Luliconazole-Loaded Thermosensitive Hydrogel as Aqueous based Nail Lacquer for the Treatment of Onychomycosis

Author(s): Rupinder K. Dhamoon, Ramesh K. Goyal, Harvinder Popli, Madhu Gupta*.

Journal Name: Drug Delivery Letters

Volume 9 , Issue 4 , 2019

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Graphical Abstract:


Abstract:

Background: Onychomycosis is a nail fungal infection which accounts for 50% of the nail diseases and is characterized by disfigurement and discoloration of nails. The current therapy includes oral and topical formulations both of which come with their own drawbacks. This has left a room for developing patient- compliant novel strategies which can facilitate drug delivery deeper into the nails effectively.

Objective: The main objective of the present work was to develop and evaluate in situ gelling thermosensitive hydrogel as an aqueous nail lacquer for the treatment of onychomycosis. The idea was to enhance permeation of Luliconazole into the nail while simultaneously solubilizing it in a hydrophilic formulation.

Methods: The sample of Luliconazole was authenticated using modern analytical techniques. The hydrogel- nail lacquer was prepared using poloxamer Pluronic F127. The formulation was evaluated in terms of drying time, viscosity, non- volatile content, pH, transition temperature, etc. In vitro study was done to check the drug release while determining release kinetics. In vitro transungual permeation study was done to check drug permeation through porcine hoof membrane. Stability studies were conducted to ensure formulation stability.

Results: The results confirmed a stable formulation with enhanced permeation through porcine hoof membrane.

Conclusion: The results support the potential use of in situ gelling thermo-sensitive hydrogels as a novel transungual formulation in the treatment of onychomycosis with a slight improvement in water resistance.

Keywords: Onychomycosis, nails, nail lacquer, hydrogel, aqueous, poloxamer, porcine hoof.

