阅读说明：本技术 双脱水己糖醇在口腔卫生中用于减少细菌菌株生长的用途 (Use of dianhydrohexitols for reducing the growth of bacterial strains in oral hygiene ) 是由 C·萨比斯 C·佩雷奥 F·德赛利 于 2018-11-30 设计创作，主要内容包括：本发明涉及双脱水己糖醇用于减少口腔和牙齿细菌菌株发育的非治疗性用途。(The present invention relates to the non-therapeutic use of dianhydrohexitols for reducing the development of oral and dental bacterial strains.)

1. Non-therapeutic use of a dianhydrohexitol for reducing the growth of a strain of oral bacteria.

2. The use according to claim 1, the dianhydrohexitol is isosorbide.

3. Use according to claim 1 or 2, of a dianhydrohexitol for use in a composition having a dianhydrohexitol content of at least 50 wt.%, preferably at least 75 wt.%, even more preferably at least 90 wt.% and most preferably at least 95 wt.%.

4. Use according to one of claims 1 to 3, characterized in that the dianhydrohexitol is used together with at least one other polyol, which is preferably selected from glycerol, hydrogenated glucose syrup, maltitol, mannitol, sorbitol, erythritol, isomalt, lactitol and xylitol, and is preferentially xylitol and maltitol, and very preferentially xylitol.

5. An oral hygiene product comprising a dianhydrohexitol, preferably isosorbide.

6. An oral hygiene product according to claim 5, further comprising at least one other polyol, preferably selected from glycerol, hydrogenated glucose syrup, maltitol, mannitol, sorbitol, erythritol, isomalt, lactitol and xylitol, and preferably xylitol and maltitol, and very preferably xylitol.

7. The oral hygiene product of any one of claims 5 and 6, having a dianhydrohexitol content of between 0.2 and 50 dry weight%, preferably from 1 to 25 dry weight%, very preferentially from 5 to 15 dry weight%.

8. The oral hygiene product of any one of claims 5 to 7 which is a toothpaste.

9. The oral hygiene product of any one of claims 5 to 7, which is a mouthwash.

10. The oral hygiene product of any one of claims 5 to 7, which is a topical care product.

Technical background and field of application

The present invention relates to the field of oral hygiene. It notably relates to the non-therapeutic use of dianhydrohexitols (1,4:3, 6-dianhydrohexitols) as agents for reducing the growth of strains of oral bacteria. The dianhydrohexitol to which the present patent application is more particularly directed is isosorbide.

In this regard, the effect of isosorbide on the growth of various oral bacterial strains is quite surprising. In particular, it was completely unexpected that isosorbide caused particularly significant reduction in the growth of undesirable bacterial strains compared to all other polyols tested by the applicant. Very surprisingly and advantageously, isosorbide provides even higher performance levels than those observed with xylitol or sorbitol, which are the two most commonly used polyols in commercial toothpastes. This teaching is notably repeated in patent application WO 2003/007902, which reviews the common use of these polyols as humectants in toothpastes, making it possible to notably slow down the hardening phenomenon of the paste. By way of example cited in said document, the product Neosorb70/70 sold by the Applicant proved to be a polyol entirely effective for the purposes described above.

The applicant indicates in the preamble that the dianhydrohexitol (1,4:3, 6-dianhydrohexitol) to which the invention is directed is also known as isohexide, this name denoting the internal dehydration products of C6 hydrogenated sugars (hexitols), such as sorbitol, mannitol and iditol.

The field of oral hygiene to which the present invention relates includes any product, whether packaged as a liquid, paste or powder, intended to maintain oral health and improve oral health by preventing the appearance of infections or lesions in the oral cavity. Specifically, this may be a problem with respect to: toothpastes which are used in a cyclic manner during brushing, mouthwashes which act throughout the oral cavity and which can be used in a cyclic or occasional manner, or topical care products which may be in the form of pastes to be applied topically to the area to be treated, for example. This type of care product is generally more targeted to the dental professional than the public, but is not so limited.

Technical problem

Certain bacterial strains tend to grow in the oral cavity and may form biofilms that produce plaque by growing on the teeth. This film or this plaque can form on the enamel, the gums or any supporting tissue of the oral cavity. In the following, the term "support tissue" will indicate without preference a support on which bacterial strains have grown, whether it be enamel, gingiva, mucous membranes or other tissues of the oral cavity.

The formation of biofilm or plaque quickly isolates the supporting tissue from the air, thereby exposing the supporting tissue and portions of the film or plaque to anaerobic conditions. These anaerobic conditions may damage supporting tissues and promote the growth of other bacterial strains, which may be more toxic.

