A polylactic acid microsphere material, its preparation method and application

Abstract

The present invention belongs to the technical field of polylactic acid materials, and specifically relates to a polylactic acid microsphere material, a preparation method thereof, and an application thereof. The present invention provides a preparation method of a polylactic acid microsphere material, comprising the following steps: mixing D-lactide, polyethylene glycol and a catalyst to carry out a ring-opening polymerization reaction to obtain a triblock copolymer; dissolving the triblock copolymer and L-polylactic acid in a good solvent of the triblock copolymer to obtain a mixed solution; spreading the mixed solution, adding a non-good solvent of the triblock copolymer on the surface of the spread solution, and then solidifying and self-assembling to obtain a polylactic acid microsphere material. The preparation method provided by the present invention has simple steps and is easy to operate, and can greatly improve the production efficiency of the polylactic acid microsphere material.

Description

Technical Field

[0001] The present invention belongs to the technical field of polylactic acid materials, and particularly relates to a polylactic acid microsphere material, a preparation method thereof, and an application thereof. Background Art

[0002] Polylactic acid (PLA) is a bio-based material. Compared with petroleum-based polymers, the preparation and use processes of PLA have less impact on the environment, and will not cause resource waste and environmental pollution. At the same time, PLA is widely sourced and can be prepared from plants such as corn, sugarcane, and cassava through processes such as starch extraction, acid hydrolysis, fermentation, and polymerization. However, PLA is a semi-crystalline polyester with a relatively slow crystallization rate and a low degree of crystallinity. It is difficult to obtain a highly ordered crystalline structure, resulting in poor mechanical properties and thermal stability. Moreover, the hydrophobic effect of PLA-based materials is not good, and they are prone to hydrolysis in a humid environment, which limits their scope of application.

[0003] Currently, the comprehensive properties of polylactic acid materials are mainly optimized by regulating their microstructures to expand their scope of application. For example, Chinese Patent CN102258786A utilizes the characteristic that the solvent in the polylactic acid solution contains an oil-water two-phase. After removing the organic solvent in the emulsion, porous polylactic acid microspheres are obtained through solidification, centrifugal washing, and freeze-drying. Another example is Chinese Patent CN102489230A, which forms a water-in-oil-in-water double emulsion in the oil-water two-phase of the solvent of the polylactic acid solution, and the oil phase is solidified to obtain an open-cell microsphere with an internally and externally penetrating pore channel. After adding a core to the microsphere, the microsphere is sealed to obtain a polymer microcapsule. The above methods obtain polylactic acid microspheres with different microstructures through one-step solidification of polymer emulsions. However, the preparation process is relatively complex, and the polymer emulsion is unstable and prone to demulsification (in the process of preparing polylactic acid microsphere materials, an amphiphilic surfactant needs to be added to improve the interfacial tension between the two phases to stabilize the emulsion. However, with the change of the solution system, too high local tension will cause the surfactant to be unable to stabilize the emulsion and demulsification will occur), which restricts the production efficiency of polylactic acid microsphere materials. Summary of the Invention

[0004] In view of this, the present invention provides a polylactic acid microsphere material, a preparation method thereof, and an application thereof. The preparation method of the polylactic acid microsphere material provided by the present invention is simple and easy to operate, and can greatly improve the production efficiency of polylactic acid microsphere materials.

[0005] To solve the above technical problems, the present invention provides a preparation method of a polylactic acid microsphere material, comprising the following steps:

[0006] Mixing D-lactide, polyethylene glycol, and a catalyst for ring-opening polymerization reaction to obtain a triblock copolymer;

[0007] Dissolve the triblock copolymer and poly(L-lactic acid) in a good solvent for the triblock copolymer to obtain a mixed solution;

[0008] After spreading the mixed solution, add a non-good solvent for the triblock copolymer to the surface of the spread solution, and then carry out solidification self-assembly to obtain a poly(lactic acid) microsphere material.

