Biodegradable polymer microspheres and their manufacturing method

Abstract

The present invention provides biodegradable polymeric microspheres and a method for producing the same. The method includes a step of polymerizing a biodegradable polymeric monomer in a mixed solution containing a biodegradable polymeric monomer, a water-soluble polymer, and a catalyst. In the present invention, the monomer and the water-soluble polymer are mixed to form a solution, and the monomer is polymerized in situ, followed by phase separation to obtain biodegradable polymeric microspheres. The production process is simple and easy to control, does not require organic solvents, is environmentally friendly, and is suitable for large-scale production.

Description

[Technical Field]

[0001] The present invention relates to the technical field of biodegradable polymeric materials, and in particular to biodegradable polymeric microspheres and a method for producing the same. [Background technology]

[0002] Biodegradable polymeric microspheres have been widely applied in many fields. For example, polylactic acid microspheres have been widely used as controlled drug release vectors, gene vectors, and polypeptide and protein drug vectors in many medical fields, such as immunology, gene therapy, tumor therapy, and ophthalmology. Polymeric microspheres are also used in fields such as 3D printing, powder coatings, ink additives, and cosmetic additives, which are also potential applications of degradable microspheres. A common feature of prior art biodegradable polymeric microspheres (e.g., patent applications CN 001281164.X, CN 20110462504.1, and CN 20191103460.X) is the environmental pollution and hazard caused by the large-scale use of organic solvents in the production process of polymeric microspheres. Therefore, there is a need in the art for biodegradable polymeric microspheres and methods for their production that do not require organic solvents during the production process. Summary of the Invention [Problem to be solved by the invention]

[0003] To solve the problems of the prior art, the present invention provides biodegradable polymeric microspheres and a method for producing the same. In the present invention, a biodegradable polymer monomer and a water-soluble polymer are mixed to form a solution, and when the biodegradable polymer / water-soluble polymer composite is obtained after in situ polymerization of the monomer, phase separation already occurs between the two. The biodegradable polymeric microspheres are obtained by washing the water-soluble polymer with water. This makes the production process simple and easy to control, does not require organic solvents, is environmentally friendly, and is suitable for large-scale production. [Means for solving the problem]

[0004] Specifically, one aspect of the present invention provides biodegradable polymeric microspheres comprising a biodegradable polymer and having a particle size of ≦20 μm.

[0005] In one or more embodiments, the biodegradable polymer is an aliphatic polyester, such as polylactic acid, polycaprolactone, polyglycolide, lactide-caprolactone copolymer, lactide-glycolide copolymer, caprolactone-glycolide copolymer, or lactide-caprolactone-glycolide copolymer.

[0006] In one or more embodiments, the biodegradable polymeric microspheres have a particle size of 0.5 to 15 μm.

[0007] In one or more embodiments, the number of biodegradable polymeric microspheres having a particle size of 1 to 6 μm accounts for 80% or more of the total number of said biodegradable polymeric microspheres.

[0008] In one or more embodiments, the biodegradable polymeric microspheres further comprise an antioxidant.

[0009] In one or more embodiments, the antioxidant is one or more selected from the group consisting of Antioxidant 168 (tris(2,4-di-t-butylphenyl)phosphite), Antioxidant 1010 (tetrakis[β-(3,5-di-t-butyl-4-hydroxyphenyl)propionate]pentaerythritol ester), Antioxidant 1098 (N,N′-bis-(3,5-di-t-butyl-4-hydroxyphenyl)propionyl)hexanediamine), Antioxidant 626 (bis(2,4-di-t-butylphenyl)pentaerythritol diphosphite), and Antioxidant THP-24 (bis(2,4-di-t-butylphenyl)pentaerythritol diphosphite).

[0010] In one or more embodiments, the mass ratio of the biodegradable polymer to the antioxidant in the biodegradable polymer microspheres is 100:(0.1 to 1).

[0011] In one or more embodiments, the biodegradable polymeric microspheres further comprise a functional material.

[0012] In one or more embodiments, the functional material is selected from the group consisting of inorganic functional powders and drugs.

[0013] In one or more embodiments, the inorganic functional powder is one or more selected from the group consisting of graphene, graphite, carbon nanotubes, and magnetic nanoparticles.

[0014] In one or more embodiments, the functional material is a drug, such as erythromycin, ibuprofen, clindamycin, amoxicillin, cephradine, acetylhelicalmycin, azithmycin, oryzanol, and the like.

[0015] In one or more embodiments, the mass ratio of the biodegradable polymer to the functional material in the biodegradable polymer microspheres is 100:(1 to 20).

[0016] Another aspect of the present invention provides a method for producing biodegradable polymeric microspheres, the method comprising the step of polymerizing a biodegradable polymeric monomer in a mixed solution containing the biodegradable polymeric monomer, a water-soluble polymer, and a catalyst, the biodegradable polymeric microspheres being preferably the biodegradable polymeric microspheres described in any of the embodiments herein.

[0017] In one or more embodiments, the biodegradable polymer monomer is a monomer of an aliphatic polyester, preferably one or more selected from the group consisting of aliphatic lactides and aliphatic lactones, such as one or more selected from the group consisting of lactide, caprolactone, and glycolide.

[0018] In one or more embodiments, the water-soluble polymer is one or more selected from the group consisting of polyoxyethylene polyoxypropylene ether block copolymers, polyacrylamide, polyvinylpyrrolidone, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, and methylcellulose.

[0019] In one or more embodiments, the mass ratio of the biodegradable polymer monomer to the water-soluble polymer in the mixed solution is 100:(20 to 300). In one or more embodiments, the catalyst is selected from the group consisting of a metal, a Lewis acid, a Lewis base, an organometallic compound, and a metal salt, such as Fe, Cu, Zn, Co, an alkali metal salt, a Schiff base, dibutylmagnesium, aluminum alkoxide, Ti[OCH(CH)], Sn(Oct), SnCl, Sn(C H ), Sn(Oct) / CH 11 OH, and Sn(Oct)2 / P(C6H5)3. In one or more embodiments, the mass ratio of the biodegradable polymer monomer to the catalyst in the mixed solution is 100:(0.1 to 2). In one or more embodiments, the mixed solution further comprises an antioxidant and / or a functional material. In one or more embodiments, the reaction temperature of the polymerization is 90 to 180°C. In one or more embodiments, the method further comprises the steps of: S1. Preparation of liquid monomer: Prepare a biodegradable polymer monomer that is liquid at room temperature, or heat and melt a biodegradable polymer monomer that is solid at room temperature to obtain a liquid monomer; S2, Preparation of mixed solution: Add water-soluble polymer to liquid monomer, and completely dissolve the water-soluble polymer in the liquid monomer to obtain a mixed solution; S3, polymerization: Add a catalyst to the mixed solution, and leave it at reaction temperature to polymerize the monomers to obtain a mixture of biodegradable polymer microspheres and water-soluble polymer; S4, post-treatment: The mixture is post-treated to obtain biodegradable polymer microspheres. [Brief explanation of the drawings]

