Polyester-polyethylene glycol block copolymers, their preparation methods and applications

Abstract

This invention relates to the field of polymer materials technology, and in particular to a polyester-polyethylene glycol block copolymer, its preparation method, and its applications. The preparation method of the polyester-polyethylene glycol block copolymer includes the following steps: using stannous octoate as a catalyst, hydroxyl-containing polyethylene glycol and cyclic ester monomers undergo a melt ring-opening polymerization reaction; in the melt ring-opening polymerization, the amount of stannous octoate is 0.01wt% to 0.047wt% of the total amount of the hydroxyl-containing polyethylene glycol and the cyclic ester monomer raw materials; the temperature of the melt ring-opening polymerization reaction is 100-140℃, and the reaction time is 48-150h. This invention synthesizes a polyester-polyethylene glycol block copolymer with residual metal, monomer, and oligomer content meeting the requirements of a drug carrier in a one-step process, eliminating the need for purification steps, shortening the process flow, improving production efficiency and product yield, and facilitating wider commercial applications.

Description

Technical Field

[0001] This invention relates to the field of polymer materials technology, and in particular to a polyester-polyethylene glycol block copolymer, its preparation method, and its application. Background Technology

[0002] Biodegradable block copolymers of polyesters and polyethylene glycol (including their monomethyl ethers) (referred to as polyester-polyethylene glycol block copolymers) have been widely studied and applied in drug delivery carriers due to their excellent biocompatibility. Polyesters are typically selected from homopolymers and / or copolymers of ester monomers such as lactide (LA), glycolide (GA), and caprolactone (CL). For example, diblock polyracemic lactide-monomethyl ether polyethylene glycol (PDLLA-MePEG) has been used to dissolve paclitaxel and docetaxel, and the resulting polymeric micelle formulations have been successfully commercialized, significantly reducing the side effects associated with traditional surfactant formulations.

[0003] The synthesis of polyester-polyethylene glycol block copolymers typically involves the ring-opening polymerization of ester monomers using the terminal hydroxyl groups of polyethylene glycol as initiators and organometallic compounds as catalysts. Specific polymerization methods can include melt polymerization or solution polymerization. Since organotin is an effective catalyst for ring-opening polymerization, it is frequently used as a catalyst in the synthesis of polyester-polyethylene glycol block copolymers. To meet the performance requirements of the polymerization reaction and the product, a relatively high content of organotin catalyst is usually required. However, due to the toxicity of metallic tin, its content in pharmaceuticals must be kept below a certain limit. To meet drug safety requirements, the polymer obtained from ring-opening polymerization needs further purification to reduce the content of residual metals, monomers, and oligomers. This results in reduced production efficiency and product yield, limiting its widespread commercial application.

[0004] In view of this, the present invention is hereby proposed. Summary of the Invention

[0005] The purpose of this invention is to provide polyester-polyethylene glycol block copolymers, their preparation methods, and applications. By employing suitable polymerization reaction conditions, polyester-polyethylene glycol block copolymers with residual metal, monomer, and oligomer content meeting the requirements of drug carriers can be synthesized in one step without further purification steps.

[0006] To achieve the above-mentioned objectives of the present invention, the first aspect of the present invention provides a method for preparing a polyester-polyethylene glycol block copolymer, comprising the following steps: using stannous octoate as a catalyst, hydroxyl-containing polyethylene glycol and cyclic ester monomers undergo a melt ring-opening polymerization reaction;

[0007] In the melt ring-opening polymerization, the amount of stannous octoate used is 0.01 wt% to 0.047 wt% of the total amount of the hydroxyl-containing polyethylene glycol and the cyclic ester monomer raw materials;

[0008] The temperature of the melt ring-opening polymerization reaction is 100–140°C, and the reaction time is 48–150 h.

[0009] In a specific embodiment of the present invention, the melt ring-opening polymerization reaction includes: reacting the mixture at 125-135°C for 10-24 hours, and then cooling to 105-115°C for 24-72 hours.

[0010] In a specific embodiment of the present invention, the stannous octoate is added directly or in the form of a premix; the premix includes:

[0011] (a) Stannous octoate; and,

[0012] (b) Any of the hydroxyl-containing polyethylene glycol and cyclic ester monomers.

[0013] In a specific embodiment of the present invention, the mass fraction of stannous octoate in the premix is ​​0.01% to 5%.

[0014] In a specific embodiment of the present invention, the melt ring-opening polymerization reaction is carried out under vacuum or a protective gas atmosphere.

[0015] In a specific embodiment of the present invention, the hydroxyl-containing polyethylene glycol includes polyethylene glycol and monomethyl ether polyethylene glycol. Further, the number-average molecular weight of the hydroxyl-containing polyethylene glycol is 200–180,000.

[0016] In a specific embodiment of the present invention, the cyclic ester monomer includes at least one selected from lactide, glycolide, and caprolactone. Further, the lactide includes at least one selected from meso lactide, racemic lactide, dextrorotatory lactide, and levorotatory lactide.

[0017] In a specific embodiment of the present invention, the mass ratio of the cyclic ester monomer to the hydroxyl-containing polyethylene glycol is (0.4-9):1.

[0018] The second aspect of the present invention provides a polyester-polyethylene glycol block copolymer, which is prepared by the method for preparing polyester-polyethylene glycol block copolymer provided in the first aspect of the present invention.

[0019] In a specific embodiment of the present invention, the polydispersity (Mw / Mn) of the polyester-polyethylene glycol block copolymer is ≤2.0. Further, the weight-average molecular weight of the polyester-polyethylene glycol block copolymer is 2000 to 200000.

[0020] In a specific embodiment of the present invention, the polyester-polyethylene glycol block copolymer satisfies at least one of the following characteristics:

[0021] (1) The content of metallic tin is ≤150ppm, preferably ≤60ppm;

[0022] (2) The residual monomer content is ≤3.0wt%, preferably ≤2.0wt%;

[0023] (3) The oligomer content is ≤3.0wt%, preferably ≤2.0wt%.

[0024] The third aspect of the present invention provides the application of a polyester-polyethylene glycol block copolymer provided in the second aspect of the present invention in the preparation of a drug carrier.

[0025] In a specific embodiment of the present invention, the drug includes at least one of nimodipine, paclitaxel, docetaxel, indomethacin, and cinacalcet hydrochloride.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] (1) The present invention uses suitable polymerization reaction conditions to synthesize polyester-polyethylene glycol block copolymers with residual metal, monomer and oligomer content that meet the requirements of drug carriers in one step. No purification step is required, which shortens the process flow, improves production efficiency and product yield, and is conducive to realizing wider commercial applications.

