Compositions comprising chlorhexidine and a depigmenting complex

Abstract

A complex consisting of lipoic acid or a salt thereof, a chelating agent such as a salt of ethylene diamine tetraacetic acid (EDTA) or analogous compounds and an ester of ascorbic acid with long-chain fatty acids, in particular ascorbyl palmitate inhibits the pigmentation of teeth induced by chlorhexidine and salts thereof. In addition to the depigmenting complex, the formulations of the invention, in the form of gels, mouthwashes, toothpastes or periodontal sprays, may contain other ingredients such as hyaluronic acid or hyaluronates, glycerophosphocholine, sweeteners, flavourings, buffering agents, viscosifying agents, mucoadhesive and filming agents, solvents, co-solvents, surfactants.

Description

[0001] COMPOSITIONS COMPRISING CHLORHEXIDINE AND A DEPIGMENTING COMPLEX

[0002] The present invention relates to compositions comprising chlorhexidine or a salt thereof and a depigmenting complex consisting of lipoic acid or a salt thereof, ascorbyl palmitate and disodium ethylenediaminetetraacetate.

[0003] BACKGROUND OF THE INVENTION

[0004] Morphologically, teeth are divided into three fundamental parts:

[0005] The crown is the visible portion that comes out of the gums and protrudes into the oral cavity, responsible for chewing. The crown is externally coated with dental enamel, the hardest element in the human body, consisting almost entirely of minerals (96% hydroxyapatite crystals). The enamel has a translucent appearance and reveals the colour of the underlying dentin.

[0006] The roots are the non-visible portion located inside the gums, responsible for the structural maintenance of the organ. Externally they are covered with cementum. The collar is the portion of the tooth where the crown enamel ends and the root cementum begins; it joins externally with the gums. It is a very important area from the point of view of dental hygiene since this is where bacterial plaque tends to accumulate. Underneath the enamel / cementum coating is dentin, the organic substance that gives teeth their colour. Histologically, it is a tissue similar to compact bones and has a yellowish colour. Inside dentin develops the dental pulp, a soft tissue that includes nerves, blood vessels and odontoblasts, the cells that produce dentin. The colour of the teeth is an individual factor: the colour of the dentin is in fact tendentially yellowish, but it has more or less accentuated shades ranging from red to grey, determining the colour of the teeth. The colourless and translucent enamel reveals the colour of the underlying dentin.

[0007] Several factors can lead to a change in tooth colour: over the years, coloured foods (tea, coffee and red wine), tobacco and medicines can make teeth yellower and duller or cause stains to appear.

[0008] Chlorhexidine is an antiseptic widely used in dentistry for the control of bacterial plaque and the prevention of oral infections. However, one of the most well-known side effects of its prolonged use is tooth pigmentation. This discoloration is due to the reaction of chlorhexidine with the compounds present in the saliva and diet, which leads to the formation of yellowish or brownish spots on the surface of the teeth.

[0009] The pigmentation caused by chlorhexidine may, in some cases, be difficult to remove with normal oral hygiene. Stains tend to form mainly on the rough surfaces of the teeth, such as in the areas between the interdental spaces and along the gum line, where it is more difficult to remove plaque with daily brushing. For these reasons, it is recommended in medical practice to limit the use of chlorhexidine to the strictly necessary period (e.g., after surgery or in situations of high inflammation) and / or to use formulations with a lower concentration (e.g., 0.06%) so as to reduce the risk of pigmentation.

[0010] To overcome these drawbacks, additives capable of counteracting the pigmenting effect of chlorhexidine have been proposed. Among these, especially sulphites and metabisulphites that act as reducing agents, interfering with the formation of chromogenic compounds that cause pigmentation.

[0011] The addition of sulphites or metabisulphites is considered an effective method of reducing the risk of pigmentation without compromising the antimicrobial efficacy of chlorhexidine. However, these additives may have an impact on the taste of the product and, in rare cases, could cause allergic reactions in sulphite-sensitive individuals. Therefore, the use of these compounds is balanced to obtain the best possible result in terms of preventing pigmentation and maintaining the tolerability of the product. Examples of formulations of chlorhexidine containing sulphites are described and exemplified in WO2023166108 in which chlorhexidine is associated with N-acetylcysteine, ascorbic acid and alkaline metabisulphites and in WO2016112998 which describes mouthwashes comprising metabisulphites, ascorbic acid, hyaluronic acid and polyvinylpyrrolidone-vinyl acetate. EP4249078 discloses sulphite- free chlorhexidine formulations comprising alkyl resorcinols.

[0012] There is still a need to have formulations of chlorhexidine or its salts free of sulphites, which have improved ability to inhibit tooth pigmentation, using safe, inexpensive and active components at low concentrations.

[0013] DESCRIPTION OF THE INVENTION

[0014] It has now been found that the pigmentation induced by chlorhexidine and its salts can be effectively inhibited by using a complex consisting of lipoic acid or a salt thereof, a chelating agent such as a salt of ethylenediamine tetraacetic acid (EDTA) or analogous compounds and an ester of ascorbic acid with long-chain fatty acids, in particular ascorbyl palmitate.

[0015] The invention therefore relates to compositions for disinfecting the oral cavity comprising chlorhexidine or a salt thereof and a depigmenting complex consisting of lipoic acid or a salt thereof, ascorbyl palmitate and a salt of ethylenediaminetetraacetic acid, preferably disodium ethylenediaminetetraacetate.

[0016] The chlorhexidine salt is preferably digluconate, in weight percentage from 1 to 0.005%, preferably from 1.0 to 0.05%.

[0017] Lipoic acid, also known as thiotic acid, is preferably in the form of a sodium salt in a weight percentage of from 0.5 to 0.01%, preferably from 0.1 to 0.05%.

