WO2006130167A1 - Materiaux bioactifs nanostructures prepares selon des techniques de sechage par pulverisation a double orifice - Google Patents

Materiaux bioactifs nanostructures prepares selon des techniques de sechage par pulverisation a double orifice Download PDF

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WO2006130167A1
WO2006130167A1 PCT/US2005/033406 US2005033406W WO2006130167A1 WO 2006130167 A1 WO2006130167 A1 WO 2006130167A1 US 2005033406 W US2005033406 W US 2005033406W WO 2006130167 A1 WO2006130167 A1 WO 2006130167A1
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solution
particles
nano
compound
calcium
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PCT/US2005/033406
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English (en)
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Laurence C. Chow
Limin Sun
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Ada Foundation
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Priority to EP05812423A priority Critical patent/EP1885650A4/fr
Publication of WO2006130167A1 publication Critical patent/WO2006130167A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F11/00—Compounds of calcium, strontium, or barium
    • C01F11/20—Halides
    • C01F11/22—Fluorides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/20—Silicates
    • C01B33/24—Alkaline-earth metal silicates

Definitions

  • the present invention comprises apparatus and preparation methods, by a spray drying technique for forming nanostructured particles of bioactive materials that have high reactivity, small particle sizes and high surface areas.
  • Such manufactured materials have performance advantages in a range of biomedical applications.
  • the mineral component of bone and teeth consists primarily of non-stoichiometric and highly substituted hydroxyapatite (HA) in poorly crystalline or nearly amorphous forms.
  • the "impurity" components that are present at significant levels in such biominerals include sodium, potassium, magnesium, and strontium substituting for calcium, carbonate for phosphate, and chloride and fluoride for hydroxyl ions.
  • HA is stable under in vivo conditions and is osteoconductive
  • synthetic HA has been widely used in hard tissue repair application, such as implant coatings and bone substitutes.
  • Other calcium phosphate phases have also been shown to be highly biocompatible and/or osteoconductive.
  • fluorapatite (FA) the calcium phosphate compounds listed in Table 1 have been used in some form of bone repair applications.
  • Calcium phosphate compounds are also useful in various dental applications.
  • a slurry or gel that contained MCPM and fluoride was used as topical F agents that produced significant amounts of both tooth-bound and loosely bound F deposition on enamel surfaces.
  • a chewing gum that contained ⁇ -TCP as an additive released sufficient amounts of calcium and phosphate ions into the oral cavity and significantly alleviated cariogenic challenges produced by sucrose.
  • a calcium phosphate cement that contained TTCP and DCPA was shown to provide effective apical seal when used as a root canal filler/seal, or as a sealer with as a retrievable master cone. The cement was also effective as a perforation sealer.
  • ACP or a TTCP+DCPA mixture has been used as the mineral source in remineralizing dental restorative materials.
  • CaF 2 which is the major product of most topically applied F (F dentifrices, F rinses, professionally applied F gel, etc.), is the source of ambient F in the mouth that is primarily responsible for the cariostatic effects of F.
  • Calcium-silicate compounds tricalcium silicate and dicalcium silicate, are the major components of mineral trioxide aggregates (MTA), a material that finds wide uses in endodontic procedures, such as root end and perforation fills and for apical closure in the apexification procedure.
  • MTA mineral trioxide aggregates
  • CSH Calcium silicate hydrates
  • XCa(OH) 2 ySiO 2 zH 2 O of varying Ca/Si/H 2 O ratios are among the products formed in MTA.
  • nanostructured is used to describe materials characterized by structural features of less than 100 nm in average size (WTEX Panel Report on Nanostructure Nanodevices, 1999). Clusters of small numbers of atoms or molecules in nanostructured materials often have properties (such as strength, electrical resistivity and conductivity, and optical absorption) that are significantly different from the properties of the same matter at the bulk scale. In the case of calcium phosphates and other bioactive inorganic materials, there are a number of reasons to believe that the combination of small particle size and high reactivity can lead to performance advantages in a range of clinical applications.
