CN115350325A - Degradable polymer microsphere with low organic solvent residue, injection preparation, preparation method and application - Google Patents

Abstract

The invention belongs to the field of non-surgical medical cosmetology, and relates to a degradable polymer microsphere with low organic solvent residue, injection preparation, preparation method and application. The method includes: step 1, fully mixing the polymer solution with an aqueous solution containing an emulsifier to obtain a microsphere emulsion; step 2, injecting the microsphere emulsion in step 1 into the aqueous solution containing a stabilizer, and at the same time, continuously The air flow is disturbed to obtain a microsphere suspension that removes the organic solvent; step 3, sieve with a liquid circulation method, resuspend the obtained target particle size microspheres, and then sieve with a liquid circulation method to obtain the treated microspheres balls and then dry. The degradable polymer microspheres not only reduce the organic solvent to less than 10ppm, but also have higher safety. The finished particle size and shape of the microspheres are more controllable. It can be quickly reconstituted, without aggregation and precipitation, and maintains good dispersion.

Description

A kind of degradable polymer microsphere with low residual organic solvent, injection preparation and preparation Methods and Applications

technical field

The invention belongs to the field of non-surgical medical cosmetology, and relates to a degradable polymer microsphere with low organic solvent residue, injection preparation, preparation method and application.

Background technique

Non-surgical minimally invasive medical cosmetology projects and light medical cosmetology projects are more easily accepted by consumers due to factors such as high safety, low risk, and small trauma. Therefore, the market acceptance and repurchase rate are relatively high. Degradable polyester materials include polylactic acid, polyglycolic acid, polycaprolactone, etc. As a regenerative facial injection product, it can achieve a filling effect by stimulating the skin's own collagen production, which is more natural and effective than physical filling products. last longer. The U.S. Food and Drug Administration approved poly-L-lactic acid (PLLA) as an injectable implant in 2004 to repair cotton flinches in HIV patients, and in 2009 to treat nasolabial folds and other wrinkled areas. Such products currently on the market are mainly composed of poly-L-lactic acid particles or microspheres. In 2021, two poly-L-lactic acid microsphere products have obtained the Class III medical device registration certificate in China and will be officially launched for sale. Microparticle products are made by pulverizing poly-L-lactic acid and then sieving. They have irregular shapes and are easier to agglomerate compared with microsphere products, which increases the difficulty and pain of injection, and has certain safety hazards. The preparation methods of poly-L-lactic acid microspheres include solvent evaporation method, spray drying method, and membrane emulsification method. Among them, the solvent evaporation method is easier to carry out large-scale preparation because of its low equipment requirements and simple operation. Patent CN110051882A introduces a preparation method of polylactic acid microspheres, by dissolving polylactic acid in methylene chloride to form a polymer solution, then adding polyvinyl alcohol aqueous solution, high-speed shear emulsification, removing the solvent, and freeze-drying to obtain polylactic acid Microspheres; patent CN102516565B disperses the polylactic acid organic solution into the water phase medium, ultrasonically disperses, stirs to completely volatilize the organic solvent, and then obtains polylactic acid microspheres through ionization, water washing, and freeze-drying.

However, there are two main problems in the existing injectable microsphere preparations for non-surgical cosmetology, one is the organic solvent residue problem in the microsphere preparation process, and the other is the long reconstitution time of the microsphere dry powder during storage, transportation and use. question. Although the solvent evaporation method can maintain the shape of the microspheres, it takes a long time, generally requiring a volatilization cycle of more than 24 hours, and the organic solvent inside the microspheres is difficult to completely volatilize through stirring, resulting in residues. The freeze-drying method takes a long time, consumes a lot of energy and costs, and requires high equipment usage, which is not conducive to large-scale production. Solvent extraction is inefficient and has residual problems with the introduction of new solvents. Heating under reduced pressure is currently the most commonly used method to remove residual organic solvents. However, during the slow heating process, when the temperature is close to the glass transition temperature of the polymer, adhesion and aggregation will occur between the microspheres, which will not only affect the morphology and Yield, but also lead to residual organic solvents inside the microspheres. In addition, although the above method can reduce the residual amount of organic solvent to a certain extent, the residual amount of organic solvent in the microspheres is still maintained at a relatively high level, which is difficult to reduce to a lower level (<50ppm), so that The safety of clinical use of microsphere preparations cannot be guaranteed. The polylactic acid microspheres disclosed in patents CN105193735A and CN105214145A are obtained by the conventional emulsification-solvent evaporation method, but there is a problem that the solvent residue is large (about 0.5%). Patent CN111973561A provides a method for removing residual organic solvents in microspheres through pre-washing, hot water washing and cold water washing. Although this method can effectively solve the problem of organic solvent residues, this process operation The steps are cumbersome and resource consumption is large, so it cannot be applied in actual production.

Therefore, it is necessary to develop a preparation method of biodegradable polymer microspheres that can reduce the residual amount of toxic solvents and organic solvent mixtures, and control the toxic and harmful residual solvents within the safe limit without affecting the microspheres. The method of product form.

In clinical use, reconstitution is often used to prepare microspheres into uniformly dispersed injections. Insufficient reconstitution will cause microsphere adhesion. After the product is fully reconstituted, it is injected into the face. After injection, it needs to be rubbed on the injection site of the face to prevent the aggregation of microspheres. Even so, it may still cause adverse reactions such as subcutaneous nodules or redness and swelling during actual use.

Taking polylactic acid microspheres as an example, most of the existing products are polylactic acid freeze-dried powder, and the particle size of the microspheres is small, usually less than 100 microns. It needs to be reconstituted by injecting physiological saline when using it, and it is generally difficult to completely reconstitute. The reconstitution time is too long, and the needle may be blocked during clinical injection. In order to improve the problem of reconstitution of microsphere products, the patent CN104258470A made polylactic acid microspheres and sodium hyaluronate into a mixed gel containing saline solution, and used it in a pre-filled injection method, but the polylactic acid microsphere material would be degraded in an aqueous environment. Slow degradation occurs, so it will affect the use effect and shelf life of the product after it is put on the shelf. Patent CN102911380A discloses a method of cross-linking and grafting hyaluronic acid and biodegradable polymers to prepare a composite gel, which also requires the use of dichloromethane, and the residual solvent is not easy to remove, which affects the safety of use. There is also a method to separate the polylactic acid microsphere freeze-dried powder from the suspending agent (quick solvent), and during use, the suspending agent system is made into a solution of a certain concentration, and added to the microsphere dry powder to realize reconstitution, but this method has not been used. It fundamentally solves the problem that microsphere dry powder is easy to aggregate and difficult to store, and the reconstitution rate is also affected by the dissolution rate of the suspending agent.

The particle size, solvent residue and method of use of polymer degradable microspheres have a great influence on the filling effect, safety and practical operation. At the same time, the volatilization process of the organic solvent also has a great influence on the morphology of the microspheres. Therefore, considering the effectiveness of microsphere filling, safety, economy of microsphere production, and ease of use, a simple and suitable for large-scale preparation, high yield of effective particle size microspheres, and organic solvent residues are required. The preparation method of low-cost degradable microspheres and the slow reconstitution injection method are technical problems that need to be solved at present.

