A high molecular weight biodegradable aliphatic polycyclic ester block copolymer and its preparation and application

Abstract

The present invention discloses a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer and its preparation and application, belonging to the field of polymer compound technology. The preparation method comprises: synthesizing a polycyclic ester copolymer diol; mixing a cyclic ester monomer A and a polycyclic ester copolymer diol under dry nitrogen conditions, adding a catalyst solution, heating and polymerizing, adjusting the temperature, adding a cyclic ester monomer B, continuing the reaction, stopping the nitrogen flow, and evacuating the mixture to obtain a white solid product, namely, a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer. The present invention uses a polycyclic ester copolymer diol that is highly compatible with the cyclic ester monomer as an initiator to avoid thermodynamic incompatibility with the matrix and kinetic hindrance, thereby obtaining a high-molecular-weight aliphatic polycyclic ester block copolymer. The present invention adopts a one-pot process to prepare the block copolymer, which has good mechanical properties, is non-toxic and harmless, and has good biocompatibility, meeting the requirements of biomedical materials.

Description

Technical Field

[0001] The present invention belongs to the technical field of polymer compounds and biomedical materials, and in particular relates to a high molecular weight biodegradable aliphatic polycyclic ester block copolymer and its preparation and application. Background Art

[0002] With the recent advancements in modern medicine and biomedical engineering, short-term implantable materials are increasingly needed for therapeutic applications in tissue engineering fields such as bone repair and cardiovascular repair. These short-term implantable materials require the following characteristics for wound healing and tissue repair: 1) controllable degradation, with complete or partial degradation during the wound recovery cycle; 2) good biocompatibility, minimizing inflammatory responses; 3) non-toxicity, facilitating tissue repair; and 4) excellent mechanical properties, enabling them to effectively support tissues and organs within a short period of time. Currently, commercially available biodegradable materials for tissue engineering scaffolds include polylactic acid (PLA), polyglycolide (PGA), polycaprolactone (PCL), and polydioxanone (PPDO). However, single biodegradable materials often suffer from issues such as difficult-to-control degradation rates, poor mechanical properties, and the potential for inflammatory responses. Therefore, modifications of single polymers are necessary to improve their practicality.

[0003] Block copolymers are formed by covalently linking two or more polymer segments with different properties. This type of copolymerization often combines the superior properties of the individual copolymer components, enabling improved and regulated mechanical and degradation properties. To date, ABA-type block copolymers of polyethers or polyesters have primarily been produced through the use of isocyanate chain extension: First, prepolymers A and B, each with a hydroxyl end group, are obtained through ring-opening polymerization of different cyclic ester monomers. Prepolymers A and B are then reacted with an isocyanate chain extender and a catalyst under specific conditions to produce an ABA-type triblock copolymer. This method has the following disadvantages: the reaction process is complex and requires extremely strict control of temperature, humidity, and system moisture. Furthermore, the poor cytocompatibility and toxicity of most isocyanates hinder their application in biomedical applications. Consequently, block copolymers prepared using these methods have limited biomedical applications. In recent years, although there have been reports on the preparation of block copolymers by ring-opening polymerization initiated by macromolecular initiators, most of the current macromolecular initiators are homopolymers, which have limitations such as thermodynamic incompatibility with monomers / growing chains and kinetic hindrance. That is, during the polymerization process, the initiator chain segments and monomers / growing chains undergo phase separation and form microphase regions. After phase separation, the monomers need to diffuse across the phase interface to contact the initiator active sites, which significantly reduces the chain growth rate. Therefore, the molecular weight of the prepared block copolymers is usually not high, and the mechanical properties are difficult to meet the requirements of medical materials. Summary of the Invention

[0004] An object of the present invention is to solve at least the above problems and / or disadvantages and to provide at least the advantages which will be described hereinafter.

[0005] To achieve these objectives and other advantages of the present invention, the present invention provides a method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer. The preparation method of the present invention is a bulk copolymerization method between cyclic lactones. A cyclic ester monomer, a catalyst, and a polycyclic ester copolymer diol initiator are added together into a fully dried polymerization bottle. Then, another cyclic ester monomer is added under controlled temperature gradient change, thereby achieving the purpose of synthesizing the block copolymer in one pot. The method comprises the following steps:

[0006] Step 1: Synthesizing polycyclic ester copolymer diol: mixing two cyclic ester monomers and 1,4-butanediol, heating and reacting to obtain polycyclic ester copolymer diol;

[0007] Step 2: Under dry nitrogen conditions, cyclic ester monomer A and polycyclic ester copolymer diol are mixed, and then a catalyst solution is added. The mixture is heated for polymerization, and then the temperature is adjusted, and cyclic ester monomer B is added. The reaction is continued, and the nitrogen flow is stopped and vacuum is applied to obtain a white solid product, which is a high molecular weight biodegradable aliphatic polycyclic ester block copolymer.