  • nano sized HA when incorporated into a TTCP+DCPA calcium phosphate cement caused a drastic reduction in setting time from 30 min to 10 — 12 min. It is anticipated that nano particles of other calcium phosphate phases, which are ingredients of the various calcium phosphate cements in clinical use, will also significantly improve the setting and other handling properties, e.g., cohesiveness, injectability, etc., of the cements.
  • apatite crystallites in human bone, enamel, dentin and cementum are all extremely small in size and can be considered as nanostructured materials.
  • HA is the prototype for bioapatites, which are in nano crystalline forms, extensive efforts have been made to produce synthetic nano HA materials.
  • Methods that have been used for preparing nano HA material include chemical precipitation, in some cases followed by spray drying or hydrothermal treatment, sol-gel approach, microemulsion techniques, precipitation from complex solution followed by microwave heating, wet chemical methods incorporating a freeze drying step, mechanochemical synthesis, and eletrodeposition.
  • 6,033,780 discloses a manufacturing method of a spherical apatite by means of a slurry comprising hydroxyapatite as its main component which is dried and powdered to prepare aggregates of primary apatite particles, preferably, spray dried to form spherical particles.
  • U.S. Patent No. 6,558,512 discloses that one method for preparing dense, rounded or substantially spherical ceramic particles such as calcium hydroxyapatite is by spray drying a slurry of about 20 to 40 weight % submicron particle size calcium hydroxyapatite.
  • 6,592,989 provides a method of synthesizing hydroxyapatite comprising the steps of preparing a mixed material slurry by dispersing calcium hydroxide powder into a phosphoric acid solution and conducting a mechanochemical milling treatment.
  • U.S. Patent No. 5,585,318 provides methods for producing non-porous controlled morphology hydroxyapatite granules of less than 8 ⁇ m by a spray-drying process. Solid or hollow spheres or doughnut shapes can be formed by controlling the volume fraction and viscosity of the slurry as well as the spray-drying conditions.
  • 6,013,591 discloses a method for preparing nanocrystalline HA that involves precipitating a particulate apatite from solution having a crystallite size of less than 250 nm and a BET surface area of at least 40 m 2 /g.
  • HA was precipitated from a solution.
  • the slurry or emulsion containing the precipitated HA was spray- dried to produce fine particles.
  • the nano HA materials are formed in a solution environment, and in most cases, the product is washed with water or other solvents to remove impurity or undesired components. Exposure of the nano particles to additional solution environments is likely to result in significant interactions between the particle surfaces and the solvent, leading to modifications of the surface properties and a reduction in the high reactivity innate to the nano particles. Thus, there has persisted the need to identify methods and apparatus for the manufacture of high purity, amorphous or nearly amorphous nano particles, especially those comprised of Ca and P.
  • the present invention comprises methods for preparing nano particles, such as HA particles, by spray drying of a solution discharged through a nozzle in such a way that the nano particles form via in situ precipitation resulting from generally controlled evaporation of the solution in a chamber.
  • the product formed is essentially free of undesired components or impurities such that the particles do not need to be washed.
  • the particles need not be exposed to any solution environment and therefore will retain their original, highly reactive surfaces.
  • nano HA particles of a range of Ca deficiency and substitution Na for Ca and carbonate for phosphate
  • the spray drying methods and apparatus described hereinafter can be used to prepare not only nano HA, but also nano forms of MCPM, DCPD and/or DCPA, and OCP by appropriately formulating the solution composition which is to be sprayed to form droplets from which the liquid is evaporated.
  • the invention is generically described as methods comprising preparation of nano structured materials using a spray drying technique employing a one-liquid nozzle or multiple liquid nozzles.
  • An important feature of the inventive spray drying process comprises evaporation of the liquid from which the nano particles are derived thereby leading to in situ precipitation of HA (or another compound of interest) that is essentially free of undesired components or impurities, hi this way the nano particles formed do not need to be washed and therefore not be exposed to any solution environment that could modify the particle surfaces.
  • This process requires that the solution being sprayed contain only calcium and phosphate ions (or constituent ions of the salt to be prepared) and an acid component in water solution, if needed, to solubilize the calcium phosphate compound.
  • the acid must preferably be sufficiently volatile so that it can be readily evaporated in the spray drying process.
