JP2004248904A - Composite for medical treatment - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composite for medical treatment which is excellent in simplicity, flexibility and compatibility with blood or ingredients of blood. <P>SOLUTION: The composite for medical treatment (A)/(B) includes at least a main material (A) and an additive (B), wherein relation of θ<SB>A/B1</SB>≤0.9×θ<SB>A0</SB>, θ<SB>A/B2</SB>≤0.8×θ<SB>A0</SB>and θ<SB>A/B2</SB><θ<SB>A/B1</SB>is realized when a static contact angle of water in a dry state of (A) is θ<SB>A0</SB>, a static contact angle of water after soaking (A)/(B) in water is θ<SB>A/B1</SB>and a static contact angle of water after soaking (A)/(B) in blood plasma is θ<SB>A/B2</SB>, although a detailed mechanism is unknown. Both of the contact angle of water after soaking in water and the contact angle of water after soaking in blood plasma of the composite for medical treatment are smaller than the contact angle of water of the main material which formes the composite, and the contact angle of water of the composite after soaking in blood plasma is smaller than the contact angle of water after soaking in water, so that the composite for medical treatment shows an excellent compatibility with blood. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

［上記化学式（４）において、Ｒ４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、水素原子は他の原子や官能基で置換されていてもよい。Ｒ２、Ｒ３は水素原子、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。Ｒ５は水素原子が他の原子や官能基で置換されていてもよい炭素数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、または前記化学式（３）の構造を有する基である。Ｒ６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り、水素原子は他の原子や官能基で置換されていてもよい。］
【００２０】
高分子材料としては、例えば、生体膜構成成分の構造に類似した構造、好ましくはリン脂質類似構造、より好ましくは前記化学式（１）、さらに好ましくは前記化学式（２）の構造を有する成分を原料のひとつとして得られるポリウレタン、ポリウレタンウレア、ポリエステル、ポリアミド、ポリアクリレート、ポリメタクリレート、ポリアクリルアミド、ポリメタクリルアミドなどや、各種アミノ基含有ポリマーを改質して前記化学式（１）、好ましくは前記化学式（２）の構造を導入したポリマーなどが例示される。
【００２１】
本発明の（Ｂ）が高分子材料である場合の好ましい形態のひとつが、前記化学式（２）の構造を有する成分を原料のひとつとして得られるポリウレタン、またはポリウレタンウレアであるが、ポリウレタン、ポリウレタンウレア、ポリウレア（以下ポリウレタン類と略記する）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。
【００２２】
本発明の（Ｂ）がポリウレタン類である場合において使用され得るジイソシアネートとしては具体的には、例えば、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）、トリレンジソシアネート、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、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、４，４’−メチレンビス（フェニルイソシアネート）が好ましく、ヘキサメチレンジイソシアネート、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。ジイソシアネートは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。芳香族ジイソシアネート、脂肪族ジイソシアネート、脂環族ジイソシアネートを併用することも可能である。
【００２３】
本発明の（Ｂ）がポリウレタン類である場合において使用され得るマクロポリオールとしては具体的には、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。さらに、ポリエーテルジオールがより好ましい。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。
【００２４】
本発明の（Ｂ）がポリウレタン類である場合において使用され得る鎖延長剤については具体的には、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。中でも、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、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などの炭素数２〜６のジオールまたはジアミンが好ましく、さらに、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、エチレンジアミン、プロピレンジアミンがより好ましい。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。ジオール、ジアミン、アミノアルコールを併用することも可能である。
【００２５】
本発明の（Ｂ）がポリウレタン類である場合において、原料のひとつとして使用される双性イオンを含有する成分は具体的には、例えば、下記化学式（５）もしくは（６）に示す化合物をジオール成分が例示される。
【化５】

【化６】

［上記化学式（５）、（６）において、Ｒ１、Ｒ４、Ｒ９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。Ｒ２、Ｒ３、Ｒ７、Ｒ８は水素原子、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。Ｒ５は水素原子が他の原子や官能基で置換されていてもよい炭素数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、または前記化学式（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（７）の構造を有する基である。］
【化７】

［式中、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。］
【００２６】
本発明の（Ｂ）が高分子材料である場合の好ましい形態のひとつが、前記化学式（２）の構造を有する成分を原料のひとつとして得られるポリアクリレート、ポリメタクリレート、ポリアクリルアミド、ポリメタクリルアミドなど（以下ポリアクリレート類と略記する）である。本発明の（Ｂ）がポリアクリレート類である場合、例えば下記化学式（８）に示すモノマーを少なくとも共重合成分のひとつとして重合して得られるポリマーが好ましく利用され得る。
【化８】

［上記化学式（８）において、Ｒ４、Ｒ１２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。Ｒ２、Ｒ３、Ｒ１１は水素原子、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。Ｒ５は水素原子が他の原子や官能基で置換されていてもよい炭素数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、または前記化学式（３）の構造を有する基である。］
【００２７】
本発明の（Ｂ）が前記化学式（２）の構造を有する成分を原料のひとつとして得られるポリアクリレート類である場合の他の共重合成分としては具体的には、例えば、本発明の（Ｂ）がポリアクリレート類である場合、メチルアクリレート、エチルアクリレート、プロピルアクリレート、ブチルアクリレート、メトキシエチルアクリレート、メチルメタクリレート、エチルメタクリレート、プロピルメタクリレート、ブチルメタクリレート、２−ヒドロキシエチルメタクリレート、Ｎ，Ｎ−ジメチルアミノエチルアクリレート、アクリルアミド、Ｎ，Ｎ−ジメチルアクリルアミド、Ｎ−イソプロピルアクリルアミド、Ｎ，Ｎ−ジメチルアミノプロピルアクリルアミド、アクリロイルモルホリンなどが例示される。これらの共重合成分は１種類でも、２種類以上を使用してもよい。
【００２８】
本発明において、（Ａ）／（Ｂ）の配合比は、重量比で１０００／１〜１／１、好ましくは１００／１〜１／１、より好ましくは５０／１〜２／１である。
【００２９】
本発明の医療用組成物には、（Ａ）、（Ｂ）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。
【００３０】
本発明の医療用組成物は血液あるいは血液構成成分との適合性に優れている。
この利点を活かして、本発明の医療用組成物は、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として広く利用され得る。
【００３１】
【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。
【００３２】
〈実施例１〉
（双性イオン含有ポリウレタンの調製）
下記化学式（９）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、Ｎ−メチルピロリドン（ＮＭＰ）１５０ｍｌ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、ヘキサメチレンジイソシアネート（ＨＤＩ）２７．２２ｇ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、４，４’−メチレンビス（フェニルイソシアネート）（ＭＤＩ）９４．４８ｇを加え、５５℃で１時間撹拌後、数平均分子量２０００のポリテトラメチレングリコール（ＰＴＭＧ）３０．２５ｇをＮＭＰ１００ｍｌ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１，４−ブタンジオール（ＢＤ）３９．６８ｇを２回に分けて添加し５５℃で１時間撹拌した。ＮＭＰ１５０ｍｌ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。ＢＤ３ｇ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１０ｌ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ポリマー１を得た。
【化９】

