JP2013203563A - Method for producing hydroxyapatite fine particle, and hydroxyapatite fine particle, and also dispersion thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing hydroxyapatite fine particles capable of obtaining high purity hydroxyapatite fine particles that have crystallinity, are excellent in dispersion stability in water, and are prevented from mixing of a calcium phosphate salt having a composition different from hydroxyapatite and other impurities, and hydroxyapatite fine particles that are of high purity and excellent in dispersion stability, and its dispersion.SOLUTION: After alkali processing a tabular crystal of dibasic calcium phosphate dihydrate in water of a pH of 12 or higher, a method for producing hydroxyapatite fine particles to which wet dispersion treatment is done in water by a media mill is used.

Description

  INDUSTRIAL APPLICABILITY The present invention is capable of obtaining high-purity hydroxyapatite fine particles having crystallinity, excellent dispersion stability in water, and having a calcium phosphate salt having a composition different from that of hydroxyapatite and other impurities prevented from being mixed. The present invention relates to a method for producing hydroxyapatite fine particles, hydroxyapatite fine particles obtained thereby, and a dispersion thereof.

  Hydroxyapatite is one type of calcium phosphate salt that constitutes bones and teeth. In recent years, the application of artificial hydroxyapatite for bone and tooth restoration has been actively studied as part of regenerative medicine. For example, it may be used for bone regeneration by embedding sintered hydroxyapatite in a bone defect. Hydroxyapatite used in such a regenerative medicine field is often used in a state where particles of hydroxyapatite having a size of about several tens of μm to several tens of mm are dispersed. Hydroxyapatite may be used alone, but in many cases, it may be used as a composite material composed of a combination of this and other materials. For example, in Patent Document 1, a composite is formed by combining hydroxyapatite and a bioabsorbable material typified by collagen, which is suitable for use as a restoration material such as a bone filling material. Show. In the case where a composite material is formed by combining hydroxyapatite with a polymer material such as collagen, it is preferable that the mechanical properties and chemical properties become uniform by mixing them together uniformly. For that purpose, the smaller the hydroxyapatite particle size, the easier it is to form a homogeneous composite, and the smaller the hydroxyapatite particle size and the better the dispersion stability, the more the above composite material is formed. It is preferable because the uniformity of is maintained. In addition, when amorphous hydroxyapatite with no crystallinity is used, the mechanical strength is insufficient, and the solubility in the acidic state is high. In particular, the solubility in the living body is too high, and the absorption disappears in a short time. This is not preferable. From this point of view, the hydroxyapatite is more preferably crystalline.

  When using a material containing hydroxyapatite as a repair material as described above, artificial hydroxy having the same properties as hydroxyapatite fine particles having crystallinity bound to collagen used as a scaffold by osteoblasts when forming living bone By using apatite fine particles, it is expected to provide a repair material having high adhesive strength with bone around the repaired portion and high biocompatibility. Furthermore, high purity hydroxyapatite microparticles that do not contain various impurities such as salts and impurities that may cause allergic reactions are desired for use as a material for implantation in living bodies. .

  On the other hand, since hydroxyapatite has a property of strongly adsorbing various proteins, its application as a packing material for chromatography has been studied for a long time. As the adsorption chromatography, hydroxyapatite was first used as a packing material for chromatography by Tisselius et al. Of Uppsala University, but Non-Patent Document 1 uses a tabular crystal dicalcium phosphate dihydrate. It is shown that a plate-like hydroxyapatite crystal can be obtained by heating in an alkaline aqueous solution. In this case, the alkaline aqueous solution is shown to be converted to hydroxyapatite if the pH is 7 or more. However, depending on the conditions, dicalcium phosphate dihydrate is completely converted to hydroxyapatite. There is a case where a mixture of the two is formed without the conversion to, and the size of the tabular crystals of hydroxyapatite formed changes from the size of the tabular calcium diphosphate dihydrate crystals of the starting material. However, it is usually a large particle of several tens of μm or more, so it does not disperse in water and settles immediately, and does not give hydroxyapatite fine particles with excellent dispersion stability in water. It was.

  As another method for forming hydroxyapatite, for example, in Patent Document 2, an aqueous slurry is prepared by mixing calcium carbonate powder and dicalcium phosphate (dihydrate) powder, and this slurry is then ground by a wet pulverizer. A method of reacting while pulverizing and mixing is shown. Since hydroxyapatite obtained by this method has low crystallinity, hydroxyapatite with high crystallinity can be obtained only after taking out the mixture after the above wet pulverization and sintering at 900 ° C. There is a problem that the hydroxyapatite particles form a sintered body to form coarse lump particles and are not dispersed in water.

  Patent Document 3 discloses a method for producing hydroxyapatite by performing a heat treatment in an aqueous solution containing an inorganic halide adjusted to pH 7 to 11 with tricalcium phosphate. The hydroxyapatite obtained by this method is characterized by being formed as needle-like crystals having a length of 1 to several μm on the surface of the raw material tricalcium phosphate powder. Since hydroxyapatite was formed in the solution, it was agglomerated without being dispersed in water.

  Patent Document 4 discloses a method for producing plate-like hydroxyapatite crystals. In this case, a plate-like hydroxyapatite crystal can be obtained simply by suspending dicalcium phosphate dihydrate and calcium carbonate powder in water and heating to 40 to 70 ° C. The hydroxyapatite in this case has crystallinity. There is a problem that the particle size is extremely low, the average particle size is as large as about 10 μm, and even if dispersed in water, the particles immediately aggregate and settle.

As another method for producing hydroxyapatite fine particles, for example, Patent Document 5 discloses that a calcium salt aqueous solution and a phosphate aqueous solution have a Ca / P molar ratio of 1.67 under the condition that the pH is adjusted to a range of 10 to 12. A method for producing a dispersion containing 70% by mass or more of hydroxyapatite particles having a particle size of 100 nm or less by gradually mixing to / 1 and further boiling is disclosed. However, the calcium phosphate salt obtained by such a method is not composed only of hydroxyapatite, but tricalcium phosphate (Ca ₃ (PO _{3 4} ) Since a salt such as ₂ ) or calcium monohydrogen phosphate (CaHPO ₄ ) is formed, there is a problem that it is difficult to obtain a material having a uniform particle composition and high purity. Furthermore, the particle diameter is not uniform, and coarse particles and aggregates may be included. These particles settle out of the aqueous dispersion immediately after dispersion, and thus there is a problem in dispersion stability.

  Patent Document 6 discloses a method of obtaining fine particles having high purity as hydroxyapatite by mixing an aqueous slurry of calcium oxide and / or calcium hydroxide and an aqueous phosphoric acid solution in a pH range of 7-12. The size of the fine particles obtained was a method of giving amorphous hydroxyapatite with a size of about several μm.

