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

[Display omitted] ⿢Reduction of daily dose of acyclovir (10 fold) required for the therapeutic activity.⿢Hybrid polymer blend nanoparticles of drug loaded in situ gel for controlled release of drug.⿢Vaginal epithelial cell viability and permeability study ensuring suitability for vaginal application.⿢First data reported on pharmacokinetic study of acyclovir through intra vaginal route of administration. 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 105mg/day has been developed. The formulation containing drug loaded polyvinyl pyrrolidone⿿Eudragit RSPO hybrid polymeric nanoparticles (Size ⿼99±3nm, Zeta ⿼+26.1±1.5mV) in 15% Pluronic F-127 gel exhibited improved permeability through vaginal membrane (KP=2.20±0.19ÿ10⿿6cm/s). The nanoparticles showed enhanced viability for vaginal epithelial cell lines up to concentration of 100⿿250μg/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±0.2μg/mL in plasma for 24h. Significant improvement in mean residence time of the drug (12.52±1.12h) was observed with a two-fold increase in the relative bioavailability (AUC0⿿24h=14.92±2.44μgh/mL) compared to that of the pure drug (7.18±1.79μgh/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.