【００３３】
（分子量の測定）
臭化リチウムを０．１％添加したＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）にポリマー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。この方法で測定した分子量は１９０００だった。
【００３４】
（組成物の調製）
主材（Ａ）としてポリエーテルスルホン（ＰＥＳ：住友化学工業社製スミカエクセル４８００Ｐ）をＤＭＦで溶解し、１ｗｔ％の濃度の溶液を調製した。同様に、添加材（Ｂ）としてポリマー１をＤＭＦで溶解し、１ｗｔ％の濃度の溶液を調製した。このＰＥＳ溶液とポリマー１溶液を９５：５の重量比で混合し、スライドガラス上に均一に乗せて、赤外線オーブン内で溶媒を除去した。減圧乾燥器内で、６０℃にて１８時間減圧乾燥して組成物フィルム１を得た。同様の操作でＰＥＳ単独のフィルム（ＰＥＳフィルム）を得た。乾燥後のフィルムは乾燥状態を保つためドライ・デシケーター内に保管し、２時間以内に接触角を測定した。
【００３５】
（主材の接触角測定）
協和界面科学株式会社製接触角計ＣＡ−Ｘ型を使用し、気温２５℃、湿度４０±５％に管理された測定室において、上記の操作で得た乾燥ＰＥＳフィルムの静的水接触角をスライドガラスに張り付いたままの状態で測定した。結果は表１に示した。
【００３６】
【表１】

条件ア、条件イ、条件ウとはそれぞれ、主材（Ａ）の乾燥状態での水の静的接触角（θ_Ａ０）、主材（Ａ）と添加材（Ｂ）を含有してなる組成物を水に浸漬した後の水の静的接触角（θ_Ａ／Ｂ１）、主材（Ａ）と添加材（Ｂ）を含有してなる組成物を血漿に浸漬した後の水の静的接触角（θ_Ａ／Ｂ２）とした時、
条件ア θ_Ａ／Ｂ１≦０．９×θ_Ａ０
条件イ θ_Ａ／Ｂ２≦０．８×θ_Ａ０
条件ウ θ_Ａ／Ｂ２＜θ_Ａ／Ｂ１
を意味する。
【００３７】
（組成物の水浸漬後の接触角測定）
上記の操作で得た乾燥組成物フィルム１をスライドガラスに張り付いたままの状態で、室温のイオン交換水に３０分間浸漬した後引き上げ、濾紙で付着水を除去した。その後、速やかに上記の方法で水の静的接触角を測定した。結果は表１に示した。
【００３８】
（組成物の血漿浸漬後の接触角測定）
上記の操作で得た乾燥組成物フィルム１をスライドガラスに張り付いたままの状態で、室温のクエン酸加牛血漿に３０分間浸漬した後引き上げ、イオン交換水でリンスした。濾紙で付着水を除去後、速やかに上記の方法で水の静的接触角を測定した。結果は表１に示した。
【００３９】
（組成物の抗血漿凝固性の評価）
上記の操作で得た乾燥組成物フィルム１をスライドガラスに張り付いたままの状態でガラスシャーレ上に乗せ、３７℃の恒温水槽に設置した。このフィルム上にクエン酸加牛血漿１００μｌを滴下し、０．０２５ｍｏｌ／ｌの塩化カルシウム水溶液１００μｌを加えて、液が混和するように穏やかに振盪した。塩化カルシウム水溶液を添加した時点から血漿が凝固（血漿が動かなくなる時点）までの経過時間を測定し、同様の操作をガラス上で行った場合の血漿凝固に要した時間で割り、相対凝固時間として表した。結果は表２に示した。
【００４０】
【表２】

【００４１】
（組成物による中空糸の作製）
主材（Ａ）としてＰＥＳ（住友化学工業社製スミカエクセル４８００Ｐ）５０００ｇ、親水化剤としてポリビニルピロリドン（ＢＡＳＦ社製コリドンＫ９０）２５ｇ、添加材（Ｂ）としてポリマーＩ１５０ｇを溶媒ＮＭＰ１１８６５ｇ、非溶媒トリエチレングリコール７９１０ｋｇに添加し、１００℃で４時間撹拌して溶解後、７０℃で１２時間静置脱泡した。この溶液を焼結フィルターで濾過し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のノズルの外側からこの紡糸原液を、内液吐出孔からＮＭＰ２０ｗｔ％水溶液の内液を吐出した。ノズルから吐出した紡糸原液は２０ｃｍの空中走行を経て、ノズル直下の凝固浴に導いた。凝固液はＮＭＰ２０ｗｔ％水溶液で温度は７０℃とした。紡糸した中空糸は水洗後、ワインダーにより巻き取り速度４５ｍ／分で巻き取り、中空糸１を得た。中空糸１の内径は２００μｍ、外径は２６０μｍで、膜厚は３０μｍであった。
【００４２】
（中空糸抗凝血性の評価）
上記の操作で得られた中空糸１を１０本束ねて両末端をシリコンチューブに挿入し、シリコン接着剤で固めて組成物マイクロモジュール（ＭＤ）１を得た。この組成物ＭＤ１にクエン酸加牛全血を封入し、透析液中に沈めて一定時間経過後、封入血をシャーレに満たした生理食塩水に滴下して状態を観察した。結果は表２に示した。
【００４３】
〈実施例２〉
（双性イオン含有アクリルアミド共重合体の調製）
トリエチレングリコールモノメチルエーテル（以下ＴＥＧ−Ｍｅと略記する）２３．０５ｇおよびトリエチルアミン１４．２０ｇをテトラヒドロフラン（以下ＴＨＦと略記する）４０ｍｌに溶解した溶液に、２−クロロ−２−オキソ−１，３，２−ジオキサホスホラン（以下ＣＯＰと略記する）をＴＨＦ７５ｍｌに溶解した溶液を、窒素気流下、−２０℃でゆっくり滴下し、滴下終了後−１０℃で３時間、その後０℃までゆっくりと昇温しながら５時間撹拌して反応を行った。その後、沈殿物を濾過、除去し、濾液を減圧乾燥して下記化学式（１０）に示す化合物（以下Ｍｅ−ＴＥＧ−ＯＰと略記する）を得た。Ｎ，Ｎ−ジメチルアミノプロピルアクリルアミド１１．５６ｇ、上記の操作で得たＭｅ−ＴＥＧ−ＯＰ２０．００ｇをＤＭＦ６０ｍｌに溶解し、窒素気流下、６０℃で６時間撹拌して反応を行った。その後、この反応混合物にｎ−ブチルメタクリレート９４．７１ｇおよび重合開始剤ＶＡ−０８６（和光純薬工業株式会社製）４ｇを加え、８０℃で２４時間撹拌して反応を行った。反応混合液をシクロヘキサンに滴下して沈殿物を回収し、減圧乾燥してポリマー２を得た。
【化１０】

