ABSTRACT RC-101 is a synthetic microbicide analog of retrocyclin, which has shown in vitro activity against X4 and R5 HIV-1. In an effort to develop a safe and effective RC-101 vaginal microbicide product, we assessed safety in ex vivo macaque and human models and efficacy using in vitro and ex vivo models. 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 by in vitro peripheral blood mononuclear cells (PBMC) assay and ex vivo human ectocervical tissue explant model. Ex vivo safety 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-1 in vitro and ex vivo in human ectocervical tissue. The 90% inhibitory concentration (IC90) for RC-101 films at 2,000 μg (IC90 = 57.5 μM) using an ex vivo model was 10-fold higher than the IC90 observed using an in vitro model (IC90 = 5.0 μM). RC-101 films were stable for 1 month at 25°C, with in vitro bioactivity maintained for up to 6 months. RC-101 was developed in a quick-dissolve film formulation that was shown to be safe in an ex vivo model and effective in in vitro and ex vivo models. 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.

The increased incidence of human immunodeficiency virus infection in women has identified an urgent need to develop a female-controlled method to prevent acquisition of human immunodeficiency virus and other sexually transmitted diseases. Women would apply the product intravaginally before intercourse. Development of such a product requires a better understanding of the permeability characteristics of the tissues with which such products would come into contact. However, limited studies have been performed in this area. In the present study, water permeability of fresh human cervical and vaginal tissue was evaluated. The average apparent permeability coefficient was found to be 8×10−5cm/s for fresh human cervical tissue and 7×10−5cm/s for fresh human vaginal tissue. Considering the lack of regularity in obtaining cervical and vaginal tissue from surgical specimens, additional tests were performed to evaluate the effect of freezing on tritiated water permeability. No statistically significant differences were observed in the permeability values obtained when comparing fresh versus frozen tissues.