Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel

Detalhes bibliográficos
Autor(a) principal: Meirinho, Sara
Data de Publicação: 2023
Outros Autores: Rodrigues, Márcio, Ferreira, Catarina, Caetano Oliveira, Rui, Fortuna, Ana, Santos, Adriana, Falcão, Amílcar, Alves, Gilberto
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10314/6260
Resumo: Perampanel (PER), a new-generation antiepileptic drug effective against different types of seizures, has already demonstrated a potential in status epilepticus therapy. Considering the growing interest of intranasal (IN) administration for nose-to-brain delivery, PER could be envisioned as a good candidate for this route, especially if formulated in a lipid-based nanosystem. With that purpose, a hydrophobic formulation (FO1.2) and a self-microemulsifying drug delivery system (SMEDDS) (FH5) loaded with PER were developed and characterized. Following PER IN administration (1 mg/kg) to mice, its pharmacokinetics was characterized and compared with intravenous and oral routes. Histopathological toxicity was also examined after a 7-day repeated dose study. FH5 homogeneously formed nanodroplets upon dispersion (20.07 ± 0.03 nm), showing a sustained in vitro PER release profile up to 4 h. By IN route, PER brain delivery was more extensive with FH5 (Cmax and AUC of 52.32 ng/g and 190.35 ng.h/g for FO1.2; 93.87 ng/g and 257.75 ng.h/g for FH5). Maximum brain concentration and total brain exposure were higher than those obtained after oral dosage, with maximum PER concentrations reached significantly faster than post-oral administration (15 min vs 2 h). An improvement in PER plasmatic concentration was also obtained, demonstrated by high relative bioavailability values (134.1% for FH5 and 107.8% for FO1.2). PER absolute plasma bioavailability after IN delivery was 55.5% for FH5 and 44.6% for FO1.2, ensuring a somewhat improved targeting of PER to the brain by the IN route compared to the IV route. No signs of toxicity were found by histopathologic evaluation. Results suggest that IN administration of PER might be a feasible and safe approach for acute and chronic epilepsy management, especially using delivery systems as SMEDDS.
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spelling Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanelBrain deliveryEpilepsyIntranasal administrationLipid-based nanosystemsPerampanelPharmacokineticsPerampanel (PER), a new-generation antiepileptic drug effective against different types of seizures, has already demonstrated a potential in status epilepticus therapy. Considering the growing interest of intranasal (IN) administration for nose-to-brain delivery, PER could be envisioned as a good candidate for this route, especially if formulated in a lipid-based nanosystem. With that purpose, a hydrophobic formulation (FO1.2) and a self-microemulsifying drug delivery system (SMEDDS) (FH5) loaded with PER were developed and characterized. Following PER IN administration (1 mg/kg) to mice, its pharmacokinetics was characterized and compared with intravenous and oral routes. Histopathological toxicity was also examined after a 7-day repeated dose study. FH5 homogeneously formed nanodroplets upon dispersion (20.07 ± 0.03 nm), showing a sustained in vitro PER release profile up to 4 h. By IN route, PER brain delivery was more extensive with FH5 (Cmax and AUC of 52.32 ng/g and 190.35 ng.h/g for FO1.2; 93.87 ng/g and 257.75 ng.h/g for FH5). Maximum brain concentration and total brain exposure were higher than those obtained after oral dosage, with maximum PER concentrations reached significantly faster than post-oral administration (15 min vs 2 h). An improvement in PER plasmatic concentration was also obtained, demonstrated by high relative bioavailability values (134.1% for FH5 and 107.8% for FO1.2). PER absolute plasma bioavailability after IN delivery was 55.5% for FH5 and 44.6% for FO1.2, ensuring a somewhat improved targeting of PER to the brain by the IN route compared to the IV route. No signs of toxicity were found by histopathologic evaluation. Results suggest that IN administration of PER might be a feasible and safe approach for acute and chronic epilepsy management, especially using delivery systems as SMEDDS.2023-01-05T14:28:48Z2023-01-05T14:28:48Z2023-01-05info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10314/6260http://hdl.handle.net/10314/6260eng0378-5173Meirinho, SaraRodrigues, MárcioFerreira, CatarinaCaetano Oliveira, RuiFortuna, AnaSantos, AdrianaFalcão, AmílcarAlves, Gilbertoinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-01-14T02:59:54Zoai:bdigital.ipg.pt:10314/6260Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T01:44:11.966194Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
title Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
spellingShingle Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
Meirinho, Sara
Brain delivery
Epilepsy
Intranasal administration
Lipid-based nanosystems
Perampanel
Pharmacokinetics
title_short Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
title_full Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
title_fullStr Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
title_full_unstemmed Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
title_sort Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel
author Meirinho, Sara
author_facet Meirinho, Sara
Rodrigues, Márcio
Ferreira, Catarina
Caetano Oliveira, Rui
Fortuna, Ana
Santos, Adriana
Falcão, Amílcar
Alves, Gilberto
author_role author
author2 Rodrigues, Márcio
Ferreira, Catarina
Caetano Oliveira, Rui
Fortuna, Ana
Santos, Adriana
Falcão, Amílcar
Alves, Gilberto
author2_role author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Meirinho, Sara
Rodrigues, Márcio
Ferreira, Catarina
Caetano Oliveira, Rui
Fortuna, Ana
Santos, Adriana
Falcão, Amílcar
Alves, Gilberto
dc.subject.por.fl_str_mv Brain delivery
Epilepsy
Intranasal administration
Lipid-based nanosystems
Perampanel
Pharmacokinetics
topic Brain delivery
Epilepsy
Intranasal administration
Lipid-based nanosystems
Perampanel
Pharmacokinetics
description Perampanel (PER), a new-generation antiepileptic drug effective against different types of seizures, has already demonstrated a potential in status epilepticus therapy. Considering the growing interest of intranasal (IN) administration for nose-to-brain delivery, PER could be envisioned as a good candidate for this route, especially if formulated in a lipid-based nanosystem. With that purpose, a hydrophobic formulation (FO1.2) and a self-microemulsifying drug delivery system (SMEDDS) (FH5) loaded with PER were developed and characterized. Following PER IN administration (1 mg/kg) to mice, its pharmacokinetics was characterized and compared with intravenous and oral routes. Histopathological toxicity was also examined after a 7-day repeated dose study. FH5 homogeneously formed nanodroplets upon dispersion (20.07 ± 0.03 nm), showing a sustained in vitro PER release profile up to 4 h. By IN route, PER brain delivery was more extensive with FH5 (Cmax and AUC of 52.32 ng/g and 190.35 ng.h/g for FO1.2; 93.87 ng/g and 257.75 ng.h/g for FH5). Maximum brain concentration and total brain exposure were higher than those obtained after oral dosage, with maximum PER concentrations reached significantly faster than post-oral administration (15 min vs 2 h). An improvement in PER plasmatic concentration was also obtained, demonstrated by high relative bioavailability values (134.1% for FH5 and 107.8% for FO1.2). PER absolute plasma bioavailability after IN delivery was 55.5% for FH5 and 44.6% for FO1.2, ensuring a somewhat improved targeting of PER to the brain by the IN route compared to the IV route. No signs of toxicity were found by histopathologic evaluation. Results suggest that IN administration of PER might be a feasible and safe approach for acute and chronic epilepsy management, especially using delivery systems as SMEDDS.
publishDate 2023
dc.date.none.fl_str_mv 2023-01-05T14:28:48Z
2023-01-05T14:28:48Z
2023-01-05
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dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10314/6260
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dc.language.iso.fl_str_mv eng
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dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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