Contents of the invention

Aiming at the technical problems existing in the prior art, the object of the present invention is to provide a kind of degradable polymer microsphere with low organic solvent residue, injection preparation and preparation method and application, this degradable polymer microsphere can not only reduce organic solvent To less than 10ppm, it can also not affect the shape of the microsphere product and ensure the regularity of the appearance of the microsphere. It has a smooth microscopic shape, and the particle size and shape of the finished microsphere are more controllable on the basis of higher safety; at the same time It overcomes the defects of long reconstitution time, cohesion and aggregation, and uneven injection of the existing microspheres used in injection preparations. The injection preparation obtained by using the degradable polymer microspheres can be quickly reconstituted without aggregation and precipitation, and maintains good dispersion.

A first aspect of the present invention provides a method for preparing degradable polymer microspheres, comprising:

Step 1, mixing the degradable polymer with an organic solvent to obtain a polymer solution; then fully mixing the polymer solution as a dispersed phase with the continuous phase of an aqueous solution containing an emulsifier to obtain a microsphere emulsion;

Step 2, inject the microsphere emulsion in step 1 into the aqueous solution containing the stabilizer, the temperature of the aqueous solution containing the stabilizer is the volatile temperature of the organic solvent, and at the same time, continue to pass the protection from the bottom of the mixed solution upwards Gas, continue to disturb the air flow to obtain the microsphere suspension from which the organic solvent is removed;

In step 3, the microsphere suspension obtained in step 2 is sieved by a liquid circulation method, and the target particle size microspheres are screened; then the microspheres of the target particle size obtained are resuspended with absolute ethanol, and then sieved by a liquid circulation method, Get the treated microspheres;

Step 4, drying the treated microspheres obtained in step 3.

According to the present invention, the weight-average molecular weight of the degradable polymer can be selected within a wide range. In a preferred embodiment of the present invention, the weight-average molecular weight of the degradable polymer is 10000-500000g/mol .

According to the present invention, the degradable polymer can be selected in a wide range, and the degradable polymer includes but is not limited to polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolact Esters, polydioxanone, polyamino acid derived carbonates, polyorthoesters, polyhydroxyalkanoates, polytrimethylene carbonates, oxalate-containing polymers, polydioxol esters One or more of polyacetal and polyanhydride;

In a preferred embodiment of the present invention, the degradable polymer is selected from one or more of polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-glycolic acid copolymer.

In a more preferred embodiment of the present invention, the degradable polymer is selected from polylactic acid, preferably, the polylactic acid is selected from L-polylactic acid, D-polylactic acid, racemic polylactic acid, meso One or more blends or copolymers of polylactic acid, or one or more selected from L-polylactic acid, D-polylactic acid, racemic polylactic acid, mesopolylactic acid and absorbable polymer The blend or copolymer formed by the material; the absorbable polymer is selected from one or more of the following polymers: polyglycolic acid, polylactic acid-co-glycolic acid, polycaprolactone, polyethylene glycol Cyclohexanone, polyamino acid derived carbonate, polyorthoester, polyhydroxyalkanoate, polytrimethylene carbonate, oxalate-containing polymer, polydioxol ester, polyacetal, polyanhydride.

According to the present invention, the organic solvent can be selected in a wide range. In a preferred embodiment of the present invention, the organic solvent is methylene chloride or an organic solvent that is miscible with methylene chloride. The solvent that solvent forms; Preferably, the organic solvent that can miscible with methylene chloride is selected from one of chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone species, preferably one selected from chloroform, acetone, tetrahydrofuran.

According to the present invention, the mass percent of the polymer in the polymer solution described in step 1 can be selected within a wide range. In a preferred embodiment of the present invention, in step 1: in the polymer solution, the polymer The mass percentage of the compound is 1%-20%, preferably 4%-10%.

According to the present invention, the mass percent of emulsifier in the aqueous solution containing emulsifier in step 1 can be selected in a wide range, and in a preferred embodiment of the present invention, the mass percent of emulsifier in the aqueous solution containing emulsifier is 0.5%-10%, preferably 1%-4%.

According to the present invention, the emulsifier can be selected in a wide range, and in a preferred embodiment of the present invention, the emulsifier is polyvinyl alcohol, carboxymethyl chitosan, gelatin, agar, hyaluronic acid at least one of the acids.

According to the present invention, the volume ratio of the polymer solution to the emulsifier solution can be selected within a wide range, and in a preferred embodiment of the present invention, the volume ratio of the polymer solution to the emulsifier solution is 1 :(1-20), preferably 1:(3-5).

In a preferred embodiment of the present invention, in step 1, the conditions for the thorough mixing of the continuous phase include: the temperature is 10-20°C, and/or, in step 1, the thorough mixing of the continuous phase is mechanical stirring ; Preferably, the shear rate of the mechanical stirring is 100-1200rpm, preferably 700-1000rpm; and/or, the stirring time is 5-60min; preferably 8-40min.

According to the present invention, the temperature of the aqueous solution containing the stabilizer can be selected within a wide range. In a preferred embodiment of the present invention, the temperature of the aqueous solution containing the stabilizer in step 2 is 40-90°C .

According to the present invention, the volume ratio of the aqueous solution containing the stabilizer to the microsphere emulsion in step 2 can be selected within a wide range. In a preferred embodiment of the present invention, the aqueous solution containing the stabilizer The volume ratio to the microsphere emulsion is 1:(1-5), preferably 1:2-1:3.

According to the present invention, the time for continuous airflow disturbance can be selected within a wide range, and in a preferred embodiment of the present invention, the time for continuous airflow disturbance is 1-2 hours.

According to the present invention, the mass percent of the stabilizing agent in the aqueous solution containing the stabilizing agent can be selected in a wide range, and in a preferred embodiment of the present invention, the mass percent of the stabilizing agent in the aqueous solution containing the stabilizing agent 2%-4%.

According to the present invention, the stabilizer can be selected in a wide range, and in a preferred embodiment of the present invention, the stabilizer is selected from carboxymethyl cellulose, carboxymethyl chitosan, alginate , xanthan powder, sodium silicate, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl alcohol, polymaleic anhydride, polyquaternary ammonium salt, polyethylene glycol, polyethoxyalkane, hydrophobically modified hydroxyl One or more of ethyl cellulose.

In a preferred embodiment of the present invention, in step 3: the liquid circulation mode is driven by a high-pressure flow pump, and preferably the flow rate of the high-pressure flow pump is 2.5-6 L/h.

In a preferred embodiment of the present invention, a standard sieve is used to sieve microspheres with a target particle size, preferably the mesh number of the standard sieve used is 800 mesh to 250 mesh.

According to the present invention, the number of double sieving in step 3 can be selected within a wide range, and in a preferred embodiment of the present invention, the number of double sieving in step 3 is 3-8 times respectively.

