Azelaic Acid: A Promising Agent for Dermatological Applications

Author(s): Anil Kumar, Rekha Rao*, Poonam Yadav

Journal Name: Current Drug Therapy

Volume 15 , Issue 3 , 2020


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Graphical Abstract:


Abstract:

Azelaic Acid (AA) is a naturally occurring 9-carbon straight-chain saturated dicarboxylic acid widely found in wheat, rye, and barley. It has been shown to possess numerous biochemical activities, such as anti-inflammatory, anti-microbial, antioxidant, anticomedolytic and anticancer. This therapeutic agent has been approved by US food Drug Administration for the treatment of mild to moderate acne and rosacea. Further, azelaic acid has been reported for the management of skin hyperpigmentation, melasma and alopecia. In this review article, several studies on azelaic acid that pointed out its bioactivities and pharmacology along with its drug delivery systems are reviewed. Additionally, an outlook on its mechanism of action is also given. Azelaic acid is an important moiety for the management of acne owing to its benefits in addressing follicular excess sebum, inflammatory action, hyperproliferation and activity against Propionibacterium acne. The commercially available topical formulations normally contain 15 to 20% AA. In the future, a broadspectrum antibacterial agent, azelaic acid can act as a pillar in acne therapy minimizing the potential risk of emergence of resistance. This review will definitely provide a new perspective for research involving this bioactive molecule.

Keywords: Antiacne, rosacea, melasma, comedolytic, hyperpigmentation, dermatology.

