Al-mahallawi A.M.Fares A.R.Abd-Elsalam W.H.Department of Pharmaceutics and Industrial PharmacyFaculty of PharmacyCairo UniversityKasr El-Ainy StreetCairo11562Egypt; Department of Pharmaceutics and Industrial PharmacyFaculty of PharmacyOctober University for Modern Science and Arts (MSA)GizaEgypt2020-01-092020-01-09201915309932https://doi.org/10.1208/s12249-019-1380-5PubMed ID 31004239https://t.ly/GgZEXScopusThe aim of this study was to incorporate methotrexate (MTX) into ultra-permeable niosomal vesicles, containing cremophor RH40 as an edge activator (EA) and polyvinyl alcohol (PVA) as a stabilizer to enhance the drug permeation. Formulae were prepared by ethanol injection method following a Box-Behnken design in order to optimize the formulation variables (EA%, stabilizer %, and sonication time). To investigate the role of both cremophor RH40 and PVA, conventional MTX niosomes and MTX niosomes containing PVA only were fabricated. Drug entrapment efficiency percent (EE%), particle size (PS) analysis, zeta potential (ZP) measurements, and transmission electron microscopy (TEM) were conducted to characterize the vesicles. Cell viability studies and ex vivo permeation experiments of the optimized formula were conducted. Lastly, in vivo skin deposition of MTX from both the optimized formula and MTX solution was performed in rats. Besides, histopathological changes in rat skin were assessed. The optimized MTX ultra-permeable niosomal formula demonstrated spherical morphology, with an EE% of 65.16% and a PS of 453.6�nm. The optimized formula showed better physical stability in comparison with that of the same composition but lacking PVA. The cell viability studies verified the superior cytotoxicity of the optimized formula, and the ex vivo permeation studies revealed its ability to improve the drug permeation. The optimized formula demonstrated a significant deposition of MTX in rat dorsal skin, and histopathological evaluation confirmed the tolerability of the optimized formula in rats upon topical application. Accordingly, ultra-permeable noisomes, as a stable nanosystem, could be promising for effective delivery of MTX. � 2019, American Association of Pharmaceutical Scientists.EnglishBox-Behnken designedge activatorhistopathologyIC 50methotrexateniosomescremophormethotrexateniosomepolyvinyl alcoholstabilizing agentantineoplastic antimetaboliteliposomemethotrexateanimal experimentanimal tissueArticlecell mediated cytotoxicitycell structurecell viabilitycontrolled studycytotoxicitydrug penetrationdrug tolerabilityencapsulationex vivo studyhigh performance liquid chromatographyhistopathologyMCF-7 cell linenonhumanphoton correlation spectroscopypriority journalratskinskin surfacetransmission electron microscopyzeta potentialanimalcell survivaldrug delivery systemdrug effectdrug formulationmaleparticle sizeskin absorptiontopical drug administrationWistar ratAdministration, TopicalAnimalsAntimetabolites, AntineoplasticCell SurvivalDrug CompoundingDrug Delivery SystemsLiposomesMaleMethotrexateParticle SizeRatsRats, WistarSkin AbsorptionArticlehttps://doi.org/10.1208/s12249-019-1380-5PubMed ID 31004239