WO2025111835A1 - Pinocembrin polymer micelle for resisting hyperuricemia and method for preparing same - Google Patents

Abstract

Provided are a pinocembrin polymer micelle for resisting hyperuricemia and a method for preparing same. The pinocembrin polymer micelle comprises 4%-18% of pinocembrin, 33%-53% of Pluronic F-127, and 31%-56% of vitamin E polyethylene glycol succinate. The flow rate ratio of the continuous phase to the dispersed phase for the microfluidic preparation of the pinocembrin polymer micelle is 1: 11-1: 10. The continuous phase is a solution of Pluronic F-127 and vitamin E polyethylene glycol succinate in methanol, and the dispersed phase is double-distilled water.

Description

A kind of pyrocatechol polymer micelle for anti-hyperuricemia and preparation method thereof Technical Field

The invention relates to a pharmaceutical preparation, in particular to a method for preparing pyralidin polymer micelles for resisting hyperuricemia.

Background Art

Pinocembrin, also known as pinocembrin, is a natural flavonoid compound of 5,7-dihydroxyflavonoids. It exists in licorice, propolis, etc. Its molecular formula is C ₁₅ H ₁₂ O ₄ , its relative molecular mass is 256.25, and it is colorless crystal. It is a very important active substance in licorice, with pharmacological activities such as antibacterial, anti-inflammatory, antioxidant, anti-tumor, cardioprotection, neuroprotection, and inhibition of xanthine oxidase activity. It is worth mentioning that both liquiritin and pinocembrin belong to dihydroflavonoids. Compared with liquiritin, the extra 5-OH on the A ring of pinocembrin forms a p-π conjugation with the benzene ring, which increases the electron cloud density on the A ring, thereby activating the A ring and the 7-OH on the A ring, and has better pharmacological activity. As a flavonoid compound, it is easily soluble in organic solvents such as methanol, ethanol and dimethyl sulfoxide, but its water solubility is low, it is difficult to absorb in the body, and its bioavailability is low, which seriously hinders its clinical application. In recent years, researchers at home and abroad have developed cyclodextrin inclusion compounds, liposomes and other dosage forms in an effort to solve these problems.

Polymer micelles are nano drug delivery systems formed by self-assembly in aqueous solution of a variety of amphiphilic block copolymers with good biocompatibility, such as Pluronic copolymers and methoxy polyethylene glycol polylactic acid (MPEG-PLA). When the concentration of block polymers in water is low, they are dispersed or adsorbed on the surface of the solution in the form of single molecules to reduce surface tension. When a certain concentration is reached, the polymers tend to be arranged in an ordered structure to form a shell-core structure with hydrophobic groups inside and hydrophilic groups outside. This concentration is called the critical micelle concentration (CMC). The lower the CMC value of the polymer, the more stable the micelles. Amphiphilic polymers self-assemble in water through various driving forces such as hydrophobic effects and electrostatic effects, embedding poorly soluble drugs in the hydrophobic core and improving the solubility of the drugs. The obtained micelles have a small particle size (usually 1-100nm) and uniform distribution, which is conducive to blood circulation, tissue penetration and cell absorption. In addition, polymer micelles are formed by simple self-assembly in solution, which is easier to mass produce than other nanocarriers (such as polymer nanoparticles and liposomes).

Hyperuricemia (HUA) is a common metabolic disease caused by purine metabolism disorders in the body, characterized by elevated uric acid levels in the body. Generally speaking, under normal physiological conditions, when the uric acid level in men and postmenopausal women exceeds 416mmol/L, and in premenopausal women exceeds 357mmol/L, it is called hyperuricemia. However, this statement is not absolute. Studies have shown that uric acid levels are also associated with age, race, and complications. Since there are many factors that affect purine metabolism, the causes of abnormal uric acid levels are multifactorial and there are obvious individual differences. 67% of uric acid is endogenous, and 33% comes from purine intake in the diet. In order to maintain normal uric acid levels in the human body every day, about 75% of uric acid is excreted through the kidneys, and the remaining 25% is excreted through the gastrointestinal tract. Excessive production of uric acid and kidney disease can lead to supersaturation of sodium urate crystals, which are deposited in the joints, increase inflammation, and cause gout. Gout is a type of arthritis that is accompanied by severe pain. In addition, there are cases where HUA has no concurrent gout symptoms, which is called asymptomatic hyperuricemia. Gout is considered to be the second disease threatening young people after type 2 diabetes.

