Synergistic enhancement of anti-migraine efficacy through supramolecular self-assembly of tizanidine with meloxicam

Migraine, a debilitating medical condition that affects a significant portion of the population, presents a complex challenge in therapeutic management. Drug–drug cocrystallization based on supramolecular self-assembly offers a promising strategy, as it not only improves the physicochemical properties of active pharmaceutical ingredients, but also unlocks their synergistic clinical potential. In this study, supramolecular self-assemblies of tizanidine and meloxicam were designed through crystal engineering to explore their combined clinical value in anti-migraine therapy. The resulting multicomponent crystal, tizanidine-meloxicam, was thoroughly characterized by crystallography, spectroscopy, and thermal analysis. It forms a stable charge-assisted hydrogen bond supramolecular network, exhibiting ∼60 % improved solubility over tizanidine and ∼ 10-fold enhancement over meloxicam. In a rat migraine model, it achieved 100 % complete remission, with sustained analgesia 1.3 times greater than the physical mixture (P < 0.05). Furthermore, solution chemistry results indicate that the enhanced therapeutic performance of tizanidine-meloxicam salt can be attributed to its sustained release rate, higher equilibrium solubility, distinct molecular conformation, and stronger interactions between the two compounds. Additionally, tizanidine-meloxicam salt could form uniform and stable molecular clusters in aqueous solution, which could further enhance its efficacy and stability. This study demonstrates that pharmaceutical multicomponent crystals is a significant strategy for the development of novel formulations with improved efficacy.