JCDSA  Vol.3 No.1 A , January 2013
New Formulation Strategies in Topical Antifungal Therapy

Fungal infections of the skin are one of the often faced with dermatological diseases in worldwide. Topical therapy is an attractive choice for the treatment of the cutaneous infections due to its advantageous such as targeting of drugs to the site of infection and reduction of the risk of systemic side effects. Currently, antifungal drugs are generally used as conventional cream and gel preparations in topical treatment. The efficiency of that treatment depends on the penetration of drugs through the target layers of the skin at the effective concentrations. However, stratum corneum, the outermost layer of the skin, is an effective barrier for penetration of drugs into deeper layers of the skin. The physicochemical characteristics of drug molecules and the types of the formulations are effective factors in topical drug delivery. Therefore, a number of formulation strategies have been investigated for delivering antifungal compounds through targeted site of the skin. This review article focuses on the new alternative formulation approaches to improve skin penetration of antifungal drugs.

Cite this paper: S. Güngör, M. Erdal and B. Aksu, "New Formulation Strategies in Topical Antifungal Therapy," Journal of Cosmetics, Dermatological Sciences and Applications, Vol. 3 No. 1, 2013, pp. 56-65. doi: 10.4236/jcdsa.2013.31A009.

[1]   M. Ameen, “Epidemiology of Superficial Fungal Infections,” Clinical Dermatology, Vol. 28, No. 2, 2010, pp. 197-201. doi:10.1016/j.clindermatol.2009.12.005

[2]   B. Havlickova and M. Friedrich, “Epidemiological Trends in Skin Mycoses Worldwide,” Mycoses, Vol. 51, Suppl. 4, 2008, pp. 2-15. doi:10.1111/j.1439-0507.2008.01606.x

[3]   A. Y. Zhang, W. L. Camp and B. E. Elewski, “Advances in Topical and Systemic Antifungals,” Clinical Dermatology, Vol. 25, No. 2, 2007, pp. 165-183. doi:10.1016/j.det.2007.01.002

[4]   P. Vermaand and K. Pathak, “Nanosized Ethanolic Vesicles Loaded with Econazole Nitrate for the Treatment of Deep Fungal Infections through Topical Gel Formulation,” Nanomedicine, Vol. 8, No. 4, 2012, pp. 489-496. doi:10.1016/j.nano.2011.07.004

[5]   C. M. Lee and H. I. Maibach, “Deep Percutaneous Penetration into Muscles and Joints,” Journal of Pharmaceutical Science, Vol. 95, No. 7, 2006, pp. 1405-1412. doi:10.1002/jps.20666

[6]   A. Williams, “Transdermal and Topical Drug Delivery: From Theory to Clinical Practice,” Pharmaceutical Press, London, 2003.

[7]   R. H. Guy, “Current Status and Future Prospects of Transdermal Drug Delivery,” Pharmaceutical Research, Vol. 13, No. 12, 1996, pp. 1765-1769. doi:10.1023/A:1016060403438

[8]   R. H. Guy, “Transdermal Drug Delivery,” In: M. SchaferKorting, Ed., Drug Delivery, Handbook of Experimental Pharmacology, Springer-Verlag, Berlin, 2010.

[9]   T. Taner and R. Mark, “Delivering Drugs by the Transdermal Route: Review and Comment,” Skin Research Technology, Vol. 14, No. 3, 2008, pp. 249-260. doi:10.1111/j.1600-0846.2008.00316.x

[10]   H. R. Neubert, “Potentials of New Nanocarriers for Dermal and Transdermal Drug Delivery,” European Journal of Pharmacy Biopharmacy, Vol. 77, No. 1, 2011, pp. 1-2. doi:10.1016/j.ejpb.2010.11.003

[11]   H. A. Benson, “Elastic Liposomes for Topical and Transdermal Drug Delivery,” Current Drug Delivery, Vol. 6, No. 3, 2009, pp. 217-226. doi:10.2174/156720109788680813

[12]   D. J. Sheehan, C. A. Hitchcock and C. M. Sibley, “Current and Emerging Azole Antifungal Agents,” Clinical Microbiology Reviews, Vol. 12, No. 1, 1999, pp. 40-79.

