Curcumin-containing oral film for healing mouth ulcers

Abstract

The invention relates to an oral film designed for use in the treatment of mouth ulcers, featuring wound-healing properties provided by its curcumin content. The film can be easily adhered to the wound and ensures prolonged interaction with the wound surface due to the slow degradation of starch, which facilitates the gradual release of curcumin. Additionally, the use of polyvinylpyrrolidone (PVP) grants the oral film bacteriostatic properties, preventing the treated mouth ulcers from becoming infected. The components of the oral film are low-cost and environmentally friendly, facilitating ease of production.

Description

[0001] CURCUMIN-CONTAINING ORAL FILM FOR HEALING MOUTH ULCERS

[0002] Technical Field

[0003] The invention relates to a bacteriostatic oral film containing curcumin, developed for use in treating ulcers formed in the mouth due to various causes. The curcumin within the structure of the oral film is absorbed by the wound through slow release, thereby accelerating the healing process of the ulcer. Additionally, the biodegradable property of the oral film enables it to disintegrate over time after being applied to the wound, providing controlled and slow release while also ensuring ease of use for patients.

[0004] State of the Art

[0005] The mouth, being the first step of the digestive system, also houses the tongue, one of the five sensory organs. Beyond its role in eating and drinking, the mouth is also used for breathing and is composed of the tongue, teeth, and gums, which are exposed to numerous bacteria and impacts throughout the day. These bacteria can enter the oral cavity from the air or through consumed food, potentially causing diseases. Since the mouth has the ability to eliminate these bacteria before they cause illnesses, it forms one of the defense mechanisms of the human body.

[0006] Mouth ulcers, also referred to as oral ulcers, are sores that form in the soft tissues of the inner regions of the mouth, such as the inner cheeks. Causes of mouth ulcers include infections, side effects of medications, smoking and alcohol use, stress, and inadequate sleep. While mouth ulcers typically do not stem from severe underlying conditions, ulcers that recur three or more times within a year may signal diseases such as Behget’s Disease or tuberculosis

[0001] , In addition to such diseases, mouth ulcers may also result from trauma, such as the teeth striking cheek tissues during speech, shouting, eating, biting the cheek, or damage caused by dental instruments during dental procedures. Although the appearance of mouth ulcers may vary from person to person, they generally present as white depressions with a diameter of 4-5 mm (sometimes larger than 1 cm) [2], These ulcers can occur on any part of the cheek tissue or tongue and cause significant pain during speech and eating. They often prevent individuals from eating and significantly reduce their quality of life. Depending on the cause of the ulcer, they generally do not heal within 10 to 15 days without treatment. Healed mouth ulcers usually do not leave visible scars on the tissue. However, due to the intense pain they cause and their interference with daily activities such as eating and speaking, many people seek various treatment methods. Moreover, like any other wound, mouth ulcers pose a risk of infection due to their nature as a disruption of tissue integrity. If an infection develops, the healing process of the ulcers can be prolonged, often necessitating the inclusion of additional treatments, such as antibiotics.

[0007] A variety of treatment methods have been developed to address mouth ulcers, which affect 10-25% of the population. These treatments are chosen based on the underlying cause of the ulcer. For minor cases, mild treatments such as topical creams are preferred. However, when the ulcer is caused by an underlying condition or infection, more intensive treatments are employed. Medications used in such intensive treatments often contain chemical components, which can lead to resistance against antibiotics or other active ingredients in patients, as well as potential side effects [3]. For these reasons, research efforts have increasingly focused on replacing chemicalbased active ingredients in mouth ulcer treatments with plant-derived alternatives in recent years. Studies have revealed that plants such as pomegranate, onion, and basil possess wound-healing properties due to their natural components, prompting further exploration of their use in treating mouth ulcers. Another plant-based compound with the potential for treating mouth ulcers is curcumin. Curcumin (diferuloylmethane) is a molecule found in turmeric (Curcuma longa L.). Despite its potential, there is a significant lack of treatment methods utilizing curcumin for mouth ulcers. Moreover, existing curcumin-based treatments in current technologies have certain disadvantages that limit their effectiveness.

