CN112875665B - Hydroxyapatite microspheres for injection filling preparation and preparation method thereof - Google Patents

Abstract

The present invention relates to hydroxyapatite microspheres for injection filling preparations and a preparation method thereof. The preparation method includes: step 1: respectively preparing calcium source solution and phosphorus source solution into calcium source solution and phosphorus source solution and mixing, adding supporting electrolyte to them, adjusting the pH of the obtained mixed solution to be slightly acidic, and then carrying out electrochemical deposition to obtain a needle-shaped submicron/nano-scale hydroxyapatite primary product; step 2: grinding and pulverizing the hydroxyapatite primary product, and then preparing a slurry; step 3: spray-drying the slurry to obtain crude hydroxyapatite microspheres; step 4: calcining the crude hydroxyapatite microspheres at high temperature; step 5: sieving the calcined crude hydroxyapatite microspheres to obtain the hydroxyapatite microspheres limestone microspheres. The preparation method of the present invention significantly improves the production efficiency. The prepared hydroxyapatite microspheres have the desired particle size distribution and high sphericity.

Description

Hydroxyapatite microspheres for injection filling preparations and preparation method thereof

technical field

The present invention relates to chemistry, chemical engineering and technology, materials science and biomedical interdisciplinary technology, in particular, to a hydroxyapatite microsphere used for injection filling preparations and a preparation method thereof, wherein the hydroxyapatite microspheres are prepared by electrochemical deposition The primary product of limestone is then prepared to obtain hydroxyapatite microspheres.

Background technique

Hydroxyapatite (HAP, Ca ₁₀ (OH) ₂ (PO ₄ ) ₆ ), also known as calcium hydroxyphosphate, is the main inorganic component of human and other animal bones. Hydroxyapatite directly prepared by chemical methods has a structure and function similar to that of human bone, so it is widely used in the fields of biomaterials, pharmacy and medicine, such as drug sustained release, serum protein separation and other fields. In particular, hydroxyapatite is often used in the restoration of autogenous bone, the coating of dental implants in stomatology, and medical plastic surgery.

Micron-sized hydroxyapatite is commonly used as a repair material and structural support material for soft tissue injuries, for example for the preparation of injectable filling preparations. If the particle size of the hydroxyapatite particles is too small, the problem of the migration of the hydroxyapatite particles from the injection site to other sites easily occurs. If the particle size is too large, aggregates that reconstitute into a gel can clog the syringe. Therefore, the particle diameter of hydroxyapatite is preferably 25 to 45 μm.

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

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

The method for preparing hydroxyapatite microspheres usually includes: firstly preparing the primary product of submicron/nanometer hydroxyapatite, and then granulating the primary product of hydroxyapatite (such as spray drying, microwave treatment, emulsion solvent volatilization treatment, etc. ), calcined at high temperature, and sieved to obtain hydroxyapatite microspheres.

Submicron/nanoscale hydroxyapatite primary products are generally prepared by wet chemical precipitation. However, the initial precipitate obtained by wet chemical precipitation contains impurities such as tricalcium phosphate and octacalcium phosphate, and requires 24-120 hours of aging to achieve the required purity of the primary product of hydroxyapatite. That is to say, the aging time required by this method is long, and the pH of the solution is too high, which is unfavorable for continuous production and environmental protection. In addition, the prepared primary product of hydroxyapatite is generally a flocculent precipitate in the solution with an irregular shape, which is not conducive to achieving the sphericity requirement of the later stage hydroxyapatite.

Therefore, there is a need for a new method of preparing hydroxyapatite microspheres with improved production efficiency. In addition, the prepared hydroxyapatite microspheres are required to have properties such as optimized particle size and high sphericity.

Contents of the invention

technical problem

One object of the present invention is to provide a method for preparing hydroxyapatite microspheres used for injection filling preparations. The preparation method of the present invention can quickly produce a large amount of hydroxyl apatite microspheres without long-term aging The primary product of apatite, and the subsequently prepared hydroxyapatite microspheres have the desired particle size distribution and high sphericity. Thus, the production efficiency of hydroxyapatite microspheres is significantly improved. In addition, the pH required for the production of primary hydroxyapatite products is lowered, reducing environmental pollution and reducing corrosion to containers.