  • the volatile acid must preferably also be a weak acid such that no significant amounts of the acid anions, which are not volatile remain present by the end of the evaporation process.
  • Precipitation of HA for example, resulted from evaporation of water in the spray drying process causing a decrease in solution pH to about 4.0. This, in turn, makes the weak acid become increasingly more undissociated and therefore readily evaporated.
  • Carbonic and acetic acids are examples of good candidates for the purpose.
  • HA-saturated solutions can be prepared by dissolving HA in a dilute acetic acid (for example, 17.5 mmol/L) solution (acetic acid-HA solution) or carbonic acid (266 mmol/L) solution (carbonic acid-HA solution).
  • acetic acid-HA solution for example, 17.5 mmol/L
  • carbonic acid (266 mmol/L) solution
  • compositions of solution to be spray dried for preparing nano particles of various calcium phosphate phases are set forth in Table 2. Because MCPM is highly soluble, the solution for the nano MCPM production can be prepared by dissolving an appropriate amount of MCPM or other sources of Ca (for example CaCO 3 ) and P (for example H 3 PO 4 ) in a solution of the desired concentration (Table 2).
  • a volatile weak acid is used to facilitate solubilization of the calcium phosphate ions.
  • the examples in Table 2 show acetic and carbonic acid as the volatile weak acids but other acids of similar properties could also be used.
  • the amount of a calcium phosphate that can be dissolved is strongly affected by the concentration of the volatile acid.
  • Table 2 shows examples of the solubility of various salts at two concentrations of carbonic acid or acetic acid.
  • a minimum amount of the volatile weak acid, necessary to keep the calcium and phosphate ions in the solution, is used to facilitate the removal of the acid in the spray drying process.
  • the spray formation and drying process in one embodiment thus comprises introduction of a solution of the compound or compounds described through a spray nozzle (nozzles) into a heated chamber where the spray particles are deliquified thereby resulting in high purity, solid, generally amorphous, nano particles collected in a precipitation.
  • nozzles spray nozzles
  • Two nozzles may be utilized for certain applications where the compounds would not otherwise adequately dissolve in a weak acid solution.
  • Another object of the invention is to provide methods for manufacture of nano particles that is efficient, and which avoids complex procedures.
  • a further object of the invention is to provide a method for manufacture of nano particles by spray drying techniques.
  • FIG. 1 is a schematic drawing which depicts an embodiment of a spray drying apparatus useful in the practice of the invention
  • Figure 2 is an x-ray diffraction pattern for HA nano particles prepared with acetic acid in accord with the invention
  • Figure 3 is transmission electron microscope image of the HA nano particles prepared with acetic acid in accord with the method of the invention.
  • Figure 4 is a high resolution transmission electron microscope image of HA nano particles prepared with acetic acid in accord with the method of the invention;
  • Figure 5 is an x-ray diffraction patterns for HA nano particles prepared with carbonic acid in accord with the method of the invention
  • Figure 6 is a transmission electron microscope image of HA nano particles prepared with carbonic acid in accord with the method of the invention.
  • Figure 7 is a graph depicting dissolution of HA in a pH 6 HA pre-saturated solution
  • Figure 8 is an x-ray diffraction pattern of nano particles of CF 2 prepared in accord with an alternative method of the invention utilizing two spray nozzles;
  • Figure 9 is a scanning electron microscope image of a nano CaF 2 sample.
  • Figure 10 is a transmission electron microscope image of a nano CaF 2 sample.
  • FIG. 1 there is depicted in a schematic view a device useful to form nano particles.
  • the apparatus depicted in Figure 1 consists of a spray nozzle 10 (SUCl 120, PNR America LLC, Poughkeepsie, NY) situated on the top of a glass column 12 (Model VM770-48, VM Glass Co., Vineland, NJ, 6" diameter), which is heated with electrical heating tapes (Model BIH 101100L, BH Thermal Co., Columbus, OH) and thermally insulated (fiberglass tape, Flextex, Montgomeryville, PA).
  • Dry HEPA filtered air is supplied at the top 14 of the column, and an electrostatic precipitator 16 (MistBuster®, Air Quality Engineering, Inc., Minneapolis, MN) connected to the lower end of the column 12 pulls air from the column, creating a steady flow of air/mist through the column 12.
