Erythropalum scandens compound granules for treating gout and preparation method thereof

Abstract

The invention discloses compound granules of erythropalum scandens for treating gout and a preparation method of the compound granules, and relates to the technical field of traditional Chinese medicine preparations. The compound granules of erythropalum scandens for treating gout are prepared from a drug-loaded magnetic Fe-based MOFs (Metal-Organic Frameworks) system, drug-loaded magnetic artemisinin liposome, soluble starch, dextrin and microcrystalline cellulose, the drug-loaded magnetic Fe-based MOFs system is prepared from catechin functionalized Fe3O4-MIL-100 (Fe), an erythropalum scandens extract and urease, wherein the catechin functionalized Fe3O4-MIL-100 (Fe) is prepared from catechin functionalized The drug-loaded magnetic artemisinin liposome is prepared from artemisinin, soya bean lecithin, cholesterol, a traditional Chinese medicine extracting solution and nano-enzyme, the surface of the drug-loaded magnetic Fe-based MOFs system is modified with the drug-loaded magnetic artemisinin liposome, so that the drug loading capacity and the drug loading stability are remarkably improved, and the drug-loaded magnetic Fe-based MOFs liposome has a strong magnetic targeting effect, accurately acts on an inflammation part, improves the bioavailability of medicinal components and effectively improves the treatment effective rate of gout.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine preparations, and specifically relates to a compound granule of Caulis Scutellariae for treating gout and a preparation method thereof. Background Art

[0002] Gouty arthritis, abbreviated as gout, is a metabolic rheumatic disease. It is mainly caused by purine metabolism disorders, which in turn causes increased blood uric acid and deposition of sodium urate microcrystals in joints, tissues and other parts, causing inflammatory symptoms such as acute joint swelling and pain. Gout often manifests as hyperuricemia in the early stages of the disease, and is often asymptomatic. If not treated in time, the disease will further develop, and recurrent gouty arthritis may occur, causing joint deformities and dysfunctions, and even disability. As uric acid continues to rise, it may also cause complications such as hypertension, diabetes, dyslipidemia, and urinary stones.

[0003] The natural course of gout is usually divided into acute attack phase, remission phase and chronic phase. The main goal of clinical treatment of gout is to relieve clinical symptoms, prevent the occurrence of complications, and reduce the recurrence rate of the disease as much as possible. Currently, three types of drugs are mainly used for treatment, namely non-steroidal anti-inflammatory drugs, colchicine and glucocorticoids. However, after discontinuation of the drug, the disease often recurs, aggravating the patient's pain and reducing the patient's quality of life. In addition, long-term use of Western medicine can easily cause adverse reactions to the patient's gastrointestinal tract, liver and kidney function and blood system. Clinical drug use has certain limitations. Traditional Chinese medicine is widely favored for its advantages such as low price, specific effect and few side effects. It can also improve the comprehensive treatment effect and has become an urgent clinical need.

[0004] The existing technology currently has the following problems:

[0005] Despite the development and use of nanocarriers, the effectiveness of traditional Chinese medicine in treating gout is still low, and its drug-carrying capacity is average, which cannot achieve better therapeutic effects. Summary of the invention

[0006] In view of the above situation, in order to overcome the defects of the prior art, the present invention proposes a compound granule of Artemisia selengensis for treating gout, comprising the following components in parts by weight: 5-10 parts of drug-loaded magnetic Fe-based MOFs system, 20-30 parts of drug-loaded magnetic artemisinin liposomes, 50-60 parts of soluble starch, 30-40 parts of dextrin, and 15-25 parts of microcrystalline cellulose.

[0007] The drug-loaded magnetic Fe-based MOFs system comprises the following components in parts by weight: 9-15 parts of catechin-functionalized Fe3O4-MIL-100 (Fe), 60-90 parts of Caulis Atractylodes extract, and 60-90 parts of urease.

[0008] The drug-loaded magnetic artemisinin liposome comprises the following components in parts by weight: 12-15 parts of artemisinin, 60-80 parts of soybean lecithin, 10-20 parts of cholesterol, 5-10 parts of traditional Chinese medicine extract, and 5-8 parts of nanozyme.

