EP1539085A2 - Composition for reinforcing apatite-based materials - Google Patents

Abstract

The invention concerns a composition comprising at least one titanium and fluorine derivative for reinforcing materials based on natural or synthetic apatite, in particular teeth, bones, dental implants and surgical prostheses. The inventive compositions enable in particular apatite materials to be enriched with titanium and fluorine. The invention also concerns a method for reinforcing apatite-based materials using said compositions, and use of titanium and fluorine derivatives to fight against staining of apatite-based material.

Description

Composition for improving the physical-chemical characteristics of apatite-based materials. its uses and process for its implementation

The invention relates to a composition intended to improve the physico-chemical characteristics of materials based on natural or artificial apatite, in particular implants. It also relates to the use of titanium derivatives for the reinforcement of apatite-based materials, as well as to a process for the reinforcement of apatite-based materials.

It also relates to the use of titanium and fluorine derivatives for the protection against coloring of apatite-based materials, in particular extrinsic coloring, as well as to a method of protection against coloring of d-based materials. 'apatite. ^"~

A large part of prostheses or implants for dental or medical use is made from titanium.

The interest of titanium in the preparation of such prostheses or implants is well known. Its mechanical properties, its high resistance to corrosion and its lightness make it a material of choice for these applications.

Titanium also shows very good compatibility with biological tissues. It generally does not alter the growth of osteoblasts, fibroblasts and gingival epithelial cells and is commonly used in the manufacture of dental or bone prostheses to replace failing tissues, including intervertebral discs and ear bones.

The very good compatibility between titanium and apatite-based fabrics is partly explained by the formation, on the surface of titanium, of a thin layer of titanium oxide capable of protecting the underlying metal and of bind to calcium atoms and phosphorus groups in apatite.

In addition, the visible part of the tooth has a natural color which changes over time. This color depends in particular on the whiteness and transparency of the dental enamel, as well as the color of the underlying dentin. Enamel and dentin are generally whiter the less mineralized their main constituent, hydroxyapatite. Thus, in the absence of anomaly, the tooth is then a white-ivory color. However, different phenomena occur over time and have an influence on the color of the teeth.

Thus, it is known that the mineralization of enamel and dentin increases throughout the life of the tooth, making it less white and less transparent.

The enamel is also subject to erosion by acidic substances and by dental caries; to wear and mechanical abrasion. These factors contribute to decrease its shine.

Finally, extrinsic stains can change the color of the tooth. For example, certain foods such as coffee, tea, blueberries contain colored pigments which can attach to the surface of the teeth and alter their shade. Other substances such as tar contained in cigarettes or certain drug treatments can act in the same way and change the color of teeth.

The document WO 0105797 describes titanium derivatives as well as their use in compositions for oral use, as a protective agent against dental caries. It is described in this document that the titanium derivative forms a protective layer on the surface of the tooth, in the form of a glaze, under pH conditions varying from approximately 6.5 to approximately 7.5.

The object of the invention is to propose a new composition for reinforcing apatite-based materials, comprising compounds derived from titanium and fluorine, capable of modifying the structure of apatite.

A first object of the invention therefore relates to such a composition. Another object of the invention relates to the use of titanium and fluorine derivatives for the reinforcement of apatite-based materials.

Another object of the invention relates to a process for reinforcing apatite-based materials. Another object of the invention relates to a new use of compounds derived from titanium and fluorine, to protect materials based on apatite against coloring, especially extrinsic.

Another object of the invention relates to a process for protecting apatite-based materials against coloring.

In the context of the present invention, the term “apatite-based materials” is understood to mean natural hydroxyapatites, in particular dental enamel, dentin, bones, as well as artificial ceramics based on calcium phosphate intended for medical applications, in particular dental implants, percutaneous or periodontal implantation devices, bone prostheses used in particular in orthopedic, maxillofacial or spinal surgery.

The composition intended to reinforce the apatite-based materials according to the invention is characterized in that it comprises at least one derivative of titanium and of fluorine corresponding to the general formula (I) below:

TiFxRy (I) in which x is an integer varying from 1 to 6 and y is 0, 1 or 2, with the condition that when y is

0, x does not represent 4 and R represents:

- a compound chosen from K, Na or NH ₄ , or

- A ligand L of formula (II) below:

wherein m is 0 or 1 and n is 0, 1 or 2; the composition according to the invention being further characterized in that it has, in the solubilized state, preferably in an aqueous medium, a pH less than or equal to 6.