[0009] Preferably, the molar ratio of D-lactide to polyethylene glycol is 0.8-1.2:1;

[0010] The catalyst is stannous octoate, dibutyltin dilaurate or tetrabutyl titanate.

[0011] Preferably, the ring-opening polymerization reaction includes a low-temperature reaction and a high-temperature reaction carried out in sequence; the temperature of the low-temperature reaction is 160-170 °C and the time is 4-6 h; the temperature of the high-temperature reaction is 175-185 °C and the time is 1.5-2.5 h.

[0012] Preferably, the mass ratio of the triblock copolymer to poly(L-lactic acid) is 0.5-5:5-9.5.

[0013] Preferably, the good solvent for the triblock copolymer is dichloromethane, chloroform, tetrahydrofuran or dioxane;

[0014] The mass ratio of the triblock copolymer to the good solvent for the triblock copolymer is 5-50:1000.

[0015] Preferably, the non-good solvent for the triblock copolymer is methanol, ethanol, ethyl acetate or water;

[0016] The mass ratio of the good solvent for the triblock copolymer to the non-good solvent for the triblock copolymer is 5-10:10.

[0017] Preferably, the temperature of the solidification self-assembly is -40-0 °C and the time is 0.5-4 h.

[0018] Preferably, after the solidification self-assembly, it further includes: drying the product obtained by the solidification self-assembly;

[0019] The temperature of the drying is 20-35 °C and the time is 24-48 h.

[0020] The present invention also provides a poly(lactic acid) microsphere material prepared by the preparation method described in the above technical solution, which is composed of poly(lactic acid) microspheres, and the average diameter of the poly(lactic acid) microspheres is 1-5 μm; the poly(lactic acid) microspheres have a porous structure, and the porosity of the poly(lactic acid) microspheres is 60-95%.

[0021] The present invention also provides an application of the poly(lactic acid) microsphere material described in the above technical solution as a drug sustained-release carrier.

[0022] The present invention provides a method for preparing a polylactic acid microsphere material, which comprises the following steps: mixing D-lactide, polyethylene glycol and a catalyst for ring-opening polymerization reaction to obtain a triblock copolymer; dissolving the triblock copolymer and L-polylactic acid in a good solvent of the triblock copolymer to obtain a mixed solution; spreading the mixed solution and adding a non-good solvent of the triblock copolymer on the surface of the spread solution for curing self-assembly to obtain a polylactic acid microsphere material. The preparation method provided by the present invention has simple steps and is easy to operate, and can greatly improve the production efficiency of the polylactic acid microsphere material. Compared with the traditional method of preparing polylactic acid microsphere materials by strong mechanical stirring, the preparation method provided by the present invention forms polylactic acid microspheres by self-assembly. Self-assembly is a spontaneous process and does not require strong stirring to generate shear force to control the size of the polylactic acid microspheres. The present invention can prepare microspheres with smaller sizes (micrometer level) by self-assembly. At the same time, the preparation method provided by the present invention does not need to add substances such as surfactants to stabilize the emulsion size during the preparation of the polylactic acid microsphere material, and there will be no phenomenon such as demulsification. The D-polylactic acid in the synthesized triblock polymer is a hydrophobic component, and polyethylene glycol is a hydrophilic component. The triblock polymer has good amphiphilicity, can well stabilize the solvent phase and the non-solvent phase, is beneficial to maintaining the stability of the system, and promotes the formation of microspheres; in addition, hydrogen bonds will be formed between the L-polylactic acid and the D-polylactic acid in the triblock polymer, and stereocomplex crystals will be formed by crystallization and curing, which can well stabilize the change of the interaction force between the two phases and further promote the formation of microspheres. Description of the Drawings

[0023] Figure 1 It is a schematic diagram of the mechanism for the formation of the polylactic acid microsphere structure in the preparation method provided by the present invention;

