Purification method of medical polyethylene glycol-polycaprolactone block copolymer

Abstract

The invention discloses a method for purifying a medical polyethylene glycol-polycaprolactone block copolymer, and belongs to the technical field of synthesis of medical high polymer materials. The purification method comprises the following steps: carrying out supercritical carbon dioxide extraction on a crude product of the polyethylene glycol-polycaprolactone block copolymer, wherein the extraction time is 30-120 minutes; and dissolving the extracted product in a solvent I, filtering with alkaline quartz sand, concentrating the filtrate, precipitating with a solvent II, and drying the precipitate to obtain the medical polyethylene glycol-polycaprolactone block copolymer. According to the purification method of the medical polyethylene glycol-polycaprolactone segmented copolymer, supercritical extraction is combined with alkaline quartz sand filtration, the steps are simple, the time is short, the tin removal effect is good, the tin content can be reduced to 20 ppm or below, the molecular weight does not obviously change before and after purification, and the product loss amount in the purification process is lower than 5%; and the solvent dosage in the purification process is less.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of medical polymer materials, in particular to a method for purifying a medical polyethylene glycol-polycaprolactone block copolymer. Background Art

[0002] The information disclosed in the background of the invention is only intended to enhance the understanding of the overall background of the invention and should not be necessarily regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Polyethylene glycol-polycaprolactone (PEG-PCL) block copolymer is a copolymer commonly used in drug delivery, biomaterials and tissue engineering. Its synthesis usually involves organic tin compounds (such as the catalyst stannous octoate or other tin catalysts). If the tin content in this material exceeds the standard, the excessive tin content may have the following effects: (1) Cytotoxicity: adversely affect cell survival, proliferation and differentiation; (2) Immunosuppression: inhibit the normal function of the immune system and increase the risk of infection; (3) Neurotoxicity: organic tin may interfere with the normal function of the nervous system; (4) Reproductive toxicity: high doses of tin compounds may cause decreased reproductive capacity; during the use or disposal of such materials, tin may enter the water body, causing water pollution and toxic effects on aquatic organisms; (4) Inflammatory response: toxic residues in the material may cause local or systemic inflammation; (5) Long-term toxic accumulation: tin compounds in the human body may accumulate through metabolism, causing chronic health problems.

[0004] In order to reduce the risk of excessive tin content, the traditional preparation method of polyethylene glycol-polycaprolactone (PEG-PCL) block copolymers often adopts the following methods: First, optimize the synthesis process: select more environmentally friendly catalysts (such as organic acid catalysts) or improve the reaction conditions to reduce the use of tin compounds, but this method often has poor catalytic effect, and the yield of the obtained PEG-PCL block copolymer is low and the molecular weight distribution is wide; Second, strict purification: remove catalyst residues through multiple steps and repeated purification (such as dialysis, recrystallization, acid washing, etc.), but the cost is the waste of solvents and product losses, which ultimately increases production costs; In addition, the molecular weight may also be degraded during repeated washing, making it difficult to ensure the consistency of molecular weight before and after treatment.

[0005] The patent with authorization announcement number CN105315444B discloses a method for purifying an injectable polyethylene glycol monomethyl ether-polylactic acid amphiphilic block copolymer, which uses a strong acid cation exchange resin combined with microporous membrane filtration to remove tin, and can obtain a refined product with a tin content of less than 10 ppm. However, the method uses a large amount of ion exchange material, and the regeneration of the ion exchange material must also be considered when using this method, which will produce a large amount of acid and alkali waste liquid and the treatment cost is high.

[0006] Therefore, how to provide a polyethylene glycol-polycaprolactone block copolymer with high efficiency, good tin removal effect, high yield and no obvious molecular chain degradation is an urgent problem to be solved. Summary of the invention

[0007] In view of this, the present invention provides a method for purifying a medical polyethylene glycol-polycaprolactone block copolymer. The purification method adopted by the present invention can reduce the tin content to below 20 ppm, and the molecular weight does not change significantly before and after purification, the molecular weight distribution is narrow (PDI<1.4), and the loss of the refined product is small, less than 5%.

