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      Development of Meloxicam-Human Serum Albumin Nanoparticles for Nose-to-Brain Delivery via Application of a Quality by Design Approach

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          Abstract

          The aim of this study was to optimize the formulation of meloxicam (MEL)-containing human serum albumin (HSA) nanoparticles for nose-to-brain via a quality by design (QbD) approach. Liquid and dried formulations of nanoparticles containing Tween 80 and without the surfactant were investigated. Various properties, such as the Z-average, zeta potential, encapsulation efficacy (EE), conjugation of MEL and HSA, physical stability, in vitro dissolution, in vitro permeability, and in vivo plasma and brain distribution of MEL were characterized. From a stability point of view, a solid product (Mel-HSA-Tween) is recommended for further development since it met the desired critical parameters (176 ± 0.3 nm Z-average, 0.205 ± 0.01 PdI, −14.1 ± 0.7 mV zeta potential) after 6 months of storage. In vitro examination showed a significantly increased drug dissolution and permeability of MEL-containing nanoparticles, especially in the case of applying Tween 80. The in vivo studies confirmed both the trans-epithelial and axonal transport of nanoparticles, and a significantly higher cerebral concentration of MEL was detected with nose-to-brain delivery, in comparison with intravenous or per os administration. These results indicate intranasal the administration of optimized MEL-containing HSA formulations as a potentially applicable “value-added” product for the treatment of neuroinflammation.

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          Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles.

          Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles. The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer. An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.
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            Evaluation of intranasal delivery route of drug administration for brain targeting

            The acute or chronic drug treatments for different neurodegenerative and psychiatric disorders are challenging from several aspects. The low bioavailability and limited brain exposure of oral drugs, the rapid metabolism, elimination, the unwanted side effects and also the high dose to be added mean both inconvenience for the patients and high costs for the patients, their family and the society. The reason of low brain penetration of the compounds is that they have to overcome the blood-brain barrier which protects the brain against xenobiotics. Intranasal drug administration is one of the promising options to bypass blood-brain barrier, to reduce the systemic adverse effects of the drugs and to lower the doses to be administered. Furthermore, the drugs administered using nasal route have usually higher bioavailability, less side effects and result in higher brain exposure at similar dosage than the oral drugs. In this review the focus is on giving an overview on the anatomical and cellular structure of nasal cavity and absorption surface. It presents some possibilities to enhance the drug penetration through the nasal barrier and summarizes some in vitro, ex vivo and in vivo technologies to test the drug delivery across the nasal epithelium into the brain. Finally, the authors give a critical evaluation of the nasal route of administration showing its main advantages and limitations of this delivery route for CNS drug targeting.
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              Impact of albumin on drug delivery--new applications on the horizon.

              Over the past decades, albumin has emerged as a versatile carrier for therapeutic and diagnostic agents, primarily for diagnosing and treating diabetes, cancer, rheumatoid arthritis and infectious diseases. Market approved products include fatty acid derivatives of human insulin or the glucagon-like-1 peptide (Levemir(®) and Victoza(®)) for treating diabetes, the taxol albumin nanoparticle Abraxane(®) for treating metastatic breast cancer which is also under clinical investigation in further tumor indications, and (99m)Tc-aggregated albumin (Nanocoll(®) and Albures(®)) for diagnosing cancer and rheumatoid arthritis as well as for lymphoscintigraphy. In addition, an increasing number of albumin-based or albumin-binding drugs are in clinical trials such as antibody fusion proteins (MM-111) for treating HER2/neu positive breast cancer (phase I), a camelid albumin-binding nanobody anti-HSA-anti-TNF-α (ATN-103) in phase II studies for treating rheumatoid arthritis, an antidiabetic Exendin-4 analog bound to recombinant human albumin (phase I/II), a fluorescein-labeled albumin conjugate (AFL)-human serum albumin for visualizing the malignant borders of brain tumors for improved surgical resection, and finally an albumin-binding prodrug of doxorubicin (INNO-206) entering phase II studies against sarcoma and gastric cancer. In the preclinical setting, novel approaches include attaching peptides with high-affinity for albumin to antibody fragments, the exploitation of albumin-binding gadolinium contrast agents for magnetic resonance imaging, and physical or covalent attachment of antiviral, antibacterial, and anticancer drugs to albumin that are permanently or transiently attached to human serum albumin (HSA) or act as albumin-binding prodrugs. This review gives an overview of the expanding field of preclinical and clinical drug applications and developments that use albumin as a protein carrier to improve the pharmacokinetic profile of the drug or to target the drug to the pathogenic site addressing diseases with unmet medical needs. Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                25 January 2020
                February 2020
                : 12
                : 2
                : 97
                Affiliations
                [1 ]Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, H-6720 Szeged, Hungary; tamas.kiss@ 123456pharm.u-szeged.hu (T.K.); arita@ 123456pharm.u-szeged.hu (R.A.); edina.pallagi@ 123456pharm.u-szeged.hu (E.P.); revesz@ 123456pharm.u-szeged.hu (P.S.-R.); csoka@ 123456pharm.u-szeged.hu (I.C.)
                [2 ]Department of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics, H-1111 Budapest, Hungary; balogh.gyorgy@ 123456pharm.u-szeged.hu (G.T.B.); gdargo@ 123456mail.bme.hu (G.D.)
                [3 ]Faculty of Pharmacy, Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Hungary; ducza@ 123456pharm.u-szeged.hu (E.D.); ivanov.anita@ 123456pharm.u-szeged.hu (A.S.-I.)
                [4 ]Faculty of Medicine, Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720 Szeged, Hungary; gaspar.robert@ 123456med.u-szeged.hu
                [5 ]Faculty of Medicine, Department of Medical Physics and Informatics, University of Szeged, H-6720 Szeged, Hungary; marki.arpad@ 123456med.u-szeged.hu
                [6 ]Interdisciplinary Excellence Centre, Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Hungary; tomosi.ferenc@ 123456med.u-szeged.hu (F.T.); kecskemeti.gabor@ 123456med.u-szeged.hu (G.K.); janaky.tamas@ 123456med.u-szeged.hu (T.J.)
                Author notes
                [* ]Correspondence: katona@ 123456pharm.u-szeged.hu ; Tel.: +36-62-545-575
                Author information
                https://orcid.org/0000-0003-1564-4813
                https://orcid.org/0000-0002-1141-8379
                https://orcid.org/0000-0002-1571-7579
                https://orcid.org/0000-0002-6657-5777
                https://orcid.org/0000-0002-5336-6052
                Article
                pharmaceutics-12-00097
                10.3390/pharmaceutics12020097
                7076499
                31991767
                71750924-09dc-4c35-a5d7-b707fb937544
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 December 2019
                : 21 January 2020
                Categories
                Article

                meloxicam,hsa nanoparticles,nose-to-brain delivery,quality by design,physical stability,in vivo animal studies,rapid equilibrium dialysis,pampa

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