{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T04:50:48Z","timestamp":1774932648852,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2018-18364-2"],"award-info":[{"award-number":["2018-18364-2"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The therapeutic use of peptides has increasingly recognized in the development of new therapies. However, the susceptible enzymatic cleavage is a barrier that needs to overcome. Nose-to-brain delivery associated with liposomes can protect peptides against biodegradation and improve the accessibility to brain targets. The aim was to develop a liposomal formulation as ghrelin carrier. The quality by design (QbD) approach was used as a strategy for method development. The initial risk assessments were carried out using a fishbone diagram. A screening design study was performed for the critical material attributes\/critical process parameters (CMAs\/CPPs) on critical quality attributes (CQAs). Liposomes were obtained by hydrating phospholipid films, followed by extrusion or homogenization, and coated with chitosan. The optimized liposome formulation was produced by high-pressure homogenization coated with chitosan, and the resulted were liposomes size 72.25 \u00b1 1.46 nm, PDI of 0.300 \u00b1 0.027, the zeta potential of 50.3 \u00b1 1.46 mV, and encapsulation efficiency of 53.2%. Moreover, chitosan coating improved performance in ex vivo permeation and mucoadhesion analyzes when compared to the uncoated liposome. In this context, chitosan coating is essential for the performance of the formulations in the ex vivo permeation and mucoadhesion analyzes. The intranasal administration of ghrelin liposomes coated with chitosan offers an innovative opportunity to treat cachexia.<\/jats:p>","DOI":"10.3390\/pharmaceutics13050686","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T12:49:49Z","timestamp":1620650989000},"page":"686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Quality by Design Approach for the Development of Liposome Carrying Ghrelin for Intranasal Administration"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2253-6688","authenticated-orcid":false,"given":"Cec\u00edlia de","family":"Barros","sequence":"first","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"}]},{"given":"Norberto","family":"Aranha","sequence":"additional","affiliation":[{"name":"Technological and Environmental Processes, University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6527-6612","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Severino","sequence":"additional","affiliation":[{"name":"Nanomedicine and Nanotechnology Laboratory (LNMed), Institute of Technology and Research (ITP), Av. Murilo Dantas, 300, Aracaju 49010-390, Sergipe, Brazil"}]},{"given":"Eliana B.","family":"Souto","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2603-1377","authenticated-orcid":false,"given":"Aleksandra","family":"Zieli\u0144ska","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3570-2470","authenticated-orcid":false,"given":"Andr\u00e9","family":"Lopes","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Science, University of Campinas, Campinas 13083-871, S\u00e3o Paulo, Brazil"}]},{"given":"Alessandra","family":"Rios","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"}]},{"given":"Fernando","family":"Batain","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-1946","authenticated-orcid":false,"given":"Kessi","family":"Crescencio","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3618-8415","authenticated-orcid":false,"given":"Marco","family":"Chaud","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"},{"name":"Technological and Environmental Processes, University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"},{"name":"College of Bioprocess and Biotechnology Engineering, University of Sorocaba, Sorocaba 18023-000, S\u00e2o Paulo, Brazil"}]},{"given":"Thais","family":"Alves","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials and Nanotechnology (LaBNUS), University of Sorocaba, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"},{"name":"Technological Innovation Agency of Sorocaba, Sorocaba Technology Park, Itavuvu Avenue, Sorocaba 18078-005, S\u00e3o Paulo, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"ref_1","first-page":"CD012229","article-title":"Ghrelin for the management of cachexia associated with cancer","volume":"2","author":"Khatib","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_2","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) \u201ccachexia-anorexia in chronic wasting diseases\u201d and \u201cnutrition in geriatrics\u201d","volume":"29","author":"Muscaritoli","year":"2010","journal-title":"Clin. Nutr."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","unstructured":"De Barros, C.T., Rios, A., Alves, T., Batain, F., Crescencio, K., Lopes, L., Zieli\u0144ska, A., Severino, P., Mazzola, P.G., and Souto, E. (2020). Cachexia: Pathophysiology and Ghrelin Liposomes for Nose-to-Brain Delivery. Int. J. Mol. 