Development and Physicochemical Characterization of An Empagliflozin-Loaded Oral Nanoemulsion: Formulation Optimization, in Vitro Release Kinetics, and Exploratory Ex Vivo Intestinal Permeation

Abstract

Background: Empagliflozin is a selective sodium–glucose cotransporter-2 (SGLT2) inhibitor used in the management of type 2 diabetes mellitus. Its intestinal permeability presents an opportunity for improving oral drug delivery through lipid-based nanocarriers. The present study aimed to develop, screen, and characterize an empagliflozin-loaded oral nanoemulsion and evaluate its in vitro drug release and exploratory ex vivo intestinal permeation performance.

Methods: Empagliflozin-loaded nanoemulsions were prepared using Capryol 90 as the oil phase, Tween 80 as the surfactant, and Transcutol P as the cosurfactant. Excipient screening and pseudo-ternary phase diagrams guided formulation development. Eight trial formulations (NE1–NE8) were subjected to preliminary physical examination and stress-stability screening. Selected formulations were evaluated for physicochemical characteristics, including droplet size, polydispersity index, zeta potential, viscosity, optical transmittance, and drug content. In vitro drug release was assessed using a diffusion-based method, while ex vivo intestinal permeation was compared with unformulated empagliflozin. Drug-content retention was also monitored over six months.

Results: The selected nanoemulsion exhibited a Z-average hydrodynamic diameter of 227.5 nm and a polydispersity index of 0.270. The Tween 80:Transcutol P ratio of 3:1 produced the largest estimated nanoemulsion-forming region (16.48%). At 12 h, cumulative apparent drug release reached 98.1% from the nanoemulsion compared with 63.2% from the unformulated suspension. The Higuchi transformation provided the strongest descriptive fit across the complete release profile (R² = 0.9900). Exploratory ex vivo intestinal permeation reached 7563.33 µg/cm² for the nanoemulsion and 5353.33 µg/cm² for unformulated empagliflozin at 24 h, corresponding to a 1.41-fold difference in cumulative transport. Drug content decreased from 99.07% to 97.64% during six months of storage, representing 98.56% retention relative to the initial value.

Conclusion: The empagliflozin-loaded nanoemulsion demonstrated favorable physicochemical characteristics, increased apparent drug release, and greater cumulative intestinal drug transfer than the unformulated suspension under the investigated experimental conditions. These findings support further evaluation of lipid-based nanoemulsions for oral empagliflozin delivery. Additional studies confirming intestinal tissue integrity, reproducibility, long-term formulation stability, and in vivo pharmacokinetic performance are required to establish improved oral bioavailability and therapeutic efficacy.