WO2002087746A1 - Dispersions d'hydroxyapatite comprenant un acide amine en tant qu'agent stabilisant, et leur procede de preparation - Google Patents
Dispersions d'hydroxyapatite comprenant un acide amine en tant qu'agent stabilisant, et leur procede de preparation Download PDFInfo
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- WO2002087746A1 WO2002087746A1 PCT/FR2002/001440 FR0201440W WO02087746A1 WO 2002087746 A1 WO2002087746 A1 WO 2002087746A1 FR 0201440 W FR0201440 W FR 0201440W WO 02087746 A1 WO02087746 A1 WO 02087746A1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/0004—Preparation of sols
- B01J13/0008—Sols of inorganic materials in water
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- 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
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- 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
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- 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
Definitions
- Hydroxyapatite dispersions comprising an amino acid as a stabilizing agent, and process for their preparation
- the present invention relates to stable aqueous colloidal dispersions of colloids with apatitic structure in which the colloids, of oblong or spherical shape, have nanometric dimensions.
- These dispersions are stabilized by stabilizers of the amino acid type, optionally in ionized form, in interaction with the surface of the colloids.
- These oblong colloids are in more or less aggregated form, and have an average length (in number) generally between 20 and 250 nm and an equivalent aspect ratio (ratio of average length (in number) to diameter equivalent) between 1 and 300.
- the colloids of spherical shape have a diameter between 10 and 100 nm, preferably between 10 and 60 nm, for example between 10 and 40 nm.
- aqueous colloidal dispersion is generally meant a system consisting of a continuous aqueous phase in which are dispersed fine solid particles of colloidal dimensions, said fine particles defining colloids at the surface of which molecules of an agent can be bound or adsorbed stabilizer or various ionic species present in the continuous aqueous phase.
- colloids with apatitic structure is meant according to the invention colloids of general formula:
- J is chosen from OH “ , F “ , CO 3 2 " and or CI " and in which certain phosphate ions (PO 4 3 “ ) or hydrogen phosphate (HPO 4 2” ) can be replaced by carbonate ions (CO 3 2 " ), and in which certain Ca 2+ cations can be replaced by metal cations M n + of alkali, alkaline earth metals or of lanthanides where n represents 1, 2 or 3, it being understood that the molar ratio of the cation M n + , when present, to Ca 2+ , varies between 0.01: 0.99 and 0.25: 0.75, and that the substitution of ions HPO 4 2 " or of PO 4 3 ' ions with CO 3 2 ions " , the incorporation of CO 3 2 ions " as J and the substitution of Ca 2+ cations by metal cations is carried out so as to satisfy the electronic balance, in particular with the creation of gaps.
- Ca 2+ when Ca 2+ is replaced by an alkali metal cation, this is Na + .
- Ca 2+ when Ca 2+ is replaced by an alkaline earth metal cation, this is Sr 2 *.
- Ca 2+ is replaced by a lanthanide cation, the latter is preferably Eu 3+ , Eu 2+ , Dy 3+ or Tb 3+ .
- lanthanide is understood to mean the elements of the group constituted by yttrium and by the elements of the periodic classification with atomic number included inclusively between 57 and 71.
- the periodic classification of the elements to which reference is made in the present description is that published in the supplement to the bulletin of the departments Chimique de France No. 1 (January 1966).
- the colloids are colloids of hydroxyapatite.
- colloids with apatitic structure also includes colloids obtained by hydrolysis of the colloids of formula I above.
- octocalcium phosphate a colloid of formula Ca 8 (HPO 4 ) 2 , 5 (PO 4 ) 3 , 5 OH 0 , 5 is obtained after hydrolysis.
- M n + a metal cation M n + .
- the M ⁇ + / Ca 2+ molar ratio varies between 0.02 / 0.98 and 0.15 / 0.85.
- Colloids with an apatite structure are generally obtained by contacting, in aqueous solution, a source of Ca 2+ and a source of PO 3 " in an appropriate pH range.
- colloids with an apatite structure are obtained, the growth of which is difficult to control and limit.
- the particle formation kinetics are often very high, so that it is difficult to stop the mineral polycondensation at the nanometric particle stage.
- particles of too large size are generally obtained in fine with a strong tendency to decantation.
- the invention provides, according to a first of its aspects, a method making it possible to control the growth of colloids with apatitic structure and leading to stable colloidal dispersions consisting of colloids of nanometric dimensions.
- the invention relates to stable, aqueous colloidal dispersions of colloids with apatitic structure, formed of relatively fine colloids, of oblong shape, of an average length (in number) between 20 and 250 nm and an equivalent aspect ratio (ratio of the average length (in number) to the equivalent diameter) of between 1 and 300, or else of spherical shape having a diameter of between 10 and 100 nm.
- These dispersions are generally formed from weakly aggregated colloids. In the case of colloids with small dimensions and weakly aggregated, the dispersions of the invention are transparent to the naked eye.
- weakly aggregated colloids is meant a percentage by number of perfectly individualized objects greater than 80%, preferably greater than 90%, advantageously greater than 95%.