【００４４】
（組成物の調製）（接触角測定）
主材（Ａ）としてＰＥＳ、添加材（Ｂ）としてポリマー２を使用し、実施例１と同様の方法で組成物フィルム２を得た。組成物フィルム２を使用し、実施例１と同様の方法で水浸漬後の接触角、血漿浸漬後の接触角を測定した。結果は表１に示した。
【００４５】
（組成物の抗血漿凝固性の評価）
組成物フィルム２を使用し、実施例１と同様の方法でクエン酸加牛血漿による抗血漿凝固性の評価を行った。結果は表２に示した。
【００４６】
〈実施例３〉
（組成物の調製）（接触角測定）
主材（Ａ）として市販の脂環族系ポリエーテルウレタンＴｅｃｏｆｌｅｘ ＥＧ８０Ａ（以下Ｔｅｃｏと略記する）、添加材（Ｂ）としてポリマー１を使用し、実施例１と同様の方法で組成物フィルム３を得た。組成物フィルム３を使用し、実施例１と同様の方法で水浸漬後の接触角、血漿浸漬後の接触角を測定した。また、同様の方法でＴｅｃｏ単独のフィルム（Ｔｅｃｏフィルム）を作製し、乾燥状態での接触角を測定した。結果は表１に示した。
【００４７】
（組成物の抗血漿凝固性の評価）
組成物フィルム３を使用し、実施例１と同様の方法でクエン酸加牛血漿による抗血漿凝固性の評価を行った。結果は表２に示した。
【００４８】
〈比較例１〉
（組成物の調製）（接触角測定）
主材（Ａ）としてＰＥＳ、添加材（Ｂ）としてＴｅｃｏを使用し、実施例１と同様の方法で組成物フィルム４を得た。組成物フィルム４を使用し、実施例１と同様の方法で水浸漬後の接触角、血漿浸漬後の接触角を測定した。結果は表１に示した。
【００４９】
（組成物の抗血漿凝固性の評価）
組成物フィルム４を使用し、実施例１と同様の方法でクエン酸加牛血漿による抗血漿凝固性の評価を行った。結果は表２に示した。
【００５０】
（組成物による中空糸の作製）（中空糸抗凝血性の評価）
添加材（Ｂ）としてＴｅｃｏを使用する以外は実施例１と同様の方法で中空糸４を作製した。中空糸４を使用し、実施例１と同様の方法で組成物ＭＤ４を作製し、実施例１と同様の方法で抗凝血性を評価した。結果は表２に示した。
【００５１】
（比較例２）
主材（Ａ）としてＰＥＳのみから成る材料の評価を行った。接触角は実施例１と同様の方法で測定し、結果は表１に示した。
【００５２】
（抗血漿凝固性の評価）
ＰＥＳフィルムを使用し、実施例１と同様の方法でクエン酸加牛血漿による抗血漿凝固性の評価を行った。結果は表２に示した。
【００５３】
（中空糸の作製）（中空糸抗凝血性の評価）
ポリマー１を添加せず、他の条件は実施例１と同様の方法でＰＥＳ製の中空糸５を作製した。中空糸５を使用して実施例１と同様の方法でマイクロモジュールＰＥＳ−ＭＤを作製し、抗凝血性を調べた。結果は表２に示した。
【００５４】
（比較例３）
主材（Ａ）としてＴｅｃｏのみから成る材料の評価を行った。接触角は実施例１と同様の方法で測定し、結果は表１に示した。
【００５５】
（抗血漿凝固性の評価）
Ｔｅｃｏフィルムを使用し、実施例１と同様の方法でクエン酸加牛血漿による抗血漿凝固性の評価を行った。結果は表２に示した。
【００５６】
【発明の効果】
本発明の医療用組成物は、水に浸漬した後の水の接触角、血漿に浸漬した後の水の接触角が、組成物を構成する主材の水の接触角に対していずれも小さく、かつ、該組成物を血漿に浸漬した後の水の接触角が、水に浸漬した後の水の接触角よりも小さいことにより、優れた血液適合性が発揮される。このような効果が発揮される理由、機構は明確でないが、親水性成分の表面近傍へのマイグレート、血漿中の特定成分の積極的な吸着などの影響が考えられる。血液あるいは血液構成成分との適合性に優れている利点を活かして、本発明の医療用組成物は、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として広く利用され得る。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a medical composition comprising at least a main material (A) and an additive (B), and having a specific characteristic of a static contact angle of water.
[0002]
[Prior art]
Materials used for medical purposes are required to have sufficient mechanical strength and durability as well as safety for living bodies. In particular, materials used in direct contact with body fluids such as blood may cause clotting, decrease / increase in blood cell components, activation of the complement system, etc. due to the defense mechanism of the living body. Excellent blood compatibility is required in order to reduce the blood pressure.
[0003]
Methods of imparting blood compatibility to medical materials include (1) materials having a surface inactivated (materials having a microheterogeneous structure such as segmented polyurethane and 2-hydroxyethyl methacrylate / styrene block copolymer). Etc.), (2) those whose surfaces are hydrophilized (such as materials grafted with polyethylene oxide chains, etc.), (3) those whose surfaces are negatively charged, and (4) those whose physiologically active substances are introduced. (Such as heparin-immobilized material and urokinase-immobilized material). In addition to these methods, there is a method that makes it difficult to recognize the material itself as a foreign substance by introducing a structure similar to a biological component. According to a report by Ishihara et al., A material copolymerized with 2-methacryloyloxyethylphosphorylcholine (MPC), which is a phospholipid-like structure that is a cell membrane constituent, can actively adsorb phospholipids in blood. It is said that the surface is pseudointimal, and excellent blood compatibility is obtained.
[0004]
Means to improve blood compatibility by hydrophilizing the surface will reduce the direct contact between the material and blood by introducing a diffuse layer of water on the material surface, thereby avoiding the activation of blood components caused by it That is the basic concept. For example, a device in which blood compatibility is improved by introducing a hydrophilic polymer into a blood contact surface is disclosed. (For example, see Patent Document 1 and Non-Patent Document 1).
[0005]
As a method of quantifying the hydrophilicity of the material surface, there is a method of measuring a contact angle with water. As a medical material, as a technology focusing on the contact angle, an anticoagulant material in which a sugar is bound to a side chain is disclosed, and the advancing contact angle of water is 80 ° to 95 °. It is a mandatory requirement. (For example, see Patent Document 2). Conventionally, the sugar structure-introduced material has been apt to cause the material to be weakened due to the strong water swelling property derived from the sugar structure, but when the contact angle is within the above range, both anticoagulant property and strength can be compatible. It has been. That is, the contact angle mentioned here is defined as an index of the water swelling property of the material, which is completely different from the idea of the present application.
[0006]
Also disclosed is a medical material characterized in that the contact angle with pure water is 90 ° or more and the contact angle with plasma is larger than the contact angle with pure water. This material is supposed to be mainly used for a porous oxygenator membrane, and is characterized in that it has the above-mentioned properties, so that it has a high repulsion with plasma and has a small plasma leak during use. (For example, see Patent Document 3). This technique is also completely different from the idea of the present application.
[0007]
Further, although a surface hydrophilic polymer molded product is disclosed, the contact angle of water is merely used as an index for quantitatively indicating hydrophilicity. (For example, see Patent Document 4). On the other hand, a quaternary ammonium-antithrombotic mucopolysaccharide complex coating material irradiated with ultraviolet rays is disclosed, and has a contact angle of 68.2 ° ± 11.7 ° to 32.1 ° ± 6.7 °. However, this is merely intended to facilitate priming by making it hydrophilic, and blood compatibility is expected exclusively from the effect of heparin, and a specific contact angle is required. It lacks the perspective that its implementation will improve blood compatibility. (For example, see Patent Document 5).
[0008]
As described above, there is a known technique in which the property of a material is defined by using a contact angle of water as an index indicating hydrophilicity as a parameter, but there are few reports on a material that exhibits a specific behavior when it comes into contact with blood.
[0009]
[Patent Document 1]
JP-A-06-228887 (pages 2-3)
[Patent Document 2]
JP-A-05-237181 (pages 2-3)
[Patent Document 3]
JP-A-10-28727 (page 3)
[Patent Document 4]
JP-A-11-172149 (pages 4-6)
[Patent Document 5]
JP 2000-288081 A (pages 2-3)
[Non-patent document 1]
J. Appl. Poly. Sci. , 72 (10), 1249-1256, 1999.
[0010]
[Problems to be solved by the present invention]
An object of the present invention is to provide a material that is excellent in simplicity and versatility, and that is excellent in compatibility with blood or blood components.
[0011]
[Means for Solving the Problems]