[0028] (2) The polyester-polyethylene glycol block copolymer prepared by the preparation method of the present invention has metal tin residue and monomer residue that meet the national standards for PLA and PLGA implant materials, and the metal tin content meets the standard requirements of option 1 (Table A.2.2) in ICH Q3D(R1) (oral ≤600ppm, injection ≤60ppm);

[0029] (3) The polyester-polyethylene glycol block copolymer of the present invention can meet the requirements as a drug carrier and can be directly used in the preparation of drug-loaded polymer micelles and other formulations. Attached Figure Description

[0030] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0031] Figure 1 The HPLC chromatogram of the polyester-polyethylene glycol block copolymer obtained in Example 13 of this invention;

[0032] Figure 2 The HPLC detection method of the present invention and 1 Comparison of lactide residues in polyester-polyethylene glycol determined by H-NMR detection method;

[0033] Figure 3 The GPC spectrum of the polyester-polyethylene glycol block copolymer obtained in Example 13 of this invention is shown below.

[0034] Figure 4 The effect of catalyst dosage and reaction time at 130°C on the residual amount of lactide in polyester-polyethylene glycol block copolymer provided by the present invention;

[0035] Figure 5 The effect of catalyst dosage and reaction time on the residual amount of lactide in polyester-polyethylene glycol block copolymer at 140°C is provided by the present invention.

[0036] Figure 6 The effect of catalyst dosage and reaction time on oligomer content in polyester-polyethylene glycol block copolymer at 130°C is provided by the present invention.

[0037] Figure 7 The present invention describes the effect of catalyst dosage and reaction time on the oligomer content in polyester-polyethylene glycol block copolymers at 140°C. Detailed Implementation

[0038] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings and specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0039] Existing synthesis of polyester-polyethylene glycol block copolymers typically employs melt polymerization or solution polymerization. Solution polymerization is relatively simple, but it requires solvents, leading to environmental degradation and increased production costs due to the large amount of solvent used. Furthermore, the solvent removal process after polymerization reduces production efficiency and increases overall costs. Melt polymerization often uses organotin catalysts such as stannous octoate. To ensure the polymerization process and product performance, 0.3 wt% (equivalent to 879 ppm tin content) or more of stannous octoate is usually added. According to the ICH Q3D guidelines and the national standards YY / T0510-2009 and YY / T 0661-2017 for PLA and PLGA implant materials, to meet pharmaceutical safety requirements, the resulting polymers need to undergo purification steps beyond just dissolution, adsorption, precipitation, and drying to reduce the content of residual metals and monomers. This results in reduced production efficiency and product yield. Moreover, the materials used in ring-opening polymerization are expensive. These factors, combined with other limitations, restrict the wider commercial application of these polymer products.

[0040] Based on this, the first aspect of the present invention provides a method for preparing a polyester-polyethylene glycol block copolymer, comprising the following steps: using stannous octoate as a catalyst, hydroxyl-containing polyethylene glycol and cyclic ester monomers undergo a melt ring-opening polymerization reaction.

[0041] In melt ring-opening polymerization, the amount of stannous octoate used is 0.01 wt% to 0.047 wt% of the total amount of hydroxyl-containing polyethylene glycol and cyclic ester monomer raw materials;

[0042] The temperature for the melt ring-opening polymerization reaction is 100–140℃, and the reaction time is 48–150 h.

[0043] In the preparation of the block copolymer of the present invention, stannous octoate is used as a catalyst, and the amount of stannous octoate added is reduced. With a certain polymerization reaction temperature and reaction time, the block copolymer obtained has a monomer residue of ≤3.0wt%, oligomer content of ≤3.0wt%, and metallic tin residue of ≤150ppm without purification. This meets the national standards for PLA and PLGA implant materials, and the metallic tin content meets the standard requirements of option 1 (Table A.2.2) in ICH Q3D(R1).

[0044] In different embodiments, the amount of stannous octoate can be 0.01 wt%, 0.015 wt%, 0.02 wt%, 0.025 wt%, 0.03 wt%, 0.035 wt%, 0.04 wt%, 0.045 wt%, 0.047 wt%, or any combination thereof, of the total amount of hydroxyl-containing polyethylene glycol and cyclic ester monomer raw materials. This significantly reduces the amount of stannous octoate added while ensuring smooth ring-opening polymerization, block copolymer molecular weight, and the content of residual monomers and oligomers meeting formulation requirements. This allows for meeting the requirements for metallic tin content in oral and even injectable formulations without purification. When the amount of stannous octoate is below the above range, it is difficult to simultaneously meet requirements for conversion rate, residual monomers, and copolymer molecular weight.

[0045] In different embodiments, the temperature of the melt ring-opening polymerization reaction can be a range of 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, or any combination thereof; the reaction time can be a range of 48h, 60h, 72h, 96h, 120h, 140h, 150h, or any combination thereof. When the above temperatures are lower than the melting point of the cyclic ester monomer, in actual operation, the preparation method includes: preheating the hydroxyl-containing polyethylene glycol to above the melting point of the cyclic ester monomer (e.g., 5–30°C above the melting point), then adding the cyclic ester monomer, and after the cyclic ester monomer melts, cooling to the corresponding melt ring-opening polymerization temperature to carry out the melt ring-opening polymerization reaction. This further helps to reduce the color of the block copolymer.

[0046] In a specific embodiment of the present invention, the method for preparing the polyester-polyethylene glycol block copolymer does not include a purification step. The purification step described herein includes, but is not limited to, dissolution, adsorption, precipitation, and drying.

[0047] In a specific embodiment of the present invention, the melt ring-opening polymerization reaction includes: reacting the mixture at 125-135°C for 10-24 hours, and then cooling to 105-115°C for 24-72 hours.

[0048] The inventors of this invention have creatively discovered that, in melt ring-opening polymerization, by using a low amount of stannous octoate and further controlling the reaction temperature—first reacting at a relatively high temperature for a period of time, then appropriately lowering the temperature for a period of time—it is possible to obtain block copolymers of the desired molecular weight while reducing the content of residual monomers and oligomers, and also reducing the color of the block copolymers. For example, the mixture can be reacted first at 125°C, 128°C, 130°C, 132°C, 135°C, or any combination thereof for 10h, 12h, 15h, 18h, 20h, 24h, or any combination thereof, and then cooled to 105°C, 108°C, 110°C, 111°C, 112°C, 113°C, 114°C, 115°C, or any combination thereof, and then reacted for another 24h, 30h, 36h, 40h, 48h, 60h, 72h, or any combination thereof. Among them, the mixture refers to a mixture of hydroxyl-containing polyethylene glycol, cyclic ester monomers and stannous octoate.

[0049] In a specific embodiment of the present invention, stannous octoate is added directly or in the form of a premix; the premix includes:

[0050] (a) Stannous octoate; and,

[0051] (b) Any of the hydroxyl-containing polyethylene glycol and cyclic ester monomers.

