Citric acid-based polyesters and methods for their preparation, medical fillers and methods for their preparation

Abstract

This application relates to a citric acid-based polyester and its preparation method, as well as a medical filler and its preparation method. The citric acid-based polyester comprises: a first polymer unit and a plurality of second polymer units; the first polymer unit includes a citric acid unit and a first polyaliphatic diol unit, the first polymer unit having a branched structure, and the citric acid unit including a plurality of terminal carbonyl groups (-C(=O)-); the second polymer units are linear polymer segments, including a second polyaliphatic diol unit and a polyester unit; the second polymer units are attached to at least a portion of the terminal carbonyl groups of the first polymer unit. The branched structure formed by the citric acid unit in the citric acid-based polyester, combined with the first polyaliphatic diol unit and the linear second polymer units, can significantly improve the toughness and mechanical properties of the material and is less prone to agglomeration. This citric acid-based polyester has promising application prospects in the field of medical fillers, such as facial fillers.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to citric acid-based polyesters and their preparation methods, medical fillers and their preparation methods. Background Technology

[0002] Citric acid-based polyesters are a class of biodegradable polymers with excellent biocompatibility. Their degradation product, citric acid, can participate in the tricarboxylic acid cycle in organisms, giving polyester microparticles unique cellular activity.

[0003] Early research on citric acid polyesters focused primarily on the elastomer field. These elastomers typically use citric acid as a polyacid component, forming specialized aliphatic polyester elastomers through co-condensation and cross-linking reactions with diols and polyols. For example, the poly(citric acid-1,8-octanediol ester) obtained by the condensation of citric acid and 1,8-octanediol has been applied in drug delivery systems and tissue engineering scaffolds, and related bone repair materials have even received FDA approval in the United States. However, the synthesis process of these materials is difficult to precisely control, easily forming three-dimensional cross-linked structures. Furthermore, they suffer from low molecular weight and insufficient mechanical properties, limiting their large-scale application in facial injectable fillers.

[0004] Furthermore, due to the excessive reactive groups in citric acid, it easily forms a three-dimensional cross-linked structure when reacting with diols. Moreover, even when the content is high, the polymers formed are still highly hygroscopic. Pure polymers without the addition of inorganic substances are soft, have high viscosity after being exposed to moisture, poor crystallinity, and are temperature-sensitive, making industrial application difficult. Summary of the Invention

[0005] Therefore, it is necessary to provide citrate-based polyesters that can improve mechanical properties and their preparation methods, as well as medical fillers and their preparation methods.

[0006] In one aspect, the present invention provides a citric acid-based polyester comprising: a first polymerization unit and a plurality of second polymerization units;

[0007] The first polymerization unit includes a citric acid unit and a first polyaliphatic diol unit. The first polymerization unit has a branched structure, and the citric acid unit includes a plurality of terminal carbonyl groups (-C(=O)-).

[0008] The second polymerization unit is a linear polymer segment, comprising a second polyaliphatic diol unit and a polyester unit;

[0009] The second polymer unit is attached to at least a portion of the terminal carbonyl group of the first polymer unit.

[0010] In some embodiments, the citric acid-based polyester satisfies at least one of the following characteristics:

[0011] The mass ratio of the first polymerization unit to the second polymerization unit is 1:(1~3);

[0012] The second polymerization unit and the first polymerization unit are connected by an ester group;

[0013] The citric acid unit in the citric acid-based polyester is 15% to 35% by mass.

[0014] In the first polymerization unit, the mass ratio of the citric acid unit to the first polyaliphatic diol unit is 10:(3~10);

[0015] In the second polymerization unit, the mass ratio of the second polyaliphatic diol unit to the polyester unit is 10:(0.5~5).

[0016] The first polyaliphatic diol unit and the second polyaliphatic diol unit each independently include any one or more of polyethylene glycol, polybutane glycol, and polypropylene glycol;

[0017] The polyester unit includes any one or more of polycaprolactone, polylactic acid ester, and polybutylene succinate.

[0018] In some embodiments, the citric acid-based polyester satisfies at least one of the following characteristics:

[0019] The weight-average molecular weight of citric acid-based polyesters is 1–100 kDa;

[0020] The weight-average molecular weights of the first polyaliphatic diol unit and the second polyaliphatic diol unit are each independently 200 to 10000 Da;

[0021] The weight-average molecular weight of the polyester unit is 300 to 10000 Da;

[0022] The weight-average molecular weight of the second polymerization unit is 700 Da to 30000 Da;

[0023] The sum of the numerical values ​​of the hydroxyl ends in the first polyaliphatic diol unit, the second polyaliphatic diol unit, and the polyester unit of each citric acid polyester molecule is 2 to 10.

[0024] A second aspect of this application provides a method for preparing a citric acid-based polyester, comprising the following steps:

[0025] Citric acid and a first polyaliphatic diol are subjected to a first polymerization reaction under the catalysis of a first catalyst to prepare a first polymer system; the first polymer has a branched structure and contains multiple terminal carboxyl groups;

[0026] The first polymer system and the second polymer are mixed and subjected to an esterification reaction to prepare a citrate-based polyester.

[0027] The second polymer is a linear polymer comprising a second polyaliphatic diol unit and a polyester unit;

[0028] The first catalyst is selected from tin-containing compounds.

[0029] In some embodiments, the method for preparing the citrate-based polyester includes at least one of the following features:

[0030] The tin-containing compounds include any one or more of stannous octoate, stannous chloride, stannous sulfate, dibutyltin diisocyanate, tri-n-butylmethoxytin, dibutyltin dilaurate, and diethyltin.

[0031] The first polyaliphatic diol includes any one or more of polyethylene glycol, polybutanediol, and polypropylene glycol;

[0032] The mass ratio of citric acid to the first polyaliphatic diol is 10:(3~10).

