Development of a polymeric micellar formulation for valspodar and assessment of its pharmacokinetics in rat

The aim of this study was to assess the potential of polymeric micelles to solubilize valspodar and modify its pharmacokinetics following intravenous and oral administration in rat. Drug-loaded methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) micellar solutions were prepared and administered either intravenously or orally to healthy Sprague-Dawley rats. Plasma pharmacokinetic parameters of valspodar in its polymeric micellar formulation were compared to its clinical formulation, which uses Cremophor EL and ethanol as solubilizing agents. High loading level was achieved for valspodar in PEO-b-PCL leading to an aqueous solubility of 2.8 mg/mL. Following i.v. administration (5 mg/kg), valspodar in the PEO-b-PCL micelles provided significantly higher (approximately 77%) plasma AUC compared to the Cremophor EL formulation. The PEO-b-PCL micelles also significantly decreased the volume of distribution (Vd(ss)) and clearance (CL) of valspodar by nearly 49% and 34%, respectively. After oral administration (10 mg/kg), the average C(max) were similar for both formulations and were both reached at approximately 2 h. The plasma unbound fraction of valspodar in the polymeric micellar formulation was significantly lower than control (8.27% versus 14.85%). Our results show that PEO-b-PCL micelles can efficiently solubilize valspodar and favorably modify its pharmacokinetic profile in rat after i.v. administration by decreasing the CL and Vd.