Medical block copolymer and preparation method thereof

Abstract

The invention provides a medical block copolymer and a preparation method thereof.The preparation method of the medical block copolymer comprises the following steps that a polyethylene glycol initiator and a tin catalyst are mixed and then subjected to pre-activation treatment, and a pre-activation solution is obtained; adding a monomer and a first solvent into the pre-activation solution to carry out polymerization reaction; the monomer is selected from one or more of D, L-lactide, caprolactone, glycolide and L-lactide. According to the preparation method of the medical block copolymer provided by the invention, through the synergistic effect of an innovative catalyst-initiator in-situ pre-activation strategy and a subsequent mild polymerization process, the technical contradictions that initiation is delayed, reaction is out of control and impurity residues are difficult to consider at the same time in a traditional synthesis method are fundamentally solved. According to the method, synchronous initiation and growth of all polymer chains are ensured, so that a product with extremely narrow molecular weight distribution (PDilt; 1.2) and extremely high batch stability can be efficiently prepared under a mild condition.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a pharmaceutical block copolymer and its preparation method. Background Technology

[0002] Polyethylene glycol-polyester block copolymers, such as polyethylene glycol monomethyl ether-polylactic acid (mPEG-PLLA), polyethylene glycol-polylactic acid (PLLA-PEG-PLLA), polyethylene glycol monomethyl ether-polycaprolactone (mPEG-PCL), polyethylene glycol-polycaprolactone (PCL-PEG-PCL), polyethylene glycol monomethyl ether-polyglycolic acid-lactide (mPEG-PLGA), and polyethylene glycol-polyglycolic acid-lactide (PLGA-PEG-PLGA), are an important class of biomedical polymer materials. Due to their excellent biocompatibility, amphiphilicity, and biodegradability, they are widely used as nanomedicine carriers, micelle formulations, and injectable hydrogels, demonstrating enormous application potential in the biomedical field.

[0003] Currently, the industrial preparation of such copolymers mainly employs ring-opening polymerization (ROP). This method typically uses polyethylene glycol (PEG) or its monomethyl ether derivative (mPEG) as a macromolecular initiator, and cyclic ester monomers such as lactide (L-LA), caprolactone (α-CL), and glycolide (GA) as raw materials, undergoing polymerization under the action of catalysts such as stannous octoate. However, those skilled in the art have discovered in practice that this conventional "one-pot" synthesis method has a significant technical challenge: initiation retardation.

[0004] The lag effect in initiation mainly stems from two aspects: First, steric hindrance and encapsulation effects. In the reaction system, the hydrophilic mPEG / PEG molecular chains tend to form random coils, causing the terminal initiation active site, the -OH group, to be encapsulated within the chain segment, resulting in significant steric hindrance and making it difficult for them to effectively contact the hydrophobic cyclic monomer and catalyst center. Second, differences in reactivity. The nucleophilic attack capability of the terminal hydroxyl groups in mPEG / PEG is significantly weaker than that of the nucleophilicity of the terminal hydroxyl groups of newly formed polyester chains during polymerization. These two factors together lead to a polymerization initiation rate that is much lower than the chain growth rate, resulting in a significant reaction induction period and overall low efficiency.

[0005] To overcome or mitigate the aforementioned hysteresis effect, some solutions have been proposed in the prior art, but these solutions all have drawbacks: The first approach is to increase the reaction temperature, for example, by performing high-temperature melt polymerization above 130°C. While high temperatures can accelerate the overall reaction rate, they can trigger intense intramolecular / intermolecular transesterification reactions. This results in a wider product molecular weight distribution (PDI) (typically >1.5) and makes the product prone to high-temperature oxidation and yellowing, which does not meet the appearance standards for pharmaceutical excipients.

[0006] The second approach is to increase the amount of catalyst. To force the reaction to start, technicians often add excessive amounts of catalyst (such as stannous octoate). While this shortens the induction period, it leads to excessive levels of tin residue in the final product, which is unacceptable for pharmaceutical excipients subject to strict pharmacopoeia standards. Furthermore, excessive catalyst significantly increases the difficulty and cost of subsequent purification processes.