[0033] The mass of the first catalyst fed is 0.05%-0.2% of the mass of the citric acid fed;

[0034] The mass ratio of the second polymer to the citric acid is (1-4):1.

[0035] In some embodiments, the method for preparing the citrate-based polyester includes at least one of the following features:

[0036] The temperature of the first polymerization reaction is 130℃-160℃;

[0037] The first polymerization reaction includes a first reaction stage and a second reaction stage. The first reaction stage is carried out in an inert atmosphere at a pressure of 100-150 kPa for 1-5 hours, and the second reaction stage is carried out under a vacuum of -98 kPa to -50 kPa for 2-24 hours.

[0038] The esterification reaction is carried out at a temperature of 130℃-160℃ for 1-10 hours.

[0039] In some embodiments, the second polymer is prepared by a method comprising the following steps:

[0040] Under the catalysis of the second catalyst, the second polyaliphatic diol and polyester monomer undergo a second polymerization reaction to prepare the second polymer;

[0041] Optionally, the step of polymerizing the second polyaliphatic diol and the polyester monomer under the catalysis of the second catalyst to prepare the second polymer includes at least one of the following features:

[0042] The polyester monomer includes a carboxylic acid containing a hydroxyl group and a lactone; optionally, the carboxylic acid containing a hydroxyl group includes any one or more of lactic acid and glycolic acid, and the lactone includes any one or more of caprolactone and valproic acid.

[0043] The second catalyst is selected from tin-containing compounds. Optionally, the second catalyst is selected from any one or more of stannous octoate, stannous chloride, stannous sulfate, dibutyltin diisocyanate, tri-n-butyl methoxytin, dibutyltin dilaurate, and diethyltin.

[0044] The mass of the second catalyst fed is 0.05%-0.2% of the mass of the polyester monomer fed;

[0045] The mass ratio of the lactone to the second polyaliphatic diol is 10:(0.5-4).

[0046] The second polymerization reaction is carried out at a temperature of 150℃-160℃ for a time of 5 h to 12 h.

[0047] The second polymerization reaction is carried out in an inert atmosphere.

[0048] A third aspect of this application provides a medical filler comprising at least one of the above-described citrate-based polyesters and citrate-based polyesters prepared by any of the above-described preparation methods.

[0049] In some embodiments, the medical filler further includes buffer salts and solvents;

[0050] Optionally, the medical filler satisfies at least one of the following characteristics:

[0051] The citrate-based polyester comprises 5% to 50% by mass in the medical filler;

[0052] The buffer salt includes any one or more of phosphate, citric acid and sodium chloride;

[0053] The solvent includes water;

[0054] The pH value of the medical filler is 6.0~7.5;

[0055] The osmotic pressure range of the medical filler is 300 mOsmol / kg to 350 mOsmol / kg.

[0056] A fourth aspect of this application provides a method for preparing a medical filler, comprising the following steps:

[0057] At least one of the above-mentioned citric acid-based polyesters and the citric acid-based polyesters prepared by any of the above-mentioned preparation methods is mixed with a buffer salt and a solvent, and a homogeneous solution is prepared under dispersion conditions.

[0058] Optionally, the dispersion conditions include stirring and heating;

[0059] Optionally, the preparation method of the medical filler further includes: sterilizing and filling the homogeneous solution.

[0060] The above preparation method utilizes a distribution polymerization approach. First, citric acid reacts with a polyaliphatic glycol to generate a first polymer containing terminal carboxyl groups. Then, this first polymer undergoes dehydration condensation with a linear second polymer containing terminal hydroxyl groups to prepare the aforementioned citric acid-based polyester. This method effectively avoids the excessive crosslinking that easily occurs when citric acid directly participates in multi-component copolymerization, thus facilitating control over the molecular weight and composition of the citric acid-based polyester. Furthermore, the entire synthesis process of the citric acid-based polyester is primarily based on melt polycondensation, avoiding the extensive use of harmful organic solvents for reaction and purification. Post-processing is simpler, better meeting the requirements of green chemistry and industrial production. The overall process is relatively simple, green, and safe. Attached Figure Description

[0061] Figure 1 Macroscopic images of the liquid filler prepared from the citric acid-based polyester of Example 1;

[0062] Figure 2 The extrusion force test diagram shows the liquid filler prepared from the citric acid-based polyester in Example 1. Detailed Implementation

[0063] To facilitate understanding of the present invention, a more complete description will be given below with reference to the accompanying drawings. Preferred embodiments of the invention are shown in the drawings. However, the invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the invention.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0065] In this application, the terms "multiple", "various", "multiple times", "several", "several", etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "one or more" means one or more or more.

[0066] In this application, "optionally", "optional", and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without".

[0067] In this application, the technical features or solutions described in open-ended language include both closed-ended technical features or solutions consisting of the listed contents and open-ended technical features or solutions that include the listed contents.

[0068] In this application, where the method flow involves multiple steps, unless otherwise explicitly stated herein, there is no strict order restriction on the execution of these steps; they can be executed in any order other than those described. Moreover, any step may include multiple sub-steps or multiple stages, which are not necessarily completed at the same time, but can be executed at different times, and their execution order is not necessarily sequential, but can be performed alternately or simultaneously with other steps or parts of the sub-steps or stages of other steps.

[0069] In this application, the terms "first aspect," "second aspect," "third aspect," "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," "fourth," etc., serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0070] Currently, while existing citrate-based polyesters possess good biocompatibility and biodegradability, their insufficient mechanical properties limit their application in the medical filler field. Furthermore, some citrate-based polyesters have high degrees of crosslinking, softening and swelling upon contact with water, yet they are difficult to form stable dispersions, making them unsuitable for conventional injection methods and inconvenient to use. To address these issues, this application provides at least one citrate-based polyester and its preparation method, as well as a medical filler and its preparation method.

