Oral care product

Abstract

The present invention relates to the use of N-acetylcysteine to enhance the effect of pyrosulfite of alkali or alkaline earth metal and ascorbic acid in combating pigmentation of tooth surfaces, tooth mucosa, dental prostheses or dental prostheses of patients treated with chlorhexidine, and an oral care product comprising chlorhexidine, at least one pyrosulfite of a base 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 effect of alkali or alkaline earth metal metabisulfite and ascorbic acid in combating tooth pigmentation in patients receiving chlorhexidine treatment, and an oral care product comprising chlorhexidine, at least one alkali or alkaline earth metal metabisulfite, ascorbic acid and N-acetylcysteine. Background Art

[0002] Chemical plaque control is one of the most important steps in many dental treatments and in ordinary home oral hygiene practices. For this purpose, many active ingredients have been produced and marketed, mainly in the form of mouthwashes, toothpastes or sprays, among which we can mainly mention chlorhexidine, essential oils, fluorine derivatives, delmopinol. However, judging by the data that have appeared in the literature in recent years, chlorhexidine still represents the most effective product today in chemical plaque control, so much so that it is adequately defined as a reference active ingredient.

[0003] Chlorhexidine is a molecule belonging to the biguanide family and is known for its remarkable activity in chemical plaque and gingivitis control. Although it is related to the intrinsic properties of the different bacterial species, it is known to have a bacteriostatic effect when used in low concentrations, while it is mainly bactericidal when used in higher concentrations. Chlorhexidine has its own antimicrobial effect thanks to the establishment of chemical bonds with anionic groups (phosphate, sulfate, carboxyl) present at the cell wall level, which leads to a significant increase in cell permeability and a change in the osmotic balance.

[0004] By virtue of its cationic properties, chlorhexidine is also known to bind:

[0005] Oral mucosa;

[0006] ·Enamel hydroxyapatite,

[0007] The secondary film present on the tooth surface,

[0008] Salivary proteins, and

[0009] Bacteria and cellular polysaccharides of bacterial origin.

[0010] When bound to these oral structures, chlorhexidine can be slowly released while maintaining effective concentrations in the microorganisms for about 8-18 hours. This effect of maintaining effective concentrations of the active ingredient for hours after administration is called substantivity and indicates the potency of the active ingredient.

[0011] Despite the many advantages of chlorhexidine in terms of pharmacological activity, this active ingredient is also known to have some annoying side effects. Among the major known side effects, the most common is certainly represented by brown pigmentation, which appears on the tooth surface and mucous membranes, especially on resin restorations or prosthetic products, thus limiting its long-term use. In particular, the binding between the pigment and hydroxyapatite is believed to be mediated by the interaction between the anionic groups of the dye molecules and the cationic groups of chlorhexidine, and once they are combined, a brown film will be formed that is difficult to remove by simple brushing.

[0012] This side effect occurs primarily after long-term use of chlorhexidine, especially with higher concentrations of chlorhexidine in formulations (0.2% or even 1% in some oral gels).

[0013] Anti-staining additives in oral care products containing chlorhexidine are known to counteract this side effect. Among these additives, the ADS system consisting of ascorbic acid and sodium metabisulfite is known to cause less tooth pigmentation without affecting the antibacterial 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).

[0014] Applicants have found that, although the ADS system consisting of ascorbic acid and sodium metabisulfite shows a clear and significant effect in combating pigmentation of surfaces, mucosa, restorations and dental prosthetic products in patients receiving chlorhexidine treatment, without affecting its antimicrobial effect, there is still a need to enhance the anti-pigmentation effect of the system ADS, especially for long-term treatment. Summary of the invention

[0015] The object of the present invention is therefore to improve and enhance the effect of alkali or alkaline earth metal pyrosulfites and ascorbic acid in combating pigmentation (or staining) of surfaces, mucous membranes, restorations and dental prosthetic products in patients receiving chlorhexidine treatment, without affecting the antimicrobial effect of chlorhexidine itself, in particular for long-term treatments.

[0016] According to the present invention, the applicants have surprisingly found that this result can be achieved by using N-acetylcysteine, in combination with alkali or alkaline earth metal pyrosulfites and ascorbic acid, which has been shown to be able to enhance the effect of alkali or alkaline earth metal pyrosulfites and ascorbic acid in combating pigmentation of surfaces, mucosa, restorations and dental prosthetic products in patients receiving chlorhexidine treatment.

[0017] Thus, the present invention in its first aspect relates to N-acetylcysteine ​​for use in a method of treating a side effect of chlorhexidine in a patient receiving chlorhexidine treatment, wherein the side effect relates to pigmentation of a tooth surface, a dental mucosa, a dental restoration or a dental prosthetic product of said patient; wherein said N-acetylcysteine ​​enhances the effect of at least one alkali or alkaline earth metal pyrosulfite and ascorbic acid in combating pigmentation of said tooth surface, dental mucosa, dental restoration or dental prosthetic product.

[0018] Surprisingly, the combination of N-acetylcysteine ​​with alkali or alkaline earth metal pyrosulfites and ascorbic acid was found to enhance its contrast effect in chlorhexidine-induced pigmentation / staining of surfaces, mucosa, restorations and dental prosthetic products without affecting the antimicrobial effect of chlorhexidine itself, even for long-term treatment.

[0019] Thanks to the specific combination of N-acetylcysteine, at least one alkali or alkaline earth metal pyrosulfite, ascorbic acid and chlorhexidine, an oral care product can be provided, which has a series of properties that can improve the performance of oral care products based on the system ADS and thus expand its application range.

[0020] Therefore, in another aspect, the present invention also relates to an oral care product comprising chlorhexidine, at least one alkali or alkaline earth metal pyrosulfite, ascorbic acid and N-acetylcysteine.