In addition, various bacterial strains are prone to produce harmful chemically corrosive acids, which have a demineralizing effect on teeth.

The activity of the biofilm or plaque in combination with the anaerobic conditions imposed on the tissue may lead to rapid degeneration of the supporting tissue, which leads to caries, lesions, inflammation or any other unwanted damage of the supporting tissue.

The main strains that should be prevented from proliferating are in particular Streptococcus mutans (Streptococcus mutans), Lactobacillus gasseri (L actinobacillus gasseri), Actinomyces naeslundii (Actinomyces naeslundii) and Actinomyces oralis (Actinomyces oris).

For this reason, it is known practice to use bactericides in order to reduce the amount of bacterial strains, or fluorinated compounds to form a sparingly soluble protective layer on the enamel of teeth.

However, these active compounds have adverse effects. In particular, these compounds often have varying degrees of toxicity and, as such, spitting most oral hygiene products is very important. The problem of toxicity is particularly important in the case of children and infants, since toxic effects manifest at lower doses than in adults, and children and infants are more prone to accidentally swallow the product.

Disclosure of Invention

Thus, there is a need for a non-toxic compound to replace active agents of conventional oral hygiene products, or at least to substantially reduce the level of these active agents without compromising the effectiveness of these products.

The present invention fills this need by the non-therapeutic use of dianhydrohexitols for reducing the growth of strains of oral bacteria.

The dianhydrohexitol is preferably isosorbide.

The effect of isosorbide on the growth of many oral bacterial strains is very surprising. In particular, it was completely unexpected that isosorbide caused particularly significant reduction in the growth of undesirable bacterial strains compared to all other polyols tested by the applicant.

Thus, the bacteriostatic or even bactericidal effect of isosorbide is at least unexpected.

The subject of the present invention is also a preventive or even therapeutic method for the treatment of the oral cavity, which comprises the application of dianhydrohexitol, isosorbide as preferred dianhydrohexitol, to the oral cavity or to the supporting tissue to be treated and subjected to dental caries, dental ulcers, gingivitis and the like.

The subject of the invention is also an oral hygiene product comprising a dianhydrohexitol, preferably the dianhydrohexitol is isosorbide.

Detailed Description

In a more detailed manner, the first subject of the invention consists of the non-therapeutic use of dianhydrohexitols for reducing the growth of strains of oral bacteria.

This use is also characterized in that: the dianhydrohexitol may be used in a composition having a dianhydrohexitol content of at least 50 wt.%, preferably at least 75 wt.%, even more preferably at least 90 wt.% and most preferably at least 95 wt.%.

This use is also characterized in that: the dianhydrohexitol may be used together with at least one other polyol, preferably chosen from glycerol, hydrogenated glucose syrup, maltitol, mannitol, sorbitol, erythritol, isomalt, lactitol and xylitol, and preferentially xylitol and maltitol, and very preferentially xylitol. In this case, the at least one polyol may constitute the remainder of 100% by weight of the composition.

The term "dianhydrohexitol composition" denotes a preparation of at least two components, one of these components being a dianhydrohexitol, it being understood that this dianhydrohexitol is the main component in the preparation.

Preferably, the composition contains at least 50% by weight, preferably at least 75%, even more preferably at least 90% and most preferably at least 95% of the dianhydrohexitol.

According to one variant, the composition may consist of an aqueous solution of dianhydrohexitol, i.e. of water and dianhydrohexitol, together with minor amounts of other optional products (such as other polyols). Preferably, the aqueous solution contains only water and dianhydrohexitol, notably at least 50% by weight, preferably at least 75% and even more preferably about 80% of said dianhydrohexitol.

According to another variant, the composition may consist of a paste, a powder or a product in the form of flakes or granules, mainly consisting of dianhydrohexitol.

In this respect, the applicant has pointed out that, in general, dianhydrohexitols are synthesized in the presence of water (or during their synthesis to produce water) by: the dianhydrohexitol is recovered in this reaction medium, immediately obtaining the composition that can be used according to the invention in the form of an aqueous solution of dianhydrohexitol. Dianhydrohexitol solutions can notably be obtained according to the processes described in the above-mentioned patent applications EP 1287000 and WO 03/043959. It is possible to choose to retain all or some of the water used during the preparation of the dianhydrohexitol, or to eliminate all of the water to obtain the product in solid form, which is returned to the aqueous solution by simply adding water, which constitutes another possibility for preparing an aqueous solution of dianhydrohexitol that can be used according to the invention.

