Oral Care Products

Abstract

The present invention relates to the use of N-acetylcysteine ​​to enhance the effectiveness of metabisulfites of alkali or alkaline earth metals and ascorbic acid in counteracting pigmentation of dental surfaces, dental mucosa, dental restorations, or dental restorations in patients treated with chlorhexidine, and to oral care products comprising chlorhexidine, at least one metabisulfite of an alkali or alkaline earth metal, ascorbic acid, and N-acetylcysteine.

Description

[Technical field]

[0001] The present invention relates to the use of N-acetylcysteine ​​to enhance the effectiveness of metabisulfites of alkali or alkaline earth metals and ascorbic acid in counteracting dental pigmentation in patients undergoing chlorhexidine treatment, and to oral care products comprising chlorhexidine, at least one metabisulfite of an alkali or alkaline earth metal, ascorbic acid, and N-acetylcysteine. [Background technology]

[0002] Chemical plaque control is one of the most important steps during many dental procedures as well as during normal household oral hygiene operations.For this purpose, many active ingredients are produced and marketed, mainly in the form of mouthwashes, toothpastes or sprays, among which we can mainly mention chlorhexidine, essential oils, fluoride derivatives, delmopinol.However, from the data emerging from the recent literature, chlorhexidine is still today the most effective product in chemical plaque control, and is therefore rightly defined as the active ingredient of reference.

[0003] Chlorhexidine is a molecule that belongs to the bisguanide family and is known for its remarkable activity in the management of chemical plaque and gingivitis. It is in fact known to have a bacteriostatic type action when used in low concentrations, but an almost bactericidal effect when used in high concentrations, which is related to the specific characteristics of different bacterial species. Chlorhexidine expresses its own antiseptic effect thanks to its ability to establish chemical bonds with anionic groups (phosphate, sulfate, carboxyl groups) present at the level of the bacterial cell wall, thus inducing a significant increase in cell permeability and a change in the osmotic balance.

[0004] Due to its cationic properties, chlorhexidine is also known to bind to the following: ·Oral mucosa, Enamel hydroxyapatite, -Secondary films present on the tooth surface, Salivary proteins, and · Bacteria and cell polysaccharides of bacterial origin.

[0005] When bound to these oral structures, chlorhexidine can be released slowly while maintaining effective concentrations against microorganisms for approximately 8 to 18 hours. This effect, which allows the active ingredient to remain in effective concentrations even hours after its administration, is called persistence and describes the strength of this active ingredient.

[0006] Despite the many advantages of chlorhexidine in terms of pharmacological activity, this active ingredient is also known to have some troublesome side effects. Among the main known side effects, the most common is certainly represented by the brownish pigmentation that occurs on the tooth surface and mucous membrane, especially in resin restorations or prosthetic products, thus limiting its long-term use. In particular, the binding of pigments to hydroxyapatite is thought to be mediated by the interaction of the anionic groups of the pigment molecules with the cationic groups of chlorhexidine, which, when bound, forms a brownish film that is very difficult to remove by simple brushing.

[0007] This side effect occurs mainly after prolonged use of chlorhexidine, especially in preparations with higher chlorhexidine concentrations (0.2% or even 1% in some oral gels).

[0008] Anti-discoloration additives are known that have the purpose of counteracting this side effect of chlorhexidine-containing oral care products. Among these additives, the ADS system, consisting of ascorbic acid and sodium metabisulfite, is known to be able to reduce tooth staining without compromising the disinfecting effect of chlorhexidine (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).

[0009] Applicant has found that while the ADS system, comprised of ascorbic acid and sodium metabisulfite, exhibits clear and discernible efficacy in counteracting pigmentation of surfaces, mucosa, restorations, and prosthetic dental products in patients undergoing chlorhexidine treatment without compromising its disinfecting efficacy, there remains a need to enhance the anti-pigmentation efficacy of the ADS system, particularly for long-term treatments. Summary of the Invention

[0010] It is therefore an object of the present invention to improve and enhance the effectiveness of alkali or alkaline earth metal metabisulfites and ascorbic acid in counteracting pigmentation (or staining) of patient surfaces, mucous membranes, restorations, and dental prosthetic products undergoing chlorhexidine treatment, particularly for long-term treatments, without compromising the disinfecting efficacy of chlorhexidine itself.

[0011] In accordance with the present invention, the applicant has surprisingly found that this result is possible by using N-acetylcysteine ​​in combination with an alkali or alkaline earth metal metabisulfite and ascorbic acid, which has been shown to enhance the effectiveness of the alkali or alkaline earth metal metabisulfite and ascorbic acid in countering pigmentation of surfaces, mucous membranes, restorations, and prosthetic dental products in patients undergoing chlorhexidine treatment.

[0012] Thus, in a first aspect, the present invention relates to N-acetylcysteine ​​for use in a method for treating side effects of chlorhexidine in a patient undergoing chlorhexidine treatment, said side effects comprising pigmentation of the patient's tooth surfaces, dental mucosa, dental restorations or dental prostheses, and said N-acetylcysteine ​​increases the effect of at least one metabisulfite of an alkali or alkaline earth metal and ascorbic acid in counteracting said pigmentation of the tooth surfaces, dental mucosa, dental restorations or dental prostheses.

[0013] Surprisingly, it has been found that the association of N-acetylcysteine ​​with alkali or alkaline earth metal metabisulfites and ascorbic acid increases the contrasting effect of chlorhexidine on pigmentation / staining of surfaces, mucosa, restorations, and prosthetic dental products, even for prolonged treatments, without impairing the disinfecting effect of chlorhexidine itself.

[0014] Thus, thanks to the specific combination of N-acetylcysteine, at least one metabisulfite of an alkali or alkaline earth metal, ascorbic acid and chlorhexidine, it is possible to provide an oral care product having various properties that are able to improve the properties of oral care products based on the ADS system, thus expanding their applicability.

