Biocompatible material microspheres and methods of making and using the same

Abstract

The application provides a kind of biocompatible material microspheres and its preparation method and application, it is related to the technical field of biomedical materials.The biocompatible material is mixed with solvent, the obtained mixed solution is atomized and first dried, to obtain semi-dry microspheres;The semi-dry microspheres are received into anti-solvent, to obtain solidified microspheres;The solidified microspheres are second dried, to obtain the biocompatible material microspheres.The application controls the drying temperature of atomized liquid to be lower than the gasification temperature of liquid, so that the microspheres after drying of mist drop are semi-dry microspheres, the particle bulk density is larger after receiving anti-solvent, the specific surface area is smaller, the obtained microspheres are applied to filling microspheres in medical and cosmetic fields, present slow degradation state, the degradation time is longer, after drug loading, the drug and carrier matrix are slowly released, especially suitable for high activity products needing long-term drug delivery.And, the application discards cyclone separator, adopts anti-solvent to receive microspheres, greatly improves the yield.

Description

A biocompatible microsphere, its preparation method and application Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a biocompatible material microsphere, its preparation method, and its application. Background Technology

[0002] Spray drying is a common method for preparing biocompatible microspheres, such as biocompatible polymer microspheres. Conventional spray drying typically uses solutions or suspensions for spray drying, often employing a two-way system: a feed system and a gas supply system. Compressed air atomizes the liquid material, and the spray and drying gas fall in the same direction. The drying gas, at a temperature higher than the vaporization temperature of the solvent, dries the atomized liquid material in a short time. This drying process is relatively mature and widely used, and due to the brief exposure to high temperatures (often within seconds), it causes minimal thermal damage to the product. However, this method also has drawbacks. Firstly, because the temperature of the drying gas is higher than the boiling point of the solvent, the microspheres generally exhibit a loose, porous morphology with a large specific surface area (the specific surface area of ​​non-smooth microspheres can typically reach tens of thousands of m²). 2 / kg, nano-sized microspheres can reach hundreds of thousands of m 2 When used as a carrier to load drugs, microspheres ( / kg) often result in excessively rapid drug release and short release time, failing to achieve a long-term sustained-release effect. Alternatively, when used as filler microspheres in the medical aesthetics field, they exhibit rapid degradation, leading to a short time for microspheres to stimulate collagen production in the medical aesthetics field, requiring repeated injections. Secondly, the use of cyclone separators to collect samples generally results in a low microsphere yield, approximately 50%. Summary of the Invention

[0003] In view of this, the purpose of this invention is to provide a biocompatible material microsphere, its preparation method, and its application. The preparation method provided by this invention can reduce the specific surface area of ​​the biocompatible material microsphere and improve the yield of the microsphere.

[0004] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0005] This invention provides a method for preparing biocompatible material microspheres, comprising the following steps:

[0006] A biocompatible material and a solvent are mixed to obtain a mixture; the mixture is a solution or a suspension; the biocompatible material is a biocompatible polymer or hydroxyapatite;

[0007] The mixture is atomized and first dried to obtain semi-dry microspheres; the temperature of the first drying is higher than room temperature and lower than the boiling point of the solvent.

[0008] The semi-dry microspheres are received in an antisolvent to obtain solidified microspheres;

[0009] The solidified microspheres are subjected to a second drying process to obtain the biocompatible material microspheres; the second drying process removes the solvent from the solidified microspheres.

[0010] Preferably, the biocompatible polymer includes one or more of polylactic acid, polyalkyl cyanoacrylate, polylactic acid-glycolic acid copolymer, polycaprolactone, hyaluronic acid, starch, albumin, gelatin, cyclodextrin, chitin, chitosan, beeswax, gum arabic, and alginate.

[0011] Preferably, when the mixture is a solution, the mass fraction of the biocompatible material in the solution is 1-10%; when the mixture is a suspension, the mass fraction of the biocompatible material in the suspension is 20-40%.

[0012] Preferably, when the mixture is a suspension, the suspension further includes a binder, which includes one or more of polyvinyl alcohol, polyvinylpyrrolidone, and cellulose-based binders; the mass fraction of the binder in the suspension is 0.5% to 5%.

