Nanoliposome-loaded antifungal drugs for dermal administration: A review

Document Type : Reviews


1 Student Research Committee, Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran

2 Infectious Diseases and Tropical Medicine Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran

3 Invasive Fungi Research Center/Department of Medical mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

4 Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran

5 Toxoplasmosis Research Center, Communicable Diseases Institute, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran



Cutaneous fungal infections are the fourth most common health problem, which involves approximately  billion people worldwide. Drug delivery to the skin seems to be the best choice for superficial fungal infections. Topical formulations can release a sufficient amount of drug in therapeutical concentrations and permeate higher layers of the skin
like the stratum corneum. As the outermost layer of the epidermis, the stratum corneum prevents the drug from penetrating the skin. Liposomes, especially nanosized as topical drug delivery systems to the skin, can show various functions depending on their size, lipids and cholesterol components, the percent of ingredients, lamellarity, and surface charge. Nanoliposomes can increase permeation through the stratum corneum, decrease systemic effects with their localizing actions, and overcome many dermal drug delivery obstacles. Antifungal drugs, such as croconazole, econazole, fluconazole, ketoconazole,
terbinafine hydrochloride, tolnaftate, and miconazole entrapped in liposomes have indicated improved skin penetration and localizing effects. According to the literature review summarized in this paper, many studies have identified liposomes as a powerful carrier for topical antifungal drug delivery to the skin. However, a few studies introduced new generations of liposomes like ethosomes and transfersomes. This paper was conducted on almost all liposomal studies of antifungal drugs with dermal application.


 Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati
M, et al. Years lived with disability (YLDs) for 1160 sequelae of
289 diseases and injuries 1990–2010: a systematic analysis for
the Global Burden of Disease Study 2010. Lancet. 2012;
2. Abastabar M, Shokohi T, Kord RR, Badali H, Hashemi SJ,
Ghasemi Z, et al. In vitro activity of econazole in comparison
with three common antifungal agents against clinical
strains isolated from superficial infections. Curr Med Mycol.
2015; 1(4):7-12.
3. de Hoog GS, Dukik K, Monod M, Packeu A, Stubbe D,
Hendrickx M, et al. Toward a novel multilocus phylogenetic
taxonomy for the dermatophytes. Mycopathologia. 2017; 182(1-
4. Kaur IP, Kakkar S. Topical delivery of antifungal agents. Expert
Opin Drug Deliv. 2010; 7(11):1303–27.
5. Donnelly RF, McCarron PA, Tunney MM. Antifungal
photodynamic therapy. Microbiol Res. 2008; 163(1):1–12.
6. Robert ME, Kalia YN. New developments in topical antifungal
therapy. Am J Drug Deliv. 2006; 4(4):231-47.
7. Bseiso EA, Nasr M, Sammour O, Abd El Gawad NA. Recent
advances in topical formulation carriers of antifungal agents.
Indian J Dermatol Venereol Leprol. 2015; 81(5):457–63.
8. Mathur M, Devi VK. Potential of novel drug delivery systems in
the management of topical candidiasis. J Drug Target. 2017;
9. Abastabar M, Mirhendi H, Hedayati MT, Shokohi T, RezaeiMatehkolaei A, Mohammadi R, et al. Genetic and morphological
diversity of the genus
Penicillium from Mazandaran and Tehran
provinces, Iran. Jundishapur J Microb. 2016 Jan;9(1).
10. Verma S, Utreja P. Vesicular nanocarrier based treatment of skin
fungal infections: Potential and emerging trends in nanoscale
pharmacotherapy. Asian J Pharm Sci. 2019; 14(2):117–29.
11. Zuber TJ, Baddam K. Superficial fungal infection of the skin:
Where and how it appears help determine therapy. Postgrad
Med. 2001; 109(1):117–20.
12. Shao PL, Huang LM, Hsueh PR. Recent advances and
challenges in the treatment of invasive fungal infections. Int J
Antimicrob Agents. 2007; 30(6):487–95.
13. Kumar L, Verma S, Bhardwaj A, Vaidya S, Vaidya B.
Eradication of superficial fungal infections by conventional and
novel approaches: a comprehensive review. Artif Cells
Nanomed Biotechnol. 2014; 42(1):32–46.
14. Yang W, Wiederhold NP, Williams RO 3rd. Drug delivery
strategies for improved azole antifungal action. Expert Opin
Drug Deliv. 2008; 5(11):1199–216.
15. Osanloo M, Assadpour S, Mehravaran A, Abastabar M, Akhtari
J. Niosome-loaded antifungal drugs as an effective nanocarrier
system: a mini review. Curr Med Mycol. 2018; 4(4):31–6.
16. Thakur K, Sharma G, Singh B, Chhibber S, Katare OP. Current
state of nanomedicines in the treatment of topical infectious
disorders. Recent Pat Antiinfect Drug Discov. 2018; 13(2):127–50.
17. Desmet E, Van Gele M, Lambert J. Topically applied lipid- and
surfactant-based nanoparticles in the treatment of skin disorders.
Expert Opin Drug Deliv. 2017; 14(1):109–22.
18. Akhtari J, Ebrahimnejad P, Rafiei A. A review on the use of
nanoparticles in the release of growth factors. J-Mazand-UnivMed-Sci. 2015;24(122):424-39.
19. Ventola CL. Progress in nanomedicine: approved and
investigational nanodrugs. Pharm Ther. 2017; 42(12):742–55.
20. Severino P, Moraes LF, Zanchetta B, Souto EB, Santana MH.
Elastic liposomes containing benzophenone-3 for sun protection
factor enhancement. Pharm Dev Technol. 2012; 17(6):661–5.
21. Santos RS, Loureiro KC, Rezende PS, Andrade LN, de Melo
Barbosa R, Santini A, et al. Innovative nanocompounds for
cutaneous administration of classical antifungal drugs: a
systematic review. J Dermatol Treat. 2019; 30(6):617-26.
22. Bozzuto G, Molinari A. Liposomes as nanomedical devices. Int
J Nanomed. 2015; 10:975-99.
23. Soliman GM. Nanoparticles as safe and effective delivery
systems of antifungal agents: achievements and challenges. Int J
Pharm. 2017; 523(1):15-32.
24. Moosavian SA, Abnous K, Akhtari J, Arabi L, Gholamzade
Dewin A, Jafari M. 5TR1 aptamer-PEGylated liposomal
doxorubicin enhances cellular uptake and suppresses tumour
growth by targeting MUC1 on the surface of cancer cells. Artif
Cells Nanomed Biotechnol. 2018; 46(8):2054-65.
25. Szoka FC, Milholland D, Barza M. Effect of lipid composition
and liposome size on toxicity and in vitro fungicidal activity of
liposome-intercalated amphotericin B. Antimicrob Agents
Chemother. 1987; 31(3):421–9.
26. Dhamoon RK, Popli H, Gupta M. Novel drug delivery strategies
for the treatment of onychomycosis. Pharm Nanotechnol. 2019;
27. Güngör S, Erdal MS, Aksu B. New formulation strategies in
topical antifungal therapy. J Cosmet Dermatol Sci Appl. 2013;
28. Schwarz JC, Kählig H, Matsko NB, Kratzel M, Husa M, Valenta
C. Decrease of liposomal size and retarding effect on
fluconazole skin permeation by lysine derivatives. J Pharm Sci.
2011; 100(7):2911–9.
29. Firooz A, Nafisi S, Maibach HI. Novel drug delivery strategies
for improving econazole antifungal action. Int J Pharm. 2015;
30. Carita AC, Eloy JO, Chorilli M, Lee RJ, Leonardi GR. Recent
advances and perspectives in liposomes for cutaneous drug
delivery. Curr Med Chem. 2018; 25(5):606-35.
31. Blank IH, Moloney J, Emslie AG. The diffusion of water across
the stratum corneum as a function of its water content. J Invest
