A kind of hydroxyapatite microsphere and preparation method thereof

Abstract

The invention discloses a method for preparing hydroxyapatite microspheres, comprising: a. adding an acid-base solution to a mixed solution containing a phosphorus source and a calcium source to adjust the pH value of the mixed solution, standing or mixing the mixed solution to obtain a hydroxyapatite emulsion; b. spray drying the hydroxyapatite emulsion obtained in step a to obtain a hydroxyapatite microparticle powder; c. mixing the hydroxyapatite microparticle powder obtained in step b with a nanoparticle aqueous solution to obtain a hydroxyapatite micro-nano aqueous solution, wherein the nanoparticle aqueous solution comprises calcium-phosphorus source nanoparticles and a cationic polymer compound; d. pouring the hydroxyapatite micro-nano aqueous solution obtained in step c into oil and stirring, filtering, drying and sintering to obtain hydroxyapatite microspheres. The hydroxyapatite microspheres have excellent surface properties and high consistency, and are suitable for applications in the fields of new materials and biomedicine.

Description

Technical Field

[0001] The invention belongs to the technical field of inorganic materials, and particularly relates to hydroxyapatite microspheres and a preparation method thereof. Background Art

[0002] Hydroxyapatite (HAp) is a key inorganic component of human bones. It has been widely studied and applied in the field of bone replacement and repair since the 1960s due to its excellent biocompatibility and bioactivity. HAp is usually presented in the form of dense or porous particles and bulk materials, and the preparation technology has reached a fairly mature level. Researchers can choose the most appropriate preparation method according to specific application requirements.

[0003] In the field of medical cosmetology, HAp is also processed into microspheres of specific particle size, combined with liquid or polymer materials for soft tissue repair. These HAp microspheres are the main ingredients of facial injection cosmetic fillers. They not only provide immediate filling effects, but also promote long-term collagen regeneration, and are therefore widely welcomed by the market. In medical beauty products, HAp microspheres of 25-45 μm in size are mainly suspended in polymer solutions. In order to prevent the microspheres from being phagocytosed by macrophages in the body and reduce skin trauma and side effects caused by injection, product specifications require that the particle size of the microspheres be strictly controlled within the range of 25-45 microns, and the morphology must remain spherical. This design gives the microspheres excellent biocompatibility and bioactivity in biomedical applications. At the same time, the spherical structure also optimizes the fluidity during injection, ensures the uniformity of injection, reduces tissue damage, and promotes harmonious integration with human tissues. However, this also increases the difficulty of preparing microspheres, making the preparation process of microspheres more complicated and raising the technical requirements to a new level.

[0004] At present, the preparation technology of hydroxyapatite (HAp) microspheres covers a variety of methods such as template method, hydrothermal method, spray drying method, microemulsion method and precipitation method. These technologies can accurately control the particle size of microspheres, achieve a narrow particle size distribution, and screen out microspheres of specific particle size through screening process. However, each method has its limitations. Although the template method is accurate, it requires cumbersome template removal steps; the hydrothermal method, precipitation method and microemulsion method have low yields and are difficult to meet industrial needs; and the spray drying method, although it has been applied in industrialization, usually requires secondary granulation, which not only increases the cost of raw materials, but also requires that the raw materials must be uniform during secondary dispersion, which is more difficult.

[0005] Therefore, it is necessary to conduct in-depth research to provide a simple and easy-to-apply method for preparing hydroxyapatite microspheres. Summary of the invention

[0006] The present invention is based on the inventor's discovery and understanding of the following facts and problems: In the process of preparing hydroxyapatite microspheres by spray drying, in order to achieve uniform dispersion during the secondary dispersion of raw materials, it is usually necessary to introduce a dispersant and a binder into the formula, as described in CN117185266A. However, this approach may introduce bubbles and form cavities during the granulation process, and may also cause the surface of the microspheres to be rough, affecting the consistency between batches. The surface properties of hydroxyapatite microspheres have a significant effect on the adhesion, proliferation and differentiation of cells. Therefore, developing a preparation technology that can fully control the particle size, particle size distribution and surface properties of microspheres is a key issue to be solved in the current research field.

[0007] The present invention aims to solve one of the technical problems in the related art to at least a certain extent. To this end, the embodiments of the present invention provide a hydroxyapatite microsphere and a preparation method thereof. The hydroxyapatite microsphere prepared by the method has excellent surface properties and high consistency, and is suitable for application in the fields of new materials and biomedicine. The preparation method of the present invention can effectively control the particle size, particle size distribution and surface properties of the microspheres, and meet the requirements of high precision and high consistency of hydroxyapatite microsphere products.

[0008] The method for preparing hydroxyapatite microspheres according to the embodiment of the present invention comprises:

[0009] a. adding an acid-base solution to a mixed solution containing a phosphorus source and a calcium source to adjust the pH value of the mixed solution, and allowing to stand or mix to obtain a hydroxyapatite emulsion;

[0010] b. spray drying the hydroxyapatite emulsion obtained in step a to obtain hydroxyapatite microparticle powder;

[0011] c. mixing the hydroxyapatite microparticle powder obtained in step b with an aqueous solution of nanoparticles to obtain a hydroxyapatite micro-nano aqueous solution, wherein the aqueous solution of nanoparticles comprises calcium-phosphorus source nanoparticles and a cationic polymer compound;

[0012] d. Pour the hydroxyapatite micro-nano aqueous solution obtained in step c into oil and stir, filter, dry and sinter to obtain hydroxyapatite microspheres.