[0007] The third approach is to use conventional solution polymerization. Adding a solvent can reduce the viscosity of the system and improve mass transfer. However, the dilution effect of the solvent reduces the concentration of reactants, resulting in an extremely slow polymerization rate. The reaction time usually requires 24 to 48 hours or even longer, and the monomer conversion rate is often difficult to achieve the desired level, making it unsuitable for large-scale production. Summary of the Invention

[0008] This invention provides a pharmaceutical block copolymer and its preparation method, which solves the defects in the preparation of polyethylene glycol-polyester block copolymers, such as the inability to simultaneously consider reaction efficiency, product quality and tin residue control. Under mild conditions, it can effectively eliminate the initiation lag effect, realize a rapid and controllable polymerization reaction, and thus obtain a block copolymer with narrow molecular weight distribution, high purity and meeting pharmaceutical grade standards.

[0009] According to a first aspect of the present invention, the present invention provides a method for preparing a pharmaceutical block copolymer, comprising the following steps: A pre-activated solution was obtained by mixing a polyethylene glycol initiator with a tin catalyst and then performing a pre-activation treatment. A monomer and a first solvent are added to the pre-activated solution to carry out a polymerization reaction; the monomer is selected from one or more of D,L-lactide, caprolactone, glycolide, and L-lactide.

[0010] Unlike existing technologies that combine monomers, initiators, and catalysts in a single process, this invention provides a method for preparing pharmaceutical block copolymers. First, a polyethylene glycol initiator and a tin catalyst are pre-activated. Utilizing the coordination mechanism between tin in the tin catalyst and the hydroxyl groups in the polyethylene glycol initiator, a coordination exchange reaction is forced between tin and the terminal hydroxyl groups before the monomer is added, forming a highly active tin-macroalkoxy (Sn-O-PEG) species. Once this active species comes into contact with monomers such as lactide and caprolactone, it can rapidly initiate ring-opening without an induction period. Thus, under mild solution polymerization conditions, high polymerization rate, ultra-narrow molecular weight distribution (PDI < 1.2), and low tin residue are simultaneously achieved.

[0011] According to the preparation method of the pharmaceutical block copolymer of the present invention, the pre-activation treatment involves mixing a polyethylene glycol initiator with a tin catalyst, evacuating the mixture under vacuum at 50-80°C for 40-80 min, and then stirring the mixture at 50-80°C for 10-90 min.

[0012] This invention employs a specific pre-activation treatment to thoroughly remove trace amounts of moisture from the system, avoiding the problems of uncontrolled molecular weight and broadened distribution caused by water acting as an impurity initiator. These specific conditions efficiently drive the coordination reaction between the tin catalyst and the terminal hydroxyl groups of the polyethylene glycol initiator, generating highly active tin-macromolecule alkoxy species in situ. By activating and purifying the initiator before polymerization begins, the initiation hysteresis period can be fundamentally eliminated, ensuring the synchronous growth of all polymer chains, thereby enabling the stable preparation of high-quality copolymers with extremely narrow molecular weight distribution and high batch stability.

[0013] In this invention, the pre-activation conditions vary depending on the molecular weight and type of the polyethylene glycol initiator. For low molecular weight polyethylene glycol initiators (e.g., 500-5000 Da), pre-activation by stirring for 10-60 minutes after vacuuming at 50-70°C is sufficient. For high molecular weight polyethylene glycol initiators (e.g., 5000-10000 Da), the activation temperature is usually raised to 70-80°C, and the activation time after vacuuming is extended to 60-90 minutes.

[0014] Preferably, the stirring reaction is carried out under the protection of an inert gas. The inert gas, for example, is high-purity nitrogen or argon with a purity greater than 99.99%.

[0015] According to the preparation method of the pharmaceutical block copolymer of the present invention, the amount of tin catalyst added is 0.05-0.1% of the monomer mass, for example, it can be 0.05%, 0.06%, 0.07%, 0.08%, 0.09% or 0.1%, etc., and of course, it can also be other values ​​within the above range, which are not limited here.