L ligands which can be used are in particular the benzoic acid derivatives, in particular hydroxy-2-benzoic acid of formula (IV) below and its derivatives:

, hydroxy-3-benzoic acid of formula (V) below and its derivatives

, hydroxy-4-benzoic acid of formula (VI) below and its derivatives

, 2,3-dihydroxy-benzoic acid of formula (VII) below and its derivatives

, dihydroxy-3,4-benzoic acid of formula (VIII) below and its derivatives

The compounds in which R represents a ligand of formula (II) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.

The compounds in which R represents a ligand of formula (II) may exist in the form of bases or of addition salts with acids. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids which are useful, for example for the purification or the isolation of the compounds, also form part of the invention.

The compounds in which R represents a ligand of formula (II) may also exist in the form of hydrates or of solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

A first example of a compound derived from titanium and fluorine according to the invention, obtained by using hydroxy-2-benzoic acid as ligand L, is the compound represented by formula (III) below:

Another example of a titanium and fluorine derivative according to the invention in which R represents a mineral compound is potassium hexafluorotitanate of formula K ₂ TiF ₆ .

Other examples of compounds which can be used in the context of the invention are sodium hexafluorotitanate of formula Na ₂ TiF ₆ and ammonium hexafluorotitanate of formula (NH ₄ ) ₂ TiF ₆ . The compounds which can be used in the context of the invention, when their method of preparation is not described, are commercially available or described in the literature, or else can be prepared according to methods which are described therein or which are known from the skilled person.

The titanium and fluorine derivatives in which R represents a ligand L of formula (II) above can be prepared according to the method described in document WO 0105797.

The compositions of the invention have a titanium content varying from approximately 10 to approximately 1000 ppm, preferably approximately 300 ppm and a fluorine ion content varying from approximately 50 to approximately 1500 ppm, preferably approximately 240 ppm.

According to one embodiment, the compositions according to the invention further comprise an additional fluorinated compound, in particular a fluorine salt, for example sodium fluoride, sodium monofluorophosphate.

This additional fluorinated compound is present in the compositions of the invention in an amount varying from about 50 to about 1500 ppm, preferably from about 100 to about 500 ppm.

The compositions of the invention have, in the solubilized state, a pH less than or equal to 6, preferably between approximately 5 and approximately 1, depending on the mode of administration of the composition. The compositions of the invention are preferably dissolved in an aqueous medium, but can also be carried out, depending in particular on the titanium and fluorine derivative used, in an organic solvent such as ethanol.

It has been demonstrated that at such pH values. the compositions of the invention allow the substitution of calcium atoms present in the apatite by titanium and the substitution of hydroxyl groups, bicarbonates or impurities present in the apatite by fluorine.

This substitution modifies the structure of apatite and makes it more resistant, not only to acid erosion and tooth decay, but also to abrasion, wear and traumatic shock. The incorporation of an additional fluorinated compound further increases the resistance of apatite to dissolution by acids.

It goes without saying that the invention can be applied not only to dental enamel and to dentin in compositions for oral use, but also to other natural apatites, for example bone tissue, or artificial, by example of ceramics.

The compositions of the invention can be presented in various usual forms for administration in a clinical situation (topical route) or for the preparation of artificial apatites.

In topical administration, the compositions of the invention may be in the form, in the case of an oral application, of a toothpaste, a powder to be diluted, a spray, a gum chew, a lozenge to suck, a dental gel, an oral implant such as a patch, a mouthwash, a solution. For application to the bone or to an artificial apatite, the compositions of the invention may be in the form of a solution, a gel, a paste, a powder to be diluted.

All of these forms in themselves are well known to those skilled in the art. In addition to the compounds derived from titanium, associated or not with a fluorine salt, the forms mentioned above can comprise excipients or conventional ingredients for each of these forms.

For example, the forms for oral application can contain anionic, amphoteric, zwitterionic, cationic or nonionic surfactants. They may also include thickening agents, cohesion agents, sweetening, humectant or refreshing agents, preserving agents, colorants, whitening agents, flavoring or flavoring agents, essential plant oils, plasticizing agents, peptizing agents, anti-tartar agents, agents that inhibit the production of volatile sulfur compounds such as zinc salts and complexes, cicatrizers, anti-bleeding agents, polishing agents, anti-plaque agents such as chlorhexidine, hexetidine, cetylpyridinium chloride, triclosan and / or enzymes such as dextranase, mutanase, lysozymes, lactoferrin or peroxidases.