Summary of the invention

The purpose of the present invention is to provide a pyralidin polymer micelle for resisting hyperuricemia and a preparation method thereof in view of the problems of poor water solubility, low in vitro release and low bioavailability of pyralidin. The present invention prepares pyralidin with poor water solubility into polymer micelles, which can significantly improve the solubility and in vitro release of pyralidin, and the preparation method thereof should be simple.

In order to achieve the above-mentioned purpose, the present invention adopts the following technical scheme: a pyralidin polymer micelle for anti-hyperuricemia, wherein the polymer micelle is Pluronic F-127 (a copolymer of propylene oxide and ethylene oxide) and vitamin E polyethylene glycol succinate as carriers to encapsulate pyralidin, and the mass fractions of each component are: pyralidin 4% to 18%, Pluronic F-127 33% to 53%, and vitamin E polyethylene glycol succinate 31% to 56%.

Furthermore, the mass fractions of each component are: pyrocatechol 11.11%, Pluronic F-127 55.56%, and vitamin E polyethylene glycol succinate 33.33%.

Furthermore, the particle size of the polymer micelle is 25 to 40 nm, the polydispersity coefficient is 0.105 to 0.184, and the encapsulation efficiency is above 90%.

A method for preparing the above-mentioned anti-hyperuricemia pyrocatechol polymer micelles comprises the following steps:

(1) According to the ratio of the components, pyrocatechol, Pluronic F-127 and vitamin E polyethylene glycol succinate were weighed and completely dissolved in an organic solvent under ultrasound-assisted conditions to serve as the continuous phase for preparing pyrocatechol polymer micelles; double distilled water was used as the dispersed phase;

(2) The prepared continuous phase and dispersed phase are placed in syringes respectively, and the syringes are placed on two calibrated constant flow pumps respectively, connected to the microfluidic chip through catheters, and the flow rates of the two phases are controlled to prepare pyrocatechol polymer micelles.

Furthermore, the flow rate ratio of the continuous phase to the dispersed phase is 1:1 to 10, preferably 1:2.

Furthermore, the dispersed phase in the conduit is injected from the middle channel, and the continuous phase is injected from the channels on both sides, and the symmetrical continuous phase shears the dispersed phase to form droplets.

Beneficial effects of the present invention:

(1) The preparation method of the pineapple polymer micelle preparation of the present invention is simple, easy to operate, low in cost, and the preparation process is easy to control; the prepared pineapple polymer micelles spontaneously form polymer micelles with a particle size of less than 50 nm when in contact with water, and have a high encapsulation rate and drug loading; the prepared pineapple polymer micelles are stored for one month at a temperature of 25±2°C and a relative humidity of 75±5%, and the particle size does not change significantly, and the EE decreases by no more than 10%, which is still above 90%. During this period, the pineapple polymer micelle solution is clear and transparent, without precipitation, and has good stability; the in vitro release of the prepared pineapple polymer micelles in four media within 24 hours is significantly higher than that of pineapple, and the in vitro cumulative release reaches more than 75%, which significantly improves the solubility and in vitro release of pineapple.

(2) The pyrocatechol polymer micelles prepared by the present invention can be directly orally administered in actual application. Pharmacokinetic studies have shown that the solubility of pyrocatechol is poor and its bioavailability is low. Encapsulating the drug in polymer micelles can improve the absorption of the drug in the body. The speed and degree of absorption of the drug can greatly improve the oral bioavailability. Based on the physical and chemical properties of the hydrophobic drug and the polymer chain that forms the micelle structure, the inner core of the micelle can dissolve a large number of pyralidin molecules. The increase in oral bioavailability may be due to the following reasons: polymer micelles, as a nano drug delivery system smaller than 100 nm, can be absorbed through adsorption and endocytosis; after most of the pyralidin is encapsulated by micelles, the effect of gastrointestinal enzymes on the drug is reduced, thereby increasing the drug concentration in the body. The prepared pyralidin polymer micelles improve the pharmacokinetic parameters of pyralidin and improve the oral bioavailability of pyralidin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a photograph of the appearance of the pyrocatechol polymer micelles prepared in Example.

