Pharmacokinetic Evaluation of Duloxetine Enteric Coated Pellets and Development of LC-MS/MS Method for Quantification of Duloxetine in Rat Plasma.

Abstract

The aim of this study was to develop and evaluate enteric coated pellets (ECP) to improve stability, solubility, dissolution and enhance oral systemic exposure of novel serotonin (5-HT) and nor-epinephrine (NE) reuptake inhibitor (SNRI), duloxetine. Along with this our study also aimed to develop a sensitive LC-MS/MS method for estimation of duloxetine in rat plasma. An attempt has been made to improve the stability and systemic exposure of duloxetine by formulating it in the form an extended release pellets and simultaneously the PK of enteric coated pellets (ECP) of duloxetine was performed in rats in parallel with suspension formulation. The optimized formulation showed approximately 2 hr lag time in drug release in both in-vitro and in-vivo system. The systemic exposure (AUC) and maximum concentration in plasma (Cmax) of enteric coated pellets (ECP) of duloxetine was significantly higher than conventional suspension formulation. A highly sensitive and rapid LC-MS/MS method has been developed and validated for the estimation of Duloxetine in rat plasma. The chromatographic separation was performed with 0.2% formic acid: acetonitrile at flow rate of 0.4 mL/min on Symmetry Shield RP-18 column with a total run time of 4.0 min. The MS/MS ion transitions monitored were 297.9        154.1 for duloxetine hydrochloride  and 515.1        276.2 for IS (telmisartan). Method validation and pre-clinical sample analysis were performed as per FDA guide lines and the results met the acceptance crieteria. The lower limit of quantification achieved was 0.1 ng/mL and the linearity was observed from 0.1 to 1500ng/mL. This novel method has been applied to pharmacokinetic study of duloxetine hydrochloride in rats. Finally it can be concluded that delayed release pellets in capsule approach can be used to improve the stability, dissolution and systemic exposure of pH senestive and poorly water-soluble drugs such as duloxetine.

KEY WORDS: solid oral dosage form, LC-MS/MS, duloxetine, enteric coated pellets