JP3601662B2 - Blood purification membrane with improved antithrombotic properties - Google Patents

Description

【００１２】
【化４】

［上記式（１）および（２）においてＲ^１ は炭素数１〜２０のアルキル基、炭素数６〜１２のアリール基、炭素数７〜２０のアラルキル基、または下記基
Ｒ^４ −（Ａ）ｎ−
（Ａはオキシエチレン、オキシプロピレン、オキシブチレン、オキシペンタメチレン、オキシヘキサメチレン基であり、これらの群から選ばれる１種または２種以上が混在してもよく、結合順はランダムでもよい。ｎは１から３０の整数である。Ｒ^４ は炭素数１〜２０のアルキル基、または炭素数６〜１２のアリール基、炭素数７〜２０のアラルキル基である。）である。Ｒ^２ 、Ｒ^３ は炭素数１〜２０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜２０のアラルキル基であり、それぞれ同じであっても異なっていてもよい。Ｒ^５ 、Ｒ^６ は炭素数２〜１０のアルキレン基であり、Ｒ^５ 、Ｒ^６ はそれぞれ同じであっても異なっていてもよい。ｍは１〜１０の整数である。Ｒ^７ は、水素原子、炭素数１〜２０のアルキル基、炭素数６〜１２のアリール基または炭素数７〜２０のアラルキル基である。］
▲２▼ 一般式（１）または（２）で表されるホスホリルコリン構造を側鎖に有するジオールを少なくともジオール成分の一部として用いて得られるポリウレタン又はポリウレタンウレアの含有量が膜に対して、０．０１〜３０重量％である上記▲１▼記載の抗血栓性の向上した血液浄化膜。
▲３▼ 一般式（１）または（２）で表されるホスホリルコリン構造に由来するリンをポリマー１ｇ当たり０．０３〜１．３０ミリモル含むポリウレタンまたはポリウレタンウレアである上記▲１▼または▲２▼記載の抗血栓性の向上した血液浄化膜。
▲４▼ 一般式（１）または（２）で表されるホスホリルコリン構造を側鎖に有するジオールを少なくともジオール成分の一部として用いて得られるポリウレタン又はポリウレタンウレアを含む製膜原液から製膜された上記▲１▼乃至▲３▼記載の抗血栓性の向上した血液浄化膜。
▲５▼ 一般式（１）または（２）で表されるホスホリルコリン構造を側鎖に有するジオールを少なくともジオール成分の一部として用いて得られるポリウレタン又はポリウレタンウレアが、少なくとも血液が接触する面にコーティングされている上記▲１▼乃至▲３▼記載の抗血栓性の向上した血液浄化膜。
以下本発明を詳細に説明する。
【００１３】
本発明において、血液浄化膜に含まれるポリウレタン又はポリウレタンウレア（以下、ポリウレタンとポリウレタンウレアを総称して「ポリウレタン類」ということがある）は、下記式（１）または（２）で表されるホスホリルコリン構造を側鎖に含むものである。
【化５】

