Apparatus and method for the production of polymer microspheres

Abstract

The application relates to a preparation device and method of polymer microspheres, which comprises the following steps: S1. respectively preparing an aqueous phase solution containing an emulsifier and an oil phase solution containing a polymer material; S2. emulsifying and shearing a mixed solution of the aqueous phase solution and the oil phase solution to obtain first polymer microsphere liquid beads; S3. a part of the first polymer microsphere liquid beads with a particle size smaller than the pore size of a first barrel-shaped screen falls into a first screening pool through screening of the first barrel-shaped screen to obtain second polymer microsphere liquid beads; S4. the second polymer microsphere liquid beads are transferred into a second barrel-shaped screen of a second screening pool, and a part of the second polymer microsphere liquid beads with a particle size smaller than the second barrel-shaped screen falls into the second screening pool through screening of the second barrel-shaped screen; and S5. third polymer microsphere liquid beads retained in the second barrel-shaped screen are transferred to a solidification tank, and polymer microspheres with a target particle size are obtained after volatilization of a solvent. The scheme avoids screen blockage, and improves the screening efficiency and yield of the polymer microspheres.

Description

Technical Field

[0001] This application relates to the field of injectable facial fillers in medical aesthetics, specifically to an apparatus and method for preparing polymer microspheres. Background Technology

[0002] In the field of medical aesthetics, biodegradable polymer microspheres prepared primarily from high-molecular polymers such as polylactic acid, polycaprolactone, and polylactic acid-polyethylene glycol copolymer are widely used in soft tissue filling, facial contouring, and skin rejuvenation treatments due to their excellent biocompatibility, safety, and biodegradability. In specific applications, uniform particle size and controlled dimensions of the microspheres are typically required. The difference between the upper and lower limits of D50 is usually controlled within 10μm to 15μm, and the overall particle size should be controlled between 20μm and 100μm. Otherwise, their medical application effects will be significantly affected: microspheres with excessively large particle sizes (>100μm) may lead to foreign body granulomas, local inflammation, or nodule formation; microspheres with excessively small particle sizes (<20μm) may be directly captured and phagocytosed by dermal giant cells or penetrate the capillary wall after implantation, thus losing their effect of stimulating collagen production.

[0003] Currently, common methods for preparing polymer microspheres include emulsification-solvent evaporation, microfluidics, and spray drying. Based on the triangular balance of "clinical needs - production costs - technical feasibility," emulsification-solvent evaporation has become the mainstream method in industrialization due to its technological maturity and economic efficiency. However, the microspheres obtained after homogeneous emulsification generally have a wide particle size distribution and large differences in particle size, with larger-sized microspheres usually accounting for a large proportion, resulting in a low yield of microspheres of the target particle size. Given the wide particle size distribution of the microspheres, sieving is one of the key steps in the emulsification-solvent evaporation process to improve the efficiency of obtaining microspheres of the target particle size. However, after solidification, whether dry or wet sieving, microspheres tend to get stuck in the sieve mesh, leading to a gradual decrease in sieving efficiency. This prevents continuous and prolonged sieving of microspheres, ultimately affecting the yield of microspheres of the target particle size and increasing production costs.

[0004] For example, CN120679722A discloses a multi-size microsphere sieving device and its sieving method for finer sieving of microspheres to meet different medical aesthetic filling needs. The device consists of a first sieving component, an anti-adhesion component, a drying component, a charge adhesion component, and a second sieving component. The first sieving component uses the physical impact force of water circulation, and the second sieving component uses electric field deflection technology to sieve the microspheres. However, this method struggles to guarantee the integrity of the microsphere morphology and still cannot avoid screen clogging. Furthermore, it requires additional spraying of electrolyte mist onto the dried particles to attach a charge to their surface before secondary sieving, making the process complex and its applicability limited.

[0005] CN117920588A discloses a device and method for continuously separating microspheres. By adjusting the pitch of a tension spring to form a spiral channel, the particle size of the microspheres entering the spiral channel is controlled, thereby achieving precise sieving of the microspheres. However, this method still cannot avoid the problem of channel blockage.

