Degradable polyester microspheres as well as preparation method and application thereof

Abstract

The invention relates to degradable polyester microspheres as well as a preparation method and application thereof. The degradable polyester microspheres comprise n polyester materials, n is larger than or equal to 2, the degradation periods of the n polyester materials are different, the mass percent a of the polyester material with the slowest degradation rate is larger than or equal to 100% * 1 / n and smaller than or equal to 90%, and the mass percent of the other polyester materials is larger than or equal to 100% * 1 / n and smaller than or equal to 90%. The mass percent of the polyester material with the relatively high degradation rate is less than or equal to the mass percent of the polyester material with the relatively low degradation rate; or, the degradation modes of the n polyester materials are different, and the mass percent b of the polyester materials adopting the body degradation mode meets 50% lt; b is less than or equal to 90%, and the mass percent c of the polyester material adopting a surface corrosion degradation mode is more than or equal to 10% and less than or equal to clt; the degradable polyester microspheres can generate acidic products more uniformly, continuously and stably to stimulate inflammatory response and collagen in-situ regeneration.

Description

Technical Field

[0001] The present invention relates to the field of medical biological macromolecular materials, and particularly to a degradable polyester microsphere, a preparation method thereof, and an application thereof. Background Art

[0002] Degradable polyester microspheres have characteristics such as a small size (usually in the range of 100 nm to 1000 μm), a large specific surface area, and degradability. They can be used as drug sustained-release carriers, skin fillers, tissue engineering scaffolds, etc. When used as a drug sustained-release carrier, as the degradable polyester microspheres degrade, the effect of drug sustained release can be achieved; when used as a skin filler, during the degradation process of the degradable polyester microspheres in the body, it will stimulate the regeneration of collagen in the body, thereby contributing to anti-aging and wrinkle removal. Moreover, the degradable polyester microspheres can be absorbed by the human body, having the advantages of high safety, no wound after injection, and a short recovery period. Degradable polyester microspheres can also be used as carriers for cells and are used in the construction of tissue engineering scaffolds. Among them, microspheres with a porous structure can be used as a cell growth framework because they have the advantage of being able to better induce cell migration and growth.

[0003] The degradation rate of degradable polyester microspheres is affected by multiple factors. Traditional degradable polyester microspheres degrade too fast in a certain same time period, strongly stimulating the occurrence of inflammation. When degradable polyester microspheres are used for drug sustained release, skin filling, and tissue engineering scaffolds, a relatively uniform degradation behavior is usually desired. Summary of the Invention

[0004] Based on this, some embodiments of the present invention provide a degradable polyester microsphere that can more uniformly and continuously stably produce acidic degradation products, stimulate an inflammatory response, and induce in-situ collagen regeneration, and a preparation method thereof.

[0005] Some other embodiments of the present invention also provide an application of the degradable polyester microsphere.

[0006] A degradable polyester microsphere, comprising: n polyester materials, where n≥2,

[0007] The degradation cycles of the n polyester materials are different, and the mass percentage a of the polyester material with the slowest degradation rate satisfies 100%×1 / n≤a≤90%, and the mass percentages of the remaining polyester materials satisfy: among the two polyester materials with different degradation cycles, the mass percentage of the polyester material with a relatively faster degradation rate ≤ the mass percentage of the polyester material with a relatively slower degradation rate; or,

[0008] The degradation modes of the n polyester materials are different, and the mass percentage b of the polyester material adopting the bulk degradation mode satisfies 50%<b≤90%, and the mass percentage c of the polyester material adopting the surface erosion degradation mode satisfies 10%≤c<50%.

[0009] In some embodiments, the n polyester materials are each independently selected from polymers formed by polymerization of one or more monomers selected from lactide, glycolide, caprolactone, trimethylene carbonate, p-dioxanone and orthoester.

[0010] In some embodiments, the degradation periods of the n polyester materials in a PBS buffer having a pH of 7.2 to 7.6 at 37° C. are each independently selected from one of 1 month to 1 year, 1 year to 3 years, and 2 years to 4 years.

[0011] In some embodiments, the polyester material having a degradation period of 1 month to 1 year in a PBS buffer having a pH of 7.2 to 7.6 at 37° C. includes one or more of the following materials: PPDO having a weight average molecular weight of 500 g / mol to 50,000 g / mol, PDLLA having a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGA having a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLCL having a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGC having a weight average molecular weight of 500 g / mol to 50,000 g / mol, PTMC having a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol, and POE having a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol;

[0012] The polyester material with a degradation period of 1 to 3 years in a PBS buffer solution with a pH of 7.2 to 7.6 at 37°C includes one or more of the following materials: PLLA with a weight average molecular weight of 10,000 to 50,000 g / mol, PPDO with a weight average molecular weight of 50,000 to 200,000 g / mol, PDLLA with a weight average molecular weight of 50,000 to 200,000 g / mol, 0g / mol PLGA, 50000g / mol to 200000g / mol PLCL, 50000g / mol to 200000g / mol PLGC, 500g / mol to 50000g / mol PCL, 50000g / mol to 200000g / mol PTMC and 50000g / mol to 200000g / mol POE;

[0013] The polyester material with a degradation period of 2 to 4 years in a PBS buffer with a pH of 7.2 to 7.6 at 37°C includes one or more of the following materials: PLLA with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PLGA with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PLCL with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PCL with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PTMC with a weight average molecular weight of 500 to 50,000 g / mol, and POE with a weight average molecular weight of 500 to 50,000 g / mol.

[0014] In some embodiments, the polyester material having a degradation period of 1 month to 1 year in a PBS buffer having a pH of 7.2 to 7.6 at 37° C. includes: PDLLA having a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLGA having a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLCL having a weight average molecular weight of 5000 g / mol to 50000 g / mol, or PLGC having a weight average molecular weight of 5000 g / mol to 50000 g / mol;

[0015] The polyester material having a degradation period of 1 to 3 years in a PBS buffer solution at a pH of 7.2 to 7.6 at 37° C. includes: PDLLA having a weight average molecular weight of 50,000 to 100,000 g / mol, PLGA having a weight average molecular weight of 50,000 to 100,000 g / mol, PLCL having a weight average molecular weight of 50,000 to 100,000 g / mol, or PLGC having a weight average molecular weight of 50,000 to 100,000 g / mol;

[0016] The polyester material with a degradation period of 2 to 4 years in a PBS buffer solution with a pH of 7.2 to 7.6 at 37°C includes: PLLA with a weight average molecular weight of 50,000 to 100,000 g / mol or PCL with a weight average molecular weight of 50,000 to 100,000 g / mol.

[0017] In some embodiments, the degradable polyester microspheres include a first polyester material and a second polyester material, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 2 to 4 years, and the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 month to 1 year; or, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 year to 3 years, and the degradation period of the second polyester material is 1 month to 1 year; or, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 2 to 4 years, and the degradation period of the second polyester material is between 1 year and 3 years.

[0018] In some embodiments, the degradable polyester microspheres further include a third polyester material, and the degradation period of the third polyester material in a PBS buffer having a pH of 7.2 to 7.6 at 37° C. is between that of the first polyester material and the second polyester material.

[0019] In some of the embodiments, the polyester material using bulk degradation includes a polymer formed by polymerization of one or more monomers of lactide, glycolide, caprolactone and dioxanone, and the polyester material using surface dissolution degradation includes a polymer formed by polymerization of one or two monomers of trimethylene carbonate and orthoester.

[0020] In some embodiments, the degradable polyester microspheres include a first polyester material and a second polyester material, the degradation mode of the first polyester material is bulk degradation, including: PLLA with a weight average molecular weight of 10000g / mol to 100000g / mol, PCL with a weight average molecular weight of 10000g / mol to 100000g / mol, PLGA with a weight average molecular weight of 10000g / mol to 100000g / mol, or PLCL with a weight average molecular weight of 10000g / mol to 100000g / mol; the degradation mode of the second polyester material is surface dissolution degradation, including: PTMC with a weight average molecular weight of 10000g / mol to 100000g / mol or POE with a weight average molecular weight of 10000g / mol to 100000g / mol.

