JP2004307567A - Hydrophilic material-containing molded product - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a molded product having an efficiently hydrophilized surface, i.e. with reduced sticking of biocomponents such as platelets or proteins. <P>SOLUTION: The hydrophilic material-containing molded product is characterized in that the ratio (RWD) of RMS (root mean square roughness) in a wet state to the RMS in a dry state is ≥0.6. The obtained molded product reduces the sticking of the biocomponents such as the platelets or proteins. The molded product is used in applications such as medical care materials in which the surface is preferably hydrophilic and smooth. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

【００１２】
ポリスルホンの具体例としては、ユーデルポリスルホンＰ−１７００、Ｐ−３５００（ソルベイ社製）、ウルトラソンＳ３０１０、Ｓ６０１０（ＢＡＳＦ社製）、ビクトレックス（住友化学）、レーデルＡ（ソルベイ社製）、ウルトラソンＥ（ＢＡＳＦ社製）等のポリスルホンが挙げられる。又、本発明で用いられるポリスルホンは上記式（１）及び／又は（２）で表される繰り返し単位のみからなるポリマーが好適ではあるが、本発明の効果を妨げない範囲で他のモノマーと共重合していても良い。また、ベンゼン環部分をアミノ基やスルホン酸基で置換修飾した様な変性ポリスルホンも用いることができる。
【００１３】
本発明の親水性物質含有成型体を製造する方法としては、疎水性ポリマーと親水性物質の混合溶液を成型する方法が挙げられる。
【００１４】
疎水性ポリマーと親水性物質の混合溶液を成型する方法について述べる。本発明でいうところの親水性物質とは水と親和性の高い物質のことであり、水に溶解する（好ましくは、水に対する溶解度（水１００ｇに溶解するグラム数）が０．１以上）か、水に対する接触角が５０°以下の物質を指す。特に疎水性ポリマーと親水性物質の混合溶液を成型する際には、親水性物質として親水性ポリマーが好適に用いられる。これは、成型体成型後に医療材料として各種水溶液や体液などと接触した場合に、全般的にポリマーのほうが各種水溶液や体液に溶出しにくいためである。
【００１５】
親水性ポリマーとしては、ポリビニルピロリドン、ポリエチレングリコール、ポリビニルアルコール、ポリエチレンイミン、ポリアクリル酸などが挙げられ、その分子量は数百〜数百万程度と選択肢は多いが、疎水性ポリマーとの相溶性の高いものであれば、これらに限定されずに用いることができる。親水性物質を成分として含む共重合ポリマーでもよい。中でも疎水性ポリマーとしてポリスルホン系ポリマーを用いた場合には、ポリスルホン系ポリマーとの相溶性が高いものとして、ポリビニルピロリドンとポリエチレングリコールを好ましく用いることができる。相溶性の良くないものを用いた場合、成型体溶液の状態で相分離を起こしてしまうため、透明成型体を製造することが困難となる。また、成型体溶液の相分離を引き起こさないものであれば、親水性物質の一種もしくは数種を適宜組み合わせても良い。
【００１６】
本発明のでいう自乗平均粗さ（ＲＭＳ）とは原子間力顕微鏡（ＡＦＭ）を用いて測定した場合の凹凸度のことであり単位はｎｍで示される。ＲＭＳはＡＦＭにより得られた３次元凹凸情報をイメージ分析ソフト（市販の原子間力顕微鏡に付属のもの）を用いて測定、計算することによって得られる。乾燥状態でのＲＭＳの測定は水に２４時間以上浸漬させた湿潤状態での成型体を２５℃、１ｍｍＨｇ以下の圧力で水分率１０％以下まで乾燥させたサンプルを用いて行う。湿潤状態での測定は、乾燥したサンプルを水に２４時間浸漬させた後に行う。血小板やタンパク質等の血液成分、フミン質などの水中の不純物の付着を抑制するためには、親水性物質が水によって適度に膨潤することが重要であり、本発明においては、これを乾燥状態の自乗平均粗さ（ＲＭＳ）に対する湿潤状態でのＲＭＳの比（ＲＷＤ＝湿潤状態でのＲＭＳ／乾燥状態でのＲＭＳ）によって示し、ＲＷＤが０．６以上であることを必要とする。さらには、１．０より大きいことがより好ましい。
【００１７】
親水性物質が少ないと、材料は乾燥状態のＲＭＳよりも小さくなることがあるが、これは、乾燥状態では親水性物質が材料表面に不均一に存在して、親水性物質の凹凸が観測されるのに対して、湿潤状態では観測され難いためと考えられる。好ましい親水性表面を得るためにはＲＷＤ値が０．６以上であることが必要であるが、１．０より大きい事が好ましい。親水性物質を多くするとＲＷＤは大きくなる傾向があるが、親水性物質に親水性ポリマーを用いた場合に、この値があまりにも多くなると、低分子量のタンパク質などが膨潤した親水性層の中に潜り込んでしまい、実質的な付着・汚れが生じてしまうことが懸念されるためにＲＷＤの値は１０以下であることが好ましく、２以下であることが好ましく、さらには１．５以下であることが好ましい。さらに、ＲＷＤの値が１．０より大きく１．５以下である表面は親水性物質が適度に表面を覆っている状態と考えられるため最も好ましい範囲である。このような表面を有する成型体は優れた親水性表面特性を有しており、医療材料として用いた場合には生体成分の付着を抑制する効果を有する。例えば、血液中の血小板付着性試験を行った際に血小板の付着を抑制することができる。
