{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T15:31:52Z","timestamp":1793028712443,"version":"4.5.0"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto Nacional de Ci\u00eancia e Tecnologia em Nanotecnologia Farmac\u00eautica"},{"name":"INCT-Nanofarma\u2014FAPESP","award":["2014\/50928-2"],"award-info":[{"award-number":["2014\/50928-2"]}]},{"DOI":"10.13039\/501100003593","name":"CNPq","doi-asserted-by":"crossref","award":["465687\/2014-8"],"award-info":[{"award-number":["465687\/2014-8"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Cachexia is a syndrome characterized by the progressive loss of muscle mass, leading to high morbidity and mortality. Ghrelin (Ghrl) exhibits orexigenic, anabolic, and anti-inflammatory properties with therapeutic potential. However, its low bioavailability limits the efficacy of systemic treatments. This study aimed to develop chitosan-coated liposomes containing Ghrl (CH-Lip + Ghrl) for intranasal administration, allowing quantification of Ghrl brain bioavailability using a system optimized for a labile neuropeptide. Methods: The formulation was prepared using thin-film hydration, followed by extrusion and chitosan coating. It was characterized based on morphology, size, zeta potential, stability, encapsulation efficiency, and cell viability. Permeation and mucoadhesion were evaluated ex vivo using porcine nasal mucosa, and cerebral bioavailability was assessed in Wistar rats. Results: CH-Lip + Ghrl had an average of 152.4 \u00b1 0.2 nm (evaluated by DLS), a polydispersity index of 0.159 \u00b1 0.018, a zeta potential of +60.8 \u00b1 6.6 mV, and an encapsulation efficiency of 53.2 \u00b1 0.8%, maintaining stability for 180 days. At 1% (v\/v) in culture medium, the formulation retained 73.2 \u00b1 8.4% of the viability in nasal epithelial cells and 81.9 \u00b1 4.8% in neuroblastoma cells. Chitosan coating increased ex vivo mucoadhesion 1.7-fold and permeation 1.3-fold. In vivo, 25 min after intranasal administration, CH-Lip + Ghrl delivered 48.2 \u00b1 8.8% of the dose to the brain, whereas free Ghrl was undetectable. Conclusions: The intranasal administration of CH-Lip + Ghrl enhances cerebral bioavailability of Ghrl. This study integrates a chemically labile neuropeptide with chitosan-coated liposomes for direct brain delivery, representing an innovative platform for future translational studies.<\/jats:p>","DOI":"10.3390\/pharmaceutics17111493","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T11:17:27Z","timestamp":1763551047000},"page":"1493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Chitosan-Coated Liposomes for Intranasal Delivery of Ghrelin: Enhancing Bioavailability to the Central Nervous System"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2253-6688","authenticated-orcid":false,"given":"Cecilia T.","family":"de Barros","sequence":"first","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, SP, Brazil"},{"name":"Biomaterials Laboratory, Faculty of Medical and Health Sciences, Pontifical Catholic University of S\u00e3o Paulo, Sorocaba 18060-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3586-9457","authenticated-orcid":false,"given":"Thais F. R.","family":"Alves","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-1946","authenticated-orcid":false,"given":"Kessi M. M.","family":"Crescencio","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6171-9305","authenticated-orcid":false,"given":"Jessica","family":"Asami","sequence":"additional","affiliation":[{"name":"Biomaterials Laboratory, Faculty of Medical and Health Sciences, Pontifical Catholic University of S\u00e3o Paulo, Sorocaba 18060-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7131-4045","authenticated-orcid":false,"given":"Moema de A.","family":"Hausen","sequence":"additional","affiliation":[{"name":"Biomaterials Laboratory, Faculty of Medical and Health Sciences, Pontifical Catholic University of S\u00e3o Paulo, Sorocaba 18060-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6327-7363","authenticated-orcid":false,"given":"Eliana A. de R.","family":"Duek","sequence":"additional","affiliation":[{"name":"Biomaterials Laboratory, Faculty of Medical and Health Sciences, Pontifical Catholic University of S\u00e3o Paulo, Sorocaba 18060-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3618-8415","authenticated-orcid":false,"given":"Marco