| Description |
Female-controlled preventative technologies are being developed to decrease HIV sexual transmission rates in resource poor regions of the world where the pandemic is most prevalent. Intravaginal rings (IVRs) comprise extended duration vaginal drug delivery vehicles which may provide sustained release of antiretrovirals at local inhibitory concentrations to prevent initial HIV infection during coitus. Few IVR formulations have been researched for HIV prophylaxis although numerous antiretrovirals are excellent candidates. Poor progress is due in part to limitations of conventional IVR technology in delivering antiretrovirals with diverse physiochemical properties and dosing requirements. Furthermore, there is limited understanding of drug vaginal pharmacokinetics and potential toxicological effects on the local environment. Consequently, in this dissertation several candidate antiretrovirals were formulated in new IVR platforms and animal models were developed to characterize the IVR formulations in vivo. In the first part of the dissertation, polyurethane IVRs were designed that delivered the potent and dual-acting pyrimidinedione congeners for up to one month. The pyrimidinediones attained concentrations throughout the nonhuman primate vaginal tract that were expected to be inhibitory against HIV, with no observed detrimental effects to the vaginal environment. In the second part of the dissertation, an IVR was developed to simultaneously deliver dapivirine and tenofovir which possess contrasting hydrophilicity and differing mechanisms of action against HIV. A two segment ring design was utilized which independently optimized tenofovir and dapivirine release by using compositionally different polyurethanes. In the final two parts of the dissertation, a hydrophilic polyurethane reservoir IVR was engineered and tested in a new sheep model, whereby tenofovir vaginal concentrations from the IVR were similar to the clinically effective tenofovir vaginal gel but for 90 day duration. The tunable IVR platform allowed for achievement of desired drug release rates and ring mechanical stiffness which were time-independent. No major toxicological effects were observed in sheep, and extensive IVR in vitro characterization was performed to ensure that a chemically and physically stabilized product was achieved. The work reported herein describes the design and characterization of antiretroviral-eluting intravaginal rings which each hold promise as preventative technologies to prevent the sexual transmission of HIV. |