[0024] Figure 2 It is a Fourier transform infrared spectrum diagram of the polylactic acid microsphere materials prepared in Examples 1 to 5;

[0025] Figure 3 It is a second heating DSC curve diagram of the polylactic acid microsphere materials prepared in Examples 1 to 5 and Comparative Example 1;

[0026] Figure 4SEM images of the polylactic acid microsphere materials prepared in Examples 1 to 5 and Comparative Example 1, where (a), (a1), and (a2) are SEM images of the polylactic acid microsphere materials prepared in Comparative Example 1 at different magnifications, (b), (b1), and (b2) are SEM images of the polylactic acid microsphere materials prepared in Example 1 at different magnifications, (c), (c1), and (c2) are SEM images of the polylactic acid microsphere materials prepared in Example 2 at different magnifications, (d), (d1), and (d2) are SEM images of the polylactic acid microsphere materials prepared in Example 3 at different magnifications, (e), (e1), and (e2) are SEM images of the polylactic acid microsphere materials prepared in Example 4 at different magnifications, and (f), (f1), and (f2) are SEM images of the polylactic acid microsphere materials prepared in Example 5 at different magnifications. Detailed implementation manners

[0027] The present invention provides a preparation method of a polylactic acid microsphere material, comprising the following steps:

[0028] Mixing D-lactide, polyethylene glycol, and a catalyst for ring-opening polymerization reaction to obtain a triblock copolymer;

[0029] Dissolving the triblock copolymer and L-polylactic acid in a good solvent of the triblock copolymer to obtain a mixed solution;

[0030] Spreading the mixed solution and adding a non-good solvent of the triblock copolymer on the surface of the spread solution, and then curing and self-assembling to obtain the polylactic acid microsphere material.

[0031] In the present invention, D-lactide, polyethylene glycol, and a catalyst are mixed for ring-opening polymerization reaction to obtain a triblock copolymer. In the present invention, preferably before the mixing, the D-lactide is purified; the polyethylene glycol is dried. In the present invention, the purification preferably comprises the following steps: mixing D-lactide and ethyl acetate in a mass ratio of 100:75 at 50-80°C, cooling and standing overnight; filtering the standing system to obtain a solid; repeating the above steps of mixing, standing, and filtering twice for the solid to obtain purified D-lactide. In the present invention, the drying is preferably vacuum drying, the temperature of the vacuum drying is preferably 90-110°C, more preferably 100°C; the vacuum degree of the vacuum drying is preferably -0.01 to -0.1 MPa, more preferably -0.05 to -0.1 MPa; the time of the vacuum drying is preferably 1.5-2.5 h, more preferably 2 h.

[0032] In the present invention, the molecular weight of the polyethylene glycol is preferably 200, 400, 600, 800 or 1000. In the present invention, the catalyst is preferably stannous octoate, dibutyltin dilaurate or tetrabutyl titanate, and more preferably stannous octoate.

[0033] In the present invention, the molar ratio of the D-lactide to the polyethylene glycol is preferably 0.8 - 1.2:1, and more preferably 1:1. In the present invention, the molar ratio of the catalyst to the D-lactide is preferably 0.8 - 1.2:1000, and more preferably 1:1000.

[0034] In the present invention, the mixing is preferably carried out under stirring conditions. The temperature of the stirring is preferably 110 - 130 °C, and more preferably 120 °C; the rotation speed of the stirring is preferably 140 - 160 r / min, and more preferably 150 r / min. The present invention has no special requirements for the stirring time, as long as the mixture can be evenly mixed. In the present invention, the D-lactide is melted under stirring conditions.