[0013] Advantages and technical effects brought by the preparation method of hydroxyapatite microspheres of the embodiment of the present invention: 1. In the embodiment of the present invention, the viscosity of the mixed solution can be adjusted by adjusting the pH of the calcium-phosphorus source mixed solution, thereby enhancing its dispersibility and stability, which is beneficial to reducing the differences between the same batch and different batches of products in the large-scale granulation microsphere process and improving the consistency of the product; 2. In the embodiment of the present invention, no binder or dispersant is required to be added before spray drying, which simplifies the subsequent treatment process and improves the safety and production efficiency of the product; 3. In the embodiment of the present invention, a one-step granulation microsphere process is adopted to avoid the generation of bubbles and the formation of cavities in the traditional secondary granulation microsphere process, thereby improving the uniformity and integrity of the microspheres, and eliminating the subsequent impurity removal step, shortening the production cycle, improving the production efficiency, and obtaining high-quality microsphere products; 4. In the embodiment of the present invention, the hydroxyapatite obtained after spray drying is The microparticle powder is mixed with the nanoparticle aqueous solution, and the electrostatic attraction and chemical bonding of the cationic polymer compound in the nanoparticle aqueous solution realize the combination of the calcium-phosphorus source nanoparticles and the hydroxyapatite micron powder, so that the calcium-phosphorus source nanoparticles can effectively fill the unevenness or non-roundness of the surface of the hydroxyapatite micron powder, and the use of the calcium-phosphorus source nanoparticles will not introduce other impurities. The cationic polymer compound is used as a bridging molecule to effectively enhance the smoothness and roundness of the surface of the hydroxyapatite microspheres, significantly improve the surface roughness of the microspheres, and at the same time improve the sphericity, and after subsequent filtration, drying and sintering treatment, the cationic polymer compound can be effectively removed, thereby ensuring the purity of the hydroxyapatite microsphere product; 5. The method of the embodiment of the present invention can effectively control the particle size, particle size distribution and surface characteristics of the microspheres, meet the requirements of high precision and high consistency for hydroxyapatite microsphere products, and can be used for biomedical materials.

[0014] In some embodiments, in step a, the calcium source includes at least one of calcium hydrogen phosphate, calcium hydrogen phosphate monohydrate, calcium hydrogen phosphate dihydrate or calcium dihydrogen phosphate, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, fluorinated apatite, chloride apatite, carbonate apatite, amorphous calcium phosphate, calcium gluconate, calcium hydrogen phosphate, calcium lactate, calcium chloride, calcium sulfate, calcium oxalate, calcium fluoride, calcium nitrate, calcium nitrate tetrahydrate, calcium chlorate, calcium perchlorate or calcium bicarbonate.

[0015] In some embodiments, in step a, the phosphorus source includes at least one of triphenylphosphine, phosphine, indium phosphide, tributylphosphine, phosphoric acid, yellow phosphorus, orthophosphate, pyrophosphate, metaphosphate, phosphate ester, adenosine diphosphate, adenosine monophosphate, guanosine triphosphate, guanosine diphosphate, phosphatidylinositol, phosphatidylinositol-3-phosphate, phosphatidylinositol-4-phosphate, O-phosphorylated serine, O-phosphorylated threonine, O-phosphorylated tyrosine, N-phosphorylated histidine, N-phosphorylated arginine, N-phosphorylated lysine, S-phosphorylated aspartic acid, N-phosphorylated glutamate or acylphosphorylated cysteine.

[0016] In some embodiments, in step a, the molar ratio of Ca in the calcium source to P in the phosphorus source is 1.53-1.98.

[0017] In some embodiments, in step a, the solid content of the mixed solution containing the calcium source and the phosphorus source is 2 wt%-45 wt%.

[0018] In some embodiments, in step a, the acid-base solution includes at least one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, perchloric acid, hydrofluoric acid, sodium hydroxide solution, potassium hydroxide solution, ammonia solution, calcium hydroxide solution, ammonium hydroxide solution, sodium carbonate solution, potassium carbonate solution, acetic acid-sodium acetate buffer, citric acid-sodium citrate buffer, boric acid-sodium borate buffer, triethylamine, pyridine, formic acid, benzoic acid, and boric acid.

[0019] In some embodiments, in step a, the pH value of the mixed solution after adjustment with the acid-base solution is 6-11.5.

[0020] In some embodiments, in step a, the standing or mixing treatment time is 0.1h-72h.

[0021] In some embodiments, in step a, the mixing treatment method includes at least one of stirring, ball milling or ultrasound. Preferably, the frequency of the ultrasound is 5-90 Hz.

[0022] In some embodiments, in step b, the spray drying temperature is 100°C-400°C.

[0023] In some embodiments, in step c, the cationic polymer compound includes at least one of polyethyleneimine, polyvinylpyridine, polydiallyldimethylammonium chloride, polylysine, polyaniline, polymethyl methacrylate, polyacrylic acid, polyquaternary ammonium salt, polyethylene oxide or polyacrylamide.

[0024] In some embodiments, in step c, the calcium-phosphorus source nanoparticles include hydroxyapatite nanoparticles. Preferably, the molar ratio of calcium to phosphorus in the calcium-phosphorus source nanoparticles is 1.53-1.98.

[0025] In some embodiments, in step c, the particle size of the calcium phosphate source nanoparticles is 1-500 nm.

[0026] In some embodiments, in step c, in the nanoparticle aqueous solution, the mass content of the calcium-phosphorus source nanoparticles is 0.1wt%-15wt%, and the mass content of the cationic polymer compound is 0.01wt%-10%.

[0027] In some embodiments, in step c, the volume ratio of the mass of the hydroxyapatite microparticle powder to the nanoparticle aqueous solution is 1 g:(1-5) ml.

[0028] In some embodiments, in step d, the oil comprises at least one of glycerol, castor oil, olive oil, soybean oil, rapeseed oil, sesame oil, coconut oil, tung oil or peanut oil.

