JP3631781B2 - Medical device whose surface has lubricity when wet - Google Patents

Description

【００１５】
また膨潤率の測定方法は以下の方法で測定する。
（１）医療用具を構成する基材を１ｃｍ×３ｃｍ×０．３ｍｍのシートに切断し（この時の重量をＷｏとする）、溶媒２５ｍｌに浸漬させる。
（２）浸漬後、即座に表面に存在する溶媒を拭き取り、重量変化（ΔＷ）を算出する。
浸漬時間に関しては、基材の寸法が著しく変化せず、要求されている物性が保持される範囲内であれば、いかなる時間でも構わないが、操作性の観点から１秒〜１０分、好ましくは１０秒〜５分、より好ましくは３０秒〜３分であることが望まれる。
【００１６】
さらに、具体的な素材としては、ポリオレフィン、変性ポリオレフィン、ハロゲン化ポリオレフィン、ポリエーテル、ポリウレタン、ポリアミド、ポリエステルあるいはこれらのブロックまたはグラフト共重合体やアロイ化成型物や多層化成形物であり、アルカリ金属アルコラート基、アミノ基、アルカリ金属アミド基、カルボン酸基、スルホン酸基、マグネシウムハライド基およびフッ素ホウ素系錯体基を含有する必要はなく、使用する溶媒に膨潤すれば良い。
【００１７】
一方、本発明において湿潤時に潤滑性を有する水溶性または水膨潤性重合体は、要求される機械的強度や潤滑性の機能により異なるが、加熱処理や触媒を添加することにより架橋するエポキシ基を有するブロックポリマーや高分子化するマクロモノマーが好適に使用される。また、患者の体温（３０〜４０℃）において吸水し、潤滑性を発現する重合体であり、架橋または不溶化した際に吸水率が１００％以下のものである。
【００１８】
さらにブロックポリマーにおいては、潤滑性を発現する部位とエポキシ基を有する部位とからなるブロック共重合体であることが望ましい。潤滑性を発現する部位は、体液や水系溶媒中において潤滑性を発現すればいかなるものであっても良いが、合成の容易性や操作性などを考慮すると、アクリルアミド、アクリルアミド誘導体よりなる重合体、Ｎ，Ｎ−ジメチルアミノエチルアクリレート、糖、リン脂質を側鎖に有する単量体を構成成分とする重合体あるいは無水マレイン酸系重合体などが挙げられる。無水マレイン酸系重合体としては、水溶解性に限定されず、無水マレイン酸系高分子を主成分としていれば不溶化されたものであっても、湿潤時に潤滑性を発現するものであれば良い。さらに、基材を膨潤させる溶媒に、重合体を溶解させてコーティングすることを考慮すると、有機溶媒にも可溶な重合体、すなわち両親媒性重合体が好ましい。
【００１９】
一方マクロモノマーにおいては、枝の部分が潤滑性を発現する部位で、幹の部分が加熱処理により架橋または高分子化するドメインを有する部位であることが望ましい。具体的には、グリシジルメタアクリレートとジメチルアクリルアミドとのマクロモノマー、グリシジルメタアクリレートと無水マレイン酸・ヒドロキシエチルメタアクリレート共重合体とのマクロモノマー、グリシジルメタアクリレートと無水マレイン酸・アクリルアミド共重合体とのマクロモノマー等が例示される。
【００２０】
さらに本発明による医療用具とは、体液や血液などと接触して用いる器具のことであり、体液や生理食塩水などの水系液体中において表面が潤滑性を有し、操作性の向上や組織粘膜の損傷の低減が可能なものである。具体的には、血管内で使用されるガイドワイヤーやカテーテル等が挙げられるが、その他にも以下の医療器が示される。
（１）胃管カテーテル、栄養カテーテル、経管栄養用チューブなどの経口もしくは経鼻的に消化器官内に挿入ないし留置されるカテーテル類。
（２）酸素カテーテル、酸素カヌラ、気管内チューブのチューブやカフ、気管切開チューブのチューブやカフ、気管内吸引カテーテルなどの経口または経鼻的に気道ないし気管内に挿入ないし留置されるカテーテル類。
（３）尿道カテーテル、導尿カテーテル、バルーンカテーテルのカテーテルやバルーンなどの尿道ないし尿管内に挿入ないし留置されるカテーテル類。
（４）吸引カテーテル、排液カテーテル、直腸カテーテルなどの各種体腔、臓器、組織内に挿入ないし留置されるカテーテル類。
（５）留置針、ＩＶＨカテーテル、サーモダイリューションカテーテル、血管造影用カテーテル、血管拡張用カテーテルおよびダイレーターあるいはイントロデューサーなどの血管内に挿入ないし留置されるカテーテル類。あるいは、これらのカテーテル用のガイドワーヤー、スタイレットなど。
（６）各種器官層入用の検査器具や治療器具、コンタクトレンズなど。
（７）ステント類や人工血管、人工気管、人工気管支など。
（８）体外循環治療用の医療器（人工肺、人工心臓、人工腎臓など）やその回路類。
【００２１】
【実施例】
以下に実施例を挙げて、本発明を具体的に説明する。
（実施例１）アジピン酸２塩化物７２．３ｇに５０℃でトリエチレングリコール２９．７ｇを滴下した後、５０℃で３時間塩酸を減圧除去して得られたオリゴエステル２２．５ｇにメチルエチルケトン４．５ｇを加え水酸化ナトリウム５ｇ、３１％過酸化水素６．９３ｇ、界面活性剤ジオクチルフォスフェート０．４４ｇ、水１２０ｇよりなる溶液に滴下し、−５℃で２０分間反応させた。反応生成物を水洗、メタノール洗浄を繰り返した後、乾燥させて分子内に複数のパーオキサイド基を有するポリ過酸化物を得た。このポリ過酸化物を開始剤として０．５ｇ、グリシジルメタクリレート（ＧＭＡ）９．５ｇを、ベンゼン３０ｇを溶媒として、８０℃、２時間減圧下で撹拌しながら重合体した。反応生成物は貧溶媒をジエチルエーテル、良溶媒をテトラヒドロフランとして精製し、分子内に複数のパーオキサイド基を有するポリグリシジルメタアクリレート（ＰＰＯ−ＧＭＡ）を得た。続いてＰＰＯ−ＧＭＡ１．０ｇをジメチルアクリルアミド９．０ｇ、溶媒としてジメチルスルフォキシド９０ｇを仕込み、減圧で密閉にした後、８０℃に加熱して１８時間重合反応を行なった。反応後、貧溶媒をジエチルエーテル、良溶媒をテトラヒドロフランとして精製し、分子内にエポキシ基材を有する湿潤時に潤滑性を発現するブロックポリマーを得た。本ポリマーはＮＭＲおよびＩＲ測定により、分子内にエポキシ基の存在が確認できた。
【００２２】
上記ブロックポリマー２重量部と触媒としてピリジン１重量部を１，４−ジオキサンに溶解した。本溶液にポリウレタン（ダウケミカル社製：ペレセン７５Ｄ）の１ｃｍ×３ｃｍ×０．３ｍｍのシートを３０秒間浸漬させた。そのときの膨潤率は、２５％であった。さらに、コーティングしたシートを６０℃、１８時間反応させ、水洗して湿潤時に潤滑性を有する表面を得た。この試料をＡＴＲ−ＩＲにより表面分析を行なったところ、コーティング前に存在していたエポキシ基のピークが認められずエーテル結合のピークが確認され、エポキシ基の架橋が確認された。