【００１８】
本発明における成型体溶液の調製については特に限定されるものではないが、成型体溶液の粘度は添加した親水性ポリマーの分子量及びその添加量に依存する傾向があるため、成型性の良い範囲となるように調製することが重要である。具体的には、成型体溶液の粘度は高くても１０００ポイズ程度までが成型に支障が少なく好ましい範囲とされる。成型溶液における親水性物質の濃度を高くするにつれて、成型体の表面はより親水性になり、生体適合性が向上する。高いＲＷＤを持つ表面は成型溶液における親水性物質の濃度を高くする事により得られる。親水性物質の濃度は疎水性ポリマーに対して２〜１００重量％が好ましく、更には３〜５０重量％が好ましい。成型体中の親水性物質濃度が２重量％未満の場合、得られる成型体表面の親水性の量が不十分となる傾向があり、高いＲＷＤをもった材料を得難い。
【００１９】
また、前述のように、分子量の大きい親水性ポリマーを用いる場合、溶液の粘度が著しく上昇するので成型性に支障のない範囲の溶液組成を選択することが好ましい。また、分子量の小さい親水性物質を用いる場合は、ＲＷＤが小さく十分な生体適合性を発揮できないことがあったり、医療材料として使用する場合に溶出する傾向がある。親水性物質としてポリマーを用いる場合には、重量平均分子量が３万〜２００万のものが好ましく用いられる。
【００２０】
成型溶液におけるポリスルホン系成型体の濃度について、親水性物質との相溶状態を発現させるために、親水性物質に対して少なくとも２０重量％以上存在することが好ましく、更には２５重量％以上存在することが好ましい。
【００２１】
成型溶液における溶媒の選択においては、ポリスルホン系成型体及び親水性物質の良溶媒が用いられる。具体的には、ジメチルアセトアミド、ジメチルホルムアミド、ジメチルスルホキシド、アセトン、アセトアルデヒド、２−メチルピロリドンなどであるがこれらに限定されない。安全性、毒性の面からジメチルアセトアミドが好ましい。高いＲＷＤを有する成型体を得るためには、ポリスルホン系成型体と親水性物質の高濃度溶液を作製後、溶媒を蒸発させることで成型体が製造できるが、これを延伸成型・射出成型・押し出し成型をすることによって様々な成型体を形成できる。たとえば円形口金から押し出せば、チューブを成型することも可能である。
【００２２】
本発明における成形体の製造方法として、親水性ポリマーと疎水性ポリマーを含む混合溶液から作成するフィルムを例に以下のとおりに示す。まず、成型体溶液をガラス板上前端に横に広げながら適量を静かに垂らし、キャスト厚みを一定にすることができるアプリケーターをガラス板上で一定の速さで手前に引き、成型体溶液をむらなく広げる公知の方法を用いる。
【００２３】
透明な成型体が必要な場合には、最適な成型条件を整えることが重要であり、親水性物質が入った成型体溶液ではキャスト中に空気中の水分による吸湿の影響で、相分離を起こしてしまうことが懸念されるために、キャスト温度については適宜最良の条件を決めなければならないが８０〜１５０度、更には１００〜１３０度が好ましい。低温でキャストする場合は吸湿しない環境下で長時間かけて成型を行う必要がある。キャスト厚みについては、薄すぎるとフィルムとして成形しにくくなる。また厚すぎると溶媒の蒸発に時間を要することとなり、５０〜５００μｍが好ましく、更には１００〜３００μｍが好ましい。
【００２４】
上記条件により成型した後、所定の水洗、剥離工程を経た後、乾燥しフィルムを得る。
【００２５】
本発明により得られる成型体は、例えば、コンタクトレンズ、眼内レンズ等の医療材料、血液回路、人工腎臓、人工肺、人工肝臓、人工心臓、人工膵臓などの人工臓器、水処理用膜などの親水性を要求として幅広く用いられる。
【００２６】
以下実施例を挙げて本発明を説明するが、本発明はこれらの例によって限定されるものではない。
【００２７】
【実施例】
用いた測定方法は以下の通りである。
（１）血小板付着実験
フィルム状の成型体を１８ｍｍφのポリスチレン製の円筒管の底に平板状に設置し、生理食塩水で満たした。３．２％クエン酸三ナトリウム２水和物水溶液と家兎新鮮血を１：９（容積比）で混合した血液を１０００ｒｐｍで１０分間遠心分離し、上清を取り出した（血漿１とする）。その後、上清を取り出したあとの血液を３０００ｒｐｍで１０分間再度遠心分離し、上清を取り出した（血漿２とする）。血漿１に血漿２を添加することで希釈（血漿２は血漿１に比べて血小板の濃度が低い）し、血小板数２０×１０^６個／ｍｌの富血小板血漿（ＰＲＰ）を調製した。準備した円筒管の生理食塩水を捨てた後ＰＲＰを１．０ｍｌ入れて３７℃にてタイテック社製ＭＩＣＲＯＴＵＢＥ ＭＩＸＥＲ（ＥＮ−３６Ｎ）を用いて１時間振盪させた。その後、生理食塩水で３回洗浄し、３％グルタルアルデヒド水溶液で血液成分の固定を行い、蒸留水にて洗浄した後、減圧乾燥を５時間以上行った。このフィルムを走査型電子顕微鏡の試料台に両面テープで貼り付けた。その後、スパッタリングにより、Ｐｔ−Ｐｄの薄膜を試料に形成させた。走査型電子顕微鏡（日立社製Ｓ８００）にて試料表面を観察し（フィルムと円筒管の接着部は血液が溜まりやすいので、主としてフィルム中央部を３０００倍で観察した）、１．０×１０^３μｍ^２の面積中の付着血小板数を数えた。観察部位２０ヶ所での平均値をとった。
【００２８】
