Development and optimization of itraconazole-loaded topical gel using DESM technique

Abstract

Deep eutectic solvent mixtures (DESM) are often less hazardous to human health, simpler to make, and cheaper than ionic liquids (ILs). Because of these benefits, there has been a recent uptick in the number of uses for DESM, such as using it as a solvent in a variety of different separation procedures. Itraconazole (ICZ) was classified as a BCS-II medication. DESM technique was used to enhance the solubility of the drug by reducing the crystallinity region of the drug molecule. In different molar ratios Drugs, carboxylic acid, and choline chloride were used. From the carboxylic acid urea showed the best solubility profile. So it was chosen for fabricating the topical gel formulations. The prepared gel exhibits a pH nearly equal to the skin pH. Increasing the carbopol amount increases the viscosity and decreases the spreadability. From the FTIR analysis, it was found that ICZ peaks were preserved in the formulations, and no extra peak suggested the absence of interaction between the drug and excipients. In the release study, it was found that the release of the drug was sustained by increases in the carbopol. Release kinetics showed the drug was released from the gel by both fickian and non-fickian mechanisms. From the docking study, it has been established that ICZ has a strong binding affinity towards candida pepsin-2 (-9.3Kcal/mol). From the above finding, it was established that the Development and optimization of itraconazole-loaded topical gel using DESM Technique was successfully prepared. In gist, it can be concluded that ICZ-based topical gel can be used against the fungal infection.

Keywords

• DESM technique
• itraconazole
• fungal infection
• carboxylic acids
• sustained drug release

References

1. [1] Alomrani AH, Al-Agamy MH, Badran MM. In vitro skin penetration and antimycotic activity of itraconazole loaded niosomes: Various non-ionic surfactants. J Drug Deliv Sci Technol. 2015; 28(8): 37-45. https://doi.org/10.1016/j.jddst.2015.04.009.
2. [2] Giri Y, Behera A, Mohanty B, Pattnaik G, Habibullah SK. Transungual drug delivery system for the topical treatment of onychomycosis: a review. Drug Deliv Lett. 2022; 12(1): 2-18. https://doi.org/10.2174/2210303112666220224110100.
3. [3] Kolimi P, Youssef AA, Narala S, Nyavanandi D, Dudhipala N, Bandari S, Repka MA. Development and characterization of itraconazole non-aqueous creams for the treatment of topical fungal infections. J Drug Deliv Sci Technol. 2022; 76(10): 103818. https://doi.org/10.1016/j.jddst.2022.103818.
4. [4] Ho HN, Le TG, Dao TT, Le TH, Dinh TT, Nguyen DH, Tran TC, Nguyen CN. Development of itraconazole-loaded polymeric nanoparticle dermal gel for enhanced antifungal efficacy. J Nanomater. 2020; 2020: 8894541. https://doi.org/10.1155/2020/8894541.
5. [5] Nesseem DI. Formulation and evaluation of itraconazole via liquid crystal for topical delivery system. J Pharm Biomed Anal. 2001; 26(3): 387-399. https://doi.org/10.1016/S0731-7085(01)00414-9.
6. [6] Vasilev NA, Surov AO, Voronin AP, Drozd KV, Perlovich GL. Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility. Int J Pharm. 2021; 599(4): 120441. https://doi.org/10.1016/j.ijpharm.2021.120441.
7. [7] Alhadid A, Mokrushina L, Minceva M. Design of deep eutectic systems: a simple approach for preselecting eutectic mixture constituents. Molecules. 2020; 25(5): 1077. https://doi.org/10.3390/molecules25051077.
8. [8] Bezold F, Minceva M. A water-free solvent system containing an L-menthol-based deep eutectic solvent for centrifugal partition chromatography applications. J Chromatogr A. 2019; 1587: 166-171. https://doi.org/10.1016/j.chroma.2018.11.083.