[0016] Because the pre-activation step of this invention improves the atom utilization efficiency of the catalyst, it enables the achievement of high conversion rates that traditional methods require excess catalyst, using only a very small amount of catalyst. This invention limits the amount of tin catalyst to 0.05-0.1%, ensuring efficient polymerization while directly controlling the residual tin content in the final product to an extremely low level (e.g., below 90 ppm). This eliminates the need for additional complex and expensive tin removal purification steps, meeting stringent pharmaceutical standards and solving the problem of excessive heavy metal residues in pharmaceutical excipients at its source.

[0017] Preferably, the tin catalyst is selected from one or more organotin catalysts; the organotin catalyst includes one or more of stannous octoate, tri-n-butylmethoxytin, and dioctyltin dilaurate.

[0018] According to the preparation method of the pharmaceutical block copolymer of the present invention, the amount of polyethylene glycol initiator added is 10-35% of the monomer mass, for example, it can be 10%, 15%, 20%, 25%, 30% or 35%, etc., and of course, it can also be other values ​​within the above range, which are not limited here.

[0019] Preferably, the polyethylene glycol initiator is selected from one or both of polyethylene glycol and polyethylene glycol monomethyl ether.

[0020] Preferably, the number average molecular weight of the polyethylene glycol initiator is 500-10000 Da.

[0021] According to the preparation method of the pharmaceutical block copolymer of the present invention, when the number average molecular weight of the polyethylene glycol initiator is greater than 5000 Da and less than or equal to 10000 Da, the polyethylene glycol initiator, the second solvent and the tin catalyst are mixed and then subjected to pre-activation treatment.

[0022] High molecular weight initiators are viscous in the molten state, which makes it difficult to disperse the catalyst uniformly and results in incomplete pre-activation reaction. This invention reduces the viscosity of the system and improves its flowability by adding a second solvent, thereby ensuring that the catalyst and the terminal hydroxyl groups of the initiator can fully and uniformly contact and react.

[0023] Preferably, the amount of the second solvent added is 20-100% of the mass of the polyethylene glycol initiator; the second solvent is selected from one or more of toluene, xylene, chlorobenzene and dichlorobenzene.

[0024] According to the preparation method of the pharmaceutical block copolymer of the present invention, the weight ratio of the first solvent to the monomer is (0.5-4):1; the first solvent is selected from one or more of xylene, toluene and dichlorobenzene.

[0025] The raw materials for preparing the pharmaceutical block copolymer, by weight, include: 1.5-5 parts of the polyethylene glycol initiator, 0.008-0.016 parts of the tin catalyst, 15-27 parts of the monomer, and 10-60 parts of the first solvent.

[0026] According to the preparation method of the pharmaceutical block copolymer of the present invention, the polymerization reaction is carried out at a temperature of 110-120°C for a time of 10-14 hours.

[0027] The polymerization temperature of this invention is much lower than that of traditional high-temperature melt polymerization (>130℃), which can greatly suppress side reactions such as intramolecular / intermolecular transesterification and thermal oxidative degradation, ensuring that the final product has an extremely narrow molecular weight distribution (PDI) and a pure white appearance. This invention can drive the polymerization reaction to proceed efficiently under mild temperature and reasonable time conditions of 10-14h, achieving a high conversion rate, and solving the problems of slow reaction rate and long production cycle of traditional low-temperature solution polymerization.

[0028] The method for preparing pharmaceutical block copolymers according to the present invention further includes the following steps: After the polymerization reaction is completed, a diluent is added to the reaction solution for dilution; the diluted reaction solution is added to a poor solvent at a temperature of -5 to 5°C for precipitation to obtain a solid crude product; the obtained solid crude product is then dried.

[0029] This invention uses a diluent to reduce the viscosity of the reaction solution, ensuring uniformity and efficiency in the subsequent precipitation process. Precipitation is carried out in a low-temperature, poorly resistant solvent at -5 to 5°C. On one hand, this utilizes solubility differences to efficiently remove unreacted monomers and residual catalysts, significantly improving product purity and whiteness. On the other hand, the low-temperature environment provides rapid quenching, instantly freezing and locking the polymer chain structure, thus perfectly maintaining the high uniformity and narrow molecular weight distribution obtained during the mild polymerization stage. The final product is a pure, white, high-quality solid product, meeting the appearance requirements of high-end implantable and injectable formulations.

