Polyester-polyethylene glycol block copolymer as well as preparation method and application thereof

Abstract

The invention relates to the technical field of high polymer materials, in particular to a polyester-polyethylene glycol block copolymer as well as a preparation method and application thereof. The preparation method of the polyester-polyethylene glycol block copolymer comprises the following steps: by taking stannous octoate as a catalyst, carrying out melt ring-opening polymerization reaction on hydroxyl-containing polyethylene glycol and cyclic ester monomers; in the melt ring-opening polymerization, the use amount of the stannous octoate is 0.01 wt%-0.047 wt% of the total amount of the hydroxyl-containing polyethylene glycol and the cyclic ester monomer raw materials; the temperature of the melting ring-opening polymerization reaction is 100-140 DEG C, and the reaction time is 48-150 hours. The polyester-polyethylene glycol block copolymer with the content of residual metal, monomers and oligomers meeting the requirements of a drug carrier is synthesized through a one-step method, the purification step is not needed, the technological process is shortened, the production efficiency and the product yield are improved, and wider commercial application can be achieved easily.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer materials, and particularly to a polyester-polyethylene glycol block copolymer, a preparation method thereof, and an application thereof. Background Art

[0002] Block copolymers of biodegradable polyesters and polyethylene glycol (including its monomethyl ether) (hereinafter referred to as polyester-polyethylene glycol block copolymers) have been widely studied and applied in drug delivery carriers, etc. due to their good biocompatibility. Polyesters are usually selected from homopolymers and / or copolymers of ester monomers such as lactide (LA), glycolide (GA), and caprolactone (CL). For example, diblock poly (D,L-lactide)-monomethyl ether polyethylene glycol (PDLLA-MePEG) is used to dissolve paclitaxel and docetaxel, and the prepared polymeric micelle formulation has been successfully commercialized, significantly reducing the side effects brought by traditional surfactant formulations.

[0003] The synthesis of polyester-polyethylene glycol block copolymers is usually carried out by ring-opening polymerization of the above-mentioned ester monomers using the hydroxyl group at the end of the polyethylene glycol chain as an initiator and an organometallic compound as a catalyst. The specific polymerization method can adopt melt polymerization or solution polymerization. Since organotin is an effective catalyst for catalytic ring-opening polymerization, it is often used as a catalyst in the synthesis of polyester-polyethylene glycol block copolymers. To meet the requirements of the polymerization reaction and the product performance, a relatively high content of organotin catalyst is usually required. Since metallic tin has certain toxicity, its content is required to be lower than a certain limit in medical drugs. To meet the drug safety requirements, the polymer obtained by ring-opening polymerization needs to be further purified to reduce the contents of residual metal, monomer, and oligomer. This has resulted in a reduction in the production process efficiency and the product yield, limiting the process of its wide commercial application.

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

[0005] The object of the present invention is to provide a polyester-polyethylene glycol block copolymer, a preparation method thereof, and an application thereof. By adopting appropriate polymerization reaction conditions, a polyester-polyethylene glycol block copolymer with the contents of residual metal, monomer, and oligomer meeting the requirements of drug carriers can be synthesized at one time without further purification steps.

[0006] To achieve the above object of the present invention, the first aspect of the present invention provides a preparation method of a polyester-polyethylene glycol block copolymer, comprising the following steps: carrying out a melt ring-opening polymerization reaction of a hydroxyl group-containing polyethylene glycol and a cyclic ester monomer using stannous octoate as a catalyst;

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

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

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

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

[0011] (a) stannous octoate; and,

[0012] (b) any one of the hydroxyl group-containing polyethylene glycol and the cyclic ester monomer.

[0013] In a specific embodiment of the present invention, in the premix, the mass fraction of the stannous octoate 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 in an inert gas atmosphere.

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

[0016] In a specific embodiment of the present invention, the cyclic ester monomer includes at least one of lactide, glycolide, and caprolactone. Further, the lactide includes at least one of meso-lactide, racemic lactide, D-lactide, and L-lactide.

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

[0018] The second aspect of the present invention provides a polyester-polyethylene glycol block copolymer, which is prepared by using the preparation method of the 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 2,000 to 200,000.

[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 tin metal content is ≤ 150 ppm, preferably ≤ 60 ppm;

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

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

[0024] The third aspect of the present invention provides an 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 adopts appropriate polymerization reaction conditions, and synthesizes a polyester-polyethylene glycol block copolymer with residual metal, monomer, and oligomer contents meeting the requirements of a drug carrier through a one-step method. Without a purification step, the process flow is shortened, the production efficiency and product yield are improved, which is conducive to achieving a wider range of commercial applications;

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

[0029] (3) The polyester-polyethylene glycol block copolymer of the present invention can meet the requirements of a drug carrier and can be directly used for the preparation of preparations such as drug-loaded polymer micelles. Description of the Drawings

[0030] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0031] Figure 1 It is the HPLC detection spectrum of the polyester-polyethylene glycol block copolymer prepared in Example 13 of the present invention;

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

[0033] Figure 3 GPC spectrogram of the polyester-polyethylene glycol block copolymer prepared in Example 13 of the present invention;

