DE10252929A1 - Using sparingly soluble calcium salt for local remineralization of teeth, useful for treating sensitive teeth, also inhibits development of caries - Google Patents

Abstract

Use of a composition (A) that contains sparingly soluble calcium salt (I) and/or its composite of particle size 1-500 nm for local remineralization of teeth.

Description

The invention relates to the use a composition for the local mineralization of teeth, thereby characterized that they have poorly water soluble calcium salt and / or whose composites contains being the hardly water-soluble Calcium salt a particle size of 1 up to 500 nm.

The increased sensitivity to pain of sensitive teeth to external stimuli, such as temperature, results primarily from the exposure of the tooth necks. The dentinal tubules present in the tooth necks are therefore also open and allow the stimuli to come into direct contact with the nerve tissue of the tooth. Nerve anesthetics such as KCl or SrCl ₂ are therefore often added to toothpastes and pastes for hypersensitive teeth.

The disadvantage is that these narcotics affect the pulp and thus the irritability of the nerve and not the cause, combat the exposed tubules. It also uses such narcotics Products containing usually after an application period of is rinsed out of the mouth for one to three minutes, so the dwell time in the oral cavity is very low and the effect of the nerve anesthetic accordingly subsides quickly.

The object of the present invention is to use an alternative, easy-to-use remedy longer Provide lasting effect that is sensitive to pain of sensitive teeth reduced without just numbing the nerves.

This task is solved by the use of a composition for the local mineralization of teeth characterized in that it contains poorly water-soluble calcium salt and / or whose composites contains being the hardly water-soluble Calcium salt a particle size of 1 up to 500 nm.

Calcium salts which are sparingly soluble in water are to be understood as those salts which are less than 0.1% by weight (1 g / l) soluble in water at 20 ° C. Such suitable salts are, for example, calcium hydroxyphosphate (Ca ₅ [OH (PO ₄ ) ₃ ]) or hydroxylapatite, calcium fluorophosphate (Ca ₅ [F (PO ₄ ) ₃ ]) or fluoroapatite, fluorine-doped hydroxyapatite with the composition Ca ₅ (PO ₄ ) ₃ (ON, F) and calcium fluoride (CaF ₂ ) or fluorite or fluorspar as well as other calcium phosphates such as di-, tri- or tetracalcium phosphate (Ca ₂ P ₂ O ₇ , Ca ₃ (PO ₄ ) ₂ , Ca ₄ P ₂ O ₉ , Oxyapatite (Ca ₁₀ (PO ₄ ) ₆ O) or non-stoichiometric hydroxyapatite (Ca _{5 – ½ ( x + y)} (PO ₄ ) _{3 – x} (HPO ₄ ) _x (OH) _{1 – y} ). Carbonate-containing calcium phosphates are also suitable ( _e.g. Ca ₅ _ _{½ (x + y + z)} (PO ₄ ) ₃ _ _x _ _z (HPO ₄ ) _x (CO ₃ ) _z (OH) _1-y ), calcium hydrogen phosphate (e.g. CaH (POa) · 2 H ₂ O) and octacalcium phosphate (e.g. Ca ₈ H ₂ (PO ₄ ) ₆ · 5 H ₂ O).

Suitable as a mineralizing agent preference is given to a finely divided, sparingly water-soluble Calcium salt, which is selected is made of hydroxyapatite, fluoroapatite, fluorine-doped hydroxyapatite and mixtures thereof. These calcium salts can best be found in the tooth material accumulate and cause mineralization.

The little or hardly water-soluble calcium salt according to the invention has a particle size or particle fineness from 1 to 500 nm. The diameter should be the particle fineness here of the particles can be understood in the direction of their greatest length extension. The average particle size refers to a volume-averaged one Value. The nanoparticles according to the invention have a larger surface / volume ratio than the microcrystalline particles and are characterized by a higher reactivity in comparison to these out. You can therefore better for the remineralization of demineralized tooth material be used. Re-storage is under remineralization of ions in bone material, i.e. the filling of imperfections within to understand the existing dental hard tissue such as enamel and dentin.

