Polyester microparticles and preparation method thereof, and injection-filled products

Abstract

The present application provides a polyester microparticle and a preparation method thereof, and an injection filling product, the preparation method comprising: pre-reacting a first reactant with a first fatty chain diol in the presence of a first catalyst to obtain a prepolymer; performing an ester exchange reaction on the prepolymer and a second reactant in the presence of a second catalyst to obtain a polyester, the number average molecular weight of the polyester being 30000Da~150000Da; pulverizing the polyester and then sieving it to obtain polyester microparticles; wherein the first reactant comprises one or more of a hydroxycarboxylic acid compound, an organic acid anhydride compound, and a first ester compound; the second reactant comprises one or more of a second ester compound, a second fatty chain diol, and a fatty chain diacid, the number average molecular weight of the second reactant being 70Da~10000Da. The preparation method provided in the present application can obtain a polyester with a relatively high molecular weight, thereby facilitating the preparation of polyester microparticles and their application in the field of injection filling.

Description

Technical Field

[0001] The present application relates to the field of biomedical technology, and in particular to polyester microparticles and a preparation method thereof, and an injection-filled product. Background Art

[0002] Polyester (such as citric acid polyester) products used in the field of injectable filling are a kind of biodegradable polymer material, which generally has excellent biocompatibility and can promote the secretion of collagen in the superficial layer of the skin. Its degradation products (such as citric acid) can generally participate in the tricarboxylic acid cycle of organisms and are products with cell activity.

[0003] Most of the current polyester products are polyester elastomers, such as citric acid polyester elastomer, which usually uses citric acid as the polyacid component, and forms a special aliphatic polyester elastomer through co-condensation and cross-linking with diols and polyols; for example, the reaction of citric acid and 1,8-octanediol can obtain polycitric acid-1,8-octanediol ester elastomer. However, during the preparation of this type of polyester elastomer, the reaction process is usually uncontrollable and cross-linking is easy to occur, and it is very easy to form a bulk cross-linked product with a low molecular weight; and this low molecular weight bulk cross-linked product is difficult to be prepared into polyester microparticles by physical methods (that is, it is very difficult to prepare it into polyester microparticles by physical methods), thus limiting its use in the field of injection filling. Summary of the invention

[0004] Based on this, the present application provides a polyester microparticle and a preparation method thereof, and an injection-filled product. The preparation method can obtain high molecular weight polyester, thereby facilitating the physical preparation of polyester microparticles and their application in the field of injection filling.

[0005] The first aspect of the present application provides a method for preparing polyester microparticles, comprising:

[0006] Pre-reacting the first reactant with the first fatty chain diol in the presence of a first catalyst to obtain a prepolymer;

[0007] The prepolymer and the second reactant are subjected to an ester exchange reaction in the presence of a second catalyst to obtain a polyester having a number average molecular weight of 30,000 Da to 150,000 Da;

[0008] The polyester is crushed and then sieved to obtain polyester particles;

[0009] Wherein, the first reactant comprises one or more of a hydroxycarboxylic acid compound, an organic acid anhydride compound and a first ester compound, the hydroxycarboxylic acid compound comprises citric acid and / or malic acid, the organic acid anhydride compound comprises citric anhydride and / or malic anhydride, and the first ester compound comprises one or more of a citrate ester compound and a malate ester compound;

[0010] The second reactant includes one or more of a second ester compound, a second fatty chain diol and a fatty chain diacid, and the molecular weight of the second reactant is 70Da-10000Da.

[0011] In some embodiments of the present application, the first reactant is the hydroxycarboxylic acid compound and / or the organic acid anhydride compound, and the second reactant is the second ester compound.

[0012] In some embodiments of the present application, the first reactant is the first ester compound, and the second reactant is the second fatty chain diol and / or the fatty chain diacid.

[0013] In some embodiments of the present application, one or more of the following conditions are met:

[0014] (1) The citric acid ester compound includes one or more of monoethyl citrate, monomethyl citrate, diethyl citrate, dimethyl citrate, triethyl citrate, trimethyl citrate and tributyl citrate;

[0015] (2) The malate ester compound includes one or more of monoethyl malate, monomethyl malate, diethyl malate and dimethyl malate.

