The willingness of a woman to use a microbicide product has been linked to reduction of dosing frequency and product convenience and appeal. Vaginal films have been identified to possess a number of attributes which women find desireable. Combining the discreet and compact nature of this platform with other advantages such as preceived ease of use, reduced leakage, enhanced drug release, and decreased disturbance of innate immune barriers, films offer a dosage form which may lead to enhanced patient acceptability and product efficacy. The feasability of on-demand delivery of pharmacetucial agents to the vagina in a safe and acceptable manner using a film has been illustrated in two separate clinical trials evaluating a dapivirine film and a tenofovir film. Human studies of the dapivirine film showed that the vaginal delivery profile was consistent with gel and ring dosage forms. Further, drug tissue levels for film matched those achieved with intravaginal ring use which were shown to be associated with protection in an ex vivo challenge assay. Although the feasiblity of utility of this platform for on-demand applications has been demonstrated, its ability to be modified for use as an extended release product has yet to be explored. The Project 1 goal is to design a non-coitally dependent vaginal film for the integrase inhibitor MK-2048 that achieves cervicovaginal tissue drug levels that are effective against the sexual acquisition of HIV for one week following a single application. In preliminary studies in the nonhuman primate model, a prototype MK-2048 film was shown to have the ability to retain significant levels of MK-2048 in the target tissue up to 96 hours post film administration following two separate acts of coitus. Within Project 1, three strategies will be explored to develop a weekly administered MK-2048 film. The primary strategy involves modification of film geometry and excipient composition to extend the release of MK-2048. Within this strategy iterative evaluation of product retention and release in the NHP model (Core B) will be used to optimize the delivery profile and achievment of protective levels of MK-2048 in the vagina (Project 2, Core C). The ability to maintain protective levels even in the context of sex will also be confirmed in this model. The developed film will be scaled up (Project 4) and evaluated in human clincial trials (Project 3). Additionally within Project 1 alternative nanotechnology based strategies for extending the window of protection with the film will be explored. Our group has previously used nanoparticles combined with the film platform to overcome vaginal drug delivery challenges. Nanoparticles containing MK-2048 will be developed and incorporated into the film platform to provide enhanced tissue retention and targeting. Finally, a highly novel and innovative approach to increase film retention will be developed.This strategy is based on the combination of micro/nanopatterns with the film platform to achieve enhanced vaginal product retention. Successful design of an MK-2048 film which provides an extended window of protection would offer a convenient option for protection against HIV infection in women.
PROJECT 1 NARRATIVE Providing acceptable options to women to protect themselves from acquiring HIV through sexual transmission will be a critical component to addressing this high priority global health issue. The design of a non-coitally dependent vaginal film which provides protection for one week would offer women a discreet, non-messy, low cost option for protection.