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Current Drug Research Reviews


ISSN (Print): 2589-9775
ISSN (Online): 2589-9783

Review Article

Onychomycosis: Current Understanding and Strategies for Enhancing Drug Delivery into Human Nail Tissue

Author(s): Rabia Aslam, Talib Hussain, Abid Mehmood Yousaf, Muhammad U. Ghori, Ikram U. Khan, Syed A.A. Rizvi and Yasser Shahzad*

Volume 13, Issue 1, 2021

Published on: 31 July, 2020

Page: [25 - 35] Pages: 11

DOI: 10.2174/2589977512666200731171505

Price: $65


Background: Onychomycosis is by far the most common finger or toe nail fungal infectious disease caused by dermatophytes, non-dermatophytic molds or yeast. It accounts for 50% of the total nail disorders, and affects patients physically, socially, and psychologically and can seriously influence their quality of life.

Objectives: Oral antifungals are routinely used to treat the nail fungal disease; however oral therapy is associated with severe side effects and longer treatment times. In recent years, drug delivery directly into the nail or nail bed has gained attention and various topical products have been tested that can cure the disease when applied topically or transungually. Nevertheless, drug penetration into and through the nail is not straightforward and requires chemicals to improve its permeability or by applying physical stress to promote drug penetration into and through the nail. This lucid review presents an overview of various causes of onychomycosis, current therapeutic approaches, and efforts aimed at increasing the permeability of nails through various strategies such as chemical, physical and mechanical methods for permeation enhancement.

Conclusion: Various strategies have been proposed for the treatment of onychomycosis, however, much research into a more precise and effective therapy is still required.

Keywords: Antifungals, dermatophytes, hydration, nail, onychomycosis, permeability, transungual, ungual drug delivery.

