Oral care product consisting of chlorhexidine, metabisulfite, ascorbic acid and N-acetylcysteine.

Abstract

Abstract\n\tThe present invention relates to the use of N-acetylcysteine ​​to enhance the effect of alkaline or alkaline earth metal sulfite metabodies and ascorbic acid in combating staining of dental surfaces, dental mucous membranes, dental restorations or dental restorations in patients treated with chlorhexidine and an oral care product comprising chlorhexidine, at least one alkaline or alkaline earth metal sulfite metabodie, ascorbic acid and N-acetylcysteine.

Description

Oral care product consisting of chlorhexidine, metabisulfite, Ascorbic acid and N-acetylcysteine Description Field of invention The present invention relates to the use of N-acetylcysteine ​​to improve the effectiveness of metabisulfite salts of alkaline or alkaline earth metals and ascorbic acid to combat tooth discoloration in patients receiving chlorhexidine treatment, as well as to a dental care product comprising chlorhexidine, at least one metabisulfite salt of an alkaline or alkaline earth metal, ascorbic acid and N-acetylcysteine. Industrial background Chemical plaque control is one of the most important steps in many dental treatments and in routine oral hygiene practices at home. For this purpose, several active ingredients are produced and marketed, often in the form of mouthwashes, toothpastes or sprays, among which chlorhexidine, essential oils, fluorine derivatives and delmopinol can be mentioned. However, considering the data obtained from the literature review in recent years, chlorhexidine remains the most effective product in chemical plaque control to the extent that it is properly defined as the reference active ingredient. Chlorhexidine is a molecule belonging to the bis-guanide family and is known for its remarkable performance in the control of chemical plaque and gingivitis. Of course, in relation to the inherent characteristics of different bacterial species, its bacteriostatic action is known when used in low concentrations, while at higher concentrations it has a bactericidal effect. Chlorhexidine expands its disinfectant effect thanks to its ability to form chemical bonds with anionic groups (phosphate, sulfate, carboxyl groups) present on the surface of the bacterial cell wall, thus causing a significant increase in cell permeability and a change in osmotic balance. Chlorhexidine binds to the following due to its cationic properties: - Oral mucous membranes - Enamel hydroxyapatite - Secondary layer present on the oral surface - salivary proteins, and - Bacteria and cellular polysaccharides of bacterial origin. Chlorhexidine, when bound to these oral structures, is capable of gradual release while maintaining effective concentrations on microorganisms for approximately 8-18 hours. This effect, which allows the active ingredient to remain in effective concentrations even hours after administration, is called "absorbability" and represents the ability of this active ingredient. Despite the numerous advantages of chlorhexidine from the point of view of pharmacological action, this active substance has several annoying side effects. Among these side effects, the most common is certainly the development of brown discoloration that appears on tooth surfaces and mucous membranes, especially in resin restorations or prosthetic products, thus limiting the long-term use of this substance. In particular, it is believed that the bonding between pigments and hydroxyapatite occurs through the interaction between the anionic groups of the dye molecules and the cationic ones of chlorhexidine, which, following the formation of the bond between them, forms a brown layer that is difficult to remove by simple brushing. This side effect occurs mainly following long-term use of chlorhexidine, especially with formulations with higher concentrations of this substance (0.2% or even 1% in some oral gels). Anti-stain additives are known to be used in oral care products containing chlorhexidine to counteract this side effect. Among these additives, the ADS system consisting of ascorbic acid and sodium metabisulfite is able to produce less tooth discoloration while not compromising the antiseptic benefits of chlorhexidine. Source: Cortellini P, Labriola A, Zambelli R, Pini Prato GP, Nieri M, Tonetti M: Chlorhexidine with an anti-discoloration system after periodontal flap surgery: a cross-over, randomized, triple-blind clinical trial. Journal of Clinical Periodontology. 35, 7: 614. 200 According to the applicant's findings, although the ADS system, consisting of ascorbic acid and sodium metabisulfite, has a distinct and significant efficacy in combating discoloration of surfaces, mucous membranes, restorations, and dental prosthetic products in patients treated with chlorhexidine, and at the same time does not reduce the disinfectant effectiveness of this substance, there is still a need to improve the anti-discoloration effect of the ADS system, especially in long-term treatments. Summary of the invention Thus, the aim of the present invention is to enhance and optimize the effect of metabisulfite salts of alkaline or alkaline earth metals and ascorbic acid in combating discoloration (or staining) of surfaces, mucous membranes, restorations and dental prosthetic products in patients undergoing chlorhexidine treatment, without compromising the disinfectant efficacy of chlorhexidine itself, especially in long-term treatments. According to the present invention, the applicant unexpectedly found that this result can be achieved by using a combination of metabisulfite salts of alkaline or alkaline earth metals and ascorbic acid, N-acetylcysteine, and it was found that this combination is capable of enhancing the effect of metabisulfite salts of alkaline or alkaline earth metals and ascorbic acid in combating discoloration of surfaces, mucous membranes, restorations and dental prosthetic products in patients treated with chlorhexidine. Accordingly, the present invention relates in a first aspect to N-acetylcysteine ​​for use in a method for treating side effects of chlorhexidine in a patient receiving chlorhexidine treatment, wherein said side effects include discoloration of dental surfaces, dental mucous membranes, dental restorations or dental prosthetic products in said patient, and wherein said N-acetylcysteine ​​enhances the effect of at least one metabisulfite salt of a basic or alkaline earth metal and ascorbic acid in combating said discoloration of dental surfaces, dental mucous membranes, dental restorations or dental prosthetic products. It has unexpectedly been found that the association of N-acetylcysteine ​​with a metabisulfite salt of a basic or alkaline earth metal and ascorbic acid enhances the neutralizing effect of chlorhexidine-induced discoloration / staining of surfaces, mucous membranes, restorations and dental prosthetic products without impairing the disinfectant efficacy of chlorhexidine itself, even in long-term treatments. Thanks to the specific combination of N-acetylcysteine, at least one metabisulfite salt of a basic or alkaline earth metal, ascorbic acid and chlorhexidine, it is possible to provide an oral care product that has a range of properties capable of improving the characteristics of oral care products based on the ADS system, thus