Oral preparation for reducing dentin erosion, oral composition and use of the preparation

Abstract

The present invention describes a preparation that reduces dentinal erosion caused by acids for mouth care compositions. The active ingredient PHMB, up until now known for its antimicrobial activity, has a new function.

Description

"Oral preparation for reducing dentin erosion, oral composition comprising the oral preparation and use of said preparation" Field of Invention

[001] The present invention pertains to the field of human needs, specifically to the field of personal hygiene, and relates to a preparation containing PHMB (polyhexamethylene biguanide) + silanol + fluoride ions. This preparation and its components are used for the prevention of dentin erosion caused by acids. History of the Invention

[002] Dental erosion caused by intrinsic or extrinsic acids is a progressive and irreversible lesion of hard dental tissue, enamel, dentin and / or cementum resulting from a chemical process that does not involve bacterial action. Unlike dental caries, erosion occurs in locations without bacterial biofilm, since this protects the dental structure from the erosive process. Dental erosion can be caused by acids of extrinsic origin, such as acidic foods or drinks and medications, or intrinsic origin, such as stomach liquids or gases, causing the loss of mineralized tissue and potentially stimulating dentin hypersensitivity.

[003] Since dental erosion is a chemical process between an acid and the dental element, some chemical factors directly influence the erosive potential of acids. The main factor influencing demineralization by erosion is the pH of the solution or food. Another factor is the presence of ions in the solution, as these determine the strength with which the dissolution of the tooth mineral occurs. The dissolution gradient of ions depends on the degree of enamel saturation in relation to the oral environment. If a given solution has a lower pH, or a lower concentration of calcium and phosphate, it will be undersaturated in relation to the tooth. This Petition 870200140709, dated 09 / 11 / 2020, page 13 / 30 2 / 14 solution has the ability to react with enamel and cause demineralization of the tooth.

[004] Dental erosion lesions occur due to non-carious, long-lasting, and frequent chemical processes, without bacterial involvement. Exposure of the tooth to a pH lower than the critical level for enamel (5.5) can dissolve hydroxyapatite crystals, depending on the concentrations of calcium and phosphate ions in saliva and the availability of fluoride to act in the remineralization process.

[005] Dental erosion resulting from acid attack can severely affect the layers of tooth materials such as enamel and dentin, leading to exposure of the dental pulp. Dentin erosion occurs when the dentin is affected after the loss of enamel or cementum of the tooth. In this document, we treat dentin erosion as part of total dental erosion.

[006] Intrinsic dental erosion can be subdivided according to the degree of severity: a) Superficial (class I) - affects only the surface of the enamel; b) Localized (class II) - affects less than 1 / 3 of the dentin and c) Extensive (class III) - destruction of more than 1 / 3 of the dentin.

[007] The most commonly observed signs and symptoms of dental erosion are dentin hypersensitivity, enamel wear presenting a smooth and shiny appearance, absence of pigmentation, and aesthetic impairment. In more severe cases, diastema formation, alteration of the vertical dimension of occlusion, muscle pain caused by occlusal instability, and temporomandibular joint dysfunction may occur.

[008] When enamel is lost or the root is exposed due to gum recession, dental erosion can reach the dentin. Dentin tissue loss by erosion is not a simple superficial process. The minerals of the peritubular dentin are initially lost, and the tubules are enlarged. Petition 870200140709, dated 09 / 11 / 2020, page 14 / 30 3 / 14

[009] Subsequently, a superficial layer of demineralized organic matrix (DOM) is detectable. The DOM is able to prevent ionic diffusion into and out of the demineralized area, modulating the progression of mineral loss. However, the DOM can be affected by enzymes or by chemical degradation, in the case of acid, and thus accelerate the process of dentin loss by dentin erosion.

[010] Treatment of dental erosion

[011] In the state of the art, it is found that the prevention of dental erosion should be done by reducing the frequency and severity of acid attack. Many authors recommend the use of fluoride as a remineralizing agent to prevent dental erosion. The appropriate treatment depends on the severity of the lesions, and may include weekly topical fluoride applications, the use of fluoride varnishes, desensitizing agents, and, when the loss of dental structure is significant, restorative treatment becomes necessary.

