KETOCONAZOLE LADEN MICROEMULSION BASED GEL FORMULATION AGAINST SKIN FUNGAL INFECTION

PAYAL JAIN; REENA SONI; SURESH K. PASWAN; PRAKASH K. SONI

doi:10.22159/ijap.2023v15i3.47456

Authors

PAYAL JAIN Nanotechnology Research Lab, Department of Pharmacy, Shri G. S. Institute of Technology and Science, Indore 452003, (M. P.), India https://orcid.org/0009-0009-6788-3470
REENA SONI Nanotechnology Research Lab, Department of Pharmacy, Shri G. S. Institute of Technology and Science, Indore 452003, (M. P.), India
SURESH K. PASWAN Nanotechnology Research Lab, Department of Pharmacy, Shri G. S. Institute of Technology and Science, Indore 452003, (M. P.), India https://orcid.org/0000-0002-0030-0914
PRAKASH K. SONI Nanotechnology Research Lab, Department of Pharmacy, Shri G. S. Institute of Technology and Science, Indore 452003, (M. P.), India https://orcid.org/0000-0002-2202-3778

DOI:

https://doi.org/10.22159/ijap.2023v15i3.47456

Keywords:

Ketoconazole, Microemulsion, Pseudoternary phase diagram, D-optimal mixture design, Optimization, Topical gel, In vitro drug release, Ex-vivo permeation

Abstract

Objective: The present research was aimed to develop ketoconazole (KT) loaded microemulsion-based gel formulation for effective topical delivery through enhanced drug solubility, improved skin permeation and reduced side effects overcoming drawbacks of conventional dosage forms.

Methods: For the selection of oil, surfactant and co-surfactant mixture (S_mix) ratio, the phase titration method was used and pseudo-ternary phase diagrams were prepared. D-optimal mixture design was employed to optimize the microemulsion system taking oil, S_mix and water as independent variables and particle size, polydispersity index, zeta potential, % transmittance and cumulative % drug release as response variables. Finally, topical gel formulation of KT-loaded microemulsion was developed and evaluated for physico-chemical properties, rheological properties, in vitro drug release kinetics and ex-vivo drug permeation.

Results: The optimized microemulsion was found to be a transparent formulation with 19.7 nm particle size, 0.268 polydispersity index,-0.2 mV zeta potential, 97.83% transmittance and 85.85% cumulative drug release at 24 h. The developed gel of optimized microemulsion possessed pH 6.20, viscosity 2178 cps, spreadability 18.634 g.cm²/sec, adhesiveness 45.989 N/mm², and cohesiveness-85.583. The in vitro drug release was found to be 69.08 % (at 24 h), showing sustained release and Higuchi kinetic profile. The developed gel exhibited 1.84-fold higher drug permeation flux as compared to the marketed product.

Conclusion: The developed gel formulation possessed all desired quality attributes and physico-chemical properties. The in vitro and ex-vivo study data proved it’s suitability as a better alternative to conventional products in the effective treatment of fungal skin infections.

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References

Kaur IP, Kakkar S. Topical delivery of antifungal agents. Expert Opin Drug Deliv. 2010;7(11):1303-27. doi: 10.1517/17425247.2010.525230, PMID 20961206.

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. doi: 10.3810/pgm.2001.01.830, PMID 11198246.

Rezabek GH, Friedman AD. Superficial fungal infections of the skin. Diagnosis and current treatment recommendations. Drugs. 1992;43(5):674-82. doi: 10.2165/00003495-199243050-00004, PMID 1379146.

Vartak R, Menon S, Patki M, Billack B, Patel K. Ebselen nanoemulgel for the treatment of topical fungal infection. Eur J Pharm Sci. 2020;148:105323. doi: 10.1016/j.ejps.2020.105323, PMID 32259677.

Sharadha M, Gowda D, Vishal Gupta N, Akhila AR. An overview on topical drug delivery system–updated review. IJRPS 2020;11(1):368-85. doi: 10.26452/ijrps.v11i1.1831.

Ashara KC, Paun JS, Soniwala MM, Chavada JR, Mori NM. Micro-emulsion based emulgel: a novel topical drug delivery system. Asian Pac J Trop Dis. 2014;4:S27-32. doi: 10.1016/S2222-1808(14)60411-4.

Sharma N, Aggarwal G, Rana AC, Bhat Z, Kumar D. A review: transdermal drug delivery system: a tool for novel drug delivery system. Int J Drug Dev Res. 2011;3:70-84.

