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Recurrent aphthous stomatitis (RAS) is a disease marked by painful oral lesions on the buccal and labial mucosa or tongue. Drug delivery systems (DDS) for RAS include topical forms that manage wound healing, cover the ulcer, and relieve the associated pain. DDS targeting the oral mucosa face a major challenge, especially the short residence times i...
Citations
... The drug delivery system also plays a crucial role in influencing the effectiveness of RAS therapy. 97 Typically, medications intended for RAS treatment are formulated in topical forms, such as gels, patches, pastes, or mouthwash. 9 This choice of the formulation is made because it can persist in the oral cavity for an extended period, providing protection against ulcer deterioration and facilitating a more rapid wound healing process. ...
Recurrent aphthous stomatitis (RAS) refers to a sore and frequently recurring inflammation of the oral tissues, distinguished by the presence of small ulcers that cause significant discomfort and cannot be attributed to any underlying disease. Different treatments have been used for RAS. This review aims to provide a comprehensive overview of the treatment options over the past decade for recurrent aphthous stomatitis (RAS), encompassing both natural and synthetic treatments. It will utilize clinical efficacy studies conducted in vivo and in vitro, along with a focus on the pharmaceutical approach through advancements in drug delivery development. We conducted a thorough literature search from 2013 to 2023 in prominent databases such as PubMed, Scopus, and Cochrane, utilizing appropriate keywords of recurrent aphthous stomatitis, and treatment. A total of 53 clinical trials with 3022 patients were included, with 35 using natural materials in their research and a total of 16 articles discussing RAS treatment using synthetic materials. All the clinical trials showed that natural and synthetic medicines seemed to benefit RAS patients by reducing pain score, ulcer size, and number of ulcers and shortening the healing duration.
... The advancement of drug delivery systems for RAS treatment is driven by three keys objectives: prolonging the residence time of the therapy at the ulcer site, delivering adequate drug concentrations to the ulcer, and alleviating pain. A promising solution entails the utilization of film formulations that act as a protective barrier for the ulcer, shielding it from external stimuli and offering relief from pain (Suharyani et al., 2021). ...
... This is attributed to the common obstacle of drug delivery to the oral mucosa, known as "saliva washout," resulting in the removal and rinsing of the drug on the mucosal surface. This issue can be addressed through the formulation of mucoadhesive film preparations, which can protect ulcers, create a barrier against external stimuli, and reduce pain to a certain extent (Suharyani et al., 2021). ...
Background: Recurrent Aphthous Stomatitis (RAS) is a common ulcerative disease of the oral mucosa which is characterized by pain, and recurrent lesions in the oral cavity. This condition is quite painful, causing difficulty in eating, speaking and swallowing. Topical medications have been used for this condition, but the obstacle in using topical medications is the difficulty of achieving drug effects due to saliva wash out. This problem can be overcome by film hydrogel formulation which can protect the ulcer and reduce the pain to some extent. α-mangostin is a xanthone isolated from the rind of the mangosteen fruit. One of the activities of α-mangostin is anti-inflammatory effects, which operate through the characteristic mechanism of inhibiting the inflammatory response. This protocol study aims to investigate the efficacy of an α-mangostin hydrogel film with a chitosan alginate base for recurrent aphthous stomatitis (RAS) in comparison with a placebo over a period of 7 days.
Study design: This is a two-arm, double blinding, randomized controlled trial enrolling patients with RAS. The efficacy test of α-mangostin Hydrogel Film will be tested against the placebo. Patients with RAS will be allocated randomly into the two arms and the hydrogel film will be administered for 7 days. The diameter of ulcer and visual analog scale (VAS) score will be used as the primary efficacy endpoint. The outcome measure will be compared between the two arms at the baseline, day 3, day 5, and at the end of 7 days.
Discussion: The purpose of this clinical research is to provide scientific evidence on the efficacy of α-mangostin hydrogel film with a chitosan alginate basis in treating recurrent aphthous stomatitis. The trial is expected to improve our capacity to scientifically confirm the anti-inflammatory effectiveness of α-mangostin compounds in a final formulation that is ready to use.
Trial registration: NCT06039774 (14 September 2023).
... Severe and constantly recurring ulcerations were indication for systemic therapy, however such approaches can generate severe side effects ranging from somnolence to nausea and gastrointestinal symptoms [10]. Several innovative drug delivery systems have been developed for the local treatment and prevention of various diseases in the oral cavity yet the efficacy in reducing ulcer size and number of ulcer only achieved by 50% to 62%. 9 No improvement after 14 days is also reported, therefore another treatment which is unaffected by salivary wash-out and presented systemic side effect with higher effectivity should be evaluated [10,11]. ...
... Meanwhile, conventional therapy included topical or systemic application of pharmacotherapy such as antimicrobial agent, anesthesia, anti-inflammatory, immunomodulator, or corticosteroids [8,11]. ...
