JP3959676B2 - Highly safe polymer composition containing phosphorus-containing polymer - Google Patents

Description

【化１０】

［上記化学式（１）および化学式（２）において、Ｒ ¹ 、Ｒ ² 、Ｒ ³ 、Ｒ ⁶ は炭素数１〜１０のアルキレン基、炭素数６〜１２のアリーレン基、または炭素数７〜１５のアラルキレン基であり、それぞれ同じでも異なっていてもよく、水素原子は他の原子や官能基で置換されていてもよい。Ｒ ⁴ 、Ｒ ⁵ 、Ｒ ⁸ は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、それぞれ同じでもよく、異なっていてもよく、各基の水素原子は他の原子や官能基で置換されていてもよい。Ｒ ⁷ は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、炭素数７〜１５のアラルキル基、または下記化学式（３）の構造を有する基である。ＸはＮ、Ｈ−Ｃもしくは下記化学式（４）の構造を有する基である。］
【化１１】

【化１２】

［上記化学式（３）および化学式（４）において、Ａは炭素数２〜１０のオキシアルキレン基であり、１種または２種以上のオキシアルキレン基が混在してもよく、それらの結合順はブロックでもランダムでもよい。また、ｎは１〜３０の整数である。Ｒ ⁹ 、Ｒ ¹⁰ は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、各基の水素原子は他の原子や官能基で置換されていてもよい。］
２．（Ｃ）下記化学式（１）または下記化学式（２）に示されるジオールをジオール成分の少なくともひとつとし、脂肪族ジイソシアネートと芳香族ジイソシアネートを併用して得られるリン含有ポリウレタンおよび／またはポリウレタンウレアと（Ｄ）望ましい機械的および／または物理的および／または化学的特性を有する高分子からなり、（Ｃ）と（Ｄ）の重量比Ｃ／Ｄが１／１０００〜１／１である高分子組成物であって、該高分子組成物４．０ｇに対し生理食塩水２０ｍｌの浴比で５０℃にて７２時間の抽出操作を行った時の抽出液中のリン濃度が１５ｐｐｍ以下であることを特徴とする高分子組成物。
【化１３】

【化１４】

［上記化学式（１）および化学式（２）において、Ｒ ¹ 、Ｒ ² 、Ｒ ³ 、Ｒ ⁶ は炭素数１〜１０のアルキレン基、炭素数６〜１２のアリーレン基、または炭素数７〜１５のアラルキレン基であり、それぞれ同じでも異なっていてもよく、水素原子は他の原子や官能基で置換されていてもよい。Ｒ ⁴ 、Ｒ ⁵ 、Ｒ ⁸ は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、それぞれ同じでもよく、異なっていてもよく、各基の水素原子は他の原子や官能基で置換されていてもよい。Ｒ ⁷ は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、炭素数７〜１５のアラルキル基、または下記化学式（３）の構造を有する基である。ＸはＮ、Ｈ−Ｃもしくは下記化学式（４）の構造を有する基である。］
【化１５】

【化１６】

［上記化（３）および化（４）において、Ａは炭素数２〜１０のオキシアルキレン基であり、１種または２種以上のオキシアルキレン基が混在してもよく、それらの結合順はブロックでもランダムでもよい。また、ｎは１〜３０の整数である。Ｒ ⁹ 、Ｒ ¹⁰ は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、各基の水素原子は他の原子や官能基で置換されていてもよい。］
また、上記の安全性と生体適合性を有する医療用高分子組成物である。
【００１５】
本発明において使用されるリン含有高分子は、分子内にウレタン結合および／またはウレア結合を有し、分子内に共有結合および／またはイオン結合によって導入されたリンを有するリン含有高分子である。一方、特開平０９−１７６３７９には、抗菌性と抗血栓性を同時に有する素材として抗凝血性を有するムコ多糖類と第４級ホスホニウムがイオン性複合体開示されている。しかし、ここに開示されているリン含有高分子は、ムコ多糖類の高分子にイオン結合によってホスホニウムを導入したリン含有高分子であるので、イオン結合によってホスホニウムが導入されているものの、分子内にウレタン結合および／またはウレア結合を含有していないので本発明のリン含有高分子ではない。
【００１６】
また、特開平０９−１８７５０２、特開平１１−０４７２６４などにムコ多糖類と第４級ホスホニウムのイオン性複合体およびポリウレタン類を成分とする組成物が開示されている。ムコ多糖類と第４級ホスホニウムのイオン性複合体を（イ）、ポリウレタン類を（ロ）とした場合、（イ）は上記の通り本発明のリン含有高分子に相当しないので、（イ）＋（ロ）は本発明の高分子組成物には相当しない。特開平０９−１８７５０２、特開平１１−０４７２６４などで使用されるポリウレタン類には共有結合および／またはイオン結合によってリンが導入されていないので、本発明のリン含有高分子には含まれない。
【００１７】
本発明のリン含有高分子の調製方法は特に限定されず、分子内にウレタン結合および／またはウレア結合、共有結合および／またはイオン結合で導入されたリンおよび重合性炭素−炭素不飽和結合を含有するモノマーの付加重合によって高分子を得る方法なども利用され得る。しかしながら本発明においては、安全性と生体適合性が優れるポリウレタン類が好ましく、ポリウレタンおよび／またはポリウレタンウレアが特に好ましい。
【００１８】
ポリウレタン類はジイソシアネート、ソフトセグメントとなるマクロポリオール、鎖延長剤の３成分から調製される。このうちジイソシアネートは芳香族系ジイソシアネート、脂肪族系ジイソシアネート（脂環族系ジイソシアネートを含む）に大別される。芳香族系ジイソシアネートは比較的反応性が高いので、ポリウレタンおよびポリウレタンウレア調製時には、得られるポリウレタンおよびポリウレタンウレアの分子量が向上して好ましい。しかしながら、酸化分解による着色や、加水分解によって発癌性の危険のある芳香族系アミンが生じる可能性がある。脂肪族系ジイソシアネートは着色の恐れは少なく、また加水分解されても発癌性物質が生成する可能性は低い。ところが一方で反応性は芳香族系ジイソシアネートよりもやや劣り、高分子調製にはより過酷な条件や、触媒の添加が必要とある。
【００１９】
本発明のリン含有高分子がポリウレタン類である場合、脂肪族系ジイソシアネートと芳香族系ジイソシアネートを併用して得られるポリウレタンおよび／またはポリウレタンウレアであることが好ましい。本発明における脂肪族系ジイソシアネートとは、脂環族系ジイソシアネートをも包含し、従来ポリウレタンおよびポリウレタンウレアの製造に用いられている脂肪族系ジイソシアネート、および今後開発されるであろう脂肪族系ジイソシアネートすべてが使用され得る。具体的には、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、ヘキサ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、デカメチレンジイソシアネート、ドデカメチレンジソシアネート、３，３’−ジイソシアナトプロピルエーテル、シクロペンタンジイソシアネート、シクロヘキサンジイソシアネート、４，４’−メチレンビス（シクロヘキシルイソシアネート）などが例示されるが、これらに限定されない。また、ジイソシアネートを形成する炭化水素骨格の水素原子が他の原子や官能基などで置換されていてもよい。これらのうち、テトラメチレンジイソシアネート、ヘキサ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が好ましく、ヘキサメチレンジイソシアネートが特に好ましい。
【００２０】
本発明のリン含有高分子がポリウレタン類である場合に使用され得る芳香族系ジイソシアネートとは、従来ポリウレタンおよびポリウレタンウレアの製造に用いられている芳香族系ジイソシアネート、および今後開発されるであろう芳香族系ジイソシアネートすべてが使用され得る。具体的には、トリレンジイソシアネート、キシリレンジイソシアネート、フェニレンジイソシアネート、ナフタレンジイソシアネート、イソシアナトベンジルイソシアネート、４，４’−メチレンビス（フェニルイソシアネート）などが例示されるが、これらに限定されない。また、ジイソシアネートを形成する炭化水素骨格の水素原子が他の原子や官能基などで置換されていてもよい。これらのうち、４，４’−メチレンビス（フェニルイソシアネート）が特に好ましい。本発明に使用される脂肪族系ジイソシアネート、芳香族系ジイソシアネートはそれぞれ１種のジイソシアネートを使用しても、２種類以上を混合して使用してもよい。
【００２１】
本発明のリン含有高分子が脂肪族系ジイソシアネートと芳香族系ジイソシアネートを併用して得られるポリウレタンおよび／またはポリウレタンウレアである場合、脂肪族系ジイソシアネートと芳香族系ジイソシアネートの使用比率は、モル比で脂肪族系ジイソシアネート／芳香族系ジイソシアネート＝１／９〜９／１、好ましくは２／８〜７／３、さらに好ましくは２／８〜６／４である。これよりも脂肪族系ジイソシアネートが多いと反応が進行しにくく、これよりも芳香族系ジイソシアネートが多いと得られるポリウレタン類が着色する恐れがある。
【００２２】
本発明のリン含有高分子がポリウレタン類である場合、成分となるマクロポリオールについては、特に制限されず、一般的なポリウレタンおよびポリウレタンウレアに使用されるマクロポリオール、および今後開発されるであろうマクロポリオールが広く利用可能である。具体的には、例えば、低分子量ジオール（例えば、エチレングリコール、プロピレングリコール、テトラメチレングリコール、ペンタメチレングリコール、ヘキサメチレングリコール、オクタメチレングリコール、デカメチレングリコール、２，２−ジメチルトリメチレングリコール、１，４−ジヒドロキシシクロヘキサン、１，４−ジヒドロキシメチルシクロヘキサンなど）とジカルボン酸またはそのエステル形成性誘導体（例えば、シュウ酸、マロン酸、コハク酸、グルタル酸、アジピン酸、セバチン酸、ドデカンジカルボン酸、テレフタル酸、イソフタル酸またはこれらの酸ハライド、活性エステル、アミドなど）を反応させて得られるポリエステルジオール、ε−カプロラクトンなどの開環重合によって得られるポリラクトンジオール、ポリエチレングリコール、ポリプロピレングリコール、ポリテトラメチレングリコールなどのポリエーテルジオール、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などの不飽和炭化水素重合体の両末端に水酸基を持ったジオール（不飽和炭化水素がジエン類である場合も含め、ポリアルキレンジオールと呼ぶものとする）、各種ポリカーボネートジオールなどが例示される。中でもポリエーテルジオール、ポリカーボネートジオールが好ましい。これらのマクロポリオールは単独で使用しても、２種以上を混合して使用してもよい。
【００２３】
本発明のリン含有高分子がポリウレタン類である場合に使用され得る鎖延長剤については、特に制限されず、一般的なポリウレタン類に使用される鎖延長剤、および今後開発されるであろう鎖延長剤が広く利用可能である。具体的には、例えば、エチレングリコール、プロピレングリコール、テトラメチレングリコール、ペンタメチレングリコール、ヘキサメチレングリコール、オクタメチレングリコール、デカメチレングリコール、２，２−ジメチルトリメチレングリコール、１，４−ジヒドロキシシクロヘキサン、１，４−ジヒドロキシメチルシクロヘキサン、ジエチレングリコール、トリエチレングリコールなどのジオール、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、キシリレンジアミン、フェニレンジアミン、４，４’−メチレンビス（フェニルアミン）などのジアミン、２−アミノエタノール、３−アミノプロパノール、４−アミノブタノールなどのアミノアルコール、さらには、ジヒドラジド（例えばシュウ酸ジヒドラジド、マロン酸ジヒドラジド、コハク酸ジヒドラジド、アジピン酸ジヒドラジド、セバシン酸ジヒドラジド、イソフタル酸ジヒドラジド）など広義のジアミンなどが例示される。これらに限らず、低分子量ジオール、ジアミン、アミノアルコールとしては、公知、新規あるいはポリウレタン類への適用例の有無に関わらずすべて適用することができる。これらの鎖延長剤は単独で使用しても、２種以上を混合して使用してもよい。
【００２４】
本発明のリン含有高分子は、下記化学式（１）もしくは（２）に示す化合物をジオール成分のひとつとして、ポリウレタン類を調製する手法がより好ましい。
【化１７】

