Preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres

Abstract

The present invention discloses a preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres. The sodium hyaluronate-coated polylactic acid microspheres are prepared by the emulsion method. On the one hand, by utilizing the good hydrophilic property of hyaluronic acid itself, the freeze-dried sodium hyaluronate-coated polylactic acid microspheres can be well redissolved in injection water, greatly reducing problems such as long redissolution time and uneven particle dispersion. On the other hand, after the sodium hyaluronate-coated polylactic acid microspheres are subcutaneously injected, the first thing they contact is sodium hyaluronate with better biocompatibility, avoiding the more irritating inflammatory phenomenon caused by direct contact with the polylactic acid microspheres. As the sodium hyaluronate on the outer layer of the microspheres is enzymatically degraded, the inner layer of polylactic acid microspheres will be exposed, further playing a role in stimulating the body's own collagen production. In addition, the preparation method of the present invention has simple technological steps and is suitable for large-scale preparation for industrial applications.

Description

Technical Field

[0001] The present invention belongs to the technical field of injectable facial fillers, and relates to a preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres. Background Art

[0002] Facial aging is a complex process affected by multiple factors, including genetic defects, light, external environment, inflammatory responses, and diseases, etc. The characteristics of facial aging mainly include soft tissue loss, collagen loss, and decreased skin hydration, etc., which in turn cause the appearance of fine lines and wrinkles on the face. Currently, cross-linked sodium hyaluronate filling needles are widely used, which physically fill and support the sunken parts of the face. However, sodium hyaluronate will be absorbed in the human body, and even the degradation time of cross-linked sodium hyaluronate gel generally does not exceed 1 year. In order to further extend the maintenance time of the filling material, degradable polymer microsphere materials have come into the public eye.

[0003] Polylactic acid (PLA) is a biodegradable polymer material approved by the US Food and Drug Administration (FDA) for use in the human body. Due to its good biocompatibility and biodegradability, polylactic acid and its copolymers have been widely used in the fields of absorbable medical devices, drug controlled release, tissue engineering, etc. After implantation, polylactic acid is first degraded into lactic acid in the body, participates in the tricarboxylic acid cycle in the process of sugar metabolism, and then is metabolized by enzymes in the body into the end products carbon dioxide and water, which are excreted from the body. After subcutaneous injection of polylactic acid material, it can stimulate subcutaneous cells to secrete a large amount of extracellular matrix mainly composed of collagen, thus promoting the production of collagen. As polylactic acid degrades, the filled area can ultimately be replaced by newly generated autologous tissue, thereby achieving long-term cosmetic effects such as improving skin quality, smoothing wrinkles, and facial shaping.

[0004] However, polylactic acid is a material with relatively strong hydrophobicity. It is very difficult to redissolve in an aqueous solution, has poor dispersibility, and is prone to aggregation and sedimentation. This leads to problems such as needle clogging during intradermal injection, increased pain for patients due to the use of a thicker needle during injection, uneven distribution of the injection material, and the appearance of subcutaneous nodules after injection. At present, sodium carboxymethyl cellulose (CMC) or cross-linked sodium hyaluronate (HA) gel is often used as a suspending agent to improve the above problems. Sodium carboxymethyl cellulose is not an endogenous substance in the human body, and in terms of its biocompatibility, it is not the best choice. Moreover, as a suspending reagent for polylactic acid products, CMC generally requires a long hydration time before it can be used for injection. Cross-linked HA gel will inevitably introduce cross-linking agents, and the removal of cross-linking agents requires a long dialysis process, which greatly prolongs the operation time of the entire process. In addition, compared with endogenous substances such as hyaluronic acid in the human body, materials with stronger hardness such as polylactic acid microspheres will be quickly recognized as foreign substances by the human body after subcutaneous injection, so foreign body reactions such as redness and inflammation are more obvious. For sensitive people, injecting pure polylactic acid microsphere products has a relatively high risk.