[0009] The raw materials of the traditional Chinese medicine extract include the following components in parts by weight: 2-3 parts of Smilax glabra, 2-3 parts of Phellodendron chinense, 2-3 parts of Scutellaria baicalensis, 2-3 parts of Radix Dioscoreae, 2-3 parts of Paeonia lactiflora, and 2-3 parts of Licorice.

[0010] The preparation method of the drug-loaded magnetic Fe-based MOFs system specifically comprises the following steps:

[0011] (1) Pour 10.0 g of crude powder of the medicinal material of the red vine that has been dried to a constant weight into 300 mL of an ethanol solution with a mass fraction of 60%, then add 2-4% of cellulase, adjust the pH to 5.0-6.0 with acetate buffer, perform enzymolysis for 40-50 min, and perform enzymolysis at a temperature of 40-50°C. After enzymolysis, boil the mixture in boiling water for 5 min to inactivate the enzyme, then perform ultrasonic treatment for 20-30 min at an ultrasonic power of 600-800 W, filter, concentrate, and freeze-dry. The alcohol extract of the red vine contains flavonoids, phenols, alkaloids, triterpenes, and coumarin compounds, and has a strong anti-inflammatory effect. It can not only inhibit the activity of xanthine oxidase and reduce serum uric acid content, but also has a protective effect on the soothing function of the vascular endothelium, and can relieve the degree of toe swelling, thereby obtaining a red vine extract;

[0012] (2) Add catechin powder and 0.04g sodium hydroxide solid to 15-20mL pure water, then add 0.15g ferrous sulfate powder, stir evenly, use 10-20% mass fraction sulfuric acid solution to adjust the pH to 11.0, then transfer to a 50mL autoclave, seal and keep at 150-160°C for 6-8h, cool to room temperature, collect black precipitate with a magnet, wash with ultrapure water 3-5 times, and dry in an oven at 50°C for 12h. Catechins are attached to the surface of Fe3O4 nanoparticles through functionalization, have strong magnetism and adsorption, enhance the stability and bioavailability of nanoparticles, and specifically enhance their pharmacological effects, thereby obtaining catechin functionalized Fe3O4 nanoparticles;

[0013] (3) 1.0-2.0 g of the catechin-functionalized Fe3O4 nanoparticles described in step (2) and 1.5 g of ferrous chloride tetrahydrate are dissolved in 40-45 mL of deionized water as solution A, and 0.7 g of trimesic acid solid and 0.4 g of sodium hydroxide solid are weighed and dissolved in 15 mL of deionized water as solution B, and then solution B is slowly dripped into solution A, stirred at room temperature for 12 h, magnetically separated, washed with deionized water and anhydrous ethanol solution for 3-5 times in sequence, and vacuum dried at 60° C. The magnetic nanoparticles are combined with Fe-based MOFs. The synergistic effect of the two has higher biosafety and higher drug loading capacity, and also has the advantage of targeted release to the lesion area, thereby obtaining catechin-functionalized Fe3O4-MIL-100 (Fe);

[0014] (4) Dissolve 3.0-5.0 mg of the catechin functionalized Fe3O4-MIL-100 (Fe) described in step (3) in 500 mL of water, add 20.0-30.0 mg of the Caulis Aristolochiae extract described in step (1) and 20.0-30.0 mg of urease, wherein urease can directly act on uric acid to promote its metabolism, and can also act on the formed uric acid stones to promote their dissolution, thereby enhancing the therapeutic effect of the Caulis Aristolochiae extract on gout. After stirring evenly, transfer to a constant temperature shaker for drug loading culture. The catechin functionalized Fe3O4-MIL-100 (Fe) carrier has a high porosity and a large specific surface area. The main active substances, Caulis Aristolochiae extract and urease, can be loaded in the internal pores of MOFs through shaker culture, thereby achieving sustained release of the drug, improving bioavailability and therapeutic effect, and then freeze-drying to obtain a drug-loaded magnetic Fe-based MOFs system;

[0015] Preferably, in step (2), the amount of catechin added is 0.2 g, and catechin can relieve gout by inhibiting the activation of NLRP3 inflammasome;

[0016] Preferably, in step (4), during the shaking incubation process, the load temperature is controlled at 25-35°C, the load speed is 100-200 rpm, and the load time is 60-90 min. The shaking incubation promotes the mixing of the drug and the carrier, allowing the drug to better enter the internal pores of the catechin-functionalized Fe3O4-MIL-100 (Fe), thereby increasing the drug loading and stability.

