JP2004359895A - Medical composition - Google Patents
Medical composition Download PDFInfo
- Publication number
- JP2004359895A JP2004359895A JP2003162501A JP2003162501A JP2004359895A JP 2004359895 A JP2004359895 A JP 2004359895A JP 2003162501 A JP2003162501 A JP 2003162501A JP 2003162501 A JP2003162501 A JP 2003162501A JP 2004359895 A JP2004359895 A JP 2004359895A
- Authority
- JP
- Japan
- Prior art keywords
- group
- chain
- succinimide
- optionally substituted
- following formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、医療用組成物、特に止血用接着剤、癒着防止材料および創傷被覆材料等として有用な医療用組成物、医療用ゲル、この組成物を用いたゲル化および接着方法、並びにこの組成物の主要成分である糖鎖誘導体およびその製造方法に関する。
【０００２】
【従来の技術】
手術時や受傷時においては、生体、特に血管に生じた破孔や損傷、接合部を安全、確実かつ迅速に封鎖する必要がある。こうした目的には、縫合や吻合時に人工繊維片を補助として用いるか、ゲル化材料が用いられてきた。
【０００３】
人工繊維片としては、天然の線維状のコラーゲンが生化学的な止血作用を奏することを利用して、これを成形した止血材料が記載されている（例えば、特許文献１）。しかしながら、天然の線維状のコラーゲンは生体内での分解性が低く、長期間残留することによって異物反応が起きる可能性がある。そこで、抗原決定基を酵素処理またはアルカリ処理して抗原性を低下させて得られるアテロコラーゲンも用いられる（例えば、特許文献２および３）。しかし、これらのアテロコラーゲンは止血性が弱いため、再線維化に加え架橋を施さないと、止血するまでの一定期間、生体内に溶解させずに留置させることは難しい。しかし、強度に架橋を加えたアテロコラーゲンは、生体適合性が低く、炎症性を発現するという報告がある（非特許文献１）。
【０００４】
ゲル化材料としては、現在、外科用接着剤、止血剤として用いられている医療用ゲル材料の殆どは、人の血漿蛋白質や、牛や豚の骨や皮といった生体材料（フィブリノゲン、ゼラチン、コラーゲンなど）を原料にして製造されている。例えば、特許文献４は、エチレンオキシドにより滅菌されたコラーゲン蛋白部分加水分解物質および多価フェノール化合物を主成分とする糊剤成分およびアルデヒド類を主成分とする硬化成分を含む生体用止血乃至組織接着剤を開示している。ここで、コラーゲン蛋白部分加水分解物質はゼラチンまたは膠である。しかし、一般に生体由来材料には肝炎ウイルス、発熱性物質、アレルゲン、牛海綿状脳症（ＢＳＥ）等が含まれているおそれがあり、感染症等に対する懸念から他の材料への置換えが望ましい。
【０００５】
そこで、人体や動物に由来する原料を用いないで製造された、化学合成による外科用接着剤や止血剤も検討されている。例えば、特許文献５には特定構造の直鎖ジアミンの塩の架橋剤として用いた分子内にカルボキシル基を有する多糖類からなる水膨潤性高分子ゲルが記載されている。カルボキシル基を有する多糖類としてはアルギン酸塩またはヒアルロン酸塩が、直鎖ジアミンの塩としてはＮ−ヒドロキシコハク酸イミド塩が挙げられている。
【０００６】
また、特許文献６には、カルボキシル基を有する多糖に、カルボニルジイミダゾール、カルボニルトリアゾール、ヨウ化クロロメチルピリジリウム（ＣＭＰ−Ｊ）、ヒドロキシベンゾトリアゾール、ｐ−ニトロフェノールｐ−ニトロフェニルトリフルオロアセテート、Ｎ−ヒドロキシスクシンイミド等と反応させてなる化合物を特定構造のポリアミンで架橋するゲル化方法が記載されている。この公報にはカルボキシル基を有する多糖としてカルボキシメチルセルロースも挙げられているが、実施可能な特性を備えたカルボキシメチルセルロースを用いた医療用接着材料は具体的には開示されていない。また、ポリアミンとしては直鎖ジアミンのみが記載されている。
【０００７】
化学合成品として現段階で実用化されているのは、シアノアクリレート系、およびポリエチレングリコール系の材料のみであるが、その性能や毒性に基づく制約から適用はごく限られたものにとどまっている。
【０００８】
【特許文献１】
特開平６−３３９４８３号公報
【特許文献２】
特開平６−１９７９４６号公報
【特許文献３】
特開平８−１９６６１４号公報
【特許文献４】
特開平１０−３１４２９４号公報
【特許文献５】
特許第３１０７７２６号
【特許文献６】
特表２００２−５２９５４９号
【非特許文献１】
Ｋｏｉｄｅ ｅｔ ａｌ．，Ｊｏｕｒｎａｌ ｏｆ Ｂｉｏｍｅｄｉｃａｌ Ｍａｔｅｒｉａｌｓ Ｒｅｓｅａｒｃｈ，２７（１）（１９９３）ｐ．７９−８７
【０００９】
【発明が解決しようとする課題】
従って、本発明は、生体適合性に優れ、迅速かつ強力に硬化し、しかも、硬化後においても適当な柔軟性を保持する医療用ゲル化材料およびその製造方法を提供することを目的とする。
【００１０】
【課題を解決するための手段】
本発明者らは、上記問題点を解決するべく検討した結果、スクシンイミド残基を側鎖に導入した鎖状多糖誘導体とポリアミンとを含む医療用ゲル化材料を見出し、本発明を完成するに至った。
【００１１】
すなわち、本発明は、以下の医療用組成物、医療用ゲル、この組成物を用いたゲル化および接着方法、並びにこの組成物の主要成分である糖鎖誘導体およびその製造方法を提供する。
【００１２】
〔１〕 スクシンイミド残基を側鎖に導入した鎖状多糖誘導体を含む第１液とポリアミンを含む第２液とを含み両者の混合によりゲル化する医療用組成物。
〔２〕 スクシンイミド残基を側鎖に導入した鎖状多糖誘導体が、多糖分子の水酸基の水素原子を、前記ポリアミンとの反応によりゲル化を起こすのに十分な量、下記式（Ｉ）：
【化１３】
【００１３】
〔３〕 スクシンイミド残基を側鎖に導入した鎖状多糖誘導体が主要構造として下記式（ＩＩ）：
【化１４】
Ｒ１は、水素原子、金属原子、炭素数１乃至３０の置換されていてもよい脂肪族炭化水素もしくは芳香族炭化水素または下記式（Ｉ）：
【化１５】
【化１６】
Ｘは、−ＯＲ１、−ＮＨＲ１（式中、Ｒ１は上記定義と同じ。）またはカルバモイル基であり、
分子中のＲ１はそれぞれ同一でも異なってもよいが、その少なくとも１個は前記式（Ｉ）のスクシンイミド含有基である。〕を繰り返し単位として含む糖鎖である前記２に記載の医療用組成物。
【００１４】
〔４〕 スクシンイミド残基を側鎖に導入した鎖状多糖誘導体の主要構造が下記式（ＩＶ）：
【化１７】