Generally, the composition according to the invention administered topically comprises compounds derived from titanium in an amount such that its titanium content is greater than 0.001% by weight, preferably between 0.01 and 0.1% by weight, more preferably between 0.01 and 0.05% by weight relative to the total weight of said preparation.

A first example of a composition according to the invention, in the form of a powder to be diluted extemporaneously for topical administration, comprises the following elements, expressed in percentages by weight relative to the total weight of the composition:

Composition A:

- compound of formula III 9% o

- mannitol 79%

- aroma 8%

- 4% sodium saccharinate

A solution containing 300 ppm of titanium, with a pH between 3.5 and 5, is obtained from a 500 mg sachet of the above composition, dissolved in 20 ml of purified water.

Another example of composition according to the invention, in the form of a powder to be diluted extemporaneously for the preparation of a solution for reinforcing artificial apatites, comprises the following elements, expressed in percentages by weight relative to the total weight of the preparation:

Composition B:

- compound of formula III 100% A solution of pH 3 and containing 1000 ppm of titanium is obtained from a 750 mg sachet of the above composition, dissolved in 100 ml of purified water.

When the composition of the invention is administered topically, the pH of the composition in the dissolved state is less than or equal to 6, preferably between approximately 5 and approximately 2.

When the composition of the invention is used to reinforce an artificial apatite, the pH of the composition, once dissolved, may be lower than in the case of topical use. Thus, the composition of the invention has in solution a pH less than or equal to 6, preferably between approximately 4 and approximately 1.

Most of the compounds derived from titanium and from fluorine which can be used in the invention, for example the compound of formula (III), are acid in aqueous solution. In certain cases, it is however necessary to adjust the pH of the composition, so that it is less than or equal to 6. In other cases, it may also be necessary to increase the pH, when the composition has the solubilized state too strong an acid character.

The pH of the composition can be adjusted, as a function of the relative acidity of the titanium and fluorine derivatives used, with additional acid or alkaline agents, as the case may be. Such agents are known in themselves for this use in compositions intended for administration to humans.

For example, acid agents which can be used are in particular citric acid, hydrochloric acid, lactic acid, phosphoric acid, tartaric acid and alkaline agents which can be used are in particular sodium hydroxide, monoethanolamine, diethanolamine, triethanolamine.

Another subject of the invention is the use of a composition comprising at least one derivative of titanium and of fluorine for the reinforcement of materials based on apatite. According to the invention, the composition comprising at least one derivative of titanium and of fluorine is as defined in the above.

The invention is particularly useful for strengthening apatite or natural or artificial hydroxyapatite as defined in the foregoing.

The invention also relates to a process for reinforcing apatite-based materials.

The method of the invention is characterized in that it comprises the step consisting in applying to the apatite-based material a composition comprising a derivative of ^"" titanium and of fluorine ^{^} as defined in the above, said composition having, in the dissolved state, a pH less than or equal to 6.

According to the method of the invention, prior to the application of the composition, a step of treatment with an acid or demineralizing compound can be carried out. Preferably, this treatment step is carried out using an acid or demineralizing agent such as citric acid, lactic acid, phosphoric acid, tartaric acid.

According to an alternative embodiment of the process of the invention, the composition applied to the apatite-based material to be reinforced comprises a derivative of titanium and of fluorine as defined in the above, and further comprises an additional fluorinated compound , especially in the form of salt, as defined in the above.

The invention also relates to the use of compounds derived from titanium and fluorine, to protect materials based on apatite against colorations, especially extrinsic.

The invention therefore consists in the use of at least one titanium and fluorine derivative corresponding to the general formula (I) below:

TiFxRy (I) in which x is an integer varying from 1 to 6 and y is 0, 1 or 2, and R represents: - a compound chosen from K, Na or NH ₄ , or a ligand L of formula (II) below:

in which m is 0 or 1 and n is 0, 1 or 2, in the form of an acid addition base or salt, as well as in the hydrate or solvate state, as anti-coloring agent for apatite-based materials in a composition for oral use.

The composition for buccal use defined above has, in the solubilized state, preferably in an aqueous medium, a pH less than or equal to 6. ^""

L ligands which can be used are in particular those described in the foregoing, in particular the compounds of formula (IV), (V), (VI), (VII), (VIII) and their derivatives.

A first example of a compound derived from titanium and fluorine which can be used in the invention is the compound of formula (III) defined in the above.

