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- Intranasal delivery of nanostructured lipid carriers, solid lipid nanoparticles and nanoemulsions: a current overview of in vivo studiesPublication . Costa, Cláudia Pina; Moreira, João Nuno; Lobo, José Manuel Sousa; Silva, Ana CatarinaThe 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.
- Thermosensitive nasal in situ gels of lipid-based nanosystems to improve the treatment of Alzheimer’s DiseasePublication . Cunha, Sara; Forbes, Ben; Lobo, José Manuel Sousa; Silva, Ana CatarinaThermosensitive in situ gels are promising formulations for the management of Alzheimer’s disease (AD), since they increase the residence time of lipid-based nanosystems in the nasal cavity, improving drug therapeutic efficacy. The purpose of this study is to prepare thermosensitive in situ gels with anticholinesterase inhibitor (RVG)-loaded nanostructured lipid carriers (NLC) and nanoemulsions to improve the residence time of the formulations in the nasal cavity. Different concentrations of thermosensitive polymers were added to the RVG-loaded NLC and to the RVG-loaded nanoemulsion to optimize the gelation temperature of the in situ gels; concentrations of 17% (%, w/w) of Kolliphor® P407 and 0.3% (%, w/w) of MethocelTM K4M were selected. The in situ gels of the RVG-loaded NLC and RVG-loaded nanoemulsion had a particle size, PDI, ZP, and pH of, respectively: 141.70 ± 0.40 nm and 146.10 ± 1.73 nm; 0.45 ± 0.00 and 0.43 ± 0.02; −4.06 ± 1.03 mV and −4.09 ± 0.71 mV, 6.60 ± 0.01 and 7.00 ± 0.02. In addition, these in situ gels showed a non-Newtonian plastic behavior, and the texture parameters presented desirable values for nasal administration. From these results, we concluded that the developed in situ gels can be used to improve the treatment of AD through the nose-to-brain route.
- Application of the Quality-by-Design (QbD) approach to improve the nose-to-brain delivery of diazepam-loaded Nanostructured Lipid Carriers (NLCs)Publication . Costa, Cláudia Pina; Cunha, Sara; Peixoto, Andreia F.; Moreira, João Nuno; Lobo, José Manuel Sousa; Silva, Ana CatarinaThe intranasal administration of nanostructured lipid carriers (NLCs) has been suggested as a promising strategy to improve the fast treatment of epilepsy. This route allows for drug passage directly from the nose to the brain, avoiding the need of bypassing the blood–brain barrier. In addition, the quality-by-design (QbD) approach is a useful tool for the optimization of manufacturing variables, resulting in effective and safe pharmaceutical formulations. The aim of this work was to use the QbD approach to optimize a NLCs formulation for the nose-to-brain delivery of diazepam. The studies began with the screening of excipients and the assessment of the lipid-drug compatibility. The central composite design was used to evaluate the effects of critical material attributes (CMAs) (ratio of solid and liquid lipids and the amount of drug and emulsifiers) on the CQAs of the diazepam-loaded NLCs formulation (particle size, polydispersity index (PDI), zeta potential (ZP) and encapsulation efficiency (EE)). The results showed that the most adequate ratios of lipids and emulsifiers were 6.65:2.85 and 4.2:0.3 (%, w/w), with values of 84.92 nm, 0.18, −18.20 mV and 95.48% for particle size, PDI, ZP and EE, respectively. This formulation was selected for further studies related to the optimization of critical process parameters (CPPs).