Albers Jessica, Alles Rainer, Matthée Karin, Knop Klaus, Nahrup Julia Schulze, Kleinebudde Peter
Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf, Germany.
Eur J Pharm Biopharm. 2009 Feb;71(2):387-94. doi: 10.1016/j.ejpb.2008.10.002. Epub 2008 Oct 11.
The aim of the study was the formulation of solid dispersions of the poorly water-soluble drug celecoxib and a polymethacrylate carrier by hot-melt extrusion. The objectives were to elucidate the mechanism of drug release from obtained extrudates and milled strands addicted to the solid-state properties of the solid dispersions and to examine and eliminate stability problems occurring under storage, exposure of mechanical stress, and in vitro dissolution. Transparent extrudates containing up to 60% drug could be prepared with a temperature setting below the melting point of celecoxib. XRPD and DSC measurements indicated the formation of a glassy solid solution, where the drug is molecularly dispersed in the carrier. The amorphous state of the glassy solid solution could be maintained during the exposure of mechanical stress in a milling process, and was stable under storage for at least 6 months. Solid-state properties and SEM images of extrudates after dissolution indicated a carrier-controlled dissolution, whereby the drug is molecularly dispersed within the concentrated carrier layer. The glassy solid solution showed a 58-fold supersaturation in 0.1 N HCl within the first 10 min, which was followed by a recrystallization process. Recrystallization could be inhibited by an external addition of HPMC.
本研究的目的是通过热熔挤出法制备难溶性药物塞来昔布与聚甲基丙烯酸酯载体的固体分散体。目标是阐明所得挤出物和研磨条带中药物释放的机制，该机制取决于固体分散体的固态性质，并研究和消除在储存、机械应力作用以及体外溶出过程中出现的稳定性问题。在低于塞来昔布熔点的温度设定下，可以制备出含药量高达60%的透明挤出物。X射线粉末衍射（XRPD）和差示扫描量热法（DSC）测量表明形成了玻璃态固溶体，其中药物分子分散在载体中。在研磨过程中的机械应力作用下，玻璃态固溶体的非晶态得以保持，并且在储存至少6个月期间是稳定的。溶出后挤出物的固态性质和扫描电子显微镜（SEM）图像表明是载体控制的溶出，即药物分子分散在浓缩的载体层内。玻璃态固溶体在0.1 N盐酸中最初10分钟内显示出58倍的过饱和度，随后是重结晶过程。通过外部添加羟丙基甲基纤维素（HPMC）可以抑制重结晶。