【化１８】

［上記化学式（１）および化学式（２）において、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁶は炭素数１〜１０のアルキレン基、炭素数６〜１２のアリーレン基、または炭素数７〜１５のアラルキレン基であり、それぞれ同じでも異なっていてもよく、水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁴、Ｒ⁵、Ｒ⁸は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、それぞれ同じでもよく、異なっていてもよく、各基の水素原子は他の原子や官能基で置換されていてもよい。Ｒ⁷は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、炭素数７〜１５のアラルキル基、または下記化学式（３）の構造を有する基である。ＸはＮ、Ｈ−Ｃもしくは下記の化学式（４）の構造を有する基である。］
【化１９】

【化２０】

［上記化学式（３）および化学式（４）において、Ａは炭素数２〜１０のオキシアルキレン基であり、１種または２種以上のオキシアルキレン基が混在してもよく、それらの結合順はブロックでもランダムでもよい。また、ｎは１〜３０の整数である。Ｒ⁹、Ｒ¹⁰は炭素数１〜１０のアルキル基、炭素数６〜１２のアリール基、または炭素数７〜１５のアラルキル基であり、各基の水素原子は他の原子や官能基で置換されていてもよい。］」。（下線部は今回の補正箇所）。
【００２５】
本発明のリン含有高分子がポリウレタン類であり、ホスホリルコリン類似構造含有ジオールを添加した場合には、例えば、次のような調製方法が例示される：ホスホリルコリン類似構造含有ジオールと脂肪族系ジイソシアネートを適当な溶媒中で混合して反応させ、これに芳香族系ジイソシアネート、続いてマクロポリオールを添加しプレポリマーを調製後、鎖延長剤を添加して高分子量のポリウレタンもしくはポリウレタンウレアを得る。この際に、ホスホリルコリン類似構造含有ジオールと脂肪族系ジイソシアネートを反応させた後、温度を下げて芳香族系ジイソシアネート、続いてマクロポリオールを添加するのが好ましい。脂肪族系ジイソシアネートを反応させる時の反応温度は５０℃〜１２０℃、好ましくは６０℃〜１００℃、芳香族ジイソシアネートを反応させる時の反応温度は３０℃〜１００℃、好ましくは４０℃〜８０℃で、脂肪族系ジイソシアネートを反応させるときの温度よりも低いことが好ましい。
【００２６】
また、ポリウレタン類を製造する際には、重合を効率的に行うため、重合触媒を添加してもよい。重合触媒としては、例えば、ジブチルジラウリン酸スズなどのスズ系触媒、テトラブトキシチタンなどのチタン系触媒などが例示される。
【００２７】
反応に使用される溶媒は、特に制限されないが、原料に対して不活性であり、原料の溶解性に優れる溶媒が好ましい。具体的には、例えば、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）、Ｎ−メチルピロリドン（ＮＭＰ）、ヘキサメチルリン酸トリアミド（ＨＭＰＡ）、テトラヒドロフラン（ＴＨＦ）、ジオキサン、ジメチルスルホキシド（ＤＭＳＯ）、トルエンなどが例示され、中でもＤＭＦ、ＤＭＡｃ、ＮＭＰが好ましい。溶媒は単独で使用しても、２種以上を混合して使用してもよい。また、無溶媒で反応を行う方法も適用できる。
【００２８】
本発明の高分子組成物を得るには、本発明に使用されるリン含有高分子および／または高分子組成物を調製後、十分な洗浄を行うことが有効な手法の一つである。具体的には、例えば、温水中に浸漬、撹拌しながら不純物を除去する手法が採用され得る。この際、温水の温度は４０℃〜９５℃、好ましくは５０℃〜９０℃、さらに好ましくは６０℃〜８０℃であり、洗浄時間は３０分〜４８時間、好ましくは６０分〜２４時間、さらに好ましくは９０分〜１２時間である。これ以下の低温、短時間の洗浄では不純物の除去効果が十分でなく、これ以上の高温、長時間の洗浄ではポリマーの分解、劣化を招く恐れがある。また、ポリマーの洗浄温水に対する浴比は１ｇ／１０ｍｌ〜１ｇ／５００ｍｌ、好ましくは１ｇ／２０ｍｌ〜１ｇ／４００ｍｌ、さらに好ましくは１ｇ／５０ｍｌ〜１ｇ／２００ｍｌである。これ以下の浴比ではリン含有高分子および／または高分子組成物が洗浄温水に十分に浸かりにくいため効果が十分に得られにくく、これ以上の浴比では多量の洗浄温水を使用することになり効率的でない。洗浄水には、界面活性剤や親水性有機溶媒を添加して洗浄効率を高めることも可能である。洗浄に有機溶媒を用いる手法も利用し得るが、溶媒残存の可能性や洗浄溶媒の処理などの観点から、上記の通り温水で洗浄することがより好ましい。
【００２９】
本発明の高分子組成物は単独であってもよく、また、ブレンド、コーティング、グラフト化、共重合などの方法で他の素材と複合して改質することも可能である。
【００３０】
本発明に使用される望ましい機械的および／または物理的および／または化学的特性を有する高分子体（以下単に高分子体と略記する）は特に制限されないが、例えば、各種用途に使用される次のような高分子体が例示される。すなわち、ポリエチレン（人工血管、血液回路、チューブなど）、ポリプロピレン（血液バッグ、血液回路、コネクター、チューブなど）、ＰＶＣ（血液バッグ、血液回路、カテーテル、チューブなど）、ポリウレタン類（人工心臓、カテーテル、チューブ、人工透析器ポッティング剤、人工肺ポッティング剤など）、ポリカーボネート（人工透析器ハウジング、人工肺ハウジングなど）、ポリスチレン（細胞培養器、コネクターなど）、シリコーン（人工肺、カテーテル、チューブ、血液回路など）、セルロースおよびセルロース誘導体（人工透析器など）、ポリフルオロカーボン（人工血管など）、ポリアクリレートおよびポリメタクリレート（コンタクトレンズ、人工透析器、カテーテル、チューブなど）、ポリアミド（縫合糸など）、ポリスルホンおよびポリエーテルスルホン（人工透析器など）、天然ゴム（導尿カテーテルなど）などである。
【００３１】
本発明で言う望ましい機械的および／または物理的および／または化学的特性とは、特定の用途に利用した際、その用途使用時に求められる特性のことを示し、具体的には、例えば、機械的強度、弾性、加工性、成型性、耐熱性、耐候性、耐光性、耐分解性、耐着色性、染色性、特定物質の吸着性、特定物質に対する不活性さ、親水性／疎水性、溶媒の接触角、溶媒への溶解性／耐溶解性、表面荷電性などが例示される。
【００３２】
本発明のリン含有高分子と高分子体の配合比は、（リン含有高分子）／（望ましい機械的および／または物理的および／または化学的特性を有する高分子）＝１／１０００〜１／１、より好ましくは１／１００〜１／１、さらに好ましくは１／５０〜１／２である。
【００３３】
本発明の（リン含有高分子）と（望ましい機械的および／または物理的および／または化学的特性を有する高分子）の配合方法は特に限定されず、公知の方法、および今後開発されるであろう方法が広く適用できる。具体的には、例えば、両者の固体同士を物理的に混合する方法（固体混合）、両者の溶液を混合する方法、あるいはリン含有ポリマー、高分子体双方を溶解可能な溶媒に投入して両者を同時に溶解、混合する方法（溶液混合）、リン含有高分子溶融液と高分子体溶融液を混合する方法（溶融混合）などが例示される。また、リン含有高分子構成成分と別の高分子体構成成分を共重合させたり、どちらかを他方にグラフト化するなど、化学的な手法によって最終的に組成物とする手法も本発明によって制限されるものではない。さらに、高分子体表面にリン含有高分子をコーティングする手法についても、本発明においては配合方法のひとつとして包含する。
【００３４】
本発明では、リン含有高分子と望ましい機械的および／または物理的および／または化学的特性を有する高分子以外の成分を添加することも制限されない。具体的には、例えば可塑剤、フィラー、着色剤、ＵＶ吸収剤、酸化防止剤、安定剤、さらには抗菌剤などを添加することも可能である。
【００３５】
本発明の高分子組成物は安定性、安全性、生体適合性に優れている。このような利点を活かして、本発明の高分子組成物は汎用用途はもちろんのこと、特に医療用材料として広く利用され得る。具体的には、例えば、血液透析膜や血漿分離膜、血液中老廃物の吸着材、人工肺用膜、血管内バルーン、血液バッグ、カテーテル、カニューレ、シャント、血液回路などの医療用具用素材、およびこれら医療用具のコーティング材などが例示される。
【００３６】
【実施例】
以下、実施例によって本発明を説明するが、本発明はこれらの実施例によって制限されるものではない。
【００３７】
〈実施例１〉
（リン含有高分子の調製）
下記化学式（８）に示す化合物（以下コリンジオールと略記する）１０．００ｇをセパラブルフラスコに秤取し、ＮＭＰ５０ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を７５℃まで加熱し、ＨＤＩ６．７５ｇを加え１時間撹拌した。反応温度を５５℃にまで下げて３０分撹拌し、ＭＤＩ２３．４３ｇを加え、５５℃で１時間撹拌後、数平均分子量２０００のＰＴＭＧ１６．０３ｇをＮＭＰ１４ｍｌに溶解して添加した。５５℃で１時間撹拌しプレポリマーを調製した。この反応混合液にＢＤ６．９２ｇを２回に分けて添加し５５℃で１時間撹拌した。ＮＭＰ４０ｍｌを加えて反応混合液を希釈し、５５℃で１２時間撹拌して反応させた。ＢＤ１ｇを加えて末端停止を行い、５５℃から徐々に室温になるまで撹拌を継続した。反応混合液を５０００ｍｌの水に落とし込んで生成物を回収し、７０℃の温水での２時間の洗浄を３回繰り返した後、減圧乾燥してリン含有高分子Ａを得た。
【化１１】

