Stabilizers for the preparation of polycaprolactone and their applications

Abstract

This invention relates to a stabilizer for preparing polycaprolactone and its application. The stabilizer is an asymmetric block copolymer comprising polycaprolactone segments and carbonyl-dependent segments, with an anchor-to-solubility ratio of 0.5 to 5.0, wherein the anchor-to-solubility ratio is the ratio of the number-average molecular weight of the carbonyl-dependent segments to that of the polycaprolactone segments. When the stabilizer of this invention is used to prepare polycaprolactone, polycaprolactone microspheres with controllable particle size range, narrow particle size distribution, and high sphericity can be obtained.

Description

Technical Field

[0001] This invention relates to the field of polymer materials technology, and in particular to a stabilizer for the preparation of polycaprolactone and its application. Background Technology

[0002] Polycaprolactone (PCL) is a semi-crystalline aliphatic polyester widely used in drug delivery systems, tissue engineering scaffolds, and cosmetic fillers due to its excellent biocompatibility, biodegradability, and drug permeability. Preparing PCL into microspheres significantly improves its drug loading and release performance as well as its injection operability.

[0003] Traditional methods for preparing polycaprolactone microspheres often employ emulsion-solvent evaporation, spray drying, or emulsion polymerization. However, these methods generally suffer from the following problems: 1) They require the use of large amounts of organic solvents, which are not only environmentally unfriendly but also pose biosafety risks due to solvent residues; 2) Emulsifiers or surfactants are typically added during the preparation process, and these substances are difficult to remove completely, potentially affecting the biocompatibility of the microspheres; 3) After traditional bulk polymerization or solution polymerization, complex post-processing such as grinding and sieving is required to obtain the microspheres, resulting in irregular particle morphology and a wide particle size distribution.

[0004] Supercritical carbon dioxide (scCO2), as a green solvent, has attracted widespread attention in the field of polymer synthesis and processing in recent years. It possesses advantages such as being non-toxic, non-flammable, chemically inert, and easily separable under reduced pressure. Studies have shown that dispersion polymerization in supercritical carbon dioxide media can yield polymer microspheres in a one-step process. However, polycaprolactone has extremely low solubility in supercritical carbon dioxide media, and the polymer chains rapidly precipitate during polymerization, resulting in amorphous blocky products rather than microspheres. Summary of the Invention

[0005] Therefore, it is necessary to provide a stabilizer for preparing polycaprolactone and its application in order to address the above problems. When the stabilizer is used to prepare polycaprolactone, polycaprolactone microspheres with controllable particle size range, narrow particle size distribution and high sphericity can be obtained.

[0006] A stabilizer for preparing polycaprolactone, wherein the stabilizer is an asymmetric block copolymer comprising polycaprolactone segments and carbonyl groups, and the anchor-solubility ratio is 0.5 to 5.0, wherein the anchor-solubility ratio is the ratio of the number-average molecular weight of the carbonyl group to that of the polycaprolactone segment.

[0007] In one embodiment, the anchor-to-solution ratio is 0.5 to 2.0;

[0008] And / or, the carbonyl hydrophilic segment is selected from at least one of fluorinated acrylate polymer segments, silicon-containing polymer segments, and perfluoropolyether polymer segments.

[0009] In one embodiment, the anchor-to-solution ratio is 0.9 to 1.9;

[0010] And / or, the end group of the polycaprolactone segment is a hydroxyl group;

[0011] And / or, the number average molecular weight of the polycaprolactone segments is 3000 g / mol to 30000 g / mol.

[0012] In one embodiment, the fluorinated acrylate polymer segment is selected from at least one of the following: polyheptadecyl acrylate segment, polydodecyl methacrylate segment, polyvinyl perfluorooctanoate segment, polyfluorooctyl ethyl methacrylate segment, poly(1H,1H,2H,2H-perfluorodecyl acrylate) and copolymer segments.

[0013] And / or, the silicon-containing polymer segment is selected from at least one of polydimethylsiloxane segments and silicon-containing acrylate copolymer segments;

[0014] And / or, the perfluoropolyether polymer segment is selected from at least one of the perfluoropolyether carboxylic acid and its derivative segments.

[0015] A method for preparing polycaprolactone microspheres, the method comprising: carrying out a ring-opening polymerization reaction of ε-caprolactone (ε-CL), the above-mentioned stabilizer for preparing polycaprolactone, and a polymerization catalyst in a supercritical carbon dioxide medium at 15 MPa to 35 MPa to obtain polycaprolactone microspheres; wherein the mass of the stabilizer is 1 wt% to 15 wt% of the mass of the ε-caprolactone.

[0016] In one embodiment, the ring-opening polymerization reaction is carried out at a temperature of 35°C to 65°C for a duration of 6 hours to 24 hours.

[0017] And / or, the mass ratio of the polymerization catalyst to the ε-caprolactone is 0.1:1000 to 10:1000;

[0018] And / or, the polycaprolactone segments of the stabilizer have the same end groups as the polycaprolactone segments of the polycaprolactone microspheres.

[0019] In one embodiment, when the polymerization catalyst is a metal catalyst, after the ring-opening polymerization reaction is completed, impurity removal is performed. The impurity removal step includes: extracting the polycaprolactone microspheres using dynamic supercritical fluid extraction (SFE) technology.

[0020] In one embodiment, the molar ratio of the carboxylic acid to the polymerization catalyst is 5:1 to 20:1;

[0021] And / or, the carboxylic acid is selected from acetic acid and / or formic acid;

[0022] And / or, the extraction temperature is 40℃~60℃, the pressure is 15MPa~25MPa, the time is 2h~6h, and the carbon dioxide flow rate is 2mL / min~5mL / min.

[0023] Polycaprolactone microspheres prepared by the method described above have an average particle size of 5 μm to 200 μm, a molecular weight distribution index of less than 1.5, and a sphericity of 0.9 to 1.0.

[0024] Application of polycaprolactone microspheres as described above in medical implants.

