<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.4 20241031//EN"
        "https://jats.nlm.nih.gov/publishing/1.4/JATS-journalpublishing1-4.dtd">
<article  article-type="research-article"        dtd-version="1.4">
            <front>

                <journal-meta>
                                                                <journal-id>j. res. pharm.</journal-id>
            <journal-title-group>
                                                                                    <journal-title>Journal of Research in Pharmacy</journal-title>
            </journal-title-group>
                                        <issn pub-type="epub">2630-6344</issn>
                                                                                            <publisher>
                    <publisher-name>Marmara University</publisher-name>
                </publisher>
                    </journal-meta>
                <article-meta>
                                        <article-id/>
                                                                <article-categories>
                                            <subj-group  xml:lang="en">
                                                            <subject>Pharmaceutical Sciences</subject>
                                                    </subj-group>
                                            <subj-group  xml:lang="tr">
                                                            <subject>Eczacılık Bilimleri</subject>
                                                    </subj-group>
                                    </article-categories>
                                                                                                                                                        <title-group>
                                                                                                                        <article-title>Synergistic antifungal potential of fluconazole-based cardamom oil oral microemulsion formulation against C. albicans</article-title>
                                                                                                    </title-group>
            
                                                    <contrib-group content-type="authors">
                                                                        <contrib contrib-type="author">
                                                                    <contrib-id contrib-id-type="orcid">
                                        https://orcid.org/0000-0003-4033-2678</contrib-id>
                                                                <name>
                                    <surname>Tiwari</surname>
                                    <given-names>Nisha</given-names>
                                </name>
                                                                    <aff>School for Advanced Sciences, Vellore Institute of Technology</aff>
                                                            </contrib>
                                                    <contrib contrib-type="author">
                                                                    <contrib-id contrib-id-type="orcid">
                                        https://orcid.org/0000-0001-5921-3420</contrib-id>
                                                                <name>
                                    <surname>Sivakumar</surname>
                                    <given-names>Amaravadi V.n.</given-names>
                                </name>
                                                                    <aff>School for Advanced Sciences, Vellore Institute of Technology</aff>
                                                            </contrib>
                                                                                </contrib-group>
                        
                                        <pub-date pub-type="pub" iso-8601-date="20250628">
                    <day>06</day>
                    <month>28</month>
                    <year>2025</year>
                </pub-date>
                                        <volume>26</volume>
                                        <issue>5</issue>
                                        <fpage>1065</fpage>
                                        <lpage>1083</lpage>
                        
                        <history>
                                    <date date-type="received" iso-8601-date="20220502">
                        <day>05</day>
                        <month>02</month>
                        <year>2022</year>
                    </date>
                                                    <date date-type="accepted" iso-8601-date="20220606">
                        <day>06</day>
                        <month>06</month>
                        <year>2022</year>
                    </date>
                            </history>
                                        <permissions>
                    <copyright-statement>Copyright © 2010, Journal of Research in Pharmacy</copyright-statement>
                    <copyright-year>2010</copyright-year>
                    <copyright-holder>Journal of Research in Pharmacy</copyright-holder>
                </permissions>
            