[0018] Disodium ethylenediaminetetraacetate is preferably present in weight percentage from 0.05 to 0.25% while ascorbyl palmitate is preferably present in weight percentage from 0.0005 to 0.05%, preferably from 0.001 to 0.05%.

[0019] The compositions of the invention may also comprise other ingredients such as hyaluronic acid or salts thereof, glycerophosphocholine, sweeteners, flavourings, buffering agents, viscosifying agents, mucoadhesive and filming agents, solvents, co-solvents, surfactants.

[0020] Suitable administration forms include mouthwashes, periodontal gels and sprays, toothpastes.

[0021] The formulations of the invention were the subject of a study carried out on 40 volunteers, predisposed to dental yellowing, of both sexes aged between 18 and 65 years, in order to compare the efficacy of a product containing a depigmenting complex according to the invention against a control product free of the depigmenting complex.

[0022] For this purpose the following evaluations were made:

[0023] - Clinical evaluation of tooth colour carried out by specialized personnel, through comparison with a standard colour (Classical A1-D4® Vita) scale at TO (basal values) and after 28 (T28d) days of daily use of the product.

[0024] - Instrumental colorimetric evaluation by 3D Anther at TO (baseline values) and after 28 (T28d) days of daily use of the product. Analysis was performed on the central teeth of each volunteer.

[0025] Mode of application

[0026] The gel of Example 1 was used 2 / 3 times over 24 hours respecting a contact time of at least 60 seconds before rinsing. Of the 40 volunteers, 20 used the active product and 20 used the non-active product. The treatment had a duration of 28 days for each volunteer.

[0027] Depigmentation efficacy evaluation

[0028] The evaluation of the depigmentation efficacy of the product was evaluated by comparing tooth staining before the start of treatment (TO) and at the end of 28 days of use (T28d).

[0029] The colour determination of the volunteer's teeth is carried out by specialized personnel, comparing the teeth with a standard colour scale, Vita Classical A1-D4®, in daylight or with standardized lamps, in a neutral colour room. The Classical A1-D4® VITA scale is a tool for the safe determination of tooth colour. The colours of the Classical VITA scale follow the following grouping:

[0030] - A1-A4: red-brown

[0031] - B1-B4: red-yellow

[0032] - C1-C4: grey

[0033] - D2-D4: red-grey

[0034] The letters therefore indicate the colour of the teeth, while the number indicates the degree of brightness of that colour, where 1 is the lightest and 4 the darkest.

[0035] Instrumental colorimetric evaluation

[0036] For instrumental colorimetric evaluation with Antera 3D, the colour change calculated using the CIELAB scale is considered.

[0037] The CIELAB colour space (also known as CIE L* a *b*) is a colour space defined by the International Commission on Illumination (CIE) in 1976. It expresses the colour as three numerical values, L* for brightness and a* and b* for the green-red and blue-yellow colour components. CIELAB was designed to be perceptually uniform with respect to human colour vision, meaning that the same amount of numerical change in these values corresponds to roughly the same amount of change visually perceived.

[0038] • Average L*. The brightness value, L*, represents the darkest black with L* = 0 and the brightest white with L* = 100.

[0039] • Average a* The a* axis represents the green-red component, with green in the negative direction and red in the positive direction.

[0040] • Average b*. The b* axis represents the blue-yellow component, with blue in the negative direction and yellow in the positive direction.

[0041] Starting from a condition of tooth yellowing, for the evaluation of the depigmenting efficacy of the tested products, the reduction of the parameter b* (blue-yellow) was evaluated.

[0042] Clinical evaluation of tooth colour

[0043] Clinical evaluation was done by VITA scale, before treatment and after 28 days (T28d) of use of the products.

[0044] Table 1 shows the percentage of volunteers who showed an improvement in the parameter analysed for both treatments. INTENSIVE CARE A

[0045] Table 1

[0046] On the basis of the results obtained, reported in Tables 2-3 and Figures 1 and 2, it can be concluded that the test product resulted in an improvement of tooth coloration in 40% of the volunteers after 28 days of daily use and a reduction of the b* parameter, i.e. tooth yellowing, of 3.0% after 28 days of daily use. This change was statistically significant.

[0047] Table 3

[0048] In comparison, the formulation of the invention proved more effective than the product without depigmenting complex and was positively judged by the maj ority of volunteers.

[0049] Similar results have been obtained in studies carried out with spray and mouthwash formulations.

[0050] Some examples of formulation of the invention are given below. EXAMPLE 1: GEL

[0051] EXAMPLE 2: SPRAY

[0052] EXAMPLE 3: MOUTHWASH

[0053] EXAMPLE 4: TOOTHPASTE

Claims

CLAIMS1. Compositions for disinfecting the oral cavity comprising chi orhexi dine or a salt thereof and a depigmenting complex consisting of lipoic acid or a salt thereof, ascorbyl palmitate and disodium ethylenediaminetetraacetate.

2. Compositions according to claim 1 comprising chlorhexidine digluconate in weight percentage from 0.005% to 1%.

3. Compositions according to claim 1 or 2 wherein the depigmenting complex consists of sodium lipoate in weight percentage from 0.5% - 0.01%, disodium ethylenediaminetetraacetate in weight percentage from 0.05% to 0.25% and ascorbyl palmitate in weight percentage from 0.0005% to 0.05%.

4. Compositions according to one or more of claims 1-3 further comprising hyaluronic acid or salts thereof, glycerophosphocholine, sweeteners, flavourings, buffering agents, viscosifying agents, mucoadhesive and filming agents, solvents, co-solvents, surfactants.

5. Compositions according to one or more of claims 1-4 in the form of mouthwash, periodontal gel, periodontal spray, toothpaste.

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