Enteric nanoparticle preparation and preparation method thereof

Abstract

The invention discloses an enteric nanoparticle preparation and a preparation method thereof, and belongs to the technical field of medicine preparation. According to the invention, PLGA and PVA are combined with Eudragit with an enteric effect, a one-step formed nanoparticle preparation is realized by using a microfluidic technology, and the preparation process is remarkably simplified. Compared with a traditional enteric-coated tablet preparation technology, the method is simpler and more efficient, has excellent enteric-coated performance and controllability, and provides an innovative solution for child medicine development.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and specifically relates to an enteric-coated nanoparticle preparation and a preparation method thereof. Background Art

[0002] As society develops, people's demand for improved healthcare continues to increase, and traditional dosage forms such as tablets, capsules, and injections are often not suitable for pediatric use. For solid oral medications, tablets are usually crushed, capsules are split, or injections are diluted to make liquid preparations that can be mixed with food or liquids; however, this change may result in inaccurate dosage of active pharmaceutical ingredients (API), leading to potential risks of overdose or treatment failure due to substandard bioavailability. Therefore, the demand for pediatric-specific drug preparations is urgent.

[0003] Some drugs need to be prepared with enteric-coated preparations to improve drug compliance and therapeutic effects due to poor stability and gastrointestinal irritation. Traditional enteric-coated preparations (such as enteric-coated tablets or capsules) usually require a multi-step process, including complex manufacturing processes such as coating and drying, with poor process stability, and it is difficult to meet the personalized needs of high efficiency and precision; liquid preparations are especially suitable for children because of their convenient and easy-to-swallow characteristics, but there is still a lack of choice for oral enteric liquid preparations on the market, and the development of enteric preparations, especially oral liquid preparations, is still in its infancy. In addition, traditional nanoparticle preparation methods such as emulsification-solvent evaporation method and double emulsification method are complex and have poor reproducibility. The microfluidic technology that has emerged in recent years has shown great potential in the controllability and uniformity of nanoparticles, but related research has mostly focused on the application of a single material (such as PLGA) and lacks material optimization for enteric effects. Therefore, developing a suitable method for the preparation of oral enteric liquid preparations has become a technical problem that needs to be solved urgently. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide an enteric-coated nanoparticle preparation and a preparation method thereof, so as to solve the technical problem that the existing enteric-coated preparations are difficult to liquefy.

[0005] To achieve the above-mentioned purpose, the technical solution adopted by the present invention is: to provide a method for preparing an enteric-coated nanoparticle preparation, comprising the following steps: dissolving a pharmaceutically active substance, PLGA and an acrylic resin (Eudragit L 100-55) in an organic solvent at a mass ratio of 0.5-1.5:4.5-5.5:4.5-5.5 to obtain an organic phase; subsequently, using a PVA solution as an aqueous phase, reacting the organic phase and the aqueous phase through a microfluidic device, and finally removing the organic solvent and centrifuging to obtain an enteric-coated nanoparticle preparation.

[0006] The organic phase is wrapped with the aqueous phase using a microfluidic device, and the solvent in the organic phase quickly diffuses into the aqueous phase, causing the organic phase solvent concentration to drop sharply. PLGA and Eudragit L100-55 have very low solubility in slightly acidic aqueous solutions, so when the solvent concentration drops to a certain level, they begin to precipitate from the solution. During the solvent replacement process, the molecular chains self-assemble to form nanoparticles through hydrophobic interactions and van der Waals forces. The hydroxyl groups in the PVA molecules are adsorbed on the surface of the nanoparticles through hydrogen bonds or electrostatic effects to form a stable surfactant layer, which further improves the dispersion stability of the nanoparticles and prevents them from aggregating.

[0007] On the basis of the above technical solution, the present invention can also be improved as follows:

[0008] Furthermore, the active substance of the drug is aspirin, metformin hydrochloride, risedronate sodium, dexlansoprazole, mesalazine, albendazole, omeprazole, mycophenolate sodium or methotrexate.