Another object of the present invention is to provide hydroxyapatite microspheres for injectable filling formulations, which have desired particle size distribution and high sphericity.

Technical solutions

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

Step 1: Calcium source and phosphorus source are formulated into calcium source solution and phosphorus source solution respectively and mixed, adding supporting electrolyte to it, adjusting the pH of the obtained mixed solution to be slightly acidic, and then performing electrochemical deposition to obtain acicular sub Micro/nano hydroxyapatite primary product;

Step 2: Grinding and pulverizing the primary product of hydroxyapatite, and then preparing a slurry;

Step 3: spray drying the slurry to obtain crude hydroxyapatite microspheres;

Step 4: Calcining the crude hydroxyapatite microspheres at high temperature;

Step 5: Sieve the calcined crude hydroxyapatite microspheres to obtain the hydroxyapatite microspheres.

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, ammonium dihydrogen phosphate or a mixture thereof,

The supporting electrolyte is any one of sodium nitrate, potassium nitrate, potassium sulfate or a mixture thereof.

In one embodiment, in step 1, the pH of the mixed solution is adjusted to 4.0-5.5, and the temperature of the mixed solution is kept constant at 25-70° C., and

The calcium source solution and the phosphorus source solution are mixed by stirring at a stirring rate of 100-500 r/min, and the stirring process is continued until the end of the electrochemical deposition.

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

Wherein the current density is 0.5-4mA/cm ² , and the electrochemical deposition time is 0.5-3h.

In one embodiment, in step 2,

mixing the ground and pulverized hydroxyapatite primary product with ultrapure water and additives to prepare a slurry with a mass fraction of 20-40wt%,

The auxiliary agent comprises one or more selected from wetting agents, emulsifiers, binders and pore-forming agents,

The wetting agent is one or more selected from Tween, sodium oxalate, cationic polyelectrolyte,

The emulsifier is one or more selected from gelatin, polylactic acid, polyamide, Tween,

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

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

The respective mass of the wetting agent, emulsifier, binder and pore-forming agent is 1-5% of the mass of the slurry.

In one embodiment, in step 3, the spray temperature is 125-500°C,

The feed rate is 10-20ml/min,

The nozzle diameter is 0.5-1.4mm.

In one embodiment, 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° C.

In one embodiment, in step 5, a manual grading sieve or a vibrating grading sieve is used for sieving, and the mesh size of the sieve is 180 mesh to 1000 mesh.

According to another aspect of the present invention, there is provided a kind of hydroxyapatite microspheres for injection filling preparation, which is prepared by the above preparation method, wherein the particle size distribution range of the hydroxyapatite microspheres is 14-85 μm , The sphericity is 75-95%.

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

Beneficial effect

Compared with the prior art of firstly preparing the primary product of hydroxyapatite by wet chemical precipitation, and then preparing hydroxyapatite microspheres, the present invention rapidly prepares acicular submicron/nano-sized hydroxyapatite by electrochemical deposition The primary product is then formulated into a slurry, followed by spray drying, high-temperature calcination, and sieving to obtain hydroxyapatite microspheres.

Compared with the wet chemical precipitation method, the electrochemical deposition method of the present invention does not need to be aged, and the same quality high-purity hydroxyapatite primary product can be prepared in a very short time, which significantly improves the overall production efficiency. In addition, the pH used in the electrochemical deposition method of the present invention is closer to neutral and more friendly to the environment.

In addition, the primary product of hydroxyapatite prepared by the electrochemical deposition method of the present invention is submicron/nano-sized needle-like crystals with high purity and regular crystal structure, which can make the hydroxyapatite microspheres prepared subsequently have more High sphericity, and can meet customized particle size distribution requirements.

Description of drawings

The accompanying drawings of this specification show preferred embodiments of the present invention, and are used together with the above-mentioned summary of the invention to further clarify the technical concept of the present invention. The present invention should not be construed as being limited to what is depicted in the drawings.

