Rivastigmine is a drug commonly used in the management of Alzheimer’s 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—CMAs) 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–Behnken 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 ± 1.9 nm and 109.0 ± 0.9 nm; 0.221 ± 0.003 and 0.196 ± 0.007; −30.6 ± 0.3 mV and −30.5 ± 0.3 mV; 97.0 ± 0.5% and 97.2 ± 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.

Current treatments for Alzheimer’s disease (AD) attenuate the progression of symptoms and aim to improve the patient’s quality of life. Licensed medicines are mostly for oral administration and are limited by the difficulty in crossing the blood–brain barrier (BBB). Here in, the nasal route has been explored as an alternative pathway that allows drugs to be directly delivered to the brain via the nasal cavity. However, clearance mechanisms in the nasal cavity impair the delivery of drugs to the brain and limit their bioavailability. To optimize nose-to-brain delivery, formulations of lipid-based nanosystems, namely nanoemulsions and nanostructured lipid carriers (NLC), formulated in situ gelling hydrogels have been proposed as approaches for nose-to-brain delivery. These formulations possess characteristics that facilitate drug transport directly to the brain, minimizing side effects and maximizing therapeutic benefits. It has been recommended that the manufacture of these drug delivery systems follows the quality by design (QbD) approach based on nasal administration requirements. This review provides an insight into the current knowledge of the AD, highlighting the need for an effective drug delivery to the brain. Considering the mounting interest in the use of nanoemulsions and NLC for nose-to-brain delivery, a description of drug transport pathways in the nasal cavity and the application of these nanosystems and their in situ hydrogels through the intranasal route are presented. Relevant preclinical studies are summarised, and the future prospects for the use of lipid-based nanosystems in the treatment of AD are emphasized.