[0005] For example: the patent with publication number CN110051882A discloses a preparation method of polylactic acid microspheres. By mixing a polylactic acid solution with a polyvinyl alcohol solution and performing high-speed shearing and freeze-drying, polylactic acid microspheres are obtained. However, the polylactic acid microspheres prepared by this method have poor dispersibility in an aqueous solution and a long redissolution time. Generally, redissolution needs to be carried out 2 days in advance before injection can be performed; application number CN201410438010.3 discloses an injectable mixed gel of polylactic acid microspheres and cross-linked hyaluronic acid and its preparation method. However, polylactic acid microspheres have poor hydrophilicity, are difficult to disperse uniformly in sodium hyaluronate gel, and are not conducive to dispersion in the human body's aqueous environment. After injection, they are prone to caking, and the introduction of toxic cross-linking agents reduces the safety of the final product; the patent document with publication number CN105126166B discloses an injectable hyaluronic acid mixed gel containing amphiphilic microspheres and its preparation method, which solves the problem of easy dispersion and difficult aggregation of microspheres to a certain extent. However, the introduction of cross-linking agent 1,4-butanediol diglycidyl ether reduces the biological safety, and the process of removing cross-linking agents by long-term dialysis also prolongs the entire reaction process. The patent document with publication number CN109010910B discloses a preparation method of injectable left-handed polylactic acid microspheres. By directly dropping an organic solution containing left-handed polylactic acid into an aqueous solution of sodium carboxymethyl cellulose / mannitol and performing freeze-drying, injectable left-handed polylactic acid microspheres are obtained. However, the size uniformity of the microspheres prepared by this method is not good, and the dispersion stability of small-molecule aqueous reagents for the microspheres also needs to be further enhanced. Summary of the Invention

[0006] The object of the present invention is to overcome the defects of the prior art and provide a preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres. The prepared sodium hyaluronate-coated polylactic acid microspheres have better biocompatibility, shorter redissolution time and better stability. On the one hand, by utilizing the good hydrophilic property of hyaluronic acid itself, the freeze-dried sodium hyaluronate-coated polylactic acid microspheres can be well redissolved in water for injection, greatly reducing problems such as long redissolution time and uneven particle dispersion. On the other hand, after the sodium hyaluronate-coated polylactic acid microspheres are subcutaneously injected, the first thing they contact is sodium hyaluronate with better biocompatibility, avoiding the more irritating inflammatory phenomenon caused by direct contact with the polylactic acid microspheres. As the outer layer of sodium hyaluronate of the microspheres undergoes enzymatic degradation, the inner layer of polylactic acid microspheres will be exposed, further playing a role in stimulating the body's own collagen production.

[0007] The technical solution for achieving the above object is: A preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, comprising the following steps:

[0008] S1, Aqueous phase preparation step: Dissolve polyvinyl alcohol in an aqueous solution, heat and stir at 70 °C to dissolve, prepare a polyvinyl alcohol solution, and then after cooling the polyvinyl alcohol solution to room temperature, add sodium hyaluronate powder, stir and mix evenly to obtain the aqueous phase;

[0009] S2, Oil phase preparation step: Dissolve polylactic acid powder in an organic solvent, mix evenly to obtain the oil phase;

[0010] S3, Microsphere preparation step: Under stirring, dropwise add the oil phase obtained in step S2 into the aqueous phase obtained in step S1, and stir at room temperature to form an emulsion;

[0011] S4, Post-treatment step: After stirring the emulsion until the reaction is completed, wash the microspheres in the emulsion by centrifugation with water multiple times, and freeze-dry to obtain sodium hyaluronate-coated polylactic acid microspheres.

[0012] In the above preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, in step S1, the molecular weight of the polyvinyl alcohol is preferably 20000 - 300000 Da, and the concentration of the polyvinyl alcohol aqueous solution is 0.3 - 2 g / mL

[0013] In the above preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, in step S1, the molecular weight of the sodium hyaluronate is preferably 400000 - 2000000 Da, and the concentration of the sodium hyaluronate in the aqueous phase is preferably 0.1 - 1.5 g / mL.

[0014] In the above preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, in step S2, the polylactic acid powder is polylactic acid (PLA) powder modified with polyethylene glycol (PEG); the organic solvent is dichloromethane or chloroform.

[0015] In the above preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, in step S2, the polyethylene glycol-modified polylactic acid powder includes poly (L-lactic acid)-polyethylene glycol (PLLA-PEG) powder, poly (D-lactic acid)-polyethylene glycol (PDLA-PEG) powder, and poly (D,L-lactic acid)-polyethylene glycol (PDLLA-PEG) powder.

[0016] In the above preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, in step S2, the molecular weight of the polyethylene glycol-modified polylactic acid powder is preferably 10,000 - 400,000 Da, and the molecular weight ratio of the polyethylene glycol segment to the polylactic acid segment is preferably (5 - 500):1, and the concentration of polylactic acid in the oil phase is 0.005 - 1.0 g / mL.