[0009] Furthermore, the organic solvent is anhydrous ethanol and / or ethyl acetate.

[0010] Furthermore, the concentration of the PVA solution is 0.5-1.5wt%, and the pH value is 3-5.

[0011] Furthermore, the flow rate ratio of the organic phase to the aqueous phase is 0.5-1.5:3-5, and the total flow rate of the organic phase and the aqueous phase is 4-6 mL / min.

[0012] Furthermore, the centrifugation is divided into two stages, specifically: first low-speed centrifugation at 900-1100 rpm for 8-12 min, and then high-speed centrifugation at 13000-17000 rpm for 30-60 min.

[0013] The invention also discloses an enteric-coated nanoparticle preparation prepared by the preparation method.

[0014] The beneficial effects of the present invention are:

[0015] 1. Taking aspirin as an example, the aspirin enteric-coated nanoparticles (AS-PLGA-EL@NPs) prepared by the method of the present invention have good sustained-release and enteric effects, good low-temperature storage stability, and better intestinal absorption and bioavailability than free aspirin and aspirin enteric-coated tablets (Bayer).

[0016] 2. The present invention does not need to be prepared by microfluidics and then enteric coating, but directly prepares the enteric preparation in one step, and the preparation method is simpler and easier. In addition, compared with the existing microfluidics research focusing on the preparation of a single material PLGA, the introduction of Eudragit L100-55 to prepare nanoparticles simultaneously makes the nanoparticles have both sustained release and enteric effects, and the functions are richer.

[0017] 3. The materials of the present invention are easy to obtain, and the prepared enteric-coated nanoparticle preparation has a good appearance and good repeatability, can be mass-produced, and is more suitable for children with dysphagia. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Optical imaging of AS-PLGA-EL@NPs nanoparticles;

[0019] Figure 2 is the SEM image of AS-PLGA-EL@NPs;

[0020] Figure 3 The particle size distribution and PDI data of AS-PLGA-EL@NPs;

[0021] Figure 4 is the Zeta potential of AS-PLGA-EL@NPs;

[0022] Figure 5 The storage stability of AS-PLGA-EL@NPs at low temperature;

[0023] Figure 6 This is the graph showing the changes in API content concentration of AS-PLGA-EL@NPs nanoparticles at low temperature;

[0024] Figure 7 is the in vitro release curve of AS-PLGA-EL@NPs;

[0025] Figure 8 This is the SEM image of AS-PLGA-EL@NPs stock solution;

[0026] Fig. 9 SEM images of AS-PLGA-EL@NPs dialyzed in artificial gastric fluid for 2 hours;

[0027] Fig.10 The SEM images of AS-PLGA-EL@NPs dialyzed in artificial intestinal fluid for 2 hours;

[0028] Fig.11 is the toxicity diagram of AS-PLGA-EL@NPs to Caco-2 cells;

[0029] Fig.12 Figure 2 shows the intestinal absorption of different concentrations of AS and AS-PLGA-EL@NPs at different stages. eff value;

[0030] Fig.13 The intestinal absorption K of different concentrations of AS and AS-PLGA-EL@NPs at different stages a value;

[0031] Fig.14 are the average absorption parameters of intestinal absorption of AS and AS-PLGA-EL@NPs at different concentrations;

[0032] Fig.15 The average drug concentration-time curves after oral administration of AS, AS-PLGA-EL@NPs and tablets to rats. DETAILED DESCRIPTION

[0033] The specific embodiments of the present invention are described below to facilitate the understanding of the present invention by those skilled in the art. If the specific conditions are not specified in the examples, the methods are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturers are not specified in the reagents or instruments used, they are all conventional products that can be purchased commercially. However, it should be clear that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, as long as various changes are within the spirit and scope of the present invention defined and determined by the attached claims, these changes are obvious, and all inventions and creations using the concept of the present invention are protected.

