{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:48:39Z","timestamp":1776401319156,"version":"3.51.2"},"reference-count":108,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,6,28]],"date-time":"2020-06-28T00:00:00Z","timestamp":1593302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Rivastigmine is a drug commonly used in the management of Alzheimer\u2019s disease that shows bioavailability problems. To overcome this, the use of nanosystems, such as nanostructured lipid carriers (NLC), administered through alternative routes seems promising. In this work, we performed a double optimization of a rivastigmine-loaded NLC formulation for direct drug delivery from the nose to the brain using the quality by design (QbD) approach, whereby the quality target product profile (QTPP) was the requisite for nose to brain delivery. The experiments started with the optimization of the formulation variables (or critical material attributes\u2014CMAs) using a central composite design. The rivastigmine-loaded NLC formulations with the best critical quality attributes (CQAs) of particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) were selected for the second optimization, which was related to the production methods (ultrasound technique and high-pressure homogenization). The most suitable instrumental parameters for the production of NLC were analyzed through a Box\u2013Behnken design, with the same CQAs being evaluated for the first optimization. For the second part of the optimization studies, were selected two rivastigmine-loaded NLC formulations: one produced by ultrasound technique and the other by the high-pressure homogenization (HPH) method. Afterwards, the pH and osmolarity of these formulations were adjusted to the physiological nasal mucosa values and in vitro drug release studies were performed. The results of the first part of the optimization showed that the most adequate ratios of lipids and surfactants were 7.49:1.94 and 4.5:0.5 (%, w\/w), respectively. From the second part of the optimization, the results for the particle size, PDI, ZP, and EE of the rivastigmine-loaded NLC formulations produced by ultrasound technique and HPH method were, respectively, 114.0 \u00b1 1.9 nm and 109.0 \u00b1 0.9 nm; 0.221 \u00b1 0.003 and 0.196 \u00b1 0.007; \u221230.6 \u00b1 0.3 mV and \u221230.5 \u00b1 0.3 mV; 97.0 \u00b1 0.5% and 97.2 \u00b1 0.3%. Herein, the HPH was selected as the most suitable production method, although the ultrasound technique has also shown effectiveness. In addition, no significant changes in CQAs were observed after 90 days of storage of the formulations at different temperatures. In vitro studies showed that the release of rivastigmine followed a non-Fickian mechanism, with an initial fast drug release followed by a prolonged release over 48 h. This study has optimized a rivastigmine-loaded NLC formulation produced by the HPH method for nose-to-brain delivery of rivastigmine. The next step is for in vitro and in vivo experiments to demonstrate preclinical efficacy and safety. QbD was demonstrated to be a useful approach for the optimization of NLC formulations for which specific physicochemical requisites can be identified.<\/jats:p>","DOI":"10.3390\/pharmaceutics12070599","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T14:24:24Z","timestamp":1593527064000},"page":"599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["Double Optimization of Rivastigmine-Loaded Nanostructured Lipid Carriers (NLC) for Nose-to-Brain Delivery Using the Quality by Design (QbD) Approach: Formulation Variables and Instrumental Parameters"],"prefix":"10.3390","volume":"12","author":[{"given":"Sara","family":"Cunha","sequence":"first","affiliation":[{"name":"UCIBIO\/REQUIMTE, MEDTECH Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Cl\u00e1udia Pina","family":"Costa","sequence":"additional","affiliation":[{"name":"UCIBIO\/REQUIMTE, MEDTECH Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-3967","authenticated-orcid":false,"given":"Joana A.","family":"Loureiro","sequence":"additional","affiliation":[{"name":"LEPABE, Department of Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal"}]},{"given":"Jorge","family":"Alves","sequence":"additional","affiliation":[{"name":"Thermo Unicam, 4470-108 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1176-9064","authenticated-orcid":false,"given":"Andreia F.","family":"Peixoto","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8193-6107","authenticated-orcid":false,"given":"Ben","family":"Forbes","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King\u2019s College London, London SE1 9NH, UK"}]},{"given":"Jos\u00e9 Manuel","family":"Sousa Lobo","sequence":"additional","affiliation":[{"name":"UCIBIO\/REQUIMTE, MEDTECH Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6923-0232","authenticated-orcid":false,"given":"Ana Catarina","family":"Silva","sequence":"additional","affiliation":[{"name":"UCIBIO\/REQUIMTE, MEDTECH Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"UFP Energy, Environment and Health Research Unit (FP ENAS), Fernando Pessoa University, 4249-004 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1177\/2042098617750555","article-title":"An update on the safety of current therapies for Alzheimer\u2019s disease: Focus on rivastigmine","volume":"9","author":"Khoury","year":"2018","journal-title":"Ther. 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