JP6290455B2 - 第1生分解性マイクロビーズ及び第2生分解性マイクロビーズを含む化学塞栓用組成物、並びにその製造方法 - Google Patents
第1生分解性マイクロビーズ及び第2生分解性マイクロビーズを含む化学塞栓用組成物、並びにその製造方法 Download PDFInfo
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Description
本発明の一具現例によれば、前記アルブミンは、生体細胞や体液中に広く分布されているタンパク質であって、動物性アルブミン及び植物性アルブミンを含む。
(a)アルブミンと陰イオン性高分子であるデキストランサルフェートとを含むビーズ製造用溶液をエマルジョン化して形成されたマイクロサイズのバブルを架橋して、アルブミンが架橋結合され、前記アルブミン架橋物内にデキストランサルフェートが含まれた第1生分解性マイクロビーズを製造する工程と、
(b)アルブミンと陰イオン性高分子であるグリコサミノグリカン類高分子とを含むビーズ製造用溶液をエマルジョン化して形成されたマイクロサイズのバブルを架橋して、アルブミンが架橋結合され、前記アルブミン架橋物内にグリコサミノグリカン類高分子が含まれた第2生分解性マイクロビーズを製造する工程と、
(c)前記第1生分解性マイクロビーズ及び前記第2生分解性マイクロビーズを一定比率で混合して容器にパッケージングする工程であって、前記第1生分解性マイクロビーズ及び前記第2生分解性マイクロビーズの配合比によって組成物の抗癌剤の放出速度が調節される工程。
(i)本発明は、抗癌剤の放出特性が異なる2種の生分解性マイクロビーズを含む化学塞栓用組成物、及びその製造方法を提供する。
(ii)本発明によれば、第1生分解性マイクロビーズ及び第2生分解性マイクロビーズの配合比を調節することによって、所望の抗癌剤の放出特性を示す化学塞栓用組成物を効率的に製造することができる。
(iii)したがって、本発明は、肝癌の化学塞栓術に有用に活用されうる。
アルブミンが架橋結合されてビーズの形態を形成し、前記アルブミン架橋物内にデキストランサルフェートが含まれたマイクロビーズを次のような方法で製造した。マイクロビーズの製造のためのアルブミン及び陰イオン性高分子の組成は、表1と同じであった。
アルブミンのアミン基(NH2−)と陰イオン性高分子であるグリコサミノグリカンのカルボキシ基(COOH−)とをアミド結合させるために、SCBH(sodium cyanoborohydride)又はEDC(1−Ethyl−3−(3−dimethylamino−propyl)carbodiimide)/NHS(N−Hydroxysuccini mide)を使った。まず、陰イオン性高分子をSCBH又はEDC/NHSを用いて活性化させた後、下記の表2の組成1〜5のようにアルブミンと反応させて結合させた。以後、それを1〜2日間透析して、未反応物を除去してビーズ製造用溶液を収得した。
前記製造例1で製造したアルブミン/デキストランサルフェートビーズは、製造例2で製造したアルブミン/グリコサミノグリカンビーズに比べて、ローディング速度が遅く、薬物の溶出速度も、非常に遅かった。これにより、本発明者らは、これらビーズの配合比を調節して、これらビーズに吸着されている薬物の放出速度を調節しようとした。混合ビーズの組成は、下記の表3に示した。
ドキソルビシンの吸着実験を次のように進行した。まず、50mgのドキソルビシンを2mlの蒸留水に溶解した。配合比によって、2mlのビーズ(アルブミン/デキストランサルフェートビーズ、アルブミン/グリコサミノグリカンビーズ、これらの混合ビーズ、DCビーズ又はヘパスフィア)を正確に取ってドキソルビシン溶液に入れ、混合した。それを常温で放置し、10、20、30、40及び60分間後に上澄み液を取ってHPLCで分析した。あらかじめ作成しておいた検量線に対比して濃度を計算すれば、50mg/2mlのドキソルビシン溶液から抜け出されたドキソルビシンの量を計算し、この値は、ドキソルビシンがビーズに吸着された量である。
薬物の溶出挙動を確認するために、溶出器を使って溶出試験を進行した。実験方法は、次の通りであった。ドキソルビシンの吸着実験を通じて、薬物50mgがローディングされたビーズ2ml(アルブミン/デキストランサルフェートビーズ、アルブミン/グリコサミノグリカンビーズ、これらの混合ビーズ、DCビーズ又はヘパスフィア)を溶出液(PBS、pH7.4)500mlが入れられたガラスベッセルに入れ、37℃でインキュベーションしながら、50rpmでかき混ぜた。溶出液は置き換えずに使い、10、20、30、40、60、90及び120分間後に上澄み液を取ってHPLCで分析した。
Claims (7)
- 架橋結合されてビーズの形態を形成するアルブミンと、前記アルブミン架橋物内に含まれた陰イオン性高分子であるデキストランサルフェートと、を含む第1生分解性マイクロビーズと、
架橋結合されてビーズの形態を形成するアルブミンと、前記アルブミン架橋物内に含まれた陰イオン性高分子であるグリコサミノグリカン類高分子と、を含む第2生分解性マイクロビーズと、を含み、
前記第1生分解性マイクロビーズ及び前記第2生分解性マイクロビーズは、これらビーズに含まれた陰イオン性高分子の静電気的引力を通じてビーズの表面に抗癌剤を吸着することができることを特徴とする化学塞栓用組成物。 - 前記組成物は、体内投与時に抗癌剤を周辺に放出し、このときの抗癌剤の放出速度は、前記組成物に含まれた第1生分解性マイクロビーズ及び前記第2生分解性マイクロビーズの配合比によって変わる請求項1に記載の組成物。
- 前記抗癌剤の放出速度は、前記第1生分解性マイクロビーズに対する前記第2生分解性マイクロビーズの比率の増加によって早くなる請求項2に記載の組成物。
- 前記抗癌剤は、アントラサイクリン系抗癌剤である請求項1に記載の組成物。
- 前記抗癌剤は、イリノテカンである請求項1に記載の組成物。
- 前記グリコサミノグリカン類高分子は、コンドロイチンサルフェート、デルマタンサルフェート、ケラタンサルフェート、ヘパランサルフェート、ヘパリン、及びヒアルロナンで構成された群から選択される請求項1に記載の組成物。
- 次の工程を含むことを特徴とする化学塞栓用組成物の製造方法:
(a)アルブミンと陰イオン性高分子であるデキストランサルフェートとが溶解されたビーズ製造用溶液をエマルジョン化して形成されたマイクロサイズのバブルを架橋して、アルブミンが架橋結合され、前記アルブミン架橋物内にデキストランサルフェートが含まれた第1生分解性マイクロビーズを製造する工程と、
(b)アルブミンと陰イオン性高分子であるグリコサミノグリカン類高分子とが溶解されたビーズ製造用溶液をエマルジョン化して形成されたマイクロサイズのバブルを架橋して、アルブミンが架橋結合され、前記アルブミン架橋物内にグリコサミノグリカン類高分子が含まれた第2生分解性マイクロビーズを製造する工程と、
(c)前記第1生分解性マイクロビーズ及び前記第2生分解性マイクロビーズを一定比率で混合して容器にパッケージングする工程であって、前記第1生分解性マイクロビーズ及び前記第2生分解性マイクロビーズの配合比によって組成物の抗癌剤の放出速度が調節される工程。
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