阅读说明：本技术 用于注射填充制剂的羟基磷灰石微球及其制备方法 (Hydroxyapatite microspheres for injection filling preparation and preparation method thereof ) 是由 黄卫民 于卓辰 于 2021-02-07 设计创作，主要内容包括：本发明涉及用于注射填充制剂的羟基磷灰石微球及其制备方法。所述制备方法包括：步骤1：将钙源、磷源分别配制成钙源溶液和磷源溶液并混合,向其中加入支持电解质,调节所得到的混合溶液的pH为微酸性,然后进行电化学沉积,得到针状亚微米/纳米级羟基磷灰石初级产物；步骤2：将所述羟基磷灰石初级产物进行研磨粉碎,然后配制成料浆；步骤3：将所述料浆进行喷雾干燥,得到羟基磷灰石微球粗品；步骤4：将所述羟基磷灰石微球粗品进行高温煅烧；步骤5：将煅烧后的羟基磷灰石微球粗品进行筛分,得到所述羟基磷灰石微球。本发明的制备方法显著提高了生产效率。所制得的羟基磷灰石微球具有所需的粒径分布和高球形度。(The invention relates to hydroxyapatite microspheres for injection filling preparations and a preparation method thereof. The preparation method comprises the following steps: step 1: respectively preparing a calcium source solution and a phosphorus source solution from a calcium source and a phosphorus source, mixing, adding a supporting electrolyte, adjusting the pH value of the obtained mixed solution to be subacidity, and then carrying out electrochemical deposition to obtain a needle-shaped submicron/nanoscale hydroxyapatite primary product; step 2: grinding and crushing the primary product of the hydroxyapatite, and preparing into slurry; and step 3: spray drying the slurry to obtain a hydroxyapatite microsphere crude product; and 4, step 4: calcining the coarse hydroxyapatite microsphere product at high temperature; and 5: and screening the calcined hydroxyapatite microsphere crude product to obtain the hydroxyapatite microsphere. The preparation method of the invention obviously improves the production efficiency. The prepared hydroxyapatite microspheres have the required particle size distribution and high sphericity.)

1. A method for preparing hydroxyapatite microspheres for injection filling formulations, wherein the method comprises:

step 1: respectively preparing a calcium source solution and a phosphorus source solution from a calcium source and a phosphorus source, mixing, adding a supporting electrolyte, adjusting the pH value of the obtained mixed solution to be subacidity, and then carrying out electrochemical deposition to obtain a needle-shaped submicron/nanoscale hydroxyapatite primary product;

step 2: grinding and crushing the primary product of the hydroxyapatite, and preparing into slurry;

and step 3: spray drying the slurry to obtain a hydroxyapatite microsphere crude product;

and 4, step 4: calcining the coarse hydroxyapatite microsphere product at high temperature;

and 5: and screening the calcined hydroxyapatite microsphere crude product to obtain the hydroxyapatite microsphere.

2. The preparation method according to claim 1, wherein in step 1, the calcium source is any one of calcium hydroxide, calcium nitrate, calcium chloride or a mixture thereof,

the phosphorus source is any one of phosphoric acid, diammonium hydrogen phosphate and ammonium dihydrogen phosphate or a mixture thereof,

the supporting electrolyte is any one of sodium nitrate, potassium nitrate and potassium sulfate or a mixture of the sodium nitrate, the potassium nitrate and the potassium sulfate.

3. The production method according to any one of claims 1 to 2, wherein in step 1, the pH of the mixed solution is adjusted to 4.0 to 5.5,

the temperature of the mixed solution is kept constant and is 25-70 ℃, and

and mixing the calcium source solution and the phosphorus source solution by stirring, wherein the stirring speed is 100-500r/min, and the stirring process is continued until the electrochemical deposition is finished.

4. The production method according to any one of claims 1 to 3, wherein in step 1, electrochemical deposition is performed using an electrolytic cell and a two-electrode system or a three-electrode system is used,

wherein the current density is 0.5-4mA/cm²The time of electrochemical deposition is 0.5-3 h.