[1]
Baswan, S.; Kasting, G.B.; Li, S.K.; Wickett, R.; Adams, B.; Eurich, S.; Schamper, R. Understanding the formidable nail barrier: A review of the nail microstructure, composition and diseases. Mycoses, 2017, 60(5), 284-295.
[http://dx.doi.org/10.1111/myc.12592] [PMID: 28098391]
[2]
Scher, K.R.; Joseph, W.; Robbins, J. Progression and recurrence of onychomycosis; Medscape, 2016, pp. 1-11.
[3]
Singal, A.; Khanna, D. Onychomycosis: Diagnosis and management. Indian J. Dermatol. Venereol. Leprol., 2011, 77(6), 659-672.
[http://dx.doi.org/10.4103/0378-6323.86475] [PMID: 22016272]
[4]
Elsayed, M.M.A. Development of topical therapeutics for management of onychomycosis and other nail disorders: A pharmaceutical perspective. J. Control. Release, 2015, 199, 132-144.
[http://dx.doi.org/10.1016/j.jconrel.2014.11.017] [PMID: 25481439]
[5]
Campbell, A.W.; Anyanwu, E.C.; Morad, M. Evaluation of the drug treatment and persistence of onychomycosis. ScientificWorldJournal, 2004, 4, 760-777.
[http://dx.doi.org/10.1100/tsw.2004.134] [PMID: 15349516]
[6]
Campione, E.; Paternò, E.J.; Costanza, G.; Diluvio, L.; Carboni, I.; Marino, D.; Favalli, C.; Chimenti, S.; Bianchi, L.; Orlandi, A. Tazarotene as alternative topical treatment for onychomycosis. Drug Des. Devel. Ther., 2015, 9, 879-886.
[http://dx.doi.org/10.2147/DDDT.S69946] [PMID: 25733808]
[7]
Westerberg, D.P.; Voyack, M.J. Onychomycosis: Current trends in diagnosis and treatment. Am. Fam. Physician, 2013, 88(11), 762-770.
[PMID: 24364524]
[8]
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]
[9]
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]
[10]
McAuley, W.J.; Jones, S.A.; Traynor, M.J.; Guesné, S.; Murdan, S.; Brown, M.B. An investigation of how fungal infection influences drug penetration through onychomycosis patient’s nail plates. Eur. J. Pharm. Biopharm., 2016, 102, 178-184.
[http://dx.doi.org/10.1016/j.ejpb.2016.03.008] [PMID: 26969264]
[11]
Leelavathi, M.; Noorlaily, M. Onychomycosis nailed. Malays. Fam. Physician, 2014, 9(1), 2-7.
[PMID: 25606290]
[12]
Patel, M.M.; Vora, Z.M. Formulation development and optimization of transungual drug delivery system of terbinafine hydrochloride for the treatment of onychomycosis. Drug Deliv. Transl. Res., 2016, 6(3), 263-275.
[http://dx.doi.org/10.1007/s13346-016-0287-x] [PMID: 26926242]
[13]
Güngör, S.; Sedef Erdal, M.; Aksu, B. New Formulation Strategies in Topical Antifungal Therapy. J. Cosmet. Dermatological Sci. Appl., 2013, 3(January), 56-65.
[14]
Baran, R.; Kaoukhov, A. Topical antifungal drugs for the treatment of onychomycosis: An overview of current strategies for monotherapy and combination therapy. J. Eur. Acad. Dermatol. Venereol., 2005, 19(1), 21-29.
[http://dx.doi.org/10.1111/j.1468-3083.2004.00988.x] [PMID: 15649187]
[15]
Murdan, S. Drug delivery to the nail following topical application. Int. J. Pharm., 2002, 236(1-2), 1-26.
[http://dx.doi.org/10.1016/S0378-5173(01)00989-9] [PMID: 11891066]
[16]
Angelo, T.; Borgheti-cardoso, N.; Taveira, F.; Gratieri, T.; Gelfuso, M. Chemical and Physical Strategies in Onychomycosis Topical Treatment. RE:view, 2016, •••, 1-15.
[17]
Gupta, A.K.; Daigle, D.; Foley, K.A. Topical therapy for toenail onychomycosis: an evidence-based review. Am. J. Clin. Dermatol., 2014, 15(6), 489-502.
[http://dx.doi.org/10.1007/s40257-014-0096-2] [PMID: 25257931]
[18]
Farren, L.; Shayler, S.; Ennos, A.R. The fracture properties and mechanical design of human fingernails. J. Exp. Biol., 2004, 207(Pt 5), 735-741.
[http://dx.doi.org/10.1242/jeb.00814] [PMID: 14747405]
[19]
Brown, M.B.; Khengar, R.H.; Turner, R.B.; Forbes, B.; Traynor, M.J.; Evans, C.R.G.; 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]
