The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue.
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.
1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Magee-Womens Research Institute , Pittsburgh, Pennsylvania.
Minlu
M
Hu
1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Magee-Womens Research Institute , Pittsburgh, Pennsylvania.
Tian
T
Zhou
2 Magee-Womens Research Institute , Pittsburgh, Pennsylvania.|3 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania.
Charlene S
CS
Dezzutti
1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Magee-Womens Research Institute , Pittsburgh, Pennsylvania.|3 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania.
Lisa C
LC
Rohan
D000282:Administration, Intravaginal; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002584:Cervix Uteri / Q000187:drug effects*; D017097:Electric Impedance; D004848:Epithelium / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D005079:Excipients / Q000008:administration & dosage*; D005260:Female; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D009924:Organ Culture Techniques; D010539:Permeability / Q000187:drug effects; D000068698:Tenofovir / Q000494:pharmacology; D014621:Vagina / Q000187:drug effects*
D019380:Anti-HIV Agents; D005079:Excipients; D000068698:Tenofovir
TEER; cervicovaginal epithelium; excipients; integrity; permeability; tenofovir