{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T06:05:09Z","timestamp":1777615509603,"version":"3.51.4"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T00:00:00Z","timestamp":1688428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["CENTRO-01-0145-FEDER-000013"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000013"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["CENTRO-01-0145-FEDER-181231"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-181231"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["SFRH\/BD\/136028\/2018"],"award-info":[{"award-number":["SFRH\/BD\/136028\/2018"]}]},{"name":"European Regional Development Fund","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"European Regional Development Fund","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"European Regional Development Fund","award":["CENTRO-01-0145-FEDER-000013"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000013"]}]},{"name":"European Regional Development Fund","award":["CENTRO-01-0145-FEDER-181231"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-181231"]}]},{"name":"European Regional Development Fund","award":["SFRH\/BD\/136028\/2018"],"award-info":[{"award-number":["SFRH\/BD\/136028\/2018"]}]},{"name":"Regional Operational Program of the Center (Centro2020)","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"Regional Operational Program of the Center (Centro2020)","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"Regional Operational Program of the Center (Centro2020)","award":["CENTRO-01-0145-FEDER-000013"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000013"]}]},{"name":"Regional Operational Program of the Center (Centro2020)","award":["CENTRO-01-0145-FEDER-181231"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-181231"]}]},{"name":"Regional Operational Program of the Center (Centro2020)","award":["SFRH\/BD\/136028\/2018"],"award-info":[{"award-number":["SFRH\/BD\/136028\/2018"]}]},{"name":"FCT","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"FCT","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"FCT","award":["CENTRO-01-0145-FEDER-000013"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000013"]}]},{"name":"FCT","award":["CENTRO-01-0145-FEDER-181231"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-181231"]}]},{"name":"FCT","award":["SFRH\/BD\/136028\/2018"],"award-info":[{"award-number":["SFRH\/BD\/136028\/2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened. Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules.<\/jats:p>","DOI":"10.3390\/pharmaceutics15071878","type":"journal-article","created":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T01:38:32Z","timestamp":1688434712000},"page":"1878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0036-4894","authenticated-orcid":false,"given":"Patr\u00edcia C.","family":"Pires","sequence":"first","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Associated Laboratory for Green Chemistry (LAQV) of the Network of Chemistry and Technology (REQUIMTE), Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}]},{"given":"Mariana","family":"Fernandes","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Francisca","family":"Nina","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Francisco","family":"Gama","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Maria F.","family":"Gomes","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Lina E.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Sara","family":"Meirinho","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4297-5108","authenticated-orcid":false,"given":"Samuel","family":"Silvestre","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Sciences, University of Beira Interior, Rua Marqu\u00eas d\u2019\u00c1vila e Bolama, 6201-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4213-0714","authenticated-orcid":false,"given":"Gilberto","family":"Alves","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1224-9191","authenticated-orcid":false,"given":"Adriana O.","family":"Santos","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.jconrel.2022.09.052","article-title":"Engineering Hybrid Nanosystems for Efficient and Targeted Delivery against Bacterial Infections","volume":"351","author":"Elhassan","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2174206","DOI":"10.1080\/10717544.2023.2174206","article-title":"Recent Progress in Nanotechnology-Based Drug Carriers for Resveratrol Delivery","volume":"30","author":"Li","year":"2023","journal-title":"Drug Delivery"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jconrel.2017.11.047","article-title":"Nanosystems in Nose-to-Brain Drug Delivery: A Review of Non-Clinical Brain Targeting Studies","volume":"270","author":"Pires","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.3109\/03639045.2015.1052081","article-title":"Nanoneurotherapeutics Approach Intended for Direct Nose to Brain Delivery","volume":"41","author":"Md","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1021\/j150580a027","article-title":"Mechanism of Formation and Structure of Micro Emulsions by Electron Microscopy","volume":"63","author":"Schulman","year":"1959","journal-title":"J. Phys. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1039\/f29757101690","article-title":"Stability of Microemulsions","volume":"71","author":"Ruckenstein","year":"1975","journal-title":"J. Chem. Soc. Faraday Trans."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1111\/j.1749-6632.1961.tb44987.x","article-title":"FORMATION OF MICROEMULSIONS BY AMINO ALKYL ALCOHOLS","volume":"92","author":"Schulman","year":"1961","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jconrel.2017.03.008","article-title":"Nanoemulsion: Concepts, Development and Applications in Drug Delivery","volume":"252","author":"Singh","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.ijpharm.2019.05.032","article-title":"Targeted Drug Delivery to the Brain via Intranasal Nanoemulsion: Available Proof of Concept and Existing Challenges","volume":"565","author":"Chatterjee","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"887","DOI":"10.2174\/1567201816666191029122740","article-title":"Drug Delivery and Targeting to the Brain Through Nasal Route: Mechanisms, Applications and Challenges","volume":"16","author":"Kashyap","year":"2019","journal-title":"Curr. Drug Deliv."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bonferoni, M., Rossi, S., Sandri, G., Ferrari, F., Gavini, E., Rassu, G., and Giunchedi, P. (2019). Nanoemulsions for \u201cNose-to-Brain\u201d Drug Delivery. