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      Intranasal agomelatine solid lipid nanoparticles to enhance brain delivery: formulation, optimization and in vivo pharmacokinetics

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          Agomelatine is a novel antidepressant drug suffering from an extensive first-pass metabolism leading to a diminished absolute bioavailability. The aim of the study is: first to enhance its absolute bioavailability, and second to increase its brain delivery.


          To achieve these aims, the nasal route was adopted to exploit first its avoidance of the hepatic first-pass metabolism to increase the absolute bioavailability, and second the direct nose-to-brain pathway to enhance the brain drug delivery. Solid lipid nanoparticles were selected as a drug delivery system to enhance agomelatine permeability across the blood–brain barrier and therefore its brain delivery.


          The optimum solid lipid nanoparticles have a particle size of 167.70 nm ±0.42, zeta potential of −17.90 mV ±2.70, polydispersity index of 0.12±0.10, entrapment efficiency % of 91.25%±1.70%, the percentage released after 1 h of 35.40%±1.13% and the percentage released after 8 h of 80.87%±5.16%. The pharmacokinetic study of the optimized solid lipid nanoparticles revealed a significant increase in each of the plasma peak concentration, the AUC(0–360 min) and the absolute bioavailability compared to that of the oral suspension of Valdoxan ® with the values of 759.00 ng/mL, 7,805.69 ng⋅min/mL and 44.44%, respectively. The optimized solid lipid nanoparticles gave a drug-targeting efficiency of 190.02, which revealed more successful brain targeting by the intranasal route compared with the intravenous route. The optimized solid lipid nanoparticles had a direct transport percentage of 47.37, which indicates a significant contribution of the direct nose-to-brain pathway in the brain drug delivery.


          The intranasal administration of agomelatine solid lipid nanoparticles has effectively enhanced both the absolute bioavailability and the brain delivery of agomelatine.

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          Most cited references 21

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          A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier

          Lipoprotein transport across the blood–brain barrier (BBB) is of critical importance for the delivery of essential lipids to the brain cells. The occurrence of a low density lipoprotein (LDL) receptor on the BBB has recently been demonstrated. To examine further the function of this receptor, we have shown using an in vitro model of the BBB, that in contrast to acetylated LDL, which does not cross the BBB, LDL is specifically transcytosed across the monolayer. The C7 monoclonal antibody, known to interact with the LDL receptor-binding domain, totally blocked the transcytosis of LDL, suggesting that the transcytosis is mediated by the receptor. Furthermore, we have shown that cholesterol-depleted astrocytes upregulate the expression of the LDL receptor at the BBB. Under these conditions, we observed that the LDL transcytosis parallels the increase in the LDL receptor, indicating once more that the LDL is transcytosed by a receptor-mediated mechanism. The nondegradation of the LDL during the transcytosis indicates that the transcytotic pathway in brain capillary endothelial cells is different from the LDL receptor classical pathway. The switch between a recycling receptor to a transcytotic receptor cannot be explained by a modification of the internalization signals of the cytoplasmic domain of the receptor, since we have shown that LDL receptor messengers in growing brain capillary ECs (recycling LDL receptor) or differentiated cells (transcytotic receptor) are 100% identical, but we cannot exclude posttranslational modifications of the cytoplasmic domain, as demonstrated for the polymeric immunoglobulin receptor. Preliminary studies suggest that caveolae are likely to be involved in the potential transport of LDL from the blood to the brain.
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            Strategy for effective brain drug delivery.

            Blood-brain barrier (BBB) together with enzymes restricts the entry of substances for maintaining the internal milieu of the brain. Because of the presence of multiple endogenous transporters, BBB allows a selective entry of nutrients and minerals across it and limits the entry of foreign substances like drugs as well as neuropharmaceutical agents. This makes the CNS treatment ineffective. The conventional drug delivery systems which release drug into general circulation fail to deliver drugs effectively to brain and is therefore not very useful in treating certain diseases that affect CNS including Alzheimer's disease, dementia, Parkinson's disease, mood disorder, AIDS, viral and bacterial meningitis. Therefore there is a need to develop and design approaches which specifically target to brain in a better and effective way. The present review enlightens about several novel approaches including nanotechnology based approach like nanoparticles, liposomes, antibody mediated delivery approach and application of genomics in brain drug targeting that would give an insight to the researchers, academia and industrialists.
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              Solid lipid nanoparticles as vehicles of drugs to the brain: current state of the art.

              Central nervous system disorders are already prevalent and steadily increasing among populations worldwide. However, most of the pharmaceuticals present on world markets are ineffective in treating cerebral diseases, because they cannot effectively cross the blood brain barrier (BBB). Solid lipid nanoparticles (SLN) are nanospheres made from biocompatible solid lipids, with unique advantages among drug carriers: they can be used as vehicles to cross the BBB. This review examines the main aspects surrounding brain delivery with SLN, and illustrates the principal mechanisms used to enhance brain uptake of the delivered drug. Copyright © 2014 Elsevier B.V. All rights reserved.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                19 June 2017
                : 11
                : 1815-1825
                [1 ]Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
                [2 ]School of Pharmacy, University of Waterloo, Waterloo, ON, Canada
                Author notes
                Correspondence: Ahmed H Elshafeey, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El Eyni Street, Cairo, Egypt, Tel +20 100 584 0261, Email ahmed.elshafeey@ 123456pharma.cu.edu.eg
                © 2017 Fatouh et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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