Abstract
PurposeUse of coital-dependent products to prevent HIV-1 transmission has resulted in mixed success. We hypothesize that incorporation of antiviral drug candidates into a novel controlled delivery system will prolong their activity, making their use coital independent, thus increasing their chance of prophylactic success.MethodsTenofovir, emtricitabine, and C5A peptide HIV microbicides were mechanically incorporated into matrices comprising a series of subliming solids. Matrix sublimation rates and drug release rates were measured in three in vitro and one in vivo environments intended to model human vaginal interior. Antiviral activity studies evaluating matrix incorporated microbicides were performed using in vitro cell cultures and human ectocervical explants.ResultsDrug release rates were identical to matrix sublimation rates, and were zero order. Differences in matrix material sublimation enthalpies determined drug release and matrix erosion rates in a thermodynamically definable manner, in vitro and in vivo. Durations of release ranging from several days to several months were readily achieved. Prolonged duration of anti HIV-1 activity was shown for matrix incorporated microbicides, using ectocervical explant and cell culture models of HIV-1 infection.ConclusionSubliming solid matrices show promise as a delivery system providing multi month intravaginal release of a wide range of HIV-1 microbicides.
Highlights
Prevention of AIDS infection in healthy women during intercourse with HIV positive partners through use of condoms or topical applications of antiviral microbicide continues to meet with limited success for a number of personal and social reasons [1]
Such delivery systems usually fail to provide inhibitory concentrations for a sufficient period of time to avert transmission that may be a result of repeated sexual activity, and the viral shedding typical of acute HIV-1 infection, and require frequent and repeated microbicide application [2]
We evaluated release of tenofovir disoproxil fumarate (TDF) a charged but poorly soluble molecule [M.W.0287], emtricitabine (FTC) an uncharged but highly water soluble molecule [M.W.0247], in addition to the biotinylated version of a novel microbicide C5A a hydrophobic, low solubility, chemically reactive eighteen amino acid peptide [M.W. 0 2,537]
Summary
Prevention of AIDS infection in healthy women during intercourse with HIV positive partners through use of condoms or topical applications of antiviral microbicide continues to meet with limited success for a number of personal and social reasons [1]. The majority of HIV-1 microbicides delivery systems under current clinical evaluation employ coital-dependent quick release formulations administered in the form of aqueous-based gels applied shortly prior to and/ or after coitus. Such delivery systems usually fail to provide inhibitory concentrations for a sufficient period of time to avert transmission that may be a result of repeated sexual activity, and the viral shedding typical of acute HIV-1 infection, and require frequent and repeated microbicide application [2]. Windows of opportunity for untreated viral spread and progression of infection can occur, requiring a switch from prophylaxis to more problematic systemic therapy, using several of the same antiviral agents employed as HIV-1 microbicides These limitations can be resolved by employing coitally.
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