[0029] In some embodiments, in step d, the drying temperature is -40-200°C.

[0030] In some embodiments, in the step d, the temperature of the sintering treatment is 500° C.-1250° C., the heating rate of the sintering treatment is 1° C.-10° C., and the time of the sintering treatment is 1 h-7 h.

[0031] The present invention also provides hydroxyapatite microspheres, which are prepared by the method of the present invention. The hydroxyapatite microspheres of the present invention have excellent smoothness, roundness and product consistency, and are suitable for applications in new materials, biomedicine and other fields.

[0032] In some embodiments, the particle size D10-D90 of the hydroxyapatite microspheres is 1-100 μm, preferably 20-60 μm.

[0033] In some embodiments, the density of the hydroxyapatite microspheres is 0.5-3.5 g / cm 3 .

[0034] The embodiment of the present invention also provides an application of hydroxyapatite microspheres in biomedical materials. The hydroxyapatite microspheres of the embodiment of the present invention have excellent surface properties and high consistency, and can be used to prepare biomedical materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is a SEM image of hydroxyapatite microspheres prepared in Example 1;

[0036] Figure 2 is a SEM image of hydroxyapatite microspheres prepared in Example 2;

[0037] Figure 3 is a SEM image of hydroxyapatite microspheres prepared in Example 3;

[0038] Figure 4 is a SEM image of hydroxyapatite microspheres prepared in Example 4;

[0039] Figure 5 is a particle size distribution diagram of hydroxyapatite microspheres prepared in Example 4;

[0040] Figure 6 is a sedimentation diagram of the hydroxyapatite emulsion at different pH values ​​prepared in Example 5 after standing for 72 hours;

[0041] Figure 7 is the SEM image of hydroxyapatite microspheres at different pH values ​​prepared in Example 5;

[0042] Figure 8 is a SEM image of hydroxyapatite microspheres prepared in Comparative Example 1;

[0043] Fig. 9 is a SEM image of hydroxyapatite microspheres prepared in Comparative Example 2;

[0044] Fig.10 is a SEM image of hydroxyapatite microspheres prepared in Comparative Example 3;

[0045] Fig.11 This is a sedimentation diagram of the hydroxyapatite emulsion prepared in Comparative Example 4 after standing for 72 hours;

[0046] Fig.12 This is the SEM image of the hydroxyapatite microspheres prepared in Comparative Example 4. DETAILED DESCRIPTION

[0047] Embodiments of the present invention are described in detail below, and examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0048] The method for preparing hydroxyapatite microspheres according to the embodiment of the present invention comprises:

[0049] a. adding an acid-base solution to a mixed solution containing a phosphorus source and a calcium source to adjust the pH value of the mixed solution, and allowing to stand or mix to obtain a hydroxyapatite emulsion;

[0050] b. spray drying the hydroxyapatite emulsion obtained in step a to obtain hydroxyapatite microparticle powder;

[0051] c. mixing the hydroxyapatite microparticle powder obtained in step b with an aqueous solution of nanoparticles to obtain a hydroxyapatite micro-nano aqueous solution, wherein the aqueous solution of nanoparticles comprises calcium-phosphorus source nanoparticles and a cationic polymer compound;

[0052] d. Pour the hydroxyapatite micro-nano aqueous solution obtained in step c into oil and stir, filter, dry and sinter to obtain hydroxyapatite microspheres.

[0053] In the preparation method of hydroxyapatite microspheres of the embodiment of the present invention, the viscosity of the mixed solution can be adjusted by adjusting the pH value of the calcium-phosphorus source mixed solution, thereby enhancing its dispersibility and stability, which is beneficial to reducing the difference between the same batch and different batches of products in the large-scale granulation microsphere process and improving the consistency of the product; in the embodiment of the present invention, no binder or dispersant is required to be added before spray drying, which simplifies the subsequent treatment process and improves the safety and production efficiency of the product; in the embodiment of the present invention, a one-step granulation microsphere process is adopted to avoid the generation of bubbles and the formation of cavities in the traditional secondary granulation microsphere process, thereby improving the uniformity and integrity of the microspheres, and eliminating the subsequent impurity removal step, shortening the production cycle, improving the production efficiency, and obtaining a high-quality microsphere product; in the embodiment of the present invention, the hydroxyapatite microparticle powder obtained after spray drying is mixed with the nanoparticle aqueous solution The mixture is mixed, and the electrostatic attraction and chemical bonding of the cationic polymer compounds in the nanoparticle aqueous solution realize the combination of the calcium-phosphorus source nanoparticles and the hydroxyapatite micron powder, so that the calcium-phosphorus source nanoparticles can effectively fill the unevenness or non-roundness of the surface of the hydroxyapatite micron powder, and the use of the calcium-phosphorus source nanoparticles will not introduce other impurities. The cationic polymer compounds are used as bridging molecules to effectively enhance the smoothness and roundness of the surface of the hydroxyapatite microspheres, significantly improve the surface roughness of the microspheres, and at the same time improve the sphericity. After subsequent filtration, drying and sintering treatments, the cationic polymer compounds can be effectively removed, thereby ensuring the purity of the hydroxyapatite microsphere product. The method of the embodiment of the present invention can effectively control the particle size, particle size distribution and surface characteristics of the microspheres, meet the requirements of high precision and high consistency for hydroxyapatite microsphere products, and can be used for biomedical materials.

[0054] In some embodiments, in step a, the calcium source includes at least one of calcium hydrogen phosphate, calcium hydrogen phosphate monohydrate, calcium hydrogen phosphate dihydrate or calcium dihydrogen phosphate, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, fluorinated apatite, chloride apatite, carbonate apatite, amorphous calcium phosphate, calcium gluconate, calcium hydrogen phosphate, calcium lactate, calcium chloride, calcium sulfate, calcium oxalate, calcium fluoride, calcium nitrate, calcium nitrate tetrahydrate, calcium chlorate, calcium perchlorate or calcium bicarbonate.

