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02626 PREFORMULATION EVALUATION OF UC-781, A POTENTIAL ANTI-HIV TOPICAL MICROBICIDE CANDIDATE Rohan, Lisa C. UC781 is a tight binding non-nucleoside reverse transcriptase inhibitor (NNRTI) exhibiting excellent activity against HIV. Due to its ability to bind tightly to target enzymes and efficiency at inactivating HIV at the virion level, it is now being considered for use in a vaginal microbicide formulation to prevent HIV infection. Present work reports the preformulation studies conducted on UC781. Stability of UC781 was evaluated using stress stability studies in which the compound was exposed to accelerated conditions of temperature, humidity, light, oxidation, and hydrolysis. UC781 was prone to oxidation and to some extent photolysis and hence needs to be protected from light and oxygen during formulation development. Given the hydrophobic nature of this compound, solubility of UC781 was determined for a number of solubilizing agents. Acute tissue toxicity was evaluated for UC781/solvent combinations. Enhancement of UC781 solubility was achieved and permeability studies conducted in human cervical tissues. Permeability of UC781 through human cervical tissue was examined using three different solvent combinations (Transcutol, Cremophor+PEG+PBS, and Cremophor +PBS) in the Franz cell system. No significant diffusion of UC781 to the receptor compartment was observed with the assay used. Although no UC781 was detected in the receptor compartment after 8 hours, mass balance calculations suggested that UC781 might be absorbed into the tissue. An HPLC assay with greater sensitivity is currently being developed to quantify UC781 at lower concentrations. Once this assay is validated permeability studies will be repeated. Dr. Lisa Cencia Rohan, Ph. D. |
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