[0021] Thanks to the presence of N-acetylcysteine, at least one alkali or alkaline earth metal pyrosulfite and ascorbic acid, the chlorhexidine-based product according to the invention is effective against oral pathologies, in particular plaque, without causing or seriously limiting the side effects of the long-term use of the active ingredient, which side effects concern pigmentation of surfaces, mucous membranes, restorations, and dental prosthetic products.

[0022] Thus, in another of its aspects, the present invention relates to an oral care product comprising chlorhexidine, at least one alkali or alkaline earth metal metabisulfite, ascorbic acid and N-acetylcysteine ​​for use in treating plaque in a patient in need thereof.

[0023] In fact, the Applicant has discovered that the use of N-acetylcysteine ​​according to the invention constitutes an innovative aspect of particular value for oral care products by improving and enhancing the effect of alkali or alkaline earth metal pyrosulfites and ascorbic acid in combating the pigmentation of surfaces, mucosa, restorations and dental prosthetic products in patients receiving antiplaque treatment with chlorhexidine. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In the attached picture:

[0025] Figure 1 The results of the 7-day and 14-day plaque index (PI) test for the groups using products A, B and C according to Example 1 are shown;

[0026] Figure 2 The 7-day and 14-day Gingival Index (GI) test results for the groups using Products A, B and C according to Example 1 are shown;

[0027] Figure 3 Shows the 7-day and 14-day Staining Index (SI) test results for groups using Products A, B, and C according to Example 1;

[0028] Figure 4 The results of the 7-day and 14-day plaque index (PI) test for the groups using products D, E and F according to Example 2 are shown;

[0029] Figure 5 shows the 7-day and 14-day Gingival Index (GI) test results for the groups using Products D, E and F according to Example 2; and

[0030] Figure 6 The 7-day and 14-day Stain Index (SI) test results for the groups using Products D, E and F according to Example 2 are shown.

[0031] Figure 7 The results of the 7-day and 14-day plaque index (PI) test for the groups using products A, B and C according to Example 3 are shown;

[0032] Figure 8 The 7-day and 14-day Gingival Index (GI) test results for the groups using Products A, B and C according to Example 3 are shown;

[0033] Fig. 9The results of the staining index (SI) test for groups using products A, B and C according to Example 3 at 7 and 14 days are shown. The three groups show different trends. The pigmentation caused by traditional mouthwash at 14 days is more than twice that of ADS mouthwash. ADS mouthwash and the "control" mouthwash (CHX, C group) showed significant differences at both T=7 days and T=14 days. At T=14 days, group B (CHX-ADS-NAC) showed a significantly lower SI value than group A (CHX-ADS). DETAILED DESCRIPTION

[0034] The present invention, in its first aspect, relates to the use of N-acetylcysteine ​​in a method for treating a side effect of chlorhexidine in a patient receiving chlorhexidine treatment, wherein the side effect relates to pigmentation of a tooth surface, a dental mucosa, a dental restoration or a dental prosthetic product of said patient, wherein said N-acetylcysteine ​​enhances the effect of at least one alkali or alkaline earth metal pyrosulfite and ascorbic acid in combating pigmentation of said tooth surface, dental mucosa, dental restoration or dental prosthetic product.

[0035] In fact, the Applicant has surprisingly found that the use of N-acetylcysteine, in combination with alkali or alkaline earth metal pyrosulfites and ascorbic acid, makes it possible to improve and enhance their effect in combating pigmentation / staining of surfaces, mucous membranes, restorations and dental prosthetic products in patients treated with chlorhexidine, without affecting the antimicrobial effect of chlorhexidine itself, which has shown a contrasting effect capable of increasing said pigmentation.

[0036] Thanks to the specific combination of N-acetylcysteine, at least one alkali or alkaline earth metal pyrosulfite, ascorbic acid and chlorhexidine, an oral care product can be provided which has a series of properties of oral care products improved based on the ADS system, thereby expanding its application range.

[0037] Therefore, in another aspect, the present invention also relates to an oral care product comprising chlorhexidine, at least one alkali or alkaline earth metal pyrosulfite, ascorbic acid and N-acetylcysteine.

[0038] The present invention may exhibit one or more aspects thereof, or one or more preferred features described below, which may be preferably combined with each other according to application requirements.

[0039] In this specification and the following claims, unless otherwise indicated, all numerical values ​​expressing quantities, parameters, percentages, etc. are preceded in each case by the term "about". In addition, all ranges of numerical values ​​include possible combinations of maximum and minimum values, and all possible intermediate ranges, as well as all possible combinations shown below.

[0040] In the present invention, the following expressions are used:

[0041] - "Weight % relative to total volume" of a product (e.g., a mouthwash) refers to the number of grams of a given component present in 100 milliliters (mL) of the product; and

[0042] - Unless otherwise indicated, "chlorhexidine" refers to the compound 1,1'-hexamethylenebis[5-(p-chlorophenyl)biguanide], its salts or complexes thereof.

[0043] Preferably, in the oral care product, the chlorhexidine is in the form of a salt or a complex. As chlorhexidine salts, for example, chlorhexidine digluconate or chlorhexidine diacetate can be used in the mouthwash according to the invention. Preferably, the oral care product according to the invention comprises chlorhexidine in the form of chlorhexidine digluconate.

[0044] Preferably, the oral care product further comprises sodium DNA. "Sodium DNA" in the present invention refers to the sodium salt of deoxyribonucleic acid, for example, obtained by extracting natural deoxyribonucleic acid from the gonadal tissue of male sturgeon and then purifying, depolymerizing and neutralizing with sodium ions.

[0045] Sodium DNA suitable for the purposes of the present invention is commercially available, for example, as Kalinat AW powder (Kalichem). In fact, the amount of sodium DNA used has been shown to be optimal for resisting the irritation of the oral mucosa by chlorhexidine, for protecting the oral mucosa and for healing possible wounds in the oral cavity, thereby also facilitating the correct nourishment of the oral mucosa itself.

