A mixture for obtaining a dental / periodontal carrier, methods for obtaining a dental / periodontal carrier, a dental / periodontal carrier, and a use of the carrier

Abstract

The subject of the invention is a mixture for obtaining a dental and / or periodontal carrier. The invention also relates to methods for obtaining a carrier from the composition, a carrier for use in dentistry and / or periodontology, and a use of the carrier for obtaining a dental and / or periodontal composition.

Description

[0001] A mixture for obtaining a dental / periodontal carrier, methods for obtaining a dental / periodontal carrier, a dental / periodontal carrier, and a use of the carrier

[0002] The subject of the solution is a mixture for obtaining a dental and / or periodontal carrier, methods for obtaining a dental and / or periodontal carrier, a dental / periodontal carrier, and a use of the carrier.

[0003] The World Health Organization (WHO) estimates that oral diseases affect nearly 3.5 billion people every year. Although the quality of care for oral disorders continues to improve worldwide, these problems still rank among the top ten most common diseases, which negatively affects the global economy. Annual expenditure on the treatment of these conditions was estimated at USD 387 billion in direct costs and another USD 323 billion in indirect costs.

[0004] The treatment of severe inflammation of the oral cavity using standard therapies, such as antibiotic therapy or mechanical cleaning, often turns out to be ineffective, leading only to short-term alleviation of the symptoms of the disease. There is an ongoing search for new solutions using formulations to treat inflammation of the gums, mucous membranes, mouth ulcers and periodontal problems. Polymer films are an excellent solution for application on mucous membranes, the tongue, and periodontal pockets, as dozens of types of polymerfilms have been designed with different properties and can be used in various applications within the oral cavity— from mucous membranes and the tongue to periodontal pockets.

[0005] The search for new dosage forms, especially in the context of carriers for active substances, stems both from the natural limitations of application sites and the inconveniences associated with conventional carriers, such as semi-solid and liquid forms. The most significant problems associated with the currently used forms include: insufficient retention time of the carrier at the application site, difficulties in achieving prolonged release of the active substance.

[0006] The intensive development of mucoadhesive preparations is becoming a promising solution to overcome these drawbacks. This dosage form ensures close contact between the medicinal substance and the application site, as well as its prolonged retention time. Additionally, it is a non-invasive method of administration that does not interfere with patients' daily activities, such as speaking and drinking, which may contribute to improved compliance with therapeutic recommendations.

[0007] The object of the invention is to provide a carrier composition for use in dentistry and / or periodontology that would enable easy incorporation of the active substance depending on the needs of the therapeutic process, easy adjustment of application parameters, i.e., mucoadhesion, blurring time, or release profile of the active substance, to therapy needs. Furthermore, the carrier, with no substance (e.g., for use as a placebo) or with an active substance, should be characterized by appropriate mechanical properties in order to easily adapt its application form in terms of its shape and size to the needs of the application site.

[0008] The first subject of the invention is a mixture for obtaining a dental / periodontal carrier, characterized in that it contains, in weight percentage, at least one of the components selected from the group comprising: a) an aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 98% to 99% in an amount of more than 0% to 7% w / w, an aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 85% to 99% in an amount of more than 0% to 7% w / w, an aqueous solution of polyvinylpyrrolidone in an amount of more than 0% to 7% w / w, an aqueous solution of pullulan in an amount of more than 0% to 3.5% w / w, an aqueous solution of methylcellulose with a viscosity of 400 cP in an amount of more than 0% to 3.5% w / w, an aqueous solution of hydroxypropyl methylcellulose in an amount of more than 0% to 2.1% w / w, an aqueous solution of methylcellulose with a viscosity of 1200-1800 mPa*s in an amount of more than 0% to 5% w / w, an aqueous solution of carboxymethyl cellulose sodium salt in an amount of more than 0% to 2.8% w / w, wherein each polymer not selected from the above group is present in an amount of 0% w / w, b) optionally, an aqueous solution of glycerine in an amount of 0% to 3.5% w / w, which acts as a plasticizer, or a mixture thereof, and c) purified water up to 100% of the weight of the composition.

[0009] In a preferred embodiment of the invention, the aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 98% to 99% has a concentration ranging from 2.5% to 7% w / w.

[0010] In another preferred embodiment of the invention, the aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 85% to 99% has a concentration ranging from 2.5% to 7% w / w. In another preferred embodiment of the invention, the aqueous solution of pullulan has a concentration ranging from 2.5% to 3.5% w / w.

[0011] In another preferred embodiment of the invention, the aqueous solution of methylcellulose with a viscosity of 400 cP has a concentration ranging from 0.5% to 3.5% w / w.

[0012] In another preferred embodiment of the invention, the aqueous solution of hydroxypropyl methylcellulose has a concentration ranging from 1.0% to 2.1% w / w.

[0013] In yet another preferred embodiment of the invention, the aqueous solution of methylcellulose with a viscosity of 1500 cP has a concentration ranging from 1% to 5% w / w.

[0014] Preferably, the solution of carboxymethyl cellulose sodium salt has a concentration of 2.8% w / w.

[0015] Preferably, the aqueous solution of methylcellulose with a viscosity of 2% aqueous solution at 20°C of 1200-1800 mPa*s has a concentration of 3% w / w.

[0016] Preferably, the aqueous solution of glycerine has a concentration of 0.15% to 3.5% w / w.

[0017] The second subject of the invention is a method for obtaining a dental / periodontal carrier, comprising preparing aqueous solutions of the components of the carrier composition, as specified in the first subject of the invention, mixing the components of the composition, characterized in that the mixture is subjected to mixing for 2 to 3 hours, then cooled to a temperature ranging from 4°C to 8°C for 24 hours, mixed again, cast into a mold, and dried for 24 to 72 hours at a temperature of 32±1°C.