[0006] CN118893732A discloses a microsphere solidification and sieving device for preventing microspheres from sticking together and using the force of an electrode plate assembly to sieve surface-charged microspheres of different sizes using electric field deflection technology. While this microsphere solidification and sieving device can simultaneously prevent microspheres from sticking together and sieve microspheres of different sizes, its application is limited to surface-charged microspheres, the sieving conditions are stringent, and its applicability is limited. Summary of the Invention

[0007] Based on this, the purpose of this application is to achieve smooth and accurate sieving of polymer microspheres with target particle size, improve sieving efficiency and yield, and make the obtained polymer microspheres have uniform particle size and appearance.

[0008] To achieve the above objectives, this application provides an apparatus for preparing polymer microspheres, comprising: A homogenizing emulsifier is used to emulsify and shear polymer materials in the presence of an emulsifier to obtain first polymer microspheres, wherein the polymer material is selected from biocompatible polymer materials used in the medical aesthetics field; The first screening tank is provided with a first barrel-shaped screen with a first screen aperture; the homogenizing emulsifier is disposed inside the first barrel-shaped screen, and the portion of the first polymer microsphere liquid droplet with a particle size smaller than the first screen aperture falls into the first screening tank in real time through the first barrel-shaped screen to obtain the second polymer microsphere liquid droplet. A second screening tank, used for screening the second polymer microsphere droplets, is provided with a second barrel-shaped screen having a smaller aperture than the first screen. The portion of the second polymer microsphere droplets with a particle size smaller than the second screen aperture falls into the second screening tank in real time through the second barrel-shaped screen. A curing tank is used to cure the third polymer microsphere droplets retained in the second barrel-shaped screen to obtain polymer microspheres with a target particle size.

[0009] Preferably, it further includes an aqueous phase preparation tank and an oil phase preparation tank connected to the interior of the first barrel-shaped screen; The aqueous phase preparation tank is used to prepare and store an aqueous phase solution containing an emulsifier, and the oil phase preparation tank is used to prepare and store an oil phase solution containing a polymer material.

[0010] To achieve the above objectives, this disclosure also provides a method for preparing polymer microspheres, the method being carried out in the preparation apparatus described in any of the foregoing claims, and comprising the following steps: S1. Prepare an aqueous solution containing an emulsifier and an oil solution containing a polymer material, respectively; S2. Emulsify and shear the mixture of the aqueous solution and the oil solution to obtain first polymer microspheres; the ratio of the aqueous solution to the oil solution is 12.5~25% (w / v). S3. The portion of the first polymer microsphere liquid droplet with a particle size smaller than the aperture of the first barrel-shaped screen falls into the first screening pool in real time after being screened by the first barrel-shaped screen, to obtain the second polymer microsphere liquid droplet; S4. The second polymer microsphere liquid droplets are transferred to the second barrel-shaped screen in the second screening tank. The portion of the second polymer microsphere liquid droplets with a particle size smaller than the second barrel-shaped screen is screened by the second barrel-shaped screen and falls into the second screening tank in real time. S5. The third polymer microsphere liquid droplets retained inside the second barrel-shaped screen are transferred to a curing tank, and after the solvent evaporates, polymer microspheres with the target particle size are obtained.

[0011] Preferably, the first screening tank and the second screening tank contain an aqueous solution at 8-12°C, and the aqueous solution is added to one-fifth to one-half of the first barrel-shaped screen and the second barrel-shaped screen.

[0012] More preferably, in step S2, the aqueous solution and the oil solution are transferred into the first barrel-shaped screen at speeds of 2~5 L / min and 0.5~2 L / min, respectively, and the speed of the homogenizing emulsifier is 1000~4000 rpm.

[0013] Preferably, after each emulsification and shearing process of 10-15 min, the second polymer microsphere droplets are transferred into the second barrel-shaped screen at a rate of 5-10 L / min. After each screening in the second screening tank for 10-20 minutes, the mixture is allowed to stand for 3-7 minutes. The third polymer droplets with the target particle size retained in the second barrel-shaped screen are then transferred to the curing tank.

[0014] More preferably, the curing conditions in step S5 are as follows: the third polymer microsphere liquid droplet in the curing tank is kept at a constant temperature of 8~12 ℃, and the organic solvent is evaporated under reduced pressure to obtain the polymer microsphere with the target particle size.