Kathe K, Kathpalia H. Film forming systems for topical and transdermal drug delivery. Asian J Pharm Sci. 2017;12(6):487-97. doi: 10.1016/j.ajps.2017.07.004, PMID 32104362.

Dudhipala N, Ay AA. Amelioration of ketoconazole in lipid nanoparticles for enhanced antifungal activity and bioavailability through oral administration for management of fungal infections. Chem Phys Lipids. 2020;232:104953. doi: 10.1016/j.chemphyslip.2020.104953, PMID 32814084.

Badawi AA, Sakran WS, Ramadan MA, El-Mancy SMS. Improvement of the microbiological activity of topical ketoconazole using microemulsion systems. J Drug Deliv Sci Technol. 2012;22(6):473-8. doi: 10.1016/S1773-2247(12)50083-3.

Date AA, Patravale VB. Microemulsions: applications in transdermal and dermal delivery. Crit Rev Ther Drug Carrier Syst. 2007;24(6):547-96. doi: 10.1615/critrevtherdrugcarriersyst.v24.i6.20, PMID 18298390.

Callender SP, Mathews JA, Kobernyk K, Wettig SD. Microemulsion utility in pharmaceuticals: implications for multi-drug delivery. Int J Pharm. 2017;526(1-2):425-42. doi: 10.1016/j.ijpharm.2017.05.005, PMID 28495500.

Egito EST, Amaral Machado L, Alencar EN, Oliveira AG. Microemulsion systems: from the design and architecture to the building of a new delivery system for multiple-route drug delivery. Drug Deliv Transl Res. 2021;11(5):2108-33. doi: 10.1007/s13346-020-00872-8, PMID 33164165.

Atanasova T, Kakalova M, Stefanof L, Petkova M, Stoyanova A, Damyanova S. Chemical composition of essential oil from rosa damascena mill., growing in new region of Bulgaria. Ukr Food J. 2016(5):492-8.

Pal PK. Evaluation, genetic diversity, recent development of distillation method, challenges and opportunities of rosa damascena: a review. J Essent Oil Bear. 2013;16(1):1-10.

Achuthan CR, Babu BH, Padikkala J. Antioxidant and hepatoprotective effects of Rosa damascena. Pharm Biol. 2003;41(5):357-61. doi: 10.1076/phbi.41.5.357.15945.

Tiwari N, Sivakumar A, Mukherjee A, Chandrasekaran N. Enhanced antifungal activity of ketoconazole using rose oil based novel microemulsion formulation. J Drug Deliv Sci Technol. 2018;47:434-44. doi: 10.1016/j.jddst.2018.07.007.

Nornoo AO, Osborne DW, Chow DS. Cremophor-free intravenous microemulsions for paclitaxel I: Formulation, cytotoxicity and hemolysis. Int J Pharm. 2008;349(1-2):108-16. doi: 10.1016/j.ijpharm.2007.07.042, PMID 17869459.

Shukla JB, Jani GK, Omri AW. Formulation and evaluation of oral self microemulsifying drug delivery system of candesartan cilexetil. Int J Pharm Pharm Sci. 2016;8(5):238-43.

Chouhan P, Saini TR. D-optimal design and development of microemulsion based transungual drug delivery formulation of ciclopirox olamine for treatment of onychomycosis. Indian J Pharm Sci. 2016;78(4):498-511. doi: 10.4172/pharmaceutical-sciences.1000145.

El-Malah Y, Nazzal S, Khanfar NM. D-Optimal mixture design: optimization of ternary matrix blends for controlled zero-order drug release from oral dosage forms. Drug Dev Ind Pharm. 2006;32(10):1207-18. doi: 10.1080/03639040600685167, PMID 17090443.

Singh PK, Iqubal MK, Shukla VK, Shuaib M. Microemulsions: current trends in novel drug delivery systems. Int J Pharm Chem Biol Sci. 2014;1(1):39-51.

Momoh MA, Franklin KC, Agbo CP, Ugwu CE, Adedokun MO, Anthony OC. Microemulsion-based approach for oral delivery of insulin: formulation design and characterization. Heliyon. 2020;6(3):e03650. doi: 10.1016/j.heliyon.2020.e03650, PMID 32258491.

