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      Optimal Design, Characterization and Preliminary Safety Evaluation of an Edible Orodispersible Formulation for Pediatric Tuberculosis Pharmacotherapy

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          Abstract

          The severity of tuberculosis (TB) in children is considered a global crisis compounded by the scarcity of pharmaceutical formulations suitable for pediatric use. The purpose of this study was to optimally develop and evaluate a pyrazinamide containing edible orodispersible film formulation potentially suitable for use in pediatrics actively infected with TB. The formulation was prepared employing aqueous-particulate blending and solvent casting methods facilitated by a high performance Box Behnken experimental design template. The optimized orodispersible formulation was mechanically robust, flexible, easy to handle, exhibited rapid disintegration with initial matrix collapse occurring under 60 s (0.58 ± 0.05 min ≡ 34.98 ± 3.00 s) and pyrazinamide release was controlled by anomalous diffusion coupled with matrix disintegration and erosion mechanisms. It was microporous in nature, light weight (57.5 ± 0.5 mg) with an average diameter of 10.5 mm and uniformly distributed pyrazinamide load of 101.13 ± 2.03 % w / w . The formulation was physicochemically stable with no evidence of destructive drug–excipient interactions founded on outcomes of characterization and environmental stability investigations. Preliminary inquiries revealed that the orodispersible formulation was cytobiocompatible, palatable and remained intact under specific storage conditions. Summarily, an edible pyrazinamide containing orodispersible film formulation was optimally designed to potentially improve TB pharmacotherapy in children, particularly the under 5 year olds.

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          Most cited references61

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          The curious characteristics of pyrazinamide: a review.

          Pyrazinamide (PZA) is an important sterilising tuberculosis drug that helps to shorten the duration of current chemotherapy regimens for tuberculosis. When first discovered, it had activity in murine tuberculosis but no apparent in vitro activity, and its subsequent use in treatment depended largely on classic experiments at Cornell University, which showed its requirement for an acid pH for activity and its sterilising activity in the mouse. Recent studies have shown that PZA enters Mycobacterium tuberculosis by passive diffusion, is converted to pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase) and is then excreted by a weak efflux pump. Protonated POA (HPOA) is reabsorbed into the bacilli under acid conditions and accumulates because the efflux pump is inefficient, causing cellular damage. Unlike other antibacterials, PZA has no defined target of action. PZA is more active against old than against actively growing cultures, probably because the energy production and efflux pump would be slowed down by low bacterial metabolism. This review deals with the activity of PZA in vitro, in macrophages and in animal models. It describes the evidence from clinical trials that it is an effective sterilising drug that acts synergistically with rifampicin. The highly diverse mutations in the PZase gene (pncA) that lead to loss of PZase activity cause PZA resistance. Methods for susceptibility determination either as tests against PZA or nicotinamide in liquid and solid media, as tests for PZase activity or for mutations in pncA, are reviewed.
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            Novel superabsorbent cellulose-based hydrogels crosslinked with citric acid

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              In vitro and in vivo toxicity assessment of nanoparticles

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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                10 August 2020
                August 2020
                : 21
                : 16
                : 5714
                Affiliations
                [1 ]Division of Pharmaceutical Sciences, School of Pharmacy, Sefako Makgatho Health Science University, Pretoria 0208, South Africa; nmatawo1@ 123456gmail.com
                [2 ]Electron Microscope Unit, Sefako Makgatho Health Science University, Pretoria 0208, South Africa; jaime.wesley-smith@ 123456smu.ac.za
                Author notes
                [†]

                Additional address: Laboratory of Parasitic Diseases, Immunobiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

                Author information
                https://orcid.org/0000-0002-0880-3997
                https://orcid.org/0000-0002-5627-5797
                Article
                ijms-21-05714
                10.3390/ijms21165714
                7460872
                32784947
                e9e2ca41-87ed-4646-9da0-9c63bcfd8fc3
                © 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
                : 26 June 2020
                : 30 July 2020
                Categories
                Article

                Molecular biology
                orodispersible formulation,pyrazinamide,pediatric drug delivery,tuberculosis,design of experiments,children,edible films

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