pharmaceutics Article Preparation of Topical Itraconazole with Enhanced Skin/Nail Permeability and In Vivo Antifungal Efficacy against Superficial Mycosis Laxman Subedi 1,† , Seung-Yub Song 1,† , Saurav Kumar Jha 1 , Sung-Ho Lee 1 , Rudra Pangeni 2 , Kyo-Tan Koo 3 , Beum Joon Kim 4 , Seung-Sik Cho 1,2, * and Jin Woo Park 1,2, *   Citation: Subedi, L.; Song, S.-Y.; Jha, S.K.; Lee, S.-H.; Pangeni, R.; Koo, K.-T.; Kim, B.J.; Cho, S.-S.; Park, J.W. Preparation of Topical Itraconazole with Enhanced Skin/Nail Permeability and In Vivo Antifungal Efficacy against Superficial Mycosis. Pharmaceutics 2021, 13, 622. https://doi.org/10.3390/ pharmaceutics13050622 Academic Editors: Marcel Popa and Anca Niculina Cadinoiu Received: 2 April 2021 Accepted: 26 April 2021 Published: 27 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Korea; laxmansubedi789@gmail.com (L.S.); tgb1007@naver.com (S.-Y.S.); saurav.balhi@gmail.com (S.K.J.); tjdgh0730@naver.com (S.-H.L.) 2 Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea; capriconpangeni@gmail.com 3 BioBelief Co., Ltd., Seoul 05841, Korea; kyotankoo@gmail.com 4 Department of Dermatology, Chung-Ang University College of Medicine, Seoul 06973, Korea; beomjoon74@gmail.com * Correspondence: sjason1@naver.com (S.-S.C.); jwpark@mokpo.ac.kr (J.W.P.); Tel.: +82-61-450-2687 (S.-S.C.); +82-61-450-2704 (J.W.P.) † These authors contributed equally to this work. Abstract: In this study, a stable and highly skin-permeable topical delivery system for itraconazole (ITZ) was designed to provide effective treatment against superficial mycosis. Herein, ITZ was incorporated into a solution composed of ethanol, benzyl alcohol, hydrochloric acid, Transcutol P, and cyclomethicone as a delivery vehicle, solubilizer, protonating agent, permeation enhancer, and spreading agent, respectively. At 72 h, the optimal topical ITZ formulation (ITZ–TF#11) exhibited 135% enhanced skin permeability, which led to increases in drug deposition in the stratum corneum, epidermis, and dermis of 479%, 739%, and 2024%, respectively, compared with the deposition of 1% ITZ in ethanol (control). Moreover, on day 7, ITZ–TF#11 demonstrated 2.09- and 2.30-fold enhanced nail flux and drug deposition, compared with the control. At a dose of 40 mg/kg/day, ITZ–TF#11 showed 323% greater lesion recovery, a 165% lower mean erythema severity score, and a 37% lower mean logarithm of viable fungal cells in skin in the treated area, compared with mice that received oral ITZ at the same dose. Overall, the findings imply that ITZ–TF#11 is a superior alternative to oral ITZ for treatment of superficial mycosis. Keywords: itraconazole; topical solution; superficial mycosis; skin penetration; nail infiltration; antifungal activity 1. Introduction Superficial mycosis is a fungal disease that is mostly confined to outer layers of skin, nail, or hair but may invade deeper tissue. This disease is common worldwide [1]. Moreover, mycosis has been reported to negatively impact host psychological and psy- chosocial factors and reduce quality of life [2]. Various types of wide-spectrum antifungal azoles (e.g., efinaconazole [EFN], fluconazole, ketoconazole, voriconazole, and itraconazole [ITZ]) are available for use in mycosis treatment. Importantly, azole groups interfere with the synthesis of ergosterol, an essential fungal membrane component, by blocking 14-α demethylase (a cytochrome P-450 enzyme). In addition, the selectivity of azole groups toward the cytochrome P-450 enzymes of fungi, rather than mammals, enables highly specific antifungal action with comparatively minimal side effects, relative to other antifun- gal treatments [3]. Among several azole-based antifungal agents, 2-butan-2-yl-4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy] phenyl]- 1-piperazinyl] phenyl]-1,2,4-triazol-3-one (ITZ) has strong keratinophilic and lipophilic Pharmaceutics 2021, 13, 622. https://doi.org/10.3390/pharmaceutics13050622 https://www.mdpi.com/journal/pharmaceutics