[0015] Preferably, in step S1, the aqueous solution is prepared as follows: Add purified water and 0.5-1.0% (w / v) polyvinyl alcohol (PVA) to the aqueous phase preparation tank, heat to 70-90 ℃, and stir until completely dissolved; After the solution is cooled to 8~12 ℃, 0.4~5% (w / v) of other emulsifiers are added to prepare the aqueous phase solution, wherein the other emulsifiers include Tween 80 and gelatin aqueous solution; The oil phase solution is prepared as follows: Add organic solvent and polymer material to the oil phase preparation tank and stir until completely dissolved; the concentration of the polymer material in the oil phase solution is 4-25% by mass.

[0016] More preferably, the organic solvent comprises a main solvent and a high-boiling-point solvent; the high-boiling-point solvent accounts for 5-30% of the main solvent by mass. The main solvent includes dichloromethane, and the high-boiling solvent includes one or more of chloroform, acetone, ethanol, N,N-dimethylformamide, 1,4-dioxane, and hexafluoroisopropanol; the high-boiling solvent is preferably a water-soluble high-boiling solvent, such as acetone or 1,4-dioxane.

[0017] Preferably, the polymer material includes one or more of polylactic acid (PLLA), polylactic acid (PDLA), racemic polylactic acid (PDLLA), polycaprolactone (PCL), polylactic acid-glycolic acid copolymer (PLGA, LA:GA=75:25~85:15), polylactic acid-ethylene glycol copolymer (PLA-PEG, PLA:PEG=80:20~99:1), and polydioxanone (PPDO), and the weight-average molecular weight of the polymer material is 5~30 w Da.

[0018] The technical solution claimed in this application achieves the following beneficial effects: 1. Real-time separation of polymer materials after emulsification and shearing to obtain microspheres of appropriate particle size, while continuously emulsifying and shearing the remaining microspheres with larger particle size in the first barrel-shaped screen, which can reduce the proportion of larger microspheres and improve production efficiency.

[0019] 2. Directly sieving uncured, soft, and elastic polymer microspheres avoids the problem of cured polymer microspheres clogging the screen during traditional microsphere particle sieving, and also avoids the problem of polymer microsphere breakage during traditional sieving of cured polymer microspheres, thus improving sieving efficiency and yield.

[0020] 3. The upper and lower limits of the polymer microsphere droplet size are restricted in the two screening processes, which can obtain polymer microsphere products with stable morphology and uniform particle size.

[0021] 4. The provided polymer preparation equipment is easy to set up and has low cost, which can solve the problem of high prices of existing molding equipment (especially molding equipment for microsphere screening).

[0022] 5. The final morphology of polymer microspheres can be controlled by adjusting the type of emulsifier in the aqueous phase, the type of organic solvent in the oil phase, and the curing conditions, thereby improving the flexibility of the process and making it suitable for the medical aesthetic injection field. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings in the following description are only embodiments of this application. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0024] Figure 1 This is a schematic diagram of the polymer microsphere preparation device in Example 1, which can achieve precise sieving of polymer microspheres with target particle size.

[0025] Figure 2 The particle size measurement results are for the polymer microspheres with the target particle size prepared in Example 2.

[0026] Figure 3 The finished polymer microspheres with the target particle size prepared in Example 2 (400x magnification under a microscope).

[0027] Figure 4 The finished polymer microspheres with the target particle size prepared in Example 3 (200x magnification under a microscope).

[0028] Figure 5 Photograph of a 40 μm sieve after 5 min for sieving the product prepared in Comparative Example 1.

[0029] Figure 6 The finished polymer microspheres with the target particle size prepared from Comparative Example 1 (100x magnification under a microscope).

[0030] Figure 7 The polymer microspheres prepared from Comparative Example 2 are shown in the image (100x magnification under a microscope).

[0031] Figure label: 1-Aqueous phase preparation tank; 2-First stirring paddle; 3-First oil bath outlet; 4 - First visible window; 5-First oil bath inlet; 6-The first lower drain port; 7-Water phase constant speed transfer electric pump; 8-Oil phase preparation tank; 9-Second stirring paddle; 10 - Second visible window; 11-Second lower drain port; 12-Oil phase constant speed transfer electric pump; 13-Homogeneous emulsifier; 14-First barrel-shaped screen; 15 - First screening tank; 16 - First conical discharge port; 17-First emulsion transfer electric pump; 18 - Third stirring paddle; 19-Second barrel-shaped screen; 20 - Second screening tank; 21-Second conical discharge port; 22-Second emulsion transfer electric pump; 23 - Third View Window; 24-Curing tank; 25 - Fourth stirring paddle; 26 - Vacuum pipe opening; 27 - Third oil bath outlet; 28 - Third oil bath entrance; 29-Material export. Detailed Implementation

[0032] To make the objectives, technical solutions, and beneficial effects of the embodiments in this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0033] <Example 1> This embodiment provides an apparatus for preparing polymer microspheres, such as... Figure 1 As shown, the device mainly consists of an aqueous phase preparation tank 1, an oil phase preparation tank 8, a homogenizing emulsifier 13, a first screening tank 15, a second screening tank 20, and a solidification tank 24.

