Transmucosal Mucoadhesive Polymeric Film, Monolayer, Oral Release

Description

/ 45 Transmucosal Mucoadhesive Polymeric Film, Monolayer, Oral Release UTILITY MODEL FIELD

[001] The present utility model is situated in the pharmaceutical field and refers to the development of a single-layer mucoadhesive polymeric film containing Triamcinolone Acetonide. This film is produced continuously by thermoextrusion through a simple method of premixing the materials and is intended for the treatment of Recurrent Aphthous Stomatitis. STATE OF THE ART

[002] The World Health Organization estimates that about half of the global population is affected by different oral diseases that cause lesions in the oral mucosa, directly affecting the physical, social and psychological well-being of individuals (World Health Organization. Available at: Oral health (who.int). Accessed on April 4, 2022; NASCIMENTO, EG PPG - Pharmaceutical Sciences, UFRN, Natal - RN, 2020).

[003] Recurrent Aphthous Stomatitis (RAS), a chronic and multifactorial inflammatory disorder characterized by the appearance of superficial ovoid and / or rounded ulcers, primarily in the non-keratinized oral mucosa, is considered the most prevalent lesion of the oral cavity, affecting up to 25% of the world's population. In more severe cases, the ulcers cause exacerbated pain for the patient and interfere with their basic daily activities such as eating, speaking, or maintaining adequate oral hygiene, impacting their quality of life. Petition 870230051318, dated 06 / 15 / 2023, page 3 / 47 / 45 of life (AHMED, MK et al. J. Multidiscip. Healthc. Ed., 13: 1595-1605, 2020; NASCIMENTO, EG PPG — Pharmaceutical Sciences, UFRN, Natal - RN, 2020; TARAKJI, B. et al. J. Int. Oral Health. Ed., 7(5): 47-80, 2015; YANG, Z. et al. BMC Oral Health. Ed. 20: 128, 2020).

[004] The use of topical anti-inflammatory drugs, particularly corticosteroids, is the most commonly used option for treating the clinical manifestations of the disease. However, more severe lesions require the use of systemic medications or a combination of these with topical medications, and severe side effects are common, including nephrotoxicity, hypertension, hyperlipidemia, Cushing's syndrome, and hematological changes (DALESSANDRI, D. et al. BMC Oral Health. Ed., 19:153, 2019; NASCIMENTO, EG PPG — Pharmaceutical Sciences, UFRN, Natal - RN, 2020).

[005] Triamcinolone Acetonide (TA), a synthetic glucocorticoid with anti-inflammatory and immunosuppressive activity, has been used in general in the topical treatment of RAS (ALTENBURG, A. et al. Dtsch. Arztebl. Int. Ed., 111: 665-73, 2014; THAKKAR, R. et al. AAPS PharmSciTech. Ed., 21:200, 2020). It is commonly used at a concentration of 0.1%, alone or in combination with topical anesthetics, in the form of ointments, pastes, creams, mouthwashes, and oral gels. However, these pharmaceutical forms do not promote effective drug release, present administration difficulties, and undergo rapid salivary clearance, reducing the contact time of the drug with the area. Petition 870230051318, of 06 / 15 / 2023, p. 4 / 47 / 45 ulcerated (ALTENBURG, A. et al. Dtsch. Arztebl. Int. Ed., 111: 665-73, 2014; BELENGUER-GUALLAR, I. et al. J. Clin. Exp. Dent. Ed., 6(2): e168-74, 2014; NASCIMENTO, EG PPG — Pharmaceutical Sciences, UFRN, Natal - RN, 2020).

[006] Thus, the most efficient treatment of EAR involves the development of alternative pharmaceutical forms that are able to combine therapeutic actives and remain within the oral cavity in intimate contact with the injured mucosa, releasing the active substances in a controlled manner for prolonged periods (MARAFON, M. et al. Boletim Informativo Geum. Ed., 7(2): 32-38, 2016; PALEM, CR et al. Pharm. Technol Dev. Ed., 18(1): 186 — 195, 2013; PARK, JB et al. Expert Opin. Drug Deliv. 2014). In this sense, a transmucosal oral release monolayer polymeric bioadhesive film containing TA and manufactured by hot-melt extrusion (HME), as presented in this utility model, can offer mechanical protection of the ulcer, increase residence time and ensure sufficient contact time at the absorption site, addressing needs not met by available therapeutic options (CHEN, M. et al. AAPS PharmSciTech. 2014).

[007] In this context, the present utility model describes obtaining a mucoadhesive formulation, through thermoextrusion, that adapts to the real needs of users, producing a transmucosal oral release monolayer bioadhesive film containing TA for the treatment of EAR, providing mechanical protection of the Petition 870230051318, dated 06 / 15 / 2023, page 5 / 47 / 45 ulcerated region and prolonged release of the active ingredient.

[008] US patent document 33093 describes the manufacture of a bioadhesive extruded film for intraoral drug delivery. The technology is directed to the production of a thin, single- or multi-layered laminated extruded film composed of water-soluble or water-insoluble polymers, which may incorporate various therapeutic agents suitable for the treatment of oral disorders, including aphthous ulcers.

[009] However, the document emphasizes that the film must have at least one bioadhesive layer and the therapeutic agent may be incorporated into one or all layers. The preparation method consists of making specific mixtures of components for each layer separately. Thus, the pharmaceutical ingredients of each layer are mixed for approximately 15 minutes, while the liquid plasticizer is slowly added to the mixture.

[010] Furthermore, the extrusion process reported by the inventors uses different temperatures, therefore requiring more complex and costly equipment with different heating zones, including in the extruder exit zone (die). Each layer is extruded separately, with the first layer being manufactured as a "free film" and successive layers extruded one on top of the other, which must be inserted into heated stainless steel rollers for the lamination process. Petition 870230051318, dated 06 / 15 / 2023, page 6 / 47 / 45

[011] Although similarities are perceived regarding the use of extrusion in the manufacture of the product, the document cited above differs significantly from the present utility model with respect to the production process, as well as the characteristics of the final product. The mucoadhesive film described in this document is monolayered, with all materials added simultaneously to the extruder, including the liquid plasticizer. The twin-screw extrusion process occurs in a single step using the same extrusion temperature throughout the process. Furthermore, there is no need for lamination of the final thermoextruded product of the present utility model, which comes out of the extruder ready for use. Finally, the mucoadhesive film provides a controlled release of the drug, a fundamental characteristic to avoid systemic adverse effects.

[012] Patent document US 6375963 describes the manufacture of a thermoextruded bioadhesive film for topical and mucosal bioadhesion application, drug delivery and preparation. The described product should not contain plasticizers conventionally used in thermoextruded films; its ideal thickness should be in the range of 0.25 to 3.0 mm and preservatives are added in a maximum proportion of 5.0% (w / w).

[013] During the processing described in the document, all materials need to be sieved through different sieves to obtain specific particle sizes. In addition, the process requires the materials to undergo oven drying cycles. Petition 870230051318, dated 06 / 15 / 2023, page 7 / 47 / 45 (50°C for 24 h) before and after mixing, carried out in a powder mixer for approximately 20 minutes. If desired, the film can be granulated or pulverized to provide a different adhesion system to the extruded film.

