A micro-nanoparticle preparation method based on evaporation-induced phase separation of a levorotatory polylactic acid solution system

Abstract

This application provides a method for preparing micro / nano particles based on evaporation-induced phase separation in a polylactic acid (PLLA) solution system, belonging to the field of polymer granulation technology. PLLA particles are dissolved in a solvent system to obtain a PLLA solution, wherein the solvent system is a monolithic or binary system; the PLLA solution is then subjected to droplet evaporation to obtain micro / nano particles. This application focuses on a polylactic acid (PLLA) solution system, utilizing evaporation-assisted phase separation to obtain micro / nano particles with controllable particle size.

Description

Technical Field

[0001] This application relates to a method for preparing micro / nano particles based on evaporation-induced phase separation in a polylactic acid (PLA) solution system, belonging to the field of polymer granulation technology. Background Technology

[0002] Polymer micro / nanoparticles / microspheres possess high specific surface areas, providing numerous reaction sites. Compared to non-porous microspheres, porous microspheres offer unique advantages, such as high porosity, larger specific surface area, lower density, and specific drug absorption and release kinetics. Currently, injectable microspheres made from polylactic acid (PLA) polymers and copolymers have been successfully applied to deliver various drugs, including cell stabilizers, anti-inflammatory agents, peptides, and hormones. Lactic acid-based polymer microspheres have wide applications in biomedicine, food packaging, and environmental remediation. In the medical field, these microspheres can serve as drug carriers for controlled drug release and targeting, and can be used to encapsulate the hydrophobic anticancer drug curcumin, delivering it to target cells at the desired therapeutic dose. Hydrophobic and oleophilic porous materials can effectively address the severe water pollution caused by oil spills and industrial wastewater discharge. For example, H Rafiq et al. prepared PLLA microspheres with nanoscale micropores on their surface (Rafiq H, Hsu IY, Uyama H. ​​Preparation of nanoporous poly(L-lactic acid) microspheres with controllable morphology via thermally-induced phase separation[J]. Polymer, 2024, 312127622-127622). These microspheres have superhydrophobic and superoleophilic properties, which have potential application value in the preparation of biodegradable and environmentally friendly adsorbent materials for oil / water separation.

[0003] There are many methods for preparing PLA microspheres, such as emulsification-solvent evaporation, microfluidics, spray drying, and phase separation. Emulsification-solvent evaporation may require additional removal of pore-forming agents or surfactants. Microfluidics allows for precise control of the nanoporous structure of PLA microspheres, but its applicability is limited and it relies on expensive equipment. Spray drying is relatively simple, but it is unsuitable for heat-sensitive polymers and can produce PLA microspheres with high polydispersity. In contrast, phase separation methods offer advantages such as simple preparation processes and low production costs, but the phase separation behavior is affected by system composition and temperature, resulting in uncontrollable microsphere size and poor uniformity. Summary of the Invention

[0004] In view of this, this application provides a method for preparing micro / nano particles based on evaporation-induced phase separation in a poly(L-lactic acid) (PLLA) solution system, thereby achieving the preparation of micro / nano particles with high specific surface area and controllable size.

[0005] Specifically, this application is implemented through the following scheme: A method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system, comprising the following steps: Step 1: Dissolve PLLA particles in a solvent system to obtain a PLLA solution; Step 2: The PLLA solution is evaporated into droplets to obtain micro / nano particles.

[0006] The above process enables the preparation of micro and nano particles with controllable size through evaporation-assisted phase separation.

[0007] Furthermore, as a preferred option: In step one, The solvent system is a unary system or a binary system. More preferably, the unary system is THF, 1,3-dioxane, ethanol, or water. The binary solvent includes a solvent and a non-solvent, wherein the solvent is any one of THF and 1,3-dioxane, and the non-solvent is ethanol or water, and the volume ratio of the solvent to the non-solvent is 70-90:10-30.

[0008] The PLLA particles were dissolved in a solvent system and then heated to 40–60°C to obtain a homogeneous PLLA solution. Stirring was performed during the heating process at a speed of 300–600 rpm to promote dissolution.

[0009] The concentration of the PLLA solution is 0.05–5 wt%, preferably 0.2–2 wt%.