FIG. 2 is a particle size distribution diagram of the pyrocatechol polymer micelles prepared in the example.

FIG3 is a transmission electron micrograph of the pyrocatechol polymer micelles prepared in Example.

Figure 4 shows the in vitro release curves of the pyralidin polymer micelles and pyralidin raw material prepared in the example in different pH media (A: pH 1.2 HCl solution, B: pH 6.8 PBS solution, C: pH 7.4 PBS solution, D: DDW).

Figure 5 is a graph showing the drug-drug curves of pyralidone raw material and pyralidone polymer micelles after oral administration to rats (n=5) (A: drug-drug curve 36 hours after oral administration, B: drug-drug curve 6 hours after oral administration).

Figure 6 shows the UA concentration in each group three hours after modeling (### compared with NC, p<0.001; * compared with MC, p<0.05; ** compared with MC, p<0.01; *** compared with MC, p<0.001; ++ compared with the corresponding dose of pyralidone raw material group, p<0.01).

Figure 7 shows the XOD activities in the serum and liver of rats in each group (compared with the XOD activities in the serum and liver of the NC group, ###p<0.001; compared with the XOD activity in the serum of the MC group, **p<0.01, ***p<0.001; compared with the XOD activity in the liver of the MC group, ^{▲▲ p} <0.01, ^▲▲▲ p<0.001).

Figure 8 shows the IL-1β levels in serum and liver of rats in each group (compared with the IL-1β levels in serum and liver of the NC group, ###p<0.001; compared with the IL-1β levels in serum of the MC group, **p<0.01, ***p<0.001; compared with the IL-1β levels in liver of the MC group, ^▲▲ p<0.01, ^▲▲▲ p<0.001).

Figure 9 shows the TNF-α levels in serum and liver of rats in each group (compared with the TNF-α levels in serum and liver of NC group, ###p<0.001; compared with the TNF-α levels in serum of MC group, **p<0.01, ***p<0.001; compared with the TNF-α levels in liver of MC group, ^▲▲ p<0.01, ^▲▲▲ p<0.001).

DETAILED DESCRIPTION

In order to enable those skilled in the art to better understand the solution of the present application, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present application.

It should be noted that the terms "including" and "having" and any variations thereof in the specification and claims of this application and the above drawings are intended to cover non-exclusive inclusions, for example, a process or method including a series of steps or units. The methods, systems, products or apparatus are not necessarily limited to those steps or elements expressly listed but may include other steps or elements not expressly listed or inherent to such processes, methods, products or apparatus.

Example 1

Screening of formulation and process for preparing pyrocatechol polymer micelles by microfluidics:

(1) Screening of formulations of pyrocatechol polymer micelles

Orthogonal experiments were used to screen the prescriptions. F127 (A), TPGS (B) and PCB (C) were selected as the factors to be investigated, and the particle size was used as the target. The particle size was detected by a laser particle size analyzer. Three levels were selected for each factor. SPSS software was used for design and an L9 (3 ⁴ ) orthogonal analysis table (Mean, n = 3) was established. The results are shown in Table 1.

Table 1

Using the range analysis method, it can be learned from the range R analysis that the influence of each factor on the micelle particle size is: TPGS>F127>PCB, and the best prescription is: A3B1C2.

(2) Screening of flow rate for preparation of pyrocatechol polymer micelles

After the continuous phase and dispersed phase were prepared according to the optimal prescription, the two-phase flow rate was screened based on particle size, polydispersity coefficient and encapsulation efficiency. The results are shown in Table 2.

Table 2

At different flow rate ratios between the continuous phase and the dispersed phase, as the flow rate of the dispersed phase increases, the particle size tends to decrease, but the change is not significant, all within the range of 50nm; the PDI also does not change significantly, all less than 0.2; but as the flow rate of the aqueous phase continues to increase, the concentration of the prepared pyrocatechol polymer micelles will become too dilute, so the two-phase flow rate ratio of 1:2 is selected as the optimal flow rate condition for preparing pyrocatechol polymer micelles.

In summary, the optimal formula for preparing pyrocatechol polymer micelles is A3B1C2, and the optimal flow rate condition is a continuous phase to dispersed phase flow rate ratio of 1:2.