[0071] According to a typical embodiment of this application, a citric acid-based polyester is provided, comprising: a first polymer unit and a plurality of second polymer units; the first polymer unit includes a citric acid unit and a first polyaliphatic diol unit, the first polymer unit having a branched structure, the citric acid unit including a plurality of terminal carbonyl groups (-C(=O)-); the second polymer unit is a linear polymer segment, including a second polyaliphatic diol unit and a polyester unit; the second polymer unit is attached to at least a portion of the terminal carbonyl groups of the first polymer unit.

[0072] The citric acid-based polyester of this application contains a first polymeric unit with an esterified structure and a second polymeric unit with linear polymer segments. Through the synergistic effect of the two, the citric acid-based polyester of this application not only has good biocompatibility and a suitable degradation rate, but also moderate hydrophilicity and hydrophobicity, good stability, and is not easily cross-linked, and has good mechanical properties. Specifically, the branched structure formed by the citric acid unit in the citric acid-based polyester, combined with the first polyaliphatic diol unit and the linear second polymeric unit, can significantly improve the toughness and mechanical properties of the material, and is not prone to agglomeration, exhibiting excellent stability. It can be made into a stable liquid medical filler that is less likely to clog needles.

[0073] This citric acid-based polyester, when used in medical fillers such as facial fillers, promotes collagen secretion and exhibits excellent biodegradability, showing promising application prospects in the field of injectable fillers.

[0074] In some embodiments, the second polymerization unit and the first polymerization unit are connected by an ester group.

[0075] In some embodiments, the mass ratio of the first polymerization unit to the second polymerization unit is 1:(1~3). Non-limitingly, the mass ratio of the first polymerization unit to the second polymerization unit is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, etc.

[0076] In some embodiments, the citric acid unit in the citric acid-based polyester is 15% to 35% by mass; non-limitingly, the citric acid unit in the citric acid-based polyester may be 15%, 20%, 25%, 30%, 35%, etc.

[0077] In some embodiments, in the first polymerization unit, the mass ratio of citric acid unit to first polyaliphatic diol unit is 10:(3~10); non-limitingly, the mass ratio of citric acid unit to first polyaliphatic diol unit can be 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10, etc.

[0078] In some embodiments, the mass ratio of the second polyaliphatic diol unit to the polyester unit in the second polymerization unit is 10:(0.5~5). Non-limitingly, the mass ratio of the second polyaliphatic diol unit to the polyester unit is 10:0.5, 10:1, 10:2, 10:3, 10:4, 10:5, etc.

[0079] In some embodiments, the first polyaliphatic diol unit and the second polyaliphatic diol unit each independently include any one or more of polyethylene glycol, polybutanediol, and polypropylene glycol;

[0080] In some embodiments, the polyester unit includes any one or more of polycaprolactone, polylactic acid ester, and polybutylene succinate. The introduction of the aforementioned polyester results in a more suitable degree of crosslinking for the citrate-based polyester, leading to greater stability in the preparation of liquid medical fillers and reducing the likelihood of needle clogging.

[0081] In some embodiments, the weight-average molecular weight of the citric acid-based polyester is 1 to 100 kDa. Non-limitingly, the weight-average molecular weight of the citric acid-based polyester can be 1 kDa, 10 kDa, 20 kDa, 30 kDa, 40 kDa, 50 kDa, 60 kDa, 70 kDa, 80 kDa, 90 kDa, 100 kDa, etc.

[0082] In some embodiments, the weight-average molecular weight of the first polyaliphatic diol unit and the second polyaliphatic diol unit is independently 200 to 10000 Da. Non-limitingly, the weight-average molecular weight of the first polyaliphatic diol unit and the second polyaliphatic diol unit can independently be 200 Da, 500 Da, 1000 Da, 3000 Da, 5000 Da, 7000 Da, 10000 Da, etc.

[0083] In some embodiments, the weight-average molecular weight of the polyester unit is 300 to 10,000 Da. Non-limitingly, the weight-average molecular weight of the polyester unit can be 300 Da, 500 Da, 1,000 Da, 3,000 Da, 5,000 Da, 7,000 Da, 10,000 Da, etc.

[0084] In some embodiments, the weight-average molecular weight of the second polymerization unit is 700 Da to 30000 Da; non-limitingly, it can be 700 Da, 2000 Da, 4000 Da, 8000 Da, 10000 Da, 15000 Da, 20000 Da, 25000 Da, 30000 Da, etc.

[0085] In some embodiments, the sum of the numerical values ​​of the hydroxyl ends in the first polyaliphatic diol unit, the second polyaliphatic diol unit, and the polyester unit of each citric acid polyester molecule is 2 to 10, and can be 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., without limitation.

[0086] According to another typical embodiment of this application, a method for preparing a citric acid-based polyester is provided, comprising the following steps: under the catalysis of a first catalyst, citric acid and a first polyaliphatic diol undergo a first polymerization reaction to prepare a first polymer system; the first polymer has a branched structure and contains multiple terminal carboxyl groups; the first polymer system and the second polymer are mixed and subjected to an esterification reaction to prepare a citric acid-based polyester; the second polymer is a linear polymer comprising a second polyaliphatic diol unit and a polyester unit; the first catalyst is selected from tin-containing compounds.

[0087] The above preparation method utilizes a distribution polymerization approach. First, citric acid reacts with a polyaliphatic glycol to generate a first polymer containing terminal carboxyl groups. Then, this first polymer undergoes dehydration condensation with a linear second polymer containing terminal hydroxyl groups to prepare the aforementioned citric acid-based polyester. This method effectively avoids the excessive crosslinking that easily occurs when citric acid directly participates in multi-component copolymerization, thus facilitating control over the molecular weight and composition of the citric acid-based polyester. Furthermore, the entire synthesis process of the citric acid-based polyester is primarily based on melt polycondensation, avoiding the extensive use of harmful organic solvents for reaction and purification. Post-processing is simpler, better meeting the requirements of green chemistry and industrial production. The overall process is relatively simple, green, and safe.