[0030] According to the method for preparing pharmaceutical block copolymers of the present invention, the diluent is selected from one or more of dichloromethane, trichloromethane, ethyl acetate, and tetrahydrofuran.

[0031] According to the preparation method of the pharmaceutical block copolymer of the present invention, the amount of diluent added is 30%-100% of the mass of the reaction solution.

[0032] According to the preparation method of the pharmaceutical block copolymer of the present invention, the undesirable solvent is selected from one or more of methanol, ethanol, diethyl ether, isopropanol and n-hexane.

[0033] According to the preparation method of the pharmaceutical block copolymer of the present invention, the diluted reaction solution is slowly added dropwise at a rate of 5-15 mL / min to a poor solvent at a temperature of -5-5℃ (preferably -1-1℃) to precipitate.

[0034] According to the preparation method of the pharmaceutical block copolymer of the present invention, the drying is carried out in a vacuum oven at 30-50°C for 10-14 hours.

[0035] According to a second aspect of the present invention, the present invention also provides a pharmaceutical block copolymer prepared by the above-described preparation method.

[0036] According to the present invention, the pharmaceutical block copolymer has a number-average molecular weight of 5-50 kDa; the molecular weight distribution (PDI) of the pharmaceutical block copolymer is <1.2; and the residual tin content in the pharmaceutical block copolymer is ≤90 ppm.

[0037] The method for preparing pharmaceutical block copolymers provided by this invention fundamentally solves the technical contradictions of traditional synthesis methods, namely, the difficulty in simultaneously addressing initiation retardation, reaction runaway, and impurity residue, through the synergistic effect of an innovative in-situ pre-activation strategy of catalyst-initiator and subsequent mild polymerization process. This method ensures simultaneous initiation and growth of all polymer chains, thereby enabling the efficient preparation of products with extremely narrow molecular weight distribution (PDI < 1.2) and extremely high batch stability under mild conditions. Simultaneously, the significantly improved catalytic efficiency results in a substantial reduction in catalyst dosage, leading to a final product with extremely low tin residue and a pure white appearance, fully meeting the stringent standards of high-end pharmaceutical excipients, and achieving a balance between high efficiency, high purity, and high quality. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0039] Example 1 This embodiment provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA (1k-14k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 1.5 g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=1000 Da) to a dry reactor. Add 8.5 mg of the catalyst stannous octoate. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 60°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for 10 min to complete the pre-activation.

[0040] Step 2: Mild solution polymerization Add 15 g of monomer L-lactide (L-LA) to the reactor. Add 30 g of solvent xylene (to bring the system to a solution state). Heat to 110°C and react at this temperature for 12 h with stirring.

[0041] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 15 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0°C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0042] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product mPEG-PLLA.

[0043] Results: Molecular weight (GPC determination): Mn≈15 kDa (highly consistent with theoretical design). Molecular weight distribution (PDI): 1.12 (extremely narrow distribution, superior to similar commercially available products). Tin residue (ICP-MS determination): 88 ppm (meets pharmaceutical standards, and this level was achieved without special tin-removing resin treatment, demonstrating the feasibility of low catalyst dosage). Appearance: Pure white powder, no yellowing.

[0044] Comparative Example 1 This comparative example provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA, which uses a traditional one-pot solution polymerization method and includes the following steps: 1.5 g mPEG (Mn = 1000 Da), 15 g lactide, 8.5 mg stannous octoate, and 30 g xylene were simultaneously added to a reaction vessel (the initiator was not pre-activated). The mixture was heated to 110 °C and reacted at this temperature for 12 h with stirring. After the reaction was complete, the reaction solution was cooled, and 15 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min.

[0045] The results showed that due to the lack of pre-activation, the initiation efficiency was low, the monomer conversion rate was only 65%, the Mn was low (about 9 kDa), and the PDI was wide (1.35), indicating that the chain growth was uneven.