expanding and developing its application possibilities. In another aspect, the present invention also relates to an oral care product comprising chlorhexidine, at least one basic or alkaline earth metal metabisulfite salt, ascorbic acid, and N-acetylcysteine. Thanks to the presence of N-acetylcysteine, at least one metabisulfite salt of a basic or alkaline earth metal and ascorbic acid, the product according to the present invention based on chlorhexidine is effective against pathogens of the oral cavity, in particular bacterial plaque, without causing or severely limiting the side effects resulting from the long-term use of that active ingredient, namely staining surfaces, mucous membranes, restorations and dental prosthetic products. Thus, in another aspect, the present invention relates to an oral care product comprising chlorhexidine, at least one basic or alkaline earth metal metabisulfite salt, ascorbic acid, and N-acetylcysteine, and is contemplated for use in treating bacterial plaque in a patient in need thereof. In fact, the applicant found that the use of N-acetylcysteine ​​according to the present invention, by improving and enhancing the effect of metabisulfite salts of basic or alkaline earth metals and ascorbic acid in combating discoloration of surfaces, mucous membranes, restorations and dental prosthetic products in patients undergoing anti-plaque treatment with chlorhexidine, provides an innovative and particularly valuable aspect in said oral care product. Brief explanation of the images In pictures: Figure 1 shows the results of the plaque index (PI) test on days 7 and 14 for groups using products A, B and C according to Example 1; Figure 2 shows the results of the gingival index (GI) test on days 7 and 14 for groups using products A, B and C according to Example 1; Figure 3 shows the results of the Staining Index (SI) test on days 7 and 14 for groups using products A, B and C according to Example 1; Figure 4 shows the results of the plaque index (PI) test on days 7 and 14 for groups using products D, E and F according to Example 2; Figure 5 shows the results of the gingival index (GI) test on days 7 and 14 for groups using products D, E and F according to Example 2; and Figure 6 shows the results of the Staining Index (SI) test on days 7 and 14 for groups using products D, E and F according to Example 2; Figure 7 shows the results of the plaque index (PI) test on days 7 and 14 for groups using products A, B and C according to Example 3; Example 8 shows the results of the gingival index (GI) test on days 7 and 14 for groups using products A, B and C according to Example 3; Figure 9 shows the results of the Staining Index (SI) test at day 7 and 14 for groups using products A, B and C as in Example 3. The three groups show different trends. The staining caused by a traditional mouthwash at day 14 is more than twice that of the ADS mouthwash. The ADS mouthwashes show significant differences from the “control” mouthwash (CHX, group C) that are statistically significant at both day 7 and day 14. Group B (CHX-ADS-NAC) showed a significantly lower SI index compared to group A (CHX-ADS) at day 14. Detailed explanation of the invention The present invention relates in a first aspect to the use of N-acetylcysteine ​​in a method for treating side effects of chlorhexidine in a patient receiving treatment with the substance, wherein said side effects include discoloration of the dental surfaces, dental mucous membranes, dental restorations or dental prosthetic products of said patient, and wherein N-acetylcysteine ​​enhances the effect of at least one metabisulfite salt of a basic or alkaline earth metal and ascorbic acid in combating said discoloration of the dental surfaces, dental mucous membranes, dental restorations or dental prosthetic products. In fact, the Applicant has unexpectedly found that it is possible to improve and enhance the effect of metabisulfite salts of basic or alkaline earth metals and ascorbic acid in combating discoloration / staining of surfaces, mucous membranes, restorations and dental prosthetic products in patients treated with chlorhexidine, without compromising the disinfectant efficacy of the substance itself. This improvement and enhancement occurs in combination with N-acetylcysteine, which has been shown to enhance the neutralizing effect against said discoloration. Therefore, thanks to the specific combination of N-acetylcysteine, at least one metabisulfite salt of a basic or alkaline earth metal, ascorbic acid and chlorhexidine, it is possible to provide an oral care product, thus providing a range of properties capable of improving the capabilities of oral care products based on the ADS system. As a result, its application is expanded. In another aspect, the present invention also relates to an oral care product comprising chlorhexidine, at least one basic or alkaline earth metal metabisulfite salt, ascorbic acid, and N-acetylcysteine. The present invention may be embodied in one or more of its aspects or in one or more of the preferred features mentioned below, which may be combined together in a preferred manner according to the requirements of the application. In the present specification and the claims attached thereto, all numerical values, including quantities, components, percentages, and the like, shall in all cases be construed as "within limits" unless otherwise specified. In addition, all ranges of numerical values ​​include all possible combinations of maximum and minimum numerical values ​​and all possible intermediate ranges, as well as those enumerated below. The following definitions are considered in the present invention: - “% by weight of the total volume” of a product, for example a mouthwash, means the amount in grams of a sample component present in 100 milliliters (mL) of that product; and - "Chlorhexidine", unless otherwise specified, means the compound 1,1′-hexamethylenebis[5-(p-chlorphenyl)biguanide] or a salt or complex thereof. Preferably, in the oral care product, chlorhexidine is provided in the form of a salt or a complex. For example, as a salt of chlorhexidine, chlorhexidine digluconate or chlorhexidine diacetate can be used in the mouthwash according to the present invention. Preferably, the oral care product according to the present invention comprises chlorhexidine in the form of chlorhexidine digluconate. Preferably, the oral care product further comprises sodium DNA. "Sodium DNA" in the present invention means the sodium salt of deoxyribonucleic acid, which is obtained, for example, by extracting native deoxyribonucleic acid from male oestrogen gonadal tissue and subsequent purification, depolymerization and neutralization with sodium ions. Sodium DNA suitable for the purposes of the present invention is commercially available. For example, the one sold under the trade name Kalinat AW powder (Kalichem). In fact, it has been found that this amount of sodium DNA is an optimal amount to counteract the irritating effect of chlorhexidine on the oral mucous membranes, exerting a protective effect on them and having a healing effect on possible wounds in the oral cavity. It therefore also causes the correct tropism of the oral mucous membranes themselves. In a preferred embodiment, said oral care product is selected from the group consisting of: mouthwash, periodontal