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Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ijpharm.2009.05.067","article-title":"Stability, liposome interaction, and in vivo pharmacology of ghrelin in liposomal suspensions","volume":"390","author":"Moeller","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jconrel.2017.05.019","article-title":"Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer\u2019s disease","volume":"260","author":"Agrawal","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1111\/1541-4337.12725","article-title":"Advancements in liposome technology: Preparation techniques and applications in food, functional foods, and bioactive delivery: A review","volume":"20","author":"Ajeeshkumar","year":"2021","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.ijpharm.2014.10.059","article-title":"Administration strategies for proteins and peptides","volume":"477","author":"Ibraheem","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.3390\/molecules13051035","article-title":"Progress in Drug Delivery to the Central Nervous System by the Prodrug Approach","volume":"13","author":"Pavan","year":"2008","journal-title":"Molecules"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3109\/10717544.2013.838713","article-title":"Insights into direct nose to brain delivery: Current status and future perspective","volume":"21","author":"Mittal","year":"2013","journal-title":"Drug Deliv."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1055\/s-0035-1559654","article-title":"Oral Delivery of Therapeutic Proteins and Peptides: An Overview of Current Technologies and Recommendations for Bridging from Approved Intravenous or Subcutaneous Administration to Novel Oral Regimens","volume":"66","author":"Philippart","year":"2015","journal-title":"Drug Res."},{"key":"ref_16","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_17","unstructured":"(2020, December 08). ICH Harmonised Tripartite Guideline. Tokyo. Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Available online: https:\/\/www.ich.org\/page\/search-index-ich-guidelines."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1208\/s12248-014-9598-3","article-title":"Understanding Pharmaceutical Quality by Design","volume":"16","author":"Yu","year":"2014","journal-title":"AAPS J."},{"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","doi-asserted-by":"crossref","first-page":"5","DOI":"10.14450\/2318-9312.v29.e1.a2017.pp5-12","article-title":"Quality by Design (Qbd) Como Ferramenta Para Otimiza\u00e7\u00e3o Dos Processos Farmac\u00eauticos","volume":"29","author":"Bezerra","year":"2017","journal-title":"Infarma Ci\u00eancias Farmac&ecircuticas"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ejpb.2012.11.021","article-title":"Nasal administration of liquid crystal precursor mucoadhesive vehicle as an alternative antiretroviral therapy","volume":"84","author":"Carvalho","year":"2013","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.molmet.2015.03.005","article-title":"Ghrelin","volume":"4","author":"Nogueiras","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.brainresbull.2018.10.009","article-title":"Evaluation of intranasal delivery route of drug administration for brain targeting","volume":"143","author":"Bors","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0168-3659(02)00363-2","article-title":"Nasal drug delivery\u2014possibilities, problems and solutions","volume":"87","author":"Illum","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ijpharm.2019.03.021","article-title":"Application of the QbD-based approach in the early development of liposomes for nasal administration","volume":"562","author":"Pallagi","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sonvico, F., Clementino, A., Buttini, F., Colombo, G., Pescina, S., Guterres, S.S., Pohlmann, A.R., and Nicoli, S. (2018). Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting. Pharmaceutics, 10.","DOI":"10.20944\/preprints201802.0077.v1"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Danaei, M., Dehghankhold, M., Ataei, S., Davarani, F.H., Javanmard, R., Dokhani, A., Khorasani, S., and Mozafari, M.R. (2018). Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10020057"},{"key":"ref_30","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_31","doi-asserted-by":"crossref","first-page":"671","DOI":"10.3109\/10717544.2014.920431","article-title":"Nasal-nanotechnology: Revolution for efficient therapeutics delivery","volume":"23","author":"Kumar","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Porfire, A., Achim, M., Barbalata, C., Rus, I., Tomuta, I., and Cristea, C. (2019). Pharmaceutical Development of Liposomes Using the QbD Approach. Liposomes\u2014Advances and Perspectives, IntechOpen.","DOI":"10.5772\/intechopen.85374"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1021\/acs.molpharmaceut.5b00088","article-title":"Nose-to-Brain Delivery: Investigation of the Transport of Nanoparticles with Different Surface Characteristics and Sizes in Excised Porcine Olfactory Epithelium","volume":"12","author":"Mistry","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_34","first-page":"298","article-title":"Microsphere transport pathways in the rabbit nasal mucosa","volume":"1","author":"Huang","year":"1996","journal-title":"Int. J. Pharm. Adv."