[13]   V. T. Andriole, “Current and Future Antifungal Therapy: New Targets for Antifungal Therapy,” International Journal of Antimicrobial Agents, Vol. 44, No. 2, 1999, pp. 151-162.

[14]   B. Di Domenico, “Novel Antifungal Drugs,” Current Opinion in Microbiology, Vol. 2, No. 5, 1999, pp. 509-515. doi:10.1016/S1369-5274(99)00009-0

[15]   M .J. O’Neil, “The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals,” 14th Edition, Merck & Co Inc., Rahway, 2006.

[16]   ChemBlink, “Online Database of Chemicals from Around the World,” 2012.

[17]   Drug Bank, “Open Data Drug and DrugTarget Database,” 2012.

[18]   Y. G. Bachhav, K. Mondon, Y. N. Kalia, R. Gurny and M. Moller, “Novel Micelle Formulations to Increase Cutaneous Bioavailability of Azole Antifungals,” Journal of Controlled Release, Vol. 153, No. 2, 2011 pp. 126-132. doi:10.1016/j.jconrel.2011.03.003

[19]   M. P. Piemi, D. Korner, S. Benita and J. P. Marty, “Positively and Negatively Charged Submicron Emulsions for Enhanced Topical Delivery of Antifungal Drugs,” Journal of Controlled Release, Vol. 58, No. 2, 1999, pp. 177-187. doi:10.1016/S0168-3659(98)00156-4

[20]   M. Schaller, H. Preidel, E. Januschke and H. C. Korting, “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,” Journal of Drug Targeting, Vol. 6, No. 5, 1999, pp. 361-372. doi:10.3109/10611869908996843

[21]   L. Keshriand and K. Pathak, “Development of Thermodynamically Stable Nanostructured Lipid Carrier System Using Central Composite Design for Zero Order Permeation of Econazole Nitrate through Epidermis,” Pharmaceutical Development and Technology, 2012, Epub ahead of Print.

[22]   V. Sanna, E. Gavini, M. Cossu, G. Rassu and P. Giunchedi, “Solid Lipid Nanoparticles (SLN) as Carriers for the Topical Delivery of Econazole Nitrate: In-Vitro Characterization, ex-Vivo and in-Vivo Studies,” Journal of Pharmacy and Pharmacology, Vol. 59, No. 8, 2007, pp. 1057-1064. doi:10.1211/jpp.59.8.0002

[23]   N. Passerini, E. Gavini, B. Albertini, G. Rassu, M. Di Sabatino, V. Sanna, P. Giunchedi and L. Rodriguez, “Evaluation of Solid Lipid Microparticles Produced by Spray Congealing for Topical Application of Econazole Nitrate,” Journal of Pharmacy and Pharmacology, Vol. 61, No. 5, 2009, pp. 559-567. doi:10.1211/jpp.61.05.0003

[24]   R. Sharma and K. Pathak, “Polymeric Nanosponges as an Alternative Carrier for Improved Retention of Econazole Nitrate onto the Skin through Topical Hydrogel Formulation,” Pharmaceutical Development and Technology, Vol. 16, No. 4, 2011, pp. 367-376. doi:10.3109/10837451003739289

[25]   E. Peira, M. E. Carlotti, C. Trotta, R. Cavalli and M. Trotta, “Positively Charged Microemulsions for Topical Application,” International Journal of Pharmacy, Vol. 346, No. 1-2, 2008, pp. 119-123. doi:10.1016/j.ijpharm.2007.05.065

[26]   R. M. Elmoslemany, O. Y. Abdallah, L. K. El-Khordagui and N. M. Khalafallah, “Propylene Glycol Liposomes as a Topical Delivery System for Miconazole Nitrate: Comparison with Conventional Liposomes,” AAPS Pharmaceutical Science Technology, Vol. 13, No. 2, 2012, pp. 723-731. doi:10.1208/s12249-012-9783-6