Graphical Abstract
Grover C, Khurana A. An update on treatment of onychomycosis. Mycoses 2012; 55(6): 541-51.
[] [PMID: 22540995]
Daniel RC. Onychomycosis: Burden of disease and the role of topical antifungal treatment. J Drugs Dermatol 2013; 12(11): 1263-6.
[PMID: 24196334]
Elewski BE. Onychomycosis: pathogenesis, diagnosis, and management. Clin Microbiol Rev 1998; 11(3): 415-29.
[] [PMID: 9665975]
Moriarty B, Hay R, Morris-Jones R. The diagnosis and management of tinea. BMJ 2012; 344(7865): e4380.
Hao J, Li SK. Transungual iontophoretic transport of polar neutral and positively charged model permeants: Effects of electrophoresis and electroosmosis. J Pharm Sci 2008; 97(2): 893-905.
[] [PMID: 17683062]
Shokoohi GR, Ansari S, Abolghazi A, et al. The first case of fingernail onychomycosis due to Neoscytalidium novaehollandiae, molecular identification and antifungal susceptibility. J Mycol Med 2020; 30(1): 100920.
[] [PMID: 31892498]
Hay R. Literature review. Onychomycosis. J Eur Acad Dermatol Venereol 2005; 19(Suppl. 1): 1-7.
[] [PMID: 16120198]
Thomas J, Jacobson GA, Narkowicz CK, Peterson GM, Burnet H, Sharpe C. Toenail onychomycosis: An important global disease burden. J Clin Pharm Ther 2010; 35(5): 497-519.
[] [PMID: 20831675]
Brown M, Turner R, Wevrett SR. Use of in vitro performance models in the assessment of drug delivery across the human nail for nail disorders. Expert Opin Drug Deliv 2018; 15(10): 983-9.
[] [PMID: 30173543]
de Berker D. Nail anatomy. Clin Dermatol 2013; 31(5): 509-15.
[] [PMID: 24079579]
Garson JC, Baltenneck F, Leroy F, Riekel C, Müller M. Histological structure of human nail as studied by synchrotron X-ray microdiffraction. Cell Mol Biol 2000; 46(6): 1025-34.
[PMID: 10976860]
Dawber RPR. The ultrastructure and growth of human nails. Arch Dermatol Res 1980; 269(2): 197-204.
[] [PMID: 6161584]
Jemec GBE, Agner T, Serup J. Transonychial water loss: Relation to sex, age and nail-plate thickness. Br J Dermatol 1989; 121(4): 443-6.
[] [PMID: 2624837]
Cohen JL, Scher RK, Pappert AS. The nail and fungus infections.Cutaneous fungal infections New York Igaku-Shoin Inc. 1992; pp. 106-22.
Murdan S. Drug delivery to the nail following topical application. Int J Pharm 2002; 236(1-2): 1-26.
[] [PMID: 11891066]
Kobayashi Y, Miyamoto M, Sugibayashi K, Morimoto Y. Drug permeation through the three layers of the human nail plate. J Pharm Pharmacol 1999; 51(3): 271-8.
[] [PMID: 10344627]
de Berker DA, André J, Baran R. Nail biology and nail science. Int J Cosmet Sci 2007; 29(4): 241-75.
[] [PMID: 18489354]
Walters KA, Flynn GL, Marvel JR. Physicochemical characterization of the human nail: Solvent effects on the permeation of homologous alcohols. J Pharm Pharmacol 1985; 37(11): 771-5.
[] [PMID: 2867157]
De Berker D, Wojnarowska F, Sviland L, Westgate GE, Dawber RP, Leigh IM. Keratin expression in the normal nail unit: Markers of regional differentiation. Br J Dermatol 2000; 142(1): 89-96.
[] [PMID: 10651700]
Lipner SR, Scher RK. Onychomycosis: Treatment and prevention of recurrence. J Am Acad Dermatol 2019; 80(4): 853-67.
[] [PMID: 29959962]
Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F, Muhn CY. Psoriasis of the nail: Anatomy, pathology, clinical presentation, and a review of the literature on therapy. J Am Acad Dermatol 2007; 57(1): 1-27.
[] [PMID: 17572277]
Hay RJ, Baran R. Onychomycosis: A proposed revision of the clinical classification. J Am Acad Dermatol 2011; 65(6): 1219-27.
[] [PMID: 21501889]
