The overall goal of the Formulation Development Core (Core C) is to provide preformulation data, formulation development efforts, and formulation assessment evaluations in support of Projects 1, 2, and 3. In addition the Core will coordinate and oversee manufacture, release, and stability assessment of all GMP supplies to be used in the proposed clinical trials in Project 3. Finally Core C will develop prototype formulations with alternate combinations identified in Project 1 and biologically relevant methods for assessment of rectal microbicide product. Given the significant anatomical and physiological differences in the rectal and vaginal compartments it is essential to design rectal specific microbicide products to effectively inhibit rectal transmission of HIV. Formulation strategies within the scope of Core activities will focus on two hypothesis centered on gel like semisolid dosage forms or enema like liquid dosage forms. Quantitative assays have been developed in the laboratory for both UC781 and TFV. These assays will be used throughout the development process. Once prototype formulations have been developed they will be evaluated for toxicity and bioactivity in Project 1. This data will be used to choose the optimal products for advancement. The optimal products will be scaled up and R&D quality material manufactured for analysis in the mouse efficacy model in Project 2. The core will continually monitor product mechanical and chemical characteristics throughout the development process. Manufacture of GMP quality material will be achieved through a contract research lab with extensive experience with manufacture of GMP quality semisolid systems. The Core will be responsible for methods transfer, development and sign off of batch records generated, assist in protocol development for product assessment methods established for GMP product release, oversee GMP batch manufacture, and review stability results obtained. Three GMP batches will be manufactured (UC781 only, TFV only, and combination). Another important outcome from the core will be the development of biologically relevant product assessment evaluations for rectal products given the current lack of such methods. The core will directly support Projects 1, 2, and 3 of this grant proposal.
Due to anatomical and physiological differences in the vaginal and rectal compartments, vaginal products will most likely not be adequately effective for protection from rectal transmission of HIV. The Formulation Development Core (Core C) has a set of objectives focused on the development of rectal specific microbicide products for delivery of tenofovir (TFV), UC781, and a combination of these two active agents.
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