Method for preparing polymer drug-loaded nanoparticles based on ultrasonic microfluidics

Abstract

The invention discloses a preparation method of polymer drug-loaded nanoparticles. According to the method, on the basis of an emulsification method, the controllable continuous preparation of the polymer drug-loaded nanoparticles is realized by utilizing an ultrasonic micro-fluidic technology. The method specifically comprises the following steps: dissolving a drug and a polymer in a water-insoluble organic solvent to serve as an organic phase, taking a surfactant aqueous solution as a water phase, introducing the two phases into ultrasonic microfluidic equipment at a certain flow velocity ratio, and emulsifying under the ultrasonic action to obtain uniform liquid drops; and removing the organic solvent by methods of stirring, rotary evaporation, vacuum centrifugation, ultrafiltration and the like to obtain the cured polymer drug-loaded nanoparticles. The nanoparticles prepared by the method are uniform in particle size and high in drug encapsulation efficiency, and can be continuously produced.

Description

Technical Field

[0001] This invention relates to the field of nanoparticle preparation technology, and specifically to a method for preparing polymer-loaded drug nanoparticles based on ultrasonic microfluidic control. Background Technology

[0002] Formulating drugs into nanoparticles can enhance drug solubility and stability, improve bioavailability, enhance drug delivery and targeting, reduce side effects, and achieve multifunctionality and combination therapy. Therefore, it is receiving increasing attention and has broad application prospects in drug development and clinical applications.

[0003] Nanoparticle carriers include various organic and inorganic materials. Among them, various high molecular weight polymers are excellent carriers for nanoparticles due to their tunable structure and properties, good biocompatibility and stability, and the ability to regulate drug release. They can also achieve targeted delivery through surface modification or functionalization. In particular, polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), and polycaprolactone (PCL) are increasingly favored and have become the preferred materials for many applications because their degradation products in vivo are water and carbon dioxide, which have very high biocompatibility.

[0004] Currently, common methods for preparing polymer nanoparticles include ultrasonic emulsification, nanoprecipitation, and microfluidics. Ultrasonic emulsification utilizes an ultrasonic probe to generate localized high and low pressure regions within a liquid, leading to bubble formation and subsequent collapse. This helps disperse the liquid into small droplets, ultimately forming nanoparticles after the organic solvent is removed. However, the uneven acoustic field distribution hinders large-scale production. Furthermore, cavitation effects can cause metal fragments to detach from the tip, posing a potential risk to the clinical application of the product. Nanoprecipitation involves dissolving the drug and polymer in a good solvent to form a homogeneous solution, then mixing it with a non-solvent (typically a solvent that is well miscible with the good solvent but has low solubility for the drug and polymer). Mixing with the non-solvent causes the drug and polymer to precipitate, forming polymer nanoparticles. Finally, the polymer nanoparticles are separated from the solution and purified to obtain the desired nanoformulation. This method suffers from uneven particle size, difficulty in scaling up production, and less than ideal encapsulation efficiency. Microfluidic methods typically combine nanoprecipitation with microfluidic technology, mixing drugs and polymer solutions with non-solvents in a microfluidic chip to obtain polymer nanoparticles with uniform particle size. However, most microfluidic channels are very narrow, limiting production volume and prone to clogging. Recently, Chen Guangwen et al. achieved excellent preparation results by combining ultrasonic microreactors with nanoprecipitation. Furthermore, because the channels of ultrasonic microreactors are significantly larger than those of ordinary microfluidic chips, production can be scaled up and is less prone to clogging (An apparatus and method for preparing nanopolymer particles using an ultrasonic microreactor, CN202111491633.3). Nevertheless, this method still suffers from the inherent drawbacks of nanoprecipitation, namely, low encapsulation efficiency for poorly soluble drugs, requiring further improvement to advance the clinical application of nanoparticles.

[0005] US Patent No. US20220273582A1 discloses a continuous method for nanoemulsification via concentration phase inversion. This involves a concentrated phase inversion within a microfluidic reactor, injecting an aqueous phase into a first microchannel, and injecting a fatty phase containing one or more fatty substances and one or more surfactants into a second microchannel. The aqueous and fatty phases are then mixed, and a suspension containing lipid nanocapsules is recovered. However, this method is only applicable to lipid systems with self-emulsifying properties. It is not suitable for carriers that are not lipids but polymers and lack self-emulsifying capabilities. Summary of the Invention

[0006] This invention addresses the shortcomings of existing technologies by providing a method for preparing polymer-loaded drug nanoparticles based on ultrasonic microfluidic control.