〔５〕 鎖状多糖誘導体における前記Ｙが炭素数１乃至３のアルキレンまたは下記式（Ｖ）：
【化１８】
【００１５】
〔６〕 鎖状多糖誘導体が、各繰り返し単位に平均０．０１個以上の前記式（Ｉ）のスクシンイミド含有基を含有する前記２乃至５のいずれかに記載の医療用組成物。
〔７〕 鎖状多糖誘導体が、透析によって低分子量の不純物を除去したものである前記１乃至６のいずれかに記載の医療用組成物。
〔８〕 ポリアミンが側鎖にアミノ基を有するポリアミンである前記１乃至７のいずれかに記載の医療用組成物。
〔９〕 前記１乃至８の医療用組成物の鎖状多糖誘導体とポリアミンとを混合して反応させて得られる医療用ゲル。
【００１６】
〔１０〕 スクシンイミド残基を側鎖に導入した鎖状多糖誘導体を含む第１液またはポリアミンを含む第２液の一方を対象面に塗付し、次いで、前記対象面に他方の液を塗付または滴下することにより対象面上をゲルで被覆するゲル化方法。
〔１１〕 スクシンイミド残基を側鎖に導入した鎖状多糖誘導体を含む第１液またはポリアミンを含む第２液の一方を第１の対象面に塗付し、次いで、第２の対象面に他方の液を塗付または滴下した後、両者を接触させてゲル化させ第１と第２の対象面を接着させる接着方法。
【００１７】
〔１２〕 下記式（ＩＩ）：
【化１９】
Ｒ１は、水素原子、炭素数１乃至３０の置換されていてもよい脂肪族炭化水素もしくは芳香族炭化水素または下記式（Ｉ）：
【化２０】
【化２１】
Ｘは、−ＯＲ１、−ＮＨＲ１（式中、Ｒ１は上記定義と同じ。）またはカルバモイル基であり、
分子中のＲ１はそれぞれ同一でも異なってもよく、その少なくとも１個は前記式（ＩＩ）のスクシンイミド含有基である。〕を繰り返し単位として含む糖鎖誘導体。
【００１８】
〔１３〕 鎖状多糖誘導体における前記Ｙが炭素数１乃至３のアルキレンまたは下記式（Ｖ）：
【化２２】
【００１９】
〔１４〕 下記式（ＶＩ）：
【化２３】
【化２４】
〔１５〕 反応が水性媒体中で行なわれ、反応後透析によって低分子量の不純物を除去する前記１４に記載の糖鎖誘導体の製造方法。
【００２０】
【発明の実施の形態】
本発明の医療用組成物は、スクシンイミド残基を側鎖に導入した鎖状多糖誘導体成分とポリアミン成分とを含む材料であり、施用時において両成分を混合して反応硬化させ、接着等の機能を果たすものである。なお、本明細書において「接着」とは、解離した組織の接着や吻合だけでなく、組織の接着、接合、被覆、補強、封鎖等を含み、「接着材料」とはこのような意味で組織に接着してこれを保護するための材料を指す。
【００２１】
（Ａ）鎖状多糖誘導体
本発明で用いるスクシンイミド残基を側鎖に導入した鎖状多糖誘導体成分は、１種の糖または複数の糖を繰り返し単位として含む概ね直線状の多糖において、糖の水酸基から誘導される側鎖にスクシンイミド残基を導入してなる。
糖は、鎖状の多糖を形成するものであれば限定されず、Ｄ−グルコース、Ｄ−マンノース、Ｄ−フルクトース、Ｄ−ガラクトース、Ｄ−キシロース、Ｄ−アラビノースまたはこれらの誘導体を含み、ホモ多糖またはヘテロ多糖のいずれでもよい。また、糖間の結合はα（１→４）、α（１→６）、β（１→４）などを含み、従って、分岐鎖を含んでもよいが、概ね直鎖状の、すなわち、明白に分子の長さ方向が定義され得る分子である。
【００２２】
鎖状多糖誘導体成分は、好ましくは以下の化合物：
【化２５】
【００２３】
（ｉ）水素原子；
（ｉｉ）炭素数１乃至３０の置換されていてもよい脂肪族炭化水素および／または芳香族炭化水素；
（ｉｉｉ）下記式（Ｉ）：
【化２６】
（ｉｖ）下記式（ＩＩＩ）：
【化２７】
【００２４】
第（ｉ）群は、糖本来の水酸基である。
第（ｉｉ）群は、糖本来の水酸基をエーテル化またはエステル化したものであり、有用な種々の修飾を含む。脂肪族炭化水素もしくは芳香族炭化水素は特に限定されず、脂肪族炭化水素基は直鎖、分岐鎖、環状のいずれでもよく任意の不飽和基を含み得るが、（ｉｉｉ）群のスクシンイミド含有基の反応を妨害しないように炭素数１乃至３０の鎖長が好ましい。これらの脂肪族炭化水素もしくは芳香族炭化水素は、生体中で有害な反応や分解を引き起こさない限りにおいて任意の置換基を有してもよく、化学的に可能であれば鎖内の炭素原子を置き換えたものをも含む。同様に、芳香環は複素環でもよい。こうした置換基の例としては、水酸基、オキシ基、アミノ基、カルボニル基、カルボキシル基、メルカプト基、チオエーテル基などが含まれる。
【００２５】
第（ｉｉｉ）群は本発明の接着作用に不可欠の基であり、従って、鎖状多糖誘導体成分中のＲ１の少なくとも１つは、第（ｉｉｉ）群のスクシンイミド含有基でなければならない。第（ｉｖ）群はその前駆体である。
【００２６】
従って、第（ｉｉｉ）群および第（ｉｖ）群中のＹは糖鎖の水酸基との反応性を有する化合物から誘導され、かつ、スクシンイミド基導入を妨害しない基である。こうした基としてはアルキレンまたはカルバモイル基が含まれる。アルキレンとしては、好ましくは炭素数１乃至３０のアルキレン、より好ましくは炭素数１乃至２０、さらに好ましくは炭素数１乃至１０、最も好ましくは炭素数１乃至５のアルキレンである。カルバモイル基は、例えば、下記式で表わされる基である。
【化２８】
式中、Ｒ３は前記Ｒ２と同様に水素原子、金属原子または炭素数１乃至３０の置換されていてもよい脂肪族炭化水素もしくは芳香族炭化水素を表わす。
従って、好ましいスクシンイミド含有Ｒ１基の例としては、
【化２９】
【化３０】
また、式（Ｉ）中、Ｘは、−ＯＲ１、−ＮＨＲ１またはカルバモイル基であり、式中、Ｒ１およびカルバモイル基は上記定義と同様である。
【００２８】
鎖状多糖誘導体は好ましくは下記式（ＩＶ）の糖鎖である。
【化３１】
【００２９】
（Ｂ）ポリアミン
ポリアミンは、分子中に２以上のアミノ基を有するものであり、エチレンジアミン、ジエチレントリアミン等のポリアルキレンポリアミンも用い得るが、側鎖にアミノ基を有する次式：
【化３２】
【００３０】
このような化合物の例としては、Ｒ４が水素原子でありＺが単結合でありＡが単結合であるポリビニルアミン、Ｒ４が水素原子でありＺがメチレンでありＡが単結合であるポリアリルアミンが挙げられる。好ましくは分子量５００以上、より好ましくは分子量１０００〜８０００程度、さらに好ましくは分子量２０００〜５０００程度のポリアリルアミンが用いられる。分子量が５００未満ではゲル強度の増加に時間を要し接着材料としての性能が劣る。分子量が過大であると粘性が大きくなり取扱性が低下するという問題がある。
【００３１】
（Ｃ）ゲル化反応
スクシンイミド残基を側鎖に導入した鎖状多糖誘導体を含む第１液またはポリアミンを含む第２液の一方を対象面に塗付し、次いで、前記対象面に他方の液を塗付または滴下してゲル状反応生成物を生じさせることによってゲル化させる重層塗布法が通常であるが、接着においては、接続または吻合すべき患部の一方に第１液（第２液）を塗布し、他方に第２液（第１液）を塗布する二面塗布法でもよい。または同時に上記２液を滴下する方法、あるいはスプレー法等の混合塗布法等も用い得る。
【００３２】
