Nose-to-brain delivery of levetiracetam after intranasal administration to mice

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

“…Although drug administration into the nose is often performed using a pipette or a polyethylene tube attached to a microsyringe/micropipette (41,42), herein we preferred to use the MicroSprayer ® Aerosolizer and to load zonisamide in an in situ-gelling hydrogel, the Pluronic F-127 vehicle. This choice was based on our recent studies that demonstrated that almost 50% of levetiracetam undergoes direct nose-tobrain delivery after its nasal administration (23,(41)(42)(43)(44)(45). Nonetheless, to increase in situ-gelling properties and m u c o a d h e s i o n , C a r b o p o l ® 9 7 4 P a n d N o v e o n ® Polycarbophil polymers were herein investigated and subjected to cellular viability tests to select the safest one for IN administration to mice.…”

“…Hence, the present research work aims at directly deliver zonisamide to the brain after intranasal administration, thereby reducing drug systemic exposure and ameliorating its safety profile. Non-invasive nose-tobrain drug transport via olfactory epithelium has revealed to be a promising strategy for chronically given central-acting drugs with potential increasing of patient compliance (22)(23)(24)(25)(26)(27). For instance, we have demonstrated that the antiepileptic drug, levetiracetam, loaded in a thermorreversible gel composed of Carbopol 974P, achieved higher concentrations in the brain 5 min after intranasal administration than after administration by classic systemic route (23).…”

“…Briefly, Pluronic f-127 (18% w/v) was dissolved in 10 mL of cold Milli-Q water and stored at 4°C overnight for complete hydration of the flakes. Subsequently, 0.02 g of Carbopol ® 974P or the same amount of Noveon ® Polycarbophil was added until complete dissolution as described in (23). The gel was selected according to the results obtained during in vitro tests (section "In Vitro Cell Viability Studies"), with Carbopol ® 974P being the polymer for which the results were more favorable.…”

“…Before quantitative analysis, both plasma (100 μL) and tissue supernatants (150 μL) were spiked with the internal standard (antipyrine, 50 μg/mL) and, then, subjected to protein precipitation with methanol and two liquid-liquid extractions with ethyl acetate in order to remove endogenous contaminants and extract zonisamide. More details of extraction and concentration procedures can be found in (23).…”

“…Non-invasive nose-tobrain drug transport via olfactory epithelium has revealed to be a promising strategy for chronically given central-acting drugs with potential increasing of patient compliance (22)(23)(24)(25)(26)(27). For instance, we have demonstrated that the antiepileptic drug, levetiracetam, loaded in a thermorreversible gel composed of Carbopol 974P, achieved higher concentrations in the brain 5 min after intranasal administration than after administration by classic systemic route (23). In theory, it has been postulated that drugs can be transported from the nasal cavity directly to cerebrospinal fluid (CSF) or brain parenchyma through two possible routes along the olfactory neurons: the olfactory nerve pathway (intracellular axonal transport) and the olfactory epithelial pathway (extracellular perineural transport).…”