[0035] In the present invention, the ring-opening polymerization reaction preferably includes a low-temperature reaction and a high-temperature reaction carried out in sequence; the temperature of the low-temperature reaction is preferably 160 - 170 °C, and more preferably 165 - 168 °C; the time of the low-temperature reaction is preferably 4 - 6 h, and more preferably 5 h; the temperature of the high-temperature reaction is preferably 175 - 185 °C, and more preferably 180 - 183 °C; the time of the high-temperature reaction is preferably 1.5 - 2.5 h, and more preferably 2 h. In the present invention, the polymerization reaches a certain degree in a low-temperature environment, and the viscosity of the system increases to hinder further reaction. Increasing the temperature can reduce the viscosity of the polymer and promote further reaction.

[0036] In the present invention, the ring-opening polymerization reaction is preferably carried out under negative pressure conditions, and the pressure of the negative pressure is preferably -0.08 - -0.1 MPa.

[0037] In the present invention, the ring-opening polymerization reaction is preferably carried out in an anhydrous, anoxic and dust-free environment. The present invention has no special requirements for the method of forming an anhydrous, anoxic and dust-free environment, and the conventional methods in the art can be used. In the examples of the present invention, the reaction vessel is purged with nitrogen for 15 min to remove air, and the reaction system is evacuated for 2 h to form an anhydrous, anoxic and dust-free environment.

[0038] In the present invention, the ring-opening polymerization reaction of D-lactide is induced by the terminal hydroxyl groups of polyethylene glycol during the ring-opening polymerization reaction to form poly(D-lactic acid), and the two terminal hydroxyl groups of polyethylene glycol are respectively combined with poly(D-lactic acid) to form a triblock copolymer.

[0039] In the present invention, the relative molecular weight of the triblock copolymer is preferably 9700 - 15000.

[0040] In the present invention, after the ring-opening polymerization reaction, it is preferably further included to purify the product after the ring-opening polymerization reaction. In the present invention, the purification treatment preferably includes the following steps: dissolving the product after the ring-opening polymerization reaction in dichloromethane and then mixing it with petroleum ether to precipitate; separating the solid and liquid in the system after precipitation, and repeating the steps of dissolution, precipitation, and solid-liquid separation 3 times to obtain a triblock copolymer. The present invention has no special requirements for the amounts of dichloromethane and petroleum ether, and dissolution and precipitation can be carried out in a conventional manner in the art. In the present invention, the solid-liquid separation is preferably filtration.

[0041] After obtaining the triblock copolymer, in the present invention, the triblock copolymer and poly(L-lactic acid) are dissolved in a good solvent for the triblock copolymer to obtain a mixed solution. In the present invention, the good solvent for the triblock copolymer is preferably dichloromethane, chloroform, tetrahydrofuran, or dioxane, more preferably dichloromethane. In the present invention, the mass ratio of the triblock copolymer to the good solvent for the triblock copolymer is preferably 5 - 50:1000, more preferably 5:1000. In the present invention, the mass ratio of the triblock copolymer to poly(L-lactic acid) is preferably 0.5 - 5:5 - 9.5, more preferably 1 - 3:7 - 9, and specifically can be 0.5:9.5, 1:9, 3:7, or 5:5.

[0042] The present invention has no special requirements for the dissolution, as long as it can be completely dissolved.

