Those who desire to develop a safe and effective microbicide continue to look toward drug delivery toprovide solutions to patient compliance, drug stability and achieving effective pharmacokinetics of themultiple active agents over an acceptable duration. This proposal describes the development and testing oftwo new long acting vaginal drug delivery systems for the prevention of HIV in women: a thermoplasticintravaginal ring and new smart vaginal gels. We will evaluate three classes of compounds that inhibit HIV-11) dual reverse transcriptase/entry inhibitors (pyrimidinediones), 2) viral nucleocapid protein Zn fingerinhibitors (S-acyl-mercaptobenzamido thioesters) and 3) a potent V3 loop inhibitor (G-quartetphosphothiolate backbone oligonucleotide 5TTGGGGTT3').
In specific aim 1, these compounds will subjectto preformulation screening of solubility and stability alone and together. Lead members of each class will beselected based on stability and appropriateness of the compound for each drug delivery system.
In specificaim 2, selected leads will be formulated in dual intravaginal ring segments made by extrusion ofthermoplastic elements containing solubilized or dispersed antiviral agents. Release rate will be measuredas a function of loading and ring composition. We will also optimize the mechanical properties anddimensions of the intravaginal ring to match vaginal ring products currently on the market. Based on stabilityand antiviral activity and toxicity results we will select two compounds form the series above and coformulatethem in conjoined dual segment rings that co-deliver two antiviral agents simultaneously at concentrationscustomized to their pharmacokinetics and pharmacodynamics. Finally in specific aim 3, we will develop thefirst non-temperature sensitive smart microbicide gel out of FDA approved materials whose properties allowit to be applied at a relatively low viscosity and whose durability and duration in the vaginal lumen wouldincrease soon after application to provide a durable and 24 hour duration gel. Two different antiviral agentsfrom above will be formulated in these gels again based on stability, toxicity and antiviral activity collected inspecific aim 1. Project 1 and 2 will interact intensely in the optimization of the gels and in the development ofthe pharmacokinetic models that will guide the design of the drug delivery systems. Project 3 will providedesign criteria for the gels and rings from human acceptability studies.
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