Polyhydroxyalkanoate microspheres as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of high polymer materials, and particularly relates to a polyhydroxyalkanoate microsphere as well as a preparation method and application thereof. The preparation method comprises the following steps: preparing a polyhydroxyalkanoate solution, preparing an emulsion, preparing polyhydroxyalkanoate microspheres, and carrying out post-treatment on the polyhydroxyalkanoate microspheres. The polyhydroxyalkanoate microspheres are prepared through an emulsification curing method, the particle size distribution of the prepared microspheres is narrow, the particle size range can be freely adjusted within 0.5-150 microns, and the porosity of the microspheres can be freely adjusted within 0.1-50%, so that a good drug carrying effect can be achieved, and the polyhydroxyalkanoate microspheres have good application prospects in the fields of medical cosmetology, drug delivery and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer materials, and in particular relates to polyhydroxyalkanoate microspheres and a preparation method and application thereof. Background Art

[0002] In materials science and biomedical engineering, polymer microspheres, as an important functional material, have broad application prospects. Among them, the most widely used are microspheres such as poly-L-lactic acid (PLLA) and polycaprolactone (PCL). The functions of polymer microspheres include: First, polymer microspheres are of great significance in the field of drug delivery. They can be used as carriers of drugs to achieve controlled release and delayed release, thereby improving the bioavailability of drugs, reducing side effects, and providing new solutions for tumor treatment, antibiotic delivery and other fields. Compared with traditional drug delivery methods, the use of polymer microspheres as carriers can more accurately control the release rate and dosage of drugs and improve the therapeutic effect. Secondly, polymer microspheres also play an important role in tissue engineering and regenerative medicine. As degradable biomaterials, PLLA and PCL microspheres can be used as cell growth scaffolds to promote tissue repair and regeneration, and are widely used in bone tissue engineering, cartilage repair, nerve regeneration and other fields. In addition, polymer microspheres are also widely used in medical materials, cosmetics and food industries. For example, they can be used to prepare medical sutures and repair membranes, as carriers of active ingredients in cosmetics, and to add flavoring agents and pigments to foods to achieve controlled and delayed release of ingredients and improve product functionality and stability. Therefore, as a functional material, polymer microspheres provide important support for fields such as drug delivery, tissue engineering, medical materials and food industry, and also provide broad space for the innovation and development of related technologies.

[0003] Polyhydroxyalkanoates (PHA) are a class of polymer materials with good biocompatibility and degradability. Due to their unique physicochemical properties, they have broad application prospects in the fields of drug delivery, tissue engineering, and medical materials. At present, the methods for preparing PHA polymer microspheres mainly include emulsification-gelation method, spray drying method, etc. These traditional methods have some challenges in microsphere particle size control, drug loading, stability, etc. For example, the emulsification-gelation method has certain limitations in cost and process control, and the spray drying method has a wide distribution of microsphere particle size, which is difficult to accurately control. Therefore, there is an urgent need for a simple and efficient preparation method to obtain PHA microspheres with uniform particle size, good stability and good performance to meet the needs of drug delivery and medical aesthetics. Summary of the invention

[0004] The first object of the present invention is to provide a method for preparing polyhydroxyalkanoate microspheres. The second object of the present invention is to provide polyhydroxyalkanoate microspheres prepared by the preparation method. The third object of the present invention is to provide applications of the polyhydroxyalkanoate microspheres.

[0005] According to a first aspect of the present invention, there is provided a method for preparing polyhydroxyalkanoate microspheres, comprising the following steps:

[0006] (1) adding polyhydroxy fatty acid to an organic solvent, stirring to dissolve, and then adding a porogen to disperse evenly to obtain a polyhydroxy fatty acid solution;

[0007] (2) adding a nonionic surfactant to water, stirring to dissolve, and then adding an ionic surfactant, stirring evenly to obtain an emulsion;

[0008] (3) emulsifying the emulsion obtained in step (2) using a homogenizer, and then adding the polyhydroxyalkanoic acid solution obtained in step (1) to the emulsion under emulsification conditions, emulsifying for 5-20 minutes, and then transferring the obtained mixed solution to mechanical stirring conditions and stirring for 5-12 hours, while stirring, heating and evaporating the solvent to obtain polyhydroxyalkanoate microspheres;

[0009] (4) Screening the polyhydroxyalkanoate microspheres obtained in step (3) and then flotation treating them to obtain polyhydroxyalkanoate microspheres with uniform particle size distribution.