Another example of a titanium and fluorine derivative which can be used according to the invention in which R represents a mineral compound, in addition to those already described in the above, is titanium tetrafluoride of formula TiF ₄ .

The compositions for buccal use which can be used to protect apatite-based materials against coloring are as defined in the above, in particular as regards their content of titanium, fluorine, the excipients which can be used, their pH, their form of administration.

An example of a composition for buccal use which can be used in the invention, in the form of a powder to be diluted extemporaneously for the preparation of an anti-coloring solution for apatites, is composition B as defined above.

The invention also relates to a process for protecting against coloring of apatite-based materials. The method of the invention is characterized in that it comprises the step consisting in applying to the apatite-based material a composition comprising a titanium and fluorine derivative as defined in the above, said composition having, in the solubilized state, a pH less than or equal to 6.

According to the method of the invention, prior to the application of the composition, a step of treatment with an acid or demineralizing compound can be carried out. Preferably, this treatment step is carried out using an acid or demineralizing agent such as citric acid, lactic acid, phosphoric acid, tartaric acid.

According to an alternative embodiment of the method of the invention, the composition applied to the apatite-based material comprises a titanium and fluorine derivative as defined in the above, and further comprises an additional fluorinated compound, in particular in the form of salt, as defined in the above.

The following examples are intended to illustrate the invention.

Example 1

To study the effects of the compositions of the invention on the reinforcement of hydroxyapatite, compositions 1 and 2 according to the invention are prepared:

Composition 1: aqueous solution of potassium hexafluorotitanate (at 200, 400 or 1000 ppm of titanium) for local application.

Composition 2: aqueous solution of the compound of formula III (at 200, 300, 400 or 1000 ppm of titanium) for local application.

Modification of the structure of hydroxyapatite

The above compositions (pH between 1 and 6) are brought into contact with commercially available hydroxyapatite powder.

The composition of hydroxyapatite after treatment is studied by photoelectron X-ray spectroscopy. The results obtained are shown in Table I below.

Board

C: control hydroxyapatite (treated with water)

X1 and X2: hydroxyapatite treated with composition 1 (solutions at 200 and 400 ppm of titanium, respectively)

Y1 and Y2: hydroxyapatite treated with composition 2 (solutions at 200 and 400 ppm of titanium, respectively)

These results show that the structure of hydroxyapatite is depleted in calcium and oxygen on contact with the compositions of the invention, and is enriched in titanium and fluorine, all the more so when the solution applied is more concentrated. .

Analysis of the samples of treated hydroxyapatite is continued by mass spectrometry. The percentage of calcium substituted by titanium and the percentage of hydroxyl groups substituted by fluorine are compared with those obtained after contacting the hydroxyapatite with a solution of sodium fluoride. The results obtained are shown in Table II below.

Table II

X3: composition 1 to 1000 ppm of titanium Y3: composition 2 to 1000 ppm of titanium NaF: sodium fluoride with fluorine content of 1000 ppm.

These results show the simultaneous substitution of calcium by titanium and hydroxyl groups by fluorine with the solutions tested. Modification of the composition of the dental enamel after topical application To evaluate the effects of the treatment by local application, freshly extracted human teeth are brought into contact with composition 2. On each tooth an experimental window is defined and separated into two parts. A moderate acid attack (phosphoric acid diluted for 1 minute) is carried out on the window. One of the halves of the window is then insulated under wax, while the other half is exposed to treatment with composition 3 at 300 ppm of titanium.

The enamel located under the treated half is examined by scanning electron microscopy. Its titanium composition was determined by elemental analysis, by means of a ray photoelectron spectroscope ^~ X. The results show a modified hydroxyapatite which is dental enamel, due to the incorporation of titanium in the long the structure.

The results show that the invention allows not only the substitution of the hydroxyl groups by fluorine, but also the substitution of calcium by titanium under the conditions of local application of the composition of the invention, in an acid medium.

Example 2

To study the effects of compounds derived from titanium and fluorine on the extrinsic colorations of the teeth, the following composition was prepared: - aqueous solution of the compound of formula III at 0.2% (corresponding to 0.036% of titanium) The solution is used in local application, at a pH around 4.6.

In vitro effect on coloring precursors A lysine precursor is used as the coloring model in the presence of a reducing sugar, which produces brown-colored melanoids by reaction.