[0018] In a preferred embodiment of the invention, the method comprises the steps of: a) preparing the mixture as specified in claim 1; b) mixing the mixture for 2 to 3 hours; c) cooling the mixture to a temperature ranging from 4°C to 8°C for 24 hours; d) mixing the mixture again; e) casting into a mold and drying for 24 to 72 hours at a temperature of 32±1°C.

[0019] Another subject of the invention is a method for obtaining a dental / periodontal carrier, characterized in that it comprises the steps of: a) preparing a preliminary mixture containing at least one polymer component specified in point a) of claim 1, and purified water; b) mixing the preliminary mixture for 2 to 3 hours; c) subjecting the preliminary mixture to freezing at a temperature of -18°C to -22°C for 1 to 4 hours; d) thawing the preliminary mixture and subjecting it to ultrasounds to remove air bubbles; e) mixing the preliminary mixture for 4 hours, then cooling it at a temperature of 4°C to 8°C for 24 hours; f) adding the optional plasticizer specified in point b) of claim 1 to the cooled preliminary mixture and continuing the mixing for 4 hours; g) casting the final mixture into a mold and drying for 24 to 72 hours at a temperature of 32±1°C.

[0020] In a preferred embodiment of the invention, the above method comprises the steps of: a) preparing a preliminary mixture containing at least one polymer component specified in point a) of the first subject of the invention, and purified water; b) mixing, freezing, thawing, subjecting to ultrasounds and mixing again the preliminary mixture, as in steps b) to e) of claim 13; c) freezing the preliminary mixture again at a temperature of -18°C to -22°C for 4 hours, followed by thawing it and subjecting it again to ultrasounds; d) adding the optional plasticizer specified in point b) of claim 1 to the preliminary mixture, and continuing the mixing for 4 hours; e) casting the final mixture into a mold and drying for 24 to 72 hours at a temperature of 32±1°C.

[0021] Another subject of the invention is a dental / periodontal carrier, formed from the mixture specified in the first subject of the invention, characterized in that it is characterized by at least one of the following properties: a) mucoadhesion value measured in a test with mucin ranging from 190 g to 271 g; b) blurring time ranging from 2 min to 24 h; c) pH of the extract formed after blurring of the formulation ranging from 6.48 to 7.43; d) contact angle measured with a goniometer ranging from 50.78° to 60.05°.

[0022] Yet another subject of the invention is the use of the dental / periodontal carrier according to the subject of the invention specified above, or obtained according to one of the methods specified above, for obtaining a dental / periodontal composition.

[0023] It is possible to obtain carriers with these properties due to the adhesive properties of the used polymers, which constitute the components of the developed formulations. The use of mucoadhesive polymer-based carriers may increase their contact with oral mucosa, which consequently promotes more effective release of active substances at the application site, and consequently higher adsorption, bioavailability and, as a result, therapeutic efficacy. The essence of the invention is a polymer formulation that enables the incorporation of active substances with potential antibacterial and anti-inflammatory properties, intended for application in inflammatory conditions of the oral cavity. The formulation also marks the current direction in the search for new application forms for substances in the non-surgical treatment of periodontitis. Developed carriers with different compositions and different disintegration times allow obtaining formulations tailored to the therapeutic needs, including the time they remain on the mucous membrane. The basis for the film formulations is polyvinyl alcohol (PVA), which provides the appropriate mechanical properties, and / or polyvinylpyrrolidone (PVP), which acts as a solubility promoter and an enhancer of mucoadhesive properties. In addition, the film skeletons constitute cellulose derivatives, including methylcellulose with low viscosity (2% solutions in the range of 300-560 mPas), methylcellulose with an average viscosity (2% solutions in the range of 1200-1800 mPas), and hydroxypropyl methylcellulose with a viscosity of 2% solutions in the range of 20-40 mPa*s.

[0024] In order to ensure adequate mucoadhesive properties and to prolong the release time of the substances incorporated in the carrier, polyvinylpyrrolidone (PVP) and carboxymethyl cellulose sodium salt (NaCMC) have been incorporated into the composition of the film formulations. These ingredients promote stronger interactions with the mucous membrane, which translates into better adhesion and prolonged therapeutic action. Due to its diverse structure and properties, the developed formulation has the potential to treat inflammation of the oral cavity more effectively, which may contribute to improving the quality of dental therapies.

[0025] Furthermore, carrier formulations according to the invention are characterized by varying blurring times and varying half-release times of the active substance, which allows designing film formulations with desired release profiles of active substances tailored to clinical needs. Importantly, the selected flexible drug form ensures convenient application, both in the doctor's office and for self-use by the patient as part of the treatment prescribed by the doctor. The flexibility of these formulations translates into their pliability and ease of forming, allowing them to be tailored to specific application sites, such as the cheek or the tongue. Additionally, they may be easily cut to the desired shape, which allows for their placement in periodontal pockets. Such versatility in application allows patients to comfortably use the drug under home conditions, which increases treatment efficacy and improves compliance with therapeutic recommendations.

[0026] A technology for producing polymer film formulations was developed, which resulted in dental carrier formulations that differed in the composition of the auxiliary substances used. The diversity of ingredients had a significant impact on their physicochemical properties, such as blurring time, flexibility, mucoadhesion, and the pH of the extract formed after blurring the formulation. By analyzing these properties, the formulation may be tailored to specific therapeutic needs, which can improve treatment efficacy in the case of oral diseases.

[0027] During the optimization of the technological process, placebo film formulations were obtained by a solvent casting method and their physical cross-linking, which allowed for obtaining the desired mechanical and mucoadhesive properties. The series contained cast masses weighing between 10 g and 70 g of gel formulation, applied to polystyrene dishes with a surface area of 92 cm2. The conducted tests used various combinations of polymer components, including both an individual polymer combined with a plasticizer and complex mixtures consisting of two, three, and four polymers with the addition of a plasticizer. One to four polymer solutions were used in various quantitative proportions, with the additional introduction of glycerol as a plasticizer. Such an approach allowed for the development of formulations with diverse physicochemical properties, which is crucial for their efficacy in therapeutic applications in the field of dentistry. The glycerol content in the composition determines the flexibility of the final product. If the carrier should be more flexible, the glycerol solution content should be 5% w / w of the composition. Reducing its content leads to a decrease in the flexibility of the carrier.

