Poly-L-lactic acid filler and preparation method thereof

Abstract

The invention belongs to the technical field of medical plastic and beauty filling agents, and particularly relates to a poly-L-lactic acid filling agent and a preparation method thereof. The poly-L-lactic acid filler comprises poly-L-lactic acid, polyvinyl alcohol, sodium hyaluronate, propylene glycol and water for injection. The particle size can be controlled, the resolubility is good, and the preparation process is simple and easy to operate.

Description

Technical Field

[0001] The present invention belongs to the technical field of medical aesthetic plastic fillers, and particularly relates to a poly-L-lactic acid filler and a preparation method thereof. Background Art

[0002] In recent years, injectable facial fillers in the medical aesthetic industry have developed rapidly and have become an indispensable part of cosmetic medicine. There are various types of facial fillers on the market, but facial fillers with good cosmetic effects, long-lasting but non-permanent efficacy, small side effects, and low incidence of adverse reactions are still relatively few. Traditional fillers will be slowly absorbed and eventually disappear after injection, only playing a temporary repair role, requiring repeated reinjections, having poor biocompatibility, and causing inflammation and other toxic side effects; while poly-L-lactic acid can achieve semi-permanent cosmetic effects by inducing a mild inflammatory reaction and stimulating fibroblasts to generate new collagen. The FDA approved the listing of a poly-L-lactic acid soft tissue filler named Sculptra in 2004 for the treatment of facial lipoatrophy related to human immunodeficiency virus infection, and approved the application of poly-L-lactic acid in nasolabial fold wrinkles and other dermal wrinkles in 2009.

[0003] Poly-L-lactic acid fillers are mostly prepared by mixing poly-L-lactic acid with sodium hyaluronate or sodium carboxymethylcellulose and freeze-drying to obtain the finished product, which has the defects of too long reconstitution time (24h), difficult reconstitution, and difficulty in uniform dispersion, resulting in needle clogging. This not only increases the operation difficulty of doctors but also reduces the experience of consumers.

[0004] CN102911380B discloses a hyaluronic acid and biodegradable polymer modifier. Poly-L-lactic acid microspheres and hyaluronic acid are subjected to a chemical reaction through carbodiimide and adipic dihydrazide to obtain an insoluble solid poly-L-lactic acid modified particle composite gel. Although it is beneficial to solve the reconstitution problem to a certain extent, the product has the defect that the removal of residual cross-linking agents and solvents does not meet the standard.

[0005] CN104258470B discloses an injectable poly-lactic acid microsphere and cross-linked hyaluronic acid mixed gel, a method of making a mixed gel of poly-L-lactic acid microspheres and sodium hyaluronate, which solves the reconstitution problem, but has the defect of complex preparation process.

[0006] CN108136068A discloses a method for manufacturing hollow porous microspheres. Through an oil-water emulsion method and using the volatility of organic solvents, a porous poly-lactic acid microsphere is prepared. This kind of microsphere lacks a stabilizer and is difficult to reconstitute and disperse into the aqueous phase.

[0007] CN109010910A discloses a preparation method of injectable poly-L-lactic acid microspheres. An aqueous solution of sodium carboxymethylcellulose / mannitol is used to pretreat and freeze-dry the poly-L-lactic acid microspheres to improve the dispersibility during reconstitution. This reconstitution method usually requires a complex filler formulation or additional microsphere pretreatment steps to address the dispersibility issue.

[0008] Existing poly-L-lactic acid fillers are prepared by making poly-L-lactic acid into microparticles or microspheres. The preparation process is complex, with poor control over particle size and high cost. During clinical injection, uneven particle size, poor reconstitution, or uneven injection can cause adverse reactions such as subcutaneous nodules or swelling. Summary of the Invention

[0009] In view of the technical problems such as complex preparation process and difficult reconstitution in the prior art, the present invention provides a poly-L-lactic acid filler and its preparation method. This filler can achieve controllable particle size, good reconstitution, and a simple and easy-to-operate preparation process.