gel, and toothpaste. Therefore, in a first preferred embodiment, the oral care product according to the invention is a mouthwash. Preferably, said mouthwash comprises chlorhexidine in an amount ranging from 0.01% to 0.30% by weight, more preferably from 0.05% to 0.30% by weight, even more preferably from 0.09% to 0.20% by weight, based on the total volume of the mouthwash. The mouthwash according to the present invention also comprises at least one metabisulfite salt of a basic or alkaline earth metal. The presence of at least one metabisulfite salt of a basic or alkaline earth metal helps to combat the problem of black discoloration of teeth, which is a side effect of chlorhexidine use. Preferably, at least one basic or alkaline earth metal metabisulfite salt is selected from the group consisting of: sodium metabisulfite, potassium metabisulfite, calcium metabisulfite. More preferably, the mouthwash according to the present invention comprises sodium metabisulfite. Preferably, in the mouthwash according to the present invention, the amount of at least one metabisulfite salt of a basic or alkaline earth metal is in the range of 0.1% to 0.5%, more preferably 0.15% to 0.3% by weight relative to the total volume of the mouthwash. The mouthwash according to the present invention further comprises ascorbic acid. Preferably, in the mouthwash according to the present invention, the amount of ascorbic acid is in the range of 0.1% to 1.0% by weight, relative to the total volume of the mouthwash. The presence of ascorbic acid also combats the problem of black discoloration of teeth, which is a side effect of using chlorhexidine. Preferably, the mouthwash according to the present invention comprises ascorbic acid and at least one alkaline or alkaline earth metal metabisulfite salt. More preferably, the amount is from 0.1% to 0.5% by weight of the at least one alkaline or alkaline earth metal metabisulfite salt and from 0.1% to 1.0% by weight of ascorbic acid, based on the total volume of the mouthwash. The aforementioned combination of components in the previously described amounts has also been shown to be particularly effective in combating the side effect of chlorhexidine, which is the creation of a black color on the teeth, and is also the basis of the ADS system. The mouthwash according to the present invention further comprises N-acetylcysteine. As will be shown in the experimental section, N-acetylcysteine ​​has been shown to enhance the effect of alkaline earth metal metabisulfite salts and ascorbic acid in combating the problem of brown discoloration of surfaces, mucous membranes, restorations, and dental prosthetic products in patients treated with chlorhexidine. Preferably, in the mouthwash according to the present invention, the amount of N-acetylcysteine ​​in the base is from 0.01% to 1.0%, more preferably from 0.2% to 0.7%, by weight relative to the total volume of the mouthwash. In addition to the above-described components, the mouthwash according to the present invention preferably comprises tribasic sodium citrate. Preferably, in the mouthwash according to the present invention, the amount of tribasic sodium citrate in the base is from 0.8% to 2.0%, more preferably from 0.8% to 1.2% by weight relative to the total volume of the mouthwash. The presence of tribasic sodium citrate in the aforementioned amounts advantageously allows for the adjustment of the mouthwash concentration to optimal indicators for use. In a preferred embodiment, the mouthwash according to the present invention comprises ascorbic acid and tribasic sodium citrate. More preferably, the mouthwash according to the present invention comprises between 0.1% and 1% by weight based on the total volume of ascorbic acid in the mouthwash and from 0.8% to 2.0% by weight based on the total volume of sodium citrate tribasic in the mouthwash. In fact, it was unexpectedly found that the aforementioned combination of ascorbic acid and tribasic sodium citrate allows the stabilization of the mouthwash formulation according to the present invention. Preferably, the mouthwash according to the present invention comprises at least one polyvinyl pyrrolidone-vinyl acetate copolymer. Polyvinyl pyrrolidone-vinyl acetate copolymers suitable for the purposes of the present invention are commercially available, for example those marketed under the name Luviskol® (BASF SE). At least one polyvinyl pyrrolidone-vinyl acetate copolymer will advantageously provide a film-forming and antiplaque function in the mouthwash according to the present invention. Preferably, in the mouthwash according to the present invention, the amount of at least one polyvinyl pyrrolidone-vinyl acetate copolymer is in the range of 0.05% to 1%, more preferably 0.3% to 1% by weight relative to the total volume of the mouthwash. Preferably, said mouthwash also comprises sodium DNA. Sodium DNA beneficially exerts a protective and healing effect on the oral mucous membranes and further limits some of the side effects associated with long-term use of chlorhexidine-based oral care products. These effects include changes in cellular structure, including cavitation (vacuolation), nuclear destruction, and enlargement of intercellular spaces. Preferably, the mouthwash contains sodium DNA in a range of 0.01% to 0.2%, more preferably 0.05% to 0.1% by weight based on the total volume of the mouthwash. In a preferred embodiment, the oral care product according to the present invention is a mouthwash comprising from 0.01% to 0.30% by weight of chlorhexidine, from 0.1% to 0.5% by weight of at least one metabisulfite salt of a basic or alkaline earth metal, from 0.1% to 1.0% by weight of ascorbic acid, from 0.01% to 1.0%, more preferably from 0.2% to 0.7% by weight of N-acetylcysteine, from 0.01% to 0.2%, more preferably from 0.01% to 0.1% by weight of sodium DNA, from 0.05% to 1%, more preferably from 0.3% to 1% by weight of at least one polyvinyl pyrrolidone-vinyl acetate copolymer, based on the total volume of the mouthwash. The mouthwash according to the present invention can include one or more other ingredients known in the industry for oral hygiene solutions. In particular, the mouthwash according to the present invention can additionally comprise one or more additives selected from the group consisting of: sweeteners, flavorings, wetting agents, preservatives, emulsifiers, dispersion regulators and food colorings. As sweeteners, the mouthwash according to the present invention can contain, for example, xylitol, sodium saccharinate, acesulfame potassium, sucralose or stevia extract. As flavorings, the mouthwash according to the present invention can contain, for example, peppermint, spearmint, camphor, anise, spearmint, cinnamon, clove or eucalyptus. As a wetting agent, the mouthwash according to the present invention can contain, for example, propylene glycol, sorbitol or glycerin. As a preservative, the mouthwash according to the present invention can contain, for example, sodium benzoate or methylisothiazolinone. As solubilizing surfactants, the mouthwash according to the present invention can contain, for example: PEG 40 hydrogenated castor oil or poloxamer 407. As a buffering agent, the mouthwash according to the present invention can contain, for example, sodium citrate or citric acid. As a colorant, the mouthwash according to the