[0052] This invention introduces stannous octoate into the polymerization reaction system in the form of a premix, which makes the addition of stannous octoate more accurate, is more conducive to improving the mixing uniformity of stannous octoate in the mixed reaction system, improves the reaction uniformity, and reduces the risk of excessively wide molecular weight distribution due to uneven reaction.

[0053] In one embodiment of the present invention, the premix may include stannous octoate and hydroxyl-containing polyethylene glycol. The preparation of the premix includes, but is not limited to, mixing the ingredients in proportion, heating to melt the hydroxyl-containing polyethylene glycol, mixing uniformly, and obtaining the premix. The heating temperature may be 70-90°C, such as 70°C, 75°C, 80°C, 85°C, 90°C, etc.

[0054] In another embodiment of the present invention, the premix may include stannous octoate and cyclic ester monomers. The preparation of the premix includes, but is not limited to, mixing a cyclohexane solution of stannous octoate with a cyclic ester monomer in a certain proportion, and then removing the cyclohexane by vacuum to obtain the premix. In the cyclohexane solution of stannous octoate, the concentration of stannous octoate may be 10-120 mg / mL, such as 10 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, etc.

[0055] In a specific embodiment of the present invention, the mass fraction of stannous octoate in the premix is ​​0.01% to 5%, for example, it can be 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5% or any combination thereof, which helps to ensure the uniformity of the stannous octoate mixture while ensuring the polymerization reaction efficiency and improve the molecular weight distribution width of the block copolymer.

[0056] In a specific embodiment of the present invention, the melt ring-opening polymerization reaction is carried out under a vacuum or a protective gas atmosphere. The protective gas atmosphere includes at least one of nitrogen and argon.

[0057] In a specific embodiment of the present invention, a cyclic ester monomer is added to molten hydroxyl-containing polyethylene glycol, mixed evenly, and then stannous octoate is added and quickly mixed evenly to carry out a melt ring-opening polymerization reaction.

[0058] In a specific embodiment of the present invention, the method further includes: pretreatment of the hydroxyl-containing polyethylene glycol; the pretreatment includes: vacuum treatment of the hydroxyl-containing polyethylene glycol in a molten state to remove moisture. Specifically, in the pretreatment, the hydroxyl-containing polyethylene glycol can be heated to 110–130°C to melt it, and vacuum treatment is performed while maintaining it in this state.

[0059] In a specific embodiment of the present invention, the hydroxyl-containing polyethylene glycol includes polyethylene glycol and monomethyl ether polyethylene glycol. Further, the number-average molecular weight of the hydroxyl-containing polyethylene glycol is 200–180,000, preferably 2,000–8,000.

[0060] The hydroxyl-containing polyethylene glycol raw material of the present invention can be a raw material that conforms to pharmacopoeia standards or is equivalent. The hydroxyl-containing polyethylene glycol of the present invention can be any one or more of linear polyethylene glycol, branched polyethylene glycol, and star-shaped polyethylene glycol.

[0061] In specific embodiments of the present invention, the cyclic ester monomers include at least one selected from lactide, glycolide (GA), and caprolactone (ε-CL). Further, the lactide includes at least one selected from meso-LA, racemic lactide (DLLA), dextrorotatory lactide (DLA), and levorotatory lactide (LLA). The purity of the cyclic ester monomer raw materials of the present invention is ≥99 wt%.

[0062] In a specific embodiment of the present invention, the mass ratio of the cyclic ester monomer to the hydroxyl-containing polyethylene glycol is (0.4–9):1, for example, it can be a range of 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 3:1, 5:1, 9:1, or any combination thereof, which is more conducive to meeting the usage requirements of polymer micelle formulations.

[0063] The second aspect of the present invention provides a polyester-polyethylene glycol block copolymer, which is prepared by the method for preparing polyester-polyethylene glycol block copolymer provided in the first aspect of the present invention.

[0064] In a specific embodiment of the present invention, the polydispersity Mw / Mn of the polyester-polyethylene glycol block copolymer is ≤2.0, preferably ≤1.2. Further, the weight-average molecular weight of the polyester-polyethylene glycol block copolymer is 2000 to 200000.

[0065] The polydispersity of the polyester-polyethylene glycol block copolymer of the present invention is determined by the ratio of the weight-average molecular weight Mw to the number-average molecular weight Mn of the polyester-polyethylene glycol block copolymer by GPC. The polyester-polyethylene glycol block copolymer prepared by the preparation method of the present invention not only has the expected molecular weight, but also has a relatively narrow molecular weight distribution width, which is more conducive to improving the stability of the polyester-polyethylene glycol block copolymer as a drug carrier formulation. In different embodiments, the polydispersity Mw / Mn of the polyester-polyethylene glycol block copolymer can be in the range of 2.0, 1.6, 1.2, 1.19, 1.18, 1.16, 1.15, 1.14, 1.12, 1.1, 1.08, 1.06 or any two of these; the weight-average molecular weight of the polyester-polyethylene glycol block copolymer can be in the range of 2000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 50000, 100000, 150000, 200000 or any two of these, meeting the formulation requirements.

[0066] In this invention, when determining the polyester-polyethylene glycol block copolymer using GPC, the specific GPC method uses a GPC KF-803L column (8.0 mm × 300 mm, 6 μm), purchased from Showa Denko Corporation, Japan; tetrahydrofuran is used as the mobile phase, with isocratic elution at a flow rate of 1.0 mL / min; the column temperature is 40 °C; the injection volume is 20 μL; the detector is an AD differential refractive index detector; and the analysis time is 15 min. Polyethylene glycol is used as the standard in the GPC determination.

[0067] In a specific embodiment of the present invention, the polyester-polyethylene glycol block copolymer satisfies at least one of the following characteristics:

[0068] (1) The tin content is ≤150ppm, preferably ≤60ppm; for example, it can be a range of 150ppm, 120ppm, 100ppm, 90ppm, 80ppm, 60ppm, 50ppm or any two of these.

[0069] (2) The residual monomer content is ≤3.0wt%, preferably ≤2.0wt%; for example, it can be a range of 3.0wt%, 2.8wt%, 2.5wt%, 2.2wt%, 2wt%, 1.8wt%, 1.5wt%, 1.2wt%, 1wt%, or any two of these.

[0070] (3) The oligomer content is ≤3.0wt%, preferably ≤2.0wt%; for example, it can be 3.0wt%, 2.5wt%, 2.2wt%, 2wt%, 1.8wt%, 1.5wt%, 1.2wt%, 1wt%, 0.9wt%, or any combination thereof. The oligomers of this invention refer to low molecular weight polymers with a molecular weight in the range of 162 to 1026.

[0071] The third aspect of the present invention provides the application of a polyester-polyethylene glycol block copolymer provided in the second aspect of the present invention in the preparation of a drug carrier.

[0072] In specific embodiments of the present invention, the drug includes, but is not limited to, at least one of nimodipine, paclitaxel, docetaxel, indomethacin, and cinacalcet hydrochloride.