5. The production method according to any one of claims 1 to 4, wherein in step 2,

mixing the ground hydroxyapatite primary product with ultrapure water and an auxiliary agent to prepare slurry with the mass fraction of 20-40 wt%,

the auxiliary agent comprises one or more selected from a wetting agent, an emulsifier, a binder and a pore-forming agent,

the wetting agent is one or more selected from tween, sodium oxalate and cationic polyelectrolyte,

the emulsifier is one or more selected from gelatin, polylactic acid, polyamide and tween,

the binder is one or more selected from polyethylene glycol and polyvinyl alcohol,

the pore-forming agent is one or more selected from carbon powder and polyethylene glycol,

the mass of the wetting agent, the emulsifying agent, the bonding agent and the pore-forming agent is 1-5% of the mass of the slurry.

6. The preparation method according to any one of claims 1 to 5, wherein in step 3, the spraying temperature is 125-500 ℃,

the feeding speed is 10-20ml/min,

the diameter of the nozzle is 0.5-1.4 mm.

7. The production method according to any one of claims 1 to 6, wherein in step 4, the high-temperature calcination is performed using a high-temperature muffle furnace or a rotary tube furnace, and the calcination temperature is 800-1400 ℃.

8. The production method according to any one of claims 1 to 7, wherein in step 5, the screening is performed using a manual classifying screen or a vibratory classifying screen, and the number of screen holes is 180 to 1000.

9. Hydroxyapatite microspheres for injectable filling preparations, prepared by the preparation method according to any one of claims 1 to 8, wherein the particle size distribution of the hydroxyapatite microspheres is in the range of 14 to 85 μm, and the sphericity is in the range of 75 to 95%.

10. The hydroxyapatite microspheres according to claim 9, wherein the particle size distribution of said hydroxyapatite microspheres is in the range of 25 to 45 μm.

Technical Field

The invention relates to cross technologies of chemistry, chemical engineering and process, materials science and biomedicine, in particular to a hydroxyapatite microsphere for injecting a filling preparation and a preparation method thereof, wherein a hydroxyapatite primary product is prepared by an electrochemical deposition method and then the hydroxyapatite microsphere is prepared.

Background

Hydroxyapatite (HAP, Ca)₁₀(OH)₂(PO₄)₆) Also known as calcium hydroxy phosphate, is the major inorganic component of human and other animal bones. The hydroxyapatite directly prepared by a chemical method has the structure and the function similar to human skeletonTherefore, the method is widely applied to the fields of biological materials, pharmacy and medicine, such as the fields of drug sustained release, serum protein separation and the like. In particular, hydroxyapatite is commonly used for autologous bone repair, dental implant coating in dentistry, medical and cosmetic plastic surgery, and the like.

Hydroxyapatite of micron particle size is commonly used as a repair material and structural support material for soft tissue injuries, for example in the preparation of injectable filling formulations. If the particle size of the hydroxyapatite particles is too small, the problem of migration of the hydroxyapatite particles from the injection site to other sites tends to occur. If the particle size is too large, the aggregates that are compounded into a gel may clog the syringe. Therefore, the particle size of the hydroxyapatite is preferably 25 to 45 μm.

In addition, if the hydroxyapatite is of an irregular, non-spherical structure, inflammation and fluid accumulation in the human body may easily occur. Therefore, the sphericity of the hydroxyapatite is required to be as high as possible.

At present, the preparation of hydroxyapatite microspheres with specific particle size distribution and high sphericity becomes an important research object.

The method of making hydroxyapatite microspheres generally comprises: firstly, preparing a submicron/nanoscale hydroxyapatite primary product, then granulating the hydroxyapatite primary product (such as spray drying, microwave treatment, emulsion solvent volatilization treatment and the like), calcining at high temperature and screening to obtain the hydroxyapatite microspheres.