[0020] [Figure 1] The SEM images of the polylactic acid microspheres produced in Examples 2, 3, 4, and 5 of the present invention are shown by scanning electron microscope. In Figure 1, a, b, c, and d represent the morphologies of the polylactic acid microspheres produced in Examples 2, 3, 4, and 5, respectively. The left side shows an SEM image at 1000x magnification, and the right side shows an SEM image at 5000x magnification. [Figure 2] 2 shows particle size distribution diagrams of the polylactic acid microspheres produced in Examples 2, 3, 4, and 5 of the present invention. In Fig. 2, a, b, c, and d show particle size distribution diagrams of the polylactic acid microspheres produced in Examples 2, 3, 4, and 5, respectively. [Figure 3] 1 shows an SEM image of polylactic acid microspheres prepared in Example 6 of the present invention. [Figure 4] 1 shows an SEM image of polylactic acid microspheres prepared in Example 7 of the present invention. [Figure 5] 1 shows an SEM image of polylactic acid microspheres prepared in Example 8 of the present invention. [Figure 6] 1 shows an SEM image of polylactic acid microspheres prepared in Example 9 of the present invention. [Figure 7] 1 shows an SEM image of polycaprolactone microspheres prepared in Example 10 of the present invention. [Figure 8] 1 shows an SEM image of polyglycolide microspheres prepared in Example 11 of the present invention. [Figure 9] 1 shows an SEM image of magnetic L-lactide / caprolactone copolymer microspheres prepared in Example 12 of the present invention. [Figure 10] 10 shows particle size distribution diagrams of the microspheres of the present invention produced in Examples 6 to 12. In Fig. 10, a, b, c, d, e, f, and g represent particle size distribution diagrams of the microspheres produced in Examples 6, 7, 8, 9, 10, 11, and 12, respectively. [Figure 11] 1 shows DSC heating graphs of polylactic acid microspheres and poloxamer 407 produced in Examples 1 and 5. [Figure 12] 1 shows ultraviolet absorption spectra of erythromycin-loaded polylactic acid microspheres and erythromycin prepared in Examples 13, 14, and 15. DETAILED DESCRIPTION OF THE INVENTION

[0021] The following describes embodiments of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed herein. Those skilled in the art can modify or change the microspheres of the present invention to obtain biodegradable polymeric microspheres with specific functions without violating the spirit and scope of the present invention, which should be covered by the claims of the present invention. The present invention can also be implemented or applied in other different specific embodiments, and each detail in the present specification can be modified or changed in various ways based on different perspectives and applications without departing from the spirit of the present invention. Furthermore, features in the specific embodiments and examples of the present invention can be combined if there is no conflict. In order to facilitate understanding of the features and advantages of the present invention by those skilled in the art, the following general explanations and definitions are provided for the terms and phrases used in the specification and claims. Unless otherwise specified, all technical and scientific terms used herein shall have the ordinary meaning that those skilled in the art would understand to apply to the present invention. In the event of a conflict, the definitions in this specification shall govern. The theories or mechanisms explained and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, i.e., the subject matter of the present invention can be practiced without being limited to any particular theory or mechanism.

[0022] In this specification, the terms "comprise," "contain," "have," and similar terms cover the meaning of "consist essentially of" and "consist of." For example, if the text discloses that "A comprises B and C," it should be considered that the text also discloses that "A consists essentially of B and C" and "A consists of B and C."

[0023] All characteristics, e.g., numerical values, quantities, contents, and concentrations, defined herein in the form of numerical or percentage ranges are for brevity and convenience only, and therefore the description of a numerical or percentage range should be considered to cover and specifically disclose all possible discrete ranges and individual numerical values ​​(including integers and fractions) within the range. In this text, percentages refer to percentages by weight and ratios refer to percentages by weight, unless otherwise stated.

[0024] In the present specification, when an embodiment or embodiments are described, it should be understood that this is not intended to limit the invention to those embodiments or embodiments. On the contrary, all alternatives, modifications, and equivalents of the methods and materials described herein are intended to be within the scope of the claims.

[0025] For the sake of brevity, the present specification does not describe all possible combinations of each embodiment or each technical feature in each embodiment. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each embodiment or example may be arbitrarily combined, and all possible combinations should be considered to be within the scope described in this specification.

[0026] The present invention has discovered that biodegradable polymer microspheres can be produced in an environmentally friendly and controllable manner without the need for organic solvents, by preparing a liquid mixture (also referred to as a mixed solution in the present invention) of a biodegradable polymer monomer and a water-soluble polymer, polymerizing the monomer in the presence of the water-soluble polymer, and then phase separation occurs between the biodegradable polymer and the water-soluble polymer formed after polymerization, and the biodegradable polymer cannot form a continuous phase when precipitated and is formed into microspheres, and the water-soluble polymer is washed with water to obtain biodegradable polymer microspheres.

[0027] The biodegradable polymer microspheres of the present invention contain a biodegradable polymer, and the mass of the biodegradable polymer usually accounts for 60% or more, for example, 70% or more, 80% or more, or 90% or more of the total mass of the biodegradable polymer microspheres of the present invention.

[0028] In the present invention, a biodegradable polymer refers to a polymer whose molecular chain can be decomposed (e.g., hydrolyzed) under certain conditions (e.g., certain humidity, temperature, pH, and / or oxygen concentration) by the action of enzymes or microorganisms (e.g., bacteria, fungi, algae, etc.). Biodegradable polymers typically contain one or more biodegradable chemical bonds selected from the group consisting of ester bonds (e.g., aliphatic ester bonds), ether bonds (e.g., aliphatic ether bonds), amide groups (e.g., peptide bonds), urethane bonds, and nitrogen-phosphorus double bonds (N=P). Biodegradable polymers include, but are not limited to, polyesters (e.g., aliphatic polyesters), polyethers (e.g., aliphatic polyethers), polyester ethers (e.g., aliphatic polyester ethers), polyamides (e.g., polyamino acids), polyorthoesters, polycarbonates, polyanhydrides, polyphosphonic nitriles, polyurethanes, etc. In some embodiments, the biodegradable polymer contained in the biodegradable polymeric microspheres of the present invention is a biodegradable aliphatic polyester, such as polylactic acid, polycaprolactone, polyglycolide, lactide-caprolactone copolymer, lactide-glycolide copolymer, caprolactone-glycolide copolymer, or lactide-caprolactone-glycolide copolymer.