  • the water and volatile weak acid in the solution are evaporated into the dry, heated air in the column and are expelled from the precipitator 16 into a hood.
  • the fine particles suspended in the flow are trapped in the precipitator 16 and collected at the end of the process.
  • the nozzle utilized in the apparatus is selected to provide spray droplets of minimum size.
  • the nozzle preferably has a diameter of the nozzle outlet passage in the range of about 12 to 15 microns for the compounds tested.
  • the temperature in the dehydration chamber is typically in the range of 100°C to about 200 0 C without dissociation or adverse impact upon the formed particles.
  • materials such as DCPA and DCPD are dehydrated at a temperature adequately under 200°C to avoid dissociation or other adverse effects upon the formed particles.
  • the flow rate of the clean air into the system will affect temperature in the forming chamber.
  • the air may or may not be preheated.
  • the size and shape of the evaporation chamber will also comprise a factor affecting air flow rates, temperature and evaporation. An arrangement which avoids spray condensing or collecting on the chamber walls is highly preferred.
  • the pH of the acid solution is also preferably controlled for reasons noted previously and preferably is about 4.0 or less. Of course, as the liquid evaporates to leave the powder particles, the effective pH increases. A weak acid is desired to preclude inclusion of acid based artifacts in the formed particles.
  • XRD Rigaku Denki Co. Ltd. The Woodlands, TX
  • Scans were performed between 10° ⁇ 2 ⁇ 50°.
  • the estimated standard uncertainty of the 2 ⁇ measurement is 0.01° and the mass fraction of a crystalline phase to be detected by XRD is about 3%. It was anticipated that the product will contain primarily amorphous materials and the location and the intensity of the broad peak were noted.
  • a ThermoNicolet NEXUS 670 FT-IR spectrometer (Thermo Nicolet, Madison, WI) was used to record the infrared spectra of the nano powders.
  • the absorbance spectra were acquired over the range of 400 cm "1 - 4000 cm '1 using a DTGS detector and KBr beam splitter, with a resolution of 2 cm "1 . Each spectrum was scanned 32 times to increase the signal-to-noise ratio. The estimated standard uncertainty of wavelength was + . 4 cm "1 .
  • Multipoint Brunauer-Emmett-Teller (BET) surface area analyses were done (Gemini 2375 Surface Area Analyzer, Micromeritics, Norcross, GA) with ultra high purity nitrogen as the adsorbate gas and liquid nitrogen as the cryogen.
  • the pressure sequence was (0.05, 0.10, 0.15, 0.20, 0.25) P/Po and the evacuation time was three minutes.
  • the analysis mode was equilibration with the equilibration time of 5 s.
  • the samples were dried in air overnight at HO 0 C (Micromeritics Flow Prep station) before the measurement. Analyses were conducted on replicate samples to established standard deviation. In this and other measurements in the present study, the standard deviation was taken as the standard uncertainty.
  • thermo gravimetric analyzer (TA Instruments - Waters LLC, New Castle, DE) was used to determine the weight loss of the nano powder sample with the increase of temperature.
  • the temperature range was from 25 0 C to 95O 0 C, and the heating rate was 10°C/min. Estimated standard uncertainty of temperature calibration was + . 5 0 C.
  • TEM Transmission electron microscopy
  • the transient nature of the dissolution behavior of HA was taken into consideration when conducting the solubility measurements as follows.
  • the solubility experiments were conducted by dissolving the nano HA sample in solutions pre-saturated with crystalline HA at pH (5.0, 5.5, and 6.0). Based on calculations using a commercially available software "Chemist" (MicroMath, Salt Lake City, UT), the solutions were prepared by equilibrating crystalline HA in 8.1 mmol/L, 2.7 mmol/L, and 0.92 mmol/L phosphoric acid solutions, that also contained 150 mmol/L KNO, as an electrolyte background, until saturation followed by filtration.
  • IAP(HA) (Ca 2+ ) 10 (PO 4 ) 6 (OH) 2 (1)
  • the nano HA particles were used as seeds to determine whether the setting time of a calcium phosphate cement (CPC) could be reduced.
