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齐拉西酮自微乳释长效混悬型口服制剂的特性评价及其生物利用度的改善和不受食物影响。

Characterization and evaluation of self-nanoemulsifying sustained-release pellet formulation of ziprasidone with enhanced bioavailability and no food effect.

机构信息

a School of Biotechnology and Pharmaceutical Engineering , Nanjing Tech University , Nanjing , China and.

b School of Pharmaceutical Sciences , Nanjing Tech University , Nanjing , China.

出版信息

Drug Deliv. 2016 Sep;23(7):2163-2172. doi: 10.3109/10717544.2014.950768. Epub 2014 Aug 22.

Abstract

The purpose of this work was to develop self-nanomulsifying drug delivery systems (SNEDDS) in sustained-release pellets of ziprasidone to enhance the oral bioavailability and overcome the food effect of ziprasidone. Preformulation studies including screening of excipients for solubility and pseudo-ternary phase diagrams suggested the suitability of Capmul MCM as oil phase, Labrasol as surfactant, and PEG 400 as co-surfactant for preparation of self-nanoemulsifying formulations. Preliminary composition of the SNEDDS formulations were selected from the pseudo-ternary phase diagrams. The prepared ziprasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized ziprasidone-SNEDDS were used to prepare ziprasidone-SNEDDS sustained-release pellets via extrusion-spheronization method. The pellets were characterized for SEM, particle size, droplet size distribution and zeta potential. In vitro drug release studies indicated the ziprsidone-SNEDDS sustained-release pellets showed sustained release profiles with 90% released within 10 h. The ziprsidone-SNEDDS sustained-release pellets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation of Zeldox as a control. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolonged actions and enhanced bioavailability with no food effect was achieved simultaneously in ziprsidone-SNEDDS sustained-release pellets compared with Zeldox in fed state. The results indicated a sustained release with prolonged actions of schizophrenia and bipolar disorder treatment.

摘要

这项工作的目的是开发齐拉西酮自微乳给药系统(SNEDDS)的缓释微丸,以提高口服生物利用度并克服齐拉西酮的食物效应。预配方研究包括对辅料的溶解度和伪三元相图进行筛选,表明 Capmul MCM 适合作为油相,Labrasol 作为表面活性剂,PEG 400 作为助表面活性剂,用于制备自微乳制剂。从伪三元相图中选择 SNEDDS 配方的初步组成。对制备的齐拉西酮-SNEDDS 制剂进行自乳化时间、pH 影响和稀释稳定性、粒径分析和 Zeta 电位测定。优化的齐拉西酮-SNEDDS 用于通过挤出-滚圆法制备齐拉西酮-SNEDDS 缓释微丸。对微丸进行 SEM、粒径、粒径分布和 Zeta 电位的表征。体外药物释放研究表明,齐拉西酮-SNEDDS 缓释微丸具有持续释放特征,10 小时内释放 90%。将齐拉西酮-SNEDDS 缓释微丸给予禁食和进食的比格犬,并将其药代动力学与作为对照的 Zeldox 商业制剂进行比较。比格犬的药代动力学研究表明,与 Zeldox 相比,齐拉西酮-SNEDDS 缓释微丸在进食状态下同时具有延长作用和增强的生物利用度,且无食物效应。结果表明,齐拉西酮-SNEDDS 缓释微丸具有延长作用,可用于治疗精神分裂症和双相情感障碍。

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