The applicant of the present application has conducted intensive studies on the background of the above-described known technology, and as a result, has arrived at the present application. That is, it is a medical composition (A) / (B) comprising at least the main material (A) and the additive (B), and has a static contact angle of water in the dry state of (A). θA0, the static contact angle of water after water immersion of (A) / (B) is θA / B1, and the static contact angle of water after plasma immersion of (A) / (B) is θA / B2. And (A) / (B) satisfying the relationship of θA / B1 ≦ 0.9 × θA0 and θA / B2 ≦ 0.8 × θA0 and θA / B2 <θA / B1 indicate that blood compatibility is particularly excellent. I found it. This relationship indicates that, first, (A) / (B) is more hydrophilic than (A), and second, (A) / (B) is more hydrophilic by contact with plasma. Is to improve. The decrease in the contact angle of the composition due to the contact with water, that is, the increase in the hydrophilicity of the material may be due to a mechanism in which the hydrophilic component migrates to the vicinity of the surface. Furthermore, an important point of the present invention is that when comparing the contact angle after contact with water and the contact angle after contact with plasma, the latter is smaller than the former. Although it is not clear why such materials exhibit good blood compatibility, the effect of plasma on promoting migration of hydrophilic components is higher, and specific components in plasma are positively adsorbed, and as a result, the material surface It is conceivable that an inert layer is introduced at the same time as the hydrophilicity of the compound increases.
[0012]
Here, the static contact angle of water alone (B) is not limited, but preferably, when the static contact angle of water in the dry state of (B) is θB0, θB0 <θA0, and more preferably Is θB0 <0.8 × θA0.
[0013]
In the present invention, the static contact angle of water in a dry state refers to a static contact angle of water measured at 40 to 70 ° C. under reduced pressure and heating and reduced pressure of 10 mmHg or less for 8 hours, and immediately measured after drying. Means the corner. Further, the static contact angle of water after immersion in water means the static contact angle of water of a sample that has been subjected to the following treatment.
1. The dried sample is immersed in room temperature water for 1 minute to 12 hours.
2. The water adhering to the surface of the sample is removed.
3. The sample from which water adhering to the surface has been removed is immediately subjected to measurement.
Further, the static contact angle of water after being immersed in plasma means the static contact angle of water of a sample subjected to the following treatment.
1. The dried sample is immersed in plasma at room temperature for 1 minute to 12 hours.
The operation of rinsing the surface of the sample pulled up from the plasma with about 2.5 ml of water is repeated two or three times.
3. Remove water adhering to the surface of the sample.
4. The sample from which water adhering to the surface has been removed is immediately subjected to measurement.
Although there is no particular limitation on the method of removing water adhering to the surface, it is preferable to avoid a method that causes excessive drying. Specifically, for example, a method of pressing filter paper or the like and sucking it out is exemplified. If it is desired to store the sample for a certain period of time for the sake of measurement, a dry desiccator can be used for a dry sample, and a wet chamber can be used for a sample after immersion in water or plasma.
[0014]
The medical composition of the present invention mainly refers to a composition obtained by blending the main material (A) and the additive (B), and the composition obtained by grafting (B) to (A), (B) may be coated.
[0015]
The medical composition of the present invention is not particularly limited in structure and the like in addition to the above requirements, but it is preferable that the additive (B) contains a zwitterion bonded by a covalent bond. At the same time, it is not limited that zwitterion is introduced into (A). In the case where (B) is blended, grafted, or coated with (A), it is preferable to introduce a zwitterion by a covalent bond in advance into the component to be (B), but (A) / (B) It may be introduced later into the component (B) of the composition.
[0016]
It is preferable that the zwitterion has a structure similar to that of at least a part of a biological membrane component, preferably a phospholipid. Specifically, it is preferably a zwitterion having a structure represented by the chemical formula (1), and more preferably a zwitterion having a structure represented by the chemical formula (2).
[0017]
Although the detailed mechanism is unknown, it is considered that the characteristic water contact angle tendency described above is realized by the effect of (B) containing zwitterions, and excellent blood compatibility is obtained.
[0018]
In the present invention, the materials and configurations of (A) and (B) are not particularly limited, but (A) is preferably a material having mechanical and / or physical and / or chemical properties as a main material. obtain. Specifically, for example, the following polymers used for various applications are exemplified. That is, polyethylene (artificial blood vessels, blood circuits, tubes, etc.), polypropylene (blood bags, blood circuits, connectors, tubes, etc.), polyvinyl chloride (blood bags, blood circuits, catheters, tubes, etc.), polyurethane and polyurethane urea (artificial Heart, catheter, tube, artificial dialyzer potting material, artificial lung potting material, etc., polycarbonate (artificial dialyzer housing, artificial lung housing, etc.), polystyrene (cell culture device, connector, etc.), silicone (artificial lung, catheter, tube) , Blood circuits), cellulose and cellulose derivatives (such as hemodialysis membranes), polyfluorocarbons (such as artificial blood vessels), polyacrylates and polymethacrylates (such as contact lenses, hemodialysis membranes, catheters and tubes). ), Polyamide (sutures), such as polysulfone and polyethersulfone (hemodialysis membrane), natural rubber (urinary catheters, etc.) and the like.
[0019]
(B) may be a polymer material or a low-molecular additive, but is preferably a polymer material in order to exhibit stable blood compatibility over a long period of time. Examples of the low-molecular additive include a natural phospholipid such as phosphatidylcholine, a structure similar to the structure of a constituent component of a biological membrane, preferably a phospholipid-like structure, more preferably the above chemical formula (1), and further more preferably the above chemical formula ( A surfactant having the structure of 2), more preferably a surfactant having the structure of the following chemical formula (4) is exemplified.
Embedded image