[0017] In the above preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, in step S3, the stirring speed when the oil phase is dropped into the water phase is preferably 100 - 1500 rpm, and the stirring reaction time is preferably 2 - 10 h.

[0018] In the above preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, in step S4, during the process of washing the microspheres by centrifugation with water multiple times, the centrifugation speed used for each water washing and centrifugation is preferably 1000 - 6000 rpm, and the centrifugation time is preferably 2 min - 20 min.

[0019] In the preparation method of the injectable sodium hyaluronate-coated polylactic acid microspheres of the present invention, sodium hyaluronate is directly introduced into the water phase, and an emulsion technology is used to coat a layer of sodium hyaluronate on the surface of the polyethylene glycol-modified polylactic acid microspheres, which has the following beneficial effects:

[0020] (1) The most commonly used method for preparing existing polylactic acid microspheres is to dissolve polylactic acid in an organic reagent as the oil phase and drop it into an aqueous solution containing a surfactant. However, the prepared polylactic acid microspheres are difficult to redissolve in an aqueous solution due to their strong hydrophobicity. In this application, polylactic acid modified with polyvinyl alcohol is used, which greatly improves the defect of poor hydrophilicity of pure polylactic acid and can improve the redissolubility and stability of the material to a certain extent. In addition, the sodium hyaluronate coated on the outer layer of the polylactic acid microspheres has excellent hydrophilic properties, which can further shorten the redissolution time in an aqueous solution and improve the dispersion uniformity and stability of the microspheres in injection water;

[0021] (2) The outer layer of the polylactic acid microspheres is wrapped with uncrosslinked sodium hyaluronate. Although crosslinked sodium hyaluronate gel can extend the degradation time, the introduced crosslinking agent will undoubtedly increase the toxicity risk. The molecular weight of the uncrosslinked sodium hyaluronate selected in this application is determined through a large number of experimental screenings. The time required for its complete degradation is much longer than the redissolution time of the microspheres in the aqueous solution. Therefore, there is no need to worry that the polylactic acid microspheres wrapped with sodium hyaluronate will be completely degraded during the redissolution process, resulting in uneven redispersion of the polylactic acid microspheres. In addition, the polyethylene glycol segment in the PLA-PEG molecule can inhibit the adhesion of substances such as plasma proteins and enzymes on the surface of PEG, inhibit the degradation of HA to a certain extent, and improve the stability of the microspheres;

[0022] (3) The sodium hyaluronate on the outer layer of the sodium hyaluronate-wrapped polylactic acid microspheres has good biocompatibility. After subcutaneous injection, the first thing the body comes into contact with is the sodium hyaluronate on the outer layer of the microspheres, with high biological safety, greatly reducing the irritation of the relatively hard polylactic acid microspheres to the body. Moreover, the water-retaining and moisturizing properties of sodium hyaluronate itself can improve the hydration state of the skin to a certain extent. Under the action of hyaluronidase, the sodium hyaluronate on the outer layer of the microspheres gradually degrades, and the polyethylene glycol-modified polylactic acid microspheres are completely exposed, starting to stimulate the regeneration of subcutaneous collagen;

[0023] (4) After the sodium hyaluronate-wrapped polylactic acid microspheres prepared by the emulsion method are redissolved in injection water, they are easy to inject and can be used as facial fillers to reduce facial wrinkles, restore the elasticity and vitality of the skin, and have a long-lasting effect and no irritation to the skin. The operation process of the present invention is simple, easy to control, and the product quality is stable, and it can be used for industrial production. Description of the Drawings

[0024] Figure 1 The picture observed under the microscope after the sodium hyaluronate-wrapped polylactic acid microspheres prepared in Example 1 are redissolved in injection water for 5 h;

[0025] Figure 2 The picture observed under the microscope after the sodium hyaluronate-wrapped polylactic acid microspheres prepared in Example 2 are redissolved in injection water for 5 h;

[0026] Figure 3 The picture observed under the microscope after the sodium hyaluronate-wrapped polylactic acid microspheres prepared in Example 3 are redissolved in injection water for 5 h;

[0027] Figure 4 The picture observed under the microscope after the sodium hyaluronate-wrapped polylactic acid microspheres prepared in Example 4 are redissolved in injection water for 5 h. Detailed Embodiments

