1. Introduction
Dermal drug delivery is a critical field of study in pharmaceutical research, with the goal of successfully administering therapeutic agents through the skin for localized or systemic effects.
A wide range of dermal preparations are available for use in product development. Within the traditional forms, solid, semi-solid, and liquid preparations are distinguished. Powders and patches are associated with the solid form applied dermally, while ointments, creams, gels, and pastes represent the semi-solid form. Solutions, emulsions, suspensions, and aerosols belong to the liquid form [
1,
2].
Only a few of the active ingredients are capable of achieving adequate transdermal penetration on their own since they need to possess suitable solubility and permeability [
3]. To achieve a systemic effect, it is necessary to develop a formulation that is capable of crossing this protective barrier by temporarily disrupting the skin barrier before it quickly returns to its original structure. Among the methods for enhancing penetration, we distinguish between passive and active approaches. Passive methods involve reducing the barrier function of the stratum corneum through the use of chemical penetration enhancers [
4,
5], increasing hydration [
6], and employing various nanostructured systems (NLC, liposome) [
7].
In addition, an increasing number of new, innovative forms are being encountered in both the pharmaceutical and cosmetic industries [
8]. In the field of dermatology, foams have gained attention [
9,
10], particularly in the treatment of sunburns, wounds, and ulcers. They are used in numerous areas, and the development of environmentally friendly designs has become paramount to reducing the environmental footprint [
11]. This has led to the gradual replacement of propellant-containing systems with propellant-free systems. The therapeutic use of dermal foams is becoming increasingly appealing to the population because of its ease of application [
12]. Foams are often utilized as a topical formulation, which allows for easier distribution and consistent covering of the affected region. Their appearance is aesthetic, non-greasy, and non-sticky, yet easily removable from the skin, thereby improving patient adherence. Foams also have good spreadability on the skin [
13], ensuring the immediate absorption of the active ingredient, and eliminating the need for vigorous rubbing [
14].
Foams have specific physical properties and a distinct structure that set them apart from other conventional drug delivery systems, such as hydrogels. Understanding the physical characteristics and structure of foams is critical for comprehending their benefits in dermal drug delivery. Foams are distinguished by their porous structure, which is formed during the foaming process [
15]. These pores are bare spots or holes inside the foam matrix that contribute to its spongy appearance. The presence of pores in foams is essential for their drug delivery capabilities. The porous nature enables the incorporation and entrapment of drugs within the foam structure, allowing for sustained release upon [
16,
17,
18] application to the skin. Additionally, this porous nature increases the accessible surface area for drug absorption, allowing for faster (immediate) drug diffusion. During formulation, it is essential to ensure the perfect dissolution of the active ingredient in the carrier excipient. Upon application, volatile components quickly evaporate from the foam applied to the skin, leading to supersaturation [
19,
20]. Consequently, a supersaturated layer forms on the epidermis in terms of the active ingredient, from which penetration initiates at a high speed due to the tremendous driving force within the system. If this process occurs rapidly, there is no opportunity for the active ingredient to crystallize since the rapid penetration causes a decrease in the concentration of the active ingredient in the foam layer. Furthermore, the linked network of foams allows for effective medication transportation across the epidermal layers, resulting in improved absorption and bioavailability [
21].
Despite numerous advantages, formulating dermal foams presents significant challenges. When designing their compositions, it is crucial for the formulation to remain on the skin for a sufficient duration. It should quickly spread to meet user preferences and provide a pleasant skin sensation. In terms of shelf life, they are stored in sealed containers, minimizing microbiological contamination. However, despite the aforementioned advantages of foams, the number of available topical foam preparations in the market remains relatively low compared to traditional formulations such as creams and gels.