Example 2

In vitro characterization of pyrocatechol polymer micelles:

Appearance observation of pyrocatechol polymer micelles: The polymer micelles prepared in Example 1 were observed to be clear and transparent at room temperature. The product is a clear colorless liquid with no precipitation and obvious Tyndall effect, as shown in Figure 1.

Determination of polymer micelle particle size: The polymer micelle solution prepared in Example 1 was taken, and the polymer micelle droplet size (DS) and polydispersity index (PDI) were measured using a Nano Brook 90PALS instrument dynamic light scattering instrument using dynamic light scattering (DLS) and phase analysis light scattering (PALS) techniques. The sample pool detection temperature was 25°C, the detection scattering angle was 90°, and the sample was measured three times in parallel. The results showed that the polymer micelle particle size was in the range of 25 to 40 nm and was uniformly distributed. The particle size distribution diagram is shown in Figure 2.

Observation of polymer micelle morphology: The polymer micelle solution prepared in Example 1 was added dropwise onto a copper mesh covered with a support film, air-dried, and stained with a 2% phosphotungstic acid solution. The mesh was naturally dried and observed under a transmission electron microscope. The pyrocatechol polymer micelle solution was spherical in shape and evenly distributed without agglomeration under a transmission electron microscope, as shown in FIG3 .

Determination of in vitro release of polymer micelles: The pyralidin polymer micelles and pyralidin of Example 1 were taken and placed in dialysis bags respectively, and their in vitro release in water, pH 1.2 hydrochloric acid solution, pH 6.8 phosphate buffer and pH 7.4 phosphate buffer was investigated. The results showed that compared with pyralidin, the pyralidin polymer micelles were dissolved more rapidly and completely, and the in vitro release rate of pyralidin could be effectively improved, as shown in Figure 4.

Example 3

Evaluation of oral bioavailability of chondrostenone polymer micelles

1. Blood sample processing method

Blood was collected from the rat's anterior orbital venous plexus in a 1.5 mL EP tube. After standing in a 37°C constant temperature water bath for 30 minutes, the blood was centrifuged at 3700 rpm for 10 minutes to obtain the upper serum. The serum was aspirated into a 1.5 mL EP tube, and the internal standard solution was added. The internal standard was vortexed to fully mix the serum. 400 μL of ethyl acetate was added, vortexed for 1 minute, and centrifuged at 10000 rpm for 10 minutes. The upper ethyl acetate extract was collected, and 400 μL of ethyl acetate was added to the EP tube containing the remaining serum. The above operation was repeated and extracted again to fully extract the pyrocatechol and internal standard substances in the serum. The two extracts were combined and dried with nitrogen in a 37°C water bath. Chromatographic methanol was added to vortex to dissolve the dried sample, and then centrifuged at 12000 rpm for 10 minutes. The supernatant was taken and the pyrocatechol content was detected by HPLC.

2. Pharmacokinetics in SD rats

Several male SD rats with standard weight were selected. After 3 days of self-adaptation under laboratory standards, they were randomly divided into two groups, namely, the pineapple raw material drug group and the pineapple polymer micelle group. No food was allowed 12 hours before the experiment, but they were allowed to drink water freely. The two groups of rats were gavaged with the same dose of pineapple raw material drug suspension and pineapple polymer micelles. After the administration, blood was collected from the orbital venous plexus of the rats at different time points. The blood samples were taken out after standing in a constant temperature water bath at 37°C for 30 minutes, centrifuged at 3700rpm for 10 minutes, and serum was collected in a 1.5mL EP tube. After the blood samples were processed by the above process, they were tested by HPLC injection, and the blood drug concentration in the rats at the corresponding time was calculated. The blood drug concentration-time curve was drawn with the sampling time point as the X-axis and the blood drug concentration of pineapple as the Y-axis, as shown in Figure 5.