[1]
Pan SY, Zhou SF, Gao SH, et al. New perspectives on how to discover drugs from herbal medicines: CAM’s outstanding contribution to modern therapeutics. Evid Based Complement Alternat Med 2013; 2013627375
[http://dx.doi.org/10.1155/2013/627375] [PMID: 23634172]
[2]
Maridass M, De Britto AJ. Origins of plant derived medicines Ethnobo Leaflets 2008; (1): 44.
[3]
Esposito E, Menegatti E, Cortesi R. Ethosomes and liposomes as topical vehicles for azelaic acid: a preformulation study. J Cosmet Sci 2004; 55(3): 253-64.
[http://dx.doi.org/10.1111/j.1467-2494.2004.00233_2.x] [PMID: 15264053]
[4]
Peira E, Carlotti ME, Cavalli R, Trotta M. Azelaic acid sodium salt in the formulation of microemulsions for topical applications. J Drug Deliv Sci Technol 2006; 16(5): 375-9.
[http://dx.doi.org/10.1016/S1773-2247(06)50068-1]
[5]
FDA; Drug and device product approvals Available from http://www. fda.gov/cder/da/ddpa995.htm/2009(Accessed on 05 March, 2009).
[6]
Bladon PT, Burke BM, Cunliffe WJ, Forster RA, Holland KT, King K. Topical azelaic acid and the treatment of acne: a clinical and laboratory comparison with oral tetracycline. Br J Dermatol 1986; 114(4): 493-9.
[http://dx.doi.org/10.1111/j.1365-2133.1986.tb02856.x] [PMID: 2938615]
[7]
Wolf JE Jr, Kerrouche N, Arsonnaud S. Efficacy and safety of once-daily metronidazole 1% gel compared with twice-daily azelaic acid 15% gel in the treatment of rosacea. Cutis 2006; 77(4): 3-11.
[PMID: 16706244]
[8]
Lowe NJ, Rizk D, Grimes P, Billips M, Pincus S. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther 1998; 20(5): 945-59.
[http://dx.doi.org/10.1016/S0149-2918(98)80076-3] [PMID: 9829446]
[9]
Kadam TV, Darekar AB, Gondkar SB, Saudagar RB. Development and validation of spectrophotometric method for determination of azelaic acid. Asian J Res Pharmaceutical Science 2015; 5: 83-5.
[http://dx.doi.org/10.5958/2231-5659.2015.00014.4]
[10]
Indian Pharmacopoeia. Government of India Ministry of Health and Family Welfare. Published by the Indian Pharmacopoeia Commission, Ghaziabad 2015; 2: 1113-4.
[11]
Available from. http://www.drugbank.ca/drugs/DB00548 (Accessed on 13 August, 2014)
[12]
Bojar RA, Holland KT, Cunliffe WJ. The in-vitro antimicrobial effects of azelaic acid upon Propionibacterium acnes strain P37. J Antimicrob Chemother 1991; 28(6): 843-53.
[http://dx.doi.org/10.1093/jac/28.6.843] [PMID: 1726169]
[13]
Nazzaroporro M, Passi S, Breathnach A, Zina G. 10 Years observations on the effect of azelaic acid on lentigo maligna. J Invest Dermatol 1986; 87: 438-8.
[14]
Breathnach AC, Nazzaro-Porro M, Passi S, Zina G. Azelaic acid therapy in disorders of pigmentation. Clin Dermatol 1989; 7(2): 106-19.
[http://dx.doi.org/10.1016/0738-081X(89)90061-8] [PMID: 2667735]
[15]
Gollnick H, Schramm M. Topical therapy in acne. J Eur Acad Dermatol Venereol 1998; 11(Suppl. 1): S8-S12.
[http://dx.doi.org/10.1111/j.1468-3083.1998.tb00901.x] [PMID: 9891903]
[16]
Fitton A, Goa KL. Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 1991; 41(5): 780-98.
[http://dx.doi.org/10.2165/00003495-199141050-00007] [PMID: 1712709]
[17]
Hebert RF. Therapeutically improved salts of azelaic acid US6,734,210 2004.
[18]
Streeper RT, Singh CU. Methods and compositions involving esters of azelaic acid and other dicarboxylic acids WO 20,060,743,79 A2 2006.
[19]
Sen M, Noronha O. Topical gel composition comprising azelaic acid US 20,100,004338 A1 2010.
[20]
Fox PS, Pedersen DE, Rolando JJ, Staub RK. Compositions having a high antiviral efficacy US 80,348,44 B2 2011.
[21]
Schmidt T, Zollner T, Friedrich M. Azelaic acid-comprising Publication formulation with added pigment US 20,120,027,862 A1 2012.