スクシンイミド基含有鎖状多糖誘導体は、そのままでも用い得るが、一般に粘性が高いため希釈して用いてもよい。希釈に用いる溶媒は特に限定されないが、生体内での使用または生体組織との接触を考慮すると、水性溶媒、特に水や希エタノール等が好ましい。通常、１〜７５質量％程度、好ましくは２〜６０質量％、より好ましくは３〜３０質量％、最も好ましくは４〜２０質量％に希釈する。また、ポリアミンを含む第２液も、そのままで用い得るが、特に広い範囲に適用する場合には水性溶媒、特に水や希エタノール等で通常、１〜７５質量％程度、好ましくは２〜６０質量％、より好ましくは３〜３０質量％、最も好ましくは４〜２０質量％に希釈して用いることが好ましい。反応に害を及ぼさない範囲の任意の塩類を含んでもよく、例えば、リン酸塩、クエン酸塩、カルボン酸塩等でｐＨを調節してもよい。好適ｐＨは、中性域ｐＨ６．５〜７．７、より好ましくはｐＨ７．３〜７．６である。
ゲル化反応は、基本的にはポリアミン分子中の複数のアミノ基が複数の多糖誘導体分子の端部カルボニル基（式（Ｉ）のＹＣＯ・・・におけるカルボニル基）と反応する架橋反応（この際、Ｎ−ヒドロキシスクシンイミドの脱離を伴う。）と考えられる。
【００３３】
（Ｄ）製造方法
本発明の医療用組成物は、上記のように実質的にはスクシンイミド残基を側鎖に導入した鎖状多糖誘導体成分とポリアミンとからなる。スクシンイミド残基を側鎖に導入した鎖状多糖誘導体成分は、スクシンイミド残基の好適タイプに応じて以下のようにして製造できる。
【００３４】
すなわち、好ましいスクシンイミド含有Ｒ１基の例としては、
（ａ）：
【化３３】
（ｂ）：
【化３４】
【００３５】
カルボキシル化多糖とＮ−ヒドロキシスクシンイミドとの間のエステル化反応は、一般的には水溶液中で行なうことができる。多糖とＮ−ヒドロキシスクシンイミドとの量比は、多糖に含有されるカルボキシル基の量によるが、通常、カルボキシル基に対して０．２５モル以上のＮ−ヒドロキシスクシンイミドを用いる。
また、カルボキシル化多糖とＮ−ヒドロキシスクシンイミドとの間のエステル化反応は、好ましくは水溶性カルボジイミドの存在下に行なう。水溶性カルボジイミドの存在によりエステル化反応が顕著に促進される。
【００３６】
本発明における水溶性カルボジイミドとしては、例えば、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド、１−シクロヘキシル−３−（２−モルホリニル−４−エチル）カルボジイミド、またはこれらの塩酸塩もしくはスルホン酸塩等が好ましく使用できる。エステル化反応の反応時間は特に限定されないが、１分間〜３時間が好ましい。また、反応温度も特に限定されないが、０〜４０℃が好ましい。水溶性カルボジイミドに加え、１−ヒドロキシルベンゾトリアゾール（ＨＯＢｔ）の存在下に反応させることによりエステル化合物がさらに効率良く生成される。可溶性カルボジイミドおよび／または１−ハイドロキシルベンゾトリアゾール（ＨＯＢｔ）の添加量は等モル程度である。
【００３７】
また、前記（ｂ）の場合、種々の方法で製造可能であるが、典型的には、はじめに多糖の水酸基−ＯＨの少なくとも１個を−ＯＣＯＮＨＣＨ（Ｒ３）ＣＯＯＲ５（Ｒ３は前記定義と同じ。Ｒ５はＲ３と同様に定義される基である。）に転換して多糖アミノ酸カーバメート誘導体とした後、これを脱エステル化し、さらにＮ−ヒドロキシスクシンイミドとの間のエステル化させることが好ましい。
【００３８】
多糖アミノ酸カーバメート誘導体の製造方法は、本発明者らによる特願２００２−８９５６５号に記載されている。すなわち、ＯＣＮ−ＨＣＨ（Ｒ３）ＣＯＯＲ５で表わされるアミノ酸エステルイソシアナートを塩化リチウム等の存在下、多糖と反応させる。ここで、アミノ酸エステルイソシアナートはアラニンエステルイソシアナート等であり、アミノ酸部分は前記の通り種々の必須アミノ酸およびその慣用の誘導体を用いることができる。もっとも、多糖アミノ酸カーバメート誘導体の製造方法は、特願２００２−８９５６５号に記載の方法に限定されるものではない。
多糖アミノ酸カーバメート誘導体の脱エステル化反応は、例えば、希アルカリ水溶液中で希水酸化ナトリウム水溶液や希水酸化カリウム水溶液等を作用させて行なうことができる。脱エステル化反応後のカルボキシル化多糖とＮ−ヒドロキシスクシンイミドとの間のエステル化反応は、前記と同様であり、一般的には水溶液中で行なうことができる。多糖とＮ−ヒドロキシスクシンイミドとの量比は、多糖に含有されるカルボキシル基の量によるが、通常、カルボキシル基に対して０．２５モル以上のＮ−ヒドロキシスクシンイミドを用いる。また、上記と同様に可溶性カルボジイミドおよび／または１−ヒドロキシルベンゾトリアゾール（ＨＯＢｔ）の存在下に反応させることによりエステル化合物が効率良く生成される。
【００３９】
後述の実施例および比較例に示すように、上記の製造方法で得たスクシンイミドエステル化多糖類はそのままではポリアミンと反応して良好なゲル化を示さない。ところが、スクシンイミドエステル化多糖類を透析することにより、ポリアミンとの反応が迅速に進行して接着剤として用い得ることが判明した。このようなスクシンイミドエステル化多糖類の透析によるポリアミンとの急速ゲル化反応は従来知られていない。
【００４０】
透析は慣用の条件に従って行なうことができるが、例えば、透過分子量１４０００以下の透析膜を用いて、２時間〜３日間程度、好ましくは１〜２日間程度かけて行なうことが好ましい。特に好適な透析は、室温で蒸留水中、所定時間（例えば、１時間）おきに蒸留水を交換することで行なうことができる。
【００４１】
（Ｅ）適用対象
本発明の医療用ゲル化材料は、前述の通り、組織の接着、接合、被覆、補強、封鎖、分離（癒着防止）などに広く用いることができる。組織は人体、動物の任意の組織を含み、さらに人工血管などの人工組織を含む。より具体的には、例えば、硬膜、腹膜、筋膜、胸膜の接着、骨あるいは軟骨の接着、実質臓器切開部の接着、皮膚の接着、神経吻合、微小血管吻合、腸管吻合、卵管吻合、植皮片あるいは創傷被覆保護材の貼付等の組織の接着を目的とした生体接着剤として用いることができる。また、本発明の医療用ゲル化材料は、血液、体液のような水分存在下においてもゲルを形成し、生体組織に対して高い接着性を示すので、実質臓器の微小血管からの出血、縫合時の縫合糸穴からの出血等の止血を目的とした止血材や、髄液、胆汁等の体液の漏出防止、鼓膜欠損の閉鎖、代用血管の閉鎖、肺手術後の空気漏れ穴の閉鎖、気管支の閉鎖、シャントチューブのシールを目的とした生体または医療材料の閉鎖材等として用いることができる。さらに外科手術によって分離された組織間の術後癒着の防止材としても有用である。
【００４２】
【実施例】
以下、実施例及び比較例により本発明を具体的に説明するが、これらは本発明を限定するものではない。なお、以下の例において「置換度」は、元素分析の結果から算出した糖鎖水酸基の置換度である。
【００４３】
実施例１：カルボキシメチルセルロースコハク酸イミドエステルの合成