[0034] Aqueous phase preparation tank 1 is used to prepare and store aqueous phase solutions containing emulsifiers. It is equipped with a first stirring paddle 2 for stirring the aqueous phase materials inside the tank, a first oil bath outlet 3 at the top of the tank, a first viewing window 4 on the tank wall for observing the interior of the aqueous phase preparation tank, a first oil bath inlet 5 at the bottom of the tank, and a first lower drain outlet 6 at the bottom of the tank. The first lower drain outlet 6 is connected to a homogenizing emulsifier 13 through a pipe, and an aqueous phase constant-speed transfer electric pump 7 is installed on this pipe.

[0035] The oil phase preparation tank 8 is used to prepare and store oil phase solutions containing polymer materials. It is equipped with a second stirring paddle 9 for stirring the oil phase materials inside the tank, a second viewing window 10 for observing the interior of the oil phase preparation tank on the tank wall, and a second lower drain port 11 at the bottom of the tank. The second lower drain port 11 is connected to a homogenizing emulsifier 13 through a pipe, and an oil phase constant speed transfer electric pump 12 is installed on the pipe.

[0036] The homogenizer 13 is used to emulsify and shear a mixture of an aqueous phase material containing an emulsifier and an oil phase material containing a polymer material to obtain first polymer microsphere droplets.

[0037] The homogenizing emulsifier 13 is disposed within the first screening tank 15, specifically inside the first barrel-shaped screen 14 located within the first screening tank 15, which is used to control the upper limit of the microsphere pore size. The first barrel-shaped screen 14 has a first screen pore size. The portion of the first polymer microsphere droplets with a particle size smaller than the first screen pore size falls into the first screening tank 15 in real time through the first barrel-shaped screen to obtain second polymer microsphere droplets. The bottom of the first screening tank 15 is provided with a first conical discharge port 16 with a gradually decreasing diameter. The first conical discharge port 16 is connected to the second screening tank 20 through a pipe, and the pipe is provided with a first emulsion transfer electric pump 17 for transferring the emulsion containing the second polymer microsphere droplets.

[0038] The second screening tank 20 is equipped with a third stirring paddle 18 for stirring materials in the tank and a second barrel-shaped screen 19 for controlling the lower limit of the microsphere pore size. The second barrel-shaped screen 19 has a second screen pore size smaller than that of the first screen. The first emulsion is transferred into the second barrel-shaped screen 19. Polymer microsphere droplets in the first emulsion with a particle size smaller than that of the second screen pore size fall into the second screening tank 20 in real time through the second barrel-shaped screen 19. The bottom of the second screening tank 20 is equipped with a second conical discharge port 21 with a gradually decreasing diameter. The material retained in the second barrel-shaped screen 19 is connected to the solidification tank 24 through a pipeline. The pipeline is equipped with a second emulsion transfer electric pump 22 for transferring the emulsion containing the third polymer microsphere droplets with the target particle size retained in the second barrel-shaped screen 19.

[0039] The curing tank 24 is used to cure the third polymer microsphere droplets to obtain polymer microspheres with the target particle size. It is equipped with a fourth stirring paddle 25 for stirring the material inside the tank, and a third viewing window 23 for observing the interior of the curing tank 24 is provided on the tank wall. The top of the curing tank 24 is equipped with a vacuum pipe port 26, the upper part is equipped with a third oil bath outlet 27, the lower part is equipped with a third oil bath inlet 28, and the bottom is equipped with a material outlet 29.

[0040] <Example 2> This embodiment provides a process for preparing polymer microspheres using the apparatus of Example 1.