  Patent Document 7 discloses a method of synthesizing hydroxyapatite fine particles by simply mixing a calcium salt aqueous solution and a phosphate aqueous solution at a constant temperature. In practice, however, monohydrogen phosphate is disclosed. Calcium and the like are mainly produced, and hydroxyapatite fine particles may not be obtained, and the dispersion stability is also lacking.

  Patent Document 8 discloses a method for producing a hydroxyapatite fine particle dispersion in which an aqueous slurry containing hydroxyapatite obtained by a reaction between an aqueous slurry of calcium hydroxide and an aqueous phosphoric acid solution is pulverized using a bead mill. However, the hydroxyapatite obtained by this method has no crystallinity, and there is a problem that inorganic substances other than hydroxyapatite are contained in a large amount as impurities.

  Patent Document 9 discloses a method for synthesizing hydroxyapatite fine particles having a particle diameter of 1 to 25 nm, but includes a soluble salt although the particle diameter is small and an ultrafiltration method is used as a method for purifying hydroxyapatite. In other words, it is not suitable as a method for industrially producing high-purity hydroxyapatite fine particles in large quantities industrially, and furthermore, it is a method for giving amorphous hydroxyapatite.

  Further, the hydroxyapatite fine particles produced in Patent Documents 5 to 9 are not preferable because they do not have crystallinity, are too soluble in a living body or in an acidic state, and are absorbed and lost in a short time. In order to obtain crystalline hydroxyapatite in the prior art, for example, crystalline hydroxyapatite fine particles are first formed by further sintering the obtained fine particles at a temperature of 1000 ° C. or higher. In this case, since the fine particles are fused with each other, precipitation occurs immediately after dispersion in water, resulting in poor dispersion stability.

  In Patent Document 10, a calcium phosphate compound is treated by heat treatment at a temperature of 400 ° C. to 1050 ° C., then milled, and further pulverized using an organic solvent to obtain spherical or oval spherical calcium phosphate particles. A method of making is disclosed. Since the hydroxyapatite fine particles synthesized by this method are sintered by heat treatment, the solubility in the living body is too low. Therefore, in the above-mentioned regenerative medicine field and gene transfer applications, etc. In addition, there are problems that are not suitable as materials, and in addition, it takes time for the heat treatment process and grinding process, the time required for production, the problems of many processes and the problem of using organic solvents, and impurities such as metals mixed in the grinding process There was a problem of contamination.

JP 2007-159935 A JP-A 63-159207 Japanese Patent Publication No.7-115850 Japanese Patent Laid-Open No. 9-40408 JP-A-3-261612 Japanese Patent Laid-Open No. 5-170413 JP 2005-263581 A JP-A-9-142817 JP 2008-69048 A JP 2006-315871 A

Tisselius A. et. al. "Archives of Biochemistry and Biophysics", vol. 65, no. 1,132-155 (1956)

  INDUSTRIAL APPLICABILITY The present invention is capable of obtaining high-purity hydroxyapatite fine particles having crystallinity, excellent dispersion stability in water, and having a calcium phosphate salt having a composition different from that of hydroxyapatite and other impurities prevented from being mixed. An object of the present invention is to provide a method for producing hydroxyapatite fine particles, and to provide hydroxyapatite fine particles having crystallinity, high purity and excellent dispersion stability, and dispersions thereof.

The above-described problems of the present invention are solved by the following invention.
1. A method for producing hydroxyapatite fine particles, wherein a plate-like crystal of dicalcium phosphate dihydrate is alkali-treated in water having a pH of 12 or more, and then wet-dispersed in water by a media mill.
2. Hydroxyapatite fine particles obtained by the method for producing hydroxyapatite fine particles according to 1 above.
3. 3. The hydroxyapatite fine particles according to 2 above, wherein the primary particles and the crystallites have a size in the range of 10 to 100 nm, and the secondary particles have a volume average particle size in the range of 0.5 to 6 μm.
4). The above 2 or 3 shows an X-ray diffraction pattern in which the diffraction peak intensity on the (002) plane near 2θ = 26 degrees is larger than the diffraction peak intensity on the (300) plane near 2θ = 33 degrees in wide angle X-ray diffraction. Hydroxyapatite fine particles.
5. In wide-angle X-ray diffraction, the ratio of the diffraction peak intensity of the (002) plane near 2θ = 26 degrees to the diffraction peak intensity of the (310) plane near 2θ = 40 degrees is in the range of 1.9-6. The hydroxyapatite fine particles according to any one of the above 2 to 4, which exhibit a pattern.
6). In wide-angle X-ray diffraction, the diffraction peak due to the (112) plane near 2θ = 32 degrees does not separate from the diffraction peaks from the (211) plane and the (300) plane, and the latter two diffraction peaks are from the (112) plane. The hydroxyapatite fine particles according to any one of 2 to 5 above, which show an X-ray diffraction pattern appearing attached to one part of a diffraction peak.
7). A hydroxyapatite fine particle dispersion containing the hydroxyapatite fine particles according to any one of 2 to 6 above.

  Hydroxyapatite fine particles that have high crystallinity, have excellent dispersion stability in water, and are capable of obtaining high-purity hydroxyapatite fine particles with a composition different from that of hydroxyapatite and prevented from mixing with other impurities And a hydroxyapatite fine particle having crystallinity, high purity and excellent dispersion stability, and a dispersion thereof can be provided.

The enlarged view before the wet dispersion process of the crystal | crystallization obtained by alkali-treating the dicalcium phosphate dihydrate of Example 1. FIG. The measurement result by the light-scattering diffraction type particle size distribution meter of the hydroxyapatite fine particle dispersion obtained in Example 1. The enlarged view by the scanning electron microscope of the hydroxyapatite microparticles | fine-particles obtained in Example 1. FIG. The wide-angle X-ray-diffraction pattern of the hydroxyapatite fine particle after the wet dispersion process obtained in Example 1. A wide-angle X-ray diffraction pattern of hydroxyapatite, which is a commercially available reagent product. The wide angle X-ray diffraction pattern of the hydroxyapatite obtained in Comparative Example 1. The wide angle X-ray diffraction pattern of the hydroxyapatite obtained in Comparative Example 2. The wide-angle X-ray-diffraction pattern of the hydroxyapatite fine particle after the wet dispersion process obtained in Example 2. The measurement result by the light-scattering diffraction type particle size distribution meter of the hydroxyapatite dispersion liquid obtained in the comparative example 3. FIG.