[0008] Preferably, in the step 1, the synthesis method of the polycyclic ester copolymer diol is: under dry nitrogen conditions, dry p-dioxanone monomer and ε-caprolactone monomer are mixed in a molar ratio of 1:1, and then 1,4-butanediol is added in an amount of one twentieth of the total molar number of ε-caprolactone monomer and p-dioxanone monomer, and the mixture is reacted at 100° C. for 24 hours to prepare a polycyclic ester copolymer diol, i.e., PPDO-PCL copolymer diol.

[0009] Preferably, in the step 1, the synthesis method of the polycyclic ester copolymer diol is: under dry nitrogen conditions, dry p-dioxanone monomer and L-lactide monomer are mixed in a molar ratio of 1:1, and then 1,4-butanediol is added in an amount of one twentieth of the total molar number of the p-dioxanone monomer and the L-lactide monomer, and the mixture is reacted at 120° C. for 24 hours to prepare the polycyclic ester copolymer diol, i.e., PPDO-PLA copolymer diol.

[0010] Preferably, in step 2, the cyclic ester monomer A is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

[0011] Preferably, in step 2, the cyclic ester monomer B is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

[0012] Preferably, in step 2, the catalyst is one or more of stannous octoate, dibutyltin dilaurate and zinc isooctanoate.

[0013] Preferably, in step 2, the catalyst is a composite catalyst; wherein the preparation method of the composite catalyst comprises the following steps:

[0014] S1. Under dry nitrogen conditions, stannous octoate and maleic anhydride are added to toluene, stirred at 60-90°C for 2-4 hours, and the excess solvent is removed by vacuum distillation to obtain modified stannous octoate;

[0015] S2. Add dibutyltin dilaurate to toluene and stir evenly to obtain a dibutyltin dilaurate / toluene solution with a concentration of 0.5~2 mol / L; add modified stannous octoate to toluene and stir evenly to obtain a modified stannous octoate / toluene solution with a concentration of 0.5~2 mol / L;

[0016] S3. Under dry nitrogen conditions, mix the dibutyltin dilaurate / toluene solution and the modified stannous octoate / toluene solution, heat to 60-80°C and stir for 1-3 hours, then add zinc isooctanoate and continue stirring for 1-2 hours. Remove excess solvent by vacuum distillation, and then treat the obtained product with low-temperature corona irradiation to obtain a composite catalyst.

[0017] Preferably, in S1, the molar ratio of stannous octoate to maleic anhydride is 2-4:1; and the molar volume ratio of stannous octoate to toluene is 1 mol:0.8-2 L.

[0018] Preferably, in S3, the mass ratio of dibutyltin dilaurate, modified stannous octoate and zinc isooctanoate is 1:1~3:0.2~1; the specific parameters of the low-temperature corona irradiation treatment are: treatment atmosphere is nitrogen, temperature is 20~30°C, voltage is 6~15kV, distance is 2~5cm, and treatment time is 3~10min.

[0019] Preferably, in step 2, the solvent of the catalyst solution is an anhydrous organic solvent, the anhydrous organic solvent is toluene, and the concentration of the catalyst solution is 0.5-2 mol / L.

[0020] Preferably, in step 2, the molar ratio of the cyclic ester monomer A to the polycyclic ester copolymer diol is 400-600:1; and the molar ratio of the cyclic ester monomer A to the cyclic ester monomer B is 1:0.5-2.

[0021] Preferably, in step 2, the amount of the catalyst used is 0.01-0.05% of the total mass of the cyclic ester monomer A and the polycyclic ester copolymer diol.

[0022] Preferably, in step 2, the mixture is heated to 60-200°C and polymerized for 3-12 hours, and then the temperature is adjusted to another temperature within the range of 60-200°C, for example, the mixture is heated to 160°C and polymerized for a certain time, and then the temperature is adjusted to 60°C or 80°C, or the mixture is heated to 60°C or 80°C and polymerized for a certain time, and then the temperature is adjusted to 160°C.

[0023] Preferably, in step 2, the reaction is continued for 30 to 33 hours, the nitrogen introduction is stopped, and the mixture is evacuated to a vacuum degree of <10 mmHg.

[0024] A high molecular weight biodegradable aliphatic polycyclic ester block copolymer prepared by the preparation method described above.

[0025] A use of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer prepared by the preparation method described above in the preparation of medical devices.