                                                                                                <abstract><p>Microemulsion has grabbed a lot of attention in the last few decades as a unique candidate for drugdelivery owing to its low viscosity, limpidness, ease of preparation, and good thermodynamic stability. The potentialto incorporate drugs from unlike lipophilicity and its spontaneous formation makes it a suitable candidate forpharmaceutical application. The objective of the current study is to enhance the solubility of Fluconazole, an antifungaldrug by formulating a microemulsion made up of cardamom oil, tween 20, and water (5:15:80). The formulations werechecked for their physiochemical properties and thermodynamic stability. An antimicrobial activity like zone ofinhibition, minimum inhibitory concentration and kill kinetics assay for optimized formulations were checked againstC. albicans. The droplet size of the system and FLZ loaded microemulsion was found to be 7.8 and 8.6nm respectively.In vitro drug release from optimized microemulsion formulation showed efficient release (78.45%) compared to the bulkAPI (7.98%) in simulated intestinal fluid. The cytoplasmic release for CDMM FLZ ME at 0.5X, 1X and 5X was 43.24%,82.11%, 91.73% respectively. In vitro toxicity demonstrated a lower toxicity rate with lower surfactant concentrationagainst human lymphocytes and its safer usage. SEM analysis depicts the morphological distortion in C. albicans thatoccurred due to the interaction with microemulsion. The results indicate cardamom oil-based microemulsion is anefficient drug delivery vehicle intended for oral usage.</p></abstract>
                                                            
            
                                                            <kwd-group>
                                                    <kwd>Antifungal</kwd>
                                                    <kwd>  Minimum Inhibitory concentration</kwd>
                                                    <kwd>  Oral drug delivery</kwd>
                                                    <kwd>  Microemulsion</kwd>
                                                    <kwd>  Thermodynamic stability</kwd>
                                            </kwd-group>
                            
                                                                                                                        </article-meta>
    </front>
    <back>
                            <ref-list>
                                    <ref id="ref1">
                        <label>1</label>
                        <mixed-citation publication-type="journal">[1] Gaikwad VL, Yadav VD, Dhavale RP, Choudhari PB, Jadhav SD. Effect of carbopol 934 and 940 on fluconazole release from topical gel formulation: a factorial approach. Curr. Pharm. Res. 2012; 2(2), 487-493.</mixed-citation>
                    </ref>
                                    <ref id="ref2">
                        <label>2</label>
                        <mixed-citation publication-type="journal">[2] Gomez- Lopez A. Antifungal therapeutic drug monitoring: focus on drugs without a clear recommendation. Clin. Microbiol. Infec.2020; 26 (11), 1481-1487. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref3">
                        <label>3</label>
                        <mixed-citation publication-type="journal">[3] Lu H, Shrivastava M, Whiteway M, Jiang Y. Candida albicans targets that potntially synergize with fluconazole. Crit. Rev. Microbiol. 2021; 47(3), 323-337. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref4">
                        <label>4</label>
                        <mixed-citation publication-type="journal">[4] de Andrade Monteiro C, dos Santos JR. Phytochemicals and Their Antifungal Potential Against Pathogenic Yeasts, Phytochemicals in Human Health. IntechOpen. (2019). [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref5">
                        <label>5</label>
                        <mixed-citation publication-type="journal">[5] Ilyas M, Sharma A. Cutaneous fungal infections in solid organ transplant recipients. Transplant. Rev. 2017; 31 (3), 158- 165. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref6">
                        <label>6</label>
                        <mixed-citation publication-type="journal">[6] Kelidari HR, Moazeni M, Babaei R, Saeedi M, Akbari J, Parkoohi PI, Nabili M, Gohar AA. Morteza- Semnani K, Nakhodchi A. Improved yeast delivery of fluconazole with a nanostructured lipid carrier system. Biomed. Pharmacother.2017; 89, 83-88. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref7">
                        <label>7</label>
                        <mixed-citation publication-type="journal">[7] Boniche C, Rossi SA, Kischkel B, Vieira Barbalho F, Nogueira D’Aurea Moura Á, Nosanchuk JD, Travassos LR, Pelleschi Taborda C. Immunotherapy against systemic fungal infections based on monoclonal antibodies. J. Fungi. 2020; 6(1), 31. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref8">
                        <label>8</label>
                        <mixed-citation publication-type="journal">[8] Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J. Antimicrob. Chemother. 2018; 73(1), i26- i32. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref9">
                        <label>9</label>
                        <mixed-citation publication-type="journal">[9] Nirmala MJ, Mukherjee A, Chandrasekaran N. A bio-based approach in designing an oral drug delivery system for fluconazole. Int. J. Pharm. Pharm. Sci. 2013; 5, 273-275.</mixed-citation>