Surprisingly it has now been found that the nanoparticulate calcium salts and / or their composites are able to not only remineralize the teeth but also close the tubules of the exposed tooth necks biomimetically. The Forming, in their nanostructure very similar to the tooth material Crystal layer, the formation of which is further referred to as neomineralization is to be understood is able to access stimuli directly to block the nerve endings. In the long term it arises with regular use a sufficiently thick layer of biomimetic material. Furthermore can also prevent the development of caries. According to the invention is under the general term mineralization both the re- and understand the neomineralization.

The composition to be used according to the invention is applied locally to the painful area on the tooth and there leave to act. Due to the good adhesion of the compositions on the tooth occurs as the primary Effect of closure of the tubules. The stimulus transmission is thereby interrupted and the acute sensitivity to pain strong decreases.

Under composite materials Composites understood that a poorly water-soluble calcium salt and as well include other components and microscopic heterogeneous, macroscopic but present homogeneous aggregates.

The finely divided calcium salts or the fine-particle calcium salt primary particles present in the composite materials can also be encased by one or more surface modification agents.

This can, for example, facilitate the production of composite materials in cases in which the nanoparticulate calcium salts are difficult to disperse. The surface mo Dification agent is adsorbed on the surface of the nanoparticles and changes them in such a way that the dispersibility of the calcium salt increases and the agglomeration of the nanoparticles is prevented.

In addition, through a surface modification the structure of the composite materials and the loading of others Components with the nanoparticulate Calcium salt can be influenced. This way it is in use of composite materials possible in mineralization processes, influence on the course and speed of the mineralization process to take.

Surface modification agents are understood to mean substances which physically adhere to the surface of the finely divided particles, but which do not react chemically with them. The individual molecules of the surface modification agents adsorbed or bound on the surface are essentially free of intermolecular bonds with one another. Surface modifiers are to be understood in particular as dispersants. Dispersants are also known to the person skilled in the art under the terms surfactants and protective colloids. Suitable surfactants or polymeric protective colloids can be found in the German patent application DE 198 58 662 A1 be removed.

The production of the composite materials according to the invention, in which the primary particles of the calcium salts surface modified can, according to analogous precipitation processes as described above, but with the precipitation of nanoparticulate Calcium salts or the composite materials in the presence of one or More surface modifiers he follows.

According to a preferred embodiment does the calcium salt, which is sparingly or poorly soluble in water, have a particle size or Particle fineness from 5 to 300 nm, in particular from 5 to 100 nm on. An advantage of these particularly small particle sizes or -fineness is that these primary particles are particularly effective Mineralization of the teeth demonstrate.

According to a particularly preferred embodiment, the calcium salts according to the invention have an elongated, in particular rod-like or needle-like shape. This has the particular advantage that they are very similar to the shape of the biological apatite (eg bone or dentin patatite) and therefore have a particularly good ability to mineralize. Such calcium salts can be made, for example, from DE 198 58 662 A1 known processes in the form of rod-shaped primary particles.

According to a preferred embodiment are 0.001 to 5% by weight of poorly water-soluble calcium salt and / or its composites included. It is preferred to use 0.01 to 2% by weight and in particular 0.1 to 1 wt .-% calcium salt and / or its composites in the composition according to the invention use.

According to a preferred embodiment contains the composition according to the invention a composite of a poorly soluble Calcium salt with a protein component.

Proteins can reach the surface of the Nanoparticles are adsorbed, creating a composite material Protein and poorly water soluble Calcium salt is formed. Surprisingly it was found that the sparingly soluble Calcium salts and especially the composites of poorly water-soluble Calcium salt with proteins in addition to remineralization of the tooth are also able to measure the extent of major damage to the dentist or tooth enamel through education completely reduce new crystals.

In particular, coagulation and agglomeration of the calcium salts by the adsorbed proteins prevents and slows crystal growth. With mineralization of a tooth, it is particularly advantageous if it is not an uncontrolled one Crystal growth takes place, which only form a loose crystal structure could. Through the protein scaffold crystal growth can be slowed down and controlled. So will a particularly dense and solid crystal structure is formed.