[0010] In step two, The droplet evaporation is performed using either direct evaporation or suppressed evaporation, both methods occurring within a specific temperature and humidity control device. During direct evaporation, water is used for humidity control. During suppressed evaporation, the water used for humidity control is replaced with a suitable solvent for dissolving PLLA; in this case, solvent vapor saturation inhibits solvent evaporation. More preferably, in the suppressed evaporation method, the droplet evaporation temperature is 30–40°C, and the humidity is 30–90%RH. Preferably, the humidity is 60–90%RH.

[0011] In particular, when the non-solvent is water, the volume ratio of water in the binary system is <12%; at this time, when the solvent is THF, the corresponding droplet evaporation humidity is 60-90%RH; when the solvent is 1,3-dioxane, the corresponding droplet evaporation humidity is 30-90%RH.

[0012] The particle size of the micro / nano particles is 0.3–1.6 mm. More preferably, the particle size of the micro / nano particles corresponding to the unary system is 1.1–1.2 mm. In the binary system: the binary system is THF / water, and the corresponding particle size of the micro / nano particles is 0.30–0.55 mm; the binary system is 1,3-dioxane / water = 90:10, and the corresponding particle size of the micro / nano particles is 0.8–1.1 mm; the binary system is 1,3-dioxane / water = 85:15, and the corresponding particle size of the micro / nano particles is 1.16–1.56 mm. Attached Figure Description

[0013] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application.

[0014] Figure 1 The SEM morphology of the product formed by the 0.2 wt% PLLA / unary system is shown in the figure. Part (a) is Example 1; Part (b) is Example 1-1; Part (c) is Example 1-2; and Part (d) is Example 1-3.

[0015] Figure 2 The SEM morphology of the 0.2 wt% PLLA / THF system products under different humidity conditions is shown.

[0016] Figure 3 The figure shows the particle size distribution of the products prepared in Examples 1-5. Part (a) in the figure represents product A, and part (b) represents product B.

[0017] Figure 4 The figures show the SEM morphology of the products formed under different conditions in the PLLA / unary system. Part (a) is Example 2, part (b) is Example 2-1, part (c) is Example 2-2, and part (d) is Example 2-3.

[0018] Figure 5 The diagrams show the thermodynamic three-phase diagrams for different binary systems. Part (a) represents PLLA / THF:H2O, and part (b) represents PLLA / Dioxane:H2O.

[0019] Figure 6 The SEM morphology of the product formed by PLLA / THF: H2O = 90:10 under different relative humidity conditions is shown in the figure. Part (a) is at 30% RH; part (b) is at 60% RH; and part (c) is at 90% RH.

[0020] Figure 7The figure shows the particle size distribution of the two products in Examples 2-4. Part (a) in the figure represents product C; part (b) represents product D.

[0021] Figure 8 The SEM morphology of the products formed by the PLLA / Dioxane: H2O = 90:10 system under different relative humidity conditions is shown in the figure. Part (a) is at 30% RH; part (b) is at 60% RH; and part (c) is at 90% RH.

[0022] Figure 9 The figure shows the particle size distribution of the PLLA / Dioxane:H2O binary system. In the figure, (a) represents product E; (b) represents product F; (c) represents product G; and (d) represents product H. Detailed Implementation

[0023] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without creative effort are within the scope of protection of this application.

[0024] Table 1: Reagents used in this embodiment .

[0025] Table 2: Instruments used in this embodiment .

[0026] Example 1 In this embodiment, a unicomponent solvent is used, and the preparation method of the micro / nano particles is as follows: Step 1: Weigh PLLA particles, add PLLA particles to the solvent THF, add a rotor, and heat and stir at 50 ℃ and 500 rpm for 4 h until completely dissolved to obtain a homogeneous 0.2 wt% PLLA solution.

[0027] Step 2: Droplet evaporation is carried out using the direct evaporation method: A homogeneous PLLA solution is quantitatively added dropwise onto a polytetrafluoroethylene film and placed in a vacuum dryer. By adding an appropriate amount of deionized water or desiccant, the temperature inside the vacuum dryer is controlled at 30 ℃ and the humidity at 40%RH. Under these conditions, the PLLA solution evaporates in the form of droplets to assist in phase separation and remove the solvent.