[0013] Preferably, when the mixture is a solution, the atomization is hydraulic atomization or pneumatic atomization; when the mixture is a suspension, the atomization is pneumatic atomization; the pressure of the hydraulic atomization is 1-5 MPa; the pressure of the pneumatic atomization is 0.1-0.8 MPa, and the liquid supply rate is greater than 0 and less than or equal to 60 mL / min.

[0014] Preferably, the first drying is airflow drying, wherein the mixture, after being atomized, comes into contact with the first drying airflow and falls in the same direction; the falling distance is 1 to 5 meters, and the flow rate of the first drying airflow is less than or equal to 5000 m³ / h. 3 / h.

[0015] Preferably, before the second drying, the solidified microspheres are further subjected to washing and sieving in sequence; the washing reagent used for washing the microspheres is the antisolvent.

[0016] Preferably, when the biocompatible material is hydroxyapatite, after the second drying, the dried microspheres are further sintered; the sintering temperature is 940-1020°C and the time is 1-24 hours.

[0017] This invention provides biocompatible material microspheres prepared by the preparation method described above, wherein the biocompatible material microspheres are solid spheres with a bulk density of 0.1–1 g / cm³. 3 Specific surface area is 20–2000 m² 2 / kg.

[0018] This invention provides the application of the biocompatible microspheres described in the above technical solution in the preparation of medical aesthetic microsphere fillers or sustained-release drug-loaded materials.

[0019] This invention provides a method for preparing biocompatible microspheres, comprising the following steps: mixing a biocompatible material and a solvent to obtain a mixture; atomizing and first drying the mixture to obtain semi-dry microspheres; the temperature of the first drying is higher than room temperature and lower than the boiling point of the solvent; receiving the semi-dry microspheres in an antisolvent to obtain solidified microspheres; and subjecting the solidified microspheres to a second drying to obtain the biocompatible microspheres. In this invention, after atomization, the drying temperature of the atomized liquid is controlled to be lower than the vaporization temperature of the liquid (i.e., lower than the boiling point of the solvent). This ensures that the microspheres after atomization are dried only on the surface (the surface is almost completely dry, while the interior is semi-dry), resulting in semi-dry microspheres. This not only saves energy but is also particularly suitable for heat-sensitive materials. Furthermore, the microspheres obtained after receiving the antisolvent have a higher particle bulk density and a smaller specific surface area. When used as filler microspheres in the medical aesthetics field, they exhibit a slow degradation state with a longer degradation time. After drug loading, the drug is slowly released from the carrier matrix, making them particularly suitable for highly active products requiring long-term drug delivery. Furthermore, this invention abandons the cyclone separator commonly used in spray drying and adopts anti-solvent to receive microspheres, which greatly improves the yield.

[0020] Furthermore, when the mixture is a solution, it can be atomized using hydraulic atomization (i.e., high-pressure spraying), which is a single-channel spray with a spray pressure as high as 1-5 MPa, resulting in high production capacity and eliminating the need for compressed air atomization. Attached Figure Description

[0021] Figure 1 shows the wet particle size distribution of the L-type polylactic acid microspheres prepared in Example 2;

[0022] Figure 2 shows the dry particle size distribution of the intermediate product of hydroxyapatite microspheres obtained before sintering in Example 4.

[0023] Figure 3 is a field scanning electron microscope image of the L-type polylactic acid microspheres prepared in Example 2;

[0024] Figure 4 is a field scanning electron microscope image of the surface of the L-type polylactic acid microspheres prepared in Example 2;

[0025] Figure 5 is a field scanning electron microscope image of the sintered hydroxyapatite microspheres prepared in Example 4.

[0026] Figure 6 is a field scanning electron microscope image of the surface of the sintered hydroxyapatite microspheres prepared in Example 4.

[0027] Figure 7 shows the gas chromatogram of solvent residue in the L-type polylactic acid microspheres prepared in Example 2.