[0046] In a preferred embodiment thereof, the oral care product is selected from the group consisting of mouthwash, periodontal gel and toothpaste.

[0047] Thus, in its first preferred embodiment, the oral care product according to the invention is a mouthwash.

[0048] Preferably, the 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, relative to the total volume of the mouthwash.

[0049] The mouthwash according to the invention also comprises at least one alkali or alkaline earth metal pyrosulfite.

[0050] The presence of at least one alkali or alkaline earth metal metabisulfite counteracts the disadvantage of dark pigmentation on the teeth (a side effect of chlorhexidine).

[0051] Preferably, the at least one alkali or alkaline earth metal metabisulfite is selected from the group consisting of sodium metabisulfite, potassium metabisulfite, calcium metabisulfite.More preferably, the mouthwash according to the invention comprises sodium metabisulfite.

[0052] Preferably, in the mouthwash according to the invention, the amount of at least one alkali or alkaline earth metal pyrosulfite ranges from 0.1% to 0.5%, more preferably from 0.15% to 0.3% by weight relative to the total volume of the mouthwash.

[0053] The mouthwash according to the invention further comprises ascorbic acid.

[0054] Preferably, in the mouthwash according to the present invention, the amount of ascorbic acid ranges from 0.1% to 1.0% by weight relative to the total volume of the mouthwash.

[0055] The presence of ascorbic acid also counteracts the disadvantage of dark pigmentation on the teeth (a side effect of chlorhexidine).

[0056] Preferably, the mouthwash according to the invention comprises ascorbic acid and at least one alkali or alkaline earth metal pyrosulfite, even more preferably 0.1% to 0.5% by weight of at least one alkali or alkaline earth metal pyrosulfite and 0.1% to 1.0% by weight of ascorbic acid relative to the total volume of the mouthwash.

[0057] This combination of components in these amounts has been shown to be particularly effective in combating the side effect of chlorhexidine in dark pigmentation on teeth and is the basis of a systemic ADS.

[0058] The mouthwash according to the invention further comprises N-acetylcysteine.

[0059] N-acetylcysteine, as will be demonstrated in the experimental part, has been shown to be able to enhance the effect of alkali or alkaline earth metal pyrosulfites and ascorbic acid in combating the disadvantages of brown pigmentation of surfaces, mucosa, restorations and dental prosthetic products in patients treated with chlorhexidine.

[0060] Preferably, in the mouthwash according to the present invention, the amount of N-acetylcysteine ​​used ranges from 0.01% to 1.0% by weight, more preferably from 0.2% to 0.7% by weight relative to the total volume of the mouthwash.

[0061] In addition to the above-mentioned components, the mouthwash according to the present invention preferably comprises trisodium citrate.

[0062] Preferably, in the mouthwash according to the present invention, the amount of trisodium citrate relative to the total volume of the mouthwash ranges from 0.8% to 2.0% by weight, more preferably from 0.8% to 1.2% by weight.

[0063] The presence of trisodium citrate in the amount described advantageously adjusts the pH of the mouthwash to an optimum value for its use.

[0064] In a preferred embodiment, the mouthwash according to the present invention comprises ascorbic acid and trisodium citrate. More preferably, the mouthwash according to the present invention comprises 0.1% to 1% by weight of ascorbic acid relative to the total volume of the mouthwash, and 0.8% to 2.0% by weight of trisodium citrate relative to the total volume of the mouthwash.

[0065] In fact, it was surprisingly found that the described combination of ascorbic acid and trisodium citrate is able to stabilize the mouthwash formulation according to the invention.

[0066] Preferably, the mouthwash according to the invention comprises at least one polyvinyl pyrrolidone-vinyl acetate copolymer. Polyvinyl pyrrolidone-vinyl acetate copolymers suitable for the purposes of the invention are commercially available, for example those available under the trade name (BASF SE) marketed under the name of BASF SE.

[0067] According to the invention, at least one polyvinyl pyrrolidone-vinyl acetate copolymer advantageously exerts a film-forming and antiplaque effect in a mouthwash.

[0068] Preferably, in the mouthwash according to the invention, the at least one polyvinyl pyrrolidone-vinyl acetate copolymer is present in an amount ranging from 0.05% to 1%, more preferably from 0.3% to 1% by weight relative to the total volume of the mouthwash.

[0069] Preferably, the mouthwash further comprises sodium DNA.

[0070] Sodium DNA advantageously acts to protect and heal the oral mucosa, further limiting some of the side effects of long-term use of chlorhexidine-based oral care products, which include changes in cell structure, including vacuolization, nuclear degeneration, and enlargement of intercellular spaces.

[0071] Preferably, in the mouthwash, the amount of sodium DNA relative to the total volume of the mouthwash ranges from 0.01% to 0.2%, more preferably, from 0.05% to 0.1%, by weight.

[0072] In its preferred embodiment, the oral care product according to the present 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 pyrosulfite, 0.1% to 1.0% by weight of ascorbic acid, 0.01% to 1.0% by weight, more preferably 0.2% to 0.7% of N-acetylcysteine, 0.01% to 0.2% by weight, more preferably 0.01% to 0.1% of sodium DNA, 0.05% to 1% by weight, more preferably 0.3% to 1% of at least one polyvinyl pyrrolidone-vinyl acetate copolymer.

[0073] The mouthwash according to the invention may contain one or more other possible components known in the art for oral hygiene solutions.

[0074] In particular, the mouthwash according to the present invention may further include one or more additives selected from the following group: sweeteners, flavoring agents, wetting agents, preservatives, emulsifiers, pH regulators, food colorings.