[0021] A method for preparing degradable polyester microspheres comprises the following steps:

[0022] adding an oil phase solution containing n kinds of polyester materials into an aqueous phase solution, stirring and emulsifying, and obtaining an oil-in-water emulsion;

[0023] volatilizing the solvent in the oil-in-water emulsion to prepare the degradable polyester microspheres;

[0024] Among them, n≥2, the degradation cycles of the n polyester materials are different, and the mass percentage a of the polyester material with the slowest degradation rate satisfies 100%×1 / n≤a≤90%, and the mass percentages of the remaining polyester materials satisfy: among the two polyester materials with different degradation cycles, the mass percentage of the polyester material with a relatively faster degradation rate ≤ the mass percentage of the polyester material with a relatively slower degradation rate; or, the degradation modes of the n polyester materials are different, and the mass percentage b of the polyester material using the bulk degradation mode satisfies 50% < b≤90%, and the mass percentage c of the polyester material using the surface erosion degradation mode satisfies 10%≤c<50%.

[0025] In some embodiments, the preparation method satisfies one or more of the following conditions:

[0026] (1) In the oil-phase solution containing n polyester materials, the total mass concentration percentage of the n polyester materials is 1% - 10%;

[0027] (2) In the aqueous solution, there is polyvinyl alcohol with a mass concentration percentage of 0.5% - 10%;

[0028] (3) The stirring and emulsifying time is 0.5h - 12h;

[0029] (4) In the step of volatilizing the solvent of the water-in-oil emulsion, the temperature is 37°C - 50°C, and the time is 6h - 12h.

[0030] The application of the degradable polyester microspheres as described above or the degradable polyester microspheres prepared by the preparation method as described above in the preparation of tissue engineering scaffolds, drug controlled-release materials, vascular embolization materials or medical aesthetic filling materials.

[0031] A medical aesthetic filling material, comprising the degradable polyester microspheres as described above or the degradable polyester microspheres prepared by the preparation method as described above.

[0032] The above-mentioned degradable polyester microspheres include n polyester materials with different degradation cycles or different degradation modes. By selecting the materials and their proportions, the degradable polyester can achieve gradient degradation or degrade at a set time to produce degradation products, more uniformly and continuously stimulate the inflammatory response, promote collagen regeneration, and reduce the risk of overly strong stimulation of inflammation due to excessive degradation in a certain same time period. Description of the Drawings

[0033] Figure 1 A photo of the degradable polyester microspheres prepared in Example 1 at 0 hour of degradation at 50°C;

[0034] Figure 2 A photo of the degradable polyester microspheres prepared in Example 1 at 1 week of degradation at 50°C;

[0035] Figure 3 This is a photo of the degradable polyester microspheres prepared in Example 1 degrading at 50° C. for 2 weeks;

[0036] Figure 4 This is a photo of the degradable polyester microspheres prepared in Example 1 degrading at 50° C. for 3 weeks;

[0037] Figure 5 These are photos of the degradable polyester microspheres prepared in Example 1 degraded at 50° C. for 4 weeks. DETAILED DESCRIPTION

[0038] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively below in conjunction with the specific embodiments. Preferred embodiments of the present invention are provided in the specific embodiments. However, the present invention 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 invention more thorough and comprehensive.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0040] Unless otherwise specified or there is a contradiction, the terms or phrases used in this invention have the following meanings:

[0041] In the present invention, "first" and "second" are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features.

[0042] In the description of the present invention, “plurality” means at least two, for example, two, three, etc., unless otherwise clearly and specifically defined.

[0043] In the present invention, "one or several" refers to any one, any two or any two or more of the listed items. Among them, "several" refers to any two or any two or more.

[0044] In the present invention, the percentage concentration involved, unless otherwise specified, refers to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of the component.

[0045] The words "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that may provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of the present invention.

[0046] When a numerical range is disclosed in the present invention, the above range is considered to be continuous and includes the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise indicated, all ranges disclosed in the present invention should be understood to include any and all subranges included therein.

[0047] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0048] The terms "including" and "having" and any variations thereof in the embodiments of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, system, product, or device that includes a series of steps or units is not limited to the listed steps or units, but may optionally include steps or units that are not listed, or may optionally include other steps or components that are inherent to these processes, methods, products, or devices.

[0049] Reference to "embodiments" in the present invention means that a particular feature, structure, or characteristic described in conjunction with the embodiments may be included in at least one embodiment of the present application. The appearance of the phrase in various places in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described in the present invention may be combined with other embodiments.

[0050] Room temperature refers to a temperature of 10°C to 30°C.

[0051] As described in the background art, traditional degradable polyester microspheres are prone to suddenly produce a large amount of acidic products (the fastest hydrolysis) or suddenly disintegrate to produce a large amount of degradation fragments or particles (the molecular weight loss reaches a certain critical value) during a certain period of the degradation process. For example, poly(L-lactic acid) (PLLA) is prone to produce a large amount of acidic products in the early stage of degradation, such as 1 to 6 months, and a large amount of microcrystalline particles will be produced in the later stage of degradation, such as about 2 to 3 years. Such degradation non-uniformities exist in a large number of degradable polyester microspheres. When degradable polyester microspheres are used for drug sustained release, skin filling, and tissue engineering scaffolds, a relatively uniform degradation behavior is usually desired, or a set degradation behavior occurs during a specific period, that is, controllable degradation. To solve this problem, the present invention provides a polyester microsphere that can degrade in a gradient or according to a set degradation, which is prepared from two or more polyester materials with different degradation rates or different degradation methods.

[0052] In a first aspect of the present invention, there is provided a degradable polyester microsphere, comprising: n polyester materials, where n≥2,

[0053] The degradation cycles of the n polyester materials are different, and the mass percentage a of the polyester material with the slowest degradation rate satisfies 1 / n≤a≤90%, and the mass percentages of the remaining polyester materials satisfy: among two polyester materials with different degradation cycles, the mass percentage of the polyester material with a relatively faster degradation rate ≤ the mass percentage of the polyester material with a relatively slower degradation rate; or,

[0054] The degradation methods of the n polyester materials are different, and the mass percentage b of the polyester material adopting the bulk degradation method satisfies 50% < b≤90%, and the mass percentage c of the polyester material adopting the surface erosion degradation method satisfies 10%≤c<50%.

[0055] The following takes the case where the degradation cycles of the n polyester materials are different and n is 2, 3, or 4 as an example for detailed description, but it can be understood that the value of n is not limited to this:

[0056] (1) When n = 2, the mass percentage a of the polyester material with a slow degradation rate satisfies 50%≤a≤90%, and the mass percentage of the polyester material with a fast degradation rate is 10% to 50%, that is, the mass ratio of the polyester material with a slow degradation rate to the polyester material with a fast degradation rate is 9:1 to 5:5. Optionally, the mass percentage of the polyester material with a slow degradation rate can be, but is not limited to, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or the range composed of any two of these values. The mass percentage of the polyester material with a fast degradation rate can be, but is not limited to, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or the range composed of any two of these values.

[0057] (2) n is 3, and the three polyester materials are arranged from long to short according to the degradation period, namely the polyester material with the slowest degradation rate, the polyester material with a medium degradation rate, and the polyester material with the fastest degradation rate, wherein the mass percentage a of the polyester material with the slowest degradation rate satisfies 100%×1 / 3≤a≤90%, and the mass percentage of the polyester material with the fastest degradation rate ≤ the mass percentage of the polyester material with a medium degradation rate. Optionally, the mass percentage of the polyester material with the slowest degradation rate can be, but is not limited to, 33%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or a range consisting of any two of these values.

