Polylactic acid composite microsphere for injection, production process and application

Abstract

The invention discloses a polylactic acid composite microsphere for injection, a production process and an application, and belongs to the technical field of medical materials. The preparation method comprises dissolving L-polylactic acid and racemic polylactic acid in an organic solvent to obtain an oil phase; dissolving an emulsifier in water to obtain an aqueous phase; mixing the oil phase and the aqueous phase under stirring, removing excess solvent, and obtaining polylactic acid composite microspheres for injection. The invention prepares composite microspheres by dissolving L-polylactic acid and racemic polylactic acid simultaneously to form an oil phase, thereby achieving the co-preparation and uniform blending of long-acting and short-acting polylactic acid microspheres; the composite microspheres prepared at the same time have a suitable particle size distribution. The skin filling composition composed of the composite microspheres prepared by the invention has few adverse reactions after being injected into the body, and can quickly increase the fullness of the skin, improve wrinkles and alleviate skin sagging problems in the early stage of injection, and can maintain long-term effects for more than 2 years.

Description

Technical Field

[0001] The present invention relates to the technical field of medical materials, and in particular to a polylactic acid composite microsphere for injection, a production process and an application thereof. Background Art

[0002] In medicine, there are often irregular shaped defects and wounds that need to be filled and repaired. In such cases, the use of injectable scaffolds is very attractive because they can easily fill irregular shaped defects in situ in a minimally invasive manner, thereby improving patient comfort and satisfaction. With the increasing demand for minimally invasive surgeries in medicine, biodegradable microspheres have also been studied as injectable cell carriers for tissue regeneration.

[0003] As a biodegradable material, polylactic acid microspheres are widely used in the field of skin fillers, such as L-polylactic acid microspheres and racemic polylactic acid microspheres, which are already on the market. Clinical authorities have confirmed that polylactic acid microspheres can stimulate the skin to regenerate collagen. However, the effect of L-polylactic acid microspheres is relatively long, which can reach more than 2 years, and there is no obvious effect at the beginning of injection; at the same time, racemic polylactic acid microspheres are easy to degrade, so they will produce effects at the beginning of injection, but their effect is relatively short, about 6-12 months. At present, a large number of literature on polylactic acid microspheres have been reported. For example, CN110051882A discloses a polylactic acid microsphere, a preparation method and an application thereof, wherein polylactic acid and a solvent are mixed to obtain a polylactic acid solution; the polylactic acid includes L-polylactic acid, D-polylactic acid or meso-polylactic acid; the solvent includes dichloromethane; and then mixed with a polyvinyl alcohol solution, sheared to obtain a suspension, and then the solvent is removed to obtain polylactic acid microspheres. This patent can obtain microspheres with smooth surface, small particle size and uniformity by using polylactic acid of different chiralities, but all of them are single polylactic acid substances dispersed in the oil phase to prepare single polylactic acid microspheres.

[0004] In the current method for preparing polylactic acid microspheres, L-polylactic acid microspheres and racemic polylactic acid microspheres are usually prepared separately, and composite microspheres are rarely obtained after homogeneous dispersion. Based on the utility of different types of polylactic acid microspheres, it is necessary to provide corresponding preparation methods. Summary of the invention

[0005] In order to solve the problems existing in the prior art, the present invention adopts a one-step preparation method, dissolving L-polylactic acid and racemic polylactic acid simultaneously to form an oil phase and then preparing composite microspheres, thereby achieving the co-preparation and uniform blending of long-acting and short-acting polylactic acid microspheres.

[0006] In order to achieve the above object, the present invention provides a production process of polylactic acid composite microspheres for injection.

[0007] Dissolving L-polylactic acid and racemic polylactic acid in an organic solvent to obtain an oil phase;

[0008] dissolving an emulsifier in water to obtain an aqueous phase;

[0009] The oil phase and the water phase are mixed under stirring, and the excess solvent is removed to obtain the polylactic acid composite microspheres for injection.

[0010] Sculptra®, an approved injectable poly-L-lactic acid filler, is a well-known poly-lactic acid collagen stimulator for the indication of "cheek wrinkle removal". In its formula, the average particle size of poly-lactic acid particles is 40~63μm, and there are also auxiliary materials such as mannitol and sodium carboxymethyl cellulose as a suspending agent.