[0028] To enable those skilled in the art of this technology to better understand the technical solution of the present invention, the following provides a detailed description of its specific implementation manners in conjunction with the accompanying drawings:

[0029] Example 1

[0030] A preparation method of injectable sodium hyaluronate-coated poly(lactic acid) microspheres, comprising the following steps:

[0031] S1, Aqueous phase preparation step: Dissolve 1.0 g of polyvinyl alcohol with a molecular weight of 47000 Da in 99.0 g of injection water, heat and stir at 70 °C for dissolution to prepare a 1% polyvinyl alcohol solution. After the polyvinyl alcohol aqueous solution is cooled to room temperature, add 0.5 g of sodium hyaluronate powder with a molecular weight of 1600000 Da thereto, and stir and mix evenly to obtain the aqueous phase;

[0032] S2, Oil phase preparation step: Dissolve 0.1 g of PLLA-PEG powder (PLLA with a molecular weight of 20000 Da and PEG with a molecular weight of 2000 Da) in 4 mL of dichloromethane, stir and mix evenly to obtain a poly(lactic acid) organic reagent solution with a concentration of 0.025 g / mL, which is the oil phase;

[0033] S3, Microsphere preparation step: At a stirring speed of 250 rpm, dropwise add the oil phase obtained in step S2 to the aqueous phase obtained in step S1 using a syringe, stir at room temperature to form an emulsion, and continue to react for 5 h;

[0034] S4, Post-treatment step: After the reaction is completed, wash and centrifuge the microspheres several times with water, where the centrifugation speed is 4000 rpm each time and the centrifugation time is 10 min. Finally, freeze-dry to obtain sodium hyaluronate-coated poly(lactic acid) microspheres.

[0035] Please refer to Figure 1 , Re-dissolve the freeze-dried sodium hyaluronate-coated poly(lactic acid) microspheres in injection water, shake vigorously to mix evenly and then let stand. After 5 h, observe under an optical microscope. The size of the polymer microspheres is 20-50 μm, and the microspheres do not aggregate and are well-dispersed. The results are as Figure 1 shown.

[0036] Example 2

[0037] A preparation method of injectable sodium hyaluronate-coated poly(lactic acid) microspheres, comprising the following steps:

[0038] S1, Preparation step of the aqueous phase: Dissolve 0.5 g of polyvinyl alcohol with a molecular weight of 205,000 Da in 99.5 g of injection water, heat and stir at 70 °C until dissolved to prepare a polyvinyl alcohol solution with a concentration of 0.5%. After the polyvinyl alcohol aqueous solution cools to room temperature, add 0.7 g of sodium hyaluronate powder with a molecular weight of 1,200,000 Da thereto, and stir and mix evenly to obtain the aqueous phase;

[0039] S2, Preparation step of the oil phase: Dissolve 0.25 g of PLLA-PEG powder (PLLA with a molecular weight of 200,000 Da and PEG with a molecular weight of 4000 Da) in 4 mL of dichloromethane, stir and mix evenly to obtain a polylactic acid organic reagent solution with a concentration of 0.0625 g / mL, which is the oil phase;

[0040] S3, Preparation step of the microspheres: At a stirring speed of 500 rpm, dropwise add the oil phase obtained in step S2 into the aqueous phase obtained in step S1 with a syringe, stir at room temperature to form an emulsion, and continue to react for 4 h;

[0041] S4, Post-treatment step: After the reaction is completed, wash and centrifuge the microspheres with water multiple times, where the centrifugation speed is 4500 rpm each time and the centrifugation time is 12 min. Finally, freeze-dry to obtain sodium hyaluronate-coated polylactic acid microspheres.

[0042] Please refer to Figure 2 , redissolve the freeze-dried sodium hyaluronate-coated polylactic acid microspheres in injection water, shake vigorously to mix evenly and then let stand. Observe under an optical microscope after 5 h. The size of the polymer microspheres is 15 - 25 μm, and the microspheres do not aggregate and are well dispersed. The results are as Figure 2 shown.

