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      The Effects of Primary Unconjugated Bile Acids on Nanoencapsulated Pharmaceutical Formulation of Hydrophilic Drugs: Pharmacological Implications

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          Abstract

          Introduction

          In a recent study, in our laboratory, primary unconjugated bile acids, commonly found in humans, chenodeoxycholic acid (CDCA), have been shown to improve stability of nanoencapsulated lipophilic drugs and improve their release profile after oral administration likely via electrokinetic stabilisation. Hence, this study aimed to examine the effects of CDCA on exerting similar effects on hydrophilic drugs.

          Methods

          Various CDCA-based formulations were produced for the orally administered hydrophilic drug, metformin. Analyses of these formulations included electrokinetic potentials, topography, drug and CDCA formulation contents, nano size distribution, heat-induced deformation and outer-core expansion indices, release profiles, shell-resistance ratio, and thermal and chemical indices. With the drug’s main target being pancreatic beta-cells, the formulations’ effects on cell viability, functions and inflammatory profiles were also investigated.

          Results and Conclusions

          CDCA-based metformin formulations exhibited improved stability and release profiles via thermal, chemical and electrokinetic effects, which were formulation-dependent suggesting potential applications of CDCA in the oral targeted delivery of hydrophilic drugs.

          Most cited references61

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          Targeting bile-acid signalling for metabolic diseases.

          Bile acids are increasingly being appreciated as complex metabolic integrators and signalling factors and not just as lipid solubilizers and simple regulators of bile-acid homeostasis. It is therefore not surprising that a number of bile-acid-activated signalling pathways have become attractive therapeutic targets for metabolic disorders. Here, we review how the signalling functions of bile acids can be exploited in the development of drugs for obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis, as well as other associated chronic diseases such as non-alcoholic steatohepatitis.
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            Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.

            Ward JB, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ní Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, Roda A, Keely SJ. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.
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              Bile acids: Chemistry, physiology, and pathophysiology

                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                23 October 2021
                2021
                : 15
                : 4423-4434
                Affiliations
                [1 ]The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University , Bentley, Perth, 6102, WA, Australia
                [2 ]Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre , Nedlands, Perth, 6009, WA, Australia
                [3 ]Fiona Stanley Hospital , Perth, WA, Australia
                [4 ]Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University , Perth, WA, Australia
                [5 ]Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad , Novi Sad, 21101, Serbia
                Author notes
                Correspondence: Hani Al-Salami Hearing Therapeutics, Biotechnology and Pharmaceutical Sciences, Curtin University , Bentley, Perth, 6102, WA, Australia Tel +61 8 9266 9816 Fax + 61 8 9266 2769 Email hani.al-salami@curtin.edu.au
                Author information
                http://orcid.org/0000-0001-7103-2067
                http://orcid.org/0000-0003-1779-0785
                http://orcid.org/0000-0002-8966-0448
                http://orcid.org/0000-0003-4895-5212
                http://orcid.org/0000-0002-1332-4392
                http://orcid.org/0000-0001-9867-8896
                http://orcid.org/0000-0002-5528-2370
                http://orcid.org/0000-0003-0049-6969
                Article
                328526
                10.2147/DDDT.S328526
                8550211
                34720580
                cc33b6f8-1524-41cf-a4ce-cc1f13e3626c
                © 2021 Mooranian 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. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 08 July 2021
                : 10 August 2021
                Page count
                Figures: 5, Tables: 1, References: 70, Pages: 12
                Funding
                Funded by: Beijing Nat-Med Biotechnology Co. Ltd;
                Funded by: European Union Horizon 2020 research project;
                Funded by: Curtin Faculty ORS-WAHAI Consortium and the Australian National Health and Medical Research;
                H Al-Salami has been and is currently receiving funding from Beijing Nat-Med Biotechnology Co. Ltd. The work is partially supported by the European Union Horizon 2020 research project and innovation program under the Marie Skłodowska-Curie Grant Agreement No 872370. Curtin Faculty ORS-WAHAI Consortium and the Australian National Health and Medical Research (APP9000597).
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                microencapsulation,diabetes mellitus,glyceryl monooleate,eudragit,chenodeoxycholic acid

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