[0034] Example 1

[0035] The invention discloses a preparation method of an enteric nanoparticle preparation, comprising the following steps: dissolving 5 mg of aspirin (AS) and 25 mg of PLGA in 0.9 mL of ethyl acetate, dissolving 25 mg of acrylic resin (Eudragit L 100-55) in 0.6 mL of anhydrous ethanol, and then mixing to obtain an organic phase; then using a PVA solution (with a concentration of 1 wt %, and pH=5) as an aqueous phase, reacting the organic phase (with a flow rate of 1 mL / min) and the aqueous phase (with a flow rate of 4 mL / min) through a microfluidic device, and then removing the organic solvent at a rotation speed of 500 rpm by magnetic stirring to intensify the aggregation of PLGA and Eudragit L 100-55 and form a nanoparticle solution with stable and uniform dispersion; finally, performing low-speed centrifugation at 1000 rpm for 10 minutes to remove unencapsulated aspirin drug crystals, and then performing high-speed centrifugation at 15000 rpm for 60 minutes to separate unencapsulated free aspirin to obtain an enteric nanoparticle preparation (AS-PLGA-EL@NPs).

[0036] Example 2

[0037] A preparation method of an enteric nanoparticle preparation comprises the following steps: dissolving 5 mg of metformin hydrochloride and 45 mg of PLGA in 1.2 mL of ethyl acetate, dissolving 45 mg of acrylic resin (Eudragit L 100-55) in 1 mL of anhydrous ethanol, and then mixing to obtain an organic phase; then using a PVA solution (with a concentration of 0.5 wt %, pH=4) as an aqueous phase, reacting the organic phase (with a flow rate of 0.5 mL / min) and the aqueous phase (with a flow rate of 3.5 mL / min) through a microfluidic device, and then removing the organic solvent at a rotation speed of 500 rpm through magnetic stirring; and finally centrifuging at a low speed of 900 rpm for 12 min, and then centrifuging at a high speed of 13000 rpm for 50 min to obtain the enteric nanoparticle preparation.

[0038] Example 3

[0039] A preparation method of an enteric nanoparticle preparation comprises the following steps: dissolving 3 mg of risedronate sodium and 11 mg of PLGA in 1 mL of ethyl acetate, dissolving 55 mg of acrylic resin (Eudragit L 100-55) in 0.8 mL of anhydrous ethanol, and then mixing to obtain an organic phase; then using a PVA solution (with a concentration of 1.5 wt %, pH=3) as an aqueous phase, reacting the organic phase (with a flow rate of 1.5 mL / min) and the aqueous phase (with a flow rate of 4.5 mL / min) through a microfluidic device, and then removing the organic solvent at a rotation speed of 500 rpm by magnetic stirring; and finally centrifuging at a low speed of 1100 rpm for 8 min, and then centrifuging at a high speed of 17000 rpm for 30 min to obtain the enteric nanoparticle preparation.

[0040] Comparative Example

[0041] The difference between this comparative example and Example 1 is that the raw material acrylic resin (Eudragit L 100-55) is omitted, and the other implementation conditions are the same as those in Example 1 to prepare AS-PLGA@NPs.

[0042] The AS-PLGA-EL@NPs sample used in the following experiments is the enteric-coated aspirin nanoparticles prepared in Example 1.

[0043] Experimental Example 1 Physical Characterization

[0044] 1. A dynamic light scattering analyzer (DLS, Malvern, ZEN3600, UK) was used to evaluate the size distribution, zeta potential and polydispersity index (PDI) of aspirin enteric-coated nanoparticles (AS-PLGA-EL@NPs), and the morphology of AS-PLGA-EL@NPs was analyzed by scanning electron microscopy (SEM, SU8010, HITACHI).