[0073] The present invention also provides a method for detecting the content of monomers and / or oligomers in polyester-polyethylene glycol block copolymers, comprising the following steps: performing high performance liquid chromatography on the test sample solution;

[0074] The conditions for the high-performance liquid chromatography detection include:

[0075] The chromatographic column was a C18 column; the column temperature was 40℃; and the detection wavelength was 210nm.

[0076] Gradient elution was performed using mobile phase A and mobile phase B at a flow rate of 1.0 mL / min; mobile phase A was a 0.1% (w / w) aqueous solution of phosphoric acid, and mobile phase B was acetonitrile.

[0077] The gradient elution process includes: 0–2 min, the volume ratio of mobile phase A to mobile phase B is 98:2; 2–25 min, the volume ratio of mobile phase A to mobile phase B changes from 98:2 to 0:100; 25–30 min, the volume ratio of mobile phase A to mobile phase B is 0:100; 30–31 min, the volume ratio of mobile phase A to mobile phase B changes from 0:100 to 98:2; 31–41 min, the volume ratio of mobile phase A to mobile phase B is 98:2.

[0078] The content of monomers in the test sample can be calculated using the external standard method. Specifically, the method for calculating the monomer content includes: injecting a series of standard working solutions of the monomer (such as lactide) into a high-performance liquid chromatograph (HPLC), measuring the corresponding peak areas under the same chromatographic conditions as the test sample solution, and plotting a standard curve with the monomer concentration of the standard working solutions as the x-axis and the peak area as the y-axis; obtaining the chromatographic peak area corresponding to the monomer in the test sample solution from the chromatogram of the test sample solution, and substituting it into the standard curve to calculate the concentration of the monomer in the test sample solution. The standard working solutions can be acetonitrile solutions of monomers with a concentration of 1–10 mg / mL.

[0079] In a specific embodiment of the present invention, the preparation of the test solution includes: dissolving the polyester-polyethylene glycol block copolymer to be tested in acetonitrile, filtering, and collecting the filtrate. Further, the concentration of the polyester-polyethylene glycol block copolymer to be tested in the test solution is 25–35 mg / mL, for example, 25 mg / mL, 28 mg / mL, 30 mg / mL, 32 mg / mL, 35 mg / mL, etc.

[0080] In a specific embodiment of the present invention, the chromatographic column is a Supersil AQ-C18, 5μm, 4.6mm×250mm.

[0081] In a specific embodiment of the present invention, the injection volume in high performance liquid chromatography detection can be 10 μL.

[0082] The detection method of this invention can rapidly and accurately determine the content of residual monomers and oligomers in polymers, which is beneficial for improving synthesis efficiency and controlling polymer quality. The residual monomer content determined by the detection method of this invention is comparable to that of existing methods. 1 The H-NMR results were highly consistent.

[0083] The Chinese meanings or full names of some of the English abbreviations involved in this invention are as follows:

[0084] DLLA: D,L-lactide, racemic lactide;

[0085] mLA: meso-lactide;

[0086] LLA: L-lactide, L-lactide;

[0087] DLA: D-lactide, dextrorotatory lactide;

[0088] CL: ε-caprolactone;

[0089] GA: glycolide;

[0090] MePEG: methoxy polyethylene glycol, polyethylene glycol monomethyl ether;

[0091] PEG: polyethylene glycol;

[0092] PLLA: poly(L-lactide);

[0093] PDLA: poly(D-lactide);

[0094] PDLLA / LLA: poly(D,L-lactide-co-L-lactide);

[0095] PDLLA / DLA: poly(D,L-lactide-co-D-lactide).

[0096] PDLLA / LLA-PEG-PDLLA / LLA: poly(D,L-lactide-co-L-lactide)-block-polyethylene glycol-block-poly(D,L-lactide-co-L-lactide);

[0097] In the PDLLA / LLA-PEG-PDLLA / LLA WX / Y / Z mentioned below, W represents the molecular weight of PEG, and X, Y and Z represent the mass fractions (wt%) of D, L-lactide, L-lactide and PEG in the polymer, respectively.

[0098] In the PLLA-PEG-PLLA WY / Z mentioned later, W represents the molecular weight of PEG, and Y and Z represent the mass fraction (wt%) of L-lactide and PEG in the polymer, respectively.

[0099] Example 1

[0100] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0101] 30g of PEG with a molecular weight of 3350 was added to a 100mL clean flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 110°C. After the PEG melted, a vacuum was applied for about 16 hours with stirring to remove residual moisture and other volatiles from the PEG. The temperature was raised to 130°C, and 10g of D,L-lactide and 10g of L-lactide were added respectively. After melting, 0.018g of stannous octoate was added, and the polymerization reaction was completed by stirring at 130°C for 96 hours to obtain the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, a brief vacuum was applied, such as for 30 minutes, before sealing.

[0102] Example 2

[0103] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0104] 30g of PEG with a molecular weight of 3350 was added to a 100mL clean flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 110°C. After the PEG melted, a vacuum was applied for approximately 16 hours with stirring to remove residual moisture and other volatiles from the PEG. The temperature was raised to 130°C, and 10g of D,L-lactide and 10g of L-lactide were added separately. After complete melting, the temperature was lowered to 110°C, and 0.0209g of stannous octoate was added. The polymerization reaction was completed by stirring at 110°C for 150 hours to obtain the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, a brief vacuum was applied (e.g., 30 minutes) before sealing.

[0105] Example 3

[0106] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0107] 30g of PEG with a molecular weight of 3350 was added to a 100mL clean flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 110°C. After the PEG melted, a vacuum was applied for approximately 16 hours with stirring to remove residual moisture and other volatiles from the PEG. The temperature was raised to 130°C, and 10g of D,L-lactide and 10g of L-lactide were added separately. After complete melting, the temperature was lowered to 100°C, and 0.0235g of stannous octoate was added. The polymerization reaction was completed by stirring at 100°C for 150 hours to obtain the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, a brief vacuum was applied (e.g., 30 minutes) before sealing.

[0108] Example 4

[0109] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0110] Add 30g of PEG with a molecular weight of 3350 to a clean 100mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 110°C. After the PEG melts, apply vacuum for approximately 16 hours with stirring to remove residual moisture and other volatiles from the PEG. Raise the temperature to 140°C and add the stannous octoate / lactide mixture. Stir at 140°C for 48 hours to complete the polymerization reaction, yielding the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, perform a brief evacuation (e.g., 30 minutes) before sealing.

[0111] The preparation of the stannous octoate / lactide mixture includes: taking 0.16 mL of a cyclohexane solution of stannous octoate with a concentration of 50 mg / mL, adding 10 g of D,L-lactide and 10 g of L-lactide, mixing well, and then removing the cyclohexane under vacuum. All of this mixture is added to the above reaction system.

