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Aphthae; Aphthous stomatitis; Sodium hyaluronate; Gel; Filmogenic/Barrier capacity

Introduction

Aphthous stomatitis, also known as aphthae, represents a very common and unpleasant oral mucosal disease that can significantly affect patient’s quality of life due to painful and stinging sensations during daily activities like speaking, eating or even drinking [1]. Caused by physical trauma, chemical injury, and microbial infection (bacterial, viral, and fungal), aphthae generally appear on non-keratinized oral mucosa areas (i.e., soft palate, inner lips, inner cheeks, floor of the mouth and ventral surface of the tongue). While a complete healing is usually reached in 10-14 days [2-4], treatments such as anti-inflammatories, corticosteroids, analgesics, antimicrobial, and lubricating agents are used to accelerate the healing process while lessening the pain [4-8]. This approach may lead to unwanted side effects, such as ranging from somnolence to nausea and gastrointestinal symptoms [9]. A potential solution to this problem comes from film-forming formulations that create a temporal physical barrier on ulcerous lesion, protecting it from oral traumas while reducing pain and fostering the healing process, without side effects [10-13]. These formulations are required to be applied several times during the day to keep up the barrier effect. Indeed, film/barrier retention in the oral cavity is mediated and influenced by both the formulation composition and administrations ways (topical gel, spray or mouth rinse). To improve patient’s compliance of film/barrier forming formulations for aphthae treatment, it is necessary to increase barrier effect duration so reducing the number of applications. With this aim, BMG PHARMA developed a new sodium hyaluronate-based medical device gel formulation (BMG0725) for aphthae treatment. In the present work, the filmogenic capability and the barrier effect of the BMG medical device is evaluated by mean of a Franz cell-based in vitro approach, and the efficacy of the gel formulation is also compared with two commercially available formulations, Alovex® Gel and Tantum® Verde SOS Afte Gel.

Materials and Method

Formulation tested

The barrier effect of a cross-linked sodium hyaluronate lipoate based gel-medical device for aphthae treatments of BMG products line, was compared with two commercially available formulations, Alovex® Gel and Tantum® Verde SOS Afte Gel. Tested formulations are described in Table 1. Alovex® Gel and Tantum® Verde SOS is registered trademark of Recordati SpA and Angelini SpA respectively.

Methods

Evaluation of the medical device filmogenic capability and barrier effect retention: The barrier effect experiments were conducted using Franz cell diffusion apparatus (PermeGear) (20 mm diameter orifice, 10 mL acceptor chamber, flat ground joint, clear glass) with Whatman 5 filter paper (GE Healthcare) as the membrane between the donor and acceptor chambers. Briefly, 500 μL of tested medical device was applied on the filter paper and evenly distributed. Then, the filter paper was placed between the donor and the acceptor chambers (water was used to fill the acceptor compartment) and left to equilibrate for 20 min. Once the equilibration step was concluded, 500 μL of a 0.5 % Trypan Blue solution were added to the donor chamber. Aliquots from the acceptor chamber were collected at pre-determined time intervals (from 0 up to 24 h depending on tested formulation) for the spectrophotometric evaluation of the presence of penetrated Trypan Blue (reading at 540 nm). The entire Franz cell system was maintained at 37.0 °C ± 0.5 °C throughout the experiment.

Statistical Analysis: Results were statistically analyzed by t-test (t-test for paired sample), using Origin Lab software (Origin Lab Corporation, Northampton, MA, US). Experiments on the gel medical device were performed in triplicate on a single batch, while, for mouth rinse and spray, two different batches in triplicate were considered. The obtained results were presented as average ± standard deviation. A p-value of ≤ 0.05 was considered significant.

Results

BMG gel medical device (BMG0725) and commercial formulations filmogenic capability and barrier effect retention

As mentioned before, aphthae are common, small, light-coloured, painful punched-out sore in the mucous membrane of the mouth, causing significant discomfort linked to the pain provoked by the continuous contact with tongue, teeth or food. As such, the simplest and more effective way to reduce the pain, while reducing the healing time, is by creating a film/barrier on the aphthae and limiting the potential contact. However, this barrier not only need to form quickly but it should also last as long as possible, to decrease the formulation application frequency. As shown in Figure 1, Table 2 and Table 3, all tested gel formulations are able to readily form an impermeable barrier. While the cross-linked sodium hyaluronate lipoate-based gel formulation (BMG0725 GEL) retains its barrier effect up to 8 h (Figure 1, Table 2 and Table 3), a significant increase in Trypan Blue absorption and a decrease in barrier retention is observed after 6 h for both tested commercial formulations, with Tantum® Verde SOS Afte Gel endowed with the worst overall barrier retention efficiency (Figure 1 and Table 2). Consequently, BMG gel formulation ensures a longer barrier effect and a longer barrier retention compared to the considered commercial formulations, reducing its application frequency while increasing its patient’s compliance.

Figure 1: Evaluation of the barrier effect of tested gel medical devices. (A) Absorption kinetic of 0.5 % Trypan Blue solution permeated in the acceptor chamber through the film/barrier and (B) barrier retention over time of tested gel medical devices. BMG0725 GEL (Black Square and line), Tantum® Verde SOS Afte (red circle and line) and Alovex® Gel (blue triangle and line). * p < 0.05

Since no permeation of Trypan Blue was observed up to 8 h, the barrier-forming ability of BMG0725 was investigated at longer times. As highlighted by Figure 2 and Table 4, a significant increase in Trypan Blue permeation is observed after 18 h, indicating that BMG0725 was able to retain its barrier effect up to 18 h (Figure 2 and Table 4).

Figure 2: Determination of the BMG0725 formulation film-forming effect duration. (A) Absorption kinetic of 0.5 % Trypan Blue solution permeated in the acceptor chamber through the film/barrier and (B) barrier retention over time of tested gel medical devices, BMG0725 GEL. The results obtained up to 8 h for the two commercial formulations, Tantum® Verde SOS Afte e Alovex® Gel, are reported for comparison reason * p < 0.05

Discussion and Conclusions

The aphthous stomatitis, usually called aphtha, is the most common form of oral ulcers and are associated with painful sensation, that worsen during normal daily activities (i.e., speaking, eating, etc.). While pharmacological treatments do exist, they are not devoid of sideeffects. As such, side effects-free film/barrier forming formulations represent an interesting solution for aphthae treatment. Indeed, once the barrier/film is formed, the aphthae is physically protected from the oral cavity environment, limiting the painful contact with the tongue, the teeth or oral microbiota. However, given the specific action of these formulations, multiple applications during the day is necessary to maintain an effective barrier, limiting in part their patient’s compliance. Results of the study indicate that the cross-linked sodium hyaluronate lipoate-based formulation produced by BMG PHARMA readily form a physical barrier on the application site effective up to 18 h. In particular, the barrier formed following the application of BMG gel formulation is effective for a longer period of time compared to that of two well-known commercial products, reducing the needed application as a consequence. In conclusion, BMG gel formulation guarantees an effective aphthae treatment with fewer applications (i.e., better patient’s compliance), reducing the pain and accelerating their healing compared to the other two formulations Alovex® Gel and Tantum® Verde SOS Afte Gel.

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