Abstract
Onychomycosis accounts for 50% of all nail disease cases and is commonly caused by dermatophytes. It was primarily considered a cosmetic problem but has been garnering attention lately due to its persistent nature and difficult treatment with relapses. With prolonged treatment duration and high cost involved in treating onychomycosis, several attempts have been made in overcoming the rigid nail barrier. The conventional treatment of onychomycosis involves oral and topical therapy. The oral antifungal agents though quite effective, are hepato-toxic and cause drug-drug interactions. Topical therapy is more patient compliant being devoid of such adverse effects but it suffers from another setback of improper nail penetration. Amorolfine and ciclopirox nail lacquers are popular market products. Since decades, efforts have been made to enhance topical delivery for efficiently treating onychomycosis. Mechanical, physical and chemical methods have been employed. Despite all the attempts made, the nail delivery issues are far from being solved. Recently, the focus has shifted to novel drug delivery systems like nanoparticles, microemulsions, polymeric films and nail lacquers for enhanced drug permeation and localized therapy. The research around the world is exploring their potential as effective treatment options. This review intends to further explore the novel delivery strategies to treat a persistent fungal infection like onychomycosis.
Keywords: Nail barrier, nanoparticles, novel strategies, onychomycosis, persistent infection, drug delivery.
Graphical Abstract
[1]
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.
[2]
McAuley WJ, Jones SA, Traynor MJ, Guesné S, Murdan S, Brown MB. An investigation of how fungal infection influences drug penetration through onychomycosis patient’s nail plates. Eur J Pharm Biopharm 2016; 102: 178-84.
[3]
Adekhandi S, Pal S, Sharma N, Juyal D. Incidence and epidemiology of onychomycosis in patients visiting a tertiary care hospital in India. Cutis 2015; 95: E20-5.
[4]
Ghannoum M, Isham N. Fungal nail infections [onychomycosis]: a never-ending story? PLoS Pathog 2014; 10(6): e1004105.
[5]
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): 1-7.
[6]
Bseiso EA, Nasr M, Sammour OA, Abd El Gawad NA. Novel nail penetration enhancer containing vesicles “nPEVs” for treatment of onychomycosis. Drug Deliv 2015; 23: 1-7.
[7]
Rocha KAD, Krawczyk-Santos AP, Andrade LM, et al. Voriconazole-loaded nanostructured lipid carriers [NLC] for drug delivery in deeper regions of the nail plate. Int J Pharm 2017; 531(1): 292-8.
[8]
Shah VH, Jobanputra A. Enhanced ungual permeation of terbinafine HCL delivered through liposome-loaded nail lacquer formulation optimized by QbD approach. AAPS PharmSciTech 2018; 19(1): 213-24.
[9]
Flores FC, Rosso RS, Cruz L, Beck RCR, Silva CB. An innovative polysaccharide nanobased nail formulation for improvement of onychomycosis treatment. Eur J Pharm Sci 2017; 100: 56-63.
[10]
Turner R, Weaver S, Caserta F, Brown MB. The inadequacies of the current treatment plans give rise to the pressing need for a topical ungual treatment, allowing site specific delivery and minimizing systemic exposure. AAPS PharmSciTech 2016; 20(1): 71-80.
[12]
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): 1-12.
[13]
Westerberg DP, Voyack MJ. Onychomycosis: current trends in diagnosis and treatment. Am Fam Physician 2014; 25(4): 762-70.
[14]
Saner MV, Kulkarni AD, Pardeshi CV. Insights into drug delivery across the nail plate barrier. J Drug Target 2014; 2330(9): 769-89.
[15]
Hafeez F, Hui X, Chiang A, Hornby S, Maibach H. Transungual delivery of ketoconazole using novel lacquer formulation. Int J Pharm 2013; 456(2): 357-61.
[16]
Paula DA, Carbinatto FM, Bagnato VS, Inada NM. A promising strategy for the treatment of onychomycosis with curcumin and photodynamic therapy. J Pharm Pharmacol 2015; 3: 434-7.
[17]
Gupta AK, Versteeg SG, Shear NH. Onychomycosis in the 21st century: an update on diagnosis, epidemiology, and treatment. J Cutan Med Surg 2017; 21(6): 525-39.