[In the above chemical formula (4), R4 is 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, and a hydrogen atom is another atom or a functional group. It may be substituted. R2 and R3 are a hydrogen atom, 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; May be substituted with another atom or a functional group. R5 is an alkyl group having 1 to 10 carbon atoms, a hydrogen atom which may be substituted with another atom or a functional group, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or the chemical formula (3 ). R6 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, and the hydrogen atom may be substituted with another atom or a functional group. ]
[0020]
As the polymer material, for example, a component having a structure similar to the structure of the constituent component of the biological membrane, preferably a phospholipid-like structure, more preferably a component having the structure of the chemical formula (1), and still more preferably a structure of the chemical formula (2) is used as a raw material. Polyurethane, polyurethane urea, polyester, polyamide, polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, etc. obtained as one of the above, and various amino group-containing polymers are modified to form the above-mentioned chemical formula (1), preferably the above-mentioned chemical formula ( Examples include polymers into which the structure of 2) is introduced.
[0021]
One preferred embodiment of the present invention in which (B) is a polymer material is a polyurethane or a polyurethane urea obtained using one of the components having the structure of the chemical formula (2) as a raw material. And polyurea (hereinafter abbreviated as polyurethanes) are prepared from three components: a diisocyanate, a macropolyol serving as a soft segment, and a chain extender.
[0022]
Specific examples of the diisocyanate that can be used when (B) of the present invention is a polyurethane include, for example, ethylene diisocyanate, trimethylene diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate, hexamethylene diisocyanate, octamethylene diisocyanate, and decaisocyanate. Methylene diisocyanate, dodecamethylene disocyanate, 3,3'-diisocyanatopropyl ether, cyclopentane diisocyanate, cyclohexane diisocyanate, 4,4'-methylene bis (cyclohexyl isocyanate), tolylene diisocyanate, xylylene diisocyanate, phenylene diisocyanate, naphthalene Diisocyanate, isocyanatobenzyl isocyanate, 4,4'-meth Although such Renbisu (phenyl isocyanate) is exemplified, without limitation. Further, 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, octamethylene diisocyanate, and 4,4'-methylene bis (phenyl isocyanate) are preferred, and hexamethylene diisocyanate and 4,4'-methylene bis (phenyl isocyanate) are particularly preferred. One type of diisocyanate may be used, or two or more types may be used in combination. It is also possible to use an aromatic diisocyanate, an aliphatic diisocyanate and an alicyclic diisocyanate together.
[0023]
Specific examples of the macropolyol that can be used when (B) of the present invention is a polyurethane include low molecular weight diols (eg, 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 acids or their ester-forming derivatives (eg, oxalic acid, malon) Acid, succinic acid, glutaric acid, adipic acid, sebacic acid, dodecanedicarboxylic acid, terephthalic acid, isophthalic acid or their acid halides, active esters, amides, etc.) Unsaturation such as polylactone diol, polyether diol such as polyethylene glycol, polypropylene glycol and polytetramethylene glycol, polybutadiene diol, polyisoprene diol and hydrogenated polyisoprene diol obtained by ring-opening polymerization of sterdiol, ε-caprolactone, etc. Examples thereof include diols having hydroxyl groups at both ends of the hydrocarbon polymer (including the case where the unsaturated hydrocarbon is a diene, referred to as polyalkylene diol), and various polycarbonate diols. Among them, polyether diol and polycarbonate diol are preferable. Furthermore, polyether diol is more preferred. These macropolyols may be used alone or as a mixture of two or more.
[0024]
Specific examples of the chain extender that can be used when (B) of the present invention is a polyurethane are, for example, ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, octamethylene glycol, Diols such as decamethylene glycol, 2,2-dimethyltrimethylene glycol, 1,4-dihydroxycyclohexane, 1,4-dihydroxymethylcyclohexane, diethylene glycol and triethylene glycol, ethylenediamine, propylenediamine, butylenediamine, hexamethylenediamine, xylylene Diamines such as diamine, phenylenediamine, 4,4'-methylenebis (phenylamine), 2-aminoethanol, 3-aminopropanol Amino alcohols such as 4-amino-butanol, furthermore, dihydrazide (such as oxalic acid dihydrazide, malonic acid dihydrazide, succinic acid dihydrazide, adipic acid dihydrazide, sebacic acid dihydrazide, isophthalic acid dihydrazide), such as broad diamines such as are exemplified. Among them, diols or diamines having 2 to 6 carbon atoms such as ethylene glycol, propylene glycol, tetramethylene glycol, pentamethylene glycol, hexamethylene glycol, ethylenediamine, propylenediamine, butylenediamine, and hexamethylenediamine are preferable. Propylene glycol, tetramethylene glycol, ethylenediamine, and propylenediamine are more preferred. These chain extenders may be used alone or in combination of two or more. It is also possible to use diols, diamines and amino alcohols in combination.
[0025]
When the component (B) of the present invention is a polyurethane, the component containing a zwitterion used as one of the raw materials is, for example, a compound represented by the following chemical formula (5) or (6). The components are exemplified.
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[In the chemical formulas (5) and (6), R1, R4, and R9 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, and are the same. However, the hydrogen atom may be substituted with another atom or a functional group. R2, R3, R7, and R8 are a hydrogen atom, 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 may be the same or different. The hydrogen atom of each group may be substituted with another atom or a functional group. R5 is an alkyl group having 1 to 10 carbon atoms, a hydrogen atom which may be substituted with another atom or a functional group, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or the chemical formula (3 ). X is N, HC or a group having a structure represented by the following chemical formula (7). ]
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[Wherein, R10 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 is substituted with another atom or a functional group. It may be. ]
[0026]
One of the preferred embodiments when (B) of the present invention is a polymer material is a polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, etc. obtained using one of the components having the structure of the chemical formula (2) as a raw material. (Hereinafter abbreviated as polyacrylates). When (B) of the present invention is a polyacrylate, for example, a polymer obtained by polymerizing a monomer represented by the following chemical formula (8) as at least one of the copolymerization components can be preferably used.
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[In the above chemical formula (8), R4 and R12 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. The hydrogen atom may be substituted with another atom or a functional group. R2, R3, and R11 are a hydrogen atom, 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 another atom or a functional group. R5 is an alkyl group having 1 to 10 carbon atoms, a hydrogen atom which may be substituted with another atom or a functional group, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 15 carbon atoms, or the chemical formula (3 ). ]
[0027]
When (B) of the present invention is a polyacrylate obtained by using a component having the structure of the chemical formula (2) as one of the raw materials, specifically, other copolymerization components include, for example, (B) of the present invention. Is a polyacrylate, methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, methoxyethyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, 2-hydroxyethyl methacrylate, N, N-dimethylaminoethyl Acrylate, acrylamide, N, N-dimethylacrylamide, N-isopropylacrylamide, N, N-dimethylaminopropylacrylamide, acryloylmorpholine and the like are exemplified. One or two or more of these copolymer components may be used.
[0028]
In the present invention, the compounding ratio of (A) / (B) is from 1000/1 to 1/1, preferably from 100/1 to 1/1, more preferably from 50/1 to 2/1 by weight.
[0029]
The addition of components other than (A) and (B) to the medical composition of the present invention is not limited. Specifically, for example, it is also possible to add a plasticizer, a filler, a colorant, a UV absorber, an antioxidant, a stabilizer, and an antibacterial agent.
[0030]
The medical composition of the present invention is excellent in compatibility with blood or blood components.
Taking advantage of this advantage, the medical composition of the present invention includes, for example, a hemodialysis membrane or a plasma separation membrane, an adsorbent for waste products in blood, an artificial lung membrane, an intravascular balloon, a blood bag, a catheter, a cannula, and a shunt. Can be widely used as materials for medical devices such as blood circuits and coating materials for these medical devices.
[0031]
【Example】
Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.
[0032]
<Example 1>
(Preparation of zwitterion-containing polyurethane)
10.00 g of a compound represented by the following chemical formula (9) (hereinafter abbreviated as choline diol) was weighed in a separable flask, and dissolved by adding 150 ml of N-methylpyrrolidone (NMP). The following operations were all performed under a nitrogen atmosphere. The solution was heated to 75 ° C., 27.22 g of hexamethylene diisocyanate (HDI) was added, and the mixture was stirred for 1 hour. The reaction temperature was lowered to 55 ° C., and the mixture was stirred for 30 minutes, 94.48 g of 4,4′-methylenebis (phenylisocyanate) (MDI) was added, and the mixture was stirred at 55 ° C. for 1 hour, followed by polytetramethylene glycol having a number average molecular weight of 2,000. 30.25 g of (PTMG) was dissolved in 100 ml of NMP and added. The mixture was stirred at 55 ° C. for 1 hour to prepare a prepolymer. To this reaction mixture, 39.68 g of 1,4-butanediol (BD) was added in two portions, and the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture was diluted by adding 150 ml of NMP, and reacted by stirring at 55 ° C. for 12 hours. The terminal was terminated by adding 3 g of BD, and stirring was continued from 55 ° C. to room temperature gradually. The reaction mixture was dropped into 10 l of water to recover the product, washed with 70 ° C. hot water for 2 hours, and dried under reduced pressure to obtain Polymer 1.
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[0033]
(Measurement of molecular weight)
Polymer A was added to and dissolved in N, N-dimethylformamide (DMF) containing 0.1% lithium bromide, and the molecular weight was measured by gel permeation chromatography (GPC). The gel column used was Shodex AD-803 / S, AD-804 / S, AD-806 / S, and AD-802 / S connected in series, and the temperature was 50 ° C and moved according to a calibration curve made of polyethylene glycol. The phase was measured with DMF containing 0.1% lithium bromide. The molecular weight measured by this method was 19000.
[0034]
(Preparation of composition)
Polyethersulfone (PES: Sumika Excel 4800P manufactured by Sumitomo Chemical Co., Ltd.) was dissolved in DMF as a main material (A) to prepare a 1 wt% solution. Similarly, polymer 1 was dissolved in DMF as an additive (B) to prepare a solution having a concentration of 1 wt%. The PES solution and the polymer 1 solution were mixed at a weight ratio of 95: 5, uniformly placed on a slide glass, and the solvent was removed in an infrared oven. The composition film 1 was dried under reduced pressure at 60 ° C. for 18 hours in a reduced pressure drier. A PES-only film (PES film) was obtained by the same operation. The dried film was kept in a dry desiccator to keep the film dry, and the contact angle was measured within 2 hours.
[0035]
(Measurement of contact angle of main material)
Using a contact angle meter CA-X manufactured by Kyowa Interface Science Co., Ltd., in a measurement room controlled at a temperature of 25 ° C. and a humidity of 40 ± 5%, the static water contact angle of the dried PES film obtained by the above operation was measured. The measurement was performed in a state of sticking to a slide glass. The results are shown in Table 1.
[0036]
[Table 1]