[0026] The present invention has at least the following beneficial effects:

[0027] (1) Using polycyclic ester copolymer diols that are highly compatible with cyclic ester monomers as initiators to avoid thermodynamic incompatibility with the matrix and kinetic hindrance, thereby obtaining high molecular weight aliphatic polycyclic ester block copolymers;

[0028] (2) Different cyclic lactone monomers are added to the polymerization bottle at different temperatures to prepare block copolymers in one pot;

[0029] (3) The operation is simple and easy. By controlling the ratio of different cyclic lactone monomers and regulating the temperature, the composition and ratio of different segments of the block copolymer can be controlled.

[0030] (4) This polymerization method can ultimately produce a series of block copolymers with good mechanical properties and adjustable degradation rates;

[0031] (5) The cyclic lactones used are non-toxic and harmless, and the copolymers themselves have good biocompatibility and can be safely degraded in the body, which can meet the requirements of biomedical materials.

[0032] Existing macromolecular initiators are mostly homopolymers, which have limitations such as thermodynamic incompatibility with monomers / growing chains and kinetic hindrance. Specifically, during the polymerization process, the initiator chain segments and monomers / growing chains undergo phase separation and form microphase regions. After phase separation, the monomers must diffuse across the phase interface to access the initiator active sites, significantly reducing the chain growth rate. As a result, the molecular weight of the resulting block copolymers is usually low, and the mechanical properties are difficult to meet the requirements of medical materials. However, the present invention uses polycyclic ester copolymer diols as initiators. By regulating the microphase separation with the monomers / growing chains, the exposure of active sites, the chain growth kinetics, and the shift of thermodynamic equilibrium through the molecular structure of the copolymer diols, it breaks through the high molecular weight bottleneck of traditional homopolymer initiators. Its core advantage lies in the dynamic compatibility matching between the copolymer diol initiator and the monomers / growing chains achieved through molecular design, providing theoretical feasibility for the synthesis of number-average high molecular weight polycyclic ester block copolymers. This method is not only applicable to cyclic ester ring-opening polymerization but can also be extended to other block copolymer systems, with important universal significance.

[0033] Other advantages, objectives and features of the present invention will be reflected in part from the following description and will be understood by those skilled in the art through study and practice of the present invention. DETAILED DESCRIPTION

[0034] The present invention is described in further detail below so that those skilled in the art can implement the invention with reference to the description.

[0035] It should be understood that terms such as “having”, “including” and “comprising” used herein do not preclude the existence or addition of one or more other elements or combinations thereof.

[0036] This invention develops a method for preparing high-molecular-weight, biodegradable aliphatic polycyclic ester block copolymers. Based on the type of cyclic ester monomer to be ring-opened, a polycyclic ester copolymer polyol with good compatibility with the cyclic ester monomer / chain extension is designed and synthesized as an initiator. By controlling the temperature, the high-molecular-weight block copolymer is prepared by leveraging the differences in equilibrium conversion and rate constants of different cyclic monomers at different temperatures. Literature review reveals that the optimal reaction temperatures for ε-caprolactone, p-dioxanone, and L-lactide are 130°C, 80°C, and 130°C, respectively (Macromolecules 2002, 35, 1504-1512; Macromolecules 2000, 33, 6982-6986). Based on these temperature parameters, a polycyclic ester copolymer diol is designed and synthesized as a macroinitiator. By controlling the temperature ramp, the high-molecular-weight block copolymer is prepared under specific conditions using different catalysts. This allows for biomedical polymer materials with varying degradation rates and mechanical properties. The reaction is mainly completed by the following steps:

[0037] 1) Repeatedly replace nitrogen gas in the polymerization bottle three times, and use a spray gun to bake out trace moisture in the bottle;

[0038] 2) Add a cyclic lactone monomer into a polymerization bottle under high-purity dry nitrogen conditions;

[0039] 3) Add the synthesized aliphatic polycyclic ester copolymer diol initiator into the above polymerization bottle;

[0040] 4) Dissolve the catalyst in an anhydrous organic solvent to prepare a solution and add it to the above polymerization bottle;

[0041] 5) Place the polymerization bottle at a certain temperature for a period of time;

[0042] 6) Performing programmed temperature control, after adjusting the temperature to a specified temperature, adding another cyclic lactone monomer and polymerizing for a period of time;

[0043] 7) After the polymerization is completed, continue vacuuming at 60°C for a period of time to purify the product.

[0044] Example 1

[0045] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0046] Step 1: Synthesis of PPDO-PCL copolymer diol: Under the continuous protection of high-purity dry nitrogen, add dry p-dioxanone monomer and ε-caprolactone monomer (molar ratio of 1:1) to a fully dried polymerization bottle. Then, add 1,4-butanediol initiator at a ratio of one twentieth of the total molar number of ε-caprolactone monomer and p-dioxanone monomer. Bulk polymerization is carried out at 100°C for 24 hours to prepare PPDO-PCL copolymer diol (PPDO-PCL-diol) with a molecular weight of 2000 Da.