[0058] (3) n is 4, and the four polyester materials are arranged from long to short according to the degradation period, namely the polyester material with the slowest degradation rate, the polyester material with the second slowest degradation rate, the polyester material with the second fastest degradation rate, and the polyester material with the fastest degradation rate, wherein the mass percentage a of the polyester material with the slowest degradation rate satisfies 25%≤a≤90%, and the mass percentage of the polyester material with the fastest degradation rate ≤ the mass percentage of the polyester material with the second fastest degradation rate ≤ the mass percentage of the polyester material with the second slowest degradation rate. Optionally, the mass percentage of the polyester material with the slowest degradation rate may be, but is not limited to, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or a range consisting of any two of these values.

[0059] The above-mentioned setting helps to prevent the early degradation from being too fast, so as to avoid stimulating a serious inflammatory response.

[0060] The degradation rate of degradable polyester microspheres is affected by multiple factors, including material composition, molecular weight, hydrophilicity, morphology, crystallization, etc. The inventors found in the experiment that when the easily hydrolyzed glycolide monomer exists in the polyester material, the degradation rate of the prepared degradable polyester microspheres is faster, such as PLGA 5050 (LA:GA molar ratio is 50:50) The degradation rate is much faster than that of pure PLA; the lower the molecular weight of the material, the faster the degradation of the prepared degradable polyester microspheres; the better the hydrophilicity of the material, the easier it is for water to penetrate into the material, and the faster the degradation; the degradation rate of solid microspheres prepared from the same material is usually faster than that of porous microspheres, mainly because the self-catalytic effect formed by the difficulty in diffusion of the acidic degradation products of the solid microspheres accelerates the degradation of the material; the degradation rate of crystalline microspheres of the degradable polyester microspheres prepared from the same material is significantly slower than that of amorphous microspheres, and the higher the crystallinity, the slower the degradation. Therefore, the degradation rate of degradable polyester microspheres can be regulated by designing the physicochemical properties of the material.

[0061] Specifically, in some embodiments, the degradation rate or degradation mode of the polyester material is controlled by adjusting the composition, ratio, molecular weight, etc. of the polyester material. Different degradation rates mainly include different molecular weight loss rates or mass loss rates.

[0062] In some embodiments, n kinds of polyester materials are each independently selected from polymers formed by polymerization of one or more monomers selected from lactide, glycolide, caprolactone, trimethylene carbonate, p-dioxanone and orthoester. For example, n kinds of polyester materials are each independently homopolymers or copolymers, homopolymers include polylactide (PLA), polycaprolactone (PCL), polytrimethylene carbonate (PTMC), polyp-dioxanone (PPDO) or polyorthoester (POE), copolymers include copolymers formed by polymerization of several monomers selected from lactide, glycolide, caprolactone, trimethylene carbonate, p-dioxanone and orthoester, for example, lactide-glycolide copolymer (PLGA), lactide-glycolide-caprolactone copolymer (PLGC), lactide-caprolactone copolymer (PLCL). The copolymer can be a random copolymer or a block copolymer.

[0063] The following is a detailed description of the degradable polyester including polyester materials with different degradation modes:

[0064] In some embodiments, different degradation modes include bulk degradation or surface dissolution. Bulk degradation means that in the early and middle stages of polyester material degradation, the mass basically does not change, while the molecular weight gradually decreases; surface dissolution degradation means that in the degradation process of polyester material, the molecular weight basically does not change, but the mass is gradually lost.

[0065] Specifically, the polyester material using bulk degradation includes a polymer formed by polymerization of one or more monomers of lactide, glycolide, caprolactone and p-dioxanone. For example, the polyester material using bulk degradation is a homopolymer or a copolymer, and the homopolymer includes polylactic acid, polyglycolide, polycaprolactone, and polydioxanone, and the copolymer includes a copolymer formed by polymerization of several monomers of lactide, glycolide, caprolactone and p-dioxanone. In a specific example, the polyester material using bulk degradation includes PLLA, PCL, PLGA or PLCL.

[0066] Specifically, the polyester material using the surface dissolution degradation method includes polytrimethylene carbonate, polyorthoester, and a copolymer formed by polymerization of trimethylene carbonate and orthoester. In a specific example, the polyester material using the surface dissolution degradation method includes PTMC or POE.

[0067] Furthermore, the polyester materials adopting the bulk degradation method include: PLLA with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol, PCL with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol, PLGA with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol, or PLCL with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol. Optionally, the weight-average molecular weight of the polyester materials adopting the bulk degradation method can be, but is not limited to, 10,000 g / mol, 20,000 g / mol, 30,000 g / mol, 40,000 g / mol, 50,000 g / mol, 60,000 g / mol, 70,000 g / mol, 80,000 g / mol, 90,000 g / mol, 100,000 g / mol, or the range composed of any two of these values.

[0068] The polyester materials adopting the surface erosion degradation method include: PTMC with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol or POE with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol. Optionally, the weight-average molecular weight of the polyester materials adopting the surface erosion degradation method can be, but is not limited to, 10,000 g / mol, 20,000 g / mol, 30,000 g / mol, 40,000 g / mol, 50,000 g / mol, 60,000 g / mol, 70,000 g / mol, 80,000 g / mol, 90,000 g / mol, 100,000 g / mol, or the range composed of any two of these values.

[0069] In some embodiments, the degradable polyester microspheres include a first polyester material and a second polyester material. The degradation method of the first polyester material is bulk degradation, including: PLLA with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol, PCL with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol, PLGA with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol, or PLCL with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol. The degradation method of the second polyester material is surface erosion degradation, including: PTMC with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol or POE with a weight-average molecular weight of 10,000 g / mol to 100,000 g / mol. The mass percentage b of the first polyester material satisfies 50% < b ≤ 90%, and the mass percentage c of the second polyester material satisfies 10% ≤ c < 50%.

[0070] The following details the solutions of the degradable polyester including polyester materials with different degradation cycles:

[0071] Based on the in vivo usage scenarios of polyester materials, such as microspheres, stents, patches, etc., the degradation cycle in this article refers to the degradation cycle in a PBS buffer environment with a pH of 7.2 to 7.6 at 37°C.

[0072] In some embodiments, the degradation periods of the n polyester materials in a PBS buffer having a pH of 7.2 to 7.6 at 37° C. are each independently selected from one of 1 month to 1 year, 1 year to 3 years, and 2 years to 4 years.

[0073] Specifically, the polyester material with a degradation time of 1 month to 1 year in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is recorded as a fast-degrading material, the polyester material with a degradation time of 1 year to 3 years in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is recorded as a medium-speed degradation material, and the polyester material with a degradation time of 2 years to 4 years in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is recorded as a slow-degrading material. It can be understood that the degradation cycles of the n types of polyester materials are slow-degrading materials, medium-speed degradation materials, and fast-degrading materials from long to short. Although the degradation cycles of medium-speed degradation materials and slow-degrading materials partially overlap, it is only necessary to satisfy that the degradation cycle of the slow-degrading material is longer than that of the medium-speed degradation material. For example, if the degradation cycle of the medium-speed degradation material is 3 years, the degradation cycle of the slow-degrading material is greater than 3 years, for example, it can be 4 years; if the degradation cycle of the medium-speed degradation material is 1 year, the degradation cycle of the slow-degrading material is greater than 1 year, for example, it can be 2 years.

[0074] In some of the embodiments, the fast-degrading material includes: PPDO with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PDLLA (polyracemic lactide) with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGA with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLCL with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGC with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PTMC with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol, and POE with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol.

[0075] Optionally, in the fast-degrading material, the weight average molecular weight of PPDO, PDLLA, PLGA, PLCL and PLGC is each independently 500 g / mol, 1000 g / mol, 2000 g / mol, 5000 g / mol, 8000 g / mol, 10000 g / mol, 15000 g / mol, 20000 g / mol, 25000 g / mol, 30000 g / mol, 35000 g / mol, 40000 g / mol, 45000 g / mol, 50000 g / mol or a range consisting of any two of these values. In the fast-degradable material, the weight-average molecular weights of PTMC and POE are independently 200,000 g / mol, 300,000 g / mol, 400,000 g / mol, 500,000 g / mol, 600,000 g / mol, 700,000 g / mol, 800,000 g / mol, 900,000 g / mol, 1,000,000 g / mol, or a range consisting of any two of these values.

