RESUMEN
Vaginal rings are currently being developed for the long-term (at least 30 days) continuous delivery of microbicides against human immunodeficiency virus (HIV). Research to date has mostly focused on devices containing a single antiretroviral compound, exemplified by the 25mg dapivirine ring currently being evaluated in a Phase III clinical study. However, there is a strong clinical rationale for combining antiretrovirals with different mechanisms of action in a bid to increase breadth of protection and limit the emergence of resistant strains. Here we report the development of a combination antiretroviral silicone elastomer matrix-type vaginal ring for simultaneous controlled release of dapivirine, a non-nucleoside reverse transcriptase inhibitor, and maraviroc, a CCR5-targeted HIV-1 entry inhibitor. Vaginal rings loaded with 25mg dapivirine and various quantities of maraviroc (50-400mg) were manufactured and in vitro release assessed. The 25mg dapivirine and 100mg maraviroc formulation was selected for further study. A 24-month pharmaceutical stability evaluation was conducted, indicating good product stability in terms of in vitro release, content assay, mechanical properties and related substances. This combination ring product has now progressed to Phase I clinical testing.
Asunto(s)
Antagonistas de los Receptores CCR5/química , Dispositivos Anticonceptivos Femeninos , Ciclohexanos/química , Sistemas de Liberación de Medicamentos , Pirimidinas/química , Inhibidores de la Transcriptasa Inversa/química , Elastómeros de Silicona/química , Triazoles/química , Antagonistas de los Receptores CCR5/administración & dosificación , Antagonistas de los Receptores CCR5/análisis , Rastreo Diferencial de Calorimetría , Ciclohexanos/administración & dosificación , Ciclohexanos/análisis , Preparaciones de Acción Retardada/análisis , Preparaciones de Acción Retardada/química , Combinación de Medicamentos , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Infecciones por VIH/prevención & control , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Calor/efectos adversos , Maraviroc , Fenómenos Mecánicos , Pirimidinas/administración & dosificación , Pirimidinas/análisis , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/análisis , Solubilidad , Triazoles/administración & dosificación , Triazoles/análisisRESUMEN
Vaginal ring devices capable of providing sustained/controlled release of incorporated actives are already marketed for steroidal contraception and estrogen replacement therapy. In recent years, there has been considerable interest in developing similar ring devices for the administration of microbicidal compounds to prevent vaginal HIV transmission. Intended to be worn continuously, such coitally independent microbicide rings are being developed to maintain effective vaginal microbicide concentrations over many weeks or months, thereby overcoming issues around timing of product application, user compliance and acceptability associated with more conventional semi-solid formulations. In this article, an overview of vaginal ring technologies is presented, followed by a review of recent advances and issues pertaining to their application for the delivery of HIV microbicides. This article forms part of a special supplement on presentations covering intravaginal rings, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.