Pha microspheres, preparation method thereof, preparation containing the same and application

Abstract

The application discloses a kind of PHA microspheres, and its preparation method, preparation and application containing it.The preparation method of PHA microspheres includes the following steps: organic phase includes polyhydroxyalkanoate and organic solvent;Water phase includes surfactant and water;Organic phase and water phase are initially mixed, after membrane emulsification, volatile organic solvent, solidification, and PHA microspheres are prepared;Wherein, volatile includes first stage volatilization and second stage volatilization;The temperature T1 of first stage volatilization is 20~30 ℃;When 50~85 vol% of organic solvent is volatilized, second stage volatilization is carried out;The temperature T2 of second stage volatilization is 30~40 ℃;The temperature T3 of solidification is 40~50 ℃;T3>T2>T1, 5 ℃≤T2-T1≤20 ℃, 5 ℃≤T3-T2≤20 ℃.The surface of PHA microspheres of the application is smooth, roundness is high, particle size is uniform, particle size is concentrated in the range of 20~60 μm, use safety is high, microsphere fluidity is good, and it is easy to inject.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical aesthetics, in particular to a PHA microsphere, a preparation method thereof, a preparation containing the same and application. BACKGROUND

[0002] PHA is a natural biopolymer polyester, and PHA and its degradation products are non-toxic and non-irritating to the human body, and do not cause serious immune rejection and allergic reactions, and have ideal biocompatibility. PHA can be prepared into microspheres and compounded with a matrix as a medical aesthetic filling material, which can not only achieve immediate filling effect, but also continuously stimulate collagen regeneration, and the effect is natural and long-lasting. In the field of medical aesthetics, the morphology of the microspheres is one of the main factors affecting the treatment effect. If the morphology of the microspheres is irregular or the surface is rough, the microspheres have more sharp contact points on the surface, and the microspheres will be recognized by the body as more threatening foreign bodies, resulting in severe and persistent inflammatory reactions, long recovery period, and bringing an undesirable experience to the beauty seekers. In addition, the rough surface will also excessively stimulate macrophages, and will promote immune cells (such as fibroblasts, lymphocytes) to wrap them in layers, forming granulomas or indurations, which are visible to the naked eye if located in the superficial dermis, affecting the appearance. In severe cases, surgery is required to remove them, causing secondary damage to the beauty seekers. The rough surface of the microspheres will also affect the flowability, causing problems such as needle blockage and high injection pushing force, increasing the difficulty of injection for doctors.

[0003] The PHA microspheres prepared by the prior art generally have problems such as surface wrinkles and low roundness. Therefore, there is an urgent need in the art to develop a PHA microsphere with a simple preparation method and a smooth surface, which ensures that the prepared microspheres have ideal use safety and flowability, and are convenient for doctors to inject. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the defects such as surface wrinkles and irregular morphology of the PHA microspheres prepared by the prior art, and to provide a PHA microsphere, a preparation method thereof, a preparation containing the same and application. The present application uses a rapid membrane emulsification method to prepare the PHA microspheres, which is more suitable for industrial production, and optimizes the preparation method, successfully prepares the PHA microspheres with a smooth surface and high roundness by controlling the conditions such as volatilization and solidification. And the particle size of the microspheres prepared by the method of the present application is uniform, most of which is concentrated in the range of 20-60 μm, the use safety is high, the occurrence of side reactions such as excessive inflammation, granuloma and nodule is reduced, the flowability of the microspheres is good, and the microspheres are easy to inject, reducing the difficulty of operation for doctors.

[0005] The present application solves the above technical problems through the following technical solutions.

[0006] This application provides a method for preparing PHA microspheres, comprising the following steps: an organic phase comprising polyhydroxyalkanoate and an organic solvent; an aqueous phase comprising a surfactant and water; the organic phase and the aqueous phase are initially mixed, followed by membrane emulsification, followed by evaporation of the organic solvent and solidification to obtain the PHA microspheres;

[0007] The evaporation includes a first-stage evaporation and a second-stage evaporation; the temperature T1 of the first-stage evaporation is 20~30℃, preferably 22~28℃, for example 21℃, 23℃, 25℃, 27℃ or 29℃; the second-stage evaporation is carried out after the organic solvent has evaporated 50vol%~85vol%; the temperature T2 of the second-stage evaporation is 30~40℃, preferably 32~38℃, for example 31℃, 33℃, 35℃, 37℃ or 39℃; the curing temperature T3 is 40~50℃, preferably 42~48℃, for example 41℃, 43℃, 45℃, 47℃ or 49℃; T3>T2>T1, 5℃≤T2-T1≤20℃, 5℃≤T3-T2≤20℃.