[0046] Comparative Example 2 This comparative example provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA, which uses a traditional one-pot solution polymerization method and adds more stannous octoate compared to Comparative Example 1. The method includes the following steps: 1.5 g mPEG, 15 g lactide, 25.5 mg stannous octoate, and 30 g xylene were simultaneously added to a reaction vessel (the initiator was not pre-activated), and the mixture was heated to 110 °C and reacted at this temperature for 12 h with stirring. After the reaction was completed, the reaction solution was cooled, and 15 g dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min.

[0047] The results showed that Mn was approximately 15 kDa, PDI was 1.25, and the product was yellowish. Compared with Example 1, if medical-grade mPEG-PLLA with a similar molecular weight and narrow PDI is to be obtained within the same reaction time, stannous octoate needs to be added twice as much. The introduction of tin will cause the product to turn yellow and be difficult to remove, making it unsuitable for the medical field.

[0048] Comparative Example 3 This comparative example provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA, comprising the following steps: 1.5 g mPEG, 15 g lactide, and 8.5 mg stannous octoate were simultaneously added to a reaction vessel, and the temperature was raised to 150 °C. The reaction was carried out at this temperature for 12 h with stirring. After the reaction was completed, the reaction system was cooled, and 15 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min.

[0049] Reaction results: Although the reaction was fast, the product was slightly yellow in appearance (thermal oxidation), the PDI was as wide as 1.6, the GPC elution curve was bimodal (severe transesterification), and due to the high viscosity, the tin catalyst was difficult to remove in the post-treatment, resulting in a high residual amount (>150 ppm).

[0050] Comparative Example 4 This comparative example provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA (1k-14k), comprising the following steps: Step 1: Dehydration and pre-activation of the system 1.5 g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=1000 Da) was added to a dry reactor. 8.5 mg of the catalyst stannous octoate was then added. High-purity nitrogen was then introduced for protection, and the mixture was stirred at the same temperature for 10 min to complete the pre-activation. This step was the same as in Example 1, except that a vacuum was not applied at 60°C; the rest of the operation remained the same.

[0051] Step 2: Mild solution polymerization Add 15 g of monomer L-lactide (L-LA) to the reactor. Add 30 g of solvent xylene (to bring the system to a solution state). Heat to 110°C and react at this temperature for 12 h with stirring.

[0052] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 15 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0°C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0053] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product mPEG-PLLA.

[0054] Results: Molecular weight (GPC determination): Mn≈9 kDa (lower than the theoretical molecular weight, presumably due to the lack of vacuuming at 60℃, resulting in higher water content in mPEG and stannous octoate, leading to a lower molecular weight). Molecular weight distribution (PDI): 1.21. Tin residue (ICP-MS determination): 89 ppm. Appearance: Pure white powder, no yellowing.

[0055] Example 2 This embodiment provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA (2k-14k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 3g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=2000Da) to a dry reactor. Add 9.2mg of the catalyst stannous octoate. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 60°C for 60 minutes. Then, purge with high-purity nitrogen and continue stirring at the same temperature for 10 minutes to complete the pre-activation.

[0056] Step 2: Mild solution polymerization Add 15 g of monomer L-lactide (L-LA) to the reactor. Add 30 g of solvent xylene (to bring the system to a solution state). Heat to 110 °C and carry out the reaction at a constant temperature for 12 h with stirring.

[0057] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 15 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0°C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0058] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 hours to obtain the final product mPEG-PLLA.

[0059] Results: Molecular weight (GPC determination): Mn≈16kDa (highly consistent with theoretical design). Molecular weight distribution (PDI): 1.14 (extremely narrow distribution, superior to commercially available similar products). Tin residue (ICP-MS determination): 79 ppm (meets pharmaceutical standards, and this level was achieved without special tin removal resin treatment, demonstrating the feasibility of low catalyst dosage). Appearance: Pure white powder, no yellowing.

[0060] Example 3 This embodiment provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA (5k-36k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 2.5 g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=5000 Da) to a dry reactor. Add 9.0 mg of the catalyst stannous octoate. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 70°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for another 60 min to complete the pre-activation.