[0007] This invention is achieved through the following technical solution:

[0008] This invention provides a method for preparing polymer-loaded drug nanoparticles based on ultrasonic microfluidics, comprising the following steps:

[0009] S1. Mix the organic phase solution and the aqueous phase solution in the microchannels of the ultrasonic microreactor;

[0010] S2, dispersed into an emulsion under ultrasonic action;

[0011] S3. Remove the organic solvent to obtain polymer-loaded drug nanoparticles;

[0012] The organic phase solution contains organic solvents, pharmaceuticals, and polymers;

[0013] The organic solvent is immiscible with water.

[0014] In some embodiments, the drug concentration in the organic phase solution is 1-50 mg / mL, and the polymer concentration is 5-200 mg / mL.

[0015] Preferably, the aqueous solution contains a surfactant. The surfactant is selected from those with biological safety characteristics.

[0016] In some embodiments, the surfactant content in the aqueous solution is 0.1-5 wt%.

[0017] Preferably, the surfactant comprises at least one selected from polyvinyl alcohol, SDS, F68, Tween 80, and didodecyl dimethyl ammonium bromide. The surfactant may also be other biosafety-compliant surfactants.

[0018] Preferably, the polymer is soluble in organic solvents but insoluble in water.

[0019] In some embodiments, the polymer includes at least one of polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), and polycaprolactone (PCL).

[0020] Preferably, the organic solvent includes at least one of dichloromethane, chloroform, diethyl ether, and ethyl acetate.

[0021] Preferably, the drug is soluble in an organic solvent.

[0022] Preferably, the diameter of the microchannel in step S1 is 1-10 mm.

[0023] Preferably, the flow rate ratio of the aqueous solution to the organic solution is 1.5-20:1. If the flow rate ratio of the aqueous solution to the organic solution is too low, droplets cannot be formed; if the flow rate ratio is too high, the resulting droplet concentration is too low, and consequently, the final nanoparticle concentration is too low, rendering it impractical.

[0024] Preferably, in steps S1-S2, the temperature is controlled to not exceed the boiling point of the organic solvent.

[0025] Preferably, the method for controlling the temperature includes air cooling.

[0026] Preferably, the microchannel material is glass, quartz, stainless steel, etc.

[0027] Preferably, the frequency of the ultrasound in step S2 is 18-40 kHz. If the ultrasound is not within this frequency range, droplets cannot be formed.

[0028] Preferably, the ultrasonic power in step S2 is 20-500W. If the ultrasonic power is lower than this, droplets cannot be formed; if it is higher than this, high temperatures are likely to occur, exceeding the boiling point of the organic solvent, making it impossible to obtain droplets with uniform particle size.

[0029] The present invention also provides polymer-loaded drug nanoparticles prepared by the above method.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) Controllable continuous production was achieved through microfluidics, which solved the problems of batch inconsistency and difficulty in scaling up batch production.

[0032] (2) The present invention utilizes the uniform sound field formed by the ultrasonic microreactor to disperse the organic phase containing drugs and polymers in the aqueous phase in the microchannel to form uniform droplets with controllable particle size. After removing the organic solvent, uniform drug-loaded polymer nanoparticles with controllable particle size are formed. Since the frequency and power of the ultrasound are controllable, the preparation effect can be stably reproduced.

[0033] (3) Because the diameter of the microchannels of the ultrasonic microreactor is 1-10 mm, which is much wider than the micron-level channels of ordinary microfluidic chips, and it has a straight structure without complex shape, it is not easy to get clogged and can achieve high production rates.

[0034] (4) By placing ultrasound around the microfluidic channel, the organic phase is broken into very small droplets by means of the cavitation effect of ultrasound. Microfluidics without ultrasound can only produce large droplets and cannot produce nanoparticles.