Background:
Recurrent aphthous stomatitis (RAS) is a common chronic inflammatory oral disease which negatively impacts the quality of life. Current therapies aim to reduce pain and healing process yet challenges such as rapid loss due to salivary flushing in topical drugs and adverse effect due to prolonged use of systemic medications require further notice. Low-level laser therapy is reported with immediate pain relief and faster healing thus preserving potential for optimal treatment modalities. This review critically analyses and summarizes the effectiveness of LLLT in reducing pain score and healing time of RAS.
Methods:
A systematic search was conducted in ScienceDirect, PubMed, and Scopus using keywords of low-level laser therapy, photo-biomodulation therapy, and recurrent aphthous stomatitis. RCTs between 1967 to June 2022, presenting characteristics of laser and reporting pain score and/or healing time of RAS after irradiation were included. Animal studies and recurrent aphthous ulcer with a history of systemic condition were excluded. Studies were critically appraised using RoB 2 tool. A meta-analysis was performed using inverse variance random effects.
Results:
Fourteen trials with a total of 664 patients were included. Reduced pain was reported in 13 studies, while shortened healing time was presented in 4. The pooling of two studies after CO2 irradiation demonstrated faster healing time compared to placebo (MD: -3.72; 95% CI: -4.18, -3.25).
Conclusion:
Pain score and healing time of RAS were reduced after irradiation with LLLT. RoB resulted in “some concerns” urging well-designed RCTs with larger samples to further assess each laser application for comparison.
Systematic review registration: PROSPERO CRD42022355737.
... The oral cavity remains moist as a result of saliva secretion, and muscle movement due to chewing and speaking also makes it show a highly dynamic characteristic (Zhang et al., 2021), these factors pose challenges in maintaining the therapeutic concentration of drugs locally. The types of agents commonly used clinically for treating such oral soft tissue diseases include mouthwashes, powders, sprays, etc., which are readily rinsed away by saliva or food, thereby diminishing their therapeutic effect (Suharyani et al., 2021). Therefore, there is an urgent need to develop drug-delivery materials that are better suited for topical treatment of oral mucosa. ...
Oral mucosal wounds exhibit an increased susceptibility to inflammation as a consequence of their direct exposure to a diverse range of microorganisms. This causes pain, slow healing, and other complications that interfere with patients’ daily activities like eating and speaking. Consequently, patients experience a significant decline in their overall quality of life. Therefore, the pursuit of novel treatment approaches is of great importance. In this study, ginsenoside Rg1, a natural active substance extracted from ginseng root, was chosen as a therapeutic agent. It was encapsulated in a screened photo-crosslinked hydrogel scaffold for the treatment of mucosal defects in the rat palate. The results demonstrated that Rg1-hydrogel possessed excellent physical and chemical properties, and that oral mucosa wounds treated with Rg1-hydrogel exhibited the greatest healing performance, as evidenced by more pronounced wound re-epithelialization, increased collagen deposition, and decreased inflammatory infiltration. Subsequent investigations in molecular biology confirmed that Rg1-hydrogel stimulated the secretion of repair-related factors and inhibited the secretion of inflammatory factors. This study demonstrated that the hydrogel containing ginsenoside Rg1 significantly promotes oral mucosal tissue healing in vivo. Based on the findings, it can be inferred that the Rg1-hydrogel has promising prospects for the therapeutic management of oral mucosal wounds.
... The example of hyaluronic acid aims at indicating possible argumentations that could be used to support the prevailing mode of action of any specific mucoadhesive polymers and justify their use in medical devices. Same argumentations could also help in answering to request for clarification issued by the competent authorities European Commission, ( ), Suharyani et al., 2021 Author contributions BV: conceptualization, bibliography curation and writing. SR and GS: editing and review of contents. ...
The paper is intended to deal with the regulatory status of the family of substance-based medical devices (SB-MD) which contain mucoadhesive polymers. Mucoadhesive formulations are mainly intended for oral/buccal, gastro-esophageal, nasal, or vaginal administration routes. They contain one or more substances/polymers of either natural, synthetic or semi-synthetic origin endowed with mucoadhesive properties. These are complex substances whose chemical-physical properties are in general well characterized. Hydration and water retaining properties, gel formation, lubricating properties are example of functional characteristics that may be involved in mucosal interaction. However, there are still uncertainties as to the underlaying mechanisms. The idea is to provide support, to the understanding of the prevailing mechanisms of action of the family of SB-MD that exploit mucoadhesion phenomenon to exert the intended therapeutic action. A case study on Hyaluronic acid as a typical representative of mucoadhesive polymers, is presented. The correct understanding of the mechanism of action of the substances/polymers involved in SB-MD is pivotal to a smooth and successful submission to the involved regulatory bodies to a positive assessment and to the final approval.
... Several studies have suggested that buccally applied liposomes provide appropriate drug concentration in the oral mucosal tissues while minimizing systematic drug effects [15,16]. In addition, liposomes can release the encapsulated drug in a more controlled pattern. ...