この実験には、コントロールが必要である。すなわち、以下のようにして作成したサンプルを、実験毎に水準にいれておく必要がある。ポリスルホン（アモコ社製Ｕｄｅｌ−Ｐ３５００）１０重量％をジメチルアセトアミド９０重量％に加えて室温で溶解し、ホットプレートにて、表面温度が１００度になっているガラス板上で厚さ２０３μｍでキャストした。表面の温度は、接触式温度計により測定した。キャスト後、５分間ホットプレート上で放置し、溶媒を蒸発させた後、ガラス板ごと、水浴へ浸漬し透明フィルムを得た。このポリスルホンフィルムの血小板付着数が４０個以下の場合は、血液の鮮度が欠けているなど、実験が失敗している可能性が高いので、その際のデータは用いることができない。
【００２９】
（２）表面ポリビニルピロリドン量の測定
表面のポリビニルピロリドン量は、Ｘ線光電子分光（ＥＳＣＡ）によって決定される。装置はＥＳＣＡＬＡＢ２２０ｉＸＬを用いた。ＥＳＣＡの測定により得た、Ｃ１ｓ、Ｎ１ｓ、Ｓ２ｐスペクトルの面積強度より、装置付属の相対感度係数を用いて窒素の表面量（Ａ）と硫黄の表面量（Ｂ）を求め、
表面ポリビニルピロリドン量（％）＝Ａｘ１１１ｘ１００／（Ａｘ１１１＋Ｂｘ４４２）よりフィルム表面ポリビニルピロリドン量を算出した。Ｘ線の入射角に対する検出器の角度は９０度にて測定を行った。
【００３０】
（３）接触角の測定
協和界面化学社製の接触角計ＣＡ−Ｄを用いて測定した。測定は室温が２５度に温調された部屋で行った。
【００３１】
（４）自乗平均粗さ（ＲＭＳ）の測定
フィルムサンプルは、５ ｍｍ四方に切り出し、スチール製円板（Ｎｉｈｏｎ ＶＥＥＣＯ， Ｔｏｋｙｏ， Ｊａｐａｎ）上に市販の透明マニキュアを用いて固定した。固定後、室温で２４時間乾燥させ、乾燥サンプルとした。コンタクトモードで、ＮＰ−Ｓプローブの１２０ μｍ， ｗｉｄｅチップを使用し（２００ μｍ， ｗｉｄｅチップは使用前に折る）は、２ ｍｍ ｘ ２ ｍｍの範囲を、オペレーティングポイント０．３ Ｖ、０．２ Ｈｚの十分遅い走査速度で観察した。Ｐゲイン、Ｉゲインは、サンプルごとに調整した（おおよそＰゲイン：８−１５、Ｉゲイン：０．００１−０．００３）。乾燥サンプルを、観察後固定円板ごと装置附属のガラスセルに透明マニキュアで固定し、ＲＯ水で２４時間十分湿潤させ、湿潤サンプルとした。湿潤サンプルも、乾燥サンプルと同じ方法で観察した。観察モード、プローブ、その他走査条件を変えないことで、乾燥状態と湿潤状態間の変化を定量的に評価することができる。測定は５カ所で行い平均値を採用した。
【００３２】
ＡＦＭ観察条件として装置に走査型プローブ顕微鏡ＳＰＭ ９５００−Ｊ３（ＳＨＩＭＡＤＺＵ， Ｋｙｏｔｏ， Ｊａｐａｎ）、観察モードはコンタクトモード、プローブはＮＰ−Ｓ（１２０ ｍｍ， ｗｉｄｅ）（Ｎｉｈｏｎ ＶＥＥＣＯ ＫＫ， Ｔｏｋｙｏ， Ｊａｐａｎ），スキャナ標準はＳｔａｎｄａｒｄ（３０ ｍｍ ｘ ３０ ｍｍ ｘ ５ ｍｍ）、走査範囲は２ ｍｍ ｘ ２ ｍｍ（画像のｚスケールは１０ ｎｍに統一）、走査速度は０．２ Ｈｚ 、画素数は５１２ ｘ ５１２の条件にて行った。画像処理は、得られた生画像から、ｘ、ｙラインごとに平均値を算出し、データからその平均値差し引いて傾斜補正し、ノイズラインは測定時のカンチレバーの針とびや瞬時的なノイズに起因する画像データ上のラインノイズを、前後のラインの明暗とそのラインの明暗が反転していることを基準とし、消去する事により行った。また、画像に空間周波数的に規則的なノイズが含まれる場合、周波数フィルタを使用して画像処理を行った。
【００３３】
ＲＭＳの算出には、オフライン機能の「面粗さ解析」を用いた。特異的な形状を拾わないように、解析範囲は１−４ μｍ^２で調整した（標準は４μｍ^２）。１次元のＲＭＳは、粗さ曲線（ＪＩＳ Ｂ６０１参照）からその平均線の方向に基準長さだけ抜き取り、この抜き取り部分の平均線の方向にＸ軸を、縦倍率の方向にＹ軸を取ったときに、以下のようにして求められる標準偏差をいう。ここでは、これを２次元に拡張したものを測定した。
ＲＭＳ＝（Σ（Ｙｉ−Ｙａｖｅ）^２／Ｎ）^０．５
Ｙｉ：任意の測定点の高さ、Ｙａｖｅ：全測定点の高さ平均、Ｎ：測定点の数
以下実施例において、「部」は「重量部」を意味する。
【００３４】
実施例１
ポリスルホン（ソルベイ社製Ｕｄｅｌ−Ｐ３５００）１０部、ポリビニルピロリドン（ＩＳＰ社製Ｋ９０ 重量平均分子量１２０万）５部をジメチルアセトアミド８５部に加え室温にて溶解し、成型溶液とした。この溶液をホットプレートにて、表面温度が１００度になっているガラス板上で厚さ２０３μｍでキャストした。表面の温度は、接触式温度計により測定した。キャスト後、５分間ホットプレート上で放置し、溶媒を蒸発させた後、ガラス板ごと、水浴へ浸漬し透明フィルムを得た（水浴に浸漬させるのは、フィルムをガラス板からはがしやすくさせるためである。）。得られたフィルムの血小板付着数は１２個であった。表面接触角は３８°であった。乾燥状態でのＲＭＳは１．６、湿潤状態でのＲＭＳは１．２、ＲＷＤは０．７であった。
【００３５】
実施例２
ポリスルホン（ソルベイ社製Ｕｄｅｌ−Ｐ３５００）１０部、ポリビニルピロリドン（ＩＳＰ社製Ｋ９０ 重量平均分子量１２０万）１０部をジメチルアセトアミド８０部に加え室温にて溶解し、成型溶液とした。実施例１と同様にして光透過率９０．３％の透明フィルムを得た。得られたフィルムの血小板付着数は７個であった。表面接触角は３５°であった。乾燥状態でのＲＭＳは１．３、湿潤状態でのＲＭＳは２．７、ＲＷＤは２．１であった。
【００３６】
比較例１
