Classifications

• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
  • A23G4/00—Chewing gum
  • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
  • A23G4/064—Chewing gum characterised by the composition containing organic or inorganic compounds containing inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/15—Compositions characterised by their physical properties
  • A61K6/17—Particle size
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/20—Protective coatings for natural or artificial teeth, e.g. sealings, dye coatings or varnish
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
  • A61K6/69—Medicaments
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
  • A61K6/831—Preparations for artificial teeth, for filling teeth or for capping teeth comprising non-metallic elements or compounds thereof, e.g. carbon
  • A61K6/838—Phosphorus compounds, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/20—Halogens; Compounds thereof
  • A61K8/21—Fluorides; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/24—Phosphorous; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/02—Inorganic materials
  • A61L27/12—Phosphorus-containing materials, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/30—Inorganic materials
  • A61L27/32—Phosphorus-containing materials, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
  • C01B25/00—Phosphorus; Compounds thereof
  • C01B25/16—Oxyacids of phosphorus; Salts thereof
  • C01B25/26—Phosphates
  • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
  • C01B25/322—Preparation by neutralisation of orthophosphoric acid
• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
  • C01B25/00—Phosphorus; Compounds thereof
  • C01B25/16—Oxyacids of phosphorus; Salts thereof
  • C01B25/26—Phosphates
  • C01B25/455—Phosphates containing halogen

Definitions

• the invention relates to rod-shaped apatite crystals which have a length-to-breadth ratio of >5 and in which the ratio of hydroxide ions to fluoride ions based on the total amount of the crystals can be simply varied. Furthermore, the invention relates to dispersions which contain such rod-shaped apatite crystals, and to a process for the preparation of the dispersions or of the apatite crystals.
• the dental enamel just like human bone, consists mainly of hydroxyapatite. Owing to mechanical stress on the teeth (e.g. when eating or else alternatively when brushing the teeth), fissures and channels result in the dental enamel, which expose pores in the interior of the tooth. Substances can rapidly penetrate into the interior of the tooth through these pores and irritate the dental nerve, as a result of which the teeth become sensitive to sweetness, heat or cold. Moreover, in the case of bacterial attack caries forms in the fissures or in the pores, which is known extensively as a very dangerous dental disease.
• a problem is the provision of rod-shaped (hydroxy)apatite crystals which make possible an effective adsorption on the tooth surface on account of an improved length-to-breadth ratio.
• the processes known hitherto for the preparation of apatite crystals usually yield crystals of spherical and irregular shape having particle sizes of >5 ⁇ m.
• processes have been published with which, in addition to the irregular and spherical shapes, rod-shaped apatite crystals having particle sizes in the submicrometer range can also be produced.
• WO 00/37033 describes suspensions of only slightly water-soluble calcium phosphates, calcium fluorides and calcium fluorophosphates, and their use in dental care compositions.
• the calcium salts contained in the suspensions are prepared by precipitation in an alkaline medium, the calcium salts being obtained in the form of crystals (primary particles) having thicknesses (diameters) of 0.005 to 0.05 ⁇ m and lengths of 0.01 to 0.15 ⁇ m.
• the precipitation of the calcium salts is carried out in the presence of agglomeration inhibitors, such as water-soluble surfactants or water-soluble polymeric protective colloids.
• suspensions of hydroxyapatite crystals and fluorine-doped hydroxyapatite crystals can also be prepared.
• the calcium salt crystals prepared in this way in some cases have rod-shaped structures.
• Inherent in the method is the disadvantage that on account of the overlapping length and breadth values of the crystals a numerically large amount of crystals is also produced whose length-to-breadth ratio is in the range from 1 to 2, i.e. these crystals have no pronounced rod form or only a slightly pronounced rod form.
• composite materials which comprise calcium salts which are poorly soluble in water, such as calcium phosphates and calcium fluorophosphates, and a protein component.
• the calcium salts which also include hydroxyapatite, fluoroapatite and fluorine-doped hydroxyapatite, are prepared by precipitating them in the alkaline medium in the presence of the protein component.