According to the present invention, there are many options for drying in step 4, such as natural blast drying, vacuum drying or freeze-drying. The method for preparing the microspheres of the present invention can reach a solvent residue of less than 10 ppm under the condition of blast drying. If vacuum drying or freeze-drying is adopted, the solvent residue is lower than the detection limit, which can be considered as no residue. By adopting the preparation method of the present invention, the requirement for drying conditions can be further reduced, and microspheres prepared by the method of the present invention can still obtain microspheres with very low residual organic solvents even if vacuum drying or freeze-drying conditions are not available.

In a preferred embodiment of the present invention, step 4 includes air-drying the microspheres obtained in step 3 to obtain degradable polymer microspheres; preferably, the air-drying temperature is 20-50°C.

In a more preferred embodiment of the present invention, the preparation method of degradable polymer microspheres, the specific steps include:

Step 1: Mix the degradable polymer with an organic solvent to obtain a polymer solution with a certain concentration; at 10-20°C, use the polymer solution as a dispersed phase and fully mix the continuous phase of the aqueous solution containing an emulsifier, and mechanically stir. Obtain microsphere emulsion;

Step 2, quickly inject the microsphere emulsion into a certain amount of aqueous solution containing a stabilizer at a temperature of 40-90°C, and at the same time, continuously feed nitrogen gas from the bottom of the mixed solution to ensure that the microspheres are evenly dispersed in the stabilizer and prevent adhesion , continue for 1-2h to fully volatilize the organic matter, and obtain a suspension of microspheres;

Step 3, the microsphere suspension is sieved by liquid circulation under the action of a high-pressure flow pump, and circulated 3-8 times to screen the target particle size microspheres, resuspend the microspheres with absolute ethanol, and then sieve by liquid circulation , cycle 3-8 times, reduce microsphere agglomeration, and obtain treated microspheres;

In step 4, the microspheres are naturally blast-dried at room temperature to obtain finished microspheres.

Based on the above preferred technical scheme, in step 1, the degradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polydioxanone, polyamino acid derived One of carbonates, polyorthoesters, polyhydroxyalkanoates, polytrimethylene carbonates, oxalate-containing polymers, polydioxol esters, polyacetals, polyanhydrides or various;

Preferably one or more selected from polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-glycolic acid copolymer;

The polylactic acid is selected from one or more blends or copolymers of L-polylactic acid, D-polylactic acid, racemic polylactic acid, and mesopolylactic acid, or selected from L-polylactic acid, dextrorotary polylactic acid Blends or copolymers of one or more of lactic acid, racemic polylactic acid, and mesopolylactic acid with other absorbable polymers.

Based on the above preferred technical solution, in step 1, the weight average molecular weight of the degradable polymer is 10000-500000 g/mol.

Based on the above-mentioned preferred technical scheme, in step 1, the organic solvent is selected from methylene chloride or a mixture of methylene chloride and an organic solvent that is miscible therewith;

The solvent miscible with dichloromethane includes one of chloroform, ethyl acetate, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, methyl ethyl ketone, preferably from chloroform, One of acetone and tetrahydrofuran.

Based on the above preferred technical solution, in step 1, the mass percentage of the polymer in the polymer solution is 1-20%, preferably 4-10%.

Based on the above-mentioned preferred technical scheme, in step 1, the emulsifier is at least one of polyvinyl alcohol, carboxymethyl chitosan, gelatin, agar, hyaluronic acid;

The mass percentage of the emulsifier aqueous solution is 0.5-10%, preferably 1-4%.

Based on the above preferred technical solution, in step 1, the volume ratio of the polymer solution to the emulsifier solution is 1:1-1:20, preferably 1:3-1:5.

Based on the above preferred technical solution, in step 1, the shear rate of the mechanical stirring is 100-1200rpm, preferably 700-1000rpm; the stirring time is 5-60min; preferably 8-40min.

Based on the above preferred technical solution, in step 2, the role of the stabilizer is to maintain the microsphere shape when the organic solvent is quickly removed, and the mass percentage of the stabilizer in the aqueous solution of the stabilizer is 2-4%.

Based on the above preferred technical scheme, in step 2, the volume ratio of the stabilizer aqueous solution to the polymer emulsion is 1:(1-5), preferably 1:2-1:3.

Based on the above-mentioned preferred technical scheme, in step 2, the stabilizer is selected from carboxymethyl cellulose, carboxymethyl chitosan, alginate, xanthan powder, sodium silicate, polyacrylamide, polyacrylic acid, polyacrylamide One or more of vinylpyrrolidone, polyvinyl alcohol, polymaleic anhydride, polyquaternary ammonium salt, polyethylene glycol, polyethoxyalkylene, hydrophobically modified hydroxyethyl cellulose.

Based on the above preferred technical solution, in step 3, the flow rate of the high-pressure flow pump is 2.5-6L/h.

Based on the above-mentioned preferred technical scheme, in step 3, the mesh number of the standard sieve used is 800 mesh-250 mesh.

The second aspect of the present invention is to provide a degradable polymer microsphere prepared by the preparation method described in the first aspect.

The residue of organic solvent (comprising methylene chloride) in the microsphere finished product obtained by the present invention is 10ppm or lower; The particle size distribution of the microsphere finished product can be accurately controlled at 20-60 microns; The microsphere finished product is regular spherical and has smooth microscopic shape.

Aiming at the disadvantages of long reconstitution time, cohesive aggregation, and uneven injection of the existing microspheres in the injection preparations in the prior art, the third aspect of the present invention is to provide an injection preparation, including the possible injections described in the second aspect. Degrades polymer microspheres and dispersants.

According to the present invention, the ratio of degradable polymer microspheres and dispersants can be selected within a wide range. In a preferred embodiment of the present invention, in terms of mass percentage, the degradable polymer microspheres The mass percentage is 10%-50%, preferably 25%-40%, and the mass percentage of the dispersant is 50%-90%, preferably 60%-75%.

In a preferred embodiment of the present invention, the size range of the dispersant is 50-300 microns.

In a preferred embodiment of the present invention, the dispersant is a microgel formed by hyaluronic acid; preferably, the weight average molecular weight of the hyaluronic acid is 10,000-2,000,000 g/mol.

In a preferred embodiment of the present invention, the dispersing agent is cross-linked hyaluronic acid, preferably, the cross-linking agent used is butanediol glycidyl ether; the content of cross-linking agent in cross-linked hyaluronic acid is transparent 0.1%-10%, preferably 3%-8%, of the quality of the hyaluronic acid.

In the present invention, the above-mentioned injection preparations are in the form of foam, floc, sheet or block.

The fourth aspect of the present invention provides a method for preparing the injection preparation described in the third aspect, comprising: mixing the degradable polymer microspheres and the dispersing agent, and freeze-drying.

In a preferred embodiment of the present invention, the mixing temperature is 0-4°C, and/or the freeze-drying time is 24-72h.