[0055] In some embodiments, in step a, the phosphorus source includes at least one of triphenylphosphine, phosphine, indium phosphide, tributylphosphine, phosphoric acid, yellow phosphorus, orthophosphate, pyrophosphate, metaphosphate, phosphate ester, adenosine diphosphate, adenosine monophosphate, guanosine triphosphate, guanosine diphosphate, phosphatidylinositol, phosphatidylinositol-3-phosphate, phosphatidylinositol-4-phosphate, O-phosphorylated serine, O-phosphorylated threonine, O-phosphorylated tyrosine, N-phosphorylated histidine, N-phosphorylated arginine, N-phosphorylated lysine, S-phosphorylated aspartic acid, N-phosphorylated glutamate or acylphosphorylated cysteine.

[0056] In the embodiments of the present invention, there is no particular limitation on the calcium source and phosphorus source used, and the calcium source and phosphorus source commonly used in the art can be applied to the present invention.

[0057] In some embodiments, in step a, the molar ratio of Ca in the calcium source to P in the phosphorus source is 1.53-1.98.

[0058] In some embodiments, in step a, the solid content of the mixed solution containing the calcium source and the phosphorus source is 2 wt%-45 wt%.

[0059] In some embodiments, in step a, the acid-base solution includes at least one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, perchloric acid, hydrofluoric acid, sodium hydroxide solution, potassium hydroxide solution, ammonia solution, calcium hydroxide solution, ammonium hydroxide solution, sodium carbonate solution, potassium carbonate solution, acetic acid-sodium acetate buffer, citric acid-sodium citrate buffer, boric acid-sodium borate buffer, triethylamine, pyridine, formic acid, benzoic acid, and boric acid. In the embodiment of the present invention, the acid and base used to adjust the mixed solution are not particularly limited, and the acid and base solutions that can be used for pH adjustment can be applied to the present invention.

[0060] In some embodiments, in step a, the pH value of the mixed solution after adjustment by the acid-base solution is 6-11.5. In the embodiments of the present invention, by preferably controlling the pH value of the mixed solution after adjustment, the viscosity of the mixed solution can be effectively adjusted, and the dispersibility and stability of the mixed solution can be enhanced.

[0061] In some embodiments, in step a, the standing or mixing treatment time is 0.1h-72h; the mixing treatment method includes at least one of stirring, ball milling or ultrasound, and preferably, the frequency of the ultrasound is 5-90Hz. In the embodiment of the present invention, after adding the acid-base adjusted calcium and phosphorus source mixed solution, the mixed solution is allowed to stand or mix to ensure the production of uniform hydroxyapatite.

[0062] In some embodiments, in step b, the spray drying temperature is 100°C-400°C.

[0063] In some embodiments, in step c, the cationic polymer compound comprises at least one of polyethyleneimine, polyvinylpyridine, polydiallyldimethylammonium chloride, polylysine, polyaniline, polymethyl methacrylate, polyacrylic acid, polyquaternary ammonium salt, polyethylene oxide or polyacrylamide. Preferably, polylysine. In the embodiment of the present invention, the preferred polymer compound is used to further enhance the combination of calcium and phosphorus source nanoparticles and hydroxyapatite micron powder, and improve the surface roughness and sphericity of the microspheres.

[0064] In some embodiments, in step c, the calcium-phosphorus source nanoparticles include hydroxyapatite nanoparticles. Preferably, the molar ratio of calcium to phosphorus in the calcium-phosphorus source nanoparticles is 1.53-1.98.

[0065] In some embodiments, in step c, the particle size of the calcium phosphate source nanoparticles is 1-500 nm. In the embodiments of the present invention, the use of calcium phosphate source nanoparticles with a preferred particle size is beneficial to further improve the smoothness and roundness of the hydroxyapatite microspheres.

[0066] In some embodiments, in step c, in the nanoparticle aqueous solution, the mass content of the calcium-phosphorus source nanoparticles is 0.1wt%-15wt%, and the mass content of the cationic polymer compound is 0.01wt%-10%.

[0067] In some embodiments, in step c, the mass ratio of the hydroxyapatite microparticle powder to the nanoparticle aqueous solution is 1 g: (1-5) ml. In the embodiment of the present invention, the dosage of the hydroxyapatite microparticle powder and the nanoparticle aqueous solution is preferably selected, which is conducive to better combination of the hydroxyapatite microparticle powder and the calcium phosphate source nanoparticles under the action of the cationic polymer compound, thereby improving the surface properties of the hydroxyapatite microspheres.

[0068] In some embodiments, in step d, the oil comprises at least one of glycerol, castor oil, olive oil, soybean oil, rapeseed oil, sesame oil, coconut oil, tung oil or peanut oil. In the embodiment of the present invention, the hydroxyapatite micro-nano aqueous solution is mixed with a preferred vegetable oil, and the oil-water solution is mixed to form an emulsion, which helps the distribution of calcium and phosphorus source nanoparticles on the surface of the hydroxyapatite microparticle powder and promotes the combination of the two, which is conducive to further forming hydroxyapatite microspheres with smooth and round surfaces.

[0069] In some embodiments, in step d, the drying comprises at least one of freeze drying and oven drying. Preferably, the drying temperature is -40-200°C.

[0070] In some embodiments, in the step d, the temperature of the sintering treatment is 500° C.-1250° C., the heating rate of the sintering treatment is 1° C.-10° C., and the time of the sintering treatment is 1 h-7 h.

