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

Abstract

Abstract. 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 watersoluble 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).

Recent Advances in the Application of Vitamin E TPGS for Drug Delivery

“…As a surfactant, TPGS shows outstanding capability to increase drug absorption through different biological barriers. For example, TPGS was used to fabricate repaglinide nanocrystals for enhancing saturation solubility and oral bioavailability up to 25.7-fold and 15.0-fold compared with free drug, respectively 26 . In Ussing chambers transport studies, TPGS can enhance drug permeation in colonic tissue 27 .…”

<p>Engineering of solidified glyburide nanocrystals for tablet formulation via loading of carriers: downstream processing, characterization, and bioavailability</p>

“…[2][3][4] In pharmaceutical research, the term nanosized is commonly applied to particle size ranging from a few nanometers to 1 µm. 5 Nanonization is an attractive approach to overcoming drug solubility issues, 6 whereby reduction in particle size increases the surface area by a large fold, leading to enhanced dissolution rate and intrinsic solubility. This in return can have a positive effect on oral bioavailability of class II Biopharmaceutical Classification System drugs.…”

Synthesis and Characterization of Mesoporous Silica Nanoparticles Loaded with Repaglinide for Dissolution Enhancement

“…The enhancement of dissolution velocity was observed in silica nanoparticles as compare to pure drug and marketed formulation. The mechanism for improved dissolution predicted is increased surface area provided by the mesoporous silica nanoparticles; reduction of the particle size of the particles and drug and availability of drug in amorphous form [27,28] .…”