present invention can contain, for example, CI 19140, CIU 42090 or CI 17200. The mouthwash according to the present invention is prepared in a known manner in the form of a solution or suspension in a suitable solvent medium, preferably water. According to a preferred embodiment, the mouthwash according to the present invention comprises the following components: 1. Water 2. Xylitol 3. Propylene glycol 4. PEG 40 Hydrogenated Castor Oil 5. Sodium acetate 6. Ascorbic acid 7. Chlorhexidine digluconate 8. Polyvinyl pyrrolidone-vinyl acetate copolymer 9. N-Acetyl Cysteine 10. Sodium DNA 11. Flavoring 12. Poloxamer 407 13. Sodium metabisulfite 14. Sodium hydroxide 15. Sodium benzoate 16. Acetic acid According to another preferred embodiment, the mouthwash according to the present invention comprises the following components: 1. Water 2. Xylitol 3. Propylene glycol 4. PEG 40 Hydrogenated Castor Oil 5. Ascorbic acid 6. Chlorhexidine digluconate 7. Polyvinylpyrrolidone-vinyl acetate copolymer 8. N-Acetyl Cysteine 9. Sodium DNA 10. Flavoring 11. Poloxamer 407 12. Sodium metabisulfite 13. Sodium citrate 14. Citric acid 15. CI 42090 16. CI 17200 In another preferred embodiment, the oral care product according to the present invention is a periodontal gel. According to a preferred embodiment, the periodontal gel according to the invention comprises the following components: 1. Water 2. Propylene glycol 3. Hydroxyethyl cellulose 4. Polyvinyl pyrrolidone-vinyl acetate copolymer 5. PEG 40 Hydrogenated Castor Oil 6. Chlorhexidine digluconate 7. N-Acetyl Cysteine 8. Sodium acetate 9. Sodium DNA 10. Mint essence 11. Peppermint oil 12. Acetic acid 13. Sodium metabisulfite 14. Ascorbic acid Preferably, the periodontal gel according to the present invention comprises between 0.5% by weight and 1.0% by weight of chlorhexidine relative to the total volume of the periodontal gel. Preferably, the periodontal gel according to the present invention comprises between 0.01% and 1.0%, more preferably between 0.2% and 0.7% by weight of N-acetylcysteine ​​based on the total volume of the periodontal gel. Preferably, the periodontal gel according to the present invention comprises sodium DNA, even more preferably in amounts of up to 0.3%, more preferably from 0.01% to 0.3% by weight relative to the total volume of the periodontal gel. As previously mentioned in the mouthwash of the present invention, sodium DNA advantageously provides a protective and healing effect on the oral mucous membranes and further limits some of the side effects associated with long-term use of chlorhexidine-based oral care products. These effects include changes in cellular structure, including cavitation (vacuolation), nuclear destruction, and enlargement of intercellular spaces. In another preferred embodiment, the oral care product according to the invention is a toothpaste. According to a preferred embodiment, the toothpaste according to the invention comprises the following components: 1. Sorbitol 2. Water 3. Silica (hydrated silica) 4. Glycerol 5. Xylitol 6. Cocamidopropyl betaine 7. Polyvinylpyrrolidone-vinyl acetate copolymer 8. PEG 40 Hydrogenated Castor Oil 9. N-Acetyl Cysteine 10. Flavoring 11. Chlorhexidine digluconate 12. Carboxymethyl cellulose 13. Ascorbic acid 14. Sodium metabisulfite 15. Sodium DNA 16. Sodium Saccharin 17. Sodium benzoate 18. Sodium citrate Preferably, the toothpaste according to the present invention comprises between 0.05% by weight and 0.2% by weight of chlorhexidine relative to the total volume of the toothpaste. Preferably, the toothpaste according to the present invention comprises ascorbic acid and at least one alkaline or alkaline earth metal metabisulfite salt, more preferably from 0.1% to 0.5% by weight of at least one alkaline or alkaline earth metal metabisulfite salt and from 0.1% to 1.0% by weight of ascorbic acid based on the total volume of the toothpaste. As previously mentioned in relation to the mouthwash and periodontal gel according to the present invention, the aforementioned composition is also particularly effective in combating the side effect of chlorhexidine of causing dark discoloration on the teeth and is the basis of the ADS system. Preferably, the toothpaste according to the present invention comprises between 0.01% and 1.0%, more preferably 0.2% and 0.7% by weight of N-acetylcysteine ​​based on the total volume of the toothpaste. Preferably, at least one inorganic fluoride can be optionally present in the toothpaste according to the invention. Preferably, in the toothpaste according to the present invention, the amount of sodium DNA in the base is from 0.01% to 0.05% by weight relative to the total volume of the toothpaste. As previously mentioned in the mouthwash of the present invention, sodium DNA advantageously provides a protective and healing effect on the oral mucous membranes and further limits some of the side effects associated with long-term use of chlorhexidine-based oral care products. These effects include changes in cellular structure, including cavitation (vacuolation), nuclear destruction, and enlargement of intercellular spaces. Thanks to the presence of N-acetylcysteine, at least one metabisulfite salt of a basic or alkaline earth metal and ascorbic acid, the product according to the present invention based on chlorhexidine is effective against pathogens of the oral cavity, in particular bacterial plaque, without causing or severely limiting the side effects resulting from the long-term use of the active ingredient, namely staining surfaces, mucous membranes, restorations and dental prosthetic products. Thus, in another aspect, the present invention relates to an oral care product comprising chlorhexidine, at least one basic or alkaline earth metal metabisulfite salt, ascorbic acid and N-acetylcysteine ​​for use in treating bacterial plaque in a patient in need thereof. In fact, the applicant claims that the use of N-acetylcysteine ​​according to the present invention, by enhancing and improving the effect of metabisulfite salts of alkaline or alkaline earth metals and ascorbic acid in combating discoloration of surfaces, mucous membranes, restorations and dental prosthetic products in patients undergoing anti-plaque treatment with chlorhexidine, creates an innovative and valuable aspect for that oral care product. Thus, in a preferred aspect, the present invention relates to the use of N-acetylcysteine ​​in a patient undergoing chlorhexidine treatment according to the first aspect of the invention, in which case the chlorhexidine treatment is carried out with an oral care product according to the present invention. Experimental section The invention will now be described by means of some examples which are merely illustrative and not limiting. Example 1 Study objective The aim of this study was to evaluate the efficacy of a 0.2% chlorhexidine mouthwash containing 0.01% w / w sodium DNA and an anti-staining ADS system (0.5% w / w sodium metabisulfite, 0.5% w / w ascorbic acid) and compare it with a mouthwash with the same composition but with an additional 0.5% w / w N-acetylcysteine. As a control group, a traditional mouthwash with 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, sodium DNA or N-acetylcysteine ​​was used. Materials and methods For this study, 15 healthy male and female volunteers between the ages of 