Enhanced Trans-Corneal Permeability of Valacyclovir by Polymethacrylic Acid Copolymers Based Ocular Microspheres: In Vivo Evaluation of Estimated Pharmacokinetic/Pharmacodynamic Indices and Simulation of Aqueous Humor Drug Concentration-Time Profile

Abstract

Poor intraocular bioavailability of valacyclovir (VACV) in the treatment of ocular viral infections is considered to be a challenging issue. Based on the fact that the polymethacrylic acid copolymers enhance the trans-corneal permeability of the encapsulated drug, the valacyclovir Eudragit® microspheres (VEM) were investigated. The VEM prepared by nonaqueous emulsification solvent evaporation method was characterized by in vitro release study, release kinetics, X-ray diffraction (XRD), and the stability studies. The ocular irritancy, in vivo ocular pharmacokinetic parameters, pharmacokinetic/pharmacodynamic indices, simulation, and histopathology studies were performed in Wistar rats to ensure ocular tolerability and clinical effectiveness of the formulation. The in vitro drug release showed initial burst and followed Fickian (R square 0.9735, n value 0.1608) type of diffusion release mechanism. The XRD and stability studies showed favorable results. The Wistar rat eyes treated with VEM showed significant increase in ACV AUC (~2.55-fold) and Cmax (1.25-fold) in aqueous humor compared to VACV solution, and the delay in Tmax infers the sustained action of the VEM. The Cmax/MIC90, AUC0-24/MIC90, AUC above MIC90, and T above MIC90 were significantly higher in VEM group and thus indicates its clinical effectiveness. The aqueous humor concentration-time profile of ACV in VEM and VACV solution was simulated in every 5.2 and 2.5 h, respectively. The photomicrograph of VEM and VACV solution treated rat retina showed normal organization and cytoarchitecture. The Eudragit®-based microspheres interact with the negatively charged conjunctival mucosa and anionic mucin of the tear film and thereby enhance intraocular VACV bioavailability.