MUCOADISHIVE BUCCAL FILM FORMULATIONS FOR USE IN THE TREATMENT OF ORAL ULCERS.

Abstract

The invention relates to mucoadhesive buccal film formulations containing hydrocortisone, obtained by solvent casting, for local application in the treatment of oral ulcers. The formulation in question contains hydrocortisone or a pharmaceutically acceptable hydrocortisone derivative, a mucoadhesive polymer system containing polyvinyl alcohol and hyaluronic acid, at least one plasticizer, and preferably TPGS. The film formulation adheres to the buccal mucosa, forming a protective layer over the ulcerated area and providing controlled local release of hydrocortisone.

Description

Mucoadhesive buccal for use in the treatment of oral ulcers. FILM FORMULATIONS Technical Area The invention describes a buccal film containing hydrocortisone with mucoadhesive properties, intended for use in the treatment of oral ulcers. It relates to their formulations. State of the Art Oral ulcers can cause pain, inflammation, burning sensation, difficulty eating and drinking, difficulty speaking, and general malaise. Oral ulcers are common oral lesions that cause decreased comfort. Treatment of oral ulcers... The general approach is to reduce symptoms, suppress inflammation, and treat the ulcerated area inside the mouth. The goal is to protect the body from the environment and support the healing process. Current treatment options include topical gels, creams, ointments, pomades, gargles, sprays, and buccal tablets. and similar local dosage forms are available. These products contain local anesthetics, antiseptics, analgesics, corticosteroids, barrier-forming compositions containing hyaluronic acid, and herbal remedies Components of the source can be used. However, due to the dynamic environment of the oral cavity, Conventional gel, ointment, or spray formulations are diluted with saliva, swallowed, or ingested orally. It moves away from the ulcerated area with its movements. Therefore, sufficient active substance is not present in the lesion area. Maintaining the desired duration and concentration is often difficult. Corticosteroids are used to treat oral ulcers symptomatically, particularly to provide a local anti-inflammatory effect. It is one of the important active ingredients used in its treatment. Hydrocortisone has previously been used for oral aphthous ulcers. It is a corticosteroid with known efficacy, studied in buccal tablet form and various topical applications. However, since hydrocortisone is a low-solubility active ingredient, it can be used in the buccal region. It will provide controlled and adequate local release, be easy for the patient to apply, and target the ulcerated area. Developing a support system that can provide physical protection is of technical importance. In the current state of the art, films, tablets, patches, nanofibers and similar systems are used for buccal application. Research is ongoing. However, a significant portion of known systems lack sufficient mucoadhesion and adequate flexibility. It is insufficient to simultaneously meet the criteria of controlled release, homogeneous film structure, and patient compliance. It remains. Hydrocortisone-containing, mucoadhesive and wound-causing agents are particularly used for the treatment of oral ulcers. capable of forming a protective, coating-like layer, scalable by solvent casting method. There is a need for a buccal film system that can be produced. Therefore, a substance that can be used in the treatment of oral ulcers, that adheres strongly to the buccal mucosa, and is suitable for ulcerative conditions. hydrocortisone can form a barrier on the area that reduces direct contact with the oral environment. A mechanically flexible and easy-to-apply mucoadhesive buccal that provides 35% controlled local release. Developing film formulations provides a solution to the technical problem. 1. Purpose of the Invention The main aim of the invention is to allow hydrocortisone, used in the treatment of oral ulcers, to remain in the ulcerated area for a longer period of time. a mucoadhesive buccal film formulation that ensures retention and controlled local release It is about developing. Another aim of the invention is to achieve effectiveness due to dilution by saliva in the oral environment and mouth movements. to reduce the problem of rapid removal of the substance from the lesion area, thus improving the effectiveness of local treatment. and to improve patient compliance. Another aim of the invention is to create a protective layer, similar to a wound dressing, over the ulcerated area. In this way, it can reduce mechanical irritation, direct contact with food, and the irritant effect of oral conditions. The goal is to provide a film / patch system. Another purpose of the invention is to combine polyvinyl alcohol, hyaluronic acid, polyvinylpyrrolidone, pullulan, beta- Suitable for cyclodextrin and similar mucoadhesive, biocompatible or healing-promoting polymers. to reduce the limitations caused by the low solubility of hydrocortisone with combinations and The goal is to obtain a film with suitable mechanical properties. Description of the Invention The invention describes a mucoadhesive buccal adhesive containing hydrocortisone for local application in the treatment of oral ulcers. It relates to a film formulation. The film formulation that is the subject of the invention is hydrocortisone or pharmaceutical. an acceptable hydrocortisone derivative, at least one mucoadhesive polymer or polymer system, most a small amount of plasticizer and preferably an adjuvant that improves solubility / stability or mechanical properties It contains the following substances. The film is produced by the solvent casting method and, when applied, is buccal. It adheres to the mucosa, forming a protective layer over the ulcerated area. The film in question, taking oral conditions into account, has a controlled local release time of 4 