Biodegradable aliphatic polycyclic ester block copolymer with high molecular weight as well as preparation and application of biodegradable aliphatic polycyclic ester block copolymer

Abstract

The invention discloses a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer and preparation and application thereof, and belongs to the technical field of high-molecular compounds. The preparation method comprises the following steps: synthesizing polycyclic ester copolymer diol; the preparation method comprises the following steps: under a dry nitrogen condition, mixing a cyclic ester monomer A and polycyclic ester copolymer glycol, adding a catalyst solution, carrying out heating polymerization, adjusting the temperature, adding a cyclic ester monomer B, continuously reacting, stopping introducing nitrogen, and vacuumizing to obtain a white solid product, namely the high-molecular-weight biodegradable aliphatic polycyclic ester segmented copolymer. According to the invention, the polycyclic ester copolymer diol highly compatible with a cyclic ester monomer is used as an initiator to avoid thermodynamic incompatibility with a matrix and dynamic hindrance, so that the aliphatic polycyclic ester segmented copolymer with high molecular weight can be obtained; the block copolymer can be prepared by adopting a one-pot method, has good mechanical properties, is non-toxic and harmless, has good biocompatibility, and can meet the requirements of biomedical materials.

Description

Technical Field

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

[0002] In recent years, with the development and progress of modern medicine and biomedical engineering, some short-term implantable materials are often required in the treatment process for tissue engineering fields such as bone tissue repair and cardiovascular repair. And in the process of wound healing and tissue repair, this kind of short-term implantable material is required to have the following characteristics: 1) The degradation time is controllable, and it degrades completely or mostly during the wound recovery period; 2) Good biocompatibility and little inflammatory reaction are caused; 3) Non-toxic and harmless to the human body, which is helpful for human tissue repair; 4) Excellent mechanical properties, and it can effectively support human tissue organs in a short time. Currently, the biodegradable materials for tissue engineering scaffolds developed on the market include polylactic acid (PLA), polyglycolide (PGA), polycaprolactone (PCL), poly(p-dioxanone) (PPDO), etc. However, single biodegradable materials often have problems such as difficult to control the degradation rate, poor mechanical properties, and easy to cause inflammatory reactions in the human body. Therefore, it is necessary to modify single polymers to improve the practicality of the materials.

[0003] A block copolymer refers to a copolymer formed by connecting two or more polymer segments with different properties through covalent bonds. This kind of copolymerization can often combine the excellent properties of each copolymer component and can realize the improvement and regulation of mechanical properties, degradation properties, etc. So far, the A-B-A type block copolymers of polyethers or polyesters are mainly prepared by using isocyanate chain extension: that is, first, prepolymers A and B with hydroxyl end groups are obtained by ring-opening polymerization of different cyclic ester monomers, and then prepolymer A, prepolymer B, isocyanate chain extender, catalyst, etc. are reacted under certain conditions to finally obtain an A-B-A type triblock copolymer. This method has the following disadvantages: the reaction process is relatively cumbersome, and the requirements for controlling temperature, humidity, and system moisture are extremely high; secondly, most isocyanates have poor cytocompatibility and toxicity and are difficult to be applied in the biomedical field. Therefore, it is very difficult to apply the block copolymers prepared by the above method in the biomedical field. In recent years, although there are also reports on the preparation of block copolymers by macromolecular initiator-initiated ring-opening polymerization, the current macromolecular initiators are mostly homopolymers and have limitations such as thermodynamic incompatibility and kinetic hindrance with monomers / growing chains, that is, during the polymerization process, the initiator segments and monomers / growing chains phase separate and form microscopic phase regions. After phase separation, the monomers need to diffuse through the phase interface to contact the initiator active sites, significantly reducing 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] One object of the present invention is to solve at least the above problems and / or deficiencies and provide at least the advantages described hereinafter.

[0005] To achieve these objects 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. The cyclic ester monomer, catalyst, and polycyclic ester copolymer diol initiator are added into a sufficiently dried polymerization flask together, and then another cyclic ester monomer is added while controlling the temperature gradient change, so as to achieve the purpose of synthesizing the block copolymer by one-pot method, including the following steps: Step 1: Synthesize polycyclic ester copolymer diol: Mix two cyclic ester monomers and 1,4-butanediol, and heat them to react to obtain polycyclic ester copolymer diol; Step 2: Under dry nitrogen conditions, mix cyclic ester monomer A and polycyclic ester copolymer diol, then add the catalyst solution, heat for polymerization, then adjust the temperature, add cyclic ester monomer B, continue the reaction, stop introducing nitrogen, and evacuate to obtain a white solid product, which is a high molecular weight biodegradable aliphatic polycyclic ester block copolymer.