[0045] Figure 1 This is a physical picture of AS-PLGA-EL@NPs nanoparticles. From the picture, it can be seen that the sample has a light blue opalescent luster and the nanoparticles are regular round ( Figure 2 The particle size of AS-PLGA-EL@NPs nanoparticles was 127.0±1.45nm and the PDI was 0.124±0.021( Figure 3 ), the particle size distribution is uniform, which meets the requirements of nano-preparation, and the potential is -12.23±1.66mV( Figure 4 ).

[0046] 2. In order to evaluate the encapsulation efficiency of AS-PLGA-EL@NPs, high-speed centrifugation was used to separate free aspirin and AS-PLGA-EL@NPs. The sample solution was first centrifuged at 1000 rpm for 10 min to remove unencapsulated aspirin drug crystals, and then centrifuged at 15000 rpm for 60 min, and the supernatant was taken to detect the free drug content. The absorbance of unencapsulated aspirin was measured at 276 nm by UV-visible spectrophotometry. The encapsulation efficiency (EE) was calculated as follows:

[0047]

[0048] Wherein, m is the free drug content in the centrifugal supernatant, mg; M0 is the drug content in the nanoparticle mixture without centrifugation, mg.

[0049] The encapsulation efficiency of aspirin in AS-PLGA-EL@NPs was calculated to be 37.43±2.26%.

[0050] Experimental Example 2 Repeatability

[0051] Three batches of AS-PLGA-EL@NPs nanoparticles were prepared repeatedly using the preparation method disclosed in Example 1. Five samples were prepared for each batch. The reproducibility was evaluated by detecting the particle size, PDI and potential. The results are shown in Table 1.

[0052] Table 1 Characterization parameters of nanoparticles between different batches (n=5)

[0053]

[0054]

[0055] It can be seen from the table that the RSDs of particle size and potential between different batches are less than 15%. Although the RSD of PDI is greater than 15%, its range is still within the required range of nanoparticles, and the overall PDI value is small, indicating that the use of microfluidics to prepare nanoparticles has high repeatability and stability.

[0056] Experimental Example 3 Low Temperature Storage Stability

[0057] In order to evaluate the stability of AS-PLGA-EL@NPs nanoparticles, the purified AS-PLGA-EL@NPs were stored in a 4℃ refrigerator for 7 days, and the changes in the particle size, PDI, zeta potential and API content concentration in the AS-PLGA-EL@NPs were measured. The changes in the particle size, PDI and zeta potential of the nanoparticles were measured by DLS; the changes in the content of the main drug were obtained by measuring the absorbance of the stored nanoparticles by UV-visible spectrophotometer each time after demulsification and then bringing it into the standard curve to calculate the concentration.

[0058] Particle size, potential, and PDI of aspirin ( Figure 5 ) and API content concentration ( Figure 6 ) showed no significant change, indicating that AS-PLGA-EL@NPs had good short-term storage stability within 7 days.

[0059] Experimental Example 4 In vitro release study

[0060] The drug release of AS-PLGA-EL@NPs was determined by in vitro dialysis. The incubation was carried out in a thermostatic oscillator at 37°C and 100 rpm. The dialysis bag containing 2 mL of nanoparticle solution was placed in 0.1N HCl solution (pH=1.2, simulated artificial gastric fluid (SGF)) for the first 2 hours. Samples were taken at 0.5h, 1h, 1.5h and 2h, and an equal amount of artificial gastric fluid was supplemented. After 2 hours, the dialysis bag containing the nanoparticle solution was transferred to phosphate buffer solution (pH=6.8, simulated artificial intestinal fluid (SIF)). Samples were taken at 2.75h, 4h, 6h, 12h, 24h, 48h and 72h, and an equal amount of artificial intestinal fluid was supplemented. The HPLC instrument was used for dual wavelength detection (at 276nm and 303nm) to determine the concentration of drug aspirin and calculate the cumulative release content.