The present invention uses tabular crystals of dicalcium phosphate dihydrate (CaHPO ₄ .2H ₂ O) as a raw material for obtaining hydroxyapatite fine particles, and this is alkali-treated under alkaline conditions having a pH of 12 or more. Furthermore, by performing wet dispersion treatment in water using a media mill, it is crystalline, has excellent dispersion stability in water, and prevents the incorporation of calcium phosphate and other impurities with a composition different from that of hydroxyapatite. It has been found that high-purity hydroxyapatite fine particles can be obtained.

  First, a method for synthesizing tabular crystals of dicalcium phosphate dihydrate will be described. As raw materials for synthesizing this, raw materials selected from various calcium salts and various phosphates are necessary. Examples of suitable raw materials for calcium salts include calcium chloride, calcium nitrate, calcium acetate and water thereof. Japanese products can be preferably used. Examples of raw materials suitable as the phosphate include disodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium hydrogen phosphate, and the like. The calcium salt and phosphate are preferably soluble in water in the pH range of 4-9. In the present invention, being soluble means that the solubility at 10 ° C. is 1% by mass or more.

  The above calcium salt and phosphate preferably form a tabular crystal dicalcium phosphate dihydrate by mixing in the range of pH 4-9, but beyond this range, for example, the pH is strong. In the case of an alkali, calcium hydroxide is produced, which may inhibit the production of the target hydroxyapatite. Alternatively, tribasic calcium phosphate may be produced when the synthesis is carried out by adding ammonia water or other amines to a pH exceeding 9. Conversely, on the acidic side where the pH is below 4, the solubility of dicalcium phosphate dihydrate increases, so the yield may decrease.

  The temperature at which the calcium salt and phosphate are reacted is usually 0 ° C. to 100 ° C., or the reaction temperature can be lowered to less than 0 ° C. However, there is a preferable reaction temperature range, and the most preferable case is a temperature in the range of −5 to 60 ° C. The dicalcium phosphate dihydrate obtained in this temperature range is a crystal having a tabular form. Selectively obtained. When the reaction is performed at a temperature lower than −5 ° C., the reaction system may partially freeze, which may hinder the stirring. When the reaction is carried out at a temperature exceeding 60 ° C., acicular crystals called monetite are formed as a by-product as a crystal form of dicalcium phosphate anhydrate separately from dicalcium phosphate dihydrate. If performed, the conversion to hydroxyapatite is very slow and may remain unreacted, which may make it difficult to obtain high-purity hydroxyapatite as one of the objects of the present invention. . In the present invention, the shape of the crystal of dicalcium phosphate dihydrate is very important, and the effect of the present invention can be recognized only when it is flat. When a calcium phosphate salt having a shape other than a plate-like crystal is present, the shape of the calcium phosphate salt does not change even when an alkali treatment described later is performed, and further obtained by performing a wet dispersion treatment with a subsequent media mill. The present invention revealed that the dispersion stability of the hydroxyapatite fine particle dispersion is poor. That is, in the present invention, when a wet dispersion treatment by a media mill is performed, hydroxyapatite fine particles having good dispersion stability are obtained by dicalcium phosphate dihydrate before being converted to hydroxyapatite. Wet dispersion treatment using, for example, hexagonal prisms, spheres, needles or squares of hydroxyapatite obtained by various other methods of the prior art, only when the shape of the crystals is flat. It is a feature that it has been found that a hydroxyapatite dispersion with good dispersion stability cannot be obtained even after the above.

  The flat crystal in the present invention means that the diagonal length in the crystal plane direction with respect to the length in the crystal thickness direction is 4 or more as the aspect ratio of the crystal of dicalcium phosphate dihydrate. The diagonal length in the crystal plane direction of the tabular crystal can be roughly determined from an enlarged photograph taken with a scanning electron microscope, but in the present invention, a preferred temperature range for producing the above-mentioned dicalcium phosphate dihydrate. Is preferably in the range of 1 to 100 μm, and the crystal aspect ratio is preferably in the range of 4 to 200.

  When mixing both using calcium salt aqueous solution and phosphate aqueous solution, both can be mixed by three types of methods. One method is a method in which an aqueous phosphate solution is added to an aqueous calcium salt solution while stirring, and the other method is an opposite method in which an aqueous calcium salt solution is added to an aqueous phosphate solution. . Or the method of mixing both aqueous solution simultaneously can also be performed. The difference in reaction conditions in these methods is that a difference occurs in the concentration ratio between the calcium salt and phosphate when they react. In the first method, the calcium salt concentration is in a large excess with respect to the phosphate, and in the second condition, the calcium salt is added under the condition that the phosphate concentration is in a large excess. become. Under the third condition of simultaneous mixing, the concentration ratio of the two can be adjusted to an arbitrary ratio.

  Each concentration in the reaction system when mixing the aqueous calcium salt solution and the aqueous phosphate solution is only easy to handle in actual operation, and is intended for a specific concentration range. There is no need to synthesize dicalcium phosphate. For example, the concentration of the calcium salt aqueous solution is preferably used at a saturation concentration or less of the calcium salt to be used. In order to avoid precipitation of the calcium salt from the aqueous solution, it is usually preferable to use a concentration lower than 9 mol / liter. The lower limit of the calcium salt concentration is not particularly limited. However, in order to increase the yield per production unit, a higher concentration is preferable, so that the calcium salt is within the range of 0.1 to 9 mol / liter for the convenience of production. It is preferable to adjust the concentration of the aqueous solution. The concentration of the aqueous phosphate solution is exactly the same as this, and it is preferable to adjust the concentration of the aqueous phosphate solution in the range of 0.1 to 9 mol / liter for the convenience of production.

  The aqueous calcium salt solution and the aqueous phosphate solution adjusted in the above concentration range can be mixed with each other by the three methods described above. For example, when the aqueous phosphate solution is added to the aqueous calcium salt solution, the mixing speed is gradually increased over a period of time ranging from about 10 minutes to 3 hours while stirring the aqueous calcium salt solution. It is preferable to add to. When mixing is performed in a shorter time than this time, the precipitated dibasic calcium phosphate salt may become agglomerated and may be difficult to purify. Moreover, there is no practical merit even if it is gradually added over a long period of time exceeding 3 hours. As a mixing method, when adding an aqueous calcium salt solution to an aqueous phosphate solution, it is also preferable to add the aqueous calcium salt solution gradually over a time range of about 10 minutes to 3 hours. When mixing an aqueous calcium salt solution and an aqueous phosphate solution simultaneously, these aqueous solutions may be mixed directly in separate containers, or both solutions may be mixed while stirring in an appropriate volume of water. The addition may be performed simultaneously or at an appropriate interval. The time from the start of addition to the completion of mixing is preferably gradually added over a time range of about 10 minutes to 3 hours.