[0028] Embodiments for carrying out the invention have been illustrated in the drawing, where Fig. 1 illustrates the schematic of preparing polymer film formulations.

[0029] Reagents used:

[0030] Sigma-Aldrich: polyvinyl alcohol (PVA, Mwt: 85,000-124,000, degree of hydrolysis: 98-99%; CAS: 9002-89-5), polyvinylpyrrolidone (PVP, K90, Mwt: 40,000, CAS: 9003-39-8), methylcellulose 400 (MC 400 cP, viscosity of 2% aqueous solution at 20°C: 300-560 cP, CAS: 9004-67-5), methylcellulose 1500 (MC, Methocel8A15C, viscosity of 2% aqueous solution at 20°C: 1200-1800 mPa*s, CAS: 9004-67-5), methylcellulose 1500 (HPMC - 5, Methocel, Colocorn, viscosity of 2% aqueous solution at 20°C: 1200-1800 mPa*s, CAS: 9004-67-5), hydroxypropylmethylcellulose (HPMC, viscosity of 2% aqueous solution at 20°C: 40-60 cP, CAS: 9004-65-3), mucin from pig stomachs (type III, bound to sialic acid: 0.5-1.5%, CAS: 84082- 64-4); VWR Chemicals: carboxymethyl cellulose sodium salt (NaCMC, viscosity of 2% aqueous solution at 25°C: 300-600 mPa*s, CAS: 9004-32-4); Fagron: glycerol (Glycerolum 85%, batch no.: 081056, CAS: 56-81-5); Honeywell: ethyl alcohol (96% v / v, CAS: 64-17-5); J. T. Baker: purified water LC-MS (CAS: 7732-18-5).

[0031] Purified water obtained by ion exchange and reverse osmosis was used in the tests, meeting the requirements of the Aqua purifica monograph published in FP XIII (04 / 2018:0008).

[0032] Example 1. Obtaining the carriers

[0033] In the first stage of the study, aqueous solutions of selected polymers were prepared in concentrations allowing them to be mixed together and cast into polystyrene dishes with an area of 92 cm2. The table lists the polymers selected for testing and the concentrations of the solutions prepared therewith, which were used in the process of selecting the composition of polymer films.

[0034] Table. 1. Polymers selected for testing and concentrations of solutions prepared therewith

[0035] PVA solutions were prepared by dissolving a weighed amount of polymer in purified water and mixing at a constant speed of 50 revolutions per minute while heating at a temperature of approximately 70°C for 24 hours. PVA and pu II u Ian solutions were prepared by dissolving a weighed amount of polymer in purified water and mixing at a constant speed of 50 revolutions per minute at room temperature for 24 hours. Meanwhile, solutions of cellulose derivatives, i.e., MC 400, MC 1500, MC A15C, HPMC and NaCMC, were prepared by adding weighed amounts of polymers to purified water at room temperature and leaving them to swell in a refrigerator at 4°C for 24 hours. After this time, the solutions were mixed using a magnetic stirrer at a speed of 50 revolutions per minute for 5 hours. All prepared polymer solutions were subjected to a sterilization process in an autoclave (SANYO, model: MLS-3750, Japan) at a temperature of 121°C for 20 minutes from the moment the indicated temperature was reached.

[0036] The design of a polymer film formulation intended for application to the oral mucosa began with the preparation of individual polymer solutions, followed by the inclusion of complex mixtures containing two, three, and four polymer solution in the process. The figure shows a schematic of the polymer film preparation process, illustrating the individual stages of the formulation process. ) Preparing the appropriate reagents for the preparation of the carrier

[0037] Polymer films were prepared in a laminar chamber using the solvent casting method, according to the table (Table 1. Polymers selected for testing and concentrations of solutions prepared therewith).

[0038] 2) After preparing appropriate polymer solutions, the preparation of the carriers was carried out. In the case of formulations based on a single polymer and a plasticizer, the process proceeded as follows: appropriate polymer solutions were prepared, which were then placed in a vessel with a stirrer, adding the appropriate amount of the plasticizer. The compositions are presented in Table 3 for A series. After thorough mixing (on a magnetic stirrer) for 2-3 hours at room temperature, the mixture was cooled to a temperature of 4 to 8°C for 24 hours. After this time, the mixture was mixed again, then cast in amounts of 10 to 70 g into polystyrene dishes with an area of 92 cm2, followed by drying in a laboratory dryer at a temperature of 32±1°C for 24-72 hours. The obtained formulations were subjected to a preliminary assessment of their film-forming properties and physicochemical properties. For the preliminary assessment of polymer films made from single polymers, the following were assessed: surface morphology of the films produced, flexibility, transparency and gloss, ease of removal from the mold, film blurring time, pH of the aqueous extract formed after blurring the film.

[0039] The described properties were assessed for all the prepared films, together with the parameters of their preparation process. The assessment used a preliminary blurring time test method consisting of placing a 2.5 cm x 2.5 cm film fragment in a beaker filled with 10.0 ml of purified water. Tightly sealed beakers were placed in a water bath with a horizontal shaking function. During the test, the temperature was maintained at 37°C±1°C and shaking at 60 cycles per minute. Blurring time was determined by measuring the time that elapsed from the moment the film fragment was placed in the beaker with water until it was completely dissolved. Film A2, prepared using PVA with a degree of hydrolysis of 98-99%, showed a significantly longer blurring time, approximately 120 minutes, compared to film Al, obtained from PVA with a degree of hydrolysis in the range of 85-89%, for which the blurring time was approximately 30 minutes. The results obtained were taken into account and provided a significant contribution to the further design of the carriers, whereby it was important to obtain both carriers with a short disintegration time and those with a longer disintegration time.