[0041] This embodiment aims to obtain the target particle size D. 50 The PLLA-PEG polymer microspheres (PLLA:PEG=95:5, Mw=150000 Da) are 30~40μm in size. The mesh size of the first barrel-shaped screen 14 in the first screening tank 15 is selected as 40μm, and the mesh size of the second barrel-shaped screen 19 in the second screening tank 20 is selected as 30μm. The implementation steps are as follows: S1. Preparation of aqueous solution: Add 200L of purified water to aqueous solution preparation tank 1, add 0.5% (m / v) of polyvinyl alcohol (PVA) to the tank, heat to 70 ℃ and stir until completely dissolved; The solution was cooled to 10 °C, and 0.4% of Tween 80 by mass of the aqueous phase was added. The mixture was stirred until completely dissolved to prepare an aqueous solution containing the composite emulsifier. S2. Preparation of oil phase solution: Add 22 kg of dichloromethane and 2 kg of trichloromethane to oil phase preparation tank 8, and add 1 kg of PLLA-PEG (PLLA:PEG=95:5, Mw=150000Da) while stirring, and stir until completely dissolved; S3. Add an aqueous solution containing the composite emulsifier obtained in step S1 at 10 °C to the first screening tank 15 and the second screening tank 20 respectively, up to 1 / 3 of the respective barrel-shaped screen. S4. Turn on the aqueous phase constant speed transfer electric pump 7 (if using an electric diaphragm pump), set the speed to 4 L / min, and introduce the aqueous phase material in the aqueous phase preparation tank 1 into the homogenizing emulsifier 13; turn on the oil phase constant speed transfer electric pump 12 (if using an electric diaphragm pump), set the speed to 1 L / min, and introduce the oil phase material in the oil phase preparation tank 8 into the homogenizing emulsifier 13. Turn on the homogenizer 13 and set the speed to 1500 rpm; after shear emulsification begins, PLLA-PEG microspheres with a particle size of less than 40 μm will flow out from the first barrel-shaped screen 14 with the water flow and be deposited at the bottom of the conical first screening tank 15; larger particles will continue to be sheared and emulsified in the first barrel-shaped screen into microspheres with a smaller particle size. S5. After emulsification and shearing for 10-15 minutes, open the valve of the first conical outlet 16 located at the bottom of the first screening tank 15, and transfer the emulsion containing polymer microspheres deposited at the bottom of the 10L tank to the second screening tank 20 at a speed of 5 L / min. Under stirring, polymer microspheres with a particle size <30 μm will flow out from the second barrel-shaped screen 19 with the water flow, and polymer microspheres with the target particle size will be retained in the second barrel-shaped screen 19. S6. After each 15 min of screening in the second screening tank 20, let it stand for 5 min, then turn on the second emulsion transfer electric pump 22 to transfer the emulsion containing polymer microspheres of the target particle size that is retained in the second barrel-shaped screen 19 to the solidification tank 24. S7. Repeat steps S5-S6 to complete the emulsification and sieving of the polymerization solution; S8. The material in curing tank 24 is kept at a constant temperature of 10 ℃. Under reduced pressure conditions of -0.03 to -0.06 MPa, the organic phase is volatilized, and PLLA-PEG microspheres are cured to obtain the target particle size D. 50 PLLA-PEG microspheres are 30~40 μm in size.

[0042] In this embodiment, the sieving process ran continuously for 4 hours without any screen clogging. Observation under a light microscope of the sieving PLLA-PEG microspheres showed that the microspheres were of uniform size, had smooth surfaces, and were undamaged (reference). Figure 2 and Figure 3 ).

[0043] <Example 3> This embodiment provides a process for preparing polymer microspheres using the apparatus of Example 1.