Example 4

Polymeric micelles of pyrocatechol improve hyperuricemia in rats

1. Establishment of Rat Hyperuricemia Model

Ten male SD rats of standard weight were randomly divided into two groups, 5 rats in each group, namely the normal control group (NC) and the model group (MC), and were raised in a standard laboratory environment for 3 days. In addition to the normal control group, the model group was given an intragastric administration of hypoxanthine suspension and intraperitoneal injection of potassium oxonate emulsion to establish a hyperuricemia rat model. Before modeling, blood was first collected from the orbital venous plexus of the rats, and then blood was collected at 1h, 2h, 3h, 4h, 5h, 6h, 8h, and 10h after modeling. After processing, the blood samples were analyzed by HPLC and the uric acid concentration was calculated to determine whether the rat hyperuricemia model has been successfully established and to determine the time for uric acid level detection. 2. Animal grouping and dosing

Fifty male SD rats of standard weight were randomly divided into 10 groups, with 5 rats in each group:

Normal control group (NC): intragastric administration of 0.9% saline;

Model group (MC): intragastric administration of 0.9% saline

Positive control group (PC): intragastric administration of allopurinol;

Low-dose group (PCB-L): intragastric administration of bromocriptine suspension (50 mg/kg);

Medium dose group of API (PCB-M): intragastric administration of chloranthone API suspension (100 mg/kg);

High-dose group (PCB-H): intragastric administration of chloranthone suspension (200 mg/kg);

Low-dose polymer micelle group (PCB-M-L): intragastric administration of bromocriptine polymer micelles (50 mg/kg);

Medium-dose polymer micelle group (PCB-M-M): intragastric administration of bromocriptine polymer micelles (100 mg/kg);

High-dose polymer micelle group (PCB-M-H): intragastric administration of pyralidin polymer micelle (200 mg/kg);

Blank polymer micelle group (B-M): blank polymer micelles were administered orally.

3. Detection indicators and methods

3.1 Determination of uric acid in serum

Drugs were administered 1 hour after modeling, and serum uric acid levels were detected 3 hours after modeling. Blood was collected from the orbital venous plexus of rats 3 hours after modeling, and the blood samples from each group were processed and uric acid levels were detected by HPLC.

3.2 Determination of xanthine oxidase (XOD) activity in serum and liver

Xanthine oxidase (XOD) can indirectly convert hypoxanthine or directly convert xanthine to uric acid. When XOD is abnormally active, it leads to uric acid metabolism disorders, thereby causing hyperuricemia. It can be seen that XOD is the key to uric acid secretion, and inhibiting the catalytic activity of XOD is crucial for the treatment of hyperuricemia. The serum of each group of rats was thawed at room temperature. Another rat liver was taken in a centrifuge tube, and low-temperature physiological saline was added at a ratio of 1:10 (g:mL). It was homogenized using a high-speed homogenizer in an ice water bath, and the homogenate was centrifuged at 10000rpm for 10min to separate the supernatant. The supernatant and serum were determined according to the operating instructions of the ELISA kit to determine the activity of xanthine oxidase (XOD) in the sample.

3.3 Detection of inflammatory factors

TNF-α is a pro-inflammatory cytokine and plays an important role in the entire inflammatory response process. It is the initiator of the cytokine regulatory network in the patient's body, has a local pro-inflammatory effect, stimulates neutrophils, and then initiates an inflammatory response. IL-1β plays a special role in the inflammatory response and is the most representative inflammatory regulator. Therefore, it is necessary to examine the levels of IL-1β and TNF-α. The serum of each group of rats was thawed at room temperature. The rat liver was taken in a centrifuge tube, and low-temperature physiological saline was added at a ratio of 1:10 (g:mL). The liver was homogenized using a high-speed homogenizer in an ice water bath, and the homogenate was centrifuged at 10000rpm for 10min to separate the supernatant. The serum and liver homogenate supernatant obtained from each group were operated according to the instructions of the ELISA kit to determine the levels of IL-1β and TNF-α.

3.4 Data processing and statistical methods

All data were expressed as mean±SD. The t-test was used to examine the significance among the groups, with P<0.05 or P<0.01 as the significance index.

4. Experimental Results

4.1 Determination of uric acid in serum

The serum uric acid values of each group are shown in Figure 6. Compared with the MC group, the uric acid levels of the B-M group and the MC group were similar, indicating that the excipients used in the polymer micelles had almost no effect on the uric acid level; the uric acid levels in the serum of PCB-L, PCB-M, PCBLH, PCB-M-L, PCB-M-M, PCB-M-H, and PC were significantly reduced (P < 0.01); and the bromocriptine polymer micelle group had a more significant effect on reducing uric acid levels than the bromocriptine raw material group. This shows that bromocriptine and its polymer micelle preparations can reduce uric acid levels and have a certain improvement effect on hyperuricemia.