【００１４】
【化６】

［上記式（１）および（２）においてＲ^１ は炭素数１〜２０のアルキル基、炭素数６〜１２のアリール基、炭素数７〜２０のアラルキル基、または下記基
Ｒ^４ −（Ａ）ｎ−
（Ａはオキシエチレン、オキシプロピレン、オキシブチレン、オキシペンタメチレン、オキシヘキサメチレン基であり、これらの群から選ばれる１種または２種以上が混在してもよく、結合順はランダムでもよい。ｎは１から３０の整数である。Ｒ^４ は炭素数１〜２０のアルキル基、または炭素数６〜１２のアリール基、炭素数７〜２０のアラルキル基である。）である。Ｒ^２ 、Ｒ^３ は炭素数１〜２０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜２０のアラルキル基であり、それぞれ同じであっても異なっていてもよい。Ｒ^５ 、Ｒ^６ は炭素数２〜１０のアルキレン基であり、Ｒ^５ 、Ｒ^６ はそれぞれ同じであっても異なっていてもよい。ｍは１〜１０の整数である。Ｒ^７ は、水素原子、炭素数１〜２０のアルキル基、炭素数６〜１２のアリール基または炭素数７〜２０のアラルキル基である。］
【００１５】
本発明のポリウレタン類は、活性水素含有化合物とジイソシアナート化合物とを反応させることによって得ることができる。
活性水素化合物としては一般式（１）または（２）で表されるホスホリルコリン基含有ジオールを必須成分とし、その他に活性水素含有化合物としてジオール及び／またはジアミンを併用することができる。これらの活性水素含有化合物については、特に限定的ではなく、イソシアナートに対して反応性を有する活性水素含有化合物を適宜選択して用いることができる。
【００１６】
本発明のポリウレタン類を得るためには、以下の（ｉ）〜（ｉｉｉ）の活性水素含有化合物を用いることができる。
（ｉ）前記一般式（１）または（２）で表されるホスホリルコリン基含有ジオール
（ｉｉ）ポリマージオール
（ｉｉｉ）鎖伸長剤
以下にこの発明で用いることが可能な活性水素含有化合物について示す。
【００１７】
前記一般式（１）および（２）で表される化合物の中で好ましい化合物を以下に例示する。
一般式（１）において、Ｒ^２ ＝Ｒ^３ ＝メチル、Ｒ^５ ＝Ｒ^６ ＝−ＣＨ_２ −ＣＨ（ＣＨ_３ ）−、ｍ＝３であるとき、Ｒ^１ ＝メチル、エチル、プロピル、イソプロピル、ブチル、ｔｅｒｔ−ブチル、ヘキシル、シクロヘキシル、オクチルなどの化合物。
一般式（１）において、Ｒ^２ ＝Ｒ^３ ＝メチル、Ｒ^５ ＝Ｒ^６ ＝−ＣＨ_２ −ＣＨ（ＣＨ_３ ）−、ｍ＝３であるとき、Ｒ^１ ＝Ｒ^４ −（Ａ）ｎ−で表されるとき、Ｒ^４ ＝メチル、エチル、プロピル、ブチル、オクチル、ラウリル、セチル又はオレイル、Ａは、オキシエチレン（ｎは例えば、３〜２０）、オキシプロピレン（ｎは例えば、３〜２０）、オキシブチレン（ｎは例えば、３〜２０）、オキシヘキサメチレン（ｎは例えば、３〜２０）、オキシエチレン−オキシプロピレン共重合体（ｎは例えば、３〜２０）などの化合物。
一般式（２）において、Ｒ^２ ＝Ｒ^３ ＝Ｒ^７ ＝メチル、Ｒ^５ ＝Ｒ^６ ＝メチレン、ｍ＝１であるとき、Ｒ１＝メチル、エチル、プロピル、イソプロピル、ブチル、ｔｅｒｔ−ブチル、ヘキシル、シクロヘキシル、オクチルなどの化合物。
一般式（２）において、Ｒ^２ ＝Ｒ^３ ＝Ｒ^７ ＝メチル、Ｒ^５ ＝Ｒ^６ ＝メチレン、ｍ＝１であるとき、Ｒ^１ ＝Ｒ^４ −（Ａ）ｎ−で表されるとき、Ｒ^４ ＝メチル、エチル、プロピル、ブチル、オクチル、ラウリル、セチル又はオレイル、Ａは、オキシエチレン（ｎは例えば、３〜２０）、オキシプロピレン（ｎは例えば、３〜２０）、オキシブチレン（ｎは例えば、３〜２０）、オキシヘキサメチレン（ｎは例えば、３〜２０）、オキシエチレン−オキシプロピレン共重合体（ｎは例えば、３〜２０）などの化合物。
【００１８】
前記一般式（１）および（２）の化合物の内で、Ｒ^１ が基Ｒ^４ −（Ａ）ｎ−であるものは、側鎖末端に親水性基であるポリオキシアルキレン基が存在することによりポリウレタン類の親水性が向上し、より生体適合性に優れたものになる。そして、この様な親水性基の存在による効果が、ホスホリルコリン基が側鎖に存在することによってホスホリルコリン基の運動性が向上することと相乗的に作用して、血液凝固因子活性抑制および血小板粘着抑制効果がより有効に発揮される。
【００１９】
ポリマージオールとしては、ポリオキシアルキレングリコール（エチレン、テトラメチレン、ヘキサメチレン等の炭素数２〜８、好ましくは２〜６程度の直鎖又は分枝鎖状のアルキレン基がエーテル結合で結合したポリオキシアルキレンの末端に水酸基が結合したもの）、ポリカーボネートジオール、ポリエステルジオール、ポリブタジエンジオール、ポリイソプレンジオール、水添ポリイソプレンジオール等を用いることができる。
本発明では、ポリマージオールとしては、モノマーの繰り返し単位数が４〜２００程度のものを用いることが好ましく、モノマーの繰り返し単位数が１０〜１５０程度のものを用いることがより好ましい。この様なポリマージオールを用いることによって、得られるポリウレタン類に適度な柔軟性を付与することができる。
【００２０】
鎖伸長剤としては、アルキレンジオールおよびアルキレンジアミンから選ばれた少なくとも１種を用いればよい。
アルキレンジオールとしては、炭素数２〜８程度、好ましくは２〜６程度の直鎖または分枝鎖状のアルキレン基の両末端に水酸基を有するアルキレンジオールを用いることが好ましい。本発明での使用に適するアルキレンジオールの具体例としては、エチレングリコール、プロピレングリコール、ブチレングリコール、１，６−ヘキサメチレングリコール、ネオペンチルグリコールなどのアルキレングリコール等を例示することができる。
アルキレンジアミンとしては、エチレンジアミン、プロピレンジアミン、ブチレンジアミン、ヘキサメチレンジアミン等の直鎖状アルキレンジアミン、１，２−ジアミノプロパン、１，３−ジアミノペンタン等の分岐状アルキレンジアミン、１，２−シクロヘキサジアミン、１，３−シクロヘキサジアミン、１，４−シクロヘキサジアミン等の環状アルキレンジアミン等を用いることができる。
鎖伸長剤としては、上記したアルキレンジオール及びアルキレンジアミンから選ばれた成分を１種単独または２種以上混合して用いることができる。鎖伸長剤を用いることにより得られるポリウレタン類に適度な硬度を付与することができる。
【００２１】
本発明で用いるポリウレタン類を得るために用いられるジイソシアネート化合物としては、特に限定はなく、従来ポリウレタン類の製造に用いられるジイソシアネート、および今後開発されるであろうジイソシアネートの全てが使用可能であり、所望の特性に応じて適宜選択して用いればよい。ジイソシアネートの具体例としては、エチレンジイソシアネート、トリメチレンジイソシアネート、テトラメチレンジイソシアネート、ペンタメチレンジイソシアネート、オクタメチレンジイソシアネート、ウンデカメチレンジイソシアネート、ドデカメチレンジイソシアネート、３，３’−ジイソシアネートプロピルエーテル、シクロペンチレン−１，３−ジイソシアネート、シクロヘキサン−１，４−ジイソシアネート、４，４’−メチレンビス（シクロヘキシルイソシアナート）、イソホロンジイソシアナートなどのアルキレンジイソシアナート類、２，４−トリレンジイソシアネート、２，６−トリレンジイソシアネート、２，４−トリレンジイソシアネートと２，６−トリレンジイソシアネートとの混合物、キシリレン−１，４−ジイソシアネート、４，４’−ジフェニルメタンジイソシアネート、４，４’−ジフェニルプロパンジイソシアネート、４−イソシアナトベンシルイソシアネート、ｍ−フェニレンジイソシアネート、ｐ−フェニレンジイソシアネート、ナフタレン−１，４−ジイソシアネート、ナフタレン−１，５−ジイソシアネート等が例示される。