[012] The action of fluoride and other active ingredients on dentin erosion

[013] An acidic solution that is ingested and comes into contact with the teeth readily dissolves calcium fluoride and removes traces of topical fluoride treatment, thus making the action of this agent in preventing erosion unlikely and limited. Several authors report the formation of a CaF₂ layer on the enamel surface after topical fluoride application. The calcium fluoride layer provides additional minerals to be dissolved during the acid attack, and thus the acids will first have to demineralize this layer, and subsequently demineralize the underlying dental enamel. In this way, enamel demineralization is delayed, but not completely prevented.

[014] New products and methods have been studied to increase calcium and phosphate supersaturation in saliva and / or biofilm, which helps in the prevention of dental erosion. Petition 870200140709, dated 09 / 11 / 2020, page 15 / 30 4 / 14

[015] Other active ingredients, such as biguanides and green tea, have been studied for their inhibitory action on DOM-degrading enzymes, such as matrix metalloproteinases (MMPs), cathepsins, and collagenases. There are also studies of ingredients that contribute to the regulation of collagen biosynthesis, such as silanols. Collagen is extremely important in DOM and consequently for dentin.

[016] Due to silanol's ability to regulate collagen biosynthesis, we hypothesize that it could act in a complementary way in the recovery of demineralized organic matrix (DOM) in combination with enzyme inhibitors and fluoridated compounds.

[017] PI200724469: This document describes an antiseptic composition containing polybiguanide with acidic radicals, such as carboxylic or phosphoric, which reduces caries, bad breath, and other oral diseases. It also shows the antimicrobial action of polybiguanide and uses high concentrations of this ingredient ranging from 1 to 20% and of fluorides ranging from 1 to 10%. It does not mention the composition's effect on preventing dentin erosion caused by acids.

[018] PI0614927: This document describes an antimicrobial composition comprising at least one component from group a (antimicrobial), one from group b (second antimicrobial) and optionally from group c (antiesthetic or fluoropolymer). PHMB is cited as an antimicrobial used in concentrations ranging from 0.1 to 99.9% of the total weight of the composition, values ​​different from those presented in the present invention. It does not mention the effect of the composition on the prevention of dentin erosion caused by exposure to acids.

[019] PI0702507: This document describes an antiseptic varnish with polybiguanide that reduces caries and other oral diseases. The varnish composition employs acrylates, plasticizers, and polybiguanide in concentrations of 3 to 80% of the formulation, which hardens after application to the tooth surface, characteristic Petition 870200140709, dated 09 / 11 / 2020, page 16 / 30 5 / 14 very different from the present invention to be described below. Furthermore, the document does not mention the use of polybiguanide in the prevention of dentin erosion caused by acid attack.

[020] US2008 / 0247972: This document describes a mouthwash to reduce or prevent halitosis, facilitate the removal of tongue coating, and decrease the concentration and formation of volatile sulfur compounds. It includes PHMB as one of the bactericides from a large list of antibacterial agents that could be used in this mouthwash. The document does not mention the use of PHMB in preventing dentin erosion caused by acid attack.

[021] Demineralized organic matrix (DOM) can be affected by enzymes available in the oral cavity, such as matrix metalloproteinases (MMPs) that mediate the hydrolysis of virtually all extracellular matrix molecules, including collagen. MMP-8 has been found to be the most common collagenase in human dentin; MMP-2 and MMP-9 have also been found in this tissue. However, DOM degradation in vivo does not depend solely on the action of MMPs. Other proteases suggest involvement in this process, such as cysteine ​​cathepsins. Cysteine ​​cathepsins are derived from the dental pulp by dentin fluid and can cleave the C-terminal telopeptide of type I collagen, possibly exposing the collagenase cleavage site after exposure to acids. Acidic pH activates cysteine ​​cathepsins, which in turn activate MMPs, resulting in DOM degradation.

[022] The present invention presents a preparation with PHMB, silanol and fluoride ions, with excellent action for reducing dentin erosion, not explicitly shown in previous studies in the state of the art. PHMB exhibits excellent dentin erosion reducing action both when used alone and in the preparation with silanol and fluoride ions.