[0017] The present invention also provides a method for preparing compound granules of Rhizoma Coptidis for treating gout, which specifically comprises the following steps:

[0018] S1. Grind Smilax glabra, Phellodendron amurense, Scutellaria baicalensis, Radix Dioscoreae, Paeonia lactiflora and Licorice, pass through a 60-80 mesh sieve, mix the Chinese medicine powders evenly, add 200-300 mL of distilled water and boil for 2-3 times, filter while hot, combine the filtrates, and then concentrate to 1 / 5 to 1 / 4 of the original volume of the filtrate, use other Chinese medicines as secondary pharmacodynamic substances, have multi-target and multi-pathway therapeutic characteristics, down-regulate the expression of TLR4, MyD88, and NF-κB, inhibit the signal transduction carried out by them, reduce the release of factors such as TNF-α, IL-1β, IL-8, and relieve gout inflammatory response, and obtain a Chinese medicine extract;

[0019] S2. Dissolve 1081.0 mg of ferric chloride hexahydrate and 471.0 mg of sodium citrate powder in 40 mL of diethylene glycol solution, react at 70-80°C for 1-2 h, add 1314.0 mg of anhydrous sodium acetate powder, react at 50-60°C for 1 h, then transfer to a hydrothermal reactor, react at 180-200°C for 6-8 h, cool to room temperature, centrifuge, collect the black product, wash with anhydrous ethanol solution for 3-5 times, and vacuum dry. Nanozyme, as an artificial enzyme, has the advantages of magnetism, good stability, and good biosafety, which makes up for the defects of urease, and obtains nanozyme;

[0020] S3, pour 60.0-80.0mg soy lecithin, 10.0-20.0mg cholesterol, and artemisinin into 30-50mL anhydrous ethanol solution, then add 5-10mL of the traditional Chinese medicine extract described in step S1 and 5.0-8.0mg of the nanozyme described in step S2, stir magnetically until completely dissolved, and use a microsyringe to slowly and uniformly inject the mixed solution into 20mL of normal saline, maintain a constant temperature of 45°C, and continuously stir magnetically to remove ethanol to fully hydrate it, then use a rotary evaporator to evaporate the ethanol under reduced pressure at 35°C, and ultrasonically treat the obtained liposome suspension in an ice bath, the ultrasonic time is 2-3min, and the ultrasonic power is 180-220W. By encapsulating the compound traditional Chinese medicine and nanozyme of the effective substance in the artemisinin liposome, the artemisinin liposome is endowed with a certain magnetism, which can target the inflammatory site, improve the bioavailability of the effective substance, and promote the aggregation of anti-inflammatory macrophages at the targeted site, so as to obtain drug-loaded magnetic artemisinin liposome;

[0021] S4, adding the drug-loaded magnetic Fe-based MOFs system to the drug-loaded magnetic artemisinin liposomes described in step S3, and ultrasonically homogenizing. During the ultrasonic homogenization, the ultrasonic temperature is 20-40°C, the ultrasonic frequency is 25-50KHz, the ultrasonic power is 600-1000W, and the ultrasonic time is 20-30min. The drug-loaded magnetic artemisinin liposomes are modified on the surface of the drug-loaded magnetic Fe-based MOFs system through electrostatic adsorption or covalent bonding, forming a double-layer separated drug-loading system, further enhancing the drug loading capacity, having a dual magnetic targeting effect, and a dual-effect combination that acts more accurately on the inflammatory site, promotes the release of the active ingredients, and improves the therapeutic efficiency to obtain the main drug;

[0022] S5, the main drug described in step S4 and soluble starch, dextrin, and microcrystalline cellulose are uniformly mixed and granulated, wherein the soluble starch, dextrin, and microcrystalline cellulose act as auxiliary materials, and the granular form is beneficial to the stability of the active ingredients and the composite carrier, and the compound granules of Chicanthus chinensis for treating gout are obtained;

[0023] Preferably, in step S3, the amount of artemisinin added is 12.0-15.0 mg. Artemisinin has good antipyretic and analgesic effects, can relieve pain symptoms, and control the increase of uric acid levels.