[0035] (5) The combination of ultrasonic technology and microfluidic technology was realized, achieving a uniform distribution of the ultrasonic field within the pipe, thereby achieving a uniform cavitation effect. This, in turn, led to the preparation of uniform droplets through emulsification. In contrast, traditional probe-type ultrasound has an uneven sound field distribution, with better emulsification closer to the probe and poorer emulsification further away, resulting in uneven droplet size distribution. Furthermore, if an ultrasonic microreactor is used in conjunction with antisolvent precipitation, where the two solvents are miscible, droplets cannot be formed.

[0036] (6) By combining ultrasonic microfluidics and emulsification, since organic solvents and water are immiscible, lipid-soluble drugs are confined within droplets of the organic phase, achieving a higher encapsulation rate than the antisolvent precipitation method.

[0037] (7) By adopting the method of the present invention, for lipid-soluble drugs, high encapsulation rate, uniform particle size, continuous production can be achieved, and the preparation process is simple, which can realize linear scale-up from laboratory scale to production scale. Attached Figure Description

[0038] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0039] Figure 1 This is a schematic diagram of the preparation process of the polymer drug-loaded nanoparticles of the present invention;

[0040] Figure 2 This is a transmission electron microscope image of the polymer drug-loaded nanoparticles prepared in Example 1 of the present invention;

[0041] Figure 3 The particle size distribution of the polymer drug-loaded nanoparticles prepared in Example 1 of this invention was determined using a laser particle size analyzer.

[0042] Figure 4 The particle size distribution of the polymer drug-loaded nanoparticles prepared in Example 2 of this invention was determined using a laser particle size analyzer.

[0043] Figure 5 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 3 of this invention was determined using a laser particle size analyzer.

[0044] Figure 6 The particle size distribution of the polymer drug-loaded nanoparticles prepared in Example 4 of this invention was determined using a laser particle size analyzer.

[0045] Figure 7 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 5 of this invention was determined using a laser particle size analyzer.

[0046] Figure 8 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 6 of this invention was determined using a laser particle size analyzer.

[0047] Figure 9 The particle size distribution of the polymer drug-loaded nanoparticles prepared in Example 7 of this invention was determined using a laser particle size analyzer.

[0048] Figure 10 The particle size distribution of the polymer drug-loaded nanoparticles prepared in Example 8 of this invention was determined using a laser particle size analyzer.

[0049] Figure 11The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 9 of this invention was determined using a laser particle size analyzer.

[0050] Figure 12 The particle size distribution of the polymer drug-loaded nanoparticles prepared in Example 10 of this invention was determined using a laser particle size analyzer.

[0051] Figure 13 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Comparative Example 1 of this invention was determined using a laser particle size analyzer. Detailed Implementation

[0052] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0053] Figure 1 This is a schematic diagram of the preparation process of polymer-loaded drug nanoparticles in Examples 1-10. A Langevin transducer was used as the ultrasonic source, and ultrasound was introduced into the microchannels of the microreactor through welding. The ultrasonic transducer and the microreactor were directly coupled, and the two were rigidly connected to vibrate as a whole.

[0054] Example 1: Curcumin PLGA Nanoparticles

[0055] An ethyl acetate solution of curcumin and PLGA was prepared as the organic phase, with PLGA concentration of 100 mg / mL and curcumin concentration of 3 mg / mL. A 1% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.1 mL / min, and the flow rate of the aqueous phase was 0.5 mL / min. The ultrasonic frequency was 20 kHz, and the microchannel material was a quartz tube with a diameter of 3 mm. The ultrasonic power was 30 W, and the residence time in the ultrasonic microreactor was 1.0 min. During the preparation process, the system temperature was controlled to not exceed 60℃ by air cooling. The collected dispersion was concentrated by centrifugation to remove ethyl acetate. Figure 2 This is a transmission electron microscope (TEM) image of the polymer-loaded drug nanoparticles prepared in Example 1 of this invention. Figure 3 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 1 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 87.65 nm and a PDI of 0.188. The concentration of free curcumin in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 94%.