[0016] In some embodiments of the present application, one or more of the following conditions are met:

[0017] (1) the second ester compound includes one or more of glycolide, lactide, caprolactone, 4-dioxanone, isosorbide, diphenyl carbonate and butylene terephthalate;

[0018] (2) The fatty chain diacid includes succinic acid and / or adipic acid;

[0019] (3) the first fatty chain diol includes one or more of 1,2-propylene glycol, 1,3-propylene glycol, 1,4-butylene glycol, methyl propanediol, 1,5-pentanediol, 1,2-pentanediol, neopentyl glycol, 1,6-hexanediol, 1,2-hexanediol, 1,8-octanediol, 1,2-octanediol, 1,10-decanediol and 1,12-dodecanediol;

[0020] (4) The first catalyst comprises one or more of toluenesulfonic acid, thionyl chloride, acetamide, tetrabutyl titanate, anion exchange resin, sodium methoxide, sodium ethoxide, sodium carbonate, metal oxides and metal salts;

[0021] (5) The second catalyst includes one or more of tetraethyl titanate, tetrabutyl titanate, tetraisopropyl titanate, boron trifluoride, stannous octoate, stannous chloride, stannous oxalate, stannous chloride, p-toluenesulfonic acid, butyl stannoic acid and organic bismuth;

[0022] (6) The second fatty chain diol includes one or more of 1,5-pentanediol, 1,2-pentanediol, neopentyl glycol, 1,6-hexanediol, 1,2-hexanediol, 1,8-octanediol, 1,2-octanediol, 1,10-decanediol and 1,12-dodecanediol.

[0023] In some embodiments of the present application, one or more of the following conditions are met:

[0024] (1) The molar ratio of the first reactant to the first fatty chain diol is 1:(0.1-1.5);

[0025] (2) The mass ratio of the prepolymer to the second reactant is 1:(0.5-10); (3) The mass of the second catalyst is equivalent to 0.01%-0.5% of the mass of the second reactant.

[0026] In some embodiments of the present application, one or more of the following conditions are met:

[0027] (1) The conditions for reacting the first reactant and the first fatty chain diol in the presence of the first catalyst are: reacting at 80° C. to 180° C. for 1 h to 72 h;

[0028] Wherein, the reaction is carried out under a vacuum negative pressure of 10Pa~1500Pa;

[0029] (2) The conditions for the transesterification reaction between the prepolymer and the second reactant in the presence of the second catalyst are: reacting at 50° C. to 220° C. for 3 h to 48 h.

[0030] The second aspect of the present application provides a polyester particle, characterized in that it is prepared by the preparation method described in the first aspect of the present application.

[0031] In some embodiments of the present application, the average particle size of the polyester microparticles is 1 μm to 1 cm.

[0032] The third aspect of the present application provides an injection-filled product, comprising the polyester particles described in the first aspect of the present application or the polyester particles prepared by the preparation method described in the second aspect of the present application.

[0033] The injection-filled product of the present application includes the polyester microparticles provided by the present application, and thus has at least the same advantages as the polyester microparticles.

[0034] The preparation method provided in the present application adopts specific reactant components and is combined with two steps of pre-reaction and ester exchange reaction. It can increase the molecular weight of polyester and obtain polyester with higher molecular weight without cross-linking reaction, thereby facilitating the physical preparation of polyester particles. The prepared polyester also has a higher protein secretion-promoting property, which is conducive to its widespread use in the field of injection filling. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the NMR spectrum of the polyester prepared in Example 1. DETAILED DESCRIPTION

[0036] In order to facilitate understanding of the present application, the present application will be described more comprehensively below. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0037] For simplicity, this application only explicitly discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form an unclearly recorded range; and any lower limit can be combined with other lower limits to form an unclearly recorded range, and any upper limit can be combined with any other upper limit to form an unclearly recorded range. In addition, although not clearly recorded, each point or single value between the range endpoints is included in the range. Thus, each point or single value can be combined with any other point or single value as its own lower limit or upper limit or with other lower limits or upper limits to form an unclearly recorded range.

