Transungual Drug Delivery System for the Topical Treatment of Onychomycosis:
A Review

Yashwant      Giri; Amulyaratna      Behera; Biswaranjan      Mohanty; Gurudutta      Pattnaik; S.K.      Habibullah
Abstract

Onychomycosis is an infection caused by a fungus that causes discoloration and thickening of the nail layer, and it is the most common nail infection in the world. Trichophyton rubrum and Trichophyton mentagrophytes var. interdigital is the most common anthropophilic dermatophytes that trigger it. Onychomycosis is caused by yeasts such as Candida albicans and Candida parapsilosis, as well as moulds such as Aspergillus spp. Treatment is determined by the type of nail invasion, the fungus genus, and the number of nails affected. Approaches towards conventional methods showed certain drawbacks, which emphasizes the need for alternate approaches to produce better therapeutic efficacy of a product. The present review focused on reporting an updated classification of Onchyomycosis, causative organisms, factors influencing drug permeation, novel treatment strategies for Onychomycosis, and drug permeation enhancement methods.
Keywords: Onychomycosis, transungual, topical drug delivery, nanoparticles, liposomes, microemulsion, hydrogels.
Graphical Abstract

[1] 
Gupta, A.K.; Albreski, D.; Del Rosso, J.Q.; Konnikov, N. The use of the new oral antifungal agents, itraconazole, terbinafine, and fluconazole to treat onychomycosis and other dermatomycoses. Curr. Probl. Dermatol.,  2001, 13(4), 213-246.
[http://dx.doi.org/10.1067/mdm.2001.108128] 
[2] 
Shirwaikar, A.A.; Thomas, T.; Shirwaikar, A.; Lobo, R.; Prabhu, K.S. Treatment of onychomycosis: an update. Indian J. Pharm. Sci.,  2008, 70(6), 710-714.
[http://dx.doi.org/10.4103/0250-474X.49088] [PMID:  21369429] 
[3] 
Gupta, A.K.; Mays, R.R.; Versteeg, S.G.; Shear, N.H.; Piguet, V. Update on current approaches to diagnosis and treatment of onychomycosis. Expert Rev. Anti Infect. Ther.,  2018, 16(12), 929-938.
[http://dx.doi.org/10.1080/14787210.2018.1544891] [PMID:  30411650] 
[4] 
Thomas, J.; Jacobson, G.A.; Narkowicz, C.K.; Peterson, G.M.; Burnet, H.; Sharpe, C. Toenail onychomycosis: an important global disease burden. J. Clin. Pharm. Ther.,  2010, 35(5), 497-519.
[http://dx.doi.org/10.1111/j.1365-2710.2009.01107.x] [PMID:  20831675] 
[5] 
Lipner, S.R.; Scher, R.K. Onychomycosis: Clinical overview and diagnosis. J. Am. Acad. Dermatol.,  2019, 80(4), 835-851.
[http://dx.doi.org/10.1016/j.jaad.2018.03.062] [PMID:  29959961] 
[6] 
Sigurgeirsson, B.; Baran, R. The prevalence of onychomycosis in the global population: a literature study. J. Eur. Acad. Dermatol. Venereol.,  2014, 28(11), 1480-1491.
[http://dx.doi.org/10.1111/jdv.12323] [PMID:  24283696] 
[7] 
Adekhandi, S.; Pal, S.; Sharma, N.; Juyal, D.; Sharma, M.; Dimri, D. Incidence and epidemiology of onychomycosis in patients visiting a tertiary care hospital in India. Cutis,  2015, 95(1), E20-E25.
[PMID:  25671453] 
[8] 
Nair, A.B.; Vaka, S.R.; Murthy, S.N. Transungual delivery of terbinafine by iontophoresis in onychomycotic nails. Drug Dev. Ind. Pharm.,  2011, 37(10), 1253-1258.
[http://dx.doi.org/10.3109/03639045.2011.568946] [PMID:  21457120] 
[9] 
Faergemann, J.; Baran, R. Epidemiology, clinical presentation and diagnosis of onychomycosis. Br. J. Dermatol.,  2003, 149(Suppl. 65), 1-4.
[http://dx.doi.org/10.1046/j.1365-2133.149.s65.4.x] [PMID:  14510968] 
[10] 
Piérard, G. Onychomycosis and other superficial fungal infections of the foot in the elderly: a pan-European survey. Dermatology,  2001, 202(3), 220-224.
[http://dx.doi.org/10.1159/000051640] [PMID:  11385227] 
[11] 
Charif, M.A.; Elewski, B.E. Prevalence of onychomycosis in the United States: results of a population based survey. J. Invest. Dermatol.,  1996, 4(106), 892.
[12] 
Elewski, B.E.; Charif, M.A. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch. Dermatol.,  1997, 133(9), 1172-1173.
[http://dx.doi.org/10.1001/archderm.1997.03890450124022] [PMID:  9301602] 
[13] 
Gupta, A.K.; Gupta, M.A.; Summerbell, R.C.; Cooper, E.A.; Konnikov, N.; Albreski, D.; MacDonald, P.; Harris, K.A. The epidemiology of onychomycosis: possible role of smoking and peripheral arterial disease. J. Eur. Acad. Dermatol. Venereol.,  2000, 14(6), 466-469.
[http://dx.doi.org/10.1046/j.1468-3083.2000.00124.x] [PMID:  11444267] 
[14] 
Gupta, A.K.; Konnikov, N.; MacDonald, P.; Rich, P.; Rodger, N.W.; Edmonds, M.W.; McManus, R.; Summerbell, R.C. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br. J. Dermatol.,  1998, 139(4), 665-671.
[http://dx.doi.org/10.1046/j.1365-2133.1998.02464.x] [PMID:  9892911] 
[15] 
Dogra, S.; Kumar, B.; Bhansali, A.; Chakrabarty, A. Epidemiology of onychomycosis in patients with diabetes mellitus in India. Int. J. Dermatol.,  2002, 41(10), 647-651.
[http://dx.doi.org/10.1046/j.1365-4362.2002.01528.x] [PMID:  12390186] 
[16] 
Vasconcellos, C.; Pereira, C.Q.; Souza, M.C.; Pelegrini, A.; Freitas, R.S.; Takahashi, J.P. Identification of fungi species in the onychomycosis of institutionalized elderly. An. Bras. Dermatol.,  2013, 88(3), 377-380.
[http://dx.doi.org/10.1590/abd1806-4841.20131884] [PMID:  23793195] 
[17] 
Gupta, A.K.; Jain, H.C.; Lynde, C.W.; Watteel, G.N.; Summerbell, R.C. Prevalence and epidemiology of unsuspected onychomycosis in patients visiting dermatologists’ offices in Ontario, Canada--a multicenter survey of 2001 patients. Int. J. Dermatol.,  1997, 36(10), 783-787.
[http://dx.doi.org/10.1046/j.1365-4362.1997.00349.x] [PMID:  9372358] 
[18] 
Gupta, A.K. Onychomycosis in the elderly. Drugs Aging,  2000, 16(6), 397-407.
[http://dx.doi.org/10.2165/00002512-200016060-00002] [PMID:  10939306] 
[19] 
Gupta, A.K.; Gupta, G.; Jain, H.C.; Lynde, C.W.; Foley, K.A.; Daigle, D.; Cooper, E.A.; Summerbell, R.C. The prevalence of unsuspected onychomycosis and its causative organisms in a multicentre Canadian sample of 30 000 patients visiting physicians’ offices. J. Eur. Acad. Dermatol. Venereol.,  2016, 30(9), 1567-1572.