  • CPC calcium phosphate cement
  • Cement hardening or setting time was measured with a Gilmore needle apparatus using a heavy Gilmore needle (453.5 g load, 1.06 mm diameter). The sample was considered set when the needle fails to leave a visible indentation when placed over the surface of the cement.
  • Two CPC mixtures were prepared.
  • the control CPC consisted of equimolar amounts of TTCP (72.9%) and DCPA (27.1%), and the experimental CPC was a mixture that consisted of 95% control CPC and 5% nano HA seeds.
  • the sample was a white powder.
  • XRD patterns showed that the material was amorphous (Figure 6).
  • TEM observations showed clusters of porous spherical amorphous that arrange from 50 nm to about 1 ⁇ m in size ( Figure 4).
  • AHA amorphous HA
  • FTIR showed the pattern of amorphous calcium phosphate with the presence of some acid phosphate (870 cm “1 ), adsorbed water (3407 cm “1 ), molecular water (16435 cm “1 ), and a large amount of trapped CO 2 (2342 cm “1 ) as well as some carbonate incorporation in the structure (870 cm “1 , 1422 cm “1 , and 1499 cm “1 ). Elemental carbon analysis showed the material also contained 9.1 percent mass fraction (9.1%) of carbon.
  • TGA Thermal gravimetric analysis
  • HA prepared from carbonic acid would likely be more soluble than crystalline HA, both because of its small particle size and CO 2 content.
  • An IAP(HA) value as high as 3.3 x 10 "94 (pIAP 93.6), compared to 1 x 10 "117 for crystalline HA, was obtained from experiments in which the nano HA was dissolved in the pH 6 HA-presaturated solution.
  • the [Ca] concentration increased from the initial value of (0.75 ⁇ 0.01) mmol/L in the crystalline HA-presaturated solution to a near a plateau value of (4.5 ⁇ 0.2) mmol/L at 10 min when the experiment ended.
  • the [P] concentration similarly increased from the initial value of (1.2 ⁇ 0.1) mmol/L to a stable value of (3.5 ⁇ 0.2) mmol/L at 5 min.
  • the pH of the solution continued to increase and reached 7.03 ⁇ 0.01 at 10 min.
  • Dissolution of the same nano HA into the pH 5 HA-presaturated solution led to initial increases in [Ca] and [P] concentrations as in the pH 6 experiment.
  • the initial increases were followed by continued decreases in these concentrations beginning at about 2 min to levels that were below the starting [Ca] and [P] concentrations.
  • the process is capable of producing HA materials that contain little or no impurity components.
  • a fair amount of acetate was found in the nano HA sample prepared with the acetic acid-HA saturated spray drying solution, and a large amount of trapped CO 2 was present in the nano HA prepared with the carbonic acid-HA saturated solution.
  • the amount of residual acid components in the spray dried product could be reduced by using a more dilute solution, i.e., with lower [Ca] and [P] concentrations, because a smaller amount of acid would be required to prepare the solution.
  • a complication with HA preparation in general is that HA has a high "affinity" for carbonate.
  • compositions of the solutions to be spray dried for preparing nano particles of several compounds are given in Table 3. It is noted that in some cases, such as in the preparation of F-substituted apatites, solution 1 will contain (Ca(OH) 2 and solution 2 will contain H 3 PO 4 and HF. Upon mixing and spray drying the two solutions, only water needs to be evaporated to produce FA or a F-substituted apatite. In other cases, an acid (or a base) is needed to solubilize the cationic (or anionic) component, and the acid will also need to be evaporated during the spray drying process. An example for this is the preparation of calcium silicate hydrate (CSH). Because SiO 2 is insoluble in acid but is slightly soluble in concentrated alkaline, amorphous SiO 2 is dissolved in a NH 4 OH solution, and NH 3 will be evaporated together with water during the spray drying process.
  • CSH calcium silicate hydrate
  • Solution 1 Ca(OH) 2 1 or 15 mmol/L; , pH from 11.3 to 12.2
  • the spray drying apparatus (Fig. 1) described for one-liquid spray drying process is used except that a 2-liquid nozzle (ViscoMistTM Air Atomizing Spray Nozzle, Lechler Inc., St. Charles, IL) is employed. This nozzle will simultaneously atomize two liquids that are mixed at the moment of atomization.