[0112] Example 5

[0113] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0114] 30 g of PEG with a molecular weight of 3350 was added to a 100 mL clean flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 110 °C. After the PEG melted, a vacuum was applied for about 16 h with stirring to remove residual moisture and other volatiles from the PEG. After heating to 140 °C, 10 g of D,L-lactide and 10 g of L-lactide were added respectively. After melting, 0.016 g of stannous octoate was added, and the polymerization reaction was completed by stirring at 140 °C for 96 h to obtain the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, a brief vacuum was applied, such as for 30 min, before sealing.

[0115] Example 6

[0116] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0117] Add 5g of PEG with a molecular weight of 6000 to a clean 10mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 2 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 5g of L-lactide, and after melting, add 0.0047g of stannous octoate. Stir at 130°C for 48 hours to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition of material, perform a brief evacuation (e.g., 30 minutes) before sealing.

[0118] Example 7

[0119] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0120] Add 5g of PEG with a molecular weight of 6000 to a clean 10mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 2 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 5g of L-lactide, and after melting, add 0.0029g of stannous octoate. Stir at 130°C for 72 hours to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition of material, perform a brief evacuation (e.g., 30 minutes) before sealing.

[0121] Example 8

[0122] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0123] Add 30g of PEG with a molecular weight of 3350 to a clean 100mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 110℃. After the PEG melts, apply vacuum for about 16 hours with stirring to remove residual moisture and other volatiles from the PEG. Raise the temperature to 130℃, then add 10g of D,L-lactide and 10g of L-lactide respectively. After melting, add 0.11g of stannous octoate / PEG 3350 mixture. Stir at 130℃ for 72 hours, then add another 0.056g of stannous octoate / PEG 3350 mixture. Continue stirring at 130℃ until the reaction has lasted 150 hours, completing the polymerization reaction and yielding the block copolymer PDLLA / LLA-PEG-PDLLA / LLA3350-20 / 20 / 60. After each addition of material, briefly evacuate the flask for 30 minutes before sealing.

[0124] The preparation of the stannous octoate / PEG 3350 mixture includes: weighing stannous octoate and PEG with a molecular weight of 3350 at a mass ratio of 1:19, melting the PEG at 80°C and mixing it evenly with the stannous octoate, and cooling to obtain the stannous octoate / PEG 3350 mixture.

[0125] Example 9

[0126] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0127] Add 4.8 g of PEG with a molecular weight of 6000 to a clean 10 mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 2 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 5 g of L-lactide, and after melting, add 0.16 g of stannous octoate / PEG 6000 mixture. Stir at 130°C for 48 hours to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0128] The preparation of the stannous octoate / PEG 6000 mixture includes: weighing stannous octoate and PEG with a molecular weight of 6000 at a mass ratio of 1:39, melting the PEG at 80°C and mixing it evenly with the stannous octoate, and cooling to obtain the stannous octoate / PEG 6000 mixture.

[0129] Example 10

[0130] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0131] Add 4.95 g of PEG with a molecular weight of 6000 to a clean 10 mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 2 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 5 g of L-lactide, and after melting, add 0.065 g of stannous octoate / PEG 6000 mixture. Stir at 130°C for 72 hours to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0132] The preparation of the stannous octoate / PEG 6000 mixture was the same as in Example 9.

[0133] Example 11

[0134] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0135] 30g of PEG with a molecular weight of 3350 was added to a 100mL clean flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 110°C. After the PEG melted, a vacuum was applied for approximately 16 hours with stirring to remove residual moisture and other volatiles from the PEG. The temperature was then raised to 130°C, and 10g of D,L-lactide and 10g of L-lactide were added respectively. After melting, 0.019g of stannous octoate was added, and the mixture was stirred at 130°C for 24 hours. Then, the temperature was lowered to 110°C, and stirring was continued for 48 hours to complete the polymerization reaction, yielding the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, a brief vacuum was applied (e.g., 30 minutes) before sealing.

[0136] Example 12

[0137] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0138] 30g of PEG with a molecular weight of 3350 was added to a clean 250mL flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 110°C. After the PEG melted, a vacuum was applied for approximately 16 hours with stirring to remove residual moisture and other volatiles from the PEG. The temperature was then raised to 130°C, and 10g of D,L-lactide and 10g of L-lactide were added separately. After melting, 0.16g of a stannous octoate / PEG 3350 mixture was added. The mixture was stirred at 130°C for 24 hours, then cooled to 110°C and stirred for another 48 hours to complete the polymerization reaction, yielding the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, a brief vacuum was applied (e.g., 30 minutes) before sealing.

[0139] The preparation of the stannous octoate / PEG 3350 mixture was the same as in Example 8.

[0140] Example 13

[0141] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0142] Add 570g of PEG with a molecular weight of 6000 to a clean 1000mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for approximately 17 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 400g of L-lactide, and after melting, add 30g of a stannous octoate / L-lactide mixture. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, yielding the block copolymer PLLA-PEG-PLLA 6000-43 / 57. After each addition of material, apply a brief vacuum (e.g., 60 minutes) before sealing.

[0143] The preparation of the stannous octoate / L-lactide mixture includes: taking 3 mL of a cyclohexane solution of stannous octoate with a concentration of 100 mg / mL, adding it to 30 g of L-lactide, mixing well, and then removing the cyclohexane under vacuum.

[0144] Example 14

[0145] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0146] Add 570g of PEG with a molecular weight of 6000 to a clean 1000mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for approximately 17 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 430g of D-lactide, and after melting, add 0.32g of stannous octoate. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, yielding the block copolymer PDLA-PEG-PDLA 6000-43 / 57. After each addition of material, perform a brief evacuation (e.g., 60 minutes) before sealing.

[0147] Example 15

[0148] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0149] Add 5.7 g of PEG with a molecular weight of 6000 to a clean 10 mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 1.5 h with stirring to remove residual moisture and other volatiles from the PEG. Add 1.43 g of D,L-lactide and 2.57 g of L-lactide respectively. After melting, add 0.3 g of stannous octoate / L-lactide mixture. Stir at 130°C for 24 h, then cool to 110°C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 6000-14.3 / 28.7 / 57. After each addition of material, apply a brief vacuum (e.g., 30 min) before sealing.

[0150] The preparation method of the stannous octoate / L-lactide mixture is described in Example 13.

[0151] Example 16

[0152] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0153] Add 5.7 g of PEG with a molecular weight of 6000 to a clean 10 mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 1.5 h with stirring to remove residual moisture and other volatiles from the PEG. Add 0.86 g of D,L-lactide and 3.14 g of L-lactide respectively. After melting, add 0.3 g of stannous octoate / L-lactide mixture. Stir at 130°C for 24 h, then cool to 110°C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 6000-8.6 / 34.4 / 57. After each addition of material, apply a brief vacuum (e.g., 30 min) before sealing.