The submicron/nanoscale hydroxyapatite primary product is generally prepared by a wet chemical precipitation method. However, the initial precipitate obtained by wet chemical precipitation contains impurities such as tricalcium phosphate, octacalcium phosphate, etc., and it takes 24-120 hours to age to reach the desired purity of the primary product of hydroxyapatite. That is, this method requires a long aging time and the pH of the solution is too high to facilitate continuous production and environmental protection. In addition, the primary product of the hydroxyapatite prepared is generally flocculent precipitate in the solution, and the shape is irregular, which is not favorable for realizing the requirement of the sphericity of the hydroxyapatite at the later stage.

Therefore, a new method for preparing hydroxyapatite microspheres with improved production efficiency is needed. In addition, the prepared hydroxyapatite microspheres have the properties of optimized particle size, high sphericity and the like.

Disclosure of Invention

Technical problem

An object of the present invention is to provide a method for preparing hydroxyapatite microspheres for injection filling preparations, which can rapidly prepare a large amount of hydroxyapatite primary products without aging for a long time by using an electrochemical deposition method, and the hydroxyapatite microspheres prepared subsequently have desired particle size distribution and high sphericity. Therefore, the production efficiency of the hydroxyapatite microspheres is remarkably improved. In addition, the pH required for preparing the primary product of hydroxyapatite is reduced, reducing environmental pollution and reducing corrosion of the vessel.

It is another object of the present invention to provide hydroxyapatite microspheres for injection filling preparations having a desired particle size distribution and high sphericity.

Technical scheme

According to an aspect of the present invention, there is provided a method for preparing hydroxyapatite microspheres for injection filling preparations, wherein the method comprises:

step 1: respectively preparing a calcium source solution and a phosphorus source solution from a calcium source and a phosphorus source, mixing, adding a supporting electrolyte, adjusting the pH value of the obtained mixed solution to be subacidity, and then carrying out electrochemical deposition to obtain a needle-shaped submicron/nanoscale hydroxyapatite primary product;

step 2: grinding and crushing the primary product of the hydroxyapatite, and preparing into slurry;

and step 3: spray drying the slurry to obtain a hydroxyapatite microsphere crude product;

and 4, step 4: calcining the coarse hydroxyapatite microsphere product at high temperature;

and 5: and screening the calcined hydroxyapatite microsphere crude product to obtain the hydroxyapatite microsphere.

In one embodiment, in step 1, the calcium source is any one of calcium hydroxide, calcium nitrate, calcium chloride or a mixture thereof,

the phosphorus source is any one of phosphoric acid, diammonium hydrogen phosphate and ammonium dihydrogen phosphate or a mixture thereof,

the supporting electrolyte is any one of sodium nitrate, potassium nitrate and potassium sulfate or a mixture of the sodium nitrate, the potassium nitrate and the potassium sulfate.

In one embodiment, in step 1, the pH of the mixed solution is adjusted to 4.0 to 5.5, the temperature of the mixed solution is kept constant and is 25 to 70 ℃, and

and mixing the calcium source solution and the phosphorus source solution by stirring, wherein the stirring speed is 100-500r/min, and the stirring process is continued until the electrochemical deposition is finished.

In one embodiment, in step 1, electrochemical deposition is carried out using an electrolytic cell, and using a two-electrode system or a three-electrode system,

wherein the current density is 0.5-4mA/cm²The time of electrochemical deposition is 0.5-3 h.

In one embodiment, in step 2,

mixing the ground hydroxyapatite primary product with ultrapure water and an auxiliary agent to prepare slurry with the mass fraction of 20-40 wt%,

the auxiliary agent comprises one or more selected from a wetting agent, an emulsifier, a binder and a pore-forming agent,

the wetting agent is one or more selected from tween, sodium oxalate and cationic polyelectrolyte,

the emulsifier is one or more selected from gelatin, polylactic acid, polyamide and tween,

the binder is one or more selected from polyethylene glycol and polyvinyl alcohol,

the pore-forming agent is one or more selected from carbon powder and polyethylene glycol,

the mass of the wetting agent, the emulsifying agent, the bonding agent and the pore-forming agent is 1-5% of the mass of the slurry.