[0006] Preferably, in the above Step 1, the synthesis method of the polycyclic ester copolymer diol is as follows: Under dry nitrogen conditions, mix dry p-dioxanone monomer and ε-caprolactone monomer in a molar ratio of 1:1, then add 1,4-butanediol which is one-twentieth of the total molar number of ε-caprolactone monomer and p-dioxanone monomer, and react at 100 °C for 24 h to prepare polycyclic ester copolymer diol, that is, PPDO-PCL copolymer diol.

[0007] Preferably, in the above Step 1, the synthesis method of the polycyclic ester copolymer diol is as follows: Under dry nitrogen conditions, mix dry p-dioxanone monomer and L-lactide monomer in a molar ratio of 1:1, then add 1,4-butanediol which is one-twentieth of the total molar number of p-dioxanone monomer and L-lactide monomer, and react at 120 °C for 24 h to prepare polycyclic ester copolymer diol, that is, PPDO-PLA copolymer diol.

[0008] Preferably, in the above Step 2, cyclic ester monomer A is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

[0009] Preferably, in the above Step 2, cyclic ester monomer B is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

[0010] Preferably, in the above Step 2, the catalyst is one or more of stannous octoate, dibutyltin dilaurate, and zinc isooctanoate.

[0011] Preferably, in the second step, the catalyst is a composite catalyst; wherein, the preparation method of the composite catalyst includes 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 h, and the excess solvent is removed by vacuum distillation to obtain modified stannous octoate; S2. Dibutyltin dilaurate is added to toluene and stirred evenly to obtain a dibutyltin dilaurate / toluene solution with a concentration of 0.5-2 mol / L; the modified stannous octoate is added to toluene and stirred evenly to obtain a modified stannous octoate / toluene solution with a concentration of 0.5-2 mol / L; S3. Under dry nitrogen conditions, the dibutyltin dilaurate / toluene solution and the modified stannous octoate / toluene solution are mixed, heated to 60-80 °C and stirred for 1-3 h, then zinc isooctanoate is added, and stirring is continued for 1-2 h. The excess solvent is removed by vacuum distillation, and then the obtained product is subjected to low-temperature corona irradiation treatment to obtain a composite catalyst.

[0012] Preferably, in S1, the molar ratio of stannous octoate to maleic anhydride is 2-4:1; the molar volume ratio of stannous octoate to toluene is 1 mol:0.8-2 L.

[0013] 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: the treatment atmosphere is nitrogen, the temperature is 20-30 °C, the voltage is 6-15 kV, the distance is 2-5 cm, and the treatment time is 3-10 min.

[0014] Preferably, in the second step, 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.

[0015] Preferably, in the second step, the molar ratio of cyclic ester monomer A to 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.

[0016] Preferably, in the second step, the dosage of the catalyst is 0.01-0.05% of the total mass of cyclic ester monomer A and polycyclic ester copolymer diol.

[0017] Preferably, in the second step, it is heated to 60-200 °C for polymerization for 3-12 h, and then the temperature is adjusted to another temperature within the range of 60-200 °C, for example, heated to 160 °C for polymerization for a certain time, and then the temperature is adjusted to 60 °C or 80 °C, or heated to 60 °C or 80 °C for polymerization for a certain time, and then the temperature is adjusted to 160 °C.

[0018] Preferably, in the second step, the reaction is continued for 30 to 33 h, nitrogen gas is stopped from being introduced, and the vacuum is pumped to a vacuum degree of <10 mmHg.

[0019] A high molecular weight biodegradable aliphatic polycyclic ester block copolymer prepared by the preparation method as described above.

[0020] Use of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer prepared by the preparation method as described above in the preparation of medical devices.

[0021] The present invention at least includes the following beneficial effects: (1) Using a polycyclic ester copolymer diol highly compatible with the cyclic ester monomer as an initiator to avoid thermodynamic incompatibility and kinetic hindrance with the matrix, so that a high molecular weight aliphatic polycyclic ester block copolymer can be obtained; (2) Adding different cyclic lactone monomers into the polymerization flask at different temperatures, and a block copolymer can be prepared by a one-pot method; (3) The operation is simple and easy. By controlling the ratio of different cyclic lactone monomers and the method of regulating the temperature, the composition and ratio of different segments of the block copolymer can be controlled; (4) Using this polymerization method, a series of block copolymers with good mechanical properties and adjustable degradation rates can be finally obtained; (5) The cyclic lactones used are all non-toxic and harmless, and the copolymer itself has good biocompatibility and can be safely degraded in vivo, which can meet the requirements of biomedical materials.