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

[0035] Figure 5 Effect of catalyst dosage and reaction time on the lactide residue content in the polyester-polyethylene glycol block copolymer provided by the present invention at 140 °C;

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

[0037] Figure 7 Effect of catalyst dosage and reaction time on the oligomer content in the polyester-polyethylene glycol block copolymer provided by the present invention at 140 °C. Detailed implementation mode

[0038] The technical solutions of the present invention will be clearly and completely described below in conjunction with the accompanying drawings and specific implementation modes. However, those skilled in the art will understand that the following described embodiments are part of the embodiments of the present invention, rather than 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 of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. For those conditions not specified in the embodiments, they shall be carried out according to the conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0039] The synthesis of existing polyester-polyethylene glycol block copolymers is usually prepared by melt polymerization or solution polymerization. Among them, the process of solution polymerization is relatively simple, but solvents need to be used. On the one hand, the environmental friendliness deteriorates. On the other hand, the use of a large amount of solvents increases the production cost, and the process of removing solvents after polymerization not only reduces the production efficiency but also increases the process cost. In the process of melt polymerization, organotin such as stannous octoate is often used as a catalyst. In order to ensure the progress of the polymerization reaction and the performance of the product, usually 0.3 wt% (equivalent to a tin content of 879 ppm) or more of stannous octoate based on the total amount of reactants is added. According to the ICH Q3D guideline, the national standards YY / T 0510-2009 and YY / T 0661-2017 for PLA and PLGA implant materials, in order to meet the requirements of drug safety, the prepared polymer needs to be purified by steps not limited to dissolution, adsorption, precipitation, drying, etc. to reduce the content of residual metals and monomers, which results in a reduction in the production process efficiency and product yield, and the materials used in ring-opening polymerization are expensive. Multiple factors limit the wider commercial application of such polymer products.

[0040] Based on this, in the first aspect of the present invention, a method for preparing a polyester-polyethylene glycol block copolymer is provided, including the following steps: using stannous octoate as a catalyst, and carrying out a melt ring-opening polymerization reaction between a hydroxyl group-containing polyethylene glycol and a cyclic ester monomer;

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

[0042] The temperature of the melt ring-opening polymerization reaction is 100 - 140 °C, 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 addition amount of stannous octoate is reduced. With a certain polymerization reaction temperature and reaction time, the prepared block copolymer, without purification, has a monomer residue ≤ 3.0 wt%, an oligomer content ≤ 3.0 wt%, and a metal tin residue ≤ 150 ppm, meeting 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).

[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 the range composed of any two of them in the total amount of hydroxyl-containing polyethylene glycol and cyclic ester monomer raw materials. Thus, while ensuring the smooth progress of ring-opening polymerization, the molecular weight of the block copolymer, and the content of residual monomers and oligomers meet the formulation requirements, the addition amount of stannous octoate can be significantly reduced, and the requirements for the content of metallic tin in oral preparations and even injection preparations can be met without purification treatment. When the amount of stannous octoate is lower than the above range, it is difficult to balance the requirements such as conversion rate, monomer residue, and copolymer molecular weight.

[0045] In different embodiments, the temperature of the melt ring-opening polymerization reaction can be 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C or the range composed of any two of them; the reaction time can be 48 h, 60 h, 72 h, 96 h, 120 h, 140 h, 150 h or the range composed of any two of them. When the above temperature is lower than the melting point of the cyclic ester monomer, in actual operation, the preparation method includes: first heating the hydroxyl-containing polyethylene glycol to above the melting point of the cyclic ester monomer (such as 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 for the melt ring-opening polymerization reaction. This is more helpful for reducing the chromaticity of the block copolymer.

[0046] In the specific embodiments of the present invention, the preparation method of the polyester-polyethylene glycol block copolymer does not include a purification step. Herein, the purification step includes but is not limited to dissolution, adsorption, precipitation, drying, etc.

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

[0048] The inventors of the present invention creatively discovered that in the melt ring-opening polymerization reaction, by using a low stannous octoate addition amount and further coordinating the regulation of the reaction temperature, first reacting at a relatively high temperature for a period of time and then appropriately reducing the temperature for a period of time, it is possible to reduce the content of residual monomers and oligomers and the chromaticity of the block copolymer while obtaining a block copolymer with the expected molecular weight. For example, the mixed material can first react at 125°C, 128°C, 130°C, 132°C, 135°C or any range composed of any two of them for 10h, 12h, 15h, 18h, 20h, 24h or any range composed of any two of them, and then cool down to 105°C, 108°C, 110°C, 111°C, 112°C, 113°C, 114°C, 115°C or any range composed of any two of them and continue to react for 24h, 30h, 36h, 40h, 48h, 60h, 72h or any range composed of any two of them. Among them, the mixed material refers to a mixture of poly(ethylene glycol) with hydroxyl groups, cyclic ester monomers and stannous octoate.

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

[0050] (a) stannous octoate; and,

[0051] (b) any one of poly(ethylene glycol) with hydroxyl groups and cyclic ester monomers.