In one embodiment, in step 3, the spray temperature is 125- > 500 deg.C,

the feeding speed is 10-20ml/min,

the diameter of the nozzle is 0.5-1.4 mm.

In one embodiment, in step 4, the high temperature calcination is carried out using a high temperature muffle furnace or a rotary tube furnace at a calcination temperature of 800-.

In one embodiment, in step 5, the screening is performed using a manual sizing screen or a vibratory sizing screen, and the mesh size is 180 to 1000 mesh.

According to another aspect of the invention, hydroxyapatite microspheres for injection filling preparations are provided, which are prepared by the preparation method, wherein the particle size distribution range of the hydroxyapatite microspheres is 14-85 μm, and the sphericity is 75-95%.

In one embodiment, the particle size distribution range of the hydroxyapatite microspheres is 25-45 μm.

Advantageous effects

Compared with the prior art of firstly preparing a hydroxyapatite primary product by a wet chemical precipitation method and then preparing hydroxyapatite microspheres, the invention quickly prepares a needle-shaped submicron/nanometer hydroxyapatite primary product by an electrochemical deposition method, then prepares slurry, and then carries out spray drying, high-temperature calcination and screening to obtain the hydroxyapatite microspheres.

Compared with a wet chemical precipitation method, the electrochemical deposition method of the invention can prepare the primary product of the hydroxyapatite with the same quality and high purity in a very short time without aging, thereby obviously improving the overall production efficiency. In addition, the pH used by the electrochemical deposition method is closer to neutral, and the electrochemical deposition method is more environment-friendly.

In addition, the primary product of the hydroxyapatite prepared by the electrochemical deposition method is a submicron/nanometer needle crystal, has high purity and regular crystal structure, can ensure that the subsequently prepared hydroxyapatite microspheres have higher sphericity and can meet the requirement of customized particle size distribution.

Drawings

The drawings in the present specification show preferred embodiments of the present invention and together with the above summary, serve to further clarify the technical idea of the invention. The invention should not be construed as being limited to what is described in the figures.

FIG. 1 is a scanning electron micrograph (30,000 times) of a submicron/nanoscale hydroxyphosphate primary product prepared according to step 1 of example 1.

Fig. 2 is a scanning electron micrograph (1,000-fold) of hydroxyapatite microspheres prepared according to example 1.

Fig. 3 is a scanning electron micrograph (1,000 fold) of hydroxyapatite microspheres prepared according to example 2.

Fig. 4 is a scanning electron micrograph (1,000-fold) of hydroxyapatite microspheres prepared according to comparative example 1.

Detailed Description

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings. The terms or words used in the present specification and claims should not be construed restrictively as general or dictionary definitions, and should be construed as meanings and concepts corresponding to technical ideas of the present invention on the basis of the principle that the inventor can appropriately define concepts of the terms to describe the invention in the best possible manner.

As used herein, "%" means weight percent unless otherwise specified. In addition, detailed descriptions of processes and components well known in the art will be omitted.

1. Preparation method of hydroxyapatite microspheres for injection filling preparation

According to one aspect of the present invention, there is provided a method for preparing hydroxyapatite microspheres for injection filling preparations, the method comprising the following steps.

Step 1: preparation of primary hydroxyapatite product

Respectively preparing a calcium source solution and a phosphorus source solution from a calcium source and a phosphorus source, mixing, adding a supporting electrolyte, adjusting the pH value of the obtained mixed solution to be subacidity, and then carrying out electrochemical deposition to obtain a needle-shaped submicron/nanoscale hydroxyapatite primary product.

The calcium source may for example be any one of calcium hydroxide, calcium nitrate, calcium chloride or a mixture thereof, preferably calcium nitrate.

The source of phosphorus may be, for example, any of phosphoric acid, diammonium phosphate, ammonium dihydrogen phosphate, or a mixture thereof, with ammonium dihydrogen phosphate being preferred.

