Submicron Matrices Embedded in a Polymeric Caplet for Extended Intravaginal Delivery of Zidovudine.

Abstract

In this study, an intravaginal delivery system able to deliver an anti-HIV-1 agent for the purpose of potentially reducing HIV-1 transmission acting over an extended duration was successfully formulated. This delivery system was a composite polymeric caplet comprising zidovudine-loaded polyethylene glycol enclatherated pectin-mucin submicron matrices embedded within a poly (D,L-lactide), magnesium stearate, Kollidon® SR, and Carbopol® 974P NF-based polymeric caplet matrix. A three-factor and three-level Box-Behnken statistical design was utilized to optimize the polymeric caplet. The optimized directly compressed composite polymeric caplet hardness was 22.1±0.3N and the matrix resilience was 62.4±0.6%. The swelling- and diffusion-controlled fractional zidovudine (AZT) release from the optimized caplet was 0.74±0.01 in simulated vaginal fluid (SVF), which increased to 0.81±0.21 in phosphate-buffered saline (PBS) simulating seminal fluid, over 30days. Caplet matrix swelling was directly related to the percentage Carbopol 974P NF composition. An intravaginal system for AZT delivery was tested in the pig model over 28days. X-ray analysis depicted delivery system swelling with matrix contrast fading over time as vaginal fluid permeated the matrix core. Plasma, vaginal fluid swab eluates, and tissue AZT concentrations were measured by gradient ultra-performance liquid chromatography (UPLC)-tandem photodiode array detection. Vaginal tissue and vaginal fluid swab eluate AZT concentrations remained above effective levels over 28days and were higher than plasma AZT concentrations, availing a system with reduced systemic toxicity and more effective inhibition of viral replication at the site of entry.