- the invention relates to a stable aqueous colloidal dispersion of colloids with apatitic structure, having a pH between 5 and 10, consisting of colloids of oblong shape with an average length (in number) between 20 and 250 nm and of an equivalent aspect ratio (ratio of the average length (in number) to the equivalent diameter) of between 1 and 300, or else of spherical shape having a diameter of between 10 and 100 nm, and comprising one or more acids amines optionally in ionized form as a stabilizing agent; said colloids having an apatite structure having the formula: Ca ⁇ 0- x (HPO 4 ) x (PO 4 ) 6- x (J) 2-x (IV) in which: x is chosen from 0, 1 or 2;
- J is chosen from OH “ , F “ , CO 3 2 “ or CI “ ; and in which certain phosphate ions (PO 4 3 “ ) or hydrogen phosphate
- HPO 4 2 " can be replaced by carbonate ions (CO 3 2" ); and in which certain Ca 2+ can be replaced by metallic cations M ⁇ + of alkali metals, alkaline earth metals or lanthanides where n represents 1, 2 or 3, it being understood that the molar ratio of the cation M ⁇ + , when it is present, at Ca 2+ , varies between 0.01: 0.99 and 0.25: 0.75, and that the substitution of HPO 4 2 " ions or PO 3" ions with CO 3 ions 2 " , the incorporation of CO 3 2" ions as J and the substitution of Ca 2+ cations by metal cations is carried out so as to satisfy the electronic balance, in particular with creation of vacancies.
- colloids of oblong shape are understood to mean colloids of parallelepipedal shape (for example in the shape of a stick) or of acicular shape.
- the equivalent diameter is the diameter that would have the colloid of corresponding acicular shape with the same average volume and the same average length.
- the equivalent diameter assigned to the cross section of the acicular colloid corresponds to the diameter of an average cross section.
- the oblong-shaped colloids are formed from colloids with a weakly aggregated apatitic structure. In general, oblong colloids have an average length (in number) of between 20 and
- colloids in the form of needle-like fibers, the average length of which generally varies between 20 and 250 nm and the equivalent diameter is between 0.5 and 5 nm; and rod-shaped colloids whose average length generally varies between 20 and 250 nm and the equivalent diameter is between 5 and 20 nm.
- Spherical colloids have a diameter generally between 10 and 100 nm, preferably between 10 and 60 nm, better still between 10 and 40 nm.
- the dispersions of the invention are either uniformly formed of oblong-shaped colloids, or uniformly formed of spherical colloids, or still formed from a mixture of colloids of oblong shape and spherical shape.
- J represents OH “ or / and F " . Not all OH ions “need to be replaced by F “ ions, but only part of the OH ions " can be replaced by F " ions.
- J is chosen from OH “ , F “ , CO 3 2 “ and CI " , it is not necessary for all the Js to be identical to each other.
- Stabilization of the colloidal dispersion is obtained by the action of a stabilizing agent.
- the stabilizing agent contributes not only to ensure the stabilization of the dispersion but also to control the growth of the colloids with apatitic structure during the preparation of the aqueous dispersion.
- the stabilizing agent is a natural or synthetic amino acid, optionally in ionized form or a mixture of these compounds.
- the ⁇ -amino acids include a carbon atom carrying an amino group, a carboxyl group, a hydrogen atom and a side group which may be a hydrogen atom (in the case of glycine) or any other monovalent organic group.
- the side groups can be in particular alkyl groups (case of alanine, valine, leucine, isoleucine and praline), substituted alkyl groups (case of threonine, serine, methionine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, arginine and lysine), arylalkyl groups (case of phenylalanine and tryptophan), substituted arylalkyl groups (case of tyrosine ), heteroalkyl groups (case of histidine).
- alkyl groups case of alanine, valine, leucine, isoleucine and praline
- substituted alkyl groups case of threonine, serine, methionine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, arginine and lysine
- arylalkyl groups case of phenylalanine and tryptophan
- the expression amino acid also includes ⁇ -, ⁇ -, ⁇ - and ⁇ -amino acids.
- synthetic ⁇ -amino acid is meant an ⁇ -amino acid which is not incorporated into a protein under the control of mRNA such as for example a fluorinated ⁇ -amino acid such as fluoroalanine, trimethylsilylalanine or an ⁇ -amino acid such than :
- ni is an integer from 1 to 6 and n 2 is an integer from 1 to 12.
- amino acids which can be used as stabilizers are either in their L form, or in their D form, or else in the form of a racemic mixture.
- ⁇ -amino acid More generally, a preferred group of ⁇ -amino acid consists of the compounds of formula:
- L represents an alkyl group optionally interrupted by an oxygen atom and / or a sulfur atom and / or a nitrogen atom, said nitrogen atom carrying a hydrogen atom or an alkyl radical, aryl, arylalkyl, alkylaryl, heteroaryl or heteroarylalkyl, and said alkyl group being optionally substituted by one or more radicals chosen from -OH, -NH 2 , guanidino, carboxy, carbamoyl, thiol, aryl (itself optionally substituted by one or more radicals T, identical or different, as defined below), heteroaryl (itself optionally substituted by one or more radicals T, identical or different as defined below);
- W represents a hydrogen atom or L and W together represent an optionally substituted alkylene chain
- T represents hydroxy, amino, guanidino, carboxy, thiol, alkylthio, alkylamino, carbamoyl, dialkylamino, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl or heteroarylalkyl.
- alkylene is meant an aliphatic, linear or branched hydrocarbon chain.
- alkyl is generally meant a branched or linear aliphatic hydrocarbon chain comprising from 1 to 18 carbon atoms, preferably from 1 to 10 carbon atoms and in particular from 1 to 6 carbon atoms.
- alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentyl, 3- methylpentyle, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-1- ethylpropyl, heptyle, 1-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1 -methylheptyl, 2- ethylhexyl, 5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and 7,7
- alkyl represents methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1 - ethylpropyl, hexyl, isohexyl, neohexyl, 1-methyl pentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl and 1 -methyl-1 -ethylpropyl.
- Aryl generally denotes an aromatic carbocyclic radical containing from 6 to 18 carbon atoms, preferably from 6 to 10 carbon atoms.
- Aryle is mono- or polycyclic and preferably mono-, bi- or tricyclic.
- the carbocyclic radical comprises more than one cyclic nucleus
- the cyclic nuclei can be condensed two by two or attached two by two by ⁇ bonds.
- heteroaryl generally means heterocyclic radicals comprising one or more heteroatoms chosen from O, S and N.
- Heteroaryl radicals include mono- and polycyclic radicals; preferably mono-, bi- or tricyclic radicals.
- each unicycle comprises from 3 to 8 links, better still from 5 to 7.
- each of the monocycles constituting the heterocycle comprises from 1 to 4 heteroatoms, better still from 1 to 3 heteroatoms.
- heteroaryls chosen from pyridine, furan, thiophene, pyrrole, pyrrazole, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole;
- each unicycle comprises from 5 to 7 vertices, such as for example chosen from indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane, benzothiofurazane, purine, quinoline, isoquinoline, cinnoline , quinazoline, quinoxaline, naphthyridines, pyrazolotriazine (such as pyrazolo-1, 3,4-triazine), pyrazolopyrimidine and pteridine; and
- each unicycle comprises from 5 to 7 vertices such as, for example, acridine, phenazine or carbazole.
- the expression "possibly interrupted by O and / or S and / or N" means that any carbon atom in the hydrocarbon chain can be replaced by an oxygen and / or sulfur and / or nitrogen atom, this carbon atom can not be located at one end of said chain hydrocarbon.
- the hydrocarbon chain which may be alkyl may comprise several oxygen and / or sulfur and / or nitrogen atoms, preferably the heteroatoms being separated from each other by at least one carbon atom, better still by at least two carbon atoms.
- the alkylene chain is interrupted by a nitrogen atom, it is preferred that the latter bear a hydrogen atom or an alkyl group.
- the stabilizing agent used is chosen from lysine, glycine, asparagine, creatine, arginine, aspartic acid, glutamic acid, serine, alanine, valine, leucine, their salts with acids or bases, and mixtures thereof.
- the stabilizing agent is chosen from lysine, creatine, glycine, alanine, asparagine, serine, their salts with acids or bases, and mixtures thereof.
- the stabilizing agent can also be the salt of an amino acid with a base or an acid, preferably with an inorganic acid or base.
- an inorganic acid mention may be made of nitric, phosphoric, phosphinic, phosphonic, hydrochloric, sulfonic and sulfuric acids.
- an inorganic base mention may be made of bases of the alkali metal or alkaline earth metal hydroxide and ammonium hydroxide type.
- the stabilizing agent can consist of one or more amino acids, optionally in ionized form.
- the stabilizing agent is generally either present in free form in the continuous medium of the colloidal dispersion, or adsorbed or bound to the surface of the colloids, or in interaction with Ca 2+ ions present in the continuous phase of the dispersion.
- the colloidal phase is predominantly of apatitic structure as defined above.
- the apatite structure represents more than 50% by weight of the colloidal phase, preferably more than 75% by weight, better still more than 80%, for example more than 85% by weight.
- the colloidal phase can also comprise other structures, such as Ca (H 2 PO 4 ) 2 ; CaHPO 4 ; CaHPO 4 , 2H 2 O or other amorphous phase based on calcium and PO 3 " , HPO 4 2" or H 2 PO 4 ' and OH " .
- the molar ratio of the total calcium present in the colloids to the total phosphorus present in the colloids varies between 1, 3 and 1, 7, better still between 1, 5 and 1, 67.
- the molar ratio of the total stabilizing agent present in the colloids or on the surface of the colloids to the total calcium present in the colloids or on the surface of the colloids it varies between 0.001 and 1.0, preferably between 0.01 and 0, 5, advantageously between 0.01 and 0.1.
- the colloidal phase contains from 60 to 100% of the total calcium, preferably from 80 to 100%, for example from 90 to 100%, better still from 95 to 100%.
- the colloidal phase contains from 80 to 100% of total phosphorus (PO 3 ' ions, HPO 4 2 “ and H 2 PO 4 " total), preferably from 90 to 100%, better still from 95 to 100%. weight.
- the calcium concentration of the dispersion is easily adjustable, according to the invention, by elimination of part of the continuous aqueous phase.
- the elimination of part of the aqueous phase can be carried out by ultrafiltration.
- the colloidal dispersion of the invention has a concentration greater than 0.25 M in calcium in the form of colloids with apatitic structure, preferably greater than 0.5 M, advantageously greater than 1 M, this concentration possibly reaching 5M.
- the pH of the colloidal dispersion of the invention varies between 5 and 9.5, better still between 6.5 and 8.5, for example between 6 and 8.
- the invention relates to a process for preparing a stable aqueous colloidal dispersion, comprising the steps consisting in: a) bringing into contact, in aqueous solution, a source of Ca 2+ cations, and a source of PO 4 anions 3 " and an amino acid as stabilizing agent or a salt thereof with an acid or a base, at a pH between 5 and 10, the respective amounts of the source of Ca 2+ and of the source of PO 4 3 " anions being such that the Ca 2+ / P molar ratio varies between 1 and 3.5, preferably between 2 and 3.2, the amount of agent stabilizer being such that the stabilizing agent / Ca molar ratio varies between 0.3 and 2.5, preferably between 0.9 and 2; b) allow the solution thus obtained to mature at a temperature of between
- source of PO 4 3 anions is meant a compound capable of releasing PO 4 3" ions in aqueous solution.