【００３８】
（リン含有高分子の分子量）
臭化リチウムを０．１％添加したＤＭＦにリン含有高分子Ａを加えて溶解し、ゲルパーミエーションクロマトグラフィー（ＧＰＣ）により分子量を測定した。ゲルカラムはＳｈｏｄｅｘ ＡＤ−８０３／Ｓ、ＡＤ−８０４／Ｓ、ＡＤ−８０６／Ｓ、ＡＤ−８０２／Ｓを直列に連結して使用し、ポリエチレングリコールで作成した検量線により、温度は５０℃、移動相は臭化リチウムを０．１％添加したＤＭＦで測定した。結果は表１に示した。
【００３９】
（リン含有高分子の抽出液リン濃度）
ＡＳＴＭ Ｆ７５０（材料抽出液のマウス全身毒性試験）の方法に引用された抽出条件である、ＡＳＴＭ Ｆ６１９（メディカル・プラスティックの抽出方法）に記載された抽出条件に準拠し、リン含有高分子Ａ４．０ｇを生理食塩水２０ｍｌに浸漬し５０℃にて７２時間の抽出操作を行った。無機応用比色分析（共立出版）第４巻、１２７〜２０６ページに記載された方法に準拠して、この抽出液を硫酸・硝酸・過塩素酸系で湿式分解後、吸光光度法によってリン含量を定量分析した。結果は表１に示した。
【００４０】
【表１】

【００４１】
（高分子組成物の調製）
高分子体として住友化学株式会社製ポリエーテルスルホン（スミカエクセル４８００Ｐ、以下ＰＥＳと略記する）１７００重量部、溶媒としてＮＭＰ７７４９重量部、非溶媒として水５００重量部に、リン含有高分子Ａ５１重量部を加え７０℃にて３時間撹拌溶解した。１時間静置して脱泡した後、焼結フィルターで未溶解物を除去してＰＥＳとリン含有高分子Ａの混合溶液を得た。この混合溶液をガラス板上に均一に乗せ、水８０重量％、ＮＭＰ２０重量％の凝固液中に一気に沈めて凝固させた。得られた平膜（フィルム状物）を５０℃の温水で２時間洗浄後減圧乾燥して平膜Ａを得た。
【００４２】
（高分子組成物の抽出液抽出液リン濃度）
上記リン含有高分子の抽出液リン濃度と同様の方法で平膜Ａの抽出を行い、抽出液中のリン濃度を測定した。結果は表２に示した。
【００４３】
【表２】

