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

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, C_max, 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.