[18]
Akhtar N, Sharma H, Pathak K. Onychomycosis: potential of nail lacquers in transungual delivery of antifungals. Scientifica 2016; 2016: 1387936.
[19]
Bhise K, Jan S, Bora D. Preungual drug delivery systems of terbinafine hydrochloride nail lacquer. Asian J Pharm 2008; 2(1): 53.
[20]
Tchernev G, Penev PK, Nenoff P, et al. Onychomycosis: Modern diagnostic and treatment approaches. Wien Med Wochenschr 2013; 163(1-2): 1-12.
[21]
Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol 2013; 31(5): 544-54.
[22]
Lecha M, Alsina M, Rodriguez JMT. An open-label, multicenter study of the combination of amorolfine nail lacquer and oral ltraconazole compared with oral ltraconazole alone in the treatment of severe toenail onychomycosis. Curr Ther Res Clin Exp 2002; 63(6): 366-79.
[23]
Baran R, Sigurgeirsson B, Berker D De, et al. 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 in. Br J Dermatol 2007; 157(1): 149-57.
[24]
Nayak P. Therapies available for the treatment of fungal nail infection. J Bioequivalence Bioavailab 2016; 8: 208-10.
[26]
Darkes MJM, Scott LJ, Goa KL. Terbinafine: a review of its use in onychomycosis in adults. Am J Clin Dermatol 2003; 4(1): 39-65.
[27]
Yin Z, Xu J, Luo DAN. A meta-analysis comparing long-term recurrences of toenail onychomycosis after successful treatment with terbinafine versus itraconazole. J Dermatolog Treat 2012; 23: 449-52.
[28]
Graham LVD, Elewski BE. Recent updates in oral terbinafine: its use in onychomycosis and tinea capitis in the US. Mycoses 2011; 54(6): e679-85.
[29]
Trivedi NA, Shah PC. A meta-analysis comparing efficacy of continuous terbinafine with intermittent itraconazole for toenail onychomycosis. Int J Dermatol 2010; 55(2): 198-9.
[30]
Korting HC, Schöllmann C. The significance of itraconazole for treatment of fungal infections of skin, nails and mucous membranes. J Dtsch Dermatol Ges 2009; 7(1): 11-20.
[31]
Tabara K, Szewczyk AE, Bienias W, et al. Amorolfine vs. Ciclopirox - lacquers for the treatment of onychomycosis. Postepy Dermatol Alergol 2015; 32(1): 40-5.
[32]
Reinel D. Topical treatment of onychomycosis with amorolfine 5% nail lacquer: comparative efficacy and tolerability of once and twice weekly use. Dermatology 1992; 184: 21-4.
[33]
Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol 2000; 43: S70-80.
[34]
Shemer A, Nathansohn N, Trau H, Amichai B, Grunwald MH. Ciclopirox nail lacquer for the treatment of onychomycosis: an open non-comparative study. J Dermatol 2010; 37(2): 137-9.
[35]
Lahfa M1, Bulai-Livideanu C, Baran R et al. Efficacy, safety and tolerability of an optimized avulsion technique with onyster® (40% urea ointment with plastic dressing) ointment compared to bifonazole-urea ointment for removal of the clinically infected nail in toenail onychomycosis: a randomized evaluator-blinded controlled study. Dermatology 2013; 226(1): 5-12.
[36]
Suthar HP, Patel NM, Solanki AD, Barot JP. Nail avulsion with adjuvant therapy in nail disorders. Arch Int Surg 2014; 4: 158-61.
[37]
Pandhi D, Verma P. Nail avulsion : indications and methods [surgical nail avulsion]. Indian J Dermatol Venereol Leprol 2012; 78(3): 299-308.
[38]
Di Chiacchio N, Kadunc BV, De Almeida AR, Madeira CL. Nail abrasion. J Cosmet Dermatol 2003; 2(3-4): 150-2.
[39]
Angelo T, Borgheti-cardoso N, Taveira F, Gratieri T, Gelfuso M. Chemical and physical strategies in onychomycosis topical treatment : a review. Med Mycol 2017; 55(5): 461-75.