  When performing the above reaction, the pH of the reaction system is adjusted to 4 to 9 as described above while the reaction is occurring by adding various acids, bases and the like to further adjust the pH in the reaction system. It can also be kept in range. Normally, when the reaction is carried out by mixing both the aqueous calcium salt solution and the aqueous phosphate solution as described above, the pH tends to be acidic as the reaction proceeds. Maintained within. However, it is also preferable to keep the pH within a narrow range more precisely, and it is particularly preferable to adjust the pH using a Tris-HCl buffer or the like. In addition, various anionic surfactants and nonionic surfactants can also be added. It is also possible to carry out the reaction by adding various polymers as water-soluble polymers, but in some cases, these additives may be incorporated into the crystals of dicalcium phosphate produced by the reaction, and the purity of the product May decrease.

  The produced dicalcium phosphate dihydrate is precipitated from the aqueous solution to form a precipitate. At this time, the resulting precipitate may be subjected to the alkali treatment described below as it is without purification, but in order to obtain hydroxyapatite with improved purity, the precipitated dicalcium phosphate dihydrate is filtered, etc. It is preferable to carry out the purification by separating by the above method and further washing with ion exchange water or the like. The purified dicalcium phosphate dihydrate is preferably subjected to subsequent alkali treatment without drying. Alternatively, it is also preferable to perform subsequent alkali treatment after drying at a temperature lower than about room temperature. However, when heat history is given by drying the dicalcium phosphate dihydrate at a temperature of room temperature or higher, for example, 90 ° C. or higher, the crystal water is lost to generate dicalcium phosphate anhydrate, When crystals are interacted with each other to produce aggregates, there is no conversion to hydroxyapatite, or the resulting hydroxyapatite is produced as aggregates when the medium is treated with alkali. Even if wet dispersion treatment with a mill is performed, it may not be obtained in the form of a fine particle dispersion. Therefore, it is most preferable to synthesize the tabular crystals of dicalcium phosphate dihydrate and subsequently perform the alkali treatment without giving a thermal history such as high temperature drying.

  Next, a method for obtaining hydroxyapatite by performing an alkali treatment using the dicalcium phosphate dihydrate obtained above will be described. The pH during the alkali treatment needs to be 12 or more, and is particularly preferable when the pH exceeds 13, since the conversion to hydroxyapatite is promoted. Conversely, when the pH is less than 12, conversion to hydroxyapatite does not proceed completely, and a mixture of hydroxyapatite and other calcium phosphate salt is formed as a product, which is not preferable. The alkali used in the present invention is particularly preferably sodium hydroxide or potassium hydroxide. The ratio of these hydroxides to be added is preferably 0.6 mol based on the following reaction formula or 1 mol slightly higher than 1 mol of dicalcium phosphate dihydrate. Most preferably, alkali is added at a ratio of 6 to 2 moles.

_{10CaHPO 4 · 2H 2 O + 6KOH} → Ca 10 (PO 4) 6 (OH) 2
+ 2K ₂ HPO ₄ + 2KH ₂ PO ₄ + 8H ₂ O

  The alkali is preferably used in the form of an aqueous solution, and the previously obtained dicalcium phosphate dihydrate is added to the alkaline aqueous solution adjusted in the range of 0.1 to 20% by mass and heated and stirred. Gives hydroxyapatite. In this case, the heating temperature is preferably 50 ° C. or higher, and more preferably in the range of 50 to 100 ° C. It is possible to carry out the treatment at a temperature exceeding 100 ° C., and it is possible to reduce the time required for the treatment, but it is not necessary to carry out the treatment particularly quickly because the treatment needs to be performed under pressure. It is not necessary to increase the processing temperature to 100 ° C. or more.

  In the alkali treatment, the heating time is preferably in the range of several minutes to 24 hours. When the crystals of dicalcium phosphate dihydrate are small, hydroxyapatite can be obtained by a relatively short treatment. When the size of the crystal is relatively large, it is preferable to perform the alkali treatment for a longer time. The most preferred treatment time is in the range of 5 minutes to 5 hours.

  The hydroxyapatite obtained by carrying out the alkali treatment under the above conditions is preferably separated and purified by a method such as filtration or centrifugation. The purified hydroxyapatite can be separated from the solid by filtration by a normal method and washing the collected solid with water. Alternatively, the hydroxyapatite dispersion can be removed by centrifuging the hydroxyapatite dispersion using a centrifuge, dispersing the precipitated solid in water again, and centrifuging again. . In any method, it is possible to easily separate high-purity hydroxyapatite by washing with water.

  The hydroxyapatite after the above alkali treatment is dried and taken out as a powder, and this may be stored and appropriately subjected to the wet dispersion treatment described below. Alternatively, the hydroxyapatite may be subjected to purification after the alkali treatment. Water may be added to form a slurry, which may be used for the following wet dispersion treatment without drying.

  In the present invention, the wet dispersion treatment by the media mill is usually performed by adding glass beads, alumina beads, and other ceramic beads in water into which hydroxyapatite has been introduced, and stirring and stirring the hydroxyapatite particles and the beads. This is a treatment method in which atomization is performed by colliding with each other and being pulverized. When processing a small amount by a batch system, a wet dispersion process can be performed by shaking for several hours using a paint conditioner. When the treatment is performed using a relatively large amount of sample, an average diameter per medium as a medium is in the range of 0.01 to 10 mm, preferably 0.1 mm, using a media disperser such as dynomill. Multiple media dispersers using ceramic beads in the range of -5 mm may be arranged in series and wet dispersion treatment may be performed in one pass, or the treatment may be repeated multiple times using one media disperser. Can also be preferably performed.

  When performing a wet dispersion treatment of hydroxyapatite using a media mill, it is preferable to use ceramic beads as the media to be used. Particularly when hydroxyapatite is dispersed, it is particularly preferable to prevent impurities derived from the beads from being mixed into the hydroxyapatite dispersion by contacting the beads with the hydroxyapatite and polishing the beads. As ceramic beads that can be used for these purposes, specifically, ceramic beads containing zirconia such as ZrO, cubic zirconia, yttrium-stabilized zirconia, and zirconia-reinforced alumina, synthetic diamond, and silicon nitride beads can be most preferably used. However, in addition to these, for example, beads such as glass beads, alumina beads, strontium titanate beads, etc. may be used. The condition of the wet dispersion process using a media disperser using such a medium is a room temperature process that is normally performed, and there are no particular restrictions on the processing time, temperature, and the like. In addition, one pass may be sufficient for the number of passes, but by performing the treatment with about 2 to 7 passes, the hydroxyapatite fine particles having a narrower particle size distribution and excellent dispersion stability can be obtained. This can be preferably performed because a dispersion can be obtained.