[0044] This embodiment aims to obtain the target particle size D. 50 The PLLA polymer microspheres are 15-25 μm in size (Mw=70000 Da). The mesh size of the first cylindrical screen 14 in the first sieving tank 15 is selected as 25 μm, and the mesh size of the second cylindrical screen 19 in the second sieving tank 20 is selected as 15 μm. The implementation steps are as follows: S1. Preparation of aqueous solution: Add 200 L of purified water to aqueous solution preparation tank 1, add 1% (m / v) polyvinyl alcohol (PVA) to the tank, heat to 70 °C and stir until completely dissolved; The solution was cooled to 10 °C, and 1% of Tween 80 by mass of the aqueous phase was added. The mixture was stirred until completely dissolved to prepare an aqueous solution containing the composite emulsifier. S2. Preparation of oil phase solution: Add 38 kg of dichloromethane and 2 kg of acetone to oil phase preparation tank 8, and add 10 kg of PLLA (Mw=70000Da) while stirring, and stir until completely dissolved; S3. Add an aqueous solution containing the composite emulsifier obtained in step S1 at 10 °C to the first screening tank 15 and the second screening tank 20 respectively, up to 1 / 3 of the respective barrel-shaped screen. S4. Turn on the aqueous phase constant speed transfer electric pump 7, set the speed to 5 L / min, and introduce the aqueous phase material in the aqueous phase preparation tank 1 into the homogenizing emulsifier 13; turn on the oil phase constant speed transfer electric pump 12, set the speed to 2 L / min, and introduce the oil phase material in the oil phase preparation tank 8 into the homogenizing emulsifier 13. Turn on the homogenizer 13 and set the speed to 3000 rpm; after the emulsification and shearing begins, PLLA microspheres with a particle size of less than 25 μm will flow out from the first barrel-shaped screen 14 with the water flow and be deposited at the bottom of the conical first screening tank 15; larger microspheres will continue to be emulsified and sheared into smaller droplets in the first barrel-shaped screen. S5. After emulsification and shearing for 10-15 minutes, open the valve of the first conical outlet 16 located at the bottom of the first screening tank 15, and transfer the emulsion containing polymer microspheres deposited at the bottom of the 10 L tank to the second screening tank at a speed of 5 L / min. Under stirring, polymer microspheres with a particle size <15 μm will flow out from the second barrel-shaped screen 19 with the water flow, and polymer microspheres with the target particle size will be retained in the second barrel-shaped screen 19. S6. After each screening in the second screening tank 20 for 15 minutes, let it stand for 5 minutes, then turn on the second emulsion transfer electric pump 22 to transfer the emulsion containing polymer microspheres of the target particle size that is retained in the second barrel-shaped screen 19 to the solidification tank 24. S7. Repeat steps S5-S6 to complete the emulsification and sieving of the polymerization solution; S8. The material in curing tank 24 is kept at a constant temperature of 10 ℃. Under reduced pressure conditions of -0.03 to -0.06 MPa, the organic phase is volatilized, and PLLA microspheres are cured to obtain the target particle size D. 50 PLLA microspheres with a diameter of 15~25 μm.

[0045] In this embodiment, the sieving process ran continuously for 4 hours without any screen clogging. Microscopic observation of the sieving PLLA microspheres showed that the microspheres were of uniform size, had smooth surfaces, and were undamaged (reference). Figure 4 ).

[0046] <Comparative Example 1> This comparative example provides a process for preparing polymer microspheres. The difference from Example 2 is that the first screening tank 15 and the second screening tank 20 are not set up. The emulsion containing PLLA-PEG polymer microsphere droplets obtained after emulsification and shearing in the homogenizing emulsifier 13 is directly transferred to the curing tank 24. After the dichloromethane evaporates and the microspheres are completely cured in the curing tank 24, the cured polymer microspheres are screened sequentially using vibrating screens with the same pore size (40 μm and 30 μm).

[0047] <Comparative Example 2> This comparative example provides a process for preparing polymer microspheres. In this comparative example: Step S1 is as follows: Add 80 L of purified water and 0.5% (w / v) of polyvinyl alcohol (PVA) to the aqueous phase preparation tank 1, heat to 70 °C and stir until completely dissolved, and then cool the solution to 10 °C. Step S2 is as follows: Add 24 kg of dichloromethane to the oil phase preparation tank 8, and add 1 kg of PLLA-PEG (PLLA:PEG=95:5, Mw=150000 Da) while stirring, and stir until completely dissolved; Step S8 is as follows: The material in the curing tank 24 is kept at a constant temperature to room temperature, and the organic phase is volatilized under normal pressure to cure PLLA-PEG microspheres.

[0048] The remaining steps are the same as in Example 2.

[0049] <Test Example> This test example focuses on the polymer microsphere particle size D obtained from Examples 1 and 2, as well as Comparative Examples 1 and 2. 50 D 10 and D 90 Tests were conducted, and the particle size distribution coefficient of the polymer microspheres was calculated.

