{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:44:26Z","timestamp":1790948666366,"version":"4.1.0"},"reference-count":108,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,7]],"date-time":"2024-01-07T00:00:00Z","timestamp":1704585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NKFI","award":["OTKA K_146148"],"award-info":[{"award-number":["OTKA K_146148"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 \u00b5m (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4\u20134.5 \u00b5m), fine particle fraction (56\u201371%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.<\/jats:p>","DOI":"10.3390\/ph17010075","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T07:59:20Z","timestamp":1704700760000},"page":"75","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A Novel Combined Dry Powder Inhaler Comprising Nanosized Ketoprofen-Embedded Mannitol-Coated Microparticles for Pulmonary Inflammations: Development, In Vitro\u2013In Silico Characterization, and Cell Line Evaluation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3419-9906","authenticated-orcid":false,"given":"Heba","family":"Banat","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, E\u00f6tv\u00f6s u.6, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0807-2781","authenticated-orcid":false,"given":"Ildik\u00f3","family":"Cs\u00f3ka","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, E\u00f6tv\u00f6s u.6, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6792-6789","authenticated-orcid":false,"given":"D\u00f3ra","family":"Par\u00f3czai","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, University of Szeged, D\u00f3m Square 10, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1300-2374","authenticated-orcid":false,"given":"Katalin","family":"Burian","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, University of Szeged, D\u00f3m Square 10, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1rp\u00e1d","family":"Farkas","sequence":"additional","affiliation":[{"name":"Centre for Energy Research, Hungarian Academy of Sciences, 1121 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5496-1710","authenticated-orcid":false,"given":"Rita","family":"Ambrus","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, E\u00f6tv\u00f6s u.6, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,7]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Inflammatory mechanisms in the lung","volume":"2","author":"Moldoveanu","year":"2008","journal-title":"J. Inflamm. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1164\/rccm.200203-183OC","article-title":"differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease","volume":"167","author":"Fabbri","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1749-6632.1994.tb00275.x","article-title":"Interactions between respiratory epithelial cells and cytokines: Relationships to lung inflammation","volume":"725","author":"Adler","year":"1994","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"808797","DOI":"10.3389\/fphar.2021.808797","article-title":"The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome","volume":"12","author":"Cesta","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s40169-015-0068-z","article-title":"Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer","volume":"4","author":"King","year":"2015","journal-title":"Clin. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.jcf.2015.03.003","article-title":"Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy","volume":"14","author":"Cantin","year":"2015","journal-title":"J. Cyst. Fibros."},{"key":"ref_7","unstructured":"Widysanto, A., and Mathew, G. (2021). Chronic Bronchitis, StatPearls Publishing."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1155\/2006\/901417","article-title":"Mucin overproduction in chronic inflammatory lung disease","volume":"13","author":"Hauber","year":"2006","journal-title":"Can. Respir. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1165\/rcmb.F262","article-title":"Making more MUCS","volume":"28","author":"Sheehan","year":"2003","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2147\/COPD.S38938","article-title":"Clinical issues of mucus accumulation in COPD","volume":"9","author":"Kim","year":"2014","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s41030-017-0043-5","article-title":"A Review on the Safety and Efficacy of Inhaled Corticosteroids in the Management of Asthma","volume":"3","author":"Ye","year":"2017","journal-title":"Pulm. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/j.rmed.2005.11.020","article-title":"Systemic side effects of inhaled corticosteroids in patients with asthma","volume":"100","author":"Dahl","year":"2006","journal-title":"Respir. Med."