Inclusion complex of carbamazepine and hydroxypropyl-β-cyclodextrin enhances nose-to-brain delivery via improved solubility.

Intranasal delivery offers a non-invasive route for transporting drugs to the brain by bypassing the blood-brain barrier. However, the limited fluid volume in the nasal cavity restricts the solubilization of poorly water-soluble drugs such as carbamazepine (CBZ). In this study, we developed an inclusion complex of CBZ with hydroxypropyl-β-cyclodextrin (HP-βCD) to enhance its solubility and facilitate nose-to-brain delivery. Phase solubility analysis and Job's plot confirmed the formation of a 1:1 complex. Powder formulations were prepared via freeze-drying and spray freeze-drying. The powders completely dissolved within 5 min and maintained their amorphous state during long-term storage. Intranasal administration of the CBZ/HP-βCD complex powders in rats resulted in significantly improved brain uptake compared with that of the CBZ bulk drug or physical mixtures. Notably, the brain-to-plasma ratio was higher for powder formulations than for liquids, suggesting enhanced direct transport to the brain. Regional brain distribution analysis revealed predominant accumulation in the olfactory bulb, likely because of its anatomical proximity and neural connections with the nasal cavity. Although this pattern is commonly observed during nose-to-brain delivery, it may limit drug access to deeper brain regions. Therefore, further optimization　using targeted strategies or delivery enhancers is required. Overall, HP-βCD inclusion complexation represents a promising approach to improve solubility, stability, and brain delivery efficiency of poorly soluble CNS-active drugs following intranasal administration.