- Examples of a source of Ca 2+ cations are calcium hydroxide, calcium oxides, water-soluble calcium salts.
- Examples of calcium salts are the salts having for anion PF 6 “ , PCI 6 “ , BF 4 “ , BCI 4 “ , SbF 6 “ , BPh 4 “ , CIO 4 “ , CF 3 SO 3 " and more generally the carboxylates derivatives of C 2 -C 10 alkylcarboxylic acids and in particular acetate.
- Other salts are calcium halides, calcium hydrogen carbonate and calcium nitrate.
- those which can be used in the context of the invention are those having a water solubility sufficient to ensure the desired concentration of Ca 2+ in the aqueous phase.
- the source of Ca 2+ cations is chosen from calcium hydroxide, calcium oxides, calcium halides, calcium nitrate, and calcium hydrogen carbonate.
- the source of PO 3 " anions is the salt of a PO 3" anion, the salt of an HPO 2 " anion or the salt of an H 2 PO 4 " anion such as ammonium salt, or an alkali metal salt or a mixture of these salts.
- n varies from 2 to 10 (and in particular the salts of the tripolyphosphate type) or else the salts of the trimetaphosphate anion (PO 3 ) 3 3 ⁇ , or the salts of the pyrophosphate anion (P2 ⁇ 7 ) 4 " .
- an acid or a base preferably an acid or a mineral base
- the bases and acid which can be used are those generally used in the art.
- NH 4 OH or NaOH will be used.
- acids which can be used are in particular HCI, H 2 SO, H 3 PO or HNO 3 .
- HNO 3 or HCI will be used.
- a buffer operating in the desired range can be used.
- a buffer ensuring a pH of 6.5 to 9 is preferably used.
- a buffer consisting of an aqueous solution of potassium dihydrogen phosphate (0.025M) and sodium hydrogen phosphate (0.025M) may be mentioned , which ensures a pH of 6.86 at 25 ° C.
- the contacting of the sources with an aqueous medium can be carried out in any way.
- the relative proportions of the compounds used respectively as a source of Ca 2+ and of PO 3 " are calculated so that the Ca / P molar ratio is between 1 and 3.5, preferably between 2 and 3.2.
- the Ca / P molar ratio takes into account all of the Ca 2+ cations introduced and all of the phosphorus introduced into the solution, whether the phosphorus is in the form H 3 PO 4 , H 2 PO 4 3 " , HPO 4 2" or PO 4 3 ' .
- the stabilizing agent is added either to the aqueous solution of Ca 2+ , or to the aqueous solution of PO 4 3 " , or to the two aqueous solutions, in which case the respective proportion of stabilizing agent added to each solution is arbitrary.
- the stabilizing agent is added to the aqueous Ca 2+ solution.
- the amount of stabilizing agent to be added to the total is defined so that the stabilizing agent / Ca molar ratio varies between 0.3 and 2.5, preferably between 0.9 and 2.
- the amount of stabilizing agent used affects the dimensions of the colloids ultimately obtained. It is in particular by controlling this parameter that it is possible to obtain transparent aqueous dispersions.
- a molar ratio of the stabilizing agent to Ca 2+ of between 1.0 and 2 leads in particular to transparent dispersions.
- the next step consists in mixing the two aqueous solutions, this mixture being used in a conventional manner with stirring.
- the pH of the two solutions is adjusted beforehand before mixing.
- This pH can be adjusted between 5 and 11, preferably between 7 and 9.5.
- the concentration of Ca 2+ cations in the solution is between 0.2 M and 2 M, preferably between 0.2 and 1 M; the concentration of PO 4 3 " , HPO 2" and H 2 PO 4 " ions total varies between 0.1 M and 1 M, preferably between 0.1 and 0.5 M; and the concentration of stabilizing agent is between 0 , 1 M and 3 M.
- the mixing can be carried out either by adding the solution of the source of Ca 2+ possibly containing the stabilizing agent, to the solution of the source of PO 3 " possibly containing the stabilizing agent or vice versa.
- This addition can be carried out instantaneously or gradually and at a constant rate.
- this addition can be performed over a period of 15 min to 6 hours, preferably from 15 min to 4 hours, advantageously from 15 min to 1 hour.
- the PO 4 3 " source solution will be gradually added to the Ca 2+ source solution containing the stabilizing agent.
- Appropriate sources consist of the hydroxides of these metals or of the salts of these metals, such as halides or nitrates.
- the metal cation is the cation of a lanthanide
- the contacting of the source of Ca 2+ with the source of PO 4 3 " generally takes place at ambient temperature, for example between 15 and 30 ° C.
- Step b) of the process of the invention is a maturing step during which the mixture of the two solutions is left to stand or stirred, the time necessary to observe the formation of colloids.
- step b) the colloidal dispersion resulting from step a) which is a milky dispersion evolves towards a colloidal dispersion, stable with respect to decantation.
- This ripening stage can be carried out at room temperature (15-30 ° C) or at a higher temperature, namely up to 180 ° C. Thus, generally, the temperature is fixed at this stage between 15 and 180 ° C, better still between 40 and 160 ° C.