[0008] In some embodiments, the polyhydroxyalkanoate is selected from one or more of PHBHHx, PHB, PHBV, P34HB, PHBVHHx, PHHx and PHO.

[0009] In some embodiments, the polyhydroxyalkanoate has a weight-average molecular weight of 1 to 15 WDa, such as 1 WDa, 3 WDa, 5 WDa, 7 WDa, 9 WDa, 11 WDa, 13 WDa, or 15 WDa.

[0010] In some embodiments, the organic solvent is selected from haloalkanes and / or esters.

[0011] The haloalkane solvent is a chloroalkane solvent, preferably selected from dichloromethane and / or trichloromethane.

[0012] The ester solvent is a C2-C6 alkyl ester of acetic acid, preferably ethyl acetate.

[0013] In some embodiments, the mass percentage of the polyhydroxyalkanoate in the organic phase is 10% to 25%, preferably 14% to 25%.

[0014] In some embodiments, the surfactant is polyvinyl alcohol, preferably at least one of polyvinyl alcohol 1788, polyvinyl alcohol 3-88, polyvinyl alcohol 4-88 and polyvinyl alcohol 5-88.

[0015] In some embodiments, the water is selected from purified water and / or water for injection.

[0016] In some embodiments, the mass percentage of the surfactant in the aqueous phase is 1% to 5%, preferably 1% to 3%, for example 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%.

[0017] In some embodiments, the viscosity of the aqueous phase is 2 to 10 mPa·s, for example 2 mPa·s, 3 mPa·s, 4 mPa·s, 5 mPa·s, 6 mPa·s, 7 mPa·s, 8 mPa·s, 9 mPa·s or 10 mPa·s.

[0018] In some embodiments, the volume ratio of the organic phase to the aqueous phase is 1:(5~15), preferably 1:(5~12), for example 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14 or 1:15.

[0019] In some embodiments, the initial mixing can be carried out under stirring conditions as is customary in the art, preferably mechanical stirring.

[0020] The mechanical stirring speed is 5~50 rpm, preferably 10~30 rpm, for example 5 rpm, 10 rpm, 15 rpm, 20 rpm, 25 rpm, 30 rpm, 35 rpm, 40 rpm, 45 rpm or 50 rpm.

[0021] In some embodiments, the initial mixing time is 20-80 min, preferably 30-60 min, for example 20 min, 30 min, 40 min, 50 min, 60 min, 70 min or 80 min.

[0022] In some embodiments, the initial mixing temperature is room temperature.

[0023] In some embodiments, the membrane emulsification uses a membrane tube with a pore size of 25-55 μm, preferably 35-50 μm, such as 40 μm or 50 μm.

[0024] In some embodiments, the membrane emulsification is performed 1 to 3 times, preferably 1 to 2 times.

[0025] In some embodiments, the membrane emulsification rate is 0.1~2 L / min, preferably 0.3~0.8 L / min, for example 0.3 L / min, 0.4 L / min, 0.5 L / min, 0.7 L / min, 0.9 L / min, 1 L / min, 1.2 L / min, 1.4 L / min, 1.6 L / min, 1.8 L / min or 2 L / min.

[0026] In some embodiments, the second stage of evaporation is performed after 60 vol% to 80 vol% of the organic solvent has evaporated; more preferably, the second stage of evaporation is performed after 70 vol% to 80 vol% of the organic solvent has evaporated. For example, the first stage of evaporation may take 8 to 30 hours, preferably 10 to 20 hours, such as 12 hours.

[0027] In some embodiments, the first stage of volatilization is carried out under stirring conditions, wherein the stirring speed is 100~400 rpm, for example 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm or 400 rpm.