[0061] Step 2: Mild solution polymerization Add 15 g of monomer L-lactide (L-LA) to the reactor. Add 45 g of solvent xylene (to bring the system to a solution state). Heat to 120°C and carry out the reaction at a constant temperature for 12 h with stirring.

[0062] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 30 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0°C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0063] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product mPEG-PLLA.

[0064] Results: Molecular weight (GPC determination): Mn≈41 kDa (highly consistent with theoretical design). Molecular weight distribution (PDI): 1.13 (extremely narrow distribution, superior to similar commercially available products). Tin residue (ICP-MS determination): 68 ppm (meets pharmaceutical standards, and this level was achieved without special tin-removing resin treatment, demonstrating the feasibility of low catalyst dosage). Appearance: Pure white powder, no yellowing.

[0065] Example 4 This embodiment provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA (10k-36k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 2.5 g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=10000 Da) to a dry reactor. Add 10.0 mg of the catalyst stannous octoate, followed by 1 g of xylene. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 60–80 °C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for 90 min to complete the pre-activation.

[0066] Step 2: Mild solution polymerization Add 15g of monomer L-lactide (L-LA) and 60g of solvent xylene to the reactor (to bring the system to a solution state). Heat to 120℃ and carry out the reaction at a constant temperature for 12h with stirring.

[0067] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 30 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0068] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product mPEG-PLLA.

[0069] Results: Molecular weight (GPC determination): Mn≈47 kDa (highly consistent with theoretical design). Molecular weight distribution (PDI): 1.19 (extremely narrow distribution, superior to commercially available similar products). Tin residue (ICP-MS determination): 81 ppm (meets pharmaceutical standards, and this level was achieved without special tin-removing resin treatment, demonstrating the feasibility of low catalyst dosage). Appearance: Pure white powder, no yellowing.

[0070] Comparative Example 5 This comparative example provides a method for preparing a pharmaceutical block copolymer mPEG-PLLA, which includes the following steps: 2.5 g mPEG (Mn = 10000 Da), 15 g lactide, 10 mg stannous octoate, and 60 g xylene were simultaneously added to a reaction vessel (the initiator was not pre-activated). The mixture was heated to 110 °C and reacted at this temperature for 12 h with stirring. After the reaction was complete, the reaction solution was cooled, and 30 g dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min.

[0071] The results showed that due to the lack of pre-activation, the initiation efficiency was low, the monomer conversion rate was only 45%, Mn≈25 kDa, and the side reactions were obvious. The product was black in color and the PDI was wide (1.53).

[0072] Example 5 This embodiment provides a method for preparing a pharmaceutical block copolymer mPEG-PCL (5k-15k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 5.0 g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=5000 Da) to a dry reactor. Add 15 mg of the catalyst stannous octoate. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 70°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for another 60 min to complete the pre-activation.

[0073] Step 2: Mild solution polymerization Add 15g of the monomer caprolactone (ε-CL) and 10g of the solvent xylene to the reactor (to bring the system to a solution state). Heat to 120℃ and carry out the reaction at a constant temperature for 12h with stirring.

[0074] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 30 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0075] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product mPEG-PCL.

[0076] Results: Molecular weight (GPC determination): Mn≈20.6 kDa (highly consistent with theoretical design). Molecular weight distribution (PDI): 1.12 (extremely narrow distribution, superior to similar commercially available products). Tin residue (ICP-MS determination): 69 ppm. Appearance: Pure white powder, no yellowing.

[0077] Example 6 This embodiment provides a method for preparing a pharmaceutical block copolymer mPEG-PLGA (1k-6.5k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 4.2 g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=1000Da) to a dry reactor. Add 16 mg of the catalyst stannous octoate. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 60°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for 10 min to complete the pre-activation.

[0078] Step 2: Mild solution polymerization Add 15g of monomers lactide (D,L-LA) and 12g of glycolide (GA) to the reactor, along with 45g of xylene solvent (to bring the system to a solution state). Heat to 120℃ and react at this temperature for 12 hours with stirring.