In the natural formation of bone material such as. of tooth enamel and dentin results in a protein matrix the orderly accumulation of hydroxyapatite in the tooth or bone, the main one consists of collagen and other proteins. In the application according to the invention of the compositions with the composites of poorly soluble Calcium salt and proteins become even more similar to natural teeth Material formed, which is a particularly good closure of holes in the dental hard tissue and in particular of dentine tubules. This biomimetic closure stays on the teeth for a particularly long time adhere and affect sensitivity to pain and protection the teeth positive and sustainable in front of tooth decay.

The in the composition according to the invention protein component contained is selected in particular from Proteins, protein degradation products and derivatives of proteins or Protein degradation products.

All proteins come as proteins independently of their origin in question, both animal and vegetable Proteins. Suitable animal proteins are e.g. Collagen, fibroin, Elastin, keratin and albumin. Suitable vegetable proteins are e.g. Wheat and wheat germ proteins (gluten), rice protein, soy protein, oat protein, Pea protein, almond protein and potato protein. Also single-cell proteins such as. Yeast protein or bacterial proteins are suitable.

Proteins preferred according to the invention are animal products such as collagen and keratin.

But the protein can also be made a vegetable or marine source.

Products that are characterized by hydrolytic, oxidative or reductive degradation of water-insoluble proteins to oligo- and polypeptide structures with lower molecular weight and with an improved water solubility are available.

The hydrolytic degradation is more insoluble in water Proteins are the main method of degradation; it can be under the catalytic Influence of acids, Alkalis or enzymes. Are preferably suitable all those protein breakdown products that are no longer broken down than to achieve water solubility required.

To the little degraded protein hydrolyzates counts for example the preferred gelatin in the context of the present invention, which Molar masses in the range of 15,000 to 400,000 D may have. gelatin is a polypeptide, primarily by hydrolysis of collagen is obtained under acidic or alkaline conditions. Especially gelatin obtained under acidic or strongly acidic conditions is preferred. The gel strength the gelatin is proportional to its molecular weight, i. H., one stronger hydrolyzed gelatin gives a lower viscous solution. The gel strength the gelatin is in bloom numbers specified. During the enzymatic cleavage of the gelatin Polymer size strong decreased, which leads to very low Bloom numbers.

Among derivatives of proteins and Protein breakdown products are chemically modified proteins or Understand protein hydrolyzates, e.g. free by acylation Amino groups, by the addition of ethylene or propylene oxide and Hydroxyl, amino or carboxyl groups or by alkylation of Hydroxyl groups of the protein or protein degradation product or one Hydroxyalkyl derivative thereof, e.g. with epoxypropyl trimethylammonium chloride or 3-chloro-2-hydroxypropyltrimethylammonium chloride.

In a particularly preferred embodiment selected the protein component from gelatin, their hydrolyzates and mixtures thereof. It should be preferred a protein component in an amount of at least 1% by weight, preferred from 1 to 50% by weight, in particular from 20 to 40% by weight.

In the composites according to the invention are the primary particles the calcium salts on the framework associated with the protein component. The proportion of protein components in such composite materials is between 0.1 and 50% by weight however, preferably between 1.0 and 45% by weight, in particular 20 to 40% by weight based on the weight of the composite material.

Hydroxyapatite nanoparticles are particularly suitable, which have a clearly recognizable crystalline morphology, whose particle fineness is therefore in the range from 5 to 300 nm. Composite materials in which the finely divided materials are also suitable slightly soluble Calcium salts with particle sizes from 5 to 300 nm together with finely divided proteins, protein hydrolyzates or derivatives thereof a spatial Form the structure in such a way that the finely divided calcium salts of the protein structure are superimposed, so to speak, spatially depict them. From such preferably suitable nanoparticulate calcium salts and protein components lead existing composite materials for a particularly good biomimetic closure of holes in teeth when used according to the invention the composition.

Calcium salts which are difficult to dissolve in water are particularly good in stick form attach to the protein chains. This leads to a significantly improved Cohesion of the composite material. Are particularly suitable primary particle with a particle fineness of 5 to 300 nm, because this is special small crystallites are very similar to the form of biological apatites and because of its small size, it also adheres even better to the protein chains can accumulate. These composites lead thereby a particularly effective remineralization and one excellent closure of holes in the tooth material due to the special ability to re-mineralize.