[0028] In some embodiments, the first stage of volatilization is natural volatilization and / or atmospheric pressure gas displacement volatilization. The flowing gas used in the gas displacement volatilization is air or nitrogen.

[0029] In some embodiments, the second stage continues to evaporate until no organic solvent residue can be detected; preferably, the evaporation time of the second stage is 10-30 hours, more preferably 15-28 hours, for example 24 hours.

[0030] In some embodiments, the second stage of volatilization is carried out under stirring conditions, wherein the stirring speed is 100~400 rpm, for example 100 rpm, 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm or 400 rpm.

[0031] In some embodiments, the second stage of volatilization is natural volatilization and / or atmospheric pressure gas displacement volatilization. The gas used in the gas displacement volatilization is air or nitrogen.

[0032] In some embodiments, the curing includes the steps of separating the microspheres in the volatilized system and hardening them in water; the volume ratio of microspheres to water is 1:(3~20), preferably 1:(5~10), for example 1:3, 1:5, 1:7, 1:9, 1:11, 1:13, 1:15, 1:17 or 1:19.

[0033] In a preferred embodiment, the method for separating the microspheres is to decan the supernatant.

[0034] In some embodiments, the curing time is sufficient to ensure that the microspheres harden and do not stick together; preferably, the curing time is 5~30h, more preferably 7~25h, for example 10h.

[0035] In some embodiments, the curing operation may be followed by at least one of washing, sieving, and drying operations, as is customary in the art.

[0036] The washing solution used is water and / or an alcohol solvent, preferably at least one of purified water, water for injection, and anhydrous ethanol.

[0037] The sieving process uses a screen mesh size of 200-600 mesh, preferably 250-500 mesh.

[0038] The drying method is selected from at least one of low-temperature freeze drying, vacuum drying, and forced-air drying.

[0039] The drying time is 4 to 40 hours, for example, 24 hours.

[0040] The temperature of the blower drying is 35~50℃, for example 45℃.

[0041] This application also provides a PHA microsphere, which is prepared by the PHA microsphere preparation method described above.

[0042] In some embodiments, the particle size of the PHA microspheres is 20~60 μm.

[0043] In some embodiments, the surface of the PHA microspheres is non-porous.

[0044] In some embodiments, the surface of the PHA microspheres is smooth.

[0045] This application also provides an injectable filler material comprising PHA microspheres as described above.

[0046] The PHA microspheres account for 5% to 40% of the mass of the injectable filler material.

[0047] The injectable filler material also includes a matrix and / or an anesthetic.

[0048] The matrix can be a matrix commonly used in the medical aesthetics field that is conducive to the dispersion of PHA microspheres, and is preferably selected from at least one of sodium carboxymethyl cellulose, collagen, free hyaluronic acid substances and cross-linked hyaluronic acid substances.

[0049] The anesthetic agent is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine, and bupivacaine, preferably lidocaine hydrochloride.

[0050] The anesthetic agent accounts for 0.2% to 0.4% of the mass of the injectable filler material.

[0051] This application also provides a method for preparing the injectable filler material as described above, which specifically includes the following steps: mixing the components of the injectable filler material.

[0052] The mixing conditions and methods can be conventional in the field; generally, it is sufficient to mix the system evenly.

[0053] The mixing process may further include a degassing process.

[0054] The degassing method can be the negative pressure degassing method commonly used in this field.

[0055] This application also provides the use of the PHA microspheres or the injectable filler material described above as raw materials in the preparation of medical or cosmetic products.

[0056] The medical or cosmetic products mentioned include filler or shaping products.

[0057] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of this application.

[0058] In this invention, the type of polyhydroxy fatty acid ester is not particularly limited, and is a commercially available PHA commonly used in the art, such as at least one of the following: copolymer of 3-hydroxybutyric acid and 3-hydroxyhexanoic acid (PHBHHx), 3-hydroxybutyrate (PHB), copolymer of 3-hydroxybutyric acid and 3-hydroxyvalerate (PHBV), copolymer of 3-hydroxybutyric acid and 4-hydroxybutyric acid (P34HB), "copolymer of 3-hydroxybutyric acid, 3-hydroxyhexanoic acid and 3-hydroxyvalerate (PHBVHHx)", polyhydroxyhexanoic acid (PHHx) and polyhydroxyoctanoic acid (PHO).