模式的に次式で示される反応によりカルボキシメチルセルロースコハク酸イミドエステルを製造した（なお、次式では、６位に誘導されたアセチル基が１／２エステル化されているが、これは説明の便宜上のためであり、必ずしもこの位置および割合で反応が進行することを示すものではない。）。
【００４４】
【化３５】
カルボキシメチルセルロース（２．５８ｇ、置換度１．２、アルドリッチ）を水（４０ｍｌ）に溶かし、Ｎ―ヒドロキシコハク酸イミド（１．１６ｇ、純正化学社製）、１−ヒドロキシベンゾトリアゾル（１．３５ｇ、関東化学社製）、１−エチル−３−（３−ジメチルアミノプロピル−カルボジイミド）（１．５５１４ｇ、ペプチド研究所製）を入れ室温で１５０分間撹拌した。反応終了後、生成物を透析膜（透過分子量１４，０００、三光純薬社製）にて２日間、蒸留水中で透析した。透析後、凍結乾燥しカルボキシメチルセルロースコハク酸イミドエステルを得た（２．０７ｇ）。生成物の溶解性を表１に示す。
【００４６】
【表１】
反応はＩＲスペクトルにより確認した。すなわち、生成物にはスクシンイミドのカルボニル基に対応する吸収（１６６０ｃｍ−１、１７３５ｃｍ−１）が新たに現れており、スクシンイミドが分子内に導入されたことを示している。
【００４８】
（２）カルボキシメチルセルロースコハク酸イミドエステルとポリアリルアミンとによるゲル化
試料瓶中、実施例１で得られたカルボキシメチルセルロースコハク酸イミドエステル（０．１ｇ）をリン酸緩衝溶液（２ｍｌ、ｐＨ７．４）に溶解させ、１０質量％ポリアリルアミン水溶液（２ｍｌ、分子量１５，０００、日東紡製）を加えて撹拌した。添加後、瞬時にゲルが生成した。生成したゲルはほとんどの溶媒に不溶性である。得られたゲルについて含水率（乾量基準、すなわち、含水時質量／乾燥時質量×１００）を測定した結果、１３０〜１７０％であった。
【００４９】
実施例２
（１）セルロース（Ｌ−ロイシンエチルエステルカーバメート）の合成
特願２００２−０８９５６５号記載の方法に準じてセルロース（Ｌ−ロイシンカーバメート）を製造した。
具体的には、セルロース（微結晶セルロース粉末（メルク社製））１ｇを塩化リチウム／Ｎ，Ｎ−ジメチルアセトアミド（脱水）の１／１０（ｗ／ｖ）溶液４５ｍｌに加え、１００℃で２４時間撹拌した。これを室温まで冷却した後、Ｌ−ロイシンエチルエステルイソシアネート１０ｇを加え、１００℃で撹拌しながら４８時間反応させた。冷却後、反応溶液を過剰量のアセトンに注ぎ入れて反応を停止した。元素分析の結果から置換度は１．６であった。
【００５０】
（２）セルロース（Ｌ−ロイシンスクシンイミドカーバメート）の合成
（１）で合成したセルロース（Ｌ−ロイシンエチルエステルカーバメート）に２ＭＮａＯＨ水溶液を加え室温で２４時間撹拌した。ろ過により不溶物を除いてセルロース（Ｌ−ロイシンカーバメート）を得た。
メタノール：蒸留水＝２：１の混合溶媒（１５ｍｌ）を入れたフラスコに上記セルロース（Ｌ−ロイシンカーバメート）（１．０１ｇ、置換度１．６）と１−エチル−３−（３−ジメチルアミノプロピル）−カルボジイミド（０．２０ｇ）を添加した。３時間後、蒸留水中で透過分子量約１４０００の透析膜を用いて透析した。２日間透析を行なった後、凍結乾燥を行ない、白色固体を得た（ポリマー収量１．１１ｇ）。得られたポリマーは、アルカリ性の水、メタノールに可溶性で、ジメチルスルホキシド、アセトン、テトラヒドロフラン、クロロホルムに不溶であった。スクシンイミドの導入率は約５０％であった。
反応は１Ｈ−ＮＭＲスペクトルにより確認した。１Ｈ−ＮＭＲ（δ／ｐｐｍ）：４．１０〜３．９０（ロイシン不斉炭素のメチレン水素）、２．７７（スクシンイミドのメチレン水素）、１．７５〜１．４４（ロイシンのメチレン水素及びメチン水素）、０．７８（ロイシンのメチル水素）。
【００５１】
（３）セルロース（Ｌ−ロイシンコハク酸イミドエステルカーバメート）とポリアリルアミンを用いたゲル化
置換度を１．００とした他は上記と同様に合成したセルロース（Ｌ−ロイシンスクシニルエステルカーバメート）０．１ｇとリン酸緩衝溶液（２ｍＬ，ｐＨ７．４）を試料管に入れ、ここへ１０ｗｔ％ポリアリルアミン水溶液（１ｍＬ）を滴下した。瞬時に系内はゲル化した。得られた白色ゲルは蒸留水でよく洗浄し、真空オーブンで加熱乾燥した（収量０．１２ｇ）。生成物はほとんどの溶媒に不溶性であった。
【００５２】
比較例１〜２
得られたカルボキシメチルセルロースコハク酸イミドエステルまたはセルロース（Ｌ−ロイシンスクシンイミドカーバメート）の透析を省略した他は実施例１または２と全く同様にゲル化を試みたが、混合物は１日以上放置してもゲル化しなかった。
【００５３】
【発明の効果】
以上詳述した通り、本発明に使用する多糖は天然多糖の誘導体および生体適合性の良い高分子のポリアミンである。この新しい糖鎖は医療材料として以下のような優れた素質を兼ね備えている。
１）入手が容易な物質から実用的なコストで再現性よく合成できる材料である。
２）原料や生成方法の選択によって物理的、化学的性質を広く制御できる。
３）安全な糖を用いているため、分解後の生成物の生物学的安全性面からも問題がない。
従って、本発明の医療用ゲル化材料は、感染の危険性をはらむ人・動物由来の材料を使用せずに既存の汎用医療材料、用具を製造する選択肢ができることによって、医療の安全向上に貢献する。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a medical composition, particularly a medical composition useful as a hemostatic adhesive, an adhesion prevention material, a wound covering material, and the like, a medical gel, a gelation and adhesion method using the composition, and this composition The present invention relates to a sugar chain derivative that is a main component of a product and a method for producing the same.
[0002]
[Prior art]
At the time of surgery or injury, it is necessary to safely, reliably and quickly seal ruptures, damages, and joints that occur in living bodies, particularly blood vessels. For these purposes, artificial fiber pieces have been used as an aid during suturing and anastomosis, or gelled materials have been used.