[0015] Thus, in a further aspect, the present invention also relates to an oral care product comprising chlorhexidine, at least one metabisulfite salt of an alkali or alkaline earth metal, ascorbic acid, and N-acetylcysteine.

[0016] Thanks to the presence of N-acetylcysteine, at least one metabisulfite of an alkali or alkaline earth metal and ascorbic acid, the products according to the invention based on chlorhexidine are effective against oral pathologies, in particular plaque pathologies, without causing or severely limiting the side effects of long-term use of said active ingredients with pigmentation of surfaces, mucous membranes, restorations and dental prosthetic products.

[0017] Thus, in a further aspect thereof, the present invention relates to an oral care product comprising chlorhexidine, at least one metabisulfite salt of an alkali or alkaline earth metal, ascorbic acid, and N-acetylcysteine, for use in treating dental plaque in a patient in need thereof.

[0018] The Applicant has indeed found that the use of N-acetylcysteine ​​according to the invention constitutes an innovative aspect of particular value for said oral care products, by improving and enhancing the effect of alkali or alkaline earth metal metabisulfites and ascorbic acid in counteracting pigmentation of surfaces, mucous membranes, restorations and dental prosthetic products in patients undergoing anti-plaque treatment with chlorhexidine.

[0019] In the figure, the following is true: [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 shows the plaque index (PI) test results for groups using products A, B and C according to Example 1 over 7 and 14 days. [Diagram 2] FIG. 2 shows the results of the gingival index (GI) test for the groups using products A, B and C according to Example 1 after 7 and 14 days. [Diagram 3]FIG. 3 shows the results of the Color Index (SI) test for 7 and 14 days for groups using products A, B and C according to Example 1. [Figure 4] FIG. 4 shows the 7-day and 14-day Plaque Index (PI) test results for the groups using products D, E and F according to Example 2. [Diagram 5] FIG. 5 shows the results of the 7-day and 14-day Gingival Index (GI) test for the groups using products D, E and F according to Example 2. [Figure 6] FIG. 6 shows the results of the Color Index (SI) test for 7 and 14 days for the groups using products D, E and F according to Example 2. [Figure 7] FIG. 7 shows the plaque index (PI) test results for the groups using products A, B and C according to Example 3 after 7 and 14 days. [Figure 8] FIG. 8 shows the results of the 7-day and 14-day Gingival Index (GI) test for the groups using products A, B and C according to Example 3. [Figure 9] FIG. 9 shows the results of the 7-day and 14-day stain index (SI) test for the groups using products A, B and C according to Example 3. The three groups show different trends. The pigmentation caused by the conventional mouthrinse at day 14 is more than double that of the ADS mouthrinse. The ADS mouthrinse shows a statistically significant difference from the "control" mouthrinse (groups CHX, C) at both T=7 days and T=14 days. Group B (CHX-ADS-NAC) also shows a significantly lower SI value than group A (CHX-ADS) at T=14 days. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] In a first aspect, the present invention relates to the use of N-acetylcysteine ​​in a method for treating side effects of chlorhexidine in a patient undergoing chlorhexidine treatment, said side effects including pigmentation of the patient's tooth surface, dental mucosa, dental restoration or dental prosthesis, and said N-acetylcysteine ​​increases the effect of at least one metabisulfite of an alkali or alkaline earth metal and ascorbic acid in counteracting said pigmentation of the tooth surface, dental mucosa, dental restoration or dental prosthesis.

[0022] The Applicant has surprisingly found that it is indeed possible to improve and enhance the effect of alkali or alkaline earth metal metabisulfites and ascorbic acid, without compromising the disinfecting effect of chlorhexidine itself, by using N-acetylcysteine, which has been shown to enhance the contrasting effect of said pigmentation in combination with alkali or alkaline earth metal metabisulfites and ascorbic acid metabisulfite in countering pigmentation / staining of patient surfaces, mucous membranes, restorations and prosthetic dental products undergoing chlorhexidine treatment.

[0023] Thus, thanks to the specific combination of N-acetylcysteine, at least one metabisulfite of an alkali or alkaline earth metal, ascorbic acid and chlorhexidine, it is possible to provide an oral care product having various properties that are able to improve the properties of oral care products based on the ADS system, thus expanding their applicability.

[0024] Thus, in a further aspect, the present invention also relates to an oral care product comprising chlorhexidine, at least one metabisulfite salt of an alkali or alkaline earth metal, ascorbic acid, and N-acetylcysteine.

[0025] The present invention can be presented in one or more of its aspects, or in one or more of the preferred features reported below, which can be preferably combined with each other according to application requirements.

[0026] Within the context of this specification and the appended claims, all numerical magnitudes expressing quantities, parameters, percentages, and the like, unless otherwise indicated, should be deemed to be preceded in all circumstances by the term "about." Moreover, all ranges of numerical magnitudes include all possible combinations of maximum and minimum numerical values ​​and all possible intermediate ranges, as well as those set forth below.

[0027] In the present invention, the expressions are as follows: "% by weight of the total volume" of a product, e.g., a mouthwash, means the amount in grams of a given ingredient present in 100 milliliters (mL) of said product; "Chlorhexidine" means, unless otherwise specified, the compound 1,1'-hexamethylenebis[5-(p-chlorophenyl)biguanide], its salts or complexes thereof.

[0028] Preferably, in the oral care product, chlorhexidine is in the form of a salt or complex. For example, chlorhexidine digluconate or chlorhexidine diacetate can be used in the mouthwash of the present invention. Preferably, the oral care product according to the present invention contains chlorhexidine in the form of chlorhexidine gluconate.

[0029] Preferably, the oral care product further comprises sodium DNA. In the present invention, "sodium DNA" refers to the sodium salt of deoxyribonucleic acid, which can be obtained, for example, by extracting natural deoxyribonucleic acid from the gonad tissue of male sturgeon, followed by purification, depolymerization, and neutralization with sodium ions.