19-29 were selected in accordance with the principles of the Declaration of Helsinki. Patients with serious systemic diseases such as cardiovascular diseases, diabetes, neurological or psychological syndromes, or infectious diseases were not included in the study. Also, patients who were unable to perform oral hygiene maneuvers correctly, patients with chronic periodontal disease with a dento-gingival gap greater than 4 mm, and individuals with fewer than 20 elements in the dental arch were excluded from the study. After registration, three bottles were prepared for each patient, which were completely identical, opaque, stable, and with a capacity of 250 ml, and the following items were poured into them: - Product A: a mouthwash with 0.2% chlorhexidine by weight, containing 0.5% by weight sodium metabisulfite, 0.5% by weight ascorbic acid and 0.01% by weight sodium DNA, based on the total volume of the mouthwash; - Product B: Same as product A, but with the addition of 0.5% by weight of N-acetylcysteine ​​relative to the total volume of the mouthwash; and - Product C: Traditional mouthwash with 0.2% chlorhexidine by weight relative to the total volume of the mouthwash. The bottles were then marked with a neutral label, with an alphanumeric code that uniquely identified the patient to whom each bottle was assigned. The reading key was kept secret by the experiment organizers until the end of the experiment so that the patient volunteers or users selected for evaluations would not be aware of the type of mouthwash they were testing. The experiment was then conducted according to the "blind" criterion. Before the start of the experiment, all patients underwent specialized oral hygiene examinations to remove existing soft and hard plaque and to zero the periodontal indices that were to be analyzed. - License Plate Index (PI), for the amount of available license plates, source: Loe H., Silness J: Periodontal disease in pregnancy. Prevalence and severity. Acta odontologica Scandinavica. 1963; 21: 533-551 - Gingival Index (GI), for the level of gingivitis, source: Silness J, Loe H: Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal conditions. Acta odontologica Scandinavica. 1964; 22: 121-135 - Staining Index (SI) for the degree of discoloration, source: Lobene RR: Effect of dentifrices on tooth stains with controlled brushing. J.Am.Dent.Assoc. 1968; 77: 849-855, Soskolne WA, Heasman PA, Stabholz A., Smart GJ, Palmer M., Flashner M., Newman HN: Sustained local delivery of chlorhexidine in the treatment of periodontitis: a multi-center study. J Clin Periodontol 1997; 68: 32-38. 15 patients were divided into three equal groups in terms of number and placed in Group A (Product A), Group B (Product B), or Group C (Product C), and then each patient was given 2 bottles of the corresponding product. Patients completed a 14-day rinsing cycle with the delivered product. The cycle consisted of rinsing with 15 ml of pure product for one minute, twice a day. During the period of use of the mouthwashes, patients did not use a toothbrush or other oral hygiene tools. Finally, patients were asked to avoid the use of substances that facilitate the deposition of color, such as coffee, tea, red wine or cigarette smoke, for at least one hour before or after rinsing, or in any case to report possible use during the day by completing a special form. After 7 and 14 days, periodontal components PI and GI were measured in addition to SI. All data were collected by a single evaluator in special folders and then analyzed with an analysis program and spreadsheet. Statistical analysis for unpaired data was performed by Student's t-test. Results All 15 volunteer patients completed the trial. There were no protocol disruptions or delays in assessment sessions. Patients followed similar diets throughout their respective treatment cycles and there were no major differences, particularly in the intake of staining agents that they were asked to report. During the measurements, the plaque index and gingival index showed a similar trend in all mouthwashes (Figures 1 and 2). In particular, a progressive accumulation of plaque on the tooth surfaces was evident in many cases. In fact, the assessment of plaque levels using a periodontal probe indicated a mostly invisible accumulation in the first week (PI=0 or 1) and a more pronounced one in the second week (also PI=2). Regarding the gingival index analysis, despite the plaque accumulation as described above, no specific gingival inflammatory conditions were observed, except for redness of the soft gingiva at a marginal level in some patients (GI=1). This confirmed the maintenance of chlorhexidine disinfection efficacy in products A and B throughout the entire treatment period with a significant duration. Instead, during the Stain Index (SI) assessment, the 3 mouthwashes showed different results in the development and spread of dental stains (pictured). Analysis of the mean indices indicated a lower tendency to stain tooth surfaces after treatment cycles with products A and B compared to those with the control mouthwash (product C). This difference, which was present even after day 7, was more pronounced after day 14 of treatment for the groups treated with products A and B compared to the group treated with product C. In addition, a tendency to form less stains was found in the group of patients treated with product B. This allowed us to confirm how the use of N-acetylcysteine ​​​​provides the basis for increasing the effectiveness of the ADS system with sodium metabisulfite and ascorbic acid to combat dental stains in patients treated with chlorhexidine. Example 2 Study objective The aim of this study was to evaluate the efficacy of a 0.2% chlorhexidine mouthwash and the ADS anti-stain system (0.5% w / w sodium metabisulfite, 0.5% w / w ascorbic acid) and compare it with a mouthwash with the same composition but with an additional 0.5% w / w N-acetylcysteine. As a control group, a traditional mouthwash with 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, or N-acetylcysteine ​​was used. Materials and methods For this study, 18 healthy male and female volunteers between the ages of 21-33 were selected in accordance with the principles of the Declaration of Helsinki. As in the Example 1 study, patients with serious systemic diseases such as cardiovascular diseases, diabetes, neurological or psychological syndromes, or infectious diseases were not included in the experiment. Also excluded were patients who were unable to perform oral hygiene maneuvers correctly, patients with chronic periodontal disease with a dento-gingival gap greater than 4 mm, and individuals with fewer than 20 elements in the dental arch. After registration, three bottles were prepared for each patient, which were completely identical, opaque, stable, and with a capacity of 250 ml, and the following items were poured into them: - Product D: a mouthwash with 0.2% chlorhexidine by weight, containing 0.5% by weight sodium metabisulfite and 0.5% by weight ascorbic acid relative to the total volume of the mouthwash; - Product E: Same as product D, but with the addition of 0.5% by weight of N-acetylcysteine ​​relative to the total volume of the mouthwash; and - Product F: Traditional mouthwash with 0.2% chlorhexidine by weight relative to the total volume of the mouthwash. As in Example 1, the bottles, which had a neutral label, were then marked with an alphanumeric code that uniquely identified the patient to whom each bottle was assigned. The reading key was kept secret by the experiment organizers until the end of the experiment so that the patient volunteers or users selected for evaluations would not be aware of the type of mouthwash they were testing. The experiment was then conducted according to the "blind" criterion. Before the start of the experiment, all patients underwent specialized oral hygiene examinations to remove existing soft and hard plaque and to zero the periodontal indices to be analyzed. These indices were: plaque index, gingival index, stain index, according to the same methods used in Example 1. 