Nanocrystal-loaded dissolving microneedles: A novel transdermal strategy for long-acting tizanidine administration

Spasticity is commonly managed with tizanidine (TZN), a centrally acting α2-adrenergic agonist. However, its clinical application is limited by poor oral bioavailability and a short elimination half-life, necessitating frequent dosing and thereby reducing patient adherence. In this study, a trilayer dissolving microneedle array patch (MAP) incorporating TZN was developed as an alternative minimally invasive platform for long-acting transdermal delivery. TZN nanocrystals (NCs) with a mean particle size of 243 ± 21 nm and a polydispersity index (PDI) < 0.2 were successfully prepared, resulting in supersaturated solubility and an increased dissolution rate. Ex vivo permeation studies demonstrated that MAP-mediated skin penetration is essential for transdermal delivery and that NC-loaded formulations provide markedly enhanced delivery efficiency. Importantly, the in vivo pharmacokinetic evaluation in Sprague-Dawley® rats demonstrated that MAPs incorporated with NCs (Cmax = 229.23 ± 72.34 ng/mL, mean retention time (MRT) (52.46 ± 13.72 h)) achieved markedly improved systemic exposure (7682.36 ± 1784.77 ng/mL∗h) compared with coarse drug-loaded MAPs (AUC0–28 days = 4936.06 ± 882.51 ng/mL∗h, p < 0.05) and intramuscular (IM) injection (AUC0–28 days = 795.99 ± 146.94 ng/mL∗h, p < 0.05). These findings suggest that the integration of TZN NCs into dissolving MAPs represents a novel and effective transdermal strategy for the sustained systemic delivery of TZN. In addition to improving patient adherence and therapeutic outcomes in spasticity management, this platform offers a generalisable approach for enhancing the transdermal delivery of poorly soluble drugs and may inform the future design of long-acting delivery for other compounds.