[0088] In some embodiments, the tin-containing compound includes any one or more of stannous octoate, stannous chloride, stannous sulfate, dibutyltin diisocyanate, tri-n-butylmethoxytin, dibutyltin dilaurate, and diethyltin.

[0089] In some embodiments, the mass of the first catalyst is 0.05%-0.2% of the mass of citric acid; non-limitingly, the mass of the first catalyst can be 0.05%, 0.1%, 0.15%, 0.2%, etc., of the mass of citric acid.

[0090] In some embodiments, the first polyaliphatic diol includes any one or more of polyethylene glycol, polybutane glycol, and polypropylene glycol.

[0091] In some embodiments, the mass ratio of citric acid to the first polyaliphatic diol is 10:(3~10). Controlling the mass ratio of citric acid to the first polyaliphatic diol within the above range helps to reduce the viscosity of the citric acid-based polyester, making it easier to use as a filler. Non-limitingly, the mass ratio of citric acid to the first polyaliphatic diol can be 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10, etc. Optionally, a mass ratio of citric acid to the first polyaliphatic diol of 10:(7~10) results in a lower viscosity of the citric acid-based polyester, making it closer to a liquid and more convenient to use.

[0092] In some embodiments, the first polymerization reaction described above is carried out in an inert gas atmosphere. Optionally, the gas forming the inert gas atmosphere includes one or more of nitrogen, argon, and helium.

[0093] In some embodiments, before the first polymerization reaction, citric acid, a first polyaliphatic glycol and a first catalyst are mixed and heated to a molten state, for example, to 80-110°C; optionally, after the above-mentioned molten state is formed, the system is evacuated until there is no boiling over, and then a gas to form an inert gas atmosphere is introduced, and then the temperature of the system is adjusted to the temperature for the first polymerization reaction to be carried out.

[0094] In some embodiments, the temperature of the first polymerization reaction is 130°C-160°C; non-limitingly, the temperature of the first polymerization reaction can be 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, 160°C, etc. Optionally, the time of the first polymerization reaction is 3 h-30 h; non-limitingly, the time of the first polymerization reaction is 3 h, 5 h, 10 h, 15 h, 20 h, 25 h, 30 h, etc.

[0095] In some embodiments, the first polymerization reaction includes a first reaction stage and a second reaction stage. The first reaction stage is carried out in an inert atmosphere at a pressure of 100-150 kPa for 1 h to 5 h, and the second reaction stage is carried out in a vacuum state of -98 kPa to -50 kPa for 2 h to 24 h.

[0096] The first polymer system formed after the first polymerization reaction is completed can be directly mixed with the second polymer without further processing to carry out the esterification reaction.

[0097] In some embodiments, the mass ratio of the second polymer to citric acid is (1-4):1. Non-limitingly, the mass ratio of the second polymer to citric acid can be 1:1, 1:2, 1:3, 1:4, etc.

[0098] In some embodiments, the esterification reaction temperature is 130°C-160°C. Non-limitingly, the esterification reaction temperature can be 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, 160°C, etc. Optionally, the esterification reaction time is 1-10 hours. Non-limitingly, the esterification reaction time can be 1 hour, 3 hours, 5 hours, 7 hours, 9 hours, 10 hours, etc.

[0099] In some embodiments, the second polymer is prepared by a method comprising the following steps: a second polyaliphatic diol and a polyester monomer undergo a second polymerization reaction under the catalysis of a second catalyst to prepare the second polymer.

[0100] Furthermore, the polyester monomer includes a carboxylic acid containing a hydroxyl group and a lactone; wherein, a lactone refers to a compound formed by the dehydration of a single molecule through an esterification reaction. Optionally, the carboxylic acid containing a hydroxyl group includes any one or more of lactic acid and glycolic acid, and the lactone includes any one or more of caprolactone and valproic acid.

[0101] Optionally, the second polymerization product system formed after the second polymerization reaction can be directly mixed with the first polymer system to carry out an esterification reaction.

[0102] Further, the second catalyst is selected from tin-containing compounds, and optionally, the second catalyst is selected from any one or more of stannous octoate, stannous chloride, stannous sulfate, dibutyltin diisocyanate, tri-n-butylmethoxytin, dibutyltin dilaurate, and diethyltin.

[0103] Furthermore, the mass of the second catalyst is 0.05%-0.2% of the mass of the polyester monomer; non-limitingly, the mass of the second catalyst can be 0.05%, 0.1%, 0.15%, 0.2%, etc. of the mass of the polyester monomer.

[0104] Furthermore, the mass ratio of lactone to the second polyaliphatic diol is 10:(0.5-4). Increasing the proportion of polyaliphatic diol can reduce the molecular weight of the second polymer and affect the viscosity of the target citric acid-based polyester. Controlling the mass ratio of lactone to the second polyaliphatic diol within the above range helps to obtain a citric acid-based polyester with both good structural stability and viscosity. Non-limitingly, the mass ratio of lactone to the second polyaliphatic diol can be 10:0.5, 10:0.6, 10:0.7, 10:0.8, 10:1, 10:1.5, 10:2, 10:2.5, 10:3, 10:3.5, 10:4, etc.

[0105] Furthermore, the temperature of the second polymerization reaction is 150℃-160℃, and non-limitingly, the temperature of the second polymerization reaction can be 150℃, 153℃, 155℃, 158℃, 160℃, etc. Optionally, the time of the second polymerization reaction is 5h~12h.

[0106] Furthermore, the second polymerization reaction is carried out in an inert atmosphere.