[0003]
As the artificial fiber piece, a hemostatic material obtained by molding natural fibrous collagen using biochemical hemostatic action is described (for example, Patent Document 1). However, natural fibrous collagen has a low degradability in vivo and may cause a foreign body reaction when it remains for a long time. Therefore, atelocollagen obtained by reducing antigenicity by enzymatic treatment or alkali treatment of an antigenic determinant is also used (for example, Patent Documents 2 and 3). However, since these atelocollagens have weak hemostatic properties, it is difficult to leave them without being dissolved in the living body for a certain period of time until hemostasis unless crosslinking is performed in addition to refibrosis. However, there is a report that atelocollagen with a cross-linked strength has low biocompatibility and develops inflammatory properties (Non-patent Document 1).
[0004]
As gelling materials, most of medical gel materials currently used as surgical adhesives and hemostatic agents are human plasma proteins and biological materials such as bones and skins of cattle and pigs (fibrinogen, gelatin, collagen, etc. Etc.). For example, Patent Document 4 discloses a hemostatic or tissue adhesive for living body containing a paste component mainly composed of a collagen protein partial hydrolyzate sterilized by ethylene oxide and a polyphenol compound and a hardening component mainly composed of aldehydes. Is disclosed. Here, the collagen protein partial hydrolyzate is gelatin or glue. However, in general, biological materials may contain hepatitis viruses, pyrogens, allergens, bovine spongiform encephalopathy (BSE), etc., and replacement with other materials is desirable because of concerns about infections and the like.
[0005]
Therefore, surgical adhesives and hemostatic agents by chemical synthesis produced without using raw materials derived from the human body or animals are also being studied. For example, Patent Document 5 describes a water-swellable polymer gel composed of a polysaccharide having a carboxyl group in the molecule used as a cross-linking agent for a salt of a linear diamine having a specific structure. Examples of the polysaccharide having a carboxyl group include alginates and hyaluronates, and examples of the linear diamine salts include N-hydroxysuccinimide salts.
[0006]
Patent Document 6 discloses a polysaccharide having a carboxyl group, carbonyldiimidazole, carbonyltriazole, chloromethylpyridylium iodide (CMP-J), hydroxybenzotriazole, p-nitrophenol p-nitrophenyl trifluoroacetate. And a gelation method in which a compound obtained by reacting with N-hydroxysuccinimide or the like is crosslinked with a polyamine having a specific structure. This publication also mentions carboxymethylcellulose as a polysaccharide having a carboxyl group, but a medical adhesive material using carboxymethylcellulose having feasible characteristics is not specifically disclosed. Moreover, only a linear diamine is described as the polyamine.
[0007]
At present, only cyanoacrylate and polyethylene glycol materials have been put into practical use as chemically synthesized products, but their applications are limited due to restrictions based on their performance and toxicity.
[0008]
[Patent Document 1]
Japanese Patent Laid-Open No. 6-339483
[Patent Document 2]
Japanese Patent Laid-Open No. 6-197946
[Patent Document 3]
JP-A-8-196614
[Patent Document 4]
JP 10-314294 A
[Patent Document 5]
Japanese Patent No. 3107726
[Patent Document 6]
Special Table 2002-529549
[Non-Patent Document 1]
Koide et al. , Journal of Biomedical Materials Research, 27 (1) (1993) p. 79-87
[0009]
[Problems to be solved by the invention]
Therefore, an object of the present invention is to provide a medical gelling material that is excellent in biocompatibility, cures quickly and strongly, and retains appropriate flexibility even after curing, and a method for producing the same.
[0010]
[Means for Solving the Problems]
As a result of studies to solve the above problems, the present inventors have found a medical gelling material containing a chain polysaccharide derivative in which a succinimide residue is introduced into a side chain and a polyamine, and have completed the present invention. It was.
[0011]
That is, the present invention provides the following medical composition, medical gel, a gelation and adhesion method using the composition, a sugar chain derivative that is a main component of the composition, and a method for producing the same.
[0012]
[1] A medical composition comprising a first liquid containing a chain polysaccharide derivative having a succinimide residue introduced in the side chain and a second liquid containing a polyamine, and gelled by mixing them together.
[2] A sufficient amount of the chain polysaccharide derivative having a succinimide residue introduced into the side chain to cause the hydrogen atom of the hydroxyl group of the polysaccharide molecule to gel by reaction with the polyamine, the following formula (I):
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[0013]
[3] A chain polysaccharide derivative in which a succinimide residue is introduced into the side chain is represented by the following formula (II) as a main structure:
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R1Is a hydrogen atom, a metal atom, an optionally substituted aliphatic hydrocarbon or aromatic hydrocarbon having 1 to 30 carbon atoms, or the following formula (I):
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X is -OR1, -NHR1(Wherein R1Is the same as above. ) Or a carbamoyl group,
R in the molecule1May be the same or different, at least one of which is a succinimide-containing group of the formula (I). ] The medical composition of said 2 which is a sugar chain which contains] as a repeating unit.
[0014]
[4] The main structure of the chain polysaccharide derivative having a succinimide residue introduced in the side chain is represented by the following formula (IV):
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[5] In the chain polysaccharide derivative, Y is alkylene having 1 to 3 carbon atoms or the following formula (V):
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[0015]
[6] The medical composition according to any one of 2 to 5, wherein the chain polysaccharide derivative contains an average of 0.01 or more succinimide-containing groups of the formula (I) in each repeating unit.
[7] The medical composition according to any one of 1 to 6 above, wherein the chain polysaccharide derivative is obtained by removing low molecular weight impurities by dialysis.
[8] The medical composition according to any one of 1 to 7, wherein the polyamine is a polyamine having an amino group in a side chain.
[9] A medical gel obtained by mixing and reacting the chain polysaccharide derivative of the medical composition of 1 to 8 and a polyamine.
[0016]
[10] One of the first liquid containing a chain polysaccharide derivative having a succinimide residue introduced into the side chain or the second liquid containing polyamine is applied to the target surface, and then the other liquid is applied to the target surface. Or the gelation method which coat | covers the object surface with a gel by dripping.
[11] One of a first liquid containing a chain polysaccharide derivative having a succinimide residue introduced into the side chain or a second liquid containing a polyamine is applied to the first target surface, and then the other is applied to the second target surface. After applying or dripping the solution, the both are brought into contact with each other to be gelled, thereby bonding the first and second target surfaces.
[0017]
[12] The following formula (II):
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R1Is a hydrogen atom, an optionally substituted aliphatic hydrocarbon or aromatic hydrocarbon having 1 to 30 carbon atoms, or the following formula (I):
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X is -OR1, -NHR1(Wherein R1Is the same as above. ) Or a carbamoyl group,
R in the molecule1May be the same or different, at least one of which is a succinimide-containing group of the formula (II). ] As a repeating unit.
[0018]
[13] In the chain polysaccharide derivative, Y is alkylene having 1 to 3 carbon atoms, or the following formula (V):
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[0019]
[14] The following formula (VI):
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[15] The method for producing a sugar chain derivative according to the above 14, wherein the reaction is carried out in an aqueous medium, and low molecular weight impurities are removed by dialysis after the reaction.
[0020]
DETAILED DESCRIPTION OF THE INVENTION
The medical composition of the present invention is a material containing a chain polysaccharide derivative component in which a succinimide residue is introduced into a side chain and a polyamine component. To fulfill. In this specification, “adhesion” includes not only adhesion and anastomosis of dissociated tissue but also adhesion, joining, covering, reinforcement, sealing, etc. of tissue, and “adhesive material” in this sense means tissue It refers to a material for adhering to and protecting this.
[0021]
(A) Chain polysaccharide derivative
The chain polysaccharide derivative component in which a succinimide residue used in the present invention is introduced into the side chain is a side chain derived from a hydroxyl group of a sugar in a generally linear polysaccharide containing one or more sugars as a repeating unit. A succinimide residue is introduced.