[0040] 3) In order to further design carriers and assess the behavior of polymer solutions during mixing and casting, followed by the assessment of the morphological and structural uniformity of films obtained in the drying process, formulations consisting of two-component mixtures of polymer solutions were prepared. For this purpose, in a laminar flow cabinet, sterilized solutions of individual polymers were prepared, according to the composition shown in the table for B, C and D series, which were mixed in weight ratios of 50:50 w / w. After combining the two polymer solutions, they were mixed at room temperature on a magnetic stirrer for 2- 4 hours. Next, the physical cross-linking of polymers was carried out at a temperature of -18°C to -22°C, which lasted 1-4 hours (the mixture must be frozen). After this time, the mixture was thawed to room temperature and subjected to sonication in an ultrasonic bath (Advantage-Lab GmbH, type: AL-04-12) at room temperature in order to remove air bubbles until they completely disappeared. It was then mixed for another 4 hours and subsequently cooled at a temperature of 4° to 8°C for up to 24 hours. After cooling, it was mixed again for 2-4 hours and a plasticizer was added, mixing on a magnetic stirrer for 4 hours. During this process, the uniformity of the mixture and the presence of air bubbles were monitored. After obtaining a uniform mixture with the composition shown in the tables for each series (B, C, D) in an amount of 10-70 g, it was cast into polystyrene dishes with an area of 92 cm2and then dried in a laboratory dryer at 32±1°C for 24-72 hours. The obtained formulations were subjected to a preliminary assessment of their film-forming properties and physicochemical properties.

[0041] 4) In order to further design carriers and assess the behavior of polymer solutions during mixing and casting, followed by the assessment of the morphological and structural uniformity of films obtained in the drying process, formulations consisting of two or three mixtures of polymer solutions were prepared. For this purpose, in a laminar flow cabinet, sterilized solutions of individual polymers prepared according to the composition shown in the tables for E, F and G series were mixed in various weight ratios. After combining the two polymer solutions, they were mixed at room temperature on a magnetic stirrer for 2-4 hours. Next, the physical cross-linking of polymers was planned at a temperature of -18°C to -22°C, which lasted 1-4 hours (the mixture must be frozen). After this time, the mixture was thawed and subjected to sonication in an ultrasonic bath (Advantage-Lab GmbH, type: AL-04-12) at room temperature in order to remove air bubbles until they completely disappeared. It was then mixed for another 4 hours and subsequently cooled at a temperature of 4° to 8°C for 24 hours. After cooling, it was mixed again for 2-4 hours at room temperature until a uniform mixture was obtained, which was then subjected to physical cross-linking again at a temperature of - 18°C to -22°C, lasting up to 4 hours (the mixture must be frozen). After this time, the mixture was thawed and again subjected to sonication in an ultrasonic bath (Advantage-Lab GmbH, type: AL-04-12) at room temperature in order to remove air bubbles until they completely disappeared. It was then mixed for another 4 hours at room temperature and next, cooled to a temperature ranging from 4° to 8°C for 24 hours, after which a plasticizer was added while mixing on a magnetic stirrer at room temperature for 4 hours. During this process, the uniformity of the mixture and the presence of air bubbles were monitored. After obtaining a uniform mixture with the composition shown in the tables for each series (E, F, G) in an amount of 10-70 g, it was cast into polystyrene dishes with an area of 92 cm2and then dried in a laboratory dryer at 32±1°C for 24-72 hours (the drying of the film must be checked and monitored). The obtained formulations were subjected to a preliminary assessment of their film-forming properties and physicochemical properties.

[0042] 5) In order to further design carriers and assess the behavior of polymer solutions during mixing and casting, followed by the assessment of the morphological and structural uniformity of films obtained in the drying process, formulations consisting of three or four mixtures of polymer solutions were prepared. In this series, NaCMC has been added to improve mucoadhesive properties. The films were prepared in a laminar flow cabinet by preparing sterilized solutions of individual polymers according to the composition shown in tables for H and I series, which were then mixed in various weight ratios. The technological process was similar to that applied to the E, F, and G series, except that the gel formulations containing polymer components were subjected to physical cross-linking, which involved cyclically freezing and thawing the formulation five times at a temperature of -18°C to -22°C (for up to 4 hours, during which the mixture had to be frozen). As a result of this cyclical freezing and thawing at room temperature, polymer crystallization occurred and the film's cross-linking increased. After each freezing step, the formulation solutions were mixed at room temperature to obtain a uniform polymer dispersion. The mixtures were then subjected to a sonication process in an ultrasonic bath until all air bubbles were completely removed. After this stage, they were mixed for another 4 hours at room temperature and were subsequently cooled to a temperature of 4° to 8°C for 24 hours. After cooling, they were mixed again for 2- 4 hours at room temperature until a uniform mixture was obtained. After five cycles, the formulations were dried at a temperature of 32°C±1°C for 24-72 hours and then stored in barrier packaging. The obtained formulations were subjected to a preliminary assessment of their film-forming properties and physicochemical properties.

[0043] Depending on whether slow or rapid release of active compounds is required, it is possible to adjust the degree of physical cross-linking of polymers at a temperature ranging from -18°C to -22°C. In this test, the degree of cross-linking was regulated by the number of cycles of freezing and thawing used. Films prepared using PVA with a degree of hydrolysis of 98-99% showed a significantly longer blurring time compared to films obtained from PVA with a degree of hydrolysis in the range of 85-89%, for which the blurring time was shorter. In addition, increased NaCMC concentration resulted in greater mucoadhesion strength. The content of the plasticizer solution, in this case 85% aqueous glycerin solution, in compositions according to this embodiment varies from 0.15% (w / w) for a carrier weight of 10 g to 3.5% (w / w) for a carrier weight of 70 g.