[0025] In this invention, the stabilizer contains polycaprolactone segments, which share the same -(O-(CH2)5-C(=O))- repeating units as the target product, polycaprolactone microspheres. Due to their structural homology, the polycaprolactone segments can strongly anchor the surface of the polycaprolactone microspheres. The carbonyl-loving segments of the stabilizer, acting as stabilizing segments, effectively inhibit collisions and aggregation of polycaprolactone microspheres during preparation, thus rapidly achieving stabilization. Simultaneously, by adjusting the anchor-to-solubility ratio, the solubility of the stabilizer and its steric hindrance during the polycaprolactone microsphere preparation reaction can be further adjusted, thereby optimizing anchoring efficiency and dispersion. Therefore, this invention, through the synergistic selection of the two stabilizer segments and the combined effect of a specific anchor-to-solubility ratio, can produce polycaprolactone microspheres with controllable particle size range, narrow particle size distribution, and high sphericity when used in the preparation of polycaprolactone microspheres. Attached Figure Description

[0026] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 This is a scanning electron microscope image of the polycaprolactone microspheres prepared in Example 2 of the present invention. Detailed Implementation

[0028] To facilitate understanding of the present invention, it will be described in more detail below. However, it should be understood that the present invention can be implemented in many different forms and is not limited to the embodiments or examples described herein. Rather, these embodiments or examples are provided to make the disclosure of the present invention more thorough and complete.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments or examples only and is not intended to limit the invention. The optional scope of the term "and / or" as used herein includes any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all the related listed items.

[0030] In this invention, numerical ranges are involved. Unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe features or characteristics, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0031] This invention provides a stabilizer for preparing polycaprolactone, wherein the stabilizer is an asymmetric block copolymer comprising polycaprolactone segments and carbonyl groups, and the anchor-solubility ratio (ASB) is 0.5 to 5.0, wherein the anchor-solubility ratio (ASB) is the ratio of the number-average molecular weight of the carbonyl group to that of the polycaprolactone segment.

[0032] In this invention, the stabilizer contains polycaprolactone segments, which share the same -(O-(CH2)5-C(=O))- repeating units as the target product, polycaprolactone microspheres. Due to their structural homology, the polycaprolactone segments can interpenetrate and co-crystallize with the growing polycaprolactone microspheres to form a strong anchor, firmly fixing the stabilizer molecules within the polycaprolactone phase and significantly improving the anchoring strength. The carbon dioxide-loving segments of the stabilizer, acting as stabilizing segments, are fully soluble in supercritical carbon dioxide media and reach a highly extended state, thereby enhancing the stability of the polycaprolactone microspheres. During the preparation of polycaprolactone microspheres, collisions and aggregation of polycaprolactone microspheres can be effectively inhibited. This asymmetric molecular configuration, with strong anchoring at one end and high extension at the other, exhibits high anchoring-extension efficiency on the surface of polycaprolactone microspheres. This can promote the orderly growth of polycaprolactone microspheres during preparation, avoid aggregation, and quickly achieve a stabilizing effect. At the same time, by controlling the anchor-solubility ratio, the solubility of the stabilizer and its steric hindrance during the reaction of preparing polycaprolactone microspheres can be further adjusted, thereby optimizing the anchoring efficiency and dispersion effect.

[0033] Therefore, by synergistically selecting the two segments of the stabilizer and working together with a specific anchor-solubility ratio, this invention can produce polycaprolactone microspheres with controllable particle size range, narrow particle size distribution, and high sphericity when used in the preparation of polycaprolactone microspheres.

[0034] Optionally, the end group of the polycaprolactone segment may be selected from at least one of bromine, trithiocarbonate, hydrogen, ester bond, triazole ring, hydroxyl, carboxyl, amino, halogen or alkoxy; preferably, the end group of the polycaprolactone segment is hydroxyl, which is more conducive to improving the anchoring ability of the polycaprolactone segment.

[0035] To obtain a better anchoring-stretching effect, the number-average molecular weight of the polycaprolactone segments can be adjusted to control the molecular size of the stabilizer, thereby optimizing its anchoring-stretching performance. Optionally, the number-average molecular weight of the polycaprolactone segments is preferably 3000 g / mol to 30000 g / mol, and can be selected from any value among 5000 g / mol, 10000 g / mol, 15000 g / mol or 20000 g / mol or any range between two.

[0036] Optionally, the carbonyl hydrophilic segment of the stabilizer may contain one or more carbonyl hydrophilic segments, such as one, two, three, or four carbonyl hydrophilic segments; the carbonyl hydrophilic segment is preferably at least one of fluorinated acrylate polymer segments, silicone polymer segments, or perfluoropolyether polymer segments.

[0037] For example, the stabilizer contains one carbon dioxide-loving segment, which is a fluorinated acrylate polymer segment, a silicone polymer segment, or a perfluoropolyether polymer segment; or, the stabilizer contains two carbon dioxide-loving segments, which are a fluorinated acrylate polymer segment and a silicone polymer segment, or a silicone polymer segment and a perfluoropolyether polymer segment, or a fluorinated acrylate polymer segment and a perfluoropolyether polymer segment; or, the stabilizer contains three carbon dioxide-loving segments, which are a fluorinated acrylate polymer segment, a silicone polymer segment, and a perfluoropolyether polymer segment.

[0038] Optionally, the fluorinated acrylate polymer segments are selected from at least one of the following: polyheptadecyl acrylate segments, polydodecyl methacrylate segments, polyvinyl perfluorooctanoate segments, polyfluorooctyl ethyl methacrylate segments, poly(1H,1H,2H,2H-perfluorodecyl acrylate) segments and their copolymer segments; the silicone polymer segments are selected from at least one of the following: polydimethylsiloxane segments and silicone acrylate copolymer segments; and the perfluoropolyether polymer segments are selected from at least one of the following: perfluoropolyether carboxylic acid segments and their derivative segments.