[22]
Taylor TJ, Fox PS, Seitz EP. Compositions having a high antiviral and antibacterial efficacy ? US 20,120,276,219 A1 2012.
[23]
Streeper RT, Izbicka E. Method of utilizing azelaic acid esters to modulate communications mediated by biological molecules US 20,140,094,516 A1 2014.
[24]
Dannaker CJ. Waterborne topical compositions for the delivery of azelaic acid for treatment of ski conditions such as acne vulgaris, rosacea seborrheic dermatitis WO 20,151,795,70 A1 2015.
[25]
Available from: https://pubchem.ncbi.nlm.nih.gov/compound/azelaic_acid#section=Top(Accessed on 18 February, 2018).
[26]
Hansch C, Leo A, Hoekman D, Livingstone DJ. Exploring QSAR: hydrophobic, electronic, and steric constants. Washington, DC: American Chemical Society 1995.
[27]
Lide DR. CRC Handbook of Chemistry and Physics. 88th. CRC Press, Taylor Francis, Boca Raton 2007; pp. 3-398.
[28]
Lewis RJ Sr. Hawley’s Condensed Chemical Dictionary. 15th ed. New York: John Wiley & Sons, Inc. 2007; p. 113.
[http://dx.doi.org/10.1002/9780470114735]
[29]
Mansour AM, Ibrahiem MM. Simultaneous determination of azelaic and benzoic acids in topical preparations by liquid chromatography. Chromatographia 2002; 55: 435-7.
[http://dx.doi.org/10.1007/BF02492273]
[30]
Available from. https://www.drugbank.ca/drugs/DB00548 (Accessed on 10 February, 2018)
[31]
Mayer-da-Silva A, Gollnick H, Detmar M, et al. Effects of azelaic acid on sebaceous gland, sebum excretion rate and keratinization pattern in human skin. An in vivo and in vitro study. Acta Derm Venereol Suppl (Stockh) 1989; 143: 20-30.
[PMID: 2475995]
[32]
Mayer-da-Silva A. Azelaic acid: pharmacology, toxicology and mechanism of action in acne. J Dermatolog Treat 1989; 1(1): 11-5.
[http://dx.doi.org/10.3109/09546638909094475]
[33]
Akamatsu H, Komura J, Asada Y, Miyachi Y, Niwa Y. Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch Dermatol Res 1991; 283(3): 162-6.
[http://dx.doi.org/10.1007/BF00372056] [PMID: 1867478]
[34]
Passi S, Picardo M, De Luca C, Breathnach AS, Nazzaro-Porro M. Scavenging activity of azelaic acid on hydroxyl radicals “in vitro”. Free Radic Res Commun 1991; 11(6): 329-38.
[http://dx.doi.org/10.3109/10715769109088931] [PMID: 1649075]
[35]
Passi S, Picardo M, Zompetta C, De Luca C, Breathnach AS, Nazzaro-Porro M. The oxyradical-scavenging activity of azelaic acid in biological systems. Free Radic Res Commun 1991; 15(1): 17-28.
[http://dx.doi.org/10.3109/10715769109049121] [PMID: 1769610]
[36]
Elewski BE, Draelos Z, Dréno B, Jansen T, Layton A, Picardo M. Rosacea - global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group. J Eur Acad Dermatol Venereol 2011; 25(2): 188-200.
[http://dx.doi.org/10.1111/j.1468-3083.2010.03751.x] [PMID: 20586834]
[37]
Sieber MA, Hegel JK. Azelaic acid: Properties and mode of action. Skin Pharmacol Physiol 2014; 27(Suppl. 1): 9-17.
[http://dx.doi.org/10.1159/000354888] [PMID: 24280644]
[38]
Nazzaro-Porro M. Azelaic acid. J Am Acad Dermatol 1987; 17(6): 1033-41.
[http://dx.doi.org/10.1016/S0190-9622(87)70294-1] [PMID: 2963038]
[39]
Sánchez-Ferrer A, Rodríguez-López JN, García-Cánovas F, García-Carmona F. Tyrosinase: a comprehensive review of its mechanism. Biochim Biophys Acta 1995; 1247(1): 1-11.
[http://dx.doi.org/10.1016/0167-4838(94)00204-T] [PMID: 7873577]
[40]
Jiménez-Cervantes C, Martínez-Esparza M, Pérez C, Daum N, Solano F, García-Borrón JC. Inhibition of melanogenesis in response to oxidative stress: transient downregulation of melanocyte differentiation markers and possible involvement of microphthalmia transcription factor. J Cell Sci 2001; 114(Pt 12): 2335-44.
