The management of the central nervous system (CNS) disorders is challenging, due to the need of drugs to cross the blood‒brain barrier (BBB) and reach the brain. Among the various strategies that have been studied to circumvent this challenge, the use of the intranasal route to transport drugs from the nose directly to the brain has been showing promising results. In addition, the encapsulation of the drugs in lipid-based nanocarriers, such as solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) or nanoemulsions (NEs), can improve nose-to-brain transport by increasing the bioavailability and site-specific delivery. This review provides the state-of-the-art of in vivo studies with lipid-based nanocarriers (SLNs, NLCs and NEs) for nose-to-brain delivery. Based on the literature available from the past two years, we present an insight into the different mechanisms that drugs can follow to reach the brain after intranasal administration. The results of pharmacokinetic and pharmacodynamics studies are reported and a critical analysis of the differences between the anatomy of the nasal cavity of the different animal species used in in vivo studies is carried out. Although the exact mechanism of drug transport from the nose to the brain is not fully understood and its effectiveness in humans is unclear, it appears that the intranasal route together with the use of NLCs, SLNs or NEs is advantageous for targeting drugs to the brain. These systems have been shown to be more effective for nose-to-brain delivery than other routes or formulations with non-encapsulated drugs, so they are expected to be approved by regulatory authorities in the coming years.

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.