},{"key":"ref_13","first-page":"PA3926","article-title":"Effect of cyclooxygenase-2 inhibition on lung inflammation and hypoxia-inducible factor-1 signalling in COPD model","volume":"50","author":"Lebedeva","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.2174\/1570163813666160119092807","article-title":"Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2","volume":"13","author":"Ahmed","year":"2016","journal-title":"Curr. Drug. Discov. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"81s","DOI":"10.18433\/J3T886","article-title":"Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond","volume":"11","author":"Rao","year":"2008","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ijpharm.2013.03.030","article-title":"Non-steroidal anti-inflammatory drug for pulmonary administration: Design and investigation of ketoprofen lysinate fine dry powders","volume":"448","author":"Stigliani","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_17","first-page":"838410","article-title":"Nanospray drying as a novel technique for the manufacturing of inhalable NSAID powders","volume":"2014","author":"Mariateresa","year":"2014","journal-title":"Sci. World J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jcf.2010.08.020","article-title":"Inhaled mannitol in patients with cystic fibrosis: A randomised open-label dose response trial","volume":"10","author":"Teper","year":"2011","journal-title":"J. Cyst. Fibros."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1089\/jamp.2013.1078","article-title":"Design, characterization, and aerosol dispersion performance modeling of advanced spray-dried microparticulate\/nanoparticulate mannitol powders for targeted pulmonary delivery as dry powder inhalers","volume":"27","author":"Li","year":"2014","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.nano.2015.01.007","article-title":"Inhalable nanoparticulate powders for respiratory delivery","volume":"11","author":"Muralidharan","year":"2015","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106158","DOI":"10.1016\/j.ejps.2022.106158","article-title":"Particle engineering in dry powders for inhalation","volume":"172","author":"Bock","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12001","DOI":"10.1073\/pnas.182233999","article-title":"Trojan particles: Large porous carriers of nanoparticles for drug delivery","volume":"99","author":"Tsapis","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s11095-007-9475-1","article-title":"Pharmaceutical Particle Engineering via Spray Drying","volume":"25","author":"Vehring","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41846","DOI":"10.1039\/D0RA07203F","article-title":"Advanced design and development of nanoparticle\/microparticle dual-drug combination lactose carrier-free dry powder inhalation aerosols","volume":"10","author":"Muralidharan","year":"2020","journal-title":"RSC Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.ijpharm.2012.11.036","article-title":"Coated particle assemblies for the concomitant pulmonary administration of budesonide and salbutamol sulphate","volume":"441","author":"Raula","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.envres.2018.11.014","article-title":"Particle deposition in the human lung: Health implications of particulate matter from different sources","volume":"169","author":"Deng","year":"2019","journal-title":"Environ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1089\/jamp.2020.29029.cd","article-title":"Deposition Mechanisms","volume":"33","author":"Darquenne","year":"2020","journal-title":"J. Aerosol. Med. Pulm. Drug. Deliv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11869-016-0424-1","article-title":"Physical properties and lung deposition of particles emitted from five major indoor sources","volume":"10","author":"Vu","year":"2017","journal-title":"Air Qual. Atmos. Health"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/0021-8502(86)90035-2","article-title":"Deposition of particles in the human respiratory tract in the size range 0.005\u201315 \u03bcm","volume":"17","author":"Heyder","year":"1986","journal-title":"J. Aerosol Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ijpharm.2017.01.032","article-title":"Aerosolizable gold nano-in-micro dry powder formulations for theragnosis and lung delivery","volume":"519","author":"Silva","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4055","DOI":"10.1002\/jps.21673","article-title":"Simultaneously manufactured nano-in-micro (SIMANIM) particles for dry-powder modified-release delivery of antibodies","volume":"98","author":"Kaye","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ejpb.2011.03.014","article-title":"Investigation of preparation parameters of nanosuspension by top-down media milling to improve the dissolution of poorly water-soluble glyburide","volume":"78","author":"Singh","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"106123","DOI":"10.1016\/j.ejps.2022.106123","article-title":"A new nanosuspension prepared with wet milling method for oral delivery of highly variable drug Cyclosporine A: Development, optimization and in vivo evaluation","volume":"171","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.powtec.2007.03.046","article-title":"Amino acid-modified spray-dried powders with enhanced aerosolisation properties for pulmonary drug delivery","volume":"178","author":"Seville","year":"2007","journal-title":"Powder Technol."