[http://dx.doi.org/10.1111/jdv.13677] [PMID:  27168494] 
[20] 
Klaassen, K.M.; Dulak, M.G.; van de Kerkhof, P.C.; Pasch, M.C. The prevalence of onychomycosis in psoriatic patients: a systematic review. J. Eur. Acad. Dermatol. Venereol.,  2014, 28(5), 533-541.
[http://dx.doi.org/10.1111/jdv.12239] [PMID:  24033871] 
[21] 
Gupta, A.K.; Taborda, P.; Taborda, V.; Gilmour, J.; Rachlis, A.; Salit, I.; Gupta, M.A.; MacDonald, P.; Cooper, E.A.; Summerbell, R.C. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int. J. Dermatol.,  2000, 39(10), 746-753.
[http://dx.doi.org/10.1046/j.1365-4362.2000.00012.x] [PMID:  11095193] 
[22] 
Gupta, A.K.; Sibbald, R.G.; Lynde, C.W.; Hull, P.R.; Prussick, R.; Shear, N.H.; De Doncker, P.; Daniel, C.R., III; Elewski, B.E. Onychomycosis in children: prevalence and treatment strategies. J. Am. Acad. Dermatol.,  1997, 36(3 Pt 1), 395-402.
[http://dx.doi.org/10.1016/S0190-9622(97)80215-0] [PMID:  9091470] 
[23] 
Gupta, A.K.; Studholme, C. Update on efinaconazole 10% topical solution for the treatment of onychomycosis. Skin Therapy Lett.,  2016, 21(6), 7-11.
[PMID:  27825175] 
[24] 
Rosen, T.; Friedlander, S.F.; Kircik, L.; Zirwas, M.J.; Stein Gold, L.; Bhatia, N.; Gupta, A.K. Onychomycosis: epidemiology, diagnosis, and treatment in a changing landscape. J. Drugs Dermatol.,  2015, 14(3), 223-233.
[PMID:  25738843] 
[25] 
Rosen, T. Tinea and onychomycosis. Semin. Cutan. Med. Surg.,  2016, 35(6), S110-S113.
[http://dx.doi.org/10.12788/j.sder.2016.035] [PMID:  27537822] 
[26] 
Ghannoum, M.A.; Hajjeh, R.A.; Scher, R.; Konnikov, N.; Gupta, A.K.; Summerbell, R.; Sullivan, S.; Daniel, R.; Krusinski, P.; Fleckman, P.; Rich, P.; Odom, R.; Aly, R.; Pariser, D.; Zaiac, M.; Rebell, G.; Lesher, J.; Gerlach, B.; Ponce-De-Leon, G.F.; Ghannoum, A.; Warner, J.; Isham, N.; Elewski, B. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J. Am. Acad. Dermatol.,  2000, 43(4), 641-648.
[http://dx.doi.org/10.1067/mjd.2000.107754] [PMID:  11004620] 
[27] 
Botek, G. Fungal nail infection: assessing the new treatment options. Cleve. Clin. J. Med.,  2003, 70(2), 110-114, 117-118.
[http://dx.doi.org/10.3949/ccjm.70.2.110] [PMID:  12636343] 
[28] 
Goldstein, A.O.; Bhatia, N.; Levy, M.L.; Rosen, T. Onychomycosis: Epidemiology, clinical features, and diagnosis; Up To Date: Waltham, MA, 2016. 
[29] 
Grover, C.; Khurana, A. Onychomycosis: newer insights in pathogenesis and diagnosis. Indian J. Dermatol. Venereol. Leprol.,  2012, 78(3), 263-270.
[http://dx.doi.org/10.4103/0378-6323.95440] [PMID:  22565425] 
[30] 
Hoy, N.Y.; Leung, A.K.; Metelitsa, A.I.; Adams, S. New concepts in median nail dystrophy, onychomycosis, and hand, foot, and mouth disease nail pathology. ISRN Dermatol.,  2012, 2012, 680163.
[http://dx.doi.org/10.5402/2012/680163] 
[31] 
Angelo, T.; Borgheti-Cardoso, L.N.; Gelfuso, G.M.; Taveira, S.F.; Gratieri, T. Chemical and physical strategies in onychomycosis topical treatment: A review. Med. Mycol.,  2017, 55(5), 461-475.
[PMID:  27703019] 
[32] 
 Bodman, MA; Krishnamurthy, K Onychomycosis. In: StatPearls;
StatPearls Publishing: Treasure Island (FL), 2022. Available from: 
          https://www.ncbi.nlm.nih.gov/books/NBK441853/
[33] 
Gupta, A.K.; Sibbald, R.G.; Andriessen, A.; Belley, R.; Boroditsky, A.; Botros, M.; Chelin, R.; Gulliver, W.; Keast, D.; Raman, M. Toenail onychomycosis-a Canadian approach with a new transungual treatment: development of a clinical pathway. J. Cutan. Med. Surg.,  2015, 19(5), 440-449.
[http://dx.doi.org/10.1177/1203475415581310] [PMID:  25857439] 
[34] 
Joyce, A.; Gupta, A.K.; Koenig, L.; Wolcott, R.; Carviel, J. Fungal diversity and onychomycosis: An analysis of 8, 816 toenail samples using quantitative PCR and next-generation sequencing. J. Am. Podiatr. Med. Assoc.,  2019, 109(1), 57-63.
[http://dx.doi.org/10.7547/17-070] [PMID:  30964314] 
[35] 
Youssef, A.B.; Kallel, A.; Azaiz, Z.; Jemel, S.; Bada, N.; Chouchen, A.; Belhadj-Salah, N.; Fakhfakh, N.; Belhadj, S.; Kallel, K. Onychomycosis: which fungal species are involved? experience of the laboratory of parasitology-mycology of the rabta hospital of tunis. J. Mycol. Med.,  2018, 28(4), 651-654.
[http://dx.doi.org/10.1016/j.mycmed.2018.07.005] [PMID:  30107987] 
[36] 
Fike, J.M.; Kollipara, R.; Alkul, S.; Stetson, C.L. Case report of onychomycosis and tinea corporis due to Microsporum gypseum. J. Cutan. Med. Surg.,  2018, 22(1), 94-96.
[http://dx.doi.org/10.1177/1203475417724439] [PMID:  28817957] 
[37] 
Pang, S.M.; Pang, J.Y.; Fook-Chong, S.; Tan, A.L. Tinea unguium onychomycosis caused by dermatophytes: a ten-year (2005–2014) retrospective study in a tertiary hospital in Singapore. SMJ,  2018, 59(10), 524.
[38] 
Sato, T.; Kitahara, H.; Honda, H.; Katsukawa, F.; Hiruma, M.; Yaguchi, T. Onychomycosis of the middle finger of a Japanese Judo athlete due to trichophyton tonsurans. Med. Mycol. J.,  2019, 60(1), 1-4.
[http://dx.doi.org/10.3314/mmj.18-00012] [PMID:  30814464] 
[39] 
Solís-Arias, M.P.; García-Romero, M.T. Onychomycosis in children. A review. Int. J. Dermatol.,  2017, 56(2), 123-130.
