Binahong leaf extract ( anredera cordifolia ) mucoadhesive patch as an alternative therapy for recurrent aphthous stomatitis

Background: Recurrent Aphthous Stomatitis (RAS) is one of the most common oral diseases of all ages. There has been no study that defines the leading cause of RAS. The utilization of binahong leaves (Anredera cordifolia) can be beneficial for the treatment of RAS as it acts as an anti-inflammatory and accelerates the proliferation of fibroblasts. The combination between binahong leaves and the mucoadhesive patch will increase the effectiveness of RAS treatment. Method: Literature study through PubMed and Google Scholar databases was conducted using PRISMA flow chart looking for the efficacy of binahong leaves (Anredera cordifolia) for mucosa wound healing and mucoadhesive patches for the treatment of RAS. Result: The search results found 31 articles that met the criteria for analysis. Flavonoids and saponins in binahong leaves extract act as an anti-inflammatory and increase the proliferation of wound healing. Mucoadhesive patch formulation can increase the effectiveness of RAS treatment on the mucosa. Conclusion: Binahong leaves extract in the form of mucoadhesive patches can be used as an alternative treatment for Recurrent Aphthous Stomatitis.

Anti-inflammatory, analgesic, and antioxidant properties are found in flavonoids, 3,4 while saponin has the potential to stimulate fibroblast proliferation to accelerate the healing process. 5 Up to this day, RAS treatments mainly use topical antiseptics, antibiotics, anti-inflammatory drugs, corticosteroids, and systemic drugs in the form of gels, creams, or ointments. These medications can adhere to the oral mucosa so that their anti-inflammatory effect has a strong potential. 6 Topical drugs that have been circulating inside the oral cavity have some drawbacks mainly the limited duration of attachment to oral mucosa and the side effects of oral candidiasis, and it can cause mucosal atrophy. 7 Therefore, an innovation needs to be developed in the form of a mucoadhesive patch.
Mucoadhesive patches are catching the eye as a treatment for oral diseases due to their superior advantages over conventional therapies. 8  Delivery of drug substances using this patch preparation is more controlled because of its ability to stick to the mucosa for a longer time compared to gel preparations, the ability to provide a protective barrier on the ulcer wound with the oral environment, and food, and it has lower side effects.
Based on the potentials of binahong leaves and mucoadhesive patches, researchers are interested in conducting a deeper literature review and combining them to find more effective alternative treatments in cases of canker sores or RAS. The purpose of this study was to determine the effectiveness of binahong leaf extract (Anredera cordifolia) in the mucoadhesive patch formula for the RAS healing process.

RESEARCH METHOD
The articles were collected based on

RESULTS
The aforementioned keywords yield a total of 3,879 articles. After undergoing a screening process based on the title, abstract, and full-text availability, the final articles used comprised 31 articles. To analyze the effect of 3% binahong leaf extract gel on post-extraction wound healing.

Human
Clinical experimental using a post-test study design with a control group.
Binahong leaf extract gel 3% can decrease the duration of time on the socket wound healing process.
Binahong leaf extract (anredera cordifolia) mucoadhesive patch as an alternative therapy for recurrent aphthous stomatitis To know the effective dose of binahong extract within its analgesic activity.
In vivo (Swiss Webster mice) Binahong leaves were extracted by the reflux method. Peripheral analgesic activity of binahong leaf extract was conducted using the Siegmund method in different doses, namely 50 mg/kg bw (body weight), 100 mg/kg bw and 200 mg/kg bw and induced with 0.6% acetic acid.
The best analgesic activity was shown by the aqueous extract of binahong leaves at doses of 100 mg/kg bw and 200 mg/kg bw which was statistically identical to the activity of aspirin.

Ulfah et al, 2019
To assess the effect of increasing sorbitol and sodium carboxymethylcellulose (CMC) on the antiulcer activity of Anredera cordifolia leaf extract in male wistar rats.

In vivo (Wistar rats)
Making binahong leaf extract preparations; extract-sorbitol combination; combination extract-sorbitol and sodium CMC. Then the test animals have induced with peptic ulcers and observed directly and histopathological tests.

The
formulation results showing the highest anti-peptic ulcer properties were in sorbitol preparations, the second highest was the combination of sorbitol and sodium CMC preparations, while the least was in the leaf extract preparations without any combination.

Mulia et al, 2017
To determine the effectiveness of the Natural Deep Eutectic Solvent (NADES) made of betaine and 1,4 butanediol as solvents during the extraction process of the binahong leaf vitexin compound.
-Combining betaine-based NADES with 1,4 butanediol in a ratio of 1:3 as a solvent for the extraction process of binahong leaves. Vitexin was analyzed qualitatively and quantitatively using HPLC.
NADES containing betaine and 1,4 butanediol are an environmentally friendly solvent for extracting vitexin from binahong leaves. The extraction process can also be carried out above the ambient temperature, as long as it does not surpass the degradation temperature of the extracted bioactive compounds.