[0076] In some of the embodiments, the medium-speed degradation material includes: PLLA with a weight average molecular weight of 10,000 g / mol to 50,000 g / mol, PPDO with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol, PDLLA with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol, PLGA with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol, PLCL with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol, PLGC with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PCL with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PTMC with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol, and POE with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol.

[0077] Optionally, in the medium-speed degradation material, the weight-average molecular weight of PLLA can be but is not limited to 10,000 g / mol, 15,000 g / mol, 20,000 g / mol, 25,000 g / mol, 30,000 g / mol, 35,000 g / mol, 40,000 g / mol, 45,000 g / mol, 50,000 g / mol or a range consisting of any two of these values. Among the medium-speed degradable materials, the weight average molecular weights of PPDO, PDLLA, PLGA, PLCL, PLGC, PTMC and POE are each independently 50,000 g / mol, 60,000 g / mol, 80,000 g / mol, 100,000 g / mol, 120,000 g / mol, 140,000 g / mol, 150,000 g / mol, 160,000 g / mol, 180,000 g / mol, 200,000 g / mol or a range consisting of any two of these values. In the medium-speed degradation material, the weight average molecular weight of PCL is 500 g / mol, 1000 g / mol, 2000 g / mol, 5000 g / mol, 8000 g / mol, 10000 g / mol, 15000 g / mol, 20000 g / mol, 25000 g / mol, 30000 g / mol, 35000 g / mol, 40000 g / mol, 45000 g / mol, 50000 g / mol or a range consisting of any two of these values.

[0078] In some of the embodiments, the slow-degrading materials include: PLLA with a weight average molecular weight of 50,000 g / mol to 1,000,000 g / mol, PLGA with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol, PLCL with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol, PCL with a weight average molecular weight of 50,000 g / mol to 1,000,000 g / mol, PTMC with a weight average molecular weight of 500 g / mol to 50,000 g / mol, and POE with a weight average molecular weight of 500 g / mol to 50,000 g / mol.

[0079] Optionally, in the slow degradation material, the weight average molecular weights of PLLA and PCL are each independently 50000 g / mol, 60000 g / mol, 80000 g / mol, 100000 g / mol, 120000 g / mol, 140000 g / mol, 150000 g / mol, 160000 g / mol, 180000 g / mol, 200000 g / mol, 300000 g / mol, 400000 g / mol, 500000 g / mol, 600000 g / mol, 700000 g / mol, 800000 g / mol, 900000 g / mol, 1000000 g / mol or a range consisting of any two of these values. In the slow-degrading material, the weight-average molecular weights of PLGA and PLCL are each independently 200,000 g / mol, 300,000 g / mol, 400,000 g / mol, 500,000 g / mol, 600,000 g / mol, 700,000 g / mol, 800,000 g / mol, 900,000 g / mol, 1,000,000 g / mol, or a range consisting of any two of these values. In the slow-degrading material, the weight-average molecular weights of PTMC and POE are each independently 500 g / mol, 1000 g / mol, 2000 g / mol, 5000 g / mol, 8000 g / mol, 10000 g / mol, 15000 g / mol, 20000 g / mol, 25000 g / mol, 30000 g / mol, 35000 g / mol, 40000 g / mol, 45000 g / mol, 50000 g / mol or a range consisting of any two of these values.

[0080] Further, in some embodiments, the fast degrading material includes: PDLLA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLGA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLCL with a weight average molecular weight of 5000 g / mol to 50000 g / mol, or PLGC with a weight average molecular weight of 5000 g / mol to 50000 g / mol.

[0081] Medium-speed degradation materials include: PDLLA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLGA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLCL with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, or PLGC with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol.

[0082] The slow-degrading material includes: PLLA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol or PCL with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol.

[0083] In some embodiments, the degradable polyester microspheres include a first polyester material and a second polyester material, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 2 to 4 years, and the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 month to 1 year; or, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 year to 3 years, and the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 month to 1 year; or, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 2 to 4 years, and the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is between 1 year and 3 years.

[0084] It is understood that the degradable polyester microspheres may further include a third polyester material, the degradation period of which is between the first polyester material and the second polyester material. In addition, the degradable polyester microspheres may further include a fourth polyester material, a fifth polyester material, etc., which have different degradation periods from the first polyester material, the second polyester material, and the third polyester material.

[0085] In some embodiments, the degradable polyester includes a first polyester material, a second polyester material and a third polyester material, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 2 to 4 years, the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 to 3 years, and the degradation period of the third polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 month to 1 year, wherein the mass percentage of the first polyester material is 33% to 90%, and the mass percentage of the second polyester material is ≥ the mass percentage of the third polyester material.

[0086] The following are detailed descriptions of several specific composition schemes of degradable polyester microspheres:

[0087] In some embodiments, the degradable polyester microspheres include a first polyester material and a second polyester material, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 2 to 4 years, the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is 1 month to 1 year, the mass percentage of the first polyester material is 50% to 90%, and the mass percentage of the second polyester material is 10% to 50%.

[0088] Specifically, the first polyester material has a degradation period of 2 to 4 years in a PBS buffer solution with a pH of 7.2 to 7.6 at 37° C., and includes one or more of the following materials: PLLA with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PLGA with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PLCL with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PCL with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PTMC with a weight average molecular weight of 500 to 50,000 g / mol, and POE with a weight average molecular weight of 500 to 50,000 g / mol.

[0089] Preferably, the first polyester material includes: PLLA having a weight average molecular weight of 50,000 to 100,000 g / mol or PCL having a weight average molecular weight of 50,000 to 100,000 g / mol.

[0090] Specifically, the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37° C. is between 1 month and 1 year, and includes one or more of the following materials: PPDO with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PDLLA with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGA with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLCL with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGC with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PTMC with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol, and POE with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol.

[0091] Preferably, the second polyester material includes: PDLLA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLGA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLCL with a weight average molecular weight of 5000 g / mol to 50000 g / mol, or PLGC with a weight average molecular weight of 5000 g / mol to 50000 g / mol.

[0092] In other embodiments, the degradation period of the first polyester material in a PBS buffer having a pH of 7.2 to 7.6 at 37°C is 1 to 3 years, the degradation period of the second polyester material in a PBS buffer having a pH of 7.2 to 7.6 at 37°C is 1 month to 1 year, the mass percentage of the first polyester material is 50% to 90%, and the mass percentage of the second polyester material is 10% to 50%.

[0093] Specifically, the first polyester material has a degradation period of 1 to 3 years in a PBS buffer solution with a pH of 7.2 to 7.6 at 37° C., and includes one or more of the following materials: PLLA with a weight average molecular weight of 10,000 to 50,000 g / mol, PPDO with a weight average molecular weight of 50,000 to 200,000 g / mol, PDLLA with a weight average molecular weight of 50,000 to 200,000 g / mol, The present invention relates to PLGA with a weight average molecular weight of 50000 g / mol to 200000 g / mol, PLCL with a weight average molecular weight of 50000 g / mol to 200000 g / mol, PLGC with a weight average molecular weight of 50000 g / mol to 200000 g / mol, PCL with a weight average molecular weight of 500 g / mol to 50000 g / mol, PTMC with a weight average molecular weight of 50000 g / mol to 200000 g / mol and POE with a weight average molecular weight of 50000 g / mol to 200000 g / mol.

[0094] Preferably, the first polyester material includes: PDLLA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLGA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLCL with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, or PLGC with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol.

[0095] Specifically, the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37° C. is between 1 month and 1 year, and includes one or more of the following materials: PPDO with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PDLLA with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGA with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLCL with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PLGC with a weight average molecular weight of 500 g / mol to 50,000 g / mol, PTMC with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol, and POE with a weight average molecular weight of 200,000 g / mol to 1,000,000 g / mol.