【００２３】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。また、１時間の煮沸においても煮沸前の潤滑性を有しており、耐久性においても優れていることが確認できた。
【００２４】
（比較例１）
密閉可能な反応容器に、グリシジルメタアクリレート１０ｇを溶媒であるジメチルスルホキシド９０ｇに溶解し、これに開始剤としてアゾビスイソブチロニトリル０．０５ｇを加え減圧下で８０℃、１８時間反応を行なった。反応後、貧溶媒をジエチルエーテル、良溶媒をテトラヒドロフランとして精製しＮＭＲ、ＩＲによりポリグリシジルアクリレートのホモポリマーであることを確認した。また、ジメチルアクリルアミド１０ｇをジメチルスルホキシド９０ｇに加え同様な方法にて重合し、ＮＭＲ、ＩＲによりポリジメチルアクリルアミドのホモポリマーであることを確認した。
【００２５】
上記ポリマー２種の２重量部を１，４−ジオキサンに溶解し、本溶液にポリウレタン（ダウケミカル社製：ペレセン７５Ｄ ）のシート１ｃｍ×３ｃｍ×０．３ ｍｍ３０秒間浸漬させた。そのときの膨潤率は２５％であった。さらに、コーティングしたシートを６０℃、１８時間反応させ、水洗して湿潤時に潤滑性を有する表面を得た。この試料をＡＴＲ−ＩＲにより表面分析を行なったところ、コーティング前に存在していたエポキシ基のピークが認められず、エーテル結合のピークが確認され、エポキシ基の架橋が確認された。
【００２６】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。しかし、１時間の煮沸後においては、ほとんど潤滑性を有しておらず、耐久性が低いことが確認された。
【００２７】
（実施例２）
実施例１と同様なブロックポリマー２重量部と触媒としてピリジン１重量部をテトラヒドロフランにに溶解しエチレン−酢酸ビニル共重合体（住友化学工業株式会社製：エバテート）の１ｃｍ×３ｃｍ×０．３ｍｍのシートを１分浸漬させた。そのときの膨潤率は１５％であった。さらに、コーティングしたシートを６０℃、１８時間反応させ、水洗して湿潤時に潤滑性を有する表面を得た。この試料をＡＴＲ−ＩＲにより表面分析を行なったところ、コーティング前に存在していたエポキシ基のピークが認められず、エーテル結合のピークが確認され、エポキシ基の架橋が確認された。
【００２８】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。また、１時間の煮沸においても煮沸前の潤滑性を有しており、耐久性においても優れていることが確認できた。
【００２９】
（比較例２）
比較例１と同様な２種のポリマー溶液にエバテートの１ｃｍ×３ｃｍ×０．３ｍｍのシートを１分浸漬させた。そのときの膨潤率は１５％であった。さらに、コーティングしたシートを６０℃、１８時間反応させ、水洗して湿潤時に潤滑性を有する表面を得た。この試料をＡＴＲ−ＩＲにより表面分析を行なったところ、コーティング前に存在していたエポキシ基のピークが認められず、エーテル結合のピークが確認され、エポキシ基の架橋が確認された。
【００３０】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。しかし、１時間の煮沸後においては、ほとんど潤滑性を有しておらず、耐久性が低いことが確認された。
【００３１】
（実施例３）
密閉可能な反応容器に、ジメチルアクリルアミド１０ｇと連鎖移動剤としてヨード酢酸１ｇさらに開始剤としてｔ−ブチルパ−オクトエイト０．０５ｇを入れ、減圧下で８０℃、８時間反応させ、ポリマー（１）を得た。このポリマー（１）の５ｇとグリシジルメタアクリレート１ｇとをベンゼン９０ｇに溶解し少量のハイドロキノンの存在下で、窒素雰囲気中６０℃、８時間反応させた。反応生成物は貧溶媒をジエチルエーテル、良溶媒をテトラヒドロフランとして精製し、ポリマー（２）を得た。得られた生成物はＮＭＲの測定によりポリマー（２）のようなマクロモノマー構造であることが確認された。
【００３２】
【化１】

【００３３】
上記ポリマー（２）の２重合部と開始剤としてアゾビスイソブチロニトリル０．０１重量部をクロロホルムに溶解し、エチレン−塩ビ共重合体（東ソー株式会社：リューロンＥ）の１ｃｍ×３ｃｍ×０．３ｍｍのシートを３０秒間浸漬させた。そのときの膨潤率は１９％であった。さらに、コーティングしたシートを６０℃、１８時間反応させ、水洗して湿潤時に潤滑性を有する表面を得た。この試料をＡＴＲ−ＩＲにより表面分析を行なったところ、コーティング前に存在していた炭素−炭素の二重結合が認められず、高分子化されていることが確認された。
【００３４】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。また、１時間の煮沸においても煮沸前の優れた潤滑性を有しており、耐久性においても優れていることが確認できた。
【００３５】
（比較例３）
比較例１と同様なポリマー２種をクロロホルムに溶解した。本溶液に上記エチレン−塩ビ共重合体の１ｃｍ×３ｃｍ×０．３ｍｍのシートを３０秒間浸漬させた。そのときの膨潤率は１９％であった。さらに、コーティングしたシートを６０℃、１８時間反応させ、水洗して湿潤時に潤滑性を有する表面を得た。この試料をＡＴＲ−ＩＲにより表面分析を行なったところ、コーティング前に存在していたエポキシ基のピークが認められず、エーテル結合のピークが確認され、エポキシ基の架橋が確認された。
【００３６】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。しかし、１時間の煮沸後においては、ほとんど潤滑性を有しておらず、耐久性が低いことが確認された。
【００３７】
（実施例４）
密閉可能な反応容器に、グリシジルメタアクリレート９．８ｇ、無水マレイン酸１４．２ｇ、開始剤としてアゾビスイソブチロニトリル０．０５ｇを溶媒であるジメチルスルホキシド９０ｇに溶解し、減圧下で８０℃、１８時間反応を行なった。反応後、貧溶媒をジエチルエーテル、良溶媒をテトラヒドロフランとして精製し、ポリマーを得た。本ポリマーはＮＭＲおよびＩＲ測定により、分子内にエポキシ基の存在が確認できた。
【００３８】