The sugar is not limited as long as it forms a chain polysaccharide, and includes D-glucose, D-mannose, D-fructose, D-galactose, D-xylose, D-arabinose or derivatives thereof, Or any of heteropolysaccharide may be sufficient. In addition, the linkage between sugars includes α (1 → 4), α (1 → 6), β (1 → 4), etc., and thus may include a branched chain. A molecule in which the length direction of the molecule can be defined.
[0022]
The chain polysaccharide derivative component is preferably the following compound:
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[0023]
(I) a hydrogen atom;
(Ii) an optionally substituted aliphatic hydrocarbon and / or aromatic hydrocarbon having 1 to 30 carbon atoms;
(Iii) The following formula (I):
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(Iv) The following formula (III):
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[0024]
Group (i) is the original hydroxyl group of sugar.
Group (ii) is an etherified or esterified hydroxyl group of the sugar, and includes various useful modifications. The aliphatic hydrocarbon or aromatic hydrocarbon is not particularly limited, and the aliphatic hydrocarbon group may be linear, branched or cyclic, and may contain any unsaturated group, but (iii) group succinimide-containing group A chain length of 1 to 30 carbon atoms is preferred so as not to interfere with the reaction. These aliphatic hydrocarbons or aromatic hydrocarbons may have an arbitrary substituent as long as they do not cause harmful reactions or decomposition in the living body, and if chemically possible, the carbon atoms in the chain are substituted. Includes replacements. Similarly, the aromatic ring may be a heterocyclic ring. Examples of such substituents include a hydroxyl group, an oxy group, an amino group, a carbonyl group, a carboxyl group, a mercapto group, and a thioether group.
[0025]
Group (iii) is an indispensable group for the adhesive action of the present invention, and therefore R in the chain polysaccharide derivative component1At least one of the groups must be a group (iii) succinimide-containing group. Group (iv) is its precursor.
[0026]
Accordingly, Y in the groups (iii) and (iv) is a group derived from a compound having reactivity with the hydroxyl group of the sugar chain and does not interfere with the introduction of the succinimide group. Such groups include alkylene or carbamoyl groups. The alkylene is preferably alkylene having 1 to 30 carbons, more preferably 1 to 20 carbons, still more preferably 1 to 10 carbons, and most preferably 1 to 5 carbons. The carbamoyl group is a group represented by the following formula, for example.
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Where R3Is R2Represents a hydrogen atom, a metal atom, or an optionally substituted aliphatic hydrocarbon or aromatic hydrocarbon having 1 to 30 carbon atoms.
Therefore, a preferred succinimide-containing R1Examples of groups include
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In the formula (I), X is —OR1, -NHR1Or a carbamoyl group, wherein R1And the carbamoyl group is as defined above.
[0028]
The chain polysaccharide derivative is preferably a sugar chain of the following formula (IV).
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[0029]
(B) Polyamine
The polyamine has two or more amino groups in the molecule, and polyalkylene polyamines such as ethylenediamine and diethylenetriamine can also be used, but the following formula having an amino group in the side chain:
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[0030]
Examples of such compounds include R4Is a hydrogen atom, Z is a single bond and A is a single bond, polyvinylamine, R4Is a hydrogen atom, Z is methylene, and A is a single bond. Preferably, polyallylamine having a molecular weight of 500 or more, more preferably about 1000 to 8000, and still more preferably about 2000 to 5000 is used. When the molecular weight is less than 500, it takes time to increase the gel strength and the performance as an adhesive material is poor. If the molecular weight is excessive, there is a problem that the viscosity increases and the handleability decreases.
[0031]
(C) Gelation reaction
Either one of the first liquid containing a chain polysaccharide derivative having a succinimide residue introduced into the side chain or the second liquid containing a polyamine is applied to the target surface, and then the other liquid is applied or dropped onto the target surface. In this method, the first solution (second solution) is applied to one of the affected areas to be connected or anastomosed, and the other is applied to the other. A two-side coating method in which the second liquid (first liquid) is applied may be used. Or the method of dripping the said 2 liquid simultaneously, or mixed application methods, such as a spray method, can also be used.
[0032]
The succinimide group-containing chain polysaccharide derivative can be used as it is, but it is generally highly viscous and may be diluted. Although the solvent used for dilution is not particularly limited, an aqueous solvent, particularly water or dilute ethanol is preferable in consideration of use in vivo or contact with living tissue. Usually, it is diluted to about 1 to 75% by mass, preferably 2 to 60% by mass, more preferably 3 to 30% by mass, and most preferably 4 to 20% by mass. The second liquid containing polyamine can also be used as it is, but when applied to a wide range, it is usually about 1 to 75% by mass, preferably 2 to 60% by mass with an aqueous solvent, particularly water or dilute ethanol. %, More preferably 3 to 30% by mass, and most preferably 4 to 20% by mass. Arbitrary salts that do not harm the reaction may be included, and the pH may be adjusted with, for example, phosphate, citrate, carboxylate and the like. The preferred pH is neutral pH 6.5 to 7.7, more preferably pH 7.3 to 7.6.
The gelation reaction is basically a crosslinking reaction in which a plurality of amino groups in a polyamine molecule react with an end carbonyl group of a plurality of polysaccharide derivative molecules (a carbonyl group in YCO in formula (I)). , With elimination of N-hydroxysuccinimide).
[0033]
(D) Manufacturing method
As described above, the medical composition of the present invention substantially comprises a chain polysaccharide derivative component having a succinimide residue introduced into the side chain and a polyamine. A chain polysaccharide derivative component in which a succinimide residue is introduced into the side chain can be produced as follows according to the preferred type of the succinimide residue.
[0034]
That is, preferable succinimide-containing R1Examples of groups include
(A):
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(B):
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[0035]
The esterification reaction between a carboxylated polysaccharide and N-hydroxysuccinimide can generally be performed in an aqueous solution. The amount ratio of polysaccharide to N-hydroxysuccinimide depends on the amount of carboxyl group contained in the polysaccharide, but usually 0.25 mol or more of N-hydroxysuccinimide is used with respect to the carboxyl group.
The esterification reaction between the carboxylated polysaccharide and N-hydroxysuccinimide is preferably performed in the presence of a water-soluble carbodiimide. The presence of the water-soluble carbodiimide significantly accelerates the esterification reaction.
[0036]
Examples of the water-soluble carbodiimide in the present invention include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 1-cyclohexyl-3- (2-morpholinyl-4-ethyl) carbodiimide, and hydrochlorides or sulfones thereof. Acid salts and the like can be preferably used. The reaction time for the esterification reaction is not particularly limited, but is preferably 1 minute to 3 hours. Moreover, although reaction temperature is not specifically limited, 0-40 degreeC is preferable. In addition to water-soluble carbodiimide, an ester compound is produced more efficiently by reacting in the presence of 1-hydroxylbenzotriazole (HOBt). The amount of soluble carbodiimide and / or 1-hydroxylbenzotriazole (HOBt) added is about equimolar.
[0037]
In the case of (b), it can be produced by various methods. Typically, however, at least one hydroxyl group -OH of the polysaccharide is firstly converted to -OCONHCH (R3COOR5(R3Is the same as defined above. R5Is R3It is a group defined similarly. ) To obtain a polysaccharide amino acid carbamate derivative, which is then deesterified and further esterified with N-hydroxysuccinimide.
