Kim Rae Man, Jang Dong-Jin, Kim Yu Chul, Yoon Jin-Ha, Min Kyoung Ah, Maeng Han-Joo, Cho Kwan Hyung
College of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae 50834, Korea.
Department of Pharmaceutical Engineering, Inje University, Gimhae 50834, Korea.
Pharmaceutics. 2018 Nov 28;10(4):247. doi: 10.3390/pharmaceutics10040247.
The aim of this work was to prepare and optimize a solid self-nanoemulsifying drug delivery system pre-concentrate (SSP) containing water-insoluble flurbiprofen (FL) using a novel pseudo-ternary phase diagram. The pseudo-ternary phase diagram, composed of FL as the drug and dispersion core, Kollisolv MCT 70 as the oil phase, and TPGS (tocopherol polyethylene glycol 1000 succinate) as the surfactant, was constructed for the determination of the SSP region. SSP was investigated in terms of particle size, physical state by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), in vitro dissolution and oral pharmacokinetics in rats. The determined SSP (FL/Kollisolv MCT 70/TPGS = 10/10/80, weight %) in the pseudo-ternary phase diagram had the melting point of 32.37 °C and uniform mean particle size of below 30 nm without any precipitation of FL in the dispersion. In the dissolution test, the SSP exhibited 95.70 ± 3.40% of release at 15 min, whereas the raw FL showed poor dissolution (i.e., 6.75 ± 1.30%) at that time point. In addition, the SSP showed the enhanced oral absorption (i.e., 1.93-fold increase in AUC) as compared to the suspension group of raw FL. Therefore, the developed SSP would be a promising drug delivery system with excellent solubilization, dissolution, and bioavailability for FL.
本研究旨在利用新型伪三元相图制备并优化一种包含水不溶性氟比洛芬（FL）的固体自纳米乳化药物递送系统预浓缩物（SSP）。构建了以FL作为药物和分散核心、Kollisolv MCT 70作为油相、TPGS（聚乙二醇1000维生素E琥珀酸酯）作为表面活性剂的伪三元相图，以确定SSP区域。从粒径、差示扫描量热法（DSC）和粉末X射线衍射（PXRD）测定的物理状态、体外溶出度以及大鼠口服药代动力学方面对SSP进行了研究。在伪三元相图中确定的SSP（FL/Kollisolv MCT 70/TPGS = 10/10/80，重量%）熔点为32.37℃，平均粒径均匀且低于30nm，分散液中无FL沉淀。在溶出度试验中，SSP在15分钟时的释放率为95.70±3.40%，而此时原料药FL的溶出度较差（即6.75±1.30%）。此外，与原料药FL的混悬液组相比，SSP的口服吸收增强（即AUC增加1.93倍）。因此，所开发的SSP将是一种有前景的药物递送系统，对FL具有优异的增溶、溶出和生物利用度。