Hay RJ, Baran R, Moore MK, Wilkinson JD. Candida onychomycosis-An evaluation of the role of Candida species in nail disease. Br J Dermatol 1988; 118(1): 47-58.
[] [PMID: 3342176]
Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert Opin Pharmacother 2012; 13(8): 1131-42.
[] [PMID: 22533461]
Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol 2013; 31(5): 544-54.
[] [PMID: 24079583]
Repka MA, O’Haver J, See CH, Gutta K, Munjal M. Nail morphology studies as assessments for onychomycosis treatment modalities. Int J Pharm 2002; 245(1-2): 25-36.
[] [PMID: 12270239]
Scher RK. Onychomycosis: Therapeutic update. J Am Acad Dermatol 1999; 40(6): S21-6.
Tanrıverdi ST, Özer Ö. Novel topical formulations of Terbinafine-HCl for treatment of onychomycosis. Eur J Pharm Sci 2013; 48(4-5): 628-36.
[] [PMID: 23295582]
Walters KA, Abdalghafor HM, Lane ME. The human nail--barrier characterisation and permeation enhancement. Int J Pharm 2012; 435(1): 10-21.
[] [PMID: 22521879]
Brown MB, Khengar RH, Turner RB, et al. Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement. Int J Pharm 2009; 370(1-2): 61-7.
[] [PMID: 19071202]
Smith KA, Hao J, Li SK. Effects of ionic strength on passive and iontophoretic transport of cationic permeant across human nail. Pharm Res 2009; 26(6): 1446-55.
[] [PMID: 19267187]
Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv 2008; 5(11): 1267-82.
[] [PMID: 18976136]
de Berker. Management of psoriatic nail disease. Semin Cutan Med Surg 2009; 28(1): 39-43.
Kobayashi Y, Komatsu T, Sumi M, et al. In vitro permeation of several drugs through the human nail plate: Relationship between physicochemical properties and nail permeability of drugs. Eur J Pharm Sci 2004; 21(4): 471-7.
[] [PMID: 14998577]
Roberts DT, Evans EG. Subungual dermatophytoma complicating dermatophyte onychomycosis. Br J Dermatol 1998; 138(1): 189-90.
[] [PMID: 9536247]
Vikas A, Rashmin P, Mrunali P, Chavan RB, Kaushik T. mechanistic insights of formulation approaches for the treatment of nail infection: Conventional and novel drug delivery approaches. AAPS PharmSciTech 2020; 21(2): 67.
[] [PMID: 31938980]
Walters KA, Flynn GL, Marvel JR. Physicochemical characterization of the human nail: Permeation pattern for water and the homologous alcohols and differences with respect to the stratum corneum. J Pharm Pharmacol 1983; 35(1): 28-33.
[] [PMID: 6131961]
Smith KA, Hao J, Li SK. Effects of organic solvents on the barrier properties of human nail. J Pharm Sci 2011; 100(10): 4244-57.
[] [PMID: 21607952]
Gunt HB, Kasting GB. Effect of hydration on the permeation of ketoconazole through human nail plate in vitro. Eur J Pharm Sci 2007; 32(4-5): 254-60.
[] [PMID: 17928205]
Hui X, Wester RC, Barbadillo S, et al. Ciclopirox delivery into the human nail plate. J Pharm Sci 2004; 93(10): 2545-8.
[] [PMID: 15349963]
Cutrín-Gómez E, Anguiano-Igea S, Delgado-Charro MB, Gómez-Amoza JL, Otero-Espinar FJ. effect on nail structure and transungual permeability of the ethanol and poloxamer ratio from cyclodextrin-soluble polypseudorotaxanes based nail lacquer. Pharmaceutics 2018; 10(3): 156.
[] [PMID: 30208659]
Narasimha Murthy S, Wiskirchen DE, Bowers CP. Iontophoretic drug delivery across human nail. J Pharm Sci 2007; 96(2): 305-11.
[] [PMID: 17080425]
Elsayed MM. Development of topical therapeutics for management of onychomycosis and other nail disorders: A pharmaceutical perspective. J Control Release 2015; 199: 132-44.
[] [PMID: 25481439]
Shanbhag PP, Jani U. Drug delivery through nails: Present and future. New Horiz Transl Med 2017; 3(5): 252-63.