[http://dx.doi.org/10.1111/ijd.13392] [PMID:  27612431] 
[40] 
Bombace, F.; Iovene, M.R.; Galdiero, M.; Martora, F.; Nicoletti, G.F.; D’Andrea, M.; Della Pepa, M.E.; Vitiello, M. Non-dermatophytic onychomycosis diagnostic criteria: an unresolved question. Mycoses,  2016, 59(9), 558-565.
[http://dx.doi.org/10.1111/myc.12504] [PMID:  27061613] 
[41] 
Bongomin, F.; Batac, C.R.; Richardson, M.D.; Denning, D.W. A review of onychomycosis due to Aspergillus species. Mycopathologia,  2018, 183(3), 485-493.
[http://dx.doi.org/10.1007/s11046-017-0222-9] [PMID:  29147866] 
[42] 
Hirose, M.; Noguchi, H.; Yaguchi, T.; Matsumoto, T.; Hiruma, M.; Fukushima, S.; Ihn, H. Onychomycosis caused by Aspergillus subramanianii. J. Dermatol.,  2018, 45(11), 1362-1366.
[http://dx.doi.org/10.1111/1346-8138.14616] [PMID:  30144137] 
[43] 
Hon, K.L.; Leung, A.K. Alopecia areata. Recent Pat. Inflamm. Allergy Drug Discov.,  2011, 5(2), 98-107.
[http://dx.doi.org/10.2174/187221311795399291] [PMID:  21453266] 
[44] 
Kimura, U.; Hiruma, M.; Kano, R.; Matsumoto, T.; Takamori, K.; Suga, Y. Onychomycosis caused by Scopulariopsis brevicaulis: The third documented case in Japan. J. Dermatol.,  2019, 46(5), e167-e168.
[http://dx.doi.org/10.1111/1346-8138.14677] [PMID:  30303252] 
[45] 
Martínez-Herrera, E.O.; Arroyo-Camarena, S.; Tejada-García, D.L.; Porras-López, C.F.; Arenas, R. Onychomycosis due to opportunistic molds. An. Bras. Dermatol.,  2015, 90(3), 334-337.
[http://dx.doi.org/10.1590/abd1806-4841.20153521] [PMID:  26131862] 
[46] 
Matsuyama, Y.; Nakamura, T.; Hagi, T.; Asanuma, K.; Sudo, A. Subungual onychomycosis due to Aspergillus niger mimicking a glomus tumor: A case report. Biomed. Rep.,  2017, 7(6), 532-534.
[http://dx.doi.org/10.3892/br.2017.994] [PMID:  29188057] 
[47] 
Mohanty, P.; Dash, S.; Mohapatra, L.; Jain, M. Total dystrophic onychomycosis due to syncephalastrum racemosum–A rare cause and its novel treatment option. Indian Dermatol. Online J.,  2019, 10(2), 171-173.
[PMID:  30984595] 
[48] 
Moreno, G.; Arenas, R. Other fungi causing onychomycosis. Clin. Dermatol.,  2010, 28(2), 160-163.
[http://dx.doi.org/10.1016/j.clindermatol.2009.12.009] [PMID:  20347658] 
[49] 
Noguchi, H.; Hiruma, M.; Miyashita, A.; Makino, K.; Miyata, K.; Ihn, H. A case of fingernail onychomycosis due to Aspergillus flavus. Med. Mycol. J.,  2016, 57(2), E21-E25.
[http://dx.doi.org/10.3314/mmj.57.E21] [PMID:  27251317] 
[50] 
Piraccini, B.M.; Alessandrini, A. Onychomycosis: a review. J. Fungi (Basel),  2015, 1(1), 30-43.
[http://dx.doi.org/10.3390/jof1010030] [PMID:  29376897] 
[51] 
Pontini, P.; Gorani, A.; Veraldi, S. Onychomycosis by Paecilomyces lilacinus. Shilography,  2016, 151(6), 706-709.
[52] 
Pote, S.T.; Khan, U.; Lahiri, K.K.; Patole, M.S.; Thakar, M.R.; Shah, S.R. Onychomycosis due to achaetomium strumarium. J. Mycol. Med.,  2018, 28(3), 510-513.
[http://dx.doi.org/10.1016/j.mycmed.2018.07.002] [PMID:  30104134] 
[53] 
Veiga, F.F.; de Castro-Hoshino, L.V.; Sato, F.; Bombassaro, A.; Vicente, V.A.; Mendes, V.; Baesso, M.L.; Negri, M.; Svidzinski, T.I. Fusarium oxysporum is an onychomycosis etiopathogenic agent. Future Microbiol.,  2018, 13(16), 1745-1756.
[http://dx.doi.org/10.2217/fmb-2018-0245] [PMID:  30507250] 
[54] 
Welsh, O.; Vera-Cabrera, L.; Welsh, E. Onychomycosis. Clin. Dermatol.,  2010, 28(2), 151-159.
[http://dx.doi.org/10.1016/j.clindermatol.2009.12.006] [PMID:  20347657] 
[55] 
Subramanya, S.H.; Subedi, S.; Metok, Y.; Kumar, A.; Prakash, P.Y.; Nayak, N. Distal and lateral subungual onychomycosis of the finger nail in a neonate: a rare case. BMC Pediatr.,  2019, 19(1), 168.
[http://dx.doi.org/10.1186/s12887-019-1549-9] [PMID:  31133007] 
[56] 
Ge, G.; Yang, Z.; Li, D.; Sybren de Hoog, G.; Shi, D. Onychomycosis with greenish-black discolorations and recurrent onycholysis caused by Candida parapsilosis. Med. Mycol. Case Rep.,  2019, 24, 48-50.
[http://dx.doi.org/10.1016/j.mmcr.2019.04.005] [PMID:  31024790] 
[57] 
Seebacher, C.; Brasch, J.; Abeck, D.; Cornely, O.; Effendy, I.; Ginter-Hanselmayer, G.; Haake, N.; Hamm, G.; Hipler, U.C.; Hof, H.; Korting, H.C.; Mayser, P.; Ruhnke, M.; Schlacke, K.H.; Tietz, H.J. German society of dermatology; German-speaking mycological society. onychomycosis. Mycoses,  2007, 50(4), 321-327.
[http://dx.doi.org/10.1111/j.1439-0507.2006.01351.x] [PMID:  17576328] 
[58] 
Asz-Sigall, D.; Tosti, A.; Arenas, R. Tinea unguium: diagnosis and treatment in practice. Mycopathologia,  2017, 182(1-2), 95-100.
[http://dx.doi.org/10.1007/s11046-016-0078-4] [PMID:  27787643] 
[59] 
Hay, R.J.; Baran, R. Onychomycosis: a proposed revision of the clinical classification. J. Am. Acad. Dermatol.,  2011, 65(6), 1219-1227.
[http://dx.doi.org/10.1016/j.jaad.2010.09.730] [PMID:  21501889] 
[60] 
Cohen, J.L. The nail and fungus infections.Cutaneous fungal infections; Cohen, J.L.; Scher, R.K.; Pappert, A.S; Elewski, B., Ed.; Lgaku-Shoin: New York, 1992. 
[61] 
Dompmartin, D.; Dompmartin, A.; Deluol, A.M.; Grosshans, E.; Coulaud, J.P. Onychomycosis and AIDS. clinical and laboratory findings in 62 patients. Int. J. Dermatol.,  1990, 29(5), 337-339.
