The central hypothesis of the application is that specific inhibitors of HIV-i fusion with target cells, whenused in combination and when properly formulated and used appropriately, could prevent the vaginal orrectal transmission of HIV-i. In Research Project II, we will focus on the critical issue of microbicideformulation and delivery. We are conscious of recent experience from large-scale trials indicating thatcompliance is a very significant issue in microbicide research and development today. Specifically, thereare now serious concerns whether a microbicide intended for use immediately prior to sexual intercourseis a truly practical proposition; poor compliance in clinical trials may easily translate to the limited usageshould any product make it to licensure. Therefore, the aim of Research Project II is to develop longlasting,coitally-independent delivery methods for entry inhibitor-based microbicides, in the form ofsustained release semi-solid formulations that are applied once daily, and controlled release vaginal ringsthat can provide a continuous and constant supply of the active compound(s) in situ for a period ofweeks/months after application of a single device. These two very different formulation strategies aredeliberately being pursued within this project on account of the widely accepted consensus that a numberof microbicide products will be required to meet the differing social and cultural preferences of women.There are four specific objectives within Project II: i) To develop controlled-release matrix and reservoirtypevaginal ring devices containing each of the small molecule entry inhibitors CMPD 167, BMS-C andAMD3465. 2) To develop novel controlled release vaginal rings ('rod-insert' rings) containing the peptideentry inhibitor T-124Q. 3) To develop controlled release vaginal rings containing combination entryinhibitors. 4) To develop sustained-release semi-solid formulations of the small molecule entry inhibitorsCMPD 167, BMS-C, AMD34&5 and T-1249, both alone and in combination, for once-daily application.The Project Leader will be R. Karl Malcolm, Ph.D., with Mark Mitchnick, Ph.D. and A. David Woolfson,Ph.D. acting as co-investigators. The vaginal ring formulation component of the Project will be conductedat the School of Pharmacy, Queen's University Belfast, UK, while the semi-solid formulation componentwill be conducted at Particle Sciences Inc. PA, US. Both groups have considerable expertise in theirrespective formulation tasks.
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