[0028] Example 1-1

[0029] This embodiment has the same setup as Embodiment 1, except that the droplet evaporation method in step two is replaced by the suppressed evaporation method: in a solvent THF vapor environment, the PLLA solution is added dropwise to a vacuum dryer covered with a polytetrafluoroethylene film, and the temperature is controlled at 30 °C to evaporate and remove the solvent.

[0030] Examples 1-2

[0031] In this embodiment, a unicomponent solvent is used, and the preparation method of the micro / nano particles is as follows: Step 1: Weigh PLLA particles, add the PLLA particles to the solvent 1,4-dioxane, add the rotor, and heat and stir at 50 ℃ and 500 rpm for 4 h until completely dissolved to obtain a homogeneous 0.2 wt% PLLA solution.

[0032] Step 2: Droplet evaporation is carried out using the direct evaporation method: A homogeneous PLLA solution is quantitatively added dropwise onto a polytetrafluoroethylene film and placed in a vacuum dryer. By adding an appropriate amount of deionized water or desiccant, the temperature inside the vacuum dryer is controlled at 30 ℃ and the humidity at 40%RH. Under these conditions, the PLLA solution evaporates in the form of droplets to assist in phase separation and remove the solvent.

[0033] Examples 1-3

[0034] This embodiment has the same setup as Embodiments 1-2, except that the droplet evaporation method in step two is replaced by the inhibited evaporation method: in the solvent Dioxane vapor environment, the PLLA solution is added dropwise to a vacuum dryer covered with a polytetrafluoroethylene film, and the temperature is controlled at 30 °C to evaporate and remove the solvent.

[0035] SEM images of the products prepared in the above four cases are shown below. Figure 1 As shown, there are significant differences in the morphology control effects of direct evaporation and suppressed evaporation in the preparation of PLLA micro / nanoparticles: Both Example 1 and Example 1-1 used THF as a solvent, but the product obtained by the direct evaporation method had a smooth, continuous film structure (see...). Figure 1 In part (a) of the text, no microsphere morphology was observed; however, the product prepared by the suppressed evaporation method had a rough surface and exhibited a filamentous crystal structure (see [reference]). Figure 1 (See part (b)); Examples 1-2 and 1-3 both used Dioxane as a solvent, whose boiling point (approximately 101 °C) differs significantly from that of THF (approximately 66 °C). During the evaporation-assisted phase separation process, THF evaporates rapidly, while Dioxane is more stable, resulting in a longer phase separation process. Therefore, the products of Examples 1-2 have a smooth microsphere structure, but the particle size distribution is relatively large (see [link to example 1]). Figure 1(c) of the document); while Examples 1-3, by suppressing evaporation and combining with more stable solvents, endowed the products with smaller microspheres, but with a bulky structure (see [reference]). Figure 1 (d) in the middle.

[0036] Therefore, for L-polylactic acid solution systems, the mono-component system Dioxane combined with the evaporation suppression method performs better in shaping micro / nano particles / microspheres.

[0037] Examples 1-4

[0038] In this embodiment, a unicomponent solvent is used, and the preparation method of the micro / nano particles is as follows: Step 1: Weigh PLLA particles, add PLLA particles to the solvent THF, add a rotor, and heat and stir at 50 ℃ and 500 rpm for 4 h until completely dissolved to obtain a homogeneous 0.2 wt% PLLA solution.

[0039] Step 2: Droplet evaporation is performed using the direct evaporation method: A homogeneous PLLA solution is quantitatively added dropwise onto a polytetrafluoroethylene film and placed in a vacuum dryer. By adding an appropriate amount of deionized water or desiccant, the temperature inside the vacuum dryer is controlled at 30 °C. Under these conditions, the PLLA solution evaporates in droplet form to assist in phase separation. The humidity is controlled at 30%RH, 60%RH, and 90%RH respectively to evaporate and remove the solvent.