[0008] In a first aspect, the present invention provides a method for purifying a medical polyethylene glycol-polycaprolactone block copolymer, comprising the following steps:

[0009] The crude product of polyethylene glycol-polycaprolactone block copolymer is subjected to supercritical carbon dioxide extraction for 30 to 120 minutes; the extracted product is then dissolved in solvent one, filtered through alkaline quartz sand, the filtrate is concentrated, precipitated through solvent two, and the precipitate is dried to obtain the medical polyethylene glycol-polycaprolactone block copolymer.

[0010] In a second aspect, the present invention provides a medical polyethylene glycol-polycaprolactone block copolymer obtained by the above purification method.

[0011] In a third aspect, the present invention provides a polyethylene glycol-polycaprolactone block copolymer microsphere, which is prepared from the above-mentioned medical polyethylene glycol-polycaprolactone block copolymer.

[0012] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0013] The purification method of the medical polyethylene glycol-polycaprolactone block copolymer provided by the present invention adopts supercritical extraction combined with alkaline quartz sand filtration. The method has simple steps, short time and good tin removal effect. The tin content can be reduced to below 20ppm, and the molecular weight does not change significantly before and after purification. The product loss in the purification process is less than 5%. The solvent consumption in the purification process is small, and the tin salt catalyst obtained by supercritical extraction can be reused. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The drawings constituting part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute an improper limitation of the present invention. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0015] Figure 1 is a hydrogen nuclear magnetic resonance spectrum of the methoxy polyethylene glycol-polycaprolactone block copolymer of Example 1 of the present invention;

[0016] Figure 2 is the infrared spectrum of the methoxy polyethylene glycol-polycaprolactone block copolymer of Example 1 of the present invention;

[0017] Figure 3 This is a scanning electron microscope image of the methoxy polyethylene glycol-polycaprolactone block copolymer microspheres of Example 1 of the present invention. DETAILED DESCRIPTION

[0018] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0019] The present invention provides a method for purifying a medical polyethylene glycol-polycaprolactone block copolymer, comprising the following steps:

[0020] The crude product of polyethylene glycol-polycaprolactone block copolymer is subjected to supercritical carbon dioxide extraction for 30 to 120 minutes; the extracted product is then dissolved in solvent one, filtered through alkaline quartz sand, the filtrate is concentrated, precipitated through solvent two, and the precipitate is dried to obtain the medical polyethylene glycol-polycaprolactone block copolymer.

[0021] The present invention first uses supercritical carbon dioxide extraction to treat the crude polyethylene glycol-polycaprolactone block copolymer. Supercritical extraction has been initially applied in the extraction of active components of traditional Chinese medicines and the removal of heavy metals; however, when it is used for heavy metal removal, it is usually necessary to add suitable ligands, modifiers and special substrates to improve the removal effect of heavy metals, which is generally referred to as supercritical coordination extraction. However, the present invention finds that even without adding ligands, modifiers and special substrates, the present invention can still obtain good tin removal effects, reducing the difficulty and cost of processing. When carbon dioxide is used as a supercritical fluid, it has the advantages of fast extraction speed, high extraction rate, low extraction temperature, good biocompatibility, non-toxicity and pollution-free. The supercritical carbon dioxide extraction time will affect the tin removal effect. If the extraction time is too short, a good tin removal effect cannot be achieved, and if the extraction time is too long, the improvement of the tin removal effect will not be greatly affected.

[0022] In the present invention, the temperature of the supercritical carbon dioxide extraction is 30-70°C, more preferably 30-50°C; the extraction pressure is 10-30 MPa.

[0023] In the present invention, the ratio of the crude polyethylene glycol-polycaprolactone block copolymer to the solvent one is 1 g: (3-7) mL; the ratio of the crude polyethylene glycol-polycaprolactone block copolymer to the solvent two is 1 g: (8-15) mL. The filtrate is concentrated until the volume is reduced by 65-85%. The present invention does not impose any particular restrictions on the concentration method, and most of the solvent can be removed by reduced pressure distillation, rotary evaporation, evaporation, heating, etc.