18 patients were divided into three equal groups in terms of number and placed in Group D (Product D), Group E (Product E), or Group F (Product F), and then each patient was given 2 bottles of the corresponding product. Patients completed a 14-day rinsing cycle with the delivered product. The cycle consisted of rinsing with 15 ml of pure product for one minute, twice a day. During the period of use of the mouthwashes, patients did not use a toothbrush or other oral hygiene tools. Finally, patients were asked to avoid the use of substances that facilitate the deposition of color, such as coffee, tea, red wine or cigarette smoke, for at least one hour before or after rinsing, or in any case to report possible use during the day by completing a special form. After 7 and 14 days, periodontal components PI and GI were measured in addition to SI. All data were collected by a single evaluator in special folders and then analyzed with an analysis program and spreadsheet. Statistical analysis for unpaired data was performed by Student's t-test. Results All 18 eligible patients completed the trial. There were no protocol disruptions or delays in assessment sessions. Patients followed similar diets throughout their respective treatment cycles and there were no major differences, particularly in the intake of staining agents that they were asked to report. Among the measurements taken, the plaque index and gingival index indices showed a similar trend in all mouthwashes (Figures 4 and 5), which was completely consistent with the cases specified in Example 1. Also, regarding the stain index (SI) evaluation, the 3 mouthwashes showed results consistent with those obtained in Example 1 (Figure 6). Analysis of the mean indices indicated a lower tendency to stain tooth surfaces after treatment cycles with products D and E compared to the control mouthwash (product F). This difference, which was still present after day 7, was more pronounced after day 14 of treatment. Furthermore, the previously mentioned tendency in Example 1, of a lower tendency to stain formation in the group of patients treated with product E, was verifiable. This allowed us to confirm how the use of N-acetylcysteine ​​could enhance the effectiveness of the ADS system with sodium metabisulfite and ascorbic acid to combat dental stains in patients treated with chlorhexidine. Example 3 Study objective The aim of this study is as follows: to evaluate the efficacy of a 0.2% chlorhexidine mouthwash and the ADS anti-stain system (0.5% w / w sodium metabisulfite, 0.5% w / w ascorbic acid) with a larger group of patients aiming to combat the onset of dental stains and to compare it with an innovative mouthwash with the same composition but with an additional 0.5% w / w of N-acetylcysteine. As a control group, a traditional mouthwash with 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid or N-acetylcysteine ​​was used. Materials and methods In the IRCCS Galeazzi structure in Milan and in two independent dental practices in that city and in Cinisello Balsamo, 60 male and female patients between the ages of 19 and 31 were selected on a voluntary basis in accordance with the principles of the Declaration of Helsinki. 60 patients underwent a disinfection treatment with suspension of oral hygiene maneuvers after surgery or extractions and periodontal or implant treatments. Patients with systemic pathologies such as cardiovascular diseases, diabetes, neurological or psychological syndromes and those who declared allergies to the components of the product used were not included in the trial. Patients who were unable to perform oral hygiene maneuvers correctly were also excluded from the trial. After registration, three bottles were prepared for each patient, which were completely identical, opaque, stable, and with a capacity of 250 ml, and the following items were poured into them: - Product A: a mouthwash with 0.2% chlorhexidine by weight, containing 0.5% by weight sodium metabisulfite, 0.5% by weight ascorbic acid and 0.01% by weight sodium DNA, based on the total volume of the mouthwash; - Product B: Same as product A, but with the addition of 0.5% by weight of N-acetylcysteine ​​relative to the total volume of the mouthwash; and - Product C: Traditional mouthwash with 0.2% chlorhexidine by weight relative to the total volume of the mouthwash. The bottles were then labeled with a neutral label, with an alphanumeric code that uniquely identified the patient to whom each bottle was assigned. The code was generated by a random code generation software program (called Random Allocation Software®). The read key was kept secret by the experimenters until the end of the experiment so that the patient volunteers or users selected for evaluations would not know which mouthwash they were testing. The experiment was then conducted according to the “blind” criterion. Before the start of the experiment, all patients underwent specialized oral hygiene examinations to remove existing soft and hard plaque and to reduce the periodontal indices that were to be analyzed to zero: - License plate index (PI), for the amount of available license plates, - Gingival Index (GI), for the level of gingival inflammation, - Staining Index (SI) for the degree of discoloration. The plaque index, gingival index, and staining index were analyzed according to the methods used in Example 1. 60 patients were divided into three equal groups in terms of number and placed in Group A (Product A), Group B (Product B), or Group C (Product C), and then each patient was given 2 bottles of the respective product, sufficient for the entire period of use. Patients completed a 14-day rinsing cycle with the delivered product and also performed chlorhexidine-based antiseptic treatments as prescribed and regularly. The cycle consisted of rinsing with 15 ml of the pure product for one minute, which had to be done twice a day. During the period of using the mouthwashes, patients did not use a toothbrush or other oral hygiene tools. Finally, patients were asked to avoid the use of substances that facilitate the deposition of color, such as coffee, tea, red wine or cigarette smoke, for at least one hour before or after rinsing, or in any case to report possible use during the day by completing a special form. After 7 and 14 days, periodontal components PI and GI were measured in addition to SI. After 14 days, patients resumed normal hygiene procedures if surgical healing allowed for restoration. All data were collected by a single evaluator in special folders and then analyzed with an analysis program and spreadsheet. Statistical analysis was performed for analysis of variance (ANOVA) test. Results Of the 60 volunteer patients selected and included in the trial, 57 completed the study. 