[0011] The present invention can improve the yield and particle uniformity of polylactic acid composite microspheres and reduce particle agglomeration by optimizing the total mass concentration of L-polylactic acid and racemic polylactic acid in the oil phase and the solvent selection, so that the average particle size range of the microspheres is closer to that of the commercially available Sculptra®. In addition, the selection and concentration of the emulsifier also have a significant effect on the shape and particle size of the microspheres.

[0012] Furthermore, the total mass concentration of L-polylactic acid and racemic polylactic acid in the oil phase is 3wt%~10wt%.

[0013] Furthermore, the mass concentration of the emulsifier in the aqueous phase is 0.5wt%~2wt%;

[0014] The emulsifier includes at least one of polyvinyl alcohol and Tween 80.

[0015] Furthermore, the organic solvent includes at least one of acetone, dichloromethane and ethyl acetate.

[0016] Although lactic acid composite microspheres with a relatively concentrated average particle size have been successfully prepared by optimizing the total mass concentration of L-polylactic acid and racemic polylactic acid and the solvent, when the proportion of racemic polylactic acid in the components is large, that is, when the proportion of racemic polylactic acid microspheres in the prepared composite microspheres is large, there are problems such as low yield of the composite microspheres and poor needle-passing performance, and it is necessary to make corresponding improvements.

[0017] Hydrolyzed collagen is a hydrolysis product of collagen, the main component of which is collagen, with an amino acid content of more than 90%, and is completely soluble in water. Succinoglycan is a type of extracellular polysaccharide composed of glucose and galactose secreted by Agrobacterium and Rhizobium, which is safe, non-toxic and has significant anti-inflammatory activity. Based on the reaction of acyl and amino groups, the present invention hydrolyzes collagen and succinoglycan in an aqueous solution under the catalysis of trivalent iron to prepare modified hydrolyzed collagen. Modified hydrolyzed collagen is added to the composite oil phase of L-polylactic acid and racemic polylactic acid. The modified hydrolyzed collagen can react with racemic polylactic acid to increase the yield of composite microspheres and improve the needle-passing performance.

[0018] Furthermore, when the L-polylactic acid and the racemic polylactic acid are dissolved, modified hydrolyzed collagen is added, and the amount of the modified hydrolyzed collagen added is 0.02 to 0.1 times the mass of the racemic polylactic acid;

[0019] The preparation method of the modified hydrolyzed collagen comprises:

[0020] The hydrolyzed collagen, succinoglycan and water are stirred and mixed, and then a water-soluble trivalent iron salt is added to react at a high temperature, and freeze-dried to obtain the modified hydrolyzed collagen. The type of the water-soluble trivalent iron salt does not need to be strictly limited, and can be illustratively at least one of ferric chloride hexahydrate, ferric nitrate nonahydrate, ferric sulfate heptahydrate, etc.

[0021] Furthermore, the mass ratio of the hydrolyzed collagen, succinoglycan, water, and water-soluble trivalent iron salt is 2-5: 0.5-1: 50-100: 0.02-0.05;

[0022] The temperature of the reaction is raised to 60-80°C.

[0023] Further, the oil phase and the water phase are stirred, specifically comprising:

[0024] At a temperature of 10-20°C, the oil phase is added at a dropwise rate of 2-20 mL / min to the aqueous phase stirred at a speed of 200-500 rpm;

[0025] Among them, the volume ratio of oil phase to water phase is 1:10~50.

[0026] Furthermore, the organic solvent contained is also recovered when the excess solvent is removed.

[0027] The present invention also provides a polylactic acid composite microsphere for injection, which is obtained by adopting the production process of the polylactic acid composite microsphere for injection, and the particle size of the polylactic acid composite microsphere for injection is 10-100 μm.

