Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 642, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2023.123145
Keywords
Perampanel; Intranasal; Brain biodistribution; Anticonvulsant; Anxiolytic
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The intranasal administration of Perampanel (PER) through the olfactory pathway showed improved brain distribution and demonstrated anticonvulsant and anxiolytic effects in mice, indicating a potential alternative to oral treatment for epilepsy and anxiety. However, it also caused some neuromotor impairment, which was improved with repeated administrations. The study supports the design of clinical trials to evaluate the efficacy of intranasal PER delivery in treating neurological-related conditions.
Perampanel (PER) is a potent third-generation antiepileptic drug only available for oral administration. Additionally, PER has shown potential in managing epilepsy comorbidities such as anxiety. Previously, we demonstrated that the intranasal (IN) administration of PER, loaded in a self-microemulsifying drug delivery system (SMEDDS), improved brain-targeting and exposure in mice. Herein, we investigated PER brain biodistribution, its anticonvulsant and anxiolytic effects, and its potential olfactory and neuromotor toxicity after IN administration to mice (1 mg/kg). PER showed a rostral-caudal brain biodistribution pattern when administered intranasally. At short times post-nasal dosing, high PER concentrations were found in olfactory bulbs (olfactory bulbs/plasma ratios of 1.266 & PLUSMN; 0.183 and 0.181 & PLUSMN; 0.027 after IN and intravenous administrations, respectively), suggesting that a fraction of the drug directly reaches brain through the olfactory pathway. In the maximal electroshock seizure test, IN PER protected 60% of mice against seizure development, a substantially higher value than the 20% protected after receiving oral PER. PER also demonstrated anxiolytic effects in open field and elevated plus maze tests. Buried food-seeking test showed no signs of olfactory toxicity. Neuromotor impairment was found in rotarod and open field tests at the times of PER maximum concentrations after IN and oral administrations. Nevertheless, neuromotor performance was improved after repeated administrations. Compared with IN vehicle, PER IN administration decreased brain levels of L-glutamate (0.91 & PLUSMN; 0.13 mg/mL vs 0.64 & PLUSMN; 0.12 mg/mL) and nitric oxide (100 & PLUSMN; 15.62% vs 56.62 & PLUSMN; 4.95%), without interfering in GABA levels. Altogether, these results suggest that the IN PER delivery through the developed SMEDDS can be a safe and promising alternative to the oral treatment, which supports the design of clinical studies to evaluate the IN PER delivery to treat epilepsy and neurological-related conditions as anxiety.
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