WO2018024649A1

WO2018024649A1 - Dental care composition comprising hydroxyapatite

Info

Publication number: WO2018024649A1
Application number: PCT/EP2017/069262
Authority: WO
Inventors: Joachim Enax; Adolf Klenk; Christoph Abels
Original assignee: Dr. Kurt Wolff Gmbh & Co. Kg
Priority date: 2016-08-01
Filing date: 2017-07-31
Publication date: 2018-02-08
Also published as: DE102016114189A1

Abstract

The present invention relates to a dental care composition which comprises hydroxyapatite, preferably synthetic hydroxyapatite, having a specific volume-based particle size distribution, and to the use thereof especially in caries prophylaxis.

Description

Dental care composition with hydroxyapatite

The present invention relates to a dentifrice composition comprising hydroxyapatite having a specific volume-based particle size distribution, and its use particularly in caries prophylaxis.

In view of the carbohydrate and sugar diet, dental care is gaining in importance in many countries. Thus, in addition to esthetic aspects, particular emphasis is placed on precaution, whereby the reduction or even avoidance of plaque and / or caries is the main focus here.

The different parts of a natural tooth are the tooth crown, the tooth neck and the tooth root, which are composed of several layers. Of these layers, one usually only sees the outer enamel, which surrounds the dentin and other layers. For example, to bite or grind food, the enamel is very hard. It consists of about 97 wt. Of hydroxyapatite, which has the following empirical formula: Ca ₅ (P0 ₄ ) 3 (OH). The dentin is also considered hard tooth substance and consists of about two thirds also of hydroxyapatite. Dentin contains proteins and water in addition to hydroxyl apatite and is therefore not as hard as enamel.

Dental caries is considered to be a multi-factorial disease, especially of enamel and dentin, with the involvement of microorganisms. Thus, in a first step on the tooth surface, a precipitate, also called pellicle, can be formed, among other things, from saliva protein. The rougher the tooth surface, the easier the precipitate can form or adhere to it. From this pellicle is then formed after a time a tooth surface covering, a few microns thick film. In this film, bacteria can then multiply and spread, and this film can be considered a biofilm. Furthermore, the bacteria mentioned in today's Food commonly present low molecular weight carbohydrates produce organic acids, such as gluconic and lactic acid.

Both these organic acids produced by bacteria and the dietary acids, such as fruit acids, can cause erosion of the hard tooth substance. Among other things, calcium phosphate is dissolved out of the enamel. If this process is not halted, or even vice versa, demineralization of the enamel and possibly also of the dentin may occur after some time. A defect in the hard tooth tissue is called a carious lesion. For example, carious lesions on the dentin layer can be identified as having a yellow to brown colouration of the corresponding part of the tooth. Thus, while carious lesions on the enamel alone can often be reduced or eliminated by re-mineralizing the enamel, in carious lesions that affect not only the enamel but also other layers, the damaged part of the tooth is usually removed and the resulting hole closed with a filling material.

In summary, it can be said that caries formation can be promoted by the interaction of the following factors: special bacteria on the pellicle

low tooth quality or mineral quality of the tooth

plaque

- low molecular weight carbohydrate-containing food

- Time

Investigations also suggest that the hydroxyapatite nanoparticles created by the natural attrition of enamel may interfere with biofilm management, and this attrition has been greatly reduced in the shift from high protein to carbohydrate foods. A possible caries prophylaxis could accordingly be due to the delivery of hydroxyl apatite nanoparticles.

In addition, there are several approaches, all of which aim to prevent tooth decay, to avoid the above-mentioned treatments.

As a current standard, caries prophylaxis with fluoride-containing dental care products can be considered. JM ten Cate, British Dental Journal, February 23, 2013, vol. 214, no. 4, pp. 161-167, describes in a review the use and mode of action In particular, fluoride-containing dental care products are expected to reduce caries through their regular use, assuming a sufficient amount of fluoride is incorporated into the hydroxyapatite structure In this way, fluorides should even be able to be used for remineralization at an early stage of tooth decay and prevent further demineralization of the dental hard material. A Fluoride sources in the mentioned dental care products are various fluoride compounds such as sodium fluoride, stannous fluoride, amine fluorides and monofmorphosphates. JM ten Cate: "The Need for Antibacterial Approaches to Improve Caries Control", Adv Dent Res 21: 8-12, August 2009, pp. 8-12, is concerned that fluoride delivery alone may not be sufficient to provide adequate caries prevention As noted above, bacteria also play a crucial role in caries formation, but the fluoride ion itself does not exhibit a pronounced antimicrobial effect. For this reason, caries prophylaxis compositions are contemplated which, in addition to fluoride, also include one or more antimicrobial substances. An example Chlorhexidine (CHX), the antimicrobial agent of the oral cavity, has been studied in many studies.