[0024] In the present invention, the alkaline quartz sand is a mixture of alkaline substances and quartz sand, and the mass ratio of alkaline substances to quartz sand is (1-2): (8-9). The present invention uses alkaline quartz sand to filter the product after extraction and dissolution. The alkaline quartz sand can remove residual organic tin impurities from the product mixture and reduce it from the stoichiometric level to 20ppm. Furthermore, the alkaline substance is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and calcium carbonate. The present invention does not impose any special restrictions on the process of alkaline quartz sand filtration, and the alkaline quartz sand filtration method commonly used in the art can be used.

[0025] In the present invention, the preparation method of the polyethylene glycol-polycaprolactone block copolymer crude product is as follows: the dried polyethylene glycol, caprolactone and tin salt are reacted at a constant temperature under the protection of an inert gas, and then dissolved with a solvent three, precipitated with a solvent four and then vacuum dried to obtain a copolymer crude product.

[0026] In the present invention, the solvent one and the solvent three are each independently selected from one or more of dimethyl sulfoxide, chloroform, xylene, n-hexane, acetonitrile, dimethylformamide, ethyl acetate, dichloromethane, butanone, and ethanol; the solvent one and the solvent three need to have good solubility for the PEG-PCL block copolymer. In order to make the solvent easier to remove, the present invention is more preferably dichloromethane. The solvent two and the solvent four are each independently selected from one or more of ether, n-octane, isohexane, toluene or petroleum ether, and the above solvents are poor solvents for the PEG-PCL block copolymer, so that it is easy to collect and dry after precipitation.

[0027] The present invention does not impose any particular limitation on the drying methods of polyethylene glycol and caprolactone, as long as the water can be completely removed to avoid adverse effects on the reaction. The present invention does not impose any special restrictions on the type of polyethylene glycol, for example, it can be selected from various types of polyethylene glycol such as methoxy polyethylene glycol (mPEG), branched polyethylene glycol, multi-arm polyethylene glycol, and cross-linked polyethylene glycol; the present invention does not impose any special restrictions on its molecular weight, which can be 100 to 10000; the polyethylene glycol of the present invention is preferably one or more of mPEG100, mPEG200, mPEG300, mPEG400, mPEG600, mPEG1000, mPEG2000, mPEG4000, mPEG6000, mPEG8000, mPEG10000, PEG100, PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000, PEG8000 or PEG10000.

[0028] In the present invention, the mass ratio of polyethylene glycol to caprolactone is (20-80):(20-80), for example, it can be 30:70, 40:60, 70:30, etc. The mass fraction of the tin salt is 0.5-2wt%, which refers to the percentage of the mass of the tin salt to the total mass of the tin salt, polyethylene glycol and caprolactone. The tin salt is selected from one or more of tin methanesulfonate, dioctyltin, triphenyltin, triethyltin, tetramethyltin, dibutyltin dilaurate or stannous octoate; in one or more embodiments of the present invention, the tin salt is selected from stannous octoate.

[0029] In the present invention, the temperature of the isothermal reaction is 90-120°C, more preferably 100-110°C; the reaction time is 10-20h, more preferably 10-15h; the inert gas is one or more of nitrogen or rare gases, preferably nitrogen in the present invention. Before adding the tin salt, the inert gas needs to be introduced to remove oxygen and residual moisture in the reaction system.

[0030] The present invention provides a medical polyethylene glycol-polycaprolactone block copolymer obtained by the above purification method. The tin content of the medical polyethylene glycol-polycaprolactone block copolymer obtained by the above purification method of the present invention is below 20 ppm, meeting the performance requirements of medical filling materials.

[0031] The present invention also provides a polyethylene glycol-polycaprolactone block copolymer microsphere, which is prepared from the above-mentioned medical polyethylene glycol-polycaprolactone block copolymer. The preparation method can be a solvent volatilization method, a double emulsification method, a spray drying method, a supercritical dispersion method, a melting method or an ion gel method, etc. The obtained polyethylene glycol-polycaprolactone block copolymer microsphere can be used to prepare a baby face needle injection.

[0032] The technical solution of the present invention is further described below in conjunction with specific examples. The present invention has no special restrictions on the sources of the reagents used in the following examples, and commercial products known to those skilled in the art can be used. In the following examples, room temperature refers to 25±3°C.