[0061] The results are as follows Figure 7 As shown, compared with simple sustained-release nanoparticles (AS-PLGA@NPs), AS-PLGA-EL@NPs have intestinal protective effects and can effectively inhibit the release of drugs in the gastric fluid environment, while being able to release rapidly in the intestinal environment to achieve directional delivery.

[0062] The morphological changes of AS-PLGA-EL@NPs nanoparticles before release, in gastric juice for 2 hours, and in artificial intestinal juice for 2 hours were photographed by scanning electron microscopy to observe whether the enteric polymer coating successfully adhered to the surface of the nanoparticles and had a protective effect on them. Figure 8 ), released in artificial gastric juice ( Fig. 9 ) showed that the nanoparticle structure was intact, while in artificial intestinal fluid ( Fig.10)The nanoparticle structure was obviously destroyed, which proved the good enteric effect of acrylic resin (Eudragit L100-55).

[0063] Experimental Example 5 Cytotoxicity Study

[0064] The CCK-8 method was used to evaluate the cytotoxicity of AS-PLGA-EL@NPs to Caco-2 cells (human intestinal epithelial cell line). Caco-2 cells were cultured at 1×10 4 The cells were seeded at a density of 100 μL in a 96-well plate and then incubated at 37°C in a 5% CO2 incubator for 24 hours. For concentration-dependent cytotoxicity experiments, the toxicity of different concentrations of AS-PLGA-EL@NP (0, 5, 10, 25, 50, 100, 200, 300 and 500 μg / mL) in Caco-2 intestinal cells was detected. The cells were incubated with different concentrations of aspirin-loaded nanoparticles for 24 hours, the medium was changed with a solution containing 90 μL of fresh medium and 10 μL of CCK-8, and incubated for another 3 hours at 37°C. The ELISA reader (LabServ, The absorbance of the solution was measured at 450 nm by Fisher Scientific and the cell viability was determined using the following formula:

[0065]

[0066] Among them, A s A is the absorbance of the experimental well; b is the absorbance of the blank well; A c The absorbance of the control well.

[0067] like Fig.11 As shown in the figure, AS-PLGA-EL@NPs did not inhibit cell growth within the concentration range of 50 μg / mL, indicating that the nanoparticles have good safety; after a concentration of 100 μg / mL, the growth of Caco-2 cells began to be gradually and significantly inhibited, and the cell survival rate decreased with the increase in the concentration of nanoparticles, indicating that the cell survival rate decreased in a concentration-dependent manner.

[0068] Experimental Example 6 Intestinal absorption study

[0069] The in vivo one-way intestinal perfusion model was used to study the in vivo intestinal absorption of free aspirin and AS-PLGA-EL@NPs in rats. The in vivo one-way intestinal perfusion model was established to study the in vivo intestinal absorption of aspirin raw materials and AS-PLGA-EL@NPs in rats. Before surgery, SD rats were fasted for 24 hours, but they were free to drink water. The rats were randomly divided into two groups (AS group and NPs group), a total of 6 groups, 3 rats in each group:

[0070] (1) AS-20: aspirin concentration of 20 μg / mL;

[0071] (2) AS-40: aspirin concentration of 40 μg / mL;

[0072] (3) AS-80: aspirin concentration of 80 μg / mL;

[0073] (4) NPs-20: AS-PLGA-EL@NPs containing aspirin at a concentration of 20 μg / mL;

[0074] (5) NPs-40: AS-PLGA-EL@NPs containing aspirin at a concentration of 40 μg / mL;

[0075] (6) NPs-80: AS-PLGA-EL@NPs contain aspirin at a concentration of 80 μg / mL;