- the ripening is carried out in a closed enclosure at a temperature below 100 ° C. and in an autoclave at a temperature above 100 ° C.
- the colloids obtained When the ripening step is carried out at a temperature below 100 ° C., in a closed enclosure, the colloids obtained preferably have an anisotropic morphology. Conversely, when one operates in an autoclave at a temperature above 100 ° C., one obtains a mixture of colloids with anisotropic morphology and colloids with isotropic morphology.
- the ripening stage is preferably carried out in a closed enclosure.
- the dispersion, conditioned in a closed enclosure, can be placed directly in an oven previously brought to the set temperature or undergo a temperature ramp up to the set temperature, the rate of temperature rise preferably varying between 0.1 ° C. / min and 10 ° C / min.
- the ripening is carried out at various temperatures.
- a first stage of ripening is carried out at a first temperature between 20 and 180 ° C.
- a second stage of ripening is carried out at a second temperature, said second temperature also being between 20 and 180 ° C.
- the second temperature is higher than said first temperature.
- the ripening time varies depending on the operating conditions and more particularly on the temperature. Usually, the ripening time varies between 15 min and 24 hours.
- the continuous phase of the colloidal dispersion can contain different species such as NH 4 + , Na + , K + , CI “ , NO 3 ' and SO 4 2" .
- These ions come either from sources of calcium and PO 3 " , or from acids and mineral bases used for pH adjustments.
- the continuous phase of the colloidal dispersion may also contain stabilizers in neutral form or in ionized form, not in interaction with the surface of the colloids, that is to say completely free, or in interaction with Ca 2+ ions present in the continuous phase of the dispersion. It is difficult to avoid the presence of various calcium or phosphorous species as well as the presence of the stabilizing agent within the aqueous continuous phase or alongside colloids with apatitic structure, so that it may be necessary to carry out a purification, for example by washing the dispersion.
- This washing can be carried out in a conventional manner per se, by ultrafiltration or dialysis.
- Ultrafiltration can be carried out in particular in air or in an atmosphere of air and nitrogen or even under nitrogen. It preferably takes place with water whose pH is adjusted to the pH of the dispersion and is, for example, implemented using 3 kD or 15 kD membranes.
- the pH of the final dispersion may be adjusted between 6 and 8.
- the size of the colloids can be determined by photometric counting from an analysis by METHR (Transmission Electron Microscopy at METHR).
- the structure of the colloids and in particular their more or less significant degree of aggregation can be determined by cryo-transmission electron microscopy by following the Dubochet method.
- the average length (in number) of the oblong colloids varies between 20 and 250 nm and their equivalent aspect ratio (ratio of the average length (in number) to the equivalent diameter) varies between 1 and 300.
- colloidal dispersions of the invention can be used in multiple applications, as such, or after isolation of the colloids with apatitic structure to form porous materials.
- colloidal dispersions of the invention can also be used after preparation of an emulsion by addition of an oily phase.
- colloidal dispersions or porous materials examples are the separation and purification of proteins, use in prostheses and use in sustained release systems.
- the isolation of the colloids can be carried out in a manner known per se: simple evaporation at room temperature, evaporation under vacuum, evaporation at temperature above 100 ° C., by ultracentrifugation or preferably drying-atomization.
- Spray drying can be described as atomizing the colloidal dispersion by means of a nozzle in a temperature enclosure.
- industrial spray dryers are the Niro or Buchi type spray dryers.
- the redispersible colloids are obtained for outlet temperatures below 150 ° C.
- the invention relates to colloids of apatitic structure redispersible in water which can be obtained by using steps consisting in: a) preparing a colloidal dispersion by implementing the method described above; b) isolating the colloids from the colloidal dispersion resulting from step a), in a manner known per se, and preferably by centrifugation.
- the hydroxyapatite colloids obtained can be used in the treatment of osteoporosis, cramps, colitis, bone fractures, insomnia, as well as in dental hygiene.
- Hydroxyapatite colloids can be used in the preparation of hydroxyapatite films, absorbent materials with high specific surface and high pore volume, encapsulation materials and catalytic materials, but also in the field of luminescence.
- colloids of the aqueous dispersions of the invention can be isolated simply by ultracentrifugation. These colloids can present, bound or adsorbed, on their surface, a certain amount of stabilizing agent. The amount of stabilizing agent present can be determined by chemical determination.
- the determination of the mass percentage of Ca of the colloids is carried out from the colloids isolated by centrifugation and dried at room temperature for 7 days, in the following manner.
- the dried colloids are dissolved by microwave attack with HNO 3 / HF / H 2 O 2 .
- the determination of Ca is then carried out by ICP / AES atomic emission by plasma induced on a Jobin Yvon Ultima device.
- the principle is an excitation of atoms in an argon plasma, with emission of photons of different wavelengths.
- a grating spectrometer allows the separation of wavelengths and the detection is carried out by a photo multiplier.
- a mass percentage of carbon on the colloids recovered by ultracentrifugation and dried at room temperature for 7 days is determined by analysis with LECO CS-044. Oxidation is carried out in the presence of the product catalyst in an induction furnace under oxygen scavenging.
- the detection and integration of CO 2 peaks is carried out by infrared.
- the colloidal dispersion obtained is transparent to the naked eye.
- Colloidal dispersions transparent to the naked eye are formed from poorly aggregated, well-individualized colloids.
- at least 80% by number of the colloids, preferably at least 90% and advantageously at least 95% by number, are not aggregated.