[0028] Figure 8 shows the gas chromatogram of the solvent residue of the L-polylactic acid microsphere reference standard used in Example 2. Detailed Implementation

[0029] This invention provides a method for preparing biocompatible material microspheres, comprising the following steps:

[0030] A biocompatible material and a solvent are mixed to obtain a mixture; the mixture is a solution or a suspension; the biocompatible material is a biocompatible polymer or hydroxyapatite;

[0031] The mixture is atomized and first dried to obtain semi-dry microspheres; the temperature of the first drying is higher than room temperature and lower than the boiling point of the solvent.

[0032] The semi-dry microspheres are received in an antisolvent to obtain solidified microspheres;

[0033] The solidified microspheres are subjected to a second drying process to obtain the biocompatible material microspheres; the second drying process removes the solvent from the solidified microspheres.

[0034] Unless otherwise specified, all raw materials and equipment involved in this invention are commercially available products in the field.

[0035] The present invention mixes biocompatible materials and solvents to obtain a mixture, wherein the mixture is a solution or a suspension.

[0036] In this invention, the biocompatible material is a biocompatible polymer or hydroxyapatite. The biocompatible polymer preferably includes one or more of polylactic acid, polyalkyl cyanoacrylate, polylactic acid-glycolic acid copolymer, polycaprolactone, hyaluronic acid, starch, albumin, gelatin, cyclodextrin, chitin, chitosan, beeswax, gum arabic, and alginate. This invention does not have specific requirements for the polylactic acid; any polylactic acid well-known to those skilled in the art can be used, such as racemic polylactic acid, dextrorotatory polylactic acid, and levuromeric polylactic acid. In this invention, the hydroxyapatite is preferably added in powder form. This invention does not have specific requirements for the solvent; it only needs to be able to dissolve or disperse the biocompatible material. When the biocompatible material is dissolved, the resulting mixture is a solution; when the biocompatible material is dispersed, the resulting mixture is a suspension. In this invention, when the biocompatible material is a biocompatible polymer, a solution is preferred; when the biocompatible material is hydroxyapatite, a suspension is preferred. Taking polylactic acid as an example of a biocompatible material, the solvent can be one or more of dichloromethane, chloroform, tetrahydrofuran, and dimethylformamide; taking hydroxyapatite as an example of a biocompatible material, the solvent can be anhydrous ethanol.

[0037] In this invention, the preferred method of mixing is to add the biocompatible material to a solvent and stir to obtain the mixture; after stirring, high-speed shearing can also be performed to ensure that the raw materials are mixed evenly.

[0038] In this invention, when the mixture is a solution, the mass fraction of biocompatible material in the solution is preferably 1% to 10%, and can be 1%, 2%, 3%, 3.5%, 4%, 5%, 7% or 10%.

[0039] In this invention, when the mixture is a suspension (such as a suspension of hydroxyapatite), the mass fraction of the biocompatible material in the suspension is preferably 20-40%, and can be 20%, 25%, 26%, 26.5%, 30%, 35%, or 40%. In this invention, when the mixture is a suspension, the suspension preferably also includes a binder, which preferably includes one or more of polyvinyl alcohol, polyvinylpyrrolidone, and cellulose-based binders, and the cellulose-based binders preferably include one or more of hydroxypropyl methylcellulose, ethylcellulose, and carboxymethyl cellulose; the mass fraction of the binder in the suspension is preferably 0.5-5%, and can be 0.8%, 1%, 2%, 2.5%, 2.6%, 3%, 4%, or 5%. In this invention, the binder facilitates the spraying of biocompatible materials with low viscosity into pellets. In this invention, the suspension preferably also includes a plasticizer, which preferably includes polyethylene glycol and / or diethyl phthalate; the plasticizer is preferably 0.1% to 10% of the binder mass, and can be 0.1%, 1%, 2%, 3%, 3.5%, 4%, 4.6%, or 10%. In this invention, the plasticizer can improve the plasticity of the microspheres and reduce the viscosity of the system.

[0040] The present invention controls the concentration of the solution or suspension within the above-mentioned range. Too low a concentration or solid content will lead to low production efficiency or microsphere collapse and severe surface shrinkage. Too high a concentration or solid content will make atomization difficult due to increased viscosity of the liquid system, and the process cannot proceed normally.