[014] The technology described in this document differs from the technology described in the aforementioned patent document by the specific use of liquid plasticizers incorporated by dripping during the prior physical mixing, before the thermoextrusion of the materials, which consists of a simple maceration for approximately 5 min. This procedure, followed by extrusion, has proven to be a sufficient condition to guarantee the homogeneity of the distribution of the components in the mixture. It should also be noted that this utility model does not involve prior and / or subsequent heat treatments or sieving of the mixture components as provided for in the invention described in patent document US 6375963.

[015] Furthermore, the resulting single-layer bioadhesive film, with the incorporated drug, is always less than 1.0 mm thick, and is designed to be comfortably accommodated in the ulcerated area, providing additional mechanical protection. This feature is essential to avoid excessive salivation by the patient and to preserve the prolonged release of the device.

[016] Furthermore, in document US 6375963 the inventors cite the use of plasticizers such as glycerol and propylene glycol as problematic in Petition 870230051318, dated 06 / 15 / 2023, p. 8 / 47 / 45 formulations whose drug is susceptible to degradation by hydrolysis, as these materials increase hygroscopicity. However, this is not the case for TA, since the main degradation mechanism of these corticosteroids is associated with oxidation, sometimes catalyzed by the presence of metal ions that can act as Lewis acids (van HEUGTEN, AJP et al. AAPS PharmSciTech. Ed., 19 (3): 1448-1453, 2018).

[017] Patent document CA 02702211 refers to extruded and extrudable compositions for the delivery of bioactive agents, the method of preparation and its use. The described product is designed to be fixed directly onto the user's mucosa and have an average dissolution time of 5 to 50 minutes, this being the estimated time for delivery of the bioactive compound. The delivery method includes the addition of ion exchange resins and, to adjust the flow capacity of the mixture within the extruder, a high-shear mixer is used that prevents the formation of agglomerates derived from residual moisture in the materials, highlighting that the use of this high-shear mixer is essential when any wet product is added to the mixture.

[018] The method of obtaining the technology described above differs from the method of obtaining the present technology, since the described processing does not require the use of high shear and / or conventional mixers; the mixing of the materials, including the liquid plasticizing agent, is carried out in a simplified manner using only simple maceration. The release of the active ingredient, in the present case. Petition 870230051318, dated 06 / 15 / 2023, page 9 / 47 / 45, utility model, also differs in that it does not use additives within the formulation that could act as permeation enhancers, this process being governed solely by the different interactions between the polymeric chains that make up the formulation, the drug molecules, and the natural conditions of the oral mucosa microenvironment. Furthermore, the present technology is designed for prolonged release, having a dissolution time exceeding the 50 minutes mentioned in the aforementioned patent document.

[019] US patent 2017 / 0071871 deals with the manufacture of fast-dissolving films for oral drug delivery incorporating taste-masking agents. The compositions can be produced by either wet casting or extrusion methods. The mixture preparation process includes the use of at least one mixer, and for extrusion processing, a water-soluble premix containing polyethylene oxide and, optionally, one or more additional polymers must be formed. The premix must also contain a component that acts to coat the active ingredient to mask the taste (polymers, oils, or waxes), forming a uniform matrix.

[020] The technology described in this document differs from the aforementioned patent application in its methodology for producing extended-release monolayer bioadhesive films. The preparation method seeks to exploit solely the advantages that the Petition 870230051318, dated 06 / 15 / 2023, page 10 / 47 / 45, states that thermoextrusion offers a solution, and no other preparation methods ("wet casting") are used. Furthermore, the physical mixing of the formulation materials prior to extrusion does not involve the use of other mixers; only a mortar and pestle are used, simplifying the process of obtaining this technology. No flavor-masking agents are introduced into the formulation, and polyethylene oxide is not used as an essential polymer. Moreover, the formulation described in this technology has slow dissolution, favoring the mechanical protection of the ulcerated area.

[021] In US patent document 4713243, the inventors describe several examples of bioadhesive extruded films for intraoral drug delivery in the treatment of oral ulcers. However, the formulation containing the drug TA involves an extremely low drug dosage, namely 0.1% (w / w). Furthermore, the extrusion process described is complex, involving at least seven different temperatures, and the resulting film does not have a controlled thickness for mechanical protection of the mucosa. In this sense, the present technology is not similar to the technology described previously.

[022] US patent 4765983 describes the production of medical adhesive tapes for application to the oral mucosa. The tapes are formed by a support layer enclosing a polymer soluble in the intestine and another layer containing a drug whose composition will be formed by a water-soluble polymer matrix. Petition 870230051318, dated 06 / 15 / 2023, page 11 / 47 / 45 The document specifies that the medicated layer can be composed of a single layer, but preferably it should be composed of two or more layers, and may contain a protective coating film for the medicated layer.

[023] In the cited document, processing can be carried out using TA, in a maximum proportion of 2.0 parts by weight and polymers such as hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC). In the procedure described by the cited authors, each mixture is dissolved in suitable organic solvents (water, ethanol, methanol, methylene chloride, among others) and the resulting solutions are spread on paper and successively subjected to drying processes to obtain each of the layers, which will form the adhesive medical tape for use on the oral mucosa.

[024] Although similarities are perceived regarding the application site and the use of some materials, the patent document cited above differs substantially from the technology described in this document with respect to the processing technique and the final product. Thermoextrusion, the processing technique used to obtain the present technology, is free of organic solvents, and its production process is continuous. Furthermore, the technology described and requested through this document allows the incorporation of TA in a proportion of up to 5.0% (w / w), more than double the load reported by the authors in the aforementioned document. Thus, unlike the proposal in the present technology, a film Petition 870230051318, dated 06 / 15 / 2023, page 12 / 47 / 45, single-layer mucoadhesive tape, the medical adhesive tape developed in US patent document 4765983 is composed of multiple layers and requires successive dissolution and drying processes on a previously constructed surface.

[025] International publication WO 2016 / 079246 refers to the manufacture of a medical film for application to the skin or mucous membranes, primarily the oral mucosa. The film may consist of one or more layers, including a support layer that is insoluble in water or saliva, and / or a layer that influences the release of the drug in the final composition. The formulation requires a significant amount of a bioadhesive substance, which can vary between 5.0 and 60%.

[026] The manufacturing process requires that the film-forming polymer – comprising between 40 and 92% of the final composition and including HPMC – be soluble in a specific solvent (ethanol, methanol, propanol, isopropanol, or mixtures thereof containing a maximum of 20% (v / v) water). On the other hand, the bioadhesive substance, including HPMC, must not dissolve in the selected solvent and, if it does dissolve, must retain at least 90% (m / v) of its content undissolved. The difference in solubility between the film-forming substance and the bioadhesive substance leads to the formation of a continuous film with small dispersed bioadhesive particles, in order to maximize the bioadhesive effect.

[027] Furthermore, the medicinal substance will form an integral part of the film when it is soluble in the solvent or mixture of solvents used; otherwise, Petition 870230051318, dated 06 / 15 / 2023, page 13 / 47 / 45, should be deposited onto the film as a separate layer or adhered directly to the already formed film. In this way, the final thickness of the bioadhesive film, especially suitable for application in the oral cavity, can be up to 5.0 mm.