[0024] The beneficial effects achieved by the present invention are as follows:

[0025] The present invention significantly improves the drug loading amount and drug loading stability by modifying the drug-loaded magnetic artemisinin liposomes on the surface of the drug-loaded magnetic Fe-based MOFs system, has a strong magnetic targeting effect, acts accurately on the inflammatory site, improves the bioavailability of the active ingredients, and effectively improves the therapeutic efficiency of gout; the drug-loaded magnetic Fe-based MOFs system carries the main active substances, namely, red cangyu extract and urease, wherein catechin functionalized Fe3O4 nanoparticles have certain magnetism and adsorption properties, and are combined with Fe-based MOFs to improve biosafety and drug loading amount, and can also release active substances in the targeted lesion area; the drug-loaded magnetic artemisinin liposomes are coated with active substances, compound Chinese medicine and nanozyme, the addition of the compound Chinese medicine makes up for the efficacy limitation of the single Chinese medicine red cangyu, and the addition of the nanozyme gives the liposome a certain magnetic effect, which makes up for the use defect of urease; the drug-loaded magnetic artemisinin liposomes The body is attached to the drug-loaded magnetic Fe-based MOFs system to form a drug-loaded system similar to an inner and outer double-layer, which not only increases the drug loading capacity, but also enhances the stability of the system drug loading, reduces drug leakage caused by fusion and rupture of liposomes during storage, and at the same time, it also has a dual high-efficiency magnetic targeting effect, significantly improves the precise release of medicinal substances in the lesion area, improves bioavailability, and improves the therapeutic effect of gout. In addition, the synergistic use of traditional Chinese medicine medicinal substances and urease and nanozyme can not only directly promote the dissolution of formed uric acid stones, but also reduce uric acid levels through multiple pathways, alleviate gout inflammatory reactions, and achieve an effective combination of prevention and treatment. The present invention uses a drug-loaded magnetic Fe-based MOFs system, a drug-loaded magnetic artemisinin liposome, soluble starch, dextrin and microcrystalline cellulose to prepare a compound particle of red cangyu vine for treating gout, which has a high drug loading capacity and magnetic targeting effect, can be accurately released at the inflammatory site, and effectively improves the therapeutic effect of gout. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a scanning electron microscope image of the drug-loaded magnetic Fe-based MOFs system prepared in Example 1 of the present invention;

[0027] Figure 2 This is a perspective electron micrograph of the drug-loaded magnetic artemisinin liposomes prepared in Example 1 of the present invention;

[0028] Figure 3 The drug loading results of Examples 1-4 and Comparative Examples 1-3 of the present invention are shown in FIG.

[0029] Figure 4 The saturation magnetization result diagram of Examples 1-4 and Comparative Examples 1-3 of the present invention;

[0030] Figure 5 The graph shows the therapeutic efficacy results of Examples 1-4 and Comparative Examples 1-3 of the present invention. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments; based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0032] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be applied to the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only and are not intended to limit the content of this application.

[0033] The experimental methods in the following examples are conventional methods unless otherwise specified; the experimental materials used in the following examples are purchased from commercial channels unless otherwise specified.

[0034] The sources of the reagents used in the examples are as follows:

[0035] Ferrous sulfate CAS No: 7720-78-7, brand Apinno, product number GC110155;

[0036] Ferric chloride hexahydrate CAS No: 10025-77-1, brand Innochem, product number A10004;

[0037] Ferrous chloride tetrahydrate CAS No: 13478-10-9, brand Innochem, product number A33005;

[0038] Soluble starch CAS No: 9005-84-9, brand Innochem, product number A48874;

[0039] Dextrin CAS No: 9004-53-9, brand Innochem, product number B04280;

[0040] Microcrystalline cellulose CAS No: 9004-34-6, brand Innochem, product number A00472;

[0041] Acetate buffer brand Aladdin, product number A397549-500ml;

[0042] Catechin CAS No: 7295-85-4, brand Apinno, product number GC74450;

[0043] Trimellitic acid CAS No: 554-95-0, brand Innochem, product number A50808;

[0044] Sodium citrate CAS No: 68-04-2, brand Innochem, product number A26822;

[0045] Diethylene glycol CAS No: 111-46-6, brand Innochem, product number A64322;

[0046] Sulfuric acid CAS No: 7664-93-9, brand Acros, product number 124640025;