[0071] The present invention also provides hydroxyapatite microspheres, which are prepared by the method of the present invention. The hydroxyapatite microspheres of the present invention have excellent smoothness, roundness and product consistency, and are suitable for applications in new materials, biomedicine and other fields.

[0072] In some embodiments, the particle size D10-D90 of the hydroxyapatite microspheres is 1-100 μm, preferably 20-60 μm, and more preferably 25-45 μm.

[0073] In some embodiments, the density of the hydroxyapatite microspheres is 0.5-3.5 g / cm 3 .

[0074] The embodiment of the present invention also provides an application of hydroxyapatite microspheres in biomedical materials. The hydroxyapatite microspheres of the embodiment of the present invention have excellent surface properties and high consistency, and can be used to prepare biomedical materials.

[0075] The present invention is described in detail below with reference to the embodiments and the accompanying drawings.

[0076] Example 1

[0077] 80.34 g of ammonium sodium hydrogen phosphate and 100 g of calcium carbonate are dissolved in 420 ml of deionized water to obtain a calcium-phosphorus source mixed solution, that is, the molar ratio of Ca in the calcium source calcium carbonate to P in the phosphorus source sodium ammonium hydrogen phosphate is 1.71; 1 M hydrochloric acid, 30 wt % ammonia water and 1 M sodium hydroxide are used to adjust the pH value of the calcium-phosphorus source mixed solution to 10.55 to obtain a calcium-phosphorus source emulsion; after the calcium-phosphorus source emulsion is allowed to stand for 36 hours, a hydroxyapatite emulsion is obtained.

[0078] The hydroxyapatite emulsion was spray-dried at a drying temperature of 160° C. to obtain hydroxyapatite microparticle powder.

[0079] 60 g of hydroxyapatite microparticle powder was mixed with 60 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 0.1 wt% polylysine and 1 wt% nanoparticles, and the nanoparticles were hydroxyapatite with a particle size of 80 nm and a calcium-phosphorus ratio of 1.67, to obtain a hydroxyapatite micro-nano aqueous solution.

[0080] The hydroxyapatite micro-nano aqueous solution was poured into 1500 ml of soybean oil, mechanically stirred at 500 rpm for 12 hours, filtered by suction, and dried at 120° C. to obtain hydroxyapatite microsphere powder.

[0081] The hydroxyapatite microsphere powder is sintered at 1050° C. to obtain hydroxyapatite microspheres.

[0082] The morphology of the hydroxyapatite microspheres prepared in this example is shown in Figure 1 ,pass Figure 1 It can be seen that each hydroxyapatite microsphere has good sphericity, and only a very small amount of irregular particles appear.

[0083] Example 2

[0084] Sodium tripolyphosphate and calcium acetate are dissolved in deionized water to obtain a calcium-phosphorus source mixed solution, wherein the molar ratio of Ca in the calcium source calcium acetate to P in the phosphorus source sodium tripolyphosphate is 1.75; 30wt% ammonia water and 1M sodium hydroxide are used to adjust the pH value of the calcium-phosphorus source mixed solution to 10.80 to obtain a calcium-phosphorus source emulsion; and the calcium-phosphorus source emulsion is allowed to stand for 36 hours to obtain a hydroxyapatite emulsion.

[0085] The hydroxyapatite emulsion was spray-dried at a drying temperature of 260° C. to obtain hydroxyapatite microparticle powder.

[0086] 40 g of hydroxyapatite microparticle powder was mixed with 160 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 1 wt% polylysine and 10 wt% nanoparticles, and the nanoparticles were a mixture of hydroxyapatite and tricalcium phosphate with a particle size of 100 nm and a calcium-phosphorus ratio of 1.71, to obtain a hydroxyapatite micro-nano aqueous solution.

[0087] The hydroxyapatite micro-nano aqueous solution was poured into 2000 ml of soybean oil, mechanically stirred at 900 rpm for 3 hours, filtered by suction, and dried at 120° C. to obtain hydroxyapatite microsphere powder.

[0088] The hydroxyapatite microsphere powder is sintered at 1090° C. to obtain hydroxyapatite microspheres.

[0089] The morphology of the hydroxyapatite microspheres prepared in this example is shown in Figure 2 ,pass Figure 2 It can be seen that the hydroxyapatite microspheres have a relatively regular spherical shape, a relatively smooth surface, and no protruding parts such as dendrites on the surface.

[0090] Example 3

[0091] A 85wt% phosphoric acid solution and 2000g of calcium carbonate are dissolved in 16000ml of deionized water to obtain a calcium-phosphorus source mixed solution, wherein the molar ratio of Ca in the calcium source calcium carbonate to P in the phosphorus source phosphoric acid is 1.69; 30wt% ammonia water and 1M sodium hydroxide are used to adjust the pH value of the calcium-phosphorus source mixed solution to 10.75 to obtain a calcium-phosphorus source emulsion; the calcium-phosphorus source emulsion is stirred at 37°C for 24 hours to obtain a hydroxyapatite emulsion.

[0092] The hydroxyapatite emulsion was spray-dried at a drying temperature of 185° C. to obtain hydroxyapatite microparticle powder.

[0093] 1000 g of hydroxyapatite microparticle powder was mixed with 1000 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 1 wt% polyvinylpyridine and 10 wt% nanoparticles, and the nanoparticles were hydroxyapatite with a particle size of 100 nm and a calcium-phosphorus ratio of 1.67, to obtain a hydroxyapatite micro-nano aqueous solution.

[0094] The hydroxyapatite micro-nano aqueous solution was poured into 5000 ml of soybean oil, mechanically stirred at 300 rpm for 12 hours, filtered, and dried at 180° C. to obtain hydroxyapatite microsphere powder.