【００２２】
本発明で用いるポリウレタン類の製造法は特に制限されなず、常法に従って有機溶媒中で前記した活性水素含有化合物とジイソシアネート化合物とを反応させればよい。有機溶媒としては、例えば、ヘキサメチルリン酸トリアミド（ＨＭＰＡ）、Ｎ−メチル−２−ピロリドン（ＮＭＰ）、Ｎ−メチルホルムアミド（ＮＭＦ）、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ−ジメチルアセトアミド（ＤＭＡｃ）、テトラヒドロフラン（ＴＨＦ）、トルエン、ジオキサン等が用いることができ、これ等の有機溶媒は混合して用いてもよい。活性水素含有化合物とジイソシアネート化合物の反応割合は、通常、ジイソシアネート化合物１当量に対して、活性水素含有化合物を０．７〜１．５当量程度とすればよく、０．８〜１．２当量程度とすることが好ましい。
具体的な反応条件については、使用するジイソシアネートやジオールの構造により異なるが、例えば、窒素雰囲気下２０〜１５０℃程度で、１〜５０時間程度撹拌しながら反応させ、この反応物を沈殿法等により生成を行う方法を例示できる。
【００２３】
また、前記の式（１）または（２）で表されるホスホリルコリン構造部分を含むジオール、ポリマージオール、アルキレンジオール等のジオール成分とジイソシアネート化合物とを、前記した方法と同様にして反応させることにより両末端にイソシアネート基を有するプレポリマーを得、このプレポリマーをＨＭＰＡ、ＮＭＰ、ＮＭＦ、ＤＭＦ、ＤＭＡｃ、ＴＨＦ等の有機溶媒に溶解した後冷却し、アルキレンジアミンを添加して鎖延長することによってポリウレタンウレアを得る方法等によって製造することもできる。
ポリウレタン類の重合時、重合を効率的に進行できるように特に制限されないが、ジブチルジラウリル酸錫、テトラブトキシチタン等の重合触媒を添加してもよい。重合触媒の添加量は、通常、反応溶液全体を基準として、１０〜１０００ｐｐｍ程度とすればよい。
【００２４】
本発明で用いるポリウレタン類１ｇに対して一般式（１）および（２）で表されるホスホリルコリン構造に由来するリンを０．０３〜１．３０ミリモル含むことが好ましい。ホスホリルコリン構造に由来するリンの含有量が０．０３ミリモルより少ないと、十分な抗血栓性が得られないことがあり、１．３０ミリモルを超えるとポリウレタン類の機械的物性が低下し、貧弱な材料になるため好ましくない。
【００２５】
本発明で用いるポリウレタン類は、重量平均分子量が３，０００〜８，０００，０００程度であり、好ましくは、５，０００〜５，０００，０００程度である。本明細書中に記載した分子量はゲルパーミネーションクロマトグラフィー（ＧＰＣ）を用いて測定した値であり、測定に用いるゲルカラムは、Ｓｈｏｄｅｘ ＡＤ−８０３／Ｓ、ＡＤ−８０４／Ｓ、ＡＤ−８０６／Ｓ、ＫＤ−８０２の４本を直列に連結したものであり、移動相としては０．１％臭化リチウムを溶解させたＤＭＦを用い、検量線をポリスチレンで引き、５０℃で測定することによって分子量を求めた。
【００２６】
このような構造を有する本発明の血液浄化膜に含まれるポリウレタン類は、生体膜を形成するホスファチジルコリン類似構造を持つホスホリルコリン基が側鎖に導入されていることにより、主鎖に導入された場合と比較して生体適合性が向上し、非常に優れた抗血栓性を発揮できる。これは、一般に高分子主鎖は絡み合っているため、性能を発揮する官能基が主鎖にあるとその性能は十分に発揮しにくいのに対して、側鎖に性能発揮部位を有していると官能基の運動が高分子主鎖に抑制されず運動性が向上し、十分に性能発揮できることによるものと考えられる。したがって、本発明の血液浄化膜が、生体適合性が良好で非常に優れた抗血栓性を発揮できるのは、ポリウレタン類にホスホリルコリン基が側鎖に導入されているため、ホスホリルコリン基の運動性が向上し、そのため、生体膜類似構造の効果が大きく現れているためと考えられる。
さらに、本発明の抗血栓性ポリウレタン類を血液浄化膜にブレンドして製膜した場合、ホスホリルコリン基は親水性であるため、膜表面に抗血栓性ポリウレタン類は局在化する。そのため、本発明の血液浄化膜が血液と接触してもその抗血栓性は維持される。
【００２７】
本発明において、ポリウレタン類の含有量は、膜に対して、０．０１〜３０重量％であることが好ましく、０．１〜２０重量％がより好ましく、１〜１０重量％であることが特に好ましい。ポリウレタン類の含有量が膜に対して０．０１重量％より少ないと、十分な抗血栓性が得られないことがあり、また３０重量％を超えると、膜の素材によっては強度が低下したり、ウレタン類の添加により膜の透過性が低下することがあるので好ましくない。通常、ポリウレタン類の含有量が増加すると抗血栓性は向上するが、ポリウレタン類の膜中への存在状態によって（例えば、膜材質中に均一に分散している場合や膜の表面に集中して存在する場合など）その効果は一概には言えない。一般的には上記範囲にあることで実用上問題のない抗血栓性を得ることが可能である。
【００２８】
本発明の血液浄化膜の利用は、血液透析膜、血液透析濾過膜、血液濾過膜などの腎不全治療に用いられる一般に人工腎臓と呼ばれるもの、血漿分離膜、人工肺等、血液と接触し、透析、濾過、ガス交換等血液に対して作用を行う全ての膜で応用することができる。また、血液浄化治療とはことなるが、血液から血漿を分離して献血するドナープラズマフェレーシス用の血漿分離膜にも応用することができるが、もっとも好ましい利用用途としては、膜と血液の接触時間が長い、持続的血液浄化治療用の膜である。
【００２９】
膜の素材としては、特に制限されることはなく、再生セルロース、鹸化セルロース、セルロースアセテート、セルローストリアセテート、修飾セルロース等のセルロース類、ポリアクリロニトリル、ポリスルホン、ポリエーテルスルホン、ポリアミド、ポリメチルメタクリレート、エチレンビニルアルコール共重合体、ポリビニルアルコール、ポリエチレン、ポリプロピレン、シリコンなどが上げられる。
【００３０】
膜の形態は特に制限されることなく、中空糸膜、管状膜、平膜などが上げられる。
【００３１】
本発明において、ポリウレタン類を膜に導入するための好ましい手法としては、ポリウレタン類を含む製膜原液から、血液浄化膜を製膜することである。すなわち、通常、血液浄化膜は、膜素材としてのポリマー、ポリマーに対する溶媒、必要により非溶媒や添加剤を加え溶解した製膜原液から製膜されるが、ポリウレタン類を添加し均一に溶解した製膜原液から製膜すれば、ポリウレタン類を含んだ血液浄化膜を得ることができる。ただしポリウレタン類の耐熱性はあまり高くない場合は、ポリマーを溶解するために高温を要する場合は、一度高温で溶解した製膜原液を冷却した後に、ポリウレタン類を添加することもできる。
【００３２】
本発明において、ポリウレタン類を膜に導入するための別の好ましい手法としては、常法により得られた血液浄化膜に、ポリウレタン類をコーティングすることである。この方法は、一旦製膜した血液浄化膜に後処理によって、ポリウレタン類を導入することになり、工程が複雑となるが、製膜時に製膜原液を高温に保たねばならない場合や、膜素材とポリウレタン類が同一の溶媒に溶解できない場合に、血液浄化膜にポリウレタンを導入するための手法として好適に用いることができる。
【００３３】
【実施例】
以下、実施例を挙げて、具体的に本発明を説明するが、本発明はこれらに何ら限定されるものではない。
（ウレタン類の製造）
【００３４】
【化７】