上記ポリマーの２重量部と触媒としてピリジン１重量部をテトラヒドロフランに溶解し、エチレン−メチルメタアクリレート共重合体（住友化学株式会社製：アクリフト） のシート１ｃｍ×３ｃｍ×０．３ ｍｍを３０秒間浸漬させた。そのときの膨潤率は、２５％であった。さらに、コーティングしたシートを６０℃、１８時間応させた。反応後、エタノール中で硫酸を触媒として無水マレイン酸を開環させ、炭酸水素ナトリウムの生理食塩水溶液を用いてアルカリ洗浄を行ない試料とした。この試料をＡＴＲ−ＩＲにより表面分析を行なったところ、コーティング前に存在していたエポキシ基のピークが認められず、エーテル結合のピークが確認され、エポキシ基の架橋が確認された。
【００３９】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。また、１時間の煮沸においても煮沸前の優れた潤滑性を有しており、耐久性においても優れていることが確認できた。
【００４０】
（比較例４）
密閉可能な反応容器に、グリシジルメタアクリレート１０ｇ、開始剤としてアゾビスイソブチロニトリル０．０２ｇを溶媒であるジメチルスルホキシド９０ｇに溶解し、減圧下で８０℃、１８時間反応を行なった。反応後、貧溶媒をジエチルエーテル、良溶媒をテトラヒドロフランとして精製し、湿潤時に潤滑性を発現するポリマーを得た。本ポリマーはＮＭＲおよびＩＲ測定により、分子内にエポキシ基を有するポリグリシジルメタアクリレートのホモポリマーであることを確認した。
【００４１】
また、密閉可能な反応容器に無水マレイン酸モノマー５ｇと光増感剤としてカンファーキノン０．１ｇを溶媒であるベンゼン５０ｇに入れ、ＵＶ照射後、減圧下で８０℃、１８時間反応を行なった。反応後、貧溶媒をジエチルエーテル、良溶媒をテトラヒドロフランとして精製し、湿潤時に潤滑性を発現するポリマーを得た。本ポリマーはＮＭＲおよびＩＲ測定により、無水マレイン酸のホモポリマーであることを確認した。
【００４２】
上記ポリマー２種の２重量部をテトラヒドロフランに溶解し、エチレン−メチルメタクリレート共重合体（住友化学株式会社製：アクリフト）のシート１ｃｍ×３ｃｍ×０．３ｍｍを３０秒間浸漬させた。そのときの膨潤率は２５％であった。さらに、コーティングしたシートを６０℃、１８時間反応させた。反応後、エタノール中で硫酸を触媒として無水マレイン酸を開環させ、炭酸水素ナトリウムの生理食塩水溶液を用いてアルカリ洗浄を行ない試料とした。この試料をＡＴＲ−ＩＲにより表面分析を行ったところ、コーティング前に存在していたエポキシ基のピークが認められず、エーテル結合のピークが確認され、エポキシ基の架橋が確認された。
【００４３】
得られたシートは生理食塩水または水に浸漬させると、優れた潤滑性を示した。しかし、１時間煮沸後においては、ほとんど潤滑性を有しておらず、耐久性が低いことが確認された。
【００４４】
（比較例５）
実施例３と同様なマクロモノマー２重量部と、開始剤としてアゾビスイソブチロニトリル０．０１重量部をメタノールに溶解し、エチレン−塩ビ共重合体（東ソー株式会社：リューロンＥ）の１ｃｍ×３ｃｍ×０．３ｍｍのシートを３０秒間浸漬させた。その時の膨潤率は０．５％であった。さらに、コーティングしたシートを６０℃、１８時間反応させた。
【００４５】
反応後、水洗直後は潤滑性を発現したが、水洗中に潤滑性が低下し、耐久性が低いことが確認された。
【００４６】
（比較例６）
実施例４と同様な重合体２重量部と触媒としてピリジン１重量部をメタノールに溶解し、エチレン−メチルメタアクリレート（住友化学株式会社：アクリフト）の１ｃｍ×３ｃｍ×０．３ｍｍのシートを３０秒浸漬させた。その時の膨潤率は０．８％であった。さらに、コーティングしたシートを６０℃、１８時間反応させた。
【００４７】
反応後、エタノール中で硫酸を触媒として無水マレイン酸を開環させ、炭酸水素ナトリウムの生理食塩水溶液を用いてアルカリ洗浄を行い試料とした。アルカリ洗浄直後は潤滑性を発現したが、洗浄中に潤滑性が低下し、耐久性が低いことが確認された。
【００４８】
【発明の効果】
以上述べたように本発明は、加熱処理により架橋または高分子化する水溶性または水膨潤性重合体を医療用具の基材を膨潤させる溶媒に溶解し該重合体溶液を作成し、該重合体溶液に医療用具の基材を浸漬し膨潤させながら、基材表面に該重合体をコーティングし、加熱処理等により基材と該重合体間に相互貫入網目構造を生成させ該重合体を基材表面に固定化したものであるため、従来のシリコンオイルやグリセリンなどを使用するものとは異なり、剥離や溶出がなく、耐久性や安全性の高い医療用具が可能となる。また、該重合体が湿潤時に潤滑性を発現するため、体内への挿入時における抵抗は少なくなり、操作性の向上、組織粘膜の損傷低減、患者の苦痛低減等の効果がある。さらに、従来のような複数回のコーティング等を必要としないため、製造工程の簡略化や工程管理が容易となる。[0001]
[Industrial application fields]
The present invention relates to a medical device. More specifically, the present invention relates to a medical device having excellent lubricity when wet by a polymer present on the surface of the material of the medical device, and a method for producing the same.
[0002]
[Prior art]
The surface of the base of medical devices such as catheters inserted into the trachea, digestive tract, urethra, blood vessels, other body cavities and tissues, and medical devices such as guide wires and stylets inserted into these are generally thrombus, tissue adhesion Many foreign body reactions are confirmed. Therefore, it is necessary to reduce the damage to the tissue, ensure that it is inserted into the target site, and also to have a lubricious surface to minimize inflammation and damage to the mucous membrane during placement in the tissue. It becomes.
[0003]