[0033] Example 1

[0034] This embodiment provides a method for preparing and purifying a methoxy polyethylene glycol-polycaprolactone block copolymer and a method for preparing copolymer microspheres.

[0035] (1) Drying of raw materials: Place mPEG4000 in a vacuum drying oven at 50°C for 7 hours to remove moisture from the raw materials. Add an appropriate amount of calcium hydride to the caprolactone monomer, seal it, and place it in a desiccator for 48 hours to completely dry the monomer.

[0036] (2) Preparation of crude methoxypolyethylene glycol-polycaprolactone block copolymer: In a dry reactor, add 40g of the pretreated mPEG4000 and 40g of caprolactone monomer, seal the reactor, heat to 100°C, and purge at constant temperature for 1 hour under nitrogen protection to further remove residual moisture and oxygen. After cooling to room temperature, quickly add 0.81g of stannous octoate as a catalyst, heat to 110°C again, and keep constant temperature stirring for 12 hours. After the reaction is completed, the reaction product is cooled to room temperature and fully dissolved in 200mL of dichloromethane to obtain a uniform solution. The solution is slowly poured into 450mL of petroleum ether and stirred thoroughly to precipitate the polymer. Collect the precipitated polymer, and after vacuum filtration, transfer the solid to a vacuum drying oven and dry at 50°C to constant weight to obtain 78g of crude product with a yield of 96.5%.

[0037] (3) Purification of crude methoxypolyethylene glycol-polycaprolactone block copolymer: 40 g of the crude product from step (2) was placed in an extraction tank of a supercritical extraction device, and the supercritical carbon dioxide extraction temperature was set to 40° C. and the extraction pressure was set to 15 MPa. After the temperature reached the set value, CO was turned on. 2 Cylinder, open CO 2 Press the run button on the high-pressure pump to start pressurizing the liquid CO 2Enter the extraction tank through a high-pressure pump. After reaching the set pressure, stop the high-pressure pump. After extraction for 60 minutes, release the pressure and collect the extracted organic tin salt. Add 200mL of dichloromethane to the purified block copolymer obtained in the extraction tank, stir until completely dissolved, filter with 100g of alkaline quartz sand (the mass ratio of potassium carbonate to quartz sand is 2:8), and collect the filtrate. The filtrate is concentrated under reduced pressure by a rotary evaporator, and 450mL of petroleum ether is added to about 50mL of the concentrated solution for re-precipitation, and the precipitate is collected. Finally, the precipitate is placed in a vacuum drying oven and dried to constant weight at 50°C to obtain 38.96g of refined product with a yield of 97.38%.

[0038] The obtained refined product is subjected to nuclear magnetic resonance hydrogen spectrum measurement, such as Figure 1 As shown, the successful synthesis of PEG-PCL block copolymers was demonstrated. Figure 2 This is the infrared spectrum of the refined product obtained in this example, 1380cm -1 The left and right are the hydroxyl-OH bending vibration peaks; 1188cm -1 The left and right sides are -COC- stretching vibration absorption peaks; 1721cm -1 The left and right are carbonyl C=O stretching vibration absorption peaks; 2945, 2858cm -1 The stretching vibration peaks of CH are on the left and right; 3431cm -1 The broad peaks appearing on the left and right are the stretching vibration peaks of -OH, indicating that the polymer contains hydroxyl end groups.