[0096] Preferably, the second polyester material includes PDLLA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLGA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLCL with a weight average molecular weight of 5000 g / mol to 50000 g / mol, or PLGC with a weight average molecular weight of 5000 g / mol to 50000 g / mol.

[0097] In some other embodiments, the degradable polyester includes a first polyester material and a second degradable polyester, the degradation period of the first polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is between 2 and 4 years, the degradation period of the second polyester material in a PBS buffer with a pH of 7.2 to 7.6 at 37°C is between 1 and 3 years, the mass percentage of the first polyester material is 50% to 90%, and the mass percentage of the second polyester material is 10% to 50%.

[0098] Specifically, the first polyester material has a degradation period of 2 to 4 years in a PBS buffer solution with a pH of 7.2 to 7.6 at 37° C., and includes one or more of the following materials: PLLA with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PLGA with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PLCL with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PCL with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PTMC with a weight average molecular weight of 500 to 50,000 g / mol, and POE with a weight average molecular weight of 500 to 50,000 g / mol.

[0099] Preferably, the first polyester material includes: PLLA having a weight average molecular weight of 50,000 to 100,000 g / mol or PCL having a molecular weight of 50,000 to 100,000 g / mol.

[0100] Specifically, the degradation period of the second polyester material in a PBS buffer solution with a pH of 7.2 to 7.6 at 37° C. is between 1 and 3 years, and includes one or more of the following materials: PLLA with a weight average molecular weight of 10,000 g / mol to 50,000 g / mol, PPDO with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol, PDLLA with a weight average molecular weight of 50,000 g / mol to 200,000 g / mol, The present invention relates to PLGA with a weight average molecular weight of 50000 g / mol to 200000 g / mol, PLCL with a weight average molecular weight of 50000 g / mol to 200000 g / mol, PLGC with a weight average molecular weight of 50000 g / mol to 200000 g / mol, PCL with a weight average molecular weight of 500 g / mol to 50000 g / mol, PTMC with a weight average molecular weight of 50000 g / mol to 200000 g / mol and POE with a weight average molecular weight of 50000 g / mol to 200000 g / mol.

[0101] Preferably, the second polyester material includes: PDLLA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLGA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLCL with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, or PLGC with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol.

[0102] Furthermore, in the above embodiment, a third polyester material may be added, whose degradation cycle is different from that of the first polyester material and the second polyester material. After the third polyester material is added, the ratio of each degradable polyester material is adjusted according to the above definition.

[0103] In some embodiments, the degradable polyester microspheres include a first polyester material, a second polyester material, and a third polyester material. The degradation period of the first polyester material is 2 to 4 years, including: PLLA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol or PCL with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol. The degradation period of the second polyester material is 1 to 3 years, including: PDLLA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLGA with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, PLCL with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol, or PLGC with a weight average molecular weight of 50,000 g / mol to 100,000 g / mol. The degradation period of the third polyester material is 1 month to 1 year, including: PDLLA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLGA with a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLCL with a weight average molecular weight of 5000 g / mol to 50000 g / mol, or PLGC with a weight average molecular weight of 5000 g / mol to 50000 g / mol. Further, in the degradable polyester microspheres, the mass percentage of the first polyester material is 33% to 90%, and the mass percentage of the second polyester material is ≥ the mass percentage of the third polyester material.

[0104] In some embodiments, the degradable polyester microspheres can achieve gradient degradation or degrade at a set time.

[0105] In some embodiments, the complete degradation cycle of the degradable polyester microspheres is divided into different time stages. If the degradable polyester microspheres are composed of n materials, the degradation cycle is divided into n time stages. Gradient degradation refers to the complete degradation of different degradable polyester materials in the divided different time stages. Specifically, taking the degradable polyester microspheres composed of poly L-lactide (PLLA, 100,000 g / mol) and L-lactide-glycolide copolymer (PLGA, 50,000 g / mol) as an example, the complete degradation cycle of the degradable polyester microspheres is three years, and the degradation cycle is divided into two time stages, namely 0 to 2 years and 2 to 4 years, wherein the PLLA (100,000 g / mol) material requires 2 to 4 years to be completely degraded, and the PLGA (50,000 g / mol) material is completely degraded within 2 years.

[0106] Degradation at a set time means that the polyester material constituting the degradable polyester microspheres is degraded within the set degradation cycle. Specifically, taking the degradable polyester microspheres composed of PCL with a molecular weight of 50,000 g / mol, PLLA with a molecular weight of 50,000 g / mol, and PLGA with a molecular weight of 50,000 g / mol as an example, PCL is expected to be completely degraded within 2 to 4 years, PLLA is expected to be completely degraded within 1.5 to 3 years, and PLGA is expected to be completely degraded within 0.5 to 2 years.

[0107] It can be understood that the degradable polyester microspheres that can achieve gradient degradation or degradation at a set time can be composed of a variety of polyester materials. The combination can be based on the selection of more than two degradation modes or polyester materials with significantly different degradation rates.

[0108] In some embodiments, the degradable polyester microspheres are solid microspheres or porous microspheres. Further, the degradable polyester is a solid microsphere, and porous microspheres are formed during the degradation process. Since the polyester materials constituting the degradable polyester microspheres have different degradation cycles, the solid microspheres will form a porous structure during the degradation process.

[0109] In some embodiments, the particle size of the degradable polyester microspheres is 100 nm to 1000 μm. For example, the particle size of the degradable polyester microspheres can be, but is not limited to, 100 nm, 500 nm, 1 μm, 50 μm, 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 800 μm, 1000 μm, or a range consisting of any two of these values.

[0110] In some embodiments, the porosity of the porous microspheres formed by the degradable polyester microspheres during the degradation process is between 10% and 90%, and the pore size is between 10nm and 100μm. For example, the porosity of the porous microspheres can be, but not limited to, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or a range consisting of any two of these values. The pore size can be, but not limited to, 10nm, 100nm, 500nm, 1μm, 10μm, 20μm, 40μm, 60μm, 80μm, 100μm, or a range consisting of any two of these values.

[0111] It can be understood that the changes in the porosity and pore size of the porous microspheres formed during the degradation process can be controlled by the ratio and selection of a variety of polyester materials, so that the porosity gradually changes from low to high during the degradation process.

[0112] The above-mentioned degradable polyester microspheres have at least the following advantages:

[0113] (1) The above-mentioned degradable polyester microspheres include n kinds of polyester materials with different degradation periods or different degradation methods. By selecting the materials and their proportions, the degradable polyester can achieve gradient degradation or degrade at a set time to produce degradation products, more evenly and continuously stimulate the inflammatory response, promote collagen regeneration, and reduce the risk of excessive and strong stimulation of inflammation during a certain same period.

[0114] (2) The above-mentioned degradable polyester microspheres contain polyester materials with different degradation rates or different degradation methods, and can gradually form porous microspheres with different pore structures from solid microspheres at different degradation stages during the degradation process. The porous structure generated at a specific degradation stage promotes cell migration and ingrowth, matches the autologous tissue regeneration process, and forms a uniform regenerated tissue. The initial solid microsphere stage can cause the body's immune inflammation, and the gradually generated porous structure during the degradation process can further induce cell migration and ingrowth, and finally the material is completely degraded and replaced by new tissue, showing good application prospects in the fields of tissue engineering and regenerative science.

[0115] (3) Since the polyester materials in the above-mentioned degradable polyester have different degradation rates or different degradation methods, when used to prepare drug sustained-release materials, a more uniform drug sustained-release effect can be achieved.

[0116] The second aspect of the present invention provides a preparation method of degradable polyester microspheres, including the following steps:

[0117] Step S110: Add an oil-phase solution containing n kinds of polyester materials to an aqueous-phase solution, stir and emulsify to obtain an oil-in-water emulsion.

