Research paper
In situ bioadhesive film-forming system for topical delivery of mometasone furoate: Characterization and biopharmaceutical properties

https://doi.org/10.1016/j.jddst.2020.101852Get rights and content

Abstract

In situ film-forming systems (FFS) are attractive drug delivery systems employed for the topical administration of drugs. They are transparent and have high substantivity and improved cosmetic attributes. Two types of polymeric materials, methyl methacrylate and cellulosic derivates, were employed for the topical delivery of mometasone furoate. A previous screening of polymers and plasticizers was performed to select the best candidates based on cosmetic characteristics. Water vapor permeability determines the occlusive profile, and it has been observed that it depends on the polymer type. The rheological, bioadhesion, and mechanical properties of the films revealed that the best candidates were Eudragit S100 and HPMC films. These polymers also exhibited the slowest drug release and limited permeation across the skin, with no alteration in the microstructure of the skin layers after diffusion experiments. Both FFS were adequate to improve patient compliance with treatment due to the cosmetic attractiveness and a potential reduction in administration frequency. They also potentially allow for administration to high-friction areas and the face.

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.

References (30)

  • M.C. Gohel et al.

    Fabrication of modified transport Fluconazole transdermal spray containing Ethyl Cellulose and Eudragit® RS100 as film formers

    AAPS PharmSciTech

    (2009)
  • N. Jadhav et al.

    Glass transition temperature: basics and application in pharmaceutical sector

    Asian J. Pharm.

    (2009)
  • Nonsterile semisolid dosage forms scale-up and postapproval changes: chemistry, manufacturing, and controls

  • Y. Zhang et al.

    DDSolver: an add-in program for modeling and comparison of drug dissolution profiles

    AAPS J.

    (2010)
  • Cited by (10)

    • Novel acyclovir-loaded film-forming gel with enhanced mechanical properties and skin permeability

      2022, Journal of Drug Delivery Science and Technology
      Citation Excerpt :

      Films formed using FFG may provide efficient topical therapy by protecting the skin from external stimuli and phenomena that can be removed through sweating or wearing off. Compared to film form, FFG is easier to use and apply and simpler to manufacture [11]. It can be freely applied regardless of the shape or curved herpes area.

    • Nanoscaffolds and role of 3D-printed surgical dressings for wound healing application

      2022, Nanotechnology and Regenerative Medicine: History, Techniques, Frontiers, and Applications
    • PLGA based film forming systems for superficial fungal infections treatment

      2021, European Journal of Pharmaceutical Sciences
      Citation Excerpt :

      Formulated FFSs are subjected to a sophisticated physicochemical testing (Nair et al., 2013) to predict the drug release profile, the skin penetration/permeation, i.e. the therapeutic effect of the drug delivery system. Method used include particularly DSC (Edwards et al., 2017; Mahnaj et al., 2011), TGA (Wu et al., 2014), XRD (Oh et al., 2017), FTIR (Šveikauskaitė and Briedis, 2017), Raman-Microscopic Characterisation (Lunter and Daniels, 2013), SEM (Monica et al., 2020; Oh et al., 2017; Pang et al., 2011; Shi et al., 2010; Zhang et al., 2014), testing of rheological behaviour (Çelebi et al., 2015), mechanical, barrier and adhesive properties (Shivakumar et al., 2010), time of solidification, stickiness of a film (Lir et al., 2007). There is an effort to find an optimal procedure for testing the drug release from FFS.

    • Enhancing chitosan solubility in alcohol: water mixtures for film-forming systems releasing with turmeric extracts

      2021, Journal of the Taiwan Institute of Chemical Engineers
      Citation Excerpt :

      These systems have been used in several applications, including tissue glues for closing incisions [14], disinfection for skin preparation before operation [15], and masking the skin for hydration treatment [16]. For topical drug delivery, FFS with various drugs or bioactive agents, for example, propolis [13], mometasone furoate [17], piperine-rich herbal mixture extract [18], betamethasone valerate [19], and lornoxicam [20] have been reported recently. To create a good film, both non-sticky formulation and minimum drying time are required.

    View all citing articles on Scopus
    View full text