[023] Detailed Description of the Invention Petition 870200140709, dated 09 / 11 / 2020, page 17 / 30 6 / 14

[024] The present invention aims to provide a preparation of ingredients that reduces dentin erosion containing PHMB and / or silanol and / or ionizable fluoride compounds.

[025] Considering the ability of PHMB or its derivatives to act as an inhibitor of enzymes that degrade DOM, silanol as an aid in collagen biosynthesis, and the protection of fluoride ions that form a CaF₂ layer on teeth, we hypothesized that the three ingredients combined could act through different pathways and in a complementary way, preventing dentin erosion. Therefore, we tested these ingredients separately and together.

[026] Several ionizable compounds in fluoride can be used in preparations such as: sodium fluoride, tin fluoride, sodium monofluorophosphate, fluoridated amine, titanium tetrafluoride, 2-bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecyl dihydrofluoride, N,N,N-Tris(2-hydroxyethyl)-N-octadecyl-1,3-diaminopropane dihydrofluoride, ammonium monofluorophosphate, calcium monofluorophosphate, potassium monofluorophosphate, potassium fluoride, ammonium fluoride, aluminum fluoride, magnesium fluoride, calcium fluoride, hexadecylammonium fluoride, 3-(N-hexadecyl-N-2-hydroxyethylammonium)propylbis(2-hydroxyethyl)ammonium dihydrofluoride, N,N,N-tris (polyoxyethylene)-N-hexadecyl propylenediamine, nicomethanol hydrofluoride, octadicenyl ammonium fluoride, sodium fluorosilicate, ammonium fluorosilicate, magnesium fluorosilicate, cetylamine hydrofluoride, oleylamine fluoride and hexyldecylamine difluoride.

[027] Silanols are organic derivatives of silicon and, when synthesized in the presence of different radicals, confer stability and specificity to the compounds. Other compounds in the silanol group may have similar action in collagen biosynthesis, such as: methylsilanol mannuronate, silanetriol arginate, ascorbyl methylsilanol pectinate, siloxanetriol alginate, silanediol salicylate, Petition 870200140709, dated 09 / 11 / 2020, page 18 / 30 7 / 14 dimethylsilanol hyaluronate, methylsilanol hydroxyproline aspartate, methylsilanol sodium lactate, silanetriol lysinate, dioleyl tocopheryl methylsilanol, dimethyl oxobenzene dioxasilane, methyl silanol carboxymethyl theophylline alginate, methylsilanol acetyltyrosine, acetylmethionyl elastinate, copper acetyltyrosinate methylsilanol, copper PCA methylsilanol, dimethiconol / methylsilanol / silicate crosspolymer, lactoyl methylsilanol elastinate, methylsilanol acetylmethionate, methylsilanol ascorbate, methylsilanol elastinate, methylsilanol glycyrrhizinate, methylsilanol hydroxyproline, methylsilanol PCA, methylsilanol PEG-7 glyceryl cocoate, methylsilanol Spirulinate, methylsilanol tri-PEG-8 glyceryl cocoate, methylsilanol / silicate crosspolymer, polysilicone-21, sodium hyaluronate dimethylsilanol, sodium mannuronate methylsilanol, sodium PCA methylsilanol, hydrolyzed collagen PG-propyl methylsilanediol, hydrolyzed keratin PG-propyl methylsilanediol, hydrolyzed keratin PG-propyl methylsilanediolPG-propyl methylsilanediol protein hydrolysate, PG-propyl methylsilanediol soy protein hydrolysate, sodium hyaluronate dimethylsilanol and silanediol sorbityl.

[028] PHMB is a broad-spectrum polymeric biguanide with antimicrobial action against Gram-positive and Gram-negative bacteria and has been used for many years as an antiseptic agent in medicine, the food industry, and in various materials to prevent bacterial growth. It is also used in the treatment of fungi and infective keratitis. Many documents describe the action of chlorhexidine (CHX) and polymeric biguanides (such as PHMB) as an oral antimicrobial and against caries. Other nomenclatures are used for PHMB such as: polyhexamethylene biguanide hydrochloride, polyaminopropyl biguanide, polyhexanide, among others. Commercial preparations are mixtures of polymeric biguanides containing 2 to 40 monomers with a primary structure of the type [-CH2)6.NH.C(=NH).NH.C(=NH).NH-]n, presented in formula I, with an average size of n=12 and a molecular mass between 400 and 800 Daltons. This Petition 870200140709, dated 09 / 11 / 2020, page 19 / 30 The 8 / 14 structure has several combinations in the terminal group that can present amides (-NH2), guanides [-HC(=NH).NH2] or cyanoguanides [-NH.C(=NH).NH.CN]. Formula 1 n being an integer between 2 and 40.