[http://dx.doi.org/10.1111/j.1365-4362.1990.tb04755.x] [PMID:  2141830] 
[62] 
Aly, R.; Berger, T. Common superficial fungal infections in patients with AIDS. Clin. Infect. Dis.,  1996, 22(Suppl. 2), S128-S132.
[http://dx.doi.org/10.1093/clinids/22.Supplement_2.S128] [PMID:  8722840] 
[63] 
Zaias, N.; Glick, B.; Rebell, G. Diagnosing and treating onychomycosis. J. Fam. Pract.,  1996, 42(5), 513-518.
[PMID:  8642370] 
[64] 
Parrish, C.A.; Sobera, J.O.; Elewski, B.E. Modification of the nail psoriasis severity index. J. Am. Acad. Dermatol.,  2005, 53(4), 745-746.
[http://dx.doi.org/10.1016/j.jaad.2004.11.044] [PMID:  16198816] 
[65] 
Tosti, A.; Baran, R.; Piraccini, B.M.; Fanti, P.A. “Endonyx” onychomycosis: a new modality of nail invasion by dermatophytes. Acta Derm. Venereol.,  1999, 79(1), 52-53.
[http://dx.doi.org/10.1080/000155599750011714] [PMID:  10086860] 
[66] 
Zaias, N. Onychomycosis. In: The Nail in Health and Disease; Springer: Dordrecht, 1980; pp. 91-113.
[67] 
Heikkilä, H.; Stubb, S. The prevalence of onychomycosis in Finland. Br. J. Dermatol.,  1995, 133(5), 699-703.
[http://dx.doi.org/10.1111/j.1365-2133.1995.tb02741.x] [PMID:  8555019] 
[68] 
Roseeuw, D. Achilles foot screening project: preliminary results of patients screened by dermatologists. J. Eur. Acad. Dermatol. Venereol.,  1999, 12(Suppl. 1), S6-S9.
[http://dx.doi.org/10.1111/j.1468-3083.1999.tb00909.x] [PMID:  10509935] 
[69] 
Rocha, K.A.D.; Krawczyk-Santos, A.P.; Andrade, L.M.; Souza, L.C.; Marreto, R.N.; Gratieri, T.; Taveira, S.F. Voriconazole-loaded nanostructured lipid carriers (NLC) for drug delivery in deeper regions of the nail plate. Int. J. Pharm.,  2017, 531(1), 292-298.
[http://dx.doi.org/10.1016/j.ijpharm.2017.08.115] [PMID:  28859937] 
[70] 
Bseiso, E.A.; Nasr, M.; Sammour, O.A.; Abd El Gawad, N.A. Novel nail penetration enhancer containing vesicles “nPEVs” for treatment of onychomycosis. Drug Deliv.,  2016, 23(8), 2813-2819.
[http://dx.doi.org/10.3109/10717544.2015.1099059] [PMID:  26447337] 
[71] 
Ferrari, J. Fungal toenail infections. BMJ Clin. Evid.,  2014, 2011, 1715.
[72] 
Matsuda, Y.; Sugiura, K.; Hashimoto, T.; Ueda, A.; Konno, Y.; Tatsumi, Y. Efficacy coefficients determined using nail permeability and antifungal activity in keratin-containing media are useful for predicting clinical efficacies of topical drugs for onychomycosis. PLoS One,  2016, 11(7), e0159661.
[http://dx.doi.org/10.1371/journal.pone.0159661] [PMID:  27441843] 
[73] 
Westerberg, D.P.; Voyack, M.J. Onychomycosis: Current trends in diagnosis and treatment. Am Fam. Phys.,  2013, 88(11), 762-770.
[PMID:  24364524] 
[74] 
da Silva, A.P.; Carbinatto, F.M.; Bagnato, V.S.; Inada, N.M. A promising strategy for the treatment of onychomycosis with curcumin and photodynamic therapy. J. Pharm. Pharmacol.,  2015, 3, 434-437.
[75] 
Firoz, S.; Sirisha, M.N.; Rajalakshmi, R. Transungual drug delivery system: a review. Int. J. Innov. Drug Disc.,  2011, 1, 9-14.
[76] 
Elkeeb, R. AliKhan, A.; Elkeeb, L.; Hui, X.; Maibach, H.I. Transungual drug delivery: current status. Int. J. Pharm.,  2010, 384(1-2), 1-8.
[http://dx.doi.org/10.1016/j.ijpharm.2009.10.002] [PMID:  19819318] 
[77] 
Pandhi, D.; Verma, P. Nail avulsion: indications and methods (surgical nail avulsion). Indian J. Dermatol. Venereol. Leprol.,  2012, 78(3), 299-308.
[http://dx.doi.org/10.4103/0378-6323.95444] [PMID:  22565429] 
[78] 
Rich, P. Nail biopsy: indications and methods. Dermatol. Surg.,  2001, 27(3), 229-234.
[PMID:  11277887] 
[79] 
de Berker, D. Nail anatomy. Clin. Dermatol.,  2013, 31(5), 509-515.
[http://dx.doi.org/10.1016/j.clindermatol.2013.06.006] [PMID:  24079579] 
[80] 
de Berker, D.A.; André, J.; Baran, R. Nail biology and nail science. Int. J. Cosmet. Sci.,  2007, 29(4), 241-275.
[http://dx.doi.org/10.1111/j.1467-2494.2007.00372.x] [PMID:  18489354] 
[81] 
André, J.; Sass, U.; Richert, B.; Theunis, A. Nail pathology. Clin. Dermatol.,  2013, 31(5), 526-539.
[http://dx.doi.org/10.1016/j.clindermatol.2013.06.005] [PMID:  24079581] 
[82] 
Fleckman, P.; Allan, C. Surgical anatomy of the nail unit. Dermatol. Surg.,  2001, 27(3), 257-260.
[PMID:  11277893] 
[83] 
Fernandez-Flores, A.; Saeb-Lima, M.; Martínez-Nova, A. Histopathology of the nail unit. Rom. J. Morphol. Embryol.,  2014, 55(2), 235-256.
[PMID:  24969971] 
[84] 
Perrin, C.; Michiels, J.F.; Pisani, A.; Ortonne, J.P. Anatomic distribution of melanocytes in normal nail unit: an immunohistochemical investigation. Am. J. Dermatopathol.,  1997, 19(5), 462-467.
[http://dx.doi.org/10.1097/00000372-199710000-00005] [PMID:  9335239] 
[85] 
Walters, K.A.; Flynn, G.L.; Marvel, J.R. Physicochemical characterization of the human nail: solvent effects on the permeation of homologous alcohols. J. Pharm. Pharmacol.,  1985, 37(11), 771-775.
[http://dx.doi.org/10.1111/j.2042-7158.1985.tb04966.x] [PMID:  2867157] 
[86] 
Walters, K.A.; Flynn, G.L.; Marvel, J.R. 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.
[http://dx.doi.org/10.1111/j.2042-7158.1983.tb04258.x] [PMID:  6131961] 
[87] 
Kobayashi, Y.; Komatsu, T.; Sumi, M.; Numajiri, S.; Miyamoto, M.; Kobayashi, D.; Sugibayashi, K.; Morimoto, Y. 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), 471-477.