For this reason, a low-friction material is used as a base material, and a lubricant is coated on the surface of the base material. For example, a low friction material such as a fluororesin or a polyethylene resin is used as a base material for these medical devices, and a fluororesin, silicon oil, olive oil, glycerin, or the like is further applied on the surface. However, with this method, permanent lubricity cannot be expected, and there has been a problem in terms of safety such as separation, elution, and desorption of a substance having lubricity from the substrate surface. In addition, there are cases where high-density polyethylene, which is a low friction material, is used as the base material, or when oil is applied to the surface, but sufficient lubricity is not obtained, and the effect is not sustained, so oil etc. is washed away. There was a concern that product management would be difficult due to the rustling or surface feel.
[0004]
U.S. Pat. No. 4,100,309 and JP-A-59-19582 disclose that a copolymer of polyvinylpyrrolidone and polyurethane is used as a material having lubricity. This method is satisfactory in terms of lubricity and sustainability, but it requires two or more kinds of applied polymers and the presence of isocyanate groups as reactive groups. Reaction of the group with a substrate having low reactivity and a polymer having lubricity is not possible and is not preferred.
[0005]
Japanese Patent Application Laid-Open No. 59-81341 discloses a method of imparting lubricity by generating an unreacted isocyanate group on the surface of a medical device and reacting this with a hydrophilic polymer that can be covalently bonded to the isocyanate group. Has been. By this method, good lubricity can be obtained, and the lubricity can be expected to be maintained to some extent. However, in this method, when the hydrophilic polymer contains N-vinyl-2-pyrrolidone or the like as a main component, the strength of the polymer is not sufficient, and thus there is a problem that lubricity is lowered by repeated use. . In addition, when coating a polymer having lubricity after coating isocyanate groups, there are concerns that the coating process may be performed more than once and the presence of unreacted isocyanate groups, which is not preferable. Absent.
[0006]
In Japanese Patent Publication No. 1-55023, a compound having active hydrogen having a main chain of a copolymer composed of two or more monomers on the surface of a medical device is bonded via a polyisocyanate compound, thereby being biocompatible. A method of imparting sex is disclosed. However, in this method, the presence of at least one of an amino group, an imino group, a carboxyl group, and a mercapto group is indispensable on the surface of the base material constituting the medical device. A medical device that does not have a functional group has a drawback that it cannot be processed.
