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微量成分の薬物を含有する内服固形製剤の製造プロセス開発とそのスケールアップ

堀部 雅史 大阪府立大学 DOI:info:doi/10.24729/00016962

2020.07.07

概要

本研究は,内服固形製剤製造における微量成分(薬物および滑沢剤)の混合工程について,バッチ式の容器回転型の混合機(V 型混合機)を用いてその混合過程を明らかにするとともに,スケールアップファクターを明らかにすることを目的とした。本目的を達成するため,離散要素法(Discrete Element Method, DEM)による数値シミュレーションを用いて混合実験の DEM シミュレーションを行うとともに,解析を行った。

さらに,近年医薬品業界で活用が進んでいる連続生産装置を用い,バッチ式と同様に微量混合の達成可能性を確認することを研究の目的とした。

以下に本論文を構成する各章の概要を紹介する。

第 1 章では,本研究の背景および本研究に関連する既往の研究をまとめ,本論文の目的と構成について述べた。

第 2 章では,薬物微量混合および滑沢剤混合におけるスケールアップファクターを明らかにすることを目的に,3 種類の異なるスケールの V 型混合機を用いてスケールアップ検討を行った。

微量混合実験では,上市されている医薬品の中には 1 錠中に 20 µg 程度しか薬物を含有しない製品もあることを考慮し,薬物濃度を 0.01%と設定し,薬物を均一に混合するため,薬物および添加剤の粒子径の影響について検討を行った。サンプリングした混合品に含まれている薬物量を適切に評価するため,液体クロマトグラフィー法により薬物量を測定した。薬物微量混合のスケールアップについては,仕込率およびフルード数を一致させた条件にて実験を行った。

滑沢剤混合実験では,滑沢剤として汎用されているステアリン酸マグネシウムを選択し,本滑沢剤を 1%含む処方にて検討を行った。滑沢剤混合実験で得られた混合末について,流動性の変化を確認するため,ゆるみかさ密度および安息角を評価した。また得られた混合末を打錠して製した錠剤について,薬物の含量均一性および錠剤の引張強度を測定した。滑沢剤混合のスケールアップでは,微量薬物混合と同様に,仕込率およびフルード数を一致させた条件で行うとともに,経時的にサンプリングした混合末および錠剤について,混合時間および総回転数によりスケールアップが可能かどうかを確認した。

第 3 章では,第 2 章で得られた実験結果を基に,離散要素法(DEM)を用いた数値シミュレーションを以下の手順で実施した。(1)V 型混合機の 3D モデル作製:実験で使用した 3 種類の V 型混合機と同じ形状および容積となるようにモデリング,(2)粒子モデルの作製:実際の粒子と同じかさ密度となるよう粒子形状および物性パラメータを設定。(3)スケールアップシミュレーション:スケールアップ実験と同様の運転条件にて DEM シミュレーションを実施。(4)シミュレーションデータの解析。

本検討を通じて,製造実験で得られた結果の検証,製造条件の妥当性評価,スケールアップファクターの解析を行った。

第 4 章では,直接打錠用の連続生産装置を用い,微量混合が可能な製造条件を調べるとともに,連続的に製造可能な製造条件の探索と最適化を行った。まず,薬物濃度を 1%と設定し,直打連続生産システムを用いて均一な混合および打錠が可能かどうか検討を実施した。更に,バッチ式と同様に薬物濃度 0.01%での混合および打錠が可能かどうかについても併せて検討を行った。薬物濃度 0.01%での検討を行う際,定量供給機の能力の範囲外となるため,1 ステップでの調製は困難であったことから,2 つのステップに分けて薬物の混合を行うことにより,直打連続生産システムにて薬物濃度 0.01%の錠剤が製造可能かどうかを検討した。

第 5 章では,本論文の結果を総括した。

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