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0378-5173(00)00661-X","article-title":"Factors involved in the production of liposomes with a high-pressure homogenizer","volume":"213","year":"2001","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3109\/08982104.2013.826243","article-title":"Applying quality by design (QbD) concept for fabrication of chitosan coated nanoliposomes","volume":"24","author":"Pandey","year":"2013","journal-title":"J. Liposome Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3109\/08982104.2014.924140","article-title":"A facile approach to manufacturing non-ionic surfactant nanodipsersions using proniosome technology and high-pressure homogenization","volume":"25","author":"Najlah","year":"2014","journal-title":"J. Liposome Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ong, S.G.M., Chitneni, M., Lee, K.S., Ming, L.C., and Yuen, K.H. (2016). Evaluation of Extrusion Technique for Nanosizing Liposomes. Pharmaceutics, 8.","DOI":"10.3390\/pharmaceutics8040036"},{"key":"ref_39","unstructured":"(2021, May 03). Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation. Washington, DC. Center for Drug Evaluation and Research- Food and Drug Administration, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/liposome-drug-products-chemistry-manufacturing-and-controls-human-pharmacokinetics-and."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5779","DOI":"10.1007\/s00216-017-0527-z","article-title":"Zeta potential: A case study of cationic, anionic, and neutral liposomes","volume":"409","author":"Smith","year":"2017","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Najlah, M., Suliman, A.S., Tolaymat, T., Kurusamy, S., Kannappan, V., Elhissi, A.M.A., and Wang, W. (2019). Development of Injectable PEGylated Liposome Encapsulating Disulfiram for Colorectal Cancer Treatment. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11110610"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"45290","DOI":"10.1039\/C6RA05574E","article-title":"Chitosan-coated liposomes encapsulating curcumin: Study of lipid\u2013polysaccharide interactions and nanovesicle behavior","volume":"6","author":"Hasan","year":"2016","journal-title":"RSC Adv."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mengoni, T., Adrian, M., Pereira, S., Santos-Carballal, B., Kaiser, M., and Goycoolea, F.M. (2017). A Chitosan\u2014Based Liposome Formulation Enhances the In Vitro Wound Healing Efficacy of Substance P Neuropeptide. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9040056"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11671-017-2256-9","article-title":"Effects of Micro-environmental pH of Liposome on Chemical Stability of Loaded Drug","volume":"12","author":"Shao","year":"2017","journal-title":"Nanoscale Res. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ijpharm.2017.12.047","article-title":"Stability, biocompatibility and antioxidant activity of PEG-modified liposomes containing resveratrol","volume":"538","author":"Caddeo","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ijpharm.2019.04.042","article-title":"Long-term storage of PEGylated liposomal oxaliplatin with improved stability and long circulation times in vivo","volume":"564","author":"Doi","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-1-4939-7352-1_8","article-title":"Imaging of Liposomes by Transmission Electron Microscopy","volume":"Volume 1682","author":"Baxa","year":"2018","journal-title":"Methods in Molecular Biology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.reactfunctpolym.2016.01.011","article-title":"Mucoadhesion: A promising approach in drug delivery system","volume":"100","author":"Mansuri","year":"2016","journal-title":"React. Funct. Polym."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"215","DOI":"10.4103\/2231-4040.90876","article-title":"A review on mucoadhesive polymer used in nasal drug delivery system","volume":"2","author":"Chaturvedi","year":"2011","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1080\/10837450.2016.1242624","article-title":"Preparation of chitosan-coated liposomes as a novel carrier system for the antiviral drug Triazavirin","volume":"23","author":"Kozhikhova","year":"2018","journal-title":"Pharm. Dev. Technol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Bruinsmann, F.A., Pigana, S., Aguirre, T., Souto, G.D., Pereira, G.G., Bianchera, A., Fasiolo, L.T., Colombo, G., Marques, M., and Pohlmann, A.R. (2019). Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery. Pharmaceutics, 11.","DOI":"10.20944\/preprints201902.0034.v1"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Popescu, R., Ghica, M.V., Dinu-P\u00eervu, C.-E., Anu\u021ba, V., Lupuliasa, D., and Popa, L. (2020). New Opportunity to Formulate Intranasal Vaccines and Drug Delivery Systems Based on Chitosan. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145016"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1023\/A:1018901302450","article-title":"Chitosan as a Novel Nasal Delivery System for Peptide Drugs","volume":"11","author":"Illum","year":"1994","journal-title":"Pharm. 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