[0038]
A method for producing a polysaccharide amino acid carbamate derivative is described in Japanese Patent Application No. 2002-89565 by the present inventors. That is, OCN-HCH (R3COOR5Is reacted with a polysaccharide in the presence of lithium chloride or the like. Here, the amino acid ester isocyanate is alanine ester isocyanate and the like, and various essential amino acids and conventional derivatives thereof can be used as the amino acid portion as described above. However, the method for producing a polysaccharide amino acid carbamate derivative is not limited to the method described in Japanese Patent Application No. 2002-89565.
The deesterification reaction of the polysaccharide amino acid carbamate derivative can be performed, for example, by reacting a dilute aqueous sodium hydroxide solution or dilute potassium hydroxide aqueous solution in a dilute alkaline aqueous solution. The esterification reaction between the carboxylated polysaccharide and N-hydroxysuccinimide after the deesterification reaction is the same as described above, and can generally be performed in an aqueous solution. The amount ratio of polysaccharide to N-hydroxysuccinimide depends on the amount of carboxyl group contained in the polysaccharide, but usually 0.25 mol or more of N-hydroxysuccinimide is used with respect to the carboxyl group. Moreover, an ester compound is efficiently produced | generated by making it react in presence of soluble carbodiimide and / or 1-hydroxyl benzotriazole (HOBt) similarly to the above.
[0039]
As shown in the below-mentioned Examples and Comparative Examples, the succinimide esterified polysaccharide obtained by the above production method reacts with the polyamine as it is and does not show good gelation. However, it has been found that by dialysis of a succinimide esterified polysaccharide, the reaction with the polyamine proceeds rapidly and can be used as an adhesive. Such a rapid gelation reaction with a polyamine by dialysis of a succinimide esterified polysaccharide has not been known.
[0040]
The dialysis can be performed according to conventional conditions. For example, it is preferable to perform dialysis with a permeation molecular weight of 14,000 or less for about 2 hours to 3 days, preferably about 1 to 2 days. Particularly suitable dialysis can be performed by exchanging distilled water at room temperature in distilled water every predetermined time (for example, 1 hour).
[0041]
(E) Application target
As described above, the medical gelling material of the present invention can be widely used for tissue adhesion, bonding, coating, reinforcement, sealing, separation (prevention of adhesion), and the like. The tissue includes any tissue of a human body or an animal, and further includes an artificial tissue such as an artificial blood vessel. More specifically, for example, dura mater, peritoneum, fascia, pleura adhesion, bone or cartilage adhesion, parenchymal organ incision adhesion, skin adhesion, nerve anastomosis, microvascular anastomosis, intestinal anastomosis, fallopian tube anastomosis It can be used as a bioadhesive for the purpose of adhesion of tissues such as sticking of skin grafts or wound covering protective materials. In addition, the medical gel material of the present invention forms a gel even in the presence of water such as blood and body fluid, and exhibits high adhesion to living tissue. Hemostatic materials intended for hemostasis such as bleeding from suture holes at times, prevention of leakage of bodily fluids such as cerebrospinal fluid, bile, closure of tympanic membrane defects, closure of substitute blood vessels, closure of air leakage holes after lung surgery, It can be used as a closure material for a living body or a medical material for the purpose of closing a bronchus or sealing a shunt tube. Furthermore, it is useful as a preventive material for postoperative adhesion between tissues separated by surgery.
[0042]
【Example】
EXAMPLES Hereinafter, although an Example and a comparative example demonstrate this invention concretely, these do not limit this invention. In the following examples, “degree of substitution” is the degree of substitution of sugar chain hydroxyl groups calculated from the results of elemental analysis.
[0043]
Example 1: Synthesis of carboxymethylcellulose succinimide ester
Carboxymethylcellulose succinimide ester was produced by a reaction schematically represented by the following formula (in the following formula, the acetyl group induced at the 6-position is ½ esterified, but this is for convenience of explanation. And does not necessarily indicate that the reaction proceeds at this position and rate.)
[0044]
Embedded image
Carboxymethylcellulose (2.58 g, substitution degree 1.2, Aldrich) was dissolved in water (40 ml), and N-hydroxysuccinimide (1.16 g, manufactured by Junsei Co., Ltd.), 1-hydroxybenzotriazole (1.35 g) And 1-ethyl-3- (3-dimethylaminopropyl-carbodiimide) (1.5514 g, manufactured by Peptide Laboratories) were added and stirred at room temperature for 150 minutes. After completion of the reaction, the product was dialyzed in distilled water for 2 days with a dialysis membrane (permeation molecular weight: 14,000, manufactured by Sanko Junyaku Co., Ltd.). After dialysis, lyophilization was performed to obtain carboxymethylcellulose succinimide ester (2.07 g). The solubility of the product is shown in Table 1.
[0046]
[Table 1]
The reaction was confirmed by IR spectrum. That is, the product has an absorption corresponding to the carbonyl group of succinimide (1660 cm-1, 1735cm-1) Has newly appeared, indicating that succinimide has been introduced into the molecule.
[0048]
(2) Gelation with carboxymethylcellulose succinimide ester and polyallylamine
In a sample bottle, the carboxymethylcellulose succinimide ester (0.1 g) obtained in Example 1 was dissolved in a phosphate buffer solution (2 ml, pH 7.4), and a 10 mass% polyallylamine aqueous solution (2 ml, molecular weight 15, 000, manufactured by Nittobo) and stirred. A gel formed instantly after the addition. The resulting gel is insoluble in most solvents. As a result of measuring the moisture content (dry basis, i.e., moisture content / dry mass x 100) of the obtained gel, it was 130 to 170%.
[0049]
Example 2
(1) Synthesis of cellulose (L-leucine ethyl ester carbamate)
Cellulose (L-leucine carbamate) was produced according to the method described in Japanese Patent Application No. 2002-089565.
Specifically, 1 g of cellulose (microcrystalline cellulose powder (manufactured by Merck & Co., Inc.)) was added to 45 ml of a 1/10 (w / v) solution of lithium chloride / N, N-dimethylacetamide (dehydrated), and the mixture was heated at 100 ° C. for 24 hours. Stir. After cooling this to room temperature, 10 g of L-leucine ethyl ester isocyanate was added and reacted for 48 hours while stirring at 100 ° C. After cooling, the reaction solution was poured into an excess amount of acetone to stop the reaction. As a result of elemental analysis, the degree of substitution was 1.6.
[0050]
(2) Synthesis of cellulose (L-leucine succinimide carbamate)
2M NaOH aqueous solution was added to the cellulose (L-leucine ethyl ester carbamate) synthesized in (1) and stirred at room temperature for 24 hours. Insolubles were removed by filtration to obtain cellulose (L-leucine carbamate).
In a flask containing methanol: distilled water = 2: 1 mixed solvent (15 ml), the above cellulose (L-leucine carbamate) (1.01 g, substitution degree 1.6) and 1-ethyl-3- (3-dimethylamino) were added. Propyl) -carbodiimide (0.20 g) was added. Three hours later, the mixture was dialyzed in distilled water using a dialysis membrane having a permeation molecular weight of about 14,000. After dialysis for 2 days, lyophilization was performed to obtain a white solid (polymer yield 1.11 g). The obtained polymer was soluble in alkaline water and methanol, and insoluble in dimethyl sulfoxide, acetone, tetrahydrofuran and chloroform. The introduction rate of succinimide was about 50%.
The reaction is1Confirmed by 1 H-NMR spectrum.1H-NMR (δ / ppm): 4.10 to 3.90 (methylene hydrogen of leucine asymmetric carbon), 2.77 (methylene hydrogen of succinimide), 1.75 to 1.44 (methylene hydrogen of leucine and methine) Hydrogen), 0.78 (methyl hydrogen of leucine).
