{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:02:55Z","timestamp":1789153375321,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o Ci\u00eancia e Tecnologia, Portugal"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Trimethyl chitosan (TMC)-coated alginate\/dextran sulfate (ADS) nanoparticles were developed as mucoadhesive nanocarriers for oral insulin delivery using a Quality-by-Design strategy. In a first screening step, a two-level factorial design was applied to evaluate the influence of ADS concentration, TMC concentration, insulin concentration, and poloxamer\u00ae concentration on particle size and encapsulation efficiency. The screening design identified the ADS-TMC pair as the main formulation parameter for particle size, while TMC and poloxamer\u00ae were the most influential factors for encapsulation efficiency. In a second step, formulation optimization was performed using a three-factor, three-level Box\u2013Behnken design in which ADS concentration, TMC concentration, and the degree of quaternization (DQ) of TMC were investigated as critical material attributes. Particle size, zeta potential, and in vitro mucoadhesion were selected as critical quality attributes. Across the Box\u2013Behnken design, the experimental formulations showed particle sizes ranging from 316 to 1340 nm, zeta potentials between +17 and +39 mV, and mucin-binding values from 7 to 87%. Numerical optimization by Design-Expert\u00ae desirability analysis identified an optimal formulation composed of 0.096% (w\/v) ADS and 0.700% (w\/v) TMC with 60% DQ. The model predicted a particle size of 316.24 nm, a zeta potential of +38.43 mV, and an in vitro mucoadhesion of 87.14%. Experimental confirmation yielded values of 330.79 nm, +37.09 mV, and 84.61%, respectively, with prediction errors below 5% for all responses. In simulated gastric medium, partial insulin leakage was observed during the first 120 min, whereas cumulative insulin release reached 54% after 5 h in simulated intestinal medium. These results demonstrate the usefulness of a QbD framework combined with desirability-based optimization for defining robust formulation conditions for mucoadhesive TMC-coated ADS nanoparticles intended for oral insulin delivery.<\/jats:p>","DOI":"10.3390\/md24060196","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:19:42Z","timestamp":1780316382000},"page":"196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Quality-by-Design Optimization of Mucoadhesive Trimethyl Chitosan-Coated Alginate\/Dextran Sulfate Nanoparticles for Oral Insulin Delivery"],"prefix":"10.3390","volume":"24","author":[{"given":"Bruno","family":"Pessoa","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5584-5260","authenticated-orcid":false,"given":"Daniel","family":"Vanzan","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Cabral","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1399-8944","authenticated-orcid":false,"given":"Antonio J.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Genetics of Cognitive Disfunction, i3S, Instituto de Biologia Molecular e Celular (IBMC), Rua Alfredo Allen, 4169-007 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20155","DOI":"10.1039\/C5RA26224K","article-title":"Impact of the in vitro gastrointestinal passage of biopolymer-based nanoparticles on insulin absorption","volume":"6","author":"Lopes","year":"2016","journal-title":"RSC Adv."},{"key":"ref_2","first-page":"109","article-title":"Nanoparticles for Oral Delivery of Insulin","volume":"Volume 4","author":"Coelho","year":"2013","journal-title":"Drug Delivery Systems: Advanced Technologies Potentially Applicable in Personalised Treatment"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2298\/CICEQ0601047R","article-title":"Design of insulin-loaded alginate nanoparticles: Influence of the calcium ion on polymer gel matrix properties","volume":"12","author":"Reis","year":"2006","journal-title":"Chem. 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