[0047] Anhydrous sodium acetate CAS No: 127-09-3, brand Innochem, product number A03654;

[0048] Soybean lecithin CAS No: 55128-59-1, brand Sinopharm, item number 69014981;

[0049] Cholesterol CAS No: 57-88-5, brand Innochem, product number A90286;

[0050] Artemisinin CAS No: 63968-64-9, brand Innochem, product number A67642;

[0051] Urease CAS No: 9002-13-5, brand Yuanye, product number S10095-20KU, specification 100u / mg;

[0052] Cellulase CAS No: 9012-54-8, brand source leaf, product number S10041-5g, specification 50u / mg;

[0053] Sodium hydroxide CAS No: 1310-73-2, brand Innochem, product number A36865;

[0054] Anhydrous ethanol CAS No: 64-17-5, brand Innochem, product number G00004.

[0055] Example 1

[0056] This embodiment proposes a compound granule of Artemisia annua for treating gout, comprising the following components in parts by weight: 10 parts of drug-loaded magnetic Fe-based MOFs system, 30 parts of drug-loaded magnetic artemisinin liposomes, 60 parts of soluble starch, 40 parts of dextrin, and 25 parts of microcrystalline cellulose.

[0057] The drug-loaded magnetic Fe-based MOFs system comprises the following components in parts by weight: 15 parts of catechin-functionalized Fe3O4-MIL-100 (Fe), 90 parts of red cang vine extract, and 90 parts of urease.

[0058] The drug-loaded magnetic artemisinin liposome comprises the following components in parts by weight: 15 parts of artemisinin, 80 parts of soybean lecithin, 20 parts of cholesterol, 10 parts of traditional Chinese medicine extract, and 8 parts of nanozyme.

[0059] The raw materials of the Chinese medicine extract include the following components in parts by weight: 3 parts of Smilax glabra, 3 parts of Phellodendron amurense, 3 parts of Scutellaria baicalensis, 3 parts of Radix Dioscoreae, 3 parts of Paeonia lactiflora, and 3 parts of Licorice.

[0060] The preparation method of the drug-loaded magnetic Fe-based MOFs system specifically comprises the following steps:

[0061] (1) Pour 10.0 g of crude powder of Caulis Achyranthis Bidentatae medicinal material dried to constant weight into 300 mL of 60% ethanol solution, then add 4% cellulase, adjust the pH to 6.0 with acetate buffer, perform enzymolysis for 50 min, and perform enzymolysis at 50°C. After enzymolysis, boil the mixture in boiling water for 5 min to inactivate the enzyme, then perform ultrasonic treatment for 30 min at an ultrasonic power of 800 W, filter, concentrate, and freeze-dry. The alcohol extract of Caulis Achyranthis Bidentatae contains flavonoids, phenols, alkaloids, triterpenes, and coumarin compounds, and has a strong anti-inflammatory effect. It can not only inhibit the activity of xanthine oxidase and reduce serum uric acid content, but also has a protective effect on the soothing function of vascular endothelium, and can relieve the degree of toe swelling. Thus, a Caulis Achyranthis Bidentatae extract is obtained.

[0062] (2) Add catechin powder and 0.04g sodium hydroxide solid to 20mL pure water, then add 0.15g ferrous sulfate powder, and the amount of catechin added is 0.2g. Catechins can relieve gout by inhibiting NLRP3 inflammasome activation. Stir evenly, adjust the pH to 11.0 with 20% sulfuric acid solution, and then transfer to a 50mL autoclave, seal and keep at 160°C for 8h. After cooling to room temperature, collect the black precipitate with a magnet, wash it with ultrapure water 5 times, and dry it in an oven at 50°C for 12h. Catechins are attached to the surface of Fe3O4 nanoparticles through functionalization, and have strong magnetism and adsorption, which enhances the stability and bioavailability of the nanoparticles and specifically enhances their pharmacological effects. Thus, catechin functionalized Fe3O4 nanoparticles are obtained.