This study aims to formulate a buccal mucoadhesive gel containing prednisolone sodium metazoate-loaded quatsomes for efficient localized therapy of recurrent aphthous ulcers. Quatsomes were prepared using a varied concentration of quaternary ammonium surfactants (QAS) and cholesterol (CHO). A 23 factorial design was conducted to address the impact of independent variables QAS type (X1), QAS to CHO molar ratio (X2), and sonication time (X3). The dependent variables were particle size (PS; Y1), polydispersity index (PDI; Y2), zeta potential (ZP; Y3), entrapment efficiency percent (EE%; Y4) and percent of drug released after 6 h (Q6%: Y5). Then, the selected quatsomes formula was incorporated into different gel bases to prepare an optimized mucoadhesive gel to be evaluated via in vivo study. The PS of the developed quatsomes ranged from 69.47 ± 0.41 to 113.28 ± 0.79 nm, the PDI from 0.207 ± 0.004 to 0.328 ± 0.004, ZP from 45.15 ± 0.19 to 68.1 ± 0.54 mV, EE% from 79.62 ± 1.44 to 98.60% ± 1.22 and Q6% from 58.39 ± 1.75 to 94.42% ± 2.15. The quatsomal mucoadhesive gel showed rapid recovery of ulcers, which was confirmed by the histological study and the evaluation of inflammatory biomarkers. These results assured the capability of the developed quatsomal mucoadhesive gel to be a promising formulation for treating buccal diseases.
... Table 6 lists sixty-two studies that investigated at various drug delivery approaches used to treat RAS. In the studies, four different preparation forms were used for the BDDS: liquids, semisolids, solids, as well as other 96 . ...
... This issue, shared by both buccal and sublingual administration methods, may be overcome by ad hoc delivery systems. In this regard, various DDSs, including fibers, strips, inserts, implants, films, gels, wafers, sprays, and microparticles, have been developed based on biomaterials with mucoadhesive properties, such as chitosan, alginate, cellulose derivatives, and carbomers [18][19][20]. As a paradigmatic example, Jin et al. created a mucoadhesive patch for the targeted administration of methotrexate in oral cancer, enabling site specificity, programmed drug release, and improved patient compliance [21]. ...
Due to its numerous advantages, such as excellent drug accessibility, rapid absorption, and bypass of first-pass metabolism, the route of drug administration that involves crossing the oral mucosa is highly favored. As a result, there is significant interest in investigating the permeability of drugs through this region. The purpose of this review is to describe the various ex vivo and in vitro models used to study the permeability of conveyed and non-conveyed drugs through the oral mucosa, with a focus on the most effective models. Currently, there is a growing need for standardized models of this mucosa that can be used for developing new drug delivery systems. Oral Mucosa Equivalents (OMEs) may provide a promising future perspective as they are capable of overcoming limitations present in many existing models.
... The acute discomfort imposed by aphthous ulcers has been treated using a variety of techniques and preparation forms for RAS treatment that contain both active ingredients and excipients [19]. Patients have not yet received a therapy Open Journal of Stomatology regimen that is immediate, efficient, has few adverse effects, and is affordable. ...
Background: Oral aphthosis has a negative impact on oral health. This study aimed to assess the effectiveness of gel formulation including diclofenac and propolis in the treatment of oral ulcers. Methods: Participants included 100 normal individuals with aphthous, excluding those having allergies to any ingredient in the diclofenac formulation. Patients were randomly assigned into two groups: one group received treatment with a combination of diclofenac potassium 3% (10 mg/g, 60 g) and propolis 5% gel (Group II), and the other group received a placebo (Group 1). The patient was evaluated using standard digital photographs and chronic oral mucosal questionnaires on days 1, 3, 5, and 7 after healing. Utilizing the Mann-Whitney U test, the two groups were compared. Each group's changes were examined using Friedman's test. Results: There was a statistically dramatic change over time in Group II. After one day, the median total score dropped statistically significantly, and from one to three days with effect size (d) 2.485, Group II demonstrated 48% complete healing and 52% partial healing, while Group I demonstrated 4% partial healing and 96% no change. Effect size (V): 0.995. Conclusions: The combination of diclofenac and propolis provided instant relief and an affordable new regimen for treating oral aphthosis.
... Various gels have been produced with the goal of achieving prolonged drug release for a local therapeutic effect. Many preparations have been developed in the past, including the discovery of the active component and excipients used as a covering agent or healing agent [5] ...
Objective:
The aim: To make a narrative assessment of the agents currently in use, with a particular emphasis on the topical agents that we frequently utilize in our practice.
Patients and methods:
Materials and methods: The main method of this work is a review of literary sources. We reviewed the literature (PubMed, Google Scholar, Web of Science, Scopus) to support and explain the interventions we use in different cases of oral mucositis patients. We decided to combine our experience with evidence-based data.
Conclusion:
Conclusions: Topical treatments alleviate and prevent oral mucositis. Topical medicines can assist maintain oral balance and moistness by modulating oral bacteria and replacing saliva.