ポリスルホン（ソルベイ社製Ｕｄｅｌ−Ｐ３５００）１０部をジメチルアセトアミド９０部に加え、実施例１と同様にして光透過率８８．９％の透明フィルムを得た。得られたフィルムの血小板付着数は７０個であった。表面接触角は８２°であった。乾燥状態でのＲＭＳは１．２、湿潤状態でのＲＭＳは０．６、ＲＷＤは０．５であった。
【００３７】
比較例２
ポリスルホン（ソルベイ社製Ｕｄｅｌ−Ｐ３５００）１０部、ポリビニルピロリドン（ＩＳＰ社製Ｋ９０ 重量平均分子量１２０万）０．０１部をジメチルアセトアミド９０部に加え、実施例１と同様にして光透過率８８．８％の透明フィルムを得た。得られたフィルムの血小板付着数は６０個であった。表面接触角は７４°であった。乾燥状態でのＲＭＳは１．４、湿潤状態でのＲＭＳは０．６、ＲＷＤは０．４であった。
【００３８】
【発明の効果】
本発明によって、血小板、タンパク質などの生体成分の付着が低減された成型体を提供することができる。[0001]
The present invention relates to a molded article containing a hydrophilic substance, and is suitably used for applications where the surface of a medical material or the like is preferably hydrophilic and smooth.
[0002]
[Prior art]
Polysulfone-based polymers such as polysulfone are excellent materials in terms of heat resistance, chemical resistance, and moldability, and are used in a wide range of fields. However, since these materials are hydrophobic, there is a problem that a lot of bio-related substances are attached, that is, biocompatibility is low.
[0003]
In order to improve them, various studies have been made.For example, there is a method of imparting hydrophilicity to polysulfone by adding an appropriate amount of a hydrophilic polymer, polyvinylpyrrolidone, and thereby suppressing contamination on a membrane. It is disclosed in Japanese Patent Publication No. 2-18695 and Japanese Patent Application Laid-Open No. 61-238834. Japanese Patent Application Laid-Open No. Sho 62-201603 discloses a method for imparting hydrophilicity to a polysulfone-based membrane by blending a graft or block copolymer comprising a hydrophilic polymer segment and a hydrophobic segment, thereby suppressing membrane fouling. It is disclosed in JP-A-63-77941. Further, JP-A-2-2862 discloses that a polysulfone hollow fiber membrane is immersed in concentrated sulfuric acid for sulfonation. Radicals generated by methods such as irradiating the polymer surface with radiation, ultraviolet light, or the like, performing plasma treatment by arc, DC glow, high frequency, microwave, corona discharge, or UV-ozone treatment are used as starting points. A method in which a radical polymerizable monomer is allowed to act on this to form a graft polymerization layer on the surface has also been widely used. For example, A. Henglein, Angew. Chem. , 70, 461 (1955) describe graft polymerization using radiation; Ogiwara, et. al. , Poym. Sci. , Polym Letter Ed. , 19, 457 (1981) propose a method of graft-polymerizing methyl methacrylate or acrylic acid using a polyvinyl acetate aqueous solution on a polypropylene surface or a polyethylene surface.