},{"key":"ref_35","first-page":"54","article-title":"Defining the \u2018Dose\u2019for Dry Powder Inhalers: The Challenge of Correlating In-Vitro Dose Delivery Results with Clinical Efficacy","volume":"20","author":"Lewis","year":"2017","journal-title":"Am. Pharm. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.ajps.2016.01.001","article-title":"Spray drying of fenofibrate loaded nanostructured lipid carriers","volume":"11","author":"Xia","year":"2016","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ajps.2015.11.038","article-title":"Impact of formulation parameters on physical characteristics of spray dried nanoemulsions and their reconstitutions","volume":"11","author":"Myat","year":"2016","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"118562","DOI":"10.1016\/j.ijpharm.2019.118562","article-title":"Influence of stabilizer type and concentration on the lung deposition and retention of resveratrol nanosuspension-in-microparticles","volume":"569","author":"Liu","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.apt.2010.09.011","article-title":"Progress in developing spray-drying methods for the production of controlled morphology particles: From the nanometer to submicrometer size ranges","volume":"22","author":"Nandiyanto","year":"2011","journal-title":"Adv. Powder Technol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"100815","DOI":"10.1016\/j.ajps.2023.100815","article-title":"Corrugated surface microparticles with chitosan and levofloxacin for improved aerodynamic performance","volume":"18","author":"Han","year":"2023","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ijpharm.2019.03.004","article-title":"A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose\/leucine formulations with application in pulmonary delivery","volume":"562","author":"Focaroli","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.partic.2023.03.013","article-title":"Micro-sized nanoaggregates: Spray-drying-assisted fabrication and applications","volume":"85","author":"Yang","year":"2023","journal-title":"Particuology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ijpharm.2017.09.024","article-title":"Development of fine solid-crystal suspension with enhanced solubility, stability, and aerosolization performance for dry powder inhalation","volume":"533","author":"Lin","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jpba.2011.05.008","article-title":"Analysis of co-spray-dried meloxicam\u2013mannitol systems containing crystalline microcomposites","volume":"56","author":"Ambrus","year":"2011","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1208\/s12248-016-0039-3","article-title":"Porous mannitol carrier for pulmonary delivery of cyclosporine A nanoparticles","volume":"19","author":"Leung","year":"2017","journal-title":"AAPS J."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kang, J.-H., Kim, Y.-J., Yang, M.-S., Shin, D.H., Kim, D.-W., Park, I.Y., and Park, C.-W. (2021). Co-Spray Dried Nafamostat Mesylate with Lecithin and Mannitol as Respirable Microparticles for Targeted Pulmonary Delivery: Pharmacokinetics and Lung Distribution in Rats. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091519"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.1002\/jps.23955","article-title":"Design, Characterization, and Aerosol Dispersion Performance Modeling of Advanced Co-Spray Dried Antibiotics with Mannitol as Respirable Microparticles\/Nanoparticles for Targeted Pulmonary Delivery as Dry Powder Inhalers","volume":"103","author":"Li","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ejpb.2015.03.023","article-title":"Spray-dried amikacin sulphate powder for inhalation in cystic fibrosis patients: The role of ethanol in particle formation","volume":"93","author":"Belotti","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.addr.2014.03.006","article-title":"Emerging inhalation aerosol devices and strategies: Where are we headed?","volume":"75","author":"Zhou","year":"2014","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ijpharm.2018.08.035","article-title":"Development of a new formulation of roflumilast for pulmonary drug delivery to treat inflammatory lung