[0043] Example 3:

[0044] A preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, comprising the following steps:

[0045] S1, Preparation step of the aqueous phase: Dissolve 1.5 g of polyvinyl alcohol with a molecular weight of 85,000 Da in 98.5 g of injection water, heat and stir at 70 °C until dissolved to prepare a polyvinyl alcohol solution with a concentration of 1.5%. After the polyvinyl alcohol aqueous solution cools to room temperature, add 1.0 g of sodium hyaluronate powder with a molecular weight of 720,000 Da thereto, and stir and mix evenly to obtain the aqueous phase;

[0046] S2, Preparation step of the oil phase: Dissolve 0.3 g of PLLA-PEG powder (PLLA with a molecular weight of 100,000 Da and PEG with a molecular weight of 1500 Da) in 3 mL of dichloromethane, stir and mix evenly to obtain a polylactic acid organic reagent solution with a concentration of 0.1 g / mL, which is the oil phase;

[0047] S3, Microsphere preparation step: At a stirring speed of 150 rpm, the oil phase obtained in step S2 was added dropwise into the aqueous phase obtained in step S1 using a syringe, and stirred at room temperature to form an emulsion, followed by continuous reaction for 6 h;

[0048] S4, Post-treatment step: After the reaction was completed, the microspheres were washed and centrifuged several times, with each centrifugation speed being 3500 rpm and the centrifugation time being 15 min. Finally, the sodium hyaluronate-coated polylactic acid microspheres were obtained by freeze-drying.

[0049] Please refer to Figure 3 , the freeze-dried sodium hyaluronate-coated polylactic acid microspheres were redissolved in water for injection, shaken vigorously and mixed well, and then allowed to stand. After 5 h, observation under an optical microscope showed that the size of the polymer microspheres was in the range of 20 - 35 μm, and the microspheres did not aggregate and were well dispersed. The results are as Figure 3 shown.

[0050] Example 4:

[0051] A method for preparing injectable sodium hyaluronate-coated polylactic acid microspheres, comprising the following steps:

[0052] S1, Aqueous phase preparation step: 1.0 g of polyvinyl alcohol with a molecular weight of 150,000 Da was dissolved in 99.0 g of water for injection, heated and stirred at 70 °C until dissolved to prepare a 1% polyvinyl alcohol solution. After the polyvinyl alcohol aqueous solution cooled to room temperature, 1.5 g of sodium hyaluronate powder with a molecular weight of 600,000 Da was added thereto, and stirred and mixed evenly to obtain the aqueous phase;

[0053] S2, Oil phase preparation step: 0.1 g of PLLA-PEG powder (PLLA with a molecular weight of 50,000 Da and PEG with a molecular weight of 1000 Da) was dissolved in 5 mL of dichloromethane, stirred and mixed evenly to obtain a polylactic acid organic reagent solution with a concentration of 0.02 g / mL, which was the oil phase;

[0054] S3, Microsphere preparation step: At a stirring speed of 250 rpm, the oil phase obtained in step S2 was added dropwise into the aqueous phase obtained in step S1 using a syringe, and stirred at room temperature to form an emulsion, followed by continuous reaction for 5 h;

[0055] S4, Post-treatment step: After the reaction was completed, the microspheres were washed and centrifuged several times, with each centrifugation speed being 4500 rpm and the centrifugation time being 15 min. Finally, the sodium hyaluronate-coated polylactic acid microspheres were obtained by freeze-drying.

[0056] Please refer to Figure 4, the freeze-dried sodium hyaluronate-coated polylactic acid microspheres were redissolved in water for injection, shaken vigorously and mixed well, and then allowed to stand. After 5 h, observation under an optical microscope showed that the size of the polymer microspheres was 25-45 μm, and the microspheres did not aggregate and were well dispersed. The results are as Figure 4 shown.

