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CN-122011349-A - Block copolymer for medicine and preparation method thereof

CN122011349ACN 122011349 ACN122011349 ACN 122011349ACN-122011349-A

Abstract

The invention provides a medical block copolymer and a preparation method thereof, and the medical block copolymer and the preparation method thereof provided by the invention comprise the following steps of mixing a polyethylene glycol initiator and a tin catalyst and then performing preactivation treatment to obtain preactivation liquid; adding a monomer and a first solvent into the preactivation liquid for polymerization reaction, wherein the monomer is one or more of D, L-lactide, caprolactone, glycolide and L-lactide. The preparation method of the medical segmented copolymer provided by the invention fundamentally solves the technical contradiction that the initiation of hysteresis, reaction runaway and impurity residue are difficult to be compatible in the traditional synthesis method through the synergistic effect of an innovative catalyst-initiator in-situ preactivation strategy and a subsequent mild polymerization process. The method ensures that all polymer chains are synchronously initiated and grown, so that products with extremely narrow molecular weight distribution (PDI < 1.2) and extremely high batch stability can be efficiently prepared under mild conditions.

Inventors

  • PAN LONG
  • WANG YUBO
  • LI YAN
  • ZHANG CHEN
  • ZHANG WANYU

Assignees

  • 天津普立美特科技有限公司

Dates

Publication Date
20260512
Application Date
20260325

Claims (10)

  1. 1. A method for preparing a block copolymer for medicine, which is characterized by comprising the following steps: Mixing polyethylene glycol initiator with tin catalyst, and performing preactivation treatment to obtain preactivation liquid; and adding a monomer and a first solvent into the preactivation liquid to carry out polymerization reaction, wherein the monomer is one or more of D, L-lactide, caprolactone, glycolide and L-lactide.
  2. 2. The method for preparing a block copolymer for medicine according to claim 1, wherein the pre-activation treatment is to mix polyethylene glycol initiator with tin catalyst, vacuum-pump for 40-80min at 50-80 ℃, and stir and react for 10-90min at 50-80 ℃; Preferably, the stirring reaction is carried out under the protection of inert gas.
  3. 3. The method for producing a block copolymer for medicine according to claim 1 or 2, wherein the tin catalyst is added in an amount of 0.05 to 0.1% by mass of the monomer; Preferably, the tin catalyst is selected from one or more of organotin catalysts, including one or more of stannous octoate, tri-n-butyl methoxytin and dioctyltin dilaurate.
  4. 4. A method of preparing a medical block copolymer according to any one of claims 1 to 3, wherein the polyethylene glycol initiator is added in an amount of 10 to 35% of the mass of the monomer; Preferably, the polyethylene glycol initiator is selected from one or two of polyethylene glycol and polyethylene glycol monomethyl ether; preferably, the polyethylene glycol initiator has a number average molecular weight of 500-10000Da.
  5. 5. The method for producing a block copolymer for medicine according to claim 4, wherein when the number average molecular weight of the polyethylene glycol initiator is greater than 5000Da and less than 10000Da, the polyethylene glycol initiator, the second solvent and the tin catalyst are mixed and then subjected to a pre-activation treatment; preferably, the addition amount of the second solvent is 20-100% of the mass of the polyethylene glycol initiator, and the second solvent is one or more selected from toluene, xylene, chlorobenzene and dichlorobenzene.
  6. 6. The method according to any one of claims 1 to 5, wherein the weight ratio of the first solvent to the monomer is (0.5 to 4): 1, and the first solvent comprises one or more of xylene, toluene and dichlorobenzene.
  7. 7. The method for producing a block copolymer for medicine according to any one of claims 1 to 6, wherein the polymerization reaction is carried out at a temperature of 110 to 120 ℃ for a time of 10 to 14 hours.
  8. 8. The method for producing a block copolymer for medicine according to any one of claims 1 to 7, further comprising the steps of: Adding a diluent into the reaction liquid to dilute after the polymerization reaction is finished, adding the diluted reaction liquid into a poor solvent with the temperature of-5-5 ℃ to precipitate to obtain a solid crude product, and drying the obtained solid crude product; Preferably, the diluent is selected from one or more of dichloromethane, chloroform, ethyl acetate and tetrahydrofuran; Preferably, the poor solvent is selected from one or more of methanol, ethanol, diethyl ether, isopropanol and n-hexane.
  9. 9. A block copolymer for pharmaceutical use, characterized by being prepared by the preparation method according to any one of claims 1 to 8.
  10. 10. The block copolymer according to claim 9, wherein the number average molecular weight of the block copolymer is 5-50kDa, the molecular weight distribution PDI of the block copolymer is less than 1.2, and the tin residue in the block copolymer is less than or equal to 90ppm.