[0040] SEM images of the products obtained under different humidity conditions are shown below. Figure 2 As shown, the morphology of the phase separation products changed significantly with increasing humidity in the evaporation environment. At low humidity, the solvent evaporated rapidly, forming a thin film with bubbles and pores on its surface (see...). Figure 2 (a) In moderate humidity, the solvent evaporation rate slows down, and the time for the PLLA molecular chains to move and align increases, resulting in a smoother film structure (see part (a)). Figure 2 (Part (b)). Under high humidity, the morphology shows a large accumulation of spherical microparticles, exhibiting a granular structure. The microspheres are plump and uniform in size, with only a small amount accumulating into a blocky structure (see [link]). Figure 2 (See section (c)). As the humidity gradually increases from 30% RH to 90% RH, the PLLA / THF system evolves from a film structure to a structure of micro-nano particle stacking, and the morphology shows a trend from porous to smooth and then to microspheres.

[0041] Therefore, the optimal humidity for the L-polylactic acid solution system is 90%RH.

[0042] The applicant further investigated the effect of humidity on the unary system Dioxane. The formation of its microsphere morphology showed a trend consistent with that of the THF system: the morphology evolution of the humidity-induced phase separation products, that is, as the relative humidity in the evaporation environment increases, the morphology gradually changes from a dense film structure to a granular and porous structure. For direct evaporation: under high humidity conditions, water vapor is more likely to participate in the non-solvent-induced phase separation process of the system, thereby promoting the formation of microsphere structures.

[0043] Examples 1-5

[0044] In this embodiment, a unicomponent solvent is used, and the preparation method of the micro / nano particles is as follows: Step 1: Weigh two sets of equal amounts of PLLA particles, add the PLLA particles to the solvents THF and Dioxane respectively, add a rotor, and heat and stir at 50 ℃ and 500 rpm for 4 h until completely dissolved to obtain homogeneous solution A and homogeneous solution B with a concentration of 0.2 wt%.

[0045] Step 2: Droplet evaporation using direct evaporation method: Quantitative sampling is performed using a syringe, and homogeneous solutions A and B are dropped onto a polytetrafluoroethylene (PTFE) film, placed in a vacuum dryer, and the temperature and humidity inside the vacuum dryer are controlled at 30 ℃ and 90%RH by adding an appropriate amount of deionized water or desiccant. Under these conditions, the PLLA solution evaporates in droplet form to assist phase separation, and the solvent is removed by controlled evaporation to obtain product A and product B.

[0046] In this case, the applicant used THF and Dioxane as solvents, respectively, and obtained products A and B by direct evaporation at 30 °C and 90% RH. The particle size of the microspheres in these products was statistically analyzed, and the results are as follows: Figure 3 As shown: The average particle size of the microspheres in product A is 1.10 μm, exhibiting a relatively symmetrical normal distribution with a narrow distribution range and good microsphere size uniformity (see...). Figure 3 (a) of the text); the average particle size of the microspheres in product B is 1.14 μm, which is slightly larger than that of the THF system. The overall dispersion is more significant, and some microspheres with larger volumes are present (see [section 1]). Figure 3 (See part (b)). Under direct evaporation and high humidity conditions, the THF system produces more uniform particle sizes, while the Dioxane particles are slightly larger than those in the THF system, resulting in greater overall dispersion. This may be because the boiling point of THF is much lower than that of Dioxane, leading to a longer phase separation time in the Dioxane system, a higher probability of microsphere collision and aggregation, and thus larger and wider-distributed microspheres. Therefore, from the perspective of particle size distribution, the optimal preparation conditions for the unary system are: using THF as a solvent, and preparing it under 90% RH conditions using a direct evaporation method.

[0047] Example 2

[0048] In this embodiment, the solvent used is a binary system THF:H2O = 90:10, and the preparation method is as follows: Step 1: Weigh PLLA particles, add the PLLA particles to the solvent THF:H2O solution, add a rotor, and heat and stir at 50℃ and 500 rpm for 4 h until completely dissolved to obtain a homogeneous 0.2 wt% PLLA solution.

[0049] Step 2: Droplet evaporation is carried out using the direct evaporation method: A homogeneous PLLA solution is quantitatively added dropwise onto a polytetrafluoroethylene film and placed in a vacuum dryer. By adding an appropriate amount of deionized water or desiccant, the temperature inside the vacuum dryer is controlled at 30 ℃ and the humidity at 40%RH. Under these conditions, the PLLA solution evaporates in the form of droplets to assist in phase separation and remove the solvent.