[0057] The preparation method of the injectable sodium hyaluronate-coated polylactic acid microspheres of the present invention uses polylactic acid modified by polyvinyl alcohol, which greatly improves the defect of poor hydrophilicity of pure polylactic acid and can improve the redissolubility and stability of the material to a certain extent. In addition, the sodium hyaluronate coated on the outer layer of the polylactic acid microspheres has excellent hydrophilic properties, which can further shorten the redissolution time in aqueous solution and improve the dispersion uniformity and stability of the microspheres in water for injection; the sodium hyaluronate coated on the outer layer of the polylactic acid microspheres is uncrosslinked sodium hyaluronate, and the time required for its complete degradation is much longer than the redissolution time of the microspheres in aqueous solution. Therefore, there is no need to worry that the sodium hyaluronate-coated polylactic acid microspheres will be completely degraded during the redissolution process, resulting in non-uniform redispersion of the polylactic acid microspheres; in addition, the polyethylene glycol segment in the PLA-PEG molecule can inhibit the adhesion of substances such as plasma proteins and enzymes on the surface of PEG, inhibit the degradation of HA to a certain extent, and improve the stability of the microspheres; the sodium hyaluronate on the outer layer of the polylactic acid microspheres has good biocompatibility. After subcutaneous injection, the sodium hyaluronate on the outer layer of the microspheres is the first to come into contact with the body, with high biological safety, greatly reducing the irritation of the relatively hard polylactic acid microspheres to the body, and the water replenishing and moisturizing properties of sodium hyaluronate itself can improve the hydration state of the skin to a certain extent. Under the action of hyaluronidase, the sodium hyaluronate on the outer layer of the microspheres gradually degrades, and the polyethylene glycol-modified polylactic acid microspheres are completely exposed, starting to stimulate the regeneration of subcutaneous collagen; after the sodium hyaluronate-coated polylactic acid microspheres prepared by the emulsion method are redissolved in water for injection, they are easy to inject, can be used as facial fillers, reduce facial wrinkles, restore the elasticity and vitality of the skin, and have a long-lasting effect and no irritation to the skin. The operation process of the present invention is simple, easy to control, and the product quality is stable, and it can be used for industrial production.

[0058] In summary, the preparation method of the injectable sodium hyaluronate-coated polylactic acid microspheres of the present invention can prepare a series of injectable sodium hyaluronate-coated polylactic acid microspheres with controllable size, uniform particles and strong biocompatibility through emulsification technology; the redissolution time of the sodium hyaluronate-coated polylactic acid microspheres in aqueous solution is short, the microspheres are evenly dispersed, the injectable effect is good, and the adverse reactions are small; in addition, the preparation method of the present invention has simple technological steps and is suitable for large-scale preparation for industrial applications.

[0059] Those of ordinary skill in the art should recognize that the above embodiments are only used to illustrate the present invention and are not intended to limit the present invention. As long as they are within the scope of the spirit of the present invention, changes and modifications to the above-described embodiments will fall within the scope of the claims of the present invention.

Claims

1. A preparation method of injectable sodium hyaluronate-coated polylactic acid microspheres, characterized in that, Comprising the following steps: S1, aqueous phase preparation step: Dissolve polyvinyl alcohol in an aqueous solution, heat and stir at 70 °C until dissolved to prepare a polyvinyl alcohol solution. Then, after cooling the polyvinyl alcohol solution to room temperature, add sodium hyaluronate powder, stir and mix evenly to obtain the aqueous phase; the molecular weight of the polyvinyl alcohol is 20,000 - 300,000 Da, and the concentration of the polyvinyl alcohol aqueous solution is 0.3 - 2 g / mL; the molecular weight of the sodium hyaluronate is 400,000 - 2,000,000 Da, and the concentration of sodium hyaluronate in the aqueous phase is 0.1 - 1.5 g / mL; S2, oil phase preparation step: Dissolve polylactic acid powder in an organic solvent, mix evenly to obtain the oil phase; the polylactic acid powder is polylactic acid powder modified with polyethylene glycol; the organic solvent is dichloromethane or chloroform; the polylactic acid powder modified with polyethylene glycol includes polylactic acid powder modified with polyethylene glycol of L-lactic acid, polylactic acid powder modified with polyethylene glycol of D-lactic acid, and polylactic acid powder modified with polyethylene glycol of racemic lactic acid; the molecular weight of the polylactic acid powder modified with polyethylene glycol is 10,000 - 400,000 Da, and the molecular weight ratio of the polyethylene glycol chain segment to the polylactic acid chain segment is (5 - 500):1, and the concentration of polylactic acid in the oil phase is 0.005 - 1.0 g / mL; S3, microsphere preparation step: Under stirring, dropwise add the oil phase obtained in step S2 into the aqueous phase obtained in step S1, and stir at room temperature to form an emulsion; the stirring speed when dropping the oil phase into the aqueous phase is 100 - 1500 rpm, and the stirring reaction time is 2 - 10 h; S4, post-treatment step: After stirring the emulsion until the reaction is complete, wash the microspheres in the emulsion by centrifugation with multiple water washes, and obtain sodium hyaluronate-coated polylactic acid microspheres after freeze-drying; during the process of washing the microspheres by centrifugation with multiple water washes, the centrifugation speed used for each water wash centrifugation is 1000 - 6000 rpm, and the centrifugation time is 2 min - 20 min.

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