[0047] Step 2. Under the continuous protection of high-purity dry nitrogen, add ε-caprolactone monomer and PPDO-PCL copolymer diol with a molecular weight of 2000 Da (molar ratio of 500:1) to a fully dried polymerization bottle, add 60 μL of 1 mol / L stannous octoate / toluene solution, and the amount of stannous octoate is 0.01% of the total mass of ε-caprolactone monomer and PPDO-PCL copolymer diol; heat the polymerization bottle to 160°C in an oil bath and polymerize for 6 h, then adjust the oil bath temperature to 60°C through the temperature control program, and then add dioxanone monomer (molar ratio with ε-caprolactone is 1:1), continue the reaction for 30 h, stop the nitrogen flow, and start vacuuming to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polydioxanone-polycaprolactone-polydioxanone block copolymer (PPDO-PCL-PPDO).

[0048] Example 2

[0049] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0050] Step 1. Synthesis of PPDO-PLA copolymer diol: Under continuous protection of high-purity dry nitrogen, add dry p-dioxanone monomer and L-lactide monomer (molar ratio of 1:1) to a fully dry polymerization bottle. Then, add 1,4-butanediol initiator at an amount of 1 / 20 of the total molar number of p-dioxanone monomer and L-lactide monomer. Bulk polymerization is carried out at 120°C for 24 hours to prepare PPDO-PLA copolymer diol (PPDO-PLA-diol) with a molecular weight of 2500 Da.

[0051] Step 2. Under the continuous protection of high-purity dry nitrogen, L-lactide monomer and PPDO-PLA copolymer diol with a molecular weight of 2500 Da (molar ratio of 500:1) were added to a fully dried polymerization bottle, and 60 μL of 1 mol / L stannous octoate / toluene solution was added. The amount of stannous octoate was 0.01% of the total mass of L-lactide monomer and PPDO-PLA copolymer diol. The polymerization bottle was heated to 160°C in an oil bath for 6 h, and then the oil bath temperature was adjusted to 60°C through the temperature control program. After that, p-dioxanone monomer (molar ratio with L-lactide was 1:1) was added and the reaction was continued for 30 h. The nitrogen was stopped and vacuum was started to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polydioxanone-polylactic acid-polydioxanone block copolymer (PPDO-PLA-PPDO).

[0052] Example 3

[0053] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0054] Step 1: Synthesis of PPDO-PCL copolymer diol: Same as Example 1;

[0055] Step 2. Under the continuous protection of high-purity dry nitrogen, add p-dioxanone monomer and PPDO-PCL copolymer diol with a molecular weight of 2000 Da (molar ratio of 500:1) to a fully dried polymerization bottle, add 60 μL of 1 mol / L stannous octoate / toluene solution, and the amount of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PCL copolymer diol; heat the polymerization bottle to 60°C in an oil bath and polymerize for 3 hours, then adjust the oil bath temperature to 160°C through the temperature control program and add ε-caprolactone monomer (molar ratio with p-dioxanone is 1:1), continue the reaction for 33 hours, stop the nitrogen flow, and start vacuuming to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polycaprolactone-polydioxanone-polycaprolactone block copolymer (PCL-PPDO-PCL).

[0056] Example 4

[0057] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0058] Step 1: Synthesis of PPDO-PLA copolymer diol: Same as Example 2;

[0059] Step 2. Under the continuous protection of high-purity dry nitrogen, add p-dioxanone monomer and PPDO-PLA copolymer diol with a molecular weight of 2500 Da (molar ratio of 500:1) to a fully dried polymerization bottle, add 60 μL of 1 mol / L stannous octoate / toluene solution, and the amount of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PLA copolymer diol; heat the polymerization bottle to 60°C in an oil bath and polymerize for 12 h, then adjust the oil bath temperature to 160°C through the temperature control program and add L-lactide monomer (molar ratio with p-dioxanone is 1:1), continue the reaction for 30 h, stop the nitrogen flow, and start vacuuming to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polylactic acid-polydioxanone-polylactic acid block copolymer (PLA-PPDO-PLA).

