Tirumalesh Cernam, Suram Dinesh, Dudhipala Narendar, Banala Nagaraj
Nanotechnology and Novel Drug Delivery Laboratory, Department of Pharmaceutics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana-506009, India.
Pharm Nanotechnol. 2020;8(2):148-160. doi: 10.2174/2211738508666200225113359.
Zotepine (ZT) is a substituted dibenzothiepine tricyclic molecule and second generation antipsychotic drug. It is available as the parenteral and oral solid dosage form, but, orally administered ZT has a poor oral bioavailability (10%) that might be due to either poor water solubility, high lipophilicity (Log P 4) and also first-pass hepatic metabolism.
The oral bioavailability of ZT was improved by loading into a nanostructured lipid carriers (NLCs) system.
Hot homogenization with probe sonication method was used for the preparation of ZT-NLCs formulations and characterized for an optimal system based on physicochemical characteristics and in vitro release. Differential scanning calorimetry (DSC), X-ray diffraction (XRD) analysis, and scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized ZT-NLC formulation. The physical stability of the optimized ZT-NLC formulation was evaluated at the refrigerator and room temperature over two months. Furthermore, in vivo pharmacokinetic (PK) studies of optimized ZT-NLC and ZT coarse suspension (ZT-CS) as control formulation, were conducted in male Wistar rats.
The optimized formulation of ZT-NLC showed Z-avg, PDI, ZP of 145.8 ± 2.5 nm, 0.18 ± 0.05, -31.6 ± 1.8 mV, respectively. In vitro release studies indicated the sustained release of ZT. DSC and XRD studies revealed the conversion of ZT into an amorphous form. SEM studies showed the spherical shape of the ZT-NLC formulation. PK studies showed 1.8-folds improvement (p<0.05) in oral bioavailability when compared with ZTCS formulation.
Overall, the results established that NLCs could be used as a new alternative delivery vehicle for the oral delivery of ZT.
佐替平（ZT）是一种取代二苯并噻庚英三环分子，属于第二代抗精神病药物。它有注射剂和口服固体剂型，但口服ZT的生物利用度较差（10%），这可能是由于其水溶性差、脂溶性高（Log P 4）以及首过肝代谢所致。
通过将ZT载入纳米结构脂质载体（NLCs）系统来提高其口服生物利用度。
采用热均质结合探头超声法制备ZT-NLCs制剂，并根据理化特性和体外释放情况对最佳系统进行表征。差示扫描量热法（DSC）、X射线衍射（XRD）分析和扫描电子显微镜（SEM）研究用于确认优化后的ZT-NLC制剂的结晶性质和形状。在冰箱和室温下对优化后的ZT-NLC制剂进行两个月的物理稳定性评估。此外，在雄性Wistar大鼠中进行了优化后的ZT-NLC和作为对照制剂的ZT粗混悬液（ZT-CS）的体内药代动力学（PK）研究。
优化后的ZT-NLC制剂的Z平均粒径、多分散指数（PDI）、ζ电位分别为145.8±2.5 nm、0.18±0.05、-31.6±1.8 mV。体外释放研究表明ZT具有缓释特性。DSC和XRD研究显示ZT转变为无定形形式。SEM研究显示ZT-NLC制剂呈球形。PK研究表明，与ZT-CS制剂相比，口服生物利用度提高了1.8倍（p<0.05）。
总体而言，结果表明NLCs可作为ZT口服给药的新型替代给药载体。