In our study, diclofenac sodium was used as an active pharmaceutical ingredient (API). Among the NSAIDs, diclofenac sodium is the only API approved by the FDA for topical use in the treatment of pain associated with osteoarthritis. Being an organic acid, diclofenac exhibits lipophilic characteristics, whereas its salts readily dissolve in water under neutral pH conditions. The mix of these two attributes enables diclofenac to effectively permeate cell membranes, encompassing the synovial lining of diarthrodial joints as well as the skin [
22]. Furthermore, the occurrence of adverse effects is minimal compared to oral administration, especially those topical formulations that contain diclofenac [
23,
24]. Various concentrations of hydrogels, creams, and other products with this API are available on the market.
Foams and hydrogels are two significant rivals within the dermal field that have been widely researched. However, it is becoming increasingly clear that foams have triumphed, outperforming hydrogels in many ways and changing dermal drug delivery [
21,
25].
Foams possess excellent stability and a prolonged shelf life due to their ability to maintain structural integrity during storage and application. Unlike hydrogels, foams are less prone to leakage or drying out, ensuring a consistent and effective drug delivery performance over an extended period.
In summary, achieving transdermal permeation is challenging, requiring the development of formulations that can temporarily disrupt the skin barrier for systemic effects. Foams, gaining attention in dermatology, offer advantages such as an easy application, aesthetic appearance, and better patient adherence. Despite their numerous benefits, formulating dermal foams poses challenges, with considerations for duration on the skin, user preferences, and shelf life. In our study, diclofenac sodium served as an active substance, showcasing its effectiveness in topical formulations. In many ways, foams are superior to hydrogels in terms of stability and extended shelf life, making them a promising dosage form in dermal drug delivery research.
Our research focused on comparing the physicochemical and biopharmaceutical properties of three drug delivery systems: foam, foam bulk liquid (a polymer solution), and a conventional hydrogel. Addressing the limited studies on medicated foams, our goal was to develop comprehensive investigational methods covering aspects such as foam stability, viscosity, pH, in vitro drug release, and ex vivo skin permeation. This includes examining the potential differences in properties between the preparations, as well as investigating the impact of diclofenac sodium (DS) at a concentration of 1% on the foam system.
4. Discussion
In this work, we compared the physicochemical and biopharmaceutical properties of foams with those of traditional hydrogel and polymer solutions.
According to the cytotoxicity assessment, the components in the formulations did not exhibit any cytotoxic impact on mesenchymal cells at the concentrations used. Therefore, we found these components to be suitable for the formulation of dermally applied preparations.
In terms of preformulation studies of foams, the presence of DS reduced foam expansion based on macroscopic observations but did not negatively impact foam stability, as confirmed by microscopic results, since it had no adverse effects on the foam structure. The pH values of both the bulk liquid/foam and the hydrogel ranged from 7 to 8, making them suitable for topical application.
Biopharmaceutical examinations revealed that the foam, as a drug delivery system, can achieve rapid drug release and deeper skin permeation compared to the hydrogel. Approximately 80% of the active ingredient was released in just 30 min using the foam, while it took approximately 5 h for the hydrogel to achieve the same outcome.
The drug release from the formulations was studied and explained using the Korsmeyer–Peppas model. The fastest release rate was observed in the case of foam formulation, which correlates with the result of drug permeation.
Results from Raman skin permeation studies demonstrated that within just 10 min, the foam concentrated in the upper layers of the epidermis and gradually permeated even deeper layers over time. The supersaturated liquid film formed during the aging of the foam could be observed after 20 min, and its effect was still detectable after 1 h. The Raman mapping results exhibited a strong correlation with the fluorescent microscopic examination, as the foam formulation maintained high light intensity even after 10 min, providing additional evidence for the system’s rapid permeation. In comparison, the hydrogel, with the greatest viscosity, hindered the permeation of DS. Therefore, it did not permeate the deeper layers of the skin even after 1 h.
The applied test methods were suitable for the complex investigation of the foam formula, including the physicochemical and biopharmaceutical properties, as well as for the detection of the potential differences between the preparations. Furthermore, it can be concluded that diclofenac sodium (DS) at a concentration of 1% did not negatively affect the stability of the foam.