*Article* **Ethyl Cellulose and Hydroxypropyl Methyl Cellulose Blended Methotrexate-Loaded Transdermal Patches: In Vitro and Ex Vivo**

**Muhammad Shahid Latif 1,†, Abul Kalam Azad 2,\*,† , Asif Nawaz <sup>1</sup> , Sheikh Abdur Rashid <sup>1</sup> , Md. Habibur Rahman <sup>3</sup> , Suliman Y. Al Omar <sup>4</sup> , Simona G. Bungau <sup>5</sup> , Lotfi Aleya <sup>6</sup> and Mohamed M. Abdel-Daim 7,\***


**Abstract:** Transdermal drug delivery systems (TDDSs) have become innovative, fascinating drug delivery methods intended for skin application to achieve systemic effects. TDDSs overcome the drawbacks associated with oral and parenteral routes of drug administration. The current investigation aimed to design, evaluate and optimize methotrexate (MTX)-loaded transdermal-type patches having ethyl cellulose (EC) and hydroxypropyl methyl cellulose (HPMC) at different concentrations for the local management of psoriasis. In vitro release and ex vivo permeation studies were carried out for the formulated patches. Various formulations (F1–F9) were developed using different concentrations of HPMC and EC. The F1 formulation having a 1:1 polymer concentration ratio served as the control formulation. ATR–FTIR analysis was performed to study drug–polymer interactions, and it was found that the drug and polymers were compatible with each other. The formulated patches were further investigated for their physicochemical parameters, in vitro release and ex vivo diffusion characteristics. Different parameters, such as surface pH, physical appearance, thickness, weight uniformity, percent moisture absorption, percent moisture loss, folding endurance, skin irritation, stability and drug content uniformity, were studied. From the hydrophilic mixture, it was observed that viscosity has a direct influence on drug release. Among all formulated patches, the F5 formulation exhibited 82.71% drug release in a sustained-release fashion and followed an anomalous non-Fickian diffusion. The permeation data of the F5 formulation exhibited about a 36.55% cumulative amount of percent drug permeated. The skin showed high retention for the F5 formulation (15.1%). The stability study indicated that all prepared formulations had very good stability for a period of 180 days. Therefore, it was concluded from the present study that methotrexate-loaded transdermal patches with EC and HPMC as polymers at different concentrations suit TDDSs ideally and improve patient compliance for the local management of psoriasis.

**Keywords:** transdermal drug delivery system (TDDS); hydroxypropyl methyl cellulose (HPMC); ethyl cellulose (EC); methotrexate; patches

**Citation:** Latif, M.S.; Azad, A.K.; Nawaz, A.; Rashid, S.A.; Rahman, M.H.; Al Omar, S.Y.; Bungau, S.G.; Aleya, L.; Abdel-Daim, M.M. Ethyl Cellulose and Hydroxypropyl Methyl Cellulose Blended Methotrexate-Loaded Transdermal Patches: In Vitro and Ex Vivo. *Polymers* **2021**, *13*, 3455. https://doi.org/10.3390/ polym13203455

Academic Editors: Ariana Hudita and Bianca Galˇ a¸ˇteanu

Received: 15 September 2021 Accepted: 4 October 2021 Published: 9 October 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**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. Introduction**

Psoriasis is a chronic inflammatory disease affecting about 1–3% of the world's population [1]. This lifelong disease has an equal gender distribution, and its incidence rate may vary from 50 to 140 new cases per 100,000 cases per year [2]. Its mortality risk is increased exponentially in terms of severe psoriasis when compared to the general population, even though it is usually not life threatening [3]. Psoriasis leads to decreased patient quality of life due to its link with high levels of morbidity and ailment. The management protocols of psoriasis vary depending upon the severity index of the disease [4].

Topical agents constitute first-line therapy, typically sufficient for active management of the disease to combat mild to moderate types of psoriasis [5]. Phototherapy and systemic management are crucial to consider when either suboptimal effects arise from topical therapies or when the intensity of the psoriasis limits the use of topical agents [6]. Currently available systemic tools comprise biological and nonbiological therapies, which are utilized as monotherapy or in combination with other modalities to manage moderate to severe psoriasis [7].

Methotrexate, orally administered retinoid, and cyclosporine represent prominent nonbiological systemic agents. Methotrexate administered via oral and parenteral routes presents an excellent therapeutic strategy to treat psoriasis owing to its epidermal cell proliferation inhibition, as well as anti-inflammatory actions at low doses [8]. However, a large number of reported toxicities due to methotrexate systemic administration, such as liver impairment, and gastric side effects, including diarrhea vomiting and stomatitis, appear [9]. Methotrexate is a folate antagonist, and it displays prominent antineoplastic activity, as well as having a use for psoriasis management [10]. It competitively inhibits the enzyme dihydrofolate reductase, leading to DNA inhibition synthesis. Methotrexate, when delivered to the psoriatic site by means of transdermal drug delivery, has the potential to reduce side effects associated with this drug and avoid first-pass metabolism [11]. A major problem with methotrexate is that the drug is hydrosoluble and available in ionized form at physiological pH (7.4), leading to limited capacity for passive diffusion [12].

To minimize the likelihood of side effects, as well as skin permeation, and to maintain a therapeutic concentration in the target tissues, numerous approaches have been proposed, such as liposomes, polymeric nanoparticles, microspheres, solid lipid nanoparticles, nanoemulsions and nanoemulsion gel and patch formulations [13]. However, transdermal patches offer numerous advantages in terms of ease of preparation, high loading capacity for hydrophilic and lipophilic drugs and long-term stability with improved dermal delivery [14]. A transdermal patch is used to deliver a specific dose of medication through the skin and into the bloodstream. Transdermal delivery provides controlled, consistent drug administration and produces continuous drug input. It has a short biological half-life and eliminates pulsed entry into the systemic circulation [15]. It is convenient and especially evident in patches that require application only once a week. Such a simple dosing regimen could enhance patient compliance with drug therapy [16].

Polymers are widely used in modern pharmaceutical technologies, and they play a vital role in drug delivery advancements. Polymers act as carriers in targeted therapies and offer controlled drug delivery while reducing the bitter taste of drugs [17]. Hydroxypropyl methylcellulose (HPMC) is a derivative of cellulose of hydrophilic nature [18]. It is widely used in controlled-release formulations due to its swelling, gelling and thickening properties. Furthermore, HPMC is nontoxic in nature, and its swelling and easy compression properties make it convenient for use in the preparation of controlled drug delivery systems [19].

Ethylcellulose (EC) is a derivative of cellulose of hydrophobic nature. It is a white to light free-flowing powder used widely in the manufacturing of controlled drug delivery systems. EC has very limited side effects; hence, it is considered safe to employ in tablets, oral capsules, ocular or vaginal preparations and topical preparations [20]. EC is an inert, hydrophobic polymer that exhibits certain properties such as good stability during storage, lack of toxicities and good compressibility, which are suitable for designing controlled drug delivery systems [21].

This study was undertaken to develop methotrexate-loaded matrix-type patches by employing a combination of hydrophilic and hydrophobic polymers, hydroxypropyl methylcellulose (HPMC) and ethyl cellulose (EC), for the pertinent and effective dermal treatment of psoriasis, with improved cutaneous deposition of methotrexate to enhance its local effect. The success associated with methotrexate through dermal application via patch formulations could also be represented by increased patient compliance due to the topical administration of therapeutic substances, representing a less invasive and more comfortable and convenient route of administration.