[0075] As a sweetener, the mouthwash according to the present invention may include, for example, xylitol, saccharin sodium, acesulfame potassium, sucralose, stevia extract.

[0076] As flavoring agents, the mouthwash according to the present invention may include, for example, mint, menthol, anethole, spearmint, cinnamon, cloves, eucalyptol.

[0077] As a humectant, the mouthwash according to the present invention may include, for example, propylene glycol, sorbitol, glycerin.

[0078] As preservatives, the mouthwash according to the present invention may include, for example, sodium benzoate, methylisothiazolinone.

[0079] As solubilizing surfactants, the mouthwash according to the present invention may include, for example, hydrogenated castor oil PEG40, poloxamer 407.

[0080] As a pH adjuster, the mouthwash according to the present invention may include, for example, sodium citrate, citric acid.

[0081] As a pigment, the mouthwash according to the present invention may include, for example, CI 19140, CIU 42090, CI 17200.

[0082] The mouthwashes according to the invention are conveniently prepared in a known manner in the form of a solution or suspension in a suitable solvent medium, preferably water.

[0083] According to a preferred embodiment, the mouthwash according to the present invention comprises the following components:

[0084] 1. Water

[0085] 2. Xylitol

[0086] 3. Propylene glycol

[0087] 4. Hydrogenated castor oil PEG 40

[0088] 5. Sodium acetate

[0089] 6. Ascorbic Acid

[0090] 7. Chlorhexidine digluconate

[0091] 8. Polyvinyl pyrrolidone-vinyl acetate copolymer

[0092] 9. N-Acetylcysteine

[0093] 10. DNA Sodium

[0094] 11. Flavoring

[0095] 12. Poloxamer 407

[0096] 13. Sodium metabisulfite

[0097] 14. Sodium hydroxide

[0098] 15. Sodium benzoate

[0099] 16. Acetic acid.

[0100] According to another preferred embodiment, the mouthwash according to the present invention comprises the following components:

[0101] 1. Water

[0102] 2. Xylitol

[0103] 3. Propylene glycol

[0104] 4. Hydrogenated castor oil PEG 40

[0105] 5. Ascorbic Acid

[0106] 6. Chlorhexidine digluconate

[0107] 7. Polyvinyl pyrrolidone-vinyl acetate copolymer

[0108] 8. N-Acetylcysteine

[0109] 9. DNA Sodium

[0110] 10. Flavoring

[0111] 11. Poloxamer 407

[0112] 12. Sodium metabisulfite

[0113] 13. Sodium citrate

[0114] 14. Citric acid

[0115] 15.CI42090

[0116] 16.CI17200.

[0117] In a further 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 present invention comprises the following components:

[0118] 1. Water

[0119] 2. Propylene glycol

[0120] 3. Hydroxyethyl Cellulose

[0121] 4. Polyvinyl pyrrolidone-vinyl acetate copolymer

[0122] 5. Hydrogenated castor oil PEG 40

[0123] 6. Chlorhexidine digluconate

[0124] 7. N-Acetylcysteine

[0125] 8. Sodium acetate

[0126] 9. DNA Sodium

[0127] 10. Menthol

[0128] 11. Peppermint Oil

[0129] 12. Acetic acid

[0130] 13. Sodium metabisulfite

[0131] 14. Ascorbic acid.

[0132] Preferably, the periodontal gel according to the present invention comprises 0.5% by weight to 1.0% by weight of chlorhexidine relative to the total volume of the periodontal gel.

[0133] Preferably, the periodontal gel according to the present invention comprises 0.01% to 1.0%, more preferably 0.2% to 0.7% by weight of N-acetylcysteine ​​relative to the total volume of the periodontal gel.

[0134] Preferably, the periodontal gel according to the invention comprises sodium DNA, even more preferably in an amount of at most 0.3% by weight, more preferably between 0.01% and 0.3% by weight relative to the total weight of the periodontal gel.

[0135] As previously mentioned, with respect to the mouthwash according to the present invention, sodium DNA advantageously plays a protective and healing role 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, nuclear degeneration and expansion of intercellular spaces.

[0136] In another further preferred embodiment, the oral care product according to the invention is a toothpaste.

[0137] According to a preferred embodiment, the toothpaste according to the present invention comprises the following components:

[0138] 1. Sorbitol

[0139] 2. Water

[0140] 3. Silicon dioxide (hydrated silicon dioxide)

[0141] 4. Glycerin

[0142] 5. Xylitol

[0143] 6. Cocamidopropyl Betaine

[0144] 7. Polyvinyl pyrrolidone-vinyl acetate copolymer

[0145] 8. Hydrogenated castor oil PEG 40

[0146] 9. N-Acetylcysteine

[0147] 10. Flavoring

[0148] 11. Chlorhexidine digluconate

[0149] 12. Carboxymethyl cellulose

[0150] 13. Ascorbic Acid

[0151] 14. Sodium metabisulfite

[0152] 15. DNA Sodium

[0153] 16. Saccharin Sodium

[0154] 17. Sodium benzoate

[0155] 18. Sodium citrate.

[0156] Preferably, the toothpaste according to the invention comprises from 0.05% to 0.2% by weight of chlorhexidine relative to the total volume of the toothpaste.

[0157] Preferably, the toothpaste according to the invention comprises ascorbic acid and at least one alkali or alkaline earth metal pyrosulfite, even more preferably 0.1% to 0.5% by weight of at least one alkali or alkaline earth metal pyrosulfite and 0.1% to 1.0% by weight of ascorbic acid relative to the total volume of the toothpaste.

[0158] As mentioned previously with regard to the mouthwash and periodontal gel according to the invention, the described combination of components is particularly effective in combating the side effects of chlorhexidine with regard to dark pigmentation on the teeth, being the basis of the ADS system.

