Browsing by Author "Peixoto, Andreia F."
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- 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).
- 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 parametersPublication . Cunha, Sara; Costa, Cláudia Pina; Loureiro, Joana A.; Alves, Jorge; Peixoto, Andreia F.; Forbes, Ben; Sousa Lobo, José Manuel; Silva, Ana CatarinaRivastigmine 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.