Optimized buccoadhesive repaglinide-loaded cubogel: In-vitro characterization and in-vivo hypoglycemic activity in a streptozotocin-induced diabetic rat model

Abstract

The limited bioavailability of orally administered repaglinide presents a significant challenge in diabetes management, which can be addressed by developing a buccoadhesive drug delivery system. In this study, repaglinide-loaded cubosomes were prepared using a top-down approach and optimized via a 3³ Box-Behnken design. The optimized formulation (Opt-RPG-CUB) was characterized for solubilization efficiency (SE%), particle size (PS), zeta potential (ZP), drug release kinetics, and morphology. To further enhance drug delivery, a 2² factorial design was utilized to incorporate varying concentrations of the gelling agents hydroxypropyl methylcellulose or carboxymethyl cellulose into Opt-RPG-CUB, forming repaglinide-loaded cubogels. Upon optimization, the cubogel with the highest desirability function, designated as Opt-RPG-Cubogel, was further evaluated for mucoadhesion, drug release kinetics, rheological properties, ex-vivo buccal permeation, and in-vivo drug permeation by confocal laser scanning microscopy and pharmacodynamic assessment in a streptozotocin-induced diabetic rat model. Results showed that Opt-RPG-CUB exhibited a SE% of 88.01 ± 3.92 %, PS of 252.55 ± 17.18 nm, and ZP of −31.13 ± 1.42 mV, with an extended drug release over 24 h and a cubic nanostructure. Opt-RPG-Cubogel exhibited strong mucoadhesion (>9 h), an extended drug release over 24 h, enhanced mucosal permeation, and improved tissue deposition. Confocal microscopy further confirmed deep mucosal penetration, while in-vivo studies demonstrated a significant reduction in blood glucose levels compared to the control. Overall, these findings highlight the potential of Opt-RPG-Cubogel as a promising buccoadhesive drug delivery system for efficient type II diabetes management.