[0028] The present invention also provides the use of the above-mentioned polylactic acid composite microspheres for injection in a skin filling compound, wherein the skin filling compound comprises 120 to 180 parts of the above-mentioned polylactic acid composite microspheres for injection, 80 to 120 parts of a suspending agent, and 120 to 150 parts of an excipient in parts by mass;

[0029] The suspending agent includes at least one of sodium carboxymethyl cellulose and sodium alginate;

[0030] The excipient includes at least one of lactose, sucrose and mannitol.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The present invention prepares composite microspheres by dissolving L-polylactic acid and racemic polylactic acid simultaneously to form an oil phase, thereby achieving the co-preparation and uniform blending of long-acting and short-acting polylactic acid microspheres; the composite microspheres prepared at the same time have a suitable particle size distribution. The skin filling composition composed of the composite microspheres prepared by the present invention has few adverse reactions after being injected into the body, can quickly increase the fullness of the skin, improve wrinkles and alleviate skin sagging problems in the early stage of injection, and can maintain long-term effects for more than 2 years. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 A hematoxylin-eosin staining image of the skin filler composition of Application Example 19 when injected into a tissue is shown, with a magnification of 40 times;

[0034] Figure 2 The figure shows the hematoxylin-eosin staining of the skin filling composition of Application Example 19 injected into the tissue 3 months ago, with a magnification of 200 times;

[0035] Figure 3 The Masson staining image of the skin filling composition of Application Example 19 when injected into the tissue is shown, with a magnification of 400 times;

[0036] Figure 4 The Masson staining image of the skin filling composition of Application Example 19 injected into the tissue 3 months after injection is shown, with a magnification of 400 times;

[0037] Figure 5 The picrosirius red staining image of the skin filling composition of Application Example 19 after being injected into the tissue for 3 months is shown;

[0038] Figure 6 The scanning electron microscope image of the dermal filler composition of Application Example 19 3 months after injection into the tissue is shown. DETAILED DESCRIPTION

[0039] The endpoints and any values ​​of the ranges disclosed in the present invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in the present invention.

[0040] Some of the raw materials used in the examples and comparative examples of the present invention are described as follows:

[0041] L-polylactic acid, CAS number is 33135-50-1;

[0042] Racemic polylactic acid, CAS number 51056-13-9;

[0043] Polyvinyl alcohol, CAS number is 9002-89-5;

[0044] Tween 80, CAS number is 9005-65-6;

[0045] Hydrolyzed collagen, CAS number 92113-31-0, average molecular weight 3000Da;

[0046] Succinoglycan, CAS number is 73667-50-2.

[0047] Other raw materials not mentioned are common raw materials. The above content is only to help illustrate the present invention and shall not be construed as a strict limitation of the present invention. Those skilled in the art can directly purchase the same / similar raw materials from the market or prepare them by themselves. These contents will not be repeated in the examples.

[0048] The following will be combined with the specific embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0049] Embodiment 1:

[0050] A production process of polylactic acid composite microspheres for injection, the steps are as follows:

[0051] S1, adding 20 g of L-polylactic acid and 20 g of racemic polylactic acid into 1000 g of dichloromethane, stirring and dissolving at a speed of 350 rpm to obtain an oil phase;

[0052] S2. At a temperature of 60° C., 1.5 g of polyvinyl alcohol and 3000 g of water were stirred at a speed of 300 rpm for 10 min to dissolve the polyvinyl alcohol, and then the temperature was lowered to 15° C. to obtain an aqueous phase;

[0053] S3. At a temperature of 15°C, add 100 mL of oil phase at a dropping speed of 10 mL / min to 3000 mL of water phase stirred at a rotation speed of 300 rpm. After the dropping is completed, a mixed system is obtained. The temperature of the mixed system is lowered to 5°C, and stirred at a rotation speed of 500 rpm for 3 hours. After removing excess solvent, the system is sieved. The sieved microspheres are vacuum dried at 60°C to obtain polylactic acid composite microspheres for injection.

[0054] Embodiment 2~embodiment 25:

[0055] Please refer to the components in Tables 1 to 3 and the production process of Example 1.