[0039] Furthermore, the stabilizer of the present invention does not have any special restrictions on the end groups of the carbonyl hydrophilic segment. For example, the end groups of the carbonyl hydrophilic segment can be carboxyl, hydroxyl, methyl, or perfluoroalkyl, etc. In this way, commercially available carbonyl hydrophilic polymers can be used directly to prepare the stabilizer without additional modification of the end groups, thereby reducing the cost of preparing the stabilizer.

[0040] In this invention, the anchor-to-solubility ratio of the stabilizer can be any value among 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5. In the reaction for preparing polycaprolactone microspheres, under the same pressure and stabilizer addition amount, as the anchor-to-solubility ratio of the stabilizer increases, the average particle size of the polycaprolactone microspheres gradually decreases. Thus, the particle size of the polycaprolactone microspheres can be controlled by adjusting the anchor-to-solubility ratio of the stabilizer. For example, when the stabilizer's solubility ratio is 0.5~2.0, the average particle size of polycaprolactone microspheres is 7μm~60μm, and as the solubility ratio increases from 0.5 to 2.0, the average particle size of polycaprolactone microspheres decreases from 60μm to 7μm; when the stabilizer's solubility ratio is 0.9~1.9, the average particle size of polycaprolactone microspheres is 8μm~45μm, and as the solubility ratio increases from 0.9 to 1.9, the average particle size of polycaprolactone microspheres decreases from 45μm to 8μm.

[0041] In summary, when the stabilizer of the present invention is used in the preparation of polycaprolactone microspheres, polycaprolactone microspheres with controllable particle size range and narrow particle size distribution can be obtained.

[0042] This invention also provides a method for preparing polycaprolactone microspheres, the method comprising: carrying out a ring-opening polymerization reaction of ε-caprolactone, the stabilizer used for preparing polycaprolactone, and a polymerization catalyst in a supercritical carbon dioxide medium at a pressure of 15 MPa to 35 MPa, for example, the pressure of the ring-opening polymerization reaction being any value or a range between 15 MPa, 20 MPa, 25 MPa, 30 MPa, or 35 MPa, to obtain polycaprolactone microspheres; wherein the mass of the stabilizer is 1 wt% to 15 wt% of the mass of the ε-caprolactone, for example, any value or a range between 1 wt%, 3 wt%, 5 wt%, 9 wt%, 11 wt%, 13 wt%, or 15 wt%.

[0043] In supercritical carbon dioxide medium, ring-opening polymerization can be initiated by trace amounts of water in the system. Therefore, by adjusting the reaction pressure of the system, the degree of water participation can be controlled, thereby controlling the initiation rate and molecular weight of the polymerization reaction. Furthermore, by synergistically regulating the anchor-solubility ratio and dosage of the stabilizer, the solubility of the stabilizer and the steric hindrance effect in the reaction process can be further adjusted, thereby optimizing the anchoring efficiency and dispersion effect, and finally obtaining polycaprolactone microspheres with controllable particle size, narrow particle size distribution and high sphericity.

[0044] To prepare polycaprolactone microspheres with controllable particle size, narrow particle size distribution, and high sphericity, the homology between the polycaprolactone segments of the stabilizer and the polycaprolactone segments of the polycaprolactone microspheres can be further improved to enhance the anchoring effect. Preferably, the end groups of the polycaprolactone segments of the stabilizer and the polycaprolactone segments of the polycaprolactone microspheres are the same. For example, when the goal is to prepare polycaprolactone microspheres with hydroxyl end groups of the polycaprolactone segments, a stabilizer with hydroxyl end groups of the polycaprolactone segments is selected; or, when the goal is to prepare polycaprolactone microspheres with carboxyl end groups of the polycaprolactone segments, a stabilizer with carboxyl end groups of the polycaprolactone segments is selected.

[0045] Optionally, the temperature of the ring-opening polymerization reaction is preferably 35℃~65℃, and can be any value or a range between 35℃, 40℃, 45℃, 50℃, 55℃, 60℃ or 65℃; the time of the ring-opening polymerization reaction is 6h~24h, and can be any value or a range between 6h, 9h, 12h, 16h, 20h or 24h. Within this reaction temperature and time range, the polymerization reaction process can be effectively controlled, thereby obtaining polycaprolactone microspheres with particle size within the target range, narrow particle size distribution and high sphericity.

[0046] Optionally, the mass ratio of the polymerization catalyst to ε-caprolactone is preferably 0.1:1000 to 10:1000, more preferably 1:1000 to 5:1000, and can be selected from any ratio of 1:1000, 2:1000, 3:1000, 4:1000 or 5:1000; the polymerization catalyst can be selected from at least one of stannous octoate, stannous chloride, dibutyldimethoxytin, dibutyltin dilaurate, diphenyltin dilaurate, aluminum isopropoxide, tetrabutyl titanate, isopropyl titanate, zinc chloride, zinc acetate, and bis[bis(trimethylsilyl)amide]zinc.

[0047] When the polymerization catalyst is a metal catalyst, after the ring-opening polymerization reaction is completed, impurity removal is performed. The impurity removal step includes: adding carboxylic acid to the product of the ring-opening polymerization reaction, so that the carboxylic acid reacts with the residues of the polymerization catalyst to generate a metal carboxylate salt soluble in supercritical carbon dioxide medium, and then using dynamic supercritical fluid extraction technology to extract the metal carboxylate salt and polycaprolactone microspheres to achieve effective separation of the metal carboxylate salt and polycaprolactone microspheres, thereby obtaining high-purity polycaprolactone microspheres. Specifically, the residual amount of polymerization catalyst in the obtained polycaprolactone microspheres is less than 20 ppm, which meets the standards for medical materials.

[0048] Furthermore, this purification process couples the ring-opening polymerization reaction with supercritical fluid extraction purification in situ within the same reactor. That is, after the ring-opening polymerization is completed, supercritical fluid extraction is performed directly to remove the polymerization catalyst without depressurization, which simplifies the preparation process and avoids the risks of contamination and degradation during the transfer of polycaprolactone microspheres.

