Bilayer chitosan-based patches for steroidal drug delivery on the oral mucosa

Clobetasol-17-proprionate (CP) is the most potent, highly lipophilic topical corticosteroid, used for the treatment of immune-mediated muco-cutaneous diseases. No commercial preparations are available for oral cavity and galenic formulations are often ineffective due to the easy displacement by saliva and muscular movements. Here, we developed and characterized a novel mucoadhesive patches for CP delivery on the oral mucosa. Bilayer chitosan (CS)-based mucoadhesive patches (CS-CP) were produced via electrophoretic deposition (EPD), and characterized for physical and biological properties. Bilayer CS-CP patches showed a porous structure at the surface towards the oral mucosa (containing CP) and a more compact occlusive backing layer (without CP). CS-CP patches displayed fast swelling (301.6 ± 0.8%) in PBS, while a sustained CP release was observed over time, both in vitro in PBS and using an ex vivo model of porcine oral mucosa, with about 40% of CP released after 6 h. CP did not affect the mucoadhesive properties of the patches. Through a 3D model of the oral mucosa, the patches’ cytocompatibility and the activity of CP released in regulating immune response-related pathways were evaluated. CS-based patches represent innovative biocompatible biomedical devices for the oral mucosa, able of successfully loading highly lipophilic drugs, including CP.

Highlights

• Highly lipophilic clobetasol proprionate (CP) is successfully loaded on chitosan-based patches via electrophoretic deposition (EPD)
• Bilayer chitosan-based patches are promising mucoadhesive delivery systems for the oral cavity
• The presence of CP does not affect the mucoadhesive properties of chitosan-based patches
• CP, after the release from patches, maintains its biological immunosuppressive activity

Introduction

Immune-mediated and autoimmune diseases involving the oral mucosa, such as recurrent aphthous stomatitis (RAS), oral lichen planus (OLP), membrane mucous pemphigoid and pemphigus vulgaris, are often associated with painful intraoral ulcers, which can impair the patient oral functions, reducing the quality of life and sociability [1].

Being the etiopathogenesis still largely unknown, all these conditions require only symptomatic treatments, and current management includes the use of immune-modulating drugs, particularly, topical steroids that are the standard of care, aiming at reducing, locally, the chronic inflammation and the exaggerated immune response [2]. Among topical steroids, clobetasol-17-propionate (CP) represents the most potent corticosteroids (Europe: class IV) on the market, available only in form of creams and ointments for dermatological topical application, due to its high lipophilicity. However, literature supports that CP is also effective for the local treatment of oral immune-mediated and autoimmune diseases [3], [4], despite the absence of a standard formulation suitable for the oral cavity. To date, galenic formulations at 0.05% (w/w) of CP in 4% hydroxyethylcellulose gel are usually prescribed to treat oral lesions, although showing poor mucoadhesive properties with an easy displacement of the drug and a reduced clinical effectiveness. The clinical success is affected by the difficult application of the drug on the oral mucosa, which is particularly challenging due to the salivary flow, having washing effects, and to the muscular activity, which mechanically displaces the drug during phonation and swallowing [5]. Moreover, the very high lipophilicity of CP can further decrease the drug-to-mucosa contact time, while increasing the unpredictability of drug local distribution, being the oral environment highly hydrophilic, instead. Strategies to improve the CP local effect, by increasing mucoadhesion and the contact time, are currently under investigation with the final aim of obtaining a more effective topical drug delivery system, thus reducing the need of systemic immunosuppressive therapies, often correlated with systemic adverse effects.

The ideal properties of a drug delivery system for the oral mucosa include high mucoadhesion and unidirectional drug release toward epithelial tissue, prolonging the mucosal exposure to the drug, thus increasing drug permeation throughout epithelial layers [6]. From a mechanical point of view, the device should also show appropriate mechanical flexibility to support any movement within the oral cavity and it should be compatible with the salivary environment that is highly hydrophilic and with an average pH of 6.7 (range 6.2 -7.6) [7]. One of the most challenging aspects, considering that CP is very lipophilic, is related to the need of loading the lipophilic drug into the mucoadhesive system and to release it towards the oral mucosa, into an aqueous environment.

Drug delivery systems for steroidal drugs in the oral mucosa have included polymeric gels, mouthwashes, sprays, particulates, films and patches [8], [9], [10], [11], [12], although only few reports focused on CP [13], [14], [15], [16]. Low drug loading efficiency, initial burst release, and the possibility of drug expulsion during storage were the main drawbacks. Bilayered buccal patches [13] have been proposed, based on polyvinylpyrrolidone (PVP) and polycaprolactone (PCL), synthetic polymers that require the need of toxic solvents for the preparation, high hydrophobicity and a lack of antimicrobial activity [17], [18]. Recently, the Rivelin®- CLO bilayer patches, which are composed of synthetic polymers, i.e. PVP and Eudragit RS100 for the mucoadhesive electrospun nanofibers loaded with CP and PCL for the occlusive backing layer, were tested in OLP patients in randomized placebo-controlled clinical trial, showing promising results [19].

Here, we propose novel bilayer mucoadhesive oral patches based on chitosan (CS), a natural polymer derived from shrimps, to propose an innovative drug delivery system, highly biocompatible and biodegradable, prepared without the need of synthetic polymers or toxic solvents. CS is a biodegradable polysaccharide with intrinsic bio-adhesive [20], anti-microbial and wound healing properties [21]. To date, CS-based buccal patches were obtained by solvent casting technique or electrophoretic deposition (EPD), loading different drugs, such as verapamil, carvedilol or lidocaine, adding additives to improve biomechanical properties, such as polyvinylpyrrolidone (PVP), methylcellulose and pectin [22], [23], [24], [25], or functionalizing CS with catechol groups [26].

The aim of this study was to synthetize and characterize innovative CS-based bilayer buccal patches, loaded with CP, via EPD. The patches displayed a bilayer design with an occlusive backing side, not loaded with the drug (towards the oral environment), and a CP-loaded side (towards the mucosa), to promote the unidirectional release of the drug to the target site. The patches were characterized from a morphological and physical point of view, then the release of CP in physiological solution was assessed. An ex vivo model of porcine oral mucosa was used to test the mucoadhesive properties of the patches and assess CP diffusion throughout the epithelial layers. Finally, an in vitro 3D model of human oral mucosa was used to verify the patches’ cytocompatibility and, via proteomics, the bioactivity of the CP released locally.

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Elena Maria Varoni, Lina Altomare, Lorenzo Bonetti, Francia Viganò, Alessandro Scalia, Marcello Manfredi, Luigi De Nardo, Lia Rimondini, Andrea Cochis, Bilayer chitosan-based patches for steroidal drug delivery on the oral mucosa,
Journal of Drug Delivery Science and Technology, 2024, 105919, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.105919.

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