An aqueous solution containing 100 mM of lysine and 100 mM of reducing sugar is prepared. The aqueous solution of the compound of formula III prepared above is mixed (50/50 v / v mixture) with the solution of lysine and reducing sugar, balanced at 60 ° C for 3 days, then diluted (1/1 v / v) either in water (solution 1) or in artificial saliva (solution 2). Control mixtures in which the solution of the compound of formula III is replaced by water are also prepared in the same way (solutions 3 and 4, respectively). The appearance of the melanoid chromophore in the mixture is measured by spectrophotometry for 15 days.

The results obtained are shown in Figure 1.

The absorbance is measured at 500 nm. It appears that, in vitro, the solution containing the titanium and fluorine derivative inhibits the formation of colored melanoid chromophore from lysine and reducing sugar.

Similar results are obtained when using iron or tin ⁱⁿ the presence of a source of sulphide ion as dye precursors.

Example 3

Protection of the tooth ex vivo against staining

To evaluate the effects of the treatment by local application, freshly extracted human teeth are brought into contact with the same solution as in Example 1. An experimental window is defined on each tooth and the remaining zone is masked under wax. The teeth are then exposed to treatment with the same solution as in Example 1.

After rinsing, the wax is removed and the teeth are immersed in an aqueous solution containing lysine and a reducing sugar, according to the model described in Example 1, at 60 ° C for 2 days.

The results show that the parts of the teeth treated with the solution containing the titanium and fluorine derivative have not undergone significant coloring, while the untreated areas are strongly colored in brown.

The protection conferred by the titanium and fluorine derivative under the conditions described is thus demonstrated directly on the tooth.