The supporting electrolyte may be, for example, any one of sodium nitrate, potassium sulfate or a mixture thereof, preferably sodium nitrate.

The calcium source and the phosphorus source are used to provide calcium ions and phosphate ions in the electrolyte, whereby when electrochemical deposition is performed, the local hydroxide concentration in the cathode region increases, and precipitates of hydroxyapatite are generated in the cathode region.

The supporting electrolyte is used for enhancing the conductivity of the solution on the premise of not generating side reaction.

The pH of the mixed solution may be adjusted using nitric acid, phosphoric acid, ammonia water, or the like, and may be adjusted to be slightly acidic, for example, pH 4.0 to 5.5. The slightly acidic pH is used for preventing unnecessary precipitation by-products from being generated in a pH range of more than 6.5, but the excessively low pH is likely to cause a strong hydrogen evolution side reaction and inhibit the generation of hydroxyapatite.

The temperature of the solution is kept constant by means of a water bath and may be, for example, 25 to 70 ℃, preferably 30 to 65 ℃, more preferably 60 ℃. When the temperature is too low, the rate of product formation in the electrodeposition step is affected. When the temperature is too high, although the deposition rate is increased, the solubility of hydroxyapatite, the pH of the solution, and a safety hazard are affected to some extent.

In one embodiment, the calcium source solution and the phosphorus source solution are mixed in the electrolytic cell with stirring, which may be at a rate of 100-500 r/min. When the stirring speed is too low, hydroxyapatite generated on the surface of the electrode is not easy to fall off; when the stirring rate is too high, the mass transfer current due to the hydrogen evolution reaction is promoted, the side reaction is enhanced, and the solution is liable to splash. The stirring process may continue until the end of the electrochemical deposition.

In the electrochemical deposition process, electrochemical deposition may be performed using an electrolytic cell, and a two-electrode system or a three-electrode system may be used. The anode and cathode materials may be conventional electrodes known in the art.

For example, in the two-electrode system, the anode may be a platinum sheet, a titanium sheet, or DSA, and the cathode may be a stainless steel sheet, a titanium mesh, or a titanium-based titanium dioxide electrode. Among them, titanium mesh is preferably used as a cathode because it has a large specific surface area and can deposit a large amount of hydroxyapatite.

In the three-electrode system, the anode and the cathode may be the same as described above, respectively, and the reference electrode may be a saturated calomel electrode.

The current density of the electrochemical deposition can be 0.5-4mA/cm². When the current density is too high, serious hydrogen evolution side reaction can occur, and the current efficiency is greatly reduced; when the current density is too low, the rate of the electrodeposition step is slow, and the production efficiency is lowered.

The time of the electrochemical deposition may be 0.5-3h, preferably 1-3h, more preferably 2-2.5 h. When the time is too short, the total amount of the product is insufficient; when the time is too long, the pH of the solution may change significantly, causing unwanted precipitation of calcium phosphate impurities.

The solid sediment can be obtained through electrochemical deposition, and is a needle-shaped submicron/nanometer hydroxyapatite primary product in a powder shape. It may be further filtered, washed, and dried for subsequent operations.

Step 2: preparation of slurry

Grinding and crushing the primary product of the hydroxyapatite obtained in the step (1) to enable the primary product to have better fluidity, and then preparing into slurry.

The grinding and pulverization can be carried out using an apparatus commonly used in the art such as a mortar, a ball mill, etc.

A solvent such as ultrapure water or deionized water may be used, and strong stirring may be applied to obtain a slurry. The resulting slurry may typically be a 20-40 wt% suspension of the primary product of hydroxyapatite. When the concentration is too high, slurry cannot be formed into balls through spray drying; when the concentration is too low, the particle diameter after spray drying becomes too small.

The addition agent can be added into the slurry with the mass fraction of 1-5% based on the total mass of the slurry. The auxiliary agents may be, for example, wetting agents, binders, pore formers, emulsifiers.