[0060] Example 5

[0061] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0062] Step 1: Synthesis of PPDO-PCL copolymer diol: Same as Example 1;

[0063] Step 2. Under the continuous protection of high-purity dry nitrogen, add ε-caprolactone monomer and PPDO-PCL copolymer diol with a molecular weight of 2000 Da (molar ratio of 500:1) to a fully dried polymerization bottle, add 60 μL of 1 mol / L dibutyltin dilaurate / toluene solution, and the amount of dibutyltin dilaurate is 0.01% of the total mass of ε-caprolactone monomer and PPDO-PCL copolymer diol; heat the polymerization bottle to 160°C in an oil bath and polymerize for 6 h, then adjust the oil bath temperature to 80°C through the temperature control program, and then add dioxanone monomer (molar ratio with ε-caprolactone is 1:1), continue the reaction for 30 h, stop the nitrogen flow, and start vacuuming to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polydioxanone-polycaprolactone-polydioxanone block copolymer (PPDO-PCL-PPDO).

[0064] Example 6

[0065] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0066] Step 1: Synthesis of PPDO-PLA copolymer diol: Same as Example 2;

[0067] Step 2. Under the continuous protection of high-purity dry nitrogen, L-lactide monomer and PPDO-PLA copolymer diol with a molecular weight of 2500 Da (molar ratio of 500:1) were added to a fully dried polymerization bottle, and 60 μL of 1 mol / L stannous octoate / toluene solution was added. The amount of stannous octoate was 0.01% of the total mass of L-lactide monomer and PPDO-PLA copolymer diol. The polymerization bottle was heated to 160°C in an oil bath for 6 h, and then the oil bath temperature was adjusted to 80°C through the temperature control program. After that, p-dioxanone monomer (molar ratio with L-lactide was 1:1) was added and the reaction was continued for 30 h. The nitrogen was stopped and vacuum was started to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polydioxanone-polylactic acid-polydioxanone block copolymer (PPDO-PLA-PPDO).

[0068] Example 7

[0069] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0070] Step 1: Synthesis of PPDO-PCL copolymer diol: Same as Example 1;

[0071] Step 2. Under the continuous protection of high-purity dry nitrogen, add p-dioxanone monomer and PPDO-PCL copolymer diol with a molecular weight of 2000 Da (molar ratio of 500:1) to a fully dried polymerization bottle, add 60 μL of 1 mol / L stannous octoate / toluene solution, and the amount of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PCL copolymer diol; heat the polymerization bottle to 80°C in an oil bath and polymerize for 3 hours, then adjust the oil bath temperature to 160°C through the temperature control program, and then add ε-caprolactone monomer (molar ratio with p-dioxanone is 1:1), continue the reaction for 33 hours, stop the nitrogen flow, and start vacuuming to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polycaprolactone-polydioxanone-polycaprolactone block copolymer (PCL-PPDO-PCL).

[0072] Example 8

[0073] A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer comprises the following steps:

[0074] Step 1: Synthesis of PPDO-PLA copolymer diol: Same as Example 2;

[0075] Step 2. Under the continuous protection of high-purity dry nitrogen, add p-dioxanone monomer and PPDO-PLA copolymer diol with a molecular weight of 2500 Da (molar ratio of 500:1) to a fully dried polymerization bottle, add 60 μL of 1 mol / L stannous octoate / toluene solution, and the amount of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PLA copolymer diol; heat the polymerization bottle to 80°C in an oil bath and polymerize for 12 h, then adjust the oil bath temperature to 160°C through the temperature control program and add L-lactide monomer (molar ratio with p-dioxanone is 1:1), continue the reaction for 30 h, stop the nitrogen flow, and start vacuuming to make the vacuum degree in the polymerization bottle 5 mmHg, and finally a white solid product was obtained, which was a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, namely polylactic acid-polydioxanone-polylactic acid block copolymer (PLA-PPDO-PLA).

[0076] Example 9

[0077] In this embodiment, composite catalyst 1 is used to replace stannous octoate, and the remaining steps are the same as those in Example 1;

[0078] The preparation method of the composite catalyst 1 comprises the following steps:

[0079] S1. Under the continuous protection of high-purity dry nitrogen, stannous octoate and maleic anhydride were added to toluene in a molar ratio of 3:1, stirred at 80°C for 3 h, and the excess solvent was removed by vacuum distillation to obtain modified stannous octoate; wherein the molar volume ratio of stannous octoate to toluene was 1 mol:1 L;

[0080] S2. Add dibutyltin dilaurate to toluene and stir evenly to obtain a dibutyltin dilaurate / toluene solution with a concentration of 1 mol / L; add modified stannous octoate to toluene and stir evenly to obtain a modified stannous octoate / toluene solution with a concentration of 1 mol / L;

[0081] S3. Under the continuous protection of high-purity dry nitrogen, a dibutyltin dilaurate / toluene solution and a modified stannous octoate / toluene solution were mixed, heated to 70°C and stirred for 2 h, and then zinc isooctanoate was added, and the stirring was continued for 1 h. The excess solvent was removed by distillation under reduced pressure, and the obtained product was subjected to low-temperature corona irradiation treatment for 5 min to obtain a composite catalyst, which was recorded as composite catalyst 1; wherein the mass ratio of dibutyltin dilaurate, modified stannous octoate and zinc isooctanoate was 1:2:0.5; the specific parameters of the low-temperature corona irradiation were: the treatment atmosphere was nitrogen, the temperature was 25°C, the voltage was 10 kV, and the distance was 3 cm.

