Central Composite Design-Optimized Dabigatran Etexilate Cubosomes for Sustained Oral Release and Enhanced In Vivo Pharmacokinetics.

OBJECTIVES: Dabigatran etexilate mesylate (DEM), a prodrug of the direct thrombin inhibitor dabigatran used for stroke prevention in nonvalvular atrial fibrillation, exhibits poor aqueous solubility, P-glycoprotein-mediated efflux, and limited oral bioavailability, which pose challenges for oral delivery. This study aimed to develop and optimize a cubosome-based nanocarrier system to enhance the oral bioavailability and sustain the release of DEM. METHODS: DEM-loaded cubosomes were prepared using glycerol monooleate (GMO) and Poloxamer 407 by melt dispersion-emulsification. A Central Composite Design (CCD) was employed to optimize formulation variables based on particle size, entrapment efficiency, and drug release responses. Optimized formulations were characterized by dynamic light scattering, TEM, FT-IR, DSC, and XRD analyses. In vitro drug release and in vivo pharmacokinetic studies in Wistar rats were performed to evaluate sustained release behavior and relative oral bioavailability enhancement. RESULTS: The optimized cubosomes exhibited nanoscale particle size (~ 19-30 nm), narrow size distribution, high entrapment efficiency (~ 87%), and sustained biphasic drug release up to 24 h. Structural characterization supported incorporation of DEM within the lipid matrix and reduced drug crystallinity. In vivo pharmacokinetic evaluation demonstrated prolonged plasma exposure and enhanced relative bioavailability compared with the marketed formulation, with approximately 2.28-fold higher relative bioavailability. CONCLUSIONS: The optimized cubosomal system effectively improved the oral delivery and sustained release of DEM. The formulation demonstrated enhanced relative bioavailability and prolonged systemic exposure, supporting further development for oral DEM delivery. Anticoagulant efficacy, gastrointestinal safety, and appropriate dosing regimens remain to be established.