[0059] All reagents and raw materials used in this application are commercially available.

[0060] The positive advancements of this application are as follows: This application uses a rapid membrane emulsification method to prepare PHA microspheres, which is more suitable for industrial production. The preparation method has been optimized, and by controlling conditions such as volatilization and curing, PHA microspheres with smooth surfaces and high sphericity have been successfully prepared. Furthermore, the PHA microspheres prepared by this application have uniform particle size, with the vast majority concentrated in the range of 20~60μm. This results in high safety in use, reducing the occurrence of side effects such as excessive inflammation, granulomas, and nodules. The microspheres also have good fluidity and are easy to inject. Attached Figure Description

[0061] Figure 1 The image shows a scanning electron microscope image of the PHA microspheres prepared in Example 1 at 400x magnification.

[0062] Figure 2 The image shows a scanning electron microscope image of the PHA microspheres prepared in Example 1 at 1000x magnification.

[0063] Figure 3 The image shows a scanning electron microscope image of the PHA microspheres prepared in Example 2 at 400x magnification.

[0064] Figure 4 The image shows a scanning electron microscope image of PHA microspheres prepared in Comparative Example 1 at 400x magnification.

[0065] Figure 5 The image of PHA microspheres prepared in Comparative Example 2 is shown in a scanning electron microscope at 350x magnification.

[0066] Figure 6 The image shows a scanning electron microscope image of the PHA microspheres prepared in Comparative Example 3 at 400x magnification. Detailed Implementation

[0067] The present application is further illustrated below by way of embodiments, but these embodiments are not intended to limit the scope of the present application. Experimental methods not specifically described in the following embodiments are performed according to conventional methods and conditions.

[0068] The reagents and raw materials used in the following examples are all commercially available, and the reagents used are of injection grade purity.

[0069] In this application, the viscosity of the aqueous phase is the viscosity obtained by measuring it using a rotational viscometer at 25°C.

[0070] Example 1

[0071] (1) Aqueous phase preparation

[0072] Purified water and polyvinyl alcohol 1788 were mixed and stirred until completely dissolved to obtain an aqueous phase; the concentration of polyvinyl alcohol 1788 in the aqueous phase was 1.5 wt%, and the viscosity of the aqueous phase was 7.4 mPa·s.

[0073] (2) Preparation of organic phase

[0074] Dichloromethane and PHBHHx (with a weight-average molecular weight of 15 WDa) were mixed and stirred until completely dissolved to obtain an organic phase; the concentration of PHBHHx in the organic phase was 16 wt%.

[0075] (3) Rapid membrane emulsification

[0076] The organic phase and the aqueous phase were mixed at a volume ratio of 1:5 and initially mixed at 45 rpm for 50 min to obtain a primary emulsion. The primary emulsion was further emulsified by a membrane emulsifier with a membrane tube pore size of 50 μm, one pass through the membrane, and a pass rate of 0.4 L / min to obtain an emulsion.

[0077] (4) Volatile dichloromethane

[0078] First stage of evaporation: Under normal pressure, at a temperature of 25°C, and with a stirring speed of 150 rpm, gas displacement evaporation occurs, with air as the displacement gas; in this stage, 70% vol% of the organic solvent evaporates.

[0079] Second stage of evaporation: under normal pressure, at a temperature of 35°C, and with a stirring speed of 150 rpm, gas displacement evaporation is carried out, with air as the displacement gas; in this stage, all remaining organic solvents are evaporated until no organic solvent residue can be detected.

[0080] (5) Curing

[0081] After the dichloromethane has completely evaporated, collect the microspheres in the suspension and pour them into water at 45°C. The volume ratio of microspheres to water is 1:8. Let it solidify for 20 hours under stirring conditions at a speed of 200 rpm.

[0082] (6) Collection

[0083] Microspheres with a particle size in the range of 20~60μm were collected by sieving and freeze-dried to obtain PHA microspheres.

[0084] Example 2

[0085] (1) Aqueous phase preparation

[0086] Purified water and polyvinyl alcohol 1788 were mixed and stirred until completely dissolved to obtain an aqueous phase; the concentration of polyvinyl alcohol 1788 in the aqueous phase was 2.5 wt%, and the viscosity of the aqueous phase was 9.7 mPa·s.