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application. It should be noted that, unless otherwise specified, the term "and / or" used herein includes any and all combinations of one or more related listed items, and "above" and "below" are inclusive of the number, and the meaning of "multiple" in "one or more" is more than two.

[0039] Herein, when it comes to a numerical interval (i.e., a numerical range), unless otherwise specified, the distribution of the optional numerical values ​​within the numerical interval is considered to be continuous and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical interval, and each numerical value between the two numerical endpoints. Unless otherwise specified, when a numerical interval only refers to integers within the numerical interval, including the two endpoint integers of the numerical range, and each integer between the two endpoints, is equivalent to directly listing each integer. When multiple numerical ranges are provided to describe features or characteristics, these numerical ranges can be combined. In other words, unless otherwise specified, the numerical ranges disclosed herein should be understood to include any and all sub-ranges included therein. The "numerical value" in the numerical interval can be any quantitative value, such as a number, a percentage, a ratio, etc. "Numerical interval" allows broadly including numerical interval types such as percentage intervals, ratio intervals, and ratio intervals.

[0040] In this article, if there are multiple steps involved in the method flow, unless there is a clear different description in this article, there is no strict order restriction for the execution of these steps, and they can be executed in other orders than described. Moreover, any step can include multiple sub-steps or multiple stages, and these sub-steps or stages are not necessarily executed at the same time, but can be executed at different times, and their execution order is not necessarily sequential, but can be executed in turn, alternating or simultaneously with other steps or parts of sub-steps or stages of other steps.

[0041] The above application content of the present application is not intended to describe each disclosed embodiment or each implementation in the present application. The following description more specifically illustrates exemplary embodiments. In many places throughout the application, guidance is provided by a series of examples, which can be used in various combinations. In each example, enumeration is only used as a representative group and should not be interpreted as exhaustive.

[0042] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0043] The term "aliphatic chain diol" refers to an organic compound that contains two hydroxyl (-OH) functional groups in its molecular structure and whose carbon skeleton is an aliphatic carbon chain.

[0044] The term "aliphatic chain diacid" refers to an organic compound that contains two carboxyl (-COOH) functional groups in its molecular structure and whose carbon skeleton is an aliphatic carbon chain.

[0045] The term "hydroxycarboxylic acid compounds" refers to organic compounds containing both hydroxyl (-OH) and carboxyl (-COOH) functional groups.

[0046] The term "organic acid anhydride compounds" refers to compounds containing an acyl group (-C(=O)-) in their molecular structure.

[0047] The term "ester compound" refers to a compound containing an ester group (-COO-) in its molecular structure.

[0048] The term "Da" refers to Dalton.

[0049] In a first aspect, the present application provides a method for preparing polyester microparticles, which may include the following steps S1 to S3:

[0050] S1: pre-reacting the first reactant with the first fatty chain diol in the presence of a first catalyst to obtain a prepolymer;

[0051] S2: performing an ester exchange reaction between the prepolymer and the second reactant in the presence of a second catalyst to obtain a polyester having a number average molecular weight of 30,000 Da to 150,000 Da;

[0052] S3: crushing the polyester and then sieving it to obtain polyester particles;

[0053] Wherein, the first reactant comprises one or more of a hydroxycarboxylic acid compound, an organic acid anhydride compound and a first ester compound, the hydroxycarboxylic acid compound comprises citric acid and / or malic acid, the organic acid anhydride compound comprises citric anhydride and / or malic anhydride, and the first ester compound comprises one or more of a citrate ester compound and a malate ester compound;

[0054] The second reactant includes one or more of a second ester compound, a second fatty chain diol and a fatty chain diacid, and the (number average) molecular weight of the second reactant is 70Da-10000Da.