Rahmawati et al, 2016
To check the standard requirements of effervescent granules from binahong leaves extract and determine the best formulation from it. To know the most effective binahong leaf extraction formulation for producing flavonoids and antioxidant activity.
-Binahong leaf extraction process using Microwave assisted extraction (MAE) method. Extract quality parameters were carried out based on the Response Surface Method (RSM) with several variables.
The levels of antioxidant activity and flavonoids are known to reach the optimal point after extraction for 13.84 minutes using 81.49% ethanol.

Mulangsri et al, 2020
To determine the antibacterial activity profile of ethanolic extract and purified extract of binahong leaves against S. epidermidis bacteria.
-Maceration method extraction using 96% ethanol as solvent. The ethanol extract of binahong leaves was then purified with nhexane as solvent. Ethanol extract and purified extract of binahong leaves were tested for antibacterial activity on S. epidermidis bacteria by agar diffusion method.
The purified extract of binahong leaves has better antibacterial activity than the ethanol extract. The concentration of purified extract required is smaller than the ethanol extract of binahong leaves in providing antibacterial activity.

Surbakti et al, 2018
Determine the secondary metabolite compounds and the potential toxicity of the binahong leaves. - The cytotoxicity of binahong leaves ethanol extract was tested by using Brine Shrimp Lethality Test (BSLT) method.
Ethanol extract of binahong leaves contains saponins, steroids, and flavonoids. The extract also carries the potential of toxicity through the BSLT test.

Laksmitaw ati et al, 2017
Observe the antiinflammatory potential of A. cordifolia and P. crocatum extracts on murine LPSinduced macrophage cells.
-Extraction of A. cordifolia and P. crocatum using the maceration method. Cell culture was performed and cell viability was evaluated using the MTS test.
The anti-inflammatory activity of A. cordifolia and P. crocatum was achieved through the inhibition of inflammatory mediators like IL-6, NO, and TNF-alpha.

Sjahid et al, 2020
To provide a solution to the limitations of obtaining phenol and flavonoid levels from binahong leaves (Anredera cordifolia) so that the efficiency of the extraction process can be achieved if needed on a large scale. Mixing PVP with chitosan on the membrane can increase thermal stability. Then PVP increases the rate of swelling ratio resulting in faster drug release (80% in less than an hour) and increases the strength of mucoadhesion.
Abo-shady et al, 2020 To develop a drug delivery system with a controlled release mucoadhesive buccal film containing HA to solve the issues with the fast wash-off of mouth rinses and gels used to treat aphthous ulcers.

In vitro
Hyaluronic acid (HA) films were made using crosslinked coagulation technique and then evaluated for physicochemical properties, mucoadhesive properties, tensile strength, and in vitro drug release ability.
Hyaluronic acid (HA) formulation produces a stronger effect and resistance to saliva and food so that it is safe, effective, and stable when used as a treatment for aphthous ulcers.

Wei et al, 2019
Investigated the drug release behaviors, antioxidant properties, anti-inflammatory attributes, and cytotoxicity of the mucoadhesive patches combined with curcuminloaded polylactic acid (PLLA) nanofibrous meshes as RAS therapy.

In vitro
Generated the electrospinning to produce curcuminencapsulated PLLA nanofibrous meshes. Then prepare the mucoadhesive patches and combine them with the curcumin PLLA nanofibrous meshes.
The mucoadhesive patches can bring a great treatment effect for RAS because the pain was reduced, and act as an anti-inflammatory, antioxidant and antibacterial. The high curcumin dose showed a good antioxidant and anti-inflammatory activity than the low dose. Also, the patch can adhere greatly to the pig buccal mucosa.

Haghpanah et al, 2015
To assess the effectiveness of bioadhesive-containing ginger for RAS treatment.
Human A randomized clinical study in 15 patients. Supplied 2 mucoadhesives; placebo (non-medicated mucoadhesive) and mucoadhesive containing the ginger extract. Then evaluated for pain, zone of inflammation, and ulcer diameter for 10 days.
Inflammation was significantly reduced on day one. However, this muco-bioadhesive containing ginger has not been able to relieve pain in RAS patients.

Zhang et al, 2019
To know the characteristics of mucoadhesive buccal films containing Ornidazole (OD) and Dexamethasone sodium phosphate (DEX).

In vivo and In vitro
Develop the OD and DEX films using the casting method or solvent printing according to the desired mucoadhesive characteristics and properties.
The combination of OD and DEX in the mucoadhesive buccal film can increase the effectiveness of the treatment of oral ulcers by distributing the drug evenly and an impermeable layer that can control the direction of drug release.

Carvalho et al, 2020
To determine the effect of bacterial nanocellulose (BNC) based patch containing hyaluronic acid (HA) and diclofenac (DCF) on the stimulation of ulcer healing in RAS.   (Table 4).    Meanwhile, the potential for saponins as antioxidants is shown through their ability to reduce superoxide through the formation of hydroperoxide intermediates to prevent biomolecular damage caused by free radicals. 17

Effectiveness of Mucoadhesive Patch in RAS healing process
The mucoadhesive patch is a drug delivery system that is used by attaching a patch to the gingiva mucosa or the inner cheek membrane. The mucoadhesive drug delivery system is more