Research Article Design and Optimization of Cationic Nanocapsules for Topical Delivery of Tretinoin: Application of the Box-Behnken Design, In Vitro Evaluation, and Ex Vivo Skin Deposition Study Saeed Ebrahimi , 1,2 Reza Mahjub , 1,2 Rasool Haddadi , 3 and Seyed Yaser Vafaei 1,2 1 Department of Pharmaceutics, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran 2 Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran 3 Department of Toxicology and Pharmacology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran Correspondence should be addressed to Seyed Yaser Vafaei; y.vafaei@umsha.ac.ir Received 3 August 2021; Revised 16 October 2021; Accepted 10 November 2021; Published 12 December 2021 Academic Editor: Javed Ali Copyright © 2021 Saeed Ebrahimi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cationic nanocapsules represent a promising approach for topical delivery purposes. We elaborated on a novel formulation based on the cationic nanocapsules to enhance the pharmacodynamic efficacy, user compliance, and photostability of tretinoin (TTN). To achieve this goal, TTN nanocapsules were prepared by the nanoprecipitation method. In order to statistically optimize formulation variables, a Box-Behnken design, using Design-Expert software, was employed. Three independent variables were evaluated: total weight of the cationic acrylic polymer (X 1 ), oil volume (X 2 ), and TTN amount (X 3 ). The particle size and encapsulation efficiency percent (EE%) were selected as dependent variables. The optimal formulation demonstrated spherical morphology under scanning electron microscopy (SEM), optimum particle size of 116.3 nm, and high EE% of 83.2%. TTN- loaded nanocapsules improved photostability compared to its methanolic solution. The in vitro release study data showed that tretinoin was released in a sustained manner compared to the free drug. The ex vivo skin permeation study demonstrated that greater drug deposition into the epidermal region rather than the deep skin was observed with a gel containing TTN-loaded nanocapsules than that of drug solution, respectively. The skin irritation test revealed that the nanoencapsulation of the drug decreased its irritancy compared to the free drug. These results revealed the promising potential of cationic nanocapsules for topical delivery of tretinoin 1. Introduction Tretinoin (TTN) is a first-generation retinoid with keratolytic and anti-inflammatory activities which is used topically in the treatment of various dermatological diseases such as photoag- ing, acne, and psoriasis [1–3]. However, its use is strongly limited due to several disadvantages such as poor aqueous solubility, physicochemical instability, and topical adverse effects such as skin irritation, dryness, and scaling [4, 5]. Encapsulation of tretinoin with various delivery systems such as solid lipid nanoparticles [6, 7], liposomes [8], and niosomes [9, 10] has been proposed to help improve its sta- bility, solubility, and efficiency. However, most reported sys- tems showed only a limited improvement in the tretinoin loading ability and efficacy [11]. Therefore, the development of a carrier system with better efficacy and fewer side effects for tretinoin is still needed. Polymeric nanoparticles have been considered promis- ing carriers for cutaneous use [12]. The main advantages of these colloidal suspensions are improvement in the protec- tion of the loaded active ingredient against physicochemical degradation as well as controlled release of drugs for a homogenous release [13, 14]. Nanocapsules are specific polymeric nanoparticles with a core-shell organization in which the polymeric wall surrounds an oily core [15]. These nanocapsules have important advantages, such as higher drug loading capacity and improved ability to protect the encapsulated drug from degradation [15, 16]. Moreover, they exhibit slow and sustained release of incorporated drugs which makes them suitable for cutaneous applications [17]. Hindawi BioMed Research International Volume 2021, Article ID 4603545, 13 pages https://doi.org/10.1155/2021/4603545