[0008] In the state of the art, both systemic and topical treatment methods utilizing curcumin are available. The topical application of curcumin in the form of gels and pastes for mouth ulcers has been reported [5,6]. It has been stated that topical use enhances the efficacy of curcumin compared to systemic use [8]. In dentistry, curcumin is predominantly used in gel forms [14,15]. However, products in gel form are only effective during the application period [5,6], while paste forms have been reported to cause complaints of burning sensations in the mouth and unwanted yellow staining in patients

[0016] . Systemic use of curcumin in the treatment of oral diseases has also been noted [7], However, systemic administration of curcumin for conditions such as oral lichen planus has not shown additional therapeutic benefits compared to systemic corticosteroid treatment [8]. Studies have reported that systemic absorption of curcumin is low [9], and it is rapidly eliminated from the body

[0020] . Additionally, when taken orally, most curcumin is converted into water-soluble metabolites, glucuronides, and sulfates, resulting in low levels of free curcumin in the bloodstream

[0011] , Systemic use may also lead to undesirable side effects, such as diarrhea [12,13].

[0009] In the state of the art, topical creams are commonly used for the treatment of mouth ulcers. These creams typically contain corticosteroid structures, also known as cortisone. Since the application of these creams on the wound often restricts speech, they are generally applied in the evening or before bedtime. However, due to the corticosteroid content of these creams, ingestion can be harmful. Furthermore, these creams are primarily used to treat mouth ulcers caused by viral infections such as Varicella or Herpes Simplex and are inadequate for treating trauma-induced ulcers, such as those caused by biting. Additionally, the corticosteroids present in these creams have numerous side effects. Short-term effects include swelling in the body, particularly in joint areas, as well as increased blood sugar and blood pressure levels. Long-term use may lead to corticosteroid accumulation in the kidneys, resulting in impaired kidney function, muscle weakness, and heart failure. Prolonged use of corticosteroids can also result in corticosteroid resistance, necessitating increased dosages during treatment. Even with medical treatments, the healing process for mouth ulcers can take up to a week and, in some cases, even longer. During this time, patients are exposed to the side effects of corticosteroid-containing creams. Considering the frequent recurrence of mouth ulcers, patients often need to use these corticosteroid-containing creams regularly and over extended periods. The aforementioned mouth ulcer cream has several drawbacks, such as being effective only for viral infection-induced ulcers while being inadequate for trauma-induced ones. Moreover, the corticosteroid content leads to short- and long-term side effects in users. The use of gels, creams, and pastes in these treatment methods depends mainly on the patient’s initiative. Disadvantages of these forms include uncertainty about whether patients are using the treatments consistently and a lack of knowledge about how long the active ingredient remains on the ulcer surface. Another example from the state of the art is the patent application CN1 14129767A, which introduces a wound surface protective adhesive designed for use on soft tissues. This protective adhesive forms a closed colloidal film on the surface of wounds in the oral cavity, esophagus, stomach, intestinal tract, and skin ulcers. The film protects the wounds, prevents the effects of external stimuli, reduces the size of the wounds, and supports their healing. The adhesive comprises a colloidal liquid phase prepared using glucomannan, carrageenan, and similar materials; an anionic polymer such as pectin; a thixotropic agent like lithium magnesium silicate; a cationic polymer made from starch; and hydroxypropyl methylcellulose as a thickening agent. Although plant-based structures can be utilized in the adhesive’s formulation, they are associated with certain side effects. For instance, glucomannan, preferred in the colloidal liquid phase, can cause bloating and gastrointestinal blockages. Research on carrageenan has indicated that it may have properties that trigger intestinal and colon cancers. Additionally, the thixotropic agent lithium magnesium silicate contains lithium metal, which can accumulate in the brain and lead to severe side effects. The adverse effects associated with the components of this adhesive, including significant health risks, lead to its low acceptance among users.

[0010] Another example from the state of the art is patent application EP3381448A1 , which introduces an oral film designed to prevent micro-bleeding on wound surfaces and enable controlled release of its components. Once adhered to the wound, this oral film gradually dissolves over time, eliminating the need for patients to remove it manually, thereby offering ease of use. The composition of the film includes alcohols and biodegradable polymers, giving the film the ability to absorb blood, saliva, and pus. Additionally, it contains disintegrants that react with blood to dissolve and release drugs through microchannels. These microchannels serve as drug delivery pathways, and their quantity and size can be adjusted to control the drug release rate. Several components can be used to impart these properties to the oral film. For example, alcohol structures like glycol and sorbitol are preferred for their construction, while crystalline cellulose is utilized for disintegration capability. However, these components are not without their drawbacks. Glycol is known to cause skin irritation, inflammation, and respiratory issues. Similarly, sorbitol can cause gas formation in individuals with sorbitol intolerance, even in very low doses. While the oral film offers ease of use, the side effects caused by its components and its limited efficacy in directly contributing to wound healing make it insufficient for the treatment of mouth sores.