[0039] (4) Preparation of methoxy polyethylene glycol-polycaprolactone block copolymer microspheres: Weigh 10 g of the refined product obtained in step (3), place it in a clean beaker, and add 20 mL of dichloromethane (DCM) as a solvent. Use a magnetic stirrer to stir at a speed of 500 rpm until it is completely dissolved to form a uniform colorless and transparent organic phase solution. If there is any solid that has not dissolved, the stirring time can be appropriately extended to ensure sufficient dissolution. In another clean beaker, weigh 1 g of polyvinyl alcohol (PVA), add 50 mL of pure water, heat and stir at 80°C until it is completely dissolved, and prepare a PVA aqueous solution with a mass fraction of 2%. After the solution is cooled to room temperature, it is set aside. At room temperature, the prepared organic phase solution is slowly added to the above-mentioned cooled PVA aqueous solution through a dropper or syringe. During this process, the aqueous phase needs to be stirred vigorously, the stirring speed is controlled at 600 rpm, and the dropping time is about 5 minutes. After the dropwise addition is completed, continue stirring for 15 minutes to initially form an emulsion. Subsequently, the mixed solution was transferred to an ultrasonic emulsifier and emulsified at a power of 300W, using intermittent ultrasound (working time 5 seconds, intermittent time 3 seconds) for 2 minutes (ultrasonic treatment can significantly improve the stability of the emulsion and control the particle size distribution of the microspheres). The ultrasonically emulsified emulsion was transferred to an open beaker, placed on a magnetic stirrer, and the speed was adjusted to 400 rpm. The organic solvent (DCM) was evaporated at room temperature to obtain a stable microsphere suspension. The obtained microsphere suspension was poured into a centrifuge tube, placed in a centrifuge, and centrifuged at 5000 rpm for 10 minutes. After centrifugation, the supernatant was discarded, and the precipitated microspheres were retained, which were then washed and dried to obtain filler microspheres. The results show that: Figure 3 As shown, the average diameter of the microspheres prepared by this method is about 36.5 μm, and the other indicators meet the industry standards.

[0040] Example 2

[0041] This embodiment provides a method for preparing and purifying a methoxy-polyethylene glycol polycaprolactone block copolymer and a method for preparing copolymer microspheres.

[0042] (1) Drying of raw materials: Place mPEG8000 in a vacuum drying oven at 50°C for 7 hours to remove moisture from the raw materials. Add an appropriate amount of calcium hydride to the caprolactone monomer, seal it, and place it in a desiccator for 48 hours to completely dry the monomer.

[0043] (2) Preparation of crude methoxypolyethylene glycol-polycaprolactone block copolymer: In a dry reactor, add 60g of mPEG8000 and 40g of caprolactone monomer after the above pretreatment, seal the reactor, heat it to 100°C, and purge it at constant temperature for 1 hour under nitrogen protection to further remove residual moisture and oxygen. After cooling to room temperature, quickly add 1.52g of stannous octoate as a catalyst, heat it to 110°C again, and keep the constant temperature stirring for 12 hours. After the reaction is completed, the reaction product is cooled to room temperature and fully dissolved in 300mL of dichloromethane to obtain a uniform solution. The solution is slowly poured into 600mL of petroleum ether and stirred thoroughly to precipitate the polymer. Collect the precipitated polymer, transfer the solid to a vacuum drying oven after vacuum filtration, and dry it to constant weight at 50°C to obtain 98.4g of crude product with a yield of 96.9%.

[0044] (3) Purification of crude methoxypolyethylene glycol-polycaprolactone block copolymer: 40 g of the crude product from step (2) was placed in an extraction tank of a supercritical extraction device, and the supercritical carbon dioxide extraction temperature was set to 50° C. and the extraction pressure was set to 20 MPa. After the temperature reached the set value, CO was turned on. 2 Cylinder, open CO 2 Press the run button on the high-pressure pump to start pressurizing the liquid CO 2 Enter the extraction tank through a high-pressure pump. After reaching the set pressure, stop the high-pressure pump. After extraction for 40 minutes, release the pressure and collect the extracted organic tin salt. Add 200mL of dichloromethane to the purified block copolymer obtained in the extraction tank, stir until completely dissolved, filter with 100g of alkaline quartz sand (the mass ratio of sodium carbonate to quartz sand is 2:8), and collect the filtrate. The filtrate is concentrated under reduced pressure by a rotary evaporator to remove the dichloromethane solvent. Add 450mL of petroleum ether to 50mL of the concentrated solution for re-precipitation, and collect the precipitate. Finally, place the precipitate in a vacuum drying oven and dry it to constant weight at 50°C to obtain 38.60g of refined product with a yield of 96.5%.