[27]   A. D. Logu, A. M. Fadda, C. Anchisi, A. M. Maccioni, C. Sinico, M. L. Schivo and F. Alhaique, “Effects of in-Vitro Activity of Miconazole and Ketoconazole in Phospholipid Formulations,” Journal of Antimicrobial Chemotherapy, Vol. 40, No. 6, 1997, pp. 889-893. doi:10.1093/jac/40.6.889

[28]   M. R. Bhalekar, V. Pokharkar, A. Madgulkar and N. Patil, “Preparation and Evaluation of Miconazole Nitrate-Loaded Solid Lipid Nanoparticles for Topical Delivery,” AAPS Pharmaceutical Science Technology, Vol. 10, No. 1, 2009, pp. 289-296. doi:10.1208/s12249-009-9199-0

[29]   A. Chudasama, V. Patel, M. Nivsarkar, K. Vasu and C. Shishoo, “Investigation of Microemulsion System for Transdermal Delivery of Itraconazole,” Journal of Advanced Pharmaceuical Technology Research, Vol. 2, No. 1, 2011, pp. 30-38.

[30]   S. Mukherjee, S. Ray and R. S. Thakur, “Design and Evaluation of Itraconazole Loaded Solid Lipid Nanoparticulate System for Improving the Antifungal Therapy,” Pakistan Journal of Pharmaceutical Science, Vol. 22, No. 2, 2009, pp. 131-138.

[31]   G. N. El-Hadidy, H. K. Ibrahim, M. I. Mohamed and M. F. El-Milligi, “Microemulsions as Vehicles for Topical Administration of Voriconazole: Formulation and in Vitro Evaluation,” Drug Development and Industrial Pharmacy, Vol. 38, No. 1, 2012, pp. 64-72. doi:10.3109/03639045.2011.590731

[32]   C. K. Song, P. Balakrishnan, C. K. Shim, S. J. Chung, S. Chong and D. D. Kim, “A Novel Vesicular Carrier, Transethosome, for Enhanced Skin Delivery of Voriconazole: Characterization and in vitro/in vivo Evaluation,” Colloids and Surfaces: B Biointerfaces, Vol. 92, 2012, pp. 299-304. doi:10.1016/j.colsurfb.2011.12.004

[33]   M. R. Patel, R. B. Patel, J. R. Parikh, A. B. Solanki and B. G. Patel, “Investigating Effect of Microemulsion Components: In vitro Permeation of Ketoconazole,” Pharmaceutical Development and Technology, Vol. 16, No. 3, 2011, pp. 250-258. doi:10.3109/10837451003610845

[34]   C. Salerno, A. M. Carlucci and C. Bregni, “Study of in Vitro Drug Release and Percutaneous Absorption of Fluconazole from Topical Dosage Forms,” AAPS Pharmaceutical Science Technology, Vol. 11, No. 2, 2010, pp. 986-993. doi:10.1208/s12249-010-9457-1

[35]   M. R. Patel, R. B. Patel, J. R. Parikh, A. B. Solanki and B. G. Patel, “Effect of Formulation Components on the in Vitro Permeation of Microemulsion Drug Delivery System of Fuconazole,” AAPS Pharmaceutical Science Technology, Vol. 10, No. 3, 2009, pp. 917-923. doi:10.1208/s12249-009-9286-2

[36]   K. R. Jadhav, V. J. Kadam and S. S. Pisal, “Formulation and Evaluation of Lecithin Organogel for Topical Delivery of Fluconazole,” Current Drug Delivery, Vol. 6, No.2, 2009, pp. 174-813. doi:10.2174/156720109787846252

[37]   H. M. El Laithy and K. M. El-Shaboury, “The Development of Cutina Lipogels and Gel Microemulsion for Topical Administration of Fluconazole,” AAPS Pharmaceutical Science Technology, Vol. 3, No. 4, 2002, p. E35.

