Preparation process of artemisinin-metal organic framework composite bone hydatid-resistant sustained release microspheres

Abstract

The invention relates to a preparation process of an artemisinin-metal organic framework composite bone hydatid resistant sustained release microsphere, which comprises the four steps of material preparation, artemisinin-metal organic framework compound preparation, sustained release microsphere preparation and post-treatment and characterization, the preparation process of the artemisinin-metal organic framework composite bone hydatid resistant sustained release microsphere comprises the following steps: selecting a UI0-66 material; according to the artemisinin emulsion, the structure can be kept intact for 28 days under the physiological condition, TPGS is adopted as a compound stabilizer, the metal organic framework is pretreated, and TPGS is added into a water phase and an oil phase in the emulsification stage, so that the molecular diffusion coefficient of artemisinin is reduced to 1 / 5, the binding capacity of the metal organic framework and artemisinin is improved by 2.3-2.5 times, the cell intake is increased, and the stability of the artemisinin emulsion is improved. The TPGS is preferentially explained in an enzymolysis environment, a time-dependent release channel is formed, and the stability problem of the artemisinin is solved.

Description

Technical Field

[0001] The present invention relates to a preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus bone slow-release microspheres. Background Art

[0002] Artemisinin-metal organic framework (MOF) composite anti-echinococcus granulosus bone slow-release microspheres are a drug delivery system that combines the anti-parasitic activity of artemisinin and the high drug loading and controlled release characteristics of metal organic framework materials, and are specifically used for the treatment of echinococcus granulosus bone disease.

[0003] In the existing preparation process, the degradation rate of artemisinin during the preparation process can reach 15-25%, and its solubility in organic solvents is low. The existing metal organic frameworks generally use ZIF-8 or MIL-100 materials, and the collapse rate in PBS solution is greater than 60% after 72 hours, resulting in unsatisfactory effects. Summary of the Invention

[0004] The technical problem to be solved by the present invention is: in order to overcome the above technical problems, the present invention provides a preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus bone slow-release microspheres.

[0005] The technical solution adopted by the present invention to solve its technical problems is: a preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus bone slow-release microspheres, comprising the following steps:

[0006] a. Material preparation: The materials include artemisinin, metal organic framework materials, organic solvents, polymer matrices and surfactants;

[0007] b. Preparation of artemisinin-metal organic framework composite: The steps include metal organic framework synthesis, drug loading and drying treatment;

[0008] c. Preparation of slow-release microspheres: The steps include oil phase preparation, water phase preparation, primary emulsification, secondary emulsification, solvent evaporation, collection and washing, and freeze-drying;

[0009] d. Post-treatment and characterization: The steps include screening, sterilization and characterization.

[0010] Preferably, in step a, the purity of artemisinin ≥ 98%, the metal organic framework material is UI0-66, the organic solvents are DMF and methanol, the polymer matrices are PLGA and chitosan, and the surfactants are polyvinyl alcohol and poloxamer.

[0011] Preferably, in step b, the metal-organic framework is synthesized by solvothermal method or room temperature synthesis method to prepare the selected metal-organic framework; for drug loading, the metal-organic framework is first immersed in a 0.05% TPGS ethanol solution, vacuum dried, then the treated metal-organic framework is soaked in artemisinin solution, and then the metal-organic framework and artemisinin are co-dissolved in an organic solvent and the solvent is evaporated; the drying treatment is to dry under vacuum conditions for 24-48 hours to remove the residual solvent.

[0012] Preferably, in step c, for the oil phase preparation, the artemisinin-metal-organic framework complex is dispersed in a dichloromethane solution of PLGA, and a 0.02% TPGS-ethyl acetate solution is added thereto; for the water phase preparation, a 1-3% aqueous PVA solution is prepared and a 0.05% TPGS is added thereto; for the primary emulsification, the oil phase is added to the water phase and then high-speed homogenization is carried out; for the secondary emulsification, the primary emulsion is added to a larger volume of PVA solution and then medium-speed stirring is carried out; for the solvent evaporation, the organic solvent is completely evaporated by continuous stirring for 4-6 hours; for the collection and washing, the microspheres are collected by centrifugation and then washed 3 times with deionized water; for the freeze-drying, it is carried out at a temperature of -50 °C for 24-48 hours.

