FR2844199A1 - 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) TiFxRy x = 1-6, but not 4 when y is 0; y = 0-2; R = K, Na, NH4 or 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

The invention relates to a composition for improving the

  physico-chemical characteristics of natural or artificial apatite-based materials, including implants. It also relates to the use of titanium derivatives for the strengthening of apatite-based materials, as well as a process for the reinforcement of apatite-based materials. A large part of dentures 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 does not generally impair the growth of osteoblasts, fibroblasts and gingival epithelial cells and is commonly used in the manufacture of dentures or bone prostheses to replace defective tissues, including

  intervertebral discs and ossicles of the ear.

  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 20 capable of protecting the underlying metal and to bind to calcium atoms and

phosphorus groups of apatite.

  WO 01 05797 discloses titanium derivatives and their use in oral compositions as an 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 conditions of

  pH ranging from about 6.5 to about 7.5.

  It is an object of the invention to provide a novel apatite-based material reinforcing composition comprising compounds derived from titanium and fluorine capable of

  to modify the structure of apatite.

  A first object of the invention therefore relates to such a composition.

  Another subject of the invention relates to the use of titanium and fluorine derivatives

  for the reinforcement of apatite-based materials.

  Another subject of the invention relates to a process for reinforcing materials with

apatite base.

  In the context of the present invention, the term "apatite-based materials" is intended to mean natural hydroxyapatites, in particular dental enamel, dentin, bone, as well as artificial ceramics based on calcium phosphate intended to medical applications, in particular dental implants, percutaneous or periodontal implantation devices, bone prostheses used in particular

  in orthopedic, maxillofacial or spinal surgery.

  The composition for reinforcing the apatite-based materials according to the invention is characterized in that it comprises at least one titanium and fluorine derivative corresponding to the following general formula (1): TiFxRy (1) in wherein x is an integer from 1 to 6 and y is 0, 1 or 2, with the proviso that when y is 0, x is not 4 and R is: - a compound selected 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; the composition according to the invention is further characterized in that it has, at

  the solubilized state, preferably in an aqueous medium, a pH of less than or equal to 6.

  L ligands that can be used include benzoic acid derivatives, especially 2-hydroxy-benzoic acid of formula (IV) below, and its COOH OH derivatives.

(IV)

  Hydroxy-3-benzoic acid of formula (V) below and its derivatives: hydroxy-3-benzoquene acid of formula (V) below and its derivatives: COOH OH (V) hydroxy-acid 4-benzene of formula (VI) below and its derivatives:

COOH OH

  (Vl) 2,3-dihydroxy-benzoic acid of formula (VII) below and its derivatives: OH (VII) OH 3,4-dihydroxy-benzoic acid of formula (VIII) below and its derivatives:

COOH OH OH

(VIII)

  The compounds in which R represents a ligand of formula (II) may comprise one or more asymmetric carbon atoms. They can therefore exist as 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 addition salts with acids. Such addition salts make

part of the invention.

  These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example for the purification or

  the isolation of the compounds, are also part of the invention.

  Compounds in which R represents a ligand of formula (II) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules 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 using ligand L as 2-hydroxybenzoate acid, is the compound represented by formula (III) below.

OH OH

O <O / \ F \ = (Ill)

F F

  Another example of a titanium and fluorine derivative according to the invention in which R represents an inorganic compound is potassium hexafluorotitanate of formula K2TiF6.

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

0105797.

  The compositions of the invention have a titanium content ranging from about 10 to about 1000 ppm, preferably about 300 ppm, and a fluorine ion content.

  ranging from about 50 to about 1500 ppm, preferably about 240 ppm.

  According to one embodiment, the compositions according to the invention furthermore 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 ranging from about 50 to about 1500 ppm, preferably about

at about 500 ppm.

  The compositions of the invention have, in the solubilized state, a pH of less than or equal to 6, preferably between about 5 and about 1, depending on the mode of administration of the composition. The dissolution of the compositions of the invention is preferably carried out in an aqueous medium, but may also be carried out, depending in particular on the titanium and fluorine derivative used, in a

  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 with titanium and the substitution of hydroxyl groups, bicarbonates or impurities present.

in '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 shocks.

  Incorporation of an additional fluorinated compound further increases the resistance

  from apatite to dissolution by acids.

  It goes without saying that the invention can be applied not only to dental enamel and 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 may be in various forms customary for administration in a clinical situation (topical route) or for

  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 for dilution, a spray, a gum chewing, a lozenge to suck, a gel

  dental implant, a mouth implant such as a patch, a mouthwash, a solution.