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11020084"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.apsb.2021.02.012","article-title":"Intranasal Delivery of Nanostructured Lipid Carriers, Solid Lipid Nanoparticles and Nanoemulsions: A Current Overview of in Vivo Studies","volume":"11","author":"Costa","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"105099","DOI":"10.1016\/j.ejps.2019.105099","article-title":"Nanoemulsions and Thermosensitive Nanoemulgels of Phenytoin and Fosphenytoin for Intranasal Administration: Formulation Development and in Vitro Characterization","volume":"141","author":"Pires","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1097\/00005537-200406000-00015","article-title":"A Numerical Simulation of Intranasal Air Temperature During Inspiration","volume":"114","author":"Lindemann","year":"2004","journal-title":"Laryngoscope"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"120040","DOI":"10.1016\/j.ijpharm.2020.120040","article-title":"Intranasal Fosphenytoin: The Promise of Phosphate Esters in Nose-to-Brain Delivery of Poorly Soluble Drugs","volume":"592","author":"Pires","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0731-7085(00)00309-5","article-title":"Direct-Injection LC\u2013MS\u2013MS Method for High-Throughput Simultaneous Quantitation of Simvastatin and Simvastatin Acid in Human Plasma","volume":"23","author":"Jemal","year":"2000","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1080\/07391102.2016.1188416","article-title":"Characterization of Interactions of Simvastatin, Pravastatin, Fluvastatin, and Pitavastatin with Bovine Serum Albumin: Multiple Spectroscopic and Molecular Docking","volume":"35","author":"Shi","year":"2017","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ijpharm.2009.05.014","article-title":"The Universality of Low-Energy Nano-Emulsification","volume":"377","author":"Anton","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1021\/acs.iecr.5b01122","article-title":"Recent Developments in Phase Inversion Emulsification","volume":"54","author":"Kumar","year":"2015","journal-title":"Ind. Eng. Chem. Res."},{"key":"ref_20","unstructured":"Nogueira Prista, L., Correia Alves, A., Ramos Morgado, R., and Sousa Lobo, J. (2011). Tecnologia Farmac\u00eautica, Funda\u00e7\u00e3o Calouste Gulbenkian. [8th ed.]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.cis.2015.01.001","article-title":"Phase Inversion Emulsification: Current Understanding and Applications","volume":"222","author":"Perazzo","year":"2015","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ejps.2006.04.016","article-title":"Formulation of Poorly Water-Soluble Drugs for Oral Administration: Physicochemical and Physiological Issues and the Lipid Formulation Classification System","volume":"29","author":"Pouton","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"104484","DOI":"10.1016\/j.ebiom.2023.104484","article-title":"Metformin and Simvastatin Exert Additive Antitumour Effects in Glioblastoma via Senescence-State: Clinical and Translational Evidence","volume":"90","author":"Torres","year":"2023","journal-title":"eBioMedicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115644","DOI":"10.1016\/j.bcp.2023.115644","article-title":"Anti-Fibrotic Effects of Statin Drugs: A Review of Evidence and Mechanisms","volume":"214","author":"Dolivo","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"109133","DOI":"10.1016\/j.yebeh.2023.109133","article-title":"Repurposing of Cholesterol-Lowering Agents in Status Epilepticus: A Neuroprotective Effect of Simvastatin","volume":"141","author":"Hanin","year":"2023","journal-title":"Epilepsy Behav."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100211","DOI":"10.1016\/j.wnsx.2023.100211","article-title":"Michael The Neuroprotective Effect of Statin in Traumatic Brain Injury: A Systematic Review","volume":"19","author":"Susanto","year":"2023","journal-title":"World Neurosurg. X"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1021\/acsbiomaterials.1c00462","article-title":"Simvastatin-Incorporated Drug Delivery Systems for Bone Regeneration","volume":"7","author":"Jin","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Pires, P.C., Rodrigues, M., Alves, G., and Santos, A.O. (2022). Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030588"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.3109\/03639045.2014.950271","article-title":"Preparation and Evaluation of SEDDS of Simvastatin by in Vivo, in Vitro and Ex Vivo Technique","volume":"41","author":"Karim","year":"2015","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ejpb.2023.04.009","article-title":"Improvement and Characterization of Oral Absorption Behavior of Clofazimine by SNEDDS: Quantitative Evaluation of Extensive Lymphatic Transport","volume":"187","author":"Yamanouchi","year":"2023","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yang, J., Liang, Z., Lu, P., Song, F., Zhang, Z., Zhou, T., Li, J., and Zhang, J. (2022). Development of a Luliconazole Nanoemulsion as a Prospective Ophthalmic Delivery System for the Treatment of Fungal Keratitis: In Vitro and In Vivo Evaluation. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102052"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"389","DOI":"10.34172\/apb.2020.047","article-title":"Self-Nanoemulsifying System Optimization for Higher Terconazole Solubilization and Non-Irritant Ocular Administration","volume":"10","author":"Yousry","year":"2020","journal-title":"Adv. Pharm. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lee, J.-H., and Lee, G.-W. (2022). Formulation Approaches for Improving the Dissolution Behavior and Bioavailability of Tolvaptan Using SMEDDS. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14020415"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kim, H.-S., Kim, C.-M., Jo, A.-N., and Kim, J.-E. (2022). Studies on Preformulation and Formulation of JIN-001 Liquisolid Tablet with Enhanced Solubility. Pharmaceuticals, 15.","DOI":"10.3390\/ph15040412"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Baral, K.C., Song, J.-G., Lee, S.H., Bajracharya, R., Sreenivasulu, G., Kim, M., Lee, K., and Han, H.-K. (2021). Enhanced Bioavailability of AC1497, a Novel Anticancer Drug Candidate, via a Self-Nanoemulsifying Drug Delivery System. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081142"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"105918","DOI":"10.1016\/j.ejps.2021.105918","article-title":"Nose-to-Brain Delivery of Phenytoin and Its Hydrophilic Prodrug Fosphenytoin Combined in a Microemulsion\u2014Formulation Development and in Vivo Pharmacokinetics","volume":"164","author":"Pires","year":"2021","journal-title":"Eur. J. Pharm. Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/7\/1878\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:05:37Z","timestamp":1760126737000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/7\/1878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,4]]},"references-count":36,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["pharmaceutics15071878"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15071878","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,4]]}}}