In a preferred embodiment of the present invention, the preparation method of the injection preparation includes:

Step 1, dispersing hyaluronic acid in an aqueous alkali solution to obtain a hyaluronic acid solution;

Step 2, adding a cross-linking agent to the hyaluronic acid solution, mixing and standing still to obtain a hyaluronic acid gel;

Step 3, immersing the hyaluronic acid gel obtained in step 2 into water, and performing swelling treatment to obtain a swollen cross-linked hyaluronic acid gel;

Step 4, using an external pressure sieving method to squeeze and sieve the swollen cross-linked hyaluronic acid gel to obtain gel particles of the target size as a dispersant;

In step 5, the degradable polymer microspheres are uniformly mixed with the dispersant, encapsulated, and freeze-dried to obtain a finished injection preparation.

In the above-mentioned technical scheme, the mass concentration of the alkaline solution in step 1 can be selected within a wide range, and in a preferred embodiment of the present invention, in step 1: the mass concentration of the alkaline solution is 0.1%-2% , preferably 0.5%-1%.

For the choice of base, it is a conventional reagent in the art, including but not limited to sodium hydroxide, which will not be repeated here.

In the above technical scheme, the mass concentration of hyaluronic acid in the hyaluronic acid solution can be selected within a wide range. In a preferred embodiment of the present invention, the mass concentration of hyaluronic acid in the hyaluronic acid solution is 1 %-20%, preferably 6%-12%.

In a preferred embodiment of the present invention, the temperature in step 1 is 10-20° C., and/or the dispersion method is stirring, preferably the stirring rate is 50-300 rpm, and the time is 24-48 hours.

In a preferred embodiment of the present invention, the amount of the cross-linking agent used in step 2 is 0.1%-10%, preferably 3%-8%, of the hyaluronic acid mass.

In a preferred embodiment of the present invention, the conditions in step 2 include: the mixing temperature is 10-20°C, preferably the resting temperature is 40-60°C, and the resting time is 3-8h.

In a preferred embodiment of the present invention, in step 3: the temperature is 10-20° C., the pH is 6.5-7.5, and the swelling treatment time is 2-24 hours.

In a preferred embodiment of the present invention, in step 4: the mesh size of the sieve used is 300 mesh-60 mesh.

In a more preferred embodiment of the present invention, the preparation method of injection preparation comprises:

Step 1, at 10-20°C, dissolve hyaluronic acid in an aqueous alkali solution, stir at a low speed, and dissolve evenly to form a hyaluronic acid solution with a certain concentration;

Step 2: Add a certain amount of cross-linking agent to the hyaluronic acid solution at 10-20°C, mix well and place it at 40-60°C for a certain period of time, and the hyaluronic acid solution will become a gel under the action of the cross-linking agent shape;

Step 3, at 10-20°C, immerse the hyaluronic acid gel obtained in step 2 in deionized water, and neutralize it with dilute hydrochloric acid until the pH value is 6.5-7.5.

Step 4, at 10-20°C, the fully swollen cross-linked hyaluronic acid gel is directly extruded and sieved by an external pressure sieving method to obtain gel particles of the target size as a dispersant;

Step 5: Mix the degradable polymer microspheres and the dispersant evenly at 0-4°C, add them into a vial, freeze-dry the vial filled with the mixture for 12 hours, and obtain the finished injection preparation after sterilization.

Based on the above preferred technical scheme, in step 1, the molecular weight of hyaluronic acid is 10000-2000000g/mol; the concentration of alkali solution is 0.1-2%, preferably 0.5-1%; the concentration of hyaluronic acid alkali solution is 1-20% , preferably 6-12%.

Based on the above preferred technical scheme, in step 1, the stirring rate is 50-300rpm, and the time is 24-48h.

Based on the above preferred technical solution, in step 2, the crosslinking agent is butanediol glycidyl ether, the dosage of the crosslinking agent is 0.1-10% of the hyaluronic acid mass, preferably 3-8%, and the reaction time is 3-8h.

Based on the above-mentioned preferred technical scheme, in step 3, the mesh number of the standard sieve used is 300 mesh-60 mesh.

Based on the preferred technical solution above, in step 4, the ratio of the degradable polymer microspheres to the dispersant is 1:125-1:500.

The fifth aspect of the present invention is to provide an injection, including the reconstituted solution and the injection preparation according to one of the third aspects or the injection preparation prepared by the preparation method according to the fourth aspect.

In a preferred embodiment of the present invention, the reconstitution solution is at least one of distilled water, physiological saline, phosphate buffer, and simulated body fluid.

According to the present invention, it can be selected within a wide range. In a preferred embodiment of the present invention, the mass ratio of the injection preparation to the reconstitution solution is 1: (1-5).

The invention relates to the preparation method of injection injection. The method includes adding a reconstitution solution to the prepared injection preparation, shaking gently, and obtaining a suspension after reconstitution.

When in use, the suspension is left to defoam, and the defoamed suspension is withdrawn with a syringe for future use.

The injection provided by the invention can be completely dissolved within 30 minutes of mixing, and the degradable polymer microspheres can be uniformly and well suspended in the solution, and can be stably dispersed for more than 1 hour. After standing for 24 hours, the degradable polymer microspheres did not obviously aggregate or precipitate, and still maintained good dispersion.

The sixth aspect of the present invention is to provide a degradable polymer microsphere described in the second aspect, the injection preparation described in the third aspect or the injection preparation prepared by the preparation method described in the fourth aspect , or the application of the injection described in the fifth aspect in the field of non-surgical cosmetology. For example, it can be used as a cosmetic material or an auxiliary agent of a cosmetic material, or a cosmetic material not intended for medical treatment.

The microspheres in the injections of the present invention are well dispersed, non-bonded, have less residual organic solvents, and are safer. Therefore, the injections of the present invention can improve wrinkles, repair soft tissues or expand volume, correct contours or fill as shallow as Deep nasolabial folds and other facial wrinkles, with high safety.

According to above-mentioned technical scheme, the present invention compares with prior art:

1. The inventors of the present invention have found through research that methylene chloride is volatile during emulsification in the prior art, and it is easy to phase-separate with the polymer in the emulsification process so that the emulsification is unstable. The present invention is preferably used at a lower temperature (preferably 10-20°C) for emulsification, the polymer solution is relatively stable, ensuring the spheroidization of microspheres, and adopting the follow-up specific method of the present invention, the residual amount of organic solvents including methylene chloride can also be reduced to below 10ppm .

2. The inventors of the present invention have also found through research that the prior art usually uses long-time magnetic stirring to volatilize methylene chloride, which is slow and affects the sphericity of the microspheres, and with the solidification of the microspheres, there will be some The solvent is solidified inside the microspheres, leaving residue. In the present invention, the polymer solution is passed into hot water at a certain temperature, and under the disturbance of the continuous air flow of the protective gas, the dichloromethane can be rapidly diffused into the dispersed phase, which not only does not affect the shape of the microsphere product, but also ensures the microsphere The regularity of the appearance can also make the organic solvent evaporate quickly on the surface and inside of the microspheres, greatly reducing the residue of dichloromethane, and greatly shortening the post-processing time.