[0010] In some embodiments, in step (1), the polyhydroxyalkanoic acid is at least one of poly 3-hydroxypropionic acid, poly 3-hydroxybutyric acid, poly 3-hydroxyvaleric acid, poly 3-hydroxyhexanoic acid, poly 4-hydroxybutyric acid, poly 5-hydroxyvaleric acid, a copolymer of 3-hydroxybutyric acid and 3-hydroxyvaleric acid, and a copolymer of 3-hydroxybutyric acid and 4-hydroxybutyric acid.

[0011] In some embodiments, in step (1), the organic solvent is dichloromethane and / or chloroform.

[0012] In some embodiments, in step (1), the concentration of polyhydroxyalkanoic acid in the polyhydroxyalkanoic acid solution is 1-15 wt %.

[0013] In some embodiments, in step (1), the porogen is at least one of diglycerol dioleate, triglycerol dioleate, and decaglycerol dioleate; and the concentration of the porogen in the polyhydroxy fatty acid solution is 0.5-10 wt %.

[0014] In some embodiments, in step (2), the nonionic surfactant is at least one of ether polyethylene glycol, alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester, and polyoxyethylene alkylamine; and the concentration of the nonionic surfactant in the emulsion is 0.1-1.5 wt%.

[0015] In some embodiments, in step (2), the ionic surfactant is at least one of sodium dodecylbenzene sulfonate, sodium 3-allyloxy-2-hydroxy-1-propane sulfonate, sodium lauryl sulfate, potassium cetyl phosphate, and sodium lauroyl sarcosinate; and the concentration of the ionic surfactant in the emulsion is 0.05-0.1 wt%.

[0016] In some embodiments, in step (3), the rotation speed of the homogenizer is 1000-12000 rpm.

[0017] In some embodiments, in step (3), the polyhydroxyalkanoic acid solution obtained in step (1) is added to the emulsion at a volume ratio of polyhydroxyalkanoic acid solution to emulsion of 1:(10-100).

[0018] In some embodiments, in step (3), the speed of mechanical stirring is 100-2000 rpm; while stirring, the temperature is raised to 30-70° C. to evaporate the solvent. Thus, the purpose of emulsification is to form droplets of the oil phase solution; the purpose of mechanical stirring is to prevent the formed droplets from reaggregating.

[0019] In some embodiments, in step (4), a sieve with a mesh size of 100-15000 is used for sieving; the flotation treatment includes the following steps: mixing the microspheres with water evenly, removing the supernatant after standing and stratifying; and the number of flotation is 10-30 times. The purpose of sieving and flotation is to obtain microspheres with a suitable particle size range and a narrower particle size range distribution.

[0020] According to a second aspect of the present invention, polyhydroxyalkanoate microspheres prepared by the above preparation method are provided.

[0021] According to the third aspect of the present invention, the use of the polyhydroxyalkanoate microspheres in the preparation of medical cosmetic products, medicines, cosmetics or foods is provided. Specifically, the products for medical cosmetic use are soft tissue fillers, etc.; the products for pharmaceutical use include postoperative anti-adhesion agents, drug carriers, and drugs for preventing and / or treating diseases, etc.

[0022] Compared with the prior art, the beneficial effects of the present invention include:

[0023] (1) The present invention prepares polyhydroxyalkanoate microspheres by an emulsification solidification method. The prepared microspheres have good particle size distribution, porous structure and degradability, which solves the current problems of low preparation efficiency, wide particle size distribution and unadjustable porosity of polyhydroxyalkanoate microspheres.

[0024] (2) The particle size distribution of the polyhydroxyalkanoate microspheres prepared by the present invention is narrow, and the particle size range can be freely adjusted within 0.5-150 μm. The porosity of the microspheres can be freely adjusted within the range of 0.1-50%, thereby achieving a good drug loading effect and having a good application prospect in the fields of medical cosmetology, drug delivery, etc.

[0025] (3) Under the same solution volume conditions, the yield of microspheres prepared by the preparation method of the present invention is higher, thereby saving preparation costs.

