Novel technologies for vaginal delivery of microbicides

There is a pressing need for microbicides-vaginally applied drug delivery systems that create a pharmacological barrier to HIV-to prevent the male-tofemale sexual transmission of HIV. Numerous antiretroviral agents with a wide range of mechanisms of inhibiting HIV are under development. Delivery systems are required that complement the antiviral agents through maximizing their safety, efficacy and user adherence within cost constraints such that they are affordable in resource poor nations with high HIV prevalence. To this end, three drug delivery systems were engineered for microbicide application in this thesis. The first delivery system was designed to promote uniform distribution and retention of the antivirals in the vaginal lumen, and provide semen triggered delivery into semen-the carrier of HIV in male-to-female sexual transmission. The delivery system consisted of a temperature and pH sensitive gel composed of a terpolymer of N-isopropylacrylamide, acrylic acid and butyl methacrylate. The neutralization of acidic pH in the vagina upon exposure to semen was used as the trigger to release the active agents from the terpolymer gel. The thermosensitive design employed was such that the delivery vehicle is applied as a liquid at room temperature to allow uniform coating, and gels postapplication to promote retention. In vitro characterizations under simulated physiological conditions confirmed that the designed system was liquid at room temperature, gels as the temperature is increased from room to body temperature, and provides burst release of active agents upon exposure to semen fluid simulant. The second and third systems were intravaginal rings (IVRs) for sustained delivery of dapivirine, a potent inhibitor of HIV replication after the virus has entered the host cells. A sustained delivery of replication inhibitors is pursued to allow enough time for antiviral drugs to diffuse into the vaginal epithelium and ensure that inhibitory concentrations are established before the viral attack. Monolithic IVRs were fabricated from biomedical grade polyurethanes and degradable polyurethanes synthesized with hydrolytically labile ester groups in the polymer backbone. The ability of the utilized polyurethane matrix to provide a zero-order delivery of dapivirine enabled a monolithic design that can be manufactured using a cost-effective melt extrusion procedure. The inexpensive IVR design loaded with a potent drug and with the high user adherence associated with IVRs offer a promising solution for an effective microbicide.