[0010] In the inventors' research, it was also found that poly-L-lactic acid is in the form of crystalline particles, which easily precipitate at the bottom after being added to the solvent, reducing the full contact with the solvent. Moreover, during mixing and stirring, due to insufficient dissolution, it exists in the solvent in the form of particles. This state not only affects the quality of poly-L-lactic acid, the treatment effect, and safety, but also increases the difficulty of microsphere preparation, leading to more complex preparation operations.

[0011] In response to the above problems, the technical solution of the present invention is as follows:

[0012] A poly-L-lactic acid filler, comprising poly-L-lactic acid, polyvinyl alcohol, sodium hyaluronate, propylene glycol, and water for injection.

[0013] Preferably, in the filler, the weight-average molecular weight of the poly-L-lactic acid is 50 - 300 KDa, and more preferably 200 KDa.

[0014] Preferably, in the filler, the weight-average molecular weight of the polyvinyl alcohol is 50 - 200 KDa, and more preferably 130 KDa.

[0015] Preferably, in the filler, the molecular weight of the sodium hyaluronate is 600 - 1000 KDa, and more preferably 800 KDa.

[0016] The present invention also provides a preparation method of a poly-L-lactic acid filler, comprising the following steps:

[0017] Dissolve poly-L-lactic acid in an organic solvent to obtain a poly-L-lactic acid solution; dissolve polyvinyl alcohol in an aqueous phase to obtain a polyvinyl alcohol solution; place the poly-L-lactic acid solution and the polyvinyl alcohol solution in an online high-speed shearer for high-speed shearing to obtain an emulsion; subject the emulsion to vacuum curing and freeze-drying to obtain poly-L-lactic acid microspheres; add a low-concentration sodium hyaluronate solution and mix with the poly-L-lactic acid microspheres, after complete infiltration, slowly add a high-concentration sodium hyaluronate solution, and mix evenly to obtain the product.

[0018] Preferably, in the preparation method, the organic solvent is dichloromethane or / and ethyl acetate.

[0019] More preferably, in the preparation method, the organic solvent is a mixed solvent of dichloromethane and ethyl acetate, and the volume ratio of dichloromethane to ethyl acetate is 2-4:1.

[0020] Preferably, in the preparation method, dissolve poly-L-lactic acid in an organic solvent to obtain a poly-L-lactic acid solution with a concentration of 50-150 mg / mL.

[0021] Preferably, in the preparation method, the aqueous phase is an aqueous solution of propylene glycol, and the volume ratio of propylene glycol to water is 1:4-10.

[0022] Preferably, in the preparation method, dissolve polyvinyl alcohol in the aqueous phase to obtain a polyvinyl alcohol solution with a mass percentage concentration of 0.5-3.0%, and more preferably a concentration of 1.0%.

[0023] Preferably, in the preparation method, the volume ratio of the poly-L-lactic acid solution to the polyvinyl alcohol solution is 1:10-1:50.

[0024] Preferably, in the preparation method, the shearing rate of high-speed shearing is 1500-4500 r / min, and the time of high-speed shearing is 5-20 min.

[0025] Preferably, in the preparation method, the process of vacuum curing is: drying at normal pressure and 30-55 °C for 30-60 min, then drying at a vacuum of 0.01-0.05 Mpa and 50-60 °C for 4-6 h, and continuing to maintain at a vacuum of 0.01-0.05 Mpa and room temperature for 30-60 min.

[0026] Preferably, in the preparation method, the process of freeze-drying is: pre-freezing at -40--45 °C for 2-4 h; sublimation drying: evacuate the freeze-dryer and maintain at 0.20 ± 0.02 mbar, heat up to -10-20 °C at a rate of 5 °C / h, and maintain for 12-18 h; desorption drying: evacuate the freeze-dryer and maintain at 0.10 ± 0.02 mbar, raise the temperature to 25-40 °C, continue drying for 20-30 h, then maintain at an ultimate vacuum for 2 h, and press the plug in a vacuum state and take out of the box.

[0027] Preferably, in the preparation method, the sodium hyaluronate solution has a low concentration of 0.01-0.05% by mass percentage concentration and a high concentration of 0.4-0.9% by mass percentage concentration.