[0056] Example 2: Paclitaxel PLGA Nanoparticles

[0057] An ethyl acetate solution of paclitaxel and PLGA was prepared as the organic phase, with PLGA concentration of 20 mg / mL and paclitaxel concentration of 2 mg / mL. A 2% sodium dodecyl sulfate aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.3 mL / min, and the flow rate of the aqueous phase was 0.9 mL / min. The ultrasonic frequency was 18 kHz, the microchannel material was glass with a diameter of 2 mm, and the ultrasonic power was 20 W. The residence time in the ultrasonic microreactor was 0.7 min. During the preparation process, the system temperature was controlled to not exceed 30 °C by air cooling. The collected dispersion was stirred to remove ethyl acetate. Figure 4 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 2 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 124.6 nm and a PDI of 0.143. The concentration of free paclitaxel in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 86%.

[0058] Example 3 Ropivacaine PLGA Nanoparticles

[0059] An ethyl acetate solution of ropivacaine and PLGA was prepared as the organic phase, with PLGA concentration of 20 mg / mL and ropivacaine concentration of 1 mg / mL. A 3% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.1 mL / min, and the flow rate of the aqueous phase was 0.7 mL / min. The ultrasonic frequency was 20 kHz, the microchannel material was stainless steel with a diameter of 5 mm, and the ultrasonic power was 500 W. The residence time in the ultrasonic microreactor was 0.75 min. During the preparation process, the system temperature was controlled to not exceed 60 °C by air cooling. The collected dispersion was subjected to ultrafiltration to remove ethyl acetate. Figure 5 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 3 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 133.6 nm and a PDI of 0.152. The concentration of free ropivacaine in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 77%.

[0060] Example 4: Docetaxel PLGA Nanoparticles

[0061] An ethyl acetate solution of docetaxel and PLGA was prepared as the organic phase, with PLGA concentration of 40 mg / mL and docetaxel concentration of 2 mg / mL. A 2% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.8 mL / min. The ultrasonic frequency was 40 kHz, the microchannel material was stainless steel with a diameter of 1 mm, and the ultrasonic power was 60 W. The residence time in the ultrasonic microreactor was 0.5 min. During the preparation process, the system temperature was controlled to not exceed 60 °C by air cooling. The collected dispersion was subjected to ultrafiltration to remove ethyl acetate. Figure 6The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 4 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 127.6 nm and a PDI of 0.130. The concentration of free docetaxel in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 69%.

[0062] Example 5 Irinotecan PLGA-PEG Nanoparticles

[0063] A dichloromethane solution of irinotecan and PLGA-PEG was prepared as the organic phase, with PLGA-PEG concentration of 20 mg / mL and irinotecan concentration of 3 mg / mL. A 2% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.1 mL / min, and the flow rate of the aqueous phase was 2.0 mL / min. The ultrasonic frequency was 20 kHz, the microchannel material was quartz with a diameter of 4 mm, and the ultrasonic power was 60 W. The mixture was held in an ultrasonic microreactor for 2.0 min. During the preparation process, the system temperature was controlled to not exceed 30 °C by air cooling. The collected dispersion was stirred to remove dichloromethane. Figure 7 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 5 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 131.6 nm and a PDI of 0.139. The concentration of free irinotecan in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 90%.

[0064] Example 6: Imiquimod PCL Nanoparticles

[0065] A dichloromethane solution of imiquimod and PCL was prepared as the organic phase, with PCL concentration of 50 mg / mL and imiquimod concentration of 2 mg / mL. A 1.5% Tween 80 aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.6 mL / min. The ultrasonic frequency was 30 kHz, the microchannel material was quartz with a diameter of 3 mm, and the ultrasonic power was 40 W. The mixture was held in an ultrasonic microreactor for 1.0 min. During the preparation process, the system temperature was controlled to not exceed 30 °C by air cooling. The collected dispersion was concentrated by centrifugation to remove dichloromethane. Figure 8 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 6 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 80.3 nm and a PDI of 0.116. The concentration of free imiquimod in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 83%.