2 patients (1 from group A and 1 from group B) did not attend the 7th day examination and 1 patient (group A) did not attend the 14th day examination. There were no protocol disruptions or delays in assessment sessions. Patients followed similar diets throughout their respective treatment cycles, and there were no major differences, particularly in the intake of staining agents that they were asked to report. Among the measurements taken, the plaque index and gingival index indices showed a similar trend across all mouthwashes (Figures 7 and 8). This finding confirmed the results of previous tests conducted in Example 1 and described above. In particular, an increasing plaque accumulation on the tooth surfaces was evident in many cases during the study period, which was higher in the presence of sutures and surgical margins. In fact, assessment of plaque levels using a periodontal probe revealed an accumulation that was mostly invisible in the first week (PI=0 or 1) and was visible by the probe in the second week (several patients with PI=2). However, no statistically significant differences between the three mouthwash formulations were extracted from the data collected regarding PI and GI. Similar to many other studies on chlorhexidine, despite the presence of plaque, no specific gingival inflammatory state was observed in the three groups when the gingival index was examined, except for mild gingival redness at the marginal level in a few patients (GI = 1). This picture (Figure 8) is also consistent with the previous test on similar formulations described in Example 1. However, the Stain Index (SI) recording when compared with the results previously obtained in Example 1, showed significant differences. In fact, the 3 mouthwashes showed different trends in the formation and development of dental stains, which can be seen in Figure 9. The analysis of the mean SI indices indeed confirms an anti-stain performance for the mouthwashes equipped with the ADS system (products A and B) compared to those with a control mouthwash containing chlorhexidine without ADS, which was statistically significant both at the 7th and 14th day observations. In fact, the ability of the ADS component to reduce dental staining caused by the use of chlorhexidine-based disinfectants, without inhibiting its antiplaque action, has been known for several years. The performance of the ADS system may vary depending on the amount of color-forming agents received by the patient during the course of use, but optimal dietary control and adherence to the physician's instructions with the antistain system can guarantee a visible antistain effect even in real clinical use conditions. The difference in SI measurements between the two groups with the ADS system (products A and B) and the case without this system (product C) was statistically significant both on the 7th and 14th day of treatment. Unexpectedly, compared to the test conducted in Example 1 on a smaller number of patients, in this test, the mouthwash with the ADS / NAC anti-stain system (Product B) showed a tendency to cause less staining, which was statistically significant compared to Group A, although this difference was only observed after 14 days. Conclusion Considering the collected and analyzed data, it can be stated that the anti-stain system investigated in this test (Anti-Discoloration System, ADS) and presented in chlorhexidine mouthwash formulations confirms the results available in the literature records, source: Van Swaaij BWM, et al.. "Does chlorhexidine mouthwash, with an anti-discoloration system, reduce tooth surface discoloration without losing its efficacy? A systematic review and meta-analysis." Int J Dent Hyg. 2020 Feb;18(1):27-43 And it appears to be more effective in combating the onset of tooth discoloration compared to traditional mouthwashes containing chlorhexidine. According to the data obtained from this study, it does not seem that the ADS anti-stain system (Product A) is able to completely eliminate the problem of tooth stains. Tooth stains are actually associated with several components, the first of which is compliance with the doctor's medication instructions and also the behavior recommended by the doctor after dental treatments. However, by examining the stain index indices (Figure 9), it is clear that the amount of stains after 14 days of use of mouthwashes containing the ADS system is much lower than index 1 (weak staining), while for traditional mouthwashes with CHX and alcohol, the index is between 1 and 2 (marked staining) with peaks that are even higher than index 2. In addition, the difference between the SI indices among the three mouthwashes in favor of the use of those containing the ADS system (Products A and B) is statistically significant both on the seventh and on the fourteenth day of the studies. Regarding the introduction of the NAC component to the mouthwash with the ADS and DNA system (Product B) according to the present invention, it was possible to observe the maintenance of the chlorhexidine disinfection efficacy and in parallel a further reduction in the amount of tooth stains was observed on the seventh day and, more importantly, on the fourteenth day. In this test, the difference between mouthwash A (Product A: CHX-ADS-DNA) and mouthwash B (Product B: CHX-ADS-DNA-NAC) in favor of the product B of the invention (CHX-ADS-DNA-NAC) was statistically significant only after fourteen days of use. Example 1, conducted on healthy volunteers, demonstrates the additional benefit of adding NEC to a chlorhexidine mouthwash and the ADS system in terms of reducing tooth stains. On the other hand, in the present example, the difference in reducing tooth discoloration seems more obvious, as it is noticeable after 14 days of examination, as described earlier. To explain this difference between the results of Examples 1 and 3, some hypotheses have been put forward. First, Example 3 concerns patients who actually underwent dental treatments that required the suspension of oral hygiene procedures: tooth extraction, implant surgery, periodontal surgery, and others. In this case, compared to healthy volunteers (Example 1), patients may have been much more inclined to follow the recommendations and, moreover, may have resisted the temptation to brush their teeth; something that cannot actually be verified when healthy volunteers were present in the studies. The greater accumulation of plaque and, consequently, the color-forming agents may have exacerbated the benefits of anti-stain systems, especially in areas where they are most needed, such as areas with surgical wounds and sutures. The significant number of patients present (Group A: 28, Group B: 29, Group C: 30) as well as the nature of the patients who were actually undergoing surgical treatments (and not healthy volunteers as in Example 1) make this test particularly noteworthy: it seems to confirm that the combination of the ED systemIt is already known in the industry that N-acetyl-cysteine ​​(NAC) can enhance the anti-ADS activity alone in clinical settings and has additional benefits in terms of patient compliance and favorable treatment outcomes.