[0087] (2) Preparation of organic phase

[0088] Dichloromethane and PHBHHx (with a weight-average molecular weight of 3 WDa) were mixed and stirred until completely dissolved to obtain an organic phase; the concentration of PHBHHx in the organic phase was 25 wt%.

[0089] (3) Rapid membrane emulsification

[0090] The organic phase and the aqueous phase were mixed at a volume ratio of 1:9 and initially mixed at 15 rpm for 60 min to obtain a primary emulsion. The primary emulsion was further emulsified by a membrane emulsifier with a membrane tube pore size of 40 μm, one pass through the membrane, and a pass rate of 0.5 L / min to obtain an emulsion.

[0091] (4) Volatile dichloromethane

[0092] First stage of evaporation: Under normal pressure, at a temperature of 25°C, and with a stirring speed of 300 rpm, gas displacement evaporation was carried out for 12 hours. The displacement gas was air. During this stage, 80% vol% of the organic solvent evaporated.

[0093] Second stage of evaporation: Vaporization was carried out under normal pressure, at a temperature of 35°C and a stirring speed of 300 rpm for 24 hours by gas replacement gas, with air as the replacement gas; in this stage, all remaining organic solvents were evaporated until no organic solvent residue could be detected.

[0094] (5) Curing

[0095] After the dichloromethane has completely evaporated, collect the microspheres in the suspension and pour them into water at 45°C. The volume ratio of microspheres to water is 1:10. Solidify for 10 hours under stirring conditions at a speed of 300 rpm.

[0096] (6) Collection

[0097] Microspheres with a particle size of 20-60 μm were collected by sieving and dried by forced air at a temperature of 45℃ for 24 hours to obtain PHA microspheres.

[0098] Comparative Example 1

[0099] Compared with Example 1, the only difference is that the volatilization conditions in step (4) are different. Gradient volatilization was not carried out. Specifically, under normal pressure, temperature of 35°C, and stirring speed of 300 rpm, gas replacement volatilization was carried out for 36 hours. The replacement gas was air. All other conditions and parameters were the same as in Example 1.

[0100] Comparative Example 2

[0101] Compared with Example 1, the only difference is the volatilization conditions in step (4). The volatilization temperature in the second stage is higher than the range specified in this application. Other conditions and parameters are the same as in Example 1. The specific operation of step (4) is as follows:

[0102] First stage of volatilization: under normal pressure, at a temperature of 25℃ and a stirring speed of 300rpm, gas replacement volatilization was carried out for 12 hours, with air as the replacement gas;

[0103] Second stage of volatilization: under normal pressure, at a temperature of 45℃ and a stirring speed of 300rpm, gas displacement volatilization was carried out for 24 hours, with air as the displacement gas.

[0104] Comparative Example 3

[0105] Compared with Example 1, the only difference is the curing temperature in step (5), which is changed from 45°C to 55°C. Other conditions and parameters are the same as in Example 1.

[0106] Effect Example

[0107] (1) The morphology of the injectable microspheres prepared in the above examples and comparative examples was observed using a scanning electron microscope. The results are shown in Table 1 and Appendix. Figures 1-6 ;in, Figure 1 This is a scanning electron microscope image of the PHA microspheres prepared in Example 1, magnified 400x. Figure 2 The image shown is a scanning electron microscope image of the PHA microspheres prepared in Example 1 at 1000x magnification. Figure 3 The image shown is a scanning electron microscope image of the PHA microspheres prepared in Example 2 at 400x magnification.Figure 4 The image shows a scanning electron microscope image of the PHA microspheres prepared in Comparative Example 1 at 400x magnification. Figure 5 The image shows a scanning electron microscope image of the PHA microspheres prepared in Comparative Example 2 at 350x magnification. Figure 6 The image shows a scanning electron microscope image of the PHA microspheres prepared in Comparative Example 3 at 400x magnification.

[0108] (2) Calculation of the yield of microspheres with target particle size

[0109] Weigh the target particle size microspheres and waste microspheres obtained by sieving in step (6) of each of the above embodiments and comparative examples. The yield of target particle size microspheres = target particle size microsphere mass / (target particle size microsphere mass + waste microsphere mass). 100%.

