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UC-781 is highly selective and potent against HIV-1. However, its hydrophobic nature (log P 5.1) and lack of aqueous solubility have limited its development as a HIV microbicide. Self-microemulsifying drug delivery systems (SMEDDSs) have been developed to enhance the water solubility and bioavailability of hydrophobic drugs, such as UC781. In this study, we show the development of UC781-loaded SMEDDS and their enhanced release of UC781 from hard gelatine capsules, when compared to UC781 powder only. The majority of antiretrovirals being evaluated as potential HIV microbicides are hydrophobic. Therefore, a SMEDDS formulation offers an alternative approach to enhancing the vaginal absorption of these microbicidal candidates.