[0026] (4) The method of the present invention not only has a high microsphere yield, but also the prepared microspheres have a porous structure, low ionic surfactant residues, and can be naturally degraded, which has good application prospects in the fields of drug delivery and medical beauty. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1-2 The SEM images of the microspheres prepared in Example 1 of the present invention and Comparative Example 1 are shown. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below in conjunction with the accompanying drawings. It is worth noting that the following examples are only for better explanation of the content of the present invention and are not intended to limit the scope of protection of the present invention. The undisclosed process steps in the examples are prior art. Unless otherwise specified, the following raw materials are commercially available.

[0029] In the following examples and comparative examples, the flotation treatment includes the following steps: mixing the microspheres and water uniformly, standing and separating the layers, and removing the supernatant.

[0030] Example 1

[0031] The preparation method of polyhydroxyalkanoate microspheres of this embodiment comprises the following steps:

[0032] (1) 100 g of poly 3-hydroxypropionic acid was added to 1 L of dichloromethane solvent, and the poly 3-hydroxypropionic acid was completely dissolved under stirring conditions. Then, 50 g of diglycerol dioleate was added and dispersed evenly to obtain a polyhydroxy fatty acid solution.

[0033] (2) 100 g of non-ionic surfactant ether polyethylene glycol was added to 10 L of deionized water and dissolved evenly, and then 10 g of ionic surfactant sodium dodecylbenzene sulfonate was added and stirred evenly to obtain an emulsion.

[0034] (3) The emulsion obtained in step (2) is emulsified using a homogenizer at a rotation speed of 1000 rpm, and then the polyhydroxyalkanoic acid solution obtained in step (1) is gradually added to the emulsion under this condition. The emulsification is stopped after 5 minutes, and then the obtained emulsion is transferred to a mechanical stirring condition and stirred at 500 rpm for 8 hours. While stirring, the temperature is raised to 45° C. to gradually evaporate the solvent to obtain polyhydroxyalkanoate microspheres.

[0035] (4) The polyhydroxyalkanoate microspheres obtained in step (3) are sieved with a 200-mesh sieve and subjected to flotation treatment 10 times to obtain polyhydroxyalkanoate microspheres with uniform particle size distribution.

[0036] Example 2

[0037] The preparation method of polyhydroxyalkanoate microspheres of this embodiment comprises the following steps:

[0038] (1) 150 g of poly 3-hydroxybutyric acid was added to 1 L of dichloromethane solvent, and the poly 3-hydroxybutyric acid was completely dissolved under stirring conditions. Then, 50 g of diglycerol dioleate was added and dispersed evenly to obtain a polyhydroxy fatty acid solution.

[0039] (2) 50 g of nonionic surfactant alkylphenol polyoxyethylene ether was added to 10 L of deionized water and dissolved evenly, and then 5 g of ionic surfactant sodium lauryl sulfate was added and stirred evenly to obtain an emulsion.

[0040] (3) The emulsion obtained in step (2) is emulsified using a homogenizer at a rotation speed of 3000 rpm, and then the polyhydroxyalkanoic acid solution obtained in step (1) is gradually added to the emulsion under this condition. The emulsification is stopped after 10 minutes, and then the obtained emulsion is transferred to a mechanical stirring condition and stirred at 800 rpm for 8 hours. While stirring, the temperature is raised to 50° C. to gradually evaporate the solvent to obtain polyhydroxyalkanoate microspheres.

[0041] (4) The polyhydroxyalkanoate microspheres obtained in step (3) were sieved with a 600-mesh sieve and subjected to flotation treatment 15 times to obtain polyhydroxyalkanoate microspheres with uniform particle size distribution.

[0042] Example 3

[0043] The preparation method of polyhydroxyalkanoate microspheres of this embodiment comprises the following steps:

[0044] (1) 50 g of poly 4-hydroxybutyric acid was added to 1 L of dichloromethane solvent, and the poly 4-hydroxybutyric acid was completely dissolved under stirring conditions. Then, 50 g of decaglycerol dioleate was added and dispersed evenly to obtain a polyhydroxy fatty acid solution.

[0045] (2) 10 g of a nonionic surfactant, polyoxyethylene fatty acid ester, was added to 10 L of deionized water and dissolved evenly. Then, 10 g of an ionic surfactant, 3-allyloxy-2-hydroxy-1-propane sulfonic acid sodium salt, was added and stirred evenly to obtain an emulsion.