Composite materials which are suitable according to the invention can be prepared by precipitation from aqueous solutions of water-soluble calcium salts with aqueous solutions of water-soluble phosphate and / or fluoride salts in the presence of protein components by various methods, as already described in the German patent application DE 199 30 335 are described.

For the preparation of the composition according to the invention is the Active ingredient, i.e. the finely divided calcium salt, which is sparingly soluble in water and / or its composites, preferably the composite material from the sparingly soluble Calcium salt and a protein component, simply added and stirred in. According to another preferred embodiment contains the composition in addition to the poorly water-soluble calcium salt and / or whose composites additionally at least one fluoride salt. Surprisingly it was found that the addition of fluoride to a synergistic reinforcement the nucleating effect of the poorly soluble calcium salts and / or lead their composites. The addition of sodium and / or potassium fluoride is particularly preferred. The mineralizing effect shows an approximately five-fold synergistic reinforcement of the nucleating effect with simultaneous addition of poorly soluble Calcium salts and small amounts of fluoride, preferably from 0.05 to 0.15 wt .-%, in particular from 0.08 to 0.12 wt .-% fluoride salt.

According to a particularly preferred embodiment is the composition of an ointment, a cream, a paste or a gel. These compositions are particularly useful Extend exposure time and the sensitive tooth necks to protect. This also ensures good applicability, so that the user can apply the compositions himself.

The preparations to be used according to the invention can in principle be based on such auxiliaries worn, a targeted application is possible. In particular, the application of the compositions with the aid of a soft toothbrush, a brush, swab or swab (eg cotton swab) is preferred locally and specifically to the area of the teeth to be treated.

Are suitable for the use according to the invention the conventional ointment bases well known to those skilled in the art.

In particular, the suspensions or Water-based gels are made to be well tolerated to ensure. The addition of suitable dispersing or wetting agents can do this serve the hardly water-soluble Keep calcium salt and / or its composites in the suspension. Organic thickeners are particularly suitable as gel formers and their derivatives.

In addition to synthetic organic thickeners are particularly natural organic thickeners, especially agar agar, carrageenan, tragacanth, Gum arabic, alginates, pectins, polyoses, guar flour, locust bean gum, Strength, Suitable for dextrins, gelatine and casein. Modified natural products are also preferred, especially carboxymethyl cellulose and other cellulose ethers, hydroxyethyl cellulose and hydroxypropyl cellulose as well as core meal ether. Synthetic organic thickeners such as Polyethers or inorganic thickeners such as polysilicic acids and / or Clay minerals (e.g. montmorillonites, zeolites or silicas) can also used according to the invention become.

A reduction or delay of water solubility (or the dissolution rate in saliva) the exposure time of the poorly water-soluble calcium salts and thus increases the Effect. So the tooth stays over it out even during the exposure time before external influences and Protected stimuli. An acute decrease in pain sensitivity along with a long-term improvement in the situation of the exposed cervicals leads at Consumers to a high level of acceptance of those to be used according to the invention Medium.

According to a further preferred embodiment, the composition contains flavorings, sweeteners, fillers and / or further auxiliaries (such as glycerol or mineral salts, for example Zn ²⁺ or Mg ²⁺ ).

Natural and identical to nature can be used as flavorings Aroma substances, in particular aroma oils such as. Peppermint oil, spearmint, Eucalyptus oil, anise oil, Fennel oil, Caraway oil and synthetic aromatic oils can be used become. This is particularly preferably done in herbal and / or cough drops as well as chewing gum.

Active ingredients such as e.g. Menthol and / or vitamins, contained in the composition according to the invention his. You can also Organophosphonates, e.g. 1-hydroxyethane-l, 1-diphosphonic acid, phosphonopropane-1,2,3-tricarbonic acid (Na salt) or 1-azacycloheptane-2,2-diphosphonic acid (Na salt), and / or pyrophosphates added, which reduce the formation of tartar.

Sweeteners such as sodium saccharin, acesulfame-K, aspartame ^®, sodium cyclamate, stevioside, thaumatin, sucrose, lactose, maltose, fructose or glycyrrhizin are also preferably contained.