[0004]
As described above, various methods are known if only the surface is made hydrophilic. Further, it is considered that the hydrophilic substance on the surface of the material needs to be present in an optimal state in order to exert its effect to the maximum, but the method has not been known so far.
[0005]
[Patent Document 1]
Japanese Patent Publication No. 2-18695 [Patent Document 2]
JP-A-61-238834 [Patent Document 3]
JP-A-62-201603 [Patent Document 4]
JP-A-63-77941 [Patent Document 5]
JP-A-2-2862 [Non-Patent Document 1]
A. Henglein, Angew. Chem. , 70, 461 (1955).
[0006]
[Problems to be solved by the invention]
The present invention is intended to solve the above-mentioned drawbacks of the prior art, and to provide a molded body whose surface is efficiently made hydrophilic, that is, platelets, proteins and other biological components are reduced in adhesion. With the goal.
[0007]
[Means for Solving the Problems]
The present invention has the following configurations to achieve the above object.
(1) A molded article containing a hydrophilic substance, wherein the ratio (RWD) of the RMS in a wet state to the root mean square roughness (RMS) in a dry state is 0.6 or more.
(2) The hydrophilic substance-containing molded article according to (1), wherein the RWD is less than 1.5.
(3) The molded article containing a hydrophilic substance according to the above (1) or (2), wherein the hydrophilic substance is a hydrophilic polymer.
(4) The molded article containing a hydrophilic substance according to the item (3), wherein the hydrophilic polymer is polyvinylpyrrolidone or polyethylene glycol.
(5) The hydrophilic substance-containing molded article according to any one of (1) to (4), which comprises a polysulfone-based polymer.
[0008]
The molded article containing a hydrophilic substance in the present invention is a molded article made of a hydrophobic polymer containing a hydrophilic substance such as a hydrophilic polymer in the molded article.
[0009]
The type of the hydrophobic polymer is not particularly limited, and examples thereof include water-insoluble polymers such as polysulfone-based polymers, polymethyl methacrylate, polyacrylonitrile, regenerated cellulose, cellulose acetate, and polyethylene-vinyl alcohol copolymer polymers. . In particular, polysulfone-based polymers have recently been widely used for hemodialysis membranes and the like. However, polysulfone-based polymers are originally molded articles having low hydrophilicity, and are particularly preferable polymers because the effects of the present invention are remarkably exhibited.
[0010]
As the polysulfone-based polymer, one having an aromatic ring, a sulfonyl group and an ether group in the main chain, for example, polysulfone represented by the following formulas (1) and (2) is preferably used. It is not limited to these. N in the formula is an integer such as 50 to 80.
[0011]
Embedded image

[0012]
Specific examples of polysulfone include Udel polysulfone P-1700, P-3500 (manufactured by Solvay), Ultrason S3010, S6010 (manufactured by BASF), Victrex (Sumitomo Chemical), Radel A (manufactured by Solvay), Ultra Polysulfone such as Son E (manufactured by BASF). The polysulfone used in the present invention is preferably a polymer composed of only the repeating units represented by the above formulas (1) and / or (2), but may be used together with other monomers as long as the effects of the present invention are not impaired. It may be polymerized. Further, a modified polysulfone in which a benzene ring moiety is substituted and modified with an amino group or a sulfonic acid group can also be used.
[0013]
Examples of the method for producing the molded article containing a hydrophilic substance of the present invention include a method of molding a mixed solution of a hydrophobic polymer and a hydrophilic substance.
[0014]
A method for molding a mixed solution of a hydrophobic polymer and a hydrophilic substance will be described. In the present invention, the hydrophilic substance is a substance having a high affinity for water, and is soluble in water (preferably, the solubility in water (the number of grams dissolved in 100 g of water) is 0.1 or more). , A substance having a contact angle with water of 50 ° or less. In particular, when molding a mixed solution of a hydrophobic polymer and a hydrophilic substance, a hydrophilic polymer is suitably used as the hydrophilic substance. This is because the polymer is generally less likely to be eluted into various aqueous solutions or body fluids when it comes into contact with various aqueous solutions or body fluids as a medical material after molding.
[0015]
Examples of the hydrophilic polymer include polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyethyleneimine, polyacrylic acid, and the like.The molecular weight of the polymer is several hundred to several million, and there are many choices. If it is high, it can be used without being limited to these. It may be a copolymer containing a hydrophilic substance as a component. In particular, when a polysulfone-based polymer is used as the hydrophobic polymer, polyvinylpyrrolidone and polyethylene glycol can be preferably used because they have high compatibility with the polysulfone-based polymer. When a material having poor compatibility is used, phase separation occurs in the state of a solution of the molded body, so that it is difficult to produce a transparent molded body. In addition, as long as it does not cause phase separation of the molded body solution, one or more kinds of hydrophilic substances may be appropriately combined.