to 8 hours. It is designed to provide and exhibit an extended residence time in the buccal mucosa. The film is flexible. And thanks to its rigid structure, it can be easily applied to the ulcerated area, and it acts as a mucoadhesive when it comes into contact with the mucosa. It exhibits behavior and forms a physical barrier over the lesion. Detailed Description of the Invention The product described in the invention is a flexible buccal device designed for local application to oral ulcer areas. It is in film / patch form. The film can be single-layered, multi-layered, double-sided, or have regional thickness variations. or it can be prepared in a cut form with specific geometries. The film size will cover the ulcer area and the buccal area. The film is adjustable to be easily placed on the mucosa. It is preferably supplied in single packs. By providing these, stability, hygiene and ease of application are ensured. The active ingredient used is hydrocortisone. Hydrocortisone is a free base, salt, ester, solvate, and hydrate. It may be found in the form of 35 or other pharmaceutically acceptable derivatives. The preferred form of the invention in applications hydrocortisone, total film-forming solution or dry film composition weight According to the data, it is found in amounts of approximately 0.01% to 5%, preferably 0.05% to 1%, and even more preferably around 0.2%. However, this rate can be adjusted according to the treatment requirement, film size, and local release profile. 2. The polymer system is selected to provide both film-forming and mucoadhesion functions. The invention describes a formulation that preferably uses a mucoadhesive and / or healing-promoting polymer system. It contains polyvinyl alcohol (PVA) and hyaluronic acid (HA). PVA, preferably around 0.5% to 20%, It can be used more preferably at a concentration of 1% to 10%, and in certain applications at around 3%. Hyaluronic acid acid, preferably around 0.01% to 10%, more preferably 0.1% to 5%, and in certain applications around It can be used in concentrations of 1% to 3%. PVA is suitable for film-forming applications and buccal application. Due to its mucoadhesive character; HA, on the other hand, in addition to its mucoadhesive behavior, keeps the ulcerated area moist. PVA and HA are preferred for their ability to support wound retention and healing. The combination promotes film integrity, mucoadhesion, flexibility, moisture retention, and wound healing. It offers advantages in these aspects. In the preferred applications of the invention, film formulation increases the solubility of hydrocortisone, D-alpha-tocopheryl polyethylene glycol to support stability and improve film properties. It may contain succinate (TPGS, Kolliphor TPGS). The film formulation may also contain polyethylene glycol, propylene a plasticizer chosen from glycol, glycerin, olive oil or a combination thereof It can be found. Propylene glycol is preferably used as a plasticizer. In some applications, the polymer system uses PVP, pullulan and / or beta-cyclodextrin or their combinations. It may include combinations of these. PVP, with its hydrophilic character and film-structure supporting effect; Pullulan, with its film-forming, biocompatible and intraoral application properties; beta-cyclodextrin in turn, the solubility and distribution properties of low-solubility active substances such as hydrocortisone It is preferable because of its contribution to improvement. Plasticizers improve film flexibility, conformity to mucosa, resistance to fracture, and homogeneity. It is used to improve [the process]. Ingredients include plasticizer, polyethylene glycol (PEG), propylene glycol (PG), glycerin, and olive oil. The oil or mixtures thereof may be selected. Propylene glycol in the preferred application of the invention. It is used at approximately 3%. TPGS, preferably at approximately 0.01% to 5%, even more preferably at 0.05% to 1%. And in certain applications, it can be found in amounts of approximately 0.1% to 0.5%. The formulation may include pH regulators, sweeteners, flavorings, and colorings as needed. preservatives, antioxidants, buffers, permeation regulators, stabilizers or buccal It may contain other excipients that are pharmaceutically acceptable for use. However, The film is made from biocompatible components with low irritant effects, making it suitable for intraoral application. is created. The developed mucoadhesive buccal film formulation contains approximately 0.2% hydrocortisone and approximately 3% PVA. It contains approximately 3% hyaluronic acid, approximately 3% propylene glycol, and approximately 0.1% TPGS. Buccal Retention time in the mucosa is between 4 and 8 hours, and concentration is at least 0.10 mJ / cm², preferably 0.30 to 0.40 mJ / cm². It has mucoadhesion values ​​within the range. In vitro release with Franz diffusion cells. In 35 studies, at least 80%, preferably 90% to 100%, of hydrocortisone is released at 8 hours. The tensile strength of the mucoadhesive buccal film formulation must be at least 1 MPa and the elongation at break must be at least 100%, preferably tensile strength approximately 2 MPa to 15 MPa, elongation at break approximately 150% to It is in the 500% range. Mucoadhesive buccal film formulation for single-layer, multi-layer, bi-layer, or regional thickness. It's a film / patch showing 40 different aspects. 