  As a method for evaluating dispersion stability, which is one of the objects of the present invention, evaluation was performed using two methods as shown in Examples described later. One method is that when a dispersion of hydroxyapatite fine particles is allowed to stand at room temperature, no agglomerates or precipitates are deposited over several days to several weeks, and the dispersion is uniformly distributed in the liquid. The dispersion stability was evaluated as good only when the dispersed state was maintained, and the dispersion stability was evaluated as poor when the accumulation of aggregates or precipitates was observed visually. . As another method, using a dispersion of hydroxyapatite fine particles immediately after producing a hydroxyapatite dispersion and after a lapse of 2 weeks, coating them on the surface of a transparent polyester film, drying and applying the hydroxyapatite When the layers were formed, the transparency of the film was compared by measuring the haze value, and a method for quantitative evaluation was performed. When the transparency of the coating layer is good both immediately after dispersion and after aging, and both have a haze value of less than 10%, the dispersed particles of the hydroxyapatite fine particle dispersion have a uniform size. In order to maintain a coating layer with good transparency, when the haze value is 10% or more immediately after dispersion and / or after aging, the dispersion contains coarse particles, Since the ratio of diffused light in the coating layer increased, it was determined that the dispersion stability was poor. One of the characteristics of the dispersion of hydroxyapatite fine particles obtained by the method for producing hydroxyapatite fine particles of the present invention is that the dispersion stability is good when evaluated by the above method.

  The dispersion of the hydroxyapatite fine particles obtained by performing the wet dispersion treatment preferably has a pH in the range of 7-12. When the pH is lower than this range, the hydroxyapatite fine particles may dissolve and the dispersion state may become unstable. In addition, when the pH range is exceeded, a large amount of alkali other than hydroxyapatite is present, which may not be suitable for obtaining a dispersion of high-purity hydroxyapatite fine particles as an object of the present invention. . In order to adjust pH to the range of 7-12, adding a trace amount acid or alkali is performed preferably. In particular, phosphate buffer solutions adjusted to various pHs mixed with sodium phosphate, sodium hydrogen phosphate, etc. and phosphoric acid, or various known buffer solutions such as Tris buffer solution, HEPES buffer, etc. with respect to hydroxyapatite. Addition at a ratio not exceeding mass% can also be preferably carried out for the purpose of keeping the pH of the dispersion stable.

  As shown in Examples described later, as a result of the above wet dispersion treatment, the size of the resulting hydroxyapatite fine particles, the size of primary particles discriminated from observation with a scanning electron microscope, is in the range of 10 to 100 nm. It is a feature of the present invention that it is a rice granular or spindle-shaped fine particle. Hydroxyapatite fine particles after wet dispersion can be taken out as fine powder by drying the dispersion. Alternatively, the dispersion aggregates by adding an organic solvent such as alcohol to the dispersion, and can be taken out as a solid by separating it by filtration. The hydroxyapatite powder taken out in this way can be subjected to X-ray diffraction measurement to determine the crystallite size. The crystallite size t by X-ray diffraction is defined by the following equation with respect to the peak of any measured diffraction spectrum.

  Here, λ is the X-ray wavelength (A), B is the half width of the peak, and θ is the Bragg angle. In the above equation, B is a value defined by the following equation.

In the above equation, B _M represents the half width of the target substance, and B _S represents the half width of the standard sample. B _S is the peak half-value width required for a sample in which the size of the crystallite with sufficiently grown crystals is sufficiently larger than that of the measurement sample.

  The primary particle of hydroxyapatite fine particles after wet dispersion treatment obtained by the present invention is the size of the smallest unit particle identified by observation with a scanning electron microscope, and the crystallite size is calculated by the above equation. Value. It is a feature of the present invention that these values are in the range of 10 to 100 nm as shown in Examples described later.

  A feature of the hydroxyapatite fine particles obtained by the present invention is that the crystals constituting the hydroxyapatite fine particles exhibit anisotropy. Specifically, the crystal orientation in the c-axis direction is more remarkable than the orientation in the a-axis direction. To appear in. That is, in wide-angle X-ray diffraction, the diffraction peak intensity on the (002) plane near 2θ = 26 degrees appears more clearly than the diffraction peak intensity on the (300) plane near 2θ = 33 degrees. As shown in Examples and Comparative Examples described later, hydroxyapatite crystals obtained by using various conventional techniques have remarkable growth in the a-axis direction represented by the (300) plane, that is, the a-plane direction. Unlike the diffraction peak from the (002) plane showing the orientation in the c-axis direction, the hydroxyapatite fine particles obtained in the present invention are different from these, and the orientation in the c-axis direction is more remarkable. It is a feature. In order to discuss such orientation quantitatively, it is necessary to numerically discuss each peak intensity ratio. As one feature of the hydroxyapatite fine particles obtained in the present invention, as will be described later, (300 ) Diffraction peaks from the plane are not clearly separated from the diffraction peaks from the (112) plane, so that the intensity of each peak cannot be expressed numerically. Therefore, instead of the diffraction peak from the (300) plane, the intensity of the diffraction peak from the (310) plane near 2θ = 40 degrees is taken as a reference, and the diffraction peak of the (002) plane near 2θ = 26 degrees. By comparing the ratio with the strength, the orientation in the c-axis direction can be compared. When such a comparison is made, as one of the characteristics of the hydroxyapatite fine particles obtained in the present invention, the (002) plane near 2θ = 26 degrees with respect to the diffraction peak intensity due to the (310) plane near 2θ = 40 degrees. Showing an X-ray diffraction pattern having a diffraction peak intensity ratio in the range of 1.9 to 6. In the hydroxyapatite crystals obtained in various conventional techniques, the ratio of both is smaller than (002) / (310) = 1.9, as can be seen from the X-ray diffraction pattern of the comparative example described later. It is in the vicinity of 1.5 to 1.7. On the other hand, the hydroxyapatite obtained by the present invention is characterized in that this ratio is in the range of 1.9 to 6, as will be clarified in Examples described later. An interesting fact is that bones in biological systems are known to exhibit strength due to the orientation of hydroxyapatite crystals in the long axis direction, and this ratio may exceed 10. Therefore, it is one of the characteristics that the hydroxyapatite fine particles obtained by the present invention have anisotropy closer to that of hydroxyapatite in living bones.