[0055] The above preparation method provided by the present application includes steps S1 to S3. In step S1, the first reactant is pre-reacted with the first fatty chain diol, so that the first reactant can preliminarily increase the length of the molecular chain by a preliminary polycondensation reaction, a ring-opening esterification reaction or an ester exchange reaction with the first fatty chain diol, thereby preliminarily increasing the number average molecular weight of the prepolymer, so that the formed prepolymer has more reaction sites. Then, in step S2, the prepolymer is subjected to an ester exchange reaction with the second reactant having a molecular weight of 70Da to 10000Da, so that the molecular chain length of the prepolymer can be further extended (rather than body cross-linking), and a polyester with a large number average molecular weight is generated, so that its number average molecular weight can reach 30000Da to 150000Da, and such a high molecular weight polyester is convenient for the physical preparation of polyester particles; then, in conjunction with the crushing and screening treatment in step S3, polyester particles can be obtained.

[0056] Therefore, the preparation method provided in the present application adopts specific reactant components, and is combined with two steps of pre-reaction and ester exchange reaction, which can increase the molecular weight of polyester and obtain polyester with higher molecular weight without cross-linking reaction, thereby facilitating the physical preparation of polyester microparticles, and further facilitating their widespread use in the field of injection filling; at the same time, the polyester microparticles prepared by the polyester can also effectively promote collagen secretion and have good biodegradability, which is conducive to their widespread use in the field of injection filling.

[0057] In some embodiments, the number average molecular weight of the polyester is 30000Da to 150000Da. For example, the number average molecular weight of the polyester can be 30000Da, 50000Da, 70000Da, 90000Da, 110000Da, 130000Da, 150000Da or within the range of any of the above values. If the molecular weight is relatively small, it is not conducive to the physical preparation of polyester particles; if the molecular weight is relatively high, the content of active ingredients such as citric acid segments and malic acid segments in the polyester will be relatively low, which is not conducive to promoting collagen secretion.

[0058] In some embodiments, the (number average) molecular weight of the second reactant may be 70Da, 100Da, 500Da, 700Da, 1000Da, 2000Da, 3000Da, 4000Da, 5000Da, 6000Da, 7000Da, 8000Da, 9000Da, 10000Da or any range thereof. This is beneficial to reduce or avoid the occurrence of body cross-linking and to generate polyester with a larger number average molecular weight by extending the molecular chain.

[0059] In some embodiments, the first reactant is the hydroxycarboxylic acid compound and / or the organic acid anhydride compound, and the second reactant is the second ester compound.

[0060] The hydroxycarboxylic acid compound and / or the organic acid anhydride compound can undergo a preliminary condensation reaction and / or a ring-opening esterification reaction with the first fatty chain diol to preliminarily extend the chain length of the prepolymer and increase its molecular weight; then the prepolymer can undergo an ester exchange reaction with the second ester compound to further extend the molecular chain and increase the molecular weight, thereby obtaining a polyester with a higher number average molecular weight, thereby facilitating the physical preparation of the polyester microparticles so that they can be formed into polyester microparticles through subsequent mechanical pulverization.

[0061] In addition, the hydroxycarboxylic acid compound can not only undergo a preliminary polycondensation reaction with the first fatty chain diol in step S1, but the hydroxyl groups it contains can also enable the remaining hydroxycarboxylic acid compounds that did not participate in the polycondensation reaction in step S1 to better participate in the ester exchange reaction in step S2, which is beneficial to further extension of the molecular chain and further increase of the molecular weight.

[0062] In some embodiments, the first reactant is the first ester compound, and the second reactant is the second fatty chain diol and / or the fatty chain diacid.

[0063] The first ester compound can undergo a preliminary transesterification reaction with the first fatty chain diol to preliminarily extend the chain length of the prepolymer and increase its molecular weight; the prepolymer can then undergo an transesterification reaction with the second fatty chain diol and / or fatty chain diacid to further extend the molecular chain and increase the molecular weight, thereby obtaining a polyester with a higher number average molecular weight, thereby facilitating the physical preparation of the polyester so that it can be formed into polyester particles through subsequent mechanical crushing.

[0064] The addition of citric acid compounds and / or malic acid compounds is beneficial to improving the toughness of polyester and enhancing the biological activity; it can be understood that the aforementioned "citric acid compounds" refer to citric acid, citric anhydride or citric acid ester compounds, and "malic acid compounds" refer to malic acid, malic anhydride or malic acid ester compounds.

