Enhanced vaginal drug delivery through the use of hypotonic formulations that induce fluid uptake

Abstract

Mucosal epithelia use osmotic gradients for fluid absorption and secretion. We hypothesized that administration of hypotonic solutions would induce fluid uptake that could be advantageous for rapidly delivering drugs through mucus to the vaginal epithelium. We found that hypotonic formulations markedly increased the rate at which small molecule drugs and muco-inert nanoparticles (mucus-penetrating particles, or MPP), but not conventional mucoadhesive nanparticles (CP), reached the vaginal epithelial surface in vivo in mice. Additionally, hypotonic formulations greatly enhanced drug and MPP delivery to the entire epithelial surface, including deep into the vaginal folds (rugae) that drugs or MPP in isotonic formulations failed to reach efficiently. However, hypotonic formulations caused unencapsulated “free” drugs to be drawn through the epithelium, reducing vaginal retention. In contrast, hypotonic formulations caused MPP to accumulate rapidly and uniformly on vaginal surfaces, ideally positioned for localized sustained drug delivery. Using a mouse model of vaginal genital herpes (HSV-2) infection, we found that hypotonic delivery of free drug led to improved immediate protection, but diminished longer-term protection. In contrast, as we previously demonstrated, hypotonic delivery of drug via MPP led to better long-term retention and protection in the vagina. Importantly, we demonstrate that slightly hypotonic formulations provided rapid and uniform delivery of MPP to the entire vaginal surface, thus enabling formulations with minimal risk of epithelial toxicity. Hypotonic formulations for vaginal drug delivery via MPP may significantly improve prevention and treatment of reproductive tract diseases and disorders.

A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02)

“…Animal studies using fluorescent labeling and histologic imaging enable a more direct assessment of mucosal coverage. 34 These studies indicate optimal mucosal coverage with isoosmolar and slightly hypotonic products. Finally, none of these methods addresses diffusion of drug or HIV into the mucosal tissue over time.…”

Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse

“…Nanoparticle size was characterized using dynamic light scattering (90° scattering angle), and ζ-potential was determined via laser Doppler anemometry with a Zetasizer Nano ZS90 (Malvern Instruments, Southborough, MA) (Table S1). We have previously found that a near-neutral ζ-potential for these particles indicates that the surface is sufficiently coated with PEG to rapidly penetrate human cervicovaginal mucus (Table S1) [22]. All measurements were performed at 25°C and according to instrument settings.…”

Polymer-based nanocarriers for vaginal drug delivery

“…In particular, the administration of mucus-penetrating NPs in a hypotonic vehicle (water) was able to enhance mucus transport. This effect was presumably related with improved particle trafficking towards the mucosa as driven by osmotic pressure [79]. Data obtained in vivo by other groups further materialized the potential of densely PEG-modified nanocarriers in improving vaginal distribution [81][82].…”

“…In this last case, differences in mucus samples and PEGylation protocols may justify contradictory data. The potential value of densely PEG-modified NPs in improving vaginal distribution of nanocarriers or nanosized drugs, including at collapsed mucosal folds, has been further demonstrated by Hanes and collaborators in both ex vivo [77] and animal in vivo [78][79][80] experiments. In particular, the administration of mucus-penetrating NPs in a hypotonic vehicle (water) was able to enhance mucus transport.…”