[0049] To more effectively remove residual polymerization catalyst, the molar ratio of carboxylic acid to polymerization catalyst is preferably 5:1 to 20:1, and can be any one of 5:1, 9:1, 13:1, 15:1, 17:1, 19:1 or 20:1 or any range between two of them. The carboxylic acid can be selected from acetic acid and / or formic acid.

[0050] Optionally, the extraction temperature is preferably 40℃~60℃, and can be any value or a range between 45℃, 50℃, 55℃ or 60℃; the extraction pressure is preferably 15MPa~25MPa, and can be any value or a range between 15MPa, 17MPa, 19MPa, 21MPa, 23MPa or 25MPa; the extraction time is preferably 2h~6h, and can be any value or a range between 2h, 3h, 4h, 5h or 6h; during extraction, the carbon dioxide (CO2) flow rate is preferably 2mL / min~5mL / min, and can be any value or a range between 2mL / min, 3mL / min, 4mL / min or 5mL / min. Controlling the extraction process within this range of pressure, temperature and CO2 flow rate improves the purity of polycaprolactone microspheres while increasing extraction efficiency.

[0051] The present invention also provides a method for preparing polycaprolactone microspheres, wherein the polycaprolactone microspheres have an average particle size of 5 μm to 200 μm, for example, any value or a range between 5 μm, 10 μm, 20 μm, 50 μm, 100 μm, 150 μm or 200 μm; the molecular weight distribution index of the polycaprolactone microspheres is less than 1.5, for example, any value or a range between 1.2, 1.3, 1.4 or 1.5; and the sphericity is 0.9 to 1.0, for example, any value or a range between 0.91, 0.93, 0.97 or 0.99.

[0052] The present invention also provides an application of the polycaprolactone microspheres in medical implants, such as the application of polycaprolactone microspheres in drug sustained-release carriers, tissue engineering scaffolds, and medical aesthetic filler materials.

[0053] The technical solution of the present invention will be further described below through specific embodiments. However, those skilled in the art will understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Unless otherwise specified, specific conditions in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used without specified manufacturers are all commercially available conventional products.

[0054] Example 1

[0055] In a thoroughly dried and nitrogen-purged Schlenk flask, 10 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0 °C. An aluminum isopropoxide-toluene solution was added, and polymerization was carried out for 30 min. The reaction was then terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain the number-average molecular weight (M). nThe concentration of terminal hydroxyl polycaprolactone (PCL-OH) is 10 kg / mol.

[0056] 10 g of PCL-OH was dissolved in 90 mL of dry tetrahydronaphthalene, and 2.8 mL of 4-methylmorpholine and 2.1 mL of 2-bromoisobutyryl bromide were added. The reaction was carried out at room temperature for 24 h. After back-filtration, the precipitate was collected in cold methanol and dried to obtain M. n Polycaprolactone (PCL-Br) with bromine end groups at a concentration of 10 kg / mol.

[0057] Under nitrogen protection, 0.039 g of NiBr2(PPh3)2 catalyst and 1 g of PCL-Br were added to a Schlenk flask, followed by the sequential addition of 3 mL of toluene, 3 mL of trifluorotoluene, and 0.55 mL of heptadecafluorodecyl acrylate (AC8). The reaction flask was placed in an oil bath at 95 °C and reacted for 72 h. After the reaction was completed, the reaction solution was diluted with tetrahydrofuran, precipitated in n-heptane, and dried to obtain the PCL-b-PAC8 block copolymer.

[0058] Example 2

[0059] The difference between Example 2 and Example 1 is only that: in a thoroughly dried Schlenk flask purged with nitrogen, 3 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 30 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of hydroxyl-terminated polycaprolactone (PCL-OH) is 3 kg / mol.

[0060] Example 3

[0061] The difference between Example 3 and Example 1 is only that: in a thoroughly dried Schlenk flask purged with nitrogen, 3.6 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 30 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of hydroxyl-terminated polycaprolactone (PCL-OH) is 3.6 kg / mol.

[0062] Example 4

[0063] The only difference between Example 4 and Example 1 is that: in a thoroughly dried Schlenk flask purged with nitrogen, 4.5 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 30 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of hydroxyl-terminated polycaprolactone (PCL-OH) is 4.5 kg / mol.

[0064] Example 5

[0065] The difference between Example 5 and Example 1 is only that: in a thoroughly dried Schlenk flask purged with nitrogen, 4.7 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 30 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of hydroxyl-terminated polycaprolactone (PCL-OH) is 4.7 kg / mol.

[0066] Example 6

[0067] The only difference between Example 6 and Example 1 is that: in a thoroughly dried Schlenk flask purged with nitrogen, 6 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 30 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of hydroxyl-terminated polycaprolactone (PCL-OH) is 6 kg / mol.

[0068] Example 7

[0069] The difference between Example 7 and Example 1 is only that: in a thoroughly dried Schlenk flask purged with nitrogen, 9 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 30 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of terminal hydroxyl polycaprolactone (PCL-OH) is 9 kg / mol.

[0070] Example 8

[0071] The difference between Example 8 and Example 1 is only that: in a thoroughly dried Schlenk flask purged with nitrogen, 18 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 30 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of terminal hydroxyl polycaprolactone (PCL-OH) is 18 kg / mol.

[0072] Example 9

[0073] Poly(dodecylfluoroheptyl methacrylate) macromolecular chain transfer agent (PDFMA-CDB) was prepared by RAFT polymerization in tetrahydrofuran solvent using isopropylphenyl dithiobenzoate (CDB) as the RAFT reagent and dodecylfluoroheptyl methacrylate (DFMA) as the monomer. By controlling the feed ratio of DFMA to CDB, a polymer with a degree of polymerization of 25, a particle size distribution index (PDI) of 1.12, and a molecular weight of 100% was prepared. n It is a 12.5 kg / mol PDFMA-CDB homopolymer.