[0095] The hydroxyapatite microsphere powder is sintered at 1200° C. to obtain hydroxyapatite microspheres.

[0096] The morphology of the hydroxyapatite microspheres prepared in this example is shown in Figure 3 ,pass Figure 3 It can be seen that the hydroxyapatite microspheres are relatively regular spherical, with uniform surface distribution and no macropores.

[0097] Example 4

[0098] 272.24 g of dipotassium hydrogen phosphate and 400 g of calcium acetate are dissolved in 2000 ml of deionized water to obtain a calcium-phosphorus source mixed solution, that is, the molar ratio of Ca in the calcium source calcium acetate to P in the phosphorus source dipotassium hydrogen phosphate is 1.62; 10 wt % ammonia water and 0.1 M sodium hydroxide are used to adjust the pH value of the calcium-phosphorus source mixed solution to 9.35 to obtain a calcium-phosphorus source emulsion; and the calcium-phosphorus source emulsion is allowed to stand for 48 hours to obtain a hydroxyapatite emulsion.

[0099] The hydroxyapatite emulsion was spray-dried at a drying temperature of 220° C. to obtain hydroxyapatite microparticle powder.

[0100] 100 g of hydroxyapatite microparticle powder was mixed with 200 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 10 wt % polyacrylic acid and 15 wt % nanoparticles, and the nanoparticles were hydroxyapatite with a particle size of 100 nm and a calcium-phosphorus ratio of 1.67, to obtain a hydroxyapatite micro-nano aqueous solution.

[0101] The hydroxyapatite micro-nano aqueous solution was poured into 5000 ml of soybean oil, mechanically stirred at 500 rpm for 12 hours, filtered, and dried at 180° C. to obtain hydroxyapatite microsphere powder.

[0102] The hydroxyapatite microsphere powder is sintered at 1200° C. to obtain hydroxyapatite microspheres.

[0103] The morphology of the hydroxyapatite microspheres prepared in this example is shown in Figure 4 ,pass Figure 4 It can be seen that the hydroxyapatite microspheres are relatively regular spheres with uniform particle size and no pores on the surface.

[0104] Figure 5 This is a particle size distribution diagram of the hydroxyapatite microspheres prepared in this example. It can be seen from the figure that the particle size of the hydroxyapatite microspheres is between 1 and 100 microns, and most of them are distributed between 25 and 45 microns.

[0105] Example 5

[0106] 790 g of diammonium hydrogen phosphate and 700 g of calcium hydroxide are dissolved in 4000 ml of deionized water to obtain a calcium-phosphorus source mixed solution, that is, the molar ratio of Ca in the calcium source calcium hydroxide to P in the phosphorus source diammonium hydrogen phosphate is 1.58; 35 wt % concentration of ammonia water is used to adjust the pH values ​​of the calcium-phosphorus source mixed solution to 9 and 11, respectively, to obtain two groups of calcium-phosphorus source emulsion samples; after the two groups of calcium-phosphorus source emulsion samples are allowed to stand for 72 hours, hydroxyapatite emulsion is obtained.

[0107] The hydroxyapatite emulsion was spray-dried at a drying temperature of 185° C. to obtain hydroxyapatite microparticle powder.

[0108] 1000 g of hydroxyapatite microparticle powder was mixed with 1000 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 1 wt% polyvinylpyridine and 10 wt% nanoparticles, and the nanoparticles were hydroxyapatite with a particle size of 100 nm and a calcium-phosphorus ratio of 1.67, to obtain a hydroxyapatite micro-nano aqueous solution.

[0109] The hydroxyapatite micro-nano aqueous solution was poured into 5000 ml of soybean oil, mechanically stirred at 300 rpm for 12 hours, filtered, and dried at 180° C. to obtain hydroxyapatite microsphere powder.

[0110] The hydroxyapatite microsphere powder is sintered at 1200° C. to obtain hydroxyapatite microspheres.

[0111] Figure 6These are pictures of each group of hydroxyapatite emulsions prepared in this example after being left to stand for 72 hours. The hydroxyapatite emulsions have excellent stability, without obvious stratification or sedimentation.

[0112] Figure 7 The morphology diagrams of the various groups of hydroxyapatite microparticle powders prepared in this embodiment show that the hydroxyapatite emulsion with excellent stability can ensure the formation of uniform spherical hydroxyapatite microparticle powders and reduce other irregular impurities.

[0113] Comparative Example 1

[0114] The method is the same as that of Example 1, except that the aqueous solution of nanoparticles does not contain polylysine. The details are as follows:

[0115] 80.34 g of ammonium sodium hydrogen phosphate and 100 g of calcium carbonate are dissolved in 420 ml of deionized water to obtain a calcium-phosphorus source mixed solution, that is, the molar ratio of Ca in the calcium source calcium carbonate to P in the phosphorus source sodium ammonium hydrogen phosphate is 1.71; 1 M hydrochloric acid, 30 wt % ammonia water and 1 M sodium hydroxide are used to adjust the pH value of the calcium-phosphorus source mixed solution to 10.55 to obtain a calcium-phosphorus source emulsion; after the calcium-phosphorus source emulsion is allowed to stand for 36 hours, a hydroxyapatite emulsion is obtained.

[0116] The hydroxyapatite emulsion was spray-dried at a drying temperature of 160° C. to obtain hydroxyapatite microparticle powder.

[0117] 60 g of hydroxyapatite microparticle powder was mixed with 60 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 1 wt % of nanoparticles, the nanoparticles were hydroxyapatite with a particle size of 80 nm and a calcium-phosphorus ratio of 1.67, to obtain a hydroxyapatite micro-nano aqueous solution.

[0118] The hydroxyapatite micro-nano aqueous solution was poured into 1500 ml of soybean oil, mechanically stirred at 500 rpm for 12 hours, filtered by suction, and dried at 120° C. to obtain hydroxyapatite microsphere powder.