[0016]
The root-mean-square roughness (RMS) as used in the present invention refers to the degree of unevenness as measured using an atomic force microscope (AFM), and the unit is expressed in nm. The RMS is obtained by measuring and calculating three-dimensional unevenness information obtained by the AFM using image analysis software (attached to a commercially available atomic force microscope). The RMS measurement in a dry state is performed using a sample obtained by drying a molded body in a wet state immersed in water for 24 hours or more at 25 ° C. and a pressure of 1 mmHg or less to a moisture content of 10% or less. The measurement in the wet state is performed after the dried sample is immersed in water for 24 hours. In order to suppress the adhesion of impurities in water such as blood components such as platelets and proteins, and humic substances, it is important that the hydrophilic substance swells moderately with water. It is indicated by the ratio of the RMS in the wet state to the root mean square (RMS) (RWD = RMS in the wet state / RMS in the dry state) and requires an RWD of 0.6 or more. Furthermore, it is more preferable that it is larger than 1.0.
[0017]
When the amount of the hydrophilic substance is small, the material may be smaller than the RMS in the dry state. However, in the dry state, the hydrophilic substance is unevenly present on the surface of the material, and the unevenness of the hydrophilic substance is observed. On the other hand, it is considered that it is difficult to be observed in a wet state. In order to obtain a preferable hydrophilic surface, the RWD value needs to be 0.6 or more, but is preferably larger than 1.0. When the amount of the hydrophilic substance is increased, the RWD tends to increase. However, when a hydrophilic polymer is used as the hydrophilic substance, if the value is too large, the hydrophilic layer in which the low molecular weight proteins and the like swell will be contained. The RWD value is preferably 10 or less, preferably 2 or less, and more preferably 1.5 or less because there is a concern that the RWD will penetrate and cause substantial adhesion and dirt. Is preferred. Further, the surface having an RWD value of more than 1.0 and not more than 1.5 is the most preferable range because it is considered that the hydrophilic substance covers the surface appropriately. A molded article having such a surface has excellent hydrophilic surface properties, and has an effect of suppressing adhesion of a biological component when used as a medical material. For example, platelet adhesion can be suppressed when a platelet adhesion test in blood is performed.
[0018]
Although there is no particular limitation on the preparation of the molded body solution in the present invention, since the viscosity of the molded body solution tends to depend on the molecular weight of the added hydrophilic polymer and the amount thereof added, the range of good moldability and It is important to prepare it. Specifically, even if the viscosity of the molded body solution is high, up to about 1000 poises is a preferable range with little hindrance to molding. As the concentration of the hydrophilic substance in the molding solution is increased, the surface of the molded body becomes more hydrophilic, and the biocompatibility is improved. Surfaces with high RWD can be obtained by increasing the concentration of hydrophilic substances in the molding solution. The concentration of the hydrophilic substance is preferably 2 to 100% by weight, more preferably 3 to 50% by weight, based on the hydrophobic polymer. When the concentration of the hydrophilic substance in the molded product is less than 2% by weight, the amount of hydrophilicity on the surface of the obtained molded product tends to be insufficient, and it is difficult to obtain a material having a high RWD.
[0019]
Further, as described above, when a hydrophilic polymer having a large molecular weight is used, the viscosity of the solution is significantly increased, so that it is preferable to select a solution composition within a range that does not hinder moldability. In addition, when a hydrophilic substance having a small molecular weight is used, RWD is so small that sufficient biocompatibility may not be exhibited, or elution tends to occur when used as a medical material. When a polymer is used as the hydrophilic substance, those having a weight average molecular weight of 30,000 to 2,000,000 are preferably used.
[0020]
The concentration of the polysulfone-based molded body in the molding solution is preferably at least 20% by weight or more, more preferably 25% by weight or more based on the hydrophilic substance in order to develop a state of compatibility with the hydrophilic substance. Is preferred.
[0021]
In selecting a solvent in the molding solution, a good solvent for the polysulfone-based molded article and the hydrophilic substance is used. Specific examples include, but are not limited to, dimethylacetamide, dimethylformamide, dimethylsulfoxide, acetone, acetaldehyde, 2-methylpyrrolidone, and the like. Dimethylacetamide is preferred in terms of safety and toxicity. In order to obtain a molded product having high RWD, a molded product can be produced by preparing a polysulfone-based molded product and a high-concentration solution of a hydrophilic substance and then evaporating the solvent. Various moldings can be formed by molding. For example, a tube can be molded by extruding from a circular base.
[0022]
As a method for producing a molded article in the present invention, a film prepared from a mixed solution containing a hydrophilic polymer and a hydrophobic polymer will be described below as an example. First, gently hang an appropriate amount while spreading the molding solution laterally on the front end of the glass plate, pull the applicator that can make the cast thickness constant at a constant speed on the glass plate, and spread the molding solution. A known method of spreading without using is used.
