{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:01:08Z","timestamp":1787029268302,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI Grant-in-Aid","doi-asserted-by":"publisher","award":["19K16465"],"award-info":[{"award-number":["19K16465"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI Grant-in-Aid","doi-asserted-by":"publisher","award":["22K06709"],"award-info":[{"award-number":["22K06709"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Estimating the dissolution behavior of a solid in the nasal mucus is challenging for solid dosage forms designed for the nasal application as the solid dissolves into nasal mucus and permeates through the mucosa. In the current study, the dissolution behavior of powders in the artificial nasal fluid was investigated using a 3D-printed chamber system to establish in vitro evaluation system for the dissolution of solid formulations that can simulate the intranasal environment in vivo. The dissolution rates of the five model drugs correlated with their solubility (r2 = 0.956, p &lt; 0.01). The permeation rate of drugs across the Calu-3 cell layers after powder application depends on the membrane permeability of the drug. An analysis of membrane permeability considering the dissolution of powders showed the possibility of characterizing whether the drug in the powder was dissolution-limited or permeation-limited. This suggests that critical information can be obtained to understand which mechanism is more effective for the improvement of drug absorption from powders. This study indicates that the elucidation of drug dissolution behavior into nasal mucus is an important factor for the formulation of nasal powders and that the in vitro system developed could be a useful tool.<\/jats:p>","DOI":"10.3390\/pharmaceutics14112350","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T06:42:17Z","timestamp":1667371337000},"page":"2350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Development of In Vitro Evaluation System for Assessing Drug Dissolution Considering Physiological Environment in Nasal Cavity"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0219-4331","authenticated-orcid":false,"given":"Daisuke","family":"Inoue","sequence":"first","affiliation":[{"name":"Department of Medical Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"},{"name":"Molecular Pharmaceutics Laboratory, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayari","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Molecular Pharmaceutics Laboratory, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideto","family":"To","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2007.03.025","article-title":"Intranasal Delivery: Physicochemical and Therapeutic Aspects","volume":"337","author":"Costantino","year":"2007","journal-title":"Int. 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Biopharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jconrel.2018.05.011","article-title":"Nose-to-Brain Drug Delivery: An Update on Clinical Challenges and Progress towards Approval of Anti-Alzheimer Drugs","volume":"281","author":"Agrawal","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1002\/jps.2600691215","article-title":"Nasal Absorption of Propranolol from Different Dosage Forms by Rats and Dogs","volume":"69","author":"Hussain","year":"1980","journal-title":"J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/0378-5173(81)90058-2","article-title":"Absorption of Drugs from the Nasal Mucosa of Rat","volume":"7","author":"Shinichiro","year":"1981","journal-title":"Int. J. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ejpb.2017.11.001","article-title":"Intranasal Immunization with Dry Powder Vaccines","volume":"122","author":"Cui","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1007\/s40265-016-0641-9","article-title":"Sumatriptan Nasal Powder: A Review in Acute Treatment of Migraine","volume":"76","author":"Scott","year":"2016","journal-title":"Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.3109\/03639045.2016.1160110","article-title":"Dry Powder Nasal Drug Delivery: Challenges, Opportunities and a Study of the Commercial Teijin Puvlizer Rhinocort Device and Formulation","volume":"42","author":"Pozzoli","year":"2016","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"120600","DOI":"10.1016\/j.ijpharm.2021.120600","article-title":"Insulin Fast-Dissolving Film for Intranasal Delivery via Olfactory Region, a Promising Approach for the Treatment of Anosmia in COVID-19 Patients: Design, in-Vitro Characterization and Clinical Evaluation","volume":"601","author":"Mohamad","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.ijbiomac.2018.01.043","article-title":"Nasal Adhesive Patches-Approach for Topical Application for Dry Nasal Syndrome","volume":"111","author":"Laffleur","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Inoue, D., Yamashita, A., and To, H. (2022). Formulation and In Vitro Characterization of a Vacuum-Dried Drug\u2013Polymer Thin Film for Intranasal Application. Polymers, 14.","DOI":"10.3390\/polym14142954"},{"key":"ref_17","first-page":"Doc07","article-title":"Physiology and Pathophysiology of Respiratory Mucosa of the Nose and the Paranasal Sinuses","volume":"9","author":"Beule","year":"2010","journal-title":"GMS Curr. Top. Otorhinolaryngol. Head Neck Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1183\/09031936.97.10102194","article-title":"Airway Liquid: A Barrier to Drug Diffusion?","volume":"10","author":"Widdicombe","year":"1997","journal-title":"Eur. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0169-409X(97)00059-8","article-title":"Nasal Mucociliary Clearance as a Factor in Nasal Drug Delivery","volume":"29","author":"Marttin","year":"1998","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ejps.2018.01.032","article-title":"The Relationship between in Vivo Nasal Drug Clearance and in Vitro Nasal Mucociliary Clearance: Application to the Prediction of Nasal Drug Absorption","volume":"117","author":"Inoue","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4462","DOI":"10.1021\/acs.molpharmaceut.8b00464","article-title":"Quantitative Estimation of the Effect of Nasal Mucociliary Function on in Vivo Absorption of Norfloxacin after Intranasal Administration to Rats","volume":"15","author":"Inoue","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.ejps.2017.09.027","article-title":"Opportunity and Challenges of Nasal Powders: Drug Formulation and Delivery","volume":"113","author":"Manniello","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.jconrel.2012.02.028","article-title":"Particles and Powders: Tools of Innovation for Non-Invasive Drug Administration","volume":"161","author":"Buttini","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ambrus, R., Gieszinger, P., G\u00e1sp\u00e1r, R., Sztojkov-Ivanov, A., Ducza, E., M\u00e1rki, \u00c1., Jan\u00e1ky, T., T\u00f6m\u00f6si, F., Kecskem\u00e9ti, G., and Szab\u00f3-R\u00e9v\u00e9sz, P. (2020). Investigation of the Absorption of Nanosized Lamotrigine Containing Nasal Powder via the Nasal Cavity. Molecules, 25.","DOI":"10.3390\/molecules25051065"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1080\/1061186X.2019.1574300","article-title":"Anti-Inflammatory Flurbiprofen Nasal Powders for Nose-to-Brain Delivery in Alzheimer\u2019s Disease","volume":"27","author":"Manniello","year":"2019","journal-title":"J. Drug Target."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1208\/s12249-016-0581-4","article-title":"Improved Flux of Levodopa via Direct Deposition of Solid Microparticles on Nasal Tissue","volume":"18","author":"Vasa","year":"2017","journal-title":"AAPS PharmSciTech"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1016\/j.xphs.2020.11.023","article-title":"Evaluation of Systemic and Mucosal Immune Responses Induced by a Nasal Powder Delivery System in Conjunction with an OVA Antigen in Cynomolgus Monkeys","volume":"110","author":"Torikai","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jconrel.2018.10.020","article-title":"Intranasal Immunization with Aluminum Salt-Adjuvanted Dry Powder Vaccine","volume":"292","author":"Thakkar","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.ejpb.2018.06.011","article-title":"Chitosan-Coated Liposome Dry-Powder Formulations Loaded with Ghrelin for Nose-to-Brain Delivery","volume":"129","author":"Salade","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/jphp.13026","article-title":"Evaluation of Inhaled Recombinant Human Insulin Dry Powders: Pharmacokinetics, Pharmacodynamics and 14-Day Inhalation","volume":"71","author":"He","year":"2019","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.ejpb.2020.02.004","article-title":"Quantitative Estimation of Drug Permeation through Nasal Mucosa Using in vitro Membrane Permeability across Calu-3 Cell Layers for Predicting in Vivo Bioavailability after Intranasal Administration to Rats","volume":"149","author":"Inoue","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1208\/s12248-011-9290-9","article-title":"BDDCS Applied to over 900 Drugs","volume":"13","author":"Benet","year":"2011","journal-title":"AAPS J."},{"key":"ref_33","first-page":"83","article-title":"Comparative Morphometry of the Nasal Cavity in Rats and Mice","volume":"135","author":"Gross","year":"1982","journal-title":"J. Anat"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.physbeh.2012.12.007","article-title":"Size of Nostril Opening as a Measure of Intranasal Volume","volume":"110\u2013111","author":"Schriever","year":"2013","journal-title":"Physiol. Behav."