• the calcium salts (at least partially) also have rod-shaped structures, a numerically large amount of crystals having a length-to-breadth ratio of 1 to 2 resulting on account of the likewise overlapping length and breadth values of the calcium salt crystals prepared using this method.
• the crystals are deposited on the surface of the high molecular weight protein component employed, as a result of which they represent the spatial structure of the protein component to a certain extent.
• These composite materials can be used for “biomineralization” (mineral crystallization in a protein matrix), i.e. protein and calcium salt crystals are incorporated into the protein matrix of the teeth or bone. Consequently, the 3-dimensional structure of the composite materials is applied to the previous (tooth) surface, while, as mentioned above, hydroxyapatite crystals form laminar, 2-dimensional layers on the (tooth) surface.
• the biomineralization process is comparatively slow and leads to composite materials applied to the (tooth) surface whose mechanical properties can differ considerably from those of the pure crystals.
• WO 98/18719 describes a process for the lengthening of rod-shaped hydroxyapatite crystals in suspensions and the adjustment or concentration of the solids content of hydroxyapatite crystals in these suspensions.
• the original crystal length of 0.05 to 0.1 ⁇ m can be increased to 0.1 to 0.5 ⁇ m with constant breadth of 0.01 to 0.02 ⁇ m
• a solids content of 7 to 96% of hydroxyapatite crystals can be established in the suspension.
• the process is complicated; moreover, it is exclusively restricted to suspensions of hydroxyapatite crystals.
• the crystal length moreover also appears to be dependent on the solids content in the suspension.
• the object underlying the invention consists in the provision of rod-shaped apatite crystals which have an improved length-to-breadth ratio compared with the prior art, and in which the ratio of hydroxide ions to fluoride ions based on the total amount of the crystals can be simply varied. At the same time, suspensions of the rod-shaped apatite crystals having a variable solids content should also be provided.
• the object is achieved by a process for the preparation of dispersions which contain the rod-shaped apatite crystals described beforehand.
• the process according to the invention contains the following steps:
• step b) at least one fluoride-containing compound is added to the mixture present as a dispersion situated in the autoclave and mixed with this dispersion over a period of time of at least 1 hour.
• the pure apatite crystals can be isolated from the dispersions thus obtained by subjecting the dispersions to drying, in particular spray drying, in an additional process step.
• the advantage of the solution according to the invention lies in the fact that a novel process is provided with which apatite crystals can be prepared which are exclusively rod-shaped. Moreover, the process is restricted not only to the preparation of hydroxyapatite crystals, but mixtures of rod-shaped hydroxyapatite crystals and rod-shaped fluoroapatite crystals or rod-shaped mixed crystals of hydroxyapatite and fluoroapatite can also be prepared.
• the rod-shaped apatite crystals prepared using the process according to the invention have a length-to-breadth ratio of >5. This means that the crystals have a length-to-breadth ratio of 5 in the “most unfavorable” case, whereas, however, there are also a significant number of crystals which have a length-to-breadth ratio of markedly greater than 5, for example 8 to 15. In most processes according to the prior art, however, as already mentioned beforehand, a numerically large amount of crystals having a length-to-breadth ratio of 1 to 2 is produced.
• a further advantage of the process according to the invention can be seen in the simple handling of the adjustment of the fluoride ion concentration.
• the hydroxyapatite crystals have already been produced in rod form
• a defined number of hydroxide ions can be replaced by fluoride ions in an ion-exchange process without the rod form of the crystals being modified in this process.
• the process according to the invention is suitably carried out in an autoclave, in particular a stirred autoclave.
• an autoclave in particular a stirred autoclave.
• other vessels or devices known to the person skilled in the art can also be used, which withstand the reaction conditions under elevated pressure.
• a mixture for example in the form of a suspension, is produced in the autoclave from the starting materials and water.
• Suitable starting materials are, as the calcium-containing component, calcium hydroxide and, as the phosphorus-containing component, phosphoric acid.
• additives such as calcium chloride, calcium nitrate (tetrahydrate), ammonium hydrogenphosphate or diammonium hydrogenphosphate can also be admixed to the reaction.
• Calcium hydroxide and phosphoric acid are particularly suitable, the latter is preferably employed in 85% strength by weight form.