Mertin D, Lippold BC. In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: Prediction of the penetration rate of antimycotics through the nail plate and their efficacy. J Pharm Pharmacol 1997; 49(9): 866-72.
[] [PMID: 9306253]
Smith KA, Hao J, Li SK. Influence of pH on transungual passive and iontophoretic transport. J Pharm Sci 2010; 99(4): 1955-67.
[] [PMID: 19904826]
Murthy SN, Waddell DC, Shivakumar HN, Balaji A, Bowers CP. Iontophoretic permselective property of human nail. J Dermatol Sci 2007; 46(2): 150-2.
[] [PMID: 17289349]
Shivakumar HN, Juluri A, Desai BG, Murthy SN. Ungual and transungual drug delivery. Drug Dev Ind Pharm 2012; 38(8): 901-11.
[] [PMID: 22149347]
Saner MV, Kulkarni AD, Pardeshi CV. Insights into drug delivery across the nail plate barrier. J Drug Target 2014; 22(9): 769-89.
[] [PMID: 24964054]
Van Hoogdalem E, Van den Hoven W, Terpstra I, Van Zijtveld J, Verschoor J, Visser J. Nail penetration of the antifungal agent oxiconazole after repeated topical application in healthy volunteers, and the effect of acetylcysteine. Eur J Pharm Sci 1997; 5(3): 119-27.
Hui X, Chan TC, Barbadillo S, Lee C, Maibach HI, Wester RC. Enhanced econazole penetration into human nail by 2-n-nonyl-1,3-dioxolane. J Pharm Sci 2003; 92(1): 142-8.
[] [PMID: 12486690]
Mohorčič M, Torkar A, Friedrich J, Kristl J, Murdan S. An investigation into keratinolytic enzymes to enhance ungual drug delivery. Int J Pharm 2007; 332(1-2): 196-201.
[] [PMID: 17097244]
Nair AB, Sammeta SM, Vaka SRK, Narasimha Murthy S. A study on the effect of inorganic salts in transungual drug delivery of terbinafine. J Pharm Pharmacol 2009; 61(4): 431-7.
[] [PMID: 19298688]
Angelo T, Borgheti-Cardoso LN, Gelfuso GM, Taveira SF, Gratieri T. Chemical and physical strategies in onychomycosis topical treatment: A review. Med Mycol 2017; 55(5): 461-75.
[PMID: 27703019]
Thapa RK, Choi JY, Go TG, et al. Development of ciclopirox nail lacquer with enhanced permeation and retention. Arch Pharm Res 2016; 39(7): 953-9.
[] [PMID: 27306785]
Khattab A, Shalaby S. optimized ciclopirox-based eudragit rlpo nail lacquer: Effect of endopeptidase enzyme as permeation enhancer on transungual drug delivery and efficiency against onychomycosis. AAPS PharmSciTech 2018; 19(3): 1048-60.
[] [PMID: 29138987]
Repka MA, Mididoddi PK, Stodghill SP. Influence of human nail etching for the assessment of topical onychomycosis therapies. Int J Pharm 2004; 282(1-2): 95-106.
[] [PMID: 15336385]
Donnelly RF, McCarron PA, Lightowler JM, Woolfson AD. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis. J Control Release 2005; 103(2): 381-92.
[] [PMID: 15763621]
Susilo R, Korting HC, Greb W, Strauss UP. Nail penetration of sertaconazole with a sertaconazole-containing nail patch formulation. Am J Clin Dermatol 2006; 7(4): 259-62.
[] [PMID: 16901186]
Boker A, Bea Y, Gowrishankar T, Eds. A double-blind, placebo-controlled, pilot study of 1% terbinafine cream delivered via toenail microconduits for the treatment of subungual onychomycosis. 65th annual meeting of the American Academy of Dermatology. Washington, DC. 2007.
Vaka SRK, Murthy SN, O’Haver JH, Repka MA. A platform for predicting and enhancing model drug delivery across the human nail plate. Drug Dev Ind Pharm 2011; 37(1): 72-9.
[] [PMID: 20545509]
Kushwaha A, Murthy RN, Murthy SN, Elkeeb R, Hui X, Maibach HI. Emerging therapies for the treatment of ungual onychomycosis. Drug Dev Ind Pharm 2015; 41(10): 1575-81.
[] [PMID: 25997365]