[0011] The limitations and inadequacies of the solutions in the current art have necessitated advancements in this field for several reasons: the creams used for treating mouth sores often contain corticosteroids and other harsh substances, making them insufficient for treating traumatic mouth sores; adhesive wound protectants include components that can trigger severe conditions such as cancer; and while existing oral films provide wound protection, they fail to contribute to wound healing. These shortcomings highlight the need for the development of improved solutions in this area.

[0012] Summary and Objectives of the Invention

[0013] The invention describes an oral film containing the plant-based structure of curcumin, designed to be applied to mouth sores. Thanks to its biodegradable properties, the oral film allows the controlled and gradual release of curcumin onto the wound, facilitating treatment through its healing properties.

[0014] One objective of the invention is to provide an oral film for the treatment of mouth sores that enables the controlled and gradual release of the active ingredient. The invention achieves this controlled and slow-release capability through the use of starch in the oral film. The starch begins to degrade upon contact with saliva, and this degradation process continues gradually for approximately 25 minutes. The release of the active ingredient starts within the first 5 minutes. These durations are determined through trials conducted with pure water. Thanks to this slow degradation, or biodegradability, the active ingredient contained in the oral film is steadily distributed onto the wound, maintaining continuous interaction with the sore and enabling prolonged treatment. Furthermore, the biodegradable nature of the oral film allows it to self-decompose after being applied to the mouth sore, eliminating the need for patients to remove the film manually, thereby offering significant ease of use.

[0015] Another objective of the invention is to provide a plant-based oral film with woundhealing properties for the treatment of mouth sores. The invention enables the use of oral film in the treatment of mouth sores by incorporating the wound-healing properties of the curcumin molecule into the film. In the oral film, hydroxypropyl methylcellulose (HPMC) ensures adhesion to the mouth sore, while starch, another component of the film, facilitates the gradual decomposition of the film in the mouth. This controlled degradation enables the release of curcumin, the active ingredient with wound-healing properties, onto the sore. The slow degradation of starch ensures that curcumin is gradually released over 25 minutes onto the wound, allowing the sore to be continuously exposed to curcumin’s healing properties throughout this period. The curcumin in the oral film provides an effective treatment for mouth sores with significantly fewer side effects compared to chemical methods, thanks to its natural wound-healing capabilities. The curcumin in turmeric is known to possess significant anti-inflammatory, antioxidant, anti-carcinogenic, anti-mutagenic, anti-coagulant, and anti-infective properties

[0017] , Due to its broad pleiotropic nature, curcumin targets various inflammatory factors, such as cytokines, interleukins, nuclear factor kappa B (NF-KB), reactive oxygen species (ROS), cyclooxygenase-2 (COX-2), C-reactive proteins, transforming growth factor-[3 (TGF-[3), and other enzymes involved in inflammation. Furthermore, curcumin has the potential to inhibit the expression of proteins such as protein kinase C (PKC), epidermal growth factor receptor tyrosine kinases (EGF-RTKs), c-jun, c-fos, c-myc, NF-KB-inducing kinase (NIK), mitogen- activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), Akt, cyclin-dependent kinases (CDKs), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and inducible nitric oxide synthase (iNOS). These properties make curcumin an effective candidate in combating numerous oral diseases, including oral submucous fibrosis, oral mucositis, oral leukoplakia, oral erythroplakia, oral candidiasis, aphthous stomatitis, oral lichen planus, dental caries, periodontitis, and gingivitis [18-21 ],

[0016] Another objective of the invention is to provide a bacteriostatic oral film for use in the treatment of mouth ulcers. One of the components of the oral film, polyvinylpyrrolidone (PVP), imparts bacteriostatic properties to the film, thereby protecting the mouth ulcer from infections. While the film slowly disintegrates and releases curcumin, the PVP protects the ulcer and its surrounding area from bacteria and potential infections. This effectively prevents unexpected infections and complications that could arise during the treatment of mouth ulcers.

[0017] Another objective of the invention is to provide an environmentally friendly and cost- effective oral film. In addition to curcumin, the oral film contains HPMC (hydroxypropyl methylcellulose), starch, and PVP. These materials impart properties such as wound healing, easy adhesion to the wound surface, and slow diffusion of curcumin to the oral film. Due to the ease of procurement and low cost of these materials, the oral film subject to the invention is easily endowed with biocompatibility properties.

[0018] This oral film aims to provide an effective treatment method for mouth ulcers by adhering effectively to the wound and then disintegrating, enabling the slow release of curcumin with its therapeutic properties. Its bacteriostatic properties protect mouth ulcers from infections while being a cost-effective and environmentally friendly treatment option.