[0022] Most of the existing macromolecular initiators are homopolymers, which have limitations such as thermodynamic incompatibility and kinetic hindrance with the monomer / growing chain, that is, during the polymerization process, the initiator segment and the monomer / growing chain undergo phase separation and form microphase regions. After phase separation, the monomer needs to diffuse through the phase interface to contact the initiator active site, significantly reducing the chain growth rate. Therefore, the molecular weight of the prepared block copolymer is usually not high, and the mechanical properties are difficult to meet the requirements of medical materials. However, in the present invention, a polycyclic ester copolymer diol is used as an initiator, and the microphase separation, active site exposure, chain growth kinetics and thermodynamic equilibrium shift between the copolymer diol and the monomer / growing chain can be regulated through the molecular structure of the copolymer diol, breaking through the high molecular weight bottleneck of traditional homopolymer initiators. Its core advantage lies in achieving dynamic compatibility matching between the copolymer diol initiator and the monomer / growing chain through molecular design, providing theoretical feasibility for synthesizing a number-average high molecular weight polycyclic ester block copolymer. This method is not only applicable to ring-opening polymerization of cyclic esters, but also can be extended to other block copolymer systems, having important universal significance.

[0023] Other advantages, objects and features of the present invention will be partly reflected by the following description, and partly will be understood by those skilled in the art through the research and practice of the present invention. Detailed implementation mode

[0024] The following further detailed description of the present invention is provided so that those skilled in the art can implement it with reference to the text of the specification.

[0025] It should be understood that terms such as "having", "comprising" and "including" used herein do not exclude the presence or addition of one or more other elements or their combinations.

[0026] The present invention has developed a preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer. According to the types of cyclic ester monomers to be ring-opened, a polycyclic ester copolymer polyol with good compatibility with the cyclic ester monomer / growing chain is designed and synthesized as an initiator, and by controlling different temperatures, a high molecular weight block copolymer is prepared by utilizing the differences in the equilibrium conversion rate and rate constant of different cyclic monomers at different temperatures. It is known from the literature that the optimal reaction temperatures of 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). According to the above temperature parameters, we designed and synthesized polycyclic ester copolymer diol as a macromolecular initiator, and by controlling the heating program, under the action of different catalysts, a high molecular weight block copolymer was prepared under certain conditions to meet the needs of biomedical polymer materials with different degradation rates and different mechanical properties. The reaction is mainly completed by the following steps: 1) The polymerization flask was evacuated and replaced with nitrogen three times repeatedly, and assisted by a spray gun baking to remove trace moisture in the flask; 2) Under the condition of high-purity dry nitrogen, a cyclic lactone monomer was added to the polymerization flask; 3) The synthesized aliphatic polycyclic ester copolymer diol initiator was added to the above polymerization flask; 4) The catalyst was dissolved in anhydrous organic solvent and configured into a solution and added to the above polymerization flask; 5) The polymerization flask was placed at a certain temperature for polymerization for a period of time; 6) Program temperature control was carried out. After the temperature was adjusted to the specified temperature, another cyclic lactone monomer was added for polymerization for a period of time; 7) After the polymerization was completed, vacuum was continuously pumped at 60 °C for a period of time to purify the product.

[0027] Example 1 A preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer, comprising the following steps: Step 1. Synthesis of PPDO-PCL copolymer diol: Under the continuous protection of high-purity dry nitrogen, dry p-dioxanone monomer and ε-caprolactone monomer (molar ratio 1:1) are added to a sufficiently dried polymerization flask. Then, 1,4-butanediol initiator, which is one-twentieth of the total molar amount of ε-caprolactone monomer and p-dioxanone monomer, is added. Bulk polymerization reaction is carried out at 100 °C for 24 h to prepare PPDO-PCL copolymer diol (PPDO-PCL-diol) with a molecular weight of 2000 Da; Step 2. Under the continuous protection of high-purity dry nitrogen, ε-caprolactone monomer and PPDO-PCL copolymer diol with a molecular weight of 2000 Da (molar ratio 500:1) are added to a sufficiently dried polymerization flask. 60 μL of stannous octanoate / toluene solution with a concentration of 1 mol / L is added, and the dosage of stannous octanoate is 0.01% of the total mass of ε-caprolactone monomer and PPDO-PCL copolymer diol. The polymerization flask is heated to 160 °C with an oil bath for 6 h, and then through the temperature control program, the oil bath temperature is adjusted to 60 °C, and then p-dioxanone monomer (molar ratio 1:1 with ε-caprolactone) is added, and the reaction continues for 30 h. Nitrogen is stopped from being introduced, and vacuum is started to make the vacuum degree in the polymerization flask 5 mmHg. Finally, a white solid product is obtained, which is a high-molecular-weight biodegradable aliphatic polyester block copolymer, namely poly(p-dioxanone)-poly(ε-caprolactone)-poly(p-dioxanone) block copolymer (PPDO-PCL-PPDO).