3. The method of sieving with liquid circulation (preferably high-pressure flow sieving) combined with ethanol cleaning saves the step of centrifuging and collecting microspheres in the prior art, which can simultaneously reduce the agglomeration of microspheres and the residue of emulsifier, and improve the screening efficiency. Efficiency, increasing the yield of microspheres with the target particle size, reducing the demand for equipment, and facilitating large-scale production.

4. Mix the microgel formed by sieving the dispersing agent (preferably cross-linked hyaluronic acid gel) with degradable polymer microspheres to make an injection preparation. After mixing with the reconstitution solution (such as physiological saline, etc.), it can quickly Reconstitution, after reconstitution, the degradable microspheres are evenly dispersed in the gel, and can maintain stability even after long-term storage (such as standing for 24 hours), without sedimentation or stratification, which solves the problem of reconstitution of injectable microsphere preparations If the time is too long, the reconstitution is not complete enough, and at the same time, some highly toxic chemical reagents will not be introduced, and it can be used immediately after dissolving, and the injection performance of the product is completely improved.

Based on the above technical scheme, the preparation method of the degradable polymer microspheres adopted in the present invention is simple and easy, does not require special equipment, and is easy to produce on a large scale. The obtained degradable polymer microspheres have good sphericity, smooth surface, low methylene chloride residue and high yield of microspheres with target particle size, and are an economical, efficient and safe method for preparing microspheres. In the present invention, the microsphere dry powder is mixed with a dispersing agent (preferably cross-linked hyaluronic acid) and freeze-dried into a foam, floc, flake or block, and directly added to a reconstitution solution (such as physiological saline, etc.) Short (less than 21 minutes), no aggregation and precipitation, and good dispersibility, it solves the problems of long reconstitution time of injections, uneven suspension and blocked injection needles, and greatly improves the safety and use effect on the human body.

Description of drawings

The degradable polymer microsphere scanning electron microscope picture in Fig. 1 embodiment 1;

The scanning electron micrograph of the degradable polymer microsphere in Fig. 2 embodiment 4;

The scanning electron micrograph of the injection preparation in Fig. 3 Example 7.

Detailed ways

The present invention is specifically described below in conjunction with specific embodiment, it is necessary to point out here that following embodiment is only used for the further description of the present invention, can not be interpreted as the restriction to protection scope of the present invention, those skilled in the art can understand the present invention according to the content of the present invention Some non-essential improvements and adjustments made by the invention still belong to the protection scope of the present invention.

In the following examples, degradable polymers such as poly-L-lactic acid pellets, polycaprolactone, and polylactic-glycolic acid were purchased from chemical reagent companies such as McLean, Bellingway, and Hines, with a weight-average molecular weight of 10,000-500,000 g/mol ;

The model of polyvinyl alcohol is 1788-L, purchased from Anhui Wanwei High-tech Materials Co., Ltd.,

Gelatin for microbiology, glue strength 250g,

The weight average molecular weight of hyaluronic acid is 200000-2000000g/mol,

Carboxymethyl chitosan substitution degree ≥ 80%.

Embodiment 1 The preparation of low organic solvent residual degradable polymer microspheres

Weigh 2g of poly-L-lactic acid pellets and dissolve them in 50ml of dichloromethane to fully dissolve to form a polylactic acid solution. At a temperature of 10°C, the polylactic acid solution was mixed as a dispersed phase with 180ml, 2% polyvinyl alcohol aqueous solution continuous phase, and mechanically stirred at a speed of 800rpm at 15°C for 15min to obtain an oil-in-water emulsion. Put the oil-in-water emulsion into 50°C, 500ml 1.5% carboxymethyl chitosan aqueous solution quickly, and at the same time, continuously feed nitrogen from the bottom of the mixed solution to ensure that the microspheres are evenly dispersed in the stabilizer and prevent Adhesion, keep for 2h to fully volatilize the solvent dichloromethane to obtain a suspension of microspheres. Under the action of a high-pressure flow pump, the microsphere suspension is sieved by a liquid circulation method at a flow rate of 4L/h, and circulated 5 times to select microspheres of 20-60 microns. The screened microspheres were resuspended with absolute ethanol, and then sieved by a liquid circulation method, and circulated 5 times to reduce the aggregation of the microspheres and obtain the treated microspheres. The fully treated microspheres are naturally air-dried to obtain the finished polylactic acid microspheres.

FIG. 1 is a scanning electron microscope picture of the degradable polymer microspheres in Example 1. It can be seen that the microspheres with smooth outer surface and particle size distribution in the range of 20-60 μm are obtained.

Embodiment 2 Preparation of degradable polymer microspheres with low organic solvent residue

Weigh 2g of poly-L-lactic acid pellets and dissolve them in 50ml of dichloromethane to fully dissolve to form a polylactic acid solution. At a temperature of 10°C, the polylactic acid solution was mixed as a dispersed phase with 180ml, 2% gelatin aqueous solution continuous phase, and mechanically stirred at a speed of 900rpm at 15°C for 15min to obtain an oil-in-water emulsion. Pour the oil-in-water emulsion into 500ml of 1.5% sodium alginate aqueous solution at 60°C quickly, and at the same time, continuously feed nitrogen gas from the bottom of the mixed solution to ensure that the microspheres are evenly dispersed in the stabilizer and prevent adhesion, and keep for 2 hours The solvent dichloromethane was fully evaporated to obtain a suspension of microspheres. Under the action of a high-pressure flow pump, the microsphere suspension is sieved by a liquid circulation method at a flow rate of 4L/h, and circulated 5 times to select microspheres of 20-60 microns. The screened microspheres were resuspended with absolute ethanol, and then sieved by a liquid circulation method, and circulated 5 times to reduce the aggregation of the microspheres and obtain the treated microspheres. The fully treated microspheres are naturally air-dried to obtain the finished polylactic acid microspheres.

Example 3 Preparation of Degradable Polymer Microspheres with Low Organic Solvent Residue

Weigh 2g of poly-L-lactic acid pellets and dissolve them in 50ml of dichloromethane to fully dissolve to form a polylactic acid solution. At a temperature of 10°C, the polylactic acid solution was mixed as a dispersed phase with a continuous phase of 180ml, 2% hyaluronic acid aqueous solution, and mechanically stirred at a speed of 800 rpm for 15 minutes at a temperature of 15°C to obtain an oil-in-water emulsion. Pour the oil-in-water emulsion into 500ml of 1.5% polyethylene glycol 2000 aqueous solution at 70°C quickly, and at the same time, continuously feed nitrogen from the bottom of the mixed solution to ensure that the microspheres are evenly dispersed in the stabilizer and prevent adhesion , Keep for 2h to fully volatilize the solvent dichloromethane to obtain a suspension of microspheres. Under the action of a high-pressure flow pump, the microsphere suspension is sieved by a liquid circulation method at a flow rate of 4L/h, and circulated 5 times to select microspheres of 20-60 microns. The screened microspheres were resuspended with absolute ethanol, and then sieved by a liquid circulation method, and circulated 5 times to reduce the aggregation of the microspheres and obtain the treated microspheres. The fully treated microspheres are naturally air-dried to obtain the finished polylactic acid microspheres.