[029] The PHMB polymer under study has an integer number of monomers between 2 and 40 and particularly between 8 and 15.

[030] In research conducted, the preparation (PHMB, silanol and fluoride) demonstrated significantly lower dentin loss results than the ingredients evaluated separately. With just one daily application of this preparation, an effective reduction in dentin erosion is observed.

[031] The research carried out was comparative with the methodology described below:

[032] Sample preparation: Sixty bovine tooth samples were cut and had the enamel removed in pre-preparation. Two coats of nail polish were applied to part of the outer surface of the dentin as a way to maintain a reference of initial total dentin thickness for the subsequent determination of dentin loss, by thickness difference.

[033] Daily treatment of samples

[034] All samples were subjected to demineralization and remineralization cycles over a period of 6 days. Each day, the samples went through the following stages: a) Demineralization - Demineralization challenges were performed daily with all samples for 5 minutes over 6 days, using a 0.87M citric acid solution (pH 2.5 and 30 ml per sample). Petition 870200140709, dated 09 / 11 / 2020, page 20 / 30 9 / 14 b) Protection - After demineralization, each group of samples was treated with one of the solutions below for 1 minute (30 mL / sample), with: • Distilled water group (control group) • CHX group (0.12%) • PHMB group (0.07%) • PHMB + silanol + fluoride group (0.07% PHMB + 0.00045% silanol + 0.0226% fluoride ions) • Fluoride solution group (0.0226% fluoride ions) c) Enzymatic Challenge - After step b, each sample group was rinsed with deionized water and then subjected for 10 minutes to the action of a bacterial collagenase (Clostridium histolyticum, 100 pg / ml, Sigma-Aldrich, USA) in a buffer containing 1 ml of 50 mM TES buffer (TESCA) pH 7.4. This step simulates the activation of MMPs in the oral cavity. d) Dentin loss measurement - Measurements were performed using contact profilometry (MarSurf GD 25, Mahr, Gottingen, Germany). Five measurements were taken at a distance of 250 µm from each other, and the average value was obtained. Nail enamel was carefully removed with a scalpel and acetone solution (1:1 in water). The height differences between the reference surface and the eroded areas were quantified in microns. e) Storage - Between demineralization and remineralization cycles, the samples were immersed in artificial saliva (1.5 mmol l·l of CaCb, 2.4 mmol l·l of KH2PO4, Na2HP04, 17 mmol l·l of KCl, 2 mmol l·l of NaSCN, 9.9 mmol l·l of NaCl, 3 mmol l·l of NH4Cl, 3 mmol l·l of urea, and 0.2 mmol l·l of glucose, pH 6.8 - 30 ml / sample).

[035] For statistical analysis of the data, GraphPad Prism software (GraphPad Software, San Diego, USA) was used. The data were checked for normality and homogeneity using the Kolmogorov-Smirnov and Bartlett tests. Petition 870200140709, dated 09 / 11 / 2020, page 21 / 30 10 / 14 respectively. Provided these criteria were met, the data were analyzed using a 2-way repeated measures ANOVA followed by Bonferroni's post-hoc test considering treatments and periods as factors (p < 0.05).

[036] Below, see the data for the average final dentin loss (pm, mean ± standard deviation) in the different study groups on the sixth day of the study: Distilled water group (negative control group) 168.2 ± 6.2 pm Fluoride group (0.0226% fluoride) 157.4 ± 6.1 pm CHX Group (0.12%) 135.3 ± 33.5 pm PHMB group (0.07%) 129.9 ± 41.2 pm PHMB + silanol + fluoride group 94.4 ± 3.9 pm Results

[037] Dentin erosion loss progressed significantly for all groups during the six days. The highest dentin loss was observed in the control samples, treated with distilled water. The lowest dentin loss was observed in the group of samples treated with the PHMB + silanol + fluoride preparation. The PHMB Group and the CHX Group led to intermediate dentin loss values ​​that were significantly lower than those found for the control (water). The fluoride-only group did not differ significantly from the negative control (water).