表２の細胞毒性の値において１００％とは、抽出原液でも細胞の増殖抑制に影響が見られなかったことを示す。
【００４４】
（高分子組成物の溶出物試験）
「透析型人工腎臓装置承認基準」昭和５８年６月２０日厚生省薬務局長通知に記載された透析膜の溶出物試験にある抽出条件に準拠して、平膜Ａ１．５ｇを注射用蒸留水１５０ｍｌに浸漬し７０℃にて１時間の溶出操作を行った。この溶出液を用いて、血液回路の品質及び試験にある溶出物試験の項目のうち、ｐＨ、過マンガン酸カリウム還元性物質（ＫＭｎＯ₄）、蒸発残留物（残渣）、紫外吸収スペクトル（ＵＶ）について評価した。結果は表２に示した。
【００４５】
（高分子組成物の細胞毒性）
薬機第９９号（平成７年６月２７日）厚生省薬務局医療機器開発課長通知に記載された、医療用具又は材料の抽出液を用いた細胞毒性試験の方法に準拠して、Ｖ７９細胞を使用し、平膜ＡのＩＣ５０（％）を求めた。結果は表２に示した。
【００４６】
（高分子組成物の急性毒性）
ＡＳＴＭ Ｆ６１９（メディカル・プラスティックの抽出方法）に記載された抽出条件に準拠してリン含有高分子Ａを抽出し、ＡＳＴＭ Ｆ７５０−８２（材料抽出液のマウス全身毒性試験）の方法に準拠して、マウスに尾静脈から５０μｌ/ｇ・マウス体重の投与量で投与し、状態の変化を観察した。結果は表２に示した。
【００４７】
〈実施例２〉
（リン含有高分子の調製）
コリンジオール１０．００ｇをセパラブルフラスコに秤取し、ＮＭＰ４０ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を７５℃まで加熱し、ＨＤＩ６．８０ｇを加え１時間撹拌した。反応温度を５０℃にまで下げて３０分撹拌し、ＴＤＩ１６．４３ｇを加え、５０℃で１時間撹拌後、数平均分子量２０００のＰＴＭＧ１３．７５ｇをＮＭＰ１５ｍｌに溶解して添加した。５０℃で１時間撹拌しプレポリマーを調製した。この反応混合液にＢＤ７．０２ｇを２回に分けて添加し５０℃で１時間撹拌した。ＮＭＰ３０ｍｌを加えて反応混合液を希釈し、５０℃で１２時間撹拌して反応させた。ＢＤ１ｇを加えて末端停止を行い、５０℃から徐々に室温になるまで撹拌を継続した。反応混合液を５０００ｍｌの水に落とし込んで生成物を回収し、７０℃の温水での２時間の洗浄を３回繰り返した後、減圧乾燥してリン含有高分子Ｂを得た。
【００４８】
（リン含有高分子の分子量）
（リン含有高分子の抽出液リン濃度）
実施例１と同様の方法でリン含有高分子Ｂの分子量、抽出液リン濃度について試験を行った。結果は表１に示した。
【００４９】
（高分子組成物の調製）
（高分子組成物の抽出液リン濃度）
（高分子組成物の溶出物試験）
（高分子組成物の細胞毒性）
（高分子組成物の急性毒性）
実施例１と同様の方法で高分子組成物を調製し、抽出液リン濃度、溶出物試験、細胞毒性、急性毒性について試験を行った。結果は表２に示した。
【００５０】
〈比較例１〉
（リン含有高分子の調製）
コリンジオール１０．００ｇをセパラブルフラスコに秤取し、ＮＭＰ４０ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を７５℃まで加熱し、ＨＤＩ２２．５５ｇを加え１時間撹拌後、数平均分子量２０００のＰＴＭＧ１３．５３ｇをＮＭＰ１４ｍｌに溶解して添加した。７５℃で１時間撹拌しプレポリマーを調製した。この反応混合液にＢＤ７．０３ｇを２回に分けて添加し７５℃で１時間撹拌した。ＮＭＰ３０ｍｌを加えて反応混合液を希釈し、７５℃で１２時間撹拌して反応させた。ＢＤ１ｇを加えて末端停止を行い、７５℃から徐々に室温になるまで撹拌を継続した。反応混合液を５０００ｍｌの水に落とし込んで生成物を回収し、７０℃の温水で２時間洗浄後減圧乾燥してリン含有高分子Ｃを得た。
【００５１】
（リン含有高分子の分子量）
（リン含有高分子の抽出液リン濃度）
実施例１と同様の方法でリン含有高分子Ｃの分子量、抽出液リン濃度について試験を行った。結果は表１に示した。
【００５２】
（高分子組成物の調製）
（高分子組成物の抽出液リン濃度）
（高分子組成物の溶出物試験）
（高分子組成物の細胞毒性）
（高分子組成物の急性毒性）
実施例１と同様の方法で高分子配合物を調製し、抽出液リン濃度、溶出物試験、細胞毒性、急性毒性について試験を行った。結果は表２に示した。
【００５３】
〈比較例２〉
（リン含有高分子の調製）
コリンジオール１０．００ｇをセパラブルフラスコに秤取し、ＮＭＰ５０ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を５５℃まで加熱し、ＭＤＩ３３．６０ｇを加え１時間撹拌後、数平均分子量２０００のＰＴＭＧ１７．１６ｇをＮＭＰ１８ｍｌに溶解して添加した。５５℃で１時間撹拌しプレポリマーを調製した。この反応混合液にＢＤ６．８７ｇを２回に分けて添加し７５℃で１時間撹拌した。ＮＭＰ４０ｍｌを加えて反応混合液を希釈し、５５℃で１２時間撹拌して反応させた。ＢＤ１ｇを加えて末端停止を行い、５５℃から徐々に室温になるまで撹拌を継続した。反応混合液を５０００ｍｌの水に落とし込んで生成物を回収し、７０℃の温水で２時間洗浄後減圧乾燥してリン含有高分子Ｄを得た。
【００５４】
（リン含有高分子の分子量）
（リン含有高分子の抽出液リン濃度）
実施例１と同様の方法でリン含有高分子Ｄの分子量、抽出液リン濃度について試験を行った。結果は表１に示した。
【００５５】
（高分子組成物の調製）
（高分子組成物の抽出液リン濃度）
（高分子組成物の溶出物試験）
（高分子組成物の細胞毒性）
（高分子組成物の急性毒性）
実施例１と同様の方法で高分子配合物を調製し、抽出液リン濃度、溶出物試験、細胞毒性、急性毒性について試験を行った。結果は表２に示した。
【００５６】
〈比較例３〉
（リン含有高分子の調製）
コリンジオール１０．００ｇ、数平均分子量１３２０のＰＴＭＧ１６．３１ｇをセパラブルフラスコに秤取し、ＤＭＡｃ２００ｍｌを加えて溶解させた。以下の操作はすべて窒素雰囲気下で行った。溶液を１００℃まで加熱し、ＨＭＤＩ２４．６４ｇをゆっくり加え、添加後５時間撹拌した。ＨＤＩ６．７７ｇをゆっくり加え、添加後１００℃で１０時間撹拌した。ＢＤ７．５３ｇをゆっくり添加し、さらに１００℃で５時間撹拌した。反応後、この反応混合液を５０００ｍｌの水に落とし込んだ。得られた沈澱物を濾別し、ＴＨＦに溶解して再びメタノールに注ぎ込み、生じた沈澱物を回収、減圧乾燥してリン含有高分子Ｅを得た。
【００５７】
（リン含有高分子の分子量）
（リン含有高分子の抽出液リン濃度）
実施例１と同様の方法でポリマーＥの分子量、抽出液リン濃度について試験を行った。結果は表１に示した。
【００５８】
（高分子組成物の調製）
（高分子組成物の抽出液リン濃度）
（高分子組成物の溶出物試験）
（高分子組成物の細胞毒性）
（高分子組成物の急性毒性）
実施例１と同様の方法で高分子配合物を調製し、抽出液リン濃度、溶出物試験、細胞毒性、急性毒性について試験を行った。結果は表２に示した。
【００５９】
【発明の効果】
実施例から明らかなように、本発明の高分子組成物は、溶出物試験での溶出物、細胞毒性、急性毒性が低く安全性が高いことがわかった。比較例の高分子組成物は溶出物試験での溶出物は低いものの、細胞毒性、急性毒性が比較的高く、安全性にやや問題があることがわかった。安全性に優れているという利点を活かして、本発明の高分子組成物は汎用用途はもちろんのこと、特に医療用材料として広く利用され得る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a polymer blend containing a phosphorus-containing polymer with little eluate and excellent stability and safety. The polymer blend of the present invention is particularly suitable for medical applications.
[0002]
[Prior art]
The material is required to have characteristics according to the application, but generally, a material having excellent mechanical characteristics, that is, excellent in strength and durability is preferable. Materials that have been researched and developed to obtain excellent mechanical properties are also applied to medical applications due to their excellent properties.
[0003]
At the same time, since medical materials are used in direct contact with living bodies, higher safety is required than in other applications. However, biological properties including safety of medical materials tended to lack sufficient consideration and consideration until recently. In particular, the elution of decomposition products, unreacted monomers, by-products and oligomers under the use conditions for medical applications, that is, contact with body fluids such as blood, is said to be a serious disadvantage for medical materials. I must.
[0004]
For example, polyvinyl chloride (PVC) is very widely used as a medical material because its hardness can be freely changed according to the amount of plasticizer added, it is relatively stable under general usage conditions, and it is inexpensive. Has been. However, in PVC, the plasticizer phthalate ester may be eluted during use. Phthalate esters have been shown to be toxic by many studies and are problematic in terms of safety.
[0005]
Silicone is also used as various types of catheters and tubes as a medical elastomer, and it is also used as a membrane material for artificial lungs due to its gas permeation properties. There are concerns about toxicity.
[0006]
Polyurethane and / or polyurea and / or polyurethaneurea (hereinafter abbreviated as “polyurethanes”) can be prepared by appropriately setting the blending ratio of macroglycol as a soft segment, diisocyanate as a hard segment and chain extender. It is possible to prepare a material having a preferable hardness without using it. It is also known that segmented polyurethane forms a microphase-separated structure and thereby exhibits excellent blood compatibility. In addition, it is relatively easy to prepare a material having a preferable functional group, for example, an amino group-containing polyurethane can be prepared by using an amino group-containing diol as one of the raw materials. Due to these advantages, polyurethane is one of polymer materials that are favorably used as medical materials. However, on the other hand, strength reduction and generation of eluate have been reported due to a hydrolysis reaction or the like during sterilization or in vivo use, which may be a problem in terms of safety.
[0007]
The medical material is required to have a characteristic that is difficult for a living body to recognize as a foreign substance, that is, biocompatibility. A cell constituting a living body is composed of a phospholipid bilayer membrane in which hydrophilic portions are arranged on the outside, and an attempt has been made to realize excellent biocompatibility with a material imitating this structure. Japanese Patent Laid-Open No. 54-063025 discloses 2-methacryloyloxyethyl phosphorylcholine, which has a choline group similar to lecithin, which is a phospholipid. There is a description of having. As a similar material, Japanese Patent Laid-Open Nos. 57-036868 and 59-199696 disclose methods for producing phospholipid analogs. Japanese Patent Laid-Open No. 60-067489 discloses a method for producing a natural polymerizable phospholipid in which an unsaturated carbon-carbon bond is introduced into a long chain hydrocarbon group. In these techniques, a polymer material can be obtained by addition polymerization using an unsaturated carbon-carbon bond. JP-T 62-500726 discloses a polyurethane containing a phosphorylcholine group. Further, JP-A-60-206835 discloses a polymer material in which the main chain is formed from repeating units of phosphorylcholine by ring-opening polymerization of a dioxaphosphorane derivative.
