Implications of phospholipid-based nanomixed micelles of olmesartan medoxomil with enhanced lymphatic drug targeting ability and systemic bioavailability

Abstract

The present study describes the systematic development of a phospholipid-based nanomixed micellar formulation of olmesartan medoxomil (OLM) surface-decorated with bile salt for improved lymphatic drug targeting ability and enhanced systemic availability. The micellar formulation was prepared from the drug and phospholipid mixture, and surface modified with sodium deoxycholate as a penetration enhancer. The formulation was systematically developed and optimized using Quality by Design (QbD) principles. Impact assessment of the formulation and process parameters was conducted by risk analysis and response surface optimization was performed using Box-Behnken experimental design. The optimized nanomixed micellar formulation exhibited a particle size of 168 nm, zeta potential of −22.4 mV and a drug loading efficiency of 70%. Drug release evaluation showed a sustained release profile with 70% release within 12 h and a nearly complete release of OLM within 24 h. A Caco-2 cell culture study on the nanomixed micelles revealed more than 90% viability and uptake of the drug within the study period of 6 h. Bidirectional permeability measurements showed over a 60% reduction in P-gp efflux of OLM from the nanomixed micelles over the pure drug studied for the period of 3 h, as calculated from the values of the efflux ratio. Pharmacokinetic evaluation in rat plasma revealed nearly 10.62 and 6.02-fold improvements in AUC0-t and Cmax of OLM from nanomixed micelles over a pure drug suspension, while lymphatic uptake evaluation in rats also revealed nearly a 3.04-fold increase in the concentration of OLM in lymph from the nanomixed micelles over the pure drug suspension within the study period of 24 h. The intestinal safety evaluation of the nanomixed micelles by histopathology analysis revealed the biocompatible nature of the formulation without any organ toxicity. Overall, the results obtained from the above in vitro and in vivo studies indicated the strong suitability of the developed nanomicellar formulation for enhancing the oral bioavailability of the drug to manage hypertension.