[0044] Table. 2. Polymer concentrations used in film technology in series A to I

[0045] 1.1. A Series

[0046] Polymer films with increased amounts of plasticizer were flexible and met the requirements regarding the assessment of surface morphology, flexibility, transparency, gloss, ease of removal from the mold, disintegration time (from 2 to 120 min) and pH of the extract after blurring (pH = 6.41 to 7.41). Formulations were cast in an amount of 10-70 g per dish. During the technological process, they required longer degassing and cooling at a temperature of 4° to 8° C. A similar recording method is used in the following examples.

[0047] Table 3. Polymer film formulation compositions prepared with individual polymers

[0048] 1.2. B Series

[0049] Films B1-B3 as well as B5 and BIO prepared with a plasticizer in concentrations ranging from 3% to 5% w / w per 100 g of formulation met specific requirements, such as: surface morphology of the films produced, flexibility, transparency, gloss, ease of removal from the mold, disintegration time (from 2.5 to 20 minutes) and pH of the extract after blurring (in the pH range = 6.59-6.70). Formulations were cast into the dishes in an amount of 10 g to 70 g. The technological process of their preparation required a longer period of degassing and cooling the formulations to a temperature ranging from 4°C to 8°C. Table. 4. Compositions of film formulations obtained from mixtures of polymer solutions in a weight ratio of 50:50 prior to the addition of glycerol from 0.15 to 3.5% w / w. Table 4a. Compositions of film formulations obtained by casting polymer mixtures prepared in 50:50 weight ratios of individual components with the addition of 5.0 g of glycerol per 100 g of formulation 1.3. C Series

[0050] The films were prepared using polymer components in a 50:50 weight ratio, with the addition of a plasticizer in concentrations ranging from 3% to 5% w / w per 100 g of formulation. The amounts of the formulation cast into the dishes ranged from 10 g to 70 g. The films marked as C4, C7-C9 and Cll met the specified requirements regarding surface morphology of the films produced, flexibility, transparency, gloss, ease of removal from the mold, disintegration time (2 to 23 minutes), and pH of the extract after blurring (in the pH range = 6.53-6.79). The technological process of their preparation required a prolonged period of degassing and cooling the formulations to a temperature ranging from 4°C to 8°C. Table. 5. Compositions of film formulations obtained from mixtures of polymer solutions in a 50:50 w / w weight ratio with the addition of glycerol from 0.15 to 3.5% w / w

[0051] Table 5a. Compositions of film formulations obtained from polymer mixtures with the addition of 5.0 g of glycerol per 100 g of formulation 1.4. D Series

[0052] The films were prepared using polymer components in a 50:50 weight ratio, with the addition of a plasticizer in concentrations ranging from 3% to 5% w / w per 100 g of formulation. Formulations were cast into dishes in an amount of 10-70 g. Films D1-D3, D5, D6, D8 and D10 met the intended requirements regarding surface morphology, flexibility, transparency, gloss, ease of removal from the mold, disintegration time (2 to 22 min) and pH of the extract after blurring (pH = 6.48-6.73). During the technological process, preparations required a longer period of degassing and cooling to a temperature ranging from 4°C to 8°C. Table. 6. Compositions of film formulations obtained from mixtures of polymer solutions in a 50:50 weight ratio of the polymer solutions with the addition of glycerol from 0.15 to 3.5% w / w

[0053] Table 6a. Compositions of film formulations prepared with a mixture of polymer solutions with the addition of 4.0 g of glycerol per 100 g of formulation

[0054] 1.5. E Series

[0055] The films were prepared in different weight ratios of polymer solutions - 50:50 for E6; 60:40 for E7 film and 40:60 for E8 with the addition of a plasticizer in concentrations ranging from 3% to 5% w / w per 100 g of formulation. The amounts of the formulation cast into the dishes ranged from 10 g to 70 g. The films marked as E6, E7, E8, E10 and E13 met the specified qualitative requirements regarding surface morphology, flexibility, transparency, gloss, ease of removal from the mold, disintegration time (up to 330 minutes) and pH of the extract after blurring (in the pH range = 6,70-6,83). The technological process of preparing the formulations for casting required a prolonged period of their degassing and cooling to a temperature ranging from 4°C to 8°C.

[0056] Table 7. Compositions of film formulations prepared with a polymer solutions mixture with the addition of glycerol in the amount of 0.15 to 3.5% w / w

[0057] Table 7a. Compositions of polymer formulations consisting of two or three polymer components with an addition of plasticizer in the amount of 4.0 g per 100 g of formulation

[0058] 1.6. F Series

[0059] The films were prepared in different weight ratios of polymer solutions. The formulations were cast into dishes in an amount ranginf from 10-70 g. Films F2-F5 and F7-F9 met the requirements regarding quality assessment, i.e., surface morphology, flexibility, transparency and gloss, ease of removal from the mold, disintegration time (from 1 to 24 h) and pH of the extract after blurring (pH = 7.04-7.09). During the technological process, the formulations required longer degassing and cooling at a temperature of 4° to 8° C. Table. 8. Compositions of film formulations prepared with a polymer solutions mixture with the addition of glycerol in the amount of 0.15 to 3.5% w / w

[0060] Table 8a. Composition of polymer formulations prepared with two or three polymer components with an addition of plasticizer in the amount of 5.0 g per 100 g of formulation

[0061] 1.7. G Series

[0062] When optimizing the compositions of G series, the effect of adding NaCMC solution to the polymer mixture, in addition to adding 3-5% w / w plasticizer per 100 g of formulation, was analyzed. In this series, two stages of physical cross-linking of the formulation were carried out by freezing and thawing the polymer mixture twice at a temperature ranging from -18°C to -22°C, maintaining constant mixing between the stages. Formulations were cast into dishes in an amount ranging from 10 to 70 g. During the preparation of the films, the ratio of PVP:NaCMC was 1:1 and PVA:cellulose derivatives was 1:1. Films G1-G8 met the requirements regarding quality assessment, comprising: surface morphology, flexibility, ease of removal from the mold, disintegration time (from 20 min to 4.5 h) and pH of the extract after blurring (pH = 7.30-7.45).