[0041] After obtaining the mixture, the present invention atomizes and first dries the mixture to obtain semi-dry microspheres.

[0042] In this invention, when the mixture is a solution, the atomization is hydraulic atomization or pneumatic atomization; when the mixture is a suspension, the atomization is pneumatic atomization. In this invention, the hydraulic atomization is high-pressure spraying, using a high-pressure nozzle (solid cone atomizing nozzle). The pressure of the hydraulic atomization is preferably 1–5 MPa, and can be 1, 1.5, 2, 2.3, 3, 3.3, 4, 4.2, or 5 MPa. The atomization flow rate can be controlled by adjusting the spray pressure. The atomization angle (a spray appearance phenomenon caused by pressure when using a solid cone atomizing nozzle) is preferably 30–72 degrees, and can be 30, 40, 50, 60, 70, or 72 degrees. In this invention, the hydraulic atomization spraying has high pressure, large flow rate, and high production capacity, with a single nozzle reaching 2–6 liters per hour, and does not require compressed air atomization. In this invention, the pneumatic atomization is performed using a pneumatic atomizing nozzle. The pressure of the pneumatic atomization is preferably 0.1–0.8 MPa, and can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.55, 0.6, or 0.7 MPa. The liquid supply rate is preferably greater than 0 and less than or equal to 60 mL / min, and can be 10, 20, 30, 40, 50, or 60 mL / min. This invention does not have any special requirements for the nozzles used for the above-mentioned hydraulic atomization and pneumatic atomization; any nozzle well known to those skilled in the art can be used.

[0043] In this invention, the first drying temperature is greater than room temperature (25°C) and less than the boiling point of the solvent. The first drying temperature can be 1–50°C lower than the boiling point of the solvent. Taking dichloromethane as an example, the first drying temperature can be 25–38.8°C, preferably 30–35°C; taking anhydrous ethanol as an example, the first drying temperature can be 28.3–77.3°C, preferably 35–40°C. In this invention, if the first drying temperature is too low, there will be more residual solvent in the microspheres. When these microspheres fall into the antisolvent, they will be soft, have poor rigidity, and be easily deformed, and they will easily stick together. If the first drying temperature is too high, the solvent will evaporate and boil rapidly, forming microspheres with a loose and porous structure.

[0044] In this invention, the first drying is preferably airflow drying, wherein the mixture, after being atomized, comes into contact with the first drying airflow and falls in the same direction. The falling distance is preferably 1 to 5 meters, which can be 1, 2, 3, 4, or 5 meters (after reaching the falling distance, it falls into the antisolvent and is received). The flow rate of the first drying airflow is preferably less than or equal to 5000 m³ / h. 3 / h can be 1000, 2000, 3000, 3600, 4000 or 5000m 3 / h; the temperature of the first drying is the temperature of the airflow (i.e., the inlet air temperature). In this invention, the atomized liquid is first dried under a dry airflow below the boiling point of the solvent, supplemented by spray pressure, drop distance, and airflow control, so that the atomized liquid is dried to a certain extent but not completely dried, resulting in semi-dry microspheres with a dry shell on the surface. In this invention, the atomization and the first drying are atomization semi-drying process.

[0045] This invention controls the drying temperature of the atomized liquid to be lower than the vaporization temperature of the liquid (i.e., the boiling point of the solvent). This results in the microspheres after the droplets are dried only on the surface to form a shell, making them semi-dry microspheres. This not only saves energy but is also particularly suitable for heat-sensitive materials. Furthermore, the microspheres obtained after being received by the antisolvent have a higher particle bulk density and a smaller specific surface area.

[0046] After obtaining the semi-dry microspheres, the present invention receives the semi-dry microspheres in an antisolvent to obtain solidified microspheres.

[0047] In this invention, the antisolvent is a solvent that cannot dissolve the biocompatible material or corresponding auxiliary materials. Taking polylactic acid as an example, the antisolvent can be water or ethanol; taking hydroxyapatite as an example, the antisolvent can be petroleum ether. This invention does not have specific requirements on the amount of antisolvent used, as long as it is sufficient to completely submerge the semi-dry microspheres. In this invention, the antisolvent acts as a curing agent, further curing the surface of the microspheres.

