ENHANCED ORAL BIOAVAILABILITY OF EDARAVONE AND REVERSE COGNITIVE DEFICITS IN AN ALZHEIMER'S DISEASE MODEL VIA A SELF-MICELLIZING SOLID DISPERSION APPROACH

Abstract

Alzheimer disease (AD) is a devastating neurodegeneraive disorder that lacks any disease-modifying drug for the prevention and treatment. The drug development for this this disease has become a holy grail as 99.6% failure rate is encountered in clinical trials. Edaravone (EDR) showed its unique therapeutic potential against Alzheimer disease (AD) by targeting multiple pathologies such as amyloid-beta, tau phosphorylation, neuroinflammation and oxidative stress. The poor oral bioavailability (BA) due to poor aqueous solubility, stability, dissolution and permeability, is a key reason for its failure in clinical trials. The aim of present research is to develop novel EDR formulation (NEF) using Self-Micellizing Solid Dispersion (SMSD) strategy and assess its safety and efficacy in transgenic AD mice model (APPSwe/PS1deE9). The development and optimisation of NEF were performed based on the improvement in aqueous solubility and stability of EDR. The optimised NEF was further characterised to understand the drug-polymer interaction and assessed by in-vitro dissolution, permeability study (everted intestine sac method), and in-vivo oral pharmacokinetic study using rats. Also, its safety and efficacy were evaluated after 3 months of treatment by oral administration. The soluplus based NEF displayed dramatic improvement in aqueous solubility (17.53-fold) and stability due to amorphization, hydrogen bonding interaction and micellization. Moreover, the NEF demonstrated significant improvement in intestinal permeability and dissolution profile of EDR. Furthermore, the oral BA of NEF showed 10.2, 16.1 and 14.8-fold enhancement compared to EDR suspension at 46, 138 and 414 μM/kg dose. Besides, our data confirms non-toxicity up to 414 μM/kg dose after 3 months and its potential to reverse AD-like cognitive deficits of APP/PS1 mice in dose dependent manner. NEF has great potential to mitigate the limitation associated with EDR and can pave the way for its clinical development for the treatment of AD.