Heterogeneous polymer composite nanoparticles loaded in situ gel for controlled release intra-vaginal therapy of genital herpes

Herpes simplex virus causes serious and contagious genital infections in high percentage of female population world-wide. Acyclovir is a clinically successful antiviral molecule till date, in-spite of limitations as poor solubility, low half-life, reduced oral bioavailability and side effects at higher doses. In the present work, controlled release in situ gelling system loaded with polymeric nanoparticles of acyclovir containing a dose of drug equivalent to 105 mg/day has been developed. The formulation containing drug loaded polyvinyl pyrrolidone-Eudragit RSPO hybrid polymeric nanoparticles (Size similar to 99 +/- 3 nm, Zeta similar to+26.1 +/- 1.5 mV) in 15% Pluronic F-127 gel exhibited improved permeability through vaginal membrane (K-p = 2.20 +/- 0.19 x 10(-6) cm/s). The nanoparticles showed enhanced viability for vaginal epithelial cell lines up to concentration of 100-250 mu g/mL. The formulation was evaluated for bioavailability and biodistribution through intra-vaginal administration in rat models. The nanoparticle in situ gel formulation maintained an average therapeutic drug level of 0.6 +/- 0.2 mu g/mL in plasma for 24 h. Significant improvement in mean residence time of the drug (12.52 +/- 1.12 h) was observed with a two-fold increase in the relative bioavailability (AUC(0-24h) =14.92 +/- 2.44 mu gh/mL) compared to that of the pure drug (7.18 +/- 1.79 mu gh/mL). The tissue distribution was 2-3 folds higher in animals treated with nanoparticles in situ gel compared to that of pure drug. Sustained release of drug in vivo was demonstrated, ensuring the suitability of the formulation for clinical therapy in female population. (C) 2016 Elsevier B.V. All rights reserved.