3 Production Methods The mucoadhesive buccal film formulation that is the subject of this invention is preferably produced by the solvent casting method. The typical steps of the production method are as follows: a) Dissolving hydrocortisone and selected polymers in a suitable solvent system or homogenizing dispersed in this way; b) Addition of plasticizer, TPGS and any other excipients to the solution; c) Homogenizing the resulting film-forming solution and removing air bubbles if necessary. removal; d) Pour the homogeneous solution onto a suitable mold, glass surface, polymeric carrier, or casting surface. pouring to the specified thickness; e) Forming a film by drying the spilled solution under controlled temperature and / or ambient conditions; f) Separating the resulting film from the surface, cutting it to the desired size and geometry, and preferably in individual pieces. packaging. The solvent system preferably contains water and ethanol. In more preferred applications, a distilled water:ethanol volumetric mixture is used. The ratio is chosen to be approximately 1:1. However, the solubility of the polymers used and the film Depending on their composition properties, they can be water, ethanol, hydroalcoholic mixtures, or pharmaceuticals. Other solvent systems can be used. Casting thickness, drying temperature, drying time and film The cutting size is optimized according to the desired mechanical properties, mucoadhesion, and release profile of the formulation. It is done. Examples The following examples are given to illustrate the scope of protection of the invention, not to explain the invention itself. It is not restrictive. Example 1 - PVA-based preformulation films PVA-based preformulation film solutions containing polymers at different concentrations, distilled water:ethanol (1:1) solvent system was used in preparation. PVA, PVP, pullulan, beta- Polymers such as cyclodextrin and hyaluronic acid have been tested in various combinations; PEG, glycerin or plasticizers such as PG were used. Later, hydrocortisone with a concentration of approximately 0.2% was used. Preliminary formulations have been prepared. Second polymer / Code HK (%) PVA (%) Plasticizer (%) auxiliary system F1-HK 0.2 10 - 3% PG 2.5% β-SD F8-HK 0.2 7.5 3% PG F10-HK 0.2 3.75 1.25% HA 3% PG F11-HK 0.2 2.5 2.5% HA 3% PG Example 2 - Design film formulations containing PVA / HA and TPGS. In the design formulations, the hydrocortisone ratio was kept constant at 0.2% and the PVA ratio at 3%; Hyaluronic acid content is 1% or 3%, plasticizer type is PEG or PG, and TPGS content is 0.1% or 0.5%. This series has been modified to include mechanical properties, mucoadhesion, active substance loading, and release profile. It has been evaluated from this perspective. Plasticizer type TPGS / Kolliphor Code HK (%) PVA (%) HA (%) (3%) FH1-HK 0.2 3 3 PEG 0.5 FH2-HK 0.2 3 1 PEG 0.5 FH3-HK 0.2 3 3 PEG 0.1 FH4-HK 0.2 3 1 PEG 0.1 FH5-HK 0.2 3 3 PG 0.1 FH6-HK 0.2 3 1 PG 0.5 FH7-HK 0.2 3 3 PG 0.5 FH8-HK 0.2 3 1 PG 0.1 Example 3 - Preferred FH5-HK formulation In a preferred application of the invention, the film formulation contains approximately 0.2% hydrocortisone, approximately 3% PVA, approximately 3% hyaluronic acid, approximately 3% propylene glycol, and approximately 0.1% TPGS / Kolliphor It is prepared to include the components in a distilled water:ethanol (1:1) solvent system. It is homogenized, poured onto a suitable surface using the solvent casting method, dried, and buccalized. It is cut to the appropriate size for the application. Characterization and Technical Impacts The developed films were evaluated based on mechanical properties, contact angle, mucoadhesion, active substance loading efficiency, and Franz diffusion cells were evaluated in terms of in vitro release studies. The results obtained... Data show that hydrocortisone-loaded PVA and PVA / HA-based films have suitable flexibility for buccal application. It has been shown to exhibit mucoadhesion and local release properties. Stress Breakage Mucoadhesion HK loading 8-hour release 24-hour release Formulation resistance Elongation (%) Work (mJ / cm²) (%) (%) (%) (MPa) 426.59 ± F1-HK 11.56 ± 2.52 0.35 ± 0.02 63.49 93.2 ± 3.1 - 16.26 310.25 ± FH5-HK 11.35 ± 1.26 0.34 ± 0.07 97.56 95.54 ± 0.4 101.64 ± 0.7 30,31 The FH5-HK formulation offers high hydrocortisone loading efficacy and suitable mucoadhesive performance. Preferred for its flexibility and controlled release profile of up to 8 hours, supported by propylene glycol. It has been evaluated as an example of an application. The formulation in question was used in the application area. It provides local release of hydrocortisone while forming a protective film layer over the ulcerated surface. Advantages of the Invention • It adheres to the buccal mucosa, providing an extended residence time in the ulcerated area. • It helps reduce systemic exposure by providing local and controlled release of hydrocortisone. • It reduces mechanical and chemical irritation by forming a protective layer over the ulcerated area. • The combination of PVA and HA supports film integrity, mucoadhesion, and wound healing. It offers its features together. • Dispersion / dissolution of low-soluble hydrocortisone with TPGS and a suitable plasticizer system. The properties and mechanical properties of the film can be improved. • Single-stage, repeatable, low-cost, and scalable casting using the solvent casting method. It offers suitable production opportunities. • Its flexible film structure, which can be individually packaged and is easy to apply, increases patient compliance. • Hydrocortisone-free mucoadhesive buccal film, a medical device-grade protective oral wound dressing. Suitable for use as a protective mucoadhesive barrier or medical device-like wound dressing. It can be considered as a platform. Industrial Applicability The invention's mucoadhesive buccal film formulation can be produced by the solvent casting method. It is applicable to industry. This system, suitable for scaling up in film production lines, is suitable. after process validation, stability studies, toxicity assessments and clinical trials It can be used in the pharmaceutical industry as an innovative local dosage form for the treatment of oral ulcers. Additionally, with the addition of different active ingredients, buccal mucositis, local inflammation, and buccal inflammation can be treated. candidiasis, dental applications and other mucosal local treatments are adaptable. It serves as a platform. 6

