The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue

Abstract

Pharmaceutical excipients are widely used in vaginal drug products. The epithelial integrity of the cervicovaginal tissue is important for HIV-1 prevention. However, the effects of excipients on cervicovaginal epithelium remain unknown. This study aims at assessing the effects of vaginal product excipients on the integrity of human cervicovaginal epithelium and on a lead HIV prevention antiretroviral drug, tenofovir (TFV). In the current study, nine excipients commonly used in vaginal formulations were incubated for 6 h with excised human ectocervical tissue. The effects of the excipients were examined by measuring the transepithelial electrical resistance (TEER), epithelial morphology, paracellular/transcellular permeability, and cell viability. The efficacy of TFV for preventing HIV-1 infection in the ex vivo cultured ectocervix was also tested. We found that disodium ethyl-enediaminetetraacetate (EDTA), sorbic acid, and benzoic acid had no effect on the tissue TEER. Butylated hydroxyanisole, glycerin, propylene glycol, methylparaben, and propylparaben slightly to moderately decreased tissue TEER, whereas citric acid significantly decreased the TEER in a time-dependent manner. Tissue morphology observed post-exposure strongly correlated with TEER data; however, a less strong correlation was observed between paracellular permeability and TEER data after exposure to different excipients. In addition, treatment with EDTA, methylparaben, and propylene glycol at tested levels had no effect on the efficacy of TFV in preventing tissue HIV-1 infection. In conclusion, the combined measurements of TEER, morphology, permeability, and viability using human cervicovaginal tissue represent a clinically relevant platform for safety evaluation of excipients and formulated products for HIV-1 prevention.

Impact of vaginal douching products on vaginal Lactobacillus, Escherichia coli and epithelial immune responses

“…Lubricant products have also been shown to impact epithelial barrier integrity, and reduce adherence of lactobacilli to vaginal epithelial cells 37 – 39 . The douching products we tested also include other compounds, which may contribute to the effects seen; citric acid (included in the iodine-based douche) has been associated with epithelial toxicity, as has benzoic acid (included in both iodine- and vinegar-based douches) to a lesser extent 40 .…”

Relating Advanced Electrospun Fiber Architectures to the Temporal Release of Active Agents to Meet the Needs of Next-Generation Intravaginal Delivery Applications

“…Tissue mimetics and ex vivo tissues have been used to assess these parameters within the context of intravaginal delivery applications [116,186,187,188,189,190,191]. One of the most common ways in which to assess intravaginal delivery is by using human ectocervical tissue explants derived from patients [187,188,189,190,191]. These explants provide a representative environment in which to measure transport by accounting for the three-dimensional structure of patient tissue.…”

The Pre-clinical Toolbox of Pharmacokinetics and Pharmacodynamics: in vitro and ex vivo Models

“…Primary epithelial cells can also be isolated (Greenhead et al, 2000) and cultured in trans-well systems as described above for epithelial cell lines, to assess safety, concentration and activity of candidate inhibitor after ex vivo dosing (Shen et al, 2018, 2019) and safety of excipients used for mucosal dosing (Hu et al, 2016). These cells can be purchased or isolated from primary tissue which involves access to surgical specimens.…”