[0107] In some embodiments, the method for preparing the above-mentioned citric acid-based polyester further includes purifying the esterification product generated after the esterification reaction; further, the purification process includes: mixing the esterification product with a good solvent to obtain an esterification product solution, separating and purifying the esterification product by column chromatography, mixing the obtained filtrate with a poor solvent to precipitate a solid, and washing and drying the solid to obtain the citric acid-based polyester. Through the above purification process, the catalyst in the reaction can be removed, resulting in a high-purity citric acid-based polyester.

[0108] Furthermore, good solvents include any one or more of tetrahydrofuran, dichloromethane, and ethyl acetate; poor solvents include any one or more of methanol, ethanol, isopropanol, diethyl ether, and isopropyl ether.

[0109] According to another typical embodiment of this application, a medical filler is provided, comprising at least one of the above-mentioned citric acid-based polyesters and citric acid-based polyesters prepared by any of the above-mentioned preparation methods. Because the medical filler of this application uses the above-mentioned citric acid-based polyester, it possesses good stability, mechanical properties, and excellent biodegradability, and has good application prospects in the field of injection filling.

[0110] In some embodiments, the aforementioned medical filler is a liquid formulation. By preparing citric acid-based polyester into a liquid formulation, i.e., preparing a citric acid-based polyester solution, the defects of solid citric acid-based polyester particles prepared by blending processes, such as the inability to purify them and the susceptibility of solid citric acid-based polyester to moisture absorption and softening, can be overcome, thus meeting the application requirements in the field of medical fillers. Furthermore, the liquid filler is easy to administer, as it can be injected using a syringe, and the liquid dispersant component is absorbed and metabolized by the body.

[0111] In some embodiments, the medical filler further includes a buffer salt and a solvent. The buffer salt enables the medical filler to have a suitable pH value.

[0112] Furthermore, the mass percentage of citric acid-based polyester in the medical filler is 5% to 50%; non-limitingly, the mass percentage of citric acid-based polyester in the medical filler can be 5%, 10%, 20%, 30%, 40%, 50%, etc.

[0113] Furthermore, the buffer salt includes any one or more of phosphates, citric acid, and sodium chloride.

[0114] Furthermore, the solvent includes water; optionally, the water content in the solvent is 90%-100% by mass.

[0115] Furthermore, the pH value of the medical filler is 6.0 to 7.5; non-limitingly, the pH value of the medical filler can be 6.0, 6.2, 6.4, 6.6, 6.8, 7, 7.2, 7.4, 7.5, etc.

[0116] Furthermore, the osmotic pressure range of the medical filler is 300 mOsmol / kg to 350 mOsmol / kg. Non-limitingly, the osmotic pressure of the medical filler can be 300 mOsmol / kg, 310 mOsmol / kg, 320 mOsmol / kg, 330 mOsmol / kg, 340 mOsmol / kg, 350 mOsmol / kg, etc.

[0117] According to another typical embodiment of this application, a method for preparing a medical filler is provided, comprising the following steps: mixing at least one of the citrate-based polyesters described above and the citrate-based polyesters prepared by any of the above preparation methods with a buffer salt and a solvent, and obtaining a homogeneous solution under dispersion conditions. The medical filler prepared by the above method has a stable structure and is convenient to use.

[0118] In some embodiments, the dispersion conditions include stirring and heating. Further, the heating temperature is 60°C to 95°C, and the stirring speed is 300 to 800 rpm.

[0119] In some embodiments, a buffer salt and a solvent are mixed to support the buffer salt solution, and the buffer salt solution is mixed with a citric acid-based polyester to prepare a homogeneous system.

[0120] In some embodiments, the preparation method of the medical filler further includes: sterilizing the homogeneous solution and filling it.

[0121] Furthermore, the sterilization method can be high temperature and high pressure sterilization. Optionally, the sterilization conditions are: a temperature of 111-121℃ and a pressure of 0.1-0.2MPa, with a treatment time of 20-40 minutes.

[0122] Furthermore, the filling containers include, but are not limited to, pre-filled syringes or vials.

[0123] The following are detailed examples.

[0124] Example 1

[0125] Citric acid-based polyesters were synthesized using the following steps:

[0126] (1) In a dry reaction flask, add 100g caprolactone, 15g PEG200 (Mn=200 Da), and 0.1g stannous octoate, and purge with nitrogen three times. After melting in an oil bath at 120℃, evacuate for 5 minutes. Restore nitrogen protection and heat to 155℃ for 6 hours. Cool to 30℃ to obtain polymer 1 (PCL-PEG-PCL). Its weight-average molecular weight (Mw) is approximately 1533 Da.

[0127] (2) In another dry reaction flask, add 50g citric acid, 25g PEG200 and 0.15g stannous octoate, heat to 100℃ under nitrogen protection to melt, and evacuate for 10 minutes. Heat to 140℃ under nitrogen protection and react for 3 hours. Then connect a vacuum pump and continue the reaction for 8 hours at 140℃ under reduced pressure (<100 Pa). Add all of the polymer 1 obtained in step (1) to this reaction flask and continue the reaction for 5 hours at 140℃ under nitrogen protection. Cool to room temperature, add 500g ethyl acetate to the reaction system, stir until completely dissolved, remove the tin catalyst by modified silica gel column chromatography, filter the solution through a 0.22-micron filter membrane, collect the filtrate, add 1L of diethyl ether, precipitate the solid, wash with pure water, and vacuum dry to obtain a pale yellow viscous polymer, namely citric acid-based polyester copolymer (denoted as PCA-PEG-PCL-1). According to GPC, its weight-average molecular weight (Mw) is approximately 7 kDa. The citric acid unit content is approximately 26%.

[0128] Example 2

[0129] Citric acid-based polyesters were synthesized using the following steps:

[0130] (1) In a dry reaction flask, add 100g caprolactone, 30g PEG600 (Mn=600 Da), and 0.1g stannous octoate, and purge with nitrogen three times. After melting in an oil bath at 120℃, evacuate for 5 minutes. Restore nitrogen protection and heat to 155℃ for 6 hours. Cool to 30℃ to obtain polymer 2 (PCL-PEG-PCL). Its weight-average molecular weight (Mw) is approximately 2600 Da.