[0050] Among them, the polymer microsphere particle size D 50 D 10 and D 90 The test was conducted in the following manner: Take an appropriate amount of polymer microspheres and add 50 mL of purified water. Turn on the stirring function of the circulating sampler of the laser particle size analyzer (LS609, Omec Instruments Co., Ltd.) to uniformly disperse the polymer microspheres in the purified water. Set parameters such as the refractive index of the polymer and start the test. According to the test report, check the D-value of the polymer microspheres. 50 D 10 and D 90 .

[0051] The distribution coefficient of polymer microsphere diameter is calculated using the following formula: Distribution coefficient = (D 90 -D 10 ) / D50 .

[0052] Table 1 records the D values ​​of the polymer microspheres obtained from the examples and comparative examples. 50 D 10 and D 90 The results also included comparisons of the particle size distribution coefficient, morphology, screen clogging during sieving, and process continuity of each polymer microsphere.

[0053] Table 1 <![CDATA[D 50 ]]> 32.073 21.429 33.704 32.652 <![CDATA[D 10 ]]> 27.716 13.718 23.182 27.034 <![CDATA[D 90 ]]> 43.687 26.751 47.961 44.175 Distribution coefficient 0.498 0.608 0.735 0.525 Microsphere morphology smooth smooth smooth Unsmooth, irregular Microsphere integrity whole whole whole Partially damaged and stuck together Network congestion situation none none Severe screen clogging occurs approximately 5 minutes after screening begins, requiring the machine to be stopped and the screen cleaned at least every 10 minutes. none Process continuity / production efficiency high high Low high

[0054] The results from Example 2 and Comparative Example 1 show that although Comparative Example 1 can obtain polymer microspheres with uniform particle size, smooth surface, and no damage, due to the method of solidifying the polymer microspheres before sieving in Comparative Example 1, obvious screen clogging occurs about 5 minutes after the start of sieving (the clogged screen is shown in the image). Figure 5 As shown in the figure, this leads to a significant decrease in the overall screening efficiency of the microspheres, requiring the machine to be stopped and the screen cleaned at least every 10 minutes.

[0055] The results of Example 2 and Comparative Example 2 show that when some experimental parameters were changed, including changing the ratio of oil phase to water phase, not adding Tween 80, not adding high-boiling-point components to the oil phase solvent, and carrying out curing at room temperature (around 25 °C) and normal pressure, although the polymer microsphere liquid droplet sieving process could run continuously for 4 hours without clogging, only polymer microspheres with uneven, irregular, partially broken, or agglomerated surface morphology as shown under a microscope could be obtained, resulting in a low yield. Figure 7 As shown.

[0056] The results above show that the proposed method, through a two-stage sieving process, can prepare polymer microspheres with uniform and smooth particle size suitable for use as fillers in medical aesthetics. Specifically, by separating appropriately sized polymer microsphere droplets in real time after emulsification and shearing, while simultaneously continuously shearing and emulsifying larger polymer microsphere droplets, the uniformity of the polymer microsphere product size can be significantly improved.

[0057] Two sieving processes control the upper and lower limits of the polymer microsphere droplet size, resulting in a more uniform final product. Furthermore, since both sieving processes involve uncured, soft-elastic polymer microsphere droplets, the problem of gradual clogging of the sieve during traditional sieving of cured polymer microspheres is eliminated, significantly improving sieving efficiency in the production process. In addition, the final morphology of the polymer microspheres can be controlled through parameter adjustments, offering high flexibility and making the resulting polymer microsphere products suitable for medical aesthetic injection applications.

[0058] The embodiments and application examples described above are merely illustrative descriptions of this application and are not intended to limit the scope of this application. Any modifications and improvements made to the technical solutions of this application by those skilled in the art without departing from the spirit of this application should fall within the protection scope defined by this application.

Claims

1. An apparatus for preparing polymer microspheres, characterized in that, include: A homogenizing emulsifier is used to emulsify and shear polymer materials in the presence of an emulsifier to obtain first polymer microspheres; The first screening tank is provided with a first barrel-shaped screen with a first screen aperture; the homogenizing emulsifier is disposed inside the first barrel-shaped screen, and the portion of the first polymer microsphere liquid droplet with a particle size smaller than the first screen aperture falls into the first screening tank in real time through the first barrel-shaped screen to obtain the second polymer microsphere liquid droplet. The second screening tank is used to screen the second polymer microsphere liquid droplets. It is equipped with a second barrel-shaped screen with a second screen aperture smaller than that of the first screen. The portion of the second polymer microsphere liquid droplets with a particle size smaller than that of the second screen aperture falls into the second screening tank in real time through the second barrel-shaped screen. and A curing tank is used to cure the third polymer microsphere droplets retained in the second barrel-shaped screen to obtain polymer microspheres with a target particle size.