[38]   J. C. Schwarz, H. Kahlig, N. B. Matsko, M. Kratzel, M. Husa and C. Valenta, “Decrease of Liposomal Size and Retarding Effect on Fluconazole Skin Permeation by Lysine Derivatives,” Journal of Pharmaceutical Science, Vol. 100, No. 7, 2011, pp. 2911-2919. doi:10.1002/jps.22513

[39]   M. Gupta, A. K. Goyal, S. R. Paliwal, R. Paliwal, N. Mishra, B. Vaidya, D. Dube, S. K. Jain and S. P. Vyas, “Development and Characterization of Effective Topical Liposomal System for Localized Treatment of Cutaneous Candidiasis,” Journal of Liposome Research, Vol. 20, No. 4, 2010, pp. 341-50. doi:10.3109/08982101003596125

[40]   M. Gupta, B. Vaidya, N. Mishra and S. P. Vyas, “Effect of Surfactants on the Characteristics of Fluconazole Niosomes for Enhanced Cutaneous Delivery,” Artificial Cells, Blood Substitutes, and Immobilization Biotechnology, Vol. 36, No. 6, 2011, pp. 376-834. doi:10.3109/10731199.2011.611476

[41]   M. K. Bhalaria, S. Naik and A. N. Misra, “Ethosomes: A Novel Delivery System for Antifungal Drugs in the Treatment of Topical Fungal Diseases,” Indian Journal of Experimental Biology, Vol. 47, No. 5, 2009, pp. 368-375.

[42]   M. Gupta and S. P. Vyas, “Development, Characterization and in vivo Assessment of Effective Lipidic Nanoparticles for Dermal Delivery of Fluconazole against Cutaneous Candidiasis,” Chemistry Physics of Lipids, Vol. 165, No. 4, 2012, pp. 454-461. doi:10.1016/j.chemphyslip.2012.01.006

[43]   F. M. Hashem, S. D. Shaker, M. K. Ghorab, M. Nasr and A. Ismail, “Formulation, Characterization, and Clinical Evaluation of Microemulsion Containing Clotrimazole for Topical Delivery,” AAPS Pharmaceutical Science Technology, Vol. 12, No. 3, 2011, pp. 879-886. doi:10.1016/j.chemphyslip.2012.01.006

[44]   R. G. S. Maheshwari, R. K. Tekade, P. A. Sharma, G. Darwhekar, A. Tyagi, R. P. Patel and D. K. Jain, “Ethosomes and Ultradeformable Liposomes for Transdermal Delivery of Clotrimazole: A Comparative Assessment,” Saudi Pharmaceutical Journal, Vol. 20, No. 2, 2012, pp. 161-170. doi:10.1016/j.chemphyslip.2012.01.006

[45]   E. B. Souto, S. A. Wissing, C. M. Barbosa and R. H. Müller, “Development of a Controlled Release Formulation Based on SLN and NLC for Topical Clotrimazole Delivery,” International Journal of Pharmacy, Vol. 278, No. 1, 2004, pp. 71-77. doi:10.1016/j.ijpharm.2004.02.032

[46]   S. Das, W. K. Ng and R. B. Tan, “Are Nanostructured Lipid Carriers (NLCs) Better than Solid Lipid Nanoparticles (SLNs): Development, Characterizations and Comparative Evaluations of Clotrimazole-Loaded SLNs and NLCs,” European Journal of Pharmaceutical Science, Vol. 47, No. 1, 2012, pp. 139-151. doi:10.1016/j.ejps.2012.05.010

[47]   Y. C. Chen, D. Z. Liu, J. J. Liu, T. W. Chang, H. O. Ho and M. T. Sheu, “Development of Terbinafine Solid Lipid Nanoparticles as a Topical Delivery System,” International Journal of Nanomedicine, Vol. 7, 2012, pp. 4409-4418.

[48]   I. Ozcan, O. Abaci, A. H. Uztan, B. Aksu, H. Boyacioglu, T. Güneri and O. Ozer, “Enhanced Topical Delivery of Terbinafine Hydrochloride with Chitosan Hydrogels,” AAPS Pharmaceutical Science Technology, Vol. 10, No. 3, 2009, pp. 1024-1031. doi:10.1208/s12249-009-9299-x

[49]   M. S. Erdal, S. Güngor and Y. Ozsoy, “Microemulsions of Naftifine Hydrochloride: Characterization of Impact on Stratum Corneum Permeability with ATR-FTIR Spectroscopy,” European Journal of Pharmaceutical Sciences, Vol. 44, 2011, pp. 159-160.

