Publication
Intranasal fosphenytoin: the promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs
dc.contributor.author | Santos, Adriana O. | |
dc.contributor.author | Pires, Patrícia C. | |
dc.contributor.author | Rodrigues, Márcio | |
dc.contributor.author | Alves, Gilberto | |
dc.contributor.author | Santos, Liliana T. | |
dc.date.accessioned | 2020-11-04T12:23:32Z | |
dc.date.available | 2020-11-04T12:23:32Z | |
dc.date.issued | 2020 | |
dc.description.abstract | Intranasal administration could increase both safety and efficacy of drugs acting on the central nervous system, but low solubility severely limits administration through this route. Phenytoin’s prodrug, fosphenytoin, is hydrophilic and freely soluble in water, but less permeable since it is dianionic. We aimed to assess whether this phosphoester prodrug could be a suitable alternative to phenytoin in intranasal delivery. Secondly, we aimed to compare simple formulation strategies in fosphenytoin delivery. Fosphenytoin formulations containing thermosensitive and/or mucoadhesive (hydroxypropyl methylcellulose, HPMC) polymers were developed, guided by viscosity, gelling temperatures, osmolality, and in vitro drug release tests. Then, a pharmacokinetic study was performed, comparing an intravenous fosphenytoin solution, an intranasal fosphenytoin solution, and intranasal fosphenytoin mucoadhesive formulations with or without albumin. Formulations containing HPMC allowed high drug strengths, and had a relatively fast release profile, which was not changed by albumin. Intranasal administration of a formulation with HPMC and albumin prolonged drug concentration over time and led to complete or even increased absolute bioavailability. Moreover, phenytoin’s blood levels did not reach the high peak obtained with intravenous administration. In conclusion, the use of phosphate ester prodrugs could be an efficient and safe strategy to increase the intranasal bioavailability of poorly soluble drugs. | pt_PT |
dc.description.sponsorship | European Regional Development funds through the Operational Programme “Centro 2020”, through the ICON project (Interdisciplinary Challenges On Neurodegeneration, reference CENTRO-01-0145-FEDER-000013). | pt_PT |
dc.description.version | info:eu-repo/semantics/acceptedVersion | pt_PT |
dc.identifier.citation | Pires, P. C., Santos, L., Rodrigues, M., Alves, G., & Santos, A. O. Intranasal fosphenytoin: the promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs. International Journal of Pharmaceutics. Accepted for publication 2020/10/29. Ref. No.: IJP-D-20-01688R1 | pt_PT |
dc.identifier.doi | https://doi.org/10.1016/j.ijpharm.2020.120040 | pt_PT |
dc.identifier.uri | http://hdl.handle.net/10400.6/10489 | |
dc.language.iso | eng | pt_PT |
dc.peerreviewed | yes | pt_PT |
dc.publisher | Elsevier | pt_PT |
dc.relation | Health Sciences Research Centre | |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | pt_PT |
dc.subject | Albumin | pt_PT |
dc.subject | Brain delivery | pt_PT |
dc.subject | Epilepsy | pt_PT |
dc.subject | Fosphenytoin | pt_PT |
dc.subject | Intranasal | pt_PT |
dc.subject | Pharmacokinetics | pt_PT |
dc.title | Intranasal fosphenytoin: the promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs | pt_PT |
dc.type | journal article | |
dspace.entity.type | Publication | |
oaire.awardTitle | Health Sciences Research Centre | |
oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00709%2F2020/PT | |
oaire.citation.title | International Journal of Pharmaceutics | pt_PT |
oaire.fundingStream | 6817 - DCRRNI ID | |
person.familyName | Oliveira dos Santos | |
person.familyName | Pires | |
person.familyName | Rodrigues | |
person.familyName | Alves | |
person.givenName | Adriana | |
person.givenName | Patrícia | |
person.givenName | Márcio José de Abreu Marques | |
person.givenName | Gilberto | |
person.identifier | L-8542-2014 | |
person.identifier.ciencia-id | 891C-417A-1534 | |
person.identifier.ciencia-id | DF1D-73CF-6BA4 | |
person.identifier.ciencia-id | 6A1B-B7C8-D70F | |
person.identifier.orcid | 0000-0002-1224-9191 | |
person.identifier.orcid | 0000-0003-0036-4894 | |
person.identifier.orcid | 0000-0002-7010-0619 | |
person.identifier.orcid | 0000-0002-4213-0714 | |
person.identifier.rid | H-4597-2011 | |
person.identifier.scopus-author-id | 14049212000 | |
person.identifier.scopus-author-id | 55513387900 | |
person.identifier.scopus-author-id | 55663631700 | |
project.funder.identifier | http://doi.org/10.13039/501100001871 | |
project.funder.name | Fundação para a Ciência e a Tecnologia | |
rcaap.rights | openAccess | pt_PT |
rcaap.type | article | pt_PT |
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