[0029] The biodegradable polymeric microspheres of the present invention typically have a particle size of ≦20 μm. In some embodiments, the biodegradable polymeric microspheres of the present invention have a particle size of 18 μm, 15 μm, 13 μm, 10 μm, 9 μm, or 8 μm or less. The biodegradable polymeric microspheres of the present invention typically have a particle size of ≧0.1 μm. In some embodiments, the biodegradable polymeric microspheres of the present invention have a particle size of 0.2 μm, 0.5 μm, 1 μm, or 2 μm or more. In some embodiments, the biodegradable polymeric microspheres of the present invention have a particle size of 0.5 to 15 μm.

[0030] In some preferred embodiments, in the biodegradable polymer microspheres of the present invention, biodegradable polymer microspheres having a particle size of 1 to 6 μm account for 80% or more of the total number of biodegradable polymer microspheres. In some embodiments, in the biodegradable polymer microspheres of the present invention, biodegradable polymer microspheres having a particle size of 1 to 6 μm account for 80% or more of the total number of biodegradable polymer microspheres. In some embodiments, in the biodegradable polymer microspheres of the present invention, the particle size is 1 to 13 μm, and the particle size is 1 to 4 μm, and the particle size is 88% or more of the total number of microspheres. In some embodiments, in the biodegradable polymer microspheres of the present invention, the particle size is 2 to 9 μm, and the particle size is 2 to 6 μm, and the particle size is 85% or more of the total number of microspheres. In some embodiments, in the biodegradable polymer microspheres of the present invention, the particle size is 1 to 8 μm, and the particle size is 3 to 6 μm, and the particle size is 80% or more of the total number of microspheres. In some embodiments, the biodegradable polymer microspheres of the present invention have a particle size of 1 to 13 μm, with biodegradable polymer microspheres having a particle size of 1 to 3 μm accounting for 75% or more of the total number of microspheres and biodegradable polymer microspheres having a particle size of 1 to 6 μm accounting for 80% or more of the total number of microspheres. In some embodiments, the biodegradable polymer microspheres of the present invention have a particle size of 1 to 3 μm, with biodegradable polymer microspheres having a particle size of 1 to 2 μm accounting for 80% or more of the total number of microspheres.

[0031] Because the polymerization temperature of some biodegradable polymers (e.g., polylactic acid) is relatively high, an appropriate amount of antioxidant may be added to the reaction system to prevent oxidation and obtain a higher molecular weight product. Therefore, in some embodiments, the biodegradable polymer microspheres of the present invention further contain an antioxidant. Antioxidants applicable to the present invention are one or more selected from the group consisting of Antioxidant 168, Antioxidant 1010, Antioxidant 1098, Antioxidant 626, and Antioxidant THP-24. When the biodegradable polymer microspheres of the present invention contain an antioxidant, the mass ratio of the biodegradable polymer to the antioxidant in the biodegradable polymer microspheres may be 100:(0.1 to 1), for example, 100:0.2, 100:0.5, 100:0.6, 100:0.7, 100:0.8, or 100:0.9. When the biodegradable polymeric microspheres of the present invention are applied to biomedical fields, they preferably contain no antioxidant or only a small amount of antioxidant, preferably only an antioxidant that is not biotoxic. In some embodiments, the biodegradable polymeric microspheres of the present invention further comprise a functional material having one or more specific functions. The functional material does not include the antioxidant. Examples of functional materials applicable to the present invention include, but are not limited to, immunological materials, controlled drug release materials, magnetic materials, conductive materials, drugs, dyes, fluorescent molecules, and pH-responsive materials. The functional material applicable to the present invention may be an organic material, an inorganic material, or an organic-inorganic composite material. The functional material applicable to the present invention may be nanometer-scale (1-100 nm) or submicron-scale (100-1000 nm) in size. In some embodiments, the functional material is an inorganic functional powder, such as graphene, graphite, carbon nanotubes, or magnetic nanoparticles. Examples of magnetic nanoparticles include, but are not limited to, cobalt ferrite nanoparticles. In some embodiments, the functional material is a drug, such as erythromycin, ibuprofen, clindamycin, amoxicillin, cephradine, acetylhelicalmycin, azithmycin, oryzanol. When the biodegradable polymer microspheres of the present invention contain a functional material, the mass ratio of the biodegradable polymer to the functional material in the biodegradable polymer microspheres may be 100:(1 to 20), for example, 100:2, 100:5, 100:10, or 100:15. Controlling the mass ratio of the functional material to the biodegradable polymer to 20:100 or less contributes to the molding of microspheres.

[0032] In some embodiments, the biodegradable polymeric microspheres of the present invention comprise a biodegradable polymer, an optional antioxidant, and an optional functional material. In some embodiments, the biodegradable polymeric microspheres of the present invention consist primarily of the biodegradable polymer, the optional antioxidant, and the optional functional material, and the combined mass of the biodegradable polymer, the optional antioxidant, and the optional functional material may account for 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, 99.5% or more, or 100% of the total mass of the biodegradable polymeric microspheres.

[0033] The biodegradable polymeric microspheres of the present invention may contain trace amounts of catalyst residues.

[0034] The biodegradable polymer in the biodegradable polymeric microspheres of the present invention may be grafted with a water-soluble polymer (eg, a polyoxyethylene polyoxypropylene ether block copolymer) as described herein.

[0035] The method for producing biodegradable polymeric microspheres of the present invention comprises a step of polymerizing a biodegradable polymeric monomer in a mixed solution containing a biodegradable polymeric monomer, a water-soluble polymer, and a catalyst.

[0036] The biodegradable polymer monomer applicable to the present invention may be any monomer known in the art for use in the production of biodegradable polymers. In some embodiments, the biodegradable polymer monomer is a monomer of an aliphatic polyester, preferably at least one selected from the group consisting of aliphatic lactides and aliphatic lactones, such as at least one selected from the group consisting of lactide (e.g., L-lactide), caprolactone, and glycolide. When multiple biodegradable polymer monomers are used, the ratio between the monomers is not particularly limited.