The aqueous solution in question may contain a single dianhydrohexitol as it may contain several of them. These dianhydrohexitols (1,4:3, 6-dianhydrohexitols) encompass isosorbide (1,4:3, 6-dianhydrosorbitol), isomannide (1,4:3, 6-dianhydromannitol), isoidide (1,4:3, 6-dianhydroidide) and mixtures of at least two of these products. Preferably, the aqueous solution contains only a single dianhydrohexitol, which is isosorbide.

Another subject of the invention consists of an oral hygiene product comprising a dihydrohexitol, preferably isosorbide. The hygiene product may be used prophylactically daily or for limited use over time.

The oral hygiene product according to the invention may notably comprise a dianhydrohexitol composition for use according to the invention.

The oral hygiene product according to the invention may also comprise at least one other polyol, preferably selected from glycerol, hydrogenated glucose syrup, maltitol, mannitol, sorbitol, erythritol, isomalt, lactitol and xylitol, and preferably xylitol and maltitol, very preferably xylitol. It should be noted that since dianhydrohexitol compositions can function inherently as humectants and water retention agents and function as effectively as these polyols, they can advantageously be substituted for all or part of these polyols used in oral hygiene product formulations.

According to a first variant, the oral hygiene product according to the invention may be a toothpaste. The toothpaste may be in the form of a paste or a powder, for example.

Alternatively, the oral hygiene product according to the invention may be a mouthwash, then usually in liquid form, either ready-to-use or requiring dilution.

Alternatively, the oral hygiene product according to the invention may be a topical care product. Topical care products include care products, particularly liquid dressings, for the treatment of gingivitis, mouth ulcers and oral wounds. In addition, for the purposes of the present invention, the topical care products comprise compositions which are applied by applying a floss, gel or wipe of the composition.

Preferably, the oral hygiene product according to the invention contains 0.2 to 50 wt.%, preferentially 1 to 25 wt.%, very preferentially 5 to 15 dry wt.% dianhydrohexitol.

Preferably, the dianhydrohexitol (1,4:3, 6-dianhydrohexitol) is selected from the group consisting of isosorbide (1,4:3, 6-dianhydrosorbitol), isomannide (1,4:3, 6-dianhydromannitol), isoidide (1,4:3, 6-dianhydroidide) and mixtures of at least two of these products. Preferably, it is isosorbide.

The oral hygiene product according to the invention may further comprise a fluorinated compound, preferably a fluorinated compound selected from sodium fluoride, sodium monofluorophosphate, tin fluoride or amine fluoride. The use of dianhydrohexitols, in particular isosorbide, in combination with fluorinated compounds provides an enhanced bactericidal effect, while enabling the amount of fluorinated compounds to be limited, and thus the overall toxicity of the oral hygiene product to be limited.

Furthermore, it is known that excess fluorine may cause dental fluorosis, which is characterized by the appearance of spots on teeth, especially in children from 1 to 4 years of age. Dianhydrohexitols, optionally in combination with polyols such as xylitol or maltitol, seem to be a solution for preventing the use of fluorinated compounds and for preparing new oral hygiene products that are healthier and safer to use, notably in the case of young children. Therefore, the subject of the present invention is also an oral hygiene product comprising a dianhydrohexitol, such as in particular isosorbide, optionally in combination with a polyol, such as in particular xylitol or maltitol, and being free of fluorinated compounds. This type of oral hygiene product is particularly advantageous as it enables to reduce the risk of toxicity and the risk of white spots on the teeth of children and infants. It should be noted that the use of dianhydrohexitols, optionally in combination with polyols such as xylitol or maltitol, can be carried out by oral application of the impregnated wipe.

The oral hygiene product according to the invention may also comprise a bactericide, preferably selected from chlorhexidine and 5-chloro-2-phenol. 5-chloro-2-phenol is sometimes referred to as triclosan. The use of dianhydrohexitols, in particular isosorbide, in combination with an antibacterial agent provides an enhanced antibacterial action, while enabling the amount of antibacterial agent to be limited, and thus the overall toxicity of the oral hygiene product to be limited. This is particularly true with occasional use of mouthwashes that use high concentrations of antiseptic. In one variant, the oral hygiene product according to the invention does not comprise any bactericidal agent; dianhydrohexitols, in particular isosorbide, make it possible to dispense with these potentially toxic fungicides.

The oral hygiene product according to the invention may furthermore comprise a surfactant, such as sodium lauryl sulphate. Sodium lauryl sulfate is a foaming agent that can enhance the action of oral hygiene products.