[0043] After obtaining the mixed solution, the present invention spreads the mixed solution and adds a non-solvent of the triblock copolymer on the surface of the spread solution, and then cures and self-assembles to obtain a polylactic acid microsphere material. In the present invention, the non-solvent of the triblock copolymer is preferably methanol, ethanol, ethyl acetate or water, and more preferably water. In the present invention, the mass ratio of the good solvent of the triblock copolymer to the non-solvent of the triblock copolymer is preferably 5-10:10, and more preferably 8-10:10. In the present invention, the density of the non-solvent of the triblock copolymer is preferably lower than that of the good solvent of the triblock copolymer. After the present invention adds the non-solvent of the triblock copolymer to the surface of the mixed solution, a double-layer mixed solution is formed. In the present invention, the density of the non-solvent of the triblock copolymer is lower than that of the good solvent of the triblock copolymer, and the volatility of the non-solvent of the triblock copolymer is lower than that of the good solvent of the triblock copolymer; in the double-layer mixed solution system, as the good solvent of the triblock copolymer volatilizes, the non-solvent of the triblock copolymer in the upper layer will diffuse into the lower-layer mixed solution, resulting in an increase in the Gibbs free energy of the polymer (triblock copolymer and poly(L-lactic acid)) molecular chains and forming a solid. The non-solvent of the triblock copolymer plays a role in solid-liquid phase separation. If two layers of solution are not formed, the good solvent and the non-solvent have good compatibility, and the effect of self-assembled microspheres cannot appear. At the same time, during the phase separation process of the polymer solution, due to the phase separation between the good solvent and the non-solvent, a polymer-rich phase and a polymer-lean phase are formed. After curing, the polymer-rich phase forms the skeleton of the porous structure, and the polymer-lean phase forms pores, thereby obtaining a polylactic acid microsphere material with a porous structure.

[0044] In the present invention, the spreading is preferably pouring the mixed solution into a glass petri dish. In the present invention, the thickness of the spread solution is preferably 1-3 mm, and more preferably 1-2 mm.

[0045] In the present invention, the temperature of the curing and self-assembly is preferably -40 to 0 °C, and more preferably -30 to -18 °C; the time of the curing and self-assembly is preferably 0.5-4 h, and more preferably 1-3 h.

[0046] The present invention limits the temperature of the curing and self-assembly within the above range, which can reduce the volatilization rate of the good solvent, make the non-solvent more stably diffuse into the mixed solution, and contribute to the formation of polylactic acid microspheres with a uniform structure.

[0047] In the present invention, after the curing and self-assembly, it preferably further includes: drying the product obtained by the curing and self-assembly; the temperature of the drying is preferably 20-35 °C, and more preferably 25-30 °C; the time of the drying is preferably 24-48 h, and more preferably 30-40 h.

[0048] The present invention can completely remove the residual solvent in the polylactic acid microsphere material through drying, avoiding the formation of a dense cortex at the liquid-solid interface of the polylactic acid microsphere material.

[0049] Figure 1 It is a schematic diagram of the formation mechanism of the polylactic acid microsphere structure in the preparation method provided by the present invention. Specifically, the two ends of the synthesized triblock copolymer are hydrophobic segments of poly(D-lactic acid) (PDLA), and the middle is a hydrophilic segment of polyethylene glycol (PEG); in the mixed solution, the concentration of the triblock copolymer is relatively dilute, showing isolated polymer spheres; in the solvent evaporation stage (solidification self-assembly), the concentration of the triblock copolymer gradually increases, and the polymer coils gradually approach each other. A stereocomplex crystal is formed by hydrogen bonding between poly(L-lactic acid) (PLLA) and the PDLA segment in the triblock copolymer, and the crystallization of the molecular chains gradually solidifies the polymer spheres to form self-assembled polylactic acid microspheres.

[0050] The present invention also provides a polylactic acid microsphere material prepared by the preparation method described in the above technical solution. It is composed of polylactic acid microspheres. The average diameter of the polylactic acid microspheres is 1-5 μm, preferably 2-4 μm; the polylactic acid microspheres have a porous structure, and the porosity of the polylactic acid microspheres is 60-95%, preferably 70-90%.

[0051] The present invention also provides the application of the polylactic acid microspheres described in the above technical solution as a drug sustained-release carrier.

[0052] In order to further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with examples, but they should not be construed as limiting the protection scope of the present invention.