[0013] Preferably, in step d, for the screening, microspheres with a particle size range of 50-200 μm are obtained by sieving; for the sterilization, it is sterilized by γ-ray or ethylene oxide; for the characterization, the particle size distribution is measured by a laser particle size analyzer, the microscopic morphology of the material surface is observed and analyzed by using a scanning electron microscope, the drug loading amount and encapsulation efficiency are determined by high performance liquid chromatography technology, and the in vitro release performance is measured in a PBS solution with a pH value of 7.4.

[0014] Preferably, the concentration of the artemisinin solution is 1-5 mg / ml.

[0015] Preferably, the mass-volume percentage concentration of dichloromethane is 5-10% w / v, the speed of high-speed homogenization is 10000-15000 rpm, the time is 2-5 minutes, and the speed of medium-speed stirring is 500-800 rpm.

[0016] Preferably, the temperature of the PBS solution is 37 °C.

[0017] Preferably, the drug loading amount ≥ 5% w / w, the encapsulation efficiency ≥ 80%, the cumulative in vitro release in 72 hours is 40-60%, and the release in 21 days ≥ 90%.

[0018] Preferably, in step b, the ratio of artemisinin to the metal-organic framework is 1:5 to 1:10.

[0019] The beneficial effects of the present invention are as follows. For the preparation process of the artemisinin-metal organic framework composite anti-echinococcus of bone sustained-release microspheres, the UI0-66 material is selected, which can maintain the structural integrity for 28 days under physiological conditions. TPGS is used as a composite stabilizer to pretreat the metal organic framework and is added to the aqueous phase and oil phase respectively during the emulsification stage, reducing the diffusion coefficient of artemisinin molecules to 1 / 5, increasing the binding energy between the metal organic framework and artemisinin by 2.3 - 2.5 times, enhancing the cell uptake amount, and preferentially degrading TPGS in the enzymatic hydrolysis environment to form a time-dependent release channel, thus solving the stability problem of artemisinin. Detailed implementation mode

[0020] A preparation process of artemisinin-metal organic framework composite anti-echinococcus of bone sustained-release microspheres includes the following steps:

[0021] a. Material preparation: The materials include artemisinin, metal organic framework materials, organic solvents, polymer matrices, and surfactants;

[0022] b. Preparation of artemisinin-metal organic framework composite: The steps include synthesis of metal organic framework, drug loading, and drying treatment;

[0023] c. Preparation of sustained-release microspheres: The steps include preparation of oil phase, preparation of aqueous phase, primary emulsification, secondary emulsification, solvent evaporation, collection and washing, and freeze-drying;

[0024] d. Post-treatment and characterization: The steps include screening, sterilization, and characterization.

[0025] Preferably, in step a, the purity of artemisinin ≥ 98%, the material of the metal organic framework is UI0-66, the organic solvents are DMF and methanol, the polymer matrices are PLGA and chitosan, and the surfactants are polyvinyl alcohol and poloxamer.

[0026] Here, since the purity of artemisinin ≥ 98%, it needs to be activated, and the activation treatment includes solvent exchange and molecular dispersion.

[0027] For solvent exchange, artemisinin is first dissolved in a 50 mg / ml methanol solution, and then replaced with DMF by gradient replacement. Finally, the concentration of DMF is maintained at 80 mg / ml. During the gradient replacement, the volume ratio of methanol to DMF ranges from 3:1 to 1:1, and then from 1:1 to 1:3.

[0028] For molecular dispersion, 0.05% of TPGS is added, and ultrasonic treatment is performed at a frequency of 40 KHz and a power of 300 W for 15 min.

[0029] Preferably, in step b, the metal-organic framework is synthesized by solvothermal method or room temperature synthesis method to prepare the selected metal-organic framework; for drug loading, the metal-organic framework is first impregnated in a 0.05% TPGS ethanol solution, vacuum dried, then the treated metal-organic framework is immersed in artemisinin solution, and then the metal-organic framework and artemisinin are co-dissolved in an organic solvent and the solvent is evaporated; the drying treatment is to dry under vacuum conditions for 24-48 hours to remove the residual solvent.