[0030] Sodium DNA suitable for the purposes of the present invention is commercially available, for example, that sold under the name Kalinat AW powder (Kalichem). Said amount of sodium DNA has in fact proven to be optimal for counteracting the irritating effect of chlorhexidine on the oral mucosa, thereby exerting a protective effect on the oral mucosa and a healing effect on possible oral wounds, and thus promoting the correct nutritional effect of the oral mucosa itself.

[0031] In a preferred embodiment thereof, said oral care product is selected from the group consisting of mouthwashes, periodontal gels, and toothpastes.

[0032] Thus, in its first preferred embodiment, the oral care product according to the invention is a mouthwash.

[0033] Preferably, the mouthwash contains chlorhexidine in an amount ranging from 0.01% to 0.30% by weight, more preferably from 0.05% to 0.30% by weight, and even more preferably from 0.09% to 0.20% by weight, based on the total volume of the mouthwash.

[0034] Mouthwashes according to the present invention also contain at least one metabisulfite salt of an alkali or alkaline earth metal.

[0035] The presence of at least one metabisulfite salt of an alkali or alkaline earth metal counteracts the side effect of chlorhexidine, which is dark pigmentation of the teeth.

[0036] Preferably, the at least one metabisulfite salt of an alkali or alkaline earth metal is selected from the group consisting of sodium metabisulfite, potassium metabisulfite, calcium metabisulfite. More preferably, the mouthwash according to the invention comprises sodium metabisulfite.

[0037] Preferably, in a mouthwash according to the present invention, the amount of at least one metabisulfite of an alkali or alkaline earth metal ranges from 0.1% to 0.5% by weight, more preferably from 0.15% to 0.3% by weight, relative to the total volume of the mouthwash.

[0038] The mouthwash according to the present invention further comprises ascorbic acid.

[0039] Preferably, in the mouthwash according to the present invention, the amount of ascorbic acid ranges from 0.1% to 1.0% by weight based on the total volume of the mouthwash.

[0040] The presence of ascorbic acid also counteracts the side effect of chlorhexidine, which is dark pigmentation of the teeth.

[0041] Preferably, the mouthwash according to the present invention comprises ascorbic acid and at least one metabisulfite of an alkali or alkaline earth metal, and even more preferably, 0.1% to 0.5% by weight of at least one metabisulfite of an alkali or alkaline earth metal, and 0.1% to 1.0% by weight of ascorbic acid, based on the total volume of the mouthwash.

[0042] This combination of ingredients in these amounts has proven particularly effective in counteracting the side effect of chlorhexidine of dark staining of the teeth and is the basis of the ADS system.

[0043] The mouthwash according to the present invention further comprises N-acetylcysteine.

[0044] As demonstrated in the experimental section, N-acetylcysteine ​​has been shown to enhance the effectiveness of alkali or alkaline earth metal metabisulfites and ascorbic acid in counteracting the defects of brown pigmentation on surfaces, mucosa, restorations, and prosthetic dental products in patients undergoing chlorhexidine treatment.

[0045] Preferably, in the mouthwash according to the present invention, the amount of N-acetylcysteine ​​ranges from 0.01% to 1.0% by weight, more preferably from 0.2% to 0.7% by weight, based on the total volume of the mouthwash.

[0046] In addition to the ingredients mentioned above, mouthwashes according to the present invention preferably contain tribasic sodium citrate.

[0047] Preferably, in the mouthwash according to the present invention, the amount of tribasic sodium citrate ranges from 0.8% to 2.0% by weight, more preferably from 0.8% to 1.2% by weight, based on the total volume of the mouthwash.

[0048] The presence of said amounts of tribasic sodium citrate advantageously makes it possible to adjust the pH of the mouthrinse to the optimum value for its use.

[0049] 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 0.1% to 1% by weight based on the total volume of ascorbic acid in the mouthwash and 0.8% to 2.0% by weight based on the total volume of the cavity rinse of tribasic sodium citrate.

[0050] Indeed, it has been surprisingly discovered that said combination of ascorbic acid and tribasic sodium citrate makes it possible to stabilise the formulation of the mouthwash according to the invention.

[0051] Preferably, the mouthwash according to the invention comprises at least one polyvinylpyrrolidone-vinyl acetate copolymer. Polyvinylpyrrolidone-vinyl acetate copolymers suitable for the purposes of the invention are commercially available, for example those sold under the name Luviskol® (BASF SE).

[0052] At least one polyvinylpyrrolidone-vinyl acetate copolymer advantageously exerts film-forming and anti-plaque properties in the mouthwash according to the invention.

[0053] Preferably, in the mouthwash according to the present invention, the amount of at least one polyvinylpyrrolidone-vinyl acetate copolymer ranges from 0.05% to 1% by weight, more preferably from 0.3% to 1% by weight, relative to the total volume of the mouthwash.

[0054] Preferably, the mouthwash also contains sodium dodecyl sulfate.

[0055] Sodium DNA advantageously exerts a protective and healing effect on the oral mucosa, further limiting some of the side effects of long-term use of chlorhexidine-based oral care products, which include alterations in cell structure, including vacuolization, degeneration of cell nuclei, and enlargement of intercellular spaces.

[0056] Preferably, in the mouthwash, the amount of sodium DNA ranges from 0.01% to 0.2% by weight, more preferably from 0.05% to 0.1% by weight, based on the total volume of the mouthwash.

[0057] In a preferred embodiment thereof, the oral care product according to the invention is a mouthwash comprising, relative to the total volume of the mouthwash, 0.01% to 0.30% by weight of chlorhexidine, 0.1% to 0.5% by weight of at least one alkali or alkaline earth metal metabisulfite, 0.1% to 1.0% by weight of ascorbic acid, 0.01% to 1.0% by weight, more preferably 0.2% to 0.7% by weight of N-acetylcysteine, 0.01% to 0.2% by weight, more preferably 0.01% to 0.1% by weight of sodium DNA, and 0.05% to 1% by weight, more preferably 0.3% to 1% by weight of at least one polyvinylpyrrolidone-vinyl acetate copolymer.