[0056] Table 1 Components of Example 2 to Example 9:

[0057] ;

[0058] Table 2 Components of Example 10 to Example 17:

[0059] ;

[0060] Table 3 Components of Example 18 to Example 25:

[0061] ;

[0062] Embodiment 26:

[0063] A production process of polylactic acid composite microspheres for injection, the steps are as follows:

[0064] S1, adding 40 g of L-polylactic acid, 40 g of racemic polylactic acid, and 1 g of modified hydrolyzed collagen to a mixed solvent of 300 g of acetone and 700 g of dichloromethane, stirring and dissolving at a rotation speed of 350 rpm to obtain an oil phase;

[0065] S2. At a temperature of 60° C., 3 g of polyvinyl alcohol and 3000 g of water were stirred at a speed of 300 rpm for 10 min to dissolve the polyvinyl alcohol, and then the temperature was lowered to 15° C. to obtain an aqueous phase;

[0066] S3. At a temperature of 15°C, add 100 mL of oil phase at a dropping speed of 10 mL / min to 3000 mL of water phase stirred at a rotation speed of 300 rpm. After the dropping is completed, a mixed system is obtained. The temperature of the mixed system is lowered to 5°C, and stirred at a rotation speed of 500 rpm for 3 hours. After removing excess solvent, the system is sieved. The sieved microspheres are vacuum dried at 60°C to obtain polylactic acid composite microspheres for injection.

[0067] The preparation method of modified hydrolyzed collagen is as follows:

[0068] 30 g of hydrolyzed collagen, 8 g of succinoglycan and 800 g of water were stirred and mixed, and then 0.2 g of ferric nitrate nonahydrate was added and the temperature was raised to 75° C. The mixture was stirred at 300 rpm for 5 h and finally transferred to -55° C. for freeze drying to obtain modified hydrolyzed collagen.

[0069] Embodiment 27:

[0070] Compared with Example 26, the difference is that the masses of L-polylactic acid and racemic polylactic acid are 20 g and 60 g, respectively.

[0071] Comparative Example 1:

[0072] Compared with Example 27, the difference is that hydrolyzed collagen is used instead of modified hydrolyzed collagen.

[0073] Comparative Example 2:

[0074] Compared with Example 27, the difference is that succinoglycan is used instead of modified hydrolyzed collagen.

[0075] Application Examples 1~29

[0076] A skin filling composition is prepared by mixing 150 g of the injectable polylactic acid composite microspheres prepared in Examples 1 to 27 or Comparative Examples 1 to 2, 90 g of sodium carboxymethyl cellulose, 127.5 g of mannitol, and 5000 g of water, followed by freeze-drying at -55°C.

[0077] Comparative Example 3:

[0078] Commercially available product: Sculptra®.

[0079] Test example:

[0080] The corresponding yield was calculated based on the total mass of L-polylactic acid and racemic polylactic acid and the mass of the microsphere materials of the embodiment and the comparative example; the particle size of the composite microspheres prepared in the embodiment and the comparative example was tested using a laser particle size analyzer, and the ratio of the distribution in the range of 40 to 60 μm was calculated. These results are shown in Table 4.

[0081] Table 4 Yield and distribution ratio results:

[0082] ;

[0083] From the results of Example 1 to Example 13, it can be seen that when the organic solvent is selected as dichloromethane, the concentration of polyvinyl alcohol and the content of left-handed polylactic acid and racemic polylactic acid in the oil phase have a certain influence on the yield and distribution ratio. Among them, when the mass concentration of left-handed polylactic acid and racemic polylactic acid in the oil phase is the same, when the concentration of polyvinyl alcohol is 0.5wt%~1.5wt%, as the concentration of polyvinyl alcohol increases, the stability of the yield and distribution ratio first increases and then decreases. Example 19, that is, when the concentration of polyvinyl alcohol is 1wt%, the mass concentration of left-handed polylactic acid and racemic polylactic acid is 4wt%, the stability of the yield and distribution ratio is better. Compared with Example 6 to Example 9, under the same conditions, Example 14 to Example 17 replaces the emulsifier from polyvinyl alcohol to Tween 80, and the stability of the yield and distribution ratio is significantly reduced, which shows that when dichloromethane is used as the oil phase solvent, using polyvinyl alcohol in reaction with the aqueous phase can prepare better polylactic acid composite microspheres. Comparing the results of Examples 6 to 9 with those of Examples 18 to 21, it is further illustrated that using dichloromethane and acetone as solvents for the oil phase is significantly better than using dichloromethane alone as a solvent; Examples 18 to 25 further illustrate that in dichloromethane and acetone as solvents for the oil phase, using polyvinyl alcohol to react with the aqueous phase can also prepare better polylactic acid composite microspheres, and Tween 80 is not suitable for the preparation conditions of the present invention.

