation using γ rays or electron beams is a preferable method because insolubilization may occur due to crosslinking of the hydrophilic polymer in the membrane. In the present invention, when polyvinyl pyrrolidone which is most preferable as the hydrophilic polymer is used, when γ-rays are irradiated at a dose in the range of about 20 KGy to 35 KGy, insolubilization due to crosslinking of polyvinyl pyrrolidone and sterilization as a medical device are simultaneously performed. This is the most practical sterilization method that can be performed.
[0057]
Simultaneous insolubilization by crosslinking of polyvinylpyrrolidone by this radiation sterilization can suppress the elution and enhance the safety of the product. Also, by this method, a large amount of polyvinylpyrrolidone can be contained in the hollow fiber of the product, so that the film has a good affinity with water and the high performance of the present application can be expressed. Needless to say, in order to insolubilize polyvinylpyrrolidone by crosslinking, a method of separately irradiating prior to sterilization is also possible. However, it is more effective to perform crosslinking and sterilization simultaneously by one irradiation. Preferred for obtaining performance membranes.
[0058]
【Example】
Hereinafter, although an Example demonstrates concretely, this invention is not limited by this. The characteristics of the present invention were evaluated by the following method.
[0059]
[Water permeability]
A small glass tube module was made using 30 hollow fibers of about 15 cm length obtained by cutting a case of a product artificial kidney completed by γ-ray sterilization, and the pressure difference between the outside and inside of the membrane, that is, The amount of water permeation was measured at a transmembrane pressure difference of about 100 mmHg, and ml / hr · mmHg · m²It was expressed as
[0060]
[Urea and vitamin B₁₂The Diaryance]
60g urea and vitamin B₁₂Dissolve 1.2 g in 60 liters of water, blood side flow rate 200 ml / min, dialysate side flow rate 500 ml / min, filtration rate 10 ml / min, blood side inlet and outlet of dialyzer, dialysate side inlet and outlet The dialysance of the blood side reference and the dialysate side reference was calculated, and the average value was used and expressed in ml / min.
[0061]
[Permeability of albumin]
2 l of beef blood of 30% hematocrit, protein concentration 6 g / dl and 37 ° C. is placed in a beaker, circulated at a blood flow rate of 200 ml / min and a transmembrane pressure difference of about 100 mmHg for 1 hour, and the filtrate obtained during that time is returned to the beaker. . Thereafter, three filtrates were collected at intervals of 15 minutes with a transmembrane pressure difference of about 60 mmHg. The albumin concentration in plasma obtained by centrifuging bovine blood was measured by the BCG method (Wako Pure Chemical Industries), the albumin concentration in the filtrate was measured by the CBB method (Tokyo Kasei), and albumin was determined from the average value of the three filtrates. The transmittance was calculated.
[0062]
[Β₂-Microglobulin removal rate]
Body weight 50 kg to 60 kg, and β before dialysis₂-Six patients with microglobulin of 25-35 mg / l, heparin as anticoagulant, blood side flow rate 200 ml / min, dialysate side flow rate 500 ml / min, dehydration amount 2.5-4. 5 liters of hemodialysis, β before and after dialysis₂-The microglobulin concentration is measured by latex agglutination immunization, the protein concentration is corrected and calculated, and the average value is used.
[0063]
[Viscosity of spinning solution] Using a B-type viscometer (Tokimec DV-BII type digital viscometer), 300 ml or more of the spinning solution was collected and measured so as not to be affected by the inner diameter of the container.
[0064]
Example 1
18 parts of polysulfone (“P-3500” manufactured by Amoco) (hereinafter simply referred to as “parts” means “parts by weight”) and polyvinylpyrrolidone (“K-30” manufactured by BASF; molecular weight of about 40,000) 6 And 3 parts of polyvinylpyrrolidone (“K-90” manufactured by BASF; molecular weight of about 1,100,000) are added to a mixed solution of 71.95 parts of dimethylacetamide and 1.05 parts of water, and the mixture is heated to 80 ° C. While maintaining the temperature, the mixture was stirred for 12 hours for dissolution to prepare a spinning dope. The spinning dope was a uniform, slightly milky white solution of 76.9 poise at 30 ° C. (113.1 poise at 20 ° C.).