[0045] (4) Preparation of methoxy polyethylene glycol-polycaprolactone block copolymer microspheres: Weigh 15 g of the refined product obtained in step (3), place it in a clean beaker, and add 30 mL of dichloromethane (DCM) as a solvent. Use a magnetic stirrer to stir at a speed of 600 rpm until it is completely dissolved to form a uniform colorless and transparent organic phase solution. If there is any solid that has not dissolved, the stirring time can be appropriately extended to ensure sufficient dissolution. In another clean beaker, weigh 1.5 g of polyvinyl alcohol (PVA), add 50 mL of pure water, heat and stir at 80°C until it is completely dissolved, and prepare a PVA aqueous solution with a mass fraction of 3%. After the solution is cooled to room temperature, it is set aside. At room temperature, slowly add the prepared organic phase solution to the above-mentioned cooled PVA aqueous solution through a dropper or syringe. During this process, the aqueous phase needs to be stirred vigorously, the stirring speed is controlled at 800 rpm, and the dropping time is about 5 minutes. After the dropwise addition is completed, continue stirring for 15 minutes to initially form an emulsion. Subsequently, the mixed solution was transferred to an ultrasonic emulsifier and emulsified at a power of 300W, using intermittent ultrasound (working time 10 seconds, intermittent time 3 seconds) for 2 minutes (ultrasonic treatment can significantly improve the stability of the emulsion and control the particle size distribution of the microspheres). The ultrasonically emulsified emulsion was transferred to an open beaker, placed on a magnetic stirrer, the speed was adjusted to 500rpm, and the organic solvent (DCM) was evaporated at room temperature to obtain a stable microsphere suspension. The obtained microsphere suspension was poured into a centrifuge tube, placed in a centrifuge, and centrifuged at 5000rpm for 10 minutes. After centrifugation, the supernatant was discarded, the precipitated microspheres were retained, and then washed and dried to obtain filler microspheres. The average diameter of the microspheres prepared by this method is about 30.5μm, and the other indicators meet industry standards.

[0046] Example 3

[0047] This embodiment provides a method for preparing and purifying a methoxy polyethylene glycol-polycaprolactone block copolymer and a method for preparing copolymer microspheres.

[0048] (1) Drying of raw materials: Place mPEG10000 in a vacuum drying oven at 50°C for 7 hours to remove moisture from the raw materials. Add an appropriate amount of calcium hydride to the caprolactone monomer, seal it, and place it in a desiccator for 48 hours to completely dry the monomer.

[0049] (2) Preparation of crude methoxypolyethylene glycol-polycaprolactone block copolymer: 30 g of mPEG10000 and 70 g of caprolactone monomer after the above pretreatment were added to a dry reactor, the reactor was sealed, the temperature was raised to 100°C, and the reactor was purged at a constant temperature for 1 hour under nitrogen protection to further remove residual moisture and oxygen. After cooling to room temperature, 1.01 g of stannous octoate was quickly added as a catalyst, the temperature was raised to 110°C again, and the reaction was stirred at a constant temperature for 12 hours. After the reaction was completed, the reaction product was cooled to room temperature and fully dissolved in 200 mL of dichloromethane to obtain a uniform solution. The solution was slowly poured into 450 mL of petroleum ether and stirred thoroughly to precipitate the polymer. The precipitated polymer was collected, and after vacuum filtration, the solid was transferred to a vacuum drying oven and dried to constant weight at 50°C to obtain 98.1 g of crude product with a yield of 97.1%.

[0050] (3) Purification of crude methoxypolyethylene glycol-polycaprolactone block copolymer: 40 g of the crude product from step (2) was placed in an extraction tank of a supercritical extraction device, and the supercritical carbon dioxide extraction temperature was set to 40° C. and the extraction pressure was set to 10 MPa. After the temperature reached the set value, CO was turned on. 2 Cylinder, open CO 2 Press the run button on the high-pressure pump to start pressurizing the liquid CO 2 Enter the extraction tank through a high-pressure pump. After reaching the set pressure, stop the high-pressure pump. After extraction for 90 minutes, release the pressure and collect the extracted organic tin salt. Add 200mL of dichloromethane to the purified block copolymer obtained in the extraction tank, stir until completely dissolved, filter with 100g of alkaline quartz sand (the mass ratio of potassium carbonate to quartz sand is 1:9), and collect the filtrate. The filtrate is concentrated under reduced pressure by a rotary evaporator to remove the dichloromethane solvent. Add 450mL of petroleum ether to 50mL of the concentrated solution for re-precipitation, and collect the precipitate. Finally, place the precipitate in a vacuum drying oven and dry it to constant weight at 50°C to obtain 39.17g of refined product with a yield of 97.93%.

