Linagliptin-loaded bilosomes for oral administration: Formulation, optimization by Box-Behnken design, in-vitro, and in-vivo assessment

Abstract

Linagliptin (LGN), BCS class III drug, is used to treat type 2 diabetes mellitus. Despite its high aqueous solubility, LGN show oral bioavailability of only 30 %, due to poor permeability, pre-systemic metabolism, and P-gp efflux. Therefore, aim of this study was to develop LGN-loaded bilosomes (LGN-BIL) to improve oral bioavailability of LGN. Box-Behnken design was used to optimize the composition of LGN-BIL prepared by solvent evaporation method. The prepared LGN-BIL were characterized for vesicle size, zeta potential, entrapment efficiency (%EE), FTIR, TEM, DSC, PXRD, ex vivo drug permeation using everted sac model and in vivo pharmacokinetic study. The prepared spherical LGN-BIL had vesicle size of 138.0 ± 2.5 nm with %EE of 84.55 ± 3.5 %. FTIR studies demonstrated formation of amide bond between LGN and sodium deoxycholate. Moreover, apparent permeability coefficient (Papp) of LGN-BIL (9.82 × 10⁻⁷ cm/min) was higher by 1.5 fold when compared to LGN dispersion (6.34 × 10⁻⁷ cm/min). The C_max and AUC_0–48 for LGN dispersion were 0.135 ± 0.02 μg/ml and 1.889 ± 0.224 μg h/mL while that for LGN-BIL were 0.554 ± 0.06 μg/mL and 9.711 ± 0.125 μg h/mL, respectively. Thus pharmacokinetic study showed 4 fold increase in C_max and 5 fold increase in AUC_0–48 of LGN when formulated into bilosomes which could be attributed to P-gp inhibition, bypassing first pass metabolism and absorption of BIL through M-cells payers’ patches and nanosize. The prepared LGN-BIL could be a prospective drug delivery vesicles for LGN circumventing the drawback of poor oral bioavailability.