Claims

1. It is a mucoadhesive buccal film formulation for local use in the treatment of oral ulcers. Its characteristic feature is hydrocortisone or a pharmaceutically acceptable hydrocortisone derivative, polyvinyl alcohol. a mucoadhesive polymer system containing (PVA) and hyaluronic acid (HA) and at least one plasticizer It contains; the film formulation in question was obtained by the solvent casting method and is buccal. When applied to the mucous membrane, hydrocortisone forms a protective layer over the ulcerated area. It ensures locally controlled release.

2. Mucoadhesive buccal film formulation according to Claim 1, with a total hydrocortisone formulation. The concentration is between 0.01% and 5% by weight, preferably between 0.05% and 1%, and even more preferably around 0.2%.

3. According to Claim 1, it is a mucoadhesive buccal film formulation, with PVA as the total formulation weight. The range is between 0.5% and 20%, preferably between 1% and 10%, and even more preferably around 3%.

4. Mucoadhesive buccal film formulation according to Claim 1, HA according to total formulation weight. The concentration is between 0.01% and 10%, preferably between 1% and 3%.

5. According to Claim 1, the mucoadhesive buccal film formulation is a mucoadhesive polymer system. It also contains polyvinylpyrrolidone (PVP), pullulan, beta-cyclodextrin, or a combination thereof.

6. A mucoadhesive buccal film formulation according to Claim 1, with polyethylene glycol as the plasticizer, Propylene glycol, glycerin, olive oil, or a combination thereof are chosen.

7. Mucoadhesive buccal film formulation according to claim 6, with total formulation as plasticizer. Approximately 3% propylene glycol is used by weight.

8. Mucoadhesive buccal film formulation according to Claim 1, based on total formulation weight. 0.01% to 5%, preferably 0.1% to 0.5% D-alpha-tocopheryl polyethylene glycol succinate (TPGS) includes.

9. Mucoadhesive buccal film formulation according to Claim 1, containing approximately 0.2% hydrocortisone, approximately It contains 3% PVA, approximately 3% hyaluronic acid, approximately 3% propylene glycol, and approximately 0.1% TPGS.

10. According to claim 1, it is a mucoadhesive buccal film formulation that remains on the buccal mucosa for 4 to 8 hours. It has a duration of stay.

11. According to claim 1, this is a mucoadhesive buccal film formulation made with a Franz diffusion cell. In in vitro release studies, at least 80%, preferably 90% to 100%, of hydrocortisone is released at 8 hours.

12. According to Claim 1, the mucoadhesive buccal film formulation is a single-layer, multi-layer film. It is in the form of a layered, double-sided, or regionally varied film / patch.

13. The method of producing the mucoadhesive buccal film formulation according to Claim 1, and its characteristic is; (a) hydrocortisone or a pharmaceutically acceptable hydrocortisone derivative containing PVA and HA The polymer system is preferably in a solvent system with a volume ratio of approximately 1:1, using distilled water:ethanol. (a) dissolving or dispersing, (b) adding plasticizer and TPGS if any, (c) the resulting (d) pouring the homogeneous film-forming solution onto a casting surface, drying the solution to form a film (e) making it into a form, cutting the resulting film into sizes suitable for buccal application and It includes the packaging steps. 7