[0051] (4) Preparation of methoxy polyethylene glycol-polycaprolactone block copolymer microspheres: Weigh 10 g of the refined product obtained in step (3), place it in a clean beaker, and add 20 mL of dichloromethane (DCM) as a solvent. Use a magnetic stirrer to stir at a speed of 800 rpm until it is completely dissolved to form a uniform colorless and transparent organic phase solution. If there is any solid that has not dissolved, the stirring time can be appropriately extended to ensure sufficient dissolution. In another clean beaker, weigh 2.5 g of polyvinyl alcohol (PVA), add 50 mL of pure water, heat and stir at 80°C until it is completely dissolved, and prepare a PVA aqueous solution with a mass fraction of 5%. After the solution is cooled to room temperature, it is set aside. At room temperature, slowly add the prepared organic phase solution to the above-mentioned cooled PVA aqueous solution through a dropper or syringe. During this process, the aqueous phase needs to be stirred vigorously, the stirring speed is controlled at 600 rpm, and the dropping time is about 5 minutes. After the dropwise addition is completed, continue stirring for 15 minutes to initially form an emulsion. Subsequently, the mixed solution was transferred to an ultrasonic emulsifier and emulsified at a power of 300W, using intermittent ultrasound (working time 8 seconds, intermittent time 2 seconds) for 2 minutes (ultrasonic treatment can significantly improve the stability of the emulsion and control the particle size distribution of the microspheres). The ultrasonically emulsified emulsion was transferred to an open beaker, placed on a magnetic stirrer, the speed was adjusted to 400rpm, and the organic solvent (DCM) was volatilized at room temperature to obtain a stable microsphere suspension. The obtained microsphere suspension was poured into a centrifuge tube, placed in a centrifuge, and centrifuged at 5000rpm for 10 minutes. After centrifugation, the supernatant was discarded, the precipitated microspheres were retained, and then washed and dried to obtain filler microspheres. The average diameter of the microspheres prepared by this method is about 46.5μm, and the other indicators meet industry standards.

[0052] Comparative Example 1

[0053] The difference between this comparative example and Example 1 is that in step (3) of this comparative example, the extraction time of supercritical extraction is 10 minutes.

[0054] Comparative Example 2

[0055] The difference between this comparative example and Example 1 is that in step (3) of this comparative example, the alkaline quartz sand filtration step is not performed, and the product after supercritical extraction is directly stirred until it is completely dissolved, and then concentrated and precipitated.

[0056] Comparative Example 3

[0057] The difference between this comparative example and Example 1 is that in step (3) of this comparative example, the product after supercritical extraction is filtered only with quartz sand without adding potassium carbonate.

[0058] Comparative Example 4

[0059] The difference between this comparative example and Example 1 is that in step (3) of this comparative example, supercritical extraction is not used, and the crude product is directly stirred until it is completely dissolved, and then filtered, concentrated and precipitated using alkaline quartz sand. The specific steps of step (3) of this comparative example are as follows:

[0060] Take 40g of the crude product of step (2), add 200mL of dichloromethane, stir until completely dissolved, filter with 100g of alkaline quartz sand (the mass ratio of potassium carbonate to quartz sand is 2:8), and collect the filtrate. The filtrate is concentrated under reduced pressure by a rotary evaporator, and 450mL of petroleum ether is added to about 50mL of the concentrated solution for reprecipitation, and the precipitate is collected. Finally, the precipitate is placed in a vacuum drying oven and dried to constant weight at 50°C to obtain 39.23g of a refined product with a yield of 98.08%.

[0061] Comparative Example 5

[0062] The difference between this comparative example and Example 1 is that step (3) of this comparative example is as follows:

[0063] Take 40g of the crude product of step (2), add 200mL of dichloromethane, stir until completely dissolved, add 10mL of 1.0M hydrochloric acid for acidification, convert the organic tin therein into inorganic tin, wash repeatedly 3 times with 150mL*3 of deionized water, separate into layers, stand, and collect the dichloromethane phase. The collected solution is concentrated under reduced pressure by a rotary evaporator, 450mL of petroleum ether is added to about 50mL of the concentrated solution for reprecipitation, and the precipitate is collected. Finally, the precipitate is placed in a vacuum drying oven and dried to constant weight at 50°C to obtain 29.43g of a refined product with a yield of 73.58%.