[0037] In the present invention, a water-soluble polymer (also referred to herein as a water-soluble polymer additive) refers to a polymer that can dissolve or swell in water to form an aqueous solution or dispersion, and has a molecular weight of 300 g / mol or more. Examples of water-soluble polymers applicable to the present invention include one or more selected from the group consisting of polyoxyethylene polyoxypropylene ether block copolymers, polyacrylamide, polyvinylpyrrolidone, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, and methylcellulose. In some embodiments, the water-soluble polymer is one or more selected from the group consisting of polyoxyethylene polyoxypropylene ether block copolymers, polyvinylpyrrolidone, polyethylene glycol, and methylcellulose. The molecular weight of the water-soluble polymer is preferably 300 to 50,000 g / mol, for example, 1,000 g / mol, 2,000 g / mol, 5,000 g / mol, 10,000 g / mol, 15,000 g / mol, 20,000 g / mol, 25,000 g / mol, 30,000 g / mol, or 40,000 g / mol. The viscosity of the methylcellulose suitable for the present invention is preferably 10,000 to 100,000 mPa·s, for example, 20,000 mPa·s, 40,000 mPa·s, or 80,000 mPa·s. Suitable polyoxyethylene polyoxypropylene ether block copolymers include diblock, triblock, and higher block copolymers, such as poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-b-PPG-b-PEG). In PEG-b-PG-b-PEG, the content of the PEG block may be 50 to 90 wt%, preferably 60 to 80 wt%, for example, 70 to 75 wt%. An example of PEG-b-PG-b-PEG is Poloxamer 407.In some embodiments, the water-soluble polymer used in the present invention is one or more selected from the group consisting of polyoxyethylene polyoxypropylene ether block copolymers (e.g., PEG-b-PPG-b-PEG) having a molecular weight of 5,000 to 20,000 g / mol, e.g., 9,000 to 1,500 g / mol, methylcellulose having a viscosity of 40,000 to 10,000 mPa·s, e.g., 80,000 to 10,000 mPa·s, polyvinylpyrrolidone having a molecular weight of 5,000 to 10,000 g / mol, e.g., 7,000 to 9,000 g / mol, and polyethylene glycol having a molecular weight of 5,000 to 1,500 g / mol, e.g., 8,000 to 12,000 g / mol. Controlling the molecular weight or viscosity of the water-soluble polymer within the above ranges contributes to phase separation occurring after polymerization of the biodegradable polymer monomer, thereby enabling the production of microspheres with a particle size that meets the requirements of the present invention.

[0038] In the polymerization mixture solution of the present invention, the mass ratio of the biodegradable polymer monomer to the water-soluble polymer is 100:(20-300), for example, 100:20, 100:30, 100:40, 100:50, 100:60, 100:70, 100:80, 100:90, 100:100, 100:150, 100:200, 100:250, or 100:300. The greater the mass ratio of the water-soluble polymer, the smaller the particle size of the produced biodegradable polymer microspheres. In some embodiments, the mass ratio of the biodegradable polymer monomer to the water-soluble polymer is 100:(20-100). In these embodiments, the particle size of the biodegradable polymer microspheres can be controlled to 0.5-15 μm, and the number of biodegradable polymer microspheres having a diameter of 1-6 μm can be controlled to 80% or more of the total number of biodegradable polymer microspheres.

[0039] In some embodiments, the method for producing biodegradable polymeric microspheres of the present invention further comprises preparing a mixed solution containing a biodegradable polymeric monomer and a water-soluble polymer, and then adding a catalyst to the mixed solution to aggregate the biodegradable polymeric monomer.

[0040] In the present invention, in an embodiment in which the biodegradable polymer monomer is liquid at ambient temperature, for example, room temperature (25°C) (e.g., caprolactone as the monomer), the biodegradable polymer monomer and the water-soluble polymer may be uniformly mixed at ambient temperature, room temperature, or under heated conditions to obtain a mixed solution. For example, the monomer and the water-soluble polymer that are liquid at room temperature may be mixed and then stirred for 20 to 40 minutes to obtain a mixed solution.

[0041] In the present invention, in an embodiment in which the biodegradable polymer monomer contains a monomer (e.g., L-lactide, glycolide) that is solid at ambient temperature, e.g., room temperature (25°C), the temperature of the mixed solution for polymerization is not lower than the melting point of the monomer that is solid at ambient temperature. When multiple monomers that are solid at ambient temperature are present, the temperature of the mixed solution is not lower than the melting point of the solid monomer with the highest melting point. The biodegradable polymer monomer may be heated to melt and maintained at that temperature for a certain period of time (e.g., 10 to 20 minutes) to obtain a liquid monomer, which may then be uniformly mixed with a water-soluble polymer to obtain a mixed solution. For example, the liquid monomer after heating and melting may be mixed with the water-soluble polymer and stirred for 20 to 40 minutes to obtain a mixed solution.

[0042] The mixed solution containing the biodegradable polymer monomer and the water-soluble polymer may further contain a functional material. Typically, the functional material is introduced into the mixed solution before adding the catalyst. For example, after the liquid monomer and the water-soluble polymer are uniformly mixed, the functional material may be added and subsequently mixed uniformly. The applicable functional material and its amount are as described above.

[0043] In the present invention, a catalyst is added to a mixed solution containing a biodegradable polymer monomer and a water-soluble polymer, and then a ring-opening polymerization reaction occurs in the biodegradable polymer monomer. The ring-opening polymerization may be anionic, cationic, or coordinate ring-opening polymerization. The catalyst used in the present invention is selected from the group consisting of metals, Lewis acids, Lewis bases, organometallic compounds, and metal salts, such as Fe, Cu, Zn, Co, alkali metal salts, Schiff bases, dibutylmagnesium, aluminum alkoxide, Ti[OCH(CH)], Sn(Oct), SnCl, Sn(CH), Sn(Oct) / CH(CH). 11 OH, and Sn(Oct)2 / P(C6H5)3. In this specification, Sn(Oct)2 / CH3(CH2) 11 OH is Sn(Oct)2 and CH3(CH2) 11 OH, among which Sn(Oct)2 and CH3(CH2) 11 The molar ratio of Sn(Oct)2 to P(C6H5)3 may be 2:1 to 1:2, e.g., 1:1. As used herein, Sn(Oct)2 / P(C6H5)3 refers to a composition of Sn(Oct)2 and P(C6H5)3, in which the molar ratio of Sn(Oct)2 to P(C6H5)3 may be 2:1 to 1:2, e.g., 1:1. In some embodiments, the catalyst is selected from the group consisting of Ti[OCH(CH3)2]4, Sn(Oct)2, Sn(Oct)2 / CH3(CH2). 11 The catalyst is one or more selected from the group consisting of OH, and Sn(Oct)2 / P(C6H5)3. In the reaction system, the mass ratio of the biodegradable polymer monomer to the catalyst is preferably 100:(0.1-2), for example, 100:0.2, 100:0.3, 100:0.4, 100:0.5, or 100:1. Because the active end groups of the water-soluble polymer consume a portion of the catalyst, more catalyst needs to be added when the water-soluble polymer content is high or the molecular weight of the water-soluble polymer is low; also, when the water-soluble polymer content is low or the molecular weight of the water-soluble polymer is high, a lower catalyst addition amount may be selected.

[0044] In the present invention, a catalyst is added to the mixed solution containing the biodegradable polymer monomer and the water-soluble polymer, and an antioxidant may also be added if necessary. Suitable antioxidants and their amounts are as described above.

