Poudel Bijay Kumar, Marasini Nirmal, Tran Tuan Hiep, Choi Han-Gon, Yong Chul Soon, Kim Jong Oh
College of Pharmacy, Yeungnam University, 214–1 Dae-Dong, Gyongsan 712–749, South Korea.
Chem Pharm Bull (Tokyo). 2012;60(11):1409-18. doi: 10.1248/cpb.c12-00502.
The aim of the present research was to systematically investigate the main, interaction and the quadratic effects of formulation variables on the performance of self-microemulsifying drug delivery system (SMEDDS) of valsartan using design of experiment. A 17-run Box-Behnken design (BBD) with 3-factors and 3-levels, including 5 replicates at the centre point, was used for fitting a 2nd-order response surface. After the preliminary screening, Labrafil M 2125 CS as oil, Tween 20 as surfactant and Capryol 90 as co-surfactant were taken as independent variables. The dependent factors (responses) were particle size, polydispersity index (PDI), dissolution after 15 min and equilibrium solubility. Coefficients were estimated by regression analysis and the model adequacy was checked by an F-test and the determination coefficient (R(2)). All the responses were optimized simultaneously by using desirability function. Our results demonstrated marked main and interaction effects of independent factors on responses. The optimized formulation consisted of 26.8% (w/w) oil, 60.1% (w/w) surfactant and 13.1% (w/w) co-surfactant, and showed average micelle size of 90.7 nm and 0.246 PDI, 91.2% dissolution after 15 min and 226.7 mg/g equilibrium solubility. For the optimized formulation, predicted value and experimental value were in close agreement. After oral administration, the optimized formulation gave more than 2-fold higher area under curve (AUC) and about 6-fold higher C(max) in rats than valsartan powder (p<0.05). The BBD facilitated in the better understanding of inherent relationship of formulation variables with the responses and in the optimization of valsartan SMEDDS in relatively time and labor effective manner.
本研究的目的是利用实验设计系统地研究制剂变量对缬沙坦自微乳化药物递送系统（SMEDDS）性能的主要、相互作用和二次效应。采用三因素三水平的17次运行Box-Behnken设计（BBD），包括在中心点的5次重复，用于拟合二阶响应面。经过初步筛选，选择Labrafil M 2125 CS作为油相、吐温20作为表面活性剂、辛酸癸酸甘油三酯作为助表面活性剂作为自变量。因变量（响应）为粒径、多分散指数（PDI）、15分钟后的溶出度和平衡溶解度。通过回归分析估计系数，并通过F检验和决定系数（R²）检查模型的充分性。使用期望函数同时优化所有响应。我们的结果表明，独立因素对响应有显著的主要和相互作用效应。优化后的制剂由26.8%（w/w）的油相、60.1%（w/w）的表面活性剂和13.1%（w/w）的助表面活性剂组成，平均胶束尺寸为90.7nm，PDI为0.246，15分钟后溶出度为91.2%，平衡溶解度为226.7mg/g。对于优化后的制剂，预测值与实验值非常接近。口服给药后，与缬沙坦粉末相比，优化后的制剂在大鼠体内的曲线下面积（AUC）高出2倍以上，Cmax高出约6倍（p<0.05）。BBD有助于更好地理解制剂变量与响应之间的内在关系，并以相对省时省力的方式优化缬沙坦SMEDDS。