The invention may be better understood by reading the following description of non-limiting embodiments and examining the accompanying drawings, in which:

FIG. 1 shows bacterial growth and biofilm formation by Streptococcus mutans strains derived from samples taken from healthy teeth under aerobic conditions in the presence of various polyols;

FIG. 2 shows bacterial growth and biofilm formation by strains of Streptococcus mutans derived from samples taken from dental caries in the presence of various polyols;

FIG. 3 shows the bacterial growth and biofilm formed by the Lactobacillus gasseri strains in the presence of various polyols under anaerobic conditions;

FIG. 4 shows the bacterial growth and biofilm formed by strains of Actinomyces naeslundii in the presence of various polyols under aerobic conditions;

FIG. 5 shows the bacterial growth and biofilm formed by strains of Actinomyces naeslundii in the presence of various polyols under anaerobic conditions; and is

FIG. 6 shows the bacterial growth and biofilm formed by strains of Actinomycetes stomatochorus in the presence of various polyols under aerobic conditions.

The following example is to quantify the effect of various polyols on the growth of various bacterial strains readily found in the oral cavity.

To demonstrate the effect of isosorbide on the growth of the main bacterial strains growing in the oral environment, four strains of interest were sampled orally: streptococcus mutans, Lactobacillus gasseri, Actinomyces naeslundii and Actinomyces oralis.

These strains were isolated and then identified in the bacteriological laboratory of the School of Rill's pharmaceutical and Biological Sciences, L ille.

The growth of these strains was then measured in the presence of isosorbide, maltitol, xylitol, psicose, sorbitol powder and dextrose monohydrate in an unrefreshed medium and incubated for 48 hours or 72 hours at 37 ℃ under aerobic or anaerobic conditions.

Growth was measured by counting bacteria on solid medium.

Bacteria that are located on surfaces or form plaque or films in the mouth grow in an aerobic environment, but once plaque or film is formed, most bacteria are in an anaerobic environment. Therefore, it is of interest to evaluate the effect of dianhydrohexitols, in particular isosorbide, both under aerobic and anaerobic conditions.

The results are expressed as L og 10 (CFU/ml).

The culture medium used was Bacto brain Heart infusion (ref 237500-BD (BHI)) and Difco^TMBrain heart infusion agar (ref. 241830-BD (BHIa)) medium.

Streptococcus Mutans (SM)

As shown in fig. 1, under aerobic conditions and on healthy teeth, at T ═ 24 hours, there was still no growth obtained with isosorbide. Then, the population decreased slightly, revealing the bacteriostatic effect of isosorbide compared to that observed for all other polyols tested.

As shown in fig. 2, very slow growth of SM was also observed for strains derived from oral samples taken from dental caries.

As shown in fig. 2, the bacterial growth varied little under anaerobic conditions, but after 96 hours of incubation, the biofilm formed in the absence of isosorbide was much more pronounced than the biofilm formed in the presence of isosorbide.

Lactobacillus gasseri

Lactobacillus gasseri only grow under anaerobic conditions. As shown in figure 3, at T ═ 24 hours, growth was still not achieved with isosorbide, and over 24 hours the population declined, revealing the inhibition by isosorbide, which was not observed with the other polyols tested.

Actinomyces naeslundii

As shown in FIG. 4, the bacterial population in the presence of isosorbide continued to decline under anaerobic conditions until it completely disappeared.

Therefore, isosorbide has a bactericidal effect.

The effect of xylitol will be noted: in the presence of xylitol, the bacterial population remained stable, while in the presence of the other polyols tested, the bacterial population underwent an exponential increase.

As shown in fig. 5, bacterial growth was still low in the presence of isosorbide under aerobic conditions relative to other polyols. A large reduction in bacterial population was observed starting at T-40 hours.

In addition, xylitol appears to inhibit bacterial growth more than the other polyols tested, and indeed, it may be advantageous to use it in combination with isosorbide.

Oral cavity actinomycetes

As shown in fig. 6, bacterial growth decreased significantly over time in the presence of isosorbide under aerobic conditions and then stabilized after 24 hours.

In the presence of allulose and xylitol, bacterial growth was slowed relative to the other polyols tested, but was still particularly much higher than that observed in the presence of isosorbide.

In all cases, a very significant reduction in the growth of the bacterial strain is therefore observed in the presence of isosorbide. This result is particularly surprising, since there is no indication that isosorbide behaves in any particular way with respect to other polyols.

Very surprisingly and advantageously, isosorbide provides even higher performance levels than those observed with xylitol or sorbitol, which are the most commonly used polyols in commercial toothpastes.

It will be understood that the embodiments described are not limitative and that the invention can be further modified without departing from its scope.

The word "or" is equivalent to "and/or" unless otherwise noted. Similarly, the word "a (a) (n)", or "one (one)" is equivalent to "at least one" unless otherwise mentioned.