[0076] Each group was perfused with Krebs-Ringer solution containing different concentrations of drug samples. Rats were anesthetized and fixed on a heated operating table to maintain the animals at 37°C. The abdomen was cut open, and the duodenum was incised and intubated and ligated at both ends. After flushing and perfusing the intestine with saline and Krebs-Ringer solution, the drug-containing Krebs-Ringer perfusion solution was replaced, and perfusion was performed at a flow rate of 0.2 mL / min and timing was performed. After 30 minutes of equilibrium, the effluent was collected, and the volume of liquid injected into the intestinal segment for 15 minutes and the effluent flowing out through the outlet for 15 minutes were recorded and weighed. The collected liquid was immediately frozen and stored at -20°C until analyzed by HPLC. The rats were killed, and the length and inner diameter of the duodenum of each rat were measured to calculate the surface area of ​​the perfused intestinal segment. In the experiment, only a single intestinal segment was used for each rat for a single test to ensure good absorption of the rat intestine.

[0077] This experiment used the mass method for volume correction to eliminate the possible impact of changes in the volume of the intestinal perfusion fluid caused by the intestinal absorption of water during the one-way intestinal perfusion test. eff ) and drug absorption rate constant (K a ) is calculated as follows:

[0078]

[0079] Among them, V in V is the volume of the instilled solution during the experimental period, mL; out The volume of the collected fluid during the experimental period, mL; M in is the mass of the infusion solution during the experimental period, g; M outis the mass of the collected liquid during the experimental period, g; ρ in is the density of the filling liquid, g / cm 3 ρ out is the density of the collected liquid, g / cm 3 ;Q in is the perfusion rate of intestinal perfusion fluid, mL / min; C in is the mass concentration of the drug in the infusion solution, μg / mL; C out is the mass concentration of the drug in the collected solution, μg / mL; r is the inner diameter of the perfused intestinal segment, cm; l is the length of the perfused intestinal segment, cm.

[0080] When P eff >1.2×10 -3 cm / min, intestinal absorption is considered good; when P eff <0.18×10 -3 cm / min, it can be considered that intestinal absorption is poor; when 0.18×10 -3 cm / min≤P eff ≤1.2×10 -3 cm / min, intestinal absorption is considered moderate.

[0081] The results are as follows Figure 12-14 As shown, the average P values ​​of different concentrations of AS groups (AS-20, AS-40 and AS-80) and NPs groups (NPs-20, NPs-40 and NPs-80) in duodenum eff The values ​​are all greater than 1.2×10 -3 cm / min, indicating that different concentrations of AS and NPs were well absorbed in the duodenal segment, and NPs had better absorption than the AS group. K a The mean values ​​of AS group and NPs were significantly higher than those of AS group, indicating that the nanoformulation prepared by the present invention is more conducive to intestinal absorption. eff and K a The increase in aspirin concentration indicates that the main way aspirin is transported into the body circulation may be passive transport, which is consistent with the existing studies that aspirin is generally considered to be passive diffusion. Therefore, in vivo intestinal absorption studies have shown that compared with aspirin API, NPs can be better absorbed in the duodenum and improve the bioavailability of the drug.

[0082] Experimental Example 7 In vivo pharmacokinetic study

[0083] Fifteen male SD rats (200±20g) were randomly divided into three groups (5 rats in each group): (1) AS group: 10 mg / kg AS by gavage; (2) NPs group: 10 mg / kg AS-PLGA-EL@NPs by gavage; (3) Tablet group: 10 mg / kg aspirin enteric-coated tablets (Bayer) by gavage. No food was allowed 12 hours before the experiment, but water was available. About 500 μL of blood was collected from the orbital vein 0-48 hours after administration and collected into a sodium heparin centrifuge tube. The blood samples were then centrifuged at 4000 rpm for 10 min, and the supernatant was collected for HPLC analysis.