[0131] (2) In another dry reaction flask, add 50g citric acid, 50g PEG400 and 0.15g stannous octoate, heat to 100℃ under nitrogen protection to melt, and evacuate for 10 minutes. Heat to 140℃ under nitrogen protection and react for 3 hours. Then connect a vacuum pump and continue the reaction for 8 hours at 140℃ under reduced pressure (<100 Pa). Add all of the polymer 2 obtained in step (1) to this reaction flask and continue the reaction for 5 hours at 140℃ under nitrogen protection. Stop the reaction, cool to room temperature, add 500g ethyl acetate to the reaction system, stir until completely dissolved, remove the tin catalyst by modified silica gel column chromatography, filter the solution through a 0.22-micron filter membrane, collect the filtrate, add 1L of diethyl ether, precipitate the solid, wash with pure water, and vacuum dry to obtain a light yellow viscous polymer, namely citric acid-based polyester copolymer (denoted as PCA-PEG-PCL-2). According to GPC, its weight-average molecular weight (Mw) is approximately 8kDa. The citric acid unit content is approximately 22%.

[0132] Example 3

[0133] Citric acid-based polyesters were synthesized using the following steps:

[0134] (1) In a dry reaction flask, add 100g caprolactone, 15g PEG200 (Mn=200 Da), and 0.1g stannous octoate, and purge with nitrogen three times. After melting in an oil bath at 140℃, evacuate for 5 minutes. Restore nitrogen protection and heat to 155℃ for 10 hours. Cool to 30℃ to obtain polymer 3 (PCL-PEG-PCL). Its weight-average molecular weight (Mw) is approximately 1533 Da.

[0135] (2) In another dry reaction flask, add 50g citric acid, 25g PEG200 and 0.15g stannous octoate, heat to 100℃ under nitrogen protection to melt, and evacuate for 10 minutes. Heat to 140℃ under nitrogen protection and react for 3 hours. Then connect a vacuum pump and continue the reaction for 10 hours at 150℃ and reduced pressure (<100 Pa). Add all of the polymer 3 obtained in step (1) to this reaction flask and continue the reaction for 5 hours at 150℃ under nitrogen protection. Stop the reaction, cool to room temperature, add 500g ethyl acetate to the reaction system, stir until completely dissolved, remove the tin catalyst by modified silica gel column chromatography, filter the solution through a 0.22-micron filter membrane, collect the filtrate, add 1L of diethyl ether, precipitate the solid, wash with pure water, and vacuum dry to obtain a pale yellow viscous polymer, namely citric acid-based polyester copolymer (denoted as PCA-PEG-PCL-3). According to GPC, its weight-average molecular weight (Mw) is approximately 9kDa. The citric acid unit content is approximately 26%.

[0136] Example 4

[0137] Citric acid-based polyesters were synthesized using the following steps:

[0138] (1) In a dry reaction flask, add 100g caprolactone, 50g PEG200 (Mn=200 Da), and 0.1g stannous octoate, and purge with nitrogen three times. After melting in an oil bath at 140℃, evacuate for 5 minutes. Restore nitrogen protection and heat to 155℃ for 10 hours. Cool to 30℃ to obtain waxy solid polymer 4 (PCL-PEG-PCL). Its weight-average molecular weight (Mw) is approximately 600 Da.

[0139] (2) In another dry reaction flask, add 50g citric acid, 5g PEG200 and 0.15g stannous octoate, heat to 100℃ under nitrogen protection to melt, and evacuate for 10 minutes. Heat to 140℃ under nitrogen protection and react for 3 hours. Then connect a vacuum pump and continue the reaction for 10 hours at 150℃ and reduced pressure (<100 Pa). Add all of the polymer 4 obtained in step (1) to this reaction flask and continue the reaction for 5 hours at 150℃ under nitrogen protection. Stop the reaction, cool to room temperature, add 500g ethyl acetate to the reaction system, stir until completely dissolved, remove the tin catalyst by modified silica gel column chromatography, filter the solution through a 0.22-micron filter membrane, collect the filtrate, add 1L of diethyl ether, precipitate the solid, wash with pure water, and vacuum dry to obtain a light yellow viscous polymer, namely citric acid-based polyester copolymer (denoted as PCA-PEG-PCL-4). According to GPC, its weight-average molecular weight (Mw) is approximately 6kDa. The citric acid unit content is approximately 20%.

[0140] Example 5

[0141] The difference from Example 1 is that in step (1), the same mass of caprolactone was replaced with lactic acid. The weight-average molecular weight (Mw) of the resulting polymer was approximately 1800 Da.

[0142] Comparative Example 1

[0143] Citric acid, L-malic acid, succinic acid, and glycerol were added to a reaction flask in a molar ratio of 1:1:1:1.7, and the mixture was purged with nitrogen three times. After melting in an oil bath at 140°C, the mixture was evacuated for 5 minutes. Nitrogen protection was then restored, and the mixture was reacted at 145°C for 1 hour to obtain a prepolymer. This prepolymer was then reacted at 135°C for 72 hours, and after cooling, a hard citric acid-based copolymer was obtained.

[0144] Comparative Example 2

[0145] Citric acid-based polyesters were synthesized using the following steps:

[0146] In a dry reaction flask, 50 g of citric acid, 25 g of PEG200, and 0.15 g of stannous octoate were added. The mixture was heated to 100 °C under nitrogen protection to melt, and then evacuated for 10 minutes. The mixture was then heated to 140 °C under nitrogen protection and reacted for 3 hours. A vacuum pump was then connected, and the reaction was continued for 8 hours at 140 °C under reduced pressure (<100 Pa). 100 g of caprolactone and 50 g of PEG200 were added to the above reaction flask, and the mixture was heated to 155 °C and reacted for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, and 500 g of ethyl acetate was added to the reaction system. After stirring until completely dissolved, the tin catalyst was removed by modified silica gel column chromatography. The solution was filtered through a 0.22 μm filter membrane, and the filtrate was collected. 1 L of diethyl ether was added, and the precipitated solid was washed with pure water and dried under vacuum to obtain a pale yellow viscous polymer, namely, a citric acid-based polyester copolymer (denoted as PCA-PEG-PCL-1). GPC analysis showed that its weight-average molecular weight (Mw) was approximately 16 kDa.