[0074] RAFT dispersion polymerization of ε-caprolactone was carried out in scCO2 using PDFMA-CDB as a macromolecular RAFT agent. 5 g of PDFMA-CDB, 10.7 g of ε-caprolactone, and azobisisobutyronitrile (AIBN) catalyst were added to a high-pressure reactor, CO2 was introduced to 30 MPa, and the reaction was carried out at 65 °C for 24 h. After the reaction was completed, the pressure was released and the product was collected to obtain the PCL-b-PDFMA block copolymer.

[0075] Example 10

[0076] M was prepared by anionic ring-opening polymerization. n The concentration was 15 kg / mol of terminally vinyl polydimethylsiloxane (PDMS-Vi). A hydrosilylation reaction was used to react PDMS-Vi with M... n PCL-b-PDMS block copolymers were obtained by coupling 10 kg / mol of terminal hydrogen-based PCL (PCL-H) with a platinum catalyst.

[0077] Example 11

[0078] In a thoroughly dried and nitrogen-purged Schlenk flask, 20 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0 °C. An aluminum isopropoxide-toluene solution was added, and polymerization was carried out for 30 min. The reaction was then terminated with dilute hydrochloric acid. The product was then precipitated in n-heptane and dried to obtain M. n The concentration of PCL-OH is 20 kg / mol.

[0079] 10g PCL-OH, 5g Krytox®157FSL, M n Perfluoropolyether carboxylic acid (PFPE-CA), N,N'-dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine (DMAP) at a concentration of 2.5 kg / mol were dissolved in anhydrous dichloromethane and reacted at room temperature for 48 h. After the reaction was completed, insoluble matter was removed by filtration, and the concentrated filtrate was then precipitated in methanol and dried to obtain PCL-b-PFPE-CA block copolymer.

[0080] Example 12

[0081] In a thoroughly dried and nitrogen-purged Schlenk flask, 10 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0 °C. An aluminum isopropoxide-toluene solution was added, and polymerization was carried out for 30 min. The reaction was then terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of PCL-OH is 10 kg / mol.

[0082] 10 g of PCL-OH was dissolved in 90 mL of dry tetrahydronaphthalene, and 2.8 mL of 4-methylmorpholine and 2.1 mL of 2-bromoisobutyryl bromide were added. The mixture was reacted at room temperature for 24 h. After filtration, the precipitate was collected in cold methanol and dried to obtain M. n The concentration of PCL-Br is 10 kg / mol.

[0083] In a Schlenk flask, 0.039 g of NiBr2(PPh3)2 and 1 g of PCL-Br were added. Under nitrogen protection, 3 mL of toluene, 3 mL of trifluorotoluene, and 0.55 mL of AC8 were added sequentially, and the reaction was carried out at 95 °C for 48 h. A sample of the reaction solution was taken to measure the conversion rate. Then, 0.55 mL of DFMA monomer was added, and the reaction was continued for another 48 h. After the reaction was completed, the solution was diluted with THF, precipitated in n-heptane, and dried to obtain PCL-b-PAC8-b-PDFMA.

[0084] Example 13

[0085] 1g of PCL-b-PAC8 prepared in Example 1 was dissolved in 10mL of THF, and 0.5g of sodium azide was added. The mixture was reacted at 50°C for 24h to convert the terminal Br group to an azide group (-N3) to obtain the azide product.

[0086] 0.5 g of the terminal vinyl PDMS prepared in Example 10 was dissolved in 5 mL of THF with 0.2 g of triphenylphosphine and 0.1 g of CuBr. The mixture was stirred at room temperature for 30 min, and then the above-mentioned azide product was added. The reaction was carried out at 60 °C for 48 h. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, precipitated in methanol, and dried to obtain PCL-b-PAC8-b-PDMS.

[0087] Comparative Example 1

[0088] In a thoroughly dried and nitrogen-purged Schlenk flask, 90 g of ε-caprolactone and 200 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide-toluene solution was added, and polymerization was carried out for 60 min. The reaction was then terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of PCL-OH is 90 kg / mol.

[0089] 10 g of the above PCL-OH was dissolved in 90 mL of dry tetrahydronaphthalene, and 2.8 mL of 4-methylmorpholine and 2.1 mL of 2-bromoisobutyryl bromide were added. The reaction was carried out at room temperature for 24 h. The reaction solution was filtered and precipitated in cold methanol, and dried to obtain PCL-Br.

[0090] Under nitrogen protection, 0.039 g of NiBr2(PPh3)2 catalyst and 1 g of PCL-Br were added to a Schlenk flask, followed by the sequential addition of 3 mL of toluene, 3 mL of trifluorotoluene, and 0.1 mL of AC8 monomer. The reaction flask was placed in an oil bath at 95 °C and reacted for 72 h. After the reaction was completed, the mixture was diluted with THF, precipitated in n-heptane, and dried to obtain the PCL-b-PAC8 block copolymer.

[0091] Comparative Example 2

[0092] The only difference between Comparative Example 2 and Example 1 is that 1.5 g of ε-caprolactone and 30 mL of dry toluene were added to a thoroughly dried and nitrogen-purged Schlenk flask, and the mixture was cooled to 0°C. An aluminum isopropoxide toluene solution was added, and after polymerization for 20 min, the reaction was terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of PCL-OH is 1.5 kg / mol.

[0093] Comparative Example 3

[0094] In a thoroughly dried and nitrogen-purged Schlenk flask, 20 g of ε-caprolactone and 100 mL of dry toluene were added, and the mixture was cooled to 0°C. An aluminum isopropoxide-toluene solution was added, and polymerization was carried out for 40 min. The reaction was then terminated with dilute hydrochloric acid. The polymer was precipitated in n-heptane and dried to obtain M. n The concentration of PCL-OH is 20 kg / mol.

[0095] Dissolve 10g of the above PCL-OH in 50 mL of dry toluene, add an appropriate amount of sodium hydride (NaH) and react at room temperature for 2 hours. Then add trichloromethylsilane (TMS-Cl) to protect the hydroxyl group, and then hydrolyze to obtain PCL-H.

