Dissolving Microneedles for Transdermal Delivery of Melatonin: Fabrication, Characterization, and In Vivo Pharmacokinetic Evaluation in Mice

Insomnia is a common physiological and psychological disorder characterized by difficulty falling or staying asleep, which negatively impacts daily functioning. Oral melatonin (MEL) is commonly used to treat insomnia and other sleep-related disorders. However, MEL has low bioavailability due to extensive first-pass metabolism and poor aqueous solubility, and its onset of action is slow. Dissolving microneedles (MNs) represent a promising minimally invasive approach to overcome these drawbacks by enhancing transdermal drug permeation and enabling systemic delivery while circumventing the gastrointestinal tract. In this study, different dissolving MN arrays composed of hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were fabricated using solvent casting and vacuum-assisted micromolding techniques. Among the tested formulations, 10% (w/v) HPMC and 10% (w/v) PVP-based formulation demonstrated favorable mechanical strength and insertion capability. MEL was successfully loaded into the MN shafts of the lead formulation with a drug loading of 1.83 ± 0.05 mg per MN patch. FTIR and DSC analyses confirmed the molecular dispersion of MEL within the polymeric matrix. In vitro release studies revealed rapid dissolution with approximately 87% of melatonin released within 60 min, whereas ex vivo tests on porcine skin showed complete microneedle dissolution within 3 min. In vivo pharmacokinetic studies in mice revealed rapid systemic absorption following MEL MN application and a prolonged elimination half-life. MEL also penetrated the central nervous system (CNS), reaching a C_max of 6.08 ± 3.65 ng/g and exhibiting a prolonged residence time in the brain. Taken together, MEL MNs hold promise as a viable transdermal delivery modality. However, further investigation is warranted to comprehensively evaluate their therapeutic efficacy.