[0019] Detailed Description of the Invention

[0020] The invention relates to a bacteriostatic oral film designed for the treatment of mouth ulcers. This oral film is enhanced with curcumin content, providing wound-healing properties. It adheres easily to the wound and, due to its slow disintegration, ensures prolonged interaction with the wound, enhancing the effectiveness of the treatment.

[0021] The oral film of the invention contains 5-7.5% by weight curcumin as the active healing agent. To enable adhesion to mouth ulcers, a 1 -3% by-weight solution of HPMC (hydroxypropyl methylcellulose) is included. For biodegradability, 6-9% by-weight starch is added, and for bacteriostatic properties, 10-15% by-weight polyvinylpyrrolidone (PVP) solutions are used to prepare the oral films. In another application of the invention, the oral film is prepared by homogenizing 6.25% by volume of curcumin, 1.25% by volume of HPMC, 7.5% by volume of starch, and 12.5% by volume of PVP. The mixture is cast using the solution casting method and left to dry in petri dishes.

[0022] Thanks to the HPMC (hydroxypropyl methylcellulose) included in the composition of the oral film, it adheres easily to the mouth ulcer. The starch in the film enables its gradual decomposition, allowing the curcumin, which has wound-healing properties, to slowly spread over the mouth ulcer. This slow decomposition ensures the controlled release of the active ingredient in curcumin onto the wound. Additionally, the PVP present in the oral film prevents the wound and surrounding tissue from being exposed to bacteria.

[0023] The preparation method of the oral film subject to the invention comprises the following steps: i. Preparing the HPMC (hydroxypropyl methylcellulose) solution by mixing it on a magnetic stirrer, ii. Mixing the starch solution until gelation occurs, iii. Mixing the prepared HPMC (hydroxypropyl methylcellulose) and starch solutions at room temperature until a homogeneous structure is achieved, iv. Adding the curcumin solution together with the polyvinylpyrrolidone solution to the HPMC-starch mixture and mixing until homogenization is achieved.

[0024] In another application of the invention, the preparation method of the oral film includes the following steps: i) Preparing a 1 -3% by weight HPMC (hydroxypropyl methylcellulose) solution by mixing it at 80°C on a magnetic stirrer at 75 rpm, ii) Preparing a 6-9% by weight starch solution by mixing it at 60°C at 75 rpm until gelation occurs, iii) Mixing the prepared HPMC (hydroxypropyl methylcellulose) and starch solutions at room temperature until a homogeneous structure is achieved, iv) Adding a 5-7.5% by-weight curcumin solution and a 10-15% by-weight polyvinylpyrrolidone solution to the HPMC-starch mixture and mixing for 2 hours until a homogeneous structure is observed, v) Processing the solution into an oral film by performing the following steps:

[0025] • Pouring the prepared homogeneous mixture into Petri dishes using the solution casting method,

[0026] • Allowing the dishes to dry at room temperature,

[0027] • Obtaining dry oral films after 36 hours.

[0028] In another application of the invention, the preparation method of the oral film includes the following steps: i) Preparing a 1.25% by volume HPMC (hydroxypropyl methylcellulose) solution by mixing it at 80°C on a magnetic stirrer at 75 rpm, ii) Preparing a 7.5% by volume starch solution by mixing it at 60°C at 75 rpm until gelation occurs, iii) Mixing the prepared HPMC (hydroxypropyl methylcellulose) and starch solutions at room temperature until a homogeneous structure is achieved, iv) Adding a 6.25% by-volume curcumin solution and a 12.5% by-volume polyvinylpyrrolidone solution to the HPMC-starch mixture and mixing for 2 hours until a homogeneous structure is observed, v) Processing the solution into an oral film by performing the following steps:

[0029] • Pouring the prepared homogeneous mixture into Petri dishes using the solution casting method,

[0030] • Allowing the dishes to dry at room temperature,

[0031] • Obtaining dry oral films after 36 hours.

[0032] The oral film subject to the invention adheres effortlessly to the targeted mouth ulcer due to the HPMC (hydroxypropyl methylcellulose) contained within it, enabling continuous interaction between the film and the wound throughout the treatment period. In the mentioned oral film, a 1 -3% by weight (in a preferred application, 1 .25% by volume) HPMC solution is prepared using distilled water. The solution is stirred at 80°C on a magnetic stirrer at 75 rpm. To this HPMC solution, a 6-9% by weight (preferably 7.5% by volume) starch solution, heated to 60°C and stirred at 75 rpm until gelation occurs, is added. This allows the final product, the oral film, to degrade slowly over the wound surface. The HPMC and starch solutions mixture is then stirred at room temperature until a homogeneous consistency is achieved.