Embodiment 4 Preparation of degradable polymer microspheres with low organic solvent residue

Weigh 2g of polycaprolactone and dissolve it in 50ml of dichloromethane to fully dissolve to form a polylactic acid solution. At a temperature of 10°C, the polylactic acid solution was mixed as a dispersed phase with a continuous phase of 180ml, 2% polyvinyl alcohol aqueous solution, and mechanically stirred at a speed of 1000rpm for 30min at a temperature of 10°C to obtain an oil-in-water emulsion. Pour the oil-in-water emulsion into 60°C, 650ml 1.5% carboxymethyl chitosan aqueous solution quickly, and at the same time, continuously feed nitrogen from the bottom of the mixed solution to ensure that the microspheres are evenly dispersed in the stabilizer and prevent adhesion , Keep for 2h to fully volatilize the solvent dichloromethane to obtain a suspension of microspheres. Under the action of a high-pressure flow pump, the microsphere suspension is sieved by a liquid circulation method at a flow rate of 4L/h, and circulated 5 times to select microspheres of 20-60 microns. The screened microspheres were resuspended with absolute ethanol, and then sieved by a liquid circulation method, and circulated 5 times to reduce the aggregation of the microspheres and obtain the treated microspheres. The fully treated microspheres are naturally air-dried to obtain the finished polylactic acid microspheres.

FIG. 2 is a scanning electron microscope image of the degradable polymer microspheres in Example 4. It can be seen that microspheres with a smooth outer surface and a particle size distribution in the range of 20-60 μm are obtained.

Example 5 Preparation of Degradable Polymer Microspheres with Low Organic Solvent Residue

Weigh 3g of polylactic acid-glycolic acid copolymer and dissolve in 50ml of dichloromethane to fully dissolve to form a polylactic acid solution. At a temperature of 10°C, the polylactic acid solution was mixed as a dispersed phase with 250ml, 3% polyvinyl alcohol aqueous solution continuous phase, and mechanically stirred at a speed of 700rpm at 20°C for 20min to obtain an oil-in-water emulsion. Put the oil-in-water emulsion into 60°C, 800ml 1.5% carboxymethyl chitosan aqueous solution quickly, and at the same time, continuously feed nitrogen gas from the bottom of the mixed solution to ensure that the microspheres are evenly dispersed in the stabilizer and prevent Adhesion, keep for 2h to fully volatilize the solvent dichloromethane to obtain a suspension of microspheres. Under the action of a high-pressure flow pump, the microsphere suspension is sieved by a liquid circulation method at a flow rate of 5 L/h, and circulated 5 times to select microspheres of 20-60 microns. The screened microspheres were resuspended with absolute ethanol, and then sieved by a liquid circulation method, and circulated 5 times to reduce the aggregation of the microspheres and obtain the treated microspheres. The fully treated microspheres are naturally air-dried to obtain the finished polylactic acid microspheres.

Example 6 Preparation of Degradable Polymer Microspheres with Low Organic Solvent Residue

Weigh 4g of poly-L-lactic acid pellets and dissolve them in 50ml of dichloromethane to fully dissolve to form a polylactic acid solution. At a temperature of 10°C, the polylactic acid solution was mixed as a dispersed phase with 200ml, 3% polyvinyl alcohol aqueous solution continuous phase, and mechanically stirred at a speed of 750rpm at 18°C for 10min to obtain an oil-in-water emulsion. Put the oil-in-water emulsion into 60°C, 700ml 1.5% carboxymethyl chitosan aqueous solution quickly, and at the same time, continuously feed nitrogen from the bottom of the mixed solution to ensure that the microspheres are evenly dispersed in the stabilizer and prevent Adhesion, keep for 2h to fully volatilize the solvent dichloromethane to obtain a suspension of microspheres. Under the action of a high-pressure flow pump, the microsphere suspension is sieved by a liquid circulation method at a flow rate of 5 L/h, and circulated 5 times to select microspheres of 20-60 microns. The screened microspheres were resuspended with absolute ethanol, and then sieved by a liquid circulation method, and circulated 5 times to reduce the aggregation of the microspheres and obtain the treated microspheres. The fully treated microspheres are naturally air-dried to obtain the finished polylactic acid microspheres.

The preparation of embodiment 7-9 injection preparation

The proportioning and preparation conditions of the injection preparations of Examples 7-9 are shown in Table 1, and the preparation method comprises the following steps:

(1) Dissolve the required amount of hyaluronic acid in an aqueous alkali solution (sodium hydroxide aqueous solution, 2% by weight) at 15°C, stir at a low speed, and dissolve evenly to form a hyaluronic acid-alkali solution of the required concentration;

(2) At 20°C, add a required amount of cross-linking agent to the hyaluronic acid solution, mix well and then place it at 40°C to stabilize for a certain period of time, and the hyaluronic acid solution becomes gel under the action of the cross-linking agent;

(3) At 10°C, select the standard mesh number in Table 1, and directly extrude and sieve the obtained cross-linked hyaluronic acid gel to obtain gel particles of the target size as a dispersant;

(4) At 4°C, take a certain amount of the degradable polymer microspheres prepared in Example 1 and mix them evenly with the dispersant, add them into a vial, freeze-dry the vial filled with the mixture for 12 hours, and then sterilize After that, the finished injection preparation is obtained.

Fig. 3 is a scanning electron micrograph of the injection preparation in Example 7, it can be seen that the microspheres are distributed inside the lyophilized hyaluronic acid.

Table 1

Comparative Example 1 Emulsion-solvent volatilization to prepare degradable polymer microspheres

At room temperature, weigh 2g of poly-L-lactic acid pellets and dissolve them in 50ml of dichloromethane to fully dissolve to form a polylactic acid solution. Mix the polylactic acid solution as the dispersed phase with 180ml, 2% polyvinyl alcohol aqueous solution continuous phase, and mechanically stir at 800rpm at 15°C for 15min to obtain an oil-in-water emulsion. The oil-in-water emulsion was heated to 40° C. and mechanically stirred at a speed of 300 rpm for 24 hours to obtain a suspension of microspheres. The microsphere suspension was sieved and rinsed 5 times with deionized water. Then rinse with absolute ethanol 5 times to obtain microspheres of specified size after treatment. The fully treated microspheres were freeze-dried for 12 hours to obtain polylactic acid microsphere dry powder.

Dichloromethane residue test

Using 7890A-5975C GC-MS, G1888A headspace analysis autosampler quantitatively test the residues of dichloromethane in the degradable polymer microsphere material obtained in Examples 1-6 and Comparative Example 1, the results are shown in Table 2 . Mass spectrometry conditions: electron bombardment ionization source, selected ion mode (SIM) m/z 49,84.

Analysis steps

1 sample processing

Weigh directly 10.00g (accurate to 0.01g) of the sample into a 50mL volumetric flask, add methanol to the mark, and seal it with a cap. Vortex on a vortex shaker until the sample is completely dissolved or mixed evenly, and pipette 10.0 mL of the sample solution into a headspace vial. Take 1mL of the upper gas after gas-liquid equilibrium, and enter the gas chromatograph for detection.