[http://dx.doi.org/10.1016/j.ejps.2003.11.008] [PMID:  14998577] 
[88] 
Mertin, D.; Lippold, B.C. In-vitro permeability of the human nail and of a keratin membrane from bovine hooves: influence of the partition coefficient octanol/water and the water solubility of drugs on their permeability and maximum flux. J. Pharm. Pharmacol.,  1997, 49(1), 30-34.
[http://dx.doi.org/10.1111/j.2042-7158.1997.tb06747.x] [PMID:  9120766] 
[89] 
 Soong, M.H. Transport properties of drugs and model compounds
across the human nail., University of Minnesota. ProQuest Dissertations
Publishing, 1991, 9202848.
[90] 
Walters, K.A.; Flynn, G.L.; Marvel, J.R. Physicochemical characterization of the human nail: I. Pressure sealed apparatus for measuring nail plate permeabilities. J. Invest. Dermatol.,  1981, 76(2), 76-79.
[http://dx.doi.org/10.1111/1523-1747.ep12525318] [PMID:  7462680] 
[91] 
Burch, G.E.; Winsor, T. Diffusion of water through dead plantar, palmar and torsal human skin and through toe nails. Arch. Derm. Syphilol.,  1946, 53(1), 39-41.
[http://dx.doi.org/10.1001/archderm.1946.01510300042009] [PMID:  21013473] 
[92] 
Malhotra, G.G.; Zatz, J.L. Characterization of the physical factors affecting nail permeation using water as a probe. J. Cosmet. Sci.,  2000, 51(6), 367-377.
[93] 
Malhotra, G.G.; Zatz, J.L. Investigation of nail permeation enhancement by chemical modification using water as a probe. J. Pharm. Sci.,  2002, 91(2), 312-323.
[http://dx.doi.org/10.1002/jps.10058] [PMID:  11835191] 
[94] 
Gupta, A.K.; Studholme, C. Novel investigational therapies for onychomycosis: an update. Expert Opin. Investig. Drugs,  2016, 25(3), 297-305.
[http://dx.doi.org/10.1517/13543784.2016.1142529] [PMID:  26765142] 
[95] 
Luiza Ribeiro de Souza, A.; Priscila Kiill, C.; Kolenyak dos Santos, F.; Marielli da Luz, G.; Rocha e Silva, H.; Chorilli, M.; Palmira Daflon Gremiao, M. Nanotechnology-based drug delivery systems for dermatomycosis treatment. Curr. Nanosci.,  2012, 8(4), 512-519.
[http://dx.doi.org/10.2174/157341312801784311] 
[96] 
Soliman, G.M. Nanoparticles as safe and effective delivery systems of antifungal agents: Achievements and challenges. Int. J. Pharm.,  2017, 523(1), 15-32.
[http://dx.doi.org/10.1016/j.ijpharm.2017.03.019] [PMID:  28323096] 
[97] 
Flores, F.C.; de Lima, J.A.; Ribeiro, R.F.; Alves, S.H.; Rolim, C.M.; Beck, R.C.; da Silva, C.B. Antifungal activity of nanocapsule suspensions containing tea tree oil on the growth of Trichophyton rubrum. Mycopathologia,  2013, 175(3-4), 281-286.
[http://dx.doi.org/10.1007/s11046-013-9622-7] [PMID:  23392821] 
[98] 
Flores, F.C.; Rosso, R.S.; Cruz, L.; Beck, R.C.; Silva, C.B. An innovative polysaccharide nanobased nail formulation for improvement of onychomycosis treatment. Eur. J. Pharm. Sci.,  2017, 100, 56-63.
[http://dx.doi.org/10.1016/j.ejps.2016.12.043] [PMID:  28063967] 
[99] 
Flores, F.C.; Chiu, W.S.; Beck, R.C.R.; da Silva, C.B.; Delgado-Charro, M.B. Enhancement of tioconazole ungual delivery: Combining nanocapsule formulation and nail poration approaches. Int. J. Pharm.,  2018, 535(1-2), 237-244.
[http://dx.doi.org/10.1016/j.ijpharm.2017.11.008] [PMID:  29126904] 
[100] 
El-Say, K.M.; El-Sawy, H.S. Polymeric nanoparticles: Promising platform for drug delivery. Int. J. Pharm.,  2017, 528(1-2), 675-691.
[http://dx.doi.org/10.1016/j.ijpharm.2017.06.052] [PMID:  28629982] 
[101] 
 Chiu, W.S.; Belsey, N.A.; Garrett, N.L.; Moger, J.; Price, G.J.;
Delgado-Charro, M.B.; Guy, R.H. Drug delivery into microneedleporated
nails from nanoparticle reservoirs. J. Control. Release,
2015, 220(Pt A), 98-106.
[http://dx.doi.org/10.1016/j.jconrel.2015.10.026] [PMID:  26478016] 
[102] 
Mahtab, A.; Anwar, M.; Mallick, N.; Naz, Z.; Jain, G.K.; Ahmad, F.J. Transungual delivery of ketoconazole nanoemulgel for the effective management of onychomycosis. AAPS PharmSciTech,  2016, 17(6), 1477-1490.
[http://dx.doi.org/10.1208/s12249-016-0488-0] [PMID:  26857516] 
[103] 
Kumar, S.; Talegaonkar, S.; Negi, L.M.; Khan, Z.I. Design and development of ciclopirox topical nanoemulsion gel for the treatment of subungual onychomycosis. Indian J Pharm Educ Res.,  2012, 46(4), 303-311.
[104] 
Bsieso, E.A.; Nasr, M.; Moftah, N.H.; Sammour, O.A.; Abd El Gawad, N.A. Could nanovesicles containing a penetration enhancer clinically improve the therapeutic outcome in skin fungal diseases? Nanomedicine (Lond.),  2015, 10(13), 2017-2031.
[http://dx.doi.org/10.2217/nnm.15.49] [PMID:  26135513] 
[105] 
Elsherif, N.I.; Shamma, R.N.; Abdelbary, G. Terbinafine hydrochloride trans-ungual delivery via nanovesicular systems: in vitrocharacterization and ex vivo evaluation. AAPS PharmSciTech,  2017, 18(2), 551-562.
[http://dx.doi.org/10.1208/s12249-016-0528-9] [PMID:  27138036] 
[106] 
Tanrıverdi, S.T.; Özer, Ö. Novel topical formulations of Terbinafine-HCl for treatment of onychomycosis. Eur. J. Pharm. Sci.,  2013, 48(4-5), 628-636.
[http://dx.doi.org/10.1016/j.ejps.2012.12.014] [PMID:  23295582] 
[107] 
Tanrıverdi, S.T.; Hilmioğlu Polat, S.; Yeşim Metin, D.; Kandiloğlu, G.; Özer, Ö. Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis: in vitroand in vivo evaluation. J. Liposome Res.,  2016, 26(2), 163-173.
[http://dx.doi.org/10.3109/08982104.2015.1067892] [PMID:  26226352] 
[108] 
Shukla, T.; Upmanyu, N.; Agrawal, M.; Saraf, S.; Saraf, S.; Alexander, A. Biomedical applications of microemulsion through dermal and transdermal route. Biomed. Pharmacother.,  2018, 108, 1477-1494.
