Curcumin delivery across excised sheep nasal mucosa from temperature sensitive gel formulations containing bioenhancers

Abstract

Curcumin has been researched extensively for its medicinal properties such as the treatment of Alzheimer’s disease, depression, and other central nervous system (CNS) conditions. Curcumin, however, exhibits extremely poor oral bioavailability due to its hydrophobic nature, low aqueous solubility, instability in the neutral and alkaline intestinal pH range and rapid hepatic metabolism. These challenges that are associated with the oral delivery of curcumin prompts for the investigation into alternative routes of delivery. The nose-to-brain delivery route has gained a considerable amount of popularity as an alternative route for the delivery of drugs with neuro-stimulatory/modulatory effects, such as curcumin. Nose-to-brain delivery poses a unique set of challenges related to the effective delivery of drugs such as mucocilliary clearance, which mediates quick removal of the applied drug from the site of administration (i.e. the nasal epithelium) that ultimately impairs nasal drug delivery. To overcome this, a thermosensitive, mucoadhesive hydrogel was formulated in this study. Such a dosage form would ensure prolonged contact time between the curcumin molecules and nasal epithelial surface area and will likely lead to more efficient absorption. The solubility issues of curcumin were addressed by means of complexation with cyclodextrin. Cyclodextrin encapsulates curcumin in a hydrophobic zone with a hydrophilic outside, which increases the aqueous solubility of curcumin. Additionally, bioenhancers were incorporated into the hydrogel to potentially increase the nasal permeability of curcumin via the modulatory effects of the bioenhancers on active transporters or tight junctions. Ex vivo evaluations of the gel formulation containing curcumin and the formulated curcumin cyclodextrin complex with bioenhancers were performed across sheep olfactory mucosa mounted between the half-cells of a Sweetana-Grass diffusion apparatus. The curcumin-HPßCD complex and, surprisingly, curcumin showed good stability under accelerated storage conditions after addition to the selected thermosensitive hydrogel formulation (HP20). The observed apparent permeability and percentage transport of curcumin during ex vivo permeability studies across sheep nasal mucosa from the formulated hydrogels was very low. This is possibly because of hydrophilic interactions between the palisade layer of Pluronic® F127 micelles and the hydrophilic outer shell of cyclodextrin or due to the sustained release properties previously seen with hydrogels with high viscosity which also contain high concentrations of Pluronic® F127. The hydrogel formulations containing bioenhancers showed increased permeability, but it was however not statistically significant.