[0154] The preparation method of the stannous octoate / L-lactide mixture is described in Example 13.

[0155] Example 17

[0156] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0157] Add 6.4 g of PEG with a molecular weight of 6000 to a clean 10 mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 1.5 h with stirring to remove residual moisture and other volatiles from the PEG. Add 0.725 g of D,L-lactide and 2.59 g of L-lactide respectively. After melting, add 0.3 g of stannous octoate / L-lactide mixture. Stir at 130°C for 24 h, then cool to 110°C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 6000-7.2 / 28.8 / 64. After each addition of material, apply a brief vacuum (e.g., 30 min) before sealing.

[0158] The preparation method of the stannous octoate / L-lactide mixture is described in Example 13.

[0159] Example 18

[0160] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0161] Add 6.4 g of PEG with a molecular weight of 6000 to a clean 10 mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 1.5 h with stirring to remove residual moisture and other volatiles from the PEG. Add 3.3 g of L-lactide, and after melting, add 0.3 g of a stannous octoate / L-lactide mixture. Stir at 130°C for 24 h, then cool to 110°C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-36 / 64. After each addition of material, apply a brief vacuum (e.g., 30 min) before sealing.

[0162] The preparation method of the stannous octoate / L-lactide mixture is described in Example 13.

[0163] Example 19

[0164] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0165] Add 320g of PEG with a molecular weight of 6000 to a clean 500mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for about 1.5 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 90g of D,L-lactide and 80g of L-lactide separately. After melting, add 10g of stannous octoate / L-lactide mixture. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 6000-18 / 18 / 64. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0166] The preparation method of the stannous octoate / L-lactide mixture is described in Example 13.

[0167] Example 20

[0168] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0169] Add 350g of PEG with a molecular weight of 6000 to a clean 500mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for approximately 17 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 150g of L-lactide, and after melting, add 0.14g of stannous octoate. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, yielding the block copolymer PLLA-PEG-PLLA 6000-30 / 70. After each addition of material, perform a brief evacuation (e.g., 120 minutes) before sealing.

[0170] Example 21

[0171] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0172] Add 350g of PEG with a molecular weight of 6000 to a clean 500mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for approximately 17 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 150g of D-lactide, and after melting, add 0.103g of stannous octoate. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, yielding the block copolymer PDLA-PEG-PDLA6000-30 / 70. After each addition of material, perform a brief evacuation (e.g., 120 minutes) before sealing.

[0173] Example 22

[0174] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0175] Add 5g of PEG with a molecular weight of 6000 to a clean 10mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for approximately 1.5 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 4.7g of D-lactide, and after melting, add 0.3g of a stannous octoate / D-lactide mixture. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, yielding the block copolymer PDLA-PEG-PDLA 6000-50 / 50. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0176] The preparation method of the stannous octoate / D-lactide mixture is described in Example 13, except that L-lactide is replaced with an equal amount of D-lactide.

[0177] Example 23

[0178] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0179] Add 6.4 g of PEG with a molecular weight of 6000 to a clean 10 mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 1.5 h with stirring to remove residual moisture and other volatiles from the PEG. Add 3.3 g of D-lactide, and after melting, add 0.3 g of a stannous octoate / D-lactide mixture. Stir at 130°C for 24 h, then cool to 110°C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PDLA-PEG-PDLA 6000-36 / 64. After each addition of material, apply a brief vacuum (e.g., 30 min) before sealing.

[0180] The preparation method of the stannous octoate / D-lactide mixture is described in Example 22.

[0181] Example 24

[0182] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0183] Add 7g of PEG with a molecular weight of 6000 to a clean 10mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for approximately 1.5 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 2.7g of D-lactide, and after melting, add 0.3g of a stannous octoate / D-lactide mixture. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, yielding the block copolymer PDLA-PEG-PDLA 6000-30 / 70. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0184] The preparation method of the stannous octoate / D-lactide mixture is described in Example 22.

[0185] Example 25

[0186] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0187] Add 7g of PEG with a molecular weight of 6000 to a clean 10mL flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply vacuum for about 1.5 hours with stirring to remove residual moisture and other volatiles from the PEG. Add 2.7g of L-lactide, and after melting, add 0.3g of a stannous octoate / L-lactide mixture. Stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 48 hours to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-30 / 70. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0188] The preparation method of the stannous octoate / L-lactide mixture is described in Example 13.

[0189] Example 26

[0190] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0191] 10 g of PEG with a molecular weight of 300 was added to a clean 250 mL flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 130 °C, and a vacuum was applied for about 1.5 h with stirring to remove residual moisture and other volatiles from the PEG. A stannous octoate / lactide mixture was added, and the mixture was stirred at 130 °C for 48 h. The temperature was then lowered to 110 °C, and stirring was continued for another 24 h to complete the polymerization reaction, yielding the block copolymer PLGA-PEG-PLGA 300-71 / 19 / 10. After each addition of material, a brief evacuation was performed (e.g., 30 min) before sealing.

[0192] The preparation of the stannous octoate / lactide mixture includes: taking 0.15 mL of a cyclohexane solution of stannous octoate with a concentration of 100 mg / mL, adding 71 g of D,L-lactide and 19 g of D,L-lactide, mixing well, and then removing the cyclohexane under vacuum. All of this mixture is added to the above reaction system.

[0193] Example 27

[0194] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0195] Add 5g of PEG with a molecular weight of 6000 to a clean 10mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for about 2 hours with stirring to remove residual moisture and other volatiles from the PEG. Add the stannous octoate / L-lactide mixture, stir at 130°C for 24 hours, then cool to 110°C and continue stirring for 72 hours to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0196] The preparation of the stannous octoate / L-lactide mixture includes: taking 100 μL of a cyclohexane solution of stannous octoate with a concentration of 10 mg / mL, adding 5 g of L-lactide, mixing well, and then removing the cyclohexane under vacuum.

[0197] Example 28

[0198] This embodiment refers to the preparation method of Example 27, the only difference being that the reaction temperature and time are different after adding the stannous octoate / L-lactide mixture.

[0199] In this embodiment, after adding the stannous octoate / L-lactide mixture, the mixture was stirred at 130°C for 48 hours, and then cooled to 110°C and stirred for another 72 hours to complete the polymerization reaction.

[0200] Example 29

[0201] This embodiment refers to the preparation method of Example 27, the only difference being that the reaction temperature and time are different after adding the stannous octoate / L-lactide mixture.

[0202] In this embodiment, after adding the stannous octoate / L-lactide mixture, the temperature was raised to 140°C and stirred for 24 hours, and then the temperature was lowered to 110°C and stirred for another 72 hours to complete the polymerization reaction.