[0082] In this embodiment, maleic anhydride is first used to modify stannous octoate to enhance Sn 2+ The Lewis acidity of the catalyst is enhanced, improving its stability and catalytic activity. Modified stannous octoate is then compounded and mixed with dibutyltin dilaurate, followed by the addition of zinc isooctanoate. The three catalysts act synergistically, resulting in a composite catalyst with higher catalytic activity, selectivity, and stability. In this example, the components are first formulated into a solution, then stirred and mixed at a certain temperature to improve the dispersion of the components and achieve more uniform mixing. Low-temperature corona irradiation treatment is then applied to enhance the catalyst's reactivity, facilitating subsequent coordination and activation with cyclic ester monomers, further enhancing catalytic activity. The composite catalyst prepared in Example 9 was used to synthesize a polydioxanone-polycaprolactone-polydioxanone block copolymer (PPDO-PCL-PPDO). The resulting copolymer has a high molecular weight and excellent mechanical properties.

[0083] Example 10

[0084] In this embodiment, composite catalyst 2 is used to replace stannous octoate, and the remaining steps are the same as those in Example 1;

[0085] The preparation method of the composite catalyst 2 comprises the following steps:

[0086] S1. Under the continuous protection of high-purity dry nitrogen, stannous octoate and maleic anhydride were added to toluene in a molar ratio of 3:1, stirred at 80°C for 3 h, and the excess solvent was removed by vacuum distillation to obtain modified stannous octoate; wherein the molar volume ratio of stannous octoate to toluene was 1 mol:1 L;

[0087] S2. Add dibutyltin dilaurate to toluene and stir evenly to obtain a dibutyltin dilaurate / toluene solution with a concentration of 1 mol / L; add modified stannous octoate to toluene and stir evenly to obtain a modified stannous octoate / toluene solution with a concentration of 1 mol / L;

[0088] S3. Under the continuous protection of high-purity dry nitrogen, a dibutyltin dilaurate / toluene solution and a modified stannous octoate / toluene solution were mixed, heated to 70°C and stirred for 3 h, and the excess solvent was removed by distillation under reduced pressure. The resulting product was then subjected to low-temperature corona irradiation for 5 min to obtain a composite catalyst, which was designated as composite catalyst 2. The mass ratio of dibutyltin dilaurate to modified stannous octoate was 1:2. The specific parameters of the low-temperature corona irradiation were as follows: the treatment atmosphere was nitrogen, the temperature was 25°C, the voltage was 10 kV, and the distance was 3 cm.

[0089] This embodiment differs from embodiment 9 only in that zinc isooctanoate is not added during the preparation of the composite catalyst.

[0090] Example 11

[0091] In this embodiment, composite catalyst 3 is used to replace stannous octoate, and the remaining steps are the same as those in Example 1;

[0092] The preparation method of the composite catalyst 3 comprises the following steps:

[0093] S1. Under the continuous protection of high-purity dry nitrogen, stannous octoate and maleic anhydride were added to toluene in a molar ratio of 3:1, stirred at 80°C for 3 h, and the excess solvent was removed by vacuum distillation to obtain modified stannous octoate; wherein the molar volume ratio of stannous octoate to toluene was 1 mol:1 L;

[0094] S2. Add dibutyltin dilaurate to toluene and stir evenly to obtain a dibutyltin dilaurate / toluene solution with a concentration of 1 mol / L; add modified stannous octoate to toluene and stir evenly to obtain a modified stannous octoate / toluene solution with a concentration of 1 mol / L;

[0095] S3. Under the continuous protection of high-purity dry nitrogen, a dibutyltin dilaurate / toluene solution and a modified stannous octoate / toluene solution were mixed, heated to 70°C and stirred for 2 h, and then zinc isooctanoate was added. The stirring was continued for 1 h, and the excess solvent was removed by vacuum distillation to obtain a composite catalyst, which was recorded as composite catalyst 3; wherein the mass ratio of dibutyltin dilaurate, modified stannous octoate and zinc isooctanoate was 1:2:0.5.