[028] The technology described in this document, even incorporating materials cited in document WO 2016 / 079246, presents significant differences in relation to the preparation method and the characteristics of the final product. The processing technique described in this document (thermoextrusion) does not involve the use of organic solvents in any stage of the manufacturing process of the monolayer mucoadhesive polymer films, which preserves several advantages regarding industrial scalability, cost reduction and production speed, as widely discussed.

[029] Patent application US 4250163 describes a method for preparing pharmaceutical forms that can be administered to the mucosa of the oral and / or nasal cavity. The formulation is designed to provide a prolonged release of the active pharmaceutical ingredient, and at least one excipient from the group of lubricants, binders, colorants, flavorings, taste maskers, among others, may be added.The preparation method requires dispersing an effective amount of drug in a water-intumescent polymeric matrix that adheres to the mucosa. The resulting mixture is molded by pressing into the desired shape (tablets, granules, fine granules, powders, or dental cones) to obtain a uniform mixture. Petition 870230051318, dated 06 / 15 / 2023, pp. 14 / 47 / 45 and homogeneous of all constituent materials of the pharmaceutical preparation.

[030] The administration of the pharmaceutical form, when produced in the form of granules, fine granules or powder, is carried out by direct spraying onto the application site or by spraying, using a suitable device. When the objective of the application is to obtain high absorption through the oral, sublingual or nasal mucosa, it is possible to apply the pharmaceutical preparation directly using forceps or by holding it with the fingers to keep it adhered for long periods of time.

[031] The patent document cites the use of materials in common with the materials cited in this document, i.e., TA, hydroxypropylcellulose, and carbopol. The process for obtaining the formulations requires mixing the materials in specific equipment and adding magnesium stearate, obtaining a powder for the production of tablets with a thickness of 1.1 mm (example 3). The powder obtained is used to fill hard gelatin capsules. The surface of these capsules is perforated, forming small holes that allow air to enter; in this way, the capsules are placed in spray containers that allow the powder mixture to be sprayed into the oral and / or nasal mucosa. Finally, the powder obtained can also be used to produce pressed discs with a thickness of 1.4 mm.

[032] Although there are similarities with regard to the application site, materials used and prolonged release of the active pharmaceutical ingredient, the differences between the Petition 870230051318, dated 06 / 15 / 2023, page 15 / 47 / 45, the aforementioned invention and the utility model described in this document are evident. The preparation method and tools used for processing the materials in this utility model are based on a thermoextrusion process, while document US 4250163 proposes that the final products be molded by pressing. Also, the final product presented in this document is a single-layer polymeric film, whose suggested application is by adhering the film to the ulcerated surface of the mucosa. Meanwhile, in the cited document, pressed tablets and / or discs with a thickness between 1.1 and 1.4 mm are obtained that should be applied with forceps or by holding them with the fingers on the oral and / or nasal mucosa for determined periods, or for direct use by spraying or for filling hard gelatin capsules that will be sprayed onto the application site, among others.

[033] International publication WO 2010 / 031819 describes the preparation of a pharmaceutical composition intended for the treatment of inflammation and associated pain, mainly in the oral mucosa, pharynx or larynx, using bioadhesive therapeutic carriers with prolonged release and containing at least one alpha-2-adrenergic receptor agonist as the active ingredient. When the objective of the invention is the treatment or prevention of aphthous ulcers affecting the oral cavity, pharynx or larynx, the pharmaceutical composition is essentially formed by clonidine and / or clonidine hydrochloride and / or any other clonidine derivative or mixtures thereof. Petition 870230051318, dated 06 / 15 / 2023, pages 16 / 47 / 45

[034] The alpha-2-adrenergic receptor agonist, its pharmacologically accepted salts or mixtures thereof, and optionally a second active ingredient, may be contained in the same homogeneous bioadhesive therapeutic system or in heterogeneous two-phase systems with different release rates, depending on whether administration is to be simultaneous or at intervals. The pharmaceutical forms described comprise homogeneous or double-layer tablets, as well as micro- and / or nano-spheres. The preparation method requires solubilization of the active ingredient in aqueous solutions that must be granulated with various diluents, binders and, at least, a bioadhesive agent. The granulated material is mixed with a lubricant and a bioadhesive agent and / or sustained-release polymer and then subjected to compression. In a preferred processing method, the initial solution is applied by spraying.Another preparation method also requires drying and calibrating the granulated solution before mixing it with the lubricant, followed by compression.

[035] The product and process described above differ substantially from the utility model described in this document, both in the premixing technique and subsequent processing of materials, and in the final product. The approach to developing pharmaceutical dosage forms for the treatment of aphthous ulcers presented in this document does not require steps involving solubilization of the active ingredient in aqueous solutions, granulation, or the addition of lubricants for subsequent processing. Petition 870230051318, dated 06 / 15 / 2023, page 17 / 47 / 45 compression; moreover, one of the advantages of the methodology claimed in this utility model is the use of a processing technique (thermoextrusion) that does not involve the use of aqueous or organic solvents. The premixing and processing method reported in this document simplifies and reduces production steps, making it industrially scalable, and optimizes the time required to obtain the final product: a ready-to-use, single-layer mucoadhesive polymeric film containing TA.

[036] Patent JP 2017 / 206486 refers to an oral mucoadhesive composition containing TA and cetylpyridinium chloride, a quaternary ammonium compound with antimicrobial activity against a broad spectrum of bacteria in the oral cavity (ALVES, D. et al. Rev. Port. Estomatol. Med. Dent. Cir. Maxilofac. Ed 53(3) : 181189, 2012). The formulations cited in the patent include: creams, ointments, mouthwashes, buccal tablets, lozenges, adhesive strips or plasters, gels, sprays, nebulized powders and the like. In addition, pharmaceutical additives such as preservatives, wetting agents, solubilizers and bases are used, as well as pH adjusting substances and fragrances. During sample preparation, the individual or mixed active compounds are homogenized with glycerin and a gelling polymer.

[037] Although the document cited above uses TA and glycerin among the components of the premixes and final products, there are notable differences with respect to the technology described in the present patent application. The monolayer film formed by thermoextrusion differs Petition 870230051318, dated 06 / 15 / 2023, pp. 18 / 47 / 45, substantially of the pharmaceutical forms described in the aforementioned patent.

[038] Patent application EP 3173067 concerns oral mucoadhesive formulations that gel in situ for buccal administration of nystatin, a corticosteroid, and at least one local anesthetic. During its processing, polymers that gel at body temperature and adhere to the oral mucosa through the action of mucoadhesive polymers must be used. The mucoadhesive polymer – Carbopol – is present in concentrations between 0.1 and 5.0% (w / w), preferably between 0.1 and 1.0% (w / w). This must be mixed with one or more gelling polymers in solution and at least one surfactant compound. The solubilization of the pharmaceutical ingredients that make up the formulations must be carried out in water, ethanol, or water / ethanol mixtures.

[039] During preparation, regardless of the temperature variation used, the gelling polymer should be dispersed in water and stirred for 2 to 4 hours until a clear and homogeneous appearance is achieved. When prepared at low temperatures, the solution should be kept in an ice bath and left to stand for 24 hours. Subsequently, the remaining components of the formulation should be added, namely the bioadhesive polymer, the surfactant, and the drug(s) solubilized in alcoholic solution. When pharmaceutical formulations are applied by spraying, they provide complete coverage of the oral cavity.