Grover C, Bansal S, Nanda S, Reddy BS, Kumar V. Combination of surgical avulsion and topical therapy for single nail onychomycosis: A randomized controlled trial. Br J Dermatol 2007; 157(2): 364-8.
[] [PMID: 17573877]
Hao J, Smith KA, Li SK. Chemical method to enhance transungual transport and iontophoresis efficiency. Int J Pharm 2008; 357(1-2): 61-9.
[] [PMID: 18321669]
Nair AB, Kim HD, Chakraborty B, et al. Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis. J Pharm Sci 2009; 98(11): 4130-40.
[] [PMID: 19340887]
Nair AB, Sammeta SM, Kim HD, Chakraborty B, Friden PM, Murthy SN. Alteration of the diffusional barrier property of the nail leads to greater terbinafine drug loading and permeation. Int J Pharm 2009; 375(1-2): 22-7.
[] [PMID: 19481686]
Kobayashi Y, Miyamoto M, Sugibayashi K, Morimoto Y. Enhancing effect of N-acetyl-l-cysteine or 2-mercaptoethanol on the in vitro permeation of 5-fluorouracil or tolnaftate through the human nail plate. Chem Pharm Bull (Tokyo) 1998; 46(11): 1797-802.
[] [PMID: 9845958]
Malhotra GG, Zatz JL. Investigation of nail permeation enhancement by chemical modification using water as a probe. J Pharm Sci 2002; 91(2): 312-23.
[] [PMID: 11835191]
Vejnovic I, Simmler L, Betz G. Investigation of different formulations for drug delivery through the nail plate. Int J Pharm 2010; 386(1-2): 185-94.
[] [PMID: 19941943]
Borgheti-Cardoso LN, Ângelo T, Gelfuso GM, et al. Topical and transdermal delivery of drug-loaded nano/microsystems with application of physical enhancement techniques. Curr Drug Targets 2016; 17(13): 1545-59.
[] [PMID: 26477464]
Barot BS, Parejiya PB, Patel HK, Mehta DM, Shelat PK. Drug delivery to the nail: Therapeutic options and challenges for onychomycosis critical reviews™ in therapeutic drug carrier systems 2014; 31(6)
Mididoddi PK, Prodduturi S, Repka MA. Influence of tartaric acid on the bioadhesion and mechanical properties of hot-melt extruded hydroxypropyl cellulose films for the human nail. Drug Dev Ind Pharm 2006; 32(9): 1059-66.
[] [PMID: 17012118]
Borgheti-Cardoso LN, Ângelo T, Gelfuso GM, Lopez RF, Gratieri T. Topical and transdermal delivery of drug-loaded nano/ microsystems with application of physical enhancement techniques. Curr Drug Targets 2016; 17(13): 1545-59.
[] [PMID: 26477464]
Kassan DG, Lynch AM, Stiller MJ. Physical enhancement of dermatologic drug delivery: Iontophoresis and phonophoresis. J Am Acad Dermatol 1996; 34(4): 657-66.
[] [PMID: 8601657]
Horwath-Winter J, Schmut O, Haller-Schober EM, Gruber A, Rieger G. Iodide iontophoresis as a treatment for dry eye syndrome. Br J Ophthalmol 2005; 89(1): 40-4.
[] [PMID: 15615744]
Nowicki K, Hummer CD III, Heidt RS Jr, Colosimo AJ. Effects of iontophoretic versus injection administration of dexamethasone. Med Sci Sports Exerc 2002; 34(8): 1294-301.
[] [PMID: 12165684]
Chen L-J, Meng Q-F, Chen Y-M, Smales RJ, Yip KH. Effect of fluoride iontophoresis on the microtensile bond strength between dentin and two adhesive systems. J Dent 2008; 36(9): 697-702.
[] [PMID: 18555580]
Darkes MJ, Scott LJ, Goa KL. Terbinafine: A review of its use in onychomycosis in adults. Am J Clin Dermatol 2003; 4(1): 39-65.
[] [PMID: 12477372]
Nair AB, Vaka SR, Sammeta SM, et al. Trans- ungual iontophoretic delivery of terbinafine. J Pharm Sci 2009; 98(5): 1788-96.
[] [PMID: 18781625]
Kreutz T, de Matos SP, Koester LS. Recent patents on permeation enhancers for drug delivery through nails. Recent Pat Drug Deliv Formul 2019; 13(3): 203-18.
[] [PMID: 31663846]
Gupta AK, Paquet M. Improved efficacy in onychomycosis therapy. Clin Dermatol 2013; 31(5): 555-63.
[] [PMID: 24079584]
