Computer-aided design and optimization of estradiol valerate nanoemulsion-loaded core-shell microneedle patches for controlled release transdermal drug delivery

Abstract

Estradiol valerate (E2V) is a hormone utilized for estrogen replacement therapy. Nonetheless, its application in pharmaceutical formulations has been limited due to its poor solubility in water and suboptimal efficacy for transdermal drug delivery. Hence, the combination of nanoemulsions (NEs) with core-shell dissolving microneedles (CS-dMNs), which encase the drug, represents a promising approach to enhance transdermal drug delivery while ensuring controlled release. This study aimed to develop E2V-NE-loaded CS-dMNs for achieving controlled transdermal release of E2V. The E2V-NEs were formulated and evaluated for parameters including droplet size, polydispersity index (PDI), and zeta potential. Subsequently, these E2V-NEs were integrated into the core of CS-dMNs. The physical and mechanical properties of E2V-NE-loaded CS-dMNs were evaluated, along with parameters such as detachment time, drug content, in vitro and in vivo skin permeation, and safety. The results indicated that E2V-NE-loaded CS-dMNs exhibited favorable physical and mechanical characteristics, enabling easy self-administration with patch detachment after 30 min, while ensuring controlled drug release from the core of dMNs. The E2V content in CS-dMNs was determined to be 0.76 ± 0.15 mg/patch. Furthermore, in vitro and in vivo skin permeation studies demonstrated a synergistic effect between NEs and MNs, achieving therapeutic drug levels sustained over a week (368.54 ± 67.93 μg/mL in in vitro and 697.45 ± 270.10 pg/mL in in vivo), with no indications of infection and complete skin healing observed within 8 h. Consequently, E2V-NE-loaded CS-dMNs present a promising alternative for achieving sustained and controlled hormone levels conveniently.