Description

Block copolymer for medicine and preparation method thereof Technical Field The invention relates to the technical field of biomedical materials, in particular to a medical segmented copolymer and a preparation method thereof. Background 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-polyglycolide lactide (mPEG-PLGA), polyethylene glycol-polyglycolide lactide (PLGA-PEG-PLGA), and the like, are important biomedical polymer materials. Because of the good biocompatibility, amphipathy and biodegradability, the polymer is widely used as nano drug carriers, micelle preparations, injectable hydrogels and the like, and has great application potential in the field of biological medicine. Currently, ring-opening polymerization (Ring-Opening Polymerization, ROP) is mainly used for industrially preparing such copolymers. In the method, polyethylene glycol (PEG) or a monomethyl ether derivative (mPEG) thereof is generally used as a macromolecular initiator, and cyclic ester monomers such as lactide (L-LA), caprolactone (ɛ -CL), glycolide (GA) and the like are used as raw materials to carry out polymerization under the action of catalysts such as stannous octoate and the like. However, in practice, the person skilled in the art finds that this conventional "one-pot" synthesis method presents a significant technical difficulty, namely the initiation of hysteresis effects. The hysteresis-inducing effect is mainly due to one of two aspects, namely steric hindrance and encapsulation effect. In the reaction system, the mPEG/PEG molecular chain serving as a hydrophilic chain segment is easy to form random coils, so that the initiating active site-hydroxyl (-OH) at the tail end of the mPEG/PEG molecular chain is wrapped in the chain segment, and larger steric hindrance is generated, so that the mPEG/PEG molecular chain is difficult to effectively contact with the hydrophobic cyclic monomer and the catalyst center. And second, the reactivity is different. The nucleophilic attack ability of the mPEG/PEG terminal hydroxyl groups is significantly weaker than the nucleophilicity of the newly formed polyester chain terminal hydroxyl groups during polymerization. Together, these two factors result in a much slower rate of initiation than the rate of chain growth of the polymerization reaction, thus leading to a significant reaction induction period and overall inefficiency. In order to overcome or alleviate the hysteresis-inducing effect, solutions have been proposed in the prior art, but these solutions have drawbacks: The first option is to raise the reaction temperature, for example, to carry out high-temperature melt polymerization at 130℃or higher. Although high temperatures can accelerate the overall reaction rate, severe intramolecular/intermolecular transesterification reactions can be initiated. This broadens the molecular weight distribution (PDI) of the product (typically > 1.5) and tends to cause high temperature oxidative yellowing of the product, which does not meet the external standards of medical excipients. The second option is to increase the catalyst usage. To force the reaction, the technician often adds an excess of catalyst (e.g., stannous octoate). Although this approach shortens the induction period, it leads to problems of exceeding the standard of heavy metal tin residues in the final product, which is unacceptable for pharmaceutical excipients that perform the strict pharmacopoeia standards. Meanwhile, excessive catalyst also greatly increases the difficulty and cost of the subsequent purification process. The third solution polymerization method is a conventional solution polymerization method. The viscosity of the system can be reduced by adding the solvent, and the mass transfer is improved. However, the dilution effect of the solvent reduces the concentration of the reactants, resulting in extremely slow polymerization rates, reaction times typically requiring 24 to 48 hours or even longer, and monomer conversions often being difficult to achieve desired levels, not suitable for large scale production. Disclosure of Invention The invention provides a medical block copolymer and a preparation method thereof, which are used for solving the defects that the reaction efficiency, the product quality, the tin residue control and the like cannot be considered when the polyethylene glycol-polyester block copolymer is prepared, and can effectively eliminate the initiation hysteresis effect under mild conditions, so as to realize rapid and controllable polymerization reaction, thereby obtaining the block copolymer with narrow molecular weight distribution, high purity and accordance with the pharmaceutical grade standard. According to