一般式（２）において、Ｒ^１ ＝Ｒ^４ −（Ａ）ｎ−であり、Ｒ^４ ＝メチル、Ａ＝オキシエチレン、ｎは平均値３．２５、Ｒ^２ ＝Ｒ^３ ＝Ｒ^７ ＝メチル、Ｒ^５ ＝Ｒ^６ ＝メチレン、ｍ＝１であるジオール ６０．００ｇ、ポリテトラメチレングリコール（平均分子量１３００）１５８．４ｇ、及びブタンジオール ３９．４４ｇを、ＤＭＡｃ ７００ｍｌに溶解させた。この溶液に４，４‘−メチレンビス（シクロヘキシルイソシアネート）２０２．００ｇをＤＭＡｃ ３００ｍｌに溶解した溶液を、アルゴンガスによって反応器内を十分に置換した後、ゆっくり滴下した。滴下後、１００℃２４時間攪拌し、重合を行った。この反応物を水 ５，０００ｍｌに攪拌しながら流し込み、生成した沈殿物を濾別し、ＴＨＦに溶解し、さらに５０ｖｏｌ％メタノール水溶液に攪拌しながら注ぎ込み、生じた沈殿物を回収して減圧乾燥し、重合体Ａを得た。得られた重合体Ａの重量平均分子量は、１２３，０００であった。
【００３５】
（実施例１）
ポリマーとしてポリエーテルスルホン（住友化学株式会社製 、スミカエクセル４８００Ｐ ）１８重量％、溶媒としてＮ−メチル−２−ピロリドン６４重量％、非溶媒としてトリエチレングリコール１６重量％、さらに親水化剤としてポリビニルピロリドンＫ９０ １重量％に重合体Ａ１重量％を添加し、５０℃にて、３時間攪拌溶解し、１時間静置脱泡した後、焼結フィルターにて、未溶解物を除去し紡糸原液を得た。スリット外径３００μｍ、スリット内径２００μｍ、内液吐出孔径１００μｍのチューブインオリフィス型ノズルの外側スリットより紡糸原液を、内液吐出孔より、水５０重量％、ＮＭＰ ４０重量％、トリエチレングリコール１０重量％の内液を吐出した。ノズルから吐出した紡糸原液は３０ｃｍの空中走行部を経て、ノズル直下の凝固浴に導いた。凝固液は水８０重量％、ＮＭＰ １６重量％、トリエチレングリコール４重量％で温度は６０℃であった。凝固した中空糸膜は、水洗後、乾燥しワインダーにて巻き取った。巻取り速度は１５ｍ／ｍｉｎであった。得られた中空糸膜の内径は２００μｍ、外径は２８０μｍであり、膜厚は４０μｍであった。
得られた中空糸膜を９６００本束ね、ダイアライザーを組み立てた。ダイアライザーの膜面積は１．５ｍ^２ であった。
【００３６】
（比較例１）
紡糸原液にポリウレタン類を添加しないことを除いて、他は実施例１と全く同じ方法で、中空糸膜を紡糸し、同様に膜面積１．５ｍ^２ のダイアライザーを得た。
【００３７】
（実施例２）
重合体ＡをＴＨＦで希釈して０．５％とし、比較例１で得られたダイアライザーの血液側にこの溶液を流通し、その後窒素気流下で乾燥することにより重合体Ａを血液透析膜血液側表面にコーティングした。コーティング前後の重量変化から、コーティング量は膜に対して３．５重量％であった。
【００３８】
（抗血栓性評価実験）
実施例１、２、比較例１で得られた、膜面積１．５ｍ^２ のダイアライザーを用いた。各ダイアライザーを生理食塩水１Ｌで洗浄した後、ＡＣＤ添加牛血液（ヘマトクリット３０％、総タンパク質濃度６．５ｇ／ｄｌ、３７℃）２Ｌを２００ｍｌ／ｍｉｎで流し、２０ｍｌ／ｍｉｎの条件で濾過し、ダイアライザーからの流出血液とろ液をリザーバーに戻す循環テストを４時間実施した。血液循環前、循環１時間後、２時間後、３時間後、終了時（４時間後）で血小板数を計測すると共に、循環テスト終了後、使用したダイアライザーを１Ｌの生理食塩水で血液側を洗浄したときに、ダイアライザー中の中空糸の残血本数を計測した。得られた結果を表１に示す。
実施例１および２のウレタン類を含む膜を用いたダイアライザーにおいて、血小板の減少が少なく、また残血が少ないことがわかる。
【００３９】
（ダイアライザー性能評価実験）
実施例１，２、比較例１で得られた膜面積１．５ｍ^２ のダイアライザーの３７℃水の透水性、血液側水溶液流量２００ｍｌ、透析液流量５００ｍｌ、３７℃での尿素、ビタミンＢ１２、ミオグロビンのクリアランスを測定した。得られた結果を表２に示す。
いずれのダイアライザーも実用上差し支えのない性能を有しており、ウレタン類の導入により膜性能が低下しないことが確認された。
【００４０】
【表１】