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1046\/j.1365-2273.2002.00544.x","article-title":"Nasal Mucosal Temperature during Respiration","volume":"27","author":"Lindemann","year":"2002","journal-title":"Clin. Otolaryngol. Allied. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.ejps.2016.09.028","article-title":"Nasal Drug Absorption from Powder Formulations: The Effect of Three Types of Hydroxypropyl Cellulose (HPC)","volume":"96","author":"Tanaka","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_37","first-page":"1071","article-title":"Nonionic Diffusion of Salicylic Acid through MDCK Cell Monolayers","volume":"261","author":"Chatton","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejps.2005.02.009","article-title":"PH-Dependent Passive and Active Transport of Acidic Drugs across Caco-2 Cell Monolayers","volume":"25","author":"Neuhoff","year":"2005","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/jps.2600760709","article-title":"Analysis of Structural Requirements for the Absorption of Drugs and Macromolecules from the Nasal Cavity","volume":"76","author":"McMartin","year":"1987","journal-title":"J. Pharm. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/bdd.2510140805","article-title":"The Structural Barrier of Absorptive Mucosae: Site Difference of the Permeability of Fluorescein Isothiocyanate-Labelled Dextran in Rabbits","volume":"14","author":"Hosoya","year":"1993","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1615\/CritRevTherDrugCarrierSyst.v21.i3.20","article-title":"Mucosal Drug Delivery: Membranes, Methodologies, and Applications","volume":"21","author":"Song","year":"2004","journal-title":"Crit. Rev. Ther. Drug Carrier Syst."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3109\/10611869808997878","article-title":"Efficacy, Safety and Mechanism of Cyclodextrins as Absorption Enhancers in Nasal Delivery of Peptide and Protein Drugs","volume":"6","author":"Marttin","year":"1998","journal-title":"J. Drug Target."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1211\/0022357011775145","article-title":"The Biopharmaceutical Aspects of Nasal Mucoadhesive Drug Delivery","volume":"53","author":"Ugwoke","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.jconrel.2014.05.003","article-title":"Chitosan in Nasal Delivery Systems for Therapeutic Drugs","volume":"190","author":"Casettari","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.2165\/00003088-200342130-00003","article-title":"Absorption Enhancers for Nasal Drug Delivery","volume":"42","author":"Davis","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ghadiri, M., Young, P., and Traini, D. (2019). Strategies to Enhance Drug Absorption via Nasal and Pulmonary Routes. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11030113"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ejps.2009.07.003","article-title":"Preparation of Zolmitriptan-Chitosan Microparticles by Spray Drying for Nasal Delivery","volume":"38","author":"Alhalaweh","year":"2009","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bartos, C., Varga, P., Szab\u00f3-R\u00e9v\u00e9sz, P., and Ambrus, R. (2021). Physico-Chemical and In Vitro Characterization of Chitosan-Based Microspheres Intended for Nasal Administration. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13050608"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.ejpb.2010.04.013","article-title":"Freeze-Dried Chitosan\/Pectin Nasal Inserts for Antipsychotic Drug Delivery","volume":"75","author":"Luppi","year":"2010","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_50","first-page":"453","article-title":"Diazepam Prodrug Stabilizes Human Aminopeptidase B during Lyophilization","volume":"17","author":"Rautiola","year":"2020","journal-title":"Mol. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"121016","DOI":"10.1016\/j.ijpharm.2021.121016","article-title":"Nasal Powders of Quercetin-\u03b2-Cyclodextrin Derivatives Complexes with Mannitol\/Lecithin Microparticles for Nose-to-Brain Delivery: In Vitro and Ex Vivo Evaluation","volume":"607","author":"Papakyriakopoulou","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ijpharm.2015.05.009","article-title":"Nasal Delivery of Analgesic Ketorolac Tromethamine Thermo- and Ion-Sensitive in Situ Hydrogels","volume":"489","author":"Li","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ejpb.2006.05.017","article-title":"Nasal Absorption of Metoclopramide from Different Carbopol\u00ae 981 Based Formulations: In Vitro, Ex Vivo and in Vivo Evaluation","volume":"64","author":"Tas","year":"2006","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Reno, F.E., Normand, P., McInally, K., Silo, S., Stotland, P., Triest, M., Carballo, D., and Pich\u00e9, C. (2015). A Novel Nasal Powder Formulation of Glucagon: Toxicology Studies in Animal Models. BMC Pharmacol. 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