Alam MS, Ali MD, Ansari MS, Sharma P. Inhibitory effects on tumor necrosis factor alpha and interleukin 12 using clobetasol propionate loaded tea tree oil nanoemulsion gel on animal model. Asian J Pharm Clin Res. 2018;11(6):182-5. doi: 10.22159/ajpcr.2018.v11i6.24888.

Kumar KJR, Muralidharan S, Dhanaraj SA. Antifungal activity of microemulsion based fluconazole gel for onychomycosis against Aspergillus niger. Int J Pharm Pharm Sci. 2012;5(1):96-102.

Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58(3):173-82. doi: 10.1016/j.biopha.2004.02.001, PMID 15082340.

Ujhelyi Z, Vecsernyes M, Feher P, Kosa D, Arany P, Nemes D. Physico-chemical characterization of self-emulsifying drug delivery systems. Drug Discov Today Technol. 2018;27:81-6. doi: 10.1016/j.ddtec.2018.06.005, PMID 30103867.

Gandhi J, Suthar D, Patel H, Shelat P, Parejiya P. Development and characterization of microemulsion based topical gel of essential oil of clove (Syzygium aromaticum) for superficial fungal infections. Adv Tradit Med (ADTM). 2021;21(3):519-34. doi: 10.1007/s13596-020-00462-6.

Patel HK, Barot BS, Parejiya PB, Shelat PK, Shukla A. Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo: ex vivo permeation and skin irritation studies. Colloids Surf B Biointerfaces. 2013;102:86-94. doi: 10.1016/j.colsurfb.2012.08.011, PMID 23000677.

Soni PK, Saini TR. Purification of drug loaded liposomal formulations by a novel stirred cell ultrafiltration technique. Pharm Nanotechnol. 2021;9(5):347-60. doi: 10.2174/2211738509666211124145848, PMID 34819014.

Wulansari A, Jufri M, Budianti A. Studies on the formulation, physical stability, and in vitro antibacterial activity of tea tree oil (Melaleuca alternifolia) nanoemulsion gel. Int J App Pharm. 2017;9(1):135-9. doi: 10.22159/ijap.2017.v9s1.73_80.

Jagdale S, Brahmane S, Chabukswar A. Optimization of microemulgel for tizanidine hydrochloride. Antiinflamm Antiallergy Agents Med Chem. 2020;19(2):158-79. doi: 10.2174/1871523018666190308123100, PMID 30854978.

Pande V, Patel S, Patil V, Sonawane R. Design expert assisted formulation of topical bioadhesive gel of sertaconazole nitrate. Adv Pharm Bull. 2014;4(2):121-30. doi: 10.5681/apb.2014.019, PMID 24511475.

Jamil L, Jan SU, Gul R. Formulation of microemulsion based gel of salbutamol sulphate and it’s in vitro studies. Int J Curr Pharm Sci. 2020:102-7. doi: 10.22159/ijcpr.2020v12i4.39093.

Mohammed WH, Ali WK, Al-Awady MJ Research. Evaluation of in vitro drug release kinetics and antibacterial activity of vancomycin HCl-loaded nanogel for topical application. J Pharm Sci. 2018;10(11):2747-56.

Soni PK, Saini TR. Formulation design and optimization of cationic-charged liposomes of brimonidine tartrate for effective ocular drug delivery by design of experiment (DoE) approach. Drug Dev Ind Pharm. 2021;47(11):1847-66. doi: 10.1080/03639045.2022.2070198, PMID 35484943.

Shinde UA, Modani SH, Singh KH. Design and development of repaglinide microemulsion gel for transdermal delivery. AAPS PharmSciTech. 2018;19(1):315-25. doi: 10.1208/s12249-017-0811-4, PMID 28717973.

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. doi: 10.1208/s12249-011-9742-7, PMID 22187363.

Kumar N, Shishu. D-optimal experimental approach for designing topical microemulsion of itraconazole: characterization and evaluation of antifungal efficacy against a standardized tinea pedis infection model in wistar rats. Eur J Pharm Sci. 2015;67:97-112. doi: 10.1016/j.ejps.2014.10.014, PMID 25445834.

Kale SN, Deore SL. Emulsion micro emulsion and nano emulsion: a review. Syst Rev Pharm. 2016;8(1):39-47. doi: 10.5530/srp.2017.1.8.

Urmaliya H, Gupta M, Agrawal A, Jain NK, Dubey A. Formulation development and evaluation of microemulsion gel of ketoconazole as an antifungal agent. Int J Pharm Sci. 2016;2:120-30.