[0045] In the present invention, the temperature of the reaction system when carrying out the polymerization reaction is 90 to 180 ° C, for example, 90 ° C, 95 ° C, 100 ° C, 105 ° C, 110 ° C, 115 ° C, 120 ° C, 125 ° C, 130 ° C, 140 ° C, 150 ° C, or 160 ° C. An appropriate reaction temperature may be selected depending on the type of biodegradable polymer monomer. For example, when the monomer is L-lactide, the reaction temperature is preferably 130 to 180 ° C, for example, 140 to 150 ° C. When the monomer is glycolide, the reaction temperature is preferably 90 to 130 ° C, for example, 110 to 120 ° C. When the monomer is caprolactone, the reaction temperature is preferably 110 to 140 ° C, for example, 120 to 130 ° C. When the monomers are L-lactide and caprolactide, the reaction temperature is preferably 110 to 140 ° C, for example, 139 to 140 ° C. The reaction is usually carried out under static conditions, which contributes to phase separation. The reaction time may be 0.5 to 24 hours, for example, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 5 hours, 10 hours, or 24 hours. During the reaction, the reaction system gradually changed from a transparent, homogeneous solution to a milky white solid. The reaction may be considered complete when the reaction system is completely cured.

[0046] After the polymerization reaction is completed, a product system containing biodegradable polymeric microspheres and a water-soluble polymer is obtained. The method for producing biodegradable polymeric microspheres of the present invention may further include a step of post-treating the product system and separating it to obtain biodegradable polymeric microspheres. The post-treatment may include, for example, cooling the product system to ambient temperature, e.g., room temperature, washing with water, filtering, and drying. The number of times of water washing may be, for example, 5 to 8 times.

[0047] In some embodiments, the biodegradable polymeric microspheres of the present invention comprise the following materials in parts by weight: Biodegradable polymer monomer: 100 parts, Water-soluble polymer additive: 20 to 300 parts, for example, 20 to 100 parts, Antioxidant: 0.1 to 1 part, for example, 0.5 to 1 part, Catalyst: 0.1 to 2 parts, for example 0.1 to 0.5 parts.

[0048] The biodegradable polymer of the present invention may further contain 1 to 20 parts by weight of a functional material relative to 100 parts by weight of the biodegradable polymer monomer of the present invention.

[0049] In some embodiments, the raw materials necessary for producing the biodegradable polymeric microspheres of the present invention comprise or consist of the following materials in parts by weight: Biodegradable polymer monomer: 100 parts, Water-soluble polymer additive: 20 to 300 parts, for example, 20 to 100 parts, Antioxidant: 0.1 to 1 part, for example, 0.5 to 1 part, Catalyst: 0.1 to 2 parts, for example 0.1-0.5 parts, Functional ingredients as needed: 1-20 parts.

[0050] Furthermore, the biodegradable polymer monomer is one or more selected from the group consisting of lactide, caprolactone, and glycolide, and further, the lactide is L-lactide.

[0051] Furthermore, the water-soluble polymer additive is at least one selected from the group consisting of polyoxyethylene polyoxypropylene ether block copolymer, polyacrylamide, polyvinylpyrrolidone, and polyethylene glycol.

[0052] Furthermore, the water-soluble polymer additive is at least one selected from the group consisting of polyoxyethylene polyoxypropylene ether block copolymer, methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.

[0053] Further, the antioxidant is one or more selected from the group consisting of antioxidant 168, antioxidant 1010, antioxidant 1098, antioxidant 626, and antioxidant THP-24.

[0054] Further, the catalyst may be selected from the group consisting of metals, Lewis acids, Lewis bases, organometallic compounds, and metal salts, such as Fe, Cu, Zn, Co, alkali metal salts, Schiff bases, dibutylmagnesium, aluminum alkoxides, Ti[OCH(CH)], Sn(Oct), SnCl, Sn(C H ), Sn(Oct) / CH 11 OH, and Sn(Oct)2 / P(C6H5)3, and the catalyst is one or more selected from the group consisting of Ti[OCH(CH3)2]4, Sn(Oct)2, Sn(Oct)2 / CH3(CH2) 11 OH, and Sn(Oct)2 / P(C6H5)3.

[0055] Furthermore, the functional material is an inorganic functional powder, and the inorganic functional powder is, for example, one or more types selected from the group consisting of graphene, graphite, carbon nanotubes, and magnetic nanoparticles.

[0056] Furthermore, the functional material is a drug, and the drug is, for example, one or more selected from the group consisting of erythromycin, ibuprofen, clindamycin, amoxicillin, cephradine, acetylhelicalmycin, azithmycin, and oryzanol.

[0057] In some embodiments, the method for producing biodegradable polymeric microspheres of the present invention involves dissolving a water-soluble polymeric additive in a continuous phase in a biodegradable polymer monomer, and then adding an antioxidant and a catalyst to promote polymerization of the monomer into biodegradable polymeric microspheres. Because the water-soluble polymeric additive is insoluble in the biodegradable polymer, it precipitates during polymerization of the monomer, causing phase separation from the biodegradable polymer, dispersing the biodegradable polymer into microspheres.

[0058] In some embodiments, the method for producing biodegradable polymeric microspheres of the present invention comprises the steps of: S1. Preparation of liquid monomer: Prepare a biodegradable polymer monomer that is liquid at room temperature, or heat and melt a biodegradable polymer monomer that is solid at room temperature to obtain a liquid monomer; S2, Preparation of mixed solution: Add water-soluble polymer to liquid monomer, and completely dissolve the water-soluble polymer in the liquid monomer to obtain a mixed solution; S3, polymerization: Add a catalyst to the mixed solution, and leave it at reaction temperature to polymerize the monomers to obtain a mixture of biodegradable polymer microspheres and water-soluble polymer; S4, post-treatment: The mixture is post-treated to obtain biodegradable polymer microspheres.

[0059] Furthermore, the manufacturing method specifically includes the following steps: S1. Preparation of liquid monomer: Prepare a biodegradable polymer monomer that is liquid at room temperature, or heat and melt a biodegradable polymer monomer that is solid at room temperature, and maintain the temperature for 10-20 minutes to obtain a liquid monomer; S2. Preparation of mixed solution: Add the water-soluble polymer to the liquid monomer and continue stirring for 20-40 minutes to completely dissolve the water-soluble polymer in the liquid monomer to obtain a mixed solution; S3, polymerization: Add an antioxidant and a catalyst to the mixed solution, and polymerize the monomer by standing or stirring at the reaction temperature, and then cool naturally to room temperature to obtain a mixture of biodegradable polymer microspheres and a water-soluble polymer; S4, Water washing: The mixture is washed with water (for example, 5 to 8 times), filtered and dried to remove the water-soluble polymer additives, thereby obtaining biodegradable polymer microspheres.