                    </ref>
                                    <ref id="ref10">
                        <label>10</label>
                        <mixed-citation publication-type="journal">[10] Ciolacu DE, Nicu R, Ciolacu F. Cellulose-based hydrogels as sustained drug-delivery systems. Mater. 2020; 13(22), 5270. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref11">
                        <label>11</label>
                        <mixed-citation publication-type="journal">[11] Nene S, Shah S, Rangaraj N, Mehra NK, Singh PK, Srivastava S. Lipid based nanocarriers: a novel paradigm for topical antifungal therapy. J. Drug. Deliv. Sci. Tech. 2021; 62, 1773. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref12">
                        <label>12</label>
                        <mixed-citation publication-type="journal">[12] Agrawal OP, Agrawal S. An overview of new drug delivery system: microemulsion. Asian. J. Pharm. Sci. Tech. 2012; 2(1), 5-12.</mixed-citation>
                    </ref>
                                    <ref id="ref13">
                        <label>13</label>
                        <mixed-citation publication-type="journal">[13] Lokhande SS. Microemulsions as Promising Delivery Systems: A Review. Asian J. Pharm. Res.2019; 9(2), 90-96. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref14">
                        <label>14</label>
                        <mixed-citation publication-type="journal">[14] Tang JL, Sun J, He ZG. Self-emulsifying drug delivery systems: strategy for improving oral delivery of poorly soluble drugs. Curr. Drug. ther. 2007; 2(1), 85-93. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref15">
                        <label>15</label>
                        <mixed-citation publication-type="journal">[15] Perry SL, McClements DJ. Recent advances in encapsulation, protection, and oral delivery of bioactive proteins and peptides using colloidal systems. Molecules. 2020; 25(5), 1161. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref16">
                        <label>16</label>
                        <mixed-citation publication-type="journal">[16] Unalan I, Boccaccini AR. Essential oils in biomedical appliactions: Recent progress and future opportunities. Curr. Opin. Biomed. Eng. 2021; 17, 100261. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref17">
                        <label>17</label>
                        <mixed-citation publication-type="journal">[17] Lizarraga‐Valderrama LR. Effects of essential oils on central nervous system: Focus on mental health. Phytother. Res. 2021; 35(2), 657-679. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref18">
                        <label>18</label>
                        <mixed-citation publication-type="journal">[18] Xavier Junior FH, Vauthier C, Morais AR, Alencar EN, Egito ES. Microemulsion systems containing bioactive natural oils: an overview on the state of the art. Drug. Dev. Ind. Pharm. 2017; 43(5), 700-714. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref19">
                        <label>19</label>
                        <mixed-citation publication-type="journal">[19] Noumi E, Snoussi M, Alreshidi MM, Rekha PD, Saptami K, Caputo L, Mancini E, Flamini G. Chemical and biological evaluation of essential oils from cardamom species. Molecules. 2018; 23(11), 2818. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref20">
                        <label>20</label>
                        <mixed-citation publication-type="journal">[20] Asghar A, Butt MS, Shahid M, Huang Q. Evaluating the antimicrobial potential of green cardamom essential oil focusing on quorum sensing inhibition of Chromobacterium violaceum. J. Food. Sci. Techol. 2017; 54(8), 2306-2315.</mixed-citation>
                    </ref>
                                    <ref id="ref21">
                        <label>21</label>
                        <mixed-citation publication-type="journal">[21] Patel V, Kukadiya H, Mashru R, Surti N, Mandal S. Development of microemulsion for solubility enhancement of clopidogrel. Iran. J. Pharm. Res. 2010; 9(4), 327-3.</mixed-citation>
                    </ref>
                                    <ref id="ref22">
                        <label>22</label>
                        <mixed-citation publication-type="journal">[22] Shinde U, Pokharkar S, Modani S. Design and evaluation of microemulsion gel system of nadifloxacin. Indian. J. Pharm. Sci. 2012; 74(3), 237. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref23">
                        <label>23</label>
                        <mixed-citation publication-type="journal">[23] Chopade VV, Chaudhari PD. Development and Evaluation of self Emulsifying Drug Delivery System for Lornoxicam. Int. J. Res. Dev. Pharm. L. Sci.2013; 2(4), 531-537.</mixed-citation>
                    </ref>
                                    <ref id="ref24">
                        <label>24</label>
                        <mixed-citation publication-type="journal">[24] Shukla JB, Jani GK, Omri AW. Formulation and Evaluation of Oral Self Micro-emulsifying Drug Delivery System of Candesartan Cilexetil. Int. J. Pharm. Sci. 2016; 8(5), 238-243.</mixed-citation>
                    </ref>
                                    <ref id="ref25">
                        <label>25</label>