比較例１においては循環終了後、ダイアライザーのおよそ１／３の糸に残血が認められた。
【００４１】
【表２】

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a blood purification membrane having improved antithrombotic properties. More specifically, the present invention relates to a blood purification membrane with improved antithrombotic properties used for hemodialysis, hemodiafiltration, hemofiltration, plasma separation, artificial lung and the like. More specifically, the present invention relates to a blood purification membrane having an improved antithrombotic property used continuously for extracorporeal circulation over a long period of time.
[0002]
[Prior art]
Blood purification therapy using membranes includes hemodialysis, hemodiafiltration, and hemofiltration, which are used to extend the life of patients with chronic renal failure, and plasma separation and exchange, which are used to treat rheumatism and hyperlipidemia, and open heart surgery There is an artificial lung sometimes used.
[0003]
In blood purification treatment using these membranes, blood is usually taken out of the body from a patient, and dialysis, filtration, diafiltration, plasma separation, oxygenation, etc. are performed by the blood purification membrane, and the blood is returned to the patient. Means called extracorporeal circulation are usually taken. Here, generally, blood taken out of the body has the property of coagulating when it comes into contact with external foreign substances, so in extracorporeal circulation, to prevent blood from coagulating in the blood purification membrane and forming a thrombus. An anticoagulant such as heparin is added to blood taken out of the body.
[0004]
In recent years, continuous hemofiltration, continuous hemodialysis, and continuous hemodiafiltration, which is called continuous hemodiafiltration, has been widely used for the treatment of postoperative renal failure, acute renal failure, acute drug poisoning, fulminant hepatitis, etc. I have. This means that hemodialysis used for the treatment of patients with chronic renal insufficiency usually takes 4-5 hours at a time, while continuous blood purification takes 12 hours to several days at a time. Extracorporeal circulation treatment is performed. This makes it possible to continuously remove pathogenic substances and water, and has a great effect on improving the above-mentioned serious diseases. In such a long-term continuous treatment, depending on the patient's condition, the amount of anticoagulant to be used is limited, or the blood is often in a state that easily coagulates. High blood compatibility and antithrombotic properties are required.
[0005]
By the way, as a material of the membrane used for such blood purification, as an artificial kidney, regenerated cellulose, saponified cellulose, cellulose diacetate, cellulose triacetate or modified cellulose obtained by immobilizing polyethylene glycol, vitamin E, etc. on the surface of the regenerated cellulose membrane. Such as celluloses, polyacrylonitrile, polysulfone, polyethersulfone, polymethyl methacrylate, ethylene vinyl alcohol copolymer, etc .; and as plasma separation membrane, cellulose triacetate, polyvinyl alcohol, polysulfone, polypropylene, etc. Polypropylene, silicone, or the like is used as the lung. These blood purification membrane materials are simply diverted general-purpose plastics and fiber materials for blood purification membrane applications, and because they are mass-produced, they can be obtained at low cost and film formation is relatively easy, Since it was not developed mainly for use as a blood purification membrane, it cannot be said that the blood purification membrane has sufficient blood compatibility and antithrombotic properties.
[0006]
Although some modified celluloses have been attempted to improve blood compatibility by immobilizing polyethylene glycol or vitamin E on the membrane surface as described above, these effects are not significant when blood comes in contact with foreign substances. It is intended to suppress complement activity, and it is difficult to say that the antithrombotic properties are sufficiently improved, and immobilizing these substances on a membrane is a complicated process for forming a membrane. And cost increase.
[0007]
In recent years, a phosphorylcholine structure has been actively studied as a biocompatible functional group. This phosphorylcholine structure is similar to a phospholipid forming a biological membrane, that is, phosphatidylcholine. For this reason, a polymer material having a phosphorylcholine structure in a molecule has a high affinity for a living body and is useful as an antithrombotic material.
For example, a polymer containing 2-methacryloyloxyethylphosphorylcholine has a structure similar to phosphatidylcholine, which is one of the components of the outer wall of the cell membrane. And it is reported that excellent blood compatibility can be obtained (for example, JP-A-54-63025, JP-A-63-96200, etc.). In addition, it has been reported that similarly excellent blood compatibility can be obtained by introducing a phosphorylcholine group into the main chain of polyurethane (JP-A-62-500726, JP-A-08-134085, and JP-A-08-14085). 08-259654, WO86 / 02933) However, these materials have not yet achieved sufficient antithrombotic properties as medical materials.
[0008]
Japanese Patent Application Laid-Open No. 7-231935 discloses an antithrombotic regenerated cellulose membrane in which a regenerated cellulose membrane is ester-bonded with a polymer acid having a molecular weight of 1,000 to 1,000,000, which is a copolymer of 2-methacryloyloxyethyl phosphorylcholine and its monomer. Although they are disclosed, they have drawbacks in that they are difficult to bond to the membrane surface, and that the bonded polymeric acid is likely to fall off.
[0009]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-mentioned problems of the prior art and to provide a membrane having sufficient biocompatibility and antithrombotic properties as a blood purification membrane.
[0010]
[Means for Solving the Problems]
The present inventors have conducted intensive studies in view of the above problems, and as a result, a blood purification membrane containing a specific structure of a polyurethane or a polyurethaneurea having a specific phosphorylcholine-like group (hereinafter abbreviated as a phosphorylcholine group) in a side chain has achieved the above object. It was found that it was possible. The present invention
{Circle around (1)} Antithrombotic properties comprising polyurethane or polyurethaneurea obtained by using a diol having a phosphorylcholine structure represented by the general formula (1) or (2) in a side chain as at least a part of a diol component. Improved blood purification membrane.
[0011]
Embedded image

[0012]
Embedded image

[In the above formulas (1) and (2), R ¹ Is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or the following group
R ⁴ -(A) n-
(A is an oxyethylene, oxypropylene, oxybutylene, oxypentamethylene, or oxyhexamethylene group, one or more selected from these groups may be mixed, and the bonding order may be random. Is an integer from 1 to 30. R ⁴ Is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms. ). R ² , R ³ Is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms, which may be the same or different. R ⁵ , R ⁶ Is an alkylene group having 2 to 10 carbon atoms; ⁵ , R ⁶ May be the same or different. m is an integer of 1 to 10. R ⁷ Is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms. ]
{Circle around (2)} The content of polyurethane or polyurethane urea obtained by using a diol having a phosphorylcholine structure represented by the general formula (1) or (2) in a side chain as at least a part of the diol component is 0% with respect to the film. (1) The blood purification membrane with improved antithrombotic properties according to (1) above, which has a content of 0.01 to 30% by weight.
(3) The above (1) or (2), which is a polyurethane or polyurethane urea containing 0.03 to 1.30 mmol of phosphorus derived from the phosphorylcholine structure represented by the general formula (1) or (2) per 1 g of the polymer. Blood purification membrane with improved antithrombotic properties.
{Circle around (4)} A film was formed from a film forming solution containing polyurethane or polyurethane urea obtained by using a diol having a phosphorylcholine structure represented by the general formula (1) or (2) in a side chain as at least a part of a diol component. The blood purification membrane with improved antithrombotic properties according to the above (1) to (3).
{Circle around (5)} A polyurethane or polyurethaneurea obtained by using a diol having a phosphorylcholine structure represented by the general formula (1) or (2) in a side chain as at least a part of a diol component is coated on at least a surface in contact with blood. The blood purification membrane with improved antithrombotic properties according to the above (1) to (3).
Hereinafter, the present invention will be described in detail.
[0013]
In the present invention, the polyurethane or polyurethane urea (hereinafter, polyurethane and polyurethane urea may be collectively referred to as “polyurethane”) contained in the blood purification membrane is phosphorylcholine represented by the following formula (1) or (2). The structure is included in the side chain.
Embedded image

