Enhanced brain delivery with lower hepatic exposure of lazaroid loaded nanostructured lipid carriers developed using a design of experiment approach

Gadgil, Prajakta; Shah, Jigar; Chow, Diana

doi:10.1016/j.ijpharm.2018.04.046

Cited by 11 publications

(5 citation statements)

References 53 publications

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“…The assays performed to obtaine NPs brain uptake demonstrated that thiamine-coated NPs associated with the BBB thiamine transporter had an increased K in between 45 and 120 s (thiamine coated NPs 9.8 ± 1.1 × 10 −3 mL/s/g) versus uncoated NPs (7.0 ± 0.3 × 10 −3 mL/s/g) [74]. Another recent study was designed to develop and optimize lazaroid loaded nano-structured lipid carriers (LAZ-NLCs) [75]. Their dimensions were chosen in the range of (150–200 nm) for enhancing lazaroid brain exposure and for bypassing the clearance mechanisms, resulting in a longer contact time with the BBB for passive diffusion.…”

Section: Mechanisms To Surpass the Blood–brain Barrier (Bbb)mentioning

confidence: 99%

Nanomaterials for Drug Delivery to the Central Nervous System

et al. 2019

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The intricate microstructure of the blood-brain barrier (BBB) is responsible for the accurate intrinsic regulation of the central nervous system (CNS), in terms of neuronal pathophysiological phenomena. Any disruption to the BBB can be associated with genetic defects triggering or with local antigenic invasion (either neurotoxic blood-derived metabolites and residues or microbial pathogens). Such events can be further related to systemic inflammatory or immune disorders, which can subsequently initiate several neurodegenerative pathways. Any degenerative process related to the CNS results in progressive and yet incurable impairment of neuronal cells. Since these particular neurons are mostly scanty or incapable of self-repair and regeneration processes, there is tremendous worldwide interest in novel therapeutic strategies for such specific conditions. Alzheimer’s and Parkinson’s diseases (AD and PD, respectively) are conditions found worldwide, being considered the most rampant degenerative pathologies related to CNS. The current therapy of these conditions, including both clinical and experimental approaches, mainly enables symptom management and subsidiary neuronal protection and even less disease regression. Still, a thorough understanding of the BBB pathophysiology and an accurate molecular and sub-molecular management of AD and PD will provide beneficial support for more specific and selective therapy. Since nanotechnology-derived materials and devices proved attractive and efficient platforms for modern biomedicine (including detection, imaging, diagnosis, medication, restoration and regeneration), a particular approach for AD and PD management relies on nanoparticle-based therapy. In this paper we will discuss relevant aspects related to the BBB and its impact on drug-based treatment and emphasize that nanoparticles are suitable and versatile candidates for the development of novel and performance-enhanced nanopharmaceuticals for neurodegenerative conditions therapy.

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Section: Mechanisms To Surpass the Blood–brain Barrier (Bbb)mentioning

confidence: 99%

Nanomaterials for Drug Delivery to the Central Nervous System

et al. 2019

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“…Afterwards, the CPPs were selected, which corresponded to the production method (high-pressure homogenization—HPH; or ultrasound technique) to produce rivastigmine-loaded NLC formulations with the desired QTPP. A central composite design was used to optimize the CMAs to achieve high quality predictions for various factors at extreme levels [ 32 , 43 , 44 ], and a Box–Behnken design was used to optimize the CPPs, analyzing the effects of three variables and requiring less experiments [ 45 , 46 , 47 ]. Finally, the pH and osmolarity of the optimized NLC formulations were adjusted to the physiological values and in vitro release studies were performed.…”

Section: Introductionmentioning

confidence: 99%

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 Parameters

et al. 2020

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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.

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“…2A and Table S1†), which was suitable for long time circulation in vivo . 29 Observation by transmission electron microscopy (TEM) confirmed that L@S/L appeared as small spheres of about 100 nm with uniform size distribution (Fig. 2B).…”

Section: Resultsmentioning

confidence: 81%