  For application to bone or artificial apatite, the compositions of the invention may be in the form of a solution, a gel, a paste,

a powder to dilute.

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

  conventional for each of these forms.

  For example, the forms for oral application may contain anionic, amphoteric, zwitterionic, cationic or nonionic surfactants. They may also comprise thickening agents, cohesive agents, sweetening agents, humectants or refreshing agents, preserving agents, dyes, bleaching agents, flavoring or flavoring agents, essential oils of plants, plasticizing agents, peptizers, anti-scale agents, inhibitors of the production of sulfur-containing volatile compounds such as zinc salts and complexes, cicatrizants, 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 0.01% by weight.

  0.05% by weight relative to the total weight of said preparation.

  The composition according to the invention, when used to reinforce an artificial apatite-based structure, may comprise a greater amount of titanium. For example, it may comprise 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 composition . An 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: - compound of formula 9% - mannitol 79% aroma 8% - sodium saccharinated 4% A solution containing 300 ppm of titanium is obtained from a 500 mg sachet of the above composition dissolved in 20 ml of purified water. , pH

between 3.5 and 5.

  Another example of a composition according to the invention, in the form of an extemporaneously dilutable powder 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 - compound of formula 1I1 100%

  From a 750 mg sachet of the above composition, dissolved in 100 ml of purified water, a solution of about pH 3 and containing 1000 ppm of titanium is obtained.

  When the composition of the invention is administered topically, the pH of the composition in the solubilized state is less than or equal to 6, preferably between

about 5 and about 2.

  When the composition of the invention is used to enhance 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 of less than or equal to 6, preferably between about 4 and about 1. Most of the compounds derived from titanium and fluorine that can be used in the invention,

  for example, the compound of formula (III), are acidic in aqueous solution.

  In some cases, however, it is necessary to adjust the pH of the composition to be less than or equal to 6. In other cases, it may also be necessary to increase the pH when the composition is present. in the solubilized state a

acidic character too strong.

  The pH of the composition can be adjusted, depending on the relative acidity of the titanium and fluorine derivatives used, with additional acidic or alkaline agents, as the case may be. Such agents are known in themselves for this use in

  compositions for administration to humans.

  For example, acid agents which may be used include citric acid, hydrochloric acid, lactic acid, phosphoric acid, tartaric acid and alkaline agents which may be used, in particular sodium hydroxide or monoethanolamine. the

  diethanolamine, triethanolamine.

  The invention also relates to the use of a composition comprising at least one titanium and fluorine derivative for reinforcing apatite-based materials.

  According to the invention, the composition comprising at least one derivative of titanium and fluorine

  is as defined in the foregoing.

  The invention is particularly useful for enhancing apatite or

  of natural or artificial hydroxyapatite as defined in the foregoing.

  The subject of the invention is also a process for reinforcing materials with

apatite base.

  The process of the invention is characterized in that it comprises the step of applying to the apatite material a composition comprising a titanium and fluorine derivative as defined above, said composition

  having, in the solubilized state, a pH of less than or equal to 6.

  According to the process of the invention, prior to the application of the composition, a

  treatment step with an acidic or demineralizing compound can be carried out.

  Preferably, this treatment step is carried out using an acidic or demineralising 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 titanium and fluorine derivative as defined in the foregoing, and furthermore comprises a fluorinated compound. additional, especially in the form of salt, as defined in the foregoing.

  The following examples are intended to illustrate the invention.

  To study the effects of the compositions of the invention on hydroxyapatite, compositions 1 and 2 according to the invention are prepared: Composition 1: aqueous solution of potassium hexafluorotitanate (at 200, 400 or

  1000 ppm titanium) for local application.

  Composition 2: aqueous solution of the compound of formula III (at 200, 300, 400 or

  1000 ppm titanium) for local application.

  Modification of the structure of the hvdroxvapatite

  The above compositions (pH 1 to 6) are contacted with commercially purchased hydroxyapatite powder.

  The composition of the hydroxyapatite after treatment is studied by X-ray photoelectron spectroscopy.

  The results obtained are shown in Table I below.

Table I

  Ca 0 Ti F Ti / Ca F / O C 21.4 63.9 - f:.

X1 18.2 58.5 3.5 6.3 0.19 0.11

X2 18.3 57.1 3.8 7.5 0.21 0.13

Y1 14.2 61.0 6.2 5.5 0.44 0.09

Y2 13.0 60.3 7.3 6.0 0.56 0.10

  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 These results show that the structure of the hydroxyapatite is depleted of calcium and oxygen in contact with the compositions of the invention, and is enriched with titanium and titanium.

  fluorine, especially since the applied solution is more concentrated.