  Furthermore, the remarkable feature recognized in the X-ray diffraction pattern is that the hydroxyapatite fine particles obtained by the present invention have diffraction peaks from the (211) plane and the (300) plane in the wide angle X-ray diffraction. One of the characteristics is that the latter two diffraction peaks do not separate from the peak, and show the X-ray diffraction pattern appearing attached to one part of the diffraction peak from the (112) plane. Here, the fact that the diffraction peaks are not separated means that the half width of each diffraction peak is not clearly obtained, and each diffraction peak overlaps, and the intensity of each peak from the baseline is different. It means the case where it cannot be separated. This means that the growth of these crystal planes does not develop clearly and the crystallinity is relatively low. As can be seen from the X-ray diffraction patterns of the comparative standard samples shown in the examples which will be described later, the hydroxyapatite crystals obtained by various conventional methods have their crystal planes clearly developed and their respective diffraction peaks. Are clearly separated, indicating that the crystallinity is higher. One of the characteristics of the hydroxyapatite fine particles obtained in the present invention is that it exhibits the diffraction pattern as described above.

  In the present invention, the hydroxyapatite fine particles form a dispersion of secondary particles by associating a plurality of the primary particles in water. The size of the secondary particle dispersion in the dispersion in water is as follows. A feature of the hydroxyapatite fine particles obtained by the present invention is that the volume average particle diameter is in the range of 0.5 to 6 μm. In addition, the size of the secondary particles in the present invention is a volume average particle diameter obtained using a light scattering diffraction particle size distribution meter, and the median diameter is mentioned as an average value.

  The hydroxyapatite fine particles obtained in the present invention can be used alone as a powder or a dispersion, or a combination of various materials is also preferably used. In particular, the biodegradable polymer is preferably used by mixing with a water-soluble polymer such as collagen, atelocollagen or gelatin. Alternatively, even water-insoluble polymers such as polylactic acid and polyglycolic acid can be preferably mixed and used in an organic solvent using the above method.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. In addition, the percentage in an Example is a mass reference | standard unless there is a notice.

Example 1
In a 1 liter flask, 73.5 grams of calcium chloride dihydrate was taken and dissolved in water to adjust the total to 500 grams. The flask was transferred onto a water bath and the internal temperature was adjusted to 30 ° C. A solution obtained by dissolving 66 grams of diammonium hydrogen phosphate in 134 grams of water was dropped into the aqueous calcium chloride solution with vigorous stirring over 1 hour using a dropping funnel (reaction temperature was 30 ° C. ). The pH of the reaction system was stable throughout the reaction at around 5.0 without any particular adjustment. After completion of dropping, the mixture was further stirred for 30 minutes, and then suction filtration was performed using a glass filter. The crystals on the filter were thoroughly washed with ion exchange water. A part of the crystal was taken out and analyzed by wide-angle X-ray diffraction measurement. As a result, it completely coincided with the diffraction pattern of dicalcium phosphate dihydrate, and no other peaks were observed. Further, when the crystal was observed by optical microscope observation and scanning electron microscope observation, it was a flat crystal (aspect ratio about 14) having a diagonal length of about 7 μm and a thickness of about 0.5 μm. It was.

  The crystals of dicalcium phosphate dihydrate obtained above were immediately transferred into a 1-liter flask after washing, added with 400 g of ion-exchanged water, transferred to an oil bath at room temperature, and stirred. To this, 18 grams of granular pellets of sodium hydroxide were added, the internal temperature was raised to 95 ° C. over 30 minutes after the addition, and stirring was carried out at this temperature for 30 minutes. The pH of the reaction system at this time was 13.5. Thereafter, the flask was removed from the oil bath and allowed to stand at room temperature. After the internal temperature was sufficiently lowered, suction filtration was performed using a glass filter, the crystals on the filter were repeatedly washed with ion-exchanged water, and dried in a drier adjusted to 70 ° C. A part of the crystal was taken out and observed with a scanning electron microscope. FIG. 1 is an enlarged view of a crystal obtained by subjecting dicalcium phosphate dihydrate of Example 1 to an alkali treatment before wet dispersion treatment. (A) is a magnification of 10,000, and the scale in the figure represents 5 μm. (B) is a magnification of 100,000, and the scale in the figure represents 500 nm. From this result, it was found that the hydroxyapatite fine particles obtained in the present invention were formed into a plate shape with a regular arrangement by alkali treatment using a plate-like crystal of dicalcium phosphate dihydrate as a template. When the crystal surface is further enlarged, the entire surface is covered with rod-shaped fine particles, the length of the rod-shaped fine particles in the major axis direction is about 50 nm, and the length on the minor axis side is about 17 nm. there were. Furthermore, as a result of analysis by wide-angle X-ray diffraction measurement, it completely coincided with the diffraction pattern of hydroxyapatite, and no other peaks were observed.

  Next, using the hydroxyapatite crystal obtained above, a wet dispersion treatment with a media mill was performed as follows. That is, 10 grams of hydroxyapatite crystals were transferred to a 0.2 liter polypropylene container, 90 grams of ion-exchanged water and 60 grams of zirconia beads having a particle size of 0.3 mm were added and sealed, and 3 hours using a paint conditioner. Shaking treatment was performed. At this time, the pH of the liquid mixture immediately before the dispersion treatment was 9.5, and the pH of the liquid after dispersion was 10.5. Thereafter, zirconia beads were separated from the dispersion using a filter cloth. Evaluation was performed as follows using the obtained dispersion liquid.

  First, the dispersion stability was evaluated. As described in the text, both the static stability and the haze value when a coating film was formed on the film were evaluated as the dispersion stability. Regarding the standing stability, when the dispersion obtained above was allowed to stand at room temperature for 1 week, a supernatant of about 2 mm was observed on the uppermost surface of the liquid, but no precipitate was observed at the bottom, which was good. Static stability was shown. Furthermore, a doctor bar (a commercially available No. 12 doctor bar is used on the surface of the film in the state immediately after dispersion and two weeks after preparation, and a coating amount of 24 grams per square meter is set as a solution. ) Was applied and dried, and almost completely transparent films were obtained in both cases. When this was measured with a haze meter, both obtained a result that the haze value was 5%. Therefore, even after 2 weeks, the dispersion state was stable, and no coarse particles or aggregates were observed.

  In order to measure the size of the dispersed hydroxyapatite fine particles using the dispersion liquid obtained above, a light scattering diffraction type particle size distribution analyzer (particle size distribution measuring device LA-920 manufactured by Horiba, Ltd.) was used. It was measured. What is measured by this method is the size of secondary particles dispersed in water as hydroxyapatite fine particles. FIG. 2 shows the measurement results of the hydroxyapatite fine particle dispersion obtained in Example 1 using a light scattering diffraction particle size distribution meter. The volume average particle size determined by measurement was 1.5 μm.