[0119] The hydroxyapatite microsphere powder is sintered at 1050° C. to obtain hydroxyapatite microspheres.

[0120] The morphology of the hydroxyapatite microspheres prepared in this comparative example is shown in Figure 8 ,pass Figure 8 It can be seen that the hydroxyapatite microspheres vary in size, most of them are non-spherical, and have a rough surface with voids.

[0121] Comparative Example 2

[0122] The method is the same as that of Example 2, except that the hydroxyapatite microparticle powder obtained after spray drying is not mixed with the nanoparticle aqueous solution, and is directly subjected to subsequent sintering treatment, as follows:

[0123] Sodium tripolyphosphate and calcium acetate are dissolved in deionized water to obtain a calcium-phosphorus source mixed solution, wherein the molar ratio of Ca in the calcium source calcium acetate to P in the phosphorus source sodium tripolyphosphate is 1.75; 30wt% ammonia water and 1M sodium hydroxide are used to adjust the pH value of the calcium-phosphorus source mixed solution to 10.80 to obtain a calcium-phosphorus source emulsion; and the calcium-phosphorus source emulsion is allowed to stand for 36 hours to obtain a hydroxyapatite emulsion.

[0124] The hydroxyapatite emulsion was spray-dried at a drying temperature of 260° C. to obtain hydroxyapatite microparticle powder.

[0125] The hydroxyapatite microsphere powder is sintered at 1090° C. to obtain hydroxyapatite microspheres.

[0126] The morphology of the hydroxyapatite microspheres prepared in this comparative example is shown in Fig. 9 ,pass Fig. 9 It can be seen that although the hydroxyapatite microspheres are spherical, their surfaces are rough and there are protrusions such as dendrites.

[0127] Comparative Example 3

[0128] The method is the same as that in Example 4, except that the PVA solution is added after the pH value of the calcium and phosphorus source mixed solution is adjusted, as follows:

[0129] 272.24 g of dipotassium hydrogen phosphate and 400 g of calcium acetate are dissolved in 2000 ml of deionized water to obtain a calcium-phosphorus source mixed solution, that is, the molar ratio of Ca in the calcium source calcium acetate to P in the phosphorus source dipotassium hydrogen phosphate is 1.62; 10 wt % ammonia water and 0.1 M sodium hydroxide are used to adjust the pH value of the calcium-phosphorus source mixed solution to 9.35, and then 3 g of 1 wt % PVA solution is added to the calcium-phosphorus source mixed solution, and mechanically stirred at 500 rpm for 1 hour to obtain a calcium-phosphorus source emulsion; after the calcium-phosphorus source emulsion is allowed to stand for 48 hours, a hydroxyapatite emulsion is obtained.

[0130] The hydroxyapatite emulsion was spray-dried at a drying temperature of 220° C. to obtain hydroxyapatite microparticle powder.

[0131] 100 g of hydroxyapatite microparticle powder was mixed with 200 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 10 wt % polyacrylic acid and 15 wt % nanoparticles, and the nanoparticles were hydroxyapatite with a particle size of 100 nm and a calcium-phosphorus ratio of 1.67, to obtain a hydroxyapatite micro-nano aqueous solution.

[0132] The hydroxyapatite micro-nano aqueous solution was poured into 5000 ml of soybean oil, mechanically stirred at 500 rpm for 12 hours, filtered, and dried at 180° C. to obtain hydroxyapatite microsphere powder.

[0133] The hydroxyapatite microsphere powder is sintered at 1200° C. to obtain hydroxyapatite microspheres.

[0134] The morphology of the hydroxyapatite microspheres prepared in this comparative example is shown in Fig.10 ,pass Fig.10 It can be seen that the hydroxyapatite microspheres are uneven in size. Although some particles are spherical, there are many macropores or hollow structures on the surface due to the introduction of PVA.

[0135] Comparative Example 4

[0136] The method is the same as that in Example 5, except that no ammonia water and sodium hydroxide are added to adjust the pH value of the calcium-phosphorus source mixed solution, as follows:

[0137] 790 g of diammonium hydrogen phosphate and 700 g of calcium hydroxide were dissolved in 4000 ml of deionized water to obtain a mixed solution of phosphate and calcium sources, i.e., the molar ratio of Ca in the calcium source calcium hydroxide to P in the diammonium hydrogen phosphate as the phosphorus source was 1.58; after the solution was allowed to stand for 72 hours, a hydroxyapatite emulsion was obtained.

[0138] The hydroxyapatite emulsion is spray-dried at a drying temperature of 185° C. to obtain hydroxyapatite fine powder.

[0139] 1000 g of hydroxyapatite microparticle powder was mixed with 1000 ml of nanoparticle aqueous solution, wherein the nanoparticle aqueous solution contained 1 wt% polyvinylpyrrole and 10 wt% nanoparticles, and the nanoparticles were hydroxyapatite with a particle size of 100 nm and a calcium-phosphorus ratio of 1.67, to obtain a hydroxyapatite micro-nano aqueous solution.

[0140] The hydroxyapatite microsphere powder is sintered at 1200° C. to obtain hydroxyapatite microspheres.

[0141] The hydroxyapatite emulsion prepared in Comparative Example 4 was left to stand for 72 hours and its sedimentation degree was tested. The results are shown in Fig.11 ,from Fig.11 and Figure 6 It can be seen that the sedimentation rate of the emulsion in Comparative Example 4 without pH adjustment is significantly greater than that in Example 5, indicating that the hydroxyapatite in the hydroxyapatite emulsion prepared by pH adjustment in Example 5 has better dispersibility.