conditions","volume":"550","author":"Suzuki","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0168-3659(00)00362-X","article-title":"Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance","volume":"70","author":"Bosquillon","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1055\/a-0649-0814","article-title":"Development of a Carrier Free Dry Powder Inhalation Formulation of Ketotifen for Pulmonary Drug Delivery","volume":"70","author":"Azari","year":"2020","journal-title":"Drug Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"353","DOI":"10.2147\/COPD.S18529","article-title":"Delivery characteristics and patients\u2019 handling of two single-dose dry-powder inhalers used in COPD","volume":"6","author":"Thorpe","year":"2011","journal-title":"Int. J. COPD"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.addr.2011.05.009","article-title":"In silico models of aerosol delivery to the respiratory tract\u2014Development and applications","volume":"64","author":"Longest","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Ignjatovi\u0107, J., \u0160u\u0161ter\u0161i\u010d, T., Bodi\u0107, A., Cviji\u0107, S., \u0110uri\u0161, J., Rossi, A., Dobri\u010di\u0107, V., Ibri\u0107, S., and Filipovi\u0107, N. (2021). Comparative assessment of in vitro and in silico methods for aerodynamic characterization of powders for inhalation. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111831"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.rmed.2016.07.013","article-title":"Inhalation device requirements for patients\u2019 inhalation maneuvers","volume":"118","author":"Haidl","year":"2016","journal-title":"Respir. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/jamp.2015.1232","article-title":"The Evolution of Pressurized Metered-Dose Inhalers from Early to Modern Devices","volume":"29","author":"Roche","year":"2016","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Nokhodchi, A., Chavan, S., and Ghafourian, T. (2023). In Vitro Dissolution and Permeability Testing of Inhalation Products: Challenges and Advances. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15030983"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.ejps.2015.12.016","article-title":"A novel formulation for solubility and content uniformity enhancement of poorly water-soluble drugs using highly-porous mannitol","volume":"83","author":"Saffari","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ejps.2018.07.030","article-title":"Novel dry powder inhaler formulation containing antibiotic using combined technology to improve aerodynamic properties","volume":"123","author":"Ambrus","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"16761","DOI":"10.1038\/s41598-017-17037-2","article-title":"Imaging viscosity of intragranular mucin matrix in cystic fibrosis cells","volume":"7","author":"Requena","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1152\/physrev.00004.2021","article-title":"Physiology and Pathophysiology of Human Airwaymucus","volume":"102","author":"Hill","year":"2022","journal-title":"Physiol. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1164\/rccm.201412-2230OC","article-title":"The relationship of mucus concentration (hydration) to mucus osmotic pressure and transport in chronic bronchitis","volume":"192","author":"Anderson","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s11242-014-0409-1","article-title":"The Influence of Functional Carrier Particles (FCPs) on the Molecular Transport Rate Through the Reconstructed Bronchial Mucus: In Vitro Studies","volume":"106","author":"Odziomek","year":"2015","journal-title":"Transp. Porous Media"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/1465-9921-10-63","article-title":"Macrorheology of cystic fibrosis, chronic obstructive pulmonary disease normal sputum","volume":"10","author":"Serisier","year":"2009","journal-title":"Respir. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.ijpharm.2017.09.018","article-title":"Physicochemical properties of mucus and their impact on transmucosal drug delivery","volume":"532","author":"Leal","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejpb.2020.07.023","article-title":"Investigation of drug dissolution and uptake from low-density DPI formulations in an impactor\u2013integrated cell culture model","volume":"155","author":"Thormann","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.ajps.2019.11.004","article-title":"Biointerface engineering nanoplatforms for cancer-targeted drug delivery","volume":"15","author":"Zhang","year":"2020","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"106247","DOI":"10.1016\/j.ejps.2022.106247","article-title":"Development of extra-fine particles containing nanosized meloxicam for deep pulmonary delivery: In vitro aerodynamic and cell line measurements","volume":"176","author":"Party","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Tanaka, T., Narazaki, M., and Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol., 