  Hydroxyapatite fine particles were observed with a scanning electron microscope using a sample that was diluted with the dispersion, dropped onto a slide glass, and dried. FIG. 3 is an enlarged view of the hydroxyapatite fine particles obtained in Example 1 using a scanning electron microscope. The magnification is 100,000 times, and the scale in the figure represents 500 nm. Compared with the previous FIG. 1B, the size and shape of the hydroxyapatite fine particles subjected to the wet dispersion treatment are greatly different from the case of FIG. It was found that the elongated rod-shaped fine particles in FIG. 1 were changed to slightly rounded rice-like elliptical particles. The primary particle size of the hydroxyapatite after wet dispersion treatment, which can be estimated from the figure, has a major axis length of about 40 nm and a minor axis side length of about 30 nm.

  A part of the above dispersion was taken out and dried using an evaporator to take out hydroxyapatite fine particles. Using this, wide angle X-ray diffraction measurement was performed. 4 is a wide-angle X-ray diffraction pattern of hydroxyapatite fine particles after wet dispersion treatment obtained in Example 1, and FIG. 5 is a wide-angle X-ray diffraction pattern of hydroxyapatite which is a commercially available reagent product. In FIG. 5, the diffraction peak from the (211) plane is observed at the maximum intensity ratio at the Bragg angle 2θ = 31.8 degrees, and then the (112) plane at 32.2 degrees and (300) at 32.9 degrees. The diffraction peaks from the surface are clearly separated. Compared with this, in FIG. 4, the diffraction peaks corresponding to these three were observed in an overlapping manner, and it was clearly understood that the peak separation was poor. Further, the half-value width at each peak is wider in FIG. 4 in comparison with FIG. 5, and the X-ray diffraction intensity itself is a relatively smaller value in FIG. . These measurement results suggest that the crystallinity of the hydroxyapatite obtained in the present invention is lower than that of the comparative reagent product, and the crystallite size is also small. In order to estimate the crystallite size specifically, in FIG. 4 and FIG. 5, paying attention to the diffraction peak from the (002) plane, which is the diffraction peak near Bragg angle 2θ = 26 degrees, the half width of this peak was measured. However, it was 0.35 degrees in FIG. 4 and 0.14 degrees in FIG. Since the crystallinity of the reagent product is very high and the size of the crystal is extremely large compared to the hydroxyapatite of the present invention, the diagram is the product of the present invention when the crystallite size of the reagent product is assumed to be infinite. The crystallite size of 4 was calculated to be 26 nm.

  Further, in FIG. 4, the peak intensity from the (002) plane near the Bragg angle of 26 degrees appears stronger than the peak intensity from the (300) plane appearing near the Bragg angle of 33 degrees, but in FIG. It was clearly understood that the intensity ratio of both was reversed. In addition, the peak intensity ratio from the (002) plane to the peak from the (310) plane, which is a diffraction peak near a Bragg angle of 40 degrees, was (002) / (310) = 2.1. On the other hand, in FIG. 5, this value is a clearly low value of 1.6.

(Comparative Example 1)
As Comparative Example 1, hydroxyapatite was synthesized by the method described in Patent Document 2. That is, in a polypropylene container having a capacity of 0.25 liter, 18 grams of dibasic calcium phosphate dihydrate, 7 grams of calcium carbonate powder, 100 grams of ion-exchanged water and 90 grams of zirconia beads having a particle size of 0.3 mm were added and sealed. The mixture was shaken for 1 hour using a paint conditioner. The obtained dispersion was filtered out, dried in a dryer at 100 ° C., baked at 900 ° C. for 1 hour using an electric furnace, then cooled and used again with a paint conditioner. Then, a wet dispersion treatment was performed in the same manner as in Example 1. A part of the dispersion was taken out and dried, and a wide-angle X-ray diffraction pattern was measured in the same manner as in Example 1. FIG. 6 shows a wide-angle X-ray diffraction pattern of hydroxyapatite obtained in Comparative Example 1. In FIG. 6, the half width of the diffraction peak from the (002) plane is 0.22 degrees, and the crystallite size obtained from this is 51 nm, which is much larger than the hydroxyapatite crystallite size of Example 1. It was a result. Further, a diffraction peak from the (211) plane is observed at the maximum intensity ratio at the Bragg angle 2θ = 31.8 degrees, and then the (112) plane at 32.2 degrees and the (300) plane at 32.9 degrees. It was found that the diffraction peaks from were clearly separated. For the sample of Comparative Example 1, it was found that the peak intensity from the (002) plane appeared smaller than the peak intensity at the (300) plane. Further, the peak intensity ratio from the (002) plane to the peak from the (310) plane was 1.4, which was clearly smaller than the result of Example 1. From the above results, the hydroxyapatite obtained in Example 1 has a crystallite size of 50 nm or less, whereas the reagent product and Comparative Example 1 show a value of 50 nm or more, (211) plane, (112 The diffraction peaks from the () plane and (300) plane overlap, and the (002) / (310) peak intensity ratio was found to be smaller than 1.9.

  The dispersion stability was evaluated in the same manner as in Example 1. Regarding the standing stability, when the dispersion obtained above was allowed to stand at room temperature, sedimentation proceeded in about 1 hour, and a supernatant of about 10 mm was observed on the top surface of the liquid, and a precipitate was observed at the bottom. Furthermore, a doctor bar (a commercially available No. 12 doctor bar is used on the surface of the film in the state immediately after dispersion and two weeks after preparation, and a coating amount of 24 grams per square meter is set as a solution. ) Was applied and dried, and it was found that both the sample immediately after dispersion and the sample coated with the dispersion after a lapse of 2 weeks had a rough surface and a large number of coarse particles were mixed. When this was measured with a haze meter, the haze value was 35% immediately after dispersion and 40% after 2 weeks. From the above results, the hydroxyapatite obtained in Comparative Example 1 was inferior in dispersion stability.

(Comparative Example 2)
As Comparative Example 2, hydroxyapatite was synthesized by the method described in Patent Document 8. That is, an aqueous phosphoric acid solution is gradually added to an aqueous slurry in which calcium hydroxide is suspended in water at an internal temperature of 30 ° C. while vigorously stirring, and the ratio of phosphoric acid to calcium hydroxide is CaO / P ₂ O. The weight ratio in terms of ₅ was added to be 1.34. The aqueous slurry after completion of the reaction was dried in a dryer at 100 ° C., and then fired at 900 ° C. for 1 hour using an electric furnace. The obtained powder was wet-dispersed in the same manner as in Example 1 using a paint conditioner. A part of the dispersion was taken out and dried, and a wide-angle X-ray diffraction pattern was measured in the same manner as in Example 1. FIG. 7 shows a wide-angle X-ray diffraction pattern of hydroxyapatite obtained in Comparative Example 2. In FIG. 7, the half-value width of the diffraction peak from the (002) plane is 0.17 degrees, and the crystallite size determined from this is 90 nm, which is much larger than the hydroxyapatite crystallite size of Example 1. It was a result. Further, a diffraction peak from the (211) plane is observed at the maximum intensity ratio at the Bragg angle 2θ = 31.8 degrees, and then the (112) plane at 32.2 degrees and the (300) plane at 32.9 degrees. It was found that the diffraction peaks from were clearly separated. For the sample of Comparative Example 2, it was found that the peak intensity from the (002) plane appeared smaller than the peak intensity of the (300) plane. Further, the peak intensity ratio from the (002) plane to the peak from the (310) plane was 1.2, which was clearly smaller than the result of Example 1. From the above results, the hydroxyapatite obtained in Example 1 has a crystallite size of 50 nm or less, whereas Comparative Example 2 shows a value of 50 nm or more, (211) plane, (112) plane It was also found that the diffraction peaks from the (300) plane overlapped, and that the (002) / (310) peak intensity ratio showed a numerical value smaller than 1.9.