[0065]
The spinning solution was discharged from an annular slit die at 30 ° C., and an injection solution prepared by mixing 60 parts of dimethylacetamide and 40 parts of water was injected from the center of the die. The length of the dry part was 250 mm, and spinning was performed at a spinning speed of 40 m / min while flowing wet air having a relative humidity of 88% through the part, and a coagulation bath at 40 ° C. (dimethylacetamide / water (weight ratio) = 20/80) The hollow fiber discharged from the coagulation bath was washed and then immersed in an aqueous solution containing 68% by weight of glycerin. After removing excess glycerin adhering to the surface, a polyester false twisted yarn of 50 denier 5 filaments (about 88 microns) around the two hollow fibers in the Z direction with 0.5 turns for the hollow fiber 10 mm A unit hollow fiber element is formed by spirally winding the unit hollow fiber element, 24 units of the unit hollow fiber element are assembled, and the same polyester thread is spirally wound in the S direction at substantially the same pitch, and a spacer is inserted in two layers. I made a bunch. 221 bundles of the hollow fiber bundles were assembled to form a hollow fiber bundle. This hollow fiber bundle was rotated in a centrifuge to remove the glycerin aqueous solution that had been replaced with the injected solution inside the hollow fiber and sealed, and a hollow fiber bundle for insertion into an artificial kidney case was obtained. The hollow fiber had an inner diameter of 200 microns and an outer diameter of 280 microns, and this hollow fiber bundle was a collection of 10,608 hollow fibers. The liquid retention of this hollow fiber bundle was 420%.
[0066]
This hollow fiber bundle was inserted into a case for an artificial kidney having an inner diameter of 40 mm, temporary caps were attached to both ends, and polyurethane was poured from the dialysate side inlet in the field of rotational centrifugal force, and then the polyurethane was solidified. . Next, remove the temporary cap, cut the vicinity of the end of the polyurethane and hollow fiber bundle protruding from both ends of the case, attach the header cap, 0.8 kg / cm²A leak test was conducted using pressurized air.
[0067]
As a result of conducting a leak test using 1000 samples, 12 defective products were generated. As a result of investigating the cause, when filling the case with the hollow fiber bundle, it was caused by a broken thread or a broken thread due to a simple work mistake caused by contact with the end or inner wall of the case. There was no leakage.
[0068]
Next, the module that passed the leak test was washed with pure water that passed through a reverse osmosis membrane at 80 ° C. for 30 minutes, packaged, and then sterilized by irradiation with 32 KGy γ-rays, effective length 195 mm, effective area 1.3 m²An artificial kidney dialyzer was created. This dialyzer passed the dialysis artificial kidney device approval criteria in all items. The water permeability of the hollow fiber cut out from this module is 815 ml / hr · mmHg · m²Module albumin permeability is 1.2%, urea dialysance is 195ml / min, vitamin B₁₂The dialysance was 143 ml / min.
[0069]
In addition, when this module is used for clinical evaluation,₂-The removal rate of microglobulin was a very high result of 73%, and there was no particular problem in using residual blood. In addition, the liquid retention of the hollow fiber bundle cut out from this module was 420%.
[0070]
Example 2
18 parts of polysulfone ("P-3500" manufactured by Amoco) and 9 parts of polyvinylpyrrolidone ("K-30" manufactured by BASF) are added to a mixed solution of 71.6 parts of dimethylacetamide and 1.40 parts of water. While stirring at 90 ° C., the mixture was stirred and dissolved for 12 hours to prepare a spinning dope. This spinning dope was 28.4 poise at 30 ° C. (38.8 poise at 20 ° C.).