The wetting agent may for example be tween, sodium oxalate, a cationic polyelectrolyte, preferably sodium oxalate. The wetting agent is used for enhancing the wetting action between the primary product of hydroxyapatite and water, so that other auxiliary agents can be better mixed with the primary product of hydroxyapatite.

The binder may for example be polyethylene glycol, polyvinyl alcohol, preferably polyethylene glycol. The binder is used for increasing the balling rate of spray drying and the sphericity of the microspheres.

The pore former may be, for example, carbon powder, polyethylene glycol, preferably polyethylene glycol. During the subsequent calcination process, the pore-forming agent can generate gaseous products to diffuse and escape, so that the porosity of the microspheres can be regulated and controlled.

The emulsifier can be gelatin, polylactic acid, polyamide, tween, preferably gelatin, polylactic acid. The emulsifier is used for improving the surface tension in turbid liquid and enabling the turbid liquid to form a uniform and stable dispersion system.

And step 3: spray drying

And carrying out spray drying on the slurry to carry out granulation, thereby obtaining a hydroxyapatite microsphere crude product.

The spray drying may be carried out using a conventional spray dryer. The spraying temperature may be 125-500 deg.C, preferably 200-300 deg.C. When the temperature is too low, the instantaneous nucleation rate decreases, the number of nucleation decreases, and the particle diameter of the resulting fine particles increases. When the temperature is too high, particle agglomeration is liable to occur, and thus the particle diameter of the particles is increased.

The feed rate of the slurry may be in the range of 10 to 20 ml/min. When the feed rate is too low, the yield is reduced and the particle size of the product is smaller. When the feed rate is too high, the amount of undried liquid increases and the particle size becomes larger.

The nozzle diameter may be 0.5-1.4 mm. When the diameter of the nozzle outlet is too large, the obtained particle size is small, and the problem that hydroxyapatite particles are easy to migrate from an injection part to other parts is likely to occur subsequently. When the diameter of the nozzle outlet is too large, the obtained particle size is too large, the filling rate of the compounded gel is reduced, and the in-vivo degradation time is prolonged.

And 4, step 4: high temperature calcination

And (4) calcining the hydroxyapatite microsphere crude product obtained in the step (3) at a high temperature. The high temperature calcination may be performed using a high temperature muffle furnace or a rotary tube furnace.

The high-temperature calcination temperature can be 800-1400 ℃, preferably 900-1100 ℃, so as to enhance the ceramic degree of the material on the premise of ensuring that the hydroxyapatite is not decomposed. If the temperature is too low, the ceramic degree cannot be enhanced; if the temperature is too high, decomposition of hydroxyapatite may result.

The high-temperature calcination time can be 0.5-2h, so as to obtain hydroxyapatite microspheres with stable properties. If the time is too short, the ceramic is not completely formed; if the time is too long, the production cost is excessively increased.

And 5: sieving

And (4) screening the calcined hydroxyapatite microsphere crude product obtained in the step (4). The screening may be performed using a hand screen or a vibratory classifying screen.

The mesh number of the screen can be 180 meshes and 1000 meshes. When the mesh number is 1000 mesh, the corresponding particle size is about 14 μm, which can screen out microspheres with too small particle size or hydroxyapatite fragments without balling. When the mesh number is 180 meshes, the corresponding particle size is about 85 μm, and the aim is to screen out a small amount of microspheres with excessive particle size or non-spherical agglomerates in the product.

Preferably, the hydroxyapatite microspheres with a particle size distribution of 25-45 μm can be obtained by sieving with a sieve with 325 mesh and 550 mesh for injection filling preparation.

2. Hydroxyapatite microspheres for injection fill formulations

According to another aspect of the invention, hydroxyapatite microspheres for injection filling preparations are provided, which are prepared by the preparation method, wherein the particle size distribution range of the hydroxyapatite microspheres is 14-85 μm, preferably 25-45 μm. In addition, the sphericity of the hydroxyapatite microspheres is 75-95%.

The particle size of the hydroxyapatite microspheres may be measured using equipment commonly used in the art, such as a particle size analyzer or a scanning electron microscope.