[0110] Table 1

[0111]

[0112] The results above indicate that the volatilization and curing temperatures during the preparation of PHA microspheres have a significant impact on the sphere formation rate and surface morphology of the microspheres.

[0113] The microspheres prepared using the methods in Examples 1 and 2 of this application are perfectly spherical with smooth surfaces, uniform particle size, and a high yield of microspheres with the target particle size (20~60μm). When formulated into a preparation, they exhibit good flowability during injection, are less prone to needle clogging, avoid triggering excessive inflammatory responses, have a short treatment recovery period, and demonstrate high safety.

[0114] The results of Comparative Example 1 show that when the evaporation is not carried out under the specific gradient evaporation conditions described in this application, the surface of the microspheres collapses, resulting in noticeable wrinkles. When these microspheres are used as injectable fillers in aesthetic medicine, their rough surface can lead to severe inflammatory reactions, a long recovery period, and a risk of granulomas or nodules. The microspheres also have poor flowability, making them prone to problems such as needle blockage and increased pushing force.

[0115] According to the results of Comparative Example 2, when the temperature during the volatilization stage exceeds the specified range, some microspheres will break and some microspheres will stick together. After solidification in step (5), a lot of fragments will float on the surface of the system. The yield of round microspheres is low, which increases production costs. Even after sieving, there will still be broken and irregular particles and sticky spheres, which will not only cause excessive inflammatory response, but the irregularity of the microspheres will also lead to poor flowability, resulting in problems such as needle blockage and increased pushing force during injection, which increases the difficulty of injection for doctors.

[0116] The results of Comparative Example 3 show that improper curing temperature control, such as exceeding the specified range, can lead to microsphere breakage, resulting in a lower yield of spherical microspheres and increased production costs. Even after sieving, irregular fine particles may still be present. This can not only cause excessive inflammatory responses but also easily lead to problems such as needle blockage and increased pushing force during injection, increasing the difficulty of injection for doctors.

[0117] Finally, it should be noted that the terms “comprising,” “including,” or any other variations thereof in this application are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0118] Although this application has been disclosed above through the description of specific embodiments, it should be understood that those skilled in the art can devise various modifications, improvements, or equivalents to this application within the spirit and scope of the appended solutions. Such modifications, improvements, or equivalents should also be considered to be included within the scope of protection claimed in this application.

Claims

1. A method for preparing PHA microspheres, characterized in that, The process includes the following steps: the organic phase includes polyhydroxy fatty acid esters and organic solvents; the aqueous phase includes surfactants and water; the organic phase and the aqueous phase are initially mixed, emulsified through a membrane, the organic solvents are evaporated, and the mixture is solidified to obtain the PHA microspheres; The volatilization includes a first-stage volatilization and a second-stage volatilization; the temperature T1 of the first-stage volatilization is 20~30℃; after 50vol%~85vol% of the organic solvent has volatilized, the second-stage volatilization is carried out until no organic solvent residue can be detected; the temperature T2 of the second-stage volatilization is 30~40℃; the curing temperature T3 is 40~50℃; T3>T2>T1, 5℃≤T2-T1≤20℃, 5℃≤T3-T2≤20℃; the polyhydroxyalkanoate is selected from one or more of PHBHHx, PHB, PHBV, P34HB, PHBVHHx, PHHx and PHO; the mass percentage of the polyhydroxyalkanoate in the organic phase is 10%~25%.

2. The method for preparing PHA microspheres as described in claim 1, characterized in that, The preparation method satisfies at least one of the following conditions (1) to (7): (1) The weight-average molecular weight of the polyhydroxy fatty acid ester is 1~15WDa; (2) The organic solvent is selected from haloalkanes and / or esters; (3) The surfactant is polyvinyl alcohol; (4) The water is selected from purified water and / or water for injection; (5) The mass percentage of the surfactant in the aqueous phase is 1% to 5%; (6) The viscosity of the aqueous phase is 2~10 mPa·s; (7) The volume ratio of the organic phase to the aqueous phase is 1:(5~15).