[038] The PHMB + silanol + fluoride group had the best inhibitory effect on dentin erosion, the observed dentin loss was 94.4 ± 3.9 pm, after 6 days. The dentin loss-reducing action of the combination of the 3 active ingredients cannot be denied, since the PHMB and Fluoride groups alone showed significantly greater dentin losses (129.9 ± 41.2 pm and 157.4 ± 6.1 pm, respectively).

[039] Knowing that the isolated fluoride group did not offer protection against dentin erosion, the isolated PHMB group had intermediate dentin loss and the group of Petition 870200140709, dated 09 / 11 / 2020, page 22 / 30 11 / 14 The combination of PHMB + silanol + fluoride surpassed the inhibitory effect on dentin erosion of all groups, indicating a synergistic combination between PHMB, silanol, and fluoride ions.

[040] Some compositions of gels, toothpastes and mouthwashes containing the preparation with the active ingredients PHMB + silanol + fluorides have been developed with the aim of preventing dentin erosion caused by the action of acids. The compositions presented in this document comprise at least one more ingredient selected below as vehicles, sweeteners, preservatives, colorant, pH regulators, surfactants, abrasives, thickener, humectant, flavoring, opacifier, antimicrobial and anti-caries agent. [041 ]The concentration of PHMB in oral care compositions aimed at preventing dentin erosion can vary from 0.01% to 0.3% and preferably from 0.02% to 0.1%.

[042] The concentration of silanol in oral care compositions aimed at preventing dentin erosion may vary from 0.0001% to 0.1% and preferably from 0.0001% to 0.01%.

[043] The concentration of fluoride ions in oral care compositions aimed at preventing dentin erosion may vary from 0.001% to 5.0% and preferably from 0.006% to 0.15%.

[044] The preparation with PHMB, silanol and fluorides contains a silanol:PHMB ratio between 1:100 and 1:700, particularly 1:155.

[045] The preparation with PHMB, silanol and fluorides contains a silanol-to-fluoride ratio between 1:40 and 1:333, particularly 1:50.

[046] The preparation with PHMB, silanol and fluorides contains silanol:fluoride:PHMB ratios of approximately 1:50:155. Petition 870200140709, dated 09 / 11 / 2020, page 23 / 30 12 / 14

[047] Below are some compositions of the present invention to exemplify the use of the PHMB + silanol + fluorides preparation without, however, restricting the use to these specific examples.

[048] Example 1: Mouthwash Composition Raw material Quantity (%) Water 82.46g Sorbitol 70% 15.00g Sodium saccharin 0.050g Sodium benzoate 0.300g Sodium phosphate 0.090g Disodium phosphate 0.050g Sodium cocoamphodiacetate 1,500 Preparation: Sodium fluoride 0.050 PHMB 20% 0.350 Methylsilanol mannuronate 0.150 Total 100.000

[049] The manufacturing process consists of the preparation of 3 phases which are subsequently added, as follows:

[050] Phase A = Weigh 1 / 3 of the total water and dissolve the ingredients: dyes, sodium saccharin, sodium benzoate, sorbitol, sodium cocoamphodiacetate. Homogenize until all ingredients are dissolved; the solution becomes clear and transparent.

[051] Phase B = Weigh 1 / 3 of the total water and dissolve the active ingredients: sodium fluoride, silanediol mannuronate, and polyaminopropyl biguanide. Homogenize. Add Phase B to Phase A. Homogenize. Petition 870200140709, dated 09 / 11 / 2020, page 24 / 30 13 / 14

[052] Phase C = Weigh 1 / 3 of the total water and dissolve the monobasic sodium phosphate and disodium phosphate. Mix until completely dissolved.

[053] Add this Phase C mixture to Phase A + Phase B. Mix until completely homogenized.