6.","DOI":"10.1101\/cshperspect.a016295"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1093\/toxsci\/68.2.488","article-title":"The role of interleukin-6 in pulmonary inflammation and injury induced by exposure to environmental air pollutants","volume":"68","author":"Yu","year":"2002","journal-title":"Toxicol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1172\/JCI117392","article-title":"Alveolar type II epithelial cells produce interleukin-6 in vitro and in vivo. Regulation by alveolar macrophage secretory products","volume":"94","author":"Crestani","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1007\/s10753-014-9984-0","article-title":"SeMet Mediates Anti-Inflammation in LPS-Induced U937 Cells Targeting NF-\u03baB Signaling Pathway","volume":"38","author":"Shen","year":"2015","journal-title":"Inflammation"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1111\/j.1476-5381.1994.tb17093.x","article-title":"Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cells: Regulation by dexamethasone","volume":"113","author":"Mitchell","year":"1994","journal-title":"Br. J. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"32978","DOI":"10.1074\/jbc.M605935200","article-title":"Lipopolysaccharide-induced cyclooxygenase-2 expression in human u937 macrophages is phosphatidic acid phosphohydrolase-1-dependent","volume":"281","author":"Grkovich","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"123070","DOI":"10.1016\/j.ijpharm.2023.123070","article-title":"Drug combinations for inhalation: Current products and future development addressing disease control and patient compliance","volume":"643","author":"Banat","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Celi, S.S., Fern\u00e1ndez-Garc\u00eda, R., Afonso-Urich, A.I., Ballesteros, M.P., Healy, A.M., and Serrano, D.R. (2023). Co-Delivery of a High Dose of Amphotericin B and Itraconazole by Means of a Dry Powder Inhaler Formulation for the Treatment of Severe Fungal Pulmonary Infections. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15112601"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"122788","DOI":"10.1016\/j.ijpharm.2023.122788","article-title":"Targeting lung macrophages for fungal and parasitic pulmonary infections with innovative amphotericin B dry powder inhalers","volume":"635","author":"Marchand","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/j.jconrel.2013.08.006","article-title":"Stability of nanosuspensions in drug delivery","volume":"172","author":"Wang","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Faizi, H.S., Vora, L.K., Nasiri, M.I., Wu, Y., Mishra, D., Anjani, Q.K., Paredes, A.J., Thakur, R.R.S., Minhas, M.U., and Donnelly, R.F. (2022). Deferasirox Nanosuspension Loaded Dissolving Microneedles for Intradermal Delivery. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14122817"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.ajps.2015.04.003","article-title":"The characterization and dissolution performances of spray dried solid dispersion of ketoprofen in hydrophilic carriers","volume":"10","author":"Chan","year":"2015","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1016\/j.apt.2018.09.039","article-title":"Impact of polymers on the aggregation of wet-milled itraconazole particles and their dissolution from spray-dried nanocomposites","volume":"29","author":"Bilgili","year":"2018","journal-title":"Adv. Powder. Technol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1111\/j.2042-7158.2010.01022.x","article-title":"Pharmaceutical nanocrystals by nanomilling: Critical process parameters, particle fracturing and stabilization methods","volume":"56","author":"Peltonen","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1016\/j.eurpolymj.2013.03.017","article-title":"Effect of polymers for aerolization properties of mannitol-based microcomposites containing meloxicam","volume":"49","author":"Buttini","year":"2013","journal-title":"Eur. Polym. J."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Bartos, C., Szab\u00f3-R\u00e9v\u00e9sz, P., Bartos, C., Katona, G., J\u00f3j\u00e1rt-Laczkovich, O., and Ambrus, R. (2016). The Effect of an Optimized Wet Milling Technology on the Crystallinity, Morphology and Dissolution. Molecules, 21.","DOI":"10.3390\/molecules21040507"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.ajps.2022.04.004","article-title":"Salvianolic acid B dry powder inhaler for the treatment of idiopathic pulmonary fibrosis","volume":"17","author":"Lu","year":"2022","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1007\/s11095-011-0456-z","article-title":"Intact Nanoparticulate Indomethacin in Fast-Dissolving Carrier Particles by Combined Wet Milling and Aerosol Flow Reactor Methods","volume":"28","author":"Laaksonen","year":"2011","journal-title":"Pharm. