Design of self-assembling anti-epileptic drug for long-acting drug delivery in vivo

Valproic acid (VPA) has been extensively used for the treatment of seizures in epilepsy. The recommended VPA concentration in the blood is in the range of 50-100 mu g mL(-1) and its therapeutic efficiency is well recognized. Since its therapeutic range is relatively narrow, strict scheduling of daily self-medication is required to optimize therapeutic outcomes and avoid adverse effects. To facilitate patient convenience in long-term and chronic therapies, the development of a sustained drug delivery system for VPA is a promising strategy. In this study, an enzyme-metabolizable block copolymer possessing a valproate ester, poly(ethylene glycol)-b-poly(vinyl valproate), was synthesized. The synthesized block copolymers formed stable nanoparticles (denoted Nano(VPA)) by self-assembly under physiological conditions and released VPA via enzymatic hydrolysis. Nano(VPA) showed improved pharmacokinetics compared to sodium valproate in vivo, and therapeutic efficacy in a pentylenetetrazol (PTZ)-induced kindling mouse model after once-weekly administration.