Introduction: Migraine is a highly prevalent and disabling neurological disorder commonly managed through monotherapy, which often provides insufficient symptom relief due to its multifactorial pathophysiology. Combination therapy emerges as a promising alternative by targeting multiple mechanisms simultaneously. Nanostructured lipid carriers (NLC) offer additional advantages, namely improved drug stability and enhanced bioavailability. In this work, two NLC formulations were developed, encapsulating zolmitriptan and ibuprofen, respectively, with the aim of combining them for intranasal administration, enabling direct nose-to-brain delivery. This strategy is expected to enhance therapeutic efficacy while offering a non-invasive and patient-friendly approach for the management of acute migraine.

Methods: The Quality by Design (QbD) approach was applied to optimize the NLC formulations with respect to the Critical Quality Attributes (CQAs) of particle size (Z-Ave), polydispersity index (PDI), zeta potential (ZP) and encapsulation efficiency (EE).

Results: The optimized zolmitriptan- and ibuprofen-loaded NLC exhibited Z-Ave, PDI, ZP, and EE values of 62.373 ± 0.567 nm and 141.333 ± 2.301 nm; 0.209 ± 0.008 and 0.205 ± 0.004; −52.463 ± 0.264 mV and −14.323 ± 0.652 mV; and 74.231 ± 0.646 % and 84.376 ± 1.594 %, respectively. Both were subsequently combined into a final formulation, which displayed suitable physicochemical properties for intranasal delivery: Z-Ave of 188.850 ± 2.333 nm, PDI of 0.233 ± 0.007, ZP of −16.297 ± 0.488 mV, osmolarity of 280 mOsm/kg, and pH of 6.06.

Conclusion: The QbD approach proved to be a valuable tool for optimizing both NLC formulations, resulting in suitable characteristics for nose-to-brain delivery. Future studies are needed to assess the cytotoxicity of the combined NLC formulation in nasal and neuronal cell lines, in order to evaluate its biocompatibility and safety for intranasal migraine therapy.