[0096] This embodiment differs from embodiment 9 only in that low-temperature corona irradiation treatment is not performed during the preparation of the composite catalyst.

[0097] Example 12

[0098] In this embodiment, composite catalyst 1 is used to replace stannous octoate, and the remaining steps are the same as those in Example 1;

[0099] The composite catalyst 1 is a mixture of dibutyltin dilaurate, modified stannous octoate and zinc isooctanoate in a mass ratio of 1:2:0.5; the preparation method of the modified stannous octoate is as follows: under the continuous protection of high-purity dry nitrogen, stannous octoate and maleic anhydride are added to toluene in a molar ratio of 3:1, stirred at 80°C for 3 hours, and the excess solvent is removed by reduced pressure distillation to obtain modified stannous octoate; wherein the molar volume ratio of stannous octoate to toluene is 1 mol:1L.

[0100] Example 13

[0101] In this embodiment, composite catalyst 2 is used to replace stannous octoate, and the remaining steps are the same as those in Example 1;

[0102] The composite catalyst 2 is a mixture of dibutyltin dilaurate, stannous octoate and zinc isooctanoate in a mass ratio of 1:2:0.5.

[0103] Comparative Example 1

[0104] A method for preparing an aliphatic polycyclic ester block copolymer comprises the following steps:

[0105] Under continuous protection of high-purity dry nitrogen, p-dioxanone cyclic ester monomer and 1,4-butanediol (molar ratio of 500:1) were added to a thoroughly dried polymerization bottle. 60 μL of a 1 mol / L stannous octoate / toluene solution was added (the amount of stannous octoate was 0.01% of the total mass of p-dioxanone and L-lactide monomers). The polymerization bottle was heated to 80°C in an oil bath for 12 h. The oil bath temperature was then adjusted to 160°C using a temperature control program, and L-lactide monomer was added (molar ratio of p-dioxanone to 1:1). The reaction was continued for 30 h. The nitrogen flow was stopped, and the vacuum in the polymerization bottle was evacuated to 5 mmHg to obtain a white solid product, which is an aliphatic polycyclic ester block copolymer, namely, polylactic acid-poly(p-dioxanone)-polylactic acid block copolymer (PLA-PPDO-PLA).

[0106] Comparative Example 2

[0107] A method for preparing an aliphatic polycyclic ester block copolymer comprises the following steps:

[0108] Under continuous protection of high-purity dry nitrogen, ε-caprolactone cyclic monomer and 1,4-butanediol (molar ratio of 500:1) were added to a thoroughly dried polymerization bottle. Then, 60 μL of a 1 mol / L stannous octoate / toluene solution was added (the amount of stannous octoate was 0.01% of the total mass of the p-dioxanone and ε-caprolactone monomers). The polymerization bottle was heated to 160°C in an oil bath for 6 h. The oil bath temperature was then adjusted to 60°C using a temperature control program, and p-dioxanone monomer (molar ratio of 1:1 to ε-caprolactone) was added. The reaction was continued for 30 h. The nitrogen flow was stopped, and the vacuum in the polymerization bottle was evacuated to 5 mmHg to obtain a white solid product, which is an aliphatic polycyclic ester block copolymer, namely, poly(p-dioxanone-polycaprolactone-poly(p-dioxanone-PCL-PPDO).

[0109] The mechanical properties and molecular weight of the block copolymers prepared in Examples 1-13 and Comparative Examples 1-2 were tested: the mechanical properties were tested in accordance with the national standard GB / T 1040.3-2006; the molecular weight was tested using a Waters 2695 Alliance HPLC model gel chromatograph. The testing process was as follows: an appropriate amount of the sample to be tested was taken into a sample bottle, and then hexafluoroisopropanol solvent was added to prepare a solution concentration of 2 to 5 mg / mL. The solution sample was then passed through a 0.45 μm filter membrane and tested on the machine. The results are shown in Table 1. It can be seen that the present invention uses a polycyclic ester copolymer diol that is highly compatible with the cyclic ester monomer as an initiator to avoid thermodynamic incompatibility with the matrix and kinetic hindrance, thereby obtaining a high molecular weight aliphatic polycyclic ester block copolymer. At the same time, it has good mechanical properties and an adjustable degradation rate. The cyclic lactones used are all non-toxic and harmless, and have good biocompatibility and can be safely degraded in vivo, meeting the requirements of biomedical materials. It can be used as a raw material for preparing implantable / non-implantable medical devices, such as thermoplastic elastomers and plastics. Compared with Comparative Example 1, Example 8 employed different initiators. The block copolymer PLA-PPDO-PLA obtained using PPDO-PLA copolymer diol (PPDO-PLA-diol) in Example 8 exhibited a higher molecular weight and superior mechanical properties. Compared with Comparative Example 2, the PPDO-PCL-PPDO in Example 1 exhibited a higher molecular weight and superior mechanical properties. Compared with Example 1, Examples 12-13 demonstrated a synergistic effect between the combination of stannous octoate, dibutyltin dilaurate, and zinc isooctanoate. Modification of the stannous octoate resulted in a better catalytic effect on the polymerization reaction, resulting in a synthesized block copolymer with a higher molecular weight. Compared with Example 1, Examples 9-11 demonstrated that the composite catalyst prepared using the method of Example 9 exhibited the best catalytic effect, resulting in a synthesized block copolymer with a higher molecular weight and superior mechanical properties.