FIG. 1 is a scanning electron micrograph (30,000 times) of the primary product of submicron/nano-scale hydroxyphosphate prepared according to step 1 of Example 1.

2 is a scanning electron micrograph (1,000 times) of the hydroxyapatite microspheres prepared according to Example 1.

3 is a scanning electron micrograph (1,000 times) of the hydroxyapatite microspheres prepared according to Example 2.

FIG. 4 is a scanning electron micrograph (1,000 times) of the hydroxyapatite microspheres prepared according to Comparative Example 1. FIG.

Detailed ways

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings. The terms or words used in this specification and claims should not be construed restrictively as common or dictionary definitions, and should be used when the inventor can properly define the concepts of the terms so as to describe the principles of the invention in the best possible way The meaning and concept corresponding to the technical thought of the present invention are interpreted on the basis of the present invention.

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

1. Preparation of Hydroxyapatite Microspheres for Injectable Filling Formulations

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

Step 1: Preparation of hydroxyapatite primary product

Calcium source and phosphorus source are respectively prepared into calcium source solution and phosphorus source solution and mixed, adding supporting electrolyte to it, adjusting the pH of the resulting mixed solution to be slightly acidic, and then performing electrochemical deposition to obtain needle-shaped submicron/nano grade hydroxyapatite primary product.

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

The phosphorus source can be, for example, any one of phosphoric acid, diammonium hydrogen phosphate, ammonium dihydrogen phosphate or a mixture thereof, preferably ammonium dihydrogen phosphate.

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

The calcium source and phosphorus source are used to provide calcium ions and phosphate ions in the electrolyte, so that when electrochemical deposition is performed, the local hydroxide concentration in the cathode area increases, and the precipitation of hydroxyapatite occurs in the cathode area things.

The supporting electrolyte is used to enhance the conductivity of the solution without causing side reactions.

Nitric acid, phosphoric acid, ammonia water, etc. can be used to adjust the pH of the mixed solution, which can be adjusted to slightly acidic, such as pH 4.0-5.5. The slightly acidic pH is used to prevent unnecessary precipitation by-products in the pH range greater than 6.5, but too low a pH can easily cause strong hydrogen evolution side reactions and inhibit the formation of hydroxyapatite.

The temperature of the solution is kept constant by a water bath, such as 25-70°C, preferably 30-65°C, more preferably 60°C. When the temperature is too low, the rate of product formation in the electrodeposition step will be affected. When the temperature is too high, although the deposition rate will be increased, it will affect the solubility of hydroxyapatite, the pH of the solution and cause safety hazards to a certain extent.

In one embodiment, the calcium source solution and the phosphorus source solution are mixed in the electrolytic cell under stirring, and the stirring rate may be 100-500 r/min. When the stirring rate is too low, the hydroxyapatite formed on the electrode surface is not easy to fall off; when the stirring rate is too high, the mass transfer current caused by the hydrogen evolution reaction is promoted, the side reaction is enhanced, and solution splashing is prone to occur. The stirring process can continue until the end of electrochemical deposition.

In the electrochemical deposition process, an electrolytic cell may be used for electrochemical deposition, and a two-electrode system or a three-electrode system may be used. Anode and cathode materials can be common electrodes known in the art.

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

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

The current density of the electrochemical deposition can be 0.5-4 mA/cm ² . When the current density is too high, serious hydrogen evolution side reactions will occur, which greatly reduces the current efficiency; when the current density is too low, the electrodeposition step rate will be slow and the production efficiency will be reduced.

The time of electrochemical deposition can be 0.5-3h, preferably 1-3h, more preferably 2-2.5h. When the time is too short, the total amount of the product will be insufficient; when the time is too long, the pH of the solution will change significantly, resulting in unnecessary calcium phosphate impurity precipitation.

The solid deposit can be obtained by electrochemical deposition, which is the primary product of acicular submicron/nanoscale hydroxyapatite in the form of powder. It can be further filtered, washed and dried for subsequent operations.