[0048] In this invention, the microspheres are flexible during the atomization process because they are not completely dried, and the microspheres are in a state of suspension and weightlessness in the airflow. Due to their own surface tension, the microspheres prepared by this method have a spherical appearance and good roundness.

[0049] In conventional spray drying, nearly half of the particles are separated into collection bags and collected as waste, and these particles are generally unusable for pharmaceuticals and medical devices. Particles within the target particle size range are collected in the collector. This invention, however, uses an anti-solvent to collect the vast majority of the falling particles, which are then solidified and sieved into microspheres of different sizes, significantly improving production efficiency. This invention eliminates the cyclone separator commonly used in conventional spray drying methods, employing an anti-solvent to receive the microspheres, greatly increasing the yield to over 50%, even reaching approximately 80%.

[0050] After obtaining the solidified microspheres, the present invention performs a second drying on the solidified microspheres to obtain the biocompatible material microspheres; the second drying removes the solvent from the solidified microspheres.

[0051] Before the second drying process, the present invention preferably further includes washing and sieving the solidified microspheres. In the present invention, the washing agent used for washing the microspheres is preferably the anti-solvent; the washing method is preferably to add the anti-solvent to the solidified microspheres and then filter. In the present invention, the washing is preferably performed multiple times, and the repeated washing ensures that the residual solvent in the microspheres initially meets the standards.

[0052] In this invention, different sieves can be used to sieve microspheres of the target particle size, which can be between 1 and 500 μm, and further subdivided into different particle size ranges such as 20-60 μm, 30-70 μm, and 60-100 μm.

[0053] This invention does not have special requirements for the temperature and time of the second drying step, as long as the solvent in the solidified microspheres is sufficiently removed. In this embodiment, the temperature of the second drying step can be 25–40°C, and the time can be 1–24 hours. The second drying can be carried out in an oven. During the second drying process, the microspheres are slowly and completely dried, and the residual solvent is completely removed, forming a solid microsphere with a relatively smooth surface, i.e., the biocompatible material microsphere.

[0054] In this invention, when the biocompatible material is hydroxyapatite, after the second drying process, the resulting dried microspheres are further subjected to sintering. The sintering temperature is preferably 940–1020°C, and the sintering time is preferably 1–24 hours. In this invention, the sintering serves to remove organic matter such as adhesives by burning them off. Simultaneously, it vitrifies the microspheres, making them resemble human bone components, thereby stimulating collagen production and achieving a cosmetic effect.

[0055] This invention employs a preparation route that uses hydraulic or pneumatic atomization, low-temperature semi-drying, and anti-solvent as a curing agent to further solidify the surface. It has the advantages of high yield, low energy consumption, and high efficiency, and is easy to implement for large-scale industrial production.

[0056] After obtaining the biocompatible material microspheres, the present invention can further package and sterilize the biocompatible material microspheres. During the packaging process, excipients may or may not be added, and the microspheres are packaged into sterile drug delivery containers. If excipients are added, 0.9 wt% sodium chloride injection solution can be added for dispersion, or water for injection and other excipients can be added for dispersion and freeze-drying to produce a sterile suspension for injection. Alternatively, suspending agents and water for injection can be added to produce a suspension for injection. In the present invention, the end product can be sterilized by irradiation or moist heat methods to achieve the corresponding sterility guarantee, or a combination of dry heat sterilization of microspheres and excipient filtration can be used for sterilization. The finished product can be further packaged for sale and use.

[0057] This invention provides biocompatible material microspheres prepared by the preparation method described above, wherein the biocompatible material microspheres are solid spheres with a bulk density of 0.1–1 g / cm³. 3 Specific surface area is 20–2000 m² 2 / kg (particle size analysis method). In this invention, the bulk density is preferably 0.1 to 0.5 g / cm³. 3 The specific surface area is preferably 60-500 m². 2 / kg, more preferably 80-300m 2 / kg, more preferably 90-250m 2 / kg.

