Method for continuously preparing magnetic drug-loaded liposome with high drug encapsulation efficiency

Abstract

The invention discloses a method for continuously preparing a magnetic drug-loaded liposome with high drug encapsulation efficiency, which specifically comprises the following steps: mixing a phospholipid dispersion liquid and a drug-magnetic nanoparticle suspension liquid in a microchannel reactor, and preliminarily forming the magnetic drug-loaded liposome with a vesicle structure from the mixed liquid under the action of an ultrasonic dispersion unit, then Taylor flow is formed in the Taylor flow generation unit, and the Taylor flow passes through the alternating magnetic field generation unit to obtain the magnetic drug-loading liposome with high drug encapsulation efficiency. According to the method, the drug encapsulation efficiency can be greatly improved, continuous preparation of the magnetic drug-loaded liposome with the high drug encapsulation efficiency is achieved, the gas-liquid mass transfer efficiency is improved by regulating and controlling the gas-liquid two-phase Taylor flow, and the continuous preparation of the magnetic drug-loaded liposome with the high drug encapsulation efficiency is achieved. The synergistic magnetocaloric effect can greatly improve the encapsulation efficiency of the drug in the magnetic liposome and the homogeneity and dispersity of the magnetic drug-loaded liposome.

Description

TECHNICAL FIELD

[0001] The application relates to a method for continuously preparing magnetic drug-loaded liposomes with high drug encapsulation efficiency. BACKGROUND

[0002] Liposomes are nanoscale vesicles formed by phospholipid bilayers, have good biocompatibility, have amphiphilic properties for hydrophilic and hydrophobic substances, encapsulate liposoluble drugs in the bilayer membrane, and encapsulate hydrophilic drugs in the internal hydrophilic structure. Because it can reduce the toxic and side effects of drugs, improve the stability of drugs in blood, and delay the degradation time of drugs, it has been reported to be applied in the field of drug delivery. Magnetic liposomes have many advantages of liposomes and magnetic nanoparticles, and give traditional liposomes the advantage of magnetic response. Through an external magnetic field, the drug encapsulated inside the liposome is precisely delivered to the predetermined site, improving the efficiency of drug delivery. However, existing liposome preparation methods, such as the thin film dispersion method, have defects such as low drug encapsulation efficiency, batch-to-batch differences in intermittent production, and complicated process. SUMMARY

[0003] The application aims to provide a method for continuously preparing magnetic drug-loaded liposomes with high drug encapsulation efficiency.

[0004] Technical scheme: The method for continuously preparing magnetic drug-loaded liposomes with high drug encapsulation efficiency comprises the following steps: mixing a phospholipid dispersion liquid and a drug-magnetic nanoparticle suspension in a microchannel reactor, preliminarily forming magnetic drug-loaded liposomes with vesicle structure under the action of an ultrasonic dispersion unit, then forming a Taylor flow in a Taylor flow generating unit, and passing the Taylor flow through an alternating magnetic field generating unit to obtain magnetic drug-loaded liposomes with high drug encapsulation efficiency.

[0005] In the Taylor flow generating unit, the gas-liquid phase flow rate ratio is 1-2, the flow rate of the liquid phase is not less than 0.5 mL / min, and the flow rate of the gas is not less than 0.5 mL / min. By adjusting the gas-liquid phase flow rate ratio to adjust the length of the gas section and the liquid section, the mass transfer effect and contact speed of the gas-liquid phase are adjusted, and the magnetic heat reaction is carried out by forming a Taylor flow, which can greatly improve the uniformity, dispersibility and drug encapsulation efficiency of the product.

[0006] The phospholipid dispersion is composed of phospholipid, cholesterol and organic solvent, the mass ratio of cholesterol to phospholipid is 0.2-0.5, the mass ratio of phospholipid to organic solvent is 0.01-0.03, and the concentration of phospholipid in the phospholipid dispersion is 200-500 μg / mL. The drug-magnetic nanoparticle suspension is composed of drug, superparamagnetic iron oxide nanoparticles and degassed water, the concentration of drug in the suspension is 100-400 μg / mL, and the concentration of superparamagnetic iron oxide nanoparticles is 10-40 μg / mL. The flow rate of the phospholipid dispersion is 0.1-0.2 mL / min, and the flow rate of the drug-magnetic nanoparticle suspension is 0.2-0.3 mL / min.