Step 2: Slurry preparation

The primary product of hydroxyapatite obtained in step (1) is ground and pulverized to make it have better fluidity, and then prepared into a slurry.

Grinding and pulverization can be carried out using equipment commonly used in this field, such as a mortar, a ball mill, and the like.

A solvent such as ultrapure water, deionized water, etc. may be used, and a slurry may be obtained by applying strong stirring. The resulting slurry may typically be a 20-40 wt% suspension of hydroxyapatite primary product. When the concentration is too high, the slurry cannot be spray-dried into balls; when the concentration is too low, the particle size after spray-drying will be too small.

Based on the total mass of the slurry, 1-5% of additives can be added to the slurry. The auxiliaries can be, for example, wetting agents, binders, pore formers, emulsifiers.

The wetting agent may eg be Tween, sodium oxalate, a cationic polyelectrolyte, preferably sodium oxalate. The wetting agent is used to enhance the wetting effect between the primary product of hydroxyapatite and water, so that other additives 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 to increase the spheroidization rate of spray drying and the sphericity of microspheres.

The pore forming agent can be, for example, carbon powder, polyethylene glycol, preferably polyethylene glycol. In the subsequent calcination process, the pore former can generate gaseous products to diffuse and escape, thereby regulating the porosity of the microspheres.

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

Step 3: Spray drying

The slurry is spray-dried for granulation, so as to obtain crude hydroxyapatite microspheres.

Spray drying can be carried out using conventional spray dryers. The spraying temperature may be 125-500°C, preferably 200-300°C. When the temperature is too low, the instantaneous nucleation speed decreases, the number of nucleation decreases, and the particle size of the obtained particles increases. When the temperature is too high, the particles are prone to agglomeration, so that the particle size increases instead.

The feed rate of the slurry can be 10-20ml/min. When the feed rate is too low, the output decreases and the particle size of the product is too small. When the feed rate is too high, the amount of undried liquid increases and the particle size becomes larger.

The nozzle diameter can be 0.5-1.4mm. When the diameter of the nozzle outlet is too large, the obtained particle size is too small, and the subsequent migration of hydroxyapatite particles from the injection site to other parts is easy to occur. When the nozzle outlet diameter is too large, the obtained particle size is too large, which will reduce the filling rate of the gel after compounding and prolong the degradation time in vivo.

Step 4: High temperature calcination

Calcining the crude hydroxyapatite microspheres obtained in 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 temperature of the high-temperature calcination can be 800-1400°C, preferably 900-1100°C, the purpose of which is to enhance the degree of ceramicization of the material on the premise of ensuring that the hydroxyapatite does not decompose. If the temperature is too low, the degree of ceramization cannot be enhanced; if the temperature is too high, it will cause the decomposition of hydroxyapatite.

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

Step 5: Sieving

The calcined crude hydroxyapatite microspheres obtained in step 4 are sieved. The sieving can be performed using a hand sieve or a vibrating classifying sieve.

The screen mesh can be 180-1000 mesh. 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 unspherical hydroxyapatite debris. When the mesh number is 180 mesh, the corresponding particle size is about 85 μm. The purpose is to sieve out a small amount of microspheres with too large particle size or agglomerates without balls in the product.

Preferably, sieves with 325 mesh and 550 mesh can be used to sieve to obtain hydroxyapatite microspheres with a particle size distribution of 25-45 μm, which are used for the preparation of injection filling preparations.

2. Hydroxyapatite Microspheres for Injectable Filler Formulations

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

The particle size of the hydroxyapatite microspheres can be measured using equipment commonly used in the art (eg, particle size analyzer or scanning electron microscope).

The sphericity of hydroxyapatite microspheres can 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 the average perimeter of the microspheres respectively, it is calculated by the following formula:

In the formula, S is the sphericity (%); A is the average surface area of the microspheres (mm ² ) measured by the software, and C is the average circumference of the microspheres (mm) measured by the software.

The hydroxyapatite microspheres of the present invention can fully meet the requirements of customized particle size distribution, and have the characteristics of high sphericity.