[0007]
Further, Japanese Patent Publication No. 1-333181 discloses a method of imparting lubricity by covalently bonding a reactive functional group present on the surface of a base material constituting a medical device and a maleic anhydride-based polymer. Has been. However, even in this method, the presence of the reactive functional group is indispensable on the surface of the base material constituting the medical device, and there is a drawback that it cannot be directly introduced into the base material not having the reactive functional group. Furthermore, when using a substrate that does not have a reactive functional group, the reactive functional group is present on the surface of the substrate by treating the substrate with a solution of a compound having a reactive functional group in advance. Although the method is described in the above publication, there is a problem that a polymer that exhibits lubricity cannot be stably bonded unless the compound is stably bonded to the substrate surface.
[0008]
Furthermore, WO90 / 01344 describes at least one of an alkali metal alcoholate group, an amino group, an alkali metal amide group, a carboxylic acid group, a sulfonic acid group, a magnesium halide group, and a fluorine-boron complex group by coating the polyurethane surface. It is disclosed that a hydrophilic polymer capable of reacting with these functional groups is immobilized on the surface by introducing and further coating operation, but there are multiple coating operations and further application to olefin materials is impossible It was quite limited as an applicable material.
[0009]
[Problems to be solved by the invention]
As described above, in order to impart lubricity on the surface of a medical device, it is most preferable to immobilize a hydrophilic polymer on the surface of a hydrophobic substrate. However, because of the durability of the hydrophilic polymer, it is effective and safe. There was no medical device that had sex.
[0010]
Accordingly, an object of the present invention is to solve the above-mentioned problems and to provide a medical device having permanent low friction in body fluids and aqueous solvents and having high safety. Furthermore, even when the base material of the medical device is a polyolefin or the like that does not have a reactive group, it is intended to provide a method for manufacturing a medical device that can easily coat the surface of the base material with a polymer having lubricity when wet. is there.
[0011]
[Means for Solving the Problems]
Such an object is achieved by the invention described below.
(1) A medical device having a lubricious surface when wet, wherein a cross-linked or polymerized product of a water-soluble or water-swellable polymer forms an interpenetrating network structure on the surface of the base material of the medical device. .
(2) The medical device having a lubricious surface when wet according to (1), wherein the polymer is a block polymer having an epoxy group.
(3) The medical device according to (1), wherein the polymer is a macromonomer and the surface has lubricity when wet.
(4) A polymer solution is prepared by dissolving a water-soluble or water-swellable polymer in a solvent in which the base material of the medical device swells, and the base material of the medical device is immersed in the solution to be swollen. A method for producing a medical device having a lubricious surface when wet, wherein the polymer is crosslinked or polymerized on the surface of the material.
[0012]
In the present invention, the surface of the base material of the medical device is swollen by a solvent, and an interpenetrating network structure is formed between the water-soluble or water-swellable polymer, thereby fixing the polymer to the base material. It is something to strengthen. The interpenetrating network structure may be formed at the interface between the base material and the polymer layer. By strengthening the bonding at the interface, a surface lubricating layer having excellent peeling resistance is formed.
[0013]
In the present invention, the base material constituting the medical device may be any material as long as the mechanical strength is large and the dimensions are not significantly changed, as long as it swells with respect to the solvent. It is desired that the swelling ratio calculated by the formula is a combination of a base material and a solvent that can coat the polymer under the conditions of 1 to 100%, preferably 5 to 40%, more preferably 10 to 30%.
[0014]
[Expression 1]

[0015]
The swelling rate is measured by the following method.
(1) A base material constituting a medical device is cut into a 1 cm × 3 cm × 0.3 mm sheet (the weight at this time is Wo) and immersed in 25 ml of a solvent.
(2) Immediately after immersion, the solvent present on the surface is wiped off, and the weight change (ΔW) is calculated.
With respect to the immersion time, any time may be used as long as the dimensions of the substrate do not change significantly and the required physical properties are maintained, but from the viewpoint of operability, 1 second to 10 minutes, preferably It is desired to be 10 seconds to 5 minutes, more preferably 30 seconds to 3 minutes.
[0016]
In addition, specific materials include polyolefins, modified polyolefins, halogenated polyolefins, polyethers, polyurethanes, polyamides, polyesters, or block or graft copolymers, alloyed molded products, and multilayered molded products, and alkali metals. It is not necessary to contain an alcoholate group, an amino group, an alkali metal amide group, a carboxylic acid group, a sulfonic acid group, a magnesium halide group, and a fluorine-boron complex group.
[0017]
On the other hand, the water-soluble or water-swellable polymer having lubricity when wet in the present invention varies depending on the required mechanical strength and lubricity function, but has an epoxy group that is crosslinked by heat treatment or addition of a catalyst. A block polymer or a macromonomer that is polymerized is preferably used. Further, it is a polymer that absorbs water at the patient's body temperature (30 to 40 ° C.) and exhibits lubricity, and has a water absorption rate of 100% or less when crosslinked or insolubilized.
[0018]
Further, the block polymer is preferably a block copolymer composed of a site exhibiting lubricity and a site having an epoxy group. The site that exhibits lubricity may be any material that exhibits lubricity in body fluids or aqueous solvents, but considering the ease of synthesis and operability, acrylamide, a polymer comprising an acrylamide derivative, Examples thereof include a polymer having a monomer having N, N-dimethylaminoethyl acrylate, sugar, and phospholipid in the side chain as a constituent, or a maleic anhydride-based polymer. The maleic anhydride polymer is not limited to water solubility, but may be insolubilized as long as the maleic anhydride polymer is a main component as long as it exhibits lubricity when wet. . Furthermore, considering that the polymer is dissolved and coated in a solvent that swells the substrate, a polymer that is soluble in an organic solvent, that is, an amphiphilic polymer is preferable.