[0007] The phospholipid can be at least one of egg phospholipid, hydrogenated soybean lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine, dilauric phosphatidyl ethanolamine, dimyristoyl phosphatidyl ethanolamine, 1-stearoyl-2-oleoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, 1-stearoyl-2-palmitoyl phosphatidylcholine, dimyristoyl phosphatidyl serine, distearoyl phosphatidyl serine or 1-palmitoyl-2-oleoyl phosphatidyl ethanolamine. The organic solvent can be one of diethylene glycol monoethyl ether, polyethylene glycol series solvents, propylene glycol or glycerol. The drug can be one of magnesium ascorbyl phosphate, resveratrol, simvastatin, doxorubicin hydrochloride, cytarabine or beclometasone dipropionate.

[0008] The ultrasonic dispersion unit is provided with a spiral pipe, the inlet end of the spiral pipe is connected with the micro-channel reactor along the fluid flow direction, and the outlet end of the spiral pipe is connected with the Taylor flow generating unit through a liquid pump; the ultrasonic dispersion unit is a constant-temperature ultrasonic device (an ultrasonic cleaning machine), the ultrasonic temperature is 20-50 ℃, and the ultrasonic power is 10-50 W; during the ultrasonic process, the spiral pipe is fixed below the liquid level of the constant-temperature ultrasonic device.

[0009] The oscillation frequency of the alternating magnetic field is 50-300 KHz, and the power is 500-5000 W; the Taylor flow stays in the alternating magnetic field for 3-5 min, preferably 4 min.

[0010] In the Taylor flow generating unit, gas-liquid two-phase Taylor flow is formed, saturated droplets are quickly obtained, then an alternating magnetic field is applied to induce the magnetic nanoparticles in the saturated droplets of Taylor flow to produce a magnetic heat effect, the temperature of the magnetic nanoparticles is increased to induce the phospholipid layer to change from a glassy state to a flow state, and the fluid in the liquid section of the gas-liquid flow is disturbed by backflow to form a sustained better mixing effect, so that more unencapsulated drugs adsorbed on the surface of the dispersed liquid and liposomes enter the liposome interior, the magnetic drug-loaded liposomes with higher drug encapsulation rate are obtained, and the continuous preparation is realized. The method can greatly improve the drug encapsulation rate and realize the continuous preparation of the magnetic drug-loaded liposomes with high drug encapsulation rate. The method can greatly improve the drug encapsulation rate in the magnetic liposomes and the uniformity and dispersity of the magnetic drug-loaded liposomes by regulating the gas-liquid two-phase Taylor flow, increasing the gas-liquid mass transfer efficiency and cooperating with the magnetic heat effect.

[0011] Advantages: Compared with the prior art, the method has the following obvious advantages: the method can ensure the stable generation of Taylor flow by accurately regulating the flow rates of the raw material channel and the drug channel and the gas-liquid phase flow rate ratio of the gas inlet pipeline and the fluid channel in the Taylor flow forming process, thereby cooperating with the magnetic heat effect to realize the efficient, continuous and stable preparation of the magnetic drug-loaded liposomes with high drug encapsulation rate; the method can effectively overcome the problems of low drug encapsulation rate, complicated process, batch difference and unstable preparation of the existing intermittent magnetic drug-loaded liposomes, and the magnetic drug-loaded liposomes prepared by the method have good uniformity, dispersity and high drug encapsulation rate. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 The structural principle diagram of the device used in the method;

[0013] Figure 2 The TEM diagram of the magnetic drug-loaded liposomes prepared in Example 1. DETAILED DESCRIPTION