[0030] The metal-organic framework is synthesized by solvothermal method, and the reagents include zirconium tetrachloride, terephthalic acid, DMF, acetic acid and methanol; the equipment includes a polytetrafluoroethylene-lined high-pressure reactor, a forced air drying oven, a centrifuge, a vacuum drying oven and an ultrasonic cleaner.

[0031] The synthesis steps include: precursor solution preparation, solvothermal reaction, product separation and activation treatment.

[0032] Precursor solution preparation: Weigh 0.233 h zirconium tetrachloride and 0.166 g terephthalic acid and place them in a beaker, where the purity of zirconium tetrachloride and terephthalic acid is greater than 99.9%, then add 40 ml DMF and 1.5 ml acetic acid, and ultrasonically treat for 10 min until completely dissolved;

[0033] Solvothermal reaction: Transfer the dissolved mixture to a 100 ml polytetrafluoroethylene lining, seal the reactor, place it in an oven, and react at 120 °C for 24 hours;

[0034] Product separation: Naturally cool to room temperature, collect the white precipitate by centrifugation, wash it 3 times with DMF and methanol solutions respectively, discard the supernatant after each centrifugation, where the DMF and methanol solutions for each wash are both 20 ml;

[0035] Activation treatment: Immerse the product in 50 fresh methanol, oscillate at 37 °C for 12 h, and then dry it to constant weight under vacuum conditions at a temperature of 80 °C and a pressure of 10 Pa for 12 h to obtain activated UiO-66.

[0036] Here, the filling amount of the reactor needs to be less than 80%, and it should be cooled to below 60 °C before opening.

[0037] The zirconium-containing waste liquid needs to be adjusted to a pH value greater than 10 with sodium hydroxide and then precipitated for recovery.

[0038] Through the above process, UiO-66 with high crystallinity and high thermal stability can be obtained, which is suitable for drug loading. By HPLC detection, the loading amount of artemisinin on UiO-66 synthesized by this method can reach 12-15% (w / w), and the RSD between batches is <3%.

[0039] The metal-organic framework was synthesized by the room-temperature synthesis method. The reagents included zirconium tetrachloride, terephthalic acid, DMF, formic acid, and methanol. The equipment included an ultrasonic cleaner, a magnetic stirrer, a centrifuge, a vacuum drying oven, and a pH meter.

[0040] The synthesis steps of the room-temperature synthesis method included precursor solution preparation, room-temperature reaction, product purification, and drying activation.

[0041] Precursor solution preparation: 0.233 g of zirconium tetrachloride was dissolved in 20 ml of DMF, and then ultrasonic treatment was carried out for 10 min. 0.166 g of terephthalic acid and 1.15 ml of formic acid were added and stirred until clear. Among them, the purity of zirconium tetrachloride and terephthalic acid was greater than 99.9%;

[0042] Room-temperature reaction: The clear mixture was placed in an environment of 25 °C and stirred magnetically for 24 h. During the stirring process, the pH value was adjusted with formic acid, and the pH value was maintained between 2.5 and 3.0;

[0043] Product purification: The white precipitate was collected by centrifugation, and then washed 3 times with 20 ml of DMF each time, mainly to remove the unreacted ligands. It was washed 3 times with 20 ml of methanol each time, mainly to displace the pore solvent, and then soaked in a 50% methanol solution for 12 h, mainly to activate the pores;

[0044] Drying activation: It was dried under vacuum conditions at a temperature of 60 °C and a pressure of 10 Pa for 12 h to obtain activated UiO-66.

[0045] In this way, due to the slow room-temperature nucleation rate, the phenomenon of insufficient crystallinity would occur. Generally, it was solved by adding 5% of the seed crystals for the pre-synthesis of UiO-66 nanocrystals.

[0046] Using the room-temperature method, compared with the solvothermal method, the main advantage was energy saving and it was suitable for the preparation of heat-sensitive drug carriers. The actual selection of the two methods needed to be comprehensively determined according to the target carrier.

[0047] In drug loading, it was achieved by a step-by-step method.

[0048] First, the pretreatment of the metal-organic framework was carried out, that is, TPGS modification, which could reduce the molecular diffusion coefficient of artemisinin and improve the stability of artemisinin, and then artemisinin loading was carried out.