[0028] Preferably, in the preparation method, for every 150 mg of poly-L-lactic acid microspheres, after adding 1-2 mL of the low-concentration sodium hyaluronate solution, 4-5 mL of the low-concentration sodium hyaluronate solution is added.

[0029] The present invention has the following outstanding advantages compared with the prior art:

[0030] 1. The poly-L-lactic acid microspheres obtained by the present invention have a round and regular shape, a smooth surface, and uniform and controllable particle sizes.

[0031] 2. The present invention uses a double-solvent system, which can achieve rapid mixing and high dispersion clinically, and further improve the redissolubility of the product.

[0032] 3. The poly-L-lactic acid filler obtained by the present invention has few adverse reactions and good user experience.

[0033] 4. The preparation method of the poly-L-lactic acid filler of the present invention is simple and is expected to realize industrial production. Description of the Drawings

[0034] Figure 1 SEM image of the poly-L-lactic acid microspheres prepared in Example 3 of the present invention

[0035] Figure 2 Particle size distribution diagram of the poly-L-lactic acid microspheres prepared in Example 3 of the present invention Detailed Embodiments

[0036] The following lists detailed embodiments to further illustrate the present invention, but does not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements according to the basic idea of the present invention, but as long as they do not depart from the basic idea of the present invention, they are within the scope of the present invention.

[0037] Example 1

[0038] Dissolve 1 g of poly(L-lactic acid) with a weight-average molecular weight of 50 KDa in a mixed solvent of dichloromethane and ethyl acetate (the volume ratio of dichloromethane to ethyl acetate is 4:1) to obtain a poly(L-lactic acid) solution with a concentration of 50 mg / mL; dissolve 2 g of polyvinyl alcohol with a weight-average molecular weight of 50 KDa in an aqueous propylene glycol solution (the volume ratio of propylene glycol to water is 1:4) to obtain a polyvinyl alcohol solution with a mass percentage concentration of 0.5%; take the aforementioned obtained poly(L-lactic acid) solution and polyvinyl alcohol solution (the volume ratio of poly(L-lactic acid) solution to polyvinyl alcohol solution is 1:10), place them in an online high-speed shear machine for high-speed shearing at a rate of 1500 r / min for 20 min to obtain an emulsion; subject the obtained emulsion to vacuum curing to remove the solvent, dry it at 30 - 50 °C for 60 min under normal pressure, then dry it at 0.01 - 0.05 Mpa and 50 - 55 °C for 6 h, and continue to maintain it at 0.01 - 0.05 Mpa and room temperature for 60 min; perform freeze-drying according to the following freeze-drying procedure: pre-freeze at -40 to -45 °C for 2 - 4 h; sublimation drying: evacuate the freeze-dryer and maintain it at 0.20 ± 0.02 mbar, heat it at 5 °C / h to -10 to 20 °C, and maintain it for 12 - 18 h; analytical drying: evacuate the freeze-dryer and maintain it at 0.10 ± 0.02 mbar, raise the temperature to 25 - 40 °C, continuously dry for 20 - 30 h, then perform ultimate vacuum for 2 h, press the stopper in the vacuum state, and take out of the box to obtain poly(L-lactic acid) microspheres; for every 150 mg of poly(L-lactic acid) microspheres, add 1 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.01% (the weight-average molecular weight of sodium hyaluronate is 600 KDa) and mix it with the poly(L-lactic acid) microspheres. After complete infiltration, slowly add 5 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.4% (the weight-average molecular weight of sodium hyaluronate is 600 KDa), and mix well to obtain the product.