[0052] The present invention introduces stannous octoate into the polymerization reaction system in the form of a premix, making the feeding of stannous octoate more accurate, more conducive to improving the mixing uniformity of stannous octoate in the mixed reaction system, enhancing the reaction uniformity, and reducing the risk of too wide molecular weight distribution caused by uneven reaction.

[0053] In one embodiment of the present invention, the premix may include stannous octoate and poly(ethylene glycol) with hydroxyl groups. The preparation of the premix includes but is not limited to: proportioning and mixing, heating to melt the poly(ethylene glycol) with hydroxyl groups, and mixing evenly to obtain the premix; the heating temperature can 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 the cyclohexane solution of stannous octoate and cyclic ester monomers evenly according to a ratio, and then evacuating to remove cyclohexane to obtain the premix; among them, in the cyclohexane solution of stannous octoate, the concentration of stannous octoate can 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, in the premix, the mass fraction of stannous octoate is 0.01% to 5%, for example, it can be 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5% or the range composed of any two of them. Thus, it is more helpful 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 vacuum or in an inert gas atmosphere. Among them, the inert gas atmosphere includes at least one of nitrogen and argon.

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

[0058] In a specific embodiment of the present invention, it further includes: pretreating the hydroxyl-containing polyethylene glycol; the pretreatment includes: subjecting the hydroxyl-containing polyethylene glycol to vacuum treatment in a molten state to remove moisture. Among them, in the pretreatment, the hydroxyl-containing polyethylene glycol can be heated to 110 - 130 °C to make it melt and keep it in this state for vacuum treatment.

[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 - 180000, preferably 2000 - 8000.

[0060] The raw material of the hydroxyl-containing polyethylene glycol of the present invention can adopt raw materials meeting the pharmacopoeia standards or equivalent ones. 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 a specific embodiment of the present invention, the cyclic ester monomers include at least one of lactide, glycolide (GA), and ε-caprolactone (ε-CL). Further, the lactide includes at least one of meso-lactide (meso-LA), racemic lactide (DLLA), D-lactide (DLA), and L-lactide (LLA). The purity of the raw material of the cyclic ester monomers of the present invention is ≥99 wt%.

[0062] In a specific embodiment of the present invention, the mass ratio of the cyclic ester monomers to the hydroxyl-containing polyethylene glycol is (0.4 - 9):1, for example, it can be 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 the range composed of any two of them. Thus, it is more beneficial to meet the use requirements of the polymer micelle preparation.

[0063] The second aspect of the present invention provides a polyester-polyethylene glycol block copolymer, which is prepared by using the preparation method of the 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 2,000 to 200,000.

[0065] The polydispersity of the polyester-polyethylene glycol block copolymer of the present invention is the ratio of the weight-average molecular weight Mw to the number-average molecular weight Mn of the polyester-polyethylene glycol block copolymer measured by GPC. The polyester-polyethylene glycol block copolymer prepared by using the preparation method of the present invention not only has an 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. For example, in different embodiments, the polydispersity Mw / Mn of the polyester-polyethylene glycol block copolymer can be 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 the range composed of any two of them; the weight-average molecular weight of the polyester-polyethylene glycol block copolymer can be 2,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 50,000, 100,000, 150,000, 200,000 or the range composed of any two of them, meeting the formulation requirements.

[0066] When the polyester-polyethylene glycol block copolymer of the present invention is measured by GPC, in the specific GPC method, the chromatographic column is GPC KF-803L (8.0 mm×300 mm, 6 μm), purchased from Showa Denko K.K. of Japan; tetrahydrofuran is used as the mobile phase, and isocratic elution is carried out 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. The standard product in the GPC measurement is polyethylene glycol.

[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 ≤150 ppm, preferably ≤60 ppm; for example, it can be 150 ppm, 120 ppm, 100 ppm, 90 ppm, 80 ppm, 60 ppm, 50 ppm or the range composed of any two of them;

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

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

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

[0072] In the specific embodiments of the present invention, the drugs include but are 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 monomer and / or oligomer content in a polyester - polyethylene glycol block copolymer, including the following steps: performing high - performance liquid chromatography detection on the test solution;

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

[0075] The chromatographic column is a C18 chromatographic column; the column temperature is 40 °C; the detection wavelength is 210 nm;

[0076] Gradient elution is performed using mobile phase A and mobile phase B, with a flow rate of 1.0 mL / min; mobile phase A is an aqueous phosphoric acid solution with a mass fraction of 0.1%, and mobile phase B is acetonitrile;

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

[0078] Among them, the external standard method can be used to calculate the content of monomers in the test sample. Specifically, the calculation method of the monomer content includes: injecting the standard series working solutions of the monomers (such as lactide) into a high performance liquid chromatograph respectively, measuring the corresponding peak areas under the same chromatographic conditions as the test sample solution, using the monomer concentration of the standard series working solutions as the abscissa and the peak areas as the ordinate to draw a standard curve; obtaining the chromatographic peak area corresponding to the monomer in the test sample solution according to 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. Among them, the standard series working solutions can be acetonitrile solutions of monomers with a monomer concentration of 1-10 mg / mL.