Example

Hereinafter, the present invention will be described in detail with reference to Examples to specifically describe the present invention. However, the embodiments 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. The embodiments of the present invention are provided so as to more fully describe the present invention to those skilled in the art.

If the experimental methods in the following examples do not indicate specific conditions, they are usually the conventional conditions in this field or the conditions suggested by the manufacturer; the raw materials and equipment used, if no special instructions, are available from commercial channels such as the conventional market Raw materials and equipment obtained.

Example 1

Hydroxyapatite microspheres for injectable fill formulations were prepared as follows.

Step 1: Preparation of hydroxyapatite primary product

Prepare 50 ml each of 0.5 M calcium nitrate solution (as calcium source) and 0.3 M diammonium hydrogen phosphate solution (as phosphorus source).

50ml of calcium nitrate solution was placed in the electrolytic cell, and then the diammonium hydrogen phosphate solution was dropped into the calcium nitrate solution at a speed of 10ml/min under the condition of stirring at a rotating speed of 200r/min. Then add a certain amount of solid sodium nitrate (as a supporting electrolyte) so that the concentration of sodium nitrate is 0.1M. Then, the pH was adjusted to 4.5 using nitric acid and ammonia water. Next, the temperature of the electrolytic cell and the solution therein is maintained at 60°C by a water bath

Next, electrochemical deposition is performed. The electrochemical deposition is a constant current deposition with a current density of 2 mA/cm ² and a deposition time of 2.5 h. The electrochemical deposition adopts a two-electrode system, a 15mm*15mm platinum sheet is used as the anode, and five 15mm*15mm titanium meshes connected in series are used as the cathode.

After electrochemical deposition, a needle-shaped hydroxyapatite deposition layer is formed on the titanium mesh, and a small amount of detached hydroxyapatite also exists in the solution. The titanium mesh is scraped and the hydroxyapatite in the solution is filtered. The two were combined, and then washed three times with 20 ml of ultrapure water each time. The obtained solid was dried in an oven at 60° C. for 2 hours, and 12 g of needle-shaped submicron/nano-sized hydroxyapatite primary products were obtained by weighing.

Step 2: Slurry preparation

The obtained acicular submicron/nanoscale hydroxyapatite primary product was pulverized with a mortar. Add 12g of ground hydroxyapatite primary product and 28g of ultrapure water into a beaker, and apply strong stirring to obtain a hydroxyapatite slurry with a mass fraction of 30wt%, which is in the form of a suspension.

Step 3: Spray drying

The hydroxyapatite slurry was spray-dried and granulated using a spray dryer, with a spray temperature of 200° C., a feed rate of 10 ml/min, and a nozzle diameter of 0.7 mm. The crude product of hydroxyapatite microspheres was obtained.

Step 4: High temperature calcination

The crude hydroxyapatite microspheres were calcined at a high temperature, and the calcining process was carried out in a rotary tube furnace at a calcining temperature of 1100° C. for 60 min.

Step 5: Sieving

The calcined crude hydroxyapatite microspheres are classified and screened with 325-mesh and 500-mesh sieves to obtain hydroxyapatite microspheres with a particle size distribution of 25-45 μm.

Example 2

Hydroxyapatite microspheres for injectable fill formulations were prepared as follows.

Step 1: Preparation of hydroxyapatite primary product

Same as Step 1 of Example 1.

Step 2: Slurry preparation

The obtained acicular submicron/nanoscale hydroxyapatite primary product was pulverized with a mortar. Add 12g of hydroxyapatite primary product and 28g of ultrapure water into a beaker, and apply strong stirring to obtain a hydroxyapatite suspension with a mass fraction of 30wt%.

The suspension was heated to 60° C. with a water bath, and a wetting agent sodium oxalate corresponding to 1 wt % of the suspension mass, and a binder polyethylene glycol corresponding to 1 wt % of the suspension mass were added. After uniform stirring, the hydroxyapatite slurry is obtained.

Step 3~5

Same as Steps 3-5 of Example 1.

