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Purpose The aim of this work was to probe cubosomes for enhanced intestinal absorption and oral bioavailability of poorly absorbable fexofenadine HCl (FEX-HCl). Materials and Methods Two cubosomal systems were fabricated utilizing glyceryl mono-oleate, a lyotropic mono lamellar lipid as oil phase and poloxamer407 as stabilizer at weight ratios of 8:2 and 7:3. The morphology of cubosomes was researched using transmission electron microscopy (TEM) and particle size was measured using photon correlation spectroscopy. FEX-HCl release was monitored in vitro. The effect of cubosomal encapsulation on intestinal absorption was assessed using in situ rabbit intestinal perfusion technique. Carrageenan induced rat paw edema model was utilized to monitor in vivo anti-inflammatory effect before and after cubosomal encapsulation. Results TEM revealed the existence of spherical and polygonal nanostructures arranged in honeycomb organization. Size measurement reflected nanoparticles with reduced size at higher poloxamer concentration. Release studies revealed liberation of FEX-HCl from cubosomes based on Higuchi kinetics model. The intestinal permeability data indicated incomplete absorption of FEX-HCl from simple aqueous solution with P-glycoprotein efflux contributing to this poor intestinal absorption. Incorporation of FEX-HCl in cubosomes enhanced membrane transport parameters. The intestinal absorption did not correlate with drug release suggesting that drug release is not the rate limiting with possible intact cubosomal transport. Cubosomal encapsulation of FEX-HCl significantly enhanced its in vivo anti-inflammatory efficacy compared to the aqueous FEX-HCl dispersion. Conclusion Cubosomes are promising novel carriers for enhancing intestinal absorption of FEX-HCl. Intact FEX-HCl-cubosomal absorption is possible via trans-lymphatic pathway but this requires further investigations.