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 μg 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.