2 Headspace Sampler Conditions

The headspace sampler conditions were as follows:

A) Vaporization chamber temperature: 80°C, quantitative tube temperature: 90°C, transfer line temperature: 100°C;

B) Gas-liquid equilibrium time: 30min.

3 Gas Chromatography Reference Conditions

The gas chromatography reference conditions are as follows:

A) Chromatographic column: HP-VOC, 30m×0.2mm×1.1μm;

B) Column temperature: keep at 35°C for 2 minutes;

C) Injection port temperature: 250°C;

D) Split ratio: 50:1;

E) Flow rate: 1.0 mL/min.

4 standard working curve drawing

Pipette 10mL of standard working solutions at all levels into headspace bottles, and detect according to the 3 chromatographic conditions. Standard working solutions at all levels (0.05μg/mL, 0.10μg/mL, 0.50μg/mL, 1.0μg/mL, 5.0μg/mL, 10μg/mL for dichloromethane, 1,1,1-trichloroethane (0.0010μg/mL, 0.0020μg/mL, 0.010μg/mL, 0.020μg/mL, 0.20μg/mL, 0.50μg/mL) concentration is the abscissa, the corresponding peak area is the ordinate, and linear regression is performed to obtain the standard curve equation.

5 determination

According to 3 chromatographic conditions, take the standard working solution and sample injection in step 1 to obtain the standard curve and the peak area of the sample solution. Check the concentration of the target compound in the sample solution from the standard curve. When necessary, the content of dichloromethane and 1,1,1 trichloroethane in the sample should be determined based on the average of the results of two independent parallel tests.

6 blank test

Except for not weighing the sample, follow the above steps.

7 Calculation of results

The content of the analyte in the sample is calculated according to the formula:

In the formula:

X—the content of dichloromethanone and 1,1,1-trichloroethane to be tested in the sample, in milligrams per kilogram (mg/kg);

C—the concentration of dichloromethane and 1,1,1-trichloroethane found on the standard curve, in micrograms per milliliter (μg/mL);

V—the volume of the sample solution, in milliliters (mL);

M—sample mass, in grams (g).

Table 2 Dichloromethane residues

Detection of Particle Size of Degradable Polymer Microspheres

The average particle size of the degradable polymer microspheres in Examples 1-6 and Comparative Example 1 was detected by dynamic light scattering method, and the results are shown in Table 3.

Table 3 Particle size of degradable polymer microsphere material

Comparative example 2 comparison of reconstitution effect

The reconstitution time and reconstitution effect of the commercially available dermal filler injection product (Comparative Example 2) and the injection preparation obtained in Examples 7-9 were compared, and the test results are shown in Table 4.

Reconstitution effect test

Take by weighing the injection preparations prepared in Examples 7-9, the commercially available microsphere injection preparations (comparative example 2) and the injection preparations in comparative example 3, fully mix with 5mL sterile water for injection, shake up and down, and observe the compounding of the injections. Dissolution time and effect after reconstitution.

Table 4 reconstitution effect

The injection preparation prepared by using the microspheres in Examples 2-6 according to the method of Example 7 was reconstituted according to the above method, and there was no aggregation and precipitation after reconstitution, and good dispersibility was maintained.

It should be noted that the above-mentioned embodiments are only used to explain the present invention, and do not constitute any limitation to the present invention. The invention has been described with reference to typical embodiments, but the words which have been used therein are words of description and explanation rather than words of limitation. The present invention can be modified within the scope of the claims of the present invention as prescribed, and the present invention can be revised without departing from the scope and spirit of the present invention. Although the invention described therein refers to specific methods, materials and examples, it is not intended that the invention be limited to the specific examples disclosed therein, but rather, the invention extends to all other methods and applications having the same function.

All publications, patent applications, patents, and other references mentioned in this specification are hereby incorporated by reference in their entirety. Unless defined otherwise, all technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art. In case of conflict, the present specification's definitions will control.

When this specification uses the prefixes "known to those skilled in the art", "prior art" or similar terms to derive materials, substances, methods, steps, devices or components, etc., the objects derived from the prefixes cover the technical field at the time of filing this application. Those which are routinely used, but also which are not presently in common use, will become recognized in the art as being suitable for similar purposes.

Neither the endpoints of the ranges nor any values disclosed in this document are to be limited to such precise ranges or values, and these ranges or values are understood to include values approaching these ranges or values. For numerical ranges, between the endpoints of each range, between the endpoints of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, these values Ranges should be considered as specifically disclosed herein. In the following, in principle, various technical solutions can be combined with each other to obtain new technical solutions, which should also be regarded as specifically disclosed herein.

In the context of this specification, except for what is explicitly stated, any matters or matters not mentioned are directly applicable to those known in the art without any change.

Moreover, any embodiment described herein can be freely combined with one or more other embodiments described herein, and the resulting technical solutions or technical ideas are regarded as a part of the original disclosure or original record of the present invention, and not It should be regarded as a new content that has not been disclosed or expected in this paper, unless those skilled in the art think that the combination is obviously unreasonable.

Claims (20)