[0014]
Embedded image

[In the above formulas (1) and (2), R ¹ Is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or the following group
R ⁴ -(A) n-
(A is an oxyethylene, oxypropylene, oxybutylene, oxypentamethylene, or oxyhexamethylene group, one or more selected from these groups may be mixed, and the bonding order may be random. Is an integer from 1 to 30. R ⁴ Is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms. ). R ² , R ³ Is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms, which may be the same or different. R ⁵ , R ⁶ Is an alkylene group having 2 to 10 carbon atoms; ⁵ , R ⁶ May be the same or different. m is an integer of 1 to 10. R ⁷ Is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms. ]
[0015]
The polyurethanes of the present invention can be obtained by reacting an active hydrogen-containing compound with a diisocyanate compound.
As the active hydrogen compound, a phosphorylcholine group-containing diol represented by the general formula (1) or (2) is an essential component, and in addition, a diol and / or a diamine can be used in combination as the active hydrogen-containing compound. The active hydrogen-containing compound is not particularly limited, and an active hydrogen-containing compound having reactivity with isocyanate can be appropriately selected and used.
[0016]
In order to obtain the polyurethanes of the present invention, the following active hydrogen-containing compounds (i) to (iii) can be used.
(I) Phosphorylcholine group-containing diol represented by formula (1) or (2)
(Ii) Polymer diol
(Iii) Chain extender
Hereinafter, active hydrogen-containing compounds that can be used in the present invention will be described.
[0017]
Preferred compounds among the compounds represented by the general formulas (1) and (2) are exemplified below.
In the general formula (1), R ² = R ³ = Methyl, R ⁵ = R ⁶ = -CH ₂ -CH (CH ₃ )-, When m = 3, R ¹ = Compounds such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, cyclohexyl, octyl and the like.
In the general formula (1), R ² = R ³ = Methyl, R ⁵ = R ⁶ = -CH ₂ -CH (CH ₃ )-, When m = 3, R ¹ = R ⁴ When represented by-(A) n-, R ⁴ = Methyl, ethyl, propyl, butyl, octyl, lauryl, cetyl or oleyl, A is oxyethylene (n is, for example, 3 to 20), oxypropylene (n is, for example, 3 to 20), oxybutylene (n is, for example, Compounds such as oxyhexamethylene (n is, for example, 3 to 20) and oxyethylene-oxypropylene copolymer (n is, for example, 3 to 20).
In the general formula (2), R ² = R ³ = R ⁷ = Methyl, R ⁵ = R ⁶ = Methylene, when m = 1, R1 = compounds such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, cyclohexyl, octyl and the like.
In the general formula (2), R ² = R ³ = R ⁷ = Methyl, R ⁵ = R ⁶ = Methylene, m = 1, R ¹ = R ⁴ When represented by-(A) n-, R ⁴ = Methyl, ethyl, propyl, butyl, octyl, lauryl, cetyl or oleyl, A is oxyethylene (n is, for example, 3 to 20), oxypropylene (n is, for example, 3 to 20), oxybutylene (n is, for example, Compounds such as oxyhexamethylene (n is, for example, 3 to 20) and oxyethylene-oxypropylene copolymer (n is, for example, 3 to 20).
[0018]
Among the compounds of the general formulas (1) and (2), R ¹ Is the group R ⁴ In the case of-(A) n-, the presence of a polyoxyalkylene group, which is a hydrophilic group, at the terminal of the side chain improves the hydrophilicity of the polyurethanes and makes the polyurethane more excellent in biocompatibility. The effect of the presence of such a hydrophilic group is synergistic with the improvement in the motility of the phosphorylcholine group due to the presence of the phosphorylcholine group in the side chain. The effect is exhibited more effectively.
[0019]
Examples of the polymer diol include polyoxyalkylene glycols (polyoxyalkylene glycols such as ethylene, tetramethylene, hexamethylene, etc., in which a linear or branched alkylene group having 2 to 8 carbon atoms, preferably about 2 to 6 carbon atoms is bonded by an ether bond). (A hydroxyl group bonded to an alkylene terminal), polycarbonate diol, polyester diol, polybutadiene diol, polyisoprene diol, hydrogenated polyisoprene diol, and the like.
In the present invention, as the polymer diol, those having a monomer repeating unit number of about 4 to 200 are preferably used, and those having a monomer repeating unit number of about 10 to 150 are more preferable. By using such a polymer diol, appropriate flexibility can be imparted to the obtained polyurethane.
[0020]
As the chain extender, at least one selected from alkylene diols and alkylene diamines may be used.
As the alkylene diol, it is preferable to use an alkylene diol having a hydroxyl group at both terminals of a linear or branched alkylene group having about 2 to 8, preferably about 2 to 6 carbon atoms. Specific examples of alkylene diols suitable for use in the present invention include alkylene glycols such as ethylene glycol, propylene glycol, butylene glycol, 1,6-hexamethylene glycol, and neopentyl glycol.
Examples of the alkylene diamine include linear alkylene diamines such as ethylene diamine, propylene diamine, butylene diamine, and hexamethylene diamine; branched alkylene diamines such as 1,2-diaminopropane and 1,3-diaminopentane; Cyclic alkylenediamines such as diamine, 1,3-cyclohexadiamine and 1,4-cyclohexadiamine can be used.
As the chain extender, a component selected from the above-described alkylene diols and alkylene diamines can be used alone or in combination of two or more. By using a chain extender, an appropriate hardness can be imparted to the obtained polyurethanes.
[0021]
The diisocyanate compound used for obtaining the polyurethanes used in the present invention is not particularly limited, and all diisocyanates conventionally used for producing polyurethanes and diisocyanates that will be developed in the future can be used. May be appropriately selected and used according to the characteristics described above. Specific examples of the diisocyanate include ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, octamethylene diisocyanate, undecamethylene diisocyanate, dodecamethylene diisocyanate, 3,3′-diisocyanate propyl ether, cyclopentylene-1, Alkylene diisocyanates such as 3-diisocyanate, cyclohexane-1,4-diisocyanate, 4,4′-methylenebis (cyclohexyl isocyanate), isophorone diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate Isocyanate, a mixture of 2,4-tolylene diisocyanate and 2,6-tolylene diisocyanate, xylylene-1,4-diene Socyanate, 4,4'-diphenylmethane diisocyanate, 4,4'-diphenylpropane diisocyanate, 4-isocyanatobensil isocyanate, m-phenylene diisocyanate, p-phenylene diisocyanate, naphthalene-1,4-diisocyanate, naphthalene-1,5 -Diisocyanate and the like.
[0022]
The method for producing the polyurethane used in the present invention is not particularly limited, and the active hydrogen-containing compound and the diisocyanate compound may be reacted in an organic solvent according to a conventional method. Examples of the organic solvent include hexamethylphosphoric triamide (HMPA), N-methyl-2-pyrrolidone (NMP), N-methylformamide (NMF), N, N-dimethylformamide (DMF), N, N-dimethyl Acetamide (DMAc), tetrahydrofuran (THF), toluene, dioxane, and the like can be used, and these organic solvents may be used as a mixture. The reaction ratio between the active hydrogen-containing compound and the diisocyanate compound is usually about 0.7 to 1.5 equivalents of the active hydrogen-containing compound per equivalent of the diisocyanate compound, and about 0.8 to 1.2 equivalents. It is preferable that
Specific reaction conditions vary depending on the structure of the diisocyanate or diol used. For example, the reaction is carried out under a nitrogen atmosphere at about 20 to 150 ° C. with stirring for about 1 to 50 hours, and the reaction product is subjected to a precipitation method or the like. A method for performing generation can be exemplified.
[0023]
Further, by reacting a diol component such as a diol, a polymer diol, or an alkylene diol containing a phosphorylcholine structure represented by the above formula (1) or (2) with a diisocyanate compound in the same manner as described above, A prepolymer having an isocyanate group at a terminal is obtained, and the prepolymer is dissolved in an organic solvent such as HMPA, NMP, NMF, DMF, DMAc, THF, and then cooled, and alkylenediamine is added to extend the polyurethane urea. Can also be produced by a method for obtaining
At the time of polymerization of the polyurethanes, there is no particular limitation so that the polymerization can proceed efficiently, but a polymerization catalyst such as tin dibutyl dilaurate and tetrabutoxy titanium may be added. Usually, the amount of the polymerization catalyst to be added may be about 10 to 1000 ppm based on the entire reaction solution.
[0024]
It is preferable to contain 0.03 to 1.30 mmol of phosphorus derived from the phosphorylcholine structure represented by the general formulas (1) and (2) per 1 g of the polyurethane used in the present invention. If the phosphorus content derived from the phosphorylcholine structure is less than 0.03 mmol, sufficient antithrombotic properties may not be obtained. If it exceeds 1.30 mmol, the mechanical properties of the polyurethanes are reduced, and the polyurethane is poor. It is not preferable because it becomes a material.
[0025]
The polyurethanes used in the present invention have a weight average molecular weight of about 3,000 to 8,000,000, preferably about 5,000 to 5,000,000. The molecular weight described in this specification is a value measured using gel permeation chromatography (GPC), and the gel column used for the measurement is Shodex AD-803 / S, AD-804 / S, AD-806 / S , KD-802 connected in series, using DMF in which 0.1% lithium bromide was dissolved as the mobile phase, drawing a calibration curve with polystyrene, and measuring the molecular weight at 50 ° C. I asked.
[0026]
Polyurethanes contained in the blood purification membrane of the present invention having such a structure, when a phosphorylcholine group having a phosphatidylcholine-like structure forming a biological membrane is introduced into the side chain, the case where introduced into the main chain. Biocompatibility is improved as compared with that, and extremely excellent antithrombotic properties can be exhibited. This is because, in general, the polymer main chain is entangled, and if the functional group that exerts performance is present in the main chain, it is difficult to exert its performance sufficiently, but it has a performance exhibiting site in the side chain This is considered to be due to the fact that the movement of the functional group is not suppressed by the polymer main chain, so that the mobility is improved and the performance can be sufficiently exhibited. Therefore, the blood purification membrane of the present invention has excellent biocompatibility and can exhibit very excellent antithrombotic properties because the phosphorylcholine group is introduced into the polyurethane in the side chain, so that the mobility of the phosphorylcholine group is low. It is considered that the effect of the biomembrane-like structure is greatly improved.
Furthermore, when the antithrombotic polyurethanes of the present invention are blended with a blood purification membrane to form a membrane, the antithrombotic polyurethanes are localized on the membrane surface because the phosphorylcholine group is hydrophilic. Therefore, even if the blood purification membrane of the present invention comes into contact with blood, its antithrombotic property is maintained.
[0027]
In the present invention, the content of the polyurethane is preferably 0.01 to 30% by weight, more preferably 0.1 to 20% by weight, and particularly preferably 1 to 10% by weight based on the film. preferable. If the content of the polyurethanes is less than 0.01% by weight with respect to the membrane, sufficient antithrombotic properties may not be obtained. If the content exceeds 30% by weight, the strength may be reduced depending on the material of the membrane. However, the addition of urethanes is not preferred because the permeability of the membrane may decrease. In general, the antithrombotic property is improved when the content of polyurethanes is increased, but depending on the state of presence of polyurethanes in the membrane (for example, when the polyurethanes are uniformly dispersed in the membrane material or concentrated on the surface of the membrane) The effect is not certain. In general, when the amount is within the above range, it is possible to obtain antithrombotic properties having no practical problem.
[0028]
Utilization of the blood purification membrane of the present invention, hemodialysis membrane, hemodiafiltration membrane, commonly referred to as artificial kidney used in the treatment of renal failure such as blood filtration membrane, plasma separation membrane, artificial lung, etc., contact with blood, It can be applied to all membranes that act on blood, such as dialysis, filtration, and gas exchange. In addition, although different from blood purification treatment, it can be applied to a plasma separation membrane for donor plasmapheresis that separates blood plasma from blood and donates the blood, but the most preferable application is contact between the membrane and blood. A long-lasting, continuous blood purification treatment membrane.
[0029]
The material for the membrane is not particularly limited, and is made of regenerated cellulose, saponified cellulose, cellulose acetate, cellulose triacetate, celluloses such as modified cellulose, polyacrylonitrile, polysulfone, polyether sulfone, polyamide, polymethyl methacrylate, ethylene vinyl. Examples include alcohol copolymers, polyvinyl alcohol, polyethylene, polypropylene, and silicone.
[0030]
The form of the membrane is not particularly limited, and examples thereof include a hollow fiber membrane, a tubular membrane, and a flat membrane.
[0031]
In the present invention, a preferable method for introducing polyurethanes into the membrane is to form a blood purification membrane from a stock solution containing polyurethanes. That is, the blood purification membrane is usually formed from a polymer as a membrane material, a solvent for the polymer, and if necessary, a non-solvent or an additive to which a membrane-forming stock solution is added and dissolved. If a membrane is formed from a membrane stock solution, a blood purification membrane containing polyurethanes can be obtained. However, when the heat resistance of polyurethanes is not so high, when a high temperature is required to dissolve the polymer, the polyurethanes can be added after cooling the film forming stock solution once dissolved at a high temperature.
[0032]
In the present invention, another preferable method for introducing the polyurethanes into the membrane is to coat the blood purification membrane obtained by a conventional method with the polyurethanes. In this method, polyurethane is introduced into the blood purification membrane once formed by post-treatment, which complicates the process.However, it is necessary to keep the stock solution at a high temperature during film formation, In the case where and the polyurethane cannot be dissolved in the same solvent, it can be suitably used as a method for introducing the polyurethane into the blood purification membrane.
[0033]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.
(Production of urethanes)
[0034]
Embedded image