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ijpharm.2018.04.034","article-title":"Influence of excipients on physical and aerosolization stability of spray dried high-dose powder formulations for inhalation","volume":"544","author":"Shetty","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ijpe.2016.02.005","article-title":"Production Economics Optimizing inventory\u2019 s contribution to profitability in a regulated utility: The Averch\u2013Johnson effect","volume":"175","author":"Li","year":"2016","journal-title":"Int. J. Prod. Econ."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ijpharm.2018.03.005","article-title":"The influence of surface active l-leucine and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) in the improvement of aerosolization of pyrazinamide and moxifloxacin co-spray dried powders","volume":"542","author":"Eedara","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Benetti, A.A., Bianchera, A., Buttini, F., Bertocchi, L., and Bettini, R. (2021). Mannitol Polymorphs as Carrier in DPIs Formulations: Isolation Characterization and Performance. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081113"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ajps.2017.08.005","article-title":"Pulmonary delivery of liposomal dry powder inhaler formulation for effective treatment of idiopathic pulmonary fibrosis","volume":"13","author":"Chennakesavulu","year":"2018","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.jcf.2021.02.011","article-title":"Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study","volume":"20","author":"Flume","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_94","unstructured":"(2023). European Pharmacopeia 11, EDQM Counsil of Europe."},{"key":"ref_95","unstructured":"USP (2022, December 18). <616> Bulk Density and Tapped Density of Powders. In United States Pharmacopeia. Available online: http:\/\/ftp.uspbpep.com\/v29240\/usp29nf24s0_c616.html."},{"key":"ref_96","unstructured":"(2023). European Pharmacopeia 11, EDQM Counsil of Europe."},{"key":"ref_97","unstructured":"USP (2012). USP 35, Food and Drug Administration."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/0021-8502(90)90121-D","article-title":"Monte Carlo modeling of aerosol deposition in human lungs. Part I: Simulation of particle transport in a stochastic lung structure","volume":"21","author":"Koblinger","year":"1990","journal-title":"J. Aerosol Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.ejps.2017.03.047","article-title":"Significance of breath-hold time in dry powder aerosol drug therapy of COPD patients","volume":"104","author":"Tomisa","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ijpharm.2017.01.070","article-title":"Aerodynamic properties and in silico deposition of meloxicam potassium incorporated in a carrier-free DPI pulmonary system","volume":"520","author":"Chvatal","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ijpharm.2017.09.057","article-title":"Experimental and computational study of the effect of breath-actuated mechanism built in the NEXThaler\u00ae dry powder inhaler","volume":"533","author":"Farkas","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_102","unstructured":"(2023). European Pharmacopeia 11, EDQM Counsil of Europe."},{"key":"ref_103","unstructured":"Parlati, C. (2008). Respirable Microparticles of Aminoglycoside Antibiotics for Pulmonary Administration. [Ph.D. Thesis, University of Parma]."},{"key":"ref_104","first-page":"181","article-title":"Measurements of Deposition, Lung Surface Area and Lung Fluid for Simulation of Inhaled Compounds","volume":"7","author":"Mercuri","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.1007\/s11095-014-1413-4","article-title":"Dissolution Testing of Powders for Inhalation: Influence of Particle Deposition and Modeling of Dissolution Profiles","volume":"31","author":"May","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Gieszinger, P., Kiss, T., Szab\u00f3-R\u00e9v\u00e9sz, P., and Ambrus, R. (2021). The Development of an In Vitro Horizontal Diffusion Cell to Monitor Nasal Powder Penetration Inline. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060809"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.addr.2017.11.002","article-title":"The role of mucus as an invisible cloak to transepithelial drug delivery by nanoparticles","volume":"124","author":"Birch","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/1\/75\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:41:38Z","timestamp":1760103698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/1\/75"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,7]]},"references-count":108,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ph17010075"],"URL":"https:\/\/doi.org\/10.3390\/ph17010075","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,7]]}}}