[0063] Table. 9. Compositions of polymer formulations prepared with a NaCMC solution and the addition of glycerol in the amount of 0.15 to 3.5% w / w

[0064]

[0065] Table 9a. Compositions of polymer formulations prepared with NaCMC solution and the addition of plasticizer in the amount of 5.0 g per 100 g of formulation

[0066] 1.8. H Series In this series, in order to ensure optimal mucoadhesive properties, the amount of NaCMC solution in relation to the polymer mixture was increased. In addition, in order to prolong blurring time of film fragments, a physical cross-linking process was carried out, which consisted of freezing and thawing the polymer mixture five times at a temperature ranging from -18 to -22°C. All of films H1-H4 met the requirements regarding the quality assessment, i.e.: surface morphology, flexibility, ease of removal from the mold, gloss, disintegration time

[0067] (from 5 min to 1.5 h) and pH of the extract after blurring (pH = 7.40-7.43).

[0068] Table 10. Compositions of polymer formulations prepared with a mixture of 4 polymers with the addition of glycerol in the amount of 0.15 to 3.5% w / w

[0069]

[0070] Table 10a. Compositions of polymer formulations prepared with a mixture of 4 polymers with the addition of plasticizer in the amount of 4.0 g per 100 g of formulation

[0071] 1.9. 1 Series At this stage of the optimization process, 3 formulations were obtained, in which a larger amount of the addition of NaCMC was used. For formulations 11-13, five stages of physical cross-linking were carried out, which consisted of freezing and thawing the polymer mixture five times at a temperature ranging from -18 to -22°C in order to prolong the blurring time of the films. During the preparation of the films, the ratio of PVP:NaCMC was 1:2. All of films 11-13 met the requirements regarding the qualitative assessment, i.e.: surface morphology, flexibility, gloss, ease of removal from the mold, disintegration time (from 5 min to 60 min) and pH of the extract after blurring (pH = 7.17-7.28).

[0072] Table. 11. Compositions of polymer formulations prepared with a mixture of 4 polymers with the addition of glycerol in the amount of 0.15 to 3.5% w / w

[0073] Table 11a. Compositions of polymer formulations prepared with a mixture of 4 polymers with the addition of plasticizer in the amount of 3.0 g per 100 g of formulation In G, H, and I series, the design of polymer films was directed towards increasing mucoadhesive properties by gradually increasing the proportion of NaCMC solution in the formulation. This strategy, used in these series, allows for precise adjustment of the adhesive properties of the film to the contact time with the mucous membrane, which is crucial for therapeutic efficacy in topical applications.

[0074] Example 2. Assessment of Polymer Films:

[0075] Measurements of thickness and mass were carried out, as well as tests of mucoadhesion strength, wettability, and blurring time, determining the pH of the extract after blurring of the polymer film, and assessing the mechanical resistance to crushing. For this purpose, 2.5 cm x 2.5 cm fragments of films were prepared, which were cut out for the measurements.

[0076] Test methods: a) Testing mucoadhesive strength

[0077] The test was performed on a 2.5 cm x 2.5 cm film fragment using a TA.XT Plus texture analyzer with a movable arm and a probe equipped with an A / Muc mucoadhesion measurement fixture (Stable Micro System, Godaiming, United Kingdom). In order to perform the measurement, a 13 mm diameter mucin disc, prepared by compressing 250 mg of powdered substance using a hydraulic press (Specac, 15t, UK) with a 13 mm diameter die (Specac 13mm DIE PT. No 3000. United Kingdom), under a pressure of 10 tons for 30 seconds, was attached to the movable arm with the probe using double-sided tape. Before the mucoadhesion test, the mucin disc was moistened with a 5% aqueous solution of mucin. Next, the arm with the probe and mucin disc was lowered at a speed of 1 mm / s into a solution of artificial saliva in a beaker with a film fragment installed in the A / Muc fixture. The artificial saliva solution used was prepared according to the composition listed in Table 1. The beaker with the immersed A / Muc fixture was placed on a magnetic stirrer with a heating function in order to simultaneously stir and maintain the fluid at a temperature of 37±1°C during the measurement. After the mucin disc came into contact with the film fragment, the lowered arm with the probe applied a force of 0.1 N for 30 seconds, followed by a programmed lifting of the arm at a speed of 1 mm / s with simultaneous measurement of the force required to remove the mucin disc from the film surface. The method was modified based on sources [1, 2], The test was repeated for three polymer film fragments sampled from different areas of the dry formulation. The results were presented as the average values from three measurements of the force required to detach the mucin disc from the film surface, along with the standard deviation. Table 1. Composition of the artificial saliva solution prepared for the mucoadhesion tests b) Test of the Blurring Time and pH Value of Extracts After Blurring

[0078] The blurring time test was conducted in a thermostatic water bath (Memmert type: WB22, Germany) at a temperature of 37±1°C with a horizontal shaking function (Memmert type: S1422, Germany). Film fragments measuring 2.5 cm x 2.5 cm were carefully weighed and placed in beakers sealed with parafilm, containing 10 ml of purified water at a temperature of 37±1°C. The beakers were then transferred to a water bath and horizontally shaken at a constant frequency of 60 cycles per minute. The blurring time was defined as the time required for the complete disintegration of the carrier, with no fragments visible to the naked eye. The pH measurements of the extracts obtained after blurring the film fragment were performed using the potentiometric method using a pH meter with a combined electrode at a temperature of 22±1°C with an accuracy of 0.01 pH units. Before measurement, the blurred film sample was left at room temperature for 1 hour. Once the time had elapsed, the pH was measured by immersing the combined electrode. The method was modified based on sources T1

[0079] [1, 3].The test was conducted in three repetitions for each sample. The results were presented as the average value from measurements along with the standard deviation. c) Contact Angle Measurements

[0080] Measurements of the contact angle were performed for optimized formulations of polymer films measuring 2.5 cm x 2.5 cm with a precision of 0.01° using a goniometer (Ossila, United Kingdom) with a built-in digital camera and software (Ossila Contact Angle) enabling image analysis. During the measurements, the camera captures images of the droplets and sends their digital record to a computer, which automatically analyzes the image. The calculations of the contact angle are based on the assumption that the shape of a droplet is a spherical sector, and knowing its height and volume allows for the calculation of the contact angle. In order to carry out the measurement, a single film fragment was placed on the device's stand and a single 50 pl drop of purified water was dispensed using an automatic pipette; then, using the camera and the software, the angle between the sample surface and the tangent to the liquid surface was measured. The method was modified based on sources [4, 5], The measurements were made for 3 film fragments cut from different areas of the dry formulation. The results were presented as the average value from measurements along with the standard deviation.