[20]
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., 2015, 7544(October), 1-7.
[PMID: 26447337]
[21]
Lahfa, M; Bulai-Livideanu, C; Baran, R; Ortonne, JP; Richert, B; Tosti, A; Piraccini, BM; Szepietowski, JC; Sibaud, V; Coubetergues, H; Voisard, JJ; Efficacy, PC 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 E, 2013, 5-12.
[22]
Patil, P.S. B. S. and T. A. Nailing The Nail Trouble By Transungal Drug Delivery, 2015, 2(2), 551-571.
[23]
Pandhi, D.; Verma, P. Nail avulsion: indications and methods (surgical nail avulsion). Indian J. Dermatol. Venereol. Leprol., 2012, 78(3), 299-308. [Surgical Nail Avulsion
[http://dx.doi.org/10.4103/0378-6323.95444] [PMID: 22565429]
[24]
Ameen, M.; Lear, J. T.; Madan, V.; Mustapa, M. F. M.; Richardson, M. British Association of Dermatologists ’ Guidelines for the Management of Onychomycosis, 2014, 937-958.
[25]
Saner, M. V; Kulkarni, A. D.; Pardeshi, C. V. Insights into Drug Delivery across the Nail Plate Barrier, 2014. 2330(9), 769-789.
[http://dx.doi.org/10.3109/1061186X.2014.929138]
[26]
Kataria, P.; Sharma, G.; Thakur, K.; Bansal, V.; Dogra, S.; Katare, O.P. Emergence of nail lacquers as potential transungual delivery system in the management of onchomycosis. Expert Opin. Drug Deliv., 2016, 13(7), 937-952.
[http://dx.doi.org/10.1080/17425247.2016.1174691] [PMID: 27054394]
[27]
Joshi, M.; Sharma, V.; Pathak, K. Matrix based system of isotretinoin as nail lacquer to enhance transungal delivery across human nail plate. Int. J. Pharm., 2015, 478(1), 268-277.
[http://dx.doi.org/10.1016/j.ijpharm.2014.11.050] [PMID: 25445993]
[28]
Akhtar, N.; Sharma, H.; Pathak, K. Onychomycosis: Potential of Nail Lacquers in Transungual Delivery of Antifungals. Scientifica (Cairo), 2016.
[29]
Bhapkar, G.-P. H.; Puttewar, T. Y.; Patil, R. Y. opic Name – Nail Lacquers in Nail Diseases, 2013, 3(9), 24-48.
[30]
Singh, N.K.; Lee, D.S. In situ gelling pH- and temperature-sensitive biodegradable block copolymer hydrogels for drug delivery. J. Control. Release, 2014, 193, 214-227.
[http://dx.doi.org/10.1016/j.jconrel.2014.04.056] [PMID: 24815421]
[31]
Tomme, S.R. Van, ; Storm, G.; Hennink, W. E. In Situ Gelling Hydrogels for Pharmaceutical and Biomedical Applications; , 2008, pp. 1-8.
[32]
Fakhari, A.; Corcoran, M.; Schwarz, A. Thermogelling properties of purified poloxamer 407. Heliyon, 2017, 3(8)e00390
[http://dx.doi.org/10.1016/j.heliyon.2017.e00390] [PMID: 28920092]
[33]
Nnamani, P. O.; Kenechukwu, F. C.; Anugwolu, C. L.; Attama, A. A. Evaluation of Hydrogels Based on Poloxamer 407 and Polyacrylic Acids for Enhanced Topical Activity of Gentamicin against Susceptible Infections., 2014, 1385-1391.
[http://dx.doi.org/10.4314/tjpr.v13i9.2]
[34]
El-Houssieny, B.M.; Hamouda, H.M. Formulation and evaluation of clotrimazole from pluronic F127 gels. Drug Discov. Ther., 2010, 4(1), 33-43.
[PMID: 22491150]
[35]
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]
[36]
Shemer, A.; Nathansohn, N.; Trau, H.; Amichai, B.; Grunwald, M.H. Ciclopirox nail lacquer for the treatment of onychomycosis: An open non-comparative study. J. Dermatol., 2010, 37(2), 137-139.
[http://dx.doi.org/10.1111/j.1346-8138.2009.00773.x] [PMID: 20175847]
[37]
Kansagra, H.; Mallick, S. Microemulsion-Based Antifungal Gel of Luliconazole for Dermatophyte Infections: Formulation, Characterization and Efficacy Studies. J. Pharm. Investig., 2016, 46(1), 21-28.
[http://dx.doi.org/10.1007/s40005-015-0209-9]
[38]
Gunt, H.B.; Kasting, G.B. Effect of hydration on the permeation of ketoconazole through human nail plate in vitro. Eur. J. Pharm. Sci., 2007, 32(4-5), 254-260.
[http://dx.doi.org/10.1016/j.ejps.2007.07.009] [PMID: 17928205]