[0058] Mouthwashes according to the present invention may contain one or more of the other possible ingredients known in the art for oral hygiene solutions.

[0059] In particular, the mouthwash according to the present invention may further comprise one or more additives selected from the group consisting of sweeteners, flavorings, humectants, preservatives, emulsifiers, pH adjusters, and food colorants.

[0060] As sweeteners, the mouthwash according to the invention may contain, for example, xylitol, sodium saccharinate, acesulfame potassium, sucralose, stevia extract.

[0061] As flavourings, the mouthwash according to the invention may contain, for example, peppermint, menthol, anethole, mentha viridis, cinnamon, clove, eucalyptol.

[0062] As humectants, mouthwashes according to the invention may contain, for example, propylene glycol, sorbitol, glycerin.

[0063] As preservatives, the mouthwash according to the invention may contain, for example, sodium benzoate, methylisothiazolinone.

[0064] As solubilising surfactants the mouthwash according to the invention may contain, for example, hydrogenated castor oil Peg 40, poloxamer 407.

[0065] As a pH adjuster, the mouthwash according to the present invention may contain, for example, sodium citrate, citric acid.

[0066] As colourants the mouthwash according to the invention may contain, for example, CI 19140, CIU 42090, CI 17200.

[0067] Mouthwashes according to the invention are conveniently prepared in known manner in the form of a solution or suspension in a suitable solvent, preferably water.

[0068] According to a preferred embodiment, the mouthwash according to the present invention comprises the following components: 1.Water 2. Xylitol 3. Propylene glycol 4. Hydrogenated Castor Oil PEG 40 5. Sodium Acetate 6. Ascorbic Acid 7. Chlorhexidine digluconate 8. Polyvinylpyrrolidone-vinyl acetate copolymer 9. N-Acetylcysteine 10. Sodium DNA 11. Flavorings 12. Poloxamer 407 13. Sodium Metabisulfite 14. Sodium hydroxide 15. Sodium Benzoate 16. Acetic acid

[0069] According to a further preferred embodiment, the mouthwash according to the invention comprises the following components: 1.Water 2. Xylitol 3. Propylene glycol 4. Hydrogenated Castor Oil PEG 40 5. Ascorbic Acid 6. Chlorhexidine digluconate 7. Polyvinylpyrrolidone-vinyl acetate copolymer 8. N-Acetylcysteine 9. Sodium DNA 10. Flavorings 11. Poloxamer 407 12. Sodium Metabisulfite 13. Sodium Citrate 14. Citric Acid 15.CI42090 16.CI17200

[0070] In a further preferred embodiment, the oral care product according to the invention is a periodontal gel.

[0071] 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. Polyvinylpyrrolidone-vinyl acetate copolymer 5. Hydrogenated Castor Oil PEG 40 6. Chlorhexidine digluconate 7. N-Acetylcysteine 8. Sodium Acetate 9. Sodium DNA 10. Menthol 11. Peppermint oil 12. Acetic acid 13. Sodium Metabisulfite 14. Ascorbic Acid

[0072] Preferably, the periodontal gel according to the present invention contains 0.5% by weight to 1.0% by weight of chlorhexidine relative to the total volume of the periodontal gel.

[0073] Preferably, the periodontal gel according to the present invention contains 0.01% to 1.0% by weight, more preferably 0.2% to 0.7% by weight, of N-acetylcysteine ​​relative to the total volume of the periodontal gel.

[0074] Preferably, the periodontal gel according to the invention comprises sodium DNA in an amount of up to 0.3% by weight, even more preferably between 0.01% and 0.3% by weight, relative to the total weight of the periodontal gel.

[0075] As already mentioned with respect to the mouthwash according to the present invention, sodium DNA advantageously exerts a protective and healing effect on the oral mucosa, further limiting some of the side effects of long-term use of chlorhexidine-based oral care products, including changes in cell structure, including vacuolization, degeneration of cell nuclei, and enlargement of intercellular spaces.

[0076] In a further preferred embodiment, the oral care product according to the present invention is a toothpaste.

[0077] According to a preferred embodiment, the toothpaste according to the invention comprises the following ingredients: 1. Sorbitol 2.Water 3. Silica (hydrated silica) 4. Glycerol 5. Xylitol 6. Cocamidopropyl Betaine 7. Polyvinylpyrrolidone-vinyl acetate copolymer 8. Hydrogenated Castor Oil PEG 40 9. N-Acetylcysteine 10. Flavorings 11. Chlorhexidine digluconate 12. Carboxymethylcellulose 13. Ascorbic Acid 14. Sodium Metabisulfite 15. Sodium DNA 16. Sodium saccharin 17. Sodium Benzoate 18. Sodium Citrate

[0078] Preferably, the toothpaste according to the invention comprises 0.05% to 0.2% by weight of chlorhexidine relative to the total volume of the toothpaste.

[0079] Preferably, the toothpaste according to the invention comprises ascorbic acid and at least one metabisulfite of an alkali or alkaline earth metal, even more preferably 0.1% to 0.5% by weight of at least one metabisulfite of an alkali or alkaline earth metal, and 0.1% to 1.0% by weight of ascorbic acid, based on the total volume of the toothpaste.

[0080] As already mentioned with respect to the mouthwash and periodontal gel according to the invention, said combination of ingredients is already particularly effective in counteracting the side effect of chlorhexidine of dark pigmentation on the teeth and is the basis of the ADS system.

[0081] Preferably, the toothpaste according to the invention comprises from 0.01% to 1.0% by weight, more preferably from 0.2% to 0.7% by weight, of N-acetylcysteine ​​relative to the total volume of the toothpaste.

[0082] Preferably, at least one inorganic fluoride may optionally be present in toothpastes according to the present invention.

[0083] Preferably, in the toothpaste of the invention, the amount of sodium DNA ranges from 0.01% to 0.05% by weight relative to the total volume of the toothpaste.