[0203] Example 30

[0204] This embodiment provides a method for preparing a polyester-polyethylene glycol block copolymer, including the following steps:

[0205] Add 5g of PEG with a molecular weight of 6000 to a clean 10mL flask equipped with a magnetic stirrer. Immerse the flask in a 130°C oil bath. After the PEG melts, apply vacuum for about 2 hours with stirring to remove residual moisture and other volatiles from the PEG. Add the stannous octoate / L-lactide mixture, stir at 130°C for 24 hours, then cool to 120°C and continue stirring for 48 hours to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition of material, apply a brief vacuum (e.g., 30 minutes) before sealing.

[0206] The preparation of the stannous octoate / L-lactide mixture includes: taking 300 μL of a cyclohexane solution of stannous octoate with a concentration of 10 mg / mL, adding 5 g of L-lactide, mixing well, and then removing the cyclohexane under vacuum.

[0207] Example 31

[0208] This embodiment refers to the preparation method of Example 30, the only difference being the reaction temperature and time after adding the stannous octoate / L-lactide mixture.

[0209] In this embodiment, after adding the stannous octoate / L-lactide mixture, the mixture was stirred at 130°C for 48 hours, and then cooled to 110°C and stirred for another 48 hours to complete the polymerization reaction.

[0210] Example 32

[0211] This embodiment refers to the preparation method of Example 30, the only difference being the reaction temperature and time after adding the stannous octoate / L-lactide mixture.

[0212] In this embodiment, after adding the stannous octoate / L-lactide mixture, the temperature was raised to 140°C and stirred for 24 hours, and then the temperature was lowered to 110°C and stirred for another 48 hours to complete the polymerization reaction.

[0213] Example 33

[0214] This embodiment provides a method for preparing a micelle formulation, comprising the following steps:

[0215] Take 0.25g of nimodipine, 12.25g of the copolymer PDLLA / LLA-PEG-PDLLA / LLA3350-20 / 20 / 60 prepared in Example 5, and 10mL of ethanol to obtain a mixed solution. Make up to 25mL with ethanol, dispense into glass bottles, and seal with a stopper for long-term storage. Dilute with D5W to obtain a nimodipine polymer micelle formulation.

[0216] Example 34

[0217] This embodiment refers to the preparation method of the micelle formulation in Example 33, except that the copolymer in Example 5 is replaced with an equal mass of the copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60 obtained in Example 12.

[0218] Comparative Example 1

[0219] Comparative Example 1 provides a method for preparing a polyester-polyethylene glycol block copolymer, referring to Example 1, except that the amount of stannous octoate is different.

[0220] In Comparative Example 1, the amount of stannous octoate used was 0.048g.

[0221] Comparative Example 2

[0222] Comparative Example 2 provides a method for preparing a polyester-polyethylene glycol block copolymer, referring to Example 1, except that the amount of stannous octoate is different and the reaction time is shortened.

[0223] Comparative Example 2 involved adding 30g of PEG with a molecular weight of 3350 to a 100mL clean flask equipped with a magnetic stirrer. The flask was immersed in an oil bath at 110°C. After the PEG melted, a vacuum was applied for approximately 16 hours with stirring to remove residual moisture and other volatiles from the PEG. The temperature was then raised to 130°C, and 10g of D,L-lactide and 10g of L-lactide were added respectively. After melting, 0.035g of stannous octoate was added, and the polymerization reaction was completed by stirring at 130°C for 48 hours, yielding the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of material, a brief vacuum was applied (e.g., 30 minutes) before sealing.

[0224] Experimental Example 1

[0225] The weight-average molecular weight, polydispersity, monomer residue, oligomer content, tin content, and color of the polyester-polyethylene glycol block copolymers prepared in different embodiments and comparative examples were tested. The test results are shown in Table 1.

[0226] Table 1 Test results of different copolymers

[0227]

[0228]

[0229]

[0230] The weight-average molecular weight (Mw) was determined by GPC. In the GPC test, the chromatographic column was a GPC KF-803L (8.0 mm × 300 mm, 6 μm), the column temperature was 40℃, the injection volume was 20 μL, the detector was an AD differential refractive index detector, and the analysis time was 15 min. The mobile phase was THF, with isocratic elution, the flow rate was 1 mL / min, and the standard was polyethylene glycol.

[0231] Polydispersity is the ratio of weight-average molecular weight Mw to number-average molecular weight Mn as determined by GPC.

[0232] The calculation method for the amount of metallic tin added is: Metallic tin added (ppm) = Percentage of stannous octoate used × 118.71 / 405.12 × 10 6 Stannous octoate usage percentage = Stannous octoate usage / (hydroxyl-containing polyethylene glycol usage + cyclic ester monomer usage).

[0233] Monomer residues were determined and calculated using HPLC, with the specific testing method as follows:

[0234] (1) Take the polyester-polyethylene glycol block copolymer to be tested, prepare an acetonitrile solution of the copolymer with a concentration of 30 mg / mL, filter it through a 0.45 μm nylon filter membrane, and collect the filtrate as the test solution.

[0235] (2) Inject the test sample solution for detection, record the chromatogram, substitute the peak area of ​​the corresponding monomer in the chromatogram into the standard curve, calculate the concentration of the monomer in the test sample solution, and then calculate the content of the monomer in the copolymer sample; wherein, the HPLC detection conditions are as follows:

[0236] Column: Supersil AQ-C18, 5μm, 4.6mm×250mm;

[0237] Mobile phase A: 0.1 wt% aqueous phosphoric acid solution; Mobile phase B: acetonitrile;

[0238] Perform gradient elution according to Table 2;

[0239] Flow rate: 1.0 mL / min;

[0240] Detection wavelength: 210nm;

[0241] Column temperature: 40℃;

[0242] Injection volume: 10 μL.

[0243] Table 2 Gradient elution program

[0244] Time / min Mobile phase A / vol.% Mobile phase B / vol.% 0 98 2 2 98 2 25 0 100 30 0 100 31 98 2 41 98 2

[0245] The method for obtaining the standard curve includes: injecting a series of DLLA standard working solutions (specifically, acetonitrile solutions of DLLA with DLLA concentrations of 1.001 mg / mL, 2.003 mg / mL, 3.004 mg / mL, 5.007 mg / mL, 6.008 mg / mL, 8.011 mg / mL, and 10.014 mg / mL) into a high-performance liquid chromatograph, measuring the corresponding peak areas under the above detection conditions, and plotting the standard curve with the monomer concentration in the standard working solutions as the x-axis and the peak area as the y-axis.

[0246] The calculation of oligomer content includes: subtracting the peak area of ​​approximately 13.5 min from the total peak area in the chromatogram determined by the corresponding HPLC method, and then substituting the peak area obtained by the DLLA standard curve. 1 H-NMR: In 1 In the H-NMR spectrum, the signal peak of the methylene group of lactide is located at δ = 5.02-5.08, and the signal peak of the methylene group in the repeating unit of polylactic acid is located at δ = 5.11-5.28. By integrating the two regions, the proportion of unreacted lactide can be calculated, and then the residual amount of lactide monomer can be calculated based on the amount of lactide raw material added in the formula.