3. The method for preparing PHA microspheres as described in claim 2, characterized in that, The preparation method satisfies at least one of the following conditions (1) to (6): (1) The haloalkane solvent is selected from dichloromethane and / or trichloromethane; (2) The ester solvent is a C2-C6 alkyl ester of acetic acid; (3) The mass percentage of the polyhydroxyalkanoate in the organic phase is 14%~25%; (4) The surfactant is at least one of polyvinyl alcohol 1788, polyvinyl alcohol 3-88, polyvinyl alcohol 4-88 and polyvinyl alcohol 5-88; (5) The mass percentage of the surfactant in the aqueous phase is 1% to 3%; (6) The volume ratio of the organic phase to the aqueous phase is 1:(5~12).

4. The method for preparing PHA microspheres according to any one of claims 1 to 3, characterized in that, The preparation method satisfies at least one of the following conditions (1) to (17): (1) The initial mixing is carried out under mechanical stirring conditions, and the mechanical stirring speed is 5~50 rpm; (2) The initial mixing time is 20~80 min; (3) The initial mixing temperature is room temperature; (4) The membrane tube used for membrane emulsification has a pore size of 25~55μm; (5) The membrane emulsification process is repeated 1 to 3 times; (6) The membrane emulsification rate is 0.1~2 L / min; (7) The second stage of evaporation is carried out after 60 vol% to 80 vol% of the organic solvent has evaporated; (8) The temperature T1 of the first stage of volatilization is 22~28℃; (9) The first stage of volatilization is carried out under stirring conditions, wherein the stirring speed is 100~400 rpm; (10) The first stage of volatilization is natural volatilization and / or atmospheric pressure gas displacement volatilization; (11) The temperature T2 of the second stage of volatilization is 32~38℃; (12) The second stage of volatilization is carried out under stirring conditions, wherein the stirring speed is 100~400 rpm; (13) The second stage of volatilization is natural volatilization and / or atmospheric pressure gas displacement volatilization; (14) The curing includes the steps of separating the microspheres in the volatilized system and hardening them in water, wherein the volume ratio of microspheres to water is 1:(3~20). (15) The curing temperature T3 is 42~48℃; (16) The curing time is 5~30h; (17) The curing process also includes at least one of washing, sieving and drying.

5. The method for preparing PHA microspheres as described in claim 4, characterized in that, The preparation method satisfies at least one of the following conditions (1) to (10): (1) During the initial mixing, the mechanical stirring speed is 10~30 rpm; (2) The initial mixing time is 30~60 min; (3) The membrane tube used for membrane emulsification has a pore size of 35~50μm; (4) The membrane emulsification process is repeated 1 to 2 times; (5) The membrane emulsification rate is 0.3~0.8 L / min; (6) The volume ratio of microspheres to water during solidification is 1:(5~10); (7) The curing time is 7~25h; (8) The washing solution used in the washing process is water and / or an alcohol solvent; (9) The sieve used for sieving has a mesh size of 200-600. (10) The drying method is selected from at least one of low temperature freeze drying, vacuum decompression drying and forced air drying.

6. A PHA microsphere, characterized in that, The PHA microspheres are prepared by the method described in any one of claims 1 to 5.

7. The PHA microspheres as described in claim 6, characterized in that, The PHA microspheres satisfy at least one of the following conditions (1) to (3): (1) The particle size of the PHA microspheres is 20~60μm; (2) The surface of the PHA microspheres is non-porous; (3) The surface of the PHA microspheres is smooth.

8. An injectable filler material, characterized in that, Including the PHA microspheres as described in claim 6 or 7.

9. The injectable filler material as described in claim 8, characterized in that, The injectable filler material satisfies the following conditions (1) and / or (2): (1) The PHA microspheres account for 5% to 40% of the mass of the injectable filler material; (2) The injectable filler material further includes a matrix and / or an anesthetic; the matrix is ​​selected from at least one of sodium carboxymethyl cellulose, collagen, free hyaluronic acid and cross-linked hyaluronic acid; the anesthetic is selected from at least one of lidocaine hydrochloride, lidocaine carbonate, tetracaine, prilocaine, procaine, mepivacaine and bupivacaine.

10. The use of PHA microspheres as described in claim 6 or 7 or injectable filler as described in claim 8 or 9 as a raw material in the preparation of medical or cosmetic products.

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