Properties of Sustained-Release Single-Dose Formulations for Vulvovaginal Candidiasis

Abstract

Vaginally applied imidazoles are the first-line treatment of vulvovaginal candidiasis (VVC). The need to develop a less messy and more patient acceptable treatment regimen led to the development of a treatment schedule from the original 3 weeks to 7 days and, then, to 3 days. Finally, it was attempted to design a single-dose treatment regimen. Currently in the US, three single-dose vaginal preparations are available: 2% butoconazole sustained release (SR) [100mg butoconazole; Gynazole-1®], 6.5% tioconazole (300mg tioconazole; Vagistat-1®), and 2% miconazole vaginal ovule (Monistat1®, combination pack providing an ovule of 1200mg of miconazole and 2% monistat cream for external use). Clotrimazole 500mg single-dose vaginal tablet was used earlier and has been withdrawn from the market. In clinical studies, treatment success is measured by the regression of signs and symptoms of VVC (clinical cure) and by the negative mycological cultures (microbiological cure). 2% butoconazole SR has been formulated in an emulsion that adheres to wet surfaces of vaginal mucosa infected with Candida albicans. After the single dose, butoconazole is gradually released from the emulsion in a sustained release fashion for 3–6 days and acts on the fungus. The results of treatment with 2% butoconazole SR were equivalent to a 7-day schedule with 2% miconazole. Adverse effects have been infrequent and usually mild. 2% butoconazole in the SR bioadhesive formulation is drug-sparing compared with treatment regimens providing a total of 300–700mg of imidazoles in 3–7 days. The second single-dose preparation, 6.5% tioconazole, for VVC provides tioconazole 300mg in a vaginal ointment. This compound has been compared with 2% miconazole in a separate and independent set of clinical trials; 2% miconazole was superior to 6.5% tioconazole in the microbiological cure rates at the first follow-up examination. The success of a single-dose antifungal treatment also depends upon the vehicle used to deliver the active drug to the target tissue. In case of 2% butoconazole SR the vehicle is formulated as a hydrophilic emulsion that adheres to the surface of the moist vaginal mucosa for 3–6 days. Representative of the orally active preparations is a single dose of fluconazole 150mg. The efficacy results of oral fluconazole are similar to the 7-day vaginal antifungal preparations; however, there is the possibility of the development of resistance and systemic adverse effects affecting the liver and kidneys. The sustained-release technology used for single dose of 2% butoconazole is an innovative approach to vaginal drug delivery.