Development of Linagliptin Ultra Fine Solid Supersaturated Bio-SNEDDS Using Triangular Mixture Design for Enhancement of Oral Bioavailability: Impact of P-gp Inhibition

Linagliptin (LIN) is a newly developed dipeptidyl peptidase 4 (DPP-4) inhibitor oral antidiabetic drug. LIN is considered a P-gp substrate, thus suffers from poor bioavailability (< 30%). The aim of this study was to develop and characterize LIN bioactive self-nanoemulsifying drug delivery system to circumvent its poor bioavailability and enhance its therapeutic efficacy.

Methodology: In this study, we developed solid supersaturated bioactive self-nanoemulsifying drug delivery system (Ss-bio-SNEDDS) of LIN, using clove oil as an oil phase, cremophor CO 40 as a surfactant, labrasol as a co-surfactant and Hydroxy-propyl-B-cyclodextrin (HPBCD) as a precipitation inhibitor (PI); all components are of established P-gp inhibition activity. Optimization was performed by means of triangular mixture design based on particle size, poly dispersity index (PDI) and percent transmittance. The two optimized formulations (F4 and F8) were designated and evaluated for stability and cloud point. Also, the effect of pH on particle size and PDI was assessed. Additionally, examination of particles’ surface morphology of the two optimized formulations was performed by transmission electron microscope (TEM). The prepared liquid supersaturated-SNEDDS (s-SNEDDS) were converted into solid supersaturated-SNEDDS (Ss-SNEDDS) via adsorption on microcrystalline cellulose (MCC). Further evaluations were carried out, including in vitro drug release, in vitro precipitation and in vivo studies.

Results: The optimized formulations F4 and F8 manifested promising characteristics concerning particle size (< 50 nm), PDI (< 0.3) and percent transmittance (> 99%). Stability study showed no phase separation or precipitation with rapid emulsification time. The two optimized formulations showed high cloud point temperature (above 70°C). TEM images of F4 and F8 showed spheroid like appearance with relatively smooth surface. Results of the in vivo study in rats revealed a significant increase in AUC of solid-F4, solid-F8 and solid supersaturated-F4 (S-F4, S-F8 and Ss-F4) by 2.32, 2.89 and 2.54 folds, respectively compared to LIN solution; with a noticeable reduction in blood glucose level at each point.

Conclusion: In a nutshell, Ss-bio-SNEDDS are considered as auspicious nano-carriers for LIN with the virtue of augmented bioavailability and possible dose reduction.