pharmaceutics Article Topical Nanoemulgel for the Treatment of Skin Cancer: Proof-of-Technology Sreeharsha Nagaraja 1,2, * , Girish Meravanige Basavarajappa 3 , Mahesh Attimarad 1 and Swati Pund 4   Citation: Nagaraja, S.; Basavarajappa, G.M.; Attimarad, M.; Pund, S. Topical Nanoemulgel for the Treatment of Skin Cancer: Proof- of-Technology. Pharmaceutics 2021, 13, 902. https://doi.org/10.3390/ pharmaceutics13060902 Academic Editors: Daniele Ribeiro de Araujo and Cristina Padula Received: 13 May 2021 Accepted: 12 June 2021 Published: 18 June 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 Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Hofuf, Al-Ahsa 31982, Saudi Arabia; mattimarad@kfu.edu.sa 2 Department of Pharmaceutics, Vidya Siri College of Pharmacy, Off Sarjapura Road, Bangalore 560035, Karnataka, India 3 Department of Biomedical Sciences, College of Medicine, King Faisal University, Al-Hofuf, Al-Ahsa 31982, Saudi Arabia; gmeravanige@kfu.edu.sa 4 Nanomedicine Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology-Bombay, Mumbai 400076, Maharashtra, India; swatipund@iitb.ac.in * Correspondence: sharsha@kfu.edu.sa; Tel.: +966-55485322 Abstract: The present study is a mechanistic validation of ‘proof-of-technology’ for the effective topical delivery of chrysin nanoemulgel for localized, efficient treatment of melanoma-affected skin. Background: Currently available treatments for skin cancer are inefficient due to systemic side effects and poor transcutaneous permeation, thereby presenting a formidable challenge for the development of novel nanocarriers. Methods: We opted for a novel approach and formulated a nanocomplex system composed of hydrophobic chrysin dissolved in a lipid mix, which was further nanoemulsified in Pluronic ® F-127 gel to enhance physicochemical and biopharmaceutic characteristics. Chrysin, a flavone extracted from passion flowers, exhibits potential anti-cancer activities; however, it has limited applicability due to its poor solubility. Pseudo-ternary phase diagrams were constructed to identify the best self-nanoemulsifying region by varying the compo- sitions of oil, Caproyl ® 90 surfactant, Tween ® 80, and co-solvent Transcutol ® HP. Chrysin-loaded nanoemulsifying compositions were characterized for various physicochemical properties. Results: This thermodynamically stable, self-emulsifying drug delivery system showed a mean droplet size of 156.9 nm, polydispersity index of 0.26, and viscosity of 9100 cps after dispersion in gel. Mechanical characterization using Texture Analyzer exhibited that the gel had a hardness of 487 g and adhesive- ness of 500 g. Ex vivo permeation through rat abdominal skin revealed significant improvement in percutaneous absorption measured as flux, the apparent permeability coefficient, the steady-state diffusion coefficient, and drug deposition. In vitro cytotoxicity on A375 and SK-MEL-2 cell lines showed a significantly improved therapeutic effect, thus ensuring reduction in dose. The safety of the product was established through biocompatibility testing on the L929 cell line. Conclusion: Aqueous, gel-based, topical, nanoemulsified chrysin is a promising technology approach for effective localized transcutaneous delivery that will help reduce the frequency and overall dose usage and ultimately improve the therapeutic index. Keywords: self-emulsifying; chrysin; ex vivo permeation; nanoemulgel; in vitro cytotoxicity; ex vivo permeation 1. Introduction The oral route is the most preferred route of drug delivery for the treatment of chronic diseases [1]. However, oral delivery of almost 50% of drugs is hampered because of high lipophilicity [2]. Nearly 40% of new drug candidates exhibit low solubility in water, which often leads to poor oral bioavailability and lack of dose proportionality [3]. The topical route for the management of skin disorders offers several advantages over the oral route and has tremendous potential for successful drug delivery. Nevertheless, the penetration Pharmaceutics 2021, 13, 902. https://doi.org/10.3390/pharmaceutics13060902 https://www.mdpi.com/journal/pharmaceutics