[0084] As already mentioned with respect to the mouthwash according to the present invention, sodium DNA advantageously exerts a protective and healing effect on the oral mucosa, further limiting some of the side effects of long-term use of chlorhexidine-based oral care products, including changes in cell structure, including vacuolization, degeneration of cell nuclei, and enlargement of intercellular spaces.

[0085] Thanks to the presence of N-acetylcysteine, at least one metabisulfite of an alkali or alkaline earth metal and ascorbic acid, the products according to the invention based on chlorhexidine are effective against oral pathologies, in particular plaque pathologies, without causing or severely limiting the side effects of long-term use of said active ingredients with pigmentation of surfaces, mucous membranes, restorations and dental prosthetic products.

[0086] Thus, in a further aspect thereof, the present invention relates to an oral care product comprising chlorhexidine, at least one metabisulfite salt of an alkali or alkaline earth metal, ascorbic acid, and N-acetylcysteine, for use in treating dental plaque in a patient in need thereof.

[0087] The Applicant has indeed found that the use of N-acetylcysteine ​​according to the invention constitutes an innovative aspect of particular value for said oral care products, by improving and enhancing the effect of alkali or alkaline earth metal metabisulfites and ascorbic acid in counteracting pigmentation of surfaces, mucous membranes, restorations and dental prosthetic products in patients undergoing anti-plaque treatment with chlorhexidine.

[0088] Therefore, in a preferred aspect thereof, the present invention relates to the use of N-acetylcysteine ​​in a patient undergoing chlorhexidine treatment according to the first aspect of the invention, said chlorhexidine treatment being carried out using an oral care product according to the present invention.

[0089] Experimental section The present invention will now be described by way of some examples thereof, to be understood for illustrative and non-limiting purposes.

[0090] Example 1 Research goal The aim of this study was to evaluate the effectiveness of a 0.2% chlorhexidine mouthrinse containing 0.01% sodium metabisulfite and an antipigmentation ADS system (0.5% sodium metabisulfite, 0.5% ascorbic acid) and to compare it with a mouthrinse having the same composition but with an additional 0.5% N-acetylcysteine. As a control group, a conventional mouthrinse was used with 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, sodium DNA or N-acetylcysteine.

[0091] material and method For this study, 15 male and female healthy volunteers aged 19-29 years were selected according to the principles of the Declaration of Helsinki. Patients with severe systemic diseases such as cardiovascular disease, diabetes, neurological or psychiatric syndromes, or infections were not included in the study. Patients who were unable to perform home oral hygiene maneuvers correctly, patients suffering from chronic periodontal disease with pockets larger than 4 mm, and subjects with fewer than 20 elements of the dental arch were also excluded from the study.

[0092] After enrolment, three bottles were prepared for each patient, which were completely identical, inert, opaque and had a volume of 250 ml, into which they were introduced. - Product A: a mouthwash containing 0.2% chlorhexidine by weight, containing 0.5% sodium metabisulfite, 0.5% ascorbic acid, and 0.01% sodium DNA by weight relative to the total volume of the mouthwash; - Product B: As product A, but with the addition of 0.5% N-acetylcysteine ​​by weight relative to the total volume of the mouthwash; and Product C: A conventional mouthwash containing 0.2% chlorhexidine by weight based on the total volume of the mouthwash.

[0093] The bottles were then given a neutral label and simply marked with an alphanumeric code that uniquely identified the assigned patient. To prevent the volunteer patients or operators selected for the evaluation from knowing which type of mouthwash they were testing, the reading key was kept unknown by the study organizers until the end of the evaluation. The study was then conducted according to a "double-blind" criteria.

[0094] Prior to the start of the study, all patients underwent a professional oral hygiene session to remove existing soft and hard plaque deposits and to bring the analyzed periodontal index to zero. - The plaque index (PI) for the amount of plaque present (Loe H., Silness J: Periodontal disease in pregnancy. Prevalence and severity. Acta odontologica Scandinavica. 1963;21:533-551). - Gingival index (GI), the level of gingival inflammation (Silness J, Loe H: Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal conditions. Acta odontologica Scandinavica. 1964;22:121-135). - Stain Index (SI) for the degree of pigmentation (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 chlorexidine in the treatment of periodontitis: a multi-center study. J Clin Periodontol 1997;68:32-38.).

[0095] The 15 patients were divided into three groups of equal number and assigned to group A (product A), group B (product B) or group C (product C), and then two bottles of the corresponding product were assigned to each patient.

[0096] The patients performed a 14-day rinse cycle with the delivered product. This cycle involved rinsing for 1 minute with 15 ml of pure product to be performed twice a day. During the period of use of the mouthwash, the patients did not brush or use any other oral hygiene device. Finally, the patients were asked not to consume substances that can promote the deposition of pigments, such as coffee, tea, red wine or cigarette smoke, less than one hour before or after rinsing, and in any case to report possible daily intakes by a special form to be filled out.

[0097] The periodontal parameters PI and GI, as well as SI, were then measured after 7 and 14 days.

[0098] All data were collected by a single examiner in a special folder and then analyzed by an analysis program and a spreadsheet. Statistical analysis was performed by Student's T-test for independent data.

[0099] result All 15 selected volunteer patients completed the study. There were no interruptions to the protocol or delays in the evaluation sessions. The patients maintained a similar dietary regimen during the treatment cycles they underwent, with no substantial differences in the intake of coloring substances, which they were asked to report on the appropriate sheets delivered to them.

[0100] In the measurements carried out, the values ​​of the plaque index and gingival index showed a similar trend for all types of mouthrinses (Figures 1 and 2). In particular, the progressive plaque accumulation on the tooth surfaces was highlighted in most cases. The assessment of the amount of plaque using a periodontal probe showed, in fact, an almost invisible accumulation in the first week (PI=0 or 1) and a more visible accumulation in the second week (also PI=2).