[0046] (3) The emulsion obtained in step (2) is emulsified using a homogenizer at a rotation speed of 5000 rpm, and then the polyhydroxyalkanoic acid solution obtained in step (1) is gradually added to the emulsion under this condition. The emulsification is stopped after 5 minutes, and then the obtained emulsion is transferred to a mechanical stirring condition and stirred at 600 rpm for 8 hours. While stirring, the temperature is raised to 45° C. to gradually evaporate the solvent to obtain polyhydroxyalkanoate microspheres.

[0047] (4) The polyhydroxyalkanoate microspheres obtained in step (3) were sieved with a 1000-mesh sieve and subjected to 20 flotation treatments to obtain polyhydroxyalkanoate microspheres with uniform particle size distribution.

[0048] Example 4

[0049] The preparation method of polyhydroxyalkanoate microspheres of this embodiment comprises the following steps:

[0050] (1) 150 g of a copolymer of 3-hydroxybutyric acid and 4-hydroxybutyric acid was added to 1 L of a dichloromethane solvent, and the copolymer of 3-hydroxybutyric acid and 4-hydroxybutyric acid was completely dissolved under stirring. Then, 100 g of triglycerol dioleate was added and dispersed evenly to obtain a polyhydroxy fatty acid solution.

[0051] (2) 25 g of nonionic surfactant fatty acid polyoxyethylene ester was added to 10 L of deionized water and dissolved evenly, and then 5 g of ionic surfactant sodium lauryl sulfate was added and stirred evenly to obtain an emulsion.

[0052] (3) The emulsion obtained in step (2) is emulsified using a homogenizer at a rotation speed of 10000 rpm, and then the polyhydroxyalkanoic acid solution obtained in step (1) is gradually added to the emulsion under this condition. The emulsification is stopped after 5 minutes, and then the obtained emulsion is transferred to a mechanical stirring condition and stirred at 1000 rpm for 8 hours. While stirring, the temperature is raised to 50° C. to gradually evaporate the solvent to obtain polyhydroxyalkanoate microspheres.

[0053] (4) The polyhydroxyalkanoate microspheres obtained in step (3) were sieved with a 5000-mesh sieve and subjected to 20 flotation treatments to obtain polyhydroxyalkanoate microspheres with uniform particle size distribution.

[0054] Comparative Example 1

[0055] The preparation method of the microspheres of this comparative example comprises the following steps:

[0056] (1) 100 g of poly (3-hydroxypropionic acid) was added into 1 L of dichloromethane solvent, and the poly (3-hydroxypropionic acid) was completely dissolved under stirring to obtain a poly (3-hydroxypropionic acid) solution.

[0057] (2) 100 g of non-ionic surfactant ether type polyethylene glycol was added to 10 L of deionized water and dissolved evenly, and then 50 g of ionic surfactant sodium dodecylbenzene sulfonate was added and stirred evenly to obtain an emulsion.

[0058] (3) The emulsion obtained in step (2) is emulsified using a homogenizer at a rotation speed of 1000 rpm, and then the poly 3-hydroxypropionic acid solution obtained in step (1) is gradually added to the emulsion under this condition. The emulsification is stopped after 5 minutes, and then the obtained emulsion is transferred to a mechanical stirring condition and stirred at 500 rpm for 8 hours. While stirring, the temperature is raised to 45° C. to gradually evaporate the solvent to obtain microspheres.

[0059] (4) The microspheres obtained in step (3) were sieved with a 200-mesh sieve and subjected to 10 flotation treatments to obtain microspheres with uniform particle size distribution.

[0060] Comparative Example 2

[0061] The preparation method of the microspheres of this comparative example comprises the following steps:

[0062] (1) 100 g of poly 3-hydroxypropionic acid was added to 1 L of dichloromethane solvent, and the poly 3-hydroxypropionic acid was completely dissolved under stirring conditions. Then, 50 g of diglycerol dioleate was added and dispersed evenly to obtain a polyhydroxy fatty acid solution.

[0063] (2) Add 10 g of the ionic surfactant sodium dodecylbenzene sulfonate into 10 L of deionized water and stir to dissolve evenly to obtain an emulsion.