[0039] Example 2

[0040] Dissolve 1 g of poly-L-lactic acid with a weight-average molecular weight of 300 KDa in dichloromethane to obtain a poly-L-lactic acid solution with a concentration of 150 mg / mL; dissolve 5 g of polyvinyl alcohol with a weight-average molecular weight of 200 KDa in an aqueous propylene glycol solution (volume ratio of propylene glycol to water is 1:10) to obtain a polyvinyl alcohol solution with a mass percentage concentration of 3.0%; take the aforementioned poly-L-lactic acid solution and polyvinyl alcohol solution (volume ratio of poly-L-lactic acid solution to polyvinyl alcohol solution is 1:50), place them in an online high-speed shearer for high-speed shearing at a rate of 4500 r / min for 5 min to obtain an emulsion; subject the obtained emulsion to vacuum curing to remove the solvent, dry it at normal pressure at 32 - 55 °C for 30 min, then dry it at a vacuum of 0.01 - 0.05 Mpa and 55 - 60 °C for 4 h, and continue to maintain it at 0.01 - 0.05 Mpa and room temperature for 30 min; perform freeze-drying according to the following freeze-drying procedure: pre-freeze at -40 to -45 °C for 2 - 4 h; sublimation drying: evacuate the freeze-dryer and maintain it at 0.20 ± 0.02 mbar, heat it at 5 °C / h to -10 to 20 °C, and maintain it for 12 - 18 h; analytical drying: evacuate the freeze-dryer and maintain it at 0.10 ± 0.02 mbar, raise the temperature to 25 - 40 °C, continuously dry for 20 - 30 h, then perform ultimate vacuum for 2 h, press the stopper in the vacuum state, take out of the box to obtain poly-L-lactic acid microspheres; for every 150 mg of poly-L-lactic acid microspheres, add 2 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.05% (weight-average molecular weight of sodium hyaluronate is 1000 KDa) and mix with the poly-L-lactic acid microspheres. After complete infiltration, slowly add 5 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.9% (weight-average molecular weight of sodium hyaluronate is 1000 KDa), and mix evenly to obtain the product.

[0041] Example 3

[0042] Dissolve 1 g of poly(L-lactic acid) with a weight-average molecular weight of 200 KDa in a mixed solvent of dichloromethane and ethyl acetate (the volume ratio of dichloromethane to ethyl acetate is 2:1) to obtain a poly(L-lactic acid) solution with a concentration of 100 mg / mL; dissolve 3 g of polyvinyl alcohol with a weight-average molecular weight of 130 KDa in an aqueous propylene glycol solution (the volume ratio of propylene glycol to water is 1:6) to obtain a polyvinyl alcohol solution with a mass percentage concentration of 1.0%; take the aforementioned poly(L-lactic acid) solution and polyvinyl alcohol solution (the volume ratio of poly(L-lactic acid) solution to polyvinyl alcohol solution is 1:40) and place them in an online high-speed shearing machine for high-speed shearing at a rate of 3000 r / min for 10 min to obtain an emulsion; subject the obtained emulsion to vacuum curing to remove the solvent, dry it at normal pressure at 38 - 46 °C for 40 min, then dry it at a vacuum of 0.01 - 0.05 Mpa and 53 - 55 °C for 5 h, and continue to maintain it at a vacuum of 0.01 - 0.05 Mpa and room temperature for 45 min; perform freeze-drying according to the following freeze-drying procedure: pre-freeze at -40 to -45 °C for 2 - 4 h; sublimation drying: evacuate the freeze-dryer and maintain it at 0.20 ± 0.02 mbar, heat it at a rate of 5 °C / h to -10 to 20 °C, and maintain it for 12 - 18 h; analytical drying: evacuate the freeze-dryer and maintain it at 0.10 ± 0.02 mbar, raise the temperature to 25 - 40 °C, continuously dry for 20 - 30 h, then perform ultimate vacuum for 2 h, press the stopper in the vacuum state, and take out of the box to obtain poly(L-lactic acid) microspheres; for every 150 mg of poly(L-lactic acid) microspheres, add 1 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.03% (the weight-average molecular weight of sodium hyaluronate is 800 KDa) and mix it with the poly(L-lactic acid) microspheres. After complete wetting, slowly add 4 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.6% (the weight-average molecular weight of sodium hyaluronate is 800 KDa), and mix well to obtain the product.