  • a 2-liquid nozzle ViscoMistTM Air Atomizing Spray Nozzle, Lechler Inc., St. Charles, IL
  • Nano particles of CaF 2 was prepared by spray drying a 10 mmol/L Ca(OH) 2 solution and a 20 mmol/L ammonium fluoride (NH 4 F) solution that were combined at the time of atomization.
  • XRD analysis (Fig. 8) showed crystalline CaF 2 despite that the particles are submicron in size.
  • the larger particles exhibited numerous spherical protuberances on the surfaces, suggesting that they were formed during the spray drying process through fusion of the much smaller particles. This suggests that well dispersed small particles could be produced by using a much lower spray rate.
  • BET measurements showed that this sample has a surface area of 35.5 m 2 /g, corresponding to a particle size of 53 nm. Transmission electron microscopic examinations confirmed that the nano calcium fluoride contained clusters comprised of still smaller particles of 10 to 15 nm in size (Fig. 3). This indicates that better dispersed individual particles can be produced by using more dilute solutions and with a lower spraying rate.
  • a Filter Paper Model for Evaluation of Fluoride Deposition by a Nano CaF 2 Prepared by the Spray Drying Method The ability of the nano CaF 2 to be attached to tooth and other oral substrate surfaces was evaluated in vitro using a filter disc model. Five filter discs (Millipore, Bedford, MA) with a pore size of 0.2 ⁇ m and pore volume of 75% were placed in 20 mL of a nano CaF 2- water suspension or a NaF solution (250 ppm total F in either case). After 1 min of exposure, the filters were rinsed twice in 50 mL of a solution saturated with respect to CaF 2 to remove particles that were not firmly attached on/in the disc or remove unreacted F ions.
  • a filter disc model Five filter discs (Millipore, Bedford, MA) with a pore size of 0.2 ⁇ m and pore volume of 75% were placed in 20 mL of a nano CaF 2- water suspension or a NaF solution (250 ppm total F in either case). After 1 min of exposure,
  • rinse and dentifrice formulations that include nano calcium fluoride:
  • Example 1 The following two F rinses, both containing 250 ppm of F, were evaluated for their efficacy in depositing F in an in vitro model.
  • Rinse Composition F deposition ( ⁇ g/cm 2 )
  • the F deposition by the inventive rinse using nano calcium fluoride as the fluoride source produced more than 7 times higher F deposition than the conventional sodium fluoride rinse.
  • the inventive rinse was about equally effective than a novel two-component rinse (US patent 5,891,448) which produce F deposition of 2.62 ⁇ 0.16 ⁇ g/cm 2 .
  • the inventive rinse has the advantage of being a single component rather than a two-component product.
  • Example 2 The following is an example of the composition of a 250 ppm F mouth rinse using the inventive nano calcium fluoride:
  • ethyl alcohol (95%) 20 grams glycerol 8.0 sorbitol (70% solution) 10 sodium lauryl sulfate 0.5 sodium lauryl sarcosinate 0.5 sodium saccharin 0.1 nano calcium fluoride 0.103 water, coloring, flavoring balance
  • Example 3 The following is an example of the composition of a 1000 ppm F dentifrice using the inventive nano calcium fluoride:
  • the first liquid contains a calcium phosphate solution given in Table 2 for preparing a calcium phosphate.
  • the second liquid contains a polymer dissolved in an aqueous solution or in a non-aqueous solvent that is miscible with water. Nano particles of calcium phosphate-polymer composites with highly homogeneous calcium phosphate/polymer intermixture are formed in the spray drying process.
  • Examples of calcium phosphates are HA, calcium-deficient HA, carbonated HA, Fluoride containing HA, amorphous calcium phosphate, tricalcium phosphate, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous, monocalcium phosphate monohydrate, and monocalcium phosphate anhydrous.
  • polymers to be used include chitosan, collagen, chrondroitin sulfate, polyamide, poly (D,L-lactide), alginate, and pectinate.
  • the methods disclosed in the invention are useful for preparing nano particles of any compound that can be formed by precinitation from an aqueous solution.