[0071]
This spinning solution was discharged from an annular slit die at 30 ° C., and an injection solution prepared by mixing 65 parts of dimethylacetamide and 35 parts of water was injected from the center of the die. The length of the dry part was 350 mm, and the part was spun at a spinning speed of 40 m / min while being exposed to humid air having a relative humidity of 84%. An artificial kidney dialyzer was prepared in the same manner as in Example 1 except for the following part. . In the middle of this, a leak test was performed using 1000 samples. As a result, 17 defective products were generated. The cause was the same as in Example 1. In addition, the liquid retention of this hollow fiber bundle was 380%.
[0072]
The effective area thus obtained is 1.3 m.²The dialysis machine passed the dialysis artificial kidney device approval criteria in all items. The water permeability of the hollow fiber cut out from this dialyzer is 710 ml / hr · mmHg · m.²The albumin permeability of the module is 0.4%, urea and vitamin B₁₂The dialysance was 194 ml / min and 139 ml / min, respectively. In addition, when this module is used for clinical evaluation,₂-The removal rate of microglobulin was 67%, and there was no particular problem in using residual blood. In addition, the liquid retention of the hollow fiber bundle cut out from this module was 380%.
[0073]
Example 3
18 parts of polysulfone (“P-3500” manufactured by Amoco) and 9 parts of polyvinylpyrrolidone (“K-30” manufactured by BASF) are added to a mixed solution of 71.8 parts of dimethylacetamide and 1.2 parts of water. While stirring at 80 ° C., the mixture was stirred for 12 hours and dissolved to prepare a spinning dope. This spinning dope was 26.8 poise at 30 ° C. Thereafter, an artificial kidney dialyzer was prepared in the same manner as in Example 1 except that the injection solution was a mixture of 60 parts of dimethylacetamide and 40 parts of water. In addition, the liquid retention of the hollow fiber bundle used here was 350%.
[0074]
The water permeability of the hollow fiber cut out from this dialyzer is 740 ml / hr · mmHg · m.²The albumin permeability of the module is 0.1%, urea and vitamin B₁₂The dialysance was 192 ml / min and 136 ml / min, respectively. In addition, when this module is used for clinical evaluation,₂-The removal rate of microglobulin was 62%, and there was no particular problem in using residual blood. In addition, the liquid retention of the hollow fiber of this dialyzer was 360%.
[0075]
Example 4
A hollow fiber bundle was prepared by collecting 170 and 306 bundles of hollow fiber bundles in the middle stage of Example 1, and these were inserted into cases for artificial kidneys having inner diameters of 35.5 mm and 46.5 mm, respectively. An artificial kidney dialyzer was prepared in the same manner as described above.
[0076]
Each effective area is 1.0m²And 1.8m²And vitamin B₁₂As a result of measuring the dialysance, it was 127 ml / min and 165 ml / min.
Example 5
Using the hollow fiber bundle in the middle stage of Example 3, making a hollow fiber bundle by changing the number of aggregates, inserting each into a case for artificial kidneys with an inner diameter of 35.5 mm, 44.0 mm and 46.5 mm, Effective area of 1.0m²1.6m²And 1.8m²The artificial kidney dialyzer was prepared in the same manner as in Example 3.
[0077]
Urea and vitamin B₁₂The dialysance of albumin and the permeability of albumin were measured. The dialysance of urea was 187 ml / min, 195 ml / min and 197 ml / min, respectively, and vitamin B₁₂The dialysance was 122 ml / min, 147 ml / min and 156 ml / min, respectively, and the albumin permeability was 0.2%, 0.1% and 0.2%, respectively.
