Skiba Mohamed, Lefébure Valentin, Bounoure Frederic, Milon Nicolas, Thomas Michael, Lefebvre Herve, Malika Lahiani-Skiba
Normandie Univ., UNIROUEN, INSERM, NORDIC UMR 1239, F-76000 Rouen, France.
Pharmaceutics. 2024 Sep 11;16(9):1194. doi: 10.3390/pharmaceutics16091194.
Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing's syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients.
已知药物的给药系统（DDSs）是各种疾病新的、更有效治疗方法的突出候选者，因为它们可能会提高药物的溶解度、溶解速度和生物利用度。米托坦（邻，对'-二氯二甲基二氯乙烷[邻，对'-DDD]）用于治疗肾上腺皮质癌，偶尔也用于治疗库欣综合征。然而，米托坦的疗效受到其口服生物利用度低的限制，这是由于其水溶性极差所致。本研究探索开发一种用于米托坦的新型粉末自乳化给药系统（P-SEDDS），以提高其口服生物利用度。该研究聚焦于载有米托坦的P-SEDDS这一新概念，以克服与其有限溶解度和高logP相关的挑战，从而提高其治疗效果，降低脱靶毒性，并避免首过代谢。仅使用α-环糊精和油精心设计P-SEDDS制剂，目标是实现稳定且高效的P-SEDDS。对优化后的制剂进行了药学性质表征，并在大鼠中研究了其药代动力学行为。结果表明，通过P-SEDDS给药时，米托坦的生物利用度显著提高，这归因于难溶性药物的溶解速度增加和吸收改善。结果表明，与传统米托坦制剂（Lysodren）相比，载有米托坦的P-SEDDS在体外和体内性能均有明显增强，由此得出结论，P-SEDDS制剂可能是提高难溶性成分溶解速率和生物利用度的一种可行且有效的策略。