[0064] Test example

[0065] The tin content of the crude product and the refined product of the embodiment and the comparative example was determined by inductively coupled plasma mass spectrometry (ICP-MS); the weight average molecular weight (Mw) of the crude product and the refined product of the embodiment and the comparative example and the molecular weight distribution (PDI) of the refined product were determined by gel permeation chromatography (GPC). The measurement results are shown in Table 1.

[0066] Table 1 Test results of crude product and refined product of Examples and Comparative Examples

[0067]

[0068] From the test results of the embodiments and comparative examples, it can be seen that the purification method of the present invention can efficiently remove the tin content in the crude product, and shortening the supercritical extraction time, not combining alkaline quartz sand filtration after supercritical extraction, combining ordinary quartz sand filtration after supercritical extraction, or only using alkaline quartz sand filtration without supercritical treatment can not reduce the tin content to below 20ppm. Acidification treatment will lead to product degradation and reduced yield after purification.

[0069] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for purifying a medical polyethylene glycol-polycaprolactone block copolymer, characterized in that: The steps include: The crude product of polyethylene glycol-polycaprolactone block copolymer is subjected to supercritical carbon dioxide extraction for 30 to 120 minutes; the extracted product is then dissolved in solvent one, filtered through alkaline quartz sand, the filtrate is concentrated, precipitated through solvent two, and the precipitate is dried to obtain the medical polyethylene glycol-polycaprolactone block copolymer.

2. The purification method according to claim 1, characterized in that The temperature of the supercritical carbon dioxide extraction is 30-70° C., and the extraction pressure is 10-30 MPa.

3. The purification method according to claim 1, characterized in that The usage ratio of the crude polyethylene glycol-polycaprolactone block copolymer to the solvent one is 1 g: (3-7) mL; the usage ratio of the crude polyethylene glycol-polycaprolactone block copolymer to the solvent two is 1 g: (8-15) mL; the filtrate is concentrated until the volume is reduced by 65-85%.

4. The purification method according to claim 1, characterized in that The alkaline quartz sand is a mixture of alkaline substances and quartz sand, and the mass ratio of the alkaline substances to the quartz sand is (1-2):(8-9); the alkaline substances are selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and calcium carbonate.

5. The purification method according to claim 1, characterized in that The preparation method of the polyethylene glycol-polycaprolactone block copolymer crude product is as follows: the dried polyethylene glycol, caprolactone and tin salt are reacted at a constant temperature under the protection of an inert gas, then dissolved with a solvent three, precipitated with a solvent four and then vacuum dried to obtain a copolymer crude product.

6. The purification method according to claim 5, characterized in that The solvent one and the solvent three are each independently selected from one or more of dimethyl sulfoxide, chloroform, xylene, n-hexane, acetonitrile, dimethylformamide, ethyl acetate, dichloromethane, butanone, and ethanol; the solvent two and the solvent four are each independently selected from one or more of ether, n-octane, isohexane, toluene, or petroleum ether.

7. The purification method according to claim 5, characterized in that The mass ratio of polyethylene glycol to caprolactone is (20-80):(20-80); the mass fraction of the tin salt is 0.5-2wt%; the tin salt is selected from one or more of tin methanesulfonate, dioctyltin, triphenyltin, triethyltin, tetramethyltin, dibutyltin dilaurate or stannous octoate.

8. The purification method according to claim 5, characterized in that The temperature of the isothermal reaction is 90-120° C., and the reaction time is 10-20 hours; the inert gas is one or more of nitrogen or rare gases.

9. The medical polyethylene glycol-polycaprolactone block copolymer obtained by the purification method according to any one of claims 1 to 8.

10. A polyethylene glycol-polycaprolactone block copolymer microsphere, characterized in that: It is prepared from the medical polyethylene glycol-polycaprolactone block copolymer described in claim 9.

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