- This state of aggregation can be viewed by transmission electron cryomicroscopy, according to the Dubochet method. This method allows observation by transmission electron microscopy (TEM) of samples kept frozen in their natural environment which is either water or organic diluents. Freezing is carried out on thin films about 50 to 100 nm thick, either in liquid ethane for the aqueous samples, or in liquid nitrogen for the others.
- TEM transmission electron microscopy
- Freezing is carried out on thin films about 50 to 100 nm thick, either in liquid ethane for the aqueous samples, or in liquid nitrogen for the others.
- Cryo MET the dispersion state of the particles is well preserved and representative of that present in the real
- the invention relates to transparent colloidal dispersions formed from colloids of oblong shape with an average length (in number) of 20 to 150 nm or of spherical shape with a diameter of 10 to 100 nm, in which at least 80% of the colloids are not aggregated, the molar ratio of the stabilizing agent to the total calcium present in the colloids or at the surface of the colloids varies between 0.001 and 1, preferably between 0.01 and 0.5, the pH of the colloidal dispersion being between 5 and 9.5.
- the stabilizing agent is chosen from alanine and lysine, optionally ionized, and a mixture of these compounds.
- the molar ratio of the stabilizing agent to calcium is preferably greater than 0.5: 1, better still greater than 1: 1;
- the pH is preferably between 5 and 9.5, better still between 7 and
- the stabilizing agent is composed of one or more amino acids optionally in ionized form, preferably it is chosen from lysine, alanine and their ionized forms; d) bringing the source of Ca 2+ cations into contact with the source of anions
- the stabilizing agent is produced by adding the solution from the source of PO 3" to the solution of the source of Ca 2+ , which contains the stabilizing agent or vice versa.
- the invention relates to the transparent dispersions which can be obtained by implementing the method of the invention in which one or more of the parameters a) to d) above have been retained.
- M denotes the molecular mass
- a solution A is prepared by adding 25.4 ml of 0.98 M phosphoric acid, or 25 millimoles of phosphorus, to a beaker. We dilute with water demineralized to a final volume of 60 cm 3 . It is adjusted to pH 9 by the addition of 6 cm 3 of concentrated ammonia 10.5 M. It is made up to 75 cm 3 with demineralized water.
- the molar ratio (Lysine: Ca) is 2.
- Solution A is added instantaneously to solution B at room temperature.
- the Ca / P ratio is equal to 3.
- the mixture is left stirring for 15 min at room temperature.
- the pH is pH 9.1.
- the mixture is transferred to a closed enclosure (Parr spray, Teflon container) and the mixture is brought to an oven previously brought to a temperature of 120 ° C.
- the duration of ripening is 16 hours.
- a transparent colloidal dispersion is obtained, the calcium concentration of which is 0.5 M and perfectly stable over time with respect to decantation.
- the well individualized colloids consist of a population of objects having an anisotropic morphology of average length of approximately 50 nm and equivalent diameter of approximately 10 nm and a second population of more isotropic morphology, spheres type, of diameter about 10 nm.
- Solution A is prepared by adding 50.8 ml of 0.98 M phosphoric acid, or 50 millimoles of phosphorus, to a beaker. Diluted with demineralized water to a final volume of 120 cm 3 . It is adjusted to pH 9 by the addition of 12 cm 3 of concentrated ammonia 10.5 M. It is made up to 150 cm 3 with demineralized water.
- Solution A is added instantaneously to solution B at room temperature.
- the Ca / P ratio is equal to 3.
- the pH is 8.6. Adjusted to pH 9 with 6 cm 3 of concentrated ammonia 10.5 M.
- the mixture is left stirring for 15 min at room temperature.
- the mixture is transferred to a closed enclosure and the mixture is allowed to mature at room temperature of 25 ° C. After 16 hours, a transparent colloidal dispersion is obtained.
- a transparent colloidal dispersion is obtained, the calcium concentration of which is 0.5 M, perfectly stable with respect to decantation over time.
- Solution A is prepared by adding 50.8 ml of 0.98 M phosphoric acid, or 50 millimoles of phosphorus, to a beaker. Diluted with demineralized water to a final volume of 120 cm 3 . It is adjusted to pH 9 by the addition of 12 cm 3 of concentrated ammonia 10.5 M. It is made up to 150 cm 3 with demineralized water.
- the mixture is made up to 130 cm 3 with demineralized water.
- the pH is 5.2.
- the pH is adjusted to 9 by adding 12 cm 3 of 10.5 M ammonia and the mixture is made up to 150 cm 3 with demineralized water.
- the molar ratio (glycine: Ca) is equal to 2.
- Solution A is instantaneously added to solution B at room temperature.
- the Ca / P ratio is equal to 3.
- the pH is 8.9.
- the mixture is left stirring for 15 min at room temperature.
- the mixture is transferred to a closed enclosure and the mixture is brought to an oven previously brought to a temperature of 80 ° C.
- the duration of ripening is 16 hours.
- a colloidal dispersion is obtained, the calcium concentration of which is 0.5 M.
- colloids made up of a population of objects having an anisotropic morphology of average length of approximately 150 nm and equivalent diameter of approximately 10 nm.
- EXAMPLE 4 A solution A is prepared by adding 25.4 ml of 0.98 M phosphoric acid, or 25 millimoles of phosphorus, to a beaker. Adjusted to pH 9 by adding 5.5 cm 3 of concentrated ammonia 10.5 M. It is made up to 75 cm 3 with demineralized water.
- the pH is 3.6.