[0043] Comparative Example 1

[0044] Dissolve 1 g of poly(L-lactic acid) with a weight-average molecular weight of 200 KDa in a mixed solvent of dichloromethane and ethyl acetate (the volume ratio of dichloromethane to ethyl acetate is 2:1) to obtain a poly(L-lactic acid) solution with a concentration of 100 mg / mL; dissolve 3 g of polyvinyl alcohol with a weight-average molecular weight of 130 KDa in water to obtain a polyvinyl alcohol solution with a mass percentage concentration of 1.0%; take the aforementioned obtained poly(L-lactic acid) solution and polyvinyl alcohol solution (the volume ratio of poly(L-lactic acid) solution to polyvinyl alcohol solution is 1:40) and place them in an on-line high-speed shearer for high-speed shearing at a rate of 3000 r / min for 10 min to obtain an emulsion; subject the obtained emulsion to vacuum curing to remove the solvent, dry it at normal pressure under the conditions of 38 - 46 °C for 40 min, then dry it under vacuum of 0.01 - 0.05 Mpa and 53 - 55 °C for 5 h, and continue to maintain it under vacuum of 0.01 - 0.05 Mpa and at room temperature for 45 min; perform freeze-drying according to the following freeze-drying procedure: pre-freeze at -40 to -45 °C for 2 - 4 h; sublimation drying: evacuate the freeze-dryer and maintain it at 0.20 ± 0.02 mbar, heat it at a rate of 5 °C / h to -10 to 20 °C, and maintain it for 12 - 18 h; analytical drying: evacuate the freeze-dryer and maintain it at 0.10 ± 0.02 mbar, raise the temperature to 25 - 40 °C, and continuously dry for 20 - 30 h, then perform ultimate vacuum for 2 h, press the stopper in the vacuum state, and take out of the box to obtain poly(L-lactic acid) microspheres; for every 150 mg of poly(L-lactic acid) microspheres, add 1 mL of sodium hyaluronate solution with a mass percentage concentration of 0.03% (the weight-average molecular weight of sodium hyaluronate is 800 KDa) and mix it with the poly(L-lactic acid) microspheres. After complete infiltration, slowly add 4 mL of sodium hyaluronate solution with a mass percentage concentration of 0.6% (the weight-average molecular weight of sodium hyaluronate is 800 KDa), and mix well to obtain the product.

[0045] Comparative Example 2

[0046] Dissolve 1 g of poly(L-lactic acid) with a weight-average molecular weight of 200 kDa in a mixed solvent of dichloromethane and ethyl acetate (the volume ratio of dichloromethane to ethyl acetate is 2:1) to obtain a poly(L-lactic acid) solution with a concentration of 100 mg / mL; dissolve 3 g of polyvinyl alcohol with a weight-average molecular weight of 130 kDa in an aqueous propylene glycol solution (the volume ratio of propylene glycol to water is 1:6) to obtain a polyvinyl alcohol solution with a mass percentage concentration of 1.0%; take the aforementioned poly(L-lactic acid) solution and polyvinyl alcohol solution (the volume ratio of poly(L-lactic acid) solution to polyvinyl alcohol solution is 1:40), place them on a magnetic stirrer, stir for 2 h to obtain an emulsion; subject the obtained emulsion to vacuum curing to remove the solvent, dry it at normal pressure under the conditions of 38 - 46 °C for 40 min, then dry it at a vacuum of 0.01 - 0.05 Mpa and 53 - 55 °C for 5 h, and continue to maintain it at a vacuum of 0.01 - 0.05 Mpa and room temperature for 45 min; perform freeze-drying according to the following freeze-drying procedure: pre-freeze at -40 - -45 °C for 2 - 4 h; sublimation drying: evacuate the freeze-dryer and maintain it at 0.20 ± 0.02 mbar, heat it at 5 °C / h to -10 - 20 °C, and maintain it for 12 - 18 h; analytical drying: evacuate the freeze-dryer and maintain it at 0.10 ± 0.02 mbar, raise the temperature to 25 - 40 °C, continuously dry for 20 - 30 h, then perform ultimate vacuum for 2 h, press the stopper in the vacuum state, take out of the box to obtain poly(L-lactic acid) microspheres; for every 150 mg of poly(L-lactic acid) microspheres, add 1 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.03% (the weight-average molecular weight of sodium hyaluronate is 800 kDa) and mix it with the poly(L-lactic acid) microspheres. After complete infiltration, slowly add 4 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.6% (the weight-average molecular weight of sodium hyaluronate is 800 kDa), and mix well to obtain the product.