[0101] Concerning the analysis of the gingival index, despite the abovementioned plaque accumulation, no specific inflammatory gingival condition was recognized, except for soft gingival reddening at marginal level in a few subjects (GI=1).

[0102] This confirmed that the disinfecting effect of chlorhexidine in Products A and B was maintained for a significant period throughout the treatment period.

[0103] During the Stain Index (SI) evaluation, the three mouthrinses instead showed different results in the occurrence of tooth pigmentation (Figure 3).

[0104] Analysis of the mean values ​​showed a lower tendency to pigmentation of the tooth surface after treatment cycles with Products A and B compared to those with the control mouthwash (Product C). Differences already present after 7 days were particularly evident after 14 days of treatment in the groups treated with Products A and B compared to the group treated with Product C.

[0105] In addition to this, there was a trend towards less pigmentation in the patient group treated with product B anyway, highlighting how the use of N-acetylcysteine ​​can enhance the effectiveness of the ADS system with sodium metabisulfite and ascorbic acid in counteracting dental pigmentation in patients receiving chlorhexidine treatment.

[0106] Example 2 Research goal The aim of this study was to evaluate the effectiveness of a 0.2% chlorhexidine mouthrinse and stain prevention ADS system (0.5% sodium metabisulfite, 0.5% ascorbic acid) and compare it with a mouthrinse with the same composition but containing an additional 0.5% N-acetylcysteine. As a control group, a conventional mouthrinse was used with 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, or N-acetylcysteine.

[0107] material and method In this study, 18 male and female healthy volunteers aged 21-33 years were selected according to the principles of the Declaration of Helsinki. Patients with severe systemic diseases such as cardiovascular disease, diabetes, neurological or psychiatric syndromes, or infections were not included in the study, as was done in the study of Example 1. Patients who were unable to perform home oral hygiene maneuvers correctly, patients suffering from chronic periodontal disease with pockets larger than 4 mm, and subjects with fewer than 20 elements of the dental arch were also excluded from the study.

[0108] After enrolment, three bottles were prepared for each patient, which were completely identical, inert, opaque and had a volume of 250 ml, into which they were introduced. - Product D: mouthwash containing 0.2% chlorhexidine by weight, containing 0.5% sodium metabisulfite, 0.5% ascorbic acid by weight relative to the total volume of the mouthwash; Product E: As product D, but with the addition of 0.5% N-acetylcysteine ​​by weight relative to the total volume of the mouthwash; and Product F: A conventional mouthwash containing 0.2% chlorhexidine by weight based on the total volume of the mouthwash.

[0109] As in Example 1, the bottles were then given a neutral label and simply marked with an alphanumeric code that uniquely identified the assigned patient. To prevent the volunteer patients or operators selected for the evaluation from knowing which type of mouthwash they were testing, the reading key was kept unknown by the study organizers until the end of the evaluation. The test was then performed according to a "double-blind" basis.

[0110] Before the start of the study, all patients underwent a professional oral hygiene session, following the same method used in Example 1, to remove existing soft and hard plaque deposits and to bring to zero the periodontal indices analyzed: plaque index, gingival index, and stain index.

[0111] The 18 patients were divided into three groups of equal number and assigned to group D (product D), group E (product E) or group F (product F), and then two bottles of the corresponding product were assigned to each patient.

[0112] The patients performed a 14-day rinse cycle with the delivered product. This cycle involved rinsing for 1 minute with 15 ml of pure product to be performed twice a day. During the period of use of the mouthwash, the patients did not brush or use any other oral hygiene device. Finally, the patients were asked not to consume substances that can promote the deposition of pigments, such as coffee, tea, red wine or cigarette smoke, less than one hour before or after rinsing, and in any case to report possible daily intakes by a special form to be filled out.

[0113] The periodontal parameters PI and GI, as well as SI, were then measured after 7 and 14 days.

[0114] All data were collected by a single examiner in a special folder and then analyzed by an analysis program and a spreadsheet. Statistical analysis was performed by Student's T-test for independent data.

[0115] result All 18 selected volunteer patients completed the study. There were no interruptions to the protocol or delays in the evaluation sessions. The patients maintained a similar dietary regimen during the treatment cycles they underwent, with no substantial differences in the intake of coloring substances, which they were asked to report on the appropriate sheets delivered to them.

[0116] In the measurements carried out, the plaque index and gingival index values ​​showed similar trends for all types of mouthrinse (Figures 4 and 5) and were in full agreement with those highlighted in Example 1.

[0117] Regarding the stain index (SI) evaluation, the three mouthwashes also showed results consistent with those obtained in Example 1 (Figure 6).

[0118] Analysis of the mean values ​​showed a lower tendency of pigmentation of the tooth surface after treatment cycles with Products D and E compared to those with the control mouthwash (Product F). The differences already present after 7 days are even more pronounced after 14 days of treatment.

[0119] In addition to this, it was possible to confirm the trend already highlighted in Example 1 of a lower tendency to develop pigmentation in the patient group treated with product E, highlighting how the use of N-acetylcysteine ​​can enhance the effectiveness of the ADS system with sodium metabisulfite and ascorbic acid in counteracting dental pigmentation in patients undergoing chlorhexidine treatment.

[0120] Example 3 Research goal The aim of this study was to evaluate, using a larger subject group, the effectiveness of a 0.2% chlorhexidine mouthrinse and an anti-stain ADS system (0.5% sodium metabisulfite, 0.5% ascorbic acid) designed to counteract the occurrence of tooth staining, and to compare it with an innovative mouthrinse with the same composition but with an additional 0.5% N-acetylcysteine ​​by weight. As a control group, a conventional mouthrinse was used with 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, or N-acetylcysteine.

