Abstract
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.
Highlights
Alzheimer’s disease is an irreversible neurodegenerative disorder characterized by neuronal deterioration that leads to the loss of cognitive functions [1,2,3]
Precirol® ATO5 was used as the solid lipid, due to its appropriate melting point (56 ◦C) and ability to form the imperfect lipid matrix of the nanostructured lipid carriers (NLC) when mixed with a liquid lipid, which provides a high drug loading capacity [54,55]
Several studies have shown that a high concentration of liquid lipids increases drug retention, as drug solubility in liquid lipids is usually higher than in solid lipids, which decreases the particle size due to the decreased viscosity and surface tension of the NLC [46,79,88]
Summary
Alzheimer’s disease is an irreversible neurodegenerative disorder characterized by neuronal deterioration that leads to the loss of cognitive functions [1,2,3]. Drugs used in clinical practice can attenuate the disease symptoms, inhibiting acetylcholinesterase activity and avoiding acetylcholine hydrolysis in the synaptic cleft [5,6]. Examples of these drugs include galantamine, donepezil, and rivastigmine [1,7]. It was reported that rivastigmine hydrogen tartrate undergoes an extensive first-pass effect in the liver, which decreases bioavailability [10,11] This molecule has a short half-life and a hydrophilic nature, which makes it difficult for it to pass through the blood brain barrier (BBB) and cerebrospinal fluid (CSF) [5,9,12]. High drug concentration and frequent dose administration are required to reach therapeutic levels, causing unpleasant cholinergic side effects, such as nausea, dyspepsia, bradycardia, and hallucinations [8,10,11]
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