2. The preparation apparatus according to claim 1, characterized in that, It also includes an aqueous phase preparation tank and an oil phase preparation tank connected to the inside of the first barrel-shaped screen; The aqueous phase preparation tank is used to prepare and store an aqueous phase solution containing an emulsifier, and the oil phase preparation tank is used to prepare and store an oil phase solution containing a polymer material.

3. A method for preparing polymer microspheres, characterized in that, The method is carried out in the preparation apparatus according to claim 1 or 2, and includes the following steps: S1. Prepare an aqueous solution containing an emulsifier and an oil solution containing a polymer material, respectively; S2. Emulsify and shear the mixture of the aqueous solution and the oil solution to obtain first polymer microspheres; the ratio of the aqueous solution to the oil solution is 12.5~25% (w / v). S3. The portion of the first polymer microsphere liquid droplet with a particle size smaller than the aperture of the first barrel-shaped screen falls into the first screening pool in real time after being screened by the first barrel-shaped screen, to obtain the second polymer microsphere liquid droplet; S4. The second polymer microsphere liquid droplets are transferred to the second barrel-shaped screen in the second screening tank. The portion of the second polymer microsphere liquid droplets with a particle size smaller than the second barrel-shaped screen is screened by the second barrel-shaped screen and falls into the second screening tank in real time. S5. The third polymer microsphere liquid droplets retained inside the second barrel-shaped screen are transferred to a curing tank, and after the solvent evaporates, polymer microspheres with the target particle size are obtained.

4. The preparation method according to claim 3, characterized in that, An aqueous solution at 8-12°C is added to the first and second screening tanks, and the aqueous solution is added to one-fifth to one-half of the first and second barrel-shaped screens.

5. The preparation method according to claim 3, characterized in that, In step S2, the aqueous solution and the oil solution are transferred into the first barrel-shaped screen at speeds of 2~5 L / min and 0.5~2 L / min, respectively, and the speed of the homogenizing emulsifier is 1000~4000 rpm.

6. The preparation method according to claim 3, characterized in that, After each emulsification and shearing process of 10-15 minutes, the second polymer microsphere droplets are transferred into the second barrel-shaped screen at a rate of 5-10 L / min. After each screening in the second screening tank for 10-20 minutes, the mixture is allowed to stand for 3-7 minutes. The third polymer droplets with the target particle size retained in the second barrel-shaped screen are then transferred to the curing tank.

7. The preparation method according to claim 3, characterized in that, The curing conditions for step S5 are as follows: the third polymer microsphere liquid droplet in the curing tank is kept at a constant temperature of 8~12 ℃, and the organic solvent is evaporated under reduced pressure to obtain the polymer microsphere with the target particle size.

8. The preparation method according to claim 3, characterized in that, In step S1, the aqueous solution is prepared as follows: Add purified water and 0.5-1.0% (w / v) polyvinyl alcohol (PVA) to the aqueous phase preparation tank, heat to 70-90 ℃, and stir until completely dissolved; After the solution is cooled to 8~12 ℃, 0.4~5% (w / v) of other emulsifiers are added to prepare the aqueous phase solution, wherein the other emulsifiers include Tween 80 and gelatin aqueous solution; The oil phase solution is prepared as follows: Add organic solvent and polymer material to the oil phase preparation tank and stir until completely dissolved; the concentration of the polymer material in the oil phase solution is 4-25% by mass.

9. The preparation method according to claim 8, characterized in that, The organic solvent includes a main solvent and a high-boiling-point solvent; by mass, the high-boiling-point solvent accounts for 5-30% of the mass of the main solvent; The main solvent includes dichloromethane, and the high-boiling-point solvent includes one or more of chloroform, acetone, ethanol, N,N-dimethylformamide, 1,4-dioxane, and hexafluoroisopropanol.

10. The preparation method according to claim 8, characterized in that, The polymer material includes one or more of polylactic acid (PLA), polylactic acid (DL), racemic polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, polylactic acid-ethylene glycol copolymer, and polydioxanone, and the weight-average molecular weight of the polymer material is 5-30 W Da.

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