[054] The PHMB 20% ingredient in the above composition is made up of water (80%) and PHMB (20%). This solution is added to the formulation at a percentage of 0.350%, which implies a final concentration of 0.07% PHMB in the mouthwash.

[055] The methylsilanol manuronate solution of the above composition is composed of: monomethylsilanetriol 0.3%; mannuronic acid 0.6%; preservatives in sufficient quantity and water in sufficient quantity to complete 100%. This solution is added to the formula in an amount of 0.150%, which implies a final concentration of 0.00045% of monomethylsilanetriol in the mouthwash.

[056] The sodium fluoride solution is added to the above composition in an amount of 0.05%, which implies a final concentration of 0.0226% of fluoride ions.

[057] Example 2: Composition of Dental Gel Raw material Quantity (%) Sorbitol 70% 58,000 Water 16,011 Hydrated silica (thickener) Hydrated silica (abrasive) 8,000 6,000 Cocamidopropyl betaine 5,000 Glycerin 3,000 Polyethylene glycol 400,000 Aroma 0.800 Titanium dioxide 0.500 Carboxymethylcellulose 0.450 Petition 870200140709, dated 09 / 11 / 2020, page 25 / 30 14 / 14 Xanthan gum 0.400 Sodium saccharin 0.300 Preparation: Sodium fluoride 0.319 Silanediol salicylate 0.150 Polyaminopropyl biguanide 0.070 Total 100,000

[058] The manufacturing process consists of the preparation of 3 phases which are subsequently added, as follows:

[059] Phase A = Weigh 1 / 3 of the total water and dissolve the sodium saccharin and titanium dioxide. Add the sorbitol. Homogenize.

[060] Phase B = Weigh 2 / 3 of the total water and dissolve the sodium fluoride, silanediol salicylate, and polyaminopropyl biguanide. Homogenize and mix Phase B into Phase A. Homogenize.

[061] Phase C = Weigh the glycerin, add the polyethylene glycol 400 and disperse the carboxymethylcellulose and xanthan gum. Mix until completely free of lumps. Add Phase C to Phase A + Phase B while stirring. Homogenize until completely incorporated and free of lumps.

[062] Next, add the silicas and mix until fully incorporated and free of lumps. Add the Flavoring and then the cocoamidopropyl betaine. Mix well.

Claims

1. Oral preparation for reducing dentin erosion CHARACTERIZED by comprising: - 0.01 to 0.3%, preferably between 0.02% and 0.1%, of PHMB according to formula 1 below, or its derivatives: Formula 1 NH NH H H H — —njn where n is an integer between 2 and 40, preferably between 8 and 15, - 0.0001% to 0.1%, preferably between 0.0001% and 0.01%, of silanol, - 0.001% to 5.0%, preferably between 0.006% and 0.15%, of fluoride ions, wherein the silanol:fluoride:PHMB ratio is 1:50:155, wherein silanol is methylsilanol manuronate or silanediol salicylate, and ions Fluorides are sodium fluoride.

2. Oral preparation for reducing dentin erosion, according to claim 1, CHARACTERIZED in that it comprises a silanol / PHMB ratio of 1:

155.

3. Oral preparation for reducing dentin erosion, according to claim 1, CHARACTERIZED in that it comprises a silanol fluoride ratio of 1:

50.

4. Oral composition for reducing dentin erosion CHARACTERIZED by the fact that it comprises the preparation, as defined in any one of claims 1 to 3, and at least one other ingredient selected from among vehicle, sweetener, preservative, pH regulator, surfactant, colorant, abrasive, thickener, humectant, flavoring, opacifier, antimicrobial and anti-caries agent. Petition 870260055865, dated 09 / 06 / 2026, page 10 / 14 2 / 2 5. Oral composition for reducing dentin erosion, according to claim 4, CHARACTERIZED in that the antimicrobial is chlorhexidine.

6. Use of the preparation, as defined in any one of claims 1 to 3, CHARACTERIZED in that it is for the preparation of dental gels, toothpastes, mouthwashes, dental floss, dental tapes, varnishes or professional dental products.

7. Use of the preparation, as defined in any one of claims 1 to 3, CHARACTERIZED by the fact that it is for the preparation of a composition useful in the treatment of the reduction or prevention of dentin erosion.