However, the use of fluorides in dental care products is also being discussed controversially, as negative side effects are feared. One of these is the so-called fluorosis, which is caused by an excessive fluoride intake and has symptoms such as nausea, vomiting and diarrhea. Other examples are bone fmorosis, which is manifested by thickening of the outer bone layer and the associated loss of elasticity and resilience of the bones, and the molten fluorosis, which can be recognized by the appearance of whitish enamel spots on the tooth surface. In addition, it is reported that the ingestion of high-dose dental care products, especially in children can trigger an acute fluoride intoxication, which can sometimes even be fatal. Furthermore, it is reported that WHO is unable to establish a value for a daily fluoride requirement since fluoride is not an essential trace element and thus there are no diagnostic parameters and no evidence of the existence of clinical symptoms of "fluoride deficiency".

The use of an antimicrobial substance such as chlorhexidine is not uncontroversial in dental care, in particular caries prophylaxis. It has been reported that a relevant effect for caries prophylaxis is not always reproducible and occurs only in a part of the cases studied. Furthermore, the antimicrobial effect of chlorhexidine is not limited to the oral caries involved in caries formation, but also includes beneficial bacteria. In addition, a long-term treatment with chlorhexidine-containing products leads to undesirable side effects, such as tooth discoloration and taste disorders.

Biomimetic tooth and mouth rinsing solutions with artificial enamel may, for example, contain zinc carbonate hydroxyapatite. This zinc carbonate hydroxyapatite is also known commercially as a microrepair. Zinc carbonate hydroxyapatite based products may alter the initial bacterial colony reduce the surface area of the enamel surface without having antimicrobial properties that can interfere with the environmental balance of the oral cavity. In addition, these products are intended to serve, among other things, for remineralization and the repair of microfine defects in enamel as well as the formation of a protective layer.

As can be seen, there continues to be a need for biomimetic or bioinspired dental care products, in particular for the prevention of caries. Therefore, it is the object of the present invention to provide a product for dental care while overcoming the disadvantages of the prior art.

In particular, a dental care product is to be provided which remineralises already existing, smaller carious lesions and / or repairs microfine defects in the enamel. Furthermore, a protective layer should be applied to the tooth and / or open dentinal tubules should be closed.

For this purpose, the above-mentioned effects are to be achieved, the disadvantages which can be associated with the use of fluoride, should be avoided.

Furthermore, the adhesion of bacteria to the enamel should be advantageously reduced without significantly disturbing the eclogical balance in the oral cavity and / or risking tooth discoloration or taste disorder.

These objects are achieved by the present application according to the claims. In particular, it could unexpectedly be found that the composition according to the invention advantageously remineralises smaller carious lesions and / or repairs microfine defects in the enamel, especially in patients with Dry mouth / salivary poverty. Furthermore, by the fiction, contemporary composition, a protective layer can be applied to the tooth and further it could be found that the enamel has a favorable solubility and resistance to acid after the application of the composition according to the invention. In addition, in the present composition to antimicrobial substances (such as chlorhexidine) can be dispensed with as an adjuvant. Thus, an excellent caries prophylaxis can be ensured, for example, without disturbing / destroying the bacterial balance in the oral cavity and without risking unpleasant side effects.

The subject of the present invention is a dentifrice composition comprising Ca ₅ (PO ₄ ) 3 (OH) in which the Xso value of the volume-based particle size distribution Q ₃ (x) is 1, 0 - 15.0 μιη, wherein the Xso value of the volume-based particle size distribution is measured by means of laser diffraction.

