Hyaluronate-incorporated edaravone nanostructured lipid carriers for nose-to-brain targeting- biphasic DoE optimization, pharmacokinetic, and brain distribution studies.

The present research aimed to develop nasal delivery for edaravone (EDR), a BCS class-IV neuroprotective agent. EDR nanostructured lipid carriers (EDR NLCs) were developed by melt-emulsification probe sonication using Geleol™ (solid lipid), Miglyol®812N and coconut oil (liquid lipid), Tween 20 (surfactant), Lipoid S75 (emulsifier) and sodium hyaluronate (SH) as mucoadhesive agent. A biphasic optimization approach for NLCs was implemented using the Plackett-Burman design and Box-Behnken design to comprehensively understand key formulation and process variables affecting critical attributes of NLCs. The mucoadhesive strength of optimized EDR-SH NLCs was 2.22-fold higher than EDR NLCs. Drug release of NLCs was 2-fold higher than EDR. The partial amorphous nature of EDR in the NLC matrix was evident from DSC and XRD results. A pharmacokinetic study in rats revealed that EDR-SH NLCs exhibited 4.42-fold, 1.27-fold and 8.75-fold enhanced AUC than EDR, EDR NLCs and marketed formulation. In brain distribution, drug targeting efficiency and direct transport percentage of EDR-SH NLCs were 2.4-fold, 1.17-fold higher than EDR, indicating efficient brain targeting via direct pathways. Thus, nasal delivery of EDR-SH NLCs improves brain targeting and provides a self-administration alternative for long-term use to mitigate neurological disorders.