Zein-alpha lipoic acid-loaded nanoparticles to enhance the oral bioavailability of dapoxetine: optimization and clinical pharmacokinetic evaluation

Abstract

Background: Premature ejaculation (PE) is the most common type of male sexual disorder with important psychological consequences. Dapoxetine (DPX), a recently approved drug for the treatment of PE, suffers from low bioavailability with large variability that ranges from 15-76% (mean 42%) after oral administration. The objective of this study is to optimize the parameters for the preparation of DPX-Zein-alpha lipoic acid (ALA) nanoparticles (NPs) to improve the bioavailability of DPX and consequently decrease therapeutic dose and adverse effect, leading to patient satisfaction and compliance.

Methods: We investigated the effect of ALA concentration, PVA concentration and stirring rate on nanoparticle size (Y₁), zeta potential (Y₂), initial DPX release (Y₃) and cumulative DPX release (Y₄). In addition, in vivo pharmacokinetic study was performed for the optimized DPX formulation on human healthy volunteers compared with marketed DPX tablet.

Results: The optimized DPX-loaded NPs showed Y₁, Y₂, Y₃, and Y₄ of 159.24 nm, 19.14 mV, 25.31% and 95.9 %, respectively. A single oral dose of 30 mg of optimized DPX-loaded NPs to human volunteers resulted in 2-fold improvement of AUC (1376.145±339.592 vs 709.178±146.307 in DPX), 4-fold increase in t_max (2.5±0.314 vs 0.583±0.144), prolongation of MRT (7.637±1.373 compared to 6.031±1.826 h), but with reduction in t_1/2 (5.283±1.077 vs 8.452±2.813).

Conclusion: The clinical findings suggest 194% enhancement of relative bioavailability of the optimized DPX-loaded NPs, potentially leading to a decrease in therapeutic dose and associated side effects in the treatment of PE.

Keywords: bioavailability; clinical pharmacokinetics; dapoxetine; mathematical experimental design; nanoparticles; premature ejaculation.