[0060] Furthermore, after preparing the mixed solution in step S2, a functional material, such as an inorganic functional powder or a drug, may be added and stirred and mixed.

[0061] Furthermore, the inorganic functional powder is at least one selected from the group consisting of graphene, graphite, carbon nanotubes, and magnetic nanoparticles.

[0062] Furthermore, in the step S3, it is preferable to allow the mixture to stand at the reaction temperature and promote the polymerization of the monomers by, for example, static casting.

[0063] The present invention has the following beneficial effects: The method for producing biodegradable polymer microspheres provided by the present invention is simple, easy to control, does not require organic solvents in the production process, reduces costs and pollution, and is suitable for large-scale industrial production.

[0064] The method for producing biodegradable polymeric microspheres provided by the present invention involves preparing a solution of a biodegradable polymer monomer and a water-soluble polymeric additive (in some embodiments, the liquid monomer is the solvent, the water-soluble polymeric additive is the solute, and the water-soluble polymeric additive dissolves in the monomer to form a solution), and the water-soluble polymeric additive forms a continuous phase on the surface of the monomer, which then undergoes phase separation after in situ polymerization of the monomer to obtain biodegradable polymeric microspheres (the water-soluble polymeric additive is insoluble in the biodegradable polymer, and when the biodegradable polymer precipitates due to the water-soluble polymeric additive, it is unable to form a continuous phase, resulting in phase separation, resulting in the formation of spheres), and the production process is simple and easy to control.

[0065] The water-soluble polymer additives can be removed by washing with water, no organic solvents are required, the technology is simple, the production costs are low, the production process is environmentally friendly, and there is great potential for industrialization.

[0066] In some embodiments of the present invention, for example, biodegradable polymer microspheres having a particle size of 0.5 to 15 μm and a relatively narrow particle size distribution can be obtained, such that the number of biodegradable polymer microspheres having a particle size of 1 to 6 μm accounts for 80% or more of the total number of biodegradable polymer microspheres.

[0067] The present invention makes it possible to prepare biodegradable polymer microspheres loaded with functional materials (eg, inorganic functional powders and drugs), which are useful for applications in fields such as immunology, gene therapy, and tumor therapy.

[0068] The present invention will be described below with specific examples. These embodiments are merely illustrative and are not intended to limit the scope of the present invention. The methods, reagents, and materials used in the examples are conventional methods, reagents, and materials in this field unless otherwise specified. All raw material compounds in the examples are commercially available.

[0069] Example 1 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 20 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The stirring speed was 100 r / min, and the mixture was stirred for 30 minutes to completely dissolve the poloxamer in the L-lactide melt, obtaining a mixed solution; S3, Polymerization: 0.5 parts by mass of antioxidant THP-24 and 0.1 parts by mass of catalyst Sn(Oct)2 were added to the mixed solution, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres were obtained.

[0070] Example 2 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 40 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The stirring speed was 100 r / min, and the poloxamer was completely dissolved in the L-lactide melt to obtain a mixed solution. S3, Polymerization: 0.6 parts by mass of antioxidant THP-24 and 0.2 parts by mass of catalyst Sn(Oct)2 were added to the mixed solution, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres were obtained.

[0071] Example 3 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 60 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The stirring speed was 100 r / min, and the mixture was then stirred for 30 minutes to completely dissolve the poloxamer in the L-lactide melt, obtaining a mixed solution; S3, Polymerization: 0.7 parts by mass of antioxidant THP-24 and 0.3 parts by mass of catalyst Sn(Oct)2 were added to the mixed solution, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres were obtained.

[0072] Example 4 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 80 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The mixture was then stirred for 30 minutes at a stirring speed of 100 r / min, until the poloxamer was completely dissolved in the L-lactide melt to obtain a mixed solution; S3, Polymerization: 0.8 parts by mass of antioxidant THP-24 and 0.4 parts by mass of catalyst Sn(Oct)2 were added to the mixed solution, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres were obtained.

[0073] Example 5 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 100 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The stirring speed was 100 r / min, and the poloxamer was completely dissolved in the L-lactide melt to obtain a mixed solution. S3, Polymerization: 1 part by mass of antioxidant THP-24 and 20.5 parts by mass of catalyst Sn(Oct) were added to the mixed solution, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres were obtained.

[0074] Example 6 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 98°C until completely melted, and the temperature was maintained for 15 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 30 parts by mass of water-soluble polymer additive methylcellulose (viscosity: 100,000 mPa·s) was added to the L-lactide melt, and the mixture was stirred and heated to 110°C. The mixture was then stirred and vacuum-dewatered for 20 minutes at a stirring speed of 100 r / min, until the methylcellulose was completely dissolved in the L-lactide melt, yielding a mixed solution. S3, Polymerization: 0.9 parts by mass of antioxidant 168 and 0.3 parts by mass of catalyst Ti[OCH(CH3)2]4 were added to the mixed solution, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and methylcellulose. S4, Water washing: The mixture was washed with water six times, filtered and dried to remove the methylcellulose, thereby obtaining polylactic acid microspheres.

[0075] Example 7 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 102°C until completely melted, and the temperature was maintained for 20 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 50 parts by mass of water-soluble polymer additive polyvinylpyrrolidone (molecular weight 8000 g / mol) was added to the L-lactide melt, and the mixture was stirred and heated to 130°C. The mixture was then stirred for 40 minutes at a stirring speed of 120 r / min, and the polyvinylpyrrolidone was completely dissolved in the L-lactide melt to obtain a mixed solution; S3, Polymerization: Mix the solution with 0.7 parts by mass of antioxidant 1010 and catalyst Sn(Oct)2 / CH3(CH2) 11 0.7 parts by mass of OH was added, and the temperature was raised to 140°C to polymerize L-lactide. After leaving the mixture to react for 2 hours, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and polyvinylpyrrolidone. S4, Water washing: The mixture was washed with water seven times, filtered and dried to remove polyvinylpyrrolidone, thereby obtaining polylactic acid microspheres.

[0076] Example 8 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 101°C until completely melted, and the temperature was maintained for 15 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 70 parts by mass of water-soluble polymer additive polyethylene glycol (molecular weight 10,000 g / mol) was added to the L-lactide melt, and the mixture was stirred and heated to 125°C. The mixture was then stirred for 25 minutes at a stirring speed of 115 r / min, until the polyethylene glycol was completely dissolved in the L-lactide melt, giving a mixed solution; S3, Polymerization: 0.5 parts by mass of catalyst Sn(Oct)2 / P(C6H5)3 (molar ratio 1:1) was added to the mixed solution, and the temperature was raised to 140°C to polymerize L-lactide. After leaving the mixture to react for 2 hours, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and polyethylene glycol. S4, Water washing: The mixture was washed with water eight times, filtered and dried to remove polyethylene glycol, thereby obtaining polylactic acid microspheres.