[0019]
On the other hand, in the macromonomer, it is desirable that the branch part is a part that exhibits lubricity and the trunk part is a part having a domain that is crosslinked or polymerized by heat treatment. Specifically, a macromonomer of glycidyl methacrylate and dimethylacrylamide, a macromonomer of glycidyl methacrylate and maleic anhydride / hydroxyethyl methacrylate copolymer, and a glycidyl methacrylate and maleic anhydride / acrylamide copolymer A macromonomer etc. are illustrated.
[0020]
Furthermore, the medical device according to the present invention is a device used in contact with body fluid, blood, etc., and the surface has lubricity in an aqueous liquid such as body fluid or physiological saline, improving operability and tissue mucosa. It is possible to reduce the damage. Specific examples include guide wires and catheters used in blood vessels, but the following medical devices are also shown.
(1) Catheters inserted or placed in the digestive organs orally or nasally, such as gastric tube catheters, nutritional catheters, tube feeding tubes and the like.
(2) Oxygen catheters, oxygen canulas, endotracheal tube tubes and cuffs, tracheostomy tube tubes and cuffs, intratracheal suction catheters, and other catheters that are inserted or placed in the trachea or trachea orally.
(3) Catheters inserted or placed in the urethra or ureter, such as urethral catheters, urinary catheters, balloon catheter catheters and balloons.
(4) Catheters inserted or placed in various body cavities, organs, tissues such as suction catheters, drainage catheters, rectal catheters.
(5) Indwelling needles, IVH catheters, thermodilution catheters, angiographic catheters, vasodilator catheters and catheters inserted or placed in blood vessels such as dilators or introducers. Alternatively, guide catheters and stylets for these catheters.
(6) Examination and treatment instruments for various organ layers, contact lenses, etc.
(7) Stents, artificial blood vessels, artificial trachea, artificial bronchi, etc.
(8) Medical devices for extracorporeal circulation treatment (artificial lung, artificial heart, artificial kidney, etc.) and their circuits.
[0021]
【Example】
The present invention will be specifically described below with reference to examples.
Example 1 29.7 g of triethylene glycol was added dropwise to 72.3 g of adipic acid dichloride at 50 ° C., and hydrochloric acid was removed under reduced pressure at 50 ° C. for 3 hours. 0.5 g was added, and the mixture was added dropwise to a solution consisting of 5 g of sodium hydroxide, 6.93 g of 31% hydrogen peroxide, 0.44 g of a surfactant dioctyl phosphate, and 120 g of water, and reacted at −5 ° C. for 20 minutes. The reaction product was repeatedly washed with water and methanol, and then dried to obtain a polyperoxide having a plurality of peroxide groups in the molecule. The polyperoxide was used as an initiator, and 0.5 g, glycidyl methacrylate (GMA) 9.5 g, and benzene 30 g as a solvent were polymerized while stirring at 80 ° C. for 2 hours under reduced pressure. The reaction product was purified by using diethyl ether as a poor solvent and tetrahydrofuran as a good solvent to obtain polyglycidyl methacrylate (PPO-GMA) having a plurality of peroxide groups in the molecule. Subsequently, 9.0 g of PPO-GMA was charged with 9.0 g of dimethylacrylamide and 90 g of dimethyl sulfoxide as a solvent. After sealing under reduced pressure, the mixture was heated to 80 ° C. and subjected to a polymerization reaction for 18 hours. After the reaction, diethyl ether antisolvent was purified good solvent as tetrahydrofuran to obtain a block polymer which express lubricity during humid having an epoxy substrate in the molecule. The presence of an epoxy group in the molecule of this polymer could be confirmed by NMR and IR measurements.
[0022]
2 parts by weight of the block polymer and 1 part by weight of pyridine as a catalyst were dissolved in 1,4-dioxane. A 1 cm × 3 cm × 0.3 mm sheet of polyurethane (manufactured by Dow Chemical Co., Ltd .: Pelecene 75D) was immersed in this solution for 30 seconds. The swelling rate at that time was 25%. Further, the coated sheet was reacted at 60 ° C. for 18 hours and washed with water to obtain a surface having lubricity when wet. When this sample was subjected to surface analysis by ATR-IR, an epoxy group peak existing before coating was not observed, but an ether bond peak was confirmed, and crosslinking of the epoxy group was confirmed.
[0023]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. Moreover, even in boiling for 1 hour, it has the lubricity before boiling, and it has confirmed that it was excellent also in durability.
[0024]
(Comparative Example 1)
In a sealable reaction vessel, 10 g of glycidyl methacrylate was dissolved in 90 g of dimethyl sulfoxide as a solvent, 0.05 g of azobisisobutyronitrile was added as an initiator, and the reaction was carried out at 80 ° C. for 18 hours under reduced pressure. . After the reaction, the poor solvent was purified with diethyl ether and the good solvent was tetrahydrofuran, and confirmed to be a homopolymer of polyglycidyl acrylate by NMR and IR. Further, 10 g of dimethylacrylamide was added to 90 g of dimethylsulfoxide and polymerized in the same manner, and confirmed to be a polydimethylacrylamide homopolymer by NMR and IR.