[0084] It is worth noting that the yield and distribution ratio of the prepared composite microspheres are significantly improved in Example 26 compared to Example 19 and Example 27 compared to Example 21. In these embodiments, the yield and distribution ratio of the prepared composite microspheres in Example 5, Example 9, Example 13, Example 17, Example 21, and Example 25, in which racemic polylactic acid accounts for a relatively high proportion, are significantly reduced compared to other embodiments, which shows that the high racemic polylactic acid is an important factor causing the unstable reaction. At the same time, the performance of the composite microspheres in Comparative Examples 1 and 2 is almost not improved. This shows that the hydrolyzed collagen contains abundant amino groups, and only the modified hydrolyzed collagen prepared by hydrolyzed collagen and succinoglycan under the catalysis of trivalent iron can act on racemic polylactic acid, making racemic polylactic acid more stable, thereby significantly improving the yield of the composite microspheres and the stability of the distribution ratio.

[0085] Take 400 mg of the skin filler composition in some application examples and the commercially available Sculptra® in comparative example 3, and use 5 mL of medical water for injection to reconstitute into a suspension for 3 minutes. The same amount of the suspension is loaded into syringes of the same model, and the syringes are pushed with the same constant pressure to discharge the suspension, and the required time is measured. The time measured in the application examples is compared with that in comparative example 3 as a measure of the needle-passing performance. The smaller the ratio, the stronger the needle-passing performance.

[0086] Table 5 Acupuncture performance results:

[0087] ;

[0088] From the results of Application Example 19, it can be seen that the present invention can prepare polylactic acid composite microspheres with good needle-passing performance by optimizing the composition of the organic solvent, the mass concentration of left-handed polylactic acid and racemic polylactic acid, and the mass concentration of the emulsifier polyvinyl alcohol. However, even at the optimized ratio, when the mass concentration of racemic polylactic acid is high, the needle-passing performance will be significantly reduced. This is because the mass concentration of racemic polylactic acid makes the prepared composite microspheres unevenly distributed, and the racemic polylactic acid microspheres that account for a larger proportion are easily blocked. Compared with Application Example 19 and Application Example 21, Application Examples 26 and 27, in which modified hydrolyzed collagen is added during the preparation of the oil phase, have significantly improved needle-passing performance. This is because the modified hydrolyzed collagen can interact well with the formed racemic polylactic acid microspheres.

[0089] 400 mg of the skin filling composition in some application examples was reconstituted with physiological saline and 0.2 mL was injected into the back skin of guinea pigs. After three days, adverse reactions such as redness, swelling, and subcutaneous nodules were observed. There were 10 guinea pigs in each group. The results are shown in Table 6.

[0090] Table 6 Injection reaction of dermal filler composition:

[0091] ;

[0092] It can be seen from Table 6 that the preferred embodiment of the present invention produces fewer adverse reactions after implantation. At the same time, the addition of modified hydrolyzed collagen makes the particle size of the racemic polylactic acid microspheres in the composite microspheres more uniform, eliminating the adverse reactions of subcutaneous nodules and redness and swelling.

[0093] The skin filler composition of Application Example 19 was reconstituted with physiological saline and 0.2 mL was injected into the back skin of guinea pigs. The state of the composite microspheres in the subcutaneous tissue at the injection site at different times was also observed. Figure 1 and Figure 2 It can be seen from the hematoxylin-eosin staining that the composite microspheres are well dispersed in the tissues at the beginning of injection. After 3 months, the racemic polylactic acid microspheres gradually decompose, and some microspheres have defects, but the morphology of some microspheres does not change significantly. This is due to the relatively stable left-handed polylactic acid microspheres. These results also illustrate that the present invention can achieve the co-preparation and uniform blending of long-acting and short-acting polylactic acid microspheres. Figure 3 and Figure 4 Masson's staining Figure 1 and Figure 2 This is consistent with the conclusions of the previous study, further illustrating that the composite microspheres have both long-term and short-term effects. Figure 5The Sirius red staining image shows that the racemic polylactic acid microspheres began to work to stimulate the production of collagen, while the L-polylactic acid microspheres did not work and did not stimulate the production of collagen. Figure 6 The scanning electron microscopy images of the tissue also showed that the racemic polylactic acid microspheres were degraded and deformed, but the left-handed polylactic acid microspheres remained round without obvious changes, which was the order of degradation.