Dermatol. 1984; 82(2):188–94.
32. El-Badry M, Fetih G, Shakeel F. Comparative topical delivery of
antifungal drug croconazole using liposome and micro-emulsionbased gel formulations. Drug Deliv. 2014; 21(1):34–43.
33. Kim MK, Chung SJ, Lee MH, Cho AR, Shim CK. Targeted and
sustained delivery of hydrocortisone to normal and stratum
corneum-removed skin without enhanced skin absorption using a
liposome gel. J Control Release. 1997; 46(3):243–51.
34. Ning M, Guo Y, Pan H, Chen X, Gu Z. Preparation, in vitro and
in vivo evaluation of liposomal/niosomal gel delivery systems
for clotrimazole. Drug Dev Ind Pharm. 2005; 31(4-5):375–83.
35. Mezei M, Gulasekharam V. Liposomes -- a selective drug
delivery system for the topical route of administration. Lotion
dosage form. Life Sci. 1980; 26(18):1473–7.
36. Mezei M, Gulasekharam V. Liposomes--a selective drug
delivery system for the topical route of administration: gel
dosage form. J Pharm Pharmacol. 1982; 34(7):473–4.
37. El Maghraby GM, Williams AC, Barry BW. Can drug-bearing
  liposomes penetrate intact skin? J Pharm Pharmacol. 2006;
38. El Maghraby GM, Barry BW, Williams AC. Liposomes and
skin: From drug delivery to model membranes. Eur J Pharm Sci.
2008; 34(4–5):203–22.
39. Schaller M, Korting HC. Interaction of liposomes with human
skin: the role of the stratum corneum. Adv Drug Deliv Rev.
1996; 18(3):303-9.
40. Bhatia A, Kumar R, Katare OP. Tamoxifen in topical liposomes:
Development, characterization and in-vitro evaluation. J Pharm
Pharm Sci. 2004; 7(2):252–9.
41. Mezei M. Biodisposition of liposome-encapsulated active
ingredients applied on the skin. Liposome dermatics. Berlin:
Springer; 1992. P. 206–14.
42. Boinpally RR, Zhou SL, Poondru S, Devraj G, Jasti BR.
Lecithin vesicles for topical delivery of diclofenac. Eur J Pharm
Biopharm. 2003; 56(3):389–92.
43. Zhang AY, Camp WL, Elewski BE. Advances in topical and
systemic antifungals. Dermatol Clin. 2007; 25(2):165–83.
44. Verma AM, Palani S. Development and in-vitro evaluation of
liposomal gel of ciclopirox olamine. Int J Pharma Bio Sci. 2010;
45. Schaller M, Preidel H, Januschke E, Korting HC. Light and
electron microscopic findings in a model of human cutaneous
candidosis based on reconstructed human epidermis following
the topical application of different econazole formulations. J
Drug Target. 1999; 6(5):361–72.
46. Korting HC, Klövekorn W, Klövekorn G. Comparative efficacy
and tolerability of econazole liposomal gel 1%, branded
econazole conventional cream 1% and generic clotrimazole
cream 1% in tinea pedis. Clin Drug Investig. 1997; 14(4):286–93.
47. Bachhav YG, Mondon K, Kalia YN, Gurny R, Möller M. Novel
micelle formulations to increase cutaneous bioavailability of
azole antifungals. J Control Release. 2011; 153(2):126–32.
48. Habib FS, Fouad EA, Fathalla D. Liposomes as an ocular
delivery system of fluconazole: In-vitro studies. Bull Pharm Sci
Assiut. 2008; 31(2):293-311.
49. Gupta M, Goyal AK, Paliwal SR, Paliwal R, Mishra N, Vaidya
B, et al. Development and characterization of effective topical
liposomal system for localized treatment of cutaneous
candidiasis. J Liposome Res. 2010; 20(4):341-50.
50. Mitkari BV, Korde SA, Mahadik KR, Kokare CR. Formulation
and evaluation of topical liposomal gel for fluconazole. Indian J
Pharm Educ Res. 2010; 44(4):324-33.
51. Rathore GS, Tanwar YS, Sharma A. Fluconazole loaded
ethosomes gel and liposomes gel : an updated review for the
treatment of deep fungal skin infection. Pharm Chem J. 2015;
52. Hedayati N, Montazer M, Mahmoudirad M, Toliyat T.
Ketoconazole and Ketoconazole/β-cyclodextrin performance on
cotton wound dressing as fungal skin treatment. Carbohydr
Polym. 2020; 240:116267.
53. Patel R, Patel H, Baria A. Formulation and evaluation of
carbopol gel containing liposomes of ketoconazole. (Part-II). Int
J Drug Deliv Technol. 2009; 1:2.
54. Dave V, Sharma S, Yadav RB, Agarwal U. Herbal liposome for
the topical delivery of ketoconazole for the effective treatment of
seborrheic dermatitis. Appl Nanosci. 2017; 7(8):973–87.
55. Guo F, Wang J, Ma M, Tan F, Li N. Skin targeted lipid vesicles
as novel nano-carrier of ketoconazole: characterization, in vitro
and in vivo evaluation. J Mater Sci Mater Med. 2015; 26(4):175.
56. Agarwal R, Katare OP. Preparation and in vitro evaluation of
miconazole nitrate-loaded topical liposomes. Pharm Technol
North Am. 2002; 26(11):48–60.
57. Singh A, Rathore P, Shukla M, Nayak S. Comparative studies on
skin permeation of miconazole using different novel carriers. Int
J Pharm Sci Res. 2010; 1(9):61–6.
58. Tanriverdi ST, Özer Ö. Novel topical formulations of
Terbinafine-HCl for treatment of onychomycosis. Eur J Pharm
Sci. 2013; 48(4-5):628-36.
59. Sudhakar B, Varma JN, Murthy KV. Formulation,
characterization and ex vivo studies of terbinafine HCl
liposomes for cutaneous delivery. Curr Drug Deliv. 2014;
60. Yadav S, Wairkar S, Invally M, Ranade S. Topical emulgel
of tolnaftate with penetration enhancer: development,
characterisation and antifungal activity. Indian J Med Res Pharm
Sci. 2017; 4(10):28-35.
61. Gunda SR, Ganesh GN. Formulation and evaluation of tolnaftate
loaded topical liposomal gel for effective skin drug delivery to
treat fungal diseases. J Chem Pharm Res. 2014; 6(10):856-66.