[0079] In a specific embodiment of the present invention, the preparation of the test sample solution includes: dissolving the polyester-polyethylene glycol block copolymer to be tested in acetonitrile and filtering to obtain the filtrate. Further, in the test sample solution, the concentration of the polyester-polyethylene glycol block copolymer to be tested is 25-35 mg / mL, and can be, 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 Supersil AQ-C18, 5 μm, 4.6 mm×250 mm.

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

[0082] By using the detection method of the present invention, the monomer residues and oligomer content in the polymer can be determined quickly and accurately, which is beneficial to improving the synthesis efficiency and controlling the polymer quality. The monomer residue amount determined by the detection method of the present invention is highly consistent with the 1 1H-NMR measurement results.

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

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

[0085] mLA: meso-lactide, meso lactide;

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

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

[0088] CL: ε-caprolactone, epsilon-caprolactone;

[0089] GA: glycolide, glycolide;

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

[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 PDLLA / LLA-PEG-PDLLA / LLA W-X / Y / Z involved in the following text, W represents the molecular weight of PEG, and X, Y, and Z respectively represent the mass fractions (wt%) of D,L-lactide, L-lactide, and PEG in the polymer;

[0098] In PLLA-PEG-PLLA W-Y / Z involved in the following text, W represents the molecular weight of PEG, and Y and Z respectively represent the mass fractions (wt%) of L-lactide and PEG in the polymer.

[0099] Example 1

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

[0101] Add 30 g of PEG with a molecular weight of 3350 to a 100 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply vacuum for about 16 h with stirring to remove residual moisture and other volatile substances in the PEG. After heating to 130 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After melting, add 0.018 g of stannous octoate, and stir at 130 °C for 96 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0102] Example 2

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

[0104] Add 30 g of PEG with a molecular weight of 3350 to a 100 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply vacuum for about 16 h with stirring to remove residual moisture and other volatile substances in the PEG. After heating to 130 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After complete melting, cool down to 110 °C, add 0.0209 g of stannous octoate, and stir at 110 °C for 150 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0105] Example 3

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

[0107] Add 30 g of PEG with a molecular weight of 3350 to a 100 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply vacuum for about 16 h with stirring to remove residual moisture and other volatile substances in the PEG. After heating to 130 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After complete melting, cool down to 100 °C, add 0.0235 g of stannous octoate, and stir at 100 °C for 150 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0108] Example 4

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

[0110] Add 30 g of PEG with a molecular weight of 3350 to a 100 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply a vacuum for about 16 h under stirring to remove residual moisture and other volatiles in the PEG. After heating to 140 °C, add the stannous octoate / lactide mixture, and stir at 140 °C for 48 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0111] Among them, the preparation of the stannous octoate / lactide mixture includes: Take 0.16 mL of a cyclohexane solution of stannous octoate with a concentration of 50 mg / mL, add 10 g of D,L-lactide and 10 g of L-lactide, mix well and evacuate to remove cyclohexane to obtain it. Add all of it to the above reaction system.

[0112] Example 5

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

[0114] Add 30 g of PEG with a molecular weight of 3350 to a 100 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply a vacuum for about 16 h under stirring to remove residual moisture and other volatiles in the PEG. After heating to 140 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After melting, add 0.016 g of stannous octoate, and stir at 140 °C for 96 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0115] Example 6

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

[0117] Add 5 g of PEG with a molecular weight of 6,000 to a 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply vacuum for about 2 h with stirring to remove volatile substances such as residual moisture in the PEG. Add 5 g of L-lactide. After melting, add 0.0047 g of stannous octoate, and stir at 130 °C for 48 h to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0118] Example 7

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

[0120] Add 5 g of PEG with a molecular weight of 6,000 to a 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply vacuum for about 2 h with stirring to remove volatile substances such as residual moisture in the PEG. Add 5 g of L-lactide. After melting, add 0.0029 g of stannous octoate, and stir at 130 °C for 72 h to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0121] Example 8

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

[0123] Add 30 g of PEG with a molecular weight of 3,350 to a 100 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply vacuum for about 16 h with stirring to remove volatile substances such as residual moisture in the PEG. After heating to 130 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After melting, first add 0.11 g of a stannous octoate / PEG 3350 mixture. When stirring at 130 °C for 72 h, add an additional 0.056 g of the stannous octoate / PEG 3350 mixture, and continue stirring at 130 °C until the reaction reaches 150 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition above, perform a short evacuation such as for 30 min and then seal.

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

[0125] Example 9

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

[0127] Add 4.8 g of PEG with a molecular weight of 6000 to a 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply a vacuum for about 2 h under stirring to remove volatile substances such as residual moisture in the PEG. Add 5 g of L-lactide. After melting, add 0.16 g of stannous octoate / PEG 6000 mixture, and stir at 130°C for 48 h to complete the polymerization reaction to obtain the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each feeding above, a short-term evacuation is performed, such as for 30 min and then sealed.