In the context of the present application, the dentifrice composition according to the invention may also comprise oral cosmetic and / or medical care products. The Cas (P0 ₄ ) ₃ (OH) comprised in the present dentifrice composition is preferably prepared synthetically. This means that the Ca ₅ (PO ₄ ) ₃ (OH) used is preferably not obtained by burning out the organic constituents from animal material such as, for example, bones. In a preferred embodiment, Cas (P0 ₄ ) ₃ (OH), also called hydroxyapatite, is present in pure form. A pure form is according to the invention exactly then

2+ 3- before, when the Ca ₅ (P0 ₄₎ ₃ (OH) containing ions (Ca, P0 ₄ ^"and ^OH") are each less than 1%, preferably less than 0.5%, still more preferably less than 0, 1% are substituted by one or more other ions. For example, in pure hydroxyapatite, the Ca ²⁺ ions are exemplified by Mg ²⁺ or Zn ²⁺ and the OH ^" ions are less than 1%, for example, fluoride or chloride, preferably less than 0.5%, more preferably less than 0, 1% substituted. Further preferably, hydroxyapatite according to the invention contains no doping, such as a zinc carbonate doping.

Thus, the composition according to the invention comprises (pure) Ca ₅ (PO ₄ ) 3 (OH), hydroxyapatite, as the only apatite component.

The X5 ₀ value of the volume-based particle size distribution Q ₃ (x) of the Ca ₅ (P0 ₄₎ ₃ (OH) is from 1, 0 to 15.0 μιη, preferably 1, 2 to 12.0 μιη, more preferably 1, 5 to 10.0 μιη, more preferably 2.0 to 5.0 μιη, wherein the Xso value of the volume-based particle size distribution is measured by laser diffraction.

For this purpose, a sample of the hydroxyapatite is first sonicated in an ultrasonic homogenizer with an energy output of 96 W for 9 minutes and then for 3 minutes in a device for sample preparation. The subsequent particle size distribution measurement (laser diffraction) is carried out in a particle size determination instrument at a temperature of 25 ° C + 0.3 ° C and the corresponding values are calculated according to the Mie theory. The measuring instruments used are exclusively commercially available devices.

In a preferred embodiment of the invention, the Ca ₅ (PO ₄ ) ₃ (OH) has a hexagonal crystal lattice in which the length of the a-axis is 0.930 to 0.950 nm, preferably 0.933 to 0.948 nm, particularly preferably 0.936 to 0.945 nm and the length the c-axis is 0.680 to 0.700 nm, preferably 0.682 to 0.696 nm, particularly preferably 0.685 to 0.692 nm. The lengths of the a-axis and the c-axis are determined by a Rietveld evaluation of the corresponding X-ray powder diffractograms. The X-ray powder diffractograms themselves are obtained by means of a measurement with a conventional powder diffractometer at the routine settings.

It is further preferred that the Ca ₅ (PO ₄ ) ₃ (OH) used according to the invention has a largely spherical crystal morphology. In particular preferred that the Ca ₅ (P0 ₄ ) 3 (OH) has no needle-shaped crystal morphology. Such a needle-like crystal morphology could entail undesirable disadvantages similar to asbestos. In a preferred embodiment, the Cas (P0 ₄ ) 3 (OH) is present in aggregated form. In this case, an aggregation is understood to mean an aggregation of molecules or particles into a larger dressing, the aggregate. This assembly or aggregate is governed by different forces and / or bonding modes, such as ionic bonding. Van der Waals forces, between which molecular forces or other chemical bonding modes are evoked and held together. The degree of aggregation and also the size of the aggregate can be determined by scanning electron microscopy. It is preferred that in Cas (P0 ₄ ) 3 (OH) in aggregated form, even after high energy input no nanoparticles can be detected. Nanoparticles are particles with a size of less than 100 nm. With regard to nanoparticles, it is not yet known if they can have an adverse effect on humans, for example after a possible penetration of the intestinal wall.

As described above, the dentifrice composition according to the invention may also comprise oral medical and / or cosmetic care products. These oral medical and / or cosmetic care products may be in any form known to those skilled in the art. The dentifrice composition according to the invention is preferably in the form of a toothpaste, a mouth gel, a gum bag or a mouth rinse.

A toothpaste, also referred to as toothpaste, can be used for mechanical tooth cleaning and is a soft or semi-solid composition for oral use, especially on the teeth. A mouth gel is a gel-like composition that can be used in the treatment of discomfort / pain, for example on the oral mucosa, gums and lips or to combat dry mouth. The Mundgel is usually applied to the painful area such as in the case of aphthae on the oral mucosa.