[0065] In some embodiments, the citrate ester compound includes one or more of monoethyl citrate, monomethyl citrate, diethyl citrate, dimethyl citrate, triethyl citrate, trimethyl citrate and tributyl citrate.

[0066] In some embodiments, the malate compound includes one or more of monoethyl malate, monomethyl malate, diethyl malate and dimethyl malate.

[0067] In some embodiments, the second ester compound includes one or more of glycolide, lactide, caprolactone, 4-dioxanone, isosorbide, diphenyl carbonate and butylene terephthalate, and can be lactide and / or caprolactone.

[0068] In some embodiments, the fatty chain diacid comprises succinic acid and / or adipic acid.

[0069] In some embodiments, the first fatty chain diol includes one or more of 1,2-propylene glycol, 1,3-propylene glycol, 1,4-butanediol, methyl propanediol, 1,5-pentanediol, 1,2-pentanediol, neopentyl glycol, 1,6-hexanediol, 1,2-hexanediol, 1,8-octanediol, 1,2-octanediol, 1,10-decanediol and 1,12-dodecanediol; and can be one or more of 1,8-octanediol, 1,3-propylene glycol and 1,4-butanediol.

[0070] In some embodiments, the second fatty chain diol includes one or more of 1,5-pentanediol, 1,2-pentanediol, neopentyl glycol, 1,6-hexanediol, 1,2-hexanediol, 1,8-octanediol, 1,2-octanediol, 1,10-decanediol and 1,12-dodecanediol.

[0071] In some embodiments, the first catalyst comprises one or more of toluenesulfonic acid, thionyl chloride, acetamide, tetrabutyl titanate, anion exchange resin, sodium methoxide, sodium ethoxide, sodium carbonate, metal oxides and metal salts. Optionally, the anion exchange resin is 717 anion exchange resin.

[0072] In some embodiments, the second catalyst includes one or more of tetraethyl titanate, tetrabutyl titanate, tetraisopropyl titanate, boron trifluoride, stannous octoate, tin tetrachloride, stannous oxalate, stannous chloride, p-toluenesulfonic acid, butyl stannoic acid and organic bismuth.

[0073] In some embodiments, the molar ratio of the first reactant to the first fatty chain diol is 1:(0.1-1.5), and can be 1:(0.5-1.2). For example, the molar ratio of the first reactant to the first fatty chain diol can be 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1 or within the range of any of the above values. In this way, it is beneficial to promote the occurrence and progress of the pre-reaction in step S1, and the first reactant and the first fatty chain diol will not be (body) cross-linked.

[0074] In some embodiments, the molar amount of the first catalyst is equivalent to 0.1% to 30% of the molar amount of the first reactant.

[0075] In some embodiments, the mass ratio of the prepolymer to the second reactant is 1:(0.5-10), and may be 1:(1-10). For example, the mass ratio of the prepolymer to the second reactant may be 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, or any range of the above values. In this way, the occurrence and progress of the transesterification reaction in step S2 are promoted, and the prepolymer and the second reactant will not be (bulk) cross-linked.

[0076] In some embodiments, the mass of the second catalyst is equivalent to 0.01% to 0.5% of the mass of the second reactant.

[0077] In some embodiments, the conditions for the reaction of the first reactant and the first fatty chain diol in the presence of the first catalyst are: reacting at 80°C to 180°C for 1h to 72h. Optionally, the reaction is carried out under a vacuum negative pressure of 10Pa to 1500Pa. In this way, it is beneficial to promote the occurrence and progress of the pre-reaction in step S1, and the reactants will not over-react, thereby retaining more reaction sites for the transesterification reaction in step S2, which is beneficial to the extension of the molecular chain and the increase of the molecular weight.

[0078] In some embodiments, the conditions for the transesterification reaction between the prepolymer and the second reactant in the presence of the second catalyst are: reacting at 50° C. to 220° C. for 3 h to 48 h. This is conducive to promoting the occurrence and progress of the transesterification reaction in step S2, and preventing the prepolymer and the second reactant from cross-linking as much as possible.

[0079] In some embodiments, the pulverizing and then sieving the polyester comprises: sieving the polyester through a ball mill to obtain active polyester particles.