[0084] The results are as follows Fig.15 As shown in Table 2, it can be seen from Table 2 that the AUC (0-∞) of AS-PLGA-EL@NPs is 203.481±86.052mg / L*h, which is higher than the AS group (179.61±23.89mg / L*h) and the tablet group (171.485±77.993mg / L*h). Compared with the AS group and the tablet group, the relative bioavailability of the NPs group was 1.133 and 1.186, respectively. The relative bioavailability is the ratio of the AUC (0-∞) of the two groups, which is consistent with the results of the in vivo intestinal absorption test, indicating that AS-PLGA-EL@NPs can improve bioavailability. Fig.15 As can be seen in the figure, the enteric coating on AS-PLGA-EL@NPs reduced the drug release in the stomach in the first 2 hours, resulting in lower blood drug concentrations than the AS group. In contrast, AS lacking an enteric coating was mainly absorbed in the stomach, indicating that enteric-coated nanoparticles greatly reduced gastric absorption, resulting in delayed Tmax and reduced Cmax, which is consistent with the drug release results ( Figure 7 ), the cumulative release rate of enteric coated nanoparticles was slower. In addition, compared with the AS group and tablet group, the t1 / 2α and t1 / 2β of AS-PLGA-EL@NPs were prolonged, indicating that the nanoparticles contained sustained-release material PLGA, and therefore had an obvious sustained-release effect. This indicates that the AS-PLGA-EL@NPs preparation prepared by the present invention has effective sustained-release properties and enteric solubility, thereby improving bioavailability.

[0085] Table 2 Pharmacokinetic parameters of AS, NPs and tablets after oral administration in rats

[0086] Grouping t1 / 2α(h) t1 / 2β(h) <![CDATA[AUC 0-∞ (mg / L*h)]]> <![CDATA[T max (h)]]> <![CDATA[C max (mg / L)]]> AS 1.521±0.742 2.368±0.47 179.61±23.89 0.9±0.224 26.050±7.038 NPs 2.648±0.57 64.882±9.912 203.481±86.052 2.2±1.095 23.843±7.155 tablet 1.896±0.567 2.538±1.167 171.485±77.993 1.85±1.41 20.730±8.650

Claims

1. A method for preparing an enteric-coated nanoparticle preparation, characterized in that: The method comprises the following steps: dissolving a drug active substance, PLGA and acrylic resin in an organic solvent at a mass ratio of 0.5-1.5:4.5-5.5:4.5-5.5 to obtain an organic phase; subsequently using a PVA solution as an aqueous phase, reacting the organic phase and the aqueous phase through a microfluidic device, and finally removing the organic solvent, centrifuging, and obtaining an enteric-coated nanoparticle preparation.

2. The method for preparing the enteric-coated nanoparticle preparation according to claim 1, characterized in that: The active pharmaceutical ingredient is aspirin, metformin hydrochloride, risedronate sodium, dexlansoprazole, mesalazine, albendazole, omeprazole, mycophenolate sodium or methotrexate.

3. The method for preparing the enteric-coated nanoparticle preparation according to claim 1, characterized in that: The organic solvent is anhydrous ethanol and / or ethyl acetate.

4. The method for preparing the enteric-coated nanoparticle preparation according to claim 1, characterized in that: The concentration of the PVA solution is 0.5-1.5wt%, and the pH value is 3-5.

5. The method for preparing the enteric-coated nanoparticle preparation according to claim 1, characterized in that: The volume ratio of the organic phase to the aqueous phase is 0.5-1.5:3.5-4.

5.

6. The method for preparing the enteric-coated nanoparticle preparation according to claim 1, characterized in that: The flow rate ratio of the organic phase to the aqueous phase is 0.5-1.5:3-5, and the total flow rate of the organic phase and the aqueous phase is 4-6 mL / min.

7. The method for preparing the enteric-coated nanoparticle preparation according to claim 1, characterized in that: The centrifugation is divided into two stages, specifically: first, low-speed centrifugation at 900-1100 rpm for 8-12 min, and then high-speed centrifugation at 13000-17000 rpm for 30-60 min.

8. An enteric-coated nanoparticle preparation, characterized in that: The method is prepared by the preparation method according to any one of claims 1 to 7.

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