[PMID: 11493672]
[41]
Briganti S, Camera E, Picardo M. Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Res 2003; 16(2): 101-10.
[http://dx.doi.org/10.1034/j.1600-0749.2003.00029.x] [PMID: 12622786]
[42]
Pérez-Bernal A, Muñoz-Pérez MA, Camacho F. Management of facial hyperpigmentation. Am J Clin Dermatol 2000; 1(5): 261-8.
[http://dx.doi.org/10.2165/00128071-200001050-00001] [PMID: 11702317]
[43]
Zaldman B, Kisilev A, Sasson Y, Garti N. Double bond oxidation of unsaturated fatty acids. J Am Oil Chem Soc 1988; 65: 611-5.
[http://dx.doi.org/10.1007/BF02540689]
[44]
Rach P, Topert M. Pharmacological investigation of azelaic acid. J Invest Dermatol 1986; 86: 327-7.
[45]
King K. The effect of azelaic acid on cutaneous microflora in vivo and in vitro. J Invest Dermatol 1985; 84: 438A.
[46]
Leeming JP, Holland KT, Bojar RA. The in vitro antimicrobial effect of azelaic acid. Br J Dermatol 1986; 115(5): 551-6.
[http://dx.doi.org/10.1111/j.1365-2133.1986.tb05764.x] [PMID: 2947607]
[47]
Bojar RA, Holland KT, Leeming JP, Cunliffe WJ. Azelaic acid: its uptake and mode of action in Staphylococcus epidermidis NCTC 11047. J Appl Bacteriol 1988; 64(6): 497-504.
[http://dx.doi.org/10.1111/j.1365-2672.1988.tb02441.x] [PMID: 2459099]
[48]
Holland KT, Bojar RA. The mechanism of action of azelaic acid in staphylococcus epidermis.In: R Marks, G Plewig (Eds), Acne and related disorders. London: Martin Dunitz 1989; pp. 241-7.
[49]
Katsambas GK, Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. comparison with vehicle and topical tretinoin. Acta Derm Venereol Suppl (Stockh) 1989; 143: 35-9.
[50]
Nazzaro-Porro M. Azelaic acid. In: Orfanos CE, Stadler R, Gollnick H, (Eds.), Dermatology in five continents.Berlin: Springer- Verlag 1988; 194-202.
[51]
Ertle T, Wiskemann A, Jänner M. Local treatment of lentigo maligna with azelaic acid. Arch Dermatol Res 1981; 271: 197-203.
[http://dx.doi.org/10.1007/BF00412547]
[52]
Nazzaro-Porro M, Passi S, Balus L, Breathnach A, Martin B, Morpurgo G. Effect of dicarboxylic acids on lentigo maligna. J Invest Dermatol 1979; 72(6): 296-305.
[http://dx.doi.org/10.1111/1523-1747.ep12531744] [PMID: 448162]
[53]
Passi S, Picardo M, Nazzaro-Porro M, Breathnach A, Confaloni AM, Serlupi-Crescenzi G. Antimitochondrial effect of saturated medium chain length (C8-C13) dicarboxylic acids. Biochem Pharmacol 1984; 33(1): 103-8.
[http://dx.doi.org/10.1016/0006-2952(84)90376-9] [PMID: 6704136]
[54]
Bargoni N, Tazartes O. On the effect of aliphatic saturated dicarboxylic acids on anaerobic glycolysis in chicken embryo. Ital J Biochem 1983; 32(6): 385-90.
[PMID: 6233235]
[55]
Freinkel RK. Metabolism of glucose-C-14 by human skin in vitro. J Invest Dermatol 1960; 34: 37-42.
[http://dx.doi.org/10.1038/jid.1960.7] [PMID: 13824821]
[56]
Jones D. Reactive oxygen species and rosacea. Cutis 2004; 74(3): 17-20, 32-34.
[PMID: 15499754]
[57]
Guzman-Sanchez DA, McMichael A. Topical uses of vitamin C: how ascorbic acid is being used in dermatology. Skin & Aging 2006; 14: 52-9.
[58]
Miyachi Y. Potential antioxidant mechanism of action for metronidazole: implications for rosacea management. Adv Ther 2001; 18(6): 237-43.
[http://dx.doi.org/10.1007/BF02850193] [PMID: 11841193]
[59]
Kuroki M, Voest EE, Amano S, et al. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest 1996; 98(7): 1667-75.
[http://dx.doi.org/10.1172/JCI118962] [PMID: 8833917]
[60]
Sundaram C, Köster W, Schallreuter KU. The effect of UV radiation and sun blockers on free radical defence in human and guinea pig epidermis. Arch Dermatol Res 1990; 282(8): 526-31.