[39]
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]
[40]
Monti, D.; Saccomani, L.; Chetoni, P.; Burgalassi, S.; Senesi, S.; Ghelardi, E.; Mailland, F.; Monti, D. Hydrosoluble Medicated Nail Lacquers : In vitro; Drug Permeation and Corresponding Antimycotic Activity, 2010, pp. 311-317.
[41]
Nogueiras-nieto, L.; Alvarez-lorenzo, C.; Sandez-macho, I.; Concheiro, A.; Otero-espinar, F.J. A.; Otero-espinar; F. J. Hydrosoluble Cyclodextrin/Poloxamer Polypseudorotaxanes at the Air/Water Interface, in Bulk Solution, and in the Gel State, 2009, pp. 2773-2782.
[42]
Jm, P.; Kk, S.; Mm, P. Formulation and Evaluation of Temperature Dependent Ophthalmic Gel Forming Solution of Brimonidine Tartrate., 2012, 1(4), 1539-1548.
[43]
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]
[44]
Bhandwalkar, M.J.; Avachat, A.M. Thermoreversible nasal in situ gel of venlafaxine hydrochloride: formulation, characterization, and pharmacodynamic evaluation. AAPS PharmSciTech, 2013, 14(1), 101-110.
[http://dx.doi.org/10.1208/s12249-012-9893-1] [PMID: 23229381]
[45]
Desai, N.J.; Maheshwari, D.G. UV Spectrophotometric Method for the Estimation of Luliconazole in Marketed Formulation (Lotion). Pharma Sci. Monit. an Int. J. Pharm. Sci., 2014, 5(2), 48-54.
[46]
R, A. R.; Kurian, N. Formulation and Evaluation of Transungual Drug Delivery of Fluconazole Using Permeation Enhancers Screened by Hydration of Nail Plate. Res. Rev. J. Pharm. Sci., 2017, 8(3), 32-45.
[47]
Chandra, R.; Kumar, S.; Aggarwal, A. Evaluation of Nail Lacquer., 2012, 2(4), 379-382.
[48]
Dhiman, D.; Kumar, S.; Mittal, A.; Sciences, A. European Journal Of Formulation & Evaluation Of Medicated Nail Lacquer Of Fluconazole., 2016, 3(4), 266-270.
[49]
Bhise, K.; Jan, S.; Bora, D. Preungual Drug Delivery Systems of Terbinafine Hydrochloride Nail Lacquer. Asian J. Pharm., 2008, 2(1), 53.
[http://dx.doi.org/10.4103/0973-8398.41567]
[50]
Myoung, Y.; Choi, H.K. Permeation of ciclopirox across porcine hoof membrane: effect of pressure sensitive adhesives and vehicles. Eur. J. Pharm. Sci., 2003, 20(3), 319-325.
[http://dx.doi.org/10.1016/j.ejps.2003.07.001] [PMID: 14592697]
[51]
Kim, J.H.; Lee, C.H.; Choi, H.K. A method to measure the amount of drug penetrated across the nail plate. Pharm. Res., 2001, 18(10), 1468-1471.
[http://dx.doi.org/10.1023/A:1012265125158] [PMID: 11697474]
[52]
Warren, J.J.; Blanchette, D.; Dawson, D.V.; Teresa, A.; Phipps, K.R.; Starr, D.; Drake, D.R. Trans-Ungual Delivery of Itraconazole Hydrochloride by Iontophoresis., 2017, 44(2), 319-335.
[53]
Crawford, F.; Hollis, S. Topical Treatments for Fungal Infections of the Skin and Nails of the Foot. Cochrane Database Syst. Rev., 2007.
[http://dx.doi.org/10.1002/14651858.CD001434.pub2]
[54]
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]
[55]
Hui, X.; Lindahl, Å.; Lamel, S.; Maibach, H.I. Onychopharmacokinetics of Terbinafine Hydrochloride Penetration from a Novel Topical Formulation into the Human Nail in vitro. Drug Dev. Ind. Pharm., 2012, 2012(39), 1-7.
[PMID: 22873754]
[56]
Maeda, J.; Nanjoh, Y.; Koga, H.; Toga, T.; Makimura, K.; Tsuboi, R. [In vitro Antifungal Activity of Luliconazole against Trichophyton spp] Med. Mycol. J., 2016, 57(1), J1-J6.
[http://dx.doi.org/10.3314/mmj.57.J1] [PMID: 26936346]
[57]
Nidhi, K.; Indrajeet, S.; Khushboo, M.; Gauri, K.; Sen, D.J. Bilayered Nail Lacquer of Terbinafine Hydrochloride for Treatment of Onychomycosis. Int. J. Drug Dev. Res., 2011, 3(2), 26-33.


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VOLUME: 9
ISSUE: 4
Year: 2019
Page: [321 - 329]
Pages: 9
DOI: 10.2174/2210303109666190520081552
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