[0080] In some embodiments, the grinding jar of the ball mill includes any one of an agate jar, a zirconia jar, a stainless steel jar, and a corundum jar.

[0081] In some embodiments, the grinding balls of the ball mill include any one of agate balls, zirconia balls, stainless steel balls, polyurethane-coated iron core balls and steel balls.

[0082] In some embodiments, the rotation speed of the ball mill is 70 rpm to 670 rpm.

[0083] In a second aspect, the present application provides a polyester particle prepared by the preparation method described in the first aspect of the present application.

[0084] In some embodiments, the average particle size of the polyester microparticles is 1 μm to 1 cm.

[0085] In a third aspect, the present application provides an injection-filled product, comprising the polyester particles described in the first reverse side of the present application or the polyester particles prepared by the preparation method described in the second aspect of the present application.

[0086] The injection filling product of the present application includes the aforementioned polyester particles, and thus has the same advantages as the polyester particles, which will not be described in detail here.

[0087] Example

[0088] The following are specific examples, which more specifically describe the contents disclosed in this application, and these examples are only for illustrative purposes, because it is obvious to those skilled in the art that various modifications and variations are made within the scope of the disclosure of this application. Unless otherwise stated, all parts, percentages, and ratios reported in the following examples are based on weight, and all reagents used in the examples are commercially available or synthesized according to conventional methods and can be used directly without further processing, and the instruments used in the examples are commercially available.

[0089] Example 1

[0090] (1) Mix citric acid, 1,8-octanediol and p-toluenesulfonic acid (the molar ratio of citric acid to 1,8-octanediol is 1:1.1, and the mass of p-toluenesulfonic acid is 10% of that of citric acid), react at 90°C for 36 hours in an anhydrous and oxygen-free environment to obtain a prepolymer. Mix the prepolymer with L-lactide (the molecular weight of L-lactide is 144.14 Da, and the mass ratio of prepolymer to lactide is 1:3) and stannous octoate (stannous octoate is equivalent to 0.05% of the mass of lactide), evacuate to 1000 Pa in an anhydrous and oxygen-free environment, and react at 180°C for 48 hours to obtain a polyester.

[0091] (2) The polyester was milled in a ball mill at a rotation speed of 150 rpm for half an hour, and then sieved to obtain polyester particles with an average particle size of 200 μm.

[0092] Example 2

[0093] (1) Triethyl citrate, 1,4-butanediol and tetrabutyl titanate were mixed (the molar ratio of triethyl citrate to 1,4-butanediol was 1:1.1, and the mass of tetrabutyl titanate was 2wt% of the total mass of the reactants), and the mixture was reacted at 100°C for 6 hours in an anhydrous and oxygen-free environment to obtain a prepolymer. The prepolymer was mixed with succinic acid, stannous octoate and tetrabutyl titanate (the molecular weight of succinic acid was 118.1Da, the mass ratio of the prepolymer to succinic acid was 1:1, and the total mass of stannous octoate and tetrabutyl titanate was equivalent to 0.5% of the mass of succinic acid), and the mixture was evacuated to 1000Pa in an anhydrous and oxygen-free environment, and the mixture was reacted at 160°C for 48 hours to obtain a polyester.

[0094] (2) The polyester was milled in a ball mill at a rotation speed of 150 rpm for half an hour, and then sieved to obtain polyester particles with an average particle size of 200 μm.

[0095] Example 3

[0096] (1) Malic anhydride, 1,3-propylene glycol and acetamide are mixed (the molar ratio of malic anhydride to 1,3-propylene glycol is 1:1.0, and the molar amount of acetamide is 0.1 times that of malic anhydride), and reacted at 60°C for 12 hours in an anhydrous and oxygen-free environment to obtain a prepolymer. The prepolymer is mixed with caprolactone monomer and tetrabutyl titanate (the molecular weight of caprolactone is 114.16 Da, the mass ratio of prepolymer to caprolactone is 1:10, and the total mass of tetrabutyl titanate is equivalent to 0.5% of the mass of caprolactone), and vacuumed to 1000 Pa in an anhydrous and oxygen-free environment, and reacted at 220°C for 48 hours to obtain polyester.