V.","family":"Chaud","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.clnu.2009.12.004","article-title":"Consensus Definition of Sarcopenia, Cachexia and Pre-Cachexia: Joint Document Elaborated by Special Interest Groups (SIG) \u201c Cachexia-Anorexia in Chronic Wasting Diseases\u201d and \u201c Nutrition in Geriatrics\u201d","volume":"29","author":"Muscaritoli","year":"2010","journal-title":"Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and Classification of Cancer Cachexia: An International Consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.cell.2023.03.028","article-title":"Cachexia: A Systemic Consequence of Progressive, Unresolved Disease","volume":"186","author":"Ferrer","year":"2023","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100120","DOI":"10.1016\/j.apjon.2022.100120","article-title":"Pathophysiology of Cachexia and Characteristics of Dysphagia in Chronic Diseases","volume":"9","author":"Matsuo","year":"2022","journal-title":"Asia Pac. J. Oncol. Nurs."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41389-020-00288-6","article-title":"Understanding the Common Mechanisms of Heart and Skeletal Muscle Wasting in Cancer Cachexia","volume":"10","author":"Rausch","year":"2021","journal-title":"Oncogenesis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/0118746098355767250325074021","article-title":"Cachexia: Unraveling Its Complex Pathophysiology and Novel Therapeutic Approaches","volume":"18","author":"Dudhat","year":"2025","journal-title":"Curr. Aging Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bilski, J., Szlachcic, A., Ptak-Belowska, A., and Brzozowski, T. (2025). Physical Activity, Exerkines, and Their Role in Cancer Cachexia. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26168011"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/jcsm.12659","article-title":"Natural Ghrelin in Advanced Cancer Patients with Cachexia, a Case Series","volume":"12","author":"Blum","year":"2021","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1002\/jcsm.13211","article-title":"EXT418, a Novel Long-Acting Ghrelin, Mitigates Lewis Lung Carcinoma Induced Cachexia in Mice","volume":"14","author":"Kerr","year":"2023","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"195","DOI":"10.4103\/CJP.CJP_59_20","article-title":"Acylated and Unacylated Ghrelin Relieve Cancer Cachexia in Mice through Multiple Mechanisms","volume":"63","author":"Zeng","year":"2020","journal-title":"Chin. J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Jiao, Z.T., and Luo, Q. (2022). Molecular Mechanisms and Health Benefits of Ghrelin: A Narrative Review. Nutrients, 14.","DOI":"10.3390\/nu14194191"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"80","DOI":"10.21037\/apm.2018.11.01","article-title":"Prokinetics and Ghrelin for the Management of Cancer Cachexia Syndrome","volume":"8","author":"Malik","year":"2019","journal-title":"Ann. Palliat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.ejps.2012.07.014","article-title":"In Vitro and in Vivo Stability and Pharmacokinetic Profile of Unacylated Ghrelin (UAG) Analogues","volume":"47","author":"Julien","year":"2012","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4158\/EP.14.2.143","article-title":"Compliance and Persistence in Pediatric and Adult Patients Receiving Growth Hormone Therapy","volume":"14","author":"Rosenfeld","year":"2008","journal-title":"Endocr. Pract."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Alabsi, W., Eedara, B.B., Encinas-Basurto, D., Polt, R., and Mansour, H.M. (2022). Nose-to-Brain Delivery of Therapeutic Peptides as Nasal Aerosols. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091870"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1517\/17425247.2012.636801","article-title":"Physicochemical and Physiological Considerations for Efficient Nose-to-Brain Targeting","volume":"9","author":"Bahadur","year":"2012","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_17","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_18","doi-asserted-by":"crossref","unstructured":"Huang, Q., Chen, X., Yu, S., Gong, G., and Shu, H. (2024). Research Progress in Brain-Targeted Nasal Drug Delivery. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1341295"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1749-6632.1978.tb22010.x","article-title":"Properties and Uses of Lipid Vesicles: An Overview","volume":"308","author":"Bangham","year":"1978","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_20","unstructured":"(2009). Biological Evaluation of Medical Devices\u2014Part 5: Tests for in Vitro Cytotoxicity (Standard No. ISO 10993-5:2009)."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1002\/jps.10123","article-title":"A New Method for Drug Transport Studies on Pig Nasal Mucosa Using a Horizontal Ussing Chamber","volume":"91","year":"2002","journal-title":"J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0928-0987(98)00023-2","article-title":"Nasal Drug Delivery\u2014Evaluation of an in Vitro Model Using Porcine Nasal Mucosa","volume":"7","author":"Wadell","year":"1999","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.jpba.2009.09.040","article-title":"Validation of a Method for the Quantitation of Ghrelin and Unacylated Ghrelin by HPLC","volume":"51","author":"Staes","year":"2010","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yanagihara, S., Kitayama, Y., Yuba, E., and Harada, A. (2023). Preparing Size-Controlled Liposomes Modified with Polysaccharide Derivatives for PH-Responsive Drug Delivery Applications. Life, 13.","DOI":"10.3390\/life13112158"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Doskocz, J., Da\u0142ek, P., Przyby\u0142o, M., Trzebicka, B., Fory\u015b, A., Kobyliukh, A., Igli\u010d, A., and Langner, M. (2021). The Elucidation of the Molecular Mechanism of the Extrusion Process. Materials, 14.","DOI":"10.3390\/ma14154278"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhang, X., Wang, M., Liu, Z., Wang, Y., Chen, L., Guo, J., Zhang, W., Zhang, Y., Yu, C., and Bie, T. (2023). Transnasal-Brain Delivery of Nanomedicines for Neurodegenerative Diseases. Front. Drug Deliv., 3.","DOI":"10.3389\/fddev.2023.1247162"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101875","DOI":"10.1016\/j.cocis.2024.101875","article-title":"Liposomes: Bridging the Gap from Lab to Pharmaceuticals","volume":"75","author":"Eugster","year":"2025","journal-title":"Curr. Opin. Colloid Interface Sci."},{"key":"ref_28","first-page":"366","article-title":"Preparation, Optimization and Characterization of Chitosan-Coated Liposomes for Solubility Enhancement of Furosemide: A Model BCS IV Drug","volume":"19","author":"Moslehi","year":"2020","journal-title":"Iran. J. Pharm. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5354","DOI":"10.1039\/D3MH00717K","article-title":"Dynamic Light Scattering and Transmission Electron Microscopy in Drug Delivery: A Roadmap for Correct Characterization of Nanoparticles and Interpretation of Results","volume":"10","author":"Filippov","year":"2023","journal-title":"Mater. Horiz."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"N\u00e9meth, Z., Cs\u00f3ka, I., Semnani Jazani, R., Sipos, B., Haspel, H., Kozma, G., K\u00f3nya, Z., and Dob\u00f3, D.G. (2022). Quality by Design-Driven Zeta Potential Optimisation Study of Liposomes with Charge Imparting Membrane Additives. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091798"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8531","DOI":"10.2147\/IJN.S147650","article-title":"Development of Coated Liposomes Loaded with Ghrelin for Nose-to-Brain Delivery for the Treatment of Cachexia","volume":"12","author":"Salade","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5381","DOI":"10.2147\/IJN.S117210","article-title":"Getting into the Brain: Liposome-Based Strategies for Effective Drug Delivery across the Blood\u2013Brain Barrier","volume":"11","author":"Vieira","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shirnoush, N., Emamifar, A., and Davati, N. (2025). Preparation and Characteristics Evaluation of Chitosan-Coated Nanoliposomes Containing Ferrous Sulfate. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-03832-9"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tan, F., Li, H., Zhang, K., Xu, L., Zhang, D., Han, Y., and Han, J. (2023). Sodium Alginate\/Chitosan-Coated Liposomes for Oral Delivery of Hydroxy-\u03b1-Sanshool: In Vitro and In Vivo Evaluation. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15072010"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"N7","DOI":"10.1111\/j.1750-3841.2008.00747.x","article-title":"Formation of Biopolymer-Coated Liposomes by Electrostatic Deposition of Chitosan","volume":"73","author":"Laye","year":"2008","journal-title":"J. Food Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1007\/s13346-020-00891-5","article-title":"Intranasal Drug Delivery: Opportunities and Toxicologic Challenges during Drug Development","volume":"12","author":"Keller","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kang, B.R., Park, J.S., Ryu, G.R., Jung, W.J., Choi, J.S., and Shin, H.M. (2022). Effect of Chitosan Coating for Efficient Encapsulation and Improved Stability under Loading Preparation and Storage Conditions of Bacillus Lipopeptides. Nanomaterials, 12.","DOI":"10.3390\/nano12234189"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"123407","DOI":"10.1016\/j.ijpharm.2023.123407","article-title":"Stability and Cytotoxicity of Biopolymer-Coated Liposomes for Use in the Oral Cavity","volume":"645","author":"Frigaard","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Syama, K., Jakubek, Z.J., Chen, S., Zaifman, J., Tam, Y.Y.C., and Zou, S. (2022). Development of Lipid Nanoparticles and Liposomes Reference Materials (II): Cytotoxic Profiles. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-23013-2"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/978-0-387-76713-0_9","article-title":"Liposomes in Biology and Medicine","volume":"620","author":"Schwendener","year":"2007","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"107070","DOI":"10.1016\/j.jddst.2025.107070","article-title":"Exploring Intranasal Delivery of Peptide and Protein Nanoparticles by a Thermoresponsive Hydrogel","volume":"110","author":"Khan","year":"2025","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gil-Gonzalo, R., Durante-Salmer\u00f3n, D.A., Pouri, S., Doncel-P\u00e9rez, E., Alc\u00e1ntara, A.R., Aranaz, I., and Acosta, N. (2024). Chitosan-Coated Liposome Formulations for Encapsulation of Ciprofloxacin and Etoposide. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16081036"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1016\/j.jasms.2005.07.012","article-title":"Evaluation of Matrix Effect and Chromatography Efficiency: New Parameters for Validation of Method Development","volume":"16","author":"Rogatsky","year":"2005","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Fu, H., Chu, L., Jiao, H., Lin, L., Liu, Y., Chen, G., Zou, L., Wang, X., and Di, X. (2022). A Highly Sensitive and Rapid LC-MS\/MS Method for Quantification of Bexarotene in Mouse Plasma and Brain Tissue: Application to Mice Pharmacokinetic Study. J. Chromatogr. B Anal. Technol. Biomed. Life Sci., 1189.","DOI":"10.1016\/j.jchromb.2021.123025"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"bqae166","DOI":"10.1210\/endocr\/bqae166","article-title":"Intranasal Delivery of a Ghrelin Mimetic Engages the Brain Ghrelin Signaling System in Mice","volume":"166","author":"Poelman","year":"2025","journal-title":"Endocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e04517","DOI":"10.1002\/smll.202504517","article-title":"Nose-to-Brain Delivery of Acyl-Ghrelin Peptide Gold Nanoconjugates for Treatment of Neurodegenerative Diseases","volume":"21","author":"Han","year":"2025","journal-title":"Small"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e70213","DOI":"10.1002\/mco2.70213","article-title":"The Nasal\u2013Brain Drug Delivery Route: Mechanisms and Applications to Central Nervous System Diseases","volume":"6","author":"Qiu","year":"2025","journal-title":"MedComm"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"115196","DOI":"10.1016\/j.addr.2024.115196","article-title":"Intranasal Drug Delivery: The Interaction between Nanoparticles and the Nose-to-Brain Pathway","volume":"207","author":"Chen","year":"2024","journal-title":"Adv. Drug Deliv. Rev."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/11\/1493\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:23:08Z","timestamp":1763702588000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/11\/1493"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":48,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["pharmaceutics17111493"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17111493","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]}}}