Condition a, condition a, and condition c are the static contact angle of water (θ) in the dry state of the main material (A), respectively._A0), The static contact angle of water (θ) after immersing the composition comprising the main material (A) and the additive (B) in water._{A / B1}), The static contact angle of water (θ) after immersing the composition comprising the main material (A) and the additive (B) in plasma._{A / B2})
Condition a θ_{A / B1}≦ 0.9 × θ_A0
Condition a θ_{A / B2}≦ 0.8 × θ_A0
Condition c θ_{A / B2}<Θ_{A / B1}
Means
[0037]
(Measurement of contact angle after immersion of composition in water)
The dry composition film 1 obtained by the above operation was immersed in ion-exchanged water at room temperature for 30 minutes while being adhered to a slide glass, then pulled up, and the attached water was removed with a filter paper. Thereafter, the static contact angle of water was immediately measured by the above method. The results are shown in Table 1.
[0038]
(Measurement of contact angle after plasma immersion of composition)
The dry composition film 1 obtained by the above operation was immersed in citrated bovine plasma at room temperature for 30 minutes while being adhered to a slide glass, pulled up, and rinsed with ion-exchanged water. After removing adhering water with a filter paper, the static contact angle of water was measured immediately by the above method. The results are shown in Table 1.
[0039]
(Evaluation of anti-plasma coagulability of composition)
The dry composition film 1 obtained by the above operation was placed on a glass petri dish while being stuck to a slide glass, and was placed in a constant temperature water bath at 37 ° C. 100 μl of citrated bovine plasma was dropped on this film, 100 μl of a 0.025 mol / l calcium chloride aqueous solution was added, and the mixture was gently shaken so as to mix. The elapsed time from the time when the calcium chloride aqueous solution was added to the time when the plasma coagulated (when the plasma stopped moving) was measured, and divided by the time required for plasma coagulation when the same operation was performed on glass, as a relative coagulation time. expressed. The results are shown in Table 2.
[0040]
[Table 2]

