Film-forming solutions for cutaneous application: current challenges and future directions in formulation design and characterization framework

Abstract

Film-forming solution (FFS) implies a novel formulation strategy for liquid preparations for cutaneous application with numerous advantages in comparison with compendial dosage forms, including flexibility of composition (active pharmaceutical ingredient (API) solution in volatile and non-volatile solvents, with film-forming polymers, plasticizers and chemical permeation agents) and the method of administration (rubbing or spraying). Research over the past two decades indicates the potential of FFS for comparable or improved dermal, regional and transdermal delivery of small-molecule drugs due to improved passive diffusion through: volatile solvents evaporation and API (super)saturation, and potential increase in stratum corneum (SC) permeability caused by excipients. Current commercial exploitation of FFS is limited due to demanding pharmaceutical development, the backbone of which is formulation design and product characterization.

This comprehensive review gives insight into the complex relationship between the formulation composition, quality attributes (physicochemical properties, microstructure) and in vitro performance (drug release and permeation) of FFS. A characterization framework is proposed, taking into account published studies, relevant pharmacopoeial standards and announced guidelines of the European Medicines Agency (EMA) and The United States Food and Drug Administration (FDA). The importance of specific tests for evaluating the transformation of FFS at the site of application and the quality attributes of the in situ formed film, was pointed out. Directions for pharmaceutical development improvement are given, including the favoring of environmentally acceptable and biocompatible excipients, introduction of in silico formulation optimization techniques and development of standardized methodology for reliable and comparable assessment of quality, efficiency and safety of FFS.

Introduction

The purpose of administration of a pharmaceutical preparation which contains one or more APIs on skin (referred hereby as cutaneous application) could be dermal, regional or transdermal drug delivery. In this article, the terms API and drug are used interchangeably. Dermal drug delivery ensure that the administered API acts locally on the surface or within the SC, epidermis or dermis of the diseased or damaged skin or its appendages such as hair and nails. The regional drug delivery from locally applied cutaneous preparations into the adjacent tissues below the skin (e.g., muscle or joint) is also considered the local site of action. Transdermal drug delivery, on the other hand, must allow penetration, permeation and absorption of the API through the vascular system of healthy, intact skin into the systemic circulation in a defined rate and extent resulting in a prolonged therapeutic effect [1], [2], [3], [4], [5], [6]. Considering the taxonomy of pharmaceutical dosage forms for cutaneous application in the European pharmacopoeia (Ph. Eur.) and the United States Pharmacopeia and the National Formulary (USP-NF), numerous disadvantages of compendial powders, liquid preparations, and semi-solid preparations can be observed (Table 1), including difficult application to a limited skin area, poor cosmetic attributes and retention at the application site, associated with the questionable dosing accuracy, safety and efficacy. Patches (i.e., transdermal patches and cutaneous patches (Ph. Eur.), or plasters (USP-NF)), on the other hand, demonstrate advantage in terms of skin retention due to their adhesive properties, however, adhesiveness vary depending on the type of patch, skin characteristics and environmental conditions and can lead to skin irritation and hypersensitivity. Moreover, patches are not suitable for application on curved surfaces, cause occlusion and require a more complex pharmaceutical development and manufacturing [7], [8], [9], [10], [11], [12], [13], [14]. In the case of chronic diseases, patches can provide drug release over several days, however, they may retain a significant amount of the drug after the intended period of use, which poses a risk of release and potential overdose if the patch is not handled properly [9], [12], [14], [15], [16].

To overcome the limitations of conventional pharmaceutical preparations for cutaneous application, the development of advanced dosage forms is an ongoing and important research area. An innovative formulation approach, which is increasingly discussed in the scientific literature, is designing of FFS that contains one or more APIs and film-forming polymers dissolved in a mixture of volatile and non-volatile solvents and which is suitable to form an in situ film shortly after application to the skin due to relatively fast evaporation of volatile ingredients [12], [15], [16], [17]. It is important to note that while the term “film-forming solution” is used in many studies in the broadest sense for different systems with and without polymers, so that any non-volatile residue with an active substance on the skin surface is considered a film, this article focuses exclusively on film-forming solutions with polymers that have the ability to form a coherent polymer film on the skin surface. The in situ formed polymer-based film is thin and often almost invisible on the skin surface which is why it is usually referred to as an invisible patch, patchless patch delivery, or invisible skin delivery [9].