[0081] All films were characterized by morphological and structural uniformity, which indicates the correct selection of the composition, appropriate technology for combining and mixing the prepared polymer mixtures, and the preferable conditions for casting and drying of the formulations. The technological optimization process has shown that the degree of physical cross-linking of polymers significantly affects their structure and properties, enabling the design of polymer films with modified kinetics of active compounds release. This allows adjusting the formulation to achieve both prolonged and accelerated release of active substances, depending on therapeutic requirements. After assessing the physicochemical properties of the films according to the invention, i.e., the thickness uniformity of dry films (in the range of 202-256 nm), average mass (in the range of 161.76-183.45 mg), mucoadhesion value measured in a test with mucin (in the range of 190.30-270.07 g), wettability of the material by measuring the contact angle (in the range of 50.78°-60.05°) (Ossila goniometer, United Kingdom, with a built-in digital camera and Ossila Contact Angle software enabling image analysis), blurring time (in the range of 2 min to 24 h), pH of the extract formed after blurring the formulation (in the pH range = 6.48-7.43). In addition, all film formulations prepared were characterized by high folding endurance. Mechanical properties of the film formulations were determined based on the method described in the publication by Vecchi et al. [Vecchi, C. F.; Cesar, G. B.; De Souza, P. R.; Caetano, W.; Bruschi, M. L. Mucoadhesive polymeric films comprising polyvinyl alcohol, polyvinylpyrrolidone, and poloxamer 407 for pharmaceutical applications (Pharm. Dev. Technol. 2021, 26, 138-149)]. Film fragments measuring 2.5 cm x 2.5 cm were prepared for testing, which were repeatedly folded at an angle of 180° at the same point until their breakage and tearing or until 300 folds were achieved without the film breaking. The formulations of polymer films developed in an optimization process involving a mixture of four polymer solutions with the addition of a plasticizer show morphological and structural uniformity, optimal mechanical and mucoadhesive properties, and prolonged total disintegration time. The percentage ratio of polymer components used, the addition of plasticizer, and the technology and conditions used in the drying process of polymer films significantly impact the morphology and structure of the films obtained. The use of polyvinyl alcohol with a degree of hydrolysis in the range of 98- 99%, as well as increasing the content of methylcellulose derivatives, such as MC 400, MC 1500 and MCA15C, relative to the content of polyvinyl alcohol, and the introduction of a physical cross-linking process of the formulations contributes to prolonging the blurring time of the prepared films. The addition of carboxymethyl cellulose sodium salt to the formulation's composition reduces the blurring time of a polymer film, while ensuring optimal mucoadhesive properties of the prepared films.

[0082] Example 3. Carrier with an incorporated single active substance

[0083] A sample carrier with an active substance was prepared based on the formulation composition from series G according to Example 1.

[0084] Clove oil in a concentration of 1-2% (Pureo, clove essential oil, 10 ml) was used as the active substance.

[0085] Using the formulation composition of series G, 30 g of the formulation was cast into a polystyrene dish with an area of 92 cm2. The mixture was prepared according to the technological procedure for series G. At the very end, clove oil was added, and then mixing was carried out for 1 hour using a magnetic stirrer. A film with clove oil is distinguished by the innovative approach to the treatment of oral diseases, offering a flexible form of administration that is more comfortable than traditional ointments or gels. Its unique formula allows for prolonged release of the active substance directly at the site of action, which translates into treatment efficacy. In addition, including natural clove oil provides analgesic, antiseptic, anti-inflammatory, and antimicrobial effects. This film is tailored to patients' needs, which allows for independent use at home conditions. In the context of modern methods of delivering active substances, this product responds to the growing demand for effective and convenient therapies for treating inflammation of the oral cavity. The test results for the carrier as above are presented in Table 12.

[0086] Table 12.

[0087] Example 4. Carrier with incorporated mixture of active substances

[0088] A concentration of 1% (w / w) hydrocortisone and 1.5 mg / ml of clove oil (Pureo, clove essential oil, 10 ml) was used. Six polymer films were selected for the incorporation of active substances. For each film, 30 g of polymer mixture was used, casting it onto a polystyrene weighing dish with an area of 92 cm2. The mixture was prepared in accordance with the technological procedure for series G, E, D, F, and A, and clove oil was added at the final stage of the process, after which the whole mixture was mixed for 1 hour using a magnetic stirrer. The properties of the obtained films are presented in Table 13 below.

[0089] Table 13.

[0090] Literature:

[0091] 1. Vecchi, C. F.; Cesar, G. B.; De Souza, P. R.; Caetano, W.; Bruschi, M. L. Mucoadhesive Polymeric Films Comprising Polyvinyl Alcohol, Polyvinylpyrrolidone, and Poloxamer 407 for Pharmaceutical Applications. Pharm. Dev. Technol. 2021, 26, 138-149.

[0092] 2. Ptaczek M., Sznitowska M.: Zjawisko mukoadhezji i jego znaczenie w aplikacji leku. [The mucoadhesion phenomena and importance in drug application] Polimery Med., 2009, 2, 49-64.