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

[0129] Example 10

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

[0131] Add 4.95 g of PEG with a molecular weight of 6000 to a 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130°C. After the PEG melts, apply a vacuum for about 2 h under stirring to remove volatile substances such as residual moisture in the PEG. Add 5 g of L-lactide. After melting, add 0.065 g of stannous octoate / PEG 6000 mixture, and stir at 130°C for 72 h to complete the polymerization reaction to obtain the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each feeding above, a short-term evacuation is performed, such as for 30 min and then sealed.

[0132] Among them, the preparation of stannous octoate / PEG 6000 mixture is the same as that in Example 9.

[0133] Example 11

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

[0135] Add 30 g of PEG with a molecular weight of 3350 to a 100 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply a vacuum of about 16 h with stirring to remove residual moisture and other volatile substances in the PEG. After raising the temperature to 130 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After melting, add 0.019 g of stannous octoate, 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 3350-20 / 20 / 60. After each addition of materials above, perform a short evacuation such as for 30 min and then seal.

[0136] Example 12

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

[0138] Add 30 g of PEG with a molecular weight of 3350 to a 250 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 110 °C. After the PEG melts, apply a vacuum of about 16 h with stirring to remove residual moisture and other volatile substances in the PEG. After raising the temperature to 130 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After melting, add 0.16 g of a stannous octoate / PEG 3350 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 3350-20 / 20 / 60. After each addition of materials above, perform a short evacuation such as for 30 min and then seal.

[0139] Among them, the preparation of the stannous octoate / PEG 3350 mixture is the same as that in Example 8.

[0140] Example 13

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

[0142] Add 570 g of PEG with a molecular weight of 6000 to a 1000 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply a vacuum for about 17 h with stirring to remove residual moisture and other volatile substances in the PEG. Add 400 g of L-lactide. After melting, add 30 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 PLLA-PEG-PLLA 6000-43 / 57. After each addition of materials above, perform a short evacuation such as for 60 min and then seal.

[0143] Among them, the preparation of the stannous octoate / L-lactide mixture includes: Take 3 mL of a cyclohexane solution of stannous octoate with a concentration of 100 mg / mL, add it to 30 g of L-lactide, mix well and evacuate to remove cyclohexane to obtain it.

[0144] Example 14

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

[0146] Add 570 g of PEG with a molecular weight of 6000 to a 1000 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply a vacuum for about 17 h with stirring to remove residual moisture and other volatile substances in the PEG. Add 430 g of D-lactide. After melting, add 0.32 g of stannous octoate. 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 6000-43 / 57. After each addition of materials above, perform a short evacuation such as for 60 min and then seal.

[0147] Example 15

[0148] This example 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 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply a vacuum for about 1.5 h with stirring to remove residual moisture and other volatile substances in 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 down 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 materials above, perform a short evacuation such as for 30 min and then seal.

[0150] Among them, the preparation method of the stannous octoate / L-lactide mixture can be seen in Example 13.

[0151] Example 16

[0152] This example provides a preparation method of 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 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply a vacuum for about 1.5 h with stirring to remove residual moisture and other volatile substances in 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 down 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 materials above, perform a short evacuation such as for 30 min and then seal.

[0154] Among them, the preparation method of the stannous octoate / L-lactide mixture can be seen in Example 13.

[0155] Example 17

[0156] This example provides a preparation method of 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 10 mL clean flask equipped with a magnetic stir bar. 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 volatile substances in 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 and stir at 130 °C for 24 h, then cool down 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 materials above, perform a short evacuation such as for 30 min and then seal.

[0158] Among them, the preparation method of the stannous octoate / L-lactide mixture is shown in Example 13.

[0159] Example 18

[0160] This example provides a preparation method of 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 10 mL clean flask equipped with a magnetic stir bar. 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 volatile substances in the PEG. Add 3.3 g of L-lactide. After melting, add 0.3 g of stannous octoate / L-lactide mixture and stir at 130 °C for 24 h, then cool down 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 materials above, perform a short evacuation such as for 30 min and then seal.

[0162] Among them, the preparation method of the stannous octoate / L-lactide mixture is shown in Example 13.

[0163] Example 19

[0164] This example provides a preparation method of a polyester-polyethylene glycol block copolymer, including the following steps:

[0165] Add 320 g of PEG with a molecular weight of 6,000 to a 500 mL clean flask equipped with a magnetic stir bar. 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 volatile substances in the PEG. Add 90 g of D,L-lactide and 80 g of L-lactide respectively. After melting, add 10 g of stannous octoate / L-lactide mixture, stir at 130 °C for 24 h, then cool down to 110 °C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 6000-18 / 18 / 64. After each addition above, perform a short evacuation such as for 30 min and then seal.

[0166] Among them, the preparation method of the stannous octoate / L-lactide mixture can be seen in Example 13.

[0167] Example 20

[0168] This example provides a preparation method of a polyester-polyethylene glycol block copolymer, including the following steps:

[0169] Add 350 g of PEG with a molecular weight of 6,000 to a 500 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply vacuum for about 17 h with stirring to remove residual moisture and other volatile substances in the PEG. Add 150 g of L-lactide. After melting, add 0.14 g of stannous octoate, stir at 130 °C for 24 h, then cool down to 110 °C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-30 / 70. After each addition above, perform a short evacuation such as for 120 min and then seal.