[0147] The citric acid-based copolymers prepared in the above embodiments and comparative examples were respectively prepared into liquid fillers according to the following methods:

[0148] Weigh 10g of citric acid-based polyester copolymer and add 90mL of phosphate (disodium hydrogen phosphate) buffer solution with pH=7.4. Stir thoroughly until completely dispersed. Heat the dispersion to 60℃ and stir at 500rpm for 30min. Fill the resulting micelle solution into vials and place them in a high-temperature and high-pressure sterilizer. Sterilize at 121℃ and 0.15MPa for 30min. After the sterilization process is completed, cool and depressurize to room temperature and pressure to obtain the liquid filler.

[0149] The macroscopic properties of the liquid fillers prepared in the above examples and comparative examples after being placed for 30 days are shown in Table 1 below.

[0150] Table 1

[0151]

[0152] The liquid filler prepared by the above method in Example 1 was placed in a 40°C constant temperature incubator. The macroscopic properties, particle size D90, pH, and osmotic pressure of the samples were periodically measured for a total of 4 weeks. The results are shown in Table 2 below. Samples after four weeks of storage... Figure 1 As shown.

[0153] The test methods for particle size D90, pH, and osmotic pressure are as follows:

[0154] Particle size D90: Dynamic light scattering laser particle size analyzer, which calculates particle size distribution based on the angle of scattered light or Brownian motion velocity of particles. The specific process is as follows:

[0155] ① Sample dilution: Dilute with a dispersion medium (such as pure water) until the light-blocking rate meets the standard.

[0156] ② Background measurement: First, measure the background of the dispersion medium.

[0157] ③ Sample measurement: After ultrasonic dispersion under stirring, the sample is injected and repeated 3 times.

[0158] ④ Data Analysis: Report the D90 (particle size corresponding to a cumulative distribution of 90%), distribution curve, and span under the volume distribution.

[0159] pH: The pH value is calculated by measuring the potential difference between the glass electrode and the reference electrode using the potentiometric method.

[0160] Osmotic pressure: Freezing point depression / vapor pressure depression: Measure the degree to which the freezing point or vapor pressure of a solution decreases due to the presence of a solute, and calculate the osmotic pressure. Refer to 0632 Determination of Osmotic Molar Concentration - Chinese Pharmacopoeia 2025 Edition.

[0161] Table 2

[0162]

[0163] *Note: 0 weeks refers to the initial state of the liquid filler after it has been prepared.

[0164] As shown in Table 2, the filler solution made of citric acid-based polyester prepared in Example 1 remained homogeneous throughout the 0 to 4 weeks, with no precipitation or stratification observed. The particle size variation was less than 10%, the pH fluctuation was less than 0.05, and the osmotic pressure change was less than 0.1%.

[0165] The liquid fillers prepared in other examples and comparative examples were placed in a 40°C constant temperature incubator and tested for four weeks (28 days in total) according to the above method. The changes in particle size D90, pH and osmotic pressure are shown in Table 3 below.

[0166] Table 3

[0167]

[0168] As can be seen from the test results in Tables 2 and 3, the filler prepared by the citric acid-based polyester provided by the present invention has good stability and is not prone to cross-linking and decomposition during storage.

[0169] The liquid fillers prepared in the above examples and comparative examples were subjected to extrusion force tests using 27G and 30G needles, respectively. The extrusion speed was 30 mm / min, and the displacement distance was 15 mm. The average extrusion force was recorded, and the results are shown in Table 4 below. The extrusion force test graph of the filler prepared from the citric acid-based polyester in Example 1 under different strokes is shown below. Figure 2 As shown.

[0170] Table 4

[0171]

[0172] The results of the above extrusion force test show that the liquid filler prepared by the citric acid-based polyester of this application has a suitable extrusion force, is not prone to needle blockage, and is easy to use.

[0173] Cytotoxicity test: The liquid fillers prepared in the above examples and comparative examples were subjected to cytotoxicity tests using the CCK8 assay, with a dosage concentration of 250 μg / ml. The procedure is as follows:

[0174] (1) Collect cells in the logarithmic growth phase and adjust the cell suspension concentration to 3×10⁻⁶. 4 ~5×10 4 cells / mL;

[0175] (2) Add cell suspension to 96 wells, 100 μL / well, fill the edges with PBS, and incubate at 37°C with 5% CO2;

[0176] (3) After culturing for 24 hours, administer the drug, set up 3 to 6 replicates, and incubate at 37°C with 5% CO2;

[0177] (4) After incubation for an appropriate time, discard the old solution and dilute 200 μl / well with serum-free medium and CCK8 at a ratio of 10:1;

[0178] (5) CCK8: After the time is up, measure the absorbance of each well at 450nm using an ELISA reader.

[0179] The cell viability results are shown in Table 5.

[0180] Table 5

[0181]

[0182] The cytotoxicity test results above show that the liquid filler prepared from the citrate-based polyester of this application has good biocompatibility.

[0183] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0184] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this invention should be determined by the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A citric acid-based polyester, characterized in that, include: A first aggregation unit and multiple second aggregation units; The first polymerization unit includes a citric acid unit and a first polyaliphatic diol unit. The first polymerization unit has a branched structure, and the citric acid unit includes a plurality of terminal carbonyl groups (-C(=O)-). The second polymerization unit is a linear polymer segment, comprising a second polyaliphatic diol unit and a polyester unit; The second polymer unit is attached to at least a portion of the terminal carbonyl group of the first polymer unit.