  The analysis of the treated hydroxyapatite samples 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

  Ca Substitution Treatment by Ti Substitution of OH by Hydroxyapatite NaF 0.3% 52.0%

X3 17.1% 63.0%

Y3 40.3% 55.3%

  X3: composition I at 1000 ppm of titanium Y3: composition 2 at 1000 ppm of titanium NaF: sodium fluoride with a fluorine content of 1000 ppm.

  These results show the simultaneous substitution of calcium with titanium and hydroxyl groups by fluorine with the tested solutions.

  Modification of the enamel composition after topical application

  To evaluate the effects of the topical treatment, freshly extracted human teeth are brought into contact with the composition 2. On each tooth an experimental window is defined and separated into two parts. A mild acid attack (phosphoric acid diluted for 1 minute) is performed on the window.

  One half of the window is then insulated under wax, while

  the other half is exposed to treatment with composition 3 at 300 ppm titanium.

  Enamel under the treated half is examined by scanning electron microscopy. Its titanium composition is determined by elemental analysis, using an X-ray photoelectron spectroscope. The results show a modification of the hydroxyapatite which constitutes the dental enamel, related to

  the deep incorporation of titanium into the structure.

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

acid medium.

2844199 12

Claims (15)

claims   1. A composition for reinforcing apatite-based materials, characterized in that it comprises 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, 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) ci -after: COOH rl r._.   with the proviso that when y is H) m (II) - ± (Ot (OH) n 'wherein m is 0 or 1 and n is 0, 1 or 2;   the composition being further characterized in that it has, in the solubilized state, preferably in an aqueous medium, a pH of less than or equal to 6.   2. Composition according to claim 1, characterized in that the ligands L are in particular the benzoic acid derivatives, in particular the 2-hydroxy-benzoic acid of formula (IV) below and its derivatives: COOH OH (IV), I hydroxy-3-benzoquene acid of formula (V) below and its derivatives: COOH (V) hydroxy-4-benzoic acid of formula (VI) below and its derivatives: ## STR2 ## 2,3-dihydroxy-benzoic acid of formula (VII) below and its derivatives: OH (VII) OH, 3,4-dihydroxy-benzoic acid of formula (VIII) below and its derivatives: COOH OOH OH (VIII)   3. Composition according to claim 1, characterized in that the compound derived from titanium and fluorine is the compound represented by the following formula (II): OH OH o., T O N O / \ O F F (111)   4. Composition according to Claim 1, characterized in that the derivative of titanium and fluorine is in particular potassium hexafluorotitanate of formula K2TiF6, sodium hexafluorotitanate of formula Na2TiF6, ammonium hexafluorotitanate of formula (NH4 ) 2TiF6.   5. Composition according to any one of claims 1 to 4, characterized in that it has a titanium content ranging from about 10 to about 1000 ppm, preferably about 300 ppm and a fluorine ion content varying from 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. weight, 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 5, characterized in that it comprises, for a use intended to strengthen an artificial apatite-based structure, a compound derived from titanium and fluorine in an amount such as that the titanium content is greater than 0.001% by weight, preferably   between about 0.01 and about 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 ranging from about 50 ppm to about 1500 ppm,   preferably from about 100 ppm to about 500 ppm.   9. Composition according to any one of claims 1 to 8, characterized   in that it is administered topically in the form of a toothpaste, a diluent, a spray, a chewing gum, a lozenge to be sucked, a gel,   an oral implant such as a patch, a mouthwash, a solution.   Use of at least one compound derived from titanium and fluorine having the following general formula (1): TiFxRy (1) wherein x is an integer from 1 to 6 and y is 0, 1 or 2 with the proviso that when y is 0, x is not 4 and R is: - a compound selected 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   for the reinforcement of apatite-based materials.   11. Use according to claim 10, characterized in that the composition   is as defined in any one of claims 2 to 9.   12. Use according to claim 10 or 11 for strengthening   natural hydroxyapatites, in particular dental enamel, dentin, bone, as well as calcium-phosphate artificial ceramics for medical applications, in particular dental implants, percutaneous or periodontal implantation devices, bone prostheses used in orthopedic, maxillofacial or spinal surgery.   A process for reinforcing apatite-based materials, comprising the step of applying to the apatite material a composition comprising a titanium-fluorine derivative as defined in any one of claims 1 to at 9, said composition having, in the solubilized state, a pH less than or equal to 6.   14. The method of claim 13, characterized in that, prior to the application of the composition, a treatment step with an acid or demineralizing compound is carried out.   15. The method of claim 14, characterized in that the acid or demineralizing compound is in particular citric acid, lactic acid, acid phosphoric, tartaric acid.