[0063] (3) 2.0 g of the catechin-functionalized Fe3O4 nanoparticles described in step (2) and 1.5 g of ferrous chloride tetrahydrate were dissolved in 45 mL of deionized water as solution A, and 0.7 g of trimesic acid solid and 0.4 g of sodium hydroxide solid were weighed and dissolved in 15 mL of deionized water as solution B. Solution B was then slowly dripped into solution A, stirred at room temperature for 12 h, magnetically separated, washed with deionized water and anhydrous ethanol solution for 5 times in sequence, and vacuum dried at 60° C. The magnetic nanoparticles were combined with Fe-based MOFs. The synergistic effect of the two had higher biosafety and higher drug loading capacity, and also had the advantages of targeted release to the lesion area, thereby obtaining catechin-functionalized Fe3O4-MIL-100 (Fe);

[0064] (4) Dissolve 5.0 mg of the catechin-functionalized Fe3O4-MIL-100 (Fe) described in step (3) in 500 mL of water, add 30.0 mg of the Caulis Atractylodes extract described in step (1) and 30.0 mg of urease. Urease can directly act on uric acid to promote its metabolism, and can also act on the formed uric acid stones to promote their dissolution, thereby enhancing the therapeutic effect of the Caulis Atractylodes extract on gout. After stirring evenly, transfer to a constant temperature shaker for drug loading culture. During the shaking culture process, the load temperature is controlled at 35°C and the load speed is controlled at 200 rpm. The loading time was 90 min, and the shaking culture promoted the mixing of the drug and the carrier, allowing it to better enter the internal pores of the catechin-functionalized Fe3O4-MIL-100 (Fe), thereby increasing the drug loading amount and stability. The catechin-functionalized Fe3O4-MIL-100 (Fe) carrier has a high porosity and a large specific surface area. The main active substances, Caulis Cangchungi extract and urease, can be loaded in the internal pores of MOFs through shaking culture to achieve sustained release of the drug, improve bioavailability and therapeutic effect, and then freeze-dry to obtain a drug-loaded magnetic Fe-based MOFs system.

[0065] This embodiment provides a method for preparing compound granules of Caulis Scutellariae for treating gout, which specifically comprises the following steps:

[0066] S1. Grind Smilax glabra, Phellodendron amurense, Scutellaria baicalensis, Radix Dioscoreae, Paeonia lactiflora and Licorice, pass through an 80-mesh sieve, mix the Chinese medicine powders evenly, add 300 mL of distilled water and boil for 3 times, filter while hot, combine the filtrates, and concentrate to 1 / 4 of the original volume of the filtrate. Use other Chinese medicines as secondary pharmacodynamic substances, have multi-target and multi-pathway therapeutic characteristics, down-regulate the expression of TLR4, MyD88, and NF-κB, inhibit the signal transduction carried out by them, reduce the release of factors such as TNF-α, IL-1β, IL-8, and relieve gout inflammatory response, and obtain a Chinese medicine extract;

[0067] S2. Dissolve 1081.0 mg of ferric chloride hexahydrate and 471.0 mg of sodium citrate powder in 40 mL of diethylene glycol solution, react at 80°C for 2 h, add 1314.0 mg of anhydrous sodium acetate powder, react at 60°C for 1 h, then transfer to a hydrothermal reactor, react at 200°C for 8 h, cool to room temperature, centrifuge, collect the black product, wash it 5 times with anhydrous ethanol solution, and vacuum dry it. Nanozyme, as an artificial enzyme, has the advantages of magnetism, good stability, and good biosafety, which makes up for the defects of urease, and obtains nanozyme;

[0068] S3, pour 80.0mg soy lecithin, 20.0mg cholesterol, and artemisinin into 50mL anhydrous ethanol solution, the amount of artemisinin added is 15.0mg, artemisinin has good antipyretic and analgesic effects, can relieve pain symptoms, and control the increase of uric acid levels, then add 10mL of the traditional Chinese medicine extract described in step S1 and 8.0mg of the nanozyme described in step S2, stir magnetically until completely dissolved, and use a micro-syringe to slowly and uniformly inject the mixed solution into 20mL of normal saline, maintaining a constant temperature of 45°C, The ethanol was removed by continuous magnetic stirring to fully hydrate the mixture, and then the ethanol was removed by reduced pressure evaporation at 35° C. using a rotary evaporator. The obtained liposome suspension was ultrasonically treated in an ice bath for 3 minutes at an ultrasonic power of 220 W. By encapsulating the compound Chinese medicine and nanozymes in the artemisinin liposomes, the artemisinin liposomes were endowed with a certain magnetic property, which could target the inflammatory site, improve the bioavailability of the drug substance, and promote the aggregation of anti-inflammatory macrophages at the targeted site, thereby obtaining drug-loaded magnetic artemisinin liposomes.