- the pH is adjusted to 9 by adding 10 cm 3 of 10.5 M ammonia and the mixture is made up to 75 cm 3 with demineralized water.
- the molar ratio (asparagine: Ca) is equal to 2.
- Solution A is added instantly to solution B at room temperature.
- the Ca / P ratio is equal to 3.
- the pH is 8.9.
- the mixture is left stirring for 15 min at room temperature.
- the mixture is transferred to a closed enclosure and the mixture is brought to an oven previously brought to a temperature of 80 ° C.
- the duration of ripening is 16 hours.
- a colloidal dispersion is obtained, the calcium concentration of which is 0.5 M.
- To 100 cm 3 of the dispersion obtained are added 200 cm 3 of demineralized water.
- Ultrafilter on a 3 KD membrane up to 100 cm 3 . We start the operation again.
- EXAMPLE 5 A solution A is prepared by adding to a beaker 50.8 ml of 0.98 M phosphoric acid, ie 50 millimoles of phosphorus which is diluted with demineralized water to a final volume of 120 cm. 3 . The pH is adjusted to 9 by adding 24 cm 3 of 4 M NaOH. The mixture is made up to 150 cm 3 with demineralized water.
- the mixture is made up to 120 cm 3 with demineralized water.
- the pH is 5.6.
- Solution A is added instantaneously to solution B at room temperature.
- the Ca / P ratio is equal to 3.
- the pH is 8.4. Adjusted to pH 9 with 7 cm 3 of NaOH 4M.
- the mixture is left stirring for 15 min at room temperature.
- the mixture is transferred to a closed enclosure and the mixture is allowed to mature at room temperature for 16 hours.
- a transparent colloidal dispersion is obtained which is stable with respect to decantation over time, the calcium concentration of which is approximately 0.5 M.
- a solution A is prepared by adding 25.4 ml of 0.98 M phosphoric acid, or 25 millimoles of phosphorus, to a beaker. It is adjusted to pH 9 by the addition of 6 cm 3 of concentrated ammonia 10.5 M. It is made up to 37.5 cm 3 with demineralized water.
- a solution B is prepared by adding to a beaker 12.3 g of
- Solution A is added instantaneously to solution B at room temperature.
- the Ca / P ratio is equal to 3.
- the mixture is left stirring for 15 min at room temperature.
- the pH is 9.3.
- the mixture is transferred to a closed enclosure (Parr spray, Teflon container) and the mixture is brought to an oven previously brought to a temperature of 80 ° C.
- the duration of ripening is 16 hours.
- a transparent colloidal dispersion is obtained, the calcium concentration of which is 1.0 M and perfectly stable over time with respect to decantation.
- a solution A is prepared by adding 8.5 ml of 0.98 M phosphoric acid, or 8.33 millimoles of phosphorus, to a beaker, which is diluted to a final volume of 20 cm 3 . It is adjusted to pH 9 by addition of ammonia. It is made up to 25 cm 3 with demineralized water.
- a solution B is prepared by adding 4.1 g of
- Solution A is added instantaneously to solution B at room temperature.
- the Ca / P ratio is equal to 3.
- the mixture is left stirring for 15 min at room temperature.
- the pH is 9.1.
- the mixture is transferred to a closed enclosure (Parr spray, Teflon container) and the mixture is brought to an oven previously brought to a temperature of 80 ° C.
- the duration of ripening is 16 hours.
- a transparent colloidal dispersion is obtained, the calcium concentration of which is 0.5 M and perfectly stable over time with respect to decantation.
- the well-individualized colloids are visualized.
- the well-individualized colloids are made up of a population of objects having an anisotropic morphology with an average length of around 80 nm and an equivalent diameter of around 10 nm.
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Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02726280A EP1381454A1 (fr) | 2001-04-27 | 2002-04-25 | Dispersions d'hydroxyapatite comprenant un acide amine en tant qu'agent stabilisant, et leur procede de preparation |
US10/474,024 US20040170699A1 (en) | 2001-04-27 | 2002-04-25 | Hydroxyapatite dispersions comprising an amino acid as stabilizing agent and method for preparing same |
BR0208385-0A BR0208385A (pt) | 2001-04-27 | 2002-04-25 | Dispersões de hidroxiapatita que compreendem um aminoácido como agente estabilizante, e seu processo de preparação |
JP2002585080A JP2004534709A (ja) | 2001-04-27 | 2002-04-25 | 安定剤としてアミノ酸を含むヒドロキシアパタイト分散液及びその製造法 |
MXPA03009682A MXPA03009682A (es) | 2001-04-27 | 2002-04-25 | Dispersiones de hidroxiapatita que comprenden aminoacido como agente estabilizador, y su proceso de preparacion. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0105747A FR2823992B1 (fr) | 2001-04-27 | 2001-04-27 | Dispersions d'hydroxyapatite comprenant un acide amine en tant qu'agent stabilisant, et leur procede de preparation |
FR01/05747 | 2001-04-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002087746A1 true WO2002087746A1 (fr) | 2002-11-07 |
Family
ID=8862805