[0097] (2) The polyester was milled in a ball mill at a rotation speed of 150 rpm for half an hour, and then sieved to obtain polyester particles with an average particle size of 200 μm.

[0098] Example 4

[0099] The preparation method is similar to that of Example 1, with the main difference being that in step (1), the molar ratio of citric acid to 1,8-octanediol is 1:1.2.

[0100] Example 5

[0101] The preparation method is similar to that of Example 1, with the main difference being that in step (1), the molar ratio of citric acid to 1,8-octanediol is 1:0.9.

[0102] Example 6

[0103] The preparation method is similar to that of Example 1, with the main difference being that in step (1), the mass ratio of the prepolymer to lactide is 1:5.

[0104] Example 7

[0105] The preparation method is similar to that of Example 1, with the main difference being that in step (1), the mass ratio of the prepolymer to lactide is 1:8.

[0106] Comparative Example 1

[0107] The preparation method is similar to that of Example 1, with the main difference being that in step (1), citric acid is replaced by an equal molar amount of succinic acid.

[0108] Comparative Example 2

[0109] The preparation method is similar to that of Example 1, with the main difference being that in step (1), the second reactant is adjusted to ethylene glycol (molecular weight 62.07 Da).

[0110] Comparative Example 3

[0111] The preparation method is similar to that of Example 1, with the main difference being that in step (1), the second reactant is adjusted to poly(ε-caprolactone) diol having a number average molecular weight of 15,000 Da.

[0112] The polyesters or polyester particles prepared in Examples 1 to 7 and Comparative Examples 1 to 3 were subjected to relevant performance tests, and the test results are shown in Table 1 below.

[0113] Among them, the test conditions or test standards for each performance test item are as follows:

[0114] (1) Number average molecular weight test and NMR test

[0115] Appropriate amounts of polyester samples were dissolved in CHCl3, and the number average molecular weight and its distribution of polyester were characterized by gel permeation chromatography (GPC, Waters 1515). Appropriate amounts of polyester samples were dissolved in CDCl3, and nuclear magnetic resonance testing was performed by nuclear magnetic resonance spectrometer (300MHz, AV3000Bruker, Germany).

[0116] (2) Average particle size test

[0117] The average particle size of polyester microparticles was measured by scanning electron microscopy (SEM).

[0118] (3) Protein secretion test

[0119] Rat mesenchymal stem cells (rBMSCs) were used as a cell model. First, 1 g of the polymer (polyester) synthesized in each example and comparative example was completely degraded in 10 mL of 0.5M NaOH, neutralized to pH 7.4 with a hydrochloric acid solution, and diluted 10 times with a PBS solution (pH 7.4) to obtain a 10× degradation product. In brief, for L929, the cells were seeded in a 24-well culture dish and cultured in complete DMEM medium at 37°C, maintaining a carbon dioxide content of 5% and a relative humidity of 95%. For a well of a 24-well plate containing about 80% confluent cells, 50 μL of the 10× degradation product of the polymer was then added to 500 μL of culture medium and then cultured for 24 hours. The expression of the type I collagen (Col1a1) gene in the cells was then detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR).

[0120] Table 1

[0121]

[0122] By comparing Examples 1 to 7 with Comparative Example 1, it can be seen that after the first reactant citric acid is replaced by succinic acid, the number average molecular weight of the prepared polyester is relatively small, and it is very difficult to prepare it into polyester microparticles by crushing. In addition, the protein secretion-promoting activity of the polyester is relatively low, indicating that the first reactant needs to be selected from the specific components of the present application.

[0123] By comparing Examples 1 to 7 with Comparative Examples 2 and 3, it can be seen that when the molecular weight of the second reactant is relatively low (Comparative Example 2), the number average molecular weight of the prepared polyester is relatively small, and it is very difficult to prepare it into polyester microparticles by pulverizing, and the protein secretion-promoting activity of the polyester is relatively low; when the molecular weight of the second reactant is relatively high (Comparative Example 3), although the number average molecular weight of the prepared polyester is relatively large, and the preparation of polyester microparticles by pulverizing can be achieved, the polyester with too large a molecular weight has relatively low protein secretion-promoting activity, which is not conducive to the application of polyester microparticles in the field of injection filling. This shows that the (number average) molecular weights of the second reactant and the polyester need to be controlled within an appropriate range.