[0028] Example 2 A preparation method of a high-molecular-weight biodegradable aliphatic polyester block copolymer, comprising the following steps: Step 1. Synthesis of PPDO-PLA copolymer diol: Under the continuous protection of high-purity dry nitrogen, dry p-dioxanone monomer and L-lactide monomer (molar ratio 1:1) are added to a sufficiently dried polymerization flask. Then, 1,4-butanediol initiator, which is one-twentieth of the total molar amount of p-dioxanone monomer and L-lactide monomer, is added. Bulk polymerization reaction is carried out at 120 °C for 24 h to prepare PPDO-PLA copolymer diol (PPDO-PLA-diol) with a molecular weight of 2500 Da; Step 2: Under the continuous protection of high-purity dry nitrogen, add L-lactide monomer and PPDO-PLA copolymer diol with a molecular weight of 2500 Da (molar ratio of 500:1) into a sufficiently dried polymerization flask. Add 60 μL of stannous octoate / toluene solution with a concentration of 1 mol / L, and the dosage of stannous octoate is 0.01% of the total mass of L-lactide monomer and PPDO-PLA copolymer diol. Heat the polymerization flask to 160 °C with an oil bath for polymerization for 6 h, then through the temperature control program, adjust the oil bath temperature to 60 °C and add p-dioxanone monomer (molar ratio with L-lactide is 1:1), continue the reaction for 30 h, stop introducing nitrogen, start to pump vacuum to make the vacuum degree in the polymerization flask 5 mmHg, and finally obtain a white solid product, which is a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, namely poly(p-dioxanone)-poly(lactic acid)-poly(p-dioxanone) block copolymer (PPDO-PLA-PPDO).

[0029] Example 3 A preparation method of a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, comprising the following steps: Step 1: Synthesize PPDO-PCL copolymer diol: the same as Example 1; 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) into a sufficiently dried polymerization flask. Add 60 μL of stannous octoate / toluene solution with a concentration of 1 mol / L, and the dosage of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PCL copolymer diol. Heat the polymerization flask to 60 °C with an oil bath for polymerization for 3 h, then through the temperature control program, adjust the oil bath temperature to 160 °C and add ε-caprolactone monomer (molar ratio with p-dioxanone is 1:1), continue the reaction for 33 h, stop introducing nitrogen, start to pump vacuum to make the vacuum degree in the polymerization flask 5 mmHg, and finally obtain a white solid product, which is a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, namely polycaprolactone-poly(p-dioxanone)-polycaprolactone block copolymer (PCL-PPDO-PCL).

[0030] Example 4 A preparation method of a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, comprising the following steps: Step 1: Synthesize PPDO-PLA copolymer diol: the same as Example 2; 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 500:1) into a fully dried polymerization flask. Add 60 μL of stannous octoate / toluene solution with a concentration of 1 mol / L. The dosage of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PLA copolymer diol. Heat the polymerization flask to 60 °C with an oil bath and polymerize for 12 h. Then, through the temperature control program, adjust the oil bath temperature to 160 °C and add L-lactide monomer (molar ratio with p-dioxanone is 1:1), and continue the reaction for 30 h. Stop introducing nitrogen and start vacuuming to make the vacuum degree in the polymerization flask 5 mmHg. Finally, a white solid product is obtained, which is a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, namely poly(lactic acid)-poly(p-dioxanone)-poly(lactic acid) block copolymer (PLA-PPDO-PLA).