[40]
Kushwaha A, Shivakumar HN, Murthy SN. Iontophoresis for drug delivery into the nail apparatus: exploring hyponychium as the site of delivery. Drug Dev Ind Pharm 2016; 42(10): 1678-82.
[41]
Nair AB, Kiran Vaka SR, Murthy SN. Transungual delivery of terbinafine by iontophoresis in onychomycotic nails. Drug Dev Ind Pharm 2011; 37(10): 1253-8.
[42]
Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert Opin Pharmacother 2012; 13(8): 1131-42.
[43]
Surender V, Renu S. Transungual drug delivery a pivotal remedy in onychomycosis. J Chem Pharm Res 2016; 8(4): 370-81.
[44]
Simmons BJ, Griffith RD, Falto-Aizpurua LA, Nouri K. An update on photodynamic therapies in the treatment of onychomycosis. J Eur Acad Dermatol Venereol 2015; 29(7): 1275-9.
[45]
Bhatta AK, Keyal U, Wang XL. Photodynamic therapy for onychomycosis: a systematic review. Photodiagn Photodyn Ther 2016; 15: 228-35.
[46]
Kline-schoder A, Le Z, Zderic V. Ultrasound-enhanced drug delivery for treatment of onychomycosis. J Ultrasound Med 2018; 37(7): 1743-52.
[47]
Abadi D, Zderic V. Ultrasound-mediated nail drug delivery system. J Ultrasound Med 2011; 30: 1723-30.
[48]
Mathew F, Bindumol KC, Paul J, Pathadan RP, Varghese V. Understanding our natural nail - Antifungal agents. Int J Pharm Pharm Sci 2014; 6: 67-73.
[49]
Gupta AK, Studholme C. Novel investigational therapies for onychomycosis: an update. Expert Opin Investig Drugs 2016; 25(3): 297-305.
[50]
Luiza RDA, Priscila KC. Kolenyak dF, et al. Nanotechnology-based drug delivery systems for dermatomycosis treatment. Curr Nanosci 2012; 8(4): 512-9.
[51]
Soliman GM. Nanoparticles as safe and effective delivery systems of antifungal agents : achievements and challenges. Int J Pharm 2017; 523(1): 15-32.
[52]
Flores FC, de Lima JA, Ribeiro RF, et al. Antifungal activity of nanocapsule suspensions containing tea tree oil on the growth of trichophyton rubrum. Mycopathologia 2013; 175(3-4): 281-6.
[53]
Flores FC, Sin W, Beck RCR, Cristiane B. Enhancement of tioconazole ungual delivery : combining nanocapsule formulation and nail poration approaches. Int J Pharm 2018; 535(1-2): 237-44.
[54]
El-say KM, El-sawy HS. Polymeric nanoparticles : promising platform for drug delivery. Int J Pharm 2017; 528(1-2): 675-91.
[55]
Chiu WS, Belsey NA, Garrett NL, et al. Drug delivery into microneedle-porated nails from nanoparticle reservoirs. J Control Release 2015; 220: 98-106.
[56]
Wang F, Yang P, Choi J, et al. Cross-linked fluorescent supramolecular nanoparticles for intradermal controlled release of antifungal drug: a therapeutic approach for onychomycosis. ACS Nano 2018; 12: 6851-9.
[57]
Mahtab A, Anwar M, Mallick N, Naz Z, Jain GK, Ahmad FJ. Transungual delivery of ketoconazole nanoemulgel for the effective management of onychomycosis. AAPS PharmSciTech 2016 Dec; 17(6): 1477-90.
[58]
Kumar S, Talegaonkar S, Negi LM, Khan ZI. Design and development of ciclopirox topical nanoemulsion gel for the treatment of subungual onychomycosis. Ind J Pharm Edu Res 2012; 46(4): 303-11.
[59]
Bsieso EA, Nasr M, Moftah NH, Sammour OA, Abd El Gawad NA. Could nanovesicles containing a penetration enhancer clinically improve the therapeutic outcome in skin fungal diseases? Nanomedicine 2015; 10(13): 2017-31.
[60]
Elsherif NI, Shamma RN, Abdelbary G. Terbinafine hydrochloride trans-ungual delivery via nanovesicular systems: in vitro characterization and ex vivo evaluation. AAPS PharmSciTech 2017; 18(2): 551-62.