2. The citric acid-based polyester according to claim 1, characterized in that, It meets at least one of the following characteristics: The mass ratio of the first polymerization unit to the second polymerization unit is 1:(1~3); The second polymerization unit and the first polymerization unit are connected by an ester group; The citric acid unit in the citric acid-based polyester is 15% to 35% by mass. In the first polymerization unit, the mass ratio of the citric acid unit to the first polyaliphatic diol unit is 10:(3~10); In the second polymerization unit, the mass ratio of the second polyaliphatic diol unit to the polyester unit is 10:(0.5~5). The first polyaliphatic diol unit and the second polyaliphatic diol unit each independently include any one or more of polyethylene glycol, polybutane glycol, and polypropylene glycol; The polyester unit includes any one or more of polycaprolactone, polylactic acid ester, and polybutylene succinate.

3. The citric acid-based polyester according to claim 1, characterized in that, It meets at least one of the following characteristics: The weight-average molecular weight of citric acid-based polyesters is 1–100 kDa; The weight-average molecular weights of the first polyaliphatic diol unit and the second polyaliphatic diol unit are each independently 200 Da to 10000 Da; The weight-average molecular weight of the polyester unit is 300 Da to 10000 Da; The weight-average molecular weight of the second polymerization unit is 700 Da to 30,000 Da; The sum of the numerical values ​​of the hydroxyl ends in the first polyaliphatic diol unit, the second polyaliphatic diol unit, and the polyester unit of each citric acid polyester molecule is 2 to 10.

4. A method for preparing citric acid-based polyester, characterized in that, Includes the following steps: Citric acid and a first polyaliphatic diol are subjected to a first polymerization reaction under the catalysis of a first catalyst to prepare a first polymer system; the first polymer has a branched structure and contains multiple terminal carboxyl groups; The first polymer system and the second polymer are mixed and subjected to an esterification reaction to prepare a citrate-based polyester. The second polymer is a linear polymer comprising a second polyaliphatic diol unit and a polyester unit; The first catalyst is selected from tin-containing compounds.

5. The method for preparing citric acid-based polyester according to claim 4, characterized in that, Includes at least one of the following features: The tin-containing compounds include any one or more of stannous octoate, stannous chloride, stannous sulfate, dibutyltin diisocyanate, tri-n-butylmethoxytin, dibutyltin dilaurate, and diethyltin. The first polyaliphatic diol includes any one or more of polyethylene glycol, polybutanediol, and polypropylene glycol; The mass ratio of citric acid to the first polyaliphatic diol is 10:(3~10). The mass of the first catalyst fed is 0.05%-0.2% of the mass of the citric acid fed; The mass ratio of the second polymer to the citric acid is (1-4):

1.

6. The method for preparing citric acid-based polyester according to claim 4, characterized in that, Includes at least one of the following features: The temperature of the first polymerization reaction is 130℃-160℃; The first polymerization reaction includes a first reaction stage and a second reaction stage. The first reaction stage is carried out in an inert atmosphere at a pressure of 100 kPa-150 kPa for 1 h-5 h, and the second reaction stage is carried out under a vacuum of -98 kPa to -50 kPa for 2 h-24 h. The esterification reaction is carried out at a temperature of 130℃-160℃ for 1-10 hours.

7. The method for preparing citric acid-based polyester according to any one of claims 4 to 6, characterized in that, The second polymer is prepared by a method comprising the following steps: Under the catalysis of the second catalyst, the second polyaliphatic diol and polyester monomer undergo a second polymerization reaction to prepare the second polymer; Optionally, the step of polymerizing the second polyaliphatic diol and the polyester monomer under the catalysis of the second catalyst to prepare the second polymer includes at least one of the following features: The polyester monomer includes a carboxylic acid containing a hydroxyl group and a lactone; optionally, the carboxylic acid containing a hydroxyl group includes any one or more of lactic acid and glycolic acid, and the lactone includes any one or more of caprolactone and valproic acid. The second catalyst is selected from tin-containing compounds. Optionally, the second catalyst is selected from any one or more of stannous octoate, stannous chloride, stannous sulfate, dibutyltin diisocyanate, tri-n-butyl methoxytin, dibutyltin dilaurate, and diethyltin. The mass of the second catalyst fed is 0.05%-0.2% of the mass of the polyester monomer fed; The mass ratio of the lactone to the second polyaliphatic diol is 10:(0.5-4). The second polymerization reaction is carried out at a temperature of 150℃-160℃ for 5 h to 12 h. The second polymerization reaction is carried out in an inert atmosphere.

8. A medical filler, characterized in that, It includes at least one of the citric acid-based polyesters according to any one of claims 1 to 3 and the citric acid-based polyesters prepared by the preparation method according to any one of claims 4 to 7.

9. The medical filler according to claim 8, characterized in that, The medical filler also includes buffer salts and solvents; Optionally, the medical filler satisfies at least one of the following characteristics: The citrate-based polyester comprises 5% to 50% by mass in the medical filler; The buffer salt includes any one or more of phosphate, citric acid and sodium chloride; The solvent includes water; The pH value of the medical filler is 6.0~7.5; The osmotic pressure range of the medical filler is 300 mOsmol / kg to 350 mOsmol / kg.

10. A method for preparing a medical filler, characterized in that, Includes the following steps: At least one of the citrate-based polyesters prepared by the preparation methods of any one of claims 1 to 3 and any one of claims 4 to 7 is mixed with a buffer salt and a solvent, and a homogeneous solution is prepared under dispersion conditions. Optionally, the dispersion conditions include stirring and heating; Optionally, the preparation method of the medical filler further includes: sterilizing and filling the homogeneous solution.

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