[0008]
These are techniques that have been studied with a focus on improving biocompatibility, but it is not always possible to give sufficient consideration to the stability and safety of materials. Since the phosphate ester portion may be cleaved by hydrolysis, it is pointed out that the material in which the phosphorylcholine group is introduced in a pendant form may be detached from the phosphate ester portion. The elution component is a substance that is thought to exist in the living body, so it is unlikely to have a fatal effect on safety, but it is related to the safety of the material in the complicated route in the living body. I think that it is enough. There is also great doubt about the persistence of the biocompatibility of the material surface that has been altered by cleavage of the phosphate ester moiety. The situation is the same for materials that incorporate phosphorylcholine into the main chain. In this case, the cleavage of the phosphate ester means fragmentation of the main chain, which significantly reduces the strength of the material and is a practical problem. Is likely to occur.
[0009]
As a technique for applying phosphorus from a viewpoint different from the biocompatibility improvement technique using a phosphorylcholine-like structure, the present inventors have disclosed a material having both antibacterial and antithrombotic properties in Japanese Patent Application Laid-Open No. 09-176379. This is a technique in which the antibacterial action of phosphonium salt and the antithrombotic action of mucopolysaccharide are fused. In JP-A-11-047264, sufficient antibacterial and antithrombotic properties are obtained when the phosphorus concentration in the extract is within a specific range. It is disclosed that sex, its durability, and safety to living bodies are exhibited. In the technique disclosed in Japanese Patent Laid-Open No. 11-047264, although attention is paid to the safety of the entire composition of the quaternary phosphonium-containing ionic complex and the polymer material, it is originally an antibacterial substance. Since an ionic complex containing a quaternary phosphonium salt that is toxic to a living body is added, it cannot be denied that there is still concern about safety.
[0010]
In addition to the approach of developing better materials by improving the properties of the polymer itself, studies have been made to achieve the required functionality by combining two or more new and / or existing materials. ing. For example, JP-T-7-50459 discloses a polymer blend comprising (A) a polymer having a zwitterionic pendant group; and (B) a polymer having desired mechanical and / or physical properties. Has been. What is disclosed here is that biocompatibility is achieved by blending a phosphorylcholine group-containing component, which has been considered to be excellent in biocompatibility, and a polymer having mechanical and / or physical properties. Technology aimed at simultaneously realizing mechanical and / or physical properties, mainly coating of phosphorylcholine group-containing components on devices with complex shapes that were difficult in the past, elution during use, base material It aims to improve the deterioration of the characteristics of the. Therefore, in this technique, it is difficult to say that safety and stability are considered sufficiently. In particular, since the component (A) is a zwitterionic group, specifically, a phosphorylcholine group, which is introduced in a pendant form from the main chain, this part is cleaved and used during hydrolysis due to hydrolysis and the like. The possibility of coming is pointed out.
[0011]
There are various indexes for evaluating the stability and safety of polymers, but there are surprisingly few that are relatively easy to implement, have good reproducibility, and can generally evaluate overall stability and safety. There are acute systemic toxicity tests, subacute toxicity tests, cytotoxicity, and the like to evaluate safety to living bodies, but it is necessary to use animals and cultured cells for experiments, and it cannot be said that it can be easily carried out. In addition, manufacturing approval standards for various medical devices are defined (for example, “dialysis-type artificial kidney device approval standards”, notification by the Director of Pharmacy of the Ministry of Health and Welfare on June 20, 1983). Although the values are shown, there are some aspects in which a polymer that meets this reference value cannot always be said to have sufficient safety.
[0012]
[Problems to be solved by the invention]
The present invention can improve stability, safety and biocompatibility, which still have problems while attempts are being made by various approaches in the prior art, and can achieve other desirable characteristics at the same time. An object is to provide a polymer composition.
[0013]
[Means for Solving the Problems]
The inventors of the present invention have already obtained a polyurethane or polyurethane urea containing a phosphate ester bond with improved antithrombogenicity obtained by using two or more types of aliphatic (including alicyclic) diisocyanates, and polyurethane. Or the composition which contains a polyurethane urea as a component was discovered (Unexamined-Japanese-Patent No. 2000-128950). Furthermore, as a result of continuing intensive studies in view of such circumstances, a polymer containing phosphorus introduced by urethane bond and / or urea bond and covalent bond and / or ionic bond in the molecule (hereinafter simply referred to as phosphorus-containing). In some cases, the polymer composition containing a high-molecular-weight composition (hereinafter sometimes abbreviated as “polymer”) is ASTM F619 (medical / extract), which is the extraction condition cited in the method of ASTM F750-82 (mouse systemic toxicity test of material extract). In accordance with the extraction conditions described in (Plastic extraction method), when extraction is performed with physiological saline and the phosphorus concentration in the extract is a specific value or less, the safety of the polymer composition is high. As a result, the present invention has been achieved.
[0014]
That is, the polymer composition of the present invention is
1. (A)A phosphorus-containing polyurethane and / or polyurethane urea obtained by using a diol represented by the following chemical formula (1) or the following chemical formula (2) as at least one diol component, and using an aliphatic diisocyanate and an aromatic diisocyanate in combination,Phosphorus-containing polyurethane and / or polyurethane-urea containing phosphorus having a phosphorus concentration of 300 ppm or less when extraction operation is carried out at 50 ° C. for 72 hours in a bath ratio of 20 ml of physiological salinePolyurethane and / or polyurethane ureaAnd (B) a polymer having desirable mechanical and / or physical and / or chemical properties, and the weight ratio A / B of (A) and (B) is 1/1000 to 1/1. A polymer composition characterized by that.
[Chemical 9]