[61]
Tanrıverdi ST, Özer Ö. Novel topical formulations of terbinafine-hcl for treatment of onychomycosis. Eur J Pharm Sci 2013; 48(4-5): 628-36.
[62]
Ye D. Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis : in vitro and in vivo evaluation. J Liposome Res 2016; 26(2): 163-73.
[63]
Shukla T, Upmanyu N, Agrawal M, Saraf S, Saraf S, Alexander A. Biomedicine & pharmacotherapy biomedical applications of microemulsion through dermal and transdermal route. Biomed Pharmacother 2018; 108: 1477-94.
[64]
Barot BS, Parejiya PB, Patel HK, Gohel MC, Shelat PK. Microemulsion-based gel of terbinafine for the treatment of onychomycosis : optimization of formulation using d-optimal design. AAPS PharmSciTech 2012; 13(1): 184-92.
[65]
Kansagra H, Mallick S. Microemulsion-based antifungal gel of luliconazole for dermatophyte infections: formulation, characterization and efficacy studies. J Pharm Investig 2016; 46(1): 21-8.
[66]
Tomme SR Van, Storm G, Hennink WE. In situ gelling hydrogels for pharmaceutical and biomedical applications. Int J Pharm 2008; 355(1-2): 1-18.
[67]
El-sherif NI, Shamma RN, 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: 253-61.
[68]
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): 631-9.
[69]
Nogueiras-nieto L, Delgado-charro MB, Otero-espinar FJ. European journal of pharmaceutics and biopharmaceutics 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): 370-7.
[70]
Iorizzo M, Mailland F, Arraiz G, Frisenda L, Caserini M. An innovative terbinafine transungual solution [p-3058]: dose finding investigation on clinical benefit in patients affected by mild-to-moderate toe onychomycosis. J Am Acad Dermatol 2013; 68(4): AB102.
[71]
Polichem SA. Study to evaluate the efficacy and
safety of p-3058 10% nail solution in the treatment of
toenail onychomycosis. Clini Trials Gov 2017;
Available at:
https://clinicaltrials.gov/ct2/show/NCT03094468.
[72]
Gupta AK, Simpson FC. Investigational drugs for onychomycosis. Expert Opin Investig Drugs 2014; 23(1): 97-106.
[73]
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): 1716-20.
[74]
Pannu J, McCarthy A, Martin A, et al. NB-002, a novel nanoemulsion with broad antifungal activity against dermatophytes, other filamentous fungi, and candida albicans. Antimicrob Agents Chemother 2009; 53(8): 3273-9.
[75]
Gupta a. Simpson F. Device-based therapies for onychomycosis treatment. Skin Therapy Lett 2012; 17(9): 4-9.
[76]
Value SJRI, Khanna S, Bajaj R, Khurana B, Srivastava K. Pharmacotherapeutic principles of ungual drug delivery system. Int J Drug Dev Res 2012; 4(3): 9-18.
[77]
Mahtab A, Anwar M, Mallick N, Naz Z, Jain GK, Ahmad FJ. Transungual delivery of ketoconazole nanoemulgel for the effective management of onychomycosis. AAPS PharmSciTech 2016; 17(6): 1477-90.
[78]
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.
Related Journals
Anti-Cancer Agents in Medicinal Chemistry
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Bioactive Compounds
Current Cancer Drug Targets
Combinatorial Chemistry & High Throughput Screening
Current Cancer Therapy Reviews
Current Diabetes Reviews
Current Drug Safety
Current Drug Targets
Current Drug Therapy
Related Books
Anthocyanins: Pharmacology and Nutraceutical Importance
Nanotechnology: A Quick Guide to Materials and Technologies
The Roles and Responsibilities of Clinical Pharmacists in Hospital Settings
Bioactive Compounds from Medicinal Plants for Cancer Therapy and Chemoprevention
Recent Advancements in Multidimensional Applications of Nanotechnology
Thin Film Nanomaterials: Synthesis, Properties and Innovative Energy Applications
Advanced Materials and Nano Systems: Theory and Experiment (Part 3)
Nanoelectronic Devices and Applications
Drug Addiction Mechanisms in the Brain
Software and Programming Tools in Pharmaceutical Research
Article Metrics
55
11