[0031] Example 5 A preparation method of a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, comprising the following steps: Step 1: Synthesize PPDO-PCL copolymer diol: same as Example 1; 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 500:1) into a fully dried polymerization flask. Add 60 μL of dibutyltin dilaurate / toluene solution with a concentration of 1 mol / L. The dosage of dibutyltin dilaurate is 0.01% of the total mass of ε-caprolactone monomer and PPDO-PCL copolymer diol. Heat the polymerization flask to 160 °C with an oil bath and polymerize for 6 h. Then, through the temperature control program, adjust the oil bath temperature to 80 °C and add p-dioxanone monomer (molar ratio with ε-caprolactone is 1:1), and continue the reaction for 30 h. Stop introducing nitrogen and start vacuuming to make the vacuum degree in the polymerization flask 5 mmHg. Finally, a white solid product is obtained, which is a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, namely poly(p-dioxanone)-poly(ε-caprolactone)-poly(p-dioxanone) block copolymer (PPDO-PCL-PPDO).

[0032] Example 6 A preparation method of a high-molecular-weight biodegradable aliphatic polycyclic ester block copolymer, comprising the following steps: Step 1: Synthesize PPDO-PLA copolymer diol: same as Example 2; Step 2: Under the continuous protection of high-purity dry nitrogen, add L-lactide monomer and PPDO-PLA copolymer diol with a molecular weight of 2500 Da (molar ratio is 500:1) into a sufficiently dried polymerization flask. Add 60 μL of stannous octoate / toluene solution with a concentration of 1 mol / L. The dosage of stannous octoate is 0.01% of the total mass of L-lactide monomer and PPDO-PLA copolymer diol. Heat the polymerization flask to 160 °C with an oil bath for polymerization for 6 h. Then, through the temperature control program, adjust the oil bath temperature to 80 °C and add p-dioxanone monomer (molar ratio with L-lactide is 1:1), and continue the reaction for 30 h. Stop introducing nitrogen and start vacuum pumping to make the vacuum degree in the polymerization flask 5 mmHg. Finally, a white solid product is obtained, which is a high-molecular-weight biodegradable aliphatic polyester block copolymer, namely poly(p-dioxanone)-poly(lactic acid)-poly(p-dioxanone) block copolymer (PPDO-PLA-PPDO).

[0033] Example 7 A preparation method of a high-molecular-weight biodegradable aliphatic polyester block copolymer, comprising the following steps: Step 1: Synthesize PPDO-PCL copolymer diol: same as Example 1; 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 is 500:1) into a sufficiently dried polymerization flask. Add 60 μL of stannous octoate / toluene solution with a concentration of 1 mol / L. The dosage of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PCL copolymer diol. Heat the polymerization flask to 80 °C with an oil bath for polymerization for 3 h. Then, through the temperature control program, adjust the oil bath temperature to 160 °C and add ε-caprolactone monomer (molar ratio with p-dioxanone is 1:1), and continue the reaction for 33 h. Stop introducing nitrogen and start vacuum pumping to make the vacuum degree in the polymerization flask 5 mmHg. Finally, a white solid product is obtained, which is a high-molecular-weight biodegradable aliphatic polyester block copolymer, namely poly(caprolactone)-poly(p-dioxanone)-poly(caprolactone) block copolymer (PCL-PPDO-PCL).

[0034] Example 8 A preparation method of a high-molecular-weight biodegradable aliphatic polyester block copolymer, comprising the following steps: Step 1: Synthesize PPDO-PLA copolymer diol: same as Example 2; 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 500:1) into a sufficiently dried polymerization flask, add 60 μL of stannous octoate / toluene solution with a concentration of 1 mol / L, and the dosage of stannous octoate is 0.01% of the total mass of p-dioxanone monomer and PPDO-PLA copolymer diol; heat the polymerization flask to 80 °C with an oil bath for polymerization for 12 h, then through the temperature control program, adjust the oil bath temperature to 160 °C and add L-lactide monomer (molar ratio with p-dioxanone is 1:1), continue the reaction for 30 h, stop introducing nitrogen, start vacuum pumping to make the vacuum degree in the polymerization flask 5 mmHg, and finally obtain a white solid product, which is a high-molecular-weight biodegradable aliphatic polyester block copolymer, namely poly(lactic acid)-poly(p-dioxanone)-poly(lactic acid) block copolymer (PLA-PPDO-PLA).