[0170] Example 21

[0171] This example provides a preparation method of a polyester-polyethylene glycol block copolymer, including the following steps:

[0172] Add 350 g of PEG with a molecular weight of 6,000 to a 500 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply vacuum for about 17 h with stirring to remove residual moisture and other volatile substances in the PEG. Add 150 g of D-lactide. After melting, add 0.103 g of stannous octoate, stir at 130 °C for 24 h, then cool down to 110 °C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PDLA-PEG-PDLA 6000-30 / 70. After each addition above, perform a short evacuation such as for 120 min and then seal.

[0173] Example 22

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

[0175] Add 5 g of PEG with a molecular weight of 6000 to a 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply a vacuum for about 1.5 h under stirring to remove volatile substances such as residual moisture in the PEG. Add 4.7 g of D-lactide. After melting, add 0.3 g of stannous octanoate / 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 6000-50 / 50. After each addition of materials above, perform a short evacuation such as for 30 min and then seal.

[0176] Among them, the preparation method of the stannous octanoate / D-lactide mixture refers to Example 13, with the only difference being that L-lactide is replaced with an equal amount of D-lactide.

[0177] Example 23

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

[0179] Add 6.4 g of PEG with a molecular weight of 6000 to a 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply a vacuum for about 1.5 h under stirring to remove volatile substances such as residual moisture in the PEG. Add 3.3 g of D-lactide. After melting, add 0.3 g of stannous octanoate / 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 materials above, perform a short evacuation such as for 30 min and then seal.

[0180] Among them, the preparation method of the stannous octanoate / D-lactide mixture refers to Example 22.

[0181] Example 24

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

[0183] Add 7 g of PEG with a molecular weight of 6,000 to a 10 mL clean flask equipped with a magnetic stir bar. 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 volatile substances in the PEG. Add 2.7 g of D-lactide. After melting, add 0.3 g of 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 6000-30 / 70. After each addition of materials above, perform a short evacuation such as for 30 min and then seal.

[0184] Among them, the preparation method of the stannous octoate / D-lactide mixture can be seen in Example 22.

[0185] Example 25

[0186] This example provides a preparation method of a polyester-polyethylene glycol block copolymer, including the following steps:

[0187] Add 7 g of PEG with a molecular weight of 6,000 to a 10 mL clean flask equipped with a magnetic stir bar. 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 volatile substances in the PEG. Add 2.7 g of L-lactide. 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 PLLA-PEG-PLLA 6000-30 / 70. After each addition of materials above, perform a short evacuation such as for 30 min and then seal.

[0188] Among them, the preparation method of the stannous octoate / L-lactide mixture can be seen in Example 13.

[0189] Example 26

[0190] This example provides a preparation method of a polyester-polyethylene glycol block copolymer, including the following steps:

[0191] Add 10 g of PEG with a molecular weight of 300 to a 250 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. Apply vacuum for about 1.5 h with stirring to remove residual moisture and other volatile substances in the PEG. Add stannous octoate / lactide mixture. Stir at 130 °C for 48 h, then cool to 110 °C and continue stirring for 24 h to complete the polymerization reaction, obtaining the block copolymer PLGA-PEG-PLGA 300-71 / 19 / 10. After each addition of materials above, perform a short evacuation such as for 30 min and then seal.

[0192] Among them, the preparation of stannous octoate / lactide mixture includes: taking 0.15 mL of 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 evenly and then evacuating to remove cyclohexane to obtain it. All are added to the above reaction system.

[0193] Example 27

[0194] This example provides a preparation method of polyester-polyethylene glycol block copolymer, which includes the following steps:

[0195] Add 5 g of PEG with a molecular weight of 6000 to a 10 mL clean flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 130 °C. After the PEG melts, under stirring, apply vacuum for about 2 h to remove residual moisture and other volatile substances in the PEG. Add the stannous octoate / L-lactide mixture, stir at 130 °C for 24 h, then cool down to 110 °C and continue stirring for 72 h to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition above, a short-term evacuation is performed, such as for 30 min and then sealed.

[0196] Among them, the preparation of stannous octoate / L-lactide mixture includes: taking 100 μL of cyclohexane solution of stannous octoate with a concentration of 10 mg / mL, adding it to 5 g of L-lactide, mixing evenly and then evacuating to remove cyclohexane to obtain it.

[0197] Example 28

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

[0199] In this example, after adding the stannous octoate / L-lactide mixture, stir at 130 °C for 48 h, then cool down to 110 °C and continue stirring for 72 h to complete the polymerization reaction.

[0200] Example 29

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

[0202] In this example, after adding the stannous octoate / L-lactide mixture, raise the temperature to 140 °C and stir for 24 h, then cool down to 110 °C and continue stirring for 72 h to complete the polymerization reaction.