[0050] Example 2-1

[0051] This embodiment is set up the same as that of embodiment 2, except that the droplet evaporation method in step two is replaced by the inhibited evaporation method: in the solvent THF vapor environment, the PLLA solution is added drop by drop in the form of a vacuum dryer covered with a polytetrafluoroethylene film, and the temperature is controlled at 30 ℃ to evaporate and remove the solvent.

[0052] Example 2-2

[0053] In this embodiment, the solvent used is a binary system of Dioxane:H2O = 90:10, and the preparation method is as follows: Step 1: Weigh PLLA particles, add them to the solvent Dioxane:H2O solution, add a rotor, and heat and stir at 50℃ and 500 rpm for 4 h until completely dissolved to obtain a homogeneous 0.2 wt% PLLA solution.

[0054] Step 2: Droplet evaporation is carried out using the direct evaporation method: A homogeneous PLLA solution is quantitatively added dropwise onto a polytetrafluoroethylene film and placed in a vacuum dryer. By adding an appropriate amount of deionized water or desiccant, the temperature inside the vacuum dryer is controlled at 30 ℃ and the humidity at 40%RH. Under these conditions, the PLLA solution evaporates in the form of droplets to assist in phase separation and remove the solvent.

[0055] Example 2-3

[0056] This embodiment has the same setup as Embodiment 2-2, except that the droplet evaporation method in step two is replaced by the suppressed evaporation method: in the solvent Dioxane vapor environment, the PLLA solution is added dropwise to a vacuum dryer covered with a polytetrafluoroethylene film, and the temperature is controlled at 30 ℃ to evaporate and remove the solvent.

[0057] The morphology of the products in Examples 2 to 2-3 is as follows: Figure 4 As shown: In the PLLA / THF:H2O system, the products obtained by direct evaporation in Example 2 were mostly microspheres. The microspheres had generally poor morphology, severe aggregation, and obvious clusters. The microspheres had dense surfaces with few pores, poor dispersibility, and were prone to adhesion (see...). Figure 4 (a) in the text. In Example 2-1, the microspheres obtained using the inhibited evaporation method lost their structure and transformed into a continuous porous network structure with interconnected channels, abundant and fine pores, forming a sponge-like porous membrane structure (see...). Figure 4 (part (b) of the text).

[0058] In the PLLA / Dioxane:H2O system, Example 2-2 shows that direct evaporation can form well-dispersed spherical particles with clear microsphere outlines, relatively uniform particle size, and a much lower degree of aggregation than the THF system. Furthermore, the microspheres are evenly distributed and the substrate is flat (see...). Figure 4 (See section (c) of the text). Examples 2-3, the method for inhibiting evaporation, mainly uses microspheres. The microspheres are smaller in size, more uniformly distributed, and have further improved dispersibility. There is no obvious agglomeration, and no continuous porous structure is formed (see...). Figure 4 (d) in the middle.

[0059] Therefore, for binary systems, the micro / nano particle forming effect of the PLLA / THF:H2O system is not ideal under the conditions of 30 ℃ and 40%RH, while the forming effect of the PLLA / Dioxane:H2O system is better, and the evaporation suppression method is more conducive to promoting smaller particle size and more uniform distribution of micro / nano particles.

[0060] Thermodynamic three-phase diagrams are the most intuitive tool for describing the phase states of a ternary system under different solvent ratios, clearly defining the homogeneous and phase-separated regions of the system. Ultraviolet-visible spectrophotometry is used to determine the phase separation points and absorbance changes in the solution, thereby identifying the phase separation boundaries and plotting the corresponding thermodynamic three-phase diagram.

[0061] Figure 5 The figure shows the thermodynamic three-phase diagrams for the PLLA / THF:H2O and PLLA / Dioxane:H2O systems. The blue area represents the homogeneous stable region, and the boundary curves represent the thermodynamic critical boundary where LL phase separation occurs. The homogeneous stable region of the PLLA / THF:H2O system is relatively narrow, existing only in the component range with a high THF content and low water and PLLA content (see...). Figure 5(See part (a) in the text); the homogeneous stable region of the PLLA / Dioxane:H2O system is significantly broadened. Even with increased water content, it can still accommodate higher concentrations of PLLA and maintain a homogeneous state. This system weakens the inductive effect of non-solvent water and improves the overall thermodynamic stability of the system (see...). Figure 5 (see part (b)). Therefore: at the same PLLA concentration, the proportion of H2O in the PLLA / THF:H2O and PLLA / Dioxane:H2O systems should not exceed 18%, i.e., THF:H2O≥82:18 and Dioxane:H2O≥82:18.

