Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration

Abstract

Purpose Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson's disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations. Methods In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. Results Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection. Conclusions This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.

Recent advances in human respiratory epithelium models for drug discovery

“…Calu-3 cells were recently used as a reference cell line for in vitro toxicity studies of intranasal delivery of zonisamide for central nervous system diseases, and were effectively used to inform subsequent in vivo testing (Gonçalves et al, 2020). This cancerous cell line has been heavily utilised to investigate the biological mechanisms (Hoffmann et al, 2020;Kong et al, 2020;Zecha et al, 2020) and efficacy of novel compounds (Felgenhauer et al, 2020;C.…”

Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation

“…This same method can be used in conscious, awake rodents by restraining the rodent via a scruff restraint, but also requires acclimation to the handling [15]. Another modified form of delivery in anesthetized rodents that is readily used is to insert a pipette tip or tubing shallowly into the nasal cavity [16][17][18]. The substrate is then delivered to the cribriform plate to allow for greater direct delivery to the CNS, limiting the amount absorbed by the turbinates or swallowed and absorbed by the gastrointestinal tract.…”

Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation

“…Indeed, IN administration has revealed to increase drug concentrations at the brain by surpassing the BBB and decreasing the influence of the P-gp–mediated efflux ( Gonçalves et al, 2021 ). Moreover, peripheral systemic exposure and adverse effects decrease, along with the development of drug–drug interactions ( Fortuna et al, 2014 ; Gonçalves et al, 2019 ; Gonçalves et al, 2020 ).…”