[0121] material and method Sixty male and female patients aged between 19 and 31 years were selected voluntarily in accordance with the principles of the Declaration of Helsinki at the IRCCS Galeazzi structure in Milan and in two freelance dental practices in Milan and Cinisello Balsamo. The 60 patients had undergone an antiseptic therapy with interruption of oral hygiene manipulations after surgery or extraction, periodontal therapy or implant therapy. Subjects who had serious systemic pathologies such as cardiovascular diseases, diabetes, neurological or psychiatric syndromes or infections and who declared allergies to the components of the products used were not included in the study. Patients who could not correctly perform oral hygiene manipulations at home were also excluded from the study.

[0122] After enrolment, three bottles were prepared for each patient, which were completely identical, inert, opaque and had a volume of 250 ml, into which they were introduced. - Product A: a mouthwash containing 0.2% chlorhexidine by weight, containing 0.5% sodium metabisulfite, 0.5% ascorbic acid, and 0.01% sodium DNA by weight relative to the total volume of the mouthwash; - Product B: As product A, but with the addition of 0.5% N-acetylcysteine ​​by weight relative to the total volume of the mouthwash; and Product C: A conventional mouthwash containing 0.2% chlorhexidine by weight based on the total volume of the mouthwash.

[0123] The bottles were then given a neutral label and simply marked with an alphanumeric code derived from the randomization software (Random Allocation Software®) that uniquely identifies the assigned patient. The reading key was kept unknown by the study sponsors until the end of the evaluation to prevent the volunteer patients or operators selected for the evaluation from knowing which type of mouthwash they were testing. The study was then conducted according to a "double-blind" criteria.

[0124] Prior to the start of the study, all patients underwent a professional oral hygiene session to remove existing soft and hard plaque deposits and to bring the analyzed periodontal index to zero. -Plaque Index (PI) for the amount of plaque present. - Gingival Index (GI) for the level of gingivitis. -Staining Index (SI) for the degree of pigmentation.

[0125] The plaque index, gingival index and stain index were analyzed according to the same methods used in Example 1.

[0126] Sixty patients were divided into three equal groups and assigned to group A (product A), group B (product B) or group C (product C), and then each patient was assigned two bottles of the corresponding product, sufficient to cover the entire period of use.

[0127] The patients performed a 14-day rinse cycle with the delivered product and regularly administered the prescribed chlorhexidine-based antiseptic treatment. This cycle included rinsing for 1 minute with 15 ml of pure product to be performed twice a day. During the period of mouthrinse use, the patients did not brush or use any other oral hygiene devices. Finally, the patients were asked not to consume substances that can promote pigment deposition, such as coffee, tea, red wine or cigarette smoke, less than one hour before or after rinsing, and in any case to report possible daily intake by a special form to be filled out.

[0128] The periodontal parameters PI and GI, in addition to SI, were then measured after 7 and 14 days. After 14 days, when surgical healing had allowed recovery, patients resumed their usual hygiene procedures.

[0129] All data were collected by a single examiner in a special data folder and then analyzed by analytical programs and spreadsheets. Statistical analysis was performed by ANOVA test for analysis of variance.

[0130] result Of the 60 volunteer patients selected and included in the study, 57 completed the study. Two patients (one in group A and one in group B) did not show up for the 7-day follow-up and one (group A) did not show up at the 14th day.

[0131] There were no interruptions to the protocol or delays in the evaluation sessions. Patients maintained similar dietary regimens during the treatment cycles they underwent, with no substantial differences in the intake of coloring substances, which they were asked to report on the appropriate sheets delivered to them.

[0132] In the measurements carried out, the plaque index and gingival index values ​​showed similar trends for all types of mouthrinse (Figures 7 and 8). This finding confirms the results of a previous study carried out and described in 1.

[0133] In particular, progressive plaque accumulation on tooth surfaces was in most cases accentuated during the observation period and was more pronounced in the presence of surgical sutures and flaps. Assessment of plaque volume with a periodontal probe showed, in fact, an almost invisible accumulation at week 1 (PI=0 or 1) and revealed by the periodontal probe at week 2 (some subjects with PI=2). However, from the collected data on PI and GI, no statistically significant differences emerged among the three mouthrinse formulations.

[0134] Despite the presence of plaque, as in many other studies involving chlorhexidine, when the gingival index was analyzed, no specific gingival inflammatory state was recognized in the three groups, except for mild reddening of the gingiva at marginal level in a few subjects (GI=1). This figure (Figure 8) is also in agreement with previous studies of the same formulation described in Example 1.

[0135] However, the stain index (SI) records showed significant differences when compared with the results previously obtained in Example 1, and as shown in Figure 9, the three mouthwashes indeed showed different trends in the occurrence of tooth staining.

[0136] The analysis on the mean SI values ​​indeed confirmed an effective pigmentation prevention for the mouthrinses with the ADS system (products A and B) compared to the control mouthrinse containing chlorhexidine without ADS (product C), which was statistically significant both at 7 and 14 days of observation.

[0137] In fact, it has been known for several years that ADS components are able to reduce tooth staining resulting from the use of antiseptics with chlorhexidine, without inhibiting their antiplaque activity. The action of the ADS system can be regulated by the amount of chromogenic substances introduced by the subject during the period of use, but good dietary management and observation of the doctor's prescription, together with the anti-staining system, can guarantee a clear anti-staining effect even under conditions of real clinical use. The difference in SI measurements between the two groups with the ADS system (products A and B) and the group without the ADS system (product C) was statistically significant both on the 7th and 14th day of treatment. Surprisingly, compared to the test carried out in Example 1 on a more limited number of subjects, in this test the mouthwash with the ADS / NAC staining prevention system (product B) showed a statistically significant tendency to less occurrence of staining compared to group A, even after only 14 days.

[0138] conclusion In light of what was collected and analyzed, it can be argued that the anti-discoloration system adopted for the analysis by this study (anti-discoloration system, ADS®) and introduced into the chlorhexidine mouthwash formulation supports the results of the literature (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 seems to be effective in counteracting the onset of tooth discoloration when compared to conventional mouthwashes with chlorhexidine.