[0023]
When a transparent molded body is required, it is important to adjust the optimal molding conditions.In the case of a molded body solution containing a hydrophilic substance, phase separation occurs due to the effect of moisture absorption in the air during casting. Since the casting temperature is concerned, the best conditions for the casting temperature must be determined appropriately, but the casting temperature is preferably 80 to 150 degrees, more preferably 100 to 130 degrees. When casting at a low temperature, it is necessary to perform molding for a long time in an environment that does not absorb moisture. Regarding the cast thickness, if it is too thin, it becomes difficult to form a film. On the other hand, if it is too thick, it takes time to evaporate the solvent, and the thickness is preferably 50 to 500 µm, more preferably 100 to 300 µm.
[0024]
After molding under the above conditions, the film is subjected to a predetermined washing and peeling step, and then dried to obtain a film.
[0025]
The molded article obtained by the present invention includes, for example, medical materials such as contact lenses and intraocular lenses, blood circuits, artificial kidneys, artificial lungs, artificial livers, artificial hearts, artificial organs such as artificial pancreas, membranes for water treatment, and the like. It is widely used with the requirement of hydrophilicity.
[0026]
Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.
[0027]
【Example】
The measuring method used is as follows.
(1) Platelet Adhesion Experiment A film-shaped molded product was placed in a plate shape on the bottom of a polystyrene cylindrical tube of 18 mmφ, and filled with physiological saline. Blood obtained by mixing a 3.2% aqueous solution of trisodium citrate dihydrate and rabbit fresh blood at 1: 9 (volume ratio) was centrifuged at 1000 rpm for 10 minutes, and the supernatant was taken out (referred to as plasma 1). . Thereafter, the blood after removing the supernatant was centrifuged again at 3000 rpm for 10 minutes, and the supernatant was removed (referred to as plasma 2). Plasma 2 was added to plasma 1 for dilution (plasma 2 had a lower platelet concentration than plasma 1) to prepare platelet-rich plasma (PRP) having a platelet count of 20 × 10 ⁶ / ml. After discarding the physiological saline in the prepared cylindrical tube, 1.0 ml of PRP was added, and the mixture was shaken at 37 ° C. for 1 hour using MICROTUBE MIXER (EN-36N) manufactured by Taitec Corporation. Thereafter, the cells were washed three times with a physiological saline solution, blood components were fixed with a 3% glutaraldehyde aqueous solution, washed with distilled water, and dried under reduced pressure for 5 hours or more. This film was attached to a sample stage of a scanning electron microscope with a double-sided tape. Thereafter, a thin film of Pt-Pd was formed on the sample by sputtering. The surface of the sample was observed with a scanning electron microscope (S800, manufactured by Hitachi, Ltd.). (Since the adhesion between the film and the cylindrical tube tends to accumulate blood, the center of the film was mainly observed at a magnification of 3000.) 1.0 × 10 ³ The number of adherent platelets in an area of μm ² was counted. The average value at 20 observation sites was taken.
[0028]
This experiment requires a control. That is, it is necessary to keep the samples prepared as described below at the level of each experiment. Polysulfone (Amoco's Udel-P3500) (10% by weight) was added to 90% by weight of dimethylacetamide, dissolved at room temperature, and cast on a hot plate to a thickness of 203 µm on a glass plate having a surface temperature of 100 ° C. . The surface temperature was measured with a contact thermometer. After casting, it was left on a hot plate for 5 minutes to evaporate the solvent, and then the glass plate was immersed in a water bath to obtain a transparent film. If the number of platelets adhered to the polysulfone film is 40 or less, there is a high possibility that the experiment has failed, such as lack of freshness of blood, and the data at that time cannot be used.
[0029]
(2) Measurement of Surface Polyvinylpyrrolidone The amount of polyvinylpyrrolidone on the surface is determined by X-ray photoelectron spectroscopy (ESCA). The device used was ESCALAB220iXL. From the surface intensities of the C1s, N1s, and S2p spectra obtained by the ESCA measurement, the surface amount of nitrogen (A) and the surface amount of sulfur (B) were determined using the relative sensitivity coefficient attached to the device.
The amount of polyvinylpyrrolidone on the film surface was calculated from the amount (%) of surface polyvinylpyrrolidone = Ax111 × 100 / (Ax111 + Bx442). The measurement was performed at an angle of 90 degrees of the detector with respect to the incident angle of the X-ray.
[0030]
(3) Measurement of contact angle The contact angle was measured using a contact angle meter CA-D manufactured by Kyowa Interface Chemistry. The measurement was performed in a room where the room temperature was adjusted to 25 degrees.
[0031]
(4) Measurement of root mean square (RMS) A film sample was cut into a square of 5 mm and fixed on a steel disc (Nihon VEECO, Tokyo, Japan) using a commercially available transparent nail polish. After fixing, it was dried at room temperature for 24 hours to obtain a dried sample. In the contact mode, a 120 μm, wide tip of the NP-S probe is used (200 μm, the wide tip is folded before use), and a range of 2 mm × 2 mm is applied to an operating point of 0.3 V, 0.2 V. Observed at a sufficiently low scan rate of Hz. P gain and I gain were adjusted for each sample (approximately P gain: 8-15, I gain: 0.001-0.003). After observation, the dried sample was fixed together with the fixed disk to a glass cell attached to the apparatus with transparent nail polish, and was sufficiently wetted with RO water for 24 hours to obtain a wet sample. Wet samples were observed in the same manner as dry samples. By keeping the observation mode, probe, and other scanning conditions unchanged, the change between the dry state and the wet state can be quantitatively evaluated. The measurement was performed at five places, and the average value was adopted.