[0094] The skin filling compositions in some application examples were also tested with reference to standard YY / T 0474-2004 “In vitro degradation test of poly (L-lactide) resin and products for surgical implants”. The results are shown in Table 7.

[0095] Table 7 In vitro degradation rate after 110 weeks:

[0096] ;

[0097] From the results in Table 7, it can be seen that in Application Examples 19 and 26 of the present invention, after 110 weeks, more than two years, a large number of polylactic acid microspheres are still not completely degraded.

[0098] In summary, the skin filling composition composed of the prepared composite microspheres of the present invention has few adverse reactions after being injected into the body, can quickly increase the fullness of the skin, improve wrinkles and alleviate skin sagging problems in the early stage of injection, and can maintain long-term effects for more than 2 years.

[0099] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A production process of polylactic acid composite microspheres for injection, characterized in that: include, Dissolving L-polylactic acid and racemic polylactic acid in an organic solvent to obtain an oil phase; dissolving an emulsifier in water to obtain an aqueous phase; The oil phase and the water phase are mixed under stirring, and the excess solvent is removed to obtain polylactic acid composite microspheres for injection; When the emulsifier is dissolved in water, modified hydrolyzed collagen is also added, wherein the amount of the modified hydrolyzed collagen added is 0.2 to 0.5 times the mass of the emulsifier; The preparation method of the modified hydrolyzed collagen comprises: The hydrolyzed collagen, succinoglycan and water are stirred and mixed, and then a water-soluble trivalent iron salt is added to react by heating, and then freeze-dried to obtain a modified hydrolyzed collagen; The mass ratio of the hydrolyzed collagen, succinoglycan, water, and water-soluble trivalent iron salt is 2-5: 0.5-1: 50-100: 0.02-0.05; The temperature of the reaction is raised to 60-80°C.

2. The production process of polylactic acid composite microspheres for injection according to claim 1, characterized in that: The total mass concentration of L-polylactic acid and racemic polylactic acid in the oil phase is 3wt% to 10wt%; The selected L-polylactic acid has a number average molecular weight of 50,000 to 500,000, and the selected racemic polylactic acid has a number average molecular weight of 50,000 to 500,000.

3. The production process of polylactic acid composite microspheres for injection according to claim 1, characterized in that: The mass concentration of the emulsifier in the aqueous phase is 0.5wt%~2wt%; The emulsifier includes at least one of polyvinyl alcohol and Tween 80.

4. The production process of polylactic acid composite microspheres for injection according to claim 1, characterized in that: The organic solvent includes at least one of acetone, dichloromethane and ethyl acetate.

5. The production process of polylactic acid composite microspheres for injection according to claim 1, characterized in that: The oil phase and the water phase are stirred, specifically comprising: At a temperature of 10-20°C, the oil phase is added at a dropwise rate of 2-20 mL / min to the aqueous phase stirred at a speed of 200-500 rpm; Among them, the volume ratio of oil phase to water phase is 1:10~50.

6. A polylactic acid composite microsphere for injection, characterized in that: The polylactic acid composite microspheres for injection are obtained by the production process of any one of claims 1 to 5, and the particle size of the polylactic acid composite microspheres for injection is 10 to 100 μm.

7. Application of injectable polylactic acid composite microspheres in skin filling composites, characterized in that: The skin filling compound comprises, by mass, 120 to 180 parts of the injectable polylactic acid composite microspheres according to claim 6, 80 to 120 parts of a suspending agent, and 120 to 150 parts of an excipient; The suspending agent includes at least one of sodium carboxymethyl cellulose and sodium alginate; The excipient includes at least one of lactose, sucrose and mannitol.

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