[0139] From the data obtained from this study, it seems that the ADS® Stain Prevention System (Product A) is not able to completely eliminate the problem of tooth staining. Tooth staining is in fact related to several factors, firstly compliance with the prescription, but also the actions suggested by the doctor after dental treatment. However, by simply analyzing the staining index values ​​(Figure 9), it can be observed that the pigmentation substance obtained after 14 days of use of the mouthwash with the ADS system remains far below value 1 (poor pigmentation), while for the conventional mouthwash against CHX with alcohol it is stable between values ​​1 and 2 (obvious pigmentation) and even has a peak above value 2. Moreover, the difference in SI values ​​of the three mouthwashes is statistically significant in favor of the use of those containing the ADS system (Products A and B) both in the 7-day and 14-day observations.

[0140] With regard to the introduction of the novel NAC component into the mouthwash with ADS and DNA system (product B), according to the present invention, it was possible to observe the maintenance of the disinfecting efficacy of chlorhexidine and, in parallel, a further reduction in the degree of tooth staining for 7 days, especially for 14 days. In this test, the difference between mouthwash A (product A: CHX-ADS-DNA) and mouthwash B (product B: CHX-ADS-DNA-NAC) was statistically significant in favor of the association of product B of the present invention (CHX-ADS-DNA-NAC) immediately after 14 days of use. Example 1, carried out on healthy volunteers, showed the further benefit resulting from the addition of NAC to the mouthwash with chlorhexidine and ADS system in terms of the reduction of tooth staining.

[0141] On the other hand, in the present example, the difference in reduction of tooth staining appears more pronounced, to the point of being significant after 14 days of observation, as shown above.

[0142] To explain this difference between the results of example 1 and example 3, several hypotheses were formulated. First, example 3 was carried out on patients who had actually undergone dental treatments that required the interruption of oral hygiene procedures, extractions, implant surgery, gum surgery, to name a few. In this case, compared to healthy volunteers (example 1), the patients may be much more inclined to comply with the recommendations and, above all, to give up the urge to brush their teeth, which is not really verifiable when healthy volunteers are involved in the study. A greater accumulation of plaque and, consequently, of chromogens may amplify the benefit of the stain prevention system, especially in the areas that need it most, such as those with surgical wounds and sutures. The already significant number of patients included (group A=28, group B=29, group C=30) as well as the nature of patients actually undergoing clinical surgical treatment (and not healthy volunteers as in example 1) make this study particularly interesting and seems to confirm that the combination of ADS systems already known in the literature with N-acetyl-cysteine ​​(NAC) can enhance the anti-pigmentation action of the ADS alone under clinical conditions, with additional benefits in terms of patient compliance and good treatment results.

Claims

1. 1. N-acetylcysteine ​​for use in a method for treating a side effect of chlorhexidine in a patient undergoing chlorhexidine treatment, said side effect comprising pigmentation of the patient's tooth surface, dental mucosa, dental restoration, or dental prosthesis, and wherein said N-acetylcysteine ​​increases the effectiveness of at least one metabisulfite of an alkali or alkaline earth metal and ascorbic acid in counteracting said pigmentation of the tooth surface, dental mucosa, dental restoration, or dental prosthesis.

2. An oral care product comprising chlorhexidine, at least one metabisulfite salt of an alkali or alkaline earth metal, ascorbic acid, and N-acetylcysteine.

3. 3. The oral care product of claim 2, wherein the chlorhexidine is in the form of a salt or complex.

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

5. The oral care product of any one of claims 2 to 4, which is selected from the group consisting of mouthwashes, periodontal gels, and toothpastes.

6. 6. The oral care product of claim 5, wherein the product is a mouthwash and the amount of chlorhexidine ranges from 0.01% to 0.30% by weight based on the total volume of the mouthwash.

7. 7. An oral care product according to claim 5 or 6, wherein the product is a mouthwash and the amount of at least one metabisulfite of an alkali or alkaline earth metal ranges from 0.1% to 0.5% relative to the total volume of the mouthwash.

8. 8. An oral care product according to any one of claims 5 to 7, wherein the product is a mouthwash and the amount of ascorbic acid ranges from 0.1% to 1.0% by weight based on the total volume of the mouthwash.

9. 9. An oral care product according to any one of claims 5 to 8, wherein the product is a mouthwash and the amount of N-acetylcysteine ​​ranges from 0.01% to 1.0% by weight based on the total volume of the mouthwash.

10. 10. The oral care product of any one of claims 5 to 9, wherein the product is a mouthwash comprising, by weight relative to the total volume of the mouthwash, 0.01% to 0.30% chlorhexidine, 0.1% to 0.5% metabisulfite of at least one alkali or alkaline earth metal, 0.1% to 1.0% ascorbic acid, 0.01% to 1.0% N-acetylcysteine, 0.01% to 0.2% sodium DNA, and 0.05% to 1% of at least one polyvinylpyrrolidone-vinyl acetate copolymer.

11. 6. The oral care product of claim 5, wherein the product is a periodontal gel, the periodontal gel comprising 0.5% to 1.0% by weight of chlorhexidine based on the total volume of the periodontal gel.

12. An oral care product according to claim 5 or 11, wherein the product is a periodontal gel and the amount of N-acetylcysteine ​​ranges from 0.01% to 1.0% by weight relative to the total volume of the periodontal gel.

13. 6. The oral care product of claim 5, wherein the product is a toothpaste comprising 0.05% to 0.2% chlorhexidine by weight based on the total volume of the toothpaste.

14. 14. An oral care product according to claim 5 or 13, wherein the product is a toothpaste and the amount of N-acetylcysteine ​​ranges from 0.01% to 1.0% by weight relative to the total volume of the toothpaste.

15. An oral care product according to any one of claims 2 to 14 for use in the treatment of at least one pathology selected from the group consisting of gingivitis, dental plaque and periodontitis.

16. N-acetylcysteine ​​for use according to claim 1, wherein said treatment with chlorhexidine is carried out with an oral care product according to any one of claims 2 to 15.

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