[040] Although a certain correspondence is found between the technology described in this document and the Petition 870230051318, dated 06 / 15 / 2023, page 19 / 47 / 45, regarding the aforementioned report concerning the use of carbopol as a mucoadhesive polymer, the differences in process and final product are evident. The monolayer mucoadhesive polymeric film processed by thermoextrusion – the subject of this utility model – uses carbopol in a proportion of 10% (w / w), an amount outside the range presented by the cited document, as well as TA as the active ingredient, without the incorporation of local anesthetics, since the mechanical protection of the ulcerated region will prevent the painful sensation caused by mechanical trauma.Furthermore, thermoextrusion is a melt mixing process and therefore does not require the use of aqueous and / or organic solvents, whereas the aforementioned invention requires the solubilization of all formulation components in aqueous or hydroalcoholic solutions that must be stirred for 2-4 hours or left to stand for 24 hours, and only then can they be applied by spraying, which can lead to complete coverage of the oral cavity. On the other hand, the thermoextruded film allows for immediate and localized application to the ulcerated area of ​​the oral mucosa, avoiding contact with non-ulcerated areas and possible undesirable effects.

[041] International publication WO 2003 / 103691 details pharmaceutical formulations and preparation methods for the treatment and prophylaxis of aphthous ulcers and lesions caused by the Herpes simplex virus. The technology provides for the administration of one or more anti-inflammatory compounds, steroidal or not, with or without the addition of... Petition 870230051318, dated 06 / 15 / 2023, pp. 20 / 47 / 45, concerning a salt or oxide of one or more polyvalent metals, the pharmaceutical form being an aqueous mucoadhesive paste intended for the prevention or treatment of aphthous ulcers.

[042] The cited document, even though presenting a common objective with the utility model described in this document, i.e., treatment of aphthous ulcers in the oral cavity, differs with respect to formulation, its application in the ulcerated region of the oral mucosa, as well as the method of preparation. The oral mucoadhesive polymeric film obtained by thermoextrusion consists of a pharmaceutical form entirely different from the technology reported in the aforementioned document, presenting physical and chemical characteristics totally distinct from those of the aqueous paste.

[043] US patent 6585997 reports a process for obtaining a double-layer, erodible, mucoadhesive device for the controlled administration of pharmaceuticals and other active compounds, which can also be manufactured without the incorporation of therapeutic agents. The device consists of a water-soluble adhesive layer, a non-adhesive bio-erodible support layer, and one or more pharmaceuticals present in one or both layers. The non-adhesive erodible layer can act as an envelope and support surface on which the adhesive layer is prepared. The preparation of the formulations requires the dissolution of the components in appropriate solvents, which may include mixtures of water, ethanol, methanol, isopropyl alcohol, and acetone, among others. The residual solvent can act Petition 870230051318, dated 06 / 15 / 2023, pp. 21 / 47 / 45 as a plasticizer and erosion modifier in the dry bilayer film.

[044] The manufacturing process used in this utility model does not use any organic or aqueous solvents, and also constitutes notable differences in the processing for obtaining the aforementioned pharmaceutical form. Furthermore, the film resulting from the thermoextrusion process is monolayered, functioning both as a medication and as mechanical protection for the ulcerated area without the need for a second layer to act as an erodible support. Nevertheless, given the nature of the thermoextrusion process, the plasticizer was carefully chosen to ensure mechanical and rheological properties suitable for the required application. On the other hand, the aforementioned patent describes the formulation of a bilayer film whose plasticizing effect results from the residual solvent content after drying. In addition, the solvent-free thermoextrusion process prevents the problems associated with the residual presence of these components in the final product.

[045] Document KR 100417259 discloses an oral formulation in cream form containing TA capable of effectively preventing and treating gingivitis, stomatitis, and periodontitis. The liquid formulation contains TA in a proportion of between 0.0001 and 0.01% (w / w), a flavonoid component that combats bad breath (0.1 to 20% w / w), an abrasive component (10 to 30% w / w), and centella asiatica extract (0.01 to 5.0% w / w); in addition to humectants, flavorings, binders, and preservatives, among others. Petition 870230051318, dated 06 / 15 / 2023, pp. 22 / 47 / 45 others. It becomes evident that the monolayer mucoadhesive polymeric film manufactured by thermoextrusion has a different use and production process when compared to the oral cream presented in the document cited above. The compositions change substantially and the TA content is higher in the final product processed by thermoextrusion.

[046] The invention WO 2017 / 120125A1 describes a topical steroid therapy for dermatological and inflammatory mucosal diseases. The preparation of liquid solutions utilizes different proportions of pharmaceutical ingredients dissolved in organic solvents that can be incorporated into gels, creams, sprays, syringes, plastic application tubes, ointments, lotions, powders or pastes, among others. The described method comprises a composition with at least one bioadhesive polymer and at least one steroid that is released in a prolonged manner. The delivery of the pharmaceutical active ingredient may optionally require the use of spray cans, paddles, films, spatulas or combinations of these accessories.

[047] Contrary to what is reported in the document cited above, the present utility model describes the methodology for processing and preparing a solid pharmaceutical form, ready for use by direct adherence to the ulcerated oral region, without the need for incorporation into other vehicles, nor the use of specific application devices. The processing technique reported in this technology does not involve the use of any organic or aqueous solvents during any of the manufacturing steps. Petition 870230051318, dated 06 / 15 / 2023, pages 23 / 47 / 45

[048] Patent document CA 2892105 refers to the manufacture of topical medications (films) for the treatment of aphthous ulcers formed from swelling polymers or water-soluble polymers and at least one active ingredient belonging to the group of tannins and / or essential oils. The processing requires the formation of one or more homogeneous dispersions of one of the active ingredients in a polymer solution or suspension. The resulting mixtures are coated with carrier materials to remove solvents or suspending agents, forming polymeric films from which different dosage forms are obtained and separated.

[049] The technology resulting from the present utility model, on the other hand, uses thermoextrusion as a processing technique for materials previously mixed by maceration, in a single step without the use of organic solvents. Therefore, it does not require steps for forming homogeneous dispersions or drying for the production of monolayer mucoadhesive polymer films. The simplicity of the processing represents advantages in terms of material use, reduced production costs, industrial scalability and manufacturing time.

[050] Scientific documents relating the use of hot-melt extrusion techniques and the production of polymer films allow for comparison and differentiation of the present technology from previously published works.

[051] In this sense, Chen and colleagues studied the influence of processing parameters and Petition 870230051318, dated 06 / 15 / 2023, pp. 24 / 47 / 45, regarding formulation factors in different performance characteristics of films produced by thermoextrusion containing miconazole, in the search for alternatives for the treatment of oral candidiasis (CHEN, M. et al. AAPS PharmSciTech. 2014). Although this work is similar to the present utility model in terms of the application site, the drug class, as well as the nature of the ulcerative lesion, are notably different.

[052] Palem and colleagues explore the production of fast-release bioadhesive oral films containing Domperidone, for systemic effect, as an attempt to avoid the deleterious effects of the first pass observed during the administration of oral pharmaceutical formulations (PALEM, CR et al. Pharm. Dev. Technol. Ed., 18(1): 186-195, 2013; PALEM, CR et al. Drug. Dev. Ind. Pharm. Early Online: 1-12, 2016). Although the article refers to bioadhesive oral films, there are notable differences in both the preparation method and the product obtained, since the monolayer adhesive described in this application is used for local effect and prolonged release only in the ulcerated region, without access to systemic circulation, since the active ingredient inserted in the formulation can lead to significant adverse effects.