For a gingival gum gel, essentially the same applies as for a mouth gel, with the gum pocket gum being applied essentially to the gum and the pockets it contains.

A mouthwash, also known as mouthwash, is a liquid that can be used, among other things, for the prophylaxis of tooth decay and other disorders in the mouth. In a particularly preferred embodiment, the composition according to the invention is in the form of a toothpaste.

In an alternative particularly preferred embodiment, the composition according to the invention is in the form of a mouthwash.

The dentifrice composition according to the invention preferably contains Ca ₅ (PO ₄ ) 3 (OH) in an amount of 2.5 to 15% by weight, preferably 3.5 to 13% by weight, in particular 4.5 to 11% by weight, based on the total weight of the dentifrice composition. It is known that the amount of Cas (P0 ₄ ) 3 (OH) can also be dependent on the form in which the dentifrice composition (toothpaste, oral gel, etc.) is present. For example, a toothpaste may contain a greater amount of Cas (P0 ₄ ) 3 (OH) than a mouthwash.

In a preferred embodiment, the dentifrice composition of the invention may contain one or more pharmaceutical or cosmetic adjuvants. These pharmaceutical or cosmetic auxiliaries are described examples game, in toothpastes, Monographs in Oral Science, Vol. 23, I ^st edition 2013.

Preferably, one or more pharmaceutical or cosmetic adjuvants comprise antimicrobials, pH regulators, xylitol, abrasives, and flavoring agents. Antimicrobial substances are substances that kill microorganisms, such as bacteria, or can greatly reduce their multiplication. In addition to antimicrobial substances with a non-specific defense against bacteria and fungi, there are also those that, for example, only act against targeted bacteria. Through the use of antimicrobial substances, for example, bad breath can also be combated. Preferably, antimicrobial substances may be contained in an amount of 0.01 to 1.0% by weight, preferably 0.05 to 0.5% by weight, in the dentifrice composition of the present invention. Examples of the antimicrobials used in oral care are zinc compounds such as zinc chloride and zinc nitrate, as well as chlorhexidine, triclosan, cetylpyridinium chloride and stannous chloride.

In a particularly preferred embodiment, the composition according to the invention contains no chlorhexidine and / or triclosan. pH regulators are substances that can adjust a specific pH range, preferably a neutral range of pH 6.5 to 7.5. In the case of an acidic composition, there would be a risk of demineralization of the tooth hard substance (erosion). Examples of pH regulators are sodium hydroxide (NaOH) or phosphoric acid (H ₃ PO ₄ ), which can be used according to the desired pH. To raise too low a pH, sodium hydroxide may be added while at too high a pH, phosphoric acid may be added.

Furthermore, the dentifrice composition according to the invention preferably contains xylitol. Xylitol can minimize the number of caries bacteria and inhibit their growth. Furthermore, xylitol can stimulate the salivation. The composition of the invention may contain xylitol in an amount of 0.5 to 10% by weight, preferably 0.7 to 8% by weight, based on the total weight of the dentifrice composition. In addition to xylitol, the composition of the invention may contain other sugar alcohols, such as sorbitol. Abrasives, also known as cleaning agents or abrasives, usually remove plaque and harmful bacteria from the tooth surface during tooth cleaning, along with the toothbrush, and may also lighten the skin. Abrasives may preferably be included in the dentifrice composition of the invention in an amount of up to 10% by weight, based on the total weight of the dentifrice composition. Examples of abrasives are whiting, marble powder and / or silicate compounds, such as silica. Flavorings may give the desired dentifrice composition of the invention. In addition, aroma substances can be saliva-stimulating, whereby the moisture of the saliva can have a positive influence on the remineralization of the tooth. An example of a saliva-stimulating flavorant is pellitorin, especially trans-pellitorin.

Furthermore, dentifrice compositions often contain fluoride compounds such as sodium fluoride, amine fluorides or zinc fluoride. In a particularly preferred embodiment, the dental care composition according to the invention contains no fluoride compound and is thus fluoride-free.

In a preferred embodiment, the dentifrice composition according to the invention is a toothpaste and contains

5 to 15 wt.%, Preferably 8 to 12 wt.% Ca ₅ (P0 ₄ ) 3 (OH) _j in which the Xso value of the volume-based particle size distribution Q ₃ (x) is 1, 0 to 15.0 μιη .