[0203] Example 30

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

[0205] Add 5 g of PEG with a molecular weight of 6000 to a 10 mL clean flask equipped with a magnetic stir bar. Immerse the flask in an oil bath at 130 °C. After the PEG melts, apply vacuum for about 2 h with stirring to remove volatile substances such as residual moisture in the PEG. Add the stannous octoate / L-lactide mixture, stir at 130 °C for 24 h, and then cool to 120 °C and continue stirring for 48 h to complete the polymerization reaction, obtaining the block copolymer PLLA-PEG-PLLA 6000-50 / 50. After each addition of materials above, perform a short evacuation such as for 30 min and then seal.

[0206] Among them, the preparation of the stannous octoate / L-lactide mixture includes: Take 300 μL of a cyclohexane solution of stannous octoate with a concentration of 10 mg / mL, add it to 5 g of L-lactide, mix well and then evacuate to remove cyclohexane to obtain it.

[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 are different.

[0209] In this embodiment, after adding the stannous octoate / L-lactide mixture, stir at 130 °C for 48 h, and then cool to 110 °C and continue stirring for 48 h 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 are different.

[0212] In this embodiment, after adding the stannous octoate / L-lactide mixture, heat up to 140 °C and stir for 24 h, and then cool to 110 °C and continue stirring for 48 h to complete the polymerization reaction.

[0213] Example 33

[0214] This embodiment provides a method for preparing a micelle preparation, which comprises the following steps:

[0215] Take 0.25 g of nimodipine, 12.25 g of the copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60 prepared in Example 5, and mix them with 10 mL of ethanol to obtain a mixed solution. Then, make up the volume to 25 mL with ethanol, dispense it into glass bottles, and it can be stored for a long time after capping. The nimodipine polymeric micelle preparation can be obtained by diluting with D5W.

[0216] Example 34

[0217] This example refers to the preparation method of the micelle preparation in Example 33, with the only difference being that the copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60 prepared in Example 12 with the same mass is used to replace the copolymer in Example 5.

[0218] Comparative Example 1

[0219] Comparative Example 1 provides a preparation method of a polyester-polyethylene glycol block copolymer. Referring to Example 1, the difference lies in the different dosages of stannous octoate.

[0220] In Comparative Example 1, the dosage of stannous octoate is 0.048 g.

[0221] Comparative Example 2

[0222] Comparative Example 2 provides a preparation method of a polyester-polyethylene glycol block copolymer. Referring to Example 1, the difference lies in the different dosages of stannous octoate and the shortened reaction time.

[0223] Comparative Example 2 includes: adding 30 g of PEG with a molecular weight of 3350 to a 100 mL clean flask equipped with a magnetic stirrer. Immerse the flask in an oil bath at 110 °C. After the PEG melts, under stirring, apply a vacuum for about 16 h to remove residual moisture and other volatile substances in the PEG. After heating to 130 °C, add 10 g of D,L-lactide and 10 g of L-lactide respectively. After melting, add 0.035 g of stannous octoate and stir at 130 °C for 48 h to complete the polymerization reaction to obtain the block copolymer PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60. After each addition of materials above, perform a short-term air extraction such as for 30 min and then seal.

[0224] Experimental Example 1

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

[0226] Table 1 Test Results of Different Copolymers

[0227]

[0228]

[0229]

[0230] Among them, the weight-average molecular weight Mw was determined by GPC; in the GPC test, the chromatographic column was GPC KF-803L (8.0 mm × 300 mm, 6 μm), the column temperature was 40 °C, 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, isocratic elution, the flow rate was 1 mL / min, and the standard was polyethylene glycol;

[0231] The polydispersity is the ratio of the weight-average molecular weight Mw to the number-average molecular weight Mn determined by GPC;

[0232] The calculation method of the tin metal addition amount is: Tin metal addition amount (ppm) = proportion of stannous octoate dosage × 118.71 / 405.12 × 10 6 ; Proportion of stannous octoate dosage = stannous octoate dosage / (amount of hydroxyl-containing polyethylene glycol + amount of cyclic ester monomer).

[0233] The monomer residue was determined and calculated by HPLC method. The specific test method is as follows:

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

[0235] (2) Inject the test 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 solution, and then calculate the content of the monomer in the copolymer sample; among them, the HPLC detection conditions are as follows:

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

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

[0238] Gradient elution was carried out according to Table 2;

[0239] Flow rate: 1.0 mL / min;

[0240] Detection wavelength: 210 nm;

[0241] Column temperature: 40 °C;

[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 the working solutions of the DLLA standard series (specifically, the solutions are acetonitrile solutions of DLLA, and the concentrations of DLLA are 1.001 mg / mL, 2.003 mg / mL, 3.004 mg / mL, 5.007 mg / mL, 6.008 mg / mL, 8.011 mg / mL, 10.014 mg / mL) into the high-performance liquid chromatograph respectively, and measuring the peak areas of the corresponding chromatograms according to the above detection conditions. Taking the monomer concentration in the working solutions of the standard series as the abscissa and the peak area as the ordinate, draw the standard curve.

[0246] The calculation of the oligomer content includes: obtaining the peak area value by subtracting the peak area around 13.5 min from the total peak area in the chromatogram measured by the corresponding HPLC method, and substituting it into the DLLA standard curve for calculation. 1 H-NMR: At 1 In the H-NMR spectrum, the signal peak of the lactide methylene is at δ = 5.02 - 5.08, and the signal peak of the methylene in the polylactic acid repeating unit is at δ = 5.11 - 5.28. Integrate the two regions to calculate the proportion of unreacted lactide, and then calculate the residual amount of lactide monomer through the dosage of lactide raw materials in the formula.