[http://dx.doi.org/10.1007/BF00371948] [PMID: 2082835]
[61]
Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol 2004; 51(4): 499-512.
[http://dx.doi.org/10.1016/j.jaad.2004.03.033] [PMID: 15389184]
[62]
Phillips DR, Rasbery JM, Bartel B, Matsuda SP. Biosynthetic diversity in plant triterpene cyclization. Curr Opin Plant Biol 2006; 9(3): 305-14.
[http://dx.doi.org/10.1016/j.pbi.2006.03.004] [PMID: 16581287]
[63]
Kim JK, Oh SM, Kwon HS, Oh YS, Lim SS, Shin HK. Anti-inflammatory effect of roasted licorice extracts on lipopolysaccharide-induced inflammatory responses in murine macrophages. Biochem Biophys Res Commun 2006; 345(3): 1215-23.
[http://dx.doi.org/10.1016/j.bbrc.2006.05.035] [PMID: 16716255]
[64]
Thiboutot D. Versatility of azelaic acid 15% gel in treatment of inflammatory acne vulgaris. J Drugs Dermatol 2008; 7(1): 13-6.
[PMID: 18246693]
[65]
Mastrofrancesco A, Ottaviani M, Aspite N, et al. Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARgamma activation. Exp Dermatol 2010; 19(9): 813-20.
[http://dx.doi.org/10.1111/j.1600-0625.2010.01107.x] [PMID: 20545756]
[66]
Briganti S, Flori E, Mastrofrancesco A, et al. Azelaic acid reduced senescence-like phenotype in photo-irradiated human dermal fibroblasts: possible implication of PPARγ. Exp Dermatol 2013; 22(1): 41-7.
[http://dx.doi.org/10.1111/exd.12066] [PMID: 23278893]
[67]
Breathnach AS. Azelaic acid: potential as a general antitumoural agent. Med Hypotheses 1999; 52(3): 221-6.
[http://dx.doi.org/10.1054/mehy.1997.0647] [PMID: 10362281]
[68]
Barbareschi M, Hendricks I, Angius A, Cattaneo M, Monti M. The anticomedonic activity of azelaic acid investigated by means of scanning electron microscopy on horny layer biopsy. J Dermatolog Treat 1991; 2: 55-7.
[http://dx.doi.org/10.3109/09546639109086775]
[69]
Passi S, Nazzaro-Porro M, Picardo M, Mingrone G, Fasella P. Metabolism of straight saturated medium chain length (C9 to C12) dicarboxylic acids. J Lipid Res 1983; 24(9): 1140-7.
[PMID: 6631243]
[70]
Maru U, Michaud P, Garrigue J, Oustrin J, Rouffiac R. Diffusion in vitro et pénétration cutanée de préparations d acide azélaïque: recherche de corrélations. J Pharm Belg 1982; 37(3): 207-13.
[PMID: 7131228]
[71]
Breathnach AS, Nazzaro-Porro M, Passi S. Azelaic acid. Br J Dermatol 1984; 111(1): 115-20.
[http://dx.doi.org/10.1111/j.1365-2133.1984.tb04025.x] [PMID: 6234914]
[72]
Picardo M, Passi S, Sirianni MC, et al. Activity of azelaic acid on cultures of lymphoma- and leukemia-derived cell lines, normal resting and stimulated lymphocytes and 3T3 fibroblasts. Biochem Pharmacol 1985; 34(10): 1653-8.
[http://dx.doi.org/10.1016/0006-2952(85)90630-6] [PMID: 4004885]
[73]
Dousset N, Douste-Blazy L. Transformation de l’acide azélaïque en acides gras monocarboxyliques in vivo chez le rat. Biochimie 1973; 55(10): 1279-85.
[http://dx.doi.org/10.1016/S0300-9084(74)80334-2] [PMID: 4793585]
[74]
Passi S, Picardo M, Mingrone G, Breathnach AS, Nazzaro-Porro M. Azelaic acid-biochemistry and metabolism. Acta Derm Venereol Suppl (Stockh) 1989; 143: 8-13.
[PMID: 2505463]
[75]
Mingrone G, Greco AV, Ciardiello A, Passo S, Nazzro-Porro M. Distribution of radiolabelled azelaic cid in eye membranes and fluids of rabbits. Exp Pathol 1984; 25(2): 85-8.
[http://dx.doi.org/10.1016/S0232-1513(84)80012-2] [PMID: 6539234]
[76]
Reis CP, Neufeld RJ, Ribeiro AJ, Veiga F, Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine: Nanotechnology. Biol Med 2006; 2: 8-21.
[77]