[Chemical Formula 10]

[In the above chemical formulas (1) and (2), R ¹ , R ² , R ^Three , R ⁶ Are an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 15 carbon atoms, which may be the same or different, and the hydrogen atom is another atom or functional group. May be substituted. R ^Four , R ^Five , R ⁸ Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, which may be the same or different from each other, It may be substituted with an atom or a functional group. R ⁷ Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure represented by the following chemical formula (3). X is N, H—C or a group having the structure of the following chemical formula (4). ]
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[In the above chemical formula (3) and chemical formula (4), A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more oxyalkylene groups may be mixed, and their bonding order is blocked. But it may be random. Moreover, n is an integer of 1-30. R ⁹ , R ^Ten Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group may be substituted with another atom or a functional group. . ]
2. (C)A phosphorus-containing polyurethane and / or polyurethane urea obtained by using a diol represented by the following chemical formula (1) or the following chemical formula (2) as at least one diol component and using an aliphatic diisocyanate and an aromatic diisocyanate in combination.And (D) a polymer having desirable mechanical and / or physical and / or chemical properties, and (C) and (D) having a weight ratio C / D of 1/1000 to 1/1 The composition has a phosphorus concentration of 15 ppm or less when 4.0 g of the polymer composition is subjected to an extraction operation at 50 ° C. for 72 hours at a bath ratio of 20 ml of physiological saline. A polymer composition characterized by the above.
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[In the above chemical formulas (1) and (2), R ¹ , R ² , R ^Three , R ⁶ Are an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 15 carbon atoms, which may be the same or different, and the hydrogen atom is another atom or functional group. May be substituted. R ^Four , R ^Five , R ⁸ Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, which may be the same or different from each other, It may be substituted with an atom or a functional group. R ⁷ Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure represented by the following chemical formula (3). X is N, H—C or a group having the structure of the following chemical formula (4). ]
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[In the above chemical formula (3) and chemical formula (4), A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more oxyalkylene groups may be mixed, and their bonding order is blocked. But it may be random. Moreover, n is an integer of 1-30. R ⁹ , R ^Ten Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group may be substituted with another atom or a functional group. . ]
  Moreover, it is a medical polymer composition having the above safety and biocompatibility.
[0015]
The phosphorus-containing polymer used in the present invention is a phosphorus-containing polymer having a urethane bond and / or a urea bond in the molecule and phosphorus introduced by a covalent bond and / or an ionic bond in the molecule. On the other hand, JP 09-176379 discloses an ionic complex of mucopolysaccharide having anticoagulability and quaternary phosphonium as a material having both antibacterial and antithrombotic properties. However, since the phosphorus-containing polymer disclosed here is a phosphorus-containing polymer in which phosphonium is introduced into the mucopolysaccharide polymer by ionic bond, phosphonium is introduced by ionic bond, Since it does not contain a urethane bond and / or a urea bond, it is not the phosphorus-containing polymer of the present invention.
[0016]
Further, JP-A 09-187502, JP-A 11-047264, and the like disclose a composition comprising an ionic complex of mucopolysaccharide and quaternary phosphonium and polyurethane as components. When the ionic complex of mucopolysaccharide and quaternary phosphonium is (b) and the polyurethane is (b), (b) does not correspond to the phosphorus-containing polymer of the present invention as described above. + (B) does not correspond to the polymer composition of the present invention. The polyurethanes used in JP-A Nos. 09-187502 and 11-047264 are not included in the phosphorus-containing polymer of the present invention because phosphorus is not introduced by covalent bonds and / or ionic bonds.
[0017]
The method for preparing the phosphorus-containing polymer of the present invention is not particularly limited, and contains phosphorus and polymerizable carbon-carbon unsaturated bonds introduced by urethane bonds and / or urea bonds, covalent bonds and / or ionic bonds in the molecule. A method of obtaining a polymer by addition polymerization of a monomer to be used can also be used. However, in the present invention, polyurethanes excellent in safety and biocompatibility are preferable, and polyurethane and / or polyurethane urea are particularly preferable.
[0018]
Polyurethanes are prepared from three components: a diisocyanate, a macropolyol serving as a soft segment, and a chain extender. Of these, diisocyanates are roughly classified into aromatic diisocyanates and aliphatic diisocyanates (including alicyclic diisocyanates). Aromatic diisocyanates have a relatively high reactivity, and therefore, when polyurethane and polyurethane urea are prepared, the molecular weight of the obtained polyurethane and polyurethane urea is preferably improved. However, coloring due to oxidative degradation and aromatic amines that can be carcinogenic may occur due to hydrolysis. Aliphatic diisocyanates are less likely to be colored and are less likely to produce carcinogens when hydrolyzed. On the other hand, the reactivity is slightly inferior to that of aromatic diisocyanate, and the preparation of a polymer requires more severe conditions and addition of a catalyst.
[0019]
When the phosphorus-containing polymer of the present invention is a polyurethane, it is preferably a polyurethane and / or polyurethane urea obtained by using an aliphatic diisocyanate and an aromatic diisocyanate in combination. The aliphatic diisocyanate in the present invention includes alicyclic diisocyanates and includes all aliphatic diisocyanates that have been used in the production of conventional polyurethanes and polyurethane ureas, and any aliphatic diisocyanates that will be developed in the future. Can be used. Specifically, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, decamethylene diisocyanate, dodecamethylene diisocyanate, 3,3′-diisocyanatopropyl ether, cyclopentane Examples thereof include, but are not limited to, diisocyanate, cyclohexane diisocyanate, and 4,4′-methylenebis (cyclohexyl isocyanate). Moreover, the hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group. Of these, tetramethylene diisocyanate, hexamethylene diisocyanate, and octamethylene diisocyanate are preferable, and hexamethylene diisocyanate is particularly preferable.
[0020]
Aromatic diisocyanates that can be used when the phosphorus-containing polymer of the present invention is a polyurethane include aromatic diisocyanates that have been used in the production of conventional polyurethanes and polyurethane ureas, and aromatics that will be developed in the future. All group diisocyanates can be used. Specific examples include tolylene diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene diisocyanate, isocyanatobenzyl isocyanate, 4,4'-methylenebis (phenyl isocyanate), but are not limited thereto. Moreover, the hydrogen atom of the hydrocarbon skeleton forming the diisocyanate may be substituted with another atom or a functional group. Of these, 4,4'-methylenebis (phenyl isocyanate) is particularly preferred. As the aliphatic diisocyanate and aromatic diisocyanate used in the present invention, one kind of diisocyanate may be used, or two or more kinds may be mixed and used.
[0021]
When the phosphorus-containing polymer of the present invention is a polyurethane and / or polyurethane urea obtained by using an aliphatic diisocyanate and an aromatic diisocyanate in combination, the use ratio of the aliphatic diisocyanate and the aromatic diisocyanate is in molar ratio. Aliphatic diisocyanate / aromatic diisocyanate = 1/9 to 9/1, preferably 2/8 to 7/3, more preferably 2/8 to 6/4. If the amount of aliphatic diisocyanate is larger than this, the reaction hardly proceeds, and if the amount of aromatic diisocyanate is larger than this, the resulting polyurethane may be colored.
[0022]
When the phosphorus-containing polymer of the present invention is a polyurethane, the component macropolyol is not particularly limited, and the macropolyol used for general polyurethane and polyurethaneurea, and the macro that will be developed in the future. Polyols are widely available. Specifically, for example, a low molecular weight diol (for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1, 4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, etc.) and dicarboxylic acid or ester-forming derivatives thereof (eg oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, dodecanedicarboxylic acid, terephthalic acid , Isophthalic acid or acid halides thereof, active esters, amides, etc.) obtained by reaction with polylactonediol obtained by ring-opening polymerization of polyester diol, ε-caprolactone, etc. Diols having hydroxyl groups at both ends of unsaturated hydrocarbon polymers such as polyether diols such as polyethylene glycol, polypropylene glycol and polytetramethylene glycol, polybutadiene diol, polyisoprene diol and hydrogenated polyisoprene diol (unsaturated carbon Examples thereof include polyalkylene diols including cases where hydrogen is a diene), and various polycarbonate diols. Of these, polyether diol and polycarbonate diol are preferable. These macropolyols may be used alone or in combination of two or more.
[0023]
The chain extender that can be used when the phosphorus-containing polymer of the present invention is a polyurethane is not particularly limited, and a chain extender used for general polyurethanes and a chain that will be developed in the future. Extenders are widely available. Specifically, for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1,4-dihydroxycyclohexane, 1 Diamines such as 1,4-dihydroxymethylcyclohexane, diethylene glycol, and triethylene glycol; diamines such as ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, xylylenediamine, phenylenediamine, and 4,4′-methylenebis (phenylamine); -Amino alcohols such as aminoethanol, 3-aminopropanol, 4-aminobutanol, as well as dihydrazides (e.g. C acid dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, isophthalic acid dihydrazide) broad diamines such as are exemplified. Not only these but low molecular weight diol, diamine, and amino alcohol can be applied regardless of the presence or absence of known, novel, or examples of application to polyurethanes. These chain extenders may be used alone or in combination of two or more.
[0024]
The phosphorus-containing polymer of the present invention has the following chemical formula (1Or (2The method of preparing polyurethanes using the compound shown in (1) as one of the diol components is more preferred.