4.2 Determination of XOD activity in serum and liver

The XOD activities in the serum and liver of each group are shown in Figure 7. The XOD activities in the serum and liver of rats in the MC group were significantly higher than those in the NC group (P < 0.001), indicating that the hyperuricemia model was successfully established. The XOD activities in the plasma and liver of rats in different dosing groups were measured, and it was found that they were significantly lower than those in the MC, and the statistical results were significant. It is speculated that pyralidin and pyralidin polymer micelles can inhibit XOD activity, reduce uric acid production, and improve hyperuricemia.

4.3 Detection of inflammatory factors

The levels of inflammatory factors in the serum and liver of each group are shown in Figure 8. The levels of inflammatory factors (IL-1β, TNF-α) in the serum and liver of rats in the MC group were significantly higher than those in the NC group (P<0.001), indicating that the HUA rat model was successfully established. The levels of inflammatory factors in the serum and liver of rats in the BM group were similar to those in the MC group, indicating that the excipients used in the micelles had no improvement effect on the levels of inflammatory factors in the HUA model caused by the combination of HX and PO. The PC group was able to reduce the levels of IL-1β and TNF-α to a level similar to that of the NC group, improving inflammation. Compared with the MC group, the levels of inflammatory factors in the serum and liver of rats in the bromocriptine raw material and bromocriptine polymer micelle administration groups decreased to varying degrees, and were dose-dependent. According to low, medium and high doses, the bromocriptine raw material group reduced the serum IL-1β level by 16.93%, 29.20%, and 37.76%, and reduced the IL-1β level in the liver by 18.48%, 21.52%, and 21.52%. 31.32%; reduced serum TNF-α levels by 6.91%, 19.73%, 25.32%, reduced liver TNF-α levels by 7.31%, 15.54%, 17.73%. At the same dose, the pyralidin polymer micelle group reduced serum IL-1β levels by 35.99%, 41.77%, 48.96%, reduced liver IL-1β levels by 27.81%, 34.29%, 38.91%; reduced serum TNF-α levels by 17.43%, 24.99%, 35.84%, reduced liver TNF-α levels by 18.83%, 26.32%, 35.28%, indicating that pyralidin polymer micelles can improve the anti-inflammatory effect of pyralidin to a certain extent.

The above research results show that the pyralidin polymer micelles in the present invention have a significant effect on improving hyperuricemia and can significantly improve the efficacy of the pyralidin raw material drug.

The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims (6)

A pyralidone polymer micelle for treating hyperuricemia, characterized in that: the polymer micelle uses Pluronic F-127 and vitamin E polyethylene glycol succinate as carriers to encapsulate pyralidone, and the mass fractions of each component are: pyralidone 4% to 18%, Pluronic F-127 33% to 53%, and vitamin E polyethylene glycol succinate 31% to 56%. The anti-hyperuricemia pyralidin polymer micelles according to claim 1 are characterized in that the mass fractions of the components are: pyralidin 11.11%, Pluronic F-127 55.56%, and vitamin E polyethylene glycol succinate 33.33%. The anti-hyperuricemia pycnogenol polymer micelles according to claim 1 are characterized in that the particle size of the polymer micelles is 25 to 40 nm, the polydispersity coefficient is 0.105 to 0.184, and the encapsulation rate is above 90%. A method for preparing the anti-hyperuricemia pyralidin polymer micelles according to any one of claims 1 to 3, characterized by comprising the following steps: (1) According to the ratio of the components, pyrocatechol, Pluronic F-127 and vitamin E polyethylene glycol succinate were weighed and completely dissolved in an organic solvent under ultrasound-assisted conditions to serve as the continuous phase for preparing pyrocatechol polymer micelles; double distilled water was used as the dispersed phase; (2) The prepared continuous phase and dispersed phase are placed in syringes respectively, and the syringes are placed on two calibrated constant flow pumps respectively, connected to the microfluidic chip through catheters, and the flow rates of the two phases are controlled to prepare pyrocatechol polymer micelles. The preparation method according to claim 4 is characterized in that the flow rate ratio of the continuous phase to the dispersed phase is 1:1-10. The preparation method according to claim 4 is characterized in that: the dispersed phase in the conduit is injected from the middle channel, the continuous phase is injected from the channels on both sides, and the symmetrical continuous phase shears the dispersed phase to form droplets.