The sphericity of the hydroxyapatite microspheres may be measured using equipment and methods commonly used in the art. For example, using a scanning electron microscope and corresponding image processing software, by measuring the average surface area and average perimeter of the microspheres, respectively, is calculated by the following formula:

wherein S is sphericity (%); a is the average surface area (mm) of the microspheres as measured by the software²) And C is the average circumference (mm) of the microspheres as measured by the software.

The hydroxyapatite microspheres of the invention can fully meet the requirement of customized particle size distribution and have the characteristic of high sphericity.

Examples

Hereinafter, the present invention will be described in detail with reference to examples to specifically describe the present invention. However, the embodiment of the present invention may be modified into various other forms and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided to more fully describe the present invention to those of ordinary skill in the art.

The experimental procedures in the following examples are generally conventional in the art or according to the manufacturer's recommendations if specific conditions are not noted; the raw materials and equipment used are those commercially available from conventional markets and the like unless otherwise specified.

Example 1

Hydroxyapatite microspheres for injection filled formulations were prepared by the following procedure.

Step 1: preparation of primary hydroxyapatite product

50ml each of 0.5M calcium nitrate solution (as a calcium source) and 0.3M diammonium phosphate solution (as a phosphorus source) were prepared.

50ml of calcium nitrate solution was placed in an electrolytic cell and then 10ml/min of diammonium phosphate solution was added dropwise to the calcium nitrate solution with stirring at a speed of 200 r/min. Then an amount of solid sodium nitrate (as supporting electrolyte) was added so that the concentration of sodium nitrate was 0.1M. Then, the pH was adjusted to 4.5 using nitric acid and aqueous ammonia. Then, the temperature of the electrolytic bath and the solution therein was maintained at 60 ℃ by means of a water bath

Subsequently, electrochemical deposition is performed. The electrochemical deposition is constant current deposition with a current density of 2mA/cm²The deposition time was 2.5 h. The electrochemical deposition adopts a two-electrode system, a 15mm by 15mm platinum sheet is selected as an anode, and five titanium nets which are connected in series and have the thickness of 15mm by 15mm are selected as a cathode.

After electrochemical deposition, needle-like hydroxyapatite deposition layers are formed on the titanium mesh, and a small amount of falling hydroxyapatite also exists in the solution. Scraping the titanium mesh, and filtering hydroxyapatite in the solution. The two were combined and then washed three times with 20ml portions of ultra pure water. The obtained solid is dried in a 60 ℃ oven for 2 hours, and 12g of needle-shaped submicron/nanometer hydroxyapatite primary product is obtained by weighing.

Step 2: preparation of slurry

Grinding and crushing the obtained needle-shaped submicron/nanometer hydroxyapatite primary product by using a mortar. 12g of ground hydroxyapatite primary product, 28g of ultrapure water, are added to a beaker and subjected to vigorous stirring to obtain a hydroxyapatite slurry with a mass fraction of 30% by weight in the form of a suspension.

And step 3: spray drying

And (3) carrying out spray drying granulation on the hydroxyapatite slurry by using a spray dryer, wherein the spraying temperature is 200 ℃, the feeding speed is 10ml/min, and the diameter of a nozzle is 0.7 mm. Obtaining a hydroxyapatite microsphere crude product.

And 4, step 4: high temperature calcination

And (3) calcining the coarse hydroxyapatite microspheres at high temperature in a rotary tube furnace at 1100 ℃ for 60 min.

And 5: sieving

And (3) sieving the calcined hydroxyapatite microsphere crude product by using a 325-mesh and 500-mesh sieve in a grading manner to obtain the hydroxyapatite microspheres with the particle size distribution of 25-45 mu m.

Example 2

Hydroxyapatite microspheres for injection filled formulations were prepared by the following procedure.

Step 1: preparation of primary hydroxyapatite product

Same as in step 1 of example 1.