• Water is understood in the process according to the invention as in particular meaning completely deionized water, optionally the water, however, can also have a high residual ion content, for example of hydroxide ions and/or protons.
• completely deionized water is introduced into the autoclave and calcium hydroxide is added to the autoclave with stirring at room temperature.
• the suspension thus obtained is warmed to 40 to 50° C. and the phosphoric acid, which is optionally diluted with completely deionized water, is allowed to run into the autoclave with stirring over a suitable period of time.
• a temperature of at least 100° C. and a pressure of >1 bar is generated in the interior of the autoclave, and these conditions are maintained for at least 1 hour, preferably 5 to 16 hours.
• the second process step is carried out at pressures between 1.5 and 6 bar, particularly preferably between 2 and 5 bar.
• Preferred temperature ranges are 105° C. to 150° C., and 110° C. to 130° C. are particularly preferred. If appropriate, temperature gradients can also be used, temperature changes also causing pressure changes.
• the conditions of the second process step are maintained for 10 to 14 hours with stirring. If appropriate, the second process step can also be carried out in less than 1 hour.
• dispersions which contain rod-shaped hydroxyapatite crystals and which are preferably homogeneous.
• the solids content of these dispersions is 5 to 70% by weight, preferably 10 to 40% by weight, particularly preferably 15 to 30% by weight, of hydroxyapatite crystals; if appropriate, the solids content can also be ⁇ 5% by weight.
• the hydroxyapatite crystals prepared in this way (nearly always) have a rod-shaped form, the length-to-breadth ratio of the (individual) crystals being ⁇ 5, but being >20 only in exceptional cases.
• a length-to-breadth ratio of 8 to 15 is preferred, particularly preferably of 9 to 12.
• rod-shaped hydroxyapatite crystals can be prepared which have a length of 0.1 to 0.2 ⁇ m and a breadth of 0.01 to 0.02 ⁇ m, in each case based on the individual crystals.
• the thickness (i.e. the 3rd dimension) of the crystals corresponds to their breadth. It is thus evident that the crystals prepared by the process according to the invention only have a length-to-breadth (or thickness) ratio of 5 in the “most unfavourable” case. This case occurs with a crystal length of 0.1 ⁇ m and a crystal breadth or thickness of 0.02 ⁇ m.
• the length-to-breadth ratio can, however, also be at most 20 (length: 0.2 ⁇ m; breadth: 0.01 ⁇ m).
• the length-to-breadth ratio of the individual crystals can be controlled by the parameters pressure, temperature and reaction time in the second process step.
• the rod-shaped hydroxyapatite crystals can also be isolated from the dispersion.
• the dispersant can be removed by simple evaporation, if appropriate with the aid of vacuum.
• the dispersion can also be subjected to freeze drying for the isolation of the apatite crystals.
• the rod-shaped hydroxyapatite crystals prepared using the process according to the invention are isolated from the dispersion by spray drying, and the device necessary for this and the carrying out of the spray drying are known to the person skilled in the art.
• the isolated hydroxyapatite crystals can be redispersed again in water without problems to give homogeneous dispersions.
• organic compounds such as water-soluble, lower alcohols and glycols, polyethylene glycols, glycerol and mixtures of the organic compounds mentioned beforehand with one another and/or with water as dispersant can also be used for the redispersion.
• a third process step (c) the hydroxide ions in the hydroxyapatite crystals prepared according to the invention can be (partially) replaced by fluoride ions.
• at least one fluoride-containing compound is added to the dispersion prepared in the second process step.
• Suitable fluoride-containing compounds are sodium fluoride, calcium fluoride, potassium fluoride and arnmonium fluoride, and sodium fluoride is preferably suitable.
• the mixture thus obtained is mixed over a period of time of at least one hour, preferably 10 to 14 hours. Preferably, it is stirred at room temperature, if appropriate higher temperature values and/or lower mixing times than 1 hour can also be used.
• the third process step is presumably based on an ion-exchange mechanism.
• fluoride-containing compounds or mixtures of fluoride-containing compounds which contain no calcium ions as cations or do not exclusively contain calcium ions
• the calcium ions of the rod-shaped apatite crystals can be partially substituted by the cations deriving from the fluoride-containing compound.