[0069] S4, adding the drug-loaded magnetic Fe-based MOFs system to the drug-loaded magnetic artemisinin liposomes described in step S3, and ultrasonically homogenizing. During the ultrasonic homogenization process, the ultrasonic temperature is 40°C, the ultrasonic frequency is 50KHz, the ultrasonic power is 1000W, and the ultrasonic time is 30min. The drug-loaded magnetic artemisinin liposomes are modified on the surface of the drug-loaded magnetic Fe-based MOFs system through electrostatic adsorption or covalent bonding, forming a double-layer separated drug-loading system, further enhancing the drug loading capacity, having a dual magnetic targeting effect, and a dual-effect combination that acts more accurately on the inflammatory site, promotes the release of the active ingredients, and improves the therapeutic efficiency to obtain the main drug;

[0070] S5. Evenly mix the main drug described in step S4 and soluble starch, dextrin and microcrystalline cellulose, and granulate them. The soluble starch, dextrin and microcrystalline cellulose act as auxiliary materials, and the granular state is beneficial to the stability of the active ingredients and the composite carrier, so as to obtain the compound granules of Chicanthus chinensis for treating gout.

[0071] In this example, the prepared drug-loaded magnetic Fe-based MOFs system was subjected to scanning electron microscopy and the drug-loaded magnetic artemisinin liposome was subjected to transmission electron microscopy to observe its microscopic morphology. Figure 1 This is a SEM image of the drug-loaded magnetic Fe-based MOFs system prepared in Example 1, magnified 10,000 times. Figure 2 This is a TEM image of the drug-loaded magnetic artemisinin liposome prepared in Example 1 at a magnification of 100,000 times. Figure 1 The drug-loaded magnetic Fe-based MOFs system prepared in this example exhibits high porosity and large specific surface area. Figure 2 The drug-loaded magnetic artemisinin liposomes prepared in this embodiment are a magnetic coating structure.

[0072] Example 2

[0073] This embodiment proposes a compound granule of Artemisia annua for treating gout, comprising the following components in parts by weight: 5 parts of drug-loaded magnetic Fe-based MOFs system, 20 parts of drug-loaded magnetic artemisinin liposomes, 50 parts of soluble starch, 30 parts of dextrin, and 15 parts of microcrystalline cellulose.

[0074] The drug-loaded magnetic Fe-based MOFs system comprises the following components in parts by weight: 9 parts of catechin-functionalized Fe3O4-MIL-100 (Fe), 60 parts of red cang vine extract, and 60 parts of urease.

[0075] The drug-loaded magnetic artemisinin liposome comprises the following components in parts by weight: 12 parts of artemisinin, 60 parts of soybean lecithin, 10 parts of cholesterol, 5 parts of traditional Chinese medicine extract, and 5 parts of nanozyme.

[0076] The raw materials of the Chinese medicine extract include the following components in parts by weight: 2 parts of Smilax glabra, 2 parts of Phellodendron amurense, 2 parts of Scutellaria baicalensis, 2 parts of Radix Dioscoreae, 2 parts of Paeonia lactiflora, and 2 parts of Licorice.

[0077] The preparation method of the drug-loaded magnetic Fe-based MOFs system specifically comprises the following steps:

[0078] (1) Pour 10.0 g of crude powder of Caulis Achyranthis Bidentatae medicinal material dried to constant weight into 300 mL of 60% ethanol solution, then add 2% cellulase, adjust the pH to 5.0 with acetate buffer, perform enzymolysis for 40 min, and perform enzymolysis at 40°C. After enzymolysis, boil the mixture in boiling water for 5 min to inactivate the enzyme, then perform ultrasonic treatment for 20 min at 600 W, filter, concentrate, and freeze-dry. The alcohol extract of Caulis Achyranthis Bidentatae contains flavonoids, phenols, alkaloids, triterpenes, and coumarin compounds, and has a strong anti-inflammatory effect. It can not only inhibit the activity of xanthine oxidase and reduce serum uric acid content, but also has a protective effect on the soothing function of vascular endothelial cells, and can relieve the degree of toe swelling. Thus, a Caulis Achyranthis Bidentatae extract is obtained.