[0077] Example 9 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 99°C until completely melted, and the temperature was maintained for 14 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 90 parts by mass of water-soluble polymer additive polyethylene glycol (molecular weight 10,000 g / mol) was added to the L-lactide melt, and the mixture was stirred and heated to 115°C. The mixture was then stirred for 35 minutes at a stirring speed of 110 r / min, and the polyethylene glycol was completely dissolved in the L-lactide melt to obtain a mixed solution; S3, Polymerization: Catalyst Sn(Oct)2 / CH3(CH2) in the mixed solution 11 0.3 parts by mass of OH (molar ratio 1:1) was added, and the temperature was raised to 140°C to polymerize L-lactide. After leaving the mixture to react for 2 hours, the mixture was naturally cooled to room temperature to obtain a mixture of polylactic acid microspheres and polyethylene glycol; S4, Water washing: The mixture was washed with water eight times, filtered and dried to remove polyethylene glycol, thereby obtaining polylactic acid microspheres.

[0078] Example 10 S1, preparation of caprolactone: 100 parts by mass of liquid caprolactone was prepared at room temperature; S2, preparation of mixed solution: 70 parts by mass of water-soluble polymer additive polyethylene glycol (molecular weight 10000 g / mol) was added to caprolactone, and then stirred for 35 minutes at a stirring speed of 110 r / min to completely dissolve polyethylene glycol in caprolactone to obtain a mixed solution; S3, polymerization: 20.3 parts by mass of catalyst Sn(Oct) was added to the mixed solution, and the temperature was raised to 130°C to polymerize caprolactone. After leaving the mixture to react for 2 hours, the mixture was naturally cooled to room temperature to obtain a mixture of caprolactone and polyethylene glycol; S4, Water washing: The mixture was washed with water eight times, filtered and dried to remove polyethylene glycol, and polycaprolactone (PCL) microspheres were obtained.

[0079] Example 11 S1, Melting of glycolide: 100 parts by mass of solid glycolide was heated to 85°C until completely melted, and the temperature was maintained for 14 minutes to obtain glycolide; S2. Preparation of mixed solution: 60 parts by mass of water-soluble polymer additive polyethylene glycol (molecular weight 10000 g / mol) was added to glycolide, and the mixture was stirred and heated to 95°C. The mixture was then stirred for 35 minutes at a stirring speed of 110 r / min, until the polyethylene glycol was completely dissolved in the glycolide to obtain a mixed solution; S3, Polymerization: 20.4 parts by mass of catalyst Sn(Oct) was added to the mixed solution, and the temperature was raised to 110°C to polymerize glycolide. After standing for 2 hours, the mixture was naturally cooled to room temperature to obtain a mixture of polyglycolide microspheres and polyethylene glycol; S4, Water washing: The mixture was washed with water eight times, filtered and dried to remove polyethylene glycol, and polyglycolide microspheres were obtained.

[0080] Example 12 S1, preparation of liquid monomer: 50 parts by mass of solid L-lactide was dissolved in 50 parts by mass of caprolactone and heated to 101°C until completely melted, and the temperature was maintained for 15 minutes to obtain a molten mixture of L-lactide and caprolactone; S2. Preparation of mixed solution: 50 parts by mass of water-soluble polymer additive polyethylene glycol (molecular weight 10,000 g / mol) and 20 parts by mass of polyvinylpyrrolidone (molecular weight 8,000 g / mol) were added to the molten mixture of L-lactide and caprolactone, and the mixture was heated to 125°C with stirring and continued stirring for 25 minutes at a stirring speed of 115 r / min, so that the polyethylene glycol and polyvinylpyrrolidone were completely dissolved in the molten mixture of L-lactide and caprolactone to obtain a mixed solution; S3, 10 parts by mass of cobalt ferrite nanoparticles were added, and the mixture was stirred for 25 minutes at a stirring speed of 115 r / min to thoroughly mix the mixture; S4, polymerization: To the material obtained in S3, 0.4 parts by mass of antioxidant 1098, 0.3 parts by mass of antioxidant 1010, and 0.2 parts by mass of catalyst Sn(Oct)2 / P(C6H5)3 and 0.4 parts by mass of Sn(Oct)2 were added, and the mixture was heated to 140°C to copolymerize L-lactide and caprolactide. After allowing to stand for 1.5 hours, the mixture was allowed to cool to room temperature, yielding a mixture of magnetic L-lactide-caprolactide copolymer microspheres, polyethylene glycol, and polyvinylpyrrolidone. S5, Water washing: The mixture was washed with water eight times, filtered and dried to remove polyethylene glycol and polyvinylpyrrolidone, yielding magnetic L-lactide-caprolactone copolymer microspheres.

[0081] Example 13 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 40 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The mixture was then stirred for 30 minutes at a stirring speed of 100 r / min, until the poloxamer was completely dissolved in the L-lactide melt to obtain a mixed solution; S3, 5 parts by mass of erythromycin was added, and the mixture was stirred for 25 minutes at a stirring speed of 115 r / min to thoroughly mix; S4, polymerization: 20.2 parts by mass of catalyst Sn(Oct) was added to the material obtained in S3, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of erythromycin, polylactic acid microspheres, and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres loaded with erythromycin were obtained.

[0082] Example 14 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 40 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The mixture was then stirred for 30 minutes at a stirring speed of 100 r / min, until the poloxamer was completely dissolved in the L-lactide melt to obtain a mixed solution; S3, 10 parts by mass of erythromycin was added, and the mixture was stirred for 25 minutes at a stirring speed of 115 r / min to thoroughly mix; S4, polymerization: 20.2 parts by mass of catalyst Sn(Oct) was added to the material obtained in S3, and the temperature was raised to 150°C to polymerize L-lactide. After leaving the mixture to react for 1 hour, the mixture was naturally cooled to room temperature to obtain a mixture of erythromycin, polylactic acid microspheres, and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres loaded with erythromycin were obtained.

[0083] Example 15 S1, Melting of L-lactide: 100 parts by mass of solid L-lactide was heated to 100°C until completely melted, and the temperature was maintained for 10 minutes to obtain an L-lactide melt; S2. Preparation of mixed solution: 40 parts by mass of water-soluble polymer additive PEG-b-PPG-b-PEG (poloxamer 407, molecular weight 9840-14600 g / mol, PEG block content 71-75 wt%) was added to the L-lactide melt, and the mixture was stirred and heated to 120°C. The mixture was then stirred for 30 minutes at a stirring speed of 100 r / min, until the poloxamer was completely dissolved in the L-lactide melt to obtain a mixed solution; S3, 15 parts by mass of erythromycin was added, and the mixture was stirred for 25 minutes at a stirring speed of 115 r / min to thoroughly mix; S4, polymerization: 20.2 parts by mass of catalyst Sn(Oct) was added to the material obtained in S3, and the temperature was raised to 150°C to polymerize L-lactide. After 1 hour of static reaction, the mixture was naturally cooled to room temperature to obtain a mixture of erythromycin, polylactic acid microspheres, and poloxamer. S4, Water washing: The mixture was washed five times with water, filtered and dried to remove the poloxamer, and polylactic acid microspheres loaded with erythromycin were obtained.