[0062] Examples 2-4

[0063] In this embodiment, the solvent used is a binary system THF:H2O = 90:10, and the preparation method is as follows: Step 1: Weigh PLLA particles, add them to THF:H2O solution, add a rotor, and heat and stir at 50 ℃ and 500 rpm for 4 h until completely dissolved to obtain a homogeneous 0.2 wt% PLLA solution.

[0064] Step 2: Droplet evaporation is performed using the direct evaporation method: A homogeneous PLLA solution is quantitatively added dropwise onto a polytetrafluoroethylene film and placed in a vacuum dryer. By adding an appropriate amount of deionized water or desiccant, the temperature inside the vacuum dryer is controlled at 30 °C. Under these conditions, the PLLA solution evaporates in droplet form to assist in phase separation. The humidity is controlled at 30%RH, 60%RH, and 90%RH respectively to evaporate and remove the solvent.

[0065] The morphology of the products obtained under different humidity conditions is as follows: Figure 6 As shown: Under low humidity conditions of 30% RH, with fewer water molecules and low ambient humidity, THF evaporation dominates the entire solvent evaporation process, while the evaporation of the aqueous phase is relatively weak; the microspheres exhibit dense packing, small particle size, and relatively uniform surface (see...). Figure 6 (See part (a)). As humidity increases to 60% RH and 90% RH, the increase in humidity promotes phase separation. Moisture from the air continuously penetrates the system, accelerating non-solvent-induced phase separation, intensifying agglomeration, gradually densifying the structure, promoting microsphere formation, resulting in more complete microsphere structures, uniform particle size, and increased quantity (see [reference]). Figure 6 (See parts (b) and (c) in the text). Therefore, in a high-humidity environment, the water vapor content is extremely high, and moisture rapidly enters the system, enhancing the non-solvent-induced phase separation effect, promoting rapid phase separation, and inducing the formation of more microspheres.

[0066] In this embodiment, the products under 60%RH and 90%RH conditions are denoted as product C and product D, respectively. The particle size of both products is statistically analyzed, and the results are as follows: Figure 7As shown: Product C has an average particle size of 0.43 μm, with most microspheres concentrated between 0.30 and 0.55 μm, exhibiting a relatively narrower distribution and better microsphere size uniformity. Product D has an average particle size of 0.40 μm, with slightly smaller microspheres, but the distribution extends towards both smaller and larger particle sizes, resulting in a wider distribution and poorer microsphere size uniformity. Increasing the evaporation humidity widens the particle size distribution and increases the variation in microsphere size.

[0067] Examples 2-5

[0068] In this embodiment, the solvent used is a binary system of Dioxane:H2O = 90:10, and the preparation method is as follows: Step 1: Weigh PLLA particles, add them to Dioxane:H2O solution, add a rotor, and heat and stir at 50℃ and 500 rpm for 4 h until completely dissolved to obtain a homogeneous 0.2 wt% PLLA solution.

[0069] Step 2: Droplet evaporation is performed using the direct evaporation method: A homogeneous PLLA solution is quantitatively added dropwise onto a polytetrafluoroethylene film and placed in a vacuum dryer. By adding an appropriate amount of deionized water or desiccant, the temperature inside the vacuum dryer is controlled at 30 °C. Under these conditions, the PLLA solution evaporates in droplet form to assist in phase separation. The humidity is controlled at 30%RH, 60%RH, and 90%RH respectively to evaporate and remove the solvent.

[0070] The morphology of the products obtained under different humidity conditions is as follows: Figure 8 As shown, the overall morphology of the microspheres exhibits a trend of decreasing particle size and increased dispersibility with increasing humidity. In the Dioxane:water = 90:10 system, a large number of irregular aggregates and adherent particles exist at 30% RH, resulting in poor microsphere regularity (see...). Figure 8 (a) of the text); when the humidity is increased to 60% RH, agglomeration decreases and the number of spherical particles increases significantly (see section (a)). Figure 8 (b) of the text); under 90% RH conditions, spherical particles with uniform particle size and excellent monodispersity can be formed (see section (b)). Figure 8 (part c) in the text.