[0058] This invention provides the application of the biocompatible microspheres described above in the preparation of medical aesthetic microsphere fillers or sustained-release drug-loaded materials. In this invention, the biocompatible microspheres have a high particle packing density, a spherical microstructure, and a relatively small specific surface area compared to conventional spray drying methods. When used as fillers in the medical aesthetic field, these microspheres exhibit slow degradation, with a degradation time of several months, such as 3-6 months. After drug loading, the drug is slowly released from the carrier matrix, making them particularly suitable for highly active products requiring long-term administration, such as sex hormones and antipsychotic drugs.

[0059] To further illustrate the present invention, the following detailed description, in conjunction with examples, of the biocompatible microspheres provided by the present invention, their preparation methods, and their applications, should not be construed as limiting the scope of protection of the present invention.

[0060] Example 1

[0061] The preparation method of biocompatible material microspheres is as follows:

[0062] 400g of polylactic acid (molecular weight 100,000) was dissolved in 4000mL of dichloromethane by stirring for 12h to obtain a dichloromethane solution of polylactic acid.

[0063] The dichloromethane solution of the L-polylactic acid was supplied under a pressure of 2.3 MPa and delivered to a hydraulic atomizing nozzle for spraying at a flow rate of 3323 mL / h and an atomization angle of 30 degrees. The atomized liquid came into contact with the drying airflow and fell in the same direction. The temperature of the drying airflow was 30°C and the airflow rate was 1 m³ / h. 3 / s, falling distance 2 meters, to obtain semi-dry microspheres;

[0064] The semi-dried microspheres were collected by using purified water as the antisolvent. The microspheres were then washed with purified water and wet-screened to remove larger and smaller microspheres. After drying, the microspheres were obtained at 35°C for 12 hours to obtain polylactic acid (PLA) microspheres.

[0065] The particle size of the obtained L-type polylactic acid microspheres was determined to be D10: 40.38 μm, D50: 73.93 μm, D90: 151.4 μm, and span: 1.502.

[0066] Example 2

[0067] The preparation method of biocompatible material microspheres is as follows:

[0068] 400g of polylactic acid (molecular weight 100,000) was dissolved in 4000mL of dichloromethane by stirring for 12h to obtain a dichloromethane solution of polylactic acid.

[0069] The dichloromethane solution of the L-polylactic acid was supplied under a pressure of 3.3 MPa and delivered to a hydraulic atomizing nozzle for spraying at a flow rate of 4063 mL / h and an atomization angle of 50 degrees. The atomized liquid came into contact with the drying airflow and fell in the same direction. The temperature of the drying airflow was 30°C, and the airflow rate was 1 m³ / h. 3 / s, falling distance 2 meters, to obtain semi-dry microspheres;

[0070] The semi-dried microspheres were collected by using purified water as the antisolvent. The microspheres were then washed with purified water and wet-screened to remove larger and smaller microspheres. After drying, the microspheres were obtained at 35°C for 12 hours to obtain polylactic acid (PLA) microspheres.

[0071] The particle sizes of the obtained L-type polylactic acid microspheres were determined to be D10: 34.06 μm, D50: 62.67 μm, D90: 111.9 μm, and span: 1.242. Gas chromatography was used for solvent residue detection; the results showed that dichloromethane was below the limit of quantitation, and the remaining solvents were not detected.

[0072] Example 3

[0073] The preparation method of biocompatible material microspheres is as follows:

[0074] 400g of polylactic acid (molecular weight 100,000) was dissolved in 4000mL of dichloromethane by stirring for 12h to obtain a dichloromethane solution of polylactic acid.

[0075] The dichloromethane solution of the L-polylactic acid was supplied under a pressure of 4.2 MPa and delivered to a hydraulic atomizing nozzle for spraying at a flow rate of 5600 mL / h and an atomization angle of 72 degrees. The atomized liquid fell in the same direction as the drying airflow, which had a temperature of 30°C and a flow rate of 1 m³ / h. 3 / s, falling distance 2 meters, to obtain semi-dry microspheres;

[0076] The semi-dried microspheres were collected by using purified water as the antisolvent. The microspheres were then washed with purified water and wet-screened to remove larger and smaller microspheres. After drying, the microspheres were obtained at 35°C for 12 hours to obtain polylactic acid (PLA) microspheres.