[0118] Wherein, n≥2, the degradation periods of the n kinds of polyester materials are different, and the mass percentage a of the polyester material with the slowest degradation rate satisfies 100%×1 / n≤a≤90%, and the mass percentages of the remaining polyester materials satisfy: among two polyester materials with different degradation periods, the mass percentage of the polyester material with a relatively faster degradation rate ≤ the mass percentage of the polyester material with a relatively slower degradation rate; or, the degradation methods of the n kinds of polyester materials are different, the mass percentage b of the polyester material using the bulk degradation method satisfies 50%<b≤90%, and the mass percentage c of the polyester material using the surface erosion degradation method satisfies 10%≤c<50%.

[0119] Specifically, the different selections of the n kinds of polyester materials are as described above and will not be elaborated.

[0120] In some embodiments, in the oil phase solution containing n polyester materials, the total mass percentage concentration of the n polyester materials is 1% to 10%. For example, the total mass percentage concentration of the n polyester materials can be, but is not limited to, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or a range consisting of any two of these values. Optionally, the total mass percentage concentration of the n polyester materials is 1% to 5%.

[0121] In some embodiments, the solvent used in the oil phase solution containing n kinds of polyester materials may be, but is not limited to, dichloromethane.

[0122] In some embodiments, the aqueous solution contains polyvinyl alcohol (PVA) at a mass percentage concentration of 0.5% to 10%. For example, the mass percentage concentration of PVA can be, but is not limited to, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or a range consisting of any two of these values. Optionally, the mass percentage concentration of PVA is 0.5% to 5%.

[0123] In some embodiments, the PVA includes one or both of PVA205 and PVA210.

[0124] In some embodiments, the stirring and emulsifying time is 0.5h to 12h. For example, the stirring and emulsifying time can be, but is not limited to, 0.5h, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, 12h, or a range consisting of any two of these values. Optionally, the stirring and emulsifying time is 0.5h to 2h.

[0125] In some embodiments, the aqueous phase solution also contains sodium chloride with a mass percentage concentration of 0.1% to 2%. For example, the mass percentage concentration of sodium chloride can be, but is not limited to, 0.1%, 0.2%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, or a range consisting of any two of these values. Since some materials have poor ball-forming properties, a small amount of sodium chloride needs to be added to facilitate ball-forming. If the material itself has good ball-forming properties, sodium chloride solution may not be added.

[0126] Step S120: volatilize the solvent in the oil-in-water emulsion to prepare degradable polyester microspheres.

[0127] In some embodiments, in the step of volatilizing the solvent of the oil-in-water emulsion, the temperature is 37° C. to 50° C. For example, the temperature can be, but is not limited to, 37° C., 38° C., 40° C., 42° C., 44° C., 46° C., 48° C., 50° C., or a range consisting of any two of these values.

[0128] In some embodiments, the time for volatilizing the solvent of the oil-in-water emulsion is 6 hours to 12 hours. For example, the time can be, but is not limited to, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or a range consisting of any two of these values.

[0129] In some embodiments, the method further includes the steps of sedimentation centrifugation, filtration separation and drying.

[0130] The preparation method of the above-mentioned degradable polyester microspheres is simple in process and easy for large-scale production. It can also enable the degradable polyester to achieve gradient degradation or degrade at a set time to produce degradation products, thereby stimulating inflammatory responses and promoting collagen regeneration more evenly, continuously and stably, and reducing the risk of excessive degradation in the same time period and strongly stimulating inflammation.

[0131] The third aspect of the present invention provides a use of degradable polyester microspheres in the preparation of tissue engineering scaffolds, drug controlled release materials, vascular embolization materials or medical cosmetic filling materials.

[0132] The above-mentioned degradable polyester microspheres are composed of polyester materials with various degradation cycles or different degradation methods. By selecting the materials and their proportions, the degradable polyester can achieve gradient degradation or degrade at a set time to produce degradation products, thereby stimulating inflammatory responses and promoting collagen regeneration more evenly, continuously and stably, reducing the risk of excessive degradation and strong stimulation of inflammation in the same time period, and can be used in the preparation of medical cosmetic filling materials.

[0133] The above-mentioned degradable polyester microspheres contain polyester materials with different degradation rates or different degradation modes, and can gradually form porous microspheres with different pore structures from solid microspheres at different degradation stages during the degradation process. The porous structure generated at a specific degradation stage promotes cell migration and growth, matching the autologous tissue regeneration process to form uniform regenerated tissue. The solid microsphere stage in the early stage can cause immune inflammation in the body, and the porous structure gradually generated during the degradation process can further induce cell migration and growth, and finally the material is completely degraded and replaced by new tissue, which has good application prospects in the fields of tissue engineering and regenerative science.

[0134] Since the polyester materials in the above-mentioned degradable polyesters have different degradation rates or different degradation modes, when used to prepare drug sustained-release materials, a more uniform drug sustained-release effect can be achieved.

[0135] The fourth aspect of the present invention also provides a medical cosmetic filling material, comprising the above-mentioned degradable polyester microspheres.

[0136] The above-mentioned degradable polyester microspheres are composed of polyester materials with different degradation cycles or different degradation methods. By selecting the materials and their proportions, the degradable polyester can achieve gradient degradation or degrade at a set time to produce degradation products. When used in medical and aesthetic filling materials, it can stimulate inflammatory responses more evenly, continuously and stably, promote collagen regeneration, and reduce the risk of excessive degradation and strong stimulation of inflammation in the same time period.

[0137] In order to make the purpose and advantages of the present invention clearer, the degradable polyester microspheres of the present invention and their effects are further described in detail in conjunction with specific examples. It should be understood that the specific examples described herein are only used to explain the present invention and shall not be used to limit the present invention. The following examples do not include other components except inevitable impurities unless otherwise specified. The drugs and instruments used in the examples are conventionally selected in the art unless otherwise specified. The experimental methods for which specific conditions are not specified in the examples are implemented according to conventional conditions, such as the conditions described in the literature and books or the methods recommended by the manufacturer.

[0138] Example 1

[0139] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PLGA (weight average molecular weight 100,000 g / mol) and PCL (weight average molecular weight 100,000 g / mol) were both synthesized in the laboratory.

[0140] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0141] (1) 5 g of PVA-205 was placed in a 500 mL flask, and 200 mL of deionized water was added and heated to 95°C to dissolve, and then cooled to room temperature to obtain an aqueous phase solution. 0.5 g of PLGA and 0.5 g of PCL were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0142] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0143] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0144] Example 2

[0145] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PLGA (weight average molecular weight 100,000 g / mol) and PLLA (weight average molecular weight 100,000 g / mol) were both synthesized in the laboratory.

[0146] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0147] (1) 5 g of PVA-205 was placed in a 500 mL flask, and 200 mL of deionized water was added and heated to 95°C to dissolve, and then cooled to room temperature to obtain an aqueous phase solution. 0.2 g of PLGA and 0.8 g of PLLA were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0148] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0149] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0150] Example 3

[0151] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PLGA (weight average molecular weight 100000 g / mol) and PCL (weight average molecular weight 150000 g / mol) were both synthesized in the laboratory.

[0152] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0153] (1) 5 g of PVA-205 was placed in a 500 mL flask, and 200 mL of deionized water was added and heated to 95°C to dissolve, and then cooled to room temperature to obtain an aqueous phase solution. 0.2 g of PLGA and 0.8 g of PCL were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0154] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0155] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0156] Example 4

[0157] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PLCL (weight average molecular weight 40000 g / mol) and PCL (weight average molecular weight 100000 g / mol) were both synthesized in the laboratory.

[0158] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0159] (1) 5 g of PVA-205 was placed in a 500 mL flask, and 200 mL of deionized water was added and heated to 95°C to dissolve, and then cooled to room temperature to obtain an aqueous phase solution. 0.5 g of PLCL and 0.5 g of PCL were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0160] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h.

[0161] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0162] Example 5

[0163] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PLCL (weight average molecular weight 40000 g / mol) and PLGA (weight average molecular weight 100000 g / mol) were both synthesized in the laboratory.

[0164] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0165] (1) 5 g of PVA-205 was placed in a 500 mL flask, and 200 mL of deionized water was added and heated to 95°C to dissolve, and then cooled to room temperature to obtain an aqueous phase solution. 0.5 g of PLGA and 0.5 g of PLCL were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0166] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h.