[0247] Figure 1 This is the HPLC detection spectrum of the polyester-polyethylene glycol block copolymer prepared in Example 13 of the present invention. It can be seen from the figure that the main peak with a retention time of about 13.5 min corresponds to lactide, and the remaining small peaks correspond to oligomers. In order to verify the accuracy of the HPLC method for detecting oligomers, we simultaneously used the HPLC detection method and 1 the H-NMR determination method to detect the residual results of lactide monomers in the polyester-polyethylene glycol block copolymer, and analyzed the correlation of the detection results of the two methods to mutually confirm the accuracy of the methods. The test results are as Figure 2 shown. It can be seen from the figure that the HPLC detection method of the present invention is 1 basically consistent with the results of the H-NMR determination method, and can quickly and accurately detect the monomer content of the copolymer.

[0248] From the test results in Table 1, it can be seen that the present invention adopts appropriate polymerization reaction conditions. Without the need for a purification step, a polyester-polyethylene glycol block copolymer with residual metal, monomer, and oligomer contents meeting the requirements of a drug carrier is synthesized by a one-step method, significantly improving the production efficiency and product yield (theoretical value 100%), and the obtained polymer has a good molecular weight distribution. Figure 3 It is the GPC spectrogram of the polyester-polyethylene glycol block copolymer prepared in Example 13. Further, by adopting a stepwise temperature reduction method, compared with constant temperature polymerization, not only the monomer residue is reduced, but also the content of oligomers is further reduced, and at the same time, the obtained polymer has a lighter color.

[0249] Figure 4 and Figure 5 respectively show the effects of the catalyst dosage and reaction time on the lactide residue in the polyester-polyethylene glycol block copolymer (PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60) obtained by constant temperature polymerization at 130°C and 140°C provided by the present invention; Figure 6 and Figure 7 respectively show the effects of the catalyst dosage and reaction time on the oligomer content in the polyester-polyethylene glycol block copolymer (PDLLA / LLA-PEG-PDLLA / LLA 3350-20 / 20 / 60) obtained by constant temperature polymerization at 130°C and 140°C provided by the present invention.

[0250] In order 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 Example 1, Example 5, Example 8, Example 11, Example 12, Example 13, Example 14, and Example 19 at different times were detected, and 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] From the above test results, it can be seen that by adopting the regulation method of the polymerization reaction temperature of the present invention, the monomer residue can be reduced, the content of oligomers can be reduced, and at the same time, the obtained polymer has a lighter color and ensures a higher production efficiency.

[0255] Experimental Example 2

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

[0257] Table 4 Preparation Test Results

[0258]

[0259] From the above test results, it can be seen that the polyester-polyethylene glycol block copolymer of the present invention can meet the requirements as a drug carrier and can be directly used for the preparation of preparations such as drug-loaded polymer micelles.

[0260] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements 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 method comprises the following steps: using stannous octoate as a catalyst, carrying out a melt ring-opening polymerization reaction of hydroxyl-containing polyethylene glycol and cyclic ester monomers; 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 temperature of the melt ring-opening polymerization reaction is 100-140° C., and the reaction time is 48-150 hours.

2. The method for preparing the polyester-polyethylene glycol block copolymer according to claim 1, characterized in that: The melt ring-opening polymerization reaction comprises: reacting the mixed material at 125-135° C. for 10-24 hours, cooling the temperature to 105-115° C. for 24-72 hours.

3. 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 comprises: (a) stannous octoate; and, (b) Any one of polyethylene glycol and cyclic ester monomers containing a hydroxyl group.

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

5. 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 protective gas atmosphere.

6. 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; Preferably, 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 monomer includes at least one of lactide, glycolide and caprolactone; Preferably, the lactide includes at least one of meso-lactide, racemic-lactide, dextro-lactide and levo-lactide.

8. 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.

9. A method for preparing a polyester-polyethylene glycol block copolymer, characterized in that: Prepared by the preparation method according to any one of claims 1 to 8; Preferably, the polydispersity Mw / Mn of the polyester-polyethylene glycol block copolymer is ≤2.0; Preferably, the weight average molecular weight of the polyester-polyethylene glycol block copolymer is 2000 to 200000; Preferably, the metal tin content in the polyester-polyethylene glycol block copolymer is ≤150ppm, preferably ≤60ppm; Preferably, the residual monomer content in the polyester-polyethylene glycol block copolymer is ≤3.0wt%, preferably ≤2.0wt%; Preferably, the oligomer content in the polyester-polyethylene glycol block copolymer is ≤3.0 wt %, preferably ≤2.0 wt %.

10. Use of the polyester-polyethylene glycol block copolymer according to claim 9 in the preparation of a drug carrier; Preferably, the drug includes at least one of nimodipine, paclitaxel, docetaxel, indomethacin and cinacalcet hydrochloride.

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