[50]   H. S. Barakat, I. A. Darwish, L. K. El-Khordagui and N. M. Khalafallah, “Development of Naftifine Hydrochloride Alcohol-Free Niosome Gel,” Drug Development and Industrial Pharmacy, Vol. 35, No. 5, 2009, pp. 631-637. doi:10.1080/03639040802498864

[51]   X. Y. Zhao, Q. Cao, L. Q. Zheng and G. Y. Zhang, “Rheological Properties and Microstructures of Gelatin Containing Microemulsion-Based Organogels, Colloids and Surfaces A,” Physicochemistry Engineering Aspects, Vol. 281, No. 1, 2006, pp. 67-73. doi:10.1016/j.colsurfa.2006.02.051

[52]   F. Fernández-Campos, B. C. Naveros, O. L. Serrano, C. A. Merino and A. C. C. Campmany, “Evaluation of Novel Nystatin Nanoemulsion for Skin Candidosis Infections,” Mycoses, Vol. 56, No. 1, 2013, pp. 70-81. doi:10.1111/j.1439-0507.2012.02202.x

[53]   K. S. Shaikh, B. Chellampillai and A. P. Pawar, “Studies on Nonionic Surfactant Bilayer Vesicles of Cicloprox Olamine,” Drug Development and Industrial Pharmacy, Vol. 36, No. 8, 2010, pp. 946-953. doi:10.3109/03639040903585150

[54]   A. Kogan and N. Garti, “Microemulsions as Transdermal Drug Delivery Vehicles,” Advances in Colloid and Interface Science, Vol. 123-126, 2006, pp. 369-385. doi:10.1016/j.cis.2006.05.014

[55]   V. P. Torchilin, “Micellar Nanocarriers: Pharmaceutical Perspectives,” Pharmaceutical Research, Vol. 24, No. 1, 2006, pp. 1-16. doi:10.1007/s11095-006-9132-0

[56]   C. Oerlemans, W. Bult, M. Bos, G. Storm, J. F.W. Nijsen, and W. E. Hennink, “Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release,” Pharmaceutical Research, Vol. 27, No. 12, 2010, pp. 2569-2589. doi:10.1007/s11095-010-0233-4

[57]   D. S. Bernardi, T. A. Pereira, N. R. Maciel, J. Bortoloto, G. S. Viera, G. C. Oliveira and P. A. Rocha-Filho, “Formation and Stability of Oil-In-Water Nanoemulsions Containing Rice Bran Oil: In vitro and in vivo Assessments,” Journal of Nanobiotechnology, Vol. 9, 2011, p. 44. doi:10.1186/1477-3155-9-44

[58]   F. Shakeel, “Criterion for Excipients Screening in the Development of Nanoemulsion Formulation of Three Anti-Inflammatory Drugs,” Pharmaceutical Development and Technology, Vol. 15, No. 2, 2010, pp. 131-138. doi:10.3109/10837450903055502

[59]   D. I. J. Morrow, P. A. McCarron, A. D. Woolfson and R. F. Donnely, “Innovative Strategies for Enhancing Topical and Transdermal Drug Delivery,” The Open Drug Delivery Journal, Vol. 1, 2007, pp. 36-59.

[60]   G. M. El Maghraby, B. W. Barry and A. C. Williams, “Liposomes and Skin: From Drug Delivery to Model Membranes,” European Journal of Pharmaceutical Sciences, Vol. 34, No. 4-5, 2008, pp. 203-222. doi:10.1016/j.ejps.2008.05.002

[61]   M. J. Choi and H. I. Maibach, “Liposomes and Niosomes as Drug Delivery Systems,” Skin Pharmacology Physiology, Vol. 18, No. 5, 2005, pp. 209-219. doi:10.1159/000086666

[62]   E. Touitou and B. W. Barry, “Enhancement in Drug Delivery,” Taylor & Francis, New York, 1997.

[63]   B. Godin and E. Touitoi, “Ethosomes: New Prospects in Trasdermal Delivery,” Critical Review in Therapeutic Drug Carrier Systems, Vol. 20, No. 1, 2003, pp. 63-102. doi:10.1615/CritRevTherDrugCarrierSyst.v20.i1.20