[http://dx.doi.org/10.1016/j.biopha.2018.10.021] [PMID:  30372850] 
[109] 
Barot, B.S.; Parejiya, P.B.; Patel, H.K.; Gohel, M.C.; Shelat, P.K. Microemulsion-based gel of terbinafine for the treatment of onychomycosis: optimization of formulation using D-optimal design. AAPS PharmSciTech,  2012, 13(1), 184-192.
[http://dx.doi.org/10.1208/s12249-011-9742-7] [PMID:  22187363] 
[110] 
Kansagra, H.; Mallick, S. Microemulsion-based antifungal gel of luliconazole for dermatophyte infections: formulation, characterization and efficacy studies. Int. J. Pharm. Investig.,  2016, 46(1), 21-28.
[http://dx.doi.org/10.1007/s40005-015-0209-9] 
[111] 
Van Tomme, S.R.; Storm, G.; Hennink, W.E. In situ gelling hydrogels for pharmaceutical and biomedical applications. Int. J. Pharm.,  2008, 355(1-2), 1-18.
[http://dx.doi.org/10.1016/j.ijpharm.2008.01.057] [PMID:  18343058] 
[112] 
Çelebi, N. Ermiş S.; Özkan, S. Development of topical hydrogels of terbinafine hydrochloride and evaluation of their antifungal activity. Drug Dev. Ind. Pharm.,  2015, 41(4), 631-639.
[http://dx.doi.org/10.3109/03639045.2014.891129] [PMID:  24576265] 
[113] 
Nogueiras-Nieto, L.; Begoña Delgado-Charro, M.; Otero-Espinar, F.J. Thermogelling hydrogels of cyclodextrin/poloxamer polypseudorotaxanes as aqueous-based nail lacquers: application to the delivery of triamcinolone acetonide and ciclopirox olamine. Eur. J. Pharm. Biopharm.,  2013, 83(3), 370-377.
[http://dx.doi.org/10.1016/j.ejpb.2012.11.004] [PMID:  23201053] 
[114] 
El-sherif, N.I.; Shamma, R.N.; Abdelbary, G. In-situ gels and nail lacquers as potential delivery systems for treatment of onychomycosis. A comparative study. J. Drug Deliv. Sci. Technol.,  2018, 43, 253-261.
[http://dx.doi.org/10.1016/j.jddst.2017.10.018] 
[115] 
Pannu, J.; McCarthy, A.; Martin, A.; Hamouda, T.; Ciotti, S.; Fothergill, A.; Sutcliffe, J. NB-002, a novel nanoemulsion with broad antifungal activity against dermatophytes, other filamentous fungi, and Candida albicans. Antimicrob. Agents Chemother.,  2009, 53(8), 3273-3279.
[http://dx.doi.org/10.1128/AAC.00218-09] [PMID:  19433562] 
[116] 
Takahata, S.; Kubota, N.; Takei-Masuda, N.; Yamada, T.; Maeda, M.; Alshahni, M.M.; Abe, S.; Tabata, Y.; Maebashi, K. Mechanism of action of ME1111, a novel antifungal agent for topical treatment of onychomycosis. Antimicrob. Agents Chemother.,  2015, 60(2), 873-880.
[http://dx.doi.org/10.1128/AAC.01790-15] [PMID:  26596944] 
[117] 
Kubota, N. In vitro human onychopharmacokinetic and pharmacodynamic analyses of ME1111, a new topical agent for onychomycosis. Antimicrob. Agents Chemother.,  2018, 62(1), e00779-e00717.
[118] 
Iorizzo, M.; Arraiz, G.; Frisenda, L.; Caserini, M.; Mailland, F. An innovative terbinafine transungual solution (P-3058): dose finding investigation on clinical benefit in patients affected by mild-to moderate toe onychomycosis. American Academy of Dermatology 71st Annual Meeting, Miami Beach, Fla2013.
[119] 
Gupta, A.K.; Simpson, F.C. Investigational drugs for onychomycosis. Expert Opin. Investig. Drugs,  2014, 23(1), 97-106.
[http://dx.doi.org/10.1517/13543784.2013.840289] [PMID:  24070182] 
[120] 
Gupta, A.K.; Simpson, F.C. New therapeutic options for onychomycosis. Expert Opin. Pharmacother.,  2012, 13(8), 1131-1142.
[http://dx.doi.org/10.1517/14656566.2012.681779] [PMID:  22533461] 
[121] 
Ghannoum, M.; Isham, N.; Herbert, J.; Henry, W.; Yurdakul, S. Activity of TDT 067 (terbinafine in Transfersome) against agents of onychomycosis, as determined by minimum inhibitory and fungicidal concentrations. J. Clin. Microbiol.,  2011, 49(5), 1716-1720.
[122] 
Gupta, A.K.; Surprenant, M.S.; Kempers, S.E.; Pariser, D.M.; Rensfeldt, K.; Tavakkol, A. Efficacy and safety of topical terbinafine 10% solution (MOB-015) in the treatment of mild to moderate distal subungual onychomycosis: A randomized, multicenter, double-blind, vehicle-controlled phase 3 study. J. Am. Acad. Dermatol.,  2021, 85(1), 95-104.
[123] 
Gupta, A.; Simpson, F. Device-based therapies for onychomycosis treatment. Skin Therapy Lett.,  2012, 17(9), 4-9.
[PMID:  23032936] 
[124] 
Mathew, F.; Bindumol, K.C.; Paul, J.I.; Pathadan, R.P.; Varghese, V.I. Understanding our natural nail-Antifungal agents. Int. J. Pharm. Pharm. Sci.,  2014, 6(2), 67-73.
[125] 
Khanna, S.; Bajaj, R.; Khurana, B.; Srivastava, K. Pharmacotherapeutic principles of ungual drug delivery system. Int J Drug Dev Res.,  2012, 3, 9-18.
[126] 
Hao, J.; Smith, K.A.; Li, S.K. Chemical method to enhance transungual transport and iontophoresis efficiency. Int. J. Pharm.,  2008, 357(1-2), 61-69.
[http://dx.doi.org/10.1016/j.ijpharm.2008.01.027] [PMID:  18321669] 
[127] 
Vejnovic, I.; Huonder, C.; Betz, G. Permeation studies of novel terbinafine formulations containing hydrophobins through human nails in vitro. Int. J. Pharm.,  2010, 397(1-2), 67-76.
[http://dx.doi.org/10.1016/j.ijpharm.2010.06.051] [PMID:  20620203] 
[128] 
Nair, A.B.; Sammeta, S.M.; Kim, H.D.; Chakraborty, B.; Friden, P.M.; Murthy, S.N. Alteration of the diffusional barrier property of the nail leads to greater terbinafine drug loading and permeation. Int. J. Pharm.,  2009, 375(1-2), 22-27.
[http://dx.doi.org/10.1016/j.ijpharm.2009.03.012] [PMID:  19481686] 
[129] 
Brown, M.B.; Khengar, R.H.; Turner, R.B.; Forbes, B.; Traynor, M.J.; Evans, C.R.; Jones, S.A. Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement. Int. J. Pharm.,  2009, 370(1-2), 61-67.
[http://dx.doi.org/10.1016/j.ijpharm.2008.11.009] [PMID:  19071202] 
[130] 
Delgado-Charro, M.B. Iontophoretic drug delivery across the nail. Drug Deliv.,  2012, 9(1), 91-103.