[0051]
(3) Gelation using cellulose (L-leucine succinimide ester carbamate) and polyallylamine
0.1 g of cellulose (L-leucine succinyl ester carbamate) and phosphate buffer solution (2 mL, pH 7.4) synthesized in the same manner as above except that the substitution degree was set to 1.00 were placed in a sample tube, and 10 wt% was added thereto. A polyallylamine aqueous solution (1 mL) was added dropwise. The system gelled instantly. The obtained white gel was thoroughly washed with distilled water and dried by heating in a vacuum oven (yield 0.12 g). The product was insoluble in most solvents.
[0052]
Comparative Examples 1-2
Gelation was attempted in the same manner as in Example 1 or 2 except that dialysis of the obtained carboxymethylcellulose succinimide ester or cellulose (L-leucine succinimide carbamate) was omitted. It did not gel.
[0053]
【The invention's effect】
As described above in detail, the polysaccharide used in the present invention is a derivative of a natural polysaccharide and a polymer polyamine having good biocompatibility. This new sugar chain has the following excellent qualities as a medical material.
1) A material that can be synthesized from a readily available substance at a practical cost with good reproducibility.
2) Physical and chemical properties can be widely controlled by selecting raw materials and production methods.
3) Since safe sugar is used, there is no problem in terms of biological safety of the product after decomposition.
Therefore, the medical gel material of the present invention contributes to the improvement of medical safety by providing an option to manufacture existing general-purpose medical materials and tools without using human- or animal-derived materials that pose a risk of infection. To do.
Claims (15)
Ｒ１は、水素原子、金属原子、炭素数１乃至３０の置換されていてもよい脂肪族炭化水素もしくは芳香族炭化水素または下記式（Ｉ）：
Ｘは、−ＯＲ１、−ＮＨＲ１（式中、Ｒ１は上記定義と同じ。）またはカルバモイル基であり、
分子中のＲ１はそれぞれ同一でも異なってもよいが、その少なくとも１個は前記式（Ｉ）のスクシンイミド含有基である。〕を繰り返し単位として含む糖鎖である請求項２に記載の医療用組成物。A chain polysaccharide derivative having a succinimide residue introduced in the side chain is represented by the following formula (II) as the main structure:
R 1 represents a hydrogen atom, a metal atom, an optionally substituted aliphatic hydrocarbon or aromatic hydrocarbon having 1 to 30 carbon atoms, or the following formula (I):
X is —OR 1 , —NHR 1 (wherein R 1 is as defined above) or a carbamoyl group,
R 1 in the molecule may be the same or different, but at least one of them is a succinimide-containing group of the formula (I). ] The medical composition of Claim 2 which is a sugar chain containing as a repeating unit.
Ｒ１は、水素原子、炭素数１乃至３０の置換されていてもよい脂肪族炭化水素もしくは芳香族炭化水素または下記式（Ｉ）：
Ｘは、−ＯＲ１、−ＮＨＲ１（式中、Ｒ１は上記定義と同じ。）またはカルバモイル基であり、
分子中のＲ１はそれぞれ同一でも異なってもよく、その少なくとも１個は前記式（ＩＩ）のスクシンイミド含有基である。〕を繰り返し単位として含む糖鎖誘導体。Formula (II) below:
R 1 represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon or aromatic hydrocarbon having 1 to 30 carbon atoms, or the following formula (I):
X is —OR 1 , —NHR 1 (wherein R 1 is as defined above) or a carbamoyl group,
R 1 in the molecule may be the same or different, and at least one of them is a succinimide-containing group of the formula (II). ] As a repeating unit.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087289A1 (en) * | 2004-03-15 | 2005-09-22 | Terumo Kabushiki Kaisha | Adhesion preventive material |
| JP2007252699A (en) * | 2006-03-24 | 2007-10-04 | Mcrotech Kk | Gel composition, material for transplantation using the same, and their manufacturing method |
| JP2011099029A (en) * | 2009-11-05 | 2011-05-19 | Teijin Ltd | Polysaccharide derivative |
| US9040309B2 (en) | 2005-10-27 | 2015-05-26 | Bio-Rad Haifa Ltd. | Binding layer and method for its preparation and uses thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55500785A (en) * | 1978-10-12 | 1980-10-16 | ||
| JPH02180903A (en) * | 1988-12-29 | 1990-07-13 | Nippon Oil & Fats Co Ltd | Crosslinked chitosan |
| JPH0824325A (en) * | 1994-05-13 | 1996-01-30 | Kuraray Co Ltd | Medical polymer gel |
| JPH08502082A (en) * | 1992-07-02 | 1996-03-05 | コラーゲン コーポレイション | Biocompatible polymer conjugate |
| JPH10502339A (en) * | 1994-06-29 | 1998-03-03 | マッセイ ユニヴァーシティー | Hydrophobic chromatography resins with ionizable groups |
| JP2002529549A (en) * | 1998-11-11 | 2002-09-10 | アクイジティオ ソチエタ ペル アツィオニ | Crosslinking method of carboxylated polysaccharide |
| JP2003503367A (en) * | 1999-06-11 | 2003-01-28 | シアウォーター・コーポレイション | Hydrogels derived from chitosan and poly (ethylene glycol) or related polymers |
-
2003
- 2003-06-06 JP JP2003162501A patent/JP4669919B2/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55500785A (en) * | 1978-10-12 | 1980-10-16 | ||
| JPH02180903A (en) * | 1988-12-29 | 1990-07-13 | Nippon Oil & Fats Co Ltd | Crosslinked chitosan |
| JPH08502082A (en) * | 1992-07-02 | 1996-03-05 | コラーゲン コーポレイション | Biocompatible polymer conjugate |
| JPH0824325A (en) * | 1994-05-13 | 1996-01-30 | Kuraray Co Ltd | Medical polymer gel |
| JPH10502339A (en) * | 1994-06-29 | 1998-03-03 | マッセイ ユニヴァーシティー | Hydrophobic chromatography resins with ionizable groups |
| JP2002529549A (en) * | 1998-11-11 | 2002-09-10 | アクイジティオ ソチエタ ペル アツィオニ | Crosslinking method of carboxylated polysaccharide |
| JP2003503367A (en) * | 1999-06-11 | 2003-01-28 | シアウォーター・コーポレイション | Hydrogels derived from chitosan and poly (ethylene glycol) or related polymers |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087289A1 (en) * | 2004-03-15 | 2005-09-22 | Terumo Kabushiki Kaisha | Adhesion preventive material |
| JPWO2005087289A1 (en) * | 2004-03-15 | 2008-01-24 | テルモ株式会社 | Anti-adhesive material |
| US7737214B2 (en) | 2004-03-15 | 2010-06-15 | Terumo Kabushiki Kaisha | Adhesion preventive material |
| JP4566189B2 (en) * | 2004-03-15 | 2010-10-20 | テルモ株式会社 | Anti-adhesive material |
| US9040309B2 (en) | 2005-10-27 | 2015-05-26 | Bio-Rad Haifa Ltd. | Binding layer and method for its preparation and uses thereof |
| EP1952152B1 (en) * | 2005-10-27 | 2015-09-23 | BIO-RAD Haifa Ltd. | Binding layer and method for its preparation and uses thereof |
| JP2007252699A (en) * | 2006-03-24 | 2007-10-04 | Mcrotech Kk | Gel composition, material for transplantation using the same, and their manufacturing method |
| JP2011099029A (en) * | 2009-11-05 | 2011-05-19 | Teijin Ltd | Polysaccharide derivative |
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| JP4669919B2 (en) | 2011-04-13 |
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