[0079] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 50 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0080] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product mPEG-PLGA.

[0081] Results: Molecular weight (GPC determination): Mn≈8 kDa. Molecular weight distribution (PDI): 1.14. Tin residue: 69 ppm. Appearance: Pure white powder, no yellowing.

[0082] Example 7 This embodiment provides a method for preparing a pharmaceutical block copolymer PLLA-PEG-PLLA (6k-2k-6k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 2.5 g of polyethylene glycol (PEG, Mn=2000Da) as a macromolecular initiator to a dry reactor. Add 8 mg of stannous octoate catalyst. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 60°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for 20 min to complete the pre-activation.

[0083] Step 2: Mild solution polymerization Add 15g of monomeric lactide (L-LA) and 30g of solvent xylene to the reactor (to bring the system to a solution state). Heat to 120℃ and carry out the reaction at a constant temperature for 12 hours with stirring.

[0084] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 50 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0085] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product PLLA-PEG-PLLA.

[0086] Results: Molecular weight (GPC determination): Mn≈14 kDa. Molecular weight distribution (PDI): 1.13. Tin residue: 75 ppm. Appearance: Pure white powder, no yellowing.

[0087] Example 8 This embodiment provides a method for preparing a pharmaceutical block copolymer PCL-PEG-PCL (10k-5k-10k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 3.75 g of the macromolecular initiator polyethylene glycol (PEG, Mn=5000Da) to a dry reactor. Add 8 mg of the catalyst stannous octoate. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 70°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for another 60 min to complete the pre-activation.

[0088] Step 2: Mild solution polymerization Add 15g of the monomer caprolactone (ε-CL) and 40g of the solvent xylene to the reactor (to bring the system to a solution state). Heat to 110℃ and carry out the reaction at a constant temperature for 12h with stirring.

[0089] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 50 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0090] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product PCL-PEG-PCL.

[0091] Results: Molecular weight (GPC determination): Mn≈24 kDa. Molecular weight distribution (PDI): 1.14. Tin residue: 80 ppm. Appearance: Pure white powder, no yellowing.

[0092] Example 9 This embodiment provides a method for preparing a pharmaceutical block copolymer PLGA-PEG-PLGA (5k-2k-5k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 3.6 g of polyethylene glycol (PEG, Mn=2000Da) as a macromolecular initiator to a dry reactor. Add 12 mg of stannous octoate catalyst. Note: No monomer or solvent is added at this stage. Evacuate the reactor at 60°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for 20 min to complete the pre-activation.

[0093] Step 2: Mild solution polymerization Add 15g of monomers lactide (D,L-LA) and 3g of glycolide (GA) to the reactor, along with 40g of xylene solvent (to bring the system to a solution state). Heat to 110℃ and react at this temperature for 12 hours with stirring.

[0094] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 50 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0095] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product PLGA-PEG-PLGA.

[0096] Results: Molecular weight (GPC determination): Mn≈12 kDa. Molecular weight distribution (PDI): 1.15. Tin residue: 81 ppm. Appearance: Pure white powder, no yellowing.

[0097] Example 10 This embodiment provides a method for preparing a pharmaceutical block copolymer mPEG-PLA (1k-6.5k), comprising the following steps: Step 1: Dehydration and pre-activation of the system Add 4.2 g of the macromolecular initiator polyethylene glycol monomethyl ether (mPEG, Mn=1000Da) to a dry reactor. Add 20 mg of the catalyst tri-n-butylmethoxytin. Evacuate the reactor at 60°C for 60 min. Then, purge with high-purity nitrogen and continue stirring at the same temperature for 10 min to complete the pre-activation.

[0098] Step 2: Mild solution polymerization Add 27g of monomeric lactide (D,L-LA) and 50g of solvent xylene to the reactor (to bring the system to a solution state). Heat to 110℃ and react at this temperature for 12 hours with stirring.