[0035] Example 9 In this example, stannous octoate was replaced with composite catalyst 1, and the other steps were the same as in Example 1; Among them, the preparation method of the composite catalyst 1 includes the following steps: S1: Under the continuous protection of high-purity dry nitrogen, add stannous octoate and maleic anhydride into toluene at a molar ratio of 3:1, stir at 80 °C for 3 h, and remove the excess solvent by vacuum distillation to obtain modified stannous octoate; among them, the molar volume ratio of stannous octoate to toluene is 1 mol:1 L; S2: Add dibutyltin dilaurate into toluene and stir evenly to obtain a dibutyltin dilaurate / toluene solution with a concentration of 1 mol / L; add the modified stannous octoate into toluene and stir evenly to obtain a modified stannous octoate / toluene solution with a concentration of 1 mol / L; S3: Under the continuous protection of high-purity dry nitrogen, mix the dibutyltin dilaurate / toluene solution and the modified stannous octoate / toluene solution, heat to 70 °C and stir for 2 h, then add zinc isooctanoate, continue to stir for 1 h, remove the excess solvent by vacuum distillation, and then perform low-temperature corona irradiation treatment on the obtained product for 5 min to obtain a composite catalyst, denoted as composite catalyst 1; among them, the mass ratio of dibutyltin dilaurate, modified stannous octoate and zinc isooctanoate is 1:2:0.5; the specific parameters of low-temperature corona irradiation are: the treatment atmosphere is nitrogen, the temperature is 25 °C, the voltage is 10 kV, and the distance is 3 cm.

[0036] In this example, maleic anhydride was first used to modify stannous octoate to enhance Sn 2+The Lewis acidity is increased to improve its stability and catalytic activity; then the modified stannous octoate is compounded and mixed with dibutyltin dilaurate, and zinc isooctoate is added. The three catalysts have a synergistic effect, and the obtained composite catalyst has higher catalytic activity, selectivity and stability; in this example, each component is first formulated into a solution, and then stirred and mixed at a certain temperature to improve the dispersibility of each component and make the mixing more uniform. Then, low-temperature corona irradiation treatment is applied to improve the reaction activity of the catalyst, which is beneficial to subsequent coordination activation with the cyclic ester monomer and further improves the catalytic activity. The composite catalyst prepared in Example 9 is used to synthesize the poly(p-dioxanone)-polycaprolactone-poly(p-dioxanone) block copolymer (PPDO-PCL-PPDO). The obtained copolymer has a high molecular weight and excellent mechanical properties.

[0037] Example 10 In this example, stannous octoate is replaced with composite catalyst 2, and the remaining steps are the same as those in Example 1; Among them, the preparation method of the composite catalyst 2 includes the following steps: S1. Under the condition of continuous protection of high-purity dry nitrogen, stannous octoate and maleic anhydride are added to toluene at a molar ratio of 3:1, stirred at 80 °C for 3 h, and the excess solvent is removed by vacuum distillation to obtain modified stannous octoate; among them, the molar volume ratio of stannous octoate to toluene is 1 mol:1 L; S2. Dibutyltin dilaurate is added to toluene and stirred evenly to obtain a 1 mol / L dibutyltin dilaurate / toluene solution; the modified stannous octoate is added to toluene and stirred evenly to obtain a 1 mol / L modified stannous octoate / toluene solution; S3. Under the condition of continuous protection of high-purity dry nitrogen, the dibutyltin dilaurate / toluene solution and the modified stannous octoate / toluene solution are mixed, heated to 70 °C and stirred for 3 h, the excess solvent is removed by vacuum distillation, and then the obtained product is subjected to low-temperature corona irradiation treatment for 5 min to obtain a composite catalyst, denoted as composite catalyst 2; among them, the mass ratio of dibutyltin dilaurate to modified stannous octoate is 1:2; the specific parameters of the low-temperature corona irradiation are: the treatment atmosphere is nitrogen, the temperature is 25 °C, the voltage is 10 kV, and the distance is 3 cm.

[0038] The difference between this example and Example 9 is only that zinc isooctoate is not added when preparing the composite catalyst.

[0039] Example 11 In this example, stannous octoate is replaced with composite catalyst 3, and the remaining steps are the same as those in Example 1; Among them, the preparation method of the composite catalyst 3 includes the following steps: S1. Under the condition of continuous protection by high-purity dry nitrogen, stannous octoate and maleic anhydride are added to toluene at a molar ratio of 3:1, stirred at 80 °C for 3 h, and the excess solvent is removed by vacuum distillation to obtain modified stannous octoate; wherein, the molar volume ratio of stannous octoate to toluene is 1 mol:1 L. S2. Dibutyltin dilaurate is added to toluene and stirred evenly to obtain a 1 mol / L dibutyltin dilaurate / toluene solution; the modified stannous octoate is added to toluene and stirred evenly to obtain a 1 mol / L modified stannous octoate / toluene solution. S3. Under the condition of continuous protection by high-purity dry nitrogen, the dibutyltin dilaurate / toluene solution and the modified stannous octoate / toluene solution are mixed, heated to 70 °C and stirred for 2 h, then zinc isooctanoate is added, and stirring is continued for 1 h. The excess solvent is removed by vacuum distillation to obtain a composite catalyst, denoted as composite catalyst 3; wherein, the mass ratio of dibutyltin dilaurate, modified stannous octoate and zinc isooctanoate is 1:2:0.5.