[0159] Preferably, the toothpaste according to the invention comprises from 0.01% to 1.0%, more preferably from 0.2% to 0.7% by weight of N-acetylcysteine ​​relative to the total volume of the toothpaste.

[0160] Preferably, at least one inorganic fluoride may optionally be present in the toothpaste according to the invention.

[0161] Preferably, in the toothpaste according to the present invention, the amount of sodium DNA relative to the total volume of the toothpaste ranges from 0.01% to 0.05%.

[0162] As previously mentioned, with respect to the mouthwash according to the present invention, sodium DNA advantageously plays a protective and healing role 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, nuclear degeneration and expansion of intercellular spaces.

[0163] Thanks to the presence of N-acetylcysteine, at least one alkali or alkaline earth metal pyrosulfite and ascorbic acid, the chlorhexidine-based product according to the invention is effective against oral pathologies, in particular bacterial plaque, without causing or seriously limiting the long-term use of the active ingredient with side effects related to pigmentation of surfaces, mucosa, restorations and dental prosthetic products.

[0164] Thus, in another of its aspects, the present invention relates to an oral care product comprising chlorhexidine, at least one alkali or alkaline earth metal metabisulfite, ascorbic acid and N-acetylcysteine ​​for use in the treatment of plaque in a patient in need thereof.

[0165] In fact, the Applicant has discovered that the use of N-acetylcysteine ​​according to the invention constitutes an innovative aspect of particular value for oral care products, by improving and enhancing the effect of alkali or alkaline earth metal pyrosulfites and ascorbic acid in combating pigmentation of surfaces, mucosa, restorations and dental prosthetic products in patients receiving antiplaque treatment with chlorhexidine.

[0166] Therefore, in its preferred aspect the present invention relates to the use of N-acetylcysteine ​​in a patient receiving chlorhexidine treatment according to the first aspect of the present invention, wherein the chlorhexidine treatment is carried out with an oral care product according to the present invention.

[0167] Experimental Section

[0168] The present invention will now be described by way of some embodiments, which should be understood to be for illustrative and non-limiting purposes.

[0169] Example 1

[0170] Research objectives

[0171] The aim of this study was to evaluate the efficacy of a 0.2% chlorhexidine mouthwash containing 0.01% sodium DNA by weight and an anti-pigmentation ADS system (0.5% sodium metabisulfite by weight, 0.5% ascorbic acid by weight) and compare it with a mouthwash with the same composition but containing an additional 0.5% N-acetylcysteine ​​by weight. A conventional mouthwash containing 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, sodium DNA or N-acetylcysteine ​​was used as a control group.

[0172] Materials and methods

[0173] This study was conducted in accordance with the principles of the Declaration of Helsinki and included 15 healthy male and female volunteers aged 19-29 years. Patients with severe systemic diseases (e.g., cardiovascular disease, diabetes, neurological or psychiatric syndromes, or infectious diseases) were not included in the trial. In addition, patients who were unable to perform home oral hygiene correctly, patients with chronic periodontal disease and periodontal pockets larger than 4 mm, and subjects with fewer than 20 elements in the dental arch were also excluded from the study.

[0174] After enrollment, prepare 3 identical, inert, opaque bottles of 250 mL for each patient and place the following:

[0175] - Product A: a 0.2% by weight chlorhexidine mouthwash containing 0.5% by weight of sodium metabisulfite, 0.5% by weight of ascorbic acid and 0.01% by weight of sodium DNA, relative to the total volume of the mouthwash;

[0176] - Product B: similar to Product A, but with an additional 0.5% by weight of N-acetylcysteine ​​relative to the total volume of the mouthwash; and

[0177] - Product C: a conventional mouthwash containing 0.2% by weight of chlorhexidine relative to the total volume of the mouthwash.

[0178] The neutrally labeled bottles were then simply marked with an alphanumeric code that uniquely identified the patient to whom they were assigned. The trial organizers kept the read key secret until the end of the evaluation to prevent the volunteer patients or operators selected for the evaluation from becoming aware of which type of mouthwash they were testing. The trial was then conducted according to "double-blind" criteria.

[0179] Before the start of the study, all patients underwent professional oral hygiene procedures to remove existing mild or severe plaque deposits and to zero the periodontal indices to be analyzed:

[0180] - Plaque index (PI), which indicates the amount of plaque present (Loe H., Silness J: Periodontal disease in pregnancy. Prevalence and severity. Acta odontologica Scandinavica. 1963; 21: 533-551).

[0181] - Gingival index (GI), which indicates the degree of gingival inflammation (Silness J, Loe H: Periodontal disease inpregnancy.

[0182] II.Correlation between oral hygiene and periodontal conditions.ActaodontologicaScandinavica.1964;22:121-135).

[0183] - Staining index (SI), indicating the degree of pigmentation (Lobene RR: Effect of dentifrices on tooth stains with controlled brushing. J. Am. Dent. Assoc. 1968; 77: 849-855, Soskolne W. A., 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:

[0184] 32-38.).

[0185] The 15 patients were divided into 3 groups of equal number and allocated to Group A (Product A), Group B (Product B), or Group C (Product C), and then 2 bottles of the corresponding product were distributed to each patient.

[0186] The patients performed a 14-day mouthwash cycle using the delivered product. The cycle consisted of rinsing the mouth with 15 mL of pure product for one minute, twice a day. During the use of the mouthwash, the patients did not brush their teeth or use any other oral hygiene tools. Finally, the patients were asked not to consume substances that can cause pigmentation, such as coffee, tea, red wine or cigarettes, within one hour before and after the mouthwash, and in any case to report the substances they may have consumed during the day by filling in a special form.

[0187] After 7 and 14 days, the periodontal parameters PI and GI were measured in addition to SI.

[0188] All data were collected by a single examiner in dedicated folders and then analyzed using analysis programs and spreadsheets. Statistical analysis was performed using the Student's T test for unpaired data.