[0071] In this embodiment, the products under 60%RH and 90%RH conditions are denoted as product E and product F, respectively; when Dioxane:H2O is replaced with 85:15, the products under 30%RH and 90%RH conditions are denoted as product G and product H, respectively. The particle size of the four products is statistically analyzed, and the results are as follows: Figure 9 As shown: In the 0.2 wt% PLLA / Dioxane:H2O = 90:10 system, the average particle size of product E is 1.02 μm (see...). Figure 9In part (a), the average particle size of product F is 0.81 μm (see [reference]). Figure 9 (See part (b)). With increasing humidity, the particle size decreases, the distribution widens, and the uniformity deteriorates. This is because with increasing humidity, water vapor penetration accelerates, leading to uneven droplet nucleation and a worsening of the microsphere particle size distribution. In the 0.2 wt% PLLA / Dioxane:H2O = 85:15 system, the average particle size of product G is 1.16 μm (see...). Figure 9 In part (c), the average particle size of product H is 1.56 μm (see [section]). Figure 9 The particle size of the (d) portion is larger than that of the 0.2 wt% PLLA / Dioxane:H2O = 90:10 system.

[0072] Compared with the PLLA / Dioxane:H2O system in Examples 2-5, the PLLA / THF:H2O system in Examples 2-4 has smaller microsphere size and narrower dispersion range, which is consistent with the characteristics of PLLA / monopolymer solvent systems.

[0073] In summary, compared to the unary system, the binary system introducing the non-solvent component water reduces the susceptibility of PLLA, thus facilitating phase separation under evaporation conditions. As the humidity in the evaporation environment increases, the rate of water vapor penetration into the droplets accelerates, promoting phase separation and resulting in better microsphere sphericity. In the binary system, a higher water content leads to the formation of more large-volume microspheres. Comparing the PLLA / THF:H2O and PLLA / Dioxane:H2O systems, the THF system exhibits smaller microsphere size, a narrower dispersion range, and better sphericity.

[0074] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system, characterized in that, The steps are as follows: Step 1: Dissolve PLLA particles in a solvent system to obtain a PLLA solution. The solvent system can be a monolithic or binary system. Step 2: The PLLA solution is evaporated into droplets to obtain micro / nano particles.

2. The method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system according to claim 1, characterized in that: In step one, the PLLA particles are dissolved in a solvent system and then heated to 40–60°C to obtain a homogeneous PLLA solution.

3. The method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system according to claim 1, characterized in that: The concentration of the PLLA solution is 0.05–5 wt%.

4. The method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system according to claim 1, characterized in that: The droplet evaporation is carried out by direct evaporation or inhibited evaporation, and the temperature of droplet evaporation is 30-40℃ and the humidity is 30-90%RH.

5. The method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system according to claim 4, characterized in that: In the direct evaporation method, water is used to control the temperature and humidity of evaporation; in the suppressed evaporation method, droplets are placed in a corresponding solvent vapor atmosphere to suppress evaporation.

6. The method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system according to claim 1, characterized in that: The particle size of the micro-nano particles is 0.3 to 1.

6.

7. A method for preparing micro / nanoparticles based on evaporation-induced phase separation of a polylactic acid (PLA) solution system according to any one of claims 1 to 6, characterized in that: The unary system is THF or 1,3-dioxane.

8. The method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (PLA) solution system according to claim 7, characterized in that: The particle size of the micro-nano particles is 1.1 to 1.

2.

9. A method for preparing micro / nanoparticles based on evaporation-induced phase separation of a polylactic acid (L-L) solution system according to any one of claims 1 to 6, characterized in that: The binary system includes a solvent and a non-solvent. The solvent is either THF or 1,3-dioxane, and the non-solvent is ethanol or water. The volume ratio of the solvent to the non-solvent is 70–90:10–30.

10. The method for preparing micro / nanoparticles based on evaporation-induced phase separation in a polylactic acid (L-L) solution system according to claim 9, characterized in that: The non-solvent is water, with a volume ratio of water in the binary system of <12%. The solvent is THF, and the corresponding droplet evaporation humidity is 60-90%RH. The solvent is 1,3-dioxane, and the corresponding droplet evaporation humidity is 30-90%RH.

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