[0099] Step 3: Precipitation and purification After the reaction was completed, the reaction solution was cooled, and 40 g of dichloromethane (DCM) was added to the crude product for dilution and dissolution. The dissolved system was then slowly added dropwise to anhydrous methanol (a poor solvent) at 0 °C using a peristaltic pump at a rate of 10 mL / min to precipitate the product. The precipitate was obtained by filtration to obtain the solid crude product.

[0100] Step 4: Drying The solid was dried in a vacuum oven at 40°C for 12 h to obtain the final product mPEG-PLA.

[0101] Results: Molecular weight (GPC determination): Mn≈7 kDa. Molecular weight distribution (PDI): 1.14. Tin residue: 78 ppm. Appearance: Pure white powder, no yellowing.

[0102] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a pharmaceutical block copolymer, characterized in that, Includes the following steps: A pre-activated solution was obtained by mixing a polyethylene glycol initiator with a tin catalyst and then performing a pre-activation treatment. A monomer and a first solvent are added to the pre-activated solution to carry out a polymerization reaction; the monomer is selected from one or more of D,L-lactide, caprolactone, glycolide, and L-lactide.

2. The method for preparing the pharmaceutical block copolymer according to claim 1, characterized in that, The pre-activation treatment involves mixing a polyethylene glycol initiator with a tin catalyst, evacuating the mixture under vacuum at 50-80°C for 40-80 minutes, and then stirring the mixture at 50-80°C for 10-90 minutes. Preferably, the stirring reaction is carried out under the protection of an inert gas.

3. The method for preparing the pharmaceutical block copolymer according to claim 1 or 2, characterized in that, The amount of tin catalyst added is 0.05-0.1% of the monomer mass; Preferably, the tin catalyst is selected from one or more organotin catalysts; the organotin catalyst includes one or more of stannous octoate, tri-n-butylmethoxytin, and dioctyltin dilaurate.

4. The method for preparing the pharmaceutical block copolymer according to any one of claims 1-3, characterized in that, The amount of the polyethylene glycol initiator added is 10-35% of the monomer mass; Preferably, the polyethylene glycol initiator is selected from one or both of polyethylene glycol and polyethylene glycol monomethyl ether; Preferably, the number average molecular weight of the polyethylene glycol initiator is 500-10000 Da.

5. The method for preparing the pharmaceutical block copolymer according to claim 4, characterized in that, When the number average molecular weight of the polyethylene glycol initiator is greater than 5000 Da and less than or equal to 10000 Da, the polyethylene glycol initiator, the second solvent and the tin catalyst are mixed and then pre-activated. Preferably, the amount of the second solvent added is 20%-100% of the mass of the polyethylene glycol initiator; the second solvent is selected from one or more of toluene, xylene, chlorobenzene and dichlorobenzene.

6. The method for preparing the pharmaceutical block copolymer according to any one of claims 1-5, characterized in that, The weight ratio of the first solvent to the monomer is (0.5-4):1; the first solvent includes one or more of xylene, toluene, and dichlorobenzene.

7. The method for preparing the pharmaceutical block copolymer according to any one of claims 1-6, characterized in that, The polymerization reaction is carried out at a temperature of 110-120℃ for 10-14 hours.

8. The method for preparing the pharmaceutical block copolymer according to any one of claims 1-7, characterized in that, It also includes the following steps: After the polymerization reaction is completed, a diluent is added to the reaction solution for dilution; the diluted reaction solution is then added to a poor solvent at a temperature of -5 to 5°C for precipitation to obtain a solid crude product; the obtained solid crude product is then dried. Preferably, the diluent is selected from one or more of dichloromethane, trichloromethane, ethyl acetate, and tetrahydrofuran; Preferably, the undesirable solvent is selected from one or more of methanol, ethanol, diethyl ether, isopropanol, and n-hexane.

9. A block copolymer for pharmaceutical use, characterized in that, It is prepared by the preparation method according to any one of claims 1-8.

10. The pharmaceutical block copolymer according to claim 9, characterized in that, The number-average molecular weight of the pharmaceutical block copolymer is 5-50 kDa; the molecular weight distribution (PDI) of the pharmaceutical block copolymer is <1.2; and the residual tin content in the pharmaceutical block copolymer is ≤90 ppm.