Ultra Rapidly Dissolving Repaglinide Nanosized Crystals Prepared via Bottom-Up and Top-Down Approach: Influence of Food on Pharmacokinetics Behavior

The present work was undertaken with the objectives of improving the dissolution velocity, related oral bioavailability, and minimizing the fasted/fed state variability of repaglinide, a poorly water-soluble anti-diabetic active by exploring the principles of nanotechnology. Nanocrystal formulations were prepared by both top-down and bottom-up approaches. These approaches were compared in light of their ability to provide the formulation stability in terms of particle size. Soluplus® was used as a stabilizer and Kolliphor™ E-TPGS was used as an oral absorption enhancer. In vitro dissolution profiles were investigated in distilled water, fasted and fed state simulated gastric fluid, and compared with the pure repaglinide. In vivo pharmacokinetics was performed in both the fasted and fed state using Wistar rats. Oral hypoglycemic activity was also assessed in streptozotocin-induced diabetic rats. Nanocrystals TD-A and TD-B showed 19.86 and 25.67-fold increase in saturation solubility, respectively, when compared with pure repaglinide. Almost 10 (TD-A) and 15 (TD-B)-fold enhancement in the oral bioavailability of nanocrystals was observed regardless of the fasted/fed state compared to pure repaglinide. Nanocrystal formulations also demonstrated significant (p < 0.001) hypoglycemic activity with faster onset (less than 30 min) and prolonged duration (up to 8 h) compared to pure repaglinide (after 60 min; up to 4 h, respectively).KEY WORDS: diabetes mellitus, fasted and fed state variability, nanocrystal, oral hypoglycemic activity, repaglinide