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[The above chemical formula (1) And chemical formula (2), R¹, R², R^Three, R⁶Are an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an aralkylene group having 7 to 15 carbon atoms, which may be the same or different, and the hydrogen atom is another atom or functional group. May be substituted. R^Four, R^Five, R⁸Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, which may be the same or different from each other, It may be substituted with an atom or a functional group. R⁷Is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or the following chemical formula (3). X is N, HC or the following chemical formula (4). ]
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[The above chemical formula (3) And chemical formula (4), A is an oxyalkylene group having 2 to 10 carbon atoms, and one or two or more oxyalkylene groups may be mixed, and their bonding order may be block or random. Moreover, n is an integer of 1-30. R⁹, R^TenIs an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group may be substituted with another atom or a functional group. . ] " (The underlined part is the current correction point).
[0025]
When the phosphorus-containing polymer of the present invention is a polyurethane and a diol containing a phosphorylcholine-like structure is added, for example, the following preparation method is exemplified: a suitable diol containing a phosphorylcholine-like structure and an aliphatic diisocyanate The mixture is reacted in a solvent and reacted, and an aromatic diisocyanate and subsequently a macropolyol are added to prepare a prepolymer, and then a chain extender is added to obtain a high molecular weight polyurethane or polyurethaneurea. At this time, it is preferable to react the phosphorylcholine-like structure-containing diol with the aliphatic diisocyanate and then add the aromatic diisocyanate and then the macropolyol at a reduced temperature. The reaction temperature when the aliphatic diisocyanate is reacted is 50 ° C to 120 ° C, preferably 60 ° C to 100 ° C, and the reaction temperature when the aromatic diisocyanate is reacted is 30 ° C to 100 ° C, preferably 40 ° C to 80 ° C. Thus, the temperature is preferably lower than the temperature at which the aliphatic diisocyanate is reacted.
[0026]
Moreover, when manufacturing polyurethane, in order to perform superposition | polymerization efficiently, you may add a polymerization catalyst. Examples of the polymerization catalyst include a tin-based catalyst such as tin dibutyldilaurate and a titanium-based catalyst such as tetrabutoxy titanium.
[0027]
The solvent used in the reaction is not particularly limited, but a solvent that is inert to the raw material and excellent in solubility of the raw material is preferable. Specifically, for example, N-methylformamide (NMF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), hexamethylphosphate triamide (HMPA) ), Tetrahydrofuran (THF), dioxane, dimethyl sulfoxide (DMSO), toluene and the like, among which DMF, DMAc and NMP are preferred. A solvent may be used individually or may be used in mixture of 2 or more types. Moreover, the method of reacting without a solvent is also applicable.
[0028]
In order to obtain the polymer composition of the present invention, it is one of effective techniques to perform sufficient washing after preparing the phosphorus-containing polymer and / or polymer composition used in the present invention. Specifically, for example, a technique of removing impurities while being immersed and stirred in warm water can be employed. At this time, the temperature of the hot water is 40 ° C. to 95 ° C., preferably 50 ° C. to 90 ° C., more preferably 60 ° C. to 80 ° C., and the washing time is 30 minutes to 48 hours, preferably 60 minutes to 24 hours. Preferably, it is 90 minutes to 12 hours. Cleaning at a lower temperature and shorter time than this is not sufficient to remove impurities, and cleaning at a higher temperature and longer time may cause degradation and degradation of the polymer. The ratio of the polymer to the washing water is 1 g / 10 ml to 1 g / 500 ml, preferably 1 g / 20 ml to 1 g / 400 ml, and more preferably 1 g / 50 ml to 1 g / 200 ml. If the bath ratio is less than this, the phosphorus-containing polymer and / or polymer composition is not sufficiently soaked in the washing warm water, so that it is difficult to obtain the effect sufficiently. If the bath ratio is higher than this, a large amount of washing warm water is used. Not efficient. It is also possible to increase the cleaning efficiency by adding a surfactant or a hydrophilic organic solvent to the cleaning water. Although a method using an organic solvent can be used for washing, washing with warm water as described above is more preferable from the viewpoint of the possibility of remaining solvent and the treatment of the washing solvent.
[0029]
The polymer composition of the present invention may be used alone or may be modified by being combined with other materials by a method such as blending, coating, grafting or copolymerization.
[0030]
The polymer body having desirable mechanical and / or physical and / or chemical properties used in the present invention (hereinafter simply referred to as a polymer body) is not particularly limited. Examples of such a polymer body are illustrated. That is, polyethylene (artificial blood vessel, blood circuit, tube, etc.), polypropylene (blood bag, blood circuit, connector, tube, etc.), PVC (blood bag, blood circuit, catheter, tube, etc.), polyurethane (artificial heart, catheter, Tube, artificial dialyzer potting agent, artificial lung potting agent, etc.), polycarbonate (artificial dialyzer housing, artificial lung housing, etc.), polystyrene (cell culture device, connector, etc.), silicone (artificial lung, catheter, tube, blood circuit, etc.) ), Cellulose and cellulose derivatives (such as artificial dialyzers), polyfluorocarbon (such as artificial blood vessels), polyacrylates and polymethacrylates (contact lenses, artificial dialyzers, catheters, tubes, etc.), polyamides (such as sutures) Polysulfone and polyether sulfone (artificial dialyzer, etc.), natural rubber (urinary catheters, etc.) and the like.
[0031]
Desirable mechanical and / or physical and / or chemical characteristics in the present invention indicate characteristics required for use in a specific application, specifically, for example, mechanical Strength, elasticity, workability, moldability, heat resistance, weather resistance, light resistance, decomposition resistance, coloring resistance, dyeability, adsorptivity of specific substances, inertness to specific substances, hydrophilicity / hydrophobicity, solvent Contact angle, solubility in solvents / resistance to dissolution, surface chargeability, and the like.
[0032]
The compounding ratio of the phosphorus-containing polymer and polymer of the present invention is (phosphorus-containing polymer) / (polymer having desirable mechanical and / or physical and / or chemical properties) = 1/1000 to 1 / 1, more preferably 1/100 to 1/1, still more preferably 1/50 to 1/2.
[0033]
The blending method of (phosphorus-containing polymer) and (polymer having desirable mechanical and / or physical and / or chemical properties) of the present invention is not particularly limited, and is a known method and will be developed in the future. The brazing method can be widely applied. Specifically, for example, both solids are physically mixed (solid mixing), both solutions are mixed, or both the phosphorus-containing polymer and polymer are put into a solvent that can dissolve both. Are simultaneously dissolved and mixed (solution mixing), a method of mixing a phosphorus-containing polymer melt and a polymer melt (melt mixing), and the like. In addition, the present invention also limits the method of finally forming a composition by a chemical method, such as copolymerizing a phosphorus-containing polymer component with another polymer component, or grafting one to the other. Is not to be done. Furthermore, the technique of coating the surface of the polymer with a phosphorus-containing polymer is also included as one of the blending methods in the present invention.
[0034]
In the present invention, addition of a component other than the phosphorus-containing polymer and the polymer having desirable mechanical and / or physical and / or chemical properties is not limited. Specifically, for example, plasticizers, fillers, colorants, UV absorbers, antioxidants, stabilizers, and antibacterial agents can be added.
[0035]
The polymer composition of the present invention is excellent in stability, safety and biocompatibility. Taking advantage of such advantages, the polymer composition of the present invention can be widely used not only for general purposes but also as a medical material. Specifically, for example, hemodialysis membranes and plasma separation membranes, blood waste adsorbents, artificial lung membranes, intravascular balloons, blood bags, catheters, cannulas, shunts, medical device materials such as blood circuits, Examples thereof include coating materials for these medical devices.
[0036]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not restrict | limited by these Examples.
[0037]
<Example 1>
(Preparation of phosphorus-containing polymer)
A compound represented by the following chemical formula (8) (hereinafter abbreviated as choline diol) 10.00 g was weighed into a separable flask, and NMP 50 ml was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C. and 6.75 g of HDI was added and stirred for 1 hour. The reaction temperature was lowered to 55 ° C. and the mixture was stirred for 30 minutes, 23.43 g of MDI was added, and after stirring at 55 ° C. for 1 hour, 16.03 g of PTMG having a number average molecular weight of 2000 was dissolved in 14 ml of NMP and added. A prepolymer was prepared by stirring at 55 ° C. for 1 hour. To this reaction mixture, 6.92 g of BD was added in two portions and stirred at 55 ° C. for 1 hour. The reaction mixture was diluted by adding 40 ml of NMP, and stirred at 55 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 55 ° C. until the temperature gradually reached room temperature. The reaction mixture was dropped into 5000 ml of water, and the product was collected. Washing with hot water at 70 ° C. for 2 hours was repeated three times, and then dried under reduced pressure to obtain phosphorus-containing polymer A.
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[0038]
(Molecular weight of phosphorus-containing polymer)
Phosphorus-containing polymer A was added and dissolved in DMF to which 0.1% of lithium bromide was added, and the molecular weight was measured by gel permeation chromatography (GPC). The gel column uses Shodex AD-803 / S, AD-804 / S, AD-806 / S, and AD-802 / S connected in series, and the temperature is 50 ° C due to the calibration curve created with polyethylene glycol. The phase was measured with DMF supplemented with 0.1% lithium bromide. The results are shown in Table 1.
[0039]
(Phosphorus concentration of phosphorus-containing polymer extract)
In accordance with the extraction conditions described in ASTM F619 (medical plastic extraction method), which is the extraction conditions cited in the method of ASTM F750 (mouse systemic toxicity test of material extract), a phosphorus-containing polymer A4.0 g Was immersed in 20 ml of physiological saline and extracted at 50 ° C. for 72 hours. Inorganic colorimetric analysis (Kyoritsu Shuppan) Vol. 4, pages 127-206, this extract was wet-decomposed in sulfuric acid / nitric acid / perchloric acid, and then phosphorous content was determined by spectrophotometry. Was quantitatively analyzed. The results are shown in Table 1.
[0040]
[Table 1]

