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Intranasal fosphenytoin: the promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs

2020Journal article Open access
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dc.contributor.authorSantos, Adriana O.
dc.contributor.authorPires, Patrícia C.
dc.contributor.authorRodrigues, Márcio
dc.contributor.authorAlves, Gilberto
dc.contributor.authorSantos, Liliana T.
dc.date.accessioned2020-11-04T12:23:32Z
dc.date.available2020-11-04T12:23:32Z
dc.date.issued2020
dc.description.abstractIntranasal 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.sponsorshipEuropean 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.versioninfo:eu-repo/semantics/acceptedVersionpt_PT
dc.identifier.citationPires, 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-20-01688R1pt_PT
dc.identifier.doihttps://doi.org/10.1016/j.ijpharm.2020.120040pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.6/10489
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationHealth Sciences Research Centre
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectAlbuminpt_PT
dc.subjectBrain deliverypt_PT
dc.subjectEpilepsypt_PT
dc.subjectFosphenytoinpt_PT
dc.subjectIntranasalpt_PT
dc.subjectPharmacokineticspt_PT
dc.titleIntranasal fosphenytoin: the promise of phosphate esters in nose-to-brain delivery of poorly soluble drugspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleHealth Sciences Research Centre
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00709%2F2020/PT
oaire.citation.titleInternational Journal of Pharmaceuticspt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameOliveira dos Santos
person.familyNamePires
person.familyNameRodrigues
person.familyNameAlves
person.givenNameAdriana
person.givenNamePatrícia
person.givenNameMárcio José de Abreu Marques
person.givenNameGilberto
person.identifierL-8542-2014
person.identifier.ciencia-id891C-417A-1534
person.identifier.ciencia-idDF1D-73CF-6BA4
person.identifier.ciencia-id6A1B-B7C8-D70F
person.identifier.orcid0000-0002-1224-9191
person.identifier.orcid0000-0003-0036-4894
person.identifier.orcid0000-0002-7010-0619
person.identifier.orcid0000-0002-4213-0714
person.identifier.ridH-4597-2011
person.identifier.scopus-author-id14049212000
person.identifier.scopus-author-id55513387900
person.identifier.scopus-author-id55663631700
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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