[0014] As Figure 1As shown, the method of the present application is realized based on a device comprising a micro-channel reactor 3, an ultrasonic dispersion unit 4, a Taylor flow generating unit 5 and an alternating magnetic field generating unit 6, the ultrasonic dispersion unit 4 is located at the discharge port side of the micro-channel reactor 3, the Taylor flow generating unit 5 is connected with the ultrasonic dispersion unit 4 through a gas flow meter 24; the micro-channel reactor 3 comprises a raw material channel 21 and a drug channel 22, the raw material channel 21 is controlled by a liquid pump I 31 and connected with a raw material liquid tank 1, the drug channel 22 is connected with a drug liquid tank 2, the raw material channel 21 and the drug channel 22 are arranged in a T shape; the ultrasonic dispersion unit 4 comprises a spiral type pipeline 23, along the fluid flow direction, the liquid inlet end of the spiral type pipeline 23 is connected with the micro-channel reactor 3, the liquid outlet end of the spiral type pipeline 23 is connected with the Taylor flow generating unit 5 through a liquid pump II 32; the ultrasonic dispersion unit 4 is a constant temperature ultrasonic device (an ultrasonic cleaning machine 24), during the ultrasonic process, the spiral type pipeline 23 is fixed below the liquid level of the constant temperature ultrasonic device; the gas inlet pipeline 25 and the fluid channel 26 in the Taylor flow generating unit 5 are arranged in a T shape, the liquid velocity is precisely controlled by the liquid pump II 32, the gas velocity is precisely controlled by the gas flow meter 27 and the flow display instrument 28; at the rear end of the Taylor flow generating unit 5, the fluid channel 29 is arranged in a spiral type through the alternating magnetic field generating unit 6.

[0015] The phospholipid dispersion stored in the raw material liquid tank 1 and the drug-magnetic nanoparticle suspension stored in the drug liquid tank 2 enter the micro-channel reactor 3 through the raw material channel 21 and the drug channel 22 respectively, at this time, the phospholipid dispersion and the drug-magnetic nanoparticle suspension are in contact, the phospholipid dispersion is fully emulsified, dispersed and self-assembled in the drug-magnetic nanoparticle suspension to form liposomes; when flowing through the ultrasonic dispersion unit 4, the liposomes are fully mixed with the drugs and the magnetic nanoparticles in the solution, the drugs and the magnetic nanoparticles are adsorbed on the surface of the liposomes to form a mixed solution; the gas (inert gas nitrogen 7) is delivered from the gas inlet pipeline 25 to the Taylor flow generating unit 5, and forms a stable Taylor flow with the mixed solution, along the fluid flow direction, the Taylor flow stably flows through the alternating magnetic field generating unit 6, the magnetic nanoparticles excite in-situ magnetic heat effect in the alternating magnetic field, local heating is generated on the surface of the liposomes in the Taylor flow, which induces the phospholipid layer to change from a glassy phase to a flowable phase, and promotes the free drugs in the solution to enter the liposomes; the fluid after flowing through the alternating magnetic field enters the storage tank 8 for collection.

[0016] Example 1

[0017] Based on Figure 1 The device is used to continuously prepare the magnetic drug-loaded liposomes with high drug encapsulation efficiency, and the method comprises the following steps:

[0018] The phospholipid dispersion and the drug-magnetic nanoparticle suspension are prepared and placed in the raw material tank 1 and the drug tank 2 respectively; in the phospholipid dispersion, the concentration of cholesterol is 40 μg / mL, and the concentration of hydrogenated soybean lecithin is 200 μg / mL; in the drug-magnetic nanoparticle suspension, the concentration of simvastatin is 400 μg / mL, and the concentration of superparamagnetic iron oxide is 40 μg / mL; (the preparation method is as follows: 0.004 g of cholesterol and 0.02 g of hydrogenated soybean lecithin are dissolved in 100 mL of diethylene glycol monoethyl ether to obtain the phospholipid dispersion; 0.04 g of simvastatin and 0.004 g of superparamagnetic iron oxide are dispersed in 100 mL of degassed water to obtain the drug-magnetic nanoparticle suspension);