[0033] The wound-healing properties of the oral film in the invention are imparted by a 5-7.5% by-weight curcumin solution (in a preferred application, 6.25% by volume). The curcumin solution is prepared by dissolving curcumin procured from herbal suppliers in distilled water. This curcumin solution is combined with a 10-15% by-weight polyvinylpyrrolidone (PVP) solution (preferably 12.5% by volume), which provides the oral film with bacteriostatic properties. Together, these solutions are added to the HPMC (hydroxypropyl methylcellulose)-starch mixture and stirred until homogeneity is achieved. The resulting solution is poured into Petri dishes using a solution casting method and left to dry at room temperature for 36 hours, completing the preparation of the oral film subject to the invention.

[0034] The oral film subject to the invention is transparent and prepared with a 1-2 mm thickness. It adheres easily to the wound, enabling the wound-healing curcumin to spread slowly over the wound during the treatment period. Additionally, the film prevents infection throughout the treatment process, thanks to its bacteriostatic properties. This provides a cost-effective and environmentally friendly method for treating mouth ulcers.

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Claims

CLAIMS1. An oral film for use in the treatment of mouth ulcers, characterized by containing curcumin as a wound-healing active ingredient, HPMC (hydroxypropyl methylcellulose) as an adhesive, starch for the controlled and slow release of curcumin, and polyvinylpyrrolidone (PVP) for bacteriostatic properties.

2. An oral film, according to claim 1 , characterized by comprising 1 -3% by weight HPMC (hydroxypropyl methylcellulose), 6-9% by weight starch, 5-7.5% by weight curcumin, and 10-15% by weight PVP.

3. An oral film according to claim 2, characterized by comprising 1 .25% by volume of HPMC (hydroxypropyl methylcellulose), 7.5% by volume of starch, 6.25% by volume of curcumin, and 12.5% by volume of PVP.

4. A method for preparing an oral film for use in the treatment of mouth ulcers, characterized by comprising the steps of: i) Preparing an HPMC (hydroxypropyl methylcellulose) solution by stirring it in a magnetic stirrer, ii) Preparing a starch solution by stirring it until gelation occurs, iii) Mixing the prepared HPMC (hydroxypropyl methylcellulose) and starch solutions at room temperature until a homogeneous structure is achieved, iv) Adding a curcumin solution along with a polyvinylpyrrolidone (PVP) solution to the HPMC-Starch mixture and stirring the resulting mixture until homogeneity is observed.

5. A method according to claim 4, characterized by comprising the following steps: i) Preparing a solution containing 1 -3% by weight HPMC (hydroxypropyl methylcellulose) by stirring at 80 °C with a magnetic stirrer at 75 rpm, ii) Preparing a solution containing 6-9% by weight starch by stirring at 60 °C until gelation occurs at 75 rpm, iii) Mixing the prepared HPMC (hydroxypropyl methylcellulose) and starch solutions at room temperature until a homogeneous structure is achieved, iv) Adding a 5-7.5% by-weight curcumin solution along with a 10-15% byweight polyvinylpyrrolidone (PVP) solution to the HPMC-Starch mixtureand stirring the resulting mixture for 2 hours until homogeneity is observed, v) Steps for converting the solution into an oral film, including:• Pouring the prepared homogeneous mixture into Petri dishes using a solution casting method,• Allowing the mixture to dry at room temperature,• Obtaining dried oral films after approximately 36 hours.

6. A method, according to claim 5, characterized by comprising the following steps: i) Preparing a solution containing 1.25% by volume HPMC (hydroxypropyl methylcellulose) by stirring at 80 °C with a magnetic stirrer at 75 rpm, ii) Preparing a solution containing 7.5% by volume starch by stirring at 60 °C until gelation occurs at 75 rpm, iii) Mixing the prepared HPMC (hydroxypropyl methylcellulose) and starch solutions at room temperature until a homogeneous structure is achieved, iv) Adding a 6.25% by-volume curcumin solution along with a 12.5% by-volume polyvinylpyrrolidone (PVP) solution to the HPMC-Starch mixture and stirring the resulting mixture for 2 hours until homogeneity is observed, v) Steps for converting the solution into an oral film, including:• Pouring the prepared homogeneous mixture into Petri dishes using a solution casting method,• Allowing the mixture to dry at room temperature,• Obtaining dried oral films after 36 hours.

7. An oral film prepared by a method according to any one of claims 4 to 6.

8. An oral film, according to claim 7, for use in the treatment of mouth ulcers.