  • the temperature under which the spray during process occurs is controllable by controlling the inlet air temperature and the temperature of the column (Fig. 1). Air temperature in the range from -185 0 C to 800 0 C can be obtained using commercially available equipment. Similarly, a wide range of the column temperatures can be readily obtained using commercially available equipment. The wide range of temperatures facilitates preparation of materials that would form most readily at different temperatures.
  • the inventive method is suitable for preparing particles from 1 nm to 100 ⁇ m in size.
  • the particle size can be controlled by (1) the concentration of the compound in the solution to be spray dried, (2) size of the atomized droplets, i.e., nozzle design.
  • Droplet size is preferably less than the final particle size and thus less than about 100 ⁇ m.
  • Chamber design is also a factor.
  • the chamber is generally designed to minimize collection of condensate i.e., liquid from on the chamber walls.
  • the purity of the compound prepared is dependent on the ability of spray drying process to remove the acid or base used to dissolve the compound in the spray drying solution.
  • the acid/base must be a weak acid/base so that a substantial portion of the acid/base is in undissociated form, and the acid/base is almost totally undissociated as the last portion of the liquid is evaporated.
  • the undissociated acid/base must also be sufficiently volatile to facilitate evaporation of the acid/base.
  • the nano particles prepared by the methods disclosed in the invention are useful in any application in which the compound is currently useful but a performance advantage can be gained by having a higher reactivity and/or smaller particle size.
  • examples of this include (1) accelerated hardening of calcium phosphate cements when one or more calcium phosphate nano particles are included in the ingredients, (2) accelerated hardening of mineral trioxide aggregate (MTA) when one or more calcium silicate nano particles are included in the ingredients, (3) desensitization of teeth by effective obturation of exposed dentin tubule opening with calcium phosphate nano particles, (4) deposition of fluoride in/on oral tissue by application of agents that contain calcium fluoride or other fluoride nano particles.
  • MTA mineral trioxide aggregate
  • Calcium containing compounds that may be used as a source of calcium for remineralization of teeth or for formulation of scaffolds for bone defects repair.
  • Examples are calcium lactate, calcium gluconate, calcium glycerophosphate, calcium acetate, calcium fumarate, calcium citrate, calcium malate, calcium chloride, calcium hydroxide, calcium oxide, calcium carbonate.
  • Phosphate containing compounds that may be used as a source of phosphate for remineralization of teeth or for formulation of scaffolds for bone defects repair.
  • Examples are the monobasic, dibasic and tribasic phosphate salts of sodium, potassium, and ammonium.
  • Fluoride containing compounds that may be used as a source of fluoride for remineralization of teeth or for formulation of scaffolds for bone defects repair.
  • Examples are sodium fluoride, potassium fluoride, fluorophosphates fluosilicate, flurortitanate, and fluorostannate salts of ammonium, sodium, potassium and calcium.

Abstract

L'invention concerne des nanoparticules de calcium et de composés phosphoreux qui sont obtenus à un état généralement amorphe extrêmement pur par séchage par pulvérisation d'une solution d'acide faible du composé et par évaporation du liquide provenant du jet pulvérisé dans une colonne chauffée, ces étapes étant suivies de la récupération des particules précipitées. Des particules d'hydroxyapatite obtenues au moyen de cet appareil et selon ces méthodes sont des types de fabrication de particules utiles dans les traitement osseux et dentaires. Les techniques de pulvérisation à double orifice sont utilisées pour des composés généralement insolubles.
PCT/US2005/033406 2005-04-29 2005-09-16 Materiaux bioactifs nanostructures prepares selon des techniques de sechage par pulverisation a double orifice WO2006130167A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1931399B1 (fr) * 2005-08-29 2010-05-26 Sanatis GmbH Composition de ciment osseux et procede de production correspondant
GB2452823B (en) * 2007-08-30 2012-08-22 Hoya Corp Method of producing fluoroapatite
US8609055B2 (en) * 2007-08-30 2013-12-17 Hoya Corporation Method of producing fluoroapatite, fluoroapatite, and adsorption apparatus

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EP1885650A4 (fr) 2011-01-05

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