[053] With regard to the preparation method, the process described in this document stands out for the compositional elements and simplicity of the production process, which involves mixing the materials (including the liquid plasticizer at a maximum concentration of 10%) in a mortar and pestle for 5 minutes prior to Petition 870230051318, dated 06 / 15 / 2023, p. 25 / 47 / 45 thermoextrusion. The work presented by Palem and colleagues indicates the use of plasticizer at a concentration of 20% for all formulations, as well as the use of drying processes for all polymers individually, at a temperature of 50°C for 24 hours, in addition to sieving all materials through a No. 35 mesh. After that, the materials are mixed in specialized equipment at 25 rpm for 10 minutes.

[054] Park and colleagues developed, through thermoextrusion, an antifungal film for use in dental prostheses with the aim of assisting in the treatment of oral candidiasis (PARK, JB et al. Expert Opin. Drug Deliv. 2014). Although the polymeric film presented in the study is produced by thermoextrusion, it differs in purpose, as well as in the components used. Furthermore, the antifungal film must be fixed onto a dental prosthesis, differing from the utility model described in this document, whose application is directly onto the ulcerated oral mucosa.

[055] Still in the context of mucoadhesive films, Regev and colleagues used thermoextrusion to manufacture a vaginal film containing the anti-HIV drug Dapirivine, with the aim of assisting existing antiretroviral therapy (REGEV, G. et al. AAPS PharmSciTech. Ed., 20:239, 2019). Although the method of obtaining the mucoadhesive film is similar to that described in this document, it is clear that the application site of the film, as well as its composition and its Petition 870230051318, dated 06 / 15 / 2023, pp. 26 / 47 / 45, regarding the purpose of treatment, differ significantly.

[056] Bhagurkar and colleagues incorporated salbutamol sulfate into thermoextruded oral films, seeking controlled delivery for systemic action of the active ingredient (BHAGURKAR, AM et al. JPP. 2018). While sharing similarities, their preparation method uses Avicel PH 101 as a filler material and salbutamol sulfate in fixed proportions for all formulations (10% and 20% w / w, respectively), modifying only the proportion of polymers and plasticizers that make up the formulation. On the other hand, the present technology aims for the local action of the active ingredient incorporated into the monolayer adhesive, not using filler material that is not functional to the formulation. In addition, the established drug proportion is 5% (w / w); this concentration, along with the composition of the monolayer film, is optimized to ensure a local effect of the drug, minimizing possible systemic effects.

[057] The study by Bahri-Najafi and colleagues cites the development of two-layer buccal films containing TA that adhere to the oral mucosa and can be used in the effective treatment of oral lesions, such as recurrent aphthous stomatitis (RAS) (BAHRI-NAJAFI, R. et al. J. Isfahan Med Sch. Ed., 30(220): 2419-31, 2013). The reported manufacturing process requires the use of solutions containing organic solvents, which must be subjected to evaporation processes of these solvents to obtain the film. One of the layers must be Petition 870230051318, dated 06 / 15 / 2023, pp. 27 / 47 / 45, is formulated from conventional bioadhesive polymers and plasticizers, while the other is formed solely from ethyl cellulose.

[058] Thus, although there are similarities in the application required for the pharmaceutical form mentioned above and the product claimed in this utility model, both the pharmaceutical technology and the process for obtaining the final product are completely different. Mucoadhesive polymeric films prepared by thermoextrusion do not require the use of organic solvents during any processing step. Furthermore, the processing presented in this proposal requires only a single preliminary step of simple premixing of the materials by maceration; therefore, subsequent drying steps are also unnecessary, and the final product can be manufactured quickly, being industrially scalable due to the consolidated technology of pharmaceutical polymer extrusion. Additionally, the product presented here is monolayered, unlike that presented by Bahri-Najafi and colleagues, which is composed of two layers of distinct composition.

[059] Ikeuchi-Takahashi and colleagues developed a matrix of non-irritating, long-acting mucoadhesive tablets for the treatment of oral thrush using mixtures of mucoadhesive polymers, hard fat as a base, and indomethacin as a model drug (IKEUCHI-TAKAHASHI, Y. et al. Drug Dev Ind Pharm. Ed., 39(8): 1254-61, 2013). Two distinct methodologies were employed to obtain the tablets. Petition 870230051318, dated 06 / 15 / 2023, pp. 28 / 47 / 45, refers to mucoadhesives, namely: i) suspension method; and ii) dissolution and drying method. In the suspension method, the fat is melted at a temperature of 40°C and the polymers, after being sieved (100 mesh), are added to the melted fat under agitation. The suspension is then added to silicone molds and kept at room temperature for 5 hours to form the tablets, resulting in pharmaceutical forms with a thickness greater than 5.70 mm.

[060] In the dissolution and drying method, the authors employ a procedure even more distinct from that described in the present utility model. In this method, polymeric solutions are prepared in ethanol, to which molten fat (40°C) is added. After drying the ethanol under vacuum, the dry solid is melted and stirred for 10 min at 70-80°C. Thus, although the focus of the study presented is the treatment of canker sores using pharmaceutical forms that adhere to the oral mucosa, both the processing and the final product are completely different from those described in the utility model.

[061] The monolayer mucoadhesive polymeric film processed by thermoextrusion does not involve the use of organic solvents or any static molds for the preparation of the pharmaceutical forms in their final format. Furthermore, the final product obtained from the thermoextrusion process is a film with a thickness of less than 1.0 mm, a fundamental characteristic to generate comfort and compliance for the user, unlike the tablet with a thickness greater than 5.70 mm obtained in the aforementioned study. Petition 870230051318, dated 06 / 15 / 2023, pages 29 / 47 / 45

[062] Mumtaz & Ch'ng developed TA buccal tablets with different proportions of poly(acrylic acid-2,5-dimethyl-1,5-hexadiene) (PADH) and hydroxypropylmethylcellulose (HPMC) (MUMTAZ, AM, CH'NG, H. Int J Pharm. 121: 129-139, 1995). For this, all components of the formulation were mixed for 5 min and subjected to compression in a hydraulic press (8 tons for 30 min). All tablets exhibited a thickness between 1.67 and 1.72 mm, depending on the formulation. It becomes evident that, even using materials incorporated in the present pharmaceutical formulation, the differences between the preparation and processing methodologies result in completely distinct pharmaceutical forms. Furthermore, the thermoextrusion process, employed in the methodology of the present utility model, results in a formulation with greater bioavailability, stability and a better dissolution profile.

[063] Pereira Fernandes' doctoral thesis covers the development and characterization of pectin- and gum-based films and tablets for the topical release of triamcinolone (PEREIRA FERNANDES, F. PPG. Drugs and Medicines - Pharmaceutical Production and Control Area. USP, São Paulo-SP, 2017). Chapter 1 of the manuscript is a literature review concerning buccal films, their methods of obtaining and characterization, as well as their applications as mucoadhesive drug delivery systems in the oral cavity. Table 3 of the aforementioned doctoral thesis contains numerous references (12 in total) with information Petition 870230051318, dated 06 / 15 / 2023, pp. 30 / 47 / 45, relevant to oral formulations in the form of adhesives and films, however, after careful reading, it is concluded that all these references use preparation and processing techniques that differ significantly from the present technology.