[0019] The prepared phospholipid dispersion and drug-magnetic nanoparticle suspension are respectively fed into the microchannel reactor 3 at flow rates of 0.2 mL / min and 0.3 mL / min, the pipeline length of the microchannel reactor 3 is 3 meters, the pipeline diameter is 3 mm, the pipeline diameter ratio of the raw material channel 21, the drug channel 22 and the microchannel reactor 3 is 1:2:2, the residence time of the mixed solution in the ultrasonic dispersion unit is controlled by controlling the number of pipeline spirally winding around the ultrasonic dispersion unit at 40°C and an ultrasonic power of 50 W, the mixed solution is ultrasonically heated at a constant temperature for 30 min in the ultrasonic dispersion unit, and the mixed solution is fully mixed to form a preliminary magnetic liposome vesicle structure, nitrogen gas is fed at a flow rate of 0.5 mL / min, the flow rate of the liquid phase is controlled by the liquid pump 32 to be 0.5 mL / min, the pipeline diameter ratio of the gas inlet pipeline 25, the fluid channel 26 and the Taylor flow generating unit 5 is 1:1:1, and a stable Taylor flow is formed in the Taylor flow generating unit 5 (the conditions for forming a stable Taylor flow in the present application are that the flow rates of the gas and the liquid are both 0.5 mL / min, the pipeline diameter ratio of the gas inlet pipeline 25, the fluid channel 26 and the Taylor flow generating unit 5 is 1:1:1, and the rates of the gas and the liquid are uniform and stable in the continuous preparation process, so that a uniform Taylor flow can be generated); the formed Taylor flow is subjected to a magnetic-thermal reaction in an alternating magnetic field with an oscillation frequency of 300 Hz for 4 min, the magnetic nanoparticles generate an in-situ magnetic-thermal effect, the surface of the liposomes in the Taylor flow is locally heated, the free drug is promoted to enter the phospholipid bilayer of the liposomes, and the magnetic drug-loaded liposomes with a drug encapsulation efficiency of 93.16% are formed; after the continuous device is reacted for 50 min, the PDI value of the obtained magnetic drug-loaded liposomes is 0.20, and the particle size is 280.4±1.2 nm. The microchannel reactor combined with the Taylor flow device can strengthen the process mass transfer efficiency, shorten the emulsification and dispersion time, and effectively improve the drug encapsulation efficiency of the magnetic drug-loaded liposomes.

[0020] By Figure 2The transmission electron microscope of (a) shows that the magnetic drug-loaded liposome particles prepared in Example 1 are uniformly distributed in whole, and the vesicles are independent of each other and do not aggregate with each other, showing good dispersibility. Figure 2 (b) shows the structure of a single liposome, and it can be clearly seen that the phospholipid membrane structure is complete, showing a regular spherical morphology. The outer layer of the liposome encapsulating the drug water core has a relatively thick shell, proving that the superparamagnetic iron oxide particles are combined.

[0021] Example 2

[0022] Based on Figure 1 The device shown in the figure is used to continuously prepare magnetic drug-loaded liposomes with high drug encapsulation efficiency. Specifically, the device comprises:

[0023] The phospholipid dispersion and the drug-magnetic nanoparticle suspension are prepared and placed in the raw material liquid tank 1 and the drug liquid tank 2, respectively. In the phospholipid dispersion, the concentration of cholesterol is 40 μg / mL, and the concentration of hydrogenated soybean lecithin is 200 μg / mL. In the drug-magnetic nanoparticle suspension, the concentration of doxorubicin hydrochloride is 400 μg / mL, and the concentration of superparamagnetic iron oxide is 40 μg / mL. (The preparation method is as follows: 0.004 g of cholesterol and 0.02 g of hydrogenated soybean lecithin are dissolved in 100 mL of glycerol to obtain a phospholipid dispersion; 0.04 g of doxorubicin hydrochloride and 0.004 g of superparamagnetic iron oxide are dispersed in 100 mL of degassed water to obtain a drug-magnetic nanoparticle suspension.)

