Development Optimization and Evaluation of Thymoquinone loaded Nanocarrier Systems

Abstract

newline x newlineABSTRACT newlineThymoquinone (TQ) a potent bioactive of Nigella sativa plant, is a well-known anti-oxidant and anti-inflammatory molecule, and has been exploited for its role in various ailments. Oral administration of TQ is associated with some serious issues like poor aqueous solubility, high first-pass metabolism, and gastrointestinal instability and thus, poor oral bioavailability. The present work, therefore proposed to enhance the low oral bioavailability and therapeutic efficacy, employing nanocarrier-based approaches. newlineTQ-loaded nanocarriers i.e., solid lipid nanopartiles(SLNs), nanostructured lipid carriers (NLCs) and self-nanoemlsifying drug delivery systems (SNEDDS) were prepared by microemulsification method employing pseudotrnary phase diagrams. NLCs were further, optimized employing Box-behnken design. All the prepared nanocarriers characterized, and evaluated for in vitro release kinetics, in vivo bioavailability, anti-inflammatory potential using carrageenan induced paw edema model, and hepato-protective potential employing paracetamol-induced hepato-toxicity in rats. Optimized nanocarrier formulations i.e., SLNs (d0.5=100nm, PDI=0.179), NLCs (d0.5=83.5nm, PDI=0.55), SNEDDS(d0.5=90nm, PDI=0.312) exhibited nanosize range with spherical morphology, and zeta potential value of 0.55 mV for SLNs, -0.64mV for NLCs, and -11.85 mV for SNEDDS respectively. Moreover optimized nanocarrier formulations exhibited high drug entrapment efficiency in the order NLCs (94.4%) gt SLNs (73.4%), and % CDR, NLCs (80%) gt SNEDDS (78.36%) gt SLNs (70.97%), respectively. The release kinetics of all the optimized nanocarrier formulations was best-fitted with Higuchi model, which indicates the controlled release behavior of the drug from lipidic matrix. XRD and DSC studies of TQ-loaded nanocarriers, revealed that intrinsic crystalline peak of TQ was absent in nanocarrier formulations, which means the complete solubilization and stability of the TQ inside the TQ-loaded nanocarrier formulations. After oral administration of a single dose of TQ-loaded nanocarriers, it showed approximately 4-fold (NLCs)gt 3.9-fold (SNEDDS) gt 3.6-fold (SLNs), enhancement in relative bioavailability vis-à-vis plain TQ suspension. Whereas, substantially higher reduction in the percent edema inhibition in paw, in comparison to the pure drug suspension and diclofenac sodium, was observed in the inflammation model. Further, TQ-loaded nanocarriers demonstrated significantly enhanced hepato-protective effect vis-à-vis pure TQ suspension and silymarin, as evidenced by reduction in the alkaline newlinexi newlinephosphate (ALP), alanine aminotransferase (ALT), aspartate transaminase (AST), bilirubin, and albumin level, and ratified by histopathological analysis. The promising outcomes of the current studies ratify the superiority of TQ-loaded nanocarriers for the treatment of inflammatory and hepatic disorders, and promising carrier system to augment oral bioavailability of this hydrophobic molecule. newlineKeywords: Nigella sativa, thymoquinone, lipidic nanocarriers, oral bioavailability, BBD, pharmacokinetic, hepato-protective