In the general formula (2), R ¹ = R ⁴ -(A) n- and R ⁴ = Methyl, A = oxyethylene, n is average value 3.25, R ² = R ³ = R ⁷ = Methyl, R ⁵ = R ⁶ = Methylene, 60.00 g of a diol with m = 1, 158.4 g of polytetramethylene glycol (average molecular weight 1300), and 39.44 g of butanediol were dissolved in 700 ml of DMAc. A solution prepared by dissolving 202.00 g of 4,4′-methylenebis (cyclohexyl isocyanate) in 300 ml of DMAc was sufficiently dropped in the reactor after sufficiently replacing the inside of the reactor with argon gas, and then slowly added dropwise. After the dropwise addition, the mixture was stirred at 100 ° C. for 24 hours to perform polymerization. This reaction product was poured into 5,000 ml of water with stirring, the formed precipitate was separated by filtration, dissolved in THF, and further poured into a 50 vol% methanol aqueous solution with stirring, and the formed precipitate was collected and dried under reduced pressure. Thus, a polymer A was obtained. The weight average molecular weight of the obtained polymer A was 123,000.
[0035]
(Example 1)
18% by weight of polyether sulfone (Sumitomo Chemical Co., Ltd., Sumika Excel 4800P) as a polymer, 64% by weight of N-methyl-2-pyrrolidone as a solvent, 16% by weight of triethylene glycol as a non-solvent, and polyvinylpyrrolidone as a hydrophilizing agent 1% by weight of polymer A was added to 1% by weight of K90, and dissolved by stirring at 50 ° C. for 3 hours. After defoaming for 1 hour, undissolved matter was removed with a sintering filter to obtain a spinning solution. Was. A spinning stock solution is supplied from the outer slit of a tube-in-orifice type nozzle having a slit outer diameter of 300 μm, a slit inner diameter of 200 μm, and an inner liquid discharge hole diameter of 100 μm, and water 50 wt%, NMP 40 wt%, and triethylene glycol 10 wt% from the inner liquid discharge hole. Was discharged. The spinning solution discharged from the nozzle was guided to a coagulation bath immediately below the nozzle via a 30 cm aerial traveling section. The coagulation liquid was 80% by weight of water, 16% by weight of NMP, and 4% by weight of triethylene glycol, and the temperature was 60 ° C. The solidified hollow fiber membrane was washed with water, dried, and wound up with a winder. The winding speed was 15 m / min. The inner diameter of the obtained hollow fiber membrane was 200 μm, the outer diameter was 280 μm, and the film thickness was 40 μm.
9600 obtained hollow fiber membranes were bundled to assemble a dialyzer. Dialyzer membrane area is 1.5m ² Met.
[0036]
(Comparative Example 1)
A hollow fiber membrane was spun in the same manner as in Example 1 except that polyurethanes were not added to the spinning dope, and a membrane area of 1.5 m ² Was obtained.
[0037]
(Example 2)
The polymer A was diluted with THF to 0.5%, and the solution was circulated on the blood side of the dialyzer obtained in Comparative Example 1, and then dried under a stream of nitrogen, whereby the polymer A was subjected to hemodialysis membrane blood. Coated on side surfaces. From the weight change before and after coating, the coating amount was 3.5% by weight based on the film.
[0038]
(Anti-thrombotic evaluation test)
A film area of 1.5 m obtained in Examples 1 and 2 and Comparative Example 1. ² Was used. After washing each dialyzer with 1 L of physiological saline, 2 L of ACD-added bovine blood (hematocrit 30%, total protein concentration 6.5 g / dl, 37 ° C.) was passed at 200 ml / min, and filtered under the conditions of 20 ml / min. A circulation test was performed for 4 hours to return the blood and the filtrate flowing out of the dialyzer to the reservoir. Before the blood circulation, 1 hour, 2 hours, 3 hours, and at the end (4 hours) after the circulation, the platelet count was measured. After the circulation test, the dialyzer used was replaced with 1 L of physiological saline using the dialyzer. At the time of washing, the number of remaining blood of the hollow fibers in the dialyzer was measured. Table 1 shows the obtained results.
In the dialyzers using the urethane-containing membranes of Examples 1 and 2, it can be seen that the decrease in platelets and the amount of residual blood are small.
[0039]
(Dializer performance evaluation experiment)
1.5 m of film area obtained in Examples 1 and 2 and Comparative Example 1 ² The water permeability of the 37 ° C. water, the flow rate of the aqueous solution on the blood side of 200 ml, the flow rate of the dialysate of 500 ml, and the clearance of urea, vitamin B12 and myoglobin at 37 ° C. were measured. Table 2 shows the obtained results.
All dialyzers have practically acceptable performance, and it was confirmed that the introduction of urethanes did not lower the membrane performance.
[0040]
[Table 1]