9. [9] Khandelwal S, Tailor YK, Kumar M. Deep eutectic solvents (DESs) as eco-friendly and sustainable solvent/catalyst systems in organic transformations. J Mol Liq. 2016; 215(3): 345-386. https://doi.org/10.1016/j.molliq.2015.12.015
10. [10] Hansen BB, Spittle S, Chen B, Poe D, Zhang Y, Klein JM, Horton A, Adhikari L, Zelovich T, Doherty BW, Gurkan B. Deep eutectic solvents: A review of fundamentals and applications. Chem Rev. 2020; 121(3): 1232-1285. https://doi.org/10.1021/acs.chemrev.0c00385
11. [11] Pätzold M, Siebenhaller S, Kara S, Liese A, Syldatk C, Holtmann D. Deep eutectic solvents as efficient solvents in biocatalysis. Trends Biotechnol. 2019; 37(9): 943-959. https://doi.org/10.1016/j.tibtech.2019.03.007.
12. [12] Oh Y, Park S, Yoo E, Jo S, Hong J, Kim HJ, Kim KJ, Oh KK, Lee SH. Dihydrogen-bonding deep eutectic solvents as reaction media for lipase-catalyzed transesterification. Biochem Eng J. 2019; 142: 34-40. https://doi.org/10.1016/j.bej.2018.11.010.
13. [13] Jablonský M, Škulcová A, Šima J. Use of deep eutectic solvents in polymer chemistry–a review. Molecules. 2019; 24(21): 3978. https://doi.org/10.3390/molecules24213978
14. [14] Roda A, Matias AA, Paiva A, Duarte AR. Polymer science and engineering using deep eutectic solvents. Polymers. 2019; 11(5): 912. https://doi.org/10.3390/polym11050912
15. [15] Aroso IM, Silva JC, Mano F, Ferreira AS, Dionísio M, Sá-Nogueira I, Barreiros S, Reis RL, Paiva A, Duarte AR. Dissolution enhancement of active pharmaceutical ingredients by therapeutic deep eutectic systems. Eur J Pharm Biopharm. 2016; 98: 57-66. https://doi.org/10.1016/j.ejpb.2015.11.002.
16. [16] Swain R, Moharana A, Habibullah S, Nandi S, Bose A, Mohapatra S, Mallick S. Ocular delivery of felodipine for the management of intraocular pressure and inflammation: Effect of film plasticizer and in vitro in vivo evaluation. Int J Pharm. 2023; 642: 123153. https://doi.org/10.1016/j.ijpharm.2023.123153.
17. [17] Feng P, Luo Y, Ke C, Qiu H, Wang W, Zhu Y, Hou R, Xu L, Wu S. Chitosan-based functional materials for skin wound repair: Mechanisms and applications. Front Bioeng Biotechnol. 2021; 9: 650598. https://doi.org/10.3389/fbioe.2021.650598.
18. [18] Alhowyan AA, Altamimi MA, Kalam MA, Khan AA, Badran M, Binkhathlan Z, Alkholief M, Alshamsan A. Antifungal efficacy of Itraconazole loaded PLGA-nanoparticles stabilized by vitamin-E TPGS: In vitro and ex vivo studies. J Microbiol Methods. 2019; 161: 87-95. https://doi.org/10.1016/j.mimet.2019.01.020.
19. [19] Yousaf R, Khan MI, Akhtar MF, Madni A, Sohail MF, Saleem A, Irshad K, Sharif A, Rana M. Development and in vitro evaluation of chitosan and glyceryl monostearate based matrix lipid polymer hybrid nanoparticles (LPHNPs) for oral delivery of itraconazole. Heliyon. 2023; 9(3): 14281. https://doi.org/10.1016/j.heliyon.2023.e14281.
20. [20] Machado Cruz R, Boleslavská T, Beránek J, Tieger E, Twamley B, Santos-Martinez MJ, Dammer O, Tajber L. Identification and pharmaceutical characterization of a new itraconazole terephthalic acid cocrystal. Pharmaceutics. 2020; 12(8) :741. https://doi.org/10.3390/pharmaceutics12080741
21. [21] Rawooth M, Habibullah SK, Qureshi D, Bharti D, Pal A, Mohanty B, Jarzębski M, Smułek W, Pal K. Effect of tamarind gum on the properties of phase-separated poly (vinyl alcohol) films. Polymers (Basel). 2022; 14(14): 2793. https://doi.org/10.3390/polym14142793.
22. [22] Swain R, Nandi S, Sahoo RN, Swain SS, Mohapatra S, Mallick S. Bentonite clay incorporated topical film formulation for delivery of trimetazidine: Control of ocular pressure and in vitro-in vivo correlation. J Drug Deliv Sci Technol. 2022; 67(1): 102956. https://doi.org/10.1016/j.jddst.2021.102956.
23. [23] Giri Y, Habibullah S, Dixit PK, Mahalik G, Mohanty B, Behera A. Development of microemulgel formulations with varied permeation enhancers for transungual delivery of luliconazole in onychomycosis management. Colloid Surface B. 2024; 234(2): 113718. https://doi.org/10.1016/j.colsurfb.2023.113718.
24. [24] Behera KP, Qureshi D, Mohanty B, Habibullah SK, Anis A, Shaikh H, Sarkar P, Verma S, Pal K. Bentonite increases the corneal permeation of the drug from the tamarind gum hydrogels. InFood, Medical, and Environmental Applications of Polysaccharides. Elsevier publishers, 2021 pp. 291-322.
25. [25] Babu A, Sivakumar G, Das A, Bharti D, Qureshi D, Habibullah SK, Satheesan A, Mohanty B, Pal K, Maji S. Preparation and characterization of novel oleogels using jasmine floral wax and wheat germ oil for oral delivery of curcumin. ACS Omega. 2022; 7(34): 30125-30136. https://doi.org/10.1021/acsomega.2c03201.
26. [26] Suman DK, Qureshi D, Behera H, Mallick SP, Habibullah SK, Mohanty B, Maji S, Anis A, Pal K. Gelatin and rice starch-based phase-separated hydrogel formulations for controlled drug delivery applications. InFood, Medical, and Environmental Applications of Polysaccharides. Elsevier publishers, 2021 pp. 263-289.