[0053] Example 1

[0054] Polyethylene glycol with a molecular weight of 200 was vacuum-dried at a vacuum degree of -0.1 MPa and a temperature of 100 °C for 2 h to obtain dried polyethylene glycol; D-lactide and ethyl acetate (the mass ratio of D-lactide to ethyl acetate was 100:75) were mixed at 70 °C and then cooled to room temperature and left to stand overnight; the standing system was filtered, and the steps of mixing, standing, and filtering were repeated twice to obtain purified D-lactide;

[0055] After purging the reaction vessel with nitrogen for 15 min, the purified D-lactide was placed in the reaction vessel. The purified D-lactide was melted at a temperature of 120 °C and a rotation speed of 150 r / min, and then dry polyethylene glycol and stannous octoate were added. The mixture was uniformly mixed at a temperature of 120 °C and a rotation speed of 150 r / min (the molar ratio of the purified D-lactide to the dry polyethylene glycol was 1:1, and the molar ratio of stannous octoate to D-lactide was 1:1000); the reaction system was evacuated for 2 h and then ring-opening polymerization reaction was carried out at 165 °C for 5 h, and then the temperature was raised to 180 °C and the reaction was continued for 2 h to obtain a crude triblock copolymer; the crude triblock copolymer was dissolved in dichloromethane and then mixed with petroleum ether to precipitate, and then filtered; the steps of dissolution, precipitation and filtration were repeated three times to obtain the purified triblock copolymer;

[0056] 0.1 g of the triblock copolymer and 0.9 g of L-polylactic acid were dissolved in 20 g of dichloromethane to obtain a mixed solution;

[0057] 5 mL of the mixed solution was poured into a glass petri dish to form a flat solution with a thickness of 1 mm, and then 5 g of ethanol non-solvent was added to the surface of the flat solution to obtain a double-layer mixed solution; the double-layer mixed solution was placed in a low-temperature environment of -18 °C for curing and self-assembly for 1 h, and then vacuum dried at 25 °C for 24 h to obtain a polylactic acid microsphere material, denoted as PDLA-PEG200-PDLA.

[0058] Example 2

[0059] The polylactic acid microsphere material denoted as PDLA-PEG400-PDLA was prepared according to the method of Example 1, except that the polyethylene glycol with a molecular weight of 200 was replaced by the polyethylene glycol with a molecular weight of 400.

[0060] Example 3

[0061] The polylactic acid microsphere material denoted as PDLA-PEG600-PDLA was prepared according to the method of Example 1, except that the polyethylene glycol with a molecular weight of 200 was replaced by the polyethylene glycol with a molecular weight of 600.

[0062] Example 4

[0063] The polylactic acid microsphere material denoted as PDLA-PEG800-PDLA was prepared according to the method of Example 1, except that the polyethylene glycol with a molecular weight of 200 was replaced by the polyethylene glycol with a molecular weight of 800.

[0064] Example 5

[0065] The polylactic acid microsphere material denoted as PDLA-PEG1000-PDLA was prepared according to the method of Example 1, except that the polyethylene glycol with a molecular weight of 200 was replaced by the polyethylene glycol with a molecular weight of 1000.

[0066] Comparative Example 1

[0067] The polylactic acid microsphere material was prepared according to the method of Example 1, except that polyethylene glycol was not added;

[0068] Specifically, it includes the following steps:

[0069] D - lactide and ethyl acetate (the mass ratio of D - lactide to ethyl acetate is 100:75) were mixed at 70°C and then cooled to room temperature and left to stand overnight; the standing system was filtered, and the steps of mixing, standing, and filtering were repeated twice to obtain purified D - lactide;

[0070] After purging the reaction vessel with nitrogen for 15 min, the purified D - lactide was placed in the reaction vessel. At a temperature of 120°C and a rotation speed of 150 r / min, the purified D - lactide was melted and stannous octoate was added, and it was mixed evenly at a temperature of 120°C and a rotation speed of 150 r / min (the molar ratio of stannous octoate to D - lactide is 1:1000); the reaction system was evacuated for 2 h and then ring - opening polymerization reaction was carried out at 165°C for 5 h, and then the temperature was raised to 180°C and the reaction was continued for 2 h to obtain crude D - polylactic acid; the crude D - polylactic acid was dissolved in dichloromethane and then mixed with petroleum ether to precipitate, and then filtered; the steps of dissolving, precipitating, and filtering were repeated three times to obtain purified D - polylactic acid;