[0047] Comparative Example 3

[0048] Dissolve 1 g of poly(L-lactic acid) with a weight-average molecular weight of 200 KDa in a mixed solvent of dichloromethane and ethyl acetate (the volume ratio of dichloromethane to ethyl acetate is 2:1) to obtain a poly(L-lactic acid) solution with a concentration of 100 mg / mL; dissolve 3 g of polyvinyl alcohol with a weight-average molecular weight of 130 KDa in an aqueous propylene glycol solution (the volume ratio of propylene glycol to water is 1:6) to obtain a polyvinyl alcohol solution with a mass percentage concentration of 1.0%; take the previously obtained poly(L-lactic acid) solution and polyvinyl alcohol solution (the volume ratio of poly(L-lactic acid) solution to polyvinyl alcohol solution is 1:40) and place them in an online high-speed shearer for high-speed shearing at a rate of 3000 r / min for 10 min to obtain an emulsion; vacuum-dry the obtained emulsion, dry it at a vacuum of 0.01 - 0.05 Mpa and 40 - 65 °C for 72 h, plug it under vacuum conditions, and take it out of the box to obtain poly(L-lactic acid) microspheres; for every 150 mg of poly(L-lactic acid) microspheres, add 1 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.03% (the weight-average molecular weight of sodium hyaluronate is 800 KDa) and mix it with the poly(L-lactic acid) microspheres. After complete infiltration, slowly add 4 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.6% (the weight-average molecular weight of sodium hyaluronate is 800 KDa), and mix well to obtain the product.

[0049] Comparative Example 4

[0050] Dissolve 1 g of poly-L-lactic acid with a weight-average molecular weight of 200 KDa in a mixed solvent of dichloromethane and ethyl acetate (the volume ratio of dichloromethane to ethyl acetate is 2:1) to obtain a poly-L-lactic acid solution with a concentration of 100 mg / mL; dissolve 3 g of polyvinyl alcohol with a weight-average molecular weight of 130 KDa in an aqueous propylene glycol solution (the volume ratio of propylene glycol to water is 1:6) to obtain a polyvinyl alcohol solution with a mass percentage concentration of 1.0%; take the aforementioned obtained poly-L-lactic acid solution and polyvinyl alcohol solution (the volume ratio of poly-L-lactic acid solution to polyvinyl alcohol solution is 1:40) and place them in an online high-speed shear machine for high-speed shearing at a rate of 3000 r / min for 10 min to obtain an emulsion; subject the obtained emulsion to vacuum curing to remove the solvent, dry it at normal pressure at 38 - 46 °C for 40 min, then dry it at a vacuum of 0.01 - 0.05 Mpa and 53 - 55 °C for 5 h, and continue to maintain it at a vacuum of 0.01 - 0.05 Mpa and at room temperature for 45 min; perform freeze-drying according to the following freeze-drying procedure: pre-freeze at -40 - -45 °C for 2 - 4 h; sublimation drying: evacuate the freeze-dryer and maintain it at 0.20 ± 0.02 mbar, heat it at 5 °C / h to -10 - 20 °C, and maintain it for 12 - 18 h; analytical drying: evacuate the freeze-dryer and maintain it at 0.10 ± 0.02 mbar, raise the temperature to 25 - 40 °C, continuously dry it for 20 - 30 h, then perform ultimate vacuum for 2 h, press the stopper in the vacuum state, take it out of the box to obtain poly-L-lactic acid microspheres; add 5 mL of a sodium hyaluronate solution with a mass percentage concentration of 0.9% (the weight-average molecular weight of sodium hyaluronate is 800 KDa) to every 150 mg of poly-L-lactic acid microspheres and mix them evenly to obtain the product.