                        <mixed-citation publication-type="journal">[25] Kizibash NA, Shah SS, Alenizi D, Nazar MF, Asif S. Design of a microemulsion-based drug delivery system for diclofenac sodium. J. Chem. Soc. Pak. 2011; 33(6), 1-6.</mixed-citation>
                    </ref>
                                    <ref id="ref26">
                        <label>26</label>
                        <mixed-citation publication-type="journal">[26] Chudasama A, Patel V, Nivsarkar M, Vasu K, Shishoo C. A novel lipid-based oral drug delivery system of nevirapine.</mixed-citation>
                    </ref>
                                    <ref id="ref27">
                        <label>27</label>
                        <mixed-citation publication-type="journal">[27] Mehta DP, Rathod H, Shah DP. Microemulsions: A potential novel drug delivery system. Int. J. Pharm. Sci. 2015; 1,48-60.</mixed-citation>
                    </ref>
                                    <ref id="ref28">
                        <label>28</label>
                        <mixed-citation publication-type="journal">[28] Kaur L, Kumar R, Rahi DK, Sinha VR. Formulation and Evaluation of Microemulsion Based Gel of oriconazole for Topical Delivery. Anti-Infective Agents. 2017; 15(2), 95-104. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref29">
                        <label>29</label>
                        <mixed-citation publication-type="journal">[29] Pfaller MA, Andes D, Diekema DJ, Espinel-Ingroff A, Sheehan D, CLSI subcommittee for Antifungal Susceptibility Testing. Wild-type MIC distributions, epidemiological cutoff values and species-specific clinical breakpoints for fluconazole and Candida: time for harmonization of CLSI and EUCAST broth microdilution methods. Drug. Resist. Update. 2010; 13(6), 180-195. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref30">
                        <label>30</label>
                        <mixed-citation publication-type="journal">[30] Hall D, Bonifas R, Stapert L, Thwaites M, Shinabarger DL, Pillar CM. In vitro potency and fungicidal activity o.f CD101, a novel echinocandin, against recent clinical isolates of Candida spp. Diagn. Micr. Infec. Dis. 2017; 89(3), 205-211. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref31">
                        <label>31</label>
                        <mixed-citation publication-type="journal">[31] Tiwari N, Sivakumar A, Mukherjee A, Chandrasekaran N. Enhanced antifungal activity of Ketoconazole using rose oil based novel microemulsion formulation. J. Drug. Deliv. Sci. Tec. 2018; 47, 434-444. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref32">
                        <label>32</label>
                        <mixed-citation publication-type="journal">[32] Ebenazer A, Franklyne JS, Tiwari N, Mukherjee A, Chandrasekaran N. In Vivo Testing and Extended Drug Release of Chitosan-Coated Itraconazole Loaded Microemulsion Using Volatile Oil Thymus vulgaris. Rev. Bras. Farmacogn. 2020; 30(2), 1-11.</mixed-citation>
                    </ref>
                                    <ref id="ref33">
                        <label>33</label>
                        <mixed-citation publication-type="journal">[33] Zhang H, Cui Y, Zhu S, Feng F, Zheng X. Characterization and antimicrobial activity of a pharmaceutical microemulsion. Int. J. Pharm. 2010; 395(1-2), 154-160. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref34">
                        <label>34</label>
                        <mixed-citation publication-type="journal">[34] He CX, He ZG, Gao JQ. Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs. Expert. Opin. Drug. Del. 2010; 7(4), 445-460. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref35">
                        <label>35</label>
                        <mixed-citation publication-type="journal">[35] Singla P, Garg S, McClements J, Jamieson O, Peeters M, Mahajan RK. Advances in the therapeutic delivery and applications of functionalized Pluronics: A critical review. Adv. Colloid Interface Sci. 2022; 299,102563. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref36">
                        <label>36</label>
                        <mixed-citation publication-type="journal">[36] Moghassemi S, Hadjizadeh A. Nano-niosomes as nanoscale drug delivery systems: an illustrated review. J. Control. Release. 2014; 185, 22-36. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref37">
                        <label>37</label>
                        <mixed-citation publication-type="journal">[37] Kale SN, Deore SL. Emulsion micro emulsion and nano emulsion: a review. Sys. Rev. Pharm. 2017; 8(1), 39. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref38">
                        <label>38</label>
                        <mixed-citation publication-type="journal">[38] Trivedi R, Kompella UB. Nanomicellar formulations for sustained drug delivery: strategies and underlying principles. Nanomedicine. 2010; 5(3), 485-505. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref39">
                        <label>39</label>
                        <mixed-citation publication-type="journal">[39] Doost AS, Sinnaeve D, De Neve L, Van der Meeren P. Influence of non-ionic surfactant type on the salt sensitivity of oregano oil-in-water emulsions. Colloid. Surf. A Physicochem. Eng. Asp. 2017; 525, 38-48. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref40">
                        <label>40</label>