[0093] 3. Garsuch V., Breitkreutz J.: Comparative investigations on different polymers for the preparation of fast dissolving oral films. J. Pharm. Pharmacol., 2010, 62, 539-545.

[0094] 4. Yuan Y., Lee T. R.: Contact angle and wetting properties. Surf. Sci. Tech., 2013, 51, 3- 34.

[0095] 5. Morales J. O., McConville J. T.: Manufacture and characterization of mucoadhesive buccal films. Eur. J. Pharm. Biopharm., 2011, 77, 187-199.

Claims

Claims1. A mixture for obtaining a dental / periodontal carrier, characterized in that it contains, in weight percentage, at least one of the components selected from the group comprising: a) an aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 98% to 99% in an amount of more than 0% to 7% w / w, an aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 85% to 99% in an amount of more than 0% to 7% w / w, an aqueous solution of polyvinylpyrrolidone in an amount of more than 0% to 7% w / w, an aqueous solution of pullulan in an amount of more than 0% to 3.5% w / w, an aqueous solution of methylcellulose with a viscosity of 400 cP in an amount of more than 0% to 3.5% w / w, an aqueous solution of hydroxypropyl methylcellulose in an amount of more than 0% to 2.1% w / w, an aqueous solution of methylcellulose with a viscosity of 1200-1800 mPa*s in an amount of more than 0% to 5% w / w, an aqueous solution of carboxymethyl cellulose sodium salt in an amount of more than 0% to 2.8% w / w, wherein each polymer not selected from the above group is present in an amount of 0% w / w, b) optionally, an aqueous solution of glycerine in an amount of 0% to 3.5% w / w, which constitutes a plasticizer, or a mixture thereof, and c) purified water up to 100% of the weight of the composition.

2. The mixture according to claim 1, characterized in that the aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 98% to 99% has a concentration of 2.5% to 7% w / w.

3. The mixture according to claim 1, characterized in that the aqueous solution of polyvinyl alcohol with a degree of hydrolysis of 85% to 99% has a concentration of 2.5% to 7% w / w.

4. The mixture according to claim 1, characterized in that the aqueous solution of pullulan has a concentration of 2.5% to 3.5% w / w.

5. The mixture according to claim 1, characterized in that the aqueous solution of methylcellulose with a viscosity of 400% has a concentration of 0.5% to 3.5% w / w.

6. The mixture according to claim 1, characterized in that the aqueous solution of hydroxypropyl methylcellulose has a concentration of 1.0% to 2.1% w / w.

7. The mixture according to claim 1, characterized in that the aqueous solution of methylcellulose with a viscosity of 1500% has a concentration of 1% to 5% w / w.

8. The mixture according to claim 1, characterized in that the aqueous solution of carboxymethyl cellulose sodium salt has a concentration of 2.8% w / w.

9. The mixture according to claim 1, characterized in that the aqueous solution of methylcellulose with a viscosity of 2% aqueous solution at 20°C of 1200-1800 mPa*s has a concentration of 3% w / w.

10. The mixture according to claim 1, characterized in that it comprises an aqueous solution of glycerine in a concentration of 0.15% to 3.5% w / w.

11. A method for obtaining a dental / periodontal carrier, comprising preparing aqueous solutions of the components of the carrier composition, as specified in claim 1, mixing the components of the composition, characterized in that the mixture is subjected to mixing for 2 to 3 hours, then cooled to a temperature ranging from 4°C to 8°C for 24 hours, mixed again, cast into a mold, and dried for 24 to 72 hours at a temperature of 32±1°C.

12. A method for obtaining a dental / periodontal carrier, characterized in that it comprises the steps of: a) preparing the mixture as specified in claim 1; b) mixing the mixture for 2 to 3 hours; c) cooling the mixture to a temperature ranging from 4°C to 8°C for 24 hours; d) mixing the mixture again; e) casting into a mold and drying for 24 to 72 hours at a temperature of 32±1°C.

13. A method for obtaining a dental / periodontal carrier, characterized in that it comprises the steps of: a) preparing a preliminary mixture containing at least one polymer component specified in point a) of claim 1, and purified water; b) mixing the preliminary mixture for 2 to 3 hours; c) subjecting the preliminary mixture to freezing at a temperature of -18°C to -22°C for 1 to 4 hours; d) thawing the preliminary mixture and subjecting it to ultrasounds to remove air bubbles; e) mixing the preliminary mixture for 4 hours, then cooling it at a temperature of 4°C to 8°C for 24 hours; f) adding the optional plasticizer specified in point b) of claim 1 to the cooled preliminary mixture and continuing the mixing for 4 hours; g) casting the final mixture into a mold and drying for 24 to 72 hours at a temperature of 32±1°C.

14. A method for obtaining a dental / periodontal carrier, characterized in that it comprises the steps of: a) preparing a preliminary mixture containing at least one polymer component specified in claim 1 and purified water; b) mixing, freezing, thawing, subjecting to ultrasounds and mixing again the preliminary mixture, as in steps b) to e) of claim 13; c) freezing the preliminary mixture again at a temperature of -18°C to - 22°C for 4 hours, followed by thawing it and subjecting it again to ultrasounds; d) adding an optional plasticizer specified in point b) of claim I to the preliminary mixture, and continuing the mixing for 4 hours; e) casting the final mixture into a mold and drying for 24 to 72 hours at a temperature of 32±1°C.

15. A dental / periodontal carrier, formed from the mixture specified in claim 1, characterized in that it is characterized by at least one of the following properties: a) mucoadhesion value measured in a test with mucin ranging from 190 g to 271 g; b) blurring time ranging from 2 min to 24 h; c) pH of the extract formed after blurring of the formulation ranging from 6.48 to 7.43; d) contact angle measured with a goniometer ranging from 50.78° to 60.05°.

16. A use of a dental / periodontal carrier as specified in claim 14, or obtained in accordance with the method specified in claim 12 or 13, for obtaining a dental / periodontal composition.

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