[0051] Comparative Example 5

[0052] 1) Preparation for poly-L-lactic acid microsphere preparation: Prepare an aqueous phase for microsphere preparation by formulating a 2% aqueous solution of polyvinyl alcohol with a weight-average molecular weight of 130 KDa; prepare an oil phase for microsphere preparation by formulating a 1% poly-L-lactic acid / dichloromethane solution with a weight-average molecular weight of 200 KDa.

[0053] 2) Method for preparing poly-L-lactic acid microspheres: Set the magnetic stirring speed to 200 rpm. According to the ratio of oil phase:aqueous phase = 1:5, first place the aqueous phase in a beaker and start magnetic stirring. Use a syringe to draw the corresponding proportion of the oil phase and slowly add the oil phase to the aqueous phase.

[0054] 3) Volatilization of organic solvents: After all the oil phase is added to the aqueous phase, place the whole device under a fume hood, turn on the exhaust, set the magnetic stirring speed to 200 rpm, and allow the organic solvents to volatilize fully. The volatilization time should be greater than 20 h.

[0055] 4) Collection of poly-L-lactic acid microspheres: Let the volatilized microspheres stand for 2 h, pour off the upper transparent solution, and collect the lower layer. Filter it using a Buchner funnel. Collect the filtered microspheres, add them to a 2% polyvinyl alcohol solution, stir to form a suspension, let it stand for 2 h, pour off the upper transparent solution, and collect the lower layer. Filter it using a Buchner funnel. Collect the filtered microspheres, add them to injection water, stir to form a suspension, let it stand for 2 h, pour off the upper transparent solution, and collect the lower layer. Filter it using a Buchner funnel. Repeat the above operation once with injection water;

[0056] 5) Drying of poly-L-lactic acid: Place the filtered microspheres in a vacuum drying oven at 40 °C for drying for 24 h to obtain poly-L-lactic acid microspheres;

[0057] 6) Add the dried poly-L-lactic acid microspheres to the cross-linked sodium hyaluronate gel at a ratio of 180 mg / ml and mix evenly to obtain a white viscous material; Load the white viscous material into a glass syringe, perform moist heat sterilization at 121 °C for 8 min, and then fill it into a pre-filled syringe while it is still hot.

[0058] Experimental Example 1 Investigation of the properties of poly-L-lactic acid microspheres

[0059] Observed by scanning electron microscope and optical microscope, the properties of the poly-L-lactic acid microspheres obtained in each example and comparative example were determined, and the diameter of the microspheres was measured.

[0060] Determination of the redissolution time and stability time: Add equal amounts of the poly-L-lactic acid microspheres obtained in each example and comparative example to an equal amount of 2% sodium carboxymethylcellulose solution and mix evenly (in a uniform suspension state), measure the redissolution time, and continue to investigate the stability at room temperature, that is, the time when obvious sedimentation, solid-liquid separation or flocculation occurs.

[0061] Table 1 Microsphere measurement results of each example and comparative example

[0062]

[0063] The results show that: The poly-L-lactic acid microspheres obtained in each example of the present invention have good properties, fast redissolution, and high stability; In Comparative Example 1, due to the fact that propylene glycol was not added to the aqueous phase during the preparation process, the dispersibility of the microspheres was affected, resulting in a slightly decreased stability of the poly-L-lactic acid microspheres; In the preparation process of Comparative Example 2, magnetic stirring was used to mix and prepare the microspheres, and the formation of the microspheres was not uniform, resulting in a decreased stability; In Comparative Examples 3 and 5, different preparation methods from the present invention were used, and the obtained microspheres had poor properties, long redissolution time, and poor stability.

[0064] Experimental Example 2

[0065] The poly-L-lactic acid microspheres obtained in Example 3 were added to a sodium hyaluronate solution with a mass percentage concentration of 0.03% and mixed with the poly-L-lactic acid microspheres. After complete infiltration, a sodium hyaluronate solution with a mass percentage concentration of 0.6% was slowly added. After mixing, the product was obtained. The measured redissolution time was 11 min, and at room temperature, the standing time exceeded 2 h.