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2002/001440 WO2002087746A1 (fr) | 2001-04-27 | 2002-04-25 | Dispersions d'hydroxyapatite comprenant un acide amine en tant qu'agent stabilisant, et leur procede de preparation |
Country Status (7)
Country | Link |
---|---|
US (1) | US20040170699A1 (fr) |
EP (1) | EP1381454A1 (fr) |
JP (1) | JP2004534709A (fr) |
BR (1) | BR0208385A (fr) |
FR (1) | FR2823992B1 (fr) |
MX (1) | MXPA03009682A (fr) |
WO (1) | WO2002087746A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102004025030A1 (de) * | 2004-05-18 | 2005-12-15 | S&C Polymer Silicon- und Composite-Spezialitäten GmbH | Nano-Apatit-Füllstoffe enthaltende härtbare Restaurationsmaterialien |
US20060239884A1 (en) * | 2003-06-30 | 2006-10-26 | Jean-Yves Chane-Ching | Nanoscale calcium phosphate tablets |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20051966A1 (it) * | 2005-10-18 | 2007-04-19 | C N R Consiglio Naz Delle Ri C | Una idrossiapatite plurisostituita ed il relativo composito con un polimero naturale e-o sintetico loro preparazione e usi |
US8287914B2 (en) | 2006-01-12 | 2012-10-16 | Rutgers, The State University Of New Jersey | Biomimetic hydroxyapatite synthesis |
US20100040668A1 (en) * | 2006-01-12 | 2010-02-18 | Rutgers, The State University Of New Jersey | Biomimetic Hydroxyapatite Composite Materials and Methods for the Preparation Thereof |
SE531779C2 (sv) * | 2007-11-26 | 2009-08-04 | Promimic Ab | Framställning av kalciumfosfatpartiklar i nanostorlek som pulver eller beläggning via bifunktionella prekursorer |
CN102076784A (zh) * | 2008-05-08 | 2011-05-25 | 3M创新有限公司 | 表面改性的纳米粒子 |
US20100226956A1 (en) * | 2009-03-06 | 2010-09-09 | Per Kjellin | Production of moldable bone substitute |
EP2561878B1 (fr) | 2010-03-31 | 2018-03-07 | Toyo Suisan Kaisha, Ltd. | Préparation de calcium et procédé pour la produire |
US9646854B2 (en) * | 2014-03-28 | 2017-05-09 | Intel Corporation | Embedded circuit patterning feature selective electroless copper plating |
CN113307242A (zh) * | 2021-06-15 | 2021-08-27 | 辽宁工程技术大学 | 一种羟基磷灰石纳米棒的制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2605229A (en) * | 1949-04-23 | 1952-07-29 | Joseph K Marcus | Calcium phosphate gels |
US3027229A (en) * | 1957-12-02 | 1962-03-27 | Diamond Lab | Method of preparing hydrated calcium phosphate gels |
EP0322250A1 (fr) * | 1987-12-23 | 1989-06-28 | Sumitomo Chemical Company, Limited | Solution de revêtement contenant de l'hydroxyapatite et procédé pour effectuer un revêtement d'hydroxyapatite utilisant ladite solution |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2381558A1 (fr) * | 1977-02-23 | 1978-09-22 | Oreal | Nouvelles emulsions du type " eau-dans-l'huile " ou " huile-dans-l'eau " et produits cosmetiques obtenus a l'aide de ces emulsions |
TW432397B (en) * | 1997-10-23 | 2001-05-01 | Sumitomo Metal Mining Co | Transparent electro-conductive structure, progess for its production, transparent electro-conductive layer forming coating fluid used for its production, and process for preparing the coating fluid |
-
2001
- 2001-04-27 FR FR0105747A patent/FR2823992B1/fr not_active Expired - Fee Related
-
2002
- 2002-04-25 US US10/474,024 patent/US20040170699A1/en not_active Abandoned
- 2002-04-25 EP EP02726280A patent/EP1381454A1/fr not_active Withdrawn
- 2002-04-25 WO PCT/FR2002/001440 patent/WO2002087746A1/fr not_active Application Discontinuation
- 2002-04-25 BR BR0208385-0A patent/BR0208385A/pt not_active IP Right Cessation
- 2002-04-25 MX MXPA03009682A patent/MXPA03009682A/es not_active Application Discontinuation
- 2002-04-25 JP JP2002585080A patent/JP2004534709A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2605229A (en) * | 1949-04-23 | 1952-07-29 | Joseph K Marcus | Calcium phosphate gels |
US3027229A (en) * | 1957-12-02 | 1962-03-27 | Diamond Lab | Method of preparing hydrated calcium phosphate gels |
EP0322250A1 (fr) * | 1987-12-23 | 1989-06-28 | Sumitomo Chemical Company, Limited | Solution de revêtement contenant de l'hydroxyapatite et procédé pour effectuer un revêtement d'hydroxyapatite utilisant ladite solution |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060239884A1 (en) * | 2003-06-30 | 2006-10-26 | Jean-Yves Chane-Ching | Nanoscale calcium phosphate tablets |
US8329762B2 (en) * | 2003-06-30 | 2012-12-11 | Innophos, Inc. | Nanometric calcium phosphate platelets |
DE102004025030A1 (de) * | 2004-05-18 | 2005-12-15 | S&C Polymer Silicon- und Composite-Spezialitäten GmbH | Nano-Apatit-Füllstoffe enthaltende härtbare Restaurationsmaterialien |
Also Published As
Publication number | Publication date |
---|---|
EP1381454A1 (fr) | 2004-01-21 |
FR2823992A1 (fr) | 2002-10-31 |
JP2004534709A (ja) | 2004-11-18 |
MXPA03009682A (es) | 2004-05-24 |
FR2823992B1 (fr) | 2003-06-20 |
US20040170699A1 (en) | 2004-09-02 |
BR0208385A (pt) | 2004-06-15 |
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