[0189] result

[0190] All 15 selected volunteer patients completed the study. There were no interruptions in the procedure and no delays in the assessment sessions. The patients maintained a similar dietary regimen during the treatment cycles they underwent, and in particular there were no substantial differences in the intake of coloring substances that they were asked to report on the corresponding delivery slips.

[0191] Among the measurements performed, the values ​​of plaque index and gingival index showed similar trends in all types of mouthwashes ( Figure 1 and Figure 2 In particular, a progressive accumulation of plaque was evident on the tooth surfaces in most cases. Evaluation of the amount of plaque with the aid of a periodontal probe showed that the accumulation was virtually invisible in the first week (PI = 0 or 1) and more visible in the second week (PI = 2).

[0192] Regarding the analysis of the gingival index, despite the above-mentioned accumulation of plaque, no specific gingival inflammation status was found except for slight gingival redness at the marginal level (GI=1) in a few subjects.

[0193] This confirms that the chlorhexidine in products A and B maintained a significant and sustained antibacterial effect throughout the treatment period.

[0194] During the evaluation of the staining index (SI), the three mouthwashes showed different results in the development of tooth pigmentation ( Figure 3 ).

[0195] The analysis of the mean values ​​showed a trend towards lower pigmentation of the tooth surface after the treatment period with products A and B compared to the control mouthwash (product C). This difference was already present after 7 days and was particularly evident in the groups treated with products A and B compared to the group treated with product C after 14 days of treatment.

[0196] Furthermore, a lower tendency for the development of pigmentation was found in all patients in the group of patients treated with Product B, which highlights how the use of N-acetylcysteine ​​enhances the effect of the ADS system with sodium metabisulfite and ascorbic acid in combating tooth pigmentation in patients treated with chlorhexidine.

[0197] Example 2

[0198] Research objectives

[0199] The purpose of this study was to evaluate the efficacy of a 0.2% chlorhexidine mouthwash and an anti-pigmentation ADS system (0.5% by weight sodium metabisulfite, 0.5% by weight ascorbic acid) and compare it to a mouthwash with the same ingredients but containing an additional 0.5% by weight N-acetylcysteine. A conventional mouthwash containing 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, or N-acetylcysteine ​​was used as a control group.

[0200] Materials and methods

[0201] This study was conducted in accordance with the principles of the Declaration of Helsinki, and 18 healthy male and female volunteers aged 21-33 years were selected. As in the study of Example 1, patients with severe systemic diseases (such as cardiovascular disease, diabetes, neurological or psychiatric syndromes or infectious diseases) were not included in the trial. In addition, patients who were unable to perform home oral hygiene correctly, patients with chronic periodontal disease and periodontal pockets greater than 4 mm, and subjects with less than 20 elements in the dental arch were also excluded from the study.

[0202] After enrollment, prepare 3 identical, inert, opaque bottles of 250 mL for each patient and place the following:

[0203] - Product D: 0.2% by weight of chlorhexidine mouthwash containing 0.5% by weight of sodium metabisulfite and 0.5% by weight of ascorbic acid relative to the total volume of the mouthwash;

[0204] - Product E: similar to Product D, but with an additional 0.5% by weight of N-acetylcysteine ​​relative to the total volume of the mouthwash; and

[0205] - Product F: a conventional mouthwash containing 0.2% by weight of chlorhexidine relative to the total volume of the mouthwash.

[0206] As in Example 1, the neutrally labeled bottles were then simply labeled with an alphanumeric code that uniquely identified the patient to whom they were assigned. The trial organizers kept the read key secret until the end of the evaluation to prevent the volunteer patients or operators selected for the evaluation from becoming aware of which type of mouthwash they were testing. The trial was then conducted according to "double-blind" criteria.

[0207] Before the start of the study, all patients received professional oral hygiene procedures to remove existing mild or severe plaque deposits and to zero the periodontal indices to be analyzed: plaque index, gingival index, and staining index (according to the same method used in Example 1).

[0208] The 18 patients were divided into 3 groups of equal number and allocated to Group D (Product D), Group E (Product E), or Group F (Product F), and then 2 bottles of the corresponding product were distributed to each patient.

[0209] The patients performed a 14-day mouthwash cycle using the delivered product. The cycle consisted of rinsing the mouth with 15 mL of pure product for one minute, twice a day. During the use of the mouthwash, the patients did not brush their teeth or use any other oral hygiene tools. Finally, the patients were asked not to consume substances that can cause pigmentation, such as coffee, tea, red wine or cigarettes, within one hour before and after the mouthwash, and in any case to report the substances they may have consumed during the day by filling in a special form.

[0210] After 7 and 14 days, the periodontal parameters PI and GI were measured in addition to SI.

[0211] All data were collected by a single examiner in dedicated folders and then analyzed using analysis programs and spreadsheets. Statistical analysis was performed using the Student's T test for unpaired data.

[0212] result

[0213] All 18 selected volunteer patients completed the study. There were no interruptions in the procedure and no delays in the assessment sessions. The patients maintained a similar dietary regimen during the treatment cycles they received, and in particular there were no substantial differences in the intake of coloring substances that they were asked to report on the corresponding delivery slips.

[0214] Among the measurements performed, the values ​​of plaque index and gingival index showed similar trends in all types of mouthwashes ( Figure 4 and Figure 5 ), which is completely consistent with the situation shown in Example 1.

[0215] Also regarding the evaluation of the staining index (SI), the results shown by the three mouthwashes were consistent with those obtained in Example 1 ( Figure 6 ).

[0216] The analysis of the mean values ​​showed a trend towards lower pigmentation on the tooth surface after the treatment period with products D and E compared to the control mouthwash (product F). This difference was already present after 7 days and was particularly evident after 14 days of treatment.

