| Description |
Over three decades have passed since the discovery of human immunodeficiency virus (HIV), and with no viable vaccine, new technologies to prevent the spread of the virus are urgently needed. Pre-exposure prophylaxis, the concept of chemically interrupting HIV transmission, effectively reduced HIV incidence in a number of clinical trials. However, it has been difficult to achieve high and consistent effectiveness in clinical trials due to variable adherence to the dosing regimens requiring frequent administration. This, along with the disproportionate burden of the HIV/AIDS pandemic in young women in sub- Saharan Africa, has catalyzed the research into long-acting, antiretroviral eluting drug delivery systems like intravaginal rings (IVR) in an attempt to increase adherence over dosage forms that require frequent administration, and provide a more consistent drug concentration where transmission occurs. However, IVR technology is generally limited to releasing small quantities of hydrophobic, low molecular weight species that can diffuse through the IVR elastomer. This dissertation describes two adaptable drug delivery platforms that increased the diversity of the drugs that can be delivered from IVRs. Polyether urethane reservoir IVRs were engineered for the delivery of the thermally and hydrolytically unstable prodrug tenofovir disoproxil fumarate. This drug presents a unique design challenge to minimize the hydrolytic drug degradation in the IVR core while also promoting hydration to solubilize and release the drug. This design delivered mg/day quantities of drug and conferred complete protection in macaques from multiple vaginal viral exposures. Next, we engineered a system that uncouples the mechanism of drug release from the interaction of the drug with the elastomer and provides nearly constant release of any stable molecule. In this system, orifices control the hydration rate of the hydrophilic matrix contained within the core of the IVR, and release of the drug-containing gel. We evaluated the utility of this system for the topical delivery of macromolecules, and multiple different small molecule antiretrovirals, specifically for the delivery of drug microparticles. This work describes the design and evaluation of antiretroviral eluting IVR systems that provide adaptable platforms for vaginal drug delivery. |