[0167] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0168] Example 6

[0169] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PCL (weight average molecular weight 100000 g / mol) and PTMC (weight average molecular weight 50000 g / mol) were both synthesized in the laboratory.

[0170] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0171] (1) 5 g of PVA-205 was placed in a 500 mL flask, 200 mL of deionized water was added, heated at 95°C to dissolve, and then cooled to room temperature as the aqueous phase solution for later use; 0.8 g of PCL and 0.2 g of PTMC were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0172] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0173] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0174] Example 7

[0175] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PLLA (weight average molecular weight 100000 g / mol), PLLA (weight average molecular weight 40000 g / mol) and PLGA (weight average molecular weight 50000 g / mol) were all synthesized in the laboratory.

[0176] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0177] (1) 5 g of PVA-205 was placed in a 500 mL flask, 200 mL of deionized water was added, the mixture was heated at 95°C to dissolve, and then cooled to room temperature to prepare an aqueous phase solution for later use; 0.5 g of PLLA (weight average molecular weight 100,000 g / mol), 0.3 g of PLLA (weight average molecular weight 40,000 g / mol) and 0.2 g of PLGA (weight average molecular weight 50,000 g / mol) were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0178] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0179] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0180] Example 8

[0181] The raw materials for preparation of this example are as follows: PVA-205 was purchased from Aladdin; PCL (weight average molecular weight 100000 g / mol), PCL (weight average molecular weight 40000 g / mol) and PLCL (weight average molecular weight 20000 g / mol) were all synthesized in the laboratory.

[0182] The preparation process of the degradable polyester microspheres of this embodiment is as follows:

[0183] (1) 5 g of PVA-205 was placed in a 500 mL flask, 200 mL of deionized water was added, the mixture was heated at 95 °C to dissolve, and then cooled to room temperature as an aqueous phase solution for later use; 0.5 g of PCL (weight average molecular weight 100,000 g / mol), 0.3 g of PCL (weight average molecular weight 40,000 g / mol) and 0.2 g of PLCL (weight average molecular weight 20,000 g / mol) were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0184] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0185] (3) The supernatant was removed by centrifugation to separate the degradable polyester microspheres of this embodiment.

[0186] Comparative Example 1

[0187] The raw materials for preparation of Comparative Example 1 are as follows: PVA-205 was purchased from Aladdin; PLLA (weight average molecular weight 100000 g / mol) was synthesized in the laboratory.

[0188] The preparation process of the degradable polyester microspheres of Comparative Example 1 is as follows:

[0189] (1) 5 g of PVA-205 was placed in a 500 mL flask, 200 mL of deionized water was added, and the mixture was heated at 95°C to dissolve, and then cooled to room temperature to prepare an aqueous phase solution for later use; 1.0 g of PLLA (weight average molecular weight 100,000 g / mol) was dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0190] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0191] (3) The supernatant was removed by centrifugation to separate and obtain the degradable polyester microspheres of Comparative Example 1.

[0192] Comparative Example 2

[0193] The raw materials for preparation of Comparative Example 2 are as follows: PVA-205 was purchased from Aladdin; PLGA (weight average molecular weight 50,000 g / mol) and PLLA (weight average molecular weight 50,000 g / mol) were both synthesized in the laboratory.

[0194] The preparation process of the degradable polyester microspheres of Comparative Example 2 is as follows:

[0195] (1) 5 g of PVA-205 was placed in a 500 mL flask, 200 mL of deionized water was added, the mixture was heated at 95°C to dissolve, and then cooled to room temperature as an aqueous phase solution for later use; 0.9 g of PLGA (weight average molecular weight 50,000 g / mol) and 0.1 g of PLLA (weight average molecular weight 50,000 g / mol) were dissolved in 20 mL of dichloromethane to obtain an oil phase solution.

[0196] (2) The oil phase solution was added to the water phase solution, and the mixture was mechanically stirred at 250 rpm for 30 min at room temperature to obtain an oil-in-water emulsion, and then the temperature was raised to 40° C. and the solvent was evaporated for 5 h to remove the solvent.

[0197] (3) The supernatant was removed by centrifugation to separate and obtain the degradable polyester microspheres of Comparative Example 2.

[0198] Degradation Characterization:

[0199] The degradable polyester microspheres in Examples 1 to 8 and Comparative Examples 1 and 2 were placed in an aqueous solution environment at a mass ratio of 1:10, placed in an environment of 50°C for natural degradation, and the aqueous solution was replaced every 7 days and observed under a microscope. The photos of the degradable polyester microspheres prepared in Example 1 at different degradation times are shown in FIG. Figure 1 to Figure 5 As shown, Figure 1 This is a photograph of the degradable polyester microspheres prepared in Example 1 degraded at 50°C at 0°C. Figure 2 This is a photo of the degradable polyester microspheres prepared in Example 1 degrading at 50°C for one week. Figure 3 This is a photo of the degradable polyester microspheres prepared in Example 1 degrading at 50°C for 2 weeks. Figure 4 This is a photo of the degradable polyester microspheres prepared in Example 1 degrading at 50°C for 3 weeks. Figure 5 The photo of the degradable polyester microspheres prepared in Example 1 after degradation at 50°C for 4 weeks. As can be seen from the figure, the photo of the degradable polyester microspheres at 0°C has some surface topological structures, and the microspheres have fine pores after 1 week of degradation. As the degradation time increases, the pores gradually expand, and obvious holes appear after 3 weeks of degradation. After 4 weeks of degradation, the pores of the microspheres are enlarged, and the original topological structure disappears and becomes porous microspheres.

[0200] The mass loss of the degradable polyester microspheres during the degradation process was tested. At the same time, nitrogen adsorption and desorption were performed on the degradable polyester microspheres prepared at different time points in different embodiments and comparative examples to determine the porosity, as shown in Table 1 below.

[0201] Table 1 Performance of degradable polyester microspheres at different degradation times in Examples and Comparative Examples

[0202]

[0203]

[0204]

[0205] As can be seen from Table 1 above, the degradable polyester microspheres prepared in the embodiment show uniform and controllable mass loss at different degradation times. As the degradation time increases, the mass loss increases uniformly. The degradable polyester microspheres in Comparative Example 1 contain only a single component of degradable material. During the degradation process, the mass loss is mainly concentrated in the middle and late stages, and almost no mass loss occurs in the early and middle stages, showing uneven degradation. The proportion of polyester materials with fast degradation rates in the degradable polyester microspheres in Comparative Example 2 is too large, resulting in too fast degradation of the degradable polyester microspheres. In addition, due to the high content of PLGA components and fast degradation, PLGA that degrades faster in the early stage can also lead to the appearance of a porous structure, but as the degradation proceeds, PLGA degrades in large quantities, and the entire system can no longer be maintained and directly disintegrates, that is, there is no porous content, and the porosity is 0.

[0206] 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.

[0207] The above-described embodiments only express several implementation methods of the present invention, which is convenient for understanding the technical solutions of the present invention in detail, but cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description and drawings can be used to interpret the contents of the claims.

Claims

1. A degradable polyester microsphere, characterized in that: Comprising: n polyester materials, where n ≥ 2, The degradation periods of the n polyester materials are different, and the mass percentage a of the polyester material with the slowest degradation rate satisfies 100%×1 / n ≤ a ≤ 90%, and the mass percentages of the remaining polyester materials satisfy: among two polyester materials with different degradation periods, the mass percentage of the polyester material with a relatively faster degradation rate ≤ the mass percentage of the polyester material with a relatively slower degradation rate; or, The degradation methods of the n polyester materials are different, and the mass percentage b of the polyester material using the bulk degradation method satisfies 50% < b ≤ 90%, and the mass percentage c of the polyester material using the surface erosion degradation method satisfies 10% ≤ c < 50%.

2. The degradable polyester microspheres according to claim 1, characterized in that: The n polyester materials are each independently selected from polymers formed by polymerization of one or more monomers selected from lactide, glycolide, caprolactone, trimethylene carbonate, p-dioxanone, and orthoester.