[0217] Furthermore, it could be demonstrated that the group of patients treated with Product E had a lower tendency to develop pigmentation (already highlighted in Example 1), which highlights how the use of N-acetylcysteine ​​enhances the effect of the ADS system with sodium metabisulfite and ascorbic acid in combating tooth pigmentation in patients receiving chlorhexidine treatment.

[0218] Example 3

[0219] Research objectives

[0220] The aim of this study was to evaluate the efficacy of a 0.2% chlorhexidine mouthwash and an anti-staining ADS system (0.5% by weight sodium metabisulfite, 0.5% by weight ascorbic acid) in combating the development of tooth staining in a larger group of subjects and to compare it with an innovative mouthwash with the same composition but containing an additional 0.5% by weight of N-acetylcysteine. A conventional mouthwash containing 0.2% chlorhexidine but without sodium metabisulfite, ascorbic acid, or N-acetylcysteine ​​was used as a control group.

[0221] Materials and methods

[0222] Sixty male and female patients aged between 19 and 31 years were selected on a voluntary basis at the IRCCS Galeazzi institution in Milan and at two liberal dental clinics in Milan and Cinisello Balsamo, in accordance with the principles of the Declaration of Helsinki. All 60 patients received antimicrobial treatment and suspended oral hygiene practices after surgery or tooth extraction, periodontal or implant treatment. Subjects with severe systemic diseases (e.g. cardiovascular disease, diabetes, neurological or psychiatric syndromes or infectious diseases) and those who declared hypersensitivity to the components of the products used were not included in the trial. In addition, patients who were unable to perform home oral hygiene practices correctly were excluded from the study.

[0223] After enrollment, prepare 3 identical, inert, opaque bottles of 250 mL for each patient and place the following:

[0224] - Product A: a 0.2% by weight chlorhexidine mouthwash containing 0.5% by weight of sodium metabisulfite, 0.5% by weight of ascorbic acid and 0.01% by weight of sodium DNA, relative to the total volume of the mouthwash;

[0225] - Product B: similar to Product A, but with an additional 0.5% by weight of N-acetylcysteine ​​relative to the total volume of the mouthwash; and

[0226] - Product C: a conventional mouthwash containing 0.2% by weight of chlorhexidine relative to the total volume of the mouthwash.

[0227] The neutral-label bottles are then simply labeled with an alphanumeric code that uniquely identifies the patient to whom they were assigned (via the Random Allocation Software). )). The trial organizers kept the access key secret until the end of the evaluation to prevent the volunteer patients or operators selected for the evaluation from realizing which type of mouthwash they were testing. The trial was then conducted according to the "double-blind" standard.

[0228] Before the start of the study, all patients underwent professional oral hygiene procedures to remove existing soft and hard plaque deposits and to zero the periodontal indices to be analyzed:

[0229] - Plaque Index (PI), which indicates the amount of plaque present.

[0230] - Gingival Index (GI), which indicates the degree of gum inflammation.

[0231] -Staining Index (SI), which indicates the degree of pigmentation.

[0232] The plaque index, gingival index and staining index were analyzed according to the same method used in Example 1.

[0233] The 60 patients were divided into 3 groups of equal number and allocated to Group A (Product A), Group B (Product B), or Group C (Product C), and then 2 bottles of the corresponding product were distributed to each patient, which was enough to cover the entire usage period.

[0234] The patients used the delivered product for a 14-day mouthwash cycle, along with their regularly prescribed chlorhexidine-based antimicrobial therapy. The cycle consisted of rinsing the mouth with 15 mL of the pure product for one minute, twice a day. During the use of the mouthwash, the patients did not brush their teeth or use any other oral hygiene tools. Finally, the patients were asked not to consume substances that could cause pigmentation, such as coffee, tea, red wine or cigarettes, within one hour before and after the mouthwash, and in any case to report the substances they might have consumed during the day by filling in a special form.

[0235] After 7 and 14 days, the periodontal parameters PI and GI were measured in addition to SI. After 14 days, if surgical healing was able to recover, the patients resumed their normal hygiene routine.

[0236] All data were collected by a single examiner in dedicated folders and then analyzed using analysis programs and spreadsheets. Statistical analysis was performed using the ANOVA test.

[0237] result

[0238] Of the 60 volunteer patients selected for the trial, 57 completed the study. Two patients (1 in group A and 1 in group B) did not show up at the 7-day follow-up, and one (group A) did not show up at the 14-day follow-up.

[0239] There were no interruptions in the procedure and no delays in the assessment sessions. The patients maintained a similar dietary regimen during the treatment cycles they received, and in particular there were no substantial differences in the intake of coloring substances that they were asked to report on the corresponding delivery slips.

[0240] Among the measurements performed, the values ​​of plaque index and gingival index showed similar trends in all types of mouthwashes ( Figure 7 and Figure 8 ). This finding confirms the results of experiments previously performed and described in Example 1.

[0241] In particular, during the observation period, a progressive accumulation of plaque was evident on the tooth surfaces in most cases, which was more pronounced in the presence of surgical sutures and flaps. The evaluation of the amount of plaque with the aid of a periodontal probe showed that the accumulation was virtually invisible in the first week (PI = 0 or 1), whereas it became evident with the periodontal probe in the second week (PI = 2 in several subjects). However, from the data collected in relation to PI and GI, no statistically significant differences were found between the three mouthwash formulas.

[0242] Similar to many other studies on chlorhexidine, despite the presence of plaque, no particular gingival inflammation was found in any of the three groups when analyzing the gingival index, except for a few subjects who showed slight gingival redness at the marginal level (GI = 1). Figure 8 ) is also consistent with previous experiments on the same formulation described in Example 1.

[0243] However, compared with the results obtained in Example 1 above, the staining index (SI) reported showed significant differences: the three mouthwashes actually showed different trends in the development of tooth pigmentation, such as Fig. 9 shown.