[0041]
(Preparation of hollow fiber from composition)
5000 g of PES (Sumika Excel 4800P manufactured by Sumitomo Chemical Co., Ltd.) as the main material (A), 25 g of polyvinylpyrrolidone (Coridone K90 manufactured by BASF) as a hydrophilizing agent, 150 g of polymer I as an additive (B), 11865 g of a solvent NMP, non-solvent triethylene Glycol was added to 7910 kg, stirred at 100 ° C. for 4 hours to dissolve, and then left at 70 ° C. for 12 hours for defoaming. This solution was filtered through a sintering filter to remove undissolved substances, and a spinning stock solution was obtained. This spinning stock solution was discharged from the outside 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 an inner liquid of a 20 wt% aqueous solution of NMP was discharged from the inner liquid discharge hole. The spinning solution discharged from the nozzle was guided in a coagulation bath immediately below the nozzle through a 20 cm aerial traveling. The coagulation liquid was a 20 wt% aqueous solution of NMP at a temperature of 70 ° C. The spun hollow fiber was washed with water and wound up by a winder at a winding speed of 45 m / min to obtain a hollow fiber 1. The inner diameter of the hollow fiber 1 was 200 μm, the outer diameter was 260 μm, and the film thickness was 30 μm.
[0042]
(Evaluation of anticoagulability of hollow fiber)
Ten hollow fibers 1 obtained by the above operation were bundled, both ends were inserted into a silicon tube, and solidified with a silicone adhesive to obtain a composition micromodule (MD) 1. Citrated beef whole blood was sealed in this composition MD1, immersed in a dialysate, and after a certain period of time, the sealed blood was dropped into a saline solution filled in a petri dish to observe the state. The results are shown in Table 2.
[0043]
<Example 2>
(Preparation of zwitterion-containing acrylamide copolymer)
In a solution of 23.05 g of triethylene glycol monomethyl ether (hereinafter abbreviated as TEG-Me) and 14.20 g of triethylamine dissolved in 40 ml of tetrahydrofuran (hereinafter abbreviated as THF), 2-chloro-2-oxo-1,3 was added. A solution of 2-dioxaphospholane (hereinafter abbreviated as COP) dissolved in 75 ml of THF was slowly added dropwise at −20 ° C. under a nitrogen stream, and after completion of the addition, the temperature was slowly increased to 0 ° C. for 3 hours at −10 ° C. The reaction was carried out by stirring for 5 hours while warming. Thereafter, the precipitate was filtered and removed, and the filtrate was dried under reduced pressure to obtain a compound represented by the following chemical formula (10) (hereinafter abbreviated as Me-TEG-OP). N, N-Dimethylaminopropylacrylamide (11.56 g) and Me-TEG-OP (20.00 g) obtained by the above operation were dissolved in DMF (60 ml), and the mixture was stirred at 60 ° C. for 6 hours in a nitrogen stream to carry out a reaction. Thereafter, 94.71 g of n-butyl methacrylate and 4 g of a polymerization initiator VA-086 (manufactured by Wako Pure Chemical Industries, Ltd.) were added to the reaction mixture, and the mixture was stirred at 80 ° C. for 24 hours to carry out a reaction. The reaction mixture was dropped into cyclohexane to collect a precipitate, which was dried under reduced pressure to obtain a polymer 2.
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[0044]
(Preparation of composition) (Measurement of contact angle)
Using PES as the main material (A) and Polymer 2 as the additive (B), a composition film 2 was obtained in the same manner as in Example 1. Using the composition film 2, the contact angle after immersion in water and the contact angle after immersion in plasma were measured in the same manner as in Example 1. The results are shown in Table 1.
[0045]
(Evaluation of anti-plasma coagulability of composition)
Using the composition film 2, the evaluation of anti-plasma coagulability with citrated bovine plasma was performed in the same manner as in Example 1. The results are shown in Table 2.
[0046]
<Example 3>
(Preparation of composition) (Measurement of contact angle)
Using a commercially available alicyclic polyether urethane Tecoflex EG80A (hereinafter abbreviated as Teco) as the main material (A) and polymer 1 as the additive (B), a composition film 3 was prepared in the same manner as in Example 1. Obtained. Using the composition film 3, the contact angle after immersion in water and the contact angle after immersion in plasma were measured in the same manner as in Example 1. In addition, a film of Teco alone (Teco film) was prepared in the same manner, and the contact angle in a dry state was measured. The results are shown in Table 1.
[0047]
(Evaluation of anti-plasma coagulability of composition)
Using the composition film 3, evaluation of anti-plasma coagulability by citrated bovine plasma was performed in the same manner as in Example 1. The results are shown in Table 2.
[0048]
<Comparative Example 1>
(Preparation of composition) (Measurement of contact angle)
Using PES as the main material (A) and Teco as the additive (B), a composition film 4 was obtained in the same manner as in Example 1. Using the composition film 4, the contact angle after immersion in water and the contact angle after immersion in plasma were measured in the same manner as in Example 1. The results are shown in Table 1.
[0049]
(Evaluation of anti-plasma coagulability of composition)
Using composition film 4, the evaluation of anti-plasma coagulability with citrated bovine plasma was performed in the same manner as in Example 1. The results are shown in Table 2.
[0050]
(Preparation of hollow fiber from composition) (Evaluation of anticoagulant property of hollow fiber)
A hollow fiber 4 was produced in the same manner as in Example 1 except that Teco was used as the additive (B). Using the hollow fiber 4, a composition MD4 was prepared in the same manner as in Example 1, and the anticoagulant was evaluated in the same manner as in Example 1. The results are shown in Table 2.
[0051]
(Comparative Example 2)
A material consisting only of PES was evaluated as the main material (A). The contact angle was measured in the same manner as in Example 1, and the results are shown in Table 1.
[0052]
(Evaluation of anti-plasma coagulability)
Using a PES film, evaluation of anti-plasma coagulability by citrated bovine plasma was performed in the same manner as in Example 1. The results are shown in Table 2.
[0053]
(Preparation of hollow fiber) (Evaluation of anticoagulant property of hollow fiber)
A hollow fiber 5 made of PES was produced in the same manner as in Example 1 except that the polymer 1 was not added. Using the hollow fiber 5, a micromodule PES-MD was produced in the same manner as in Example 1, and the anticoagulant property was examined. The results are shown in Table 2.
[0054]
(Comparative Example 3)
A material consisting of only Teco was evaluated as the main material (A). The contact angle was measured in the same manner as in Example 1, and the results are shown in Table 1.
[0055]
(Evaluation of anti-plasma coagulability)
Using a Teco film, the anticoagulability of citrated bovine plasma was evaluated in the same manner as in Example 1. The results are shown in Table 2.
[0056]
【The invention's effect】
The medical composition of the present invention, the contact angle of water after immersion in water, the contact angle of water after immersion in plasma, both smaller than the contact angle of water of the main material constituting the composition. In addition, since the contact angle of water after immersing the composition in plasma is smaller than the contact angle of water after immersion in water, excellent blood compatibility is exhibited. The reason why such an effect is exerted and the mechanism are not clear, but it is considered that the effect is caused by migration of a hydrophilic component to the vicinity of the surface, active adsorption of a specific component in plasma, and the like. Taking advantage of the excellent compatibility with blood or blood components, the medical composition of the present invention is, for example, a hemodialysis membrane or a plasma separation membrane, an adsorbent for waste products in blood, an artificial lung membrane, It can be widely used as a material for medical devices such as an intravascular balloon, a blood bag, a catheter, a cannula, a shunt, and a blood circuit, and a coating material for these medical devices.