[0041]
(Preparation of polymer composition)
As a polymer, 1700 parts by weight of polyethersulfone (Sumika Excel 4800P, hereinafter abbreviated as PES) manufactured by Sumitomo Chemical Co., Ltd., NMP7749 parts by weight as a solvent, 500 parts by weight of water as a non-solvent, 51 parts by weight of phosphorus-containing polymer A The mixture was stirred and dissolved at 70 ° C. for 3 hours. After leaving for 1 hour to degas, undissolved material was removed with a sintered filter to obtain a mixed solution of PES and phosphorus-containing polymer A. This mixed solution was uniformly placed on a glass plate, and submerged in a coagulation solution of 80% by weight of water and 20% by weight of NMP to be coagulated. The obtained flat membrane (film-like product) was washed with warm water at 50 ° C. for 2 hours and then dried under reduced pressure to obtain a flat membrane A.
[0042]
(Polymer composition extract extract phosphorus concentration)
Extraction of the flat membrane A was performed in the same manner as the phosphorus concentration of the phosphorus-containing polymer extract, and the phosphorus concentration in the extract was measured. The results are shown in Table 2.
[0043]
[Table 2]

100% of the cytotoxicity values in Table 2 indicate that no influence was observed on cell growth inhibition even with the extracted stock solution.
[0044]
(Elution test of polymer composition)
In accordance with the extraction conditions in the dialysis membrane eluate test described in the “dialysis-type artificial kidney device approval criteria” June 20, 1983, notification of the Director of Pharmacy, Ministry of Health and Welfare, 1.5 g of flat membrane A was distilled water for injection. It was immersed in 150 ml and subjected to elution operation at 70 ° C. for 1 hour. Using this eluate, the pH, potassium permanganate reducing substance (KMnO) among the quality of blood circuit and the items of eluate test in the test_Four), Evaporation residue (residue), and ultraviolet absorption spectrum (UV). The results are shown in Table 2.
[0045]
(Cytotoxicity of polymer composition)
In accordance with the method of cytotoxicity test using extract of medical device or material described in Drug Machine No.99 (June 27, 1995), Notification of Director of Medical Device Development, Ministry of Health and Welfare, V79 cells The IC50 (%) of flat membrane A was determined. The results are shown in Table 2.
[0046]
(Acute toxicity of polymer composition)
Extracting phosphorus-containing polymer A in accordance with the extraction conditions described in ASTM F619 (Medical Plastic Extraction Method), and in accordance with the method of ASTM F750-82 (Material Extraction Mouse Systemic Toxicity Test), Mice were dosed from the tail vein at a dose of 50 μl / g · mouse weight, and the change in condition was observed. The results are shown in Table 2.
[0047]
<Example 2>
(Preparation of phosphorus-containing polymer)
10.00 g of cholinediol was weighed into a separable flask, and 40 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 6.80 g of HDI was added and stirred for 1 hour. The reaction temperature was lowered to 50 ° C. and stirred for 30 minutes, 16.43 g of TDI was added, and after stirring for 1 hour at 50 ° C., 13.75 g of PTMG having a number average molecular weight of 2000 was dissolved in 15 ml of NMP and added. The prepolymer was prepared by stirring at 50 ° C. for 1 hour. To this reaction mixture, 7.02 g of BD was added in two portions and stirred at 50 ° C. for 1 hour. 30 ml of NMP was added to dilute the reaction mixture, and the reaction was stirred at 50 ° C. for 12 hours. 1 g of BD was added to terminate the end, and stirring was continued from 50 ° C. until the temperature gradually reached room temperature. The reaction mixture was dropped into 5000 ml of water, and the product was collected. Washing with hot water at 70 ° C. for 2 hours was repeated 3 times, followed by drying under reduced pressure to obtain phosphorus-containing polymer B.
[0048]
(Molecular weight of phosphorus-containing polymer)
(Phosphorus concentration of phosphorus-containing polymer extract)
Tests were conducted on the molecular weight of the phosphorus-containing polymer B and the extract phosphorus concentration in the same manner as in Example 1. The results are shown in Table 1.
[0049]
(Preparation of polymer composition)
(Phosphorus concentration of polymer composition extract)
(Elution test of polymer composition)
(Cytotoxicity of polymer composition)
(Acute toxicity of polymer composition)
A polymer composition was prepared in the same manner as in Example 1, and tested for extract phosphorus concentration, eluate test, cytotoxicity, and acute toxicity. The results are shown in Table 2.
[0050]
<Comparative example 1>
(Preparation of phosphorus-containing polymer)
10.00 g of cholinediol was weighed into a separable flask, and 40 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 22.55 g of HDI was added and stirred for 1 hour, and 13.53 g of PTMG having a number average molecular weight of 2000 was dissolved in 14 ml of NMP and added. The mixture was stirred at 75 ° C. for 1 hour to prepare a prepolymer. To this reaction mixture, 7.03 g of BD was added in two portions and stirred at 75 ° C. for 1 hour. 30 ml of NMP was added to dilute the reaction mixture, and the mixture was stirred at 75 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 75 ° C. until the temperature gradually reached room temperature. The reaction mixture was dropped into 5000 ml of water to recover the product, washed with hot water at 70 ° C. for 2 hours and then dried under reduced pressure to obtain phosphorus-containing polymer C.
[0051]
(Molecular weight of phosphorus-containing polymer)
(Phosphorus concentration of phosphorus-containing polymer extract)
The test was performed for the molecular weight of the phosphorus-containing polymer C and the extract phosphorus concentration in the same manner as in Example 1. The results are shown in Table 1.
[0052]
(Preparation of polymer composition)
(Phosphorus concentration of polymer composition extract)
(Elution test of polymer composition)
(Cytotoxicity of polymer composition)
(Acute toxicity of polymer composition)
A polymer formulation was prepared in the same manner as in Example 1, and tested for extract phosphorus concentration, eluate test, cytotoxicity, and acute toxicity. The results are shown in Table 2.
[0053]
<Comparative example 2>
(Preparation of phosphorus-containing polymer)
10.00 g of cholinediol was weighed into a separable flask, and 50 ml of NMP was added and dissolved. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 55 ° C., 33.60 g of MDI was added and stirred for 1 hour, and then 17.16 g of PTMG having a number average molecular weight of 2000 was dissolved in 18 ml of NMP and added. A prepolymer was prepared by stirring at 55 ° C. for 1 hour. To this reaction mixture, 6.87 g of BD was added in two portions and stirred at 75 ° C. for 1 hour. The reaction mixture was diluted by adding 40 ml of NMP, and stirred at 55 ° C. for 12 hours for reaction. 1 g of BD was added to terminate the end, and stirring was continued from 55 ° C. until the temperature gradually reached room temperature. The reaction mixture was dropped into 5000 ml of water to recover the product, washed with hot water at 70 ° C. for 2 hours, and then dried under reduced pressure to obtain phosphorus-containing polymer D.
[0054]
(Molecular weight of phosphorus-containing polymer)
(Phosphorus concentration of phosphorus-containing polymer extract)
Tests were conducted on the molecular weight of the phosphorus-containing polymer D and the extract phosphorus concentration in the same manner as in Example 1. The results are shown in Table 1.
[0055]
(Preparation of polymer composition)
(Phosphorus concentration of polymer composition extract)
(Elution test of polymer composition)
(Cytotoxicity of polymer composition)
(Acute toxicity of polymer composition)
A polymer formulation was prepared in the same manner as in Example 1, and tested for extract phosphorus concentration, eluate test, cytotoxicity, and acute toxicity. The results are shown in Table 2.
[0056]
<Comparative Example 3>
(Preparation of phosphorus-containing polymer)
10.00 g of choline diol and 16.31 g of PTMG having a number average molecular weight of 1320 were weighed in a separable flask and dissolved by adding 200 ml of DMAc. The following operations were all performed under a nitrogen atmosphere. The solution was heated to 100 ° C. and 24.64 g of HMDI was added slowly and stirred for 5 hours after the addition. 6.77 g of HDI was slowly added, followed by stirring at 100 ° C. for 10 hours. 7.53 g of BD was slowly added and further stirred at 100 ° C. for 5 hours. After the reaction, the reaction mixture was dropped into 5000 ml of water. The resulting precipitate was filtered off, dissolved in THF and poured into methanol again. The resulting precipitate was collected and dried under reduced pressure to obtain phosphorus-containing polymer E.
[0057]
(Molecular weight of phosphorus-containing polymer)
(Phosphorus concentration of phosphorus-containing polymer extract)
In the same manner as in Example 1, the molecular weight of polymer E and the extract phosphorus concentration were tested. The results are shown in Table 1.
[0058]
(Preparation of polymer composition)
(Phosphorus concentration of polymer composition extract)
(Elution test of polymer composition)
(Cytotoxicity of polymer composition)
(Acute toxicity of polymer composition)
A polymer formulation was prepared in the same manner as in Example 1, and tested for extract phosphorus concentration, eluate test, cytotoxicity, and acute toxicity. The results are shown in Table 2.
[0059]
【The invention's effect】
As is clear from the examples, the polymer composition of the present invention was found to have low eluate, cytotoxicity and acute toxicity in the eluate test and high safety. Although the polymer composition of the comparative example had a low eluate in the eluate test, it was found that the cytotoxicity and acute toxicity were relatively high, and there were some safety problems. Utilizing the advantage of being excellent in safety, the polymer composition of the present invention can be widely used not only for general purposes but also as a medical material.

Claims (3)

(A) A phosphorus-containing polyurethane and / or polyurethane urea obtained by using a diol represented by the following chemical formula (1) or the following chemical formula (2) as at least one diol component and using an aliphatic diisocyanate and an aromatic diisocyanate in combination. The phosphorus content in the extract is 300 ppm or less when the phosphorus-containing polyurethane and / or polyurethane urea is subjected to an extraction operation at 50 ° C. for 72 hours at a bath ratio of 20 ml of physiological saline. It comprises polyurethane and / or polyurethane urea and (B) a polymer having desirable mechanical and / or physical and / or chemical properties, and the weight ratio A / B of (A) to (B) is 1/1000. A polymer composition characterized by being 1/1.

[In the above chemical formulas (1) and (2), R ¹ , R ² , R ³ , R ⁶ are each an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an alkyl group having 7 to 15 carbon atoms. Aralkylene groups, which may be the same or different, and the hydrogen atom may be substituted with another atom or a functional group. R ⁴ , R ⁵ and R ⁸ are each an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, which may be the same or different, The hydrogen atom of each group may be substituted with other atoms or functional groups. R ⁷ is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure represented by the following chemical formula (3). X is N, H—C or a group having the structure of the following chemical formula (4). ]

[In the above chemical formula (3) and chemical formula (4), A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more oxyalkylene groups may be mixed, and their bonding order is blocked. But it may be random. Moreover, n is an integer of 1-30. R ⁹ and R ¹⁰ are an alkyl group having 1 to ¹⁰ carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group is substituted with another atom or a functional group May be. ] (C) Phosphorus-containing polyurethane and / or polyurethane urea obtained by using a diol represented by the following chemical formula (1) or the following chemical formula (2) as at least one diol component and using an aliphatic diisocyanate and an aromatic diisocyanate in combination (D A polymer composition comprising a polymer having desirable mechanical and / or physical and / or chemical properties, wherein the weight ratio C / D of (C) and (D) is 1/1000 to 1/1. The phosphorus concentration in the extract is 15 ppm or less when the polymer composition is subjected to an extraction operation at 50 ° C. for 72 hours at a bath ratio of 20 ml of physiological saline with respect to 4.0 g of the polymer composition. A polymer composition.

[In the above chemical formulas (1) and (2), R ¹ , R ² , R ³ , R ⁶ are each an alkylene group having 1 to 10 carbon atoms, an arylene group having 6 to 12 carbon atoms, or an alkyl group having 7 to 15 carbon atoms. Aralkylene groups, which may be the same or different, and the hydrogen atom may be substituted with another atom or a functional group. R ⁴ , R ⁵ and R ⁸ are each an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, which may be the same or different, The hydrogen atom of each group may be substituted with other atoms or functional groups. R ⁷ is an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or a group having a structure represented by the following chemical formula (3). X is N, H—C or a group having the structure of the following chemical formula (4). ]

[In the above chemical formula (3) and chemical formula (4), A is an oxyalkylene group having 2 to 10 carbon atoms, and one or more oxyalkylene groups may be mixed, and their bonding order is blocked. But it may be random. Moreover, n is an integer of 1-30. R ⁹ and R ¹⁰ are an alkyl group having 1 to ¹⁰ carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 15 carbon atoms, and the hydrogen atom of each group is substituted with another atom or a functional group May be. ] Medical polymer composition having a safety and biocompatibility consisting claim 1 or 2 polymeric composition.