[064] The processing of materials requires their solubilization in different organic solvents, which need to be subjected to drying processes that can take several hours until the solvents completely evaporate. As previously discussed, the product described in this document, a single-layer mucoadhesive polymeric film produced by thermoextrusion, does not require the use of any solvents in any of the processing steps, thus speeding up its manufacture and avoiding lengthy drying procedures that, above all, are difficult to standardize because they depend on factors such as pressure, temperature, solid-gas surface area, and relative humidity of the drying environment.

[065] Furthermore, Table 4 of the cited thesis presents some references on materials used in the development of mucoadhesive buccal films. Six of these references use preparation methodologies that also involve the evaporation of organic solvents, showing undeniable differences with the present technology, as discussed previously. On the other hand, there are 2 references cited in this review study whose preparation procedures involve the use of thermoextrusion as a processing technique, Petition 870230051318, dated 06 / 15 / 2023, pages 31 / 47 / 45, differing from the present technology in the following ways:

[066] Repka and colleagues investigated in vivo the bioadhesive properties of films containing hydroxypropyl cellulose (HPC) in high proportion (>90% (w / w) in all formulations (REPKA, MA et al. JCR. Ed., 70: 341-351, 2001). In the methodology described in the study, all materials, except the active ingredient, are subjected to drying in an oven for 48 hours at 50 °C. Then, using a solids and liquids mixer previously fed with HPC, plasticizer and other components of the formulation are added slowly and mixed for 30 min. These mixtures are extruded to obtain the respective films. Although the film described is produced by thermoextrusion, the method of preparing the mixtures prior to the extrusion process differs from the preparation method described in this document.Furthermore, the results reported in the aforementioned studies involve the administration of another active ingredient, Vitamin E TPGS®, especially studying the adhesive properties of said formulation on skin samples, whose physiological structure differs abruptly from the oral mucosa. In addition, the reported formulations also differ significantly in the composition of the present technology, where the maximum proportion of HPC reaches 55% (w / w).

[067] In another study by Repka and colleagues, the effect of hydroxypropylmethylcellulose when incorporated into thermoextruded films was investigated. Petition 870230051318, dated 06 / 15 / 2023, p. 32 / 47 / 45 hydroxypropylcellulose for the potential development of mucoadhesive oral delivery forms (REPKA, MA et al. Eur J Pharm Biopharm. Ed., 59(1): 189-196, 2005). All powders were mixed in specific equipment for 20 min and the mixture was dried in an oven at 50 °C for 24 h. Only after this were the formulations processed in an extruder with four heating zones, under the following temperature conditions: zones 1 and 2 of the mixer at 140 °C, zone 3 at 143 °C and final zone (extruder outlet), between 150 and 156 °C. It is also reported that there is a need to incorporate polyethylene oxide as an adjuvant for the thermal processing of polymer blends.

[068] Even though similarities were found in some of the materials used, the differences during the processing of the formulations are notable. The premixing method of the present technology is carried out for 5 minutes through simple maceration, without the need for additional equipment or drying processes. Additionally, all formulations in the study cited above incorporated hydroxypropylcellulose in proportions greater than 80% (w / w), while in this utility model the maximum proportion is 55% (w / w). Also, the thermoextrusion processing described in this document is carried out at a temperature of 150 °C, not requiring extruders with multiple stages of distinct heating nor adjuvants for the processing of the materials.

[069] In the work of Low and colleagues, orodispersible films for drugs were developed. Petition 870230051318, dated 06 / 15 / 2023, pp. 33 / 47 / 45 highly permeable substances that undergo significant clearance due to the first-pass effect (LOW, AQJ et al. Int J Pharm. Ed., 455(1-2): 138-147, 2013). In all formulations, the solid pharmaceutical ingredients were sieved separately in specific equipment at 42 rpm, and the plasticizing substance was maintained at 14% (w / v), being incorporated by liquid injection through a feed port of the extruder, which was programmed to increase and decrease the extrusion temperature through 4 specific zones of the equipment, varying around 30 °C in all formulations tested. The extruded material was then transported to a roller compaction system and calendered into films using 2 counter-rotating rollers with specific speed and pressure.

[070] Conversely, the present technology uses thermoextrusion to manufacture non-orodispersible, sustained-release, monolayer mucoadhesive polymeric films, since one of the objectives of the pharmaceutical form is to provide additional mechanical protection to the ulcerated area. The simple premixing method detailed here does not require sieving of the solid materials and allows the liquid plasticizer to be incorporated concomitantly during the maceration process. Furthermore, to transform the extruded material into film form, the use of compacting rollers is not necessary; the equipment used allows the adaptation of an output piece or "die" through which the film is formed directly. Also, the extrusion process Petition 870230051318, dated 06 / 15 / 2023, pages 34 / 47 / 45, describes that the procedure is performed under a constant temperature of 150 °C.

[071] Finally, Chapter 2 of the aforementioned doctoral thesis develops and characterizes pectin and gellan gum-based buccal films containing TA. However, the 8 formulations reported are produced using techniques that involve the use and evaporation of organic solvents, and are not related to the technology now being claimed.

[072] That being said, the state of the art does not foresee or suggest the development of a dense (non-porous) mucoadhesive polymeric film with a thickness of less than 1.0 mm that guarantees the prolonged release of triamcinolone acetonide, at a concentration of 5% (w / w) for the treatment of EAR, obtained by a simplified extrusion process. BRIEF DESCRIPTION OF THE FIGURES:

[073] The utility model can be better understood based on Figures 1 to 6, whose description follows below:

[074] Figure 1 shows, on the left, the continuous and homogeneous output of the material processed by thermoextrusion and, on the right, the thermoextruded single-layer bioadhesive film.

[075] Figure 2 shows SEM micrographs of the monolayer bioadhesive film (a) surface (1000X) and (b) cross-section (130X).

[076] Figure 3 shows the differential scanning calorimetry (DSC) analysis of triamcinolone acetonide (TA); physical mixture (PM) and bioadhesive film. Petition 870230051318, dated 06 / 15 / 2023, pp. 35 / 47 / 45 thermoextruded monolayer (HME). The melting peak of TA, along with the apparent moisture absorption by the MF and HME samples, are highlighted in the dashed blue and red boxes, respectively. The melting peak temperature of TA is indicated.

[077] Figure 4 shows the first derivative of the thermogravimetric (DTG) curve of triamcinolone acetonide (TA); physical mixture (MF) and thermoextruded monolayer polymeric bioadhesive film (HME). The initial decomposition temperature (Td) is indicated along with the mass loss events in percentage.

[078] Figure 5 shows the x-ray diffraction (XRD) spectrum of triamcinolone acetonide (TA); physical mixture (PM) and thermoextruded monolayer polymeric bioadhesive film (HME).

[079] Figure 6 shows the in vitro release profile of the pure drug (control) and the drug incorporated into the thermoextruded polymer matrix (HME Adhesive). DETAILED DESCRIPTION OF THE UTILITY MODEL

[080] The present technology refers to a single-layer polymeric bioadhesive film less than 1.0 mm thick, capable of releasing the active ingredient TA in a controlled manner aiming at a local therapeutic effect and, at the same time, providing mechanical protection to the ulcerated region in the treatment of Recurrent Aphthous Stomatitis.

