Transdermal delivery of breakthrough therapeutics for the management of treatment-resistant and post-partum depression

For the first time in over three decades, the year 2019 saw the approval of two new classes of antidepressants: Spravato (TM) esketamine intranasal spray for treatment-resistant depression, and Zulresso (R) 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 mu g/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 mu g/cm(2)), and the application of anodal iontophoresis (681.93 +/- 74.35 mu g/cm(2)) on ablated skin, was observed within one hour. Microporation of skin using laser was more effective than micmneedles, 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%).