From 0.05 to 0.5% by weight, preferably from 0.07 to 0.35% by weight, zinc salt, in particular zinc chloride,

0.01 to 0.6% by weight, preferably 0.015 to 0.4% by weight, antimicrobial substance, in particular cetylpyridinium chloride,

0.1 to 3% by weight, preferably 0.3 to 2.0% by weight, pH regulator, in particular phosphoric acid, From 3 to 10% by weight, preferably from 4 to 8% by weight, of xylitol,

1 to 10 wt.%, Preferably 2 to 8 wt.%, Abrasivstoff, in particular silica and

0.25 to 5% by weight, preferably 1.5 to 4.5% by weight, of flavoring agent, in particular of pellitorin, the data in% by weight referring to the total weight of the dental care composition. The pH is in a neutral range of pH 6.5 to 7.5.

In an alternative preferred embodiment, the dentifrice composition of the invention is a mouthwash and contains

2 to 7 wt.%, Preferably 3 to 6 wt.% Ca ₅ (P0 ₄ ) 3 (OH) _j at which the Xso value of the volume-based particle size distribution Q ₃ (x) 1, 0

- 15.0 μιη,

0.2 to 1.0% by weight, preferably 0.3 to 0.7% by weight, zinc salt, in particular zinc PCA,

0.01 to 0.06% by weight, preferably 0.015 to 0.04% by weight, antimicrobial substance, in particular cetylpyridinium chloride,

- 0, 1-3 wt.% PH regulator,

0.5 to 2 wt.%, Preferably 0.75 to 1, 5 wt.%, Xylitol and 0.25 to 5 wt.% Flavoring agent, in particular pellitorin,

the data in% by weight relate to the total weight of the dental care composition. The pH is in a neutral range of pH 6.5 to 7.5.

Furthermore, the present invention relates to the dentifrice composition of the invention for use in the prophylaxis (prevention) and treatment of caries. By using the dentifrice composition according to the invention, the tooth hard substance, in particular the enamel, is protected from harmful bacteria for a time prior to the increased colonization. In addition, the dentifrice composition according to the invention remelted so that caries, especially at an early stage, for example, by the repair of microcracks can be treated. In a preferred embodiment, the dentifrice composition of the present invention can be used in the prevention and treatment of caries in people with xerostomia (dry mouth).

Some medications and diseases can cause dry mouth. This often applies to older people. The caries risk is particularly high in people with dry mouth, as the mineralizing effect is limited due to the low salivation. In the case of the composition according to the invention, the hydroxylapatite is already present and does not have to be formed by remineralization.

Another object of the present invention is Ca ₅ (PO ₄ ) 3 (OH), in which the Xs ₀ value of the volume-based particle size distribution Q ₃ (x) is 1, 0 to 15.0 μιη, for use in prevention and treatment of caries, wherein the Xso value of the volume-based particle size distribution is measured by laser diffraction. It has been found that by Cas (P0 ₄ ) ₃ (OH), in which the Xso value of the volume-based particle size distribution Q ₃ (x) is 1, 0 to 15.0 μιη, the settlement of harmful bacteria on the Tooth enamel can be reduced or even prevented without, for example, anti-microbial substances that can affect bacteria in the entire oral cavity must be used. The invention will be explained below by way of examples.

Example 1:

Three different commercially available samples of hydroxyapatite, Cas (P0 ₄ ) ₃ (OH), were measured. Volume-based particle size distribution Q3 (x): The Xso value of the volume-based particle size distribution Q ₃ (x) was determined as described in the above description and the following values were obtained:

X-Ray Powder Diffractograms: X-ray powder diffractograms were taken as described above. FIGS. 1 to 3 show that the samples have only one mineral phase, namely that of the pure Ca ₅ (PO ₄ ) ₃ (OH).