• those rod-shaped apatite crystals in which the calcium ions are partially replaced by the cations deriving from the fluoride-containing compounds should also be included by the formula Ca 5 (PO 4 ) 3 (OH) x F y .
• rod-shaped apatite crystals of the formula Ca 5 (PO 4 ) 3 (OH) x F y can be prepared in which the length-to-breadth ratio of the crystals is ⁇ 5, preferably 8 to 15, particularly preferably 9 to 12. It is furthermore preferred that the thickness of the crystals corresponds to their breadth.
• any desired values for y from 0 to 1 can be set; this is controlled by the amount of the fluoride-containing compounds added, the temperature values and the duration of the mixing process in the third process step.
• the rod-shaped apatite crystals of the formula Ca 5 (PO 4 ) 3 (OH) x F y contained in the dispersion can be surrounded by one or more surface-modifying agents.
• Surface-modifying agents are understood as meaning substances which adhere physically to the surface of the crystals, but do not react chemically with these.
• Surface-modifying agents are particularly to be understood as meaning dispersants; the latter are known to the person skilled in the art, for example, also under the terms emulsifiers, protective colloids, wetting agents or detergents. Suitable surface-modifying agents are described, for example, in WO 01/01930.
• antiallergics and/or antiinflammatory active compounds can be used as surface-modifying agents.
• the surface-modifying agents are applied to the surface of the rod-shaped apatite crystals following the process for the preparation of rod-shaped apatite crystals according to the invention by processes known to the person skilled in the art.
• the apatite crystals of the formula Ca 5 (PO 4 ) 3 (OH) x F y prepared using the process according to the invention are suitable in isolated form and/or in the form of dispersions for use as a remineralizing component for teeth and/or bone.
• the apatite crystals can be present both in cleansing and care formulations and in formulations for the treatment of tooth and bone defects. Tooth gels, toothpastes (or tooth creams), mouthwash (or mouth rinses) and chewing gum may be mentioned in particular.
• the apatite crystals according to the present invention are used as a constituent of formulations for the induction or promotion of the new growth of bone tissue and for the coating of implants.
• the hydroxyapatite obtained consisted of stalk-shaped crystals of prismatic cross-section with breadths and thicknesses of 0.01 to 0.02 ⁇ m and lengths of 0.1 to 0.2 ⁇ m.
• the specific surface area was 49.4 m 2 /g.
• Example 2 was carried out analogously to example 1. After the dispersion containing the hydroxyapatite had been cooled to room temperature, 0.168 kg of sodium fluoride was added to the autoclave and the dispersion was stirred at room temperature for a further 12 h.
• the suspension was then drawn off from the autoclave.
• the X-ray diffractogram of a dried sample showed that about 20 mol % of the hydroxide ions, based on the total amount of the crystals, had been replaced by fluoride ions.
• the form and the dimensions of the crystals have not changed compared with those of the crystals from example 1.
• the specific surface area was 49.4 m 2 /g.
• Example 2 was repeated with the difference that after 20 min the reaction contents were heated at 100° C. to 150° C. and the reaction time at this temperature was reduced to 4 h. The pressure under these conditions was 4.5 bar. After the dispersion containing the hydroxyapatite had been cooled to room temperature, 0.067 kg of sodium fluoride was added.
• the X-ray diffractogram of the dried sample showed that about 8 mol % of the hydroxide ions, based on the total amount of the crystals, had been replaced by fluoride ions.
• the specific surface area was 46.8 m 2 /g
• the Ca/P ratio was 1.65
• the shape and the dimensions of the crystals corresponded to those from example 1.
• a solids content of 21.3% was determined for the dispersion thus obtained after cooling.
• the X-ray diffractograms of the crystals which were isolated from the dispersion showed the diffraction reflections of hydroxyapatite.
• the hydroxyapatite had the form of irregular spheres having diameters of 0.4 to 5 ⁇ m.

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• 2002
  • 2002-06-20 US US10/480,809 patent/US20040171471A1/en not_active Abandoned
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  • 2002-06-20 CN CNB028124537A patent/CN1250449C/zh not_active Expired - Fee Related
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