[0096] Octamethylcyclotetrasiloxane (D4, approximately 50 g) was added to a dry reaction flask, using tetramethyldivinyldisiloxane as the end-capping agent and tetramethylammonium hydroxide as the catalyst. The reaction was carried out at 90 °C for 8 h. After the reaction was completed, low-boiling substances were removed under reduced pressure to obtain terminal vinyl PDMS.

[0097] 10 g of PCL-H and 5 g of PDMS-Vi were dissolved in 100 mL of dry toluene, and 20 mg of chloroplatinic acid catalyst was added. The mixture was reacted at 80 °C for 24 h under nitrogen protection. After the reaction was completed, the catalyst was removed by filtration, the filtrate was concentrated and precipitated in methanol, and dried to obtain PCL-b-PDMS-b-PCL triblock copolymer.

[0098] Comparative Example 4

[0099] In a thoroughly dried ampoule purged with nitrogen, 0.244 g of 2,2'-bipyridine (bpy) ligand, 0.075 g of CuBr catalyst, 4.75 g of styrene, and 1.42 g of acrylonitrile were added, followed by 0.203 g of ethyl α-bromoisobutyrate as initiator. The reaction was carried out at 100 °C for 5 h. After the reaction was completed, 8 mL of tetrahydrofuran was added to dissolve the initiator, which was then precipitated in n-hexane, filtered, and dried to obtain the PSAN-Br macromolecular initiator.

[0100] In a thoroughly dried ampoule purged with nitrogen, 0.016 g of bpy ligand, 0.0049 g of CuBr catalyst, 1.0 g of PSAN-Br macromolecular initiator, 6 mL of trifluorotoluene solvent, 2 mL of tetrahydrofuran solvent, and 1.0 g of FOMA monomer were added. The mixture was then placed in an oil bath at 110 °C for 72 h. The reaction was terminated by precipitation in n-hexane, filtration, and drying to obtain a PSAN-b-PFOMA block copolymer, wherein the M of the PSAN segment... n The M of the PFOMA segment is 10 kg / mol. n It is 10 kg / mol.

[0101] The block copolymers prepared in Examples 1-13 and Comparative Examples 1-3 were subjected to nuclear magnetic resonance hydrogen spectrum or fluorine spectrum analysis, Fourier transform infrared spectroscopy and gel permeation chromatography (GPC) tests to obtain the anchor-solid ratio and structural characteristics of the block copolymers. The results are shown in Table 1.

[0102] Table 1

[0103]

[0104] Application Example 1

[0105] The PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 0.9, prepared using the method of Example 1, was used as a stabilizer in the preparation of polycaprolactone microspheres.

[0106] A 100 mL high-pressure reactor was dried and purged with CO2 for displacement. 10.7 g of ε-caprolactone, 16 mg of dibutyldimethoxytin catalyst, and stabilizer were weighed out. The amount of stabilizer was 5 wt% of the mass of ε-caprolactone. The mixture was quickly injected into the reactor and sealed. Liquid CO2 was injected through an ISCO pump until the system pressure reached 14 MPa. The reactor was heated to 40 °C. After the pressure stabilized at 30 MPa, the polymerization reaction was carried out at a stirring rate of 300 rpm for 15 h.

[0107] After the reaction was complete, the system temperature was maintained at 40℃, and glacial acetic acid was injected into the reactor using a high-pressure pump. The amount of glacial acetic acid added was 10 times the molar amount of the dibutyldimethoxytin catalyst. Dynamic extraction was carried out at a pressure of 15 MPa and a CO2 flow rate of 3 mL / min for 4.5 h. After extraction, CO2 was slowly released to obtain M. n The polycaprolactone microspheres have a density of 24.2 kg / mol.

[0108] Application Example 2

[0109] The only difference between Application Example 2 and Application Example 1 is that the amount of stabilizer used in the polymerization reaction is 1 wt% of the mass of ε-caprolactone.

[0110] The polycaprolactone microspheres prepared in this application example have M n It is 23.5 kg / mol. Figure 1 The scanning electron microscope image of the polycaprolactone microspheres shows that they have good sphericity and no irregular particles are present.

[0111] Application Example 3

[0112] The only difference between Application Example 3 and Application Example 1 is that the amount of stabilizer used in the polymerization reaction is 10 wt% of the mass of ε-caprolactone.

[0113] The polycaprolactone microspheres prepared in this application example have M n It is 24.8 kg / mol.

[0114] Application Example 4

[0115] The only difference between Application Example 4 and Application Example 1 is that the amount of stabilizer used in the polymerization reaction is 15 wt% of the mass of ε-caprolactone.

[0116] Application Example 5

[0117] The PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 1.9, prepared using the method of Example 5, was used as a stabilizer in the preparation of polycaprolactone microspheres.

[0118] A 100 mL high-pressure reactor was dried and purged with CO2 for displacement. 10.7 g of ε-caprolactone, 16 mg of dibutyldimethoxytin catalyst, and stabilizer were weighed out. The amount of stabilizer was 5 wt% of the mass of ε-caprolactone. The mixture was quickly injected into the reactor and sealed. Liquid CO2 was injected through an ISCO pump until the system pressure reached 14 MPa. The reactor was heated to 40 °C. After the pressure stabilized at 30 MPa, the polymerization reaction was carried out at a stirring rate of 300 rpm for 15 h.

[0119] After the reaction was completed, the system temperature was maintained at 40℃, and glacial acetic acid was injected into the reactor using a high-pressure pump. The amount of glacial acetic acid added was 10 times the molar amount of the dibutyldimethoxytin catalyst. Dynamic extraction was carried out at a pressure of 15 MPa and a CO2 flow rate of 3 mL / min for 4.5 h. After extraction, CO2 was slowly released to obtain polycaprolactone microspheres.

[0120] Application Example 6

[0121] The only difference between Application Example 6 and Application Example 5 is that after the polymerization reaction is completed, the reactor is cooled to 15°C and CO2 is slowly released to collect the obtained polycaprolactone microspheres.