[081] The mucoadhesive formulation consists of: Hydroxypropylcellulose (55%, w / w), hydroxypropylmethylcellulose (20%, w / w) and variations Petition 870230051318, dated 06 / 15 / 2023, pp. 36 / 47 / 45 of acrylic acid crosslinked polymer (carbomer; 10% w / w); 10% glycerin (plasticizer); and TA (preferably 5% w / w).

[082] All components of the pharmaceutical formulation that make up the monolayer polymeric bioadhesive film (polymer matrix, drug and liquid plasticizer) must be subjected to a simplified physical mixing process, employing simple maceration. The polymeric matrix may consist of, but is not limited to, hydroxypropylcellulose (55% w / w), hydroxypropylmethylcellulose (20% w / w) and variations of acrylic acid crosslinked polymer (carbomer; 10% w / w). The proportions used may be modified, these materials preferably being biocompatible, biodegradable and non-toxic.

[083] The plasticizers used include glycerin, citric acid, triethyl citrate, dibutyl phthalate, silicones, poly(propylene glycol), among others. Glycerin is preferably used at a maximum concentration of 10%.

[084] Furthermore, among the drugs that can be used as an active ingredient, individually or in combination, the following can be mentioned, but are not limited to: corticosteroids, such as TA (preferably 5%, w / w); synthetic or natural anti-inflammatory drugs, such as naringenin or ibuprofen; local anesthetics, such as lidocaine; silver metallic nanoparticles, among others. The incorporation of the drug within the polymeric matrix of the monolayer bioadhesive film must be Petition 870230051318, dated 06 / 15 / 2023, pp. 37 / 47 / 45, carried out directly through thermoextrusion. In this technique, a mixture of polymers, plasticizer, and drug(s) are inserted into the apparatus to produce the monolayer polymeric bioadhesive film.

[085] The sustained-release mechanism depends on the physicochemical characteristics of the polymeric matrix, as well as its interaction with the active ingredient molecules and the natural characteristics of the oral mucosa microenvironment. The release mechanism allows the drug to remain in close contact with the ulcerated area while it is being released in a prolonged manner at the application site of the bioadhesive film, providing mechanical protection of the lesion and meeting basic patient needs not met by other preparations on the market, providing a feeling of physical well-being and contributing to improving the user's quality of life.

[086] The formulation obtained does not employ organic solvents at any stage of production or in the final product, providing important benefits in terms of production and use. The oral mucosa is especially sensitive to solvents such as ethanol and isopropyl alcohol, and even residual amounts of these materials could aggravate the ulcerative state of the oral region in patients with EAR. Furthermore, the local action of the formulation will prevent the indiscriminate distribution of the drug into the systemic circulation, avoiding the side effects of solvent-based drugs.

[087] The present technology describes the simplified manufacturing process, through thermoextrusion, Petition 870230051318, dated 06 / 15 / 2023, pages 38 / 47 / 45 of said single-layer polymeric bioadhesive film containing TA for the treatment of Recurrent Aphthous Stomatitis. The technology provides a simple processing method, without material waste, which allows for streamlining and reducing the time required for material preparation during the pre-extrusion stage (physical mixing).

[088] The preparation method is straightforward, using a simple and quick premixing process of the materials. The homogeneous mixture then undergoes a hot-melt extrusion process to produce the single-layer polymeric bioadhesive film. In general, the process consists of the steps described below: A.) Weighing and mixing the formulation components; B) Addition of liquid plasticizer; C) Thermoextrusion of the formulation.

[089] Step (A) consists of weighing and mixing the formulation components. During this step, the formulation components (polymer matrix, drug and plasticizer) must be weighed in the required proportions and in suitable containers, separately. Once weighed, the solid materials must be mechanically macerated.

[090] Step (B) consists of adding the liquid plasticizer. The liquid plasticizer, glycerin at a final concentration of 10% (w / w) in the formulation, is the last component to be incorporated, being dripped directly onto the physical mixture of powders obtained in step (A). The mixing must be continuous until a uniform consistency is achieved. Petition 870230051318, dated 06 / 15 / 2023, pages 39 / 47 / 45

[091] Step (C) consists of the thermoextrusion of the formulation. The physical mixture prepared in step (B) is used to continuously feed the thermoextrusion equipment (rotary conical twin screw thermoextruder). The extrusion conditions are set at 150°C and 75 rpm, based on the thermal and mechanical stability of the polymers that make up the matrix and the active ingredient, to obtain a film with a homogeneous appearance, allowing adequate extrusion of the material and with continuous flow.

[092] The molten material inside the thermoextruder shows adequate behavior during its processing, with fast, homogeneous and continuous outflow, resulting in the formation of compact polymeric films, with a smooth, whitish and / or translucent appearance, flexible enough to be manually and constantly pulled, showing a uniform thickness of less than 1 mm (Figure 1), even in the absence of pulling at the extruder outlet.

[093] In this sense, thermoextrusion processing is carried out without recirculation of the material and at a single, constant temperature, both at the material inlet and at the outlet nozzle or “die”. The preparation method used simplifies the production steps and allows for the rapid, simple, efficient and non-wasteful production of a thermoextruded single-layer polymeric bioadhesive film with sufficient flexibility to be fixed to hard-to-reach surfaces within the oral cavity.

[094] In another aspect, the present technology is Petition 870230051318, dated 06 / 15 / 2023, pages 40 / 47 / 45, refers to the use of a formulation in the form of a single-layer polymeric bioadhesive film for the treatment of recurrent aphthous stomatitis. In this sense, the present technology offers a more efficient way to treat recurrent aphthous stomatitis, with inherent advantages that include: i. The speed and simplicity of the pharmaceutical dosage form preparation method; ii. Ease of use, since the single-layer polymer film has sufficient flexibility for application to hard-to-reach ulcerated areas; iii. Greater treatment efficacy, since the composition and thickness of the pharmaceutical form allow for prolonged release of the drug at the site of the condition, avoiding the use of complementary systemic oral treatment and, consequently, reducing the incidence of adverse reactions. iv. Mechanical protection of the ulcerated area while releasing the drug in a controlled manner, reducing pain and improving the patient's quality of life. BEST EXECUTION OF THE INVENTION

[095] The examples below are presented in order to illustrate in detail certain embodiments of the utility model. It is important to note that the present utility model is not limited to the examples cited and can be used in all applications. Petition 870230051318, dated 06 / 15 / 2023, pages 41 / 47 / 45 described or in any other equivalent variations. EXAMPLE 1: ANALYTICAL METHODS

[096] The drug content of thermoextruded monolayer polymeric bioadhesive films and its quantification in in vitro release studies are determined by spectrophotometer operated at 240 nm. To demonstrate the assay (n= 3), a portion of the film containing the equivalent of 2.5 mg of TA is dissolved in acetonitrile under stirring and heating (40°C) for 1 h. The linearity obtained in the range of 0.5 to 30.0 pg mL-1 shows a correlation coefficient (r2) of 0.997.