Claims

Claims 1. An oral care product comprising chlorhexidine, at least one basic or alkaline earth metal metabisulfite salt, ascorbic acid and N-acetylcysteine.

2. An oral care product according to claim 1, wherein the chlorhexidine is in the form of a salt or a complex.

3. An oral care product according to claim 1 or 2, comprising sodium DNA.

4. An oral care product according to any one of claims 1 to 3, selected from the group consisting of: mouthwash, periodontal gel and toothpaste.

5. An oral care product according to claim 4, wherein said product is a mouthwash and the amount of chlorhexidine is in the range of 0.01% to 0.30% by weight relative to the total volume of the mouthwash.

6. An oral care product according to claim 4 or 5, wherein said product is a mouthwash and the amount of at least one alkaline or alkaline earth metal metabisulfite salt in the base is from 0.1% to 0.5% based on the total volume of the mouthwash.

7. An oral care product according to any one of claims 4 to 6, wherein said product is a mouthwash and the amount of ascorbic acid in the base is from 0.1% to 1.0% by weight, based on the total volume of the mouthwash.

8. An oral care product according to any one of claims 4 to 7, wherein said product is a mouthwash and the amount of N-acetyl-cysteine ​​in the base is from 0.01% to 1.0% by weight based on the total volume of the mouthwash.

9. An oral care product according to any one of claims 4 to 8, wherein said product is a mouthwash comprising from 0.01% to 0.30% by weight of chlorhexidine, from 0.1% to 0.5% by weight of at least one alkaline or alkaline earth metal metabisulfite salt, from 0.1% to 1.0% by weight of ascorbic acid, from 0.01% to 1.0% by weight of N-acetyl-cysteine, from 0.01% to 0.2% by weight of sodium DNA, from 0.05% to 1% by weight of at least one polyvinyl pyrrolidone-vinyl acetate copolymer, based on the total volume of the mouthwash.

10. The oral care product of claim 4, wherein said product is a periodontal gel comprising between 0.5% by weight and 1.0% by weight of chlorhexidine based on the total volume of the periodontal gel.

11. An oral care product according to claim 4 or 10, wherein the product is a periodontal gel and the amount of N-acetylcysteine ​​is in the range of 0.01% to 1.0% by weight relative to the total volume of the periodontal gel.

12. An oral care product according to claim 4, wherein said product is a toothpaste comprising 0.05% by weight to 0.2% by weight of chlorhexidine based on the total volume of the toothpaste.

13. An oral care product according to claim 4 or 12, wherein said product is a toothpaste and the amount of N-acetylcysteine ​​is in the range of 0.01% to 1.0% by weight based on the total volume of the toothpaste.

14. An oral care product according to any one of claims 1 to 13 for use in the treatment of at least one pathology selected from the group consisting of gingivitis, bacterial plaque and gingivitis.

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