Research paperIn situ bioadhesive film-forming system for topical delivery of mometasone furoate: Characterization and biopharmaceutical properties
Graphical abstract
Introduction
Interest in film-forming systems (FFS) has been increasing because of their technological and cosmetic attractiveness compared with traditional topical formulations such as creams, liquids, ointments, gels, etc.
There are two main production techniques for films. On the one hand, the solvent casting method obtains films before applying them to the skin. A polymeric solution in pure organic solvent is deposited onto an inner material, where the solvent evaporates, thus obtaining thin films that are ready to be administrated. On the other hand, in situ FFS are administrated in liquid state and, once deposited, the solvent evaporates and a film is formed on the skin [1]. This last approximation is more interesting for topical delivery because it allows for adjusting the formulation dose and surface depending on the disease extension. A second skin layer is obtained, which protects the underlying tissue from external chemical and mechanical damage. Moreover, some polymers allow us to obtain films with peel-off properties, so they could be easily removed from the application site when required. Films also have improved biopharmaceutical benefits, because when the solvent evaporates, the drug concentration (as well as the thermodynamic activity) in the formulation increases and leads to an increase in diffusion into the skin [1]. The polymer network acts as a drug reservoir and its use showed good patient compliance.
There are a vast number of polymers on the market with different physical and chemical characteristics, making the selection of the appropriate one difficult. A case-by-case approach is usually preferred. The most widely used polymers to obtain in situ FFS are cellulosic and methacrylate derivates, covering a high range of polarity. Schroeder et al. [2] performed a large screening using Eudragit RL, E100, S100 and NE 40D, chitosan, PVP, PVP/VA, hydroxy propyl cellulose (HPC), silicones, and polyurethanes to study their characteristics, but they did not evaluate their ability to deliver a drug or their biopharmaceutical behavior. Gohel and Nagori [3] developed and evaluated the delivery of fluconazole through Eudragit RS100 and Ethyl Cellulose FFS by means of factorial design, but they used methanol and acetone, which are not highly biocompatible, as solvents. Lunter and Daniels [4] used Eudragit NE and RS 30 emulsion for the topical delivery of antipruritic drugs, as film-forming emulsions usually take a long time to form the film on the skin. They used the solvent casting method to obtain them. Frederiksen et al. [5] used HPC, Eudragit NE, and RS and acrylate polymers for betamethasone skin delivery with different plasticizers, demonstrating that FFS are able to prolong drug delivery into the skin. No references were found for in situ FFS with Eudragit L100 or L100-55 polymers, and only a few described and characterized Eudragit S100 and HPMC as in situ film formers to deliver drugs into the skin.
Another important factor to consider when films are developed is the addition of plasticizers. These compounds usually reduce the glass transition temperature and the minimum temperature of film formation because they are placed between the polymer chain, increasing free volume and allowing free movement at lower temperatures. Glycerol, triethyl citrate, medium chain triglycerides, polyethylene glycol, and propylene glycol are usually employed to achieve this aim [6]. As a result, the film flexibility, appearance, and drug release could be improved. Flexibility is an important property for skin films to allow them to adapt to body movements and to the viscoelastic behavior of the skin.
Finally, the bioadhesion and resistance to friction (substantivity) of FFS to the skin are crucial for the therapeutic index, determining the residence time, continuous release, and skin absorption under the tight contact of the film with the skin [7]. As previously stated, FFS act as drug reservoirs, which, together with the adhesiveness, could reduce the administration frequency, thereby improving patient compliance. To achieve adequate bioadhesion, correct polymer selection is important. Cellulose derivates, acrylic polymers derivates, and other natural gums are usually employed to obtain topical adhesive formulation, but they need to be formulated to obtain an FFS instead of a classical hydrogel formulation. In this last case, bioadhesion is obtained but with poor or no resistance to friction.
Corticoids are among the most commonly prescribed drugs to treat inflammatory and autoimmune topical diseases. They are usually classified into four groups according to their potency, from low to ultra-high potency. Their potency mainly depends on the dose and formulation type, with the most occlusive vehicle being the most potent medicine. Potency is usually evaluated by cutaneous vasoconstriction (blanching effect) [29]. Despite their effectiveness, drugs can induce adverse side effects when applied topically, as skin atrophy, skin microbiome alterations, striae, and telangiectasias, which could limit their use on certain body parts such as the face and flexures. Atrophy is caused by the antiproliferative effect on dermal fibroblasts and keratinocytes [8]. Mometasone furoate is a moderately potent corticosteroid [29] used topically (as an emulsion) to treat psoriasis and several eczematous skin disorders not on the face. Compared with other corticoids, mometasone has improved efficacy, reduced adverse effects, and a longer duration of action compared with betamethasone. Clinical studies have demonstrated a good clinical profile for both adults and children, a low tendency to atrophy, and low sensitization [30].
There are no corticosteroid formulations on the market based on FFS; in the literature, we only found references to a betamethasone FFS [5]. We proposed several in situ bioadhesive FFS with an improved cosmetic profile to modulate the biopharmaceutical profile (delivery and skin permeation) of topically applied mometasone furoate. Polymers Eudragit L100–55, S100, HPMC, and HPC are used for this purpose, and have been poorly described in the literature, or not at all. The objective of this work is to perform a deep mechanistic characterization of the proposed systems, pointing out the viscoelasticity behavior and the relationship with the formulation's microstructure and its biopharmaceutical properties. Based on the characterization carried out, an FFS prototype is proposed. A promising new drug delivery system is presented for the topical administration of mometasone furoate.
Section snippets
Materials
Mometasone furoate (Crystal Pharma S.A. Boecillo, Valladolid, Spain), isopropanol (IPA) (Scharlab S.L, Sentmenat, Spain), triethyl citrate (TEC) (Sigma-Aldrich química, S.L, Madrid, Spain), medium-chain triglycerides (MCT) (IoI Oleochemicals, GmbH, Hamburg, Germany), propylenglycol (PPG) (Quimidroga, S.A, Barcelona, Spain), polyethyleneglycol 300 (PEG 300) (Quimidroga, S.A, Barcelona, Spain), Eudragit E100, Eudragit L100, and Eudragit L100-55 (Evonik Röhm GmbH, Darmstadt, Germany), Metolose
Preformulation and formulation selection of FFS
Different polymers (HPC, HPMC, chitosan, and polymethacrylates) and solvents (PPG, IPA, H2O, and NMP) were chosen based on their film-forming ability, solvent properties, and good biocompatibility profile. Several combinations of polymers and pure or solvent mixtures were prepared to check their solubility and compatibility. One of the necessary characteristics of an FFS is forming a film in situ and rapidly, once deposited on the skin. Then, mixtures (solvent‒polymer) with a drying time of up
Conclusions
We successfully developed and characterized different film-forming systems based on different polymer types (cellulosic and methyl methacrylate). All polymer types presented desirable cosmetic and technological attributes. In general, they are transparent, show low drying times, leave a smooth feeling on the skin, and have good flexibility and adhesion to the skin; Eudragit S100 and HPMC have the best mechanical properties for skin administration. Different occlusion behavior was obtained for
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Labella-Lorite Monica: Investigation, Methodology, Supervision, Writing - review & editing. Gonzalez Jordi: Funding acquisition, Project administration. Fernandez-Campos Francisco: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing.
Acknowledgments
We would like to thank Francisco Otero of the Pharmaceutical Technology department (Faculty of Pharmacy, University of Santiago de Compostela, Spain) for making available the techniques used in this research and for technical support.
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