In particular, as a humectant Glycerin, 1,2-propylene glycol I, sorbitol, xylitol and polyethylene glycols be used.

As preservatives everyone can approved preservatives are used, e.g. sorbine or benzoic acid and their derivatives, e.g. Sodium benzoate and parahydroxybenzoate (Sodium salt) and especially their esters, such as the Methyl, ethyl or propyl ester of parahydroxybenzoic acid, sulfur dioxide or sulfurous acid, Sodium or potassium nitrite.

Buffer substances, such as primary, secondary or tertiary Alkali phosphates or citric acid or sodium citrate, dyes and pigments to achieve a appealing appearance also be included.

According to the invention, wound healing and anti-inflammatory Active ingredients, e.g. Allantoin, urea, azulene, panthenol, acefylsalicylic acid derivatives, plant extracts or vitamins such as Retinol or tocopherol may be included.

On cleaning bodies, abrasive or polishing materials, as used in toothpastes or toothpaste, especially to reinforce the Cleaning performance when brushing teeth are contained in the preparations to be used according to the invention to be dispensed with.

According to a preferred embodiment the composition has a viscosity of 2000 to 12000 mPa · s, in particular 5000 to 9000 mPas on.

The viscosity values given refer to measurements with a cone-plate viscometer with a 60 mm cone and 2 ° cone angle at a temperature of 25 ° C and a shear rate of 10 s ^–1 .

Advantageously solve such compositions with high viscosity worse from the tooth and also the resolution in watery saliva is reduced. The good adhesion to the tooth increases the exposure time and thus promotes the formation of the open spaces, especially the dentinal tubules, occlusive new biomimetic mineral layers. The compositions should but still be viscous enough to be a simple one that can be carried out by the home user Allow application.

The following examples are intended to illustrate the invention explain, without restricting it to:

Example:

1. Preparation of the compositions:

To prepare the apatite-gelatin composite, 2000 ml of demineralized water are placed in a 4 l beaker thermostated at 25 ° C., in which 44.10 g (0.30 mol) of CaCl ₂ .2H ₂ O (Fisher Chemicals pa) are dissolved. Separately, 35 g of gelatin (type A, DGF-Stoess, Eberbach) are dissolved in 350 ml of demineralized water at about 50 ° C. Both solutions are combined and stirred vigorously with a propeller stirrer. The pH is adjusted to 7.0 with dilute aqueous base.

300 ml of a 0.6 M (NH ₄ ) ₂ HPO4 solution, which had previously been adjusted to pH 7.0, were uniformly pumped into this gelatin and calcium salt solution with vigorous stirring within 120 min using an automated addition apparatus. The pH value is kept constant at pH 7.0 by the controlled addition of dilute aqueous base. After the addition is complete, stirring is continued for 24 h.

Then the dispersion in Centrifuge cup filled and the solids content separated from the solution by centrifugation. By five times shake up of the backlog in demineralized water and subsequent centrifugation the salts are largely washed out, so that no more chloride is detectable.

1.2 Production of Apatite-Protein Composite Containers gels:

Apatite-gelatin composite, water, glycerin and maltitol syrup are heated to 70 ° C. with vigorous stirring (400 rpm). Lecithin is dissolved in the warm solution, then Optamint ^{® is} added. Carboxymethyl cellulose, xylitol and sorbitol are premixed dry in a beaker and then added in portions while increasing the stirring speed to 750 rpm. After stirring for 20 minutes, paraben K (8.6% by weight of ethyl paraben and 5.7% by weight in benzyl alcohol) is added and the temperature is kept at 70 ° C. for a further 10 minutes. Finally, the precipitated silica (Sipernat ^® 320 DS, Degussa AG) is metered in, at the same time the stirring speed is increased to 1100 rpm and the temperature is held for a further 10 minutes.

1.3 Production of fluoride Gels with apatite-gelatin composite:

Analogous to the production of the fluoride-free Gels are also made of fluoride-containing gels. Half of The amount of sorbitol is added as described above, while the other half premixed with the sodium fluoride in a second beaker and then also in portions while increasing the stirring speed to 730 rpm is added.