Evaporation of volatile ingredients can also ensure the achievement of a state of saturation or even supersaturation of the drug within the film. Although the concept of (super)saturation in the field of local/transdermal drug delivery has been considered since 1960, the formulation of a stable system in which the drug concentration is in a (super)saturated state and optimisation of local/transdermal drug delivery have been intensively studied in recent decades. Among the various methods to achieve the state of (super)saturation, the method of evaporating the volatile solvent from the FFS has proven to be highly effective, practical, and feasible so far [18]. A significant outcome of (super)saturation is achievement of therapeutic efficacy with lower doses of the drug, which not only reduces the production costs of the pharmaceutical product but also contributes to a potential increase in its safety [9], [16], [18], [19]. Table 1 shows the various advantages of FFS in terms of convenience for application and drug delivery enhancement as well as fewer disadvantages over compendial dosage forms. Furthermore, the scale-up and manufacturing of FFS are considered relatively simple and cost-effective, especially when compared to transdermal patches. In addition, the film formed on the injured skin surface may ensure the absorption of exudate, represents a physical barrier for contaminants and microorganisms, and may provide the favorable conditions for wound healing [9], [15], [18], [20], [21], [22]. In spite the recognized advantages, the number of FFS-based commercial products is still limited. The topical testosterone solution under the name Axiron®/Axxeron® (Eli Lilly, the USA) was approved by the FDA in 2010, and since 2011, it has been registered in the USA, Canada, Australia, Germany, Brazil, and South Korea [28]. This produst contains testosterone dissolved in a mixture of volatile solvents (ethanol and isopropyl alcohol), with the addition of a penetration enhancer (octisalate) and a polymer (povidone) that forms a film on the skin surface after application. For safe application, a packaging system was developed with an applicator integrated into the solution container, which the patient rotates for 180° to activate the release of 1.5 ml of solution containing a therapeutic dose of 30 mg of testosterone, which is then rubbed directly from the applicator onto the armpit [9], [18], [29], [30]. The commercial breakthrough of FFS-type products stimulated research in this area. Over the past two decades, numerous scientific papers have been published that discuss the development of various FFS formulations for cutaneous application. Table 2 illustrates the composition and potential of FFS for:

dermal delivery of antifungal agents (fluconazole [31], clotrimazole [32] and voriconazole [33]), ropivacaine [34], corticosteroids (betamethasone 17-valerate [35], [36], and mometasone furoate [37]);
regional delivery of meloxicam [39];
transdermal delivery of ethinylestradiol [40] and an alcoholic extract of a piperine-rich herbal mixture [42].

The cited studies clearly demonstrate the potential of the optimized FFS formulations to improve dermal, regional or transdermal drug delivery (Table 2). Gohel and Nagori developed an FFS spray for cutaneous application with the aim at prolonging the release of fluconazole for the treatment of fungal skin infections. The optimized formulation (Table 2) was selected based on the results of spray angle evaluation, in vitro drug release from the FFS, and water washability. Additionally, the positive effect of an eutectic mixture of camphor and menthol (1:1 ratio) on the in vitro percutaneous penetration of fluconazole through shed snake skin, used as a biological membrane, was confirmed [31]. Paradkar et al. develop the optimized FFS spray formulation included 1% clotrimazole and 10% eutectic mixture of camphor and menthol as the penetration enhancers (Table 2) for treatment of fungal skin infections. This formulation exhibited a significantly higher release and penetration rate of clotrimazole through rat skin compared to other formulations, in vitro local antifungal activity towards Candida albicans, and did not cause irritation, rash, or itching in the study participants [32]. In the optimized FFS spray formulation with voriconazole 0.5% (Table 2), the 10% eutectic mixture of camphor and menthol significantly contributed to increase the in vitro drug penetration through rat skin by 1.68-fold [33]. The antinociceptive effect of ropivacaine from the developed optimized FFS formulation was tested on rats, with results comparable to those of a commercially available lidocaine gel [34]. The optimized FFS with meloxicam (Table 2) demonstrated similar anti-inflammatory effect with orally administered meloxicam dispersion in a carrageenan induced paw edema test on male Sprague-Dawley rats. There was no significant difference in COX-2 expression or caspase-1 activation measured using Western blot analysis, between meloxicam-loaded FFS and oral meloxicam dispersion [39]. The optimized FFS formulation (Table 2) developed by Schroeder et al., enable higher permeation of ethinylestradiol in vitro across the human epidermis and transdermal delivery in vivo (pig) than the commercial transdermal patch over 24 hours [40].

Previously commented and several other studies in this field [35], [36], [37], [41], [42] also highlight the very complex relationship between the formulation parameters (i.e., qualitative and quantitative composition), quality attributes and performance of FFS. Hence, the pharmaceutical development of the new FFS type products for cutaneous application is a challenging task. Although FFS is not listed explicitly as a compendial dosage form in Ph. Eur. and USP-NF, in the pharmaceutical development of products of this type, the relevant pharmacopoeial standards could be used. Additionally, in October 2022, FDA made available a draft guidance for industry on physicochemical and structural (collectively, “Q3”) characterization of topical drug products, including solutions, with intention to assist applicants who are submitting abbreviated new drug applications (ANDAs) [43]. The FDA draft guidance pointed that the Q3 attributes of a drug product, that may have the potential to impact product performance, are sensitive to the formulation design and manufacturing processes. Furthermore, in September 2024, EMA announced the adoption of the „Guideline on quality and equivalence of locally applied, locally acting cutaneous products“, which applies to new marketing authorisation applications and post approval changes, and comes into effect in April 2025 [1]. Taking into account the EMA guideline, FFS formulation development should include consideration of several aspects relevant for product quality, safety and efficacy, such as: therapeutic objectives and product design; the degree of saturation and the risks of precipitation of the API in the drug product; the delivery of the API to the site of action including the influence of solvents and permeation enhancers; patient acceptability and usability of the drug product (e.g. ease of administration, spreadability); transformation of the product upon administration due to evaporation of volatile solvents and excipients as necessary for effective drug delivery. This article aims to review the current scientific knowledge on formulation design (APIs and excipients) and characterization of quality atributes and performance of FFS for cutaneous application, on the basis of which a comprehensive strategy with potential to facilitate formulation development of new products can be conceived as well as to propose directions for its further improvement.

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