[0071] 0.1 g of D - polylactic acid and 0.9 g of L - polylactic acid were dissolved in 20 g of dichloromethane to obtain a mixed solution;

[0072] 5 mL of the mixed solution was poured into a glass petri dish to form a flat - laying solution with a thickness of 1 mm, and then 5 g of ethanol was added to the surface of the flat - laying solution to obtain a double - layer mixed solution; the double - layer mixed solution was placed in a low - temperature environment of - 18°C for solid - state self - assembly for 1 h and then vacuum - dried at 25°C for 24 h to obtain the polylactic acid microsphere material.

[0073] The polylactic acid microsphere materials prepared in Examples 1 - 5 were subjected to Fourier transform infrared detection to obtain Fourier transform infrared spectra (FTIR), as Figure 2 shown. From Figure 2 it was not only possible to see the CH3 absorption peak at 2996 cm -1 and the CH absorption peak between 1350 - 1310 cm -1 , but also the vibration peak of CH2 at 2880 cm -1 was observed. CH and CH3 come from PDLA, and CH2 comes from PEG. These characteristic absorption peaks can confirm the successful synthesis of the triblock copolymer PDLA - PEG - PDLA, that is, the successful introduction of the PEG segment into PDLA.

[0074] The poly(lactic acid) microsphere materials prepared in Examples 1-5 and Comparative Example 1 were detected using a differential scanning calorimeter, and the second heating DSC curve was obtained, as shown in Figure 3 shown. It can be seen from Figure 3 that the endothermic peak at 170 °C corresponds to the melting peak of the homogeneous crystal, and the endothermic peak at 220 °C represents the melting peak of the stereocomplex crystal; it indicates that the synthesized pure PDLA molecules cannot induce the PLLA chains to form stereocomplex crystals. When a triblock polymer is added, the stereocomplex crystallization peak appears, and the cold crystallization peak temperature decreases. When the PEG molecular weight is above 400, a crystallization peak appears near 100 °C, indicating microphase separation.

[0075] The poly(lactic acid) microsphere materials prepared in Examples 1-5 and Comparative Example 1 were detected using a scanning electron microscope, and the scanning electron microscope images were obtained, as shown in Figure 4 shown, where (a), (a1) and (a2) are SEM images of the poly(lactic acid) microsphere materials prepared in Comparative Example 1 at different magnifications, (b), (b1) and (b2) are SEM images of the poly(lactic acid) microsphere materials prepared in Example 1 at different magnifications, (c), (c1) and (c2) are SEM images of the poly(lactic acid) microsphere materials prepared in Example 2 at different magnifications, (d), (d1) and (d2) are SEM images of the poly(lactic acid) microsphere materials prepared in Example 3 at different magnifications, (e), (e1) and (e2) are SEM images of the poly(lactic acid) microsphere materials prepared in Example 4 at different magnifications, (f), (f1) and (f2) are SEM images of the poly(lactic acid) microsphere materials prepared in Example 5 at different magnifications. It can be seen from Figure 4 that pure PDLA molecules cannot induce the PLLA chains to form a regular microsphere structure. The triblock polymer introducing PEG chains can induce the formation of a regular microsphere structure. As the PEG chain molecular weight increases, the diameter of the spheres gradually increases. The microsphere structure is mainly obtained by the solidification of poly(lactic acid) during the phase separation process. The pure PDLA molecules lack hydrophilic segments and cannot stabilize the emulsion. At the same time, the flexibility of the PDLA chains is poor and they cannot combine with the PLLA chains. Pure PDLA molecules alone cannot induce PLLA to form stereocomplex crystals; the addition of PEG makes the triblock polymer have a certain flexibility, so that stereocomplex crystals can be formed. The failure to form stereocomplex crystals indicates that solidification cannot occur at the interface between the solvent phase and the nonsolvent phase, and a uniform microsphere structure cannot be formed.

