Characterisation, in-vitro and in-vivo evaluation of valproic acid-loaded nanoemulsion for improved brain bioavailability Suk Fei Tan a , Brian P. Kirby b , Johnson Stanslas c and Hamidon Bin Basri a a Neuroscience Cluster, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor, Malaysia, b School of Pharmacy, Royal College of Surgeons in Ireland, Dublin 2, Ireland and c Pharmacotherapeutic Unit, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor, Malaysia Keywords blood–brain barrier; in-vitro model; parenteral nanoemulsion; pharmacokinetics; valproic acid Correspondence Hamidon Bin Basri, Neuroscience Cluster, Department of Medicine, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 Serdang, Selangor, Malaysia. E-mail: hamidon@upm.edu.my Received March 14, 2017 Accepted July 17, 2017 doi: 10.1111/jphp.12800 Abstract Objective This study was aimed to investigate the potential of formulated val- proic acid-encapsulated nanoemulsion (VANE) to improve the brain bioavail- ability of valproic acid (VPA). Methods Valproic acid-encapsulated nanoemulsions were formulated and physi- cally characterised (osmolarity, viscosity, drug content, drug encapsulation effi- ciency). Further investigations were also conducted to estimate the drug release, cytotoxic profile, in-vitro blood–brain barrier (BBB) permeability, pharmacoki- netic parameter and the concentration of VPA and VANE in blood and brain. Key findings Physical characterisation confirmed that VANE was suitable for parenteral administration. Formulating VPA into nanoemulsion significantly reduced the cytotoxicity of VPA. In-vitro drug permeation suggested that VANEs crossed the BBB as freely as VPA. Pharmacokinetic parameters of VANE-treated rats in plasma and brain showed F3 VANE had a remarkable improvement in AUC, prolongation of half-life and reduction in clearance compared to VPA. Given the same extent of in-vitro BBB permeation of VPA and VANE, the higher bioavailability of VANE in brain was believed to have due to higher concentra- tion of VANE in blood. The brain bioavailability of VPA was improved by pro- longing the half-life of VPA by encapsulating it within the nanoemulsion-T80. Conclusions Nanoemulsion containing VPA has alleviated the cytotoxic effect of VPA and improved the plasma and brain bioavailability for parenteral delivery of VPA. Introduction Valproic acid (VPA) is a simple branched monocarboxylic acid molecule. It has a broad spectrum of efficacy being widely used as a treatment in all types of seizures and is especially effective in the treatment of idiopathic gener- alised seizures. [1] VPA is also known to be carried into the brain via organic anion transporter located at the blood– brain barrier (BBB) layer. [2] However, the bioavailability of VPA in the brain is low. In spite of its wide spectrum of activity, it has many potentially serious side effects and is problematic when administered intravenously. Hepatotoxi- city is a rare but well-documented side effect of valproic acid. One proposed reason is that drug becomes trapped in reticuloendothelial system (RES) producing metabolites such as 4-ene-VPA, which has possible involvement in idiosyncratic hepatotoxicity incidence. [3] A rat study reported the beta oxidation of 4-ene-VPA to reactive inter- mediate such as 2-propy-2, 4-pentadienoic acid (2, 4-diene VPA) had utilised large amount of mitochondrial glu- tathione. [4] Glutathione is important to reduce the oxida- tive modification which eventually reduced cell death. [5] Conclusively, greater uptake of VPA by RES means higher incidence of side effect and less drug available for therapeu- tic effects. On the other hand, while the brain uptake of VPA is efficient, it is limited by the low bioavailability in blood. [2] Hence, an improvement in drug delivery in the brain needs can be addressed by improving the bioavailabil- ity of VPA in the blood without elevating the treatment dose. Factors that affect the plasma exposure of drug/ © 2017 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 69 (2017), pp. 1447–1457 1447 Research Paper Downloaded from https://academic.oup.com/jpp/article/69/11/1447/6127872 by guest on 26 August 2022