[0124] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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.

[0125] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the attached claims.

Claims

1. A method for preparing polyester microparticles, characterized in that: include: Pre-reacting the first reactant with the first fatty chain diol in the presence of a first catalyst to obtain a prepolymer; The prepolymer and the second reactant are subjected to an ester exchange reaction in the presence of a second catalyst to obtain a polyester having a number average molecular weight of 30,000 Da to 150,000 Da; The polyester is crushed and then sieved to obtain polyester particles; Wherein, the first reactant comprises one or more of a hydroxycarboxylic acid compound, an organic acid anhydride compound and a first ester compound, the hydroxycarboxylic acid compound comprises citric acid and / or malic acid, the organic acid anhydride compound comprises citric anhydride and / or malic anhydride, and the first ester compound comprises one or more of a citrate ester compound and a malate ester compound; The first fatty chain diol includes one or more of 1,3-propylene glycol, 1,4-butanediol, 1,8-octanediol, 1,2-propylene glycol, 1,2-octanediol, methyl propanediol, 1,5-pentanediol, neopentyl glycol, 1,2-pentanediol, 1,6-hexanediol and 1,2-hexanediol; The second reactant includes one or more of a second ester compound and a fatty chain diacid, the second ester compound includes one or more of glycolide, lactide and caprolactone, the fatty chain diacid includes succinic acid and / or adipic acid, and the molecular weight of the second reactant is 70Da~10000Da.

2. The preparation method according to claim 1, characterized in that: The first reactant is the hydroxycarboxylic acid compound and / or the organic acid anhydride compound, and the second reactant is the second ester compound.

3. The preparation method according to claim 1, characterized in that: The first reactant is the first ester compound, and the second reactant is the fatty chain diacid.

4. The preparation method according to any one of claims 1 to 3, characterized in that Meet one or more of the following conditions: (1) The citric acid ester compound includes one or more of monoethyl citrate, monomethyl citrate, diethyl citrate, dimethyl citrate, triethyl citrate, trimethyl citrate and tributyl citrate; (2) The malate ester compound includes one or more of monoethyl malate, monomethyl malate, diethyl malate and dimethyl malate.

5. The preparation method according to any one of claims 1 to 3, characterized in that Meet one or more of the following conditions: (1) The first catalyst comprises one or more of toluenesulfonic acid, thionyl chloride, acetamide, tetrabutyl titanate, anion exchange resin, sodium methoxide, sodium ethoxide, metal oxides and metal salts; (2) The second catalyst includes one or more of tetraethyl titanate, tetrabutyl titanate, tetraisopropyl titanate, boron trifluoride, stannous octoate, tin tetrachloride, stannous oxalate, stannous chloride, p-toluenesulfonic acid, butyl stannoic acid and organic bismuth.

6. The preparation method according to any one of claims 1 to 3, characterized in that Meet one or more of the following conditions: (1) The molar ratio of the first reactant to the first fatty chain diol is 1:(0.1-1.5); (2) The mass ratio of the prepolymer to the second reactant is 1:(0.5-10); (3) The mass of the second catalyst is equivalent to 0.01% to 0.5% of the mass of the second reactant.

7. The preparation method according to any one of claims 1 to 3, characterized in that Meet one or more of the following conditions: (1) The conditions for reacting the first reactant with the first fatty chain diol in the presence of the first catalyst are: reacting at 80° C. to 180° C. for 1 h to 72 h; Wherein, the reaction is carried out under a vacuum negative pressure of 10Pa~1500Pa; (2) The conditions for the transesterification reaction between the prepolymer and the second reactant in the presence of the second catalyst are: reacting at 50° C. to 220° C. for 3 h to 48 h.

8. A polyester microparticle, characterized in that: It is prepared by the preparation method according to any one of claims 1 to 7.

9. An injection-filled product, characterized in that: The polyester particles include the polyester particles described in any one of claims 1 to 7 or the polyester particles prepared by the preparation method described in claim 8.

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