FR2852511A1 - Composition for strengthening apatite-based materials, e.g. teeth, bones and implants, comprises a titanium fluoride compound - Google Patents

Abstract

Composition for strengthening apatite-based materials comprises a titanium fluoride compound (I) and has a pH of 6 or less in solution. Composition for strengthening apatite-based materials comprises a titanium fluoride compound of formula (I) and has a pH of 6 or less in solution. (I) TiF xR y x : 1-6, but not 4 when y is 0; y : 0-2; R : K, Na, NH 4or a benzene or mono-, di- or trihydroxybenzene ligand. An independent claim is also included for a method for reinforcing apatite-based materials by applying the above composition to the material, optionally after treatment with an acid or demineralizing compound.

Description

Use of titanium and fluorine derivatives for protection against

  coloring of apatite-based materials, process for protecting against coloring of materials

based on apatite.

  The invention relates to the use of titanium and fluorine derivatives for protection against coloring of apatite-based materials, in particular extrinsic coloring, as well as to a method of protection against coloring of based materials apatite.

  In the context of the present invention, the term "apatite-based materials" means natural hydroxyapatites, in particular teeth, and more particularly dental enamel and dentin, as well as artificial ceramics based on phosphate of calcium intended for medical applications, in particular dental implants, periodontal devices. 15 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. 35 Other substances such as the tar contained in cigarettes or certain medicinal treatments can act in the same way and modify the color of the teeth.

  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 derivatives form a protective layer on the surface of the tooth, in the form of a glaze.

  The object of the invention is a new use of compounds derived from titanium and fluorine, to protect materials based on apatite against coloring, especially extrinsic.

  A first object of the invention therefore relates to such use.

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

  The invention therefore consists in the use of at least one titanium and fluorine derivative corresponding to the general formula (1) below: TiFxRy (1) 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 NH4, or - a ligand L of formula (II) below:

COOH

  (OH) m (II) (OH) n in which m is 0 or 1 and n is 0, 1 or 2, as an 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 the benzoic acid derivatives, in particular hydroxy-2-benzoic acid of formula (IV) below and its derivatives:

COOH

OH

  WJ (IV) hydroxy-3-benzoic acid of formula (V) below and its derivatives: COOH z (V) OH 15, hydroxy-4-benzoic acid of formula (VI) below and its derivatives: COOH (Vl) 20

OH

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

OH (Vil)

OH

  30, dihydroxy-3,4-benzoic acid of formula (VIII) below and its derivatives: COOH (VIII) 35 OH

OH

  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 are 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) can also exist in the form of hydrates or 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 from fluorine which can be used in the invention, obtained by using hydroxy-2benzoic acid as ligand L, is the compound represented by the formula (III) below:

OH OH

F (

F F

  Another example of a titanium and fluorine derivative which can be used in the invention in which R represents a mineral compound is potassium hexafluorotitanate of formula K2TiF6.

  Other examples of compounds which can be used in the context of the invention are titanium tetrafluoride of formula TiF4, sodium hexafluorotitanate of formula Na2TiF6 and ammonium hexafluorotitanate of formula (NH4) 2TiF6.

  s 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. of 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 for buccal use which can be used in the invention have a content of titanium varying from approximately 10 to approximately 1000 ppm, preferably approximately 300 ppm and a content of fluorine ions varying from approximately 50 to approximately 1500 ppm, preferably around 240 ppm.

  According to one embodiment, the compositions for oral use usable in 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 in an amount ranging from about 50 to about 1500 ppm, preferably from about 100 to about 500 ppm.

  The compositions for buccal use which can be used in 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 dissolution of the compositions is preferably carried out 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.

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

  In topical administration, the compositions for buccal use which can be used in the invention may be in the form, in the case of buccal application, of a toothpaste, of a powder to be diluted, of a spray, of '' a chewing gum, a lozenge to suck, a dental gel, an oral implant such as a patch, a mouthwash, a solution.

  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 may contain anionic, amphoteric, zwitterionic, cationic or nonionic surfactants. They can 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 which 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 for oral use usable in 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 relative to the total weight of said preparation.

  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 artificial apatites, comprises the following elements, expressed in percentages by weight relative to the total weight of the preparation: - compound of formula 11I 100% A solution of pH 3 is obtained from a 750 mg sachet of the above composition, dissolved in 100 ml of purified water and containing 1000 ppm of titanium.

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

  Most of the compounds derived from titanium and 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 can be adjusted, depending on 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, monkethanolamine, diethanolamine, triethanolamine.

  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 compounds derived from titanium and fluorine on the extrinsic stains of the teeth, the following composition was prepared: - aqueous solution of the compound of formula 111 at 0.2% (corresponding to 0.036% of titanium) The solution is used in local application, at a pH approximately 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 lysine and 100 mM reducing sugar is prepared. The aqueous solution of the compound of formula 111 prepared above is mixed (50/50 v / v mixture) with the solution of lysine and reducing sugar, equilibrated at 600C 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 111 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 ions as coloring precursors.

Example 2

  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 area remaining 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 brown.

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

Claims (12)

claims   1. 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 NH4, or - a ligand L of formula (II) below: COOH   (OH) m (II) (OH) n in which m is 0 or 1 and n is 0, 1 or 2; as an anti-coloring agent for apatite-based materials in a composition for oral use.   2. Use according to claim 1, characterized in that the composition has, in the solubilized state, preferably in an aqueous medium, a pH less than or equal to 20 to 6.   3. Use according to claim I or 2, characterized in that the ligands L are in particular the derivatives of benzoic acid, in particular 2-hydroxybenzoic acid of formula (IV) below and its derivatives: COOH OH   OHW (IV) 30, hydroxy-3-benzoic acid of formula (V) below and its derivatives: COOH (V) Oh he   Hydroxy-4-benzdfoic acid of formula (VI) below and its derivatives: COOH 5C OH (Vl)   Dihydroxy-2,3-benzoic acid of formula (VII) COOH below and its derivatives: (Vii) OH   15, dihydroxy-3,4-benzoic acid of formula (VIII) below and its derivatives: COOH (VIII) OH 20 OH   4. Use according to claim 1 or 2, characterized in that the compound derived from titanium and fluorine is the compound represented by the following formula (Ill): OH OH Ti "   0 / \ FO F F (111) 5. Use according to claim 1, characterized in that the titanium and fluorine derivative is in particular titanium tetrafluoride of formula TiF4, potassium hexafluorotitanate of formula K2TiF6, sodium hexafluorotitanate of formula Na2TiF6, I ' ammonium hexafluorotitanate of formula (NH4) 2TiF6.   6. Use according to any one of claims 1 to 5, 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.   7. Use according to any one of claims 1 to 5, 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.   8. Composition according to any one of claims 1 to 7, 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.   9. Use according to any one of claims 1 to 8, characterized in that the composition is administered topically in the form of a toothpaste, a powder to be diluted, a spray, a gum chew, a lozenge to suck, a gel, an oral implant such as a patch, a mouthwash, a solution.   10. 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 1 to 9, said composition having, in the dissolved state, a pH less than or equal to 6.   11. Method according to claim 10, characterized in that, prior to the application of the composition, a step of treatment with an acid or demineralizing compound is carried out.   12. Method according to claim 11, characterized in that the acid or demineralizing compound is in particular citric acid, lactic acid, phosphoric acid, tartaric acid.