[0064] (3) The emulsion obtained in step (2) is emulsified using a homogenizer at a rotation speed of 1000 rpm, and then the polyhydroxy fatty acid solution obtained in step (1) is gradually added to the emulsion under this condition. The emulsification is stopped after 5 minutes, and then the obtained emulsion is transferred to a mechanical stirring condition and stirred at 500 rpm for 8 hours. While stirring, the temperature is raised to 45° C. to gradually evaporate the solvent to obtain microspheres.

[0065] (4) The microspheres obtained in step (3) were sieved with a 200-mesh sieve and subjected to 10 flotation treatments to obtain microspheres with uniform particle size distribution.

[0066] Comparative Example 3

[0067] The preparation method of the microspheres of this comparative example comprises the following steps:

[0068] (1) 100 g of poly 3-hydroxypropionic acid was added to 1 L of dichloromethane solvent, and the poly 3-hydroxypropionic acid was completely dissolved under stirring conditions. Then, 50 g of diglycerol dioleate was added and dispersed evenly to obtain a polyhydroxy fatty acid solution.

[0069] (2) Add 20 g of the ionic surfactant sodium dodecylbenzene sulfonate into 10 L of deionized water and stir to dissolve evenly to obtain an emulsion.

[0070] (3) The emulsion obtained in step (2) is emulsified using a homogenizer at a rotation speed of 1000 rpm, and then the polyhydroxy fatty acid solution obtained in step (1) is gradually added to the emulsion under this condition. The emulsification is stopped after 5 minutes, and then the obtained emulsion is transferred to a mechanical stirring condition and stirred at 500 rpm for 8 hours. While stirring, the temperature is raised to 45° C. to gradually evaporate the solvent to obtain microspheres.

[0071] (4) The microspheres obtained in step (3) were sieved with a 200-mesh sieve and subjected to 10 flotation treatments to obtain microspheres with uniform particle size distribution.

[0072] In order to verify whether the polyhydroxyalkanoate microspheres prepared by the present invention achieve the expected effect, the yield, morphology, and residual content of ionic surfactant of the microspheres prepared in Examples 1-4 and Comparative Examples 1-3 were measured.

[0073] 1. Microsphere yield

[0074] The obtained microspheres were weighed to obtain the amount of microspheres, and the microsphere yield was calculated according to the initial amount of polyhydroxy fatty acid added: Microsphere yield (%) = microsphere amount / initial amount × 100%.

[0075] Table 1 Microsphere yields of different embodiments and comparative examples

[0076] Example Initial feed amount (g) Microsphere amount (g) Microsphere yield (%) Example 1 100 82.3 82.3 Example 2 150 123.6 82.4 Example 3 50 41.5 83.0 Example 4 150 119.8 79.9 Comparative Example 1 100 80.1 80.1 Comparative Example 2 100 0 0 Comparative Example 3 100 79.8 79.8

[0077] As can be seen from Table 1, the microsphere yield of Examples 1-4 of the present invention is above 79.9%, which is higher than the conventional method of Comparative Examples 2 and 3, indicating that the method of the present invention has a higher microsphere yield and can greatly reduce solvent emissions.

[0078] 2. Residual amount of ionic surfactant

[0079] Since ionic surfactants can cause certain cytotoxicity when used in practice, it is important to control the residual amount of ionic surfactants. The residual amount of ionic surfactants in the microspheres was determined by inductively coupled plasma mass spectrometry (ICP-MS). The specific determination method is as follows: 0.1 g of microspheres were taken, 10 mL of concentrated nitric acid was added to digest, and then the volume was fixed to 10 mL. The Na content was determined by ICP-MS, and the content of ionic surfactants was calculated.

[0080] Table 2 Residual amount of ionic surfactant in microspheres of different embodiments and comparative examples

[0081]

[0082]

[0083] It can be seen from Table 2 that the residual amount of ionic surfactant in the microspheres prepared in Examples 1-4 of the present invention is less than 0.010 mg / g, which is significantly lower than that in Comparative Example 3, indicating that the microspheres prepared by the method of the present invention have a lower residual amount of ionic surfactant, which is more advantageous for subsequent applications of the microspheres.

[0084] 3. Microsphere morphology

[0085] The SEM images of the microspheres prepared in Example 1 and Comparative Example 1 are as follows: Figure 1-2 As shown, Figure 1 This is the SEM image of the microspheres prepared in Example 1. Figure 2 This is the SEM image of the microspheres prepared in Comparative Example 1.