[0066] Example 7: Quercetin PLGA Nanoparticles

[0067] An ethyl acetate solution of quercetin and PLGA was prepared as the organic phase, with PLGA concentration of 30 mg / mL and quercetin concentration of 5 mg / mL. A 1.5% didodecyl dimethyl ammonium bromide aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.1 mL / min, and the flow rate of the aqueous phase was 1.3 mL / min. The ultrasonic frequency was 30 kHz, the microchannel material was stainless steel with a diameter of 10 mm, and the ultrasonic power was 500 W. The residence time in the ultrasonic microreactor was 1.0 min. During the preparation process, the system temperature was controlled to not exceed 30 °C by air cooling. The collected dispersion was dialyzed to remove ethyl acetate. Figure 9 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 7 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 119.7 nm and a PDI of 0.167. The concentration of free quercetin in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 78%.

[0068] Example 8: Probucol PLGA-PEG Nanoparticles

[0069] A dichloromethane solution of probucol and PLGA-PEG was prepared as the organic phase, with PLGA concentration of 30 mg / mL and probucol concentration of 3 mg / mL. A 1% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.4 mL / min, and the flow rate of the aqueous phase was 2.4 mL / min. The ultrasonic frequency was 20 kHz, the microchannel material was stainless steel with a diameter of 5 mm, and the ultrasonic power was 200 W. The mixture was held in an ultrasonic microreactor for 1.0 min. During the preparation process, the system temperature was controlled to not exceed 30 °C by air cooling. The collected dispersion was dialyzed to remove dichloromethane. Figure 10 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 8 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 124.6 nm and a PDI of 0.143. Ultrafiltration was then used to determine the concentration of free probucol in the ultrafiltrate, and the encapsulation efficiency was calculated to be 84%.

[0070] Example 9: Tacrolimus PLA Nanoparticles

[0071] A 1:1 solution of tacrolimus and PLA in ethyl acetate and dichloromethane was prepared as the organic phase, with PLA concentration of 30 mg / mL and tacrolimus concentration of 2 mg / mL. A 1% F68 aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.3 mL / min. The ultrasonic frequency was 20 kHz, the microchannel material was quartz with a diameter of 2 mm, and the ultrasonic power was 30 W. The mixture was held in an ultrasonic microreactor for 1.0 min. During the preparation process, the system temperature was controlled to not exceed 30 °C by air cooling. The collected dispersion was concentrated by centrifugation to remove ethyl acetate and dichloromethane. Figure 11The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 9 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 92.29 nm and a PDI of 0.147. The concentration of free tacrolimus in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 98%.

[0072] Example 10: Triamcinolone acetonide PLGA nanoparticles

[0073] A chloroform solution of triamcinolone acetonide and PLGA was prepared as the organic phase, with PLGA concentration of 150 mg / mL and triamcinolone acetonide concentration of 10 mg / mL. A 1% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.6 mL / min. The ultrasonic frequency was 20 kHz, the microchannel material was quartz with a diameter of 2 mm, and the ultrasonic power was 30 W. The mixture was held in an ultrasonic microreactor for 1.0 min. During the preparation process, the system temperature was controlled to not exceed 50 °C by air cooling. The collected dispersion was then subjected to rotary evaporation to remove chloroform. Figure 12 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Example 10 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 131.5 nm and a PDI of 0.155. The concentration of free triamcinolone in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 83%.

[0074] Comparative Example 1: Docetaxel PLGA Nanoparticles

[0075] An acetone solution of docetaxel and PLGA was prepared as the organic phase, with PLGA concentration of 40 mg / mL and docetaxel concentration of 2 mg / mL. A 2% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.8 mL / min. The ultrasonic frequency was 40 kHz, the microchannel material was stainless steel with a diameter of 1 mm, and the ultrasonic power was 60 W. The mixture was held in an ultrasonic microreactor for 0.5 min. The collected dispersion was then subjected to ultrafiltration to remove acetone. Figure 13 The particle size distribution of the polymer-loaded drug nanoparticles prepared in Comparative Example 1 of this invention was determined using a laser particle size analyzer. The obtained nanoparticles had a particle size of 196.1 nm and a PDI of 0.425. The concentration of free docetaxel in the ultrafiltrate was determined by ultrafiltration, and the encapsulation efficiency was calculated to be 47%.