Crystallographic properties: Using the Rietveld analysis of the corresponding X-ray powder diffraction patterns, the lengths of the a- and c-axes of the hexagonal crystal lattice were determined and the following values were obtained:

Example 2:

A toothpaste was made containing the following ingredients:

Demineralized water 117.99 g (39.33%) xylitol 21.00 g (7.00%)

Zinc chloride 0.60 g (0.20%)

Glycerine 39.00 g (13.00%)

Sorbitol solution 45.00 g (15.00%) Sodium carboxymethylcellulose) 3.00 g (1.00%)

Aroma 3.00 g (1.00%)

N-cetylpyridinium chloride 0.060 g (0.020%)

Hydroxylapatite 30.00 g (10.00%)

Aroma 1.05 g (0.35%)

Silica 15.00 g (5.00%)

Silica, highly dispersed 7.50 g (2.50%)

Sodium methyl cocoyl taurate 3.00 g (1.00%)

Sodium cocoylglycinate 3.00 g (1.00%)

Tetrapotassium pyrophosphate 9.00 g (3.00%)

Ortho-phosphoric acid 1.80 g (0.60%)

The toothpaste is a light beige, homogeneous, creamy paste with a taste of menthol and anise and an average pH of 7.2.

Example 3:

A mouthwash was prepared containing the following ingredients:

Purified Water 6202.98 g (68.922%) hydroxyethylcellulose 36.00 g (0.40%) N-cetylpyridinium chloride 1.80 g (0.02%) zinc PCA 45.00 g (0.50%) xylitol 90.00 g (1, 00%)

Sweetener 0.72 g (0.008%)

Aloe Vera Powder 4.50 g (0.05%) Glycerin 1980.00 g (22.00%) Aroma 45.00 g (0.50%) Vegetol Matricaria 45.00 g (0.50%)

Sodium methyl cocoyl taurate 9.00 g (0.10%) tetrapotassium pyrophosphate 45.00 g (0.50%) Disodium pyrophosphate 45.00 g (0.50%)

Hydroxylapatite 450.00 g (5.00%)

The mouthwash is a whitish suspension with a taste of menthol and anise and has an averaged pH of 6.6.

Claims

claims

1. dentifrice composition, comprising: - Ca ₅ (P0 ₄₎ 3 (OH) _j wherein the X ₅ o-value of the volume-based particle size distribution Q ₃ (x) 1.0 to 15.0 is μιη, wherein the X ₅ o Value of the volume-based particle size distribution is determined by means of laser diffraction.

The dentifrice composition according to claim 1, wherein the X ₅ o value of the volume-based particle size distribution Q ₃ (x) of Cas (P0 ₄ ) ₃ (OH) is 2.0 to 5.0 μm.

The dentifrice composition according to claim 1 or 2, wherein Ca ₅ (PO ₄ ) ₃ (OH) has a hexagonal crystal lattice in which the length of the a-axis is 0.93 to 0.95 nm and the length of the c-axis is 0, 68 to 0.70 nm, wherein the length of the α-axis and that of the c-axis is determined by a Rietveld evaluation of the corresponding X-ray powder diffractograms.

The dentifrice composition of claim 3, wherein Cas (PO ₄ ) ₃ (OH) has no needle-shaped crystal morphology.

The dentifrice composition according to any one of claims 1 to 4, wherein Ca ₅ (PO ₄ ) ₃ (OH) is in aggregated form.

The dentifrice composition of any one of claims 1 to 5, wherein the dentifrice composition is a dentifrice, oral gel, gum pocket or mouthwash gel.

The dentifrice composition according to any one of claims 1 to 6, wherein the dentifrice composition comprises Cas (P0 ₄ ) ₃ (OH) in an amount of 2.5 to 15% by weight, based on the total weight of the dentifrice composition.

The dentifrice composition of any one of claims 1 to 7, wherein the dentifrice composition contains one or more pharmaceutical or cosmetic adjuvants.

The dentifrice composition of claim 8, wherein one or more pharmaceutical excipients comprises antimicrobials, pH regulators, xylitol, abrasive and flavoring agents.

The dentifrice composition of claim 9, wherein the antimicrobial substance does not comprise chlorhexidine or triclosan.

The dentifrice composition of any one of claims 8 to 10, wherein the dentifrice composition does not contain a fluoride compound (s).

12. Use of the dental care composition according to any one of claims 1 to 1 1 in the treatment and prophylaxis of caries.

13. Ca ₅ (P0 ₄ ) ₃ (OH) in which the Xso value of the volume-based particle size distribution Q ₃ (x) is 1, 0 to 15.0 μιη, for use in the treatment and prevention of caries, wherein the Xso value of the volume-based particle size distribution is determined by means of laser diffraction.