Eradication of superficial fungal infections by conventional and novel approaches: a comprehensive review

Figures & data

Table I. Marketed formulations available for treatment of superficial fungal infections.

Drug	Brand name	Dosage form	Dose	Manufacturer
Clotrimazole	Lotrimin (1%)	Cream	Twice daily	Schering
	Gyne-Lotrimin (1%)	Cream	Twice daily	Schering-Plough
	Mycelex-G (1%)	Cream	Twice daily	Miles
Miconazole	Manistat-ermD (2%)	Cream	Twice daily	Pfizer
	Micatin (2%)	Cream	Twice daily	Ortho-McNeil Pharmaceutical
Ketoconazole	Xolegel gel (2%)	Gel	Once daily	Stiefel Labs
	Nizoral (2%)	Cream	Twice daily	Janssen
Econazole	Spectazole (1%)	Cream	Twice daily	Ortho
	Econail (5%)	Nail lacquer	Once daily	Macrochem corporation
Sertaconazole	Ertaczo (2%)	Cream	Twice daily	Ortho Neutrogena
Ciclopirox	Laprox (0.77%)	Cream	Twice daily	Hoechst-Marrion-Roussel
	Laprox (0.77%)	Gel	Once daily	Aventis Pharma
Terbinafine	Lamisil (1%)	Cream	Twice daily	Merz Pharmaceuticals
Fluconazole	Flucomet (0.3%)	Eye drops	3 times a day	Sun (Milmet)
	Syscan (0.3%)	Eye drops	3 times a day	Torrent
	Zocon (0.3%)	Eye drops	3 times a day	FDC
Natamycin	Natacyn (5%)	Ophthalmic Suspension	One drop instilled in conjuctival sac two hourly	Alcon
Ciclopiroxamine	Onylac (8%)	Nail lacquer	Once daily	Cipla
	Penlac (8%)	Nail lacquer	Once daily	Dermik
	Nailon (8%)	Nail lacquer	Once daily	Protech biosystem
Amorolfine	Loceryl (5%)	Nail lacquer	Once daily	Roche Lab

Table II. Important characteristics of antifungal drugs used topically.

Class	Name	Mol.mass (Daltons)	Log P	Drug interactions (Orally)
Azoles (Triazoles)	Fluconazole	306.27	0.4	Drug interactions with oral hypoglycemic, benzodiazepines and antiepileptic drugs
	Itraconazole	705.63	6.5	Interaction with antibiotic like clarithromycin, erythromycin, HMG-COA inhibitors like lovastatin, smivastatin and benzodiazepine like alprazolam and diazepam
Azole (Imidazole)	Clotrimazole	344.84	6.1	When taken orally it shows many interactions as it is specific inhibitor of cytochrome P450 (CYP3A4)
	Miconazole	416.12	6.1	Interaction with oral anticoagulants, Antipsychotic and HMG-COA inhibitors
	Ketoconazole	531.44	4.0	Interaction with antimuscarinic drugs, oral anticoagulants and H2-receptor antagonists
	Econazole	381.68	5.5	There are no known significant interactions
Hydroxypyridones	Ciclopirox	207.27	2.3	–
Allylamines	Terbinafine	291.43	5.9	Interactions with trycyclic antidepressants, Rifampin and cimetidine
	Naftifine	287.40	6.4	–
Benzylamine derivative	Butenafine	317.47	6.6	–

Figure 1. Fate of drugs in the skin in unformulated form or when it is formulated in a suitable drug delivery system.

Figure 2. Fate of drugs in eye.

Figure 3. Novel drug delivery systems for treatment of subcutaneous fungal infections.

Table III. A brief overview of novel drug delivery systems of various antifungal drugs used subcutaneously.

