Evaluation of microporous polycaprolactone matrices for controlled delivery of antiviral microbicides to the female genital tract

Abstract

Acyclovir (ACV) as a model antiviral microbicide, was incorporated in controlled-release polycaprolactone (PCL) matrices designed for application as intra-vaginal ring inserts (IVRs). Microporous materials incorporating acyclovir up to a level of ~10 % w/w were produced by rapidly cooling suspensions of drug powder in PCL solution followed by solvent extraction from the hardened matrices. Around 21, 50 and 78 % of the drug content was gradually released from matrices over 30 days in simulated vaginal fluid at 37 °C, corresponding to drug loadings of 5.9, 7.0 and 9.6 % w/w. The release behaviour of matrices having the lowest drug loading followed a zero order model, whereas, the release kinetics of 7.0 and 9.6 % ACV-loaded PCL matrices could be described effectively by the Higuchi model, suggesting that Fickian diffusion is controlling drug release. Corresponding values of the diffusion co-efficient for ACV in the PCL matrices of 3.16 × 10(-9) and 1.07 × 10(-8) cm(2)/s were calculated. Plaque reduction assays provided an IC50 value of 1.09 μg/mL for acyclovir against HSV-2 and confirmed the antiviral activity of released acyclovir against HSV-2 replication in primate kidney cells (Vero) at levels ~70 % that of non-formulated acyclovir at day 30. Estimated minimum in vivo acyclovir concentrations produced by a PCL IVR (19 μg/mL) exceeded by a factor of 20 the IC50 value against HSV-2 and the reported ACV vaginal concentrations in women (0.5-1.0 μg/mL) following oral administration. These findings recommend further investigations of PCL matrices for vaginal delivery of antiviral agents in the treatment and prevention of sexually transmitted infections such as AIDS.