Claims (10)

A medical composition comprising at least the main material (A) and the additive material (B) and coming into contact with a body fluid, wherein the static contact angle of water (θ) in a dry state of the main material (A) is _A0 ), the static contact angle of water after the medical composition is immersed in water (θ _{A / B1} ), and the static contact angle of water after the medical composition is immersed in plasma (θ _{A / B2} )
θ _{A / B1} ≦ 0.9 × θ _A0
And θ _{A / B2} ≦ 0.8 × θ _A0
And θ _{A / B2} <θ _{A / B1}
A medical composition, characterized in that: The medical composition according to claim 1, wherein the additive (B) has a zwitterion bonded by a covalent bond. 3. The medical composition according to claim 2, wherein the zwitterion has a structure similar to the structure of at least a part of the constituent components of the biological membrane. The medical composition according to claim 3, wherein the constituent component of the biological membrane is a phospholipid. The medical composition according to claim 4, which has a structure represented by the following chemical formula (1).

[In the above chemical formula (1), R is 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, and the hydrogen atom of each group is other atom or It may be substituted with a functional group. ] The medical composition according to claim 5, which has a structure represented by the following chemical formula (2) in a side chain.

[In the chemical formula (2), R1 and R4 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, and may be the same or different. The hydrogen atom may be substituted with another atom or a functional group. R2 and R3 are a hydrogen atom, 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; May be substituted with another atom or a functional group. R5 represents 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, a hydrogen atom of which may be substituted with another atom or a functional group, or a compound represented by the following chemical formula (3) ). ]

[In the formula, A is an oxyalkylene group having 2 to 10 carbon atoms, one or more oxyalkylene groups may be mixed, and the bonding order thereof may be block or random. N is an integer of 1 to 30. R5 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. Good. ] A medical material comprising the medical composition according to any one of claims 1, 2, 3, 4, 5, and 6. A medical material comprising the medical composition according to any one of claims 1, 2, 3, 4, 5, and 6 as a main component. A medical device containing the medical material according to claim 7. A medical device containing the medical material according to claim 8.