[0066] The poly-L-lactic acid microspheres obtained in Example 3 were added to a sodium hyaluronate solution with a mass percentage concentration of 0.1% and mixed with the poly-L-lactic acid microspheres. After complete infiltration, a sodium hyaluronate solution with a mass percentage concentration of 2% was slowly added. After mixing, the product was obtained. The measured redissolution time was 20 min, and at room temperature, the standing time exceeded 1.5 h.

[0067] The weight-average molecular weight of sodium hyaluronate used in Experimental Example 2 was 800 KDa.

[0068] Experimental Example 3

[0069] The fillers prepared in the examples and comparative examples were used for a filler experiment in the intradermal area of New Zealand white rabbits. The specific method was as follows: 27 male New Zealand white rabbits with a body weight of 2.0 - 2.5 kg were randomly grouped and evenly divided into 9 groups, with 3 rabbits in each group. One group was used as a blank control without a filler experiment, and the experimental results were averaged. The injection method was as follows: 6 points were injected into each rabbit, 0.2 mL at each point, subcutaneously injected into the back skin of the white rabbit. After 1 month, 3 months, and 24 months, whether there were adverse reactions such as redness, swelling, and subcutaneous nodules, as well as the encapsulation of skin fibrotic connective tissue, were observed. The reaction results after injection are shown in Table 2.

[0070] Table 2 Reaction results of the poly-L-lactic acid microspheres obtained in each example and comparative example after injection

[0071]

[0072] The results showed that: compared with the comparative examples, the poly-L-lactic acid facial fillers obtained in each example of the present invention had no irritating effect on the skin, were completely encapsulated by fibrotic connective tissue, and had a long local retention time.

Claims

1. A poly-L-lactic acid filler, characterized in that: The filler comprises poly-L-lactic acid, polyvinyl alcohol, sodium hyaluronate, propylene glycol and water for injection.

2. The filler according to claim 1, characterized in that In the filler, the weight average molecular weight of the poly-L-lactic acid is 50 to 300 Kda.

3. The filler according to claim 1, characterized in that In the filler, the weight average molecular weight of the polyvinyl alcohol is 50 to 200 KDa.

4. The filler according to claim 1, characterized in that In the filler, the molecular weight of sodium hyaluronate is 600-1000Kda.

5. A method for preparing the filler as claimed in claim 1, characterized in that: The preparation method comprises the following steps: dissolving poly-L-lactic acid in an organic solvent to obtain a poly-L-lactic acid solution; dissolving polyvinyl alcohol in an aqueous phase to obtain a polyvinyl alcohol solution; placing the poly-L-lactic acid solution and the polyvinyl alcohol solution in an online high-speed shearing machine for high-speed shearing to obtain an emulsion; vacuum solidifying and freeze-drying the emulsion to obtain poly-L-lactic acid microspheres; adding a low-concentration sodium hyaluronate solution to mix with the poly-L-lactic acid microspheres, and after complete infiltration, slowly adding a high-concentration sodium hyaluronate solution and mixing to obtain the microspheres.

6. The preparation method according to claim 5, characterized in that: In the preparation method, the organic solvent is dichloromethane or ethyl acetate.

7. The preparation method according to claim 5, characterized in that: In the preparation method, the aqueous phase is an aqueous solution of propylene glycol, wherein the volume ratio of propylene glycol to water is 1:4-10.

8. The preparation method according to claim 5, characterized in that: In the preparation method, poly-L-lactic acid is dissolved in an organic solvent to obtain a poly-L-lactic acid solution with a concentration of 50 to 150 mg / mL.

9. The preparation method according to claim 5, characterized in that: In the preparation method, polyvinyl alcohol is dissolved in an aqueous phase to obtain a polyvinyl alcohol solution with a mass percent concentration of 0.5 to 3.0%.

10. The preparation method according to claim 5, characterized in that: In the preparation method, the volume ratio of the poly-L-lactic acid solution to the polyvinyl alcohol solution is 1:10 to 1:50.

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