Drug	Novel formulation for topical delivery	Findings	References
Miconazole	Liposome	Prepared system had good size or stability characteristics and enhanced permeation properties in skin.	Agarwal and Katare (2002)
	Charged Submicron emulsion	Enhancement of topical bioavailability of drug by using the charged microemulsion that could be due to the binding affinity droplets to the skin.	Piemi et al. (1999)
	Niosomes	Developed formulation showed 92.10% drug release in 24 h so could be effective in elimination of topical fungal infections.	Firthouse et al. (2011)
	Solid lipid nanoparticles (SLN)	Gel containing SLN compared with marketed gel and the prepared gel showed enhanced skin-targeting effect.	Bhalekar et al. (2009)
	Microcapsules	Microcapsules showed higher activity compared to the commercial antifungal ointment of miconazole.	Yeun et al. (2011)
Fluconazole	Liposomes, Niosomes	Liposomal gel could produce 14.2 folds higher drug accumulation when compared with that of plain gel while accumulation was 3.3 folds more in case of niosomal gel.	Gupta et al. (2010)
	Oleic acid vesicles	Vesicle could penetrate the stratum corneum and retained the drug accumulated in epidermal part of skin.	Zakir et al. (2010)
	Ethosomes, liposomes	Drug diffused from ethosomes was twice than that from liposomes and three times higher than that from hydroethanolic solution across rat skin.	Bhalaria et al. (2009)
	Microemulsion	High percutaneous absorption, good antifungal activity and high stability.	Shah et al. (2009)
	Solid lipid nanoparticles (SLN)	SLN prepared showed improved dermal localization and sustained fashion over 24 h.	Gupta et al. (2011)
	SLN & NLC	NLC showed better skin retention and effective skin targeting effect compared to SLN.	Gupta and Vyas (2012)
	Microsphere	When drug was in crystalline form, loading of drug was high and loading of drug was low when it was used in amorphous form/molecular dispersion form.	Rivera et al. (2004)
	Micelles	Micellar formulation could enhance cutaneous bioavailability of azole antifungal to a greater extent.	Bachhav et al. (2011)
Clotrimazole	Liposomes, Niosomes	Liposomal and niosomal gel showed good retention in vaginal tissue and did not show any adverse effect on the vaginal morphology at 24 h of postdose.	Ning et al. (2005)
	Microemulsion	Microemulsion-based hydrogel of the clotrimazole showed high skin retention and high in-vitro antifungal activity against Candida albicans as compared to conventional cream.	Hashem et al. (2011)
	Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs)	NLCs showed high entrapment efficiency and faster release profile as compared to SLNs with same concentration of lipid and SLNs showed a better occlusive capacity as that of NLCs at the same concentration of lipid.	Souto et al. (2004)
	Micelles	Micellar formulation could enhance cutaneous bioavailability of azole antifungal.	Bachhav et al. (2011)
Ketoconazole	Liposomes	Liposomal encapsulation showed more drug retention compared with plain gel and plain drug cream.	Patel et al. (2009)
	Microemulsion	Globule size of microemulsion affected its antifungal efficacy and it was observed that small globule size made microemulsion an excellent carrier for promoting in-vitro skin permeation of ketoconazole (KTZ).	Patel et al. (2010)
	Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs)	SLNs were stable on storage for three months but they got degraded on exposure to the light while NLCs stabilized the drug but aqueous NLCs dispersion showed size increase during storage.	Souto and Muller (2005)
	SLN-Dextran hydrogel	Prepared system was biocompatible in nature whose rheological properties can be conveniently and easily adjusted by changing the derivatization degree or the concentration of the polymer, in order to assure a semisolid consistency, a good spread-ability and a pleasant texture, or to remain in the application site when necessary.	Paolicellia et al. (2011)
Econazole	Ethosomes	Optimized formulation showed controlled release of econazole nitrate for 12 h across the rat skin and percent drug diffused from ethosomes was nearly twofold higher than liposomal and hydroethanolic gels.	Verma and Pathak (2012)
	Microspheres	Microsphere prepared from the polaxamer showed improvement in solubility, in-vitro bioavailability of the low solubility drug, mucoadhesive strength and in in-vitro antifungal activity Candida albicans.	Albertini et al. (2009)
Terbinafine	Niosomes	Carbopol gel containing tween 40 niosomes showed maximum antifungal activity.	Sathali and Rajalakhmi (2010)
Griseofulvin	Niosomes	Proniosomal gel had six folds higher skin permeation as that of plain formulation.	Kassem et al. (2005)
	Deformable membrane vesicles (DMV)	Optimized DMVs showed remarkably higher drug permeation and skin retention compared to liposomes and they were found histopathologically safe.	Aggarwal and Goindi (2012)
Itraconazole	Microemulsion	Microemulsion with 1.5% w/w drug loading was found beneficial for the topical delivery of the itraconazole.	Lee et al. (2010)
	Niosomes	High drug entrapment was observed in niosomes along with good penetration in skin.	Ataei et al. (2011)

Figure 4. Confocal microscopic images of oleic acid vesicle in rat skin.

Table IV. List of patents associated with novel treatment of superficial fungal infections.

Title of patent	Drug	Delivery system	Route of administration	Patent number	Inventors
Allylamine-containing liposomes	Terbinafine	Liposomes	Dermal/Systemic/Pulmonal	United States Patent 7820720	Bodmer et al. (2003)
Nanoemulsion for treating onychomycosis	Terbinafine/Miconazole	Nano-emulsion	Dermal/Nail	WIPO Patent Application WO/2009/132342	Baker et al. (2009)
Topical terbinafine formulations and methods of administering same for the treatment of fungal infections	Terbinafine	Niosomes	Dermal	United States Patent 7820720	Cevc and Vierl (2010)
Terbinafine compositions for onychomycosis treatment	Terbinafine	Ethosomes	Nail	WIPO Patent Application WO/2010/086723	Touitou and Elka (2010)

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