[0040] In this example, the difference from Example 9 is only that during the preparation of the composite catalyst, no low-temperature corona irradiation treatment is carried out.

[0041] Example 12 In this example, the stannous octoate is replaced with the compound catalyst 1, and the remaining steps are the same as those in Example 1. Among them, the compound catalyst 1 is a mixture of dibutyltin dilaurate, modified stannous octoate and zinc isooctanoate mixed at a mass ratio of 1:2:0.5; the preparation method of the modified stannous octoate is: under the condition of continuous protection by high-purity dry nitrogen, stannous octoate and maleic anhydride are added to toluene at a molar ratio of 3:1, stirred at 80 °C for 3 h, and the excess solvent is removed by vacuum distillation to obtain modified stannous octoate; wherein, the molar volume ratio of stannous octoate to toluene is 1 mol:1 L.

[0042] Example 13 In this example, the stannous octoate is replaced with the compound catalyst 2, and the remaining steps are the same as those in Example 1. Among them, the compound catalyst 2 is a mixture of dibutyltin dilaurate, stannous octoate and zinc isooctanoate mixed at a mass ratio of 1:2:0.5.

[0043] Comparative Example 1 A method for preparing an aliphatic polycyclic ester block copolymer includes the following steps: Under the condition of continuous protection by high-purity dry nitrogen, the p-dioxanone cyclic ester monomer and 1,4-butanediol (molar ratio of 500:1) were added to a sufficiently dried polymerization flask, and 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 monomer and the L-lactide monomer; the polymerization flask was heated to 80 °C by an oil bath for 12 h, and then through a temperature control program, the oil bath temperature was adjusted to 160 °C and the L-lactide monomer (molar ratio with p-dioxanone of 1:1) was added, and the reaction continued for 30 h. Nitrogen was stopped from being introduced, and vacuum was started to make the vacuum degree in the polymerization flask 5 mmHg. Finally, a white solid product was obtained, which was the aliphatic polycyclic ester block copolymer, namely poly(lactic acid)-poly(p-dioxanone)-poly(lactic acid) block copolymer (PLA-PPDO-PLA).

[0044] Comparative Example 2 A preparation method of an aliphatic polycyclic ester block copolymer, comprising the following steps: Under the condition of continuous protection by high-purity dry nitrogen, the ε-caprolactone cyclic monomer and 1,4-butanediol (molar ratio of 500:1) were added to a sufficiently dried polymerization flask, and 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 monomer and the ε-caprolactone monomer; the polymerization flask was heated to 160 °C by an oil bath for 6 h, and then through a temperature control program, the oil bath temperature was adjusted to 60 °C and the p-dioxanone monomer (molar ratio with ε-caprolactone of 1:1) was added, and the reaction continued for 30 h. Nitrogen was stopped from being introduced, and vacuum was started to make the vacuum degree in the polymerization flask 5 mmHg. Finally, a white solid product was obtained, which was the aliphatic polycyclic ester block copolymer, namely poly(p-dioxanone)-poly(caprolactone)-poly(p-dioxanone) block copolymer (PPDO-PCL-PPDO).

[0045] The mechanical properties and molecular weights of the block copolymers prepared in Examples 1-13 and Comparative Examples 1-2 were tested: The mechanical property test was carried out in accordance with the national standard GB / T 1040.3-2006; the molecular weight test was performed using a gel chromatography instrument of the waters 2695 Alliance HPLC model. The test 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 with a concentration of 2-5 mg / mL. Then, the solution sample was passed through a 0.45 μm filter membrane and then tested on the machine. The results are shown in Table 1. It can be seen that in the present invention, a polycyclic ester copolymer diol highly compatible with the cyclic ester monomer was used as an initiator to avoid thermodynamic incompatibility with the matrix and kinetic hindrance, thereby obtaining an aliphatic polycyclic ester block copolymer with a high molecular weight. At the same time, it has good mechanical properties and an adjustable degradation rate. All the cyclic lactones used are non-toxic and harmless, and they have good biocompatibility themselves and can be safely degraded in vivo, meeting the requirements of biomedical materials and can be used as raw materials for preparing implantable / non-implantable medical devices, such as thermoplastic elastomers, plastics, etc. Among them, when comparing Example 8 with Comparative Example 1, different initiators were used. The block copolymer PLA-PPDO-PLA obtained by using PPDO-PLA copolymer diol (PPDO-PLA-diol) in Example 8 has a higher molecular weight and more excellent mechanical properties; when comparing Example 1 with Comparative Example 2, PPDO-PCL-PPDO in Example 1 has a higher molecular weight and more excellent mechanical properties. When comparing Examples 12-13 with Example 1, the combined use of stannous octoate, dibutyltin dilaurate and zinc isooctanoate has a certain synergistic effect. After the modification treatment of stannous octoate, the catalytic effect on the polymerization reaction is better, and the molecular weight of the synthesized block copolymer is higher; when comparing Examples 9-11 with Example 1, the composite catalyst prepared by the method of Example 9 has the best catalytic effect, the molecular weight of the synthesized block copolymer is higher, and the mechanical properties are more excellent.