[0110] Table 1

[0111]

[0112] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the description and implementation methods. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to the specific details and embodiments shown and described herein.

Claims

1. A method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, characterized in that: The following steps are involved: Step 1: Synthesis of polycyclic ester copolymer diol: Under dry nitrogen conditions, dry p-dioxanone monomer and ε-caprolactone monomer are mixed in a molar ratio of 1:1, and then 1,4-butanediol is added in an amount of one twentieth of the total molar number of the ε-caprolactone monomer and the p-dioxanone monomer, and the mixture is reacted at 100° C. for 24 hours to prepare a polycyclic ester copolymer diol, i.e., PPDO-PCL copolymer diol; Step 2: Under dry nitrogen conditions, cyclic ester monomer A and polycyclic ester copolymer diol are mixed, and then a catalyst solution is added, and the mixture is heated for polymerization. Then, the temperature is adjusted, and cyclic ester monomer B is added, and the reaction is continued. The nitrogen flow is stopped, and the mixture is vacuumed to obtain a white solid product, which is a high molecular weight biodegradable aliphatic polycyclic ester block copolymer; In the step 2, the solvent of the catalyst solution is toluene, the solute is the composite catalyst, and the concentration is 0.5-2 mol / L; the preparation method of the composite catalyst comprises the following steps: S1. Under dry nitrogen conditions, stannous octoate and maleic anhydride are added to toluene, stirred at 60-90°C for 2-4 hours, and the excess solvent is removed by vacuum distillation to obtain modified stannous octoate; S2. Add dibutyltin dilaurate to toluene and stir evenly to obtain a dibutyltin dilaurate / toluene solution with a concentration of 0.5~2 mol / L; add modified stannous octoate to toluene and stir evenly to obtain a modified stannous octoate / toluene solution with a concentration of 0.5~2 mol / L; S3. Under dry nitrogen conditions, mix the dibutyltin dilaurate / toluene solution and the modified stannous octoate / toluene solution, heat to 60-80°C and stir for 1-3 hours, then add zinc isooctanoate and continue stirring for 1-2 hours. Remove excess solvent by vacuum distillation, and then treat the obtained product with low-temperature corona irradiation to obtain a composite catalyst.

2. The method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer according to claim 1, wherein: In step 1, the synthesis method of the polycyclic ester copolymer diol is replaced by: under dry nitrogen conditions, dry p-dioxanone monomer and L-lactide monomer are mixed in a molar ratio of 1:1, and then 1,4-butanediol is added in an amount of one twentieth of the total molar number of the p-dioxanone monomer and the L-lactide monomer, and the mixture is reacted at 120° C. for 24 hours to prepare the polycyclic ester copolymer diol, i.e., PPDO-PLA copolymer diol.

3. The method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer according to claim 1, wherein: In the step 2, the cyclic ester monomer A is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

4. The method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer according to claim 1, wherein: In the step 2, the cyclic ester monomer B is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

5. The method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer according to claim 1, wherein: In the step 2, the molar ratio of the cyclic ester monomer A to the polycyclic ester copolymer diol is 400-600:1; The molar ratio of cyclic ester monomer A to cyclic ester monomer B is 1:0.5-2.

6. The method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer according to claim 1, wherein: In the step 2, the amount of the catalyst used is 0.01-0.05% of the total mass of the cyclic ester monomer A and the polycyclic ester copolymer diol.

7. The method for preparing a high molecular weight biodegradable aliphatic polycyclic ester block copolymer according to claim 1, wherein: In the step 2, the polymerization is carried out at 60-200° C. for 3-12 hours, and then the temperature is adjusted to another temperature within the range of 60-200° C., and the cyclic ester monomer B is added. The reaction is continued for 30-33 hours, and the nitrogen is stopped, and the mixture is evacuated to a vacuum degree of <10 mmHg.

8. Use of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer prepared by the preparation method according to any one of claims 1 to 7 in the preparation of medical devices.

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