[0122] Application Example 7

[0123] The only difference between Application Example 7 and Application Example 5 is that after the pressure stabilizes at 20 MPa, the polymerization reaction is carried out at a stirring rate of 300 rpm for 15 hours.

[0124] Application Example 8

[0125] The only difference between Application Example 8 and Application Example 5 is that after the pressure stabilizes at 15 MPa, the polymerization reaction is carried out at a stirring rate of 300 rpm for 15 hours.

[0126] Application Example 9

[0127] The only difference between Application Example 9 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 3.0 prepared by the preparation method of Example 2 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0128] Application Example 10

[0129] The only difference between Application Example 10 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 2.5 prepared by the preparation method of Example 3 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0130] Application Example 11

[0131] The only difference between Application Example 11 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 2.0 prepared by the preparation method of Example 4 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0132] Application Example 12

[0133] The only difference between Application Example 12 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 1.5 prepared by the preparation method of Example 6 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0134] Application Example 13

[0135] The only difference between Application Example 13 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 1.0 prepared by the preparation method of Example 7 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0136] Application Example 14

[0137] The only difference between Application Example 14 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 0.5 prepared by the preparation method of Example 8 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0138] Application Example 15

[0139] The only difference between Application Example 15 and Application Example 1 is that the PCL-b-PDFMA block copolymer with an anchor-solubility ratio of 0.625 prepared by the preparation method of Example 9 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0140] The polycaprolactone microspheres prepared in this application example have M n It is 23.8 kg / mol.

[0141] Application Example 16

[0142] The only difference between Application Example 16 and Application Example 1 is that the PCL-b-PDMS block copolymer with an anchor-solubility ratio of 1.5 prepared by the preparation method of Example 10 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0143] The polycaprolactone microspheres prepared in this application example have M n It is 24.6 kg / mol.

[0144] Application Example 17

[0145] The only difference between Application Example 17 and Application Example 1 is that the PCL-b-PFPE-CA block copolymer with an anchor-solubility ratio of 0.125 prepared by the preparation method of Example 11 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0146] Application Example 18

[0147] The only difference between Application Example 18 and Application Example 1 is that the PCL-b-PAC8-b-PDFMA block copolymer with an anchor-solubility ratio of 1.75 prepared by the preparation method of Example 12 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0148] Application Example 19

[0149] The only difference between Application Example 19 and Application Example 1 is that the PCL-b-PAC8-b-PDMS block copolymer with an anchor-solubility ratio of 1.90 prepared by the preparation method of Example 13 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0150] Application Comparative Example 1

[0151] The only difference between Comparative Example 1 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 0.1 prepared using the preparation method of Comparative Example 1 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0152] Application Comparative Example 2

[0153] The only difference between Comparative Example 2 and Application Example 1 is that the PCL-b-PAC8 block copolymer with an anchor-solubility ratio of 6.0 prepared using the preparation method of Comparative Example 2 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0154] Application Comparative Example 3

[0155] The only difference between Comparative Example 3 and Application Example 1 is that the PCL-b-PDMS-b-PCL block copolymer with an anchor-solubility ratio of 0.5 prepared using the preparation method of Comparative Example 3 is used as a stabilizer in the preparation of polycaprolactone microspheres.

[0156] Application Comparative Example 4

[0157] The only difference between Comparative Example 4 and Application Example 1 is that the PSAN-b-PFOMA block copolymer prepared using the preparation method of Comparative Example 4 was used as a stabilizer in the preparation of polycaprolactone microspheres. The resulting polycaprolactone was in block form and no microsphere morphology was obtained.

[0158] Application Comparative Example 5

[0159] The only difference between Comparative Example 5 and Application Example 1 is that the product Krytox® 157FSL, M n Perfluoropolyether carboxylic acid (PFPE-CA) at a concentration of 2.5 kg / mol was used as a stabilizer in the preparation of polycaprolactone microspheres. The resulting polycaprolactone particles were irregular with a very wide particle size distribution (10 μm to 200 μm) and exhibited a large amount of agglomeration, indicating that this homopolymer stabilizer lacked an anchoring segment, had poor stabilizing effect, and produced a large amount of agglomeration.

[0160] Application Comparative Example 6

[0161] The only difference between Comparative Example 6 and Application Example 1 is that the 100 mL high-pressure reactor was dried and purged with CO2 for displacement. 10.7 g of ε-caprolactone and 16 mg of dibutyldimethoxytin catalyst were weighed, mixed, and quickly injected into the reactor and sealed. Liquid CO2 was injected using an ISCO pump until the system pressure reached 14 MPa. The reactor was heated to 40°C, and after the pressure stabilized at 30 MPa, a polymerization reaction was carried out at a stirring rate of 300 rpm for 15 hours. After the reaction, large clumps of polycaprolactone adhered to the reactor wall were obtained.

[0162] The polycaprolactone microspheres prepared in Application Examples 1, 15 to 19 were subjected to 1H NMR or fluorine NMR and Fourier transform infrared spectroscopy to obtain the structural characteristics of the polycaprolactone microspheres. The results are shown in Table 2.

[0163] Table 2

[0164]

[0165] The average particle size and PDI of the polycaprolactone microspheres prepared in the above application examples were detected by scanning electron microscopy (SEM) and GPC. The short axis (shortest diameter of the particle projection, r) and long axis (longest diameter of the particle projection, R) of the polycaprolactone microspheres in multiple sets of SEM images were recorded, and the arithmetic mean of r / R of each set was taken as the sphericity of the sample. The Sn metal residue of the polycaprolactone microspheres prepared in the above application examples was detected by inductively coupled plasma spectroscopy (ICP). The results are shown in Table 3.

[0166] Table 3

[0167]

[0168] Table 3 shows that the dispersion and ring-opening polymerization of polycaprolactone microspheres can be regulated in ultra-near carbon dioxide media by using asymmetric block copolymer stabilizers designed with "homogeneous anchoring". Among them, the anchor-solvent ratio, stabilizer dosage and system pressure have significant regulatory effects on the particle size, particle size distribution and sphericity of polycaprolactone microspheres, and polycaprolactone microspheres can be effectively and stably prepared by different types of carbon dioxide-loving blocks.