1. A preparation method of degradable polymer microspheres, comprising: Step 1, mixing the degradable polymer with an organic solvent to obtain a polymer solution; then mixing the polymer solution as a dispersed phase with an aqueous solution containing an emulsifier as a continuous phase to obtain a microsphere emulsion; Step 2, inject the microsphere emulsion in step 1 into the aqueous solution containing the stabilizer, the temperature of the aqueous solution containing the stabilizer is the volatile temperature of the organic solvent, and at the same time, continue to pass the protection from the bottom of the mixed solution upwards Gas, continue to disturb the air flow to obtain the microsphere suspension from which the organic solvent is removed; In step 3, the microsphere suspension obtained in step 2 is sieved by a liquid circulation method, and the target particle size microspheres are screened; then the microspheres of the target particle size obtained are resuspended with absolute ethanol, and then sieved by a liquid circulation method, Get the treated microspheres; Step 4, drying the treated microspheres obtained in step 3. 2. The preparation method according to claim 1, characterized in that: The weight average molecular weight of the degradable polymer is 10000-500000g/mol; and/or, The degradable polymer is selected from polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polydioxanone, polyamino acid derived carbonate, polyorthoester, polyhydroxyalkane One or more of acid esters, polytrimethylene carbonate, oxalate-containing polymers, polydioxol esters, polyacetals and polyanhydrides; It is preferably one or more selected from polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-glycolic acid copolymer. 3. The preparation method according to claim 1, characterized in that: The degradable polymer is selected from polylactic acid, preferably, The polylactic acid is selected from one or more blends or copolymers of L-polylactic acid, D-polylactic acid, racemic polylactic acid, and mesopolylactic acid, or selected from L-polylactic acid, dextrorotary polylactic acid Blends or copolymers of one or more of lactic acid, racemic polylactic acid, and mesopolylactic acid with absorbable polymers; The absorbable polymer is selected from one or more of the following polymers: Polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polydioxanone, polyamino acid derived carbonate, polyorthoester, polyhydroxyalkanoate, polytrimethylene carbonate, containing Polymers of oxalates, polydioxol esters, polyacetals, polyanhydrides. 4. The preparation method according to claim 1, characterized in that: Described organic solvent is dichloromethane or the solvent that is formed by dichloromethane and the organic solvent that can miscible with dichloromethane; Preferably, The organic solvent that can be miscible with dichloromethane is selected from the one in chloroform, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, methyl ethyl ketone, preferably from chloroform, One of acetone and tetrahydrofuran. 5. according to the preparation method described in one of claim 1-4, it is characterized in that: In step 1: In the polymer solution, the mass percentage of the polymer is 1%-20%, preferably 4%-10%; and/or, The mass percentage of the emulsifier in the aqueous solution containing the emulsifier is 0.5%-10%, preferably 1%-4%; and/or, The emulsifier is at least one of polyvinyl alcohol, carboxymethyl chitosan, gelatin, agar, hyaluronic acid; and/or, The volume ratio of the polymer solution to the emulsifier solution is 1:(1-20), preferably 1:(3-5). 6. according to the preparation method described in one of claim 1-4, it is characterized in that: In step 1, the conditions for sufficient mixing of the continuous phase include: The temperature is 10-20°C, and/or, in step 1, the continuous phase is fully mixed by mechanical stirring; Preferably, The shear rate of the mechanical stirring is 100-1200rpm, preferably 700-1000rpm; and/or, the stirring time is 5-60min; preferably 8-40min. 7. according to the preparation method described in one of claim 1-4, it is characterized in that: In step 2: The temperature of the aqueous solution containing the stabilizer is 40-90°C; and/or, The volume ratio of the aqueous solution containing the stabilizer to the microsphere emulsion is 1:(1-5), preferably 1:2-1:3; and/or, The time for continuous airflow disturbance is 1-2h. 8. according to the preparation method described in one of claim 1-4, it is characterized in that: The mass percentage of the stabilizer in the aqueous solution containing the stabilizer is 2%-4%; and/or, Described stabilizer is selected from carboxymethyl cellulose, carboxymethyl chitosan, alginate, xanthan powder, sodium silicate, polyacrylamide, polyacrylic acid, polyvinylpyrrolidone, polyvinyl alcohol, polymaleic anhydride , polyquaternary ammonium salt, polyethylene glycol, polyethoxyalkane, one or more of hydrophobically modified hydroxyethyl cellulose. 9. according to the preparation method described in one of claim 1-4, it is characterized in that: In step 3: The liquid circulation mode is driven by a high-pressure flow pump, preferably the flow rate of the high-pressure flow pump is 2.5-6L/h; and/or, a standard sieve is used to screen the target particle size microspheres, preferably the mesh number of the standard sieve used is 800 mesh -250 mesh; And/or, the times of twice sieving in step 3 are respectively 3-8 times. 10. The preparation method according to any one of claims 1-4, characterized in that: The method of drying in step 4 includes air drying the microspheres obtained in step 3 to obtain degradable polymer microspheres; Preferably, the air drying temperature is 20-50°C. 11. A degradable polymer microsphere prepared according to the preparation method described in any one of claims 1-10; preferably, the particle size distribution range of the degradable polymer microsphere is 20-60 microns, and /or, the total amount of residual organic solvent in the degradable polymer microspheres is not higher than 10ppm; and/or, The degradable polymer microspheres are regular spherical and have a smooth microscopic shape. 12. An injection preparation, comprising the degradable polymer microspheres of claim 11 and a dispersing agent. 13. The injection preparation according to claim 12, characterized in that: In terms of mass percentage, the mass percentage of the degradable polymer microspheres is 10%-50%, preferably 25%-40%, and the mass percentage of the dispersant is 50%-90%, preferably is 60%-75%, and/or, the size range of the dispersant is 50-300 microns; Preferably, the dispersing agent is a microgel formed by hyaluronic acid, more preferably, the weight average molecular weight of the hyaluronic acid is 10000-2000000 g/mol. 14. The injection preparation according to claim 12, characterized in that: The dispersing agent is cross-linked hyaluronic acid, preferably, The cross-linking agent used in the cross-linked hyaluronic acid is butanediol glycidyl ether; The content of the cross-linking agent in the cross-linked hyaluronic acid is 0.1%-10%, preferably 3%-8%, of the mass of the hyaluronic acid. 15. A preparation method of the injection preparation according to claim 12 or 13 or 14, comprising: Mixing and freeze-drying the degradable polymer microspheres and dispersant; Preferably, the mixing temperature is 0-4°C, and/or the freeze-drying time is 24-72h. 16. A preparation method of the injection preparation according to claim 15, comprising: Step 1, dispersing hyaluronic acid in an aqueous alkali solution to obtain a hyaluronic acid solution; Step 2, adding a cross-linking agent to the hyaluronic acid solution, mixing and standing still to obtain a hyaluronic acid gel; Step 3, immersing the hyaluronic acid gel obtained in step 2 into water, and performing swelling treatment to obtain a swollen cross-linked hyaluronic acid gel; Step 4, using an external pressure sieving method to squeeze and sieve the swollen cross-linked hyaluronic acid gel to obtain gel particles of the target size as a dispersant; In step 5, the degradable polymer microspheres are uniformly mixed with the dispersant, encapsulated, and freeze-dried to obtain a finished injection preparation. 17. The preparation method according to claim 16, characterized in that: In step 1: The mass concentration of the alkaline solution is 0.1%-2%, preferably 0.5%-1%; and/or, The mass concentration of hyaluronic acid in the hyaluronic acid solution is 1%-20%, preferably 6%-12%; and/or, The temperature is 10-20°C, and/or the dispersion method is stirring, preferably the stirring rate is 50-300rpm, and the time is 24-48h. 18. The preparation method according to claim 16, characterized in that: The amount of the cross-linking agent in step 2 is 0.1%-10% of the hyaluronic acid mass, preferably 3%-8%; and/or, the conditions in step 2 include: the mixing temperature is 10-20°C, preferably static The standing temperature is 40-60°C, and the standing time is 3-8h; and/or, In step 3: the temperature is 10-20°C, the pH is 6.5-7.5, and the swelling treatment time is 2-24h; and/or, In step 4: the mesh number of the sieve used is 300 mesh-60 mesh. 19. An injection, comprising complex solution and the injection preparation according to one of claims 12-14 or the injection preparation prepared by the preparation method according to one of claims 15-18; Preferably, The reconstituted solution is at least one of distilled water, physiological saline, phosphate buffer saline, and simulated body fluid; and/or, the mass ratio of the injection preparation to the reconstituted solution is 1: (1-5). 20. A degradable polymer microsphere according to claim 11, the injection preparation according to one of claims 12-14 or the injection preparation prepared by the preparation method according to one of claims 15-18, or the injection preparation according to one of claims 15-18. Application of the injection described in claim 19 in the field of non-surgical cosmetology.

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