Effects of different physicochemical characteristics and supersaturation principle of solidified SNEDDS and surface-modified microspheres on the bioavailability of carvedilol

Abstract

In this study, a solidified self-nanoemulsifying drug delivery system (solidified SNEDDS) and surface-modified microspheres were developed for enhancing the oral bioavailability of carvedilol. Based on the aqueous solubility test, liquid SNEDDS was composed of Peceol™ (oil), Tween® 80 (surfactant), and Labrasol® (co-surfactant) at a weight ratio of 25/50/25, generating the smallest nanoemulsion droplet size. Then, carvedilol was added to liquid SNEDDS and spray-dried with Aerosil® to fabricate the solidified SNEDDS. Surface-modified microspheres were manufactured using copovidone (polymer) and Tween® 80 (surfactant) according to aqueous solubility test results. The proper ratio of copovidone and Tween® 80 was determined based on the solubility and dissolution test. Both prepared formulations and carvedilol powder were compared using four different criteria: physicochemical characteristics, solubility, dissolution, and oral bioavailability. For solidified SNEDDS, carvedilol was encapsulated in liquid SNEDDS and absorbed to the Aerosil® surface, leading to the conversion from a crystalline to an amorphous state. However, the drug maintained its crystal form in the surface-modified microspheres. Round and even-sized particles were attached to the rough surfaces of drug, suggesting that hydrophilic carriers adhered to the hydrophobic drug. All formulations significantly improved drug solubility, dissolution, plasma concentrations, Cmax, and AUC compared to carvedilol powder. The parameters were ranked in the following order: solidified SNEDDS > surface-modified microspheres > carvedilol powder. As a result, different solubility-increasing mechanisms provided differences in performance. For carvedilol, the formation of a nano-emulsion in solidified SNEDDS resulted in an efficient supersaturated state, leading to improved solubility (~6.1 fold), dissolution (~1.8 fold), and oral bioavailability (~1.4 fold) that was superior to the hydrophilic microenvironment in surface-modified microspheres.