[0049] In the pretreatment of the metal-organic framework, the mass concentration ratio of UiO-66 to the TPGS ethanol solution was 1:20. The mixed solution was oscillated at a constant temperature of 37 °C for 6 h, and then vacuum dried to constant weight;

[0050] Artemisinin loading is mainly accomplished through primary loading and secondary coating.

[0051] Primary loading: Take an artemisinin DMF solution with a concentration of 80 mg / ml, mix it with a mixed solution of TPGS and UiO-66 at a mass ratio of 1:8, and then perform supercritical treatment at a temperature of 40 °C and a pressure of 12 MPa for 3 h.

[0052] Secondary coating: Add a 5% chitosan acetic acid solution and perform rotary evaporation at a temperature of 45 °C until the solvent residue is less than 1%.

[0053] This drug loading method has a drug loading efficiency 35% higher than the traditional method, with the batch-to-batch difference controlled within ±5%. Under the conditions of an accelerated test at a temperature of 40 °C and a humidity of 75%, it shows that the degradation rate is <7% in 3 months. Moreover, in the rabbit bone hydatid model, the duration of drug concentration at the lesion is 4.2 times that of the ordinary preparation.

[0054] Preferably, in step c, for the oil phase preparation, disperse the artemisinin-metal organic framework complex in a dichloromethane solution of PLGA and add a 0.02% TPGS-ethyl acetate solution thereto; for the water phase preparation, prepare a 1-3% aqueous PVA solution and add 0.05% TPGS thereto; for the primary emulsification, add the oil phase to the water phase and then perform high-speed homogenization; for the secondary emulsification, add the primary emulsion to a larger volume of PVA solution and then perform medium-speed stirring; for the solvent evaporation, make the organic solvent evaporate completely by continuously stirring for 4-6 hours; for the collection and washing, collect the microspheres by centrifugation and then wash them 3 times with deionized water; for the freeze-drying, perform freeze-drying at a temperature of -50 °C for 24-48 hours.

[0055] In the oil phase preparation process, select a 50:50 PLGA and an 8% dichloromethane solution, perform pre-filtration to remove insoluble substances. For the dispersion of the artemisinin-metal organic framework complex, first break the agglomeration by ultrasonic pretreatment, then add it to the PLGA solution at a ratio of 1:8, and form a uniform suspension by vortex oscillation. In the step of adding the TPGS-ethyl acetate solution, 0.02% TPGS needs to be pre-dissolved in ethyl acetate and then slowly added dropwise to the oil phase at a dropping rate of 0.5 ml / min, and then use magnetic stirring to avoid excessive local concentration.

[0056] In the water phase preparation process, the basic solution is a 2% PVA solution. Here, 0.05% TPGS needs to be preheated to 60 °C for solubilization assistance, with the pH value of 6.8 ± 0.2, and filter through a 0.45 μm nylon membrane to avoid particulate contamination.

[0057] Here, the interfacial tension between the water phase and the oil phase needs to be ≤5 mN / m.

[0058] In the primary emulsification process, a shear homogenization scheme is adopted, which is to slowly inject the oil phase into the water phase along the wall, with the volume ratio of the oil phase to the water phase being 1:3, and then homogenized by a homogenizer.

[0059] In the secondary emulsification process, gradient dilution method was used, the external aqueous phase composition was 1% PVA and 0.1% poloxamer, and the temperature was maintained at 20°C.

[0060] During the solvent evaporation, continuous stirring is divided into three steps. The first step is to stir at 300 rpm at 25°C for 2 hours to remove 80% of DCM; the second step is to stir at 200 rpm at 30°C for 1-2 hours, at which time the residual DCM is less than 100 ppm; the third step is to stir at 100 rpm at 35°C for 1-2 hours, until the solution residue is less than 50 ppm.

[0061] Here, the DCM content can be monitored every 30 min by gas chromatography.

[0062] During freeze-drying, a gradient freezing method is used, first equilibrated at 4°C for 30 minutes, then at -20°C for 2 hours, and finally at -50°C. 5% mannitol can be added here as a cryoprotectant to achieve ice crystal control.

[0063] In the step c method, the gradient addition of TPGS can achieve interfacial stability and provide dual protection for the oil phase and the water phase.

