School of Pharmacy, Nanjing Tech University, 5th Mofan Road, Nanjing, 210009, China.
AAPS PharmSciTech. 2018 May;19(4):1847-1859. doi: 10.1208/s12249-018-0991-6. Epub 2018 Apr 10.
In this paper, a novel self-nanoemulsifying drug delivery system (SNEDDS) was used to improve the oral bioavailability in fasted state and diminish the food effect for rivaroxaban. Oil, surfactant, and co-surfactant were selected by saturated solubility study. IPM, Tween80, and 1,2-propanediol were finally selected as oil, surfactant, and co-surfactant, respectively. The pseudo-ternary-phase diagram was utilized to optimize the preliminary composition of SNEDDS formulation. The optimized rivaroxaban-SNEDDS formulation was selected by central composite design (CCD) of response surface methodology. Optimized SNEDDS formulation was evaluated for drug content, self-emulsifying time, droplet size, zeta potential, polydispersity index, Fourier transform-infrared (FTIR) spectroscopy, and transmission electron microscope (TEM). The drug dissolution profile compared to the commercial formulation Xarelto® (20 mg rivaroxaban) was determined in four different media (pH 1.2HCl, pH 4.5NaAc-HAc, pH 6.8PBS, and water). The result indicated that the SNEDDS formulation had successfully increased the drug solubility in four different media. A HPLC-MS method that indicated a high sensitivity, strong attribute, and high accuracy characteristic was built to measure the drug concentration in plasma. The fast/fed in vivo pharmacokinetics studies of SNEDDS formulation and Xarelto® were carried out in adult beagle dog, rivaroxaban with no food effect was achieved in SNEDDS formulation compared with Xarelto® in fed state. The result suggested that SNEDDS formulation in this study is useful to increase the oral bioavailability and diminish the food effect in fasted state.
在本论文中，我们采用了一种新颖的自微乳药物传递系统（SNEDDS）来提高利伐沙班在禁食状态下的口服生物利用度并减少食物效应。通过饱和溶解度研究选择油相、表面活性剂和助表面活性剂。最终选择异丙醇（IPM）、吐温 80 和 1,2-丙二醇分别作为油相、表面活性剂和助表面活性剂。采用伪三元相图来优化 SNEDDS 制剂的初步组成。通过响应面法的中心复合设计（CCD）选择优化的利伐沙班 SNEDDS 制剂。对优化的 SNEDDS 制剂进行药物含量、自乳化时间、粒径、Zeta 电位、多分散指数、傅里叶变换红外光谱（FTIR）和透射电子显微镜（TEM）评估。与商业制剂 Xarelto®（20mg 利伐沙班）相比，在四种不同介质（pH 1.2 HCl、pH 4.5 NaAc-HAc、pH 6.8 PBS 和水）中比较了药物溶出度。结果表明，SNEDDS 制剂成功提高了四种不同介质中的药物溶解度。建立了一种 HPLC-MS 方法，该方法具有高灵敏度、强属性和高精度的特点，用于测量血浆中的药物浓度。在成年比格犬中进行了 SNEDDS 制剂和 Xarelto®的快速/进食体内药代动力学研究，与 Xarelto®在进食状态相比，SNEDDS 制剂使利伐沙班在禁食状态下无食物效应。结果表明，本研究中的 SNEDDS 制剂有助于提高口服生物利用度并减少禁食状态下的食物效应。
