Development and bioavailability testing of an estetrol and estetrol-zinc-containing vaginal hydrogel: a novel...

Genitourinary syndrome of menopause (GSM) significantly impacts postmenopausal women, yet conventional treatments, such as vaginal estrogen creams, have limitations related to adherence and efficacy. This study aims to develop and evaluate a novel hydroxyethyl cellulose (HEC)-based bioadhesive vaginal hydrogel containing estetrol (E4) and estetrol-zinc, with hydroxypropyl-β-cyclodextrin (HPβCD) as an excipient, to enhance drug retention, bioavailability, and patient compliance.

The hydrogel formulations (E4/200 and E4/200/CN) were prepared and characterized for solubility, stability, and drug release. In vitro biocompatibility was assessed using HaCaT keratinocyte and reconstituted human vaginal epithelium models through methyl tetrazolinium (MTT) and lactate dehydrogenase (LDH) cytotoxicity assays. Permeability was evaluated using a reconstructed vaginal epithelial model. Statistical significance was determined using appropriate tests ( t test, ANOVA).

The phase-solubility study demonstrated a stable 1:1 complexation between E4 and HPβCD, improving drug solubility. The hydrogels exhibited excellent biocompatibility, without cytotoxic effects on vaginal epithelial cells ( P <0.0001). Permeability testing confirmed E4 retention within vaginal tissues, reducing systemic exposure. The hydrogel formulations ensured sustained and controlled drug release.

The estetrol-containing HEC-based and HPβCD-based vaginal hydrogel is nontoxic, and the estetrol is readily bioavailable. The formulation enhances estetrol bioavailability while ensuring localized, controlled release and optimizing therapeutic efficacy. Future clinical trials are required to confirm in vivo effectiveness and long-term safety.