[0247] Figure 1 The figure shows the HPLC chromatogram of the polyester-polyethylene glycol block copolymer obtained in Example 13 of this invention. As can be seen from the figure, the main peak with a retention time of approximately 13.5 min corresponds to lactide, and the remaining smaller peaks correspond to oligomers. To verify the accuracy of the HPLC method for detecting oligomers, we simultaneously applied HPLC detection and... 1 The H-NMR method was used to detect residual lactide monomers in polyester-polyethylene glycol block copolymers. The correlation between the results of the two methods was analyzed to mutually verify the accuracy of the methods. The test results are as follows: Figure 2 As shown in the figure, the HPLC detection method of the present invention is similar to... 1 The results of the H-NMR determination method are basically consistent, and it can quickly and accurately detect the monomer content of the copolymer.

[0248] As can be seen from the test results in Table 1, the present invention uses suitable polymerization reaction conditions to synthesize polyester-polyethylene glycol block copolymers with residual metal, monomer, and oligomer content that meet the requirements of drug carriers in a one-step process without the need for purification steps. This significantly improves production efficiency and product yield (theoretical value 100%), and the resulting polymer has a good molecular weight distribution. Figure 3 The image shows the GPC spectrum of the polyester-polyethylene glycol block copolymer obtained in Example 13. Furthermore, by employing a stepwise temperature reduction method, compared to isothermal polymerization, not only was monomer residue reduced, but the oligomer content was further reduced, and the resulting polymer had a lighter color.

[0249] Figure 4 and Figure 5 The present invention provides the effects of catalyst dosage and reaction time on the residual amount of lactide in polyester-polyethylene glycol block copolymer (PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60) obtained by isothermal polymerization at 130°C and 140°C, respectively. Figure 6 and Figure 7 The present invention provides the effects of catalyst dosage and reaction time on the oligomer content in polyester-polyethylene glycol block copolymer (PDLLA / LLA-PEG-PDLLA / LLA3350-20 / 20 / 60) obtained by isothermal polymerization at 130°C and 140°C, respectively.

[0250] To further compare the effects of different polymerization temperature conditions on monomer residue and oligomer content, the monomer content and oligomer content of the reaction systems of Examples 1, 5, 8, 11, 12, 13, 14, and 19 were tested at different times. The test results are shown in Table 3.

[0251] Table 3. Monomer content and oligomer content of different reaction systems at different times.

[0252]

[0253]

[0254] The test results above show that the polymerization reaction temperature control method of the present invention can reduce monomer residue and oligomer content, while the resulting polymer has a lighter color and ensures high production efficiency.

[0255] Experiment Example 2

[0256] The formulations prepared in Examples 33 and 34 were diluted 20 times using D5W, and the diluted formulations were tested. The test results are shown in Table 4.

[0257] Table 4. Formulation test results

[0258]

[0259] The test results above show that the polyester-polyethylene glycol block copolymer of the present invention can meet the requirements as a drug carrier and can be directly used in the preparation of drug-loaded polymer micelles and other formulations.

[0260] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a polyester-polyethylene glycol block copolymer, characterized in that, The process includes the following steps: using stannous octoate as a catalyst, hydroxyl-containing polyethylene glycol and cyclic ester monomers undergo melt ring-opening polymerization. In the melt ring-opening polymerization, the amount of stannous octoate used is 0.01wt% to 0.047wt% of the total amount of the hydroxyl-containing polyethylene glycol and the cyclic ester monomer raw materials; The melt ring-opening polymerization reaction includes: reacting the mixture at 125-135°C for 10-24 hours, then cooling to 105-115°C and reacting for 24-72 hours.

2. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 1, characterized in that, The stannous octoate is added directly or in the form of a premix; the premix includes: (a) Stannous octoate; and, (b) Any of the hydroxyl-containing polyethylene glycol and cyclic ester monomers.

3. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 2, characterized in that, In the premix, the mass fraction of stannous octoate is 0.01% to 5%.

4. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 1, characterized in that, The melt ring-opening polymerization reaction is carried out under vacuum or a protective gas atmosphere.

5. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 1, characterized in that, The hydroxyl-containing polyethylene glycol includes polyethylene glycol and monomethyl ether polyethylene glycol.

6. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 5, characterized in that, The number average molecular weight of the hydroxyl-containing polyethylene glycol is 200 to 180,000.

7. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 1, characterized in that, The cyclic ester monomers include at least one of lactide, glycolide, and caprolactone.

8. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 7, characterized in that, The lactide includes at least one of meso lactide, racemic lactide, dextrorotatory lactide, and levorotatory lactide.

9. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 1, characterized in that, The mass ratio of the cyclic ester monomer to the hydroxyl-containing polyethylene glycol is (0.4–9):

1.

10. A polyester-polyethylene glycol block copolymer, characterized in that, It is prepared by the preparation method according to any one of claims 1 to 8.

11. The polyester-polyethylene glycol block copolymer according to claim 10, characterized in that, The polydispersity of the polyester-polyethylene glycol block copolymer is Mw / Mn ≤ 2.

0.

12. The polyester-polyethylene glycol block copolymer according to claim 10, characterized in that, The weight-average molecular weight of the polyester-polyethylene glycol block copolymer is 2,000 to 200,000.

13. The polyester-polyethylene glycol block copolymer according to claim 10, characterized in that, The tin content in the polyester-polyethylene glycol block copolymer is ≤150ppm.

14. The polyester-polyethylene glycol block copolymer according to claim 13, characterized in that, The tin content in the polyester-polyethylene glycol block copolymer is ≤60ppm.

15. The polyester-polyethylene glycol block copolymer according to claim 10, characterized in that, The residual monomer content in the polyester-polyethylene glycol block copolymer is ≤3.0wt%.

16. The polyester-polyethylene glycol block copolymer according to claim 15, characterized in that, The residual monomer content in the polyester-polyethylene glycol block copolymer is ≤2.0wt%.

17. The polyester-polyethylene glycol block copolymer according to claim 15, characterized in that, The oligomer content in the polyester-polyethylene glycol block copolymer is ≤3.0wt%.

18. The polyester-polyethylene glycol block copolymer according to claim 15, characterized in that, The oligomer content in the polyester-polyethylene glycol block copolymer is ≤2.0wt%.

19. The use of the polyester-polyethylene glycol block copolymer according to any one of claims 10 to 18 in the preparation of a drug carrier.

20. The application according to claim 19, characterized in that, The drug includes at least one of nimodipine, paclitaxel, docetaxel, indomethacin, and cinacalcet hydrochloride.

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