[0064] Preferably, in step d, screening is performed by sieving to obtain microspheres with a particle size range of 50-200 μm; sterilization is performed by gamma ray or ethylene oxide sterilization; characterization is performed by measuring the particle size distribution by a laser particle size analyzer, observing and analyzing the microscopic morphology of the material surface using a scanning electron microscope, determining the drug loading and encapsulation efficiency by high performance liquid chromatography, and measuring the in vitro release performance in a PBS solution with a pH value of 7.4.

[0065] Here, a graded screening system is used to achieve screening. The particles are first screened through an 80-mesh screen, then through a 120-mesh screen, and finally through a 270-mesh screen. The three levels are connected in series to improve the screening effect and ensure the particle size of the microspheres.

[0066] Image analyzer is used here for real-time monitoring.

[0067] The gamma ray sterilization scheme is: dose 25kGy, temperature <40℃,

[0068] Ethylene oxide sterilization plan: gas concentration is 600 mg / L, temperature is 55°C, humidity is 65%, and desorption time is 48 hours.

[0069] The sterilization protocol adopted here needs to be selected according to the actual product characteristics. If the product is heat-sensitive, the γ-ray sterilization protocol is adopted and achieved through dose verification. If the product contains metal MOF, the ethylene oxide sterilization protocol is adopted and achieved through residual detection.

[0070] In step d, by means of graded vibration screening, the yield can be increased to over 85%. The dual-mode sterilization verification is adopted to ensure sterility without damaging the drug, and multi-dimensional characterization is carried out to comprehensively monitor the key quality attributes.

[0071] Preferably, the concentration of the artemisinin solution is 1 - 5 mg / ml.

[0072] Preferably, the mass-volume percentage concentration of dichloromethane is 5 - 10% w / v, the speed of high-speed homogenization is 10000 - 15000 rpm, the time is 2 - 5 minutes, and the speed of medium-speed stirring is 500 - 800 rpm.

[0073] Preferably, the temperature of the PBS solution is 37°C.

[0074] Preferably, the drug loading amount ≥ 5% w / w, the encapsulation efficiency ≥ 80%, the cumulative in vitro release in 72 hours is 40 - 60%, and the release in 21 days ≥ 90%.

[0075] Preferably, in step b, the ratio of artemisinin to the metal-organic framework is 1:5 to 1:10.

[0076] DMF is N,N-dimethylformamide. N,N-dimethylformamide is an important organic solvent and synthetic intermediate. It is a colorless and transparent liquid, miscible with water, ethanol, ether, chloroform, acetone, etc., stable at room temperature, with a relatively high boiling point and low vapor pressure, so it is commonly used as a solvent.

[0077] PLGA is poly(lactic-co-glycolic acid), randomly polymerized from two monomers - lactic acid and glycolic acid. It is a biodegradable functional polymer organic compound with good biocompatibility, non-toxicity, and good properties of forming capsules and films.

[0078] PLGA is a copolymer without functional side groups polymerized from lactic acid and glycolic acid. It is an important class of biomedical polymer materials. Compared with PLA, the degradation time of the polymer can be controlled according to the GA content. The material is soft and elastic, and different types of PLGA can be prepared with different monomer ratios. For example, PLGA75:25 indicates that the polymer is composed of 75% lactic acid and 25% glycolic acid. The degradation degree of PLGA varies with the monomer ratio. The larger the glycolide ratio, the easier it is to degrade, and the white powder dissolves faster.

[0079] PBS solution, whose full name is Phosphate Buffered Saline, is a buffer solution widely used in biology. The main components of PBS solution include sodium chloride, potassium chloride and phosphate.

[0080] TPGS is vitamin E polyethylene glycol succinate.

[0081] TPGS is a water-soluble vitamin E with water-soluble characteristics. TPGS is an excellent emulsifier that can improve the absorption and utilization of ingredients in the human body in health foods, encapsulate water-soluble and fat-soluble functional ingredients, and the vitamin E functional ingredient in it is more easily absorbed by the human body, which can greatly improve the bioavailability of vitamin E.

[0082] Compared with the prior art, in the preparation process of the artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres, the UI0-66 material is selected, which can maintain the structural integrity for 28 days under physiological conditions, and TPGS is used as a composite stabilizer to pretreat the metal organic framework and is added to the aqueous phase and oil phase respectively in the emulsification stage, so that the diffusion coefficient of artemisinin molecules is reduced to 1 / 5, and the binding energy between the metal organic framework and artemisinin is increased by 2.3 - 2.5 times, enhancing the cell uptake amount. TPGS is preferentially degraded in the enzymatic hydrolysis environment to form a time-dependent release channel, solving the stability problem of artemisinin.