[0076] The average particle size and porosity of the poly(lactic acid) microspheres were obtained according to the following method, and the results are listed in Table 1. The average particle size of the poly(lactic acid) microspheres was obtained by counting the microsphere sizes in the scanning electron microscope images. At least 100 samples of each sample were counted and the average value was taken. The porosity of the microspheres was calculated by density. First, the density of the microspheres was weighed using a density balance and denoted as ρ0. It was calculated by formula 1, where ρ is the density of poly(lactic acid) 1.24 g / cm3 , where P is the porosity of the polylactic acid microspheres.

[0077] P% = (1 - ρ0 / ρ) Formula 1.

[0078] Table 1 Performance parameters of the polylactic acid microspheres prepared in Example 1 and Comparative Example 1

[0079] Example Average particle size (μm) Porosity (%) Example 1 1.89μm 92％ Example 2 1.77μm 91％ Example 3 2.74μm 88％ Example 4 2.42μm 95％ Example 5 2.19μm 92％ Comparative Example 1 2.65μm 77％

[0080] As can be seen from Table 1, the polylactic acid microsphere material with smaller size and good structural stability can be prepared according to the preparation method provided by the present invention.

[0081] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing a polylactic acid microsphere material, comprising the following steps: Mixing D-lactide, polyethylene glycol and a catalyst for ring-opening polymerization reaction to obtain a triblock copolymer; Dissolving the triblock copolymer and L-polylactic acid in a good solvent of the triblock copolymer to obtain a mixed solution; Spreading the mixed solution and adding a non-good solvent of the triblock copolymer on the surface of the spread solution, and then performing solidification self-assembly to obtain a polylactic acid microsphere material.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the D-lactide to the polyethylene glycol is 0.8 to 1.2:1; The catalyst is stannous octoate, dibutyltin dilaurate or tetrabutyl titanate.

3. The preparation method according to claim 1 or 2, characterized in that The ring-opening polymerization reaction includes performing a low-temperature reaction and a high-temperature reaction in sequence; the temperature of the low-temperature reaction is 160 to 170 °C and the time is 4 to 6 h; the temperature of the high-temperature reaction is 175 to 185 °C and the time is 1.5 to 2.5 h.

4. The preparation method according to claim 1, characterized in that, The mass ratio of the triblock copolymer to the L-polylactic acid is 0.5 to 5:5 to 9.

5.

5. The preparation method according to claim 1 or 4, characterized in that, The good solvent of the triblock copolymer is dichloromethane, chloroform, tetrahydrofuran or dioxane; The mass ratio of the triblock copolymer to the good solvent of the triblock copolymer is 5 to 50:1000.

6. The preparation method according to claim 1, characterized in that The non-good solvent of the triblock copolymer is methanol, ethanol, ethyl acetate or water; The mass ratio of the good solvent of the triblock copolymer to the non-good solvent of the triblock copolymer is 5 to 10:

10.

7. According to the preparation method described in claim 1, characterized in that, The temperature of the solidification self-assembly is -40 to 0 °C and the time is 0.5 to 4 h.

8. The preparation method according to claim 1 or 7, characterized in that, After the solidification self-assembly, it further includes: drying the product obtained by the solidification self-assembly; The temperature of the drying is 20 to 35 °C and the time is 24 to 48 h.

9. The polylactic acid microsphere material prepared by the preparation method according to any one of claims 1 to 8, characterized in that, Composed of polylactic acid microspheres, the average diameter of the polylactic acid microspheres is 1 to 5 μm; the polylactic acid microspheres have a porous structure, and the porosity of the polylactic acid microspheres is 60 to 95%.

10. Use of the polylactic acid microsphere material according to claim 9 in the preparation of a drug sustained-release carrier.

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