For the first time in over three decades, the year 2019 saw the approval of two new classes of
antidepressants: Spravato™
esketamine intranasal spray for
treatment-resistant depression, and Zulresso®
brexanolone infusion against
post-partum depression. Although both
therapies were granted "breakthrough" designations, topical application of both drugs could offer several advantages over their current routes of administration. However, delivery of their high therapeutic doses (0.5 mg/kg
ketamine in 1 h; 90 µg/kg/h
brexanolone over 52 h) is unachievable by conventional means. We evaluated physical enhancement techniques such as iontophoresis, microneedle-treatment, and ablative
laser for the rapid delivery of
ketamine. Additionally, the sustained delivery of
brexanolone across microporated skin employing chemical enhancers and novel microemulsions was also accomplished. The target therapeutic flux of
ketamine after skin pre-treatment with
laser (534.51 ± 146.93 µg/cm2), and the application of anodal iontophoresis (681.93 ± 74.35 µg/cm2) on ablated skin, was observed within one hour. Microporation of skin using
laser was more effective than microneedles, for the delivery of
ketamine as well as
brexanolone. The developed microemulsions resulted in significantly higher transdermal delivery across
laser-treated skin. Although
brexanolone demonstrated higher solubility in the w/o microemulsion (21.31 ± 0.14 mg/mL) than the o/w microemulsion (10.69 ± 0.09 mg/mL), percutaneous absorption from the o/w microemulsion (6.04 ± 0.16%) was significantly higher than the w/o microemulsion (1.92 ± 0.02%).