Mouth Ulcer Management via Oral Films: A Critical Review of Formulation, Evaluation, and Future Directions

Abstract

Mouth ulcers are a widespread and debilitating condition. Recent research suggests that riboflavin, a B-complex vitamin, may offer a promising treatment option due to its antioxidant and anti-inflammatory effects. This review delves into the development and efficacy of riboflavin oral films, a novel delivery system that enhances bioavailability and targets the affected area. We summarize the current research on riboflavin oral films, discussing their benefits, challenges, and therapeutic potential in treating mouth ulcers. This comprehensive review serves as a valuable resource for researchers, formulation scientists, and clinicians seeking to optimize riboflavin oral films for mouth ulcer treatment.

Keywords

Introduction

A mouth ulcer, sometimes referred to as an oral or mucosal ulcer, is an uncomfortable, round or oval sore that develops on the oral cavity's mucous membrane, usually on the inside of the lips or cheeks. These ulcers are frequent and can result from a number of factors, frequently without a significant underlying medical issue. Iron, vitamin B12, vitamin C, and other nutritional deficiencies, as well as poor mouth hygiene, infections, stress, indigestion, mechanical injury, food allergies, hormonal imbalances, and specific skin conditions, are common triggers. Because they entail the erosion or loss of some of the delicate tissue lining the mouth, mouth ulcers also known as aphthous ulcers can be uncomfortable during eating, drinking, or tooth brushing.^[1]As a coenzyme in the metabolism of proteins, lipids, and carbohydrates all essential for the creation of cellular energy riboflavin, also known as vitamin B2, plays a critical role in cellular growth and maintenance. It has a crucial role in preserving mucosal integrity, particularly when it comes to oral health. Powers (2003) asserts that riboflavin is necessary for the production of glutathione, an antioxidant that shields cells from oxidative stress and is especially important for mucosal tissue healing.^[7] Oral films have emerged as a promising delivery system for riboflavin, offering enhanced bioavailability and targeted delivery to the affected area. This review aims to provide a comprehensive overview of riboflavin oral films, encompassing their formulation, physicochemical properties, and therapeutic efficacy, with a focus on their potential applications in treating mouth ulcers.

1.1.Introduction of Oral films :-  A unique strategy for individuals who have trouble swallowing pills or capsules was the use of fast-dissolving films for oral delivery. Swallowing solid dosage forms is a challenge for elderly, juvenile, and dysphasic patients with a variety of medical issues. According to one study, 26% of 1576 individuals had trouble swallowing medications.^[2]The goal of oral dissolving films is to dissolve or disintegrate in a matter of seconds. They have benefits like easy dosing, quick start of action, and water-free administration. Absorption through the oral mucosa is feasible for rapidly dissolving active medicinal components, which could enhance bioavailability.^[3]

1.2.Ideal properties of Oral fims:-  oral films should possess properties such as thinness, flexibility, smooth texture, uniform thickness, rapid dissolution, high bioavailability, stability, compatibility, neutral taste and odor, and comfortable mouthfeel to ensure effective and patient-friendly drug delivery.

Figure 1 : Oral Films

1.3.Ideal Characteristics of oral fims :-^[4]

• A thin, attractive film.
• It comes in a variety of sizes and forms.
• It is unobtrusive.
• It  has excellent mucoadhesion,
• It dissolves and releases quickly.

1.4.Classification of oral films:-

Table1. Classification of oral films.^[5] 

There are three different subtypes of oral films:

• Flash release wafers
• Mucoadhesive melt away wafers
• Mucoadhesive sustained release wafers  

2.Overvieww of the oral cavity:-

Figure 2 .Anatomy of oral mucosa

The basement membrane, lamina propria, submucosa, and stratified squamous epithelium are some of the layers that make up the oral mucosa. The oral mucosa is in between the intestine and epidermis in terms of permeability. Interestingly, the permeability of the buccal mucosa is 4–4000 times higher than that of the skin. Furthermore, because the oral mucosa varies in structure and function, different areas of the oral cavity have different amounts of permeability.^[6]

Sublingual gland:-Located under the tongue, the sublingual glands play a crucial role in saliva production, facilitating food lubrication, bolus formation, and swallowing. Additionally, these glands enable direct drug absorption into the systemic circulation due to their thinness, high permeability, and rich blood supply. The sublingual glands produce mucin, which contributes to saliva production, making them a vital component of the oral cavity. The oral cavity is lined with a mucous membrane composed of squamous cells and mucous glands, which facilitate saliva production through salivary glands, including the parotid, submandibular, and submaxillary glands. Saliva mixes with food, enabling easy chewing and swallowing. The absorption of drugs into systemic circulation is inversely proportional to the thickness of the absorption layer. The sublingual route offers the fastest absorption, followed by buccal, gingival, and palatal routes. Due to its high permeability and rich blood supply, the sublingual route enables rapid onset of action, making it suitable for drugs with short delivery periods and frequent dosing regimens.^[5]

Mechanism of Absorption:-

Upon sublingual administration, drugs are rapidly absorbed into the bloodstream through the reticulated vein beneath the oral mucosa, bypassing the gastrointestinal tract. The absorbed drugs are then transported through the facial, internal jugular, and braciocephalic veins, eventually draining into systemic circulation. This direct access to the bloodstream enables rapid absorption, with the sublingual route exhibiting 3-10 times greater absorption than the oral route, surpassed only by intravenous injection. The primary mechanism of drug absorption through the oral mucosa is passive diffusion across the lipoidal membrane.^[8]