[0077] The particle size of the obtained poly-L-lactic acid microspheres was determined to be D10: 24.95 μm, D50: 46.99 μm, D90: 80.52 μm, and span: 1.182.

[0078] Table 1 shows the atomization conditions and particle size of the L-type polylactic acid microspheres prepared in Examples 1-3. The production capacity and microsphere particle size range can be adjusted by changing the spray pressure.

[0079] Table 1. Atomization conditions and particle size of L-polylactic acid microspheres prepared in Examples 1-3

[0080]

[0081] The microspheres obtained in the above three embodiments are prepared according to the conventional freeze-drying process for injection, which are the finished product L-polylactic acid microspheres for injection.

[0082] Example 4

[0083] The preparation method of biocompatible material microspheres is as follows:

[0084] Preparation of adhesive: Slowly add 10g of polyvinylpyrrolidone (K30) to 1000mL of anhydrous ethanol stirred at 180r / min over 15min to disperse it, then stir at 180r / min for 30min to completely dissolve it. Add 0.01g of polyethylene glycol (polyethylene glycol 1500) as a plasticizer, and stir at 180r / min for 10min to obtain an anhydrous ethanol solution of polyvinylpyrrolidone.

[0085] Pulping: Add 400g of hydroxyapatite powder (60nm) to the above glue, stir vigorously at 1000r / min for 30min, then shear at 12500r / min for 5min, and degas by ultrasonication for 15min to obtain hydroxyapatite suspension slurry.

[0086] Spraying: The slurry is supplied by a peristaltic pump at 10 mL / min and delivered to an air pressure atomizing nozzle for spraying. The air pressure is 0.55 MPa. The atomized liquid comes into contact with the drying airflow and falls in the same direction. The temperature of the drying airflow is 35°C, and the airflow rate is 1 m³ / min. 3 / s, falling distance 2 meters, to obtain semi-dry microspheres;

[0087] Receiving: The semi-dry microspheres were received by continuously cooling petroleum ether to 8°C as the antisolvent. The microspheres were then washed with petroleum ether and wet sieve to remove larger and smaller microspheres. After that, they were dried at 35°C for 12 hours to obtain the intermediate product of hydroxyapatite microspheres.

[0088] Testing: The dry particle size of the obtained hydroxyapatite microsphere intermediate product was determined to be D10: 59.91 μm, D50: 101.3 μm, D90: 185.6 μm, and span: 1.239. The specific surface area was 24.98 m². 2 / kg, bulk density 0.27g / cm³ 3 .

[0089] Sintering: The intermediate hydroxyapatite microspheres were placed in a corundum crucible in a box-type resistance furnace and sintered at 942℃ for 1 hour to obtain the final vitrified hydroxyapatite microspheres, also known as "microcrystalline ceramics". Dry particle size analysis showed a D50 of 63.53 μm, a D90 of 278.0 μm, and a specific surface area of ​​207.8 m². 2 / kg, bulk density is 0.45g / cm³ 3 After sintering, the product becomes vitrified, and the particle size shrinks due to the bonding of microsphere crystals, resulting in a smaller particle diameter and an increased specific surface area and density. Because of the high-temperature sintering process, organic matter, including solvents and binders, is carbonized and burned; therefore, no solvent residue was detected. After further adding excipients to prepare the finished suspension formulation, it is dispensed into glass vials for injection, thus becoming the hydroxyapatite microsphere suspension for injection.

[0090] Figure 1 shows the wet particle size distribution (laser scattering method) of polylactic acid microspheres prepared in Example 2. It can be seen that the microspheres have a good normal distribution.

[0091] Figure 2 shows the dry particle size distribution (laser scattering method) of the intermediate product of hydroxyapatite microspheres obtained before sintering in Example 4. It can be seen that the microspheres have a good normal distribution.

[0092] Figure 3 shows a field scanning electron microscope image of the L-type polylactic acid microspheres prepared in Example 2. It can be seen that the microspheres are relatively round, and after drying, they shrink slightly, indicating they are solid microspheres without any loose or porous structures.

