Formulation Development of Retrocyclin 1 Analog RC-101 as an Anti-HIV Vaginal Microbicide Product

Abstract

ABSTRACTRC-101 is a synthetic microbicide analog of retrocyclin, which has shownin vitroactivity against X4 and R5 HIV-1. In an effort to develop a safe and effective RC-101 vaginal microbicide product, we assessed safety inex vivomacaque and human models and efficacy usingin vitroandex vivomodels. A polyvinyl-alcohol vaginal film containing RC-101 (100 μg/film) was developed. Formulation assessment was conducted by evaluating disintegration, drug content, mechanical properties, and stability. Efficacy was evaluated byin vitroperipheral blood mononuclear cells (PBMC) assay andex vivohuman ectocervical tissue explant model.Ex vivosafety studies were conducted by exposing RC-101 to an excised monkey reproductive tract and excised human ectocervical tissue. RC-101 100 μg films were shown to be safe to human and monkey tissue and effective against HIV-1in vitroandex vivoin human ectocervical tissue. The 90% inhibitory concentration (IC90) for RC-101 films at 2,000 μg (IC90= 57.5 μM) using anex vivomodel was 10-fold higher than the IC90observed using anin vitromodel (IC90= 5.0 μM). RC-101 films were stable for 1 month at 25°C, within vitrobioactivity maintained for up to 6 months. RC-101 was developed in a quick-dissolve film formulation that was shown to be safe in anex vivomodel and effective inin vitroandex vivomodels. RC-101 film formulations were shown to maintain bioactivity for a period of 6 months. Findings from the present study contribute to the development of a safe and effective topical microbicide product.