Formulation of Self-Microemulsifying Drug Delivery System (SMEDDS) by D-optimal Mixture Design for Enhancing Oral Bioavailability of DN200428 (Cathepsin K Inhibitor)

Abstract

DN200428 is a new compound designed and synthesized to treat osteoporosis as a cathepsin K inhibitor. Its poor aqueous solubility is expected to result in low bioavailability after oral administration. The objective of this study is to formulate self-microemulsifying drug delivery systems (SMEDDS) for enhancing the oral bioavailability of DN200428. Solubility studies of DN200428 were performed to select the suitable oil, surfactant and cosurfactant. Pseudoternary phase diagrams were plotted to identify the microemulsion region and to determine the range of components in isotropic mixture. The D-optimal mixture design and the desirability function was introduced to optimize the formulation of SMEDDS with the optimum physicochemical characteristics, i.e., high drug concentration at 15 minutes after dilution in simulated gastric fluid (SGF) and high solubilized capacity. Pharmacokinetic study was performed in rats, and the drug concentration in plasma samples was assayed using the high-performance liquid chromatography with fluorescence detector (HPLC-FL). The optimized DN200428-loaded SMEDDS formulation consisted of 5.0% of Capmul MCM EP (oil), 75.0% of Tween 20 (surfactant) and 20.0% of Carbitol (co-surfactant). The droplet size of microemulsion formed by the optimized formulation was 10.7 ± 1.6 nm. Transmission electron microscopy (TEM) analysis was confirmed the spherical shape of the microemulsion. Pharmacokinetic studies showed that the relative oral bioavailability of DN2000428-loaded SMEDDS increased up to 3-fold when compared with its solution in DMSO:PEG400 (8:92). Thus, it can be concluded that the formulation of SMEDDS could be a promising approach to improve oral bioavailability of DN200428.