3. The degradable polyester microspheres according to claim 1 or 2, characterized in that: The degradation periods of the n polyester materials in PBS buffer with a pH of 7.2 - 7.6 at 37°C are each independently selected from one of 1 month - 1 year, 1 year - 3 years, and 2 years - 4 years.

4. The degradable polyester microspheres according to claim 3, characterized in that: The polyester materials with a degradation period of 1 month - 1 year in PBS buffer with a pH of 7.2 - 7.6 at 37°C include one or more of the following materials: PPDO with a weight average molecular weight of 500 g / mol - 50000 g / mol, PDLLA with a weight average molecular weight of 500 g / mol - 50000 g / mol, PLGA with a weight average molecular weight of 500 g / mol - 50000 g / mol, PLCL with a weight average molecular weight of 500 g / mol - 50000 g / mol, PLGC with a weight average molecular weight of 500 g / mol - 50000 g / mol, PTMC with a weight average molecular weight of 200000 g / mol - 1000000 g / mol, and POE with a weight average molecular weight of 200000 g / mol - 1000000 g / mol; The polyester materials with a degradation period of 1 year - 3 years in PBS buffer with a pH of 7.2 - 7.6 at 37°C include one or more of the following materials: PLLA with a weight average molecular weight of 10000 g / mol - 50000 g / mol, PPDO with a weight average molecular weight of 50000 g / mol - 200000 g / mol, PDLLA with a weight average molecular weight of 50000 g / mol - 200000 g / mol, PLGA with a weight average molecular weight of 50000 g / mol - 200000 g / mol, PLCL with a weight average molecular weight of 50000 g / mol - 200000 g / mol, PLGC with a weight average molecular weight of 50000 g / mol - 200000 g / mol, PCL with a weight average molecular weight of 500 g / mol - 50000 g / mol, PTMC with a weight average molecular weight of 50000 g / mol - 200000 g / mol, and POE with a weight average molecular weight of 50000 g / mol - 200000 g / mol; The polyester material with a degradation period of 2 to 4 years in a PBS buffer with a pH of 7.2 to 7.6 at 37°C includes one or more of the following materials: PLLA with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PLGA with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PLCL with a weight average molecular weight of 200,000 to 1,000,000 g / mol, PCL with a weight average molecular weight of 50,000 to 1,000,000 g / mol, PTMC with a weight average molecular weight of 500 to 50,000 g / mol, and POE with a weight average molecular weight of 500 to 50,000 g / mol.

5. The degradable polyester microspheres according to claim 4, characterized in that: The polyester material having a degradation period of 1 month to 1 year in a PBS buffer having a pH of 7.2 to 7.6 at 37° C. includes: PDLLA having a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLGA having a weight average molecular weight of 5000 g / mol to 50000 g / mol, PLCL having a weight average molecular weight of 5000 g / mol to 50000 g / mol, or PLGC having a weight average molecular weight of 5000 g / mol to 50000 g / mol; The polyester material having a degradation period of 1 to 3 years in a PBS buffer solution at a pH of 7.2 to 7.6 at 37° C. includes: PDLLA having a weight average molecular weight of 50,000 to 100,000 g / mol, PLGA having a weight average molecular weight of 50,000 to 100,000 g / mol, PLCL having a weight average molecular weight of 50,000 to 100,000 g / mol, or PLGC having a weight average molecular weight of 50,000 to 100,000 g / mol; The polyester material with a degradation period of 2 to 4 years in a PBS buffer solution with a pH of 7.2 to 7.6 at 37°C includes: PLLA with a weight average molecular weight of 50,000 to 100,000 g / mol or PCL with a weight average molecular weight of 50,000 to 100,000 g / mol.

6. The degradable polyester microspheres according to claim 4 or 5, characterized in that: The degradable polyester microspheres include a first polyester material and a second polyester material, wherein the degradation period of the first polyester material in a PBS buffer with a pH value of 7.2 to 7.6 at 37° C. is 2 to 4 years, and the degradation period of the second polyester material in a PBS buffer with a pH value of 7.2 to 7.6 at 37° C. is 1 month to 1 year; or, the degradation period of the first polyester material in a PBS buffer with a pH value of 7.2 to 7.6 at 37° C. is 1 year to 3 years, and the degradation period of the second polyester material is 1 month to 1 year; or, the degradation period of the first polyester material in a PBS buffer with a pH value of 7.2 to 7.6 at 37° C. is 2 to 4 years, and the degradation period of the second polyester material is between 1 year and 3 years.

7. The degradable polyester microspheres according to claim 6, characterized in that: The degradable polyester microspheres further include a third polyester material, and the degradation period of the third polyester material in a PBS buffer solution with a pH of 7.2 - 7.6 at 37°C is between that of the first polyester material and the second polyester material.

8. The degradable polyester microspheres according to claim 1, characterized in that: The polyester materials adopting the bulk degradation method include polymers formed by polymerization of one or several monomers selected from lactide, glycolide, caprolactone, and p-dioxanone. The polyester materials adopting the surface erosion degradation method include polymers formed by polymerization of one or two monomers selected from trimethylene carbonate and orthoester.

9. The degradable polyester microspheres according to claim 8, characterized in that: The degradable polyester microspheres include a first polyester material and a second polyester material. The degradation method of the first polyester material is bulk degradation, including: PLLA with a weight-average molecular weight of 10,000 g / mol - 100,000 g / mol, PCL with a weight-average molecular weight of 10,000 g / mol - 100,000 g / mol, PLGA with a weight-average molecular weight of 10,000 g / mol - 100,000 g / mol, or PLCL with a weight-average molecular weight of 10,000 g / mol - 100,000 g / mol. The degradation method of the second polyester material is surface erosion degradation, including: PTMC with a weight-average molecular weight of 10,000 g / mol - 100,000 g / mol, or POE with a weight-average molecular weight of 10,000 g / mol - 100,000 g / mol.

10. A method for preparing degradable polyester microspheres, characterized in that: It includes the following steps: Adding an oil-phase solution containing n polyester materials into an aqueous solution, stirring and emulsifying to obtain an oil-in-water emulsion; Volatilizing the solvent in the oil-in-water emulsion to prepare the degradable polyester microspheres; Wherein, n ≥ 2, the degradation periods of the n polyester materials are different, and the mass percentage a of the polyester material with the slowest degradation rate satisfies 100%×1 / n ≤ a ≤ 90%, and the mass percentages of the remaining polyester materials satisfy: in two polyester materials with different degradation periods, the mass percentage of the polyester material with a relatively faster degradation rate ≤ the mass percentage of the polyester material with a relatively slower degradation rate; or, the degradation methods of the n polyester materials are different, the mass percentage b of the polyester materials adopting the bulk degradation method satisfies 50% < b ≤ 90%, and the mass percentage c of the polyester materials adopting the surface erosion degradation method satisfies 10% ≤ c < 50%.

11. The method for preparing degradable polyester microspheres according to claim 10, characterized in that: The preparation method satisfies one or several of the following conditions: (1) In the oil-phase solution containing n polyester materials, the total mass concentration percentage of the n polyester materials is 1% - 10%; (2) In the aqueous solution, it contains polyvinyl alcohol with a mass concentration percentage of 0.5% - 10%; (3) The stirring and emulsifying time is 0.5 h - 12 h; (4) In the step of volatilizing the solvent of the oil-in-water emulsion, the temperature is 37°C - 50°C, and the time is 6 h - 12 h.

12. The application of the degradable polyester microspheres according to any one of claims 1 - 9 or the degradable polyester microspheres prepared by the preparation method according to any one of claims 10 - 11 in the preparation of tissue engineering scaffolds, drug controlled-release materials, vascular embolization materials, or medical aesthetic filling materials.

13. A medical cosmetic filling material, characterized in that: The invention comprises the degradable polyester microspheres as claimed in any one of claims 1 to 9 or the degradable polyester microspheres prepared by the preparation method as claimed in any one of claims 10 to 11.

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