[http://dx.doi.org/10.1517/17425247.2012.642364] [PMID:  22149385] 
[131] 
Murthy, S.N.; Waddell, D.C.; Shivakumar, H.N.; Balaji, A.; Bowers, C.P. Iontophoretic permselective property of human nail. J. Dermatol. Sci.,  2007, 46(2), 150-152.
[http://dx.doi.org/10.1016/j.jdermsci.2006.12.010] [PMID:  17289349] 
[132] 
Amichai, B.; Nitzan, B.; Mosckovitz, R.; Shemer, A. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. Br. J. Dermatol.,  2010, 162(1), 46-50.
[http://dx.doi.org/10.1111/j.1365-2133.2009.09414.x] [PMID:  19785609] 
[133] 
Dutet, J.; Delgado-Charro, M.B. Electroosmotic transport of mannitol across human nail during constant current iontophoresis. J. Pharm. Pharmacol.,  2010, 62(6), 721-729.
[http://dx.doi.org/10.1211/jpp.62.06.0008] [PMID:  20636859] 
[134] 
Manda, P.; Sammeta, S.M.; Repka, M.A.; Murthy, S.N. Iontophoresis across the proximal nail fold to target drugs to the nail matrix. J. Pharm. Sci.,  2012, 101(7), 2392-2397.
[http://dx.doi.org/10.1002/jps.23139] [PMID:  22487899] 
[135] 
Nair, A.B.; Kim, H.D.; Chakraborty, B.; Singh, J.; Zaman, M.; Gupta, A.; Friden, P.M.; Murthy, S.N. Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis. J. Pharm. Sci.,  2009, 98(11), 4130-4140.
[http://dx.doi.org/10.1002/jps.21711] [PMID:  19340887] 
[136] 
Narasimha Murthy, S.; Wiskirchen, D.E.; Bowers, C.P. Iontophoretic drug delivery across human nail. J. Pharm. Sci.,  2007, 96(2), 305-311.
[http://dx.doi.org/10.1002/jps.20757] [PMID:  17080425] 
[137] 
Maeda, N.; Mizuno, N.; Ichikawa, K. Nail abrasion: a new treatment for ingrown toe-nails. J. Dermatol.,  1990, 17(12), 746-749.
[http://dx.doi.org/10.1111/j.1346-8138.1990.tb03023.x] [PMID:  2086619] 
[138] 
Behl, P.N. Abrasion in the treatment of nail disorders. Indian J. Dermatol.,  1973, 18(4), 77-79.
[PMID:  4273104] 
[139] 
Jeremiasse, H.P. Treatment of nail infections with griseofulvin combined with abrasion. Trans. St Johns Hosp. Dermatol. Soc.,  1960, 45, 92-93.
[PMID:  13789962] 
[140] 
Repka, M.A.; Mididoddi, P.K.; Stodghill, S.P. Influence of human nail etching for the assessment of topical onychomycosis therapies. Int. J. Pharm.,  2004, 282(1-2), 95-106.
[http://dx.doi.org/10.1016/j.ijpharm.2004.06.010] [PMID:  15336385] 
[141] 
Salter, S.A.; Ciocon, D.H.; Gowrishankar, T.R.; Kimball, A.B. Controlled nail trephination for subungual hematoma. Am. J. Emerg. Med.,  2006, 24(7), 875-877.
[http://dx.doi.org/10.1016/j.ajem.2006.03.029] [PMID:  17098113] 
[142] 
Murdan, S. Enhancing the nail permeability of topically applied drugs. Expert Opin. Drug Deliv.,  2008, 5(11), 1267-1282.
[http://dx.doi.org/10.1517/17425240802497218] [PMID:  18976136] 
[143] 
 Chang, P.M.; Chang, C.H.; Chang, Y.C. Nail lacquer composition
with hyposensitivity. United States patent application US
14151256, 2015.
[144] 
 Napolez, A. Nail penetration device for delivery of anti-fungal
treatments. United States patent application US 15877759, 2018.
[145] 
 Niedermeyer, W.H. Nanoparticle compositions and methods for
treating onychomychosis. Patent US 10201571, 2019.
[146] 
 Kim, N.H.; Cho, Y.B.; Jeong, S.Y.; Bae, B.C.; Lee, J.S.; Lee, J.W.;
Cho, H.K. Nail lacquer composition containing ciclopirox. United
States patent application US 15555619, 2018.
[147] 
 Zhong, Y. Plant extraction formula applied to onychomycosis and
tinea pedis. CN109303815A, 2019.
[148] 
 Mailland, F.; Legora, M.; Ceriani, D.; Iob, G. Topical antifungal
composition for treating onychomycosis. US 10172811, 2019.
[149] 
 Swenholt, K.G. Nail fungus treatment and composition.
US20100159031A1, 2016.
[150] 
 Capriotti, J.; Capriotti, K. Antifungal composition for treatment of
skin and nail. JP2018048159A, 2018.
[151] 
 Lindahl, A. Novel antifungal composition. RU2013136147A, 2015.
[152] 
 Sekiya, K. External preparation for treating ringworm and method
for applying the same. JP2012162511A, 2012.
[153] 
 Weijun, L. Film coating agent for treating onychomycosis and
preparation method thereof. CN102488702A, 2012.
[154] 
 Rockhill, T.; Beeson, W.H. Excipient system for topical delivery of
pharmaceutical agents. United States patent application US
16392830, 2019.
[155] 
 Willers, C. Topical pharmaceutical compositions comprising
terbinafine and urea. EP2664327A1, 2013.
[156] 
 Tausk, F. Treatment of nail disorders. US2016008274A1, 2014.
[157] 
 Natori, N; Takabe, H; Ishimaru, T; Iseki, H; Karasawa, K External
preparation for treating trichophytosis unguium. WO2019088005,
2019.
[158] 
 Selner, M. Penetrating carrier, anti-fungal composition using the
same and method for treatment of dermatophyte.
WO2010037089A1, 2010.
[159] 
 Nagpal, S.; Goyal, A.; Narang, RK. Formulation and evaluation of
itraconazole loaded niosomal gel for the treatment of onychomycosis.
IN3107DE2013A, 2015.
[160] 
 Lu, H. Pharmaceutical composition for treating leuconychia.
CN105CN105193726A, 2015.
[161] 
Schein, J.R.; Gause, D.; Stier, D.M.; Lubeck, D.P.; Bates, M.M.; Fisk, R. Onychomycosis. Baseline results of an observational study. J. Am. Podiatr. Med. Assoc.,  1997, 87(11), 512-519.
[http://dx.doi.org/10.7547/87507315-87-11-512] [PMID:  9397656] 
[162] 
Scher, R.K. Onychomycosis: a significant medical disorder. J. Am. Acad. Dermatol.,  1996, 35(3 Pt 2), S2-S5.
[http://dx.doi.org/10.1016/S0190-9622(96)90061-4] [PMID:  8784302] 
[163] 
Piraccini, B.M.; Sisti, A.; Tosti, A. Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J. Am. Acad. Dermatol.,  2010, 62(3), 411-414.
[http://dx.doi.org/10.1016/j.jaad.2009.04.062] [PMID:  20159308] 
[164] 
Scher, R.K.; Baran, R. Onychomycosis in clinical practice: factors contributing to recurrence. Br. J. Dermatol.,  2003, 149(Suppl. 65), 5-9.