Claims

claims 1. Composition intended to reinforce apatite-based materials, characterized in that it comprises at least one derivative of titanium and of fluorine corresponding to the general formula (I) below: TiFxRy (I) in which x is an integer varying from 1 to 6 and y is 0, 1 or 2, with the condition that when y is 0, x does not represent 4 and R represents: - a compound chosen from K, Na or NH ₄ , or - A ligand L of formula (II) below: wherein m is 0 or 1 and n is 0, 1 or 2; in the base state or in addition salt to an acid, as in the hydrate or solvate state, the composition being further characterized in that it has, in the solubilized state, preferably in an aqueous medium, a pH less than or equal to 6. 2. Composition according to claim 1, characterized in that the ligands L are in particular the derivatives of benzoic acid, in particular hydroxy-2-benzoic acid of formula (IV) below and its derivatives: , hydroxy-3-benzoic acid of formula (V) below and its derivatives , hydroxy-4-benzoic acid of formula (VI) below and its derivatives , 2,3-dihydroxy-benzoic acid of formula (VII) below and its derivatives: ^~~ , dihydroxy-3,4-benzoic acid of formula (VIII) below and its derivatives 3. Composition according to claim 1, characterized in that the compound derived from titanium and fluorine is the compound represented by the following formula (III): 4. Composition according to claim 1, characterized in that the titanium and fluorine derivative is in particular potassium hexafluorotitanate of formula K ₂ TiF ₆ , sodium hexafluorotitanate of formula Na ₂ TiF ₆ , ammonium hexafluorotitanate of formula (NH ₄ ) ₂ TiF ₆ . 5. Composition according to any one of claims 1 to 4, characterized in that it has a titanium content varying from approximately 10 to approximately 1000 ppm, preferably approximately 300 ppm and a content of fluorine ions varying d about 50 to about 1500 ppm, preferably about 240 ppm. 6. Composition according to any one of claims 1 to 5, characterized in that it comprises, for topical administration, a compound derived from titanium and fluorine in an amount such that the titanium content is greater than 0.001% by weight, preferably between 0.01 and 0.1% by weight, more preferably between 0.01% and 0.05% by weight relative to the total weight of said composition. 7. Composition according to any one of claims 1 to 6, characterized in that it further comprises an additional fluorinated compound, in particular a fluorine salt, for example sodium fluoride or sodium monofluorophosphate, in an amount varying from about 50 ppm to about 1500 ppm, preferably from about 100 ppm to about 500 ppm. 8. Composition according to any one of claims 1 to 7, characterized in that it is administered topically in the form of a toothpaste, a powder to be diluted, a spray, a chewing gum , a lozenge to suck, a gel, an oral implant such as a patch, a mouthwash, a solution. 9. Use of at least one compound derived from titanium and fluorine corresponding to the general formula (I) below: TiFxRy (I) in which x is an integer varying from 1 to 6 and y is 0, 1 or 2, with the condition that when y is 0, x does not represent 4 and R represents: a compound chosen from K, Na or NH ₄ , or - a ligand L of formula (II) below: in which m is 0 or 1 and n is 0, 1 or 2, in the base or acid addition salt state, as well as in the hydrate or solvate state, for the reinforcement of apatite-based materials. 10. Use according to claim 9, characterized in that the composition is as defined in any one of claims 2 to 8. 11. Use according to claim 9 or 10 for the reinforcement of natural hydroxyapatites, in particular dental enamel, dentin, bones, as well as artificial ceramics based on calcium phosphate intended for medical applications, in particular dental implants, percutaneous or periodontal implantation devices, bone prostheses used in orthopedic, maxillofacial or spinal surgery. 12. A method of reinforcing apatite-based materials, comprising the step of applying to the apatite-based material a composition comprising a titanium and fluorine derivative as defined in any one of claims 1 to 8, said composition having, in the solubilized state, a pH less than or equal to 6. 13. Method according to claim 12, characterized in that, prior to the application of the composition, a step of treatment with an acid or demineralizing compound is carried out. 14. Method according to claim 13, characterized in that the acid or demineralizing compound is in particular citric acid, lactic acid, phosphoric acid, tartaric acid. 15. Use of at least one titanium and fluorine derivative corresponding to the general formula (I) below: TiFxRy (I) in which x is an integer varying from 1 to 6 and y is 0, 1 or 2, and R represents a compound chosen from K, Na or NH ₄ , or a ligand L of formula (II) below: wherein m is 0 or 1 and n is 0, 1 or 2; in the base state or in addition salt to an acid, as well as in the hydrate or solvate state, as an anti-coloring agent for apatite-based materials in a composition for use oral. 16. Use according to claim 15, characterized in that the composition has, in the solubilized state, preferably in an aqueous medium, a pH less than or equal to 6. 17. Use according to claim 15 or 16, characterized in that the ligands L are in particular the derivatives of benzoic acid, in particular hydroxy-2-benzoic acid of formula (IV) below and its derivatives: , hydroxy-3-benzoic acid of formula (V) below and its derivatives , hydroxy-4-benzoic acid of formula (VI) below and its derivatives: , 2,3-dihydroxy-benzoic acid of formula (VII) below and its derivatives: , dihydroxy-3,4-benzoic acid of formula (VIII) below and its derivatives 18. Use according to claim 15 or 16, characterized in that the compound derived from titanium and fluorine is the compound represented by the following formula (III): 19. Use according to claim 15, characterized in that the titanium and fluorine derivative is in particular titanium tetrafluoride of formula TiF ₄ , potassium hexafluorotitanate of formula K ₂ TiF ₆ , sodium hexafluorotitanate of formula Na ₂ TiF ₆ , ammonium hexafluorotitanate of formula (NH ₄ ) ₂ TiF ₆ . 20. Use according to any one of claims 15 to 19, characterized in that the composition has a titanium content varying from approximately 10 to approximately 1000 ppm, preferably approximately 300 ppm and a content of fluorine ions varying d about 50 to about 1500 ppm, preferably about 240 ppm. 21. Use according to any one of claims 15 to 19, characterized in that the composition comprises, for topical administration, a compound derived from titanium and fluorine in an amount such that the titanium content is greater than 0.001% by weight, preferably between 0.01 and 0.1% by weight relative to the total weight of said composition. 22. Composition according to any one of claims 15 to 21, characterized in that it further comprises an additional fluorinated compound, in particular a fluorine salt, for example sodium fluoride or sodium monofluorophosphate, in an amount varying from about 50 ppm to about 1500 ppm, preferably from about 100 ppm to about 500 ppm. 23. Use according to any one of claims 15 to 22, characterized in that the composition is administered topically in the form of a toothpaste, a diluting powder, a spray, a chewing gum , a lozenge to suck, a gel, an oral implant such as a patch, a mouthwash, a solution. 24. A method of protecting apatite-based materials against coloring, comprising the step of applying to the apatite-based material a composition comprising a titanium and fluorine derivative as defined in any one of claims 15 to 23, said composition having, in the dissolved state, a pH less than or equal to 6. 25. The method of claim 24, characterized in that, prior to the application of the composition, a step of treatment with an acid or demineralizing compound is carried out. 26. The method of claim 25, characterized in that the acid or demineralizing compound is in particular citric acid, lactic acid, phosphoric acid, tartaric acid.