[0025]
Two parts by weight of the above two polymers were dissolved in 1,4-dioxane, and a sheet of polyurethane (manufactured by Dow Chemical Co .: Pelecene 75D) 1 cm × 3 cm × 0.3 mm 30 seconds was immersed in this solution. The swelling rate at that time was 25%. Further, the coated sheet was reacted at 60 ° C. for 18 hours and washed with water to obtain a surface having lubricity when wet. When this sample was subjected to surface analysis by ATR-IR, the peak of the epoxy group existing before coating was not observed, the peak of the ether bond was confirmed, and the crosslinking of the epoxy group was confirmed.
[0026]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. However, it was confirmed that after boiling for 1 hour, it had almost no lubricity and its durability was low.
[0027]
(Example 2)
2 parts by weight of the same block polymer as in Example 1 and 1 part by weight of pyridine as a catalyst were dissolved in tetrahydrofuran, and an ethylene-vinyl acetate copolymer (manufactured by Sumitomo Chemical Co., Ltd .: Evaate) was 1 cm × 3 cm × 0.3 mm. The sheet was immersed for 1 minute. The swelling rate at that time was 15%. Further, the coated sheet was reacted at 60 ° C. for 18 hours and washed with water to obtain a surface having lubricity when wet. When this sample was subjected to surface analysis by ATR-IR, the peak of the epoxy group existing before coating was not observed, the peak of the ether bond was confirmed, and the crosslinking of the epoxy group was confirmed.
[0028]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. Moreover, even in boiling for 1 hour, it has the lubricity before boiling, and it has confirmed that it was excellent also in durability.
[0029]
(Comparative Example 2)
A 1 cm × 3 cm × 0.3 mm sheet of evertate was immersed in two polymer solutions similar to Comparative Example 1 for 1 minute. The swelling rate at that time was 15%. Further, the coated sheet was reacted at 60 ° C. for 18 hours and washed with water to obtain a surface having lubricity when wet. When this sample was subjected to surface analysis by ATR-IR, the peak of the epoxy group existing before coating was not observed, the peak of the ether bond was confirmed, and the crosslinking of the epoxy group was confirmed.
[0030]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. However, it was confirmed that after boiling for 1 hour, it had almost no lubricity and its durability was low.
[0031]
(Example 3)
In a sealable reaction vessel, 10 g of dimethylacrylamide, 1 g of iodoacetic acid as a chain transfer agent and 0.05 g of t-butyl peroctoate as an initiator were added and reacted at 80 ° C. for 8 hours under reduced pressure to obtain polymer (1). It was. 5 g of this polymer (1) and 1 g of glycidyl methacrylate were dissolved in 90 g of benzene and reacted in a nitrogen atmosphere at 60 ° C. for 8 hours in the presence of a small amount of hydroquinone. The reaction product was purified using diethyl ether as a poor solvent and tetrahydrofuran as a good solvent to obtain a polymer (2). The obtained product was confirmed to have a macromonomer structure such as polymer (2) by NMR measurement.
[0032]
[Chemical 1]

[0033]
Two polymer parts of the polymer (2) and 0.01 part by weight of azobisisobutyronitrile as an initiator are dissolved in chloroform, and 1 cm × 3 cm × 0 of an ethylene-vinyl chloride copolymer (Tosoh Corporation: Lueron E). A 3 mm sheet was immersed for 30 seconds. The swelling rate at that time was 19%. Further, the coated sheet was reacted at 60 ° C. for 18 hours and washed with water to obtain a surface having lubricity when wet. When this sample was subjected to surface analysis by ATR-IR, the carbon-carbon double bond existing before coating was not observed, and it was confirmed that the sample was polymerized.
[0034]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. Moreover, even in boiling for 1 hour, it had excellent lubricity before boiling, and it was confirmed that the durability was also excellent.
[0035]
(Comparative Example 3)
Two polymers similar to Comparative Example 1 were dissolved in chloroform. A 1 cm × 3 cm × 0.3 mm sheet of the ethylene-vinyl chloride copolymer was immersed in this solution for 30 seconds. The swelling rate at that time was 19%. Further, the coated sheet was reacted at 60 ° C. for 18 hours and washed with water to obtain a surface having lubricity when wet. When this sample was subjected to surface analysis by ATR-IR, the peak of the epoxy group existing before coating was not observed, the peak of the ether bond was confirmed, and the crosslinking of the epoxy group was confirmed.
[0036]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. However, it was confirmed that after boiling for 1 hour, it had almost no lubricity and its durability was low.
[0037]
(Example 4)
In a sealable reaction vessel, 9.8 g of glycidyl methacrylate, 14.2 g of maleic anhydride, 0.05 g of azobisisobutyronitrile as an initiator were dissolved in 90 g of dimethyl sulfoxide as a solvent, and the mixture was heated at 80 ° C. under reduced pressure. The reaction was performed for 18 hours. After the reaction, the polymer was obtained by purifying the poor solvent as diethyl ether and the good solvent as tetrahydrofuran. The presence of an epoxy group in the molecule of this polymer could be confirmed by NMR and IR measurements.
[0038]
2 parts by weight of the above polymer and 1 part by weight of pyridine as a catalyst are dissolved in tetrahydrofuran, and a 1 cm × 3 cm × 0.3 mm sheet of an ethylene-methyl methacrylate copolymer (manufactured by Sumitomo Chemical Co., Ltd .: ACLIFT) is immersed for 30 seconds. I let you. The swelling rate at that time was 25%. Further, the coated sheet was allowed to react at 60 ° C. for 18 hours. After the reaction, maleic anhydride was ring-opened using sulfuric acid as a catalyst in ethanol, and alkali washing was performed using a physiological saline solution of sodium hydrogen carbonate to prepare a sample. When this sample was subjected to surface analysis by ATR-IR, the peak of the epoxy group existing before coating was not observed, the peak of the ether bond was confirmed, and the crosslinking of the epoxy group was confirmed.