Reis CP, Gomes A, Rijo P, et al. Development and evaluation of a novel topical treatment for acne with azelaic acid-loaded nanoparticles. Microsc Microanal 2013; 19(5): 1141-50.
[http://dx.doi.org/10.1017/S1431927613000536] [PMID: 23673203]
[78]
Pradhan M, Singh D, Singh MR. Novel colloidal carriers for psoriasis: current issues, mechanistic insight and novel delivery approaches. J Control Release 2013; 170(3): 380-95.
[http://dx.doi.org/10.1016/j.jconrel.2013.05.020] [PMID: 23770117]
[79]
Dubey V, Mishra D, Jain M, Kumar N. Novel methothrexate-based topical therapies for effective treatment of psoriasis. Clin Dermatol 2008; 24: 124-30.
[80]
Mbah CC, Builders PF, Attama AA. Nanovesicular carriers as alternative drug delivery systems: ethosomes in focus. Expert Opin Drug Deliv 2014; 11(1): 45-59.
[http://dx.doi.org/10.1517/17425247.2013.860130] [PMID: 24294974]
[81]
Panyosak A, Manosroi J, Rojanasakul Y, Manosroi A. Safety assessment of azelaic acid and its derivatives entrapped in nanovesicles. Hum Exp Toxicol 2009; 28(6-7): 387-92.
[http://dx.doi.org/10.1177/0960327109105164] [PMID: 19755450]
[82]
Ma H, Yu M, Tan F, Li N. Improved percutaneous delivery of azelaic acid employing microemulsion as nanocarrier: formulation optimization, in vitro and in vivo evaluation. RSC Advances 2015; 5: 28985-95.
[http://dx.doi.org/10.1039/C5RA00713E]
[83]
Bajaj J, Sharma J. Formulation and evaluation of topical azelaic acid gel. J Chem Pharm Res 2015; 7: 616-20.
[84]
Bahadur B, Ed. Liquid crystals: applications and uses 1990; 1.
[http://dx.doi.org/10.1142/1013]
[85]
Aytekin M, Gursoy RN, Ide S, Soylu EH, Hekimoglu S. Formulation and characterization of liquid crystal systems containing azelaic acid for topical delivery. Drug Dev Ind Pharm 2013; 39(2): 228-39.
[http://dx.doi.org/10.3109/03639045.2012.671829] [PMID: 22480294]
[86]
Gallarate M, Mittone E, Carlotti ME, Trotta M, Piccerelle P. Formulation of dry emulsion for topical applications. J Dispers Sci Technol 2009; 30: 823-33.
[http://dx.doi.org/10.1080/01932690802643998]
[87]
Kongmuang S, Tepsukon KO, Yodwandee P, Laovanichkul P. Azelaic Acid Dry Emulsion. Adv Mat Res 2015; 1060: 29-32.
[88]
Available from : https://en.wikipedia.org/wiki/Cream (Accessed on December 5, 2017).
[89]
Hu F, Mah K, Teramura DJ. Effects of dicarboxylic acids on normal and malignant melanocytes in culture. Br J Dermatol 1986; 114(1): 17-26.
[http://dx.doi.org/10.1111/j.1365-2133.1986.tb02775.x] [PMID: 3942687]
[90]
Lemic-Stojcevic L, Nias AH, Breathnach AS. Effect of azelaic acid on melanoma cells in culture. Exp Dermatol 1995; 4(2): 79-81.
[http://dx.doi.org/10.1111/j.1600-0625.1995.tb00226.x] [PMID: 7640879]
[91]
Addo-Boadu K, Wojta J, Christ G, Hufnagl P, Pehamberger H, Binder BR. Azelaic acid decreases the fibrinolytic potential of cultured human melanoma cells in vitro. Cancer Lett 1996; 103(2): 125-9.
[http://dx.doi.org/10.1016/0304-3835(96)04185-7] [PMID: 8635147]
[92]
Manosroi A, Panyosak A, Rojanasakul Y, Manosroi J. Characteristics and anti-proliferative activity of azelaic acid and its derivatives entrapped in bilayer vesicles in cancer cell lines. J Drug Target 2007; 15(5): 334-41.
[http://dx.doi.org/10.1080/10611860701349315] [PMID: 17541842]
[93]
Pan Y, Liu D, Wei Y, et al. Azelaic acid exerts antileukemic activity in acute myeloid leukemia. Front Pharmacol 2017; 8: 359.
[http://dx.doi.org/10.3389/fphar.2017.00359] [PMID: 28659796]


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Article Details

VOLUME: 15
ISSUE: 3
Year: 2020
Published on: 14 October, 2020
Page: [181 - 193]
Pages: 13
DOI: 10.2174/1574885514666190904160228

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