[0024] The prepared phospholipid dispersion and the drug-magnetic nanoparticle suspension are respectively introduced into the microchannel reactor 3 at a flow rate of 0.2 mL / min and 0.3 mL / min, the pipe diameter of the microchannel reactor 3 is 3 mm, the pipe diameter ratio of the raw material channel 21, the drug channel 22 and the microchannel reactor 3 is 1:2:2, the residence time of the mixed solution in the ultrasonic dispersion unit is controlled by controlling the number of pipe loops in the ultrasonic dispersion unit at 40°C and an ultrasonic power of 50 W, the mixed solution is ultrasonically treated at a constant temperature for 30 min by looping the pipe of the microchannel reactor 30 times in the ultrasonic dispersion unit, and the mixed solution is sufficiently mixed to form a preliminary magnetic liposome vesicle structure, nitrogen gas is introduced at a flow rate of 0.5 mL / min, the flow rate of the liquid phase is controlled by the liquid pump 32 to be 0.5 mL / min, and the pipe diameter ratio of the gas inlet pipe 25, the fluid channel 26 and the Taylor flow generating unit 5 is 1:1:1, and a stable Taylor flow is formed in the Taylor flow generating unit 5; the formed Taylor flow is subjected to a magnetothermal reaction in an alternating magnetic field with an oscillation frequency of 300 Hz for 4 min, the in-situ magnetothermal effect of the magnetic nanoparticles occurs, the surface of the liposomes in the Taylor flow is locally heated, the free drug is promoted to enter the phospholipid bilayer of the liposomes, and the magnetic drug-loaded liposomes with a drug encapsulation efficiency of 91.4% are formed; after 50 minutes of continuous device reaction, the PDI value of the obtained magnetic drug-loaded liposomes is 0.22±0.05, and the particle size is 260±2.4 nm.

[0025] Example 3

[0026] Based on Figure 1 The device shown in the method for continuously preparing magnetic drug-loaded liposomes with high drug encapsulation efficiency, specifically:

[0027] The phospholipid dispersion and the drug-magnetic nanoparticle suspension are prepared and respectively placed in the raw material liquid tank 1 and the drug liquid tank 2; in the phospholipid dispersion, the concentration of cholesterol is 40 μg / mL, and the concentration of hydrogenated soybean lecithin is 200 μg / mL; in the drug-magnetic nanoparticle suspension, the concentration of magnesium ascorbyl phosphate is 400 μg / mL, and the concentration of superparamagnetic iron oxide is 40 μg / mL; (the preparation method is as follows: 0.004 g of cholesterol and 0.02 g of hydrogenated soybean lecithin are dissolved in 100 mL of propylene glycol to obtain the phospholipid dispersion; 0.04 g of magnesium ascorbyl phosphate and 0.004 g of superparamagnetic iron oxide are dispersed in 100 mL of degassed water to obtain the drug-magnetic nanoparticle suspension).