[0086] from Figure 1-2 It can be seen that the microspheres prepared in Example 1 have a porous structure, while the microspheres prepared in Comparative Example 1 do not have a porous structure. This indicates that the present invention can obtain microspheres with a porous structure by adding a porogen.

[0087] The above are only some specific embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the creative concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing polyhydroxyalkanoate microspheres, characterized in that: The steps include: (1) adding polyhydroxy fatty acid into an organic solvent to dissolve it, and then adding a porogen to disperse it to obtain a polyhydroxy fatty acid solution; (2) adding a nonionic surfactant into water to dissolve it, then adding an ionic surfactant and stirring to obtain an emulsion; (3) emulsifying the emulsion obtained in step (2) using a homogenizer, and then adding the polyhydroxyalkanoic acid solution to the emulsion under emulsification conditions, emulsifying for 5-20 minutes, and then transferring the obtained mixed solution to mechanical stirring conditions, and heating and evaporating the solvent while stirring to obtain polyhydroxyalkanoate microspheres; (4) Screening the polyhydroxyalkanoate microspheres and then performing flotation treatment to obtain polyhydroxyalkanoate microspheres with uniform particle size distribution.

2. The method for preparing polyhydroxyalkanoate microspheres according to claim 1, characterized in that: In step (1), the polyhydroxyalkanoic acid is at least one of poly 3-hydroxypropionic acid, poly 3-hydroxybutyric acid, poly 3-hydroxyvaleric acid, poly 3-hydroxyhexanoic acid, poly 4-hydroxybutyric acid, poly 5-hydroxyvaleric acid, a copolymer of 3-hydroxybutyric acid and 3-hydroxyvaleric acid, and a copolymer of 3-hydroxybutyric acid and 4-hydroxybutyric acid; The organic solvent is dichloromethane and / or chloroform; The concentration of polyhydroxyalkanoic acid in the polyhydroxyalkanoic acid solution is 1-15 wt %.

3. The method for preparing polyhydroxyalkanoate microspheres according to claim 1 or 2, characterized in that: In step (1), the porogen is at least one of diglycerol dioleate, triglycerol dioleate, and decaglycerol dioleate; The concentration of the porogen in the polyhydroxyalkanoic acid solution is 0.5-10 wt %.

4. The method for preparing polyhydroxyalkanoate microspheres according to claim 1 or 2, characterized in that: In step (2), the nonionic surfactant is at least one of alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester, and polyoxyethylene alkylamine; and the concentration of the nonionic surfactant in the emulsion is 0.1-1.5wt%.

5. The method for preparing polyhydroxyalkanoate microspheres according to claim 1 or 2, characterized in that: In step (2), the ionic surfactant is at least one of sodium dodecylbenzene sulfonate, sodium 3-allyloxy-2-hydroxy-1-propane sulfonate, sodium lauryl sulfate, potassium cetyl phosphate, and sodium lauroyl sarcosinate; and the concentration of the ionic surfactant in the emulsion is 0.05-0.1wt%.

6. The method for preparing polyhydroxyalkanoate microspheres according to claim 1 or 2, characterized in that: In step (3), the speed of the homogenizer is 1000-12000 rpm; The polyhydroxy fatty acid solution obtained in step (1) is added to the emulsion at a volume ratio of polyhydroxy fatty acid solution to emulsion of 1:(10-100).

7. The method for preparing polyhydroxyalkanoate microspheres according to claim 1 or 2, characterized in that: In step (3), the rotation speed of the mechanical stirring is 100-2000 rpm; while stirring, the temperature is raised to 30-70° C. to evaporate the solvent.

8. The method for preparing polyhydroxyalkanoate microspheres according to claim 1 or 2, characterized in that: In step (4), sieving is performed using a sieve with a mesh size of 100-15000 mesh; The flotation treatment comprises the following steps: mixing the microspheres and water uniformly, standing and separating the layers, and removing the supernatant; the flotation times are 10-30 times.

9. Polyhydroxyalkanoate microspheres prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the polyhydroxyalkanoate microspheres according to claim 9 in the preparation of medical cosmetic products, medicines, cosmetics or foods.

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