[097] For the determination of TA during in vitro release, the linearity obtained in the range of 0.5 to 15.0 pg mL-1 shows a correlation coefficient (r2) of 0.998. The method is validated according to the parameters of the International Conference on Harmonisation. EXAMPLE 2: PHYSICAL-CHEMICAL CHARACTERIZATION OF THE FILM THERMOEXTRUDED SINGLE-LAYER POLYMERIC BIOADHESIVE

[098] The thermoextruded monolayer bioadhesive film must be analyzed in order to establish the relevant physicochemical characteristics that allow verifying the feasibility of the manufacturing methodology described in this utility model.

[099] Micrographs of the thermoextruded monolayer polymeric bioadhesive films are obtained by Scanning Electron Microscopy (SEM) and are shown in Figure 2 (a,b). The morphological aspects allow observation of the smooth surface of the Petition 870230051318, dated 06 / 15 / 2023, pp. 42 / 47 / 45: Polymeric bioadhesive films, without visible ruptures and without apparent evidence of drug particles in the crystalline state (Figure 2a). The micrograph of the cross-section of the polymeric bioadhesive film (Figure 2b) allows the identification of the formation of a single-layer product, in which no drug crystals are observed, showing the successful incorporation of the active ingredient into the polymeric matrix and the compatibility of the selected polymeric matrix.

[100] Thermal analyses are performed in order to establish the thermal behavior of the active ingredient and the polymeric matrix, comparing the physical mixture of the components with the monolayer polymeric bioadhesive film obtained by thermoextrusion.

[101] Differential Scanning Calorimetry (DSC) is performed to obtain information regarding the characteristic melting peak of the active ingredient and its behavior within the formulation. Samples of 2.0 to 4.0 mg are placed in sealed aluminum capsules and analyzed under a nitrogen atmosphere with a flow rate of 50 mL min-1 and a heating rate of 10°C min-1, from 25 to 300°C. The results are presented in Figure 3. The melting event associated with TA is observed for the pure drug, around 291°C. However, this thermal event is not evidenced in the physical mixture of materials, nor in the monolayer polymeric bioadhesive film obtained by thermoextrusion. This result shows high solubility of the drug in the molten polymeric matrix and, consequently, a prevalence of its amorphous state within the polymeric matrix. Petition 870230051318, dated 06 / 15 / 2023, pages 43 / 47 / 45

[102] Furthermore, a large endothermic event can be observed between 160 and 230°C in the physical mixture and in the thermoextruded monolayer polymeric bioadhesive film, this being more pronounced in the physical mixture, showing evaporation of the plasticizer.

[103] To obtain information regarding drug stability and sample decomposition profile, thermogravimetric analyses are performed in platinum capsules under a nitrogen flow of 50 mL min-1 and a heating rate of 10°C min-1, from 25 to 500°C. The result is represented by the graph of the first derivative of the thermogravimetric curve (DTG), in Figure 4. The DTG curve shows evaporation of the plasticizer.

[104] On the other hand, it is possible to observe how the initial degradation temperature of the drug (Td= 304 °C) is shifted to higher temperatures in the physical mixture and in the thermoextruded monolayer polymeric bioadhesive film (Td= 346°C and 341°C, respectively). It is also observed that the drug degradation events are divided into three stages, with the initial stage, involving a 40% loss of mass, being the main one; While in the physical mixture and in the thermoextruded monolayer polymeric bioadhesive film, a single mass loss event is observed at similar temperatures, starting at least 37°C above the Td recorded for the pure drug, possibly involving the degradation of the formulation components in a single step. Thus, based on the results of the thermal analysis along with the drug content found during the assay of the monolayer polymeric bioadhesive films Petition 870230051318, dated 06 / 15 / 2023, pp. 44 / 47 / 45 thermoextruded (>95%), attests to the compatibility and stability of the developed drug system.

[105] Complementarily, X-ray diffraction (XRD) spectroscopy is collected to confirm the SEM and DSC results regarding the amorphization of the drug within the polymeric matrix, both in the physical mixture and in the thermoextruded monolayer polymeric bioadhesive film (Figure 5). Analysis of the pure drug confirms its highly crystalline nature, reflected in the characteristic peaks around 2θ, at 9°, 14°, 17° and 26°. However, the polymeric mixture containing the drug, whether in the physical mixture or in the thermoextruded bioadhesive film, showed a predominantly amorphous XRD profile, which was more pronounced in the thermoextruded sample, suggesting an important interaction between the polymeric chains and the drug molecules during processing.

[106] Mucoadhesion is a fundamental analysis parameter for the technology presented in this document, since the produced pharmaceutical form must be able to remain adhered to the oral mucosa for a determined time that allows the sustained release of the active ingredient directly in the ulcerated region, with a local effect, also providing mechanical protection of the lesion. Analyses performed using mucin discs that came into contact for 30 s with samples of the thermoextruded monolayer polymeric bioadhesive film (n= 3), result in adhesive strength peaks (maximum detachment force) around 0.5N, confirming the mucoadhesive characteristic of the systems. Petition 870230051318, dated 06 / 15 / 2023, pages 45 / 47 / 45

[107] Finally, the thermoextruded monolayer polymeric bioadhesive film is characterized by its drug release capability in in vitro assays. The TA release profile from the thermoextruded bioadhesive films, expressed as the percentage of drug released (Figure 6), is determined using modified Franz-type diffusion cells (n=4). Hydrophilic synthetic cellulose acetate membranes are placed between the receptor and donor compartments. The receiving compartment is filled with 15 mL of a 50% v / v solution of 0.1 M phosphate buffer (pH 6.8) and PA ethanol, ensuring sink conditions. In the donor compartment, a portion of the thermoextruded bioadhesive film is placed over the membrane, and the system is moistened with 100 µL of 50% v / v ethanol:water solution. 3 mL aliquots are collected at 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, and 6.0 h, with immediate replacement of the withdrawn volume. All aliquots are filtered with a 0.45 µm nylon membrane and analyzed for TA content. As a control, 1.90 mg of TA (average drug content in the film portions used) is placed on the synthetic membrane in the donor compartment of the Franz cells (n=4), following the procedure already described. The system is maintained at 37.0 ± 0.5 °C.

[108] The thermoextruded single-layer polymeric bioadhesive film is capable of promoting sustained drug release, demonstrating that the material processing described in this document and the technique used can facilitate release, Petition 870230051318, dated 06 / 15 / 2023, pp. 46 / 47 / 45, promoting or increasing the solubility of the drug in the receptor medium, the polymeric bioadhesive film may act by improving the pharmacokinetic performance of the drug to be used while providing mechanical protection of the ulcerated region, since its integrity is maintained. Petition 870230051318, dated 06 / 15 / 2023, page 47 / 47

Claims

1 / 1 CLAIMS 1. MONOLAYER POLYMERIC BIOADHESIVE FILM, characterized by having a thickness of 1.0 mm and releasing the active ingredient in a controlled manner for a local therapeutic effect and, at the same time, providing mechanical protection to the ulcerated area in the treatment of Recurrent Aphthous Stomatitis, comprising: (1) hydroxypropylcellulose, at a concentration of 55% (w / w), hydroxypropylmethylcellulose, at a concentration of 20% (w / w) and crosslinked acrylic acid polymer (carbomer) at a concentration of 10% (w / w); (2) glycerin, at a concentration of 10% (plasticizer); and (3) the active ingredient Triamcinolone Acetonide, at a concentration of 5% (w / w). Petition 870230032602, dated 04 / 19 / 2023, page 55 / 152

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