[http://dx.doi.org/10.1046/j.1365-2133.149.s65.5.x] [PMID:  14510969] 
[165] 
Ingber, A. Intermittent low dose itraconazole treatment for onychomycosis-long term follow-up. Med. Mycol.,  2001, 39(6), 471-473.
[http://dx.doi.org/10.1080/mmy.39.6.471.473] [PMID:  11798050] 
[166] 
Tosti, A.; Piraccini, B.M.; Stinchi, C.; Colombo, M.D. Relapses of onychomycosis after successful treatment with systemic antifungals: a three-year follow-up. Dermatology,  1998, 197(2), 162-166.
[http://dx.doi.org/10.1159/000017990] [PMID:  9732167] 
[167] 
Sigurgeirsson, B.; Olafsson, J.H.; Steinsson, J.B.; Paul, C.; Billstein, S.; Evans, E.G. Long-term effectiveness of treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded prospective follow-up study. Arch. Dermatol.,  2002, 138(3), 353-357.
[http://dx.doi.org/10.1001/archderm.138.3.353] [PMID:  11902986] 
[168] 
Gupta, A.K.; Daigle, D.; Carviel, J.L. The role of biofilms in onychomycosis. J. Am. Acad. Dermatol.,  2016, 74(6), 1241-1246.
[http://dx.doi.org/10.1016/j.jaad.2016.01.008] [PMID:  27012826] 
[169] 
Gupta, A.K.; Versteeg, S.G.; Shear, N.H. Confirmatory testing prior to treating toenail onychomycosis is recommended in Canada. J. Cutan. Med. Surg.,  2018, 22(2), 244-245.
[http://dx.doi.org/10.1177/1203475417746126] [PMID:  29995444] 
[170] 
Vlahovic, T.C. Onychomycosis: evaluation, treatment options, managing recurrence, and patient outcomes. Clin. Podiatr. Med. Surg.,  2016, 33(3), 305-318.
[http://dx.doi.org/10.1016/j.cpm.2016.02.001] [PMID:  27215153] 
[171] 
Lipner, S.R.; Scher, R.K. Management of onychomycosis and co-existing tinea pedis. J. Drugs Dermatol.,  2015, 14(5), 492-494.
[PMID:  25942668] 
[172] 
Gupta, A.K.; Cernea, M.; Foley, K.A. Improving cure rates in onychomycosis. J. Cutan. Med. Surg.,  2016, 20(6), 517-531.
[http://dx.doi.org/10.1177/1203475416653734] [PMID:  27313230] 
[173] 
Shemer, A.; Gupta, A.K.; Kamshov, A.; Babaev, M.; Farhi, R.; Daniel, C.R., III; Foley, K.A. Topical antifungal treatment prevents recurrence of toenail onychomycosis following cure. Dermatol. Ther. ,  2017, 30(5), e12545.
[http://dx.doi.org/10.1111/dth.12545] [PMID:  28856784] 
[174] 
Tosti, A.; Elewski, B.E. Onychomycosis: practical approaches to minimize relapse and recurrence. Skin Appendage Disord.,  2016, 2(1-2), 83-87.
[http://dx.doi.org/10.1159/000448056] [PMID:  27843933] 
[175] 
Saner, M.V.; Kulkarni, A.D.; Pardeshi, C.V. Insights into drug delivery across the nail plate barrier. J. Drug Target.,  2014, 22(9), 769-789.
[http://dx.doi.org/10.3109/1061186X.2014.929138] [PMID:  24964054] 
[176] 
Hafeez, F.; Hui, X.; Chiang, A.; Hornby, S.; Maibach, H. Transungual delivery of ketoconazole using novel lacquer formulation. Int. J. Pharm.,  2013, 456(2), 357-361.
[http://dx.doi.org/10.1016/j.ijpharm.2013.08.082] [PMID:  24029171] 
[177] 
Lipner, S.R.; Scher, R.K. Onychomycosis: Treatment and prevention of recurrence. J. Am. Acad. Dermatol.,  2019, 80(4), 853-867.
[http://dx.doi.org/10.1016/j.jaad.2018.05.1260] [PMID:  29959962] 
[178] 
Gupta, A.K.; Versteeg, S.G.; Shear, N.H. Onychomycosis in the 21st century: an update on diagnosis, epidemiology, and treatment. J. Cutan. Med. Surg.,  2017, 21(6), 525-539.
[http://dx.doi.org/10.1177/1203475417716362] [PMID:  28639462] 
[179] 
Akhtar, N.; Sharma, H.; Pathak, K. Onychomycosis: potential of nail lacquers in transungual delivery of antifungals. Scientifica (Cairo),  2016, 2016, 1387936.
[http://dx.doi.org/10.1155/2016/1387936] [PMID:  27123362] 
[180] 
Faergemann, J.; Anderson, C.; Hersle, K.; Hradil, E.; Nordin, P.; Kaaman, T.; Molin, L.; Pettersson, A. Double-blind, parallel-group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis. J. Am. Acad. Dermatol.,  1995, 32(5 Pt 1), 750-753.
[http://dx.doi.org/10.1016/0190-9622(95)91454-4] [PMID:  7722020] 
[181] 
Jan, S.; Bora, D.; Bhise, K. Preungual drug delivery systems of terbinafine hydrochloride nail lacquer. Asian J. Pharm.,  2014, 2(1), 53-56.
[182] 
Tchernev, G.; Penev, P.K.; Nenoff, P.; Zisova, L.G.; Cardoso, J.C.; Taneva, T.; Ginter-Hanselmayer, G.; Ananiev, J.; Gulubova, M.; Hristova, R.; Nocheva, D.; Guarneri, C.; Martino, G.; Kanazawa, N. Onychomycosis: modern diagnostic and treatment approaches. Wien. Med. Wochenschr.,  2013, 163(1-2), 1-12.
[http://dx.doi.org/10.1007/s10354-012-0139-3] [PMID:  23053563] 
[183] 
Gupta, A.K.; Paquet, M.; Simpson, F.C. Therapies for the treatment of onychomycosis. Clin. Dermatol.,  2013, 31(5), 544-554.
[http://dx.doi.org/10.1016/j.clindermatol.2013.06.011] [PMID:  24079583] 
[184] 
Lecha, M.; Alsina, M.; Rodriguez, J.M.; de Erenchun, F.R.; Mirada, A.; Rossi, A.B. An open-label, multicenter study of the combination of amorolfine nail lacquer and oral itraconazole compared with oral itraconazole alone in the treatment of severe toenail onychomycosis. Curr. Ther. Res. Clin. Exp.,  2002, 63(6), 366-379.
[http://dx.doi.org/10.1016/S0011-393X(02)80040-6] 
[185] 
Baran, R.; Sigurgeirsson, B.; de Berker, D.; Kaufmann, R.; Lecha, M.; Faergemann, J.; Kerrouche, N.; Sidou, F. A multicentre, randomized, controlled study of the efficacy, safety and cost-effectiveness of a combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement. Br. J. Dermatol.,  2007, 157(1), 149-157.
[http://dx.doi.org/10.1111/j.1365-2133.2007.07974.x] [PMID:  17553051] 
Cite As
Drug Delivery Letters

Transungual Drug Delivery System for the Topical Treatment of Onychomycosis: A Review

Abstract

Graphical Abstract