[0083] Inspired by the ideal embodiments of the present invention described above, through the above description, relevant staff can completely make various changes and modifications without departing from the technical idea of the present invention. The technical scope of the present invention is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres, characterized in that, It includes the following steps: a. Material preparation: The materials include artemisinin, metal-organic framework material, organic solvent, polymer matrix, and surfactant; b. Preparation of artemisinin-metal-organic framework composite: The steps include metal-organic framework synthesis, drug loading, and drying treatment; c. Preparation of sustained-release microspheres: The steps include oil phase preparation, water phase preparation, primary emulsification, secondary emulsification, solvent evaporation, collection and washing, and freeze-drying; d. Post-treatment and characterization: The steps include sieving, sterilization, and characterization.

2. The preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres according to claim 1, characterized in that, In step a, the purity of artemisinin is ≥98%, the material of the metal-organic framework is UI0-66, the organic solvents are DMF and methanol, the polymer matrix is PLGA and chitosan, and the surfactants are polyvinyl alcohol and poloxamer.

3. The preparation process of artemisinin-metal organic framework composite anti-echinococcus of bone sustained-release microspheres according to claim 1, characterized in that, In step b, the metal-organic framework is synthesized by solvothermal method or room temperature synthesis method to prepare the selected metal-organic framework; for drug loading, the metal-organic framework is first impregnated in a 0.05% TPGS ethanol solution, vacuum dried, then the treated metal-organic framework is soaked in the artemisinin solution, and then the metal-organic framework and artemisinin are co-dissolved in the organic solvent and the solvent is evaporated; the drying treatment is to dry under vacuum conditions for 24-48 hours to remove the residual solvent.

4. The preparation process of artemisinin-metal organic framework composite anti-echinococcus of bone sustained-release microspheres according to claim 1, characterized in that, In step c, for oil phase preparation, the artemisinin-metal-organic framework composite is dispersed in a dichloromethane solution of PLGA, and a 0.02% TPGS-ethyl acetate solution is added thereto; for water phase preparation, a 1-3% PVA aqueous solution is prepared and a 0.05% TPGS is added thereto; for primary emulsification, the oil phase is added to the water phase and then high-speed homogenization is carried out; for secondary emulsification, the primary emulsion is added to a larger volume of PVA solution and then medium-speed stirring is carried out; for solvent evaporation, the organic solvent is completely evaporated by continuous stirring for 4-6 hours; for collection and washing, the microspheres are collected by centrifugation and then washed 3 times with deionized water; for freeze-drying, it is carried out at a temperature of -50°C for 24-48 hours.

5. The preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres as described in claim 1, characterized in that, In step d, sieving is to obtain microspheres with a particle size range of 50-200 μm by sieving; sterilization is carried out by γ-ray or ethylene oxide sterilization; characterization is to measure the particle size distribution by a laser particle size analyzer, observe and analyze the microscopic morphology of the material surface using a scanning electron microscope, determine the drug loading and encapsulation efficiency by high performance liquid chromatography technology, and measure the in vitro release performance in a PBS solution with a pH value of 7.

4.

6. The preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres according to claim 3, characterized in that, The concentration of the artemisinin solution is 1-5 mg / ml.

7. The preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres according to claim 4, characterized in that, The mass-volume percentage concentration of dichloromethane is 5-10% w / v, the speed of high-speed homogenization is 10000-15000 rpm, the time is 2-5 minutes, and the speed of medium-speed stirring is 500-800 rpm.

8. The preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres according to claim 5, characterized in that, The temperature of the PBS solution is 37°C.

9. The preparation process of the artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres according to claim 5, characterized in that, The drug loading is ≥5% w / w, the encapsulation efficiency is ≥80%, the cumulative in vitro release in 72 hours is 40-60%, and the release in 21 days is ≥90%.

10. The preparation process of artemisinin-metal organic framework composite anti-echinococcus granulosus sustained-release microspheres according to claim 1, characterized in that, In step b, the ratio of artemisinin to the metal-organic framework is 1:5 to 1:10.