[0093] Figure 4 shows a field scanning electron microscope image of the surface of the L-type polylactic acid microspheres prepared in Example 2 (at a different magnification than Figure 3). The surface is dense, uneven, and contains pores.

[0094] Figure 5 shows a field scanning electron microscope image of the sintered porcelainized hydroxyapatite microspheres prepared in Example 4. It can be seen that the microspheres are relatively round, with a dense surface, and are solid microspheres, without any loose or porous structures.

[0095] Figure 6 shows a field scanning electron microscope image of the surface of the sintered vitrified hydroxyapatite microspheres prepared in Example 4 (at different magnifications than Figure 5). It can be seen that after sintering, the organic material is burned off, leaving behind vitrified hydroxyapatite nanoparticles sintered together.

[0096] Figure 7 shows the gas chromatogram of the solvent residue test of the L-polylactic acid microspheres prepared in Example 2, and Figure 8 shows the gas chromatogram of the solvent residue test of the L-polylactic acid microsphere reference standard used in Example 2. It can be seen that the solvent dichloromethane and solvent-related impurities used are all below the limit of quantitation and close to the limit of detection.

[0097] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing biocompatible material microspheres, characterized in that, Includes the following steps: A biocompatible material and a solvent are mixed to obtain a mixture; the mixture is a solution or a suspension; the biocompatible material is a biocompatible polymer or hydroxyapatite; the mixture is atomized and subjected to a first drying process to obtain semi-dry microspheres; the temperature of the first drying process is higher than room temperature and lower than the boiling point of the solvent. When the mixture is a solution, the atomization is hydraulic atomization or pneumatic atomization; when the mixture is a suspension, the atomization is pneumatic atomization; the pressure of the hydraulic atomization is 1~5MPa. The pressure of the pneumatic atomization is 0.1~0.8MPa, and the liquid supply rate is greater than 0 and less than or equal to 60mL / min; the first drying is airflow drying, and the mixed liquid, after atomization, comes into contact with the airflow of the first drying and falls in the same direction; the falling distance is 1~5 meters, and the flow rate of the airflow of the first drying is less than or equal to 5000m³. 3 / h; The semi-dried microspheres are received in an antisolvent to obtain solidified microspheres; The solidified microspheres are subjected to a second drying process to obtain the biocompatible material microspheres; The second drying process removes the solvent from the solidified microspheres; The biocompatible material microspheres are solid spheres with a bulk density of 0.1~1 g / cm³. 3 Specific surface area is 20~2000m² 2 / kg.

2. The preparation method according to claim 1, characterized in that, The biocompatible polymers include one or more of polylactic acid, polyalkyl cyanoacrylate, polylactic acid-glycolic acid copolymer, polycaprolactone, hyaluronic acid, starch, albumin, gelatin, cyclodextrin, chitin, chitosan, beeswax, gum arabic, and alginate.

3. The preparation method according to claim 1, characterized in that, When the mixture is a solution, the mass fraction of the biocompatible material in the solution is 1-10%; when the mixture is a suspension, the mass fraction of the biocompatible material in the suspension is 20-40%.

4. The preparation method according to claim 1 or 3, characterized in that, When the mixture is a suspension, the suspension also includes a binder, which includes one or more of polyvinyl alcohol, polyvinylpyrrolidone, and cellulose-based binders; the mass fraction of the binder in the suspension is 0.5-5%.

5. The preparation method according to claim 1, characterized in that, Before the second drying process, the solidified microspheres are washed and sieved sequentially; the washing agent used for washing the microspheres is the antisolvent.

6. The preparation method according to claim 1, characterized in that, When the biocompatible material is hydroxyapatite, the second drying process further includes sintering the dried microspheres; the sintering temperature is 940~1020℃ and the time is 1~24h.

7. The biocompatible material microspheres prepared by the preparation method according to any one of claims 1 to 6, wherein the biocompatible material microspheres are solid spheres with a bulk density of 0.1 to 1 g / cm³. 3 Specific surface area is 20~2000m² 2 / kg.

8. The application of the biocompatible microspheres of claim 7 in the preparation of medical aesthetic microsphere fillers or sustained-release drug-loaded materials.

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