Development of isradipine loaded self-nano emulsifying powders for improved oral delivery: in vitro and in vivo evaluation

摘要

Isradipine (ISR) is a potent calcium channel blocker with low oral bioavailability due to low aqueous solubility, extensive first-pass metabolism and P-glycoprotein (P-gp)-mediated efflux transport. In the present investigation, an attempt was made to develop isradipine-loaded self-nano emulsifying powders (SNEP) for improved oral delivery. The liquid self-nano emulsifying formulations (L-SNEF/SNEF) of isradipine were developed using vehicles with highest drug solubility, i.e. Labrafil (R) M 2125 CS as oil phase, Capmul (R) MCM L8 and Cremophor (R) EL as surfactant/co-surfactant mixture. The developed formulations revealed desirable characteristics of self-emulsifying system such as nano-size globules ranging from 32.7 to 40.2 nm, rapid emulsification (around 60 s), thermodynamic stability and robustness to dilution. The optimized stable self-nano emulsifying formulation (SNEF2) was transformed into SNEP using Neusilin US2 (SNEPN) as adsorbent inert carrier, which exhibited similar characteristics of liquid SNEF. The solid state characterization of SNEPN by Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopic studies shown transformation of crystalline drug into amorphous form or molecular state without any chemical interaction. The in vitro dissolution of SNEPN compared to pure drug was indicated by 18-fold increased drug release within 5 min. In vivo pharmacokinetic studies in Wistar rats showed significant improvement of oral bioavailability of isradipine from SNEPN with 3- and 2.5-fold increments in peak drug concentration (C-max), area under curve (AUC(0-infinity)) compared to pure isradipine. In conclusion, these results signify the improved oral delivery of isradipine from developed SNEP.