[0028] The prepared phospholipid dispersion and drug-magnetic nanoparticle suspension are respectively fed into the microchannel reactor 3 at a flow rate of 0.2 mL / min and 0.3 mL / min, the pipeline length of the microchannel reactor 3 is 3 meters, the pipeline diameter is 3 mm, the pipeline diameter ratio of the raw material channel 21, the drug channel 22 and the microchannel reactor 3 is 1:2:2, the residence time of the mixed solution in the ultrasonic dispersion unit is controlled by controlling the pipeline winding number of the ultrasonic dispersion unit at 40°C and an ultrasonic power of 50 W, the pipeline is spirally wound for 30 turns to make the mixed solution ultrasonically react at a constant temperature for 30 min in the ultrasonic dispersion unit, and the mixed solution is fully mixed to form a preliminary magnetic liposome vesicle structure, nitrogen gas is fed at a flow rate of 0.5 mL / min, the flow rate of the liquid phase is controlled by the liquid pump 32 to be 0.5 mL / min, the pipeline diameter ratio of the gas inlet pipeline 25, the fluid channel 26 and the Taylor flow generating unit 5 is 1:1:1, and a stable Taylor flow is formed in the Taylor flow generating unit 5; the formed Taylor flow is subjected to a magnetic heating reaction in an alternating magnetic field with an oscillation frequency of 300 Hz for 4 min, the magnetic nanoparticles generate an in-situ magnetic heating effect, the surface of the liposomes in the Taylor flow is locally heated, the free drug is promoted to enter the phospholipid bilayer of the liposomes, and the magnetic drug-loaded liposomes with a drug encapsulation efficiency of 95.8% are formed; after the continuous device reacts for 50 minutes, the PDI value of the obtained magnetic drug-loaded liposomes is 0.21±0.01, and the particle size is 252.8±5.8 nm.

[0029] Comparative Example 1

[0030] The prepared phospholipid dispersion and drug-magnetic nanoparticle suspension are respectively fed into the microchannel reactor 3 at a flow rate of 0.2 mL / min and 0.3 mL / min, the pipeline length of the microchannel reactor 3 is 3 meters, the pipeline diameter is 3 mm, the pipeline diameter ratio of the raw material channel 21, the drug channel 22 and the microchannel reactor 3 is 1:2:2, the residence time of the mixed solution in the ultrasonic dispersion unit is controlled by controlling the pipeline winding number of the ultrasonic dispersion unit at 40°C and an ultrasonic power of 50 W, the pipeline is spirally wound for 30 turns to make the mixed solution ultrasonically react at a constant temperature for 30 min in the ultrasonic dispersion unit, and the mixed solution is fully mixed to form a preliminary magnetic liposome vesicle structure, nitrogen gas is fed at a flow rate of 0.5 mL / min, the flow rate of the liquid phase is controlled by the liquid pump 32 to be 0.5 mL / min, the pipeline diameter ratio of the gas inlet pipeline 25, the fluid channel 26 and the Taylor flow generating unit 5 is 1:1:1, and a stable Taylor flow is formed in the Taylor flow generating unit 5; the formed Taylor flow is subjected to a magnetic heating reaction in an alternating magnetic field with an oscillation frequency of 300 Hz for 4 min, the magnetic nanoparticles generate an in-situ magnetic heating effect, the surface of the liposomes in the Taylor flow is locally heated, the free drug is promoted to enter the phospholipid bilayer of the liposomes, and the magnetic drug-loaded liposomes with a drug encapsulation efficiency of 95.8% are formed; after the continuous device reacts for 50 minutes, the PDI value of the obtained magnetic drug-loaded liposomes is 0.21±0.01, and the particle size is 252.8±5.8 nm.

[0031] Comparative Example 2

[0032] Comparative Example 2 is compared with Example 1, the only difference is that there is no Taylor flow generating unit in the device, and finally the magnetic drug-loaded liposomes with a drug encapsulation efficiency of 65.5% are formed, after the device reacts for 40 minutes, the PDI value of the obtained magnetic drug-loaded liposomes is 0.35±0.14, and the particle size is 214±5.4 nm.

[0033] Comparative Example 3

[0034] Comparative Example 3 Compared with Example 1, the only difference is that there is no ultrasonic dispersion unit in the device, and finally the drug encapsulation rate of the magnetic drug-loaded liposome is 70.3%, and the PDI value of the magnetic drug-loaded liposome obtained after 20 minutes of reaction of the device is 0.31±0.12, and the particle size is 186.5±4.1 nm.

[0035] Comparative Example 4

[0036] Comparative Example 4 Compared with Example 1, the only difference is that there is no alternating magnetic field generating unit in the device, and finally the drug encapsulation rate of the magnetic drug-loaded liposome is 60.2%, and the PDI value of the magnetic drug-loaded liposome obtained after 40 minutes of reaction of the device is 0.34±0.17, and the particle size is 175.4±5.4 nm.

