a School of Pharmaceutical Sciences , Nanjing Tech University , Nanjing , China.
Drug Dev Ind Pharm. 2018 Jun;44(6):969-981. doi: 10.1080/03639045.2018.1425428. Epub 2018 Jan 25.
The present research indicated that a new self-microemulsifying drug delivery systems (SMEDDS) were used to reduce the food effect of poorly water-soluble drug cinacalcet and enhance the bioavailability in beagle dogs by oral gavage. Ethyl oleate, OP-10, and PEG-200 was selected as the oil phase, surfactant and co-surfactant of cinacalcet-SMEDDS by the solubility and phase diagram studies. Central Composite Design-Response Surface Methodology was used to determine the ratio of surfactant and co-surfactant, the amount of oil for optimizing the SMEDDS formation. The prepared formulations were further characterized by the droplet size, self-microemulsifying time, zeta potential, polydispersity index (PDI), and robustness to dilution. The in vitro release profile of cinacalcet-SMEDDS was determined in four different release medium and in fasted state and fed state of simulated gastrointestinal fluid. Cinaclcet-SMEDDS were implemented under fed and fasted state in dogs and product REGPARA was used as a comparison to the prepared formulation in the pharmacokinetics. The result showed the components of SMEDDS, the amount of oil, the ratio of surfactant, and co-surfactant was optimized using solubility, pseudo-ternary phase diagram studies, and response surface methodology. In vitro drug release studies indicated that the cinacalcet-SMEDDS eliminated the effect of pH variability in release medium and variational gastroenteric environments with improved drug release performance. Pharmacokinetic studies revealed that the profiles of cinacalcet-SMEDDS were similar both in the fasted and fed state compared with commercial product, indicating the formulation significantly promoted the absorption, enhanced bioavailability and had no food effect essentially. It is concluded that poorly water-soluble drug cinacalcet was improved in the solubility and bioavailability by using a successful oral dosage form the SMEDDS, and eliminated food effect as well.
本研究表明，采用新的自微乳给药系统（SMEDDS）可减少难溶性药物西那卡塞的食物效应，并通过口服灌胃提高在比格犬中的生物利用度。通过溶解度和相图研究，选择油酸乙酯、OP-10 和聚乙二醇 200 作为西那卡塞-SMEDDS 的油相、表面活性剂和助表面活性剂。采用中心复合设计-响应面法确定表面活性剂和助表面活性剂的比例、油相的用量，以优化 SMEDDS 的形成。通过粒径、自微乳时间、Zeta 电位、多分散指数（PDI）和稀释稳定性进一步表征制备的制剂。在四种不同的释放介质中以及在模拟胃肠道的空腹和进食状态下，测定西那卡塞-SMEDDS 的体外释放曲线。在犬中实施西那卡塞-SMEDDS 空腹和进食状态，并将制备的制剂与市售产品 REG-PARA 进行药代动力学比较。结果表明，采用溶解度、拟三元相图研究和响应面法优化了 SMEDDS 的组成、油相的用量、表面活性剂和助表面活性剂的比例。体外药物释放研究表明，西那卡塞-SMEDDS 消除了释放介质中 pH 值变化和变异性胃肠道环境对药物释放性能的影响。药代动力学研究表明，与市售产品相比，西那卡塞-SMEDDS 在空腹和进食状态下的药代动力学特征相似，表明该制剂显著促进了吸收，提高了生物利用度，基本上没有食物效应。总之，采用成功的口服剂型 SMEDDS 可提高难溶性药物西那卡塞的溶解度和生物利用度，并消除食物效应。