Step 2: preparation of slurry

Grinding and crushing the obtained needle-shaped submicron/nanometer hydroxyapatite primary product by using a mortar. 12g of a hydroxyapatite primary product and 28g of ultrapure water were added to a beaker, and strong stirring was applied to obtain a hydroxyapatite suspension having a mass fraction of 30 wt%.

Heating the suspension to 60 ℃ by using a water bath, and adding a wetting agent sodium oxalate which accounts for 1 wt% of the mass of the suspension and a binding agent polyethylene glycol which accounts for 1 wt% of the mass of the suspension. And stirring uniformly to obtain hydroxyapatite slurry.

Step 3 to step 5

The procedure is the same as in steps 3 to 5 of example 1.

Comparative example 1

Step 1: preparation of primary hydroxyapatite product

The primary product of hydroxyapatite is prepared by a wet chemical precipitation method. Specifically, 0.5M calcium nitrate and 50mL each of 0.3M ammonium dihydrogen phosphate were mixed uniformly, and the pH was adjusted to 10.5, followed by stirring in a water bath at 60 ℃ for 1 hour. Then aged at 37 ℃ for 120h to obtain flocculent precipitate. Similarly to example 1, it was filtered, washed and dried to obtain 12g of primary product of hydroxyapatite.

Step 2 to step 5

The procedure is the same as in steps 2 to 5 of example 1.

Experimental example 1 surface morphology observation of hydroxyapatite Primary product and hydroxyapatite microspheres

The primary product of acicular submicron/nanoscale hydroxyapatite obtained in step 1 of example 1 was observed for surface morphology by scanning electron microscope, and the results are shown in fig. 1. As can be seen from FIG. 1, the primary product of the hydroxyapatite is very regular in shape and is needle-shaped crystal, which is beneficial to preparing microspheres with improved sphericity, mechanical properties and the like in the later stage.

The hydroxyapatite microspheres obtained in example 1, example 2 and comparative example 1 were observed for surface morphology by a scanning electron microscope, and fig. 2, fig. 3 and fig. 4 were obtained, respectively. As can be seen from FIGS. 2 to 4, hydroxyapatite microspheres with a particle size distribution of 25 to 45 μm were obtained in each of examples 1 and 2 and comparative example 1.

Experimental example 2 sphericity measurement of hydroxyapatite microspheres

The average circumference and the average area of the hydroxyapatite microspheres obtained in example 1, example 2 and comparative example 1 were measured using image-pro plus software (version number 6.0.0.260for Windows 2000/XP Professional) of Media Cybernetics, respectively, and the sphericity was calculated using the following formulas:

wherein S is sphericity (%); a is the average surface area (mm) of the microspheres as measured by the software²) And C is the average circumference (mm) of the microspheres as measured by the software. The results are shown in table 1 below.

TABLE 1

	Sphericity of microsphere (%)
		Example 1	82.4
Example 2	85.0
		Comparative example	67.3

As can be seen from table 1, the microspheres of example 1 are significantly superior to those of comparative example 1 in terms of sphericity, and thus the microspheres of example 1 are more suitable for use in the preparation of injectable filling formulations. It is thus confirmed that the primary product of acicular hydroxyapatite prepared by electrochemical deposition according to the present invention can improve the sphericity of the finally obtained hydroxyapatite microspheres.

In addition, the microspheres of example 2 are superior to the microspheres of example 1 in terms of sphericity. It can be seen that by adding an auxiliary agent in step 2 to formulate a slurry, the sphericity of the finally obtained microspheres can be improved.

Experimental example 3 comparison of production efficiency

The time for forming the hydroxyapatite precipitate in step 1 of example 1 and the time for forming the hydroxyapatite precipitate in step 1 of comparative example 1 are summarized as the following table 2.

TABLE 2

As can be seen from table 2 above, the time for forming hydroxyapatite precipitates in step 1 of example 1 is significantly less than the time for forming hydroxyapatite precipitates in step 1 of comparative example 1. It was thus confirmed that the production efficiency of example 1 was significantly higher than that of comparative example 1.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.