The gels produced in this way have a viscosity of 7200 to 8100 mPa s ^-1 measured at a temperature of 25 ° C and a shear rate of 10 s ^-1 with the BOHLIN CS 10 cone-plate viscometer with air bearing and 60 mm cone at 2 ° Cone angle on. Table 1: Gel

2. pH measurements in artificial Saliva:

2.1 method:

The composition containing the sparingly water-soluble calcium salt or its composites is placed in a saline solution, the content of inorganic salts of which is that of body liquids as corresponds to saliva, blood or plasma (Simulated Body Fluid, SBF) and which is accordingly supersaturated with regard to the precipitation of calcium phosphate. Such compositions can be used as a model for body fluids, as already described in Liu et. al, Cells and Materials (1997), 7, pp. 41-51).

For the present study, an SBF ("Simulated Body Fluid") was used, which consists of an aqueous solution of the following salts:
Na ⁺ 14 mM PO ₄ ^3- 4.7 mm
K ⁺ 21mM Cl ^- 30mM
Ca ²⁺ 1.8mM

At 37 ° C were 70 mg of the compositions dissolved in 25 ml of SBF and the subsequent pH change using a pH electrode (Inlab 410, Mettler Toledo; measuring device: Consort, Multi Parameter Analyzer C833) tracked.

2.2 Measurement results:

In 1 shows the pH value curves between 2 min and 30 min after addition for gels of apatite-protein composites in SBF which were either fluoride-free or mixed with 0.0015% by weight sodium fluoride. An apatite-protein composite gel mixed with small amounts of fluoride salt therefore shows a significantly higher drop in pH than a gel without the fluoride salt.

These pH changes can be explained by a calcium phosphate precipitation from artificial saliva induced by the poorly water-soluble calcium salt or its composites, which is measured according to the following equation, using the falling pH value in the "SBF": 10 CaCl ₂ + 6 Na ₂ HPO ₄ + 2 H ₂ O → Ca ₁₀ (OH) ₂ (PO ₄ ) ₆ + 12 NaCl + 8 HCl

The mode of action of the poorly soluble calcium salts (without wishing to be restricted to this theory) is not only based on the results in the provision of calcium and / or phosphate ions for incorporation into the dentinal tubules and the tooth enamel. In addition, the poorly soluble calcium salt is particularly able to separate from the calcium and phosphate ions present in the natural saliva of humans in supersaturated concentrations (cf. 1 ). This nucleation effect leads to the build-up of new tooth material (new mineralization), in particular the enamel and / or dentine, from the body's own reservoirs.

Therefore, advantageously the amounts of calcium water which are difficult to dissolve in water are kept small without the re-and re-mineralization effects weakening. The particulate calcium salt can therefore be used as a seed for the natural Calcium and phosphate ions occurring in saliva act.

Claims (11)

Use of a composition for the local mineralization of teeth, characterized in that it contains poorly water-soluble calcium salt and / or its composites, the poorly water-soluble calcium salt having a particle size of 1 to 500 nm. Use according to claim 1, characterized in that that the calcium salt is selected is made of fluorapatite, hydroxylapatite, fluorine-doped hydroxylapatite and mixtures thereof. Use according to one of claims 1 or 2, characterized in that that the hardly water soluble Calcium salt has a particle size between 5 and 100 nm. Use according to one of the preceding claims characterized that the difficultly water-soluble calcium salt in the form of rod-shaped crystals is present. Use according to one of the preceding claims, characterized characterized that they from 0.01 to 2 wt .-%, in particular of Contains 0.1 to 1 wt .-% calcium salt and / or its composites. Use according to one of the preceding claims, characterized characterized that they are a composite of calcium salt and protein component contains. Use according to claim 6, characterized in that that the protein component is selected from gelatin, casein or their hydrolyzates, especially gelatin. Use according to one of the preceding claims, characterized in that the together also contains fluoride salts. Use according to one of the preceding claims, characterized characterized that the composition is an ointment, cream, paste or is a gel. Use according to one of the preceding claims, characterized characterized that they contain flavorings, sweeteners, fillers and / or other auxiliary substances contains. Use according to one of the preceding claims, characterized characterized that the composition has a viscosity of 2000 up to 12000 mPas, in particular 5000 to 9000 mPa · s having.