[0039]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. Moreover, even in boiling for 1 hour, it had excellent lubricity before boiling, and it was confirmed that the durability was also excellent.
[0040]
(Comparative Example 4)
In a sealable reaction vessel, 10 g of glycidyl methacrylate and 0.02 g of azobisisobutyronitrile as an initiator were dissolved in 90 g of dimethyl sulfoxide as a solvent and reacted at 80 ° C. for 18 hours under reduced pressure. After the reaction, the poor solvent was purified as diethyl ether and the good solvent as tetrahydrofuran to obtain a polymer that exhibited lubricity when wet. This polymer was confirmed by NMR and IR measurements to be a homopolymer of polyglycidyl methacrylate having an epoxy group in the molecule.
[0041]
Further, 5 g of maleic anhydride monomer and 0.1 g of camphorquinone as a photosensitizer were placed in 50 g of benzene as a solvent in a sealable reaction vessel, and reacted at 80 ° C. under reduced pressure for 18 hours after UV irradiation. After the reaction, the poor solvent was purified as diethyl ether and the good solvent as tetrahydrofuran to obtain a polymer that exhibited lubricity when wet. This polymer was confirmed to be a homopolymer of maleic anhydride by NMR and IR measurements.
[0042]
Two parts by weight of the above two polymers were dissolved in tetrahydrofuran, and a 1 cm × 3 cm × 0.3 mm sheet of an ethylene-methyl methacrylate copolymer (manufactured by Sumitomo Chemical Co., Ltd .: ACLIFT) was immersed for 30 seconds. The swelling rate at that time was 25%. Further, the coated sheet was reacted at 60 ° C. for 18 hours. After the reaction, maleic anhydride was ring-opened using sulfuric acid as a catalyst in ethanol, and alkali washing was performed using a physiological saline solution of sodium hydrogen carbonate to prepare a sample. When this sample was subjected to surface analysis by ATR-IR, the peak of the epoxy group existing before coating was not observed, the peak of the ether bond was confirmed, and the crosslinking of the epoxy group was confirmed.
[0043]
The obtained sheet exhibited excellent lubricity when immersed in physiological saline or water. However, it was confirmed that after boiling for 1 hour, it had almost no lubricity and low durability.
[0044]
(Comparative Example 5)
2 parts by weight of the same macromonomer as in Example 3 and 0.01 part by weight of azobisisobutyronitrile as an initiator were dissolved in methanol, and 1 cm × ethylene-vinyl chloride copolymer (Tosoh Corporation: Luuron E) A 3 cm × 0.3 mm sheet was immersed for 30 seconds. The swelling rate at that time was 0.5%. Further, the coated sheet was reacted at 60 ° C. for 18 hours.
[0045]
After the reaction, it exhibited lubricity immediately after washing with water, but it was confirmed that the lubricity decreased during washing with water and the durability was low.
[0046]
(Comparative Example 6)
2 parts by weight of the same polymer as in Example 4 and 1 part by weight of pyridine as a catalyst are dissolved in methanol, and a 1 cm × 3 cm × 0.3 mm sheet of ethylene-methyl methacrylate (Sumitomo Chemical Co., Ltd .: ACRIFT) is used for 30 seconds. Soaked. The swelling rate at that time was 0.8%. Further, the coated sheet was reacted at 60 ° C. for 18 hours.
[0047]
After the reaction, maleic anhydride was ring-opened using sulfuric acid as a catalyst in ethanol, and the sample was washed with alkali using a physiological saline solution of sodium bicarbonate. Immediately after alkali cleaning, lubricity was exhibited, but it was confirmed that the lubricity decreased during cleaning and the durability was low.
[0048]
【The invention's effect】
As described above, in the present invention, a water-soluble or water-swellable polymer that is crosslinked or polymerized by heat treatment is dissolved in a solvent that swells the base material of a medical device to prepare the polymer solution. While the base material of the medical device is immersed in a solution and swollen, the polymer is coated on the surface of the base material, and an interpenetrating network structure is generated between the base material and the polymer by a heat treatment or the like to form the base material. Because it is fixed on the surface, unlike conventional silicone oil or glycerin, there is no peeling or elution, and a highly durable and safe medical device is possible. In addition, since the polymer exhibits lubricity when wet, the resistance during insertion into the body is reduced, and there are effects such as improved operability, reduced tissue mucosal damage, and reduced patient pain. Furthermore, since the conventional multiple coatings are not required, the manufacturing process can be simplified and process management can be facilitated.

Claims (5)

A water-soluble or water-swellable polymer is dissolved in a solvent in which a polymer substrate constituting a medical device that does not have a reactive group that reacts with the polymer swells at a swelling rate of 1 to 100%. A solution is prepared, the polymer substrate is immersed in the solution to swell, and the polymer is cross-linked or polymerized on the surface of the polymer substrate. A medical device having a lubricious surface when wet, characterized in that an interpenetrating network structure is formed therebetween. The medical device according to claim 1, wherein the polymer is a block polymer having an epoxy group, and the surface has lubricity when wet. 3. The medical device having a lubricious surface when wet according to claim 2, wherein the block polymer is a block copolymer comprising a site exhibiting lubricity and a site having an epoxy group. Tools. 4. The medical device having a lubricious surface when wet according to claim 3, wherein the site exhibiting lubricity is a polymer composed of acrylamide or an acrylamide derivative. The medical device according to claim 1, wherein the polymer is a macromonomer, and the surface has lubricity when wet.