[0078]
Example 6
18 parts of polysulfone (“P-3500” manufactured by Amoco), 6 parts of polyvinylpyrrolidone (“K-30” manufactured by BASF) and 3 parts of polyvinylpyrrolidone (“K-90” manufactured by BASF) In addition to a mixed solution of 85 parts and 1.15 parts of water, the mixture was stirred and dissolved for 12 hours while keeping at 90 ° C. to prepare a spinning dope. This spinning dope was 71.4 poise at 30 ° C.
[0079]
The spinning solution was discharged from an annular slit die at 40 ° C., and an injection solution prepared by mixing 58 parts of dimethylacetamide and 42 parts of water was injected from the center of the die. The length of the dry part was 350 mm, and the artificial kidney dialyzer was introduced into the coagulation bath at 45 ° C. at a spinning speed of 42 m / min while flowing humid air having a relative humidity of 85% through the part. Produced. In addition, the liquid retention of the hollow fiber bundle at the time of insertion into the case for an artificial kidney in the middle stage was 410%.
[0080]
The effective area thus obtained is 1.3 m.²The water permeability of the hollow fiber cut out from the dialyzer was 810 ml / hr · mmHg · m²Albumin permeability is 0.6%, urea and vitamin B₁₂The dialysance was 195 ml / min and 142 ml / min, respectively. In addition, when this module is used for clinical evaluation,₂-The removal rate of microglobulin was 74%, and there was no particular problem in using residual blood. The module had a hollow fiber retention rate of 420%.
[0081]
Example 7
An artificial kidney dialyzer was produced in the same manner as in Example 6 except that the stock solution of Example 6 was used and an infusion solution prepared by mixing 56 parts of dimethylacetamide and 44 parts of water was used. In addition, the liquid retention of the hollow fiber bundle in the middle stage was 400%.
[0082]
The effective area thus obtained is 1.3 m.²The water permeability of the hollow fiber cut out from the dialyzer was 760 ml / hr · mmHg · m²Albumin permeability is 0.2%, urea and vitamin B₁₂The dialysance was 194 ml / min and 140 ml / min, respectively. In addition, when this module is used for clinical evaluation,₂-The removal rate of microglobulin was 71%, and there was no particular problem in using residual blood. The module had a hollow fiber retention rate of 410%.
[0083]
Example 8
18 parts of polysulfone (“P-3500” manufactured by Amoco), 7 parts of polyvinylpyrrolidone (“K-30” manufactured by BASF) and 2 parts of polyvinylpyrrolidone (“K-90” manufactured by BASF) are combined with 71. In addition to a mixed solution of 85 parts and 1.15 parts of water, the mixture was stirred and dissolved for 12 hours while keeping at 90 ° C. to prepare a spinning dope. This spinning dope was 53.0 poise at 30 ° C.
[0084]
This spinning dope is discharged from an annular slit die at 40 ° C., and an injection solution prepared by mixing 60 parts of dimethylacetamide and 40 parts of water is injected from the center of the die, and then artificially produced in the same manner as in Example 6. A kidney dialyzer was made. In addition, the liquid retention of the hollow fiber bundle in the middle stage was 390%.
[0085]
The effective area thus obtained is 1.3 m.²The water permeability of the hollow fiber cut out from the dialyzer was 680 ml / hr · mmHg · m²Albumin permeability is 0.3%, urea and vitamin B₁₂The dialysance was 193 ml / min and 140 ml / min, respectively.
[0086]
Comparative Example 1
A mixed solution of 18 parts of polysulfone ("P-3500" manufactured by Amoco) and 9 parts of polyvinylpyrrolidone ("K-30" manufactured by BASF), 44 parts of dimethylacetamide, 28 parts of dimethylsulfoxide and 1.0 part of water. In addition to the above, the mixture was dissolved by stirring for 15 hours while keeping at 80 ° C. to prepare a spinning dope. This spinning dope was 32.9 poise at 30 ° C. This spinning dope was discharged from an annular slit die at 30 ° C., and an injection solution in which 60 parts of dimethylacetamide and 40 parts of water were mixed was injected from the center of the die. Hereinafter, an artificial kidney dialyzer was prepared in the same manner as in Example 1.