In Comparative Example 1, after the end of the circulation, residual blood was observed in about 1/3 of the thread of the dialyzer.
[0041]
[Table 2]

Claims (5)

It has an improved antithrombotic property characterized by containing a polyurethane or polyurethaneurea obtained by using a diol having a phosphorylcholine structure represented by the general formula (1) or (2) in a side chain as at least a part of a diol component. Blood purification membrane.

[The formula (1) and ^{R 1} in (2) is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or the following radicals ^R 4, - (A) n-
(A is an oxyethylene, oxypropylene, oxybutylene, oxypentamethylene, or oxyhexamethylene group, one or more selected from these groups may be mixed, and the bonding order may be random. Is an integer of 1 to 30. R ⁴ is an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms. R ² and R ³ are an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms, and may be the same or different. R ⁵ and R ⁶ are an alkylene group having 2 to 10 carbon atoms, and R ⁵ and R ⁶ may be the same or different. m is an integer of 1 to 10. R ⁷ is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms. ] The content of the polyurethane or polyurethaneurea obtained by using the diol having a phosphorylcholine structure represented by the general formula (1) or (2) in the side chain as at least a part of the diol component is 0.01 to 10% with respect to the film. The blood purification membrane with improved antithrombotic properties according to claim 1, which is 30% by weight. The antithrombotic property improvement according to claim 1 or 2, wherein the polyurethane or polyurethaneurea contains 0.03 to 1.30 mmol of phosphorus derived from the phosphorylcholine structure represented by the general formula (1) or (2) per 1 g of the polymer. Blood purification membrane. 2. A film is formed from a stock solution containing polyurethane or polyurethaneurea obtained by using a diol having a phosphorylcholine structure represented by the general formula (1) or (2) in a side chain as at least a part of a diol component. 4. A blood purification membrane having improved antithrombotic properties according to any one of items 3 to 3. A polyurethane or polyurethane urea obtained by using a diol having a phosphorylcholine structure represented by the general formula (1) or (2) in a side chain as at least a part of a diol component is coated on at least a surface that comes into contact with blood. The blood purification membrane according to claim 1, wherein the blood purification membrane has improved antithrombotic properties.