[0084] The polylactic acid microspheres produced in Examples 2, 3, 4, and 5 were selected and their morphologies were observed under a scanning electron microscope, yielding the SEM image shown in Figure 1. Here, the left side is an SEM image of the same sample at 1000x magnification, and the right side is an SEM image of the same sample at 5000x magnification, where a is the morphology of the polylactic acid microspheres produced in Example 2, b is the morphology of the polylactic acid microspheres produced in Example 3, c is the morphology of the polylactic acid microspheres produced in Example 4, and d is the morphology of the polylactic acid microspheres produced in Example 5. It can be seen from Figure 1 that the lactic acid microspheres produced in Examples 2 to 5 were all approximately spherical particles.

[0085] Furthermore, the particle size distribution of the polylactic acid microspheres produced in Examples 2, 3, 4 and 5 was analyzed using a laser particle size analyzer, and the particle size distribution diagram of the polylactic acid microspheres shown in FIG. 2 was obtained. Graph a shows the particle size distribution of polylactic acid microspheres prepared in Example 2, with particle sizes ranging from 1 to 13 μm and with 88% or more of the polylactic acid microspheres distributed within the 1 to 4 μm range; graph b shows the particle size distribution of polylactic acid microspheres prepared in Example 3, with particle sizes ranging from 2 to 9 μm and with 85% or more of the polylactic acid microspheres distributed within the 2 to 6 μm range; graph c shows the particle size distribution of polylactic acid microspheres prepared in Example 4, with particle sizes ranging from 1 to 8 μm and with 80% or more of the polylactic acid microspheres distributed within the 3 to 6 μm range; and graph d shows the particle size distribution of polylactic acid microspheres prepared in Example 5, with particle sizes ranging from 1 to 13 μm and with 75% or more of the polylactic acid microspheres distributed within the 1 to 3 μm range and 80% or more of the polylactic acid microspheres distributed within the 1 to 6 μm range.

[0086] The morphology of the microspheres produced in Examples 6 to 12 was observed with a scanning electron microscope, and the SEM images shown in Figures 3 to 9 were obtained. It can be seen that the microspheres produced in Examples 6 to 12 were all approximately spherical particles.

[0087] The microspheres produced in Examples 6 to 12 were subjected to particle size distribution analysis using a laser particle size analyzer, and the particle size distribution diagram of the microspheres shown in Figure 10 was obtained. The microspheres produced in Examples 6 to 12 have particle sizes of 1 to 3 μm, and the content of microspheres with a particle size distribution of 1 to 2 μm is 80% or more.

[0088] The polylactic acid microspheres and pure poloxamer samples prepared in Examples 1 and 5 were selected for thermal analysis, resulting in the DSC graph shown in Figure 11. The absorption peak at 172.2°C for the sample of Example 1 represents the melting temperature of polylactic acid. The melting absorption peak temperature for the sample of Example 5 was 160.1°C, significantly lower than that of the sample of Example 1. This is thought to be because poloxamer participates in the polymerization reaction process and forms grafts with polylactic acid, destroying the crystalline integrity of polylactic acid and lowering its melting point.

[0089] 12 shows UV absorption spectra of the samples of Examples 13 to 15. The characteristic peak at 235 nm corresponds to the absorption peak of erythromycin. The encapsulation rates of erythromycin in the microspheres produced in Examples 13, 14, and 15, calculated from the absorption peak intensity ratios at 235 nm of pure erythromycin and the microspheres, were 42%, 45%, and 48%, respectively.

[0090] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Those skilled in the art can modify or change the microspheres in the above examples to obtain biodegradable polymeric microspheres with certain functions without violating the spirit and scope of the present invention, and these should still be covered by the claims of the present invention.

Claims

1. A method for producing biodegradable polymeric microspheres, comprising: S1, preparation of liquid monomer: a step of preparing a biodegradable polymer monomer that is liquid at room temperature, or heating and melting a biodegradable polymer monomer that is solid at room temperature to obtain a liquid monomer; S2, preparing a mixed solution: adding a water-soluble polymer to the liquid monomer and completely dissolving the water-soluble polymer in the liquid monomer to obtain a mixed solution; S3, polymerization: a step of adding a catalyst to the mixed solution, leaving the mixed solution at a reaction temperature to polymerize the monomers, and obtaining a mixture of biodegradable polymeric microspheres and a water-soluble polymer; S4, post-treatment: a step of post-treating the mixture to obtain biodegradable polymer microspheres; A method for producing biodegradable polymeric microspheres, comprising:

2. The method according to claim 1, wherein the biodegradable polymer monomer is at least one selected from aliphatic polyester monomers.

3. The method described in claim 1, characterized in that the biodegradable polymer monomer is one or more selected from the group consisting of aliphatic lactides and aliphatic lactones.

4. The method described in claim 1, characterized in that the biodegradable polymer monomer is one or more selected from the group consisting of lactide, caprolactone, and glycolide.

5. The method according to claim 1, wherein the water-soluble polymer is one or more selected from the group consisting of polyoxyethylene polyoxypropylene ether block copolymer, polyacrylamide, polyvinylpyrrolidone, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, and methylcellulose, and / or the mass ratio of the biodegradable polymer monomer to the water-soluble polymer in the mixed solution is 100:(20 to 300).

6. 2. The method of claim 1, wherein the catalyst is at least one selected from the group consisting of metals, Lewis acids, Lewis bases, organometallic compounds, and metal salts.

7. The method of claim 1, characterized in that the catalyst is one or more selected from the group consisting of Fe, Cu, Zn, Co, alkali metal salts, Schiff bases, dibutylmagnesium, aluminum alkoxides, Ti[OCH(CH3)2]4, Sn(Oct)2, SnCl4, Sn(C6H5)4, Sn(Oct)2 / CH3(CH2)11OH, and Sn(Oct)2 / P(C6H5)3.

8. The method described in claim 1, characterized in that in the mixed solution, the mass ratio of the biodegradable polymer monomer to the catalyst is 100:(0.1 to 2).

9. The method of claim 1 , wherein the mixed solution further comprises an antioxidant and / or a functional material.

10. The method according to claim 1, wherein the polymerization reaction temperature is 90 to 180°C.

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