[0032]
Scanning probe microscope SPM 9500-J3 (SHIMADZU, Kyoto, Japan) was used as the AFM observation conditions, the contact mode was the observation mode, the probe was NP-S (120 mm, wide) (Nihon VEECO KK, Tokyo, Japan), and the scanner. Standard is Standard (30 mm x 30 mm x 5 mm), scanning range is 2 mm x 2 mm (z scale of image is unified to 10 nm), scanning speed is 0.2 Hz, and number of pixels is 512 x 512. I went in. In the image processing, the average value is calculated for each of the x and y lines from the obtained raw image, the average value is subtracted from the data to correct the inclination, and the noise line is reduced to the jump of the cantilever needle and instantaneous noise at the time of measurement. The resulting line noise on the image data was erased on the basis of the inversion of the brightness of the preceding and succeeding lines and the brightness of that line being reversed. Further, when the image contains regular noise in spatial frequency, image processing was performed using a frequency filter.
[0033]
For the calculation of the RMS, "surface roughness analysis" of an offline function was used. The analysis range was adjusted to 1-4 μm ² so as not to pick up a specific shape (standard is 4 μm ² ). In the one-dimensional RMS, the roughness curve (see JIS B601) is sampled by a reference length in the direction of the average line, and the X axis is taken in the direction of the average line of the sampled portion, and the Y axis is taken in the direction of the longitudinal magnification. Sometimes, it refers to the standard deviation obtained as follows. Here, this was expanded to two dimensions and measured.
RMS = (Σ (Yi−Yave) ² / N) ^0.5
Yi: height of any measurement point, Yave: average height of all measurement points, N: number of measurement points. In the following examples, "parts" means "parts by weight".
[0034]
Example 1
10 parts of polysulfone (Udel-P3500, manufactured by Solvay) and 5 parts of polyvinylpyrrolidone (K90, weight average molecular weight: 1.2 million, manufactured by ISP) were added to 85 parts of dimethylacetamide and dissolved at room temperature to prepare a molding solution. This solution was cast on a hot plate to a thickness of 203 μm on a glass plate having a surface temperature of 100 ° C. The surface temperature was measured with a contact thermometer. After casting, the glass plate was left on a hot plate for 5 minutes to evaporate the solvent, and then immersed in a water bath together with the glass plate to obtain a transparent film (the film was immersed in a water bath so that the film could be easily peeled off from the glass plate). is there.). The number of platelets adhered to the obtained film was 12. The surface contact angle was 38 °. The RMS in the dry state was 1.6, the RMS in the wet state was 1.2, and the RWD was 0.7.
[0035]
Example 2
10 parts of polysulfone (Udel-P3500 manufactured by Solvay) and 10 parts of polyvinylpyrrolidone (K90 weight average molecular weight 1.2 million manufactured by ISP) were added to 80 parts of dimethylacetamide, and dissolved at room temperature to obtain a molding solution. A transparent film having a light transmittance of 90.3% was obtained in the same manner as in Example 1. The number of platelets adhered to the obtained film was 7. The surface contact angle was 35 °. The RMS in the dry state was 1.3, the RMS in the wet state was 2.7, and the RWD was 2.1.
[0036]
Comparative Example 1
10 parts of polysulfone (Udel-P3500 manufactured by Solvay) was added to 90 parts of dimethylacetamide, and a transparent film having a light transmittance of 88.9% was obtained in the same manner as in Example 1. The number of platelets adhered to the obtained film was 70. The surface contact angle was 82 °. The RMS in the dry state was 1.2, the RMS in the wet state was 0.6, and the RWD was 0.5.
[0037]
Comparative Example 2
10 parts of polysulfone (Udel-P3500 manufactured by Solvay) and 0.01 part of polyvinylpyrrolidone (K90 weight average molecular weight 1.2 million manufactured by ISP) were added to 90 parts of dimethylacetamide, and the light transmittance was 88.8 in the same manner as in Example 1. % Of a transparent film was obtained. The number of platelets adhered to the obtained film was 60. The surface contact angle was 74 °. The RMS in the dry state was 1.4, the RMS in the wet state was 0.6, and the RWD was 0.4.
[0038]
【The invention's effect】
According to the present invention, it is possible to provide a molded article in which adhesion of biological components such as platelets and proteins is reduced.

Claims (5)

A molded article containing a hydrophilic substance, wherein the ratio of the root mean square roughness in a wet state to the root mean square roughness in a dry state is 0.6 or more. The said ratio is less than 1.5, The hydrophilic substance containing molded object of Claim 1 characterized by the above-mentioned. The hydrophilic substance-containing molded article according to claim 1 or 2, wherein the hydrophilic substance is a hydrophilic polymer. 4. The molded article according to claim 3, wherein the hydrophilic polymer is polyvinylpyrrolidone or polyethylene glycol. The hydrophilic substance-containing molded article according to any one of claims 1 to 4, further comprising a polysulfone-based polymer.