[0087]
The water permeability of the hollow fiber cut out from this dialyzer is 830 ml / hr · mmHg · m.²The albumin permeability of the module is 0.2%, vitamin B₁₂The dialysance was 132 ml / min. In addition, when this module is used for clinical evaluation,₂-The removal rate of microglobulin was a low value of 49%. In addition, the liquid retention of the hollow fiber of this dialyzer was 340%.
[0088]
Comparative Example 2
After washing the hollow fiber from the coagulation bath of Example 1, it was immersed in an aqueous solution containing 45% by weight of glycerin. After removing excess glycerin adhering to the surface, it was wound around a hexagonal skein with a side of 30 cm, dried by ventilation at room temperature, and cut out from the skein to produce a hollow fiber bundle. The liquid retention of this hollow fiber bundle was 270%. This hollow fiber bundle is a collection of 10,608 hollow fibers. The hollow fiber bundle was inserted into a case for an artificial kidney having an inner diameter of 40 mm, and dry air in the vertical direction was applied to both end faces of the hollow fiber bundle to separate the ends of the yarn bundle. After forming a plate, injecting pressurized air from the dialysate side and filling the blood side with water and conducting a leak test by the bubble point method, γ-ray sterilization is performed in the same manner as in Example 1 to artificial kidney A dialyzer was made.
[0089]
The water permeability of the hollow fiber cut out from this module is 410 ml / hr · mmHg · m²Albumin permeability is 0.3%, urea dialysance is 190ml / min, vitamin B₁₂The dialysance was as low as 125 ml / min. That is, in the case of addition of glycerin at a low concentration, tube sheet formation without a spacer is easy, but the permeability of the hollow fiber is deteriorated by drying, and it is difficult to produce a high-performance artificial kidney like the present invention. Met. In addition, the liquid retention of the hollow fiber of this dialyzer was 300%.
[0090]
【The invention's effect】
According to the present invention, an artificial kidney having a high water permeability, a high uremic substance removal performance, and an appropriate albumin permeability can be stably maintained while maintaining the good characteristics of the membrane obtained during hollow fiber spinning. And can be manufactured easily.

Claims (5)

A spinning solution comprising a polysulfone-based resin and a hydrophilic polymer, hollow fiber spun using a mixture of an organic solvent or an organic solvent and water as injection liquid, is impregnated with wetting holding material, wetting holding material solution Create a hollow fiber bundle in the attached state, insert the hollow fiber bundle into a module case for artificial kidney, create a tube sheet, create an intermediate product, wash the wet holding material with water, and then sterilize it the method of manufacturing a hollow fiber type artificial kidney in you, after washing to remove the wet holding material at temperatures above 55 ℃ of heating water, water 20KGy least in a state filled, with a dose of the range 35KGy A method for producing a polysulfone-based hollow fiber type artificial kidney, characterized by irradiating gamma rays and crosslinking a hydrophilic polymer to insolubilize the polymer . Polysulfone-based hollow fiber, wherein the permeability of albumin is 0.3% or more and 2.0% or less, and the dialysance of vitamin B _{12 in} a module having a membrane area of 1.3 m ² is 140 or more Type artificial kidney. Membrane area 1.3m ² Β in clinical use in hemodialysis mode in the module ₂ -The removal rate of microglobulin is 60% or more, The polysulfone-based hollow fiber artificial kidney according to claim 1 or 2. Membrane area 1.3m ² Β in clinical use in hemodialysis mode in the module ₂ The polysulfone-based hollow fiber artificial kidney according to claim 1 or 2, wherein the removal rate of microglobulin is 70% or more. The polysulfone-based hollow fiber artificial kidney according to any one of claims 1 to 4, wherein the hydrophilic polymer is polyvinylpyrrolidone.