Assessment of in Vivo Pharmacokinetics and Pharmacodynamics of Tolbutamide Nanoformulations

Abstract

Tolbutamide is an anti-diabetic drug used in the adjuvant therapy for type-II diabetes as the inhibitor of sodium‐glucose co‐transporter-2 in the renal tubules. The poor solubility and permeability of the drug show limitations in the formulation development and therapeutic plasma concentration. The objective of the work was to improve the solubilityand dissolution of the BCS class IV drug through surfactant stabilized nanosuspension formulation. Nanoparticle were developed by Nano precipitation-solvent evaporationmethod using Poly vinyl alcohol and Pluronic as surfactants at 1%, 3% and 5% concentration. Formulation optimized with Pluronic exhibited nano size particles (81-117nm) with monodisperse nature and high stability zeta potential. The nanosuspension prepared using 1% and 3% Pluronic F127 showed 2-fold and 5- fold increase in the drug dissolution compared to the pure drug aqueous dispersion. The optimum formulations CGF2 nanosuspension and CC1 solid dispersion were selected for the in vivo pharmacokinetic and pharmacodynamics studies to compare against the pure drug aqueous dispersion. In pharmacodynamic studies, both the nano-formulations depicted similar and significant improvement in the reduction of mean plasma glucose levelcompared to the unmodified drug. In pharmacokinetics, about 3-folds and 4.5-folds increase in bioavailability (than the pure drug) was demonstrated by the nanosuspension and solid dispersion, respectively. Histopathological analysis revealed minimal hepatotoxicity associated with the nanosuspension formulation. The results provide evidence for the prominent enhancement of the bioavailability of the BCS class IV drug, due to increase in the solubility and permeability.  This study could confirm the utilization of Tolbutamide nanoformulations to replace the conventional oral dosage form administration to achieve better clinical response