                        <mixed-citation publication-type="journal">[40] Muzaffar FA, Singh UK, Chauhan L. Review on microemulsion as futuristic drug delivery. Int. J. Pharm. Pharm. Sci. 2013; 5(3), 39-53.</mixed-citation>
                    </ref>
                                    <ref id="ref41">
                        <label>41</label>
                        <mixed-citation publication-type="journal">[41] Pavankumar KM, Prathiban S. Design and characterization of Fluconazole microemulsion formulated with Lemongrass oil. J. Pharm. Sci. Innov.2021; 10(3), 80-86. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref42">
                        <label>42</label>
                        <mixed-citation publication-type="journal">[42] Fernandes AV, Pydi CR, Verma R, Jose J, Kumar L. Design, preparation and in vitro characterization of fluconazole loaded nanostructured lipid carriers. Braz. J. Pharm. Sci. 2020; 56, 1. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref43">
                        <label>43</label>
                        <mixed-citation publication-type="journal">[43] Hu L, Wu H, Niu F, Yan C, Yang X, Jia Y. Design of fenofibrate microemulsion for improved bioavailability. Int. J. Pharm. 2011; 420(2), 251-255. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref44">
                        <label>44</label>
                        <mixed-citation publication-type="journal">[44] Khan AA, Mudassir J, Mohtar N, Darwis Y. Advanced drug delivery to the lymphatic system: lipid-based nanoformulations. Int. J. Nanomedicine. 2013; 8, 2733-2744. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref45">
                        <label>45</label>
                        <mixed-citation publication-type="journal">[45] Chinnappan S, Chia LY, Chow JC, Tan WH, Yap HQ. Recent Advances in Delivery of Antifungal agents - A review. J. Young. Pharm. 2020; 12(3), 193-196. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref46">
                        <label>46</label>
                        <mixed-citation publication-type="journal">[46] Nirmala MJ, Mukherjee A, Chandrasekaran N. Improved efficacy of fluconazole against candidiasis using bio‐based microemulsion technique. Appl. Biochem. Biotechnol. 2013; 60
(4), 417-429. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref47">
                        <label>47</label>
                        <mixed-citation publication-type="journal">[47] Danby CS, Boikov D, Rautemaa-Richardson R, Sobel JD. Effect of pH on in vitro susceptibility of Candida glabrata and Candida albicans to 11 antifungal agents and implications for clinical use. Antimicrob. Agents Chemother. 2012; 56(3), 1403-1406. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref48">
                        <label>48</label>
                        <mixed-citation publication-type="journal">[48] Ganeshkumar A, Suvaithenamudhan S, Rajaram R. In Vitro and In Silico Analysis of Ascorbic Acid Towards Lanosterol 14-α-Demethylase Enzyme of Fluconazole-Resistant Candida albicans. Curr. Microbiol. 2021; 78(1), 292-302.
[CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref49">
                        <label>49</label>
                        <mixed-citation publication-type="journal">[49] Locke JB, Almaguer AL, Donatelli JL, Bartizal KF. Time-kill kinetics of rezafungin (CD101) in vagina-simulative medium for fluconazole-susceptible and fluconazole-resistant Candida albicans and non-albicans Candida species. Infect. Dis. Obstet. Gynecol. 2018. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref50">
                        <label>50</label>
                        <mixed-citation publication-type="journal">[50] Neglo D, Adzaho F, Agbo IA, Arthur R, Sedohia D, Tettey CO, Waikhom SD. Antibiofilm Activity of Azadirachta indica and Catharanthus roseus and Their Synergistic Effects in Combination with Antimicrobial Agents against Fluconazole-Resistant Candida albicans Strains and MRSA. Evid.-based Complement. Altern. Med. 2022; 2022. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref51">
                        <label>51</label>
                        <mixed-citation publication-type="journal">[51] Mehrandish S, Mirzaeei S. A review on Ocular novel drug delivery systems of antifungal drugs: functional evaluation and comparision of conventional and novel dosage forms. Adv. Pharm. Bull. 2021; 11(1), 28-38. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref52">
                        <label>52</label>
                        <mixed-citation publication-type="journal">[52] Chaiyana W, Anuchapreeda S, Leelapornpisid P, Phongpradist R, Viernstein H, Mueller M. Development of microemulsion delivery system of essential oil from Zingiber cassumunar Roxb. rhizome for improvement of stability and anti-inflammatory activity. AAPS Pharm. Sci. Tech. 2017; 18(4), 1332-1342. [CrossRef]</mixed-citation>
                    </ref>
                                    <ref id="ref53">
                        <label>53</label>
                        <mixed-citation publication-type="journal">[53] Sundaramoorthy R, Velusamy Y, Balaji AP, Mukherjee A, Chandrasekaran N. Comparative cytotoxic and genotoxic effects of permethrin and its nanometric form on human erythrocytes and lymphocytes in vitro. Chem. Biol. Interact. 2016; 257, 119-124. [CrossRef]</mixed-citation>
                    </ref>
                            </ref-list>
                    </back>
    </article>