[0046] Table 1 Although the embodiments of the present invention have been disclosed as above, it is not limited to the applications listed in the specification and embodiments. It can be fully applied to various fields suitable for the present invention. For those familiar with the field, additional modifications can be easily made. Therefore, without departing from the general concept defined by the claims and the equivalent scope, the present invention is not limited to the specific details and the embodiments shown and described here.

Claims

1. A method for preparing a biodegradable aliphatic polycyclic ester block copolymer with high molecular weight, characterized in that, It includes the following steps: Step 1, synthesize polycyclic ester copolymer diol: Mix two cyclic ester monomers and 1,4-butanediol, and heat for reaction to obtain polycyclic ester copolymer diol; Step 2, under dry nitrogen conditions, mix cyclic ester monomer A and polycyclic ester copolymer diol, then add a catalyst solution, heat for polymerization, then adjust the temperature, add cyclic ester monomer B, continue the reaction, stop introducing nitrogen, and evacuate to obtain a white solid product, which is a high molecular weight biodegradable aliphatic polycyclic ester block copolymer.

2. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer according to claim 1, characterized in that, In the said Step 1, the synthesis method of the polycyclic ester copolymer diol is: Under dry nitrogen conditions, mix dry p-dioxanone monomer and ε-caprolactone monomer in a molar ratio of 1:1, then add 1,4-butanediol which is one-twentieth of the total molar amount of ε-caprolactone monomer and p-dioxanone monomer, and react at 100 °C for 24 h to prepare polycyclic ester copolymer diol, that is, PPDO-PCL copolymer diol.

3. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer as described in claim 1, characterized in that, In the said Step 1, the synthesis method of the polycyclic ester copolymer diol is: Under dry nitrogen conditions, mix dry p-dioxanone monomer and L-lactide monomer in a molar ratio of 1:1, then add 1,4-butanediol which is one-twentieth of the total molar amount of p-dioxanone monomer and L-lactide monomer, and react at 120 °C for 24 h to prepare polycyclic ester copolymer diol, that is, PPDO-PLA copolymer diol.

4. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer as claimed in claim 1, characterized in that, In the said Step 2, the cyclic ester monomer A is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

5. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer as claimed in claim 1, characterized in that, In the said Step 2, the cyclic ester monomer B is one or more of p-dioxanone, ε-caprolactone, and L-lactide.

6. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer as described in claim 1, characterized in that, In the said Step 2, the catalyst is one or more of stannous octoate, dibutyltin dilaurate, and zinc isooctoate; the solvent of the catalyst solution is toluene, and the concentration is 0.5 - 2 mol / L.

7. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer as described in claim 1, characterized in that, In the said 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 the cyclic ester monomer A to the cyclic ester monomer B is 1:0.5 - 2.

8. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer as described in claim 1, characterized in that, In the said Step 2, the dosage of the catalyst is 0.01 - 0.05% of the total mass of the cyclic ester monomer A and the polycyclic ester copolymer diol.

9. The preparation method of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer as described in claim 1, characterized in that, In the said Step 2, heat to 60 - 200 °C for polymerization for 3 - 12 h, then adjust the temperature to another temperature within the range of 60 - 200 °C, add cyclic ester monomer B, continue the reaction for 30 - 33 h, stop introducing nitrogen, and evacuate to a vacuum degree < 10 mmHg.

10. Use of a high molecular weight biodegradable aliphatic polycyclic ester block copolymer prepared by the preparation method according to any one of claims 1 - 9 in the preparation of medical devices.

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