[0244] The analysis of the mean SI values ​​indeed confirmed that the mouthwashes equipped with the ADS system (products A and B) had an effective anti-pigmentation effect compared to the control mouthwash containing chlorhexidine without ADS (product C), which was statistically significant both at the 7-day observation and at the 14-day observation.

[0245] In fact, it has been known for many years that the ADS ingredient is able to reduce tooth pigmentation caused by the use of antibacterial agents containing chlorhexidine without inhibiting its anti-plaque activity. The effect of the ADS system will be affected by the amount of color-causing substances ingested by the subject during use, but good dietary control and compliance with the doctor's prescription, together with the anti-pigmentation system, can guarantee a significant anti-staining effect even under the conditions of actual clinical use. The difference in SI measurements between the two groups using the ADS system (products A and B) and the group not using the ADS system (product C) was statistically significant at both 7 and 14 days. Surprisingly, compared with the test conducted on a more limited number of subjects in Example 1, in this test, the mouthwash containing the ADS / NAC anti-staining system (product B) showed a trend towards less pigmentation, which was statistically significant compared to group A even after only 14 days.

[0246] in conclusion

[0247] Based on the results collected and analyzed, it can be said that the anti-staining system (anti-discoloration system, ) confirmed 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 appears to be effective in combating the occurrence of tooth pigmentation compared with traditional chlorhexidine mouthwashes.

[0248] From the data obtained in this study, The anti-staining system (product A) does not seem to completely eliminate the problem of tooth pigmentation. Tooth staining is actually related to multiple factors, first of all the compliance with the prescription, but also to the behavior recommended by the doctor after the dental treatment. However, by simply analyzing the staining index value ( Fig. 9) It can be observed that the pigmentation entity obtained after 14 days of use of the mouthwash with the ADS system is still well below value 1 (hypopigmentation), while for the conventional CHX alcohol mouthwash it is between value 1 and value 2 (obvious pigmentation), with the peak value even exceeding value 2. Moreover, the differences between the SI values ​​of the three mouthwashes at 7 and 14 days of observation are statistically significant, supporting the use of mouthwashes containing the ADS system (products A and B).

[0249] With the introduction of the novel NAC component in a mouthwash containing an ADS and DNA system (Product B), according to the present invention, it was observed that the antibacterial efficacy of chlorhexidine was maintained and, at the same time, the extent of tooth pigmentation was further reduced at day 7, surpassing all groups at day 14. In this trial, the difference between mouthwash A (Product A: CHX-ADS-DNA) and mouthwash B (Product B: CHX-ADS-DNA-NAC) was statistically significant only after 14 days of use, supporting the relevance of Product B (CHX-ADS-DNA-NAC) according to the present invention. Example 1, performed on healthy volunteers, shows that the addition of NAC to a mouthwash containing chlorhexidine and an ADS system provides a further benefit in reducing tooth pigmentation.

[0250] On the other hand, in this example, the difference in the reduction of tooth staining was more pronounced, reaching a significant level after 14 days of observation as previously mentioned.

[0251] Several hypotheses have been proposed to explain the differences between the results of Examples 1 and 3. First, Example 3 was conducted in real patients undergoing dental treatments that required a break from oral hygiene procedures (e.g. tooth extractions, implant surgery, gum surgery). In this case, the patients might have been more inclined to comply with the recommendations than the healthy volunteers (Example 1) and, most importantly, they might have given up the temptation to brush their teeth, which cannot really be verified in studies involving healthy volunteers. The large accumulation of plaque, and therefore of chromogens, might have magnified the benefits of the anti-staining system, especially in those areas where it is most needed, such as those with surgical wounds and sutures. The large number of patients that have been included (Group A = 28, Group B = 29, Group C = 30) and the nature of the patients undergoing actual clinical surgical treatments (not healthy volunteers as in Example 1) make this trial particularly interesting: it seems to confirm what is known in the literature that the combination of the ADS system with N-acetylcysteine ​​(NAC) can enhance the anti-staining effect of ADS alone in clinical conditions, with further benefits in terms of patient compliance and good treatment results.

Claims

1. N-acetylcysteine ​​for use in a method of treating a side effect of chlorhexidine in a patient receiving chlorhexidine therapy, wherein the side effect relates to pigmentation of a tooth surface, a dental mucosa, a dental restoration or a dental prosthetic product of the patient, wherein the N-acetylcysteine ​​enhances the effect of at least one alkali or alkaline earth metal pyrosulfite and ascorbic acid in combating pigmentation of the tooth surface, dental mucosa, a dental restoration or a dental prosthetic product.

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

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

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

5. The oral care product according to any one of claims 2 to 4, selected from the group consisting of: mouthwash, periodontal gel and toothpaste.

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

7. The oral care product according to claim 5 or 6, wherein the product is a mouthwash and the amount of at least one alkali or alkaline earth metal pyrosulfite is in the range of 0.1% to 0.5% relative to the total volume of the mouthwash.

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 relative to the total volume of the mouthwash.

9. The 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 relative to the total volume of the mouthwash.

10. An oral care product according to any one of claims 5 to 9, wherein the product 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 pyrosulfite, 0.1% to 1.0% by weight of ascorbic acid, 0.01% to 1.0% by weight of N-acetylcysteine, 0.01% to 0.2% by weight of sodium DNA, 0.05% to 1% by weight of at least one polyvinylpyrrolidone-vinyl acetate copolymer.

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

12. The 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. The oral care product according to claim 5, wherein the product is a toothpaste comprising 0.05% by weight to 0.2% by weight of chlorhexidine relative to the total volume of the toothpaste.

14. The 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 condition selected from the group consisting of gingivitis, bacterial plaque and periodontitis.

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

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