Lipid-based nanosystem of edaravone: development, optimization, characterization andin vitro/in vivoevaluation

Abstract

Edaravone (EDR) is a well-recognized lipophilic free radical scavenger for diseases including neurodegenerative disease, cardiovascular disease, and cancer. However, its oral use is restricted due to poor oral bioavailability (BA). The aim of present research was to enable its oral use by developing a lipid-based nanosystem (LNS). The components of LNS including oil, surfactants, and co-surfactants were selected based on their potential to maximize the solubilization in gastrointestinal (GI) fluids, reduce its glucuronidation and improve transmembrane permeability. The liquid LNS (L-LNS) with Capryol™ PGMC (Oil), Cremophor RH 40:Labrasol:TPGS 1000 (1:0.8:0.2) (Surfactant) and Transcutol P (Co-surfactant) were optimized to form microemulsion having droplet size (16.25 nm), polydispersity index (0.039), % Transmittance (99.85%), and self-emulsification time (32 s). It significantly improved the EDR loading as well as its metabolism and permeability profile during transport across the GI tract. To overcome the possible drawbacks of L-LNS, Aerosil 200 was used to formulate solid LNS (S-LNS), and its concentration was optimized based on flow properties. S-LNS possessed all quality attributes of L-LNS confirmed by solid-state characterization, reconstitution ability, and stability study. The dissolution rate of EDR was significantly enhanced with L-LNS and S-LNS in simulated gastric, and intestinal fluids. The pharmacokinetic study revealed significant improvement in relative BA, C, and t with L-LNS and S-LNS against EDR suspension. Moreover, S-LNS showed superior cellular uptake and neuroprotective effect compared to EDR in SH-SY5Y695 cell line. An appropriate selection of the components of LNS could enable effective oral delivery of challenging therapeutics that are conventionally used by the parenteral administration.

Self-Nanoemulsifying Drug Delivery Systems Containing Plantago lanceolata—An Assessment of Their Antioxidant and Antiinflammatory Effects

“…It is supported by Li et al [ 23 ] experiment that stable SNEDDS-persimmon leaf extract formulations were prepared and linear in vitro-in vivo correlation was observed. Lipid-based nanosystems are also enable to increase the bioavailability of APIs, and hence more effective formulations can be developed [ 24 ]. The degree of efficacy depends on the types of oil, surfactant, and co-surfactant in these nano-emulsifying systems [ 25 ].…”

Sistemas de entrega de fármacos autoemulsificables: una plataforma de desarrollo alternativa para la industria farmacéutica colombiana

“…Similarmente, Parikh et al [129] obtuvieron resultados positivos en la formulación de un sistema sólido de Edaravone mediante la adsorción de un SMEDDS líquido en Aerosil 200. Dicho sistema demostró ser capaz de mantener los atributos de calidad escogidos para la forma líquida (tamaño de gota, índice de polidispersidad, % transmitancia, tiempo de emulsificación) y a su vez mostró un desempeño superior en cuanto a los parámetros farmacocinéticos logrando un aumento de 7,45 veces en magnitud en C max , 9,29 veces en AUC y 9,29 veces en la biodisponibilidad relativa en comparación con una suspensión de Edaravone.…”

“…Se expresa constitutivamente en una variedad de tejidos donde funciona como moduladora de la salida de una amplia variedad de sustratos a través de la membrana celular [97]. En la membrana del epitelio intestinal la P-gp es capaz de reconocer como sustrato a muchos principios activos (por ejemplo, Paclitaxel [58], Edaravona [129], Atazanavir [62], Darunavir [51], Emodina [142], etc.) lo que da como resultado su salida de regreso hacia el lumen intestinal, reduciendo significativamente su biodisponibilidad.…”

“…Por lo tanto, es recomendable que el punto de nube para los SEDDS esté por encima de la temperatura corporal [107,113]. Para la determinación del punto de nube se diluye una cantidad de la formulación en agua destilada, generalmente, en una proporción 1:100 y se introduce en un baño de agua donde se somete a un incremente gradual de la temperatura [97,129,151].…”

Self-nanomicellizing solid dispersion of edaravone: part I – oral bioavailability improvement

“… 27 Based on this, the liquid and solid lipid-based nanosystem (LNS) of EDR revealed 10.79- and 9.29-fold improvement in oral BA of EDR compared to EDR suspension, respectively, due to significant improvement in solubility, modulation of Pgp efflux pump, and inhibition of uridine 5-diphospho-glucuronosyl-transferase (UGT) enzymes. 31 However, solid dispersion-based formulation showed improvement in solubility, stability, and BA compared to lipid-based formulations in case of clopidogrel napadisilate. 32 Also, the issues associated specifically with self-microemulsifying drug delivery system could restrict its chronic use including high surfactant concentration, which causes gastrointestinal irritation and chemical instabilities of drugs.…”