Comparative example 1

Step 1: Preparation of hydroxyapatite primary product

Hydroxyapatite primary product was prepared by wet chemical precipitation. Specifically, 50 mL of 0.5 M calcium nitrate and 0.3 M ammonium dihydrogen phosphate were mixed uniformly, and the pH was adjusted to 10.5, and stirred in a water bath at 60° C. for 1 h. Then aged at 37°C for 120h to obtain a flocculent precipitate. Similar to Example 1, it was filtered, washed, and dried to obtain 12 g of the primary product of hydroxyapatite.

Step 2~5

Same as Steps 2-5 of Example 1.

Experimental example 1 Observation of the surface morphology of the primary product of hydroxyapatite and hydroxyapatite microspheres

The surface morphology of the acicular submicron/nanoscale hydroxyapatite primary product obtained in step 1 of Example 1 was observed with a scanning electron microscope, and the results are shown in FIG. 1 . It can be seen from Figure 1 that the obtained primary product of hydroxyapatite has a regular shape and is needle-like crystals, which is conducive to the preparation of microspheres with improved sphericity and mechanical properties in the later stage.

The surface morphology of the hydroxyapatite microspheres obtained in Example 1, Example 2 and Comparative Example 1 was observed with a scanning electron microscope, and Figures 2, 3 and 4 were obtained respectively. It can be seen from Figures 2 to 4 that in Example 1, Example 2 and Comparative Example 1, hydroxyapatite microspheres with a particle size distribution of 25-45 μm were obtained.

Experimental Example 2 Sphericity Measurement of Hydroxyapatite Microspheres

Use the image-pro plus software (version number 6.0.0.260forWindows 2000/XP Professional) of Media Cybernetics company to carry out average circumference and average area respectively to the hydroxyapatite microsphere of embodiment 1, embodiment 2 and comparative example 1 gain and calculate the sphericity using the following formula:

In the formula, S is the sphericity (%); A is the average surface area of the microspheres (mm ² ) measured by the software, and C is the average circumference of the microspheres (mm) measured by the software. The results are shown in Table 1 below.

Table 1

Sphericity of microspheres (%) Example 1 82.4 Example 2 85.0 comparative example 67.3

It can be seen from Table 1 that in terms of sphericity, the microspheres of Example 1 are significantly better than the microspheres of Comparative Example 1, so the microspheres of Example 1 are more suitable for preparing injection filling preparations. It was thus confirmed that the acicular hydroxyapatite primary product prepared by electrochemical deposition of the present invention can improve the sphericity of the final 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 additives in step 2 to prepare the slurry, the sphericity of the final microspheres can be improved.

Comparison of Experimental Example 3 Production Efficiency

The time for forming hydroxyapatite deposits in step 1 of Example 1 and the time for forming hydroxyapatite deposits in step 1 of comparative example 1 are summarized in Table 2 below.

Table 2

It can be seen from the above Table 2 that the time for forming hydroxyapatite deposits in step 1 of Example 1 is significantly shorter than the time for forming hydroxyapatite deposits in step 1 of Comparative Example 1. From this, it was confirmed that the production efficiency of Example 1 was significantly higher than that of Comparative Example 1.

Although preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitute.

Claims (10)

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 4.0-5.5, 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: sieving the calcined hydroxyapatite microsphere crude product to obtain the hydroxyapatite microsphere,

wherein the particle size distribution range of the hydroxyapatite microspheres is 14-85 μm, and the sphericity is 75-95%.

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 claim 1, wherein in step 1,

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 claim 1, 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 0.5-3h.

5. The production method according to claim 1, 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 20-40wt%,

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 process according to claim 1, wherein in step 3, the spraying temperature is 125 to 500 ℃,

the feeding speed is 10-20ml/min,

the diameter of the nozzle is 0.5-1.4mm.

7. The production method according to claim 1, 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 to 1400 ℃.

8. The method according to claim 1, wherein in step 5, the screening is performed using a manual classifying screen or a vibration classifying screen, and the number of the 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.

10. The hydroxyapatite microspheres according to claim 9, wherein said hydroxyapatite microspheres have a particle size distribution ranging from 25 to 45 μ ι η.

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