  Further, in Comparative Example 2, the dispersion stability was evaluated in the same manner as in Example 1. Regarding the standing stability, when the dispersion obtained above was allowed to stand at room temperature, sedimentation proceeded in about 1 hour, and a supernatant of about 10 mm was observed on the top surface of the liquid, and a precipitate was observed at the bottom. Furthermore, a doctor bar (a commercially available No. 12 doctor bar is used on the surface of the film in the state immediately after dispersion and two weeks after preparation, and a coating amount of 24 grams per square meter is set as a solution. ) Was applied and dried, and it was found that both the sample immediately after dispersion and the sample coated with the dispersion after a lapse of 2 weeks had a rough surface and a large number of coarse particles were mixed. When this was measured with a haze meter, the haze value was 30% immediately after dispersion and 40% after 2 weeks. From the above results, the hydroxyapatite obtained in Comparative Example 2 was inferior in dispersion stability.

(Example 2)
A dicalcium phosphate dihydrate plate-like crystal was prepared in the same manner as in Example 1, except that the reaction temperature when adding the diammonium hydrogen phosphate aqueous solution to the calcium chloride aqueous solution was adjusted to 50 ° C. A hydroxyapatite fine particle dispersion was prepared by performing an alkali treatment and a wet dispersion treatment using a media mill in the same manner as described above. As an evaluation of the dispersion stability, regarding the standing stability, when the obtained dispersion was left to stand at room temperature for 1 week, a supernatant of about 2 mm was observed on the top surface of the liquid, but no precipitate was observed at the bottom. The stability was still good. Furthermore, a doctor bar (a commercially available No. 12 doctor bar is used on the surface of the film in the state immediately after dispersion and two weeks after preparation, and a coating amount of 24 grams per square meter is set as a solution. ) Was applied and dried, and almost completely transparent films were obtained in both cases. When this was measured with a haze meter, both obtained a result that the haze value was 6%. Therefore, even after 2 weeks, the dispersion state was stable, and no coarse particles or aggregates were observed. Furthermore, in order to measure the size of the dispersed hydroxyapatite fine particles using the dispersion liquid obtained above, the volume average particle diameter was 1. It was 1 μm. Further, a part of the dispersion was taken out and dried using an evaporator, and hydroxyapatite fine particles were taken out. Using this, wide angle X-ray diffraction measurement was performed. FIG. 8 is a wide-angle X-ray diffraction pattern of the hydroxyapatite fine particles after wet dispersion treatment obtained in Example 2. In FIG. 8, the half width of the diffraction peak from the (002) plane was 0.32 degrees, and the crystallite size calculated from this was 30 nm. The (002) / (310) peak intensity ratio was 4.2. The characteristics of other diffraction peaks coincided with the characteristics seen in FIG. Further, as a result of observing hydroxyapatite fine particles with a scanning electron microscope using a sample diluted with a hydroxyapatite dispersion and dropped onto a slide glass and dried, an observation image similar to that in Example 1 was obtained. It was confirmed that hydroxyapatite fine particles having the same size and shape were produced.

(Comparative Example 3)
In Example 1, the alkali treatment was performed, and the hydroxyapatite before being subjected to the wet dispersion treatment was dispersed in water, and the dispersion was performed using an ultrasonic disperser. Immediately settled and a stable dispersion could not be prepared. Subsequently, a high-speed shearing disperser (manufactured by Tokushu Kika Kogyo Co., Ltd., TK homodisper L type) was used for 30 minutes at a rotational speed of 2000 rpm, but a stable dispersion could not be produced. FIG. 9 shows the measurement results of the hydroxyapatite dispersion obtained in Comparative Example 3 using a light scattering diffraction particle size distribution meter. The volume average particle size determined by measurement was 7.0 μm.

  Since the hydroxyapatite fine particles obtained by the production method of the present invention and the dispersion thereof have appropriate crystallinity, they can be used as bone and tooth restoration materials for regenerative medical applications, for example, and combined with various polymer materials It can be used as a sheet-like material or a film coating material as a composite material produced in the above manner. Furthermore, use as a vector carrying DNA used for genetic recombination, use as an adsorbent, chromatographic carrier, ion exchange material, catalyst, antibacterial agent, etc. and use as a nucleating agent in plastic film molding Can also be used.

Claims (7)

  A method for producing hydroxyapatite fine particles, wherein a plate-like crystal of dicalcium phosphate dihydrate is alkali-treated in water having a pH of 12 or more, and then wet-dispersed in water by a media mill.   Hydroxyapatite fine particles obtained by the method for producing hydroxyapatite fine particles according to claim 1.   The hydroxyapatite fine particles according to claim 2, wherein the size of the primary particles and crystallites is in the range of 10 to 100 nm, and the volume average particle diameter of the secondary particles is in the range of 0.5 to 6 µm.   The wide-angle X-ray diffraction shows an X-ray diffraction pattern in which the diffraction peak intensity on the (002) plane near 2θ = 26 degrees is larger than the diffraction peak intensity on the (300) plane near 2θ = 33 degrees. 3. Hydroxyapatite fine particles according to 3.   In wide-angle X-ray diffraction, the ratio of the diffraction peak intensity of the (002) plane near 2θ = 26 degrees to the diffraction peak intensity of the (310) plane near 2θ = 40 degrees is in the range of 1.9-6. The hydroxyapatite fine particles according to any one of claims 2 to 4, which exhibit a pattern.   In wide-angle X-ray diffraction, the diffraction peak due to the (112) plane near 2θ = 32 degrees does not separate from the diffraction peaks from the (211) plane and the (300) plane, and the latter two diffraction peaks are from the (112) plane. The hydroxyapatite fine particles according to any one of claims 2 to 5, which exhibit an X-ray diffraction pattern appearing attached to one part of a diffraction peak.   A hydroxyapatite fine particle dispersion containing the hydroxyapatite fine particles according to any one of claims 2 to 6.