Sumikawa M, Egawa T, Honda I, Yamamoto Y, Sumikawa Y, Kubota M. Effects of foot care intervention including nail drilling combined with topical antifungal application in diabetic patients with onychomycosis. J Dermatol 2007; 34(7): 456-64.
[] [PMID: 17584323]
Salter SA, Ciocon DH, Gowrishankar TR, Kimball AB. Controlled nail trephination for subungual hematoma. Am J Emerg Med 2006; 24(7): 875-7.
[] [PMID: 17098113]
Chiu WS, Belsey NA, Garrett NL, et al. Drug delivery into microneedle-porated nails from nanoparticle reservoirs. J Control Release 2015; 220(Pt A): 98-106.
[] [PMID: 26478016]
Cordoba Díaz D, Losa Iglesias ME, Becerro de Bengoa Vallejo R, Cordoba Diaz M. Transungual delivery of ciclopirox is increased 3-4 fold by mechanical fenestration of human nail plate in an in vitro model. Pharmaceutics 2019; 11(1): E29.
[] [PMID: 30646496]
Šveikauskaitė I, Pockevičius A, Briedis V. Potential of chemical and physical enhancers for transungual delivery of amorolfine hydrochloride. Materials (Basel) 2019; 12(7): 1028.
[] [PMID: 30925734]
Nguyen HX, Banga AK. Effect of ablative laser on in vitro transungual delivery. Int J Pharm 2018; 544(2): 402-14.
[] [PMID: 28951347]
Shahzad Y, Louw R, Gerber M, du Plessis J. Breaching the skin barrier through temperature modulations. J Control Release 2015; 202: 1-13.
[] [PMID: 25616160]
Vogel A, Noack J, Hüttman G, Paltauf G. Mechanisms of femtosecond laser nanosurgery of cells and tissues. Appl Phys B 2005; 81(8): 1015-47.
Neev J, Silva LBD, Feit MD, Perry MD, Rubenchik AM, Stuart BC. Ultrashort pulse lasers for hard tissue ablation. IEEE J Sel Top Quantum Electron 1996; 2(4): 790-800.
Vanstone S, Stone JM, Gordeev SN, Guy RH. Mechanism of human nail poration by high-repetition-rate, femtosecond laser ablation. Drug Deliv Transl Res 2019; 9(5): 956-67.
[] [PMID: 31016477]
Vanstone S, Cordery SF, Stone JM, Gordeev SN, Guy RH. Precise laser poration to control drug delivery into and through human nail. J Control Release 2017; 268: 72-7.
Barot BS, Parejiya PB, Patel HK, Mehta DM, Shelat PK. Drug delivery to the nail: Therapeutic options and challenges for onychomycosis Crit Rev Ther Drug Carrier Syst 2014; 31(6): 459-94.
Abadi D, Zderic V. Ultrasound-mediated nail drug delivery system. J Ultrasound Med 2011; 30(12): 1723-30.
[] [PMID: 22124008]
Di Chiacchio N, Kadunc BV, de Almeida ART, Madeira CL. Nail abrasion. J Cosmet Dermatol 2003; 2(3-4): 150-2.
[] [PMID: 17163921]
Maeda N, Mizuno N, Ichikawa K. Nail abrasion: A new treatment for ingrown toe-nails. J Dermatol 1990; 17(12): 746-9.
[] [PMID: 2086619]
Richert B. Physical treatment of onychomycosis. Onychomycosis. 2020.
Elkeeb R, AliKhan A, Elkeeb L, Hui X, Maibach HI. Transungual drug delivery: Current status. Int J Pharm 2010; 384(1-2): 1-8.
[] [PMID: 19819318]
Effendy I, Kolczak H, Friederich H. Noncompliance relevant variables in patients with onychomycosis. Wien Med Wochenschr 1989; 139(15-16): 356-6.
Succi IB, Bernardes-Engemann AR, Orofino-Costa R. Intermittent therapy with terbinafine and nail abrasion for dermatophyte toe onychomycosis: A pilot study. Mycoses 2013; 56(3): 327-32.
[] [PMID: 23294342]
Hettinger DF, Valinsky MS. Treatment of onychomycosis with nail avulsion and topical ketoconazole. J Am Podiatr Med Assoc 1991; 81(1): 28-32.
[] [PMID: 1825225]
Kawa N, Lee KC, Anderson RR, Garibyan L. Onychomycosis: A review of new and emerging topical and device-based treatments. J Clin Aesthet Dermatol 2019; 12(10): 29-34.
[PMID: 32038746]

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