[0076] Comparative Example 2

[0077] An ethyl acetate solution of docetaxel and PLGA was prepared as the organic phase, with PLGA concentration of 40 mg / mL and docetaxel concentration of 2 mg / mL. A 2% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.8 mL / min. No sonication was used. The microchannel was made of stainless steel with a diameter of 1 mm. During the preparation process, the system temperature was controlled to not exceed 60℃ by air cooling. A homogeneous system could not be obtained; the collected liquid was a segmented viscous liquid, which precipitated as a white precipitate after stirring, and nanoparticles could not be obtained.

[0078] Comparative Example 3

[0079] An ethyl acetate solution of docetaxel and PLGA was prepared as the organic phase, with PLGA concentration of 40 mg / mL and docetaxel concentration of 2 mg / mL. Pure water was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.8 mL / min. The ultrasonic frequency was 40 kHz, the microchannel material was stainless steel with a diameter of 1 mm, and the ultrasonic power was 60 W. The mixture was held in the ultrasonic microreactor for 0.5 min. During the preparation process, the system temperature was controlled to not exceed 60℃ using air cooling. The collected liquid was a white, turbid liquid, which precipitated as a white precipitate after stirring, and nanoparticles could not be obtained.

[0080] Comparative Example 4

[0081] An ethyl acetate solution of docetaxel and PLGA was prepared as the organic phase, with PLGA concentration of 40 mg / mL and docetaxel concentration of 2 mg / mL. A 2% PVA aqueous solution was used as the aqueous phase. The flow rate of the organic phase was 0.2 mL / min, and the flow rate of the aqueous phase was 0.8 mL / min. The ultrasonic frequency was 40 kHz, the microchannel material was stainless steel with a diameter of 1 mm, and the ultrasonic power was 60 W. The microchannel was held in an ultrasonic microreactor for 0.5 min. No air cooling was used during the preparation process. The collected liquid was a white turbid liquid, which precipitated as a white precipitate after stirring, and nanoparticles could not be obtained.

[0082] In summary, the method of this invention, based on emulsification, utilizes ultrasonic microfluidics to achieve controllable and continuous preparation of polymer-loaded drug nanoparticles. Specifically, the drug and polymer are dissolved in a water-immiscible organic solvent as the organic phase, and an aqueous surfactant solution is introduced into an ultrasonic microfluidic device at a specific flow rate ratio. Emulsification occurs under ultrasonic action, resulting in uniform droplets. The organic solvent is removed by methods such as stirring, rotary evaporation, vacuum centrifugation, and ultrafiltration to obtain solidified polymer-loaded drug nanoparticles. The nanoparticles prepared by this method have uniform particle size, high drug encapsulation efficiency, and can be produced continuously.

[0083] It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. Unless otherwise specified, the embodiments and features described in these embodiments can be arbitrarily combined with each other.

Claims

1. A method for preparing polymer-loaded drug nanoparticles based on ultrasonic microfluidic control, characterized in that, Includes the following steps: S1. Mix the organic phase solution and the aqueous phase solution in the microchannels of the ultrasonic microreactor; S2, dispersed into an emulsion under ultrasonic action; S3. Remove the organic solvent to obtain polymer-loaded drug nanoparticles; The organic phase solution contains an organic solvent, a drug, and a polymer; the organic solvent is immiscible with water.

2. The method according to claim 1, characterized in that, The aqueous solution contains a surfactant.

3. The method according to claim 2, characterized in that, The surfactant includes at least one of polyvinyl alcohol, SDS, F68, Tween 80, and didodecyl dimethyl ammonium bromide.

4. The method according to claim 1, characterized in that, The polymer is soluble in organic solvents but insoluble in water.

5. The method according to claim 1, characterized in that, The organic solvent includes at least one of dichloromethane, chloroform, diethyl ether, and ethyl acetate.

6. The method according to claim 1, characterized in that, The diameter of the microchannel in step S1 is 1-10 mm.

7. The method according to claim 1, characterized in that, The flow rate ratio of the aqueous phase solution to the organic phase solution is 1.5-20:

1.

8. The method according to claim 1, characterized in that, In steps S1-S2, the temperature is controlled by air cooling to ensure it does not exceed the boiling point of the organic solvent.

9. The method according to claim 1, characterized in that, The frequency of the ultrasound in step S2 is 18-40kHz and the power is 20-500W.

10. A polymer-loaded drug nanoparticle, characterized in that, It is prepared by any one of claims 1-9.

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