[0037] Comparative Example 5

[0038] Comparative Example 5 Compared with Example 1, the only difference is that the gas-liquid phase flow rate ratio in the Taylor flow generating unit is 10:1 (nitrogen gas with a flow rate of 5 mL / min is introduced, and the flow rate of the liquid phase is 0.5 mL / min), and finally the drug encapsulation rate of the magnetic drug-loaded liposome is 67.9%; after 45 minutes of reaction, the PDI value of the magnetic drug-loaded liposome obtained is 0.34±0.21, and the particle size is 152.8±15.8 nm.

Claims

1. A method for continuously preparing magnetic drug-loaded liposomes with high drug encapsulation efficiency, characterized in that, Specifically, the phospholipid dispersion liquid and the drug-magnetic nanoparticle suspension are mixed in a micro-channel reactor, the mixture is preliminarily formed into liposomes with vesicle structure under the action of an ultrasonic dispersion unit, then Taylor flow is formed in a Taylor flow generating unit, and the Taylor flow passes through an alternating magnetic field generating unit to obtain magnetic drug-loaded liposomes with high drug encapsulation efficiency.

2. The method of claim 1, wherein: In the Taylor flow generating unit, the gas-liquid phase flow rate ratio is 1-2, the flow rate of the liquid phase is not less than 0.5 mL / min, and the flow rate of the gas is not less than 0.5 mL / min.

3. The method of claim 1, wherein: The phospholipid dispersion liquid is obtained by dissolving phospholipid and cholesterol in an organic solvent; in the phospholipid dispersion liquid, the concentration of the phospholipid is 200-500 μg / mL; the mass ratio of the cholesterol to the phospholipid is 0.2-0.5, and the mass ratio of the phospholipid to the organic solvent is 0.01-0.

03.

4. The method of claim 3, wherein: The phospholipid is at least one of egg phospholipid, hydrogenated soybean lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine, dilauric phosphatidyl ethanolamine, dimyristoyl phosphatidyl ethanolamine, 1-stearoyl-2-oleoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, 1-stearoyl-2-palmitoyl phosphatidylcholine, dimyristoyl phosphatidyl serine, distearoyl phosphatidyl serine, or 1-palmitoyl-2-oleoyl phosphatidyl ethanolamine; and the organic solvent is one of diethylene glycol monoethyl ether, polyethylene glycol, propylene glycol, or glycerol.

5. The method of claim 1, wherein: The drug-magnetic nanoparticle suspension is obtained by dispersing a drug and magnetic nanoparticles in degassed water; in the drug-magnetic nanoparticle suspension, the concentration of the drug is 100-400 μg / mL, and the concentration of the magnetic nanoparticles is 10-40 μg / mL.

6. The method of claim 5, wherein: The drug is one of ascorbic acid magnesium phosphate, resveratrol, simvastatin, doxorubicin hydrochloride, cytarabine, or beclometasone dipropionate.

7. The method of claim 1, wherein: The flow rate of the phospholipid dispersion liquid is 0.1-0.2 mL / min, and the flow rate of the drug-magnetic nanoparticle suspension is 0.2-0.3 mL / min.

8. The method of claim 1, wherein: The ultrasonic dispersion unit is provided with a spiral pipe, and the inlet end of the spiral pipe is connected with the micro-channel reactor along the fluid flow direction, and the outlet end of the spiral pipe is connected with the Taylor flow generating unit through a liquid pump.

9. The method of claim 8, wherein: The ultrasonic dispersion unit is a constant-temperature ultrasonic device, the ultrasonic temperature is 20-50 ℃, and the ultrasonic power is 10-50 W; during the ultrasonic process, the spiral pipe is fixed below the liquid surface of the constant-temperature ultrasonic device.

10. The method of claim 1, wherein: The oscillation frequency of the alternating magnetic field is 50-300 KHz; and the reaction residence time of the Taylor flow in the alternating magnetic field is 3-5 min.

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