[0142] Fig.12 This is a morphology picture of the hydroxyapatite microparticle powder prepared in Comparative Example 4. It can be seen that the hydroxyapatite microparticle powder formed by the hydroxyapatite emulsion with poor stability in Comparative Example 4 contains a large number of non-spherical particles with large differences in size.

[0143] The performance of the hydroxyapatite microspheres prepared in each embodiment and comparative example was tested, and the test results are shown in Table 1.

[0144] Table 1

[0145]

[0146] In the present invention, the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0147] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing hydroxyapatite microspheres, characterized in that: include: a. adding an acid-base solution to a mixed solution containing a phosphorus source and a calcium source to adjust the pH value of the mixed solution, allowing the mixed solution to stand or mix to obtain a hydroxyapatite emulsion; b. spray drying the hydroxyapatite emulsion obtained in step a to obtain hydroxyapatite microparticle powder; c. mixing the hydroxyapatite microparticle powder obtained in step b with an aqueous solution of nanoparticles to obtain a hydroxyapatite micro-nano aqueous solution, wherein the aqueous solution of nanoparticles comprises calcium-phosphorus source nanoparticles and a cationic polymer compound; d. Pour the hydroxyapatite micro-nano aqueous solution obtained in step c into oil and stir, filter, dry and sinter to obtain hydroxyapatite microspheres.

2. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In the step a, the calcium source includes at least one of calcium hydrogen phosphate, calcium hydrogen phosphate monohydrate, calcium hydrogen phosphate dihydrate or calcium dihydrogen phosphate, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, fluorinated apatite, chloride apatite, carbonate apatite, amorphous calcium phosphate, calcium gluconate, calcium hydrogen phosphate, calcium lactate, calcium chloride, calcium sulfate, calcium oxalate, calcium fluoride, calcium nitrate, calcium nitrate tetrahydrate, calcium chlorate, calcium perchlorate or calcium bicarbonate; and / or, the phosphorus source comprises at least one of triphenylphosphine, phosphine, indium phosphide, tributylphosphine, phosphoric acid, yellow phosphorus, orthophosphate, pyrophosphate, metaphosphate, phosphate ester, adenosine diphosphate, adenosine monophosphate, guanosine triphosphate, guanosine diphosphate, phosphatidylinositol, phosphatidylinositol-3-phosphate, phosphatidylinositol-4-phosphate, O-phosphorylated serine, O-phosphorylated threonine, O-phosphorylated tyrosine, N-phosphorylated histidine, N-phosphorylated arginine, N-phosphorylated lysine, S-phosphorylated aspartic acid, N-phosphorylated glutamic acid or acylphosphorylated cysteine; And / or, the molar ratio of Ca in the calcium source to P in the phosphorus source is 1.53-1.98; And / or, the solid content of the mixed solution containing the calcium source and the phosphorus source is 2wt%-45wt%.

3. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In the step a, the acid-base solution includes at least one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, citric acid, perchloric acid, hydrofluoric acid, sodium hydroxide solution, potassium hydroxide solution, ammonia solution, calcium hydroxide solution, ammonium hydroxide solution, sodium carbonate solution, potassium carbonate solution, acetic acid-sodium acetate buffer, citric acid-sodium citrate buffer, boric acid-sodium borate buffer, triethylamine, pyridine, formic acid, benzoic acid, and boric acid; And / or, the pH value of the mixed solution after adjustment by the acid-base solution is 6-11.5; And / or, the standing or mixing treatment time is 0.1h-72h; And / or, the mixing treatment method includes at least one of stirring, ball milling or ultrasound, and preferably, the frequency of the ultrasound is 5-90 Hz.

4. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In the step b, the spray drying temperature is 100°C-400°C.

5. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In the step c, the cationic polymer compound includes at least one of polyethyleneimine, polyvinylpyridine, polydiallyldimethylammonium chloride, polylysine, polyaniline, polymethyl methacrylate, polyacrylic acid, polyquaternary ammonium salt, polyethylene oxide or polyacrylamide; And / or, the calcium-phosphorus source nanoparticles include hydroxyapatite nanoparticles. Preferably, the molar ratio of calcium to phosphorus in the calcium-phosphorus source nanoparticles is 1.53-1.

98.

6. The method for preparing hydroxyapatite microspheres according to claim 1 or 5, characterized in that: In the step c, the particle size of the calcium-phosphorus source nanoparticles is 1-500 nm; And / or, in the nanoparticle aqueous solution, the mass content of the calcium-phosphorus source nanoparticles is 0.1wt%-15wt%, and the mass content of the cationic polymer compound is 0.01wt%-10%; And / or, the mass ratio of the hydroxyapatite microparticle powder to the volume ratio of the nanoparticle aqueous solution is 1 g:(1-5) ml.

7. The method for preparing hydroxyapatite microspheres according to claim 1, characterized in that: In step d, the oil comprises at least one of glycerol, castor oil, olive oil, soybean oil, rapeseed oil, sesame oil, coconut oil, tung oil or peanut oil; And or, the drying temperature is -40-200°C; And or, the sintering temperature is 500°C-1250°C, the heating rate of the sintering is 1°C-10°C, and the sintering time is 1h-7h.

8. A hydroxyapatite microsphere, characterized in that: The method according to any one of claims 1 to 7 is adopted.

9. The hydroxyapatite microspheres according to claim 8, characterized in that The particle size D10-D90 of the hydroxyapatite microspheres is 1-100 μm, preferably 20-60 μm; And / or, the density of the hydroxyapatite microspheres is 0.5-3.5 g / cm 3 .

10. Use of the hydroxyapatite microspheres prepared by the method according to any one of claims 1 to 7 or the hydroxyapatite microspheres according to claim 8 or 9 in biomedical materials.

Images