3. Marketed Films:-

3.1.Methods of Preparation of mouth dissolving oral films:-

 Solvent casting method:-Polymers that are water soluble are dissolved to create a Homogeneous solution. Drugs and other water-soluble Ingredients are given a little amount of water to dissolve in. Continuous stirring is used to combine the two solutions. Applying a vacuum removes air bubbles that have become Entrapped. The produced solution is cast onto Petri dish and Then divided into bits.^[9][14]

Semisolid casting method:-This method is recommended when film preparation calls for acid-insoluble polymers. The semisolid casting method uses heat-controlled drums to cast gel material into the films or ribbons. A film-forming solution and an acid-insoluble polymer solution in sodium hydroxide or ammonium hydroxide are combined to make gel mass. Acids cannot dissolve the polymers cellulose acetate butyrate and cellulose acetate phthalate. It is recommended to use a ratio of 1:4 between acid-insoluble and film-forming polymers.^[10]

Hot melt extrusion:- This procedure makes use of a hot melt extruder. Using heat, a polymer is shaped into a film using this approach. The hopper is filled with a mixture of dry pharmaceutical components, including API, which are then transported, combined, heated, and extruded out in a molten condition by the extruder. The film is cast using the molten mass that is created in this way. The casting and drying procedure is an essential phase. Numerous benefits come with this technology, including the drug carrier mix's shorter residence durations and lower temperature, the lack of organic solvents, the ability to operate continuously, the ability to minimize product waste, excellent control over operating parameters, and the potential for scaling up.^[11][12]

Solid dispersion:-When one or more active chemicals are dispersed in an inert carrier in a solid form while amorphous hydrophilic polymers are present, this is referred to as solid dispersion. This process involves dissolving medications in appropriate solvents, which are subsequently added to the polyethylene glycol melt below 70 degrees Celsius. Then, using dies, solid dispersions are ultimately formed into the films.^[13]

Rolling method:-A drug-containing solution or suspension is rolled on a carrier in the rolling method. Water and a combination of water and alcohol make up the majority of the solvent. After drying on the rollers, the film is cut into the appropriate sizes and shapes. Using a high shear processor, other ingredients, including the active substance, are dissolved in a tiny amount of aqueous solvent. A uniform viscous solution is created when water-soluble hydrocolloids dissolve in water.^[15]

Evaluation of mouth dissolving oral films:-

Tensile strength:-Tensile strength is maximum stress applied to at which film specimen breakes. It is Calculated by the load at rupture divided by the cross Section area of the film Tensile strength = F max/A film.^[16]

Youngs modulus: - It is use to estimate stiffness. It is found as balance applied stress to the strain area.^[17]

Thickness:-Thickness of a buccal film is influenced by distribution uniformity of components of in the region.it is determind by, Youngs modulus = force of corresponding strain/cross sectional the formulation. Thickness range should be 5-200 micro meter. It is measured by a digital Vernier caliper or a micrometer Screw gauge.^[18]

Surface pH:-To identify whether film produces any irritation to buccal mucosa, the surface pH of all formulation is Measured after swelling. The pH of the film’s surface must be checked. The film’s surface pH should be Neutral, i.e., 7, or near to 7. For this, a mixed pH electrode can be utilized. The pH is determined by putting The electrode in contact with the film and noting the pH measurement. This test is performed on at least 6 Films, and the mean SD may be computed to get the final surface pH value.^[19]

Assay/Content uniformity:-By estimating the drug content in each film, it was possible to determine whether the drug was distributed Uniformly in the formulation. In each formulation, three films are taken randomly from six films. Individually weighed films were dissolved in the solvent system for 30 min while being continuously stirred On a water bath for 6 hours at a temperature of 37 °C.^[15] Standard method should be followed as per Pharmacopoeia for different drugs, content uniformity should be within the limit of 85-115%.^[20]

Folding endurance:-Folding endurance represents the brittleness or mechanical strength of the film. It is determined manually, By folding the film repeatedly at the same line until it breaks. The value of folding endurance represents the Number of times film folded without breakage.^[21]

In vitro disintegration test:-When film is exposed to water or saliva the time taken by the film to        disintegrate or break is considered as Disintegration time. The medium used is phosphate buffer. Disintegration time should be between 5-30 sec.^[21]

In vitro dissolution test:-The dissolution is the amount of drug from the formulation, which goes into the solution at standard Condition of temperature and solvent. The selection of dissolution media is very important and most of the Time the film floats on the medium, therefore sink condition can be considered. Temperature preferred Should be 37°C at 50 rpm.^[22]

Storage and Packaging of Films:-Fast dissolving films comes in a number of storage and packaging choices. The packaging stage allows Medicine manufacturers to be more flexible with their products. For films, single packaging is required; the Most typical packaging shape is an aluminum bag. The Rapid card, a proprietary and patented packaging System developed for the Rapid films. Each side of the fast card stores three raid films and is the same size As a credit card. Every dose can be taken separately.^[22]

CONCLUSION :-

Riboflavin oral films demonstrate promising potential in mitigating mouth ulcers, offering a novel and effective therapeutic strategy.The topical delivery of riboflavin via oral films presents a viable approach to alleviate mouth ulcer symptoms and promote oral health.Riboflavin oral films exhibit therapeutic benefits in managing mouth ulcers, underscoring their potential as a valuable adjunctive treatment option.The application of riboflavin oral films may provide a safe and effective means of reducing the incidence and severity of mouth ulcers. The evidence suggests that riboflavin oral films hold promise as a treatment for mouth ulcers, warranting further investigation and clinical translation.

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