[0169] As can be seen from Application Examples 5 and 6, using carboxylic acid and SFE technology for extraction as a means of impurity removal allows polymerization and purification to be completed in the same reactor, effectively removing residual polymerization catalyst with a residual amount of less than 20 ppm.

[0170] As can be seen from Application Examples 9 to 14, when the stabilizer dosage is 5 wt%, the polymerization pressure is 30 MPa, and the polymerization temperature is 40 °C, the particle size of polycaprolactone microspheres gradually decreases from 60 μm to 7 μm when the anchor-solubility ratio increases from 0.5 to 2.0. When the anchor-solubility ratio is greater than 2.0, the particle size no longer decreases significantly, and when the anchor-solubility ratio is equal to 3.0, the particle size increases slightly (9 μm), which may be due to a small amount of agglomeration of the polycaprolactone microspheres. Therefore, it can be seen that the optimal range for the anchor-solubility ratio of the stabilizer is 0.5 to 2.0, and within this range, the polycaprolactone microspheres show a gradual decreasing trend as the anchor-solubility ratio of the stabilizer increases.

[0171] The average particle size, PDI, and sphericity of the polycaprolactone microspheres prepared by comparative examples 1 to 3 were tested, and the results are shown in Table 4.

[0172] Table 4

[0173]

[0174] The data from Application Example 1, Application Comparative Example 1, and Application Comparative Example 2 show that both excessively small and excessively large anchor-solubilization ratios are detrimental to the stable preparation of polycaprolactone microspheres. An anchor-solubilization ratio in the range of 0.9 to 1.9 can more stably prepare polycaprolactone microspheres.

[0175] As can be seen from the data of Application Example 1 and Application Comparative Example 3, the PCL-b-PDMS-b-PCL block copolymer has a symmetrical structure. Although the polycaprolactone segments at both ends are homologous to the target product polycaprolactone microspheres, when used as a stabilizer, the symmetrical structure is prone to "bridging" on the surface of the polycaprolactone microspheres, which promotes aggregation.

[0176] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0177] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A stabilizer for preparing polycaprolactone, characterized in that, The stabilizer is an asymmetric block copolymer comprising polycaprolactone segments and carbon dioxide-loving segments, with an anchor-to-solubility ratio of 0.5 to 5.0, wherein the anchor-to-solubility ratio is the ratio of the number-average molecular weight of the carbon dioxide-loving segments to that of the polycaprolactone segments.

2. The stabilizer for preparing polycaprolactone according to claim 1, characterized in that, The anchoring-to-solidification ratio is 0.5~2.0; And / or, the carbonyl hydrophilic segment is selected from at least one of fluorinated acrylate polymer segments, silicon-containing polymer segments, and perfluoropolyether polymer segments.

3. The stabilizer for preparing polycaprolactone according to claim 2, characterized in that, The anchor-to-solid ratio is 0.9~1.9; And / or, the end group of the polycaprolactone segment is a hydroxyl group; And / or, the number average molecular weight of the polycaprolactone segments is 3000 g / mol to 30000 g / mol.

4. The stabilizer for preparing polycaprolactone according to claim 2, characterized in that, The fluorinated acrylate polymer segments are selected from at least one of the following: polyheptafluorodecyl acrylate segments, polydodecylfluoroheptyl methacrylate segments, polyvinyl perfluorooctanoate segments, polyfluorooctyl ethyl methacrylate segments, poly(1H,1H,2H,2H-perfluorodecyl acrylate) and their copolymer segments. And / or, the silicon-containing polymer segment is selected from at least one of polydimethylsiloxane segments and silicon-containing acrylate copolymer segments; And / or, the perfluoropolyether polymer segment is selected from at least one of the perfluoropolyether carboxylic acid and its derivative segments.

5. A method for preparing polycaprolactone microspheres, characterized in that, The preparation method includes: carrying out a ring-opening polymerization reaction of ε-caprolactone, the stabilizer for preparing polycaprolactone according to any one of claims 1 to 4, and a polymerization catalyst in a supercritical carbon dioxide medium at 15 MPa to 35 MPa to obtain polycaprolactone microspheres; wherein the mass of the stabilizer is 1 wt% to 15 wt% of the mass of the ε-caprolactone.

6. The method for preparing polycaprolactone microspheres according to claim 5, characterized in that, The ring-opening polymerization reaction is carried out at a temperature of 35℃ to 65℃ for a time of 6h to 24h. And / or, the mass ratio of the polymerization catalyst to the ε-caprolactone is 0.1:1000 to 10:1000; And / or, the polycaprolactone segments of the stabilizer have the same end groups as the polycaprolactone segments of the polycaprolactone microspheres.

7. The method for preparing polycaprolactone microspheres according to claim 5 or claim 6, characterized in that, When the polymerization catalyst is a metal catalyst, after the ring-opening polymerization reaction is completed, impurity removal is performed. The impurity removal step includes: adding carboxylic acid and then extracting using dynamic supercritical fluid extraction technology to obtain the polycaprolactone microspheres.

8. The method for preparing polycaprolactone microspheres according to claim 7, characterized in that, The molar ratio of the carboxylic acid to the polymerization catalyst is 5:1 to 20:1; And / or, the carboxylic acid is selected from acetic acid and / or formic acid; And / or, the extraction temperature is 40℃~60℃, the pressure is 15MPa~25MPa, the time is 2h~6h, and the carbon dioxide flow rate is 2mL / min~5mL / min.

9. A polycaprolactone microsphere prepared by the method according to any one of claims 5 to 8, characterized in that, The polycaprolactone microspheres have an average particle size of 5 μm to 200 μm, a molecular weight distribution index of less than 1.5, and a sphericity of 0.9 to 1.

0.

10. The application of the polycaprolactone microspheres as described in claim 9 in medical implants.

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