Enhanced dissolution, permeation and oral bioavailability of aripiprazole mixed micelles: In vitro and in vivo evaluation.

Abstract

Aripiprazole (ARP) is an antipsychotic drug approved for the treatment of schizophrenia. It is poorly water-soluble and undergoes extensive hepatic metabolism and P-gp efflux, which lead to poor bioavailability and increased dose-related side effects. This study focuses on the preparation of mixed micelles (MM) to enhance the aqueous solubility, oral bioavailability, and blood-brain barrier permeation of ARP. For this purpose, Soluplus and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected for micelle preparation (ARP-MM). Micelles with borneol as penetration enhancer were also considered (ARP-B-MM). The optimized formulations have sizes of ca 50nm, defined in distilled water, narrow size distribution (polydispersity index ≤0.1), and high encapsulation efficiency (greater than98%). Both formulations can be freeze-dried without losing their chemical-physical characteristics and are stable during storage for three months. The mixed micelles resulted stable in enzyme free-simulated gastric fluid (SGF, pH 1.2), simulated intestinal fluid (SIF, pH 6.8), and in serum. The in vitro ARP release was evaluated in the same biorelevant media, (SGF and SIF), and it disclosed that both micelles can give prolonged drug release. Furthermore, ARP solubility is greatly increased when loaded into mixed micelles. The absorption and efflux of ARP-loaded micelles were studied in vitro, employing two artificial membranes (Parallel Artificial Membrane Permeability Assay for the intestinal, PAMPA-GI, and the blood-brain barrier, PAMPA-BBB), to simulate the intestinal and brain epithelium, and the brain microvascular endothelial cell line hCMEC/D3. ARP-MM and ARP-B-MM increase the effective permeability of ARP by a factor of about three in the case of PAMPA-GI and about two for PAMPA-BBB. Furthermore, the P-gp mediated efflux was decreased by about six times in the case of ARP-MM and by about four times in the case of ARP-B-MM, compared to unformulated ARP. Finally, both ARP-loaded mixed micelles ameliorate the bioavailability of ARP, as demonstrated by the increase of the pharmacokinetic parameters, such as Cmax, AUC0-24h, and t1/2.