[0079] (2) Add catechin powder and 0.04g sodium hydroxide solid to 15mL pure water, then add 0.15g ferrous sulfate powder, and the amount of catechin added is 0.2g. Catechins can relieve gout by inhibiting NLRP3 inflammasome activation. Stir evenly, adjust the pH to 11.0 with 10% sulfuric acid solution, and then transfer to a 50mL autoclave, seal and keep at 150°C for 6h. After cooling to room temperature, collect the black precipitate with a magnet, wash it with ultrapure water 3 times, and dry it in an oven at 50°C for 12h. Catechins are attached to the surface of Fe3O4 nanoparticles through functionalization, and have strong magnetism and adsorption, which enhances the stability and bioavailability of the nanoparticles and specifically enhances their pharmacological effects. Thus, catechin functionalized Fe3O4 nanoparticles are obtained.

[0080] (3) 1.0 g of the catechin-functionalized Fe3O4 nanoparticles described in step (2) and 1.5 g of ferrous chloride tetrahydrate were dissolved in 40 mL of deionized water as solution A, and 0.7 g of trimesic acid solid and 0.4 g of sodium hydroxide solid were weighed and dissolved in 15 mL of deionized water as solution B. Solution B was then slowly dripped into solution A, stirred at room temperature for 12 h, magnetically separated, washed with deionized water and anhydrous ethanol solution three times in sequence, and vacuum dried at 60° C. The magnetic nanoparticles were combined with Fe-based MOFs. The synergistic effect of the two had higher biosafety and higher drug loading capacity, and also had the advantages of targeted release to the lesion area, thereby obtaining catechin-functionalized Fe3O4-MIL-100 (Fe);

[0081] (4) Dissolve 3.0 mg of the catechin-functionalized Fe3O4-MIL-100 (Fe) described in step (3) in 500 mL of water, add 20.0 mg of the Caulis Atractylodes extract described in step (1) and 20.0 mg of urease. Urease can directly act on uric acid to promote its metabolism, and can also act on the formed uric acid stones to promote their dissolution, thereby enhancing the therapeutic effect of the Caulis Atractylodes extract on gout. After stirring evenly, transfer to a constant temperature shaker for drug loading culture. During the shaking culture process, the load temperature is controlled at 25°C and the load speed is 100 rpm. The loading time was 60 min, and the shaking culture promoted the mixing of the drug and the carrier, allowing it to better enter the internal pores of the catechin-functionalized Fe3O4-MIL-100 (Fe), thereby increasing the drug loading amount and stability. The catechin-functionalized Fe3O4-MIL-100 (Fe) carrier had a high porosity and a large specific surface area. The main active substances, the extract of Caulis Cangquilla and urease, could be loaded in the internal pores of MOFs through shaking culture, thereby achieving sustained release of the drug, improving bioavailability and therapeutic effects, and then freeze-dried to obtain a drug-loaded magnetic Fe-based MOFs system.

[0082] This embodiment provides a method for preparing compound granules of Caulis Scutellariae for treating gout, which specifically comprises the following steps:

[0083] S1. Grind Smilax glabra, Phellodendron amurense, Scutellaria baicalensis, Radix Dioscoreae, Paeonia lactiflora and Licorice, pass through a 60-mesh sieve, mix the Chinese medicine powders evenly, add 200 mL of distilled water and boil twice, filter while hot, combine the filtrates, and concentrate to 1 / 5 of the original volume of the filtrate, use other Chinese medicines as secondary pharmacodynamic substances, have multi-target and multi-pathway therapeutic characteristics, down-regulate the expression of TLR4, MyD88, and NF-κB, inhibit the signal transduction carried out by them, reduce the release of factors such as TNF-α, IL-1β, IL-8, and relieve gout inflammatory response, and obtain a Chinese medicine extract;

[0084] S2. Dissolve 1081.0 mg of ferric chloride hexahydrate and 471.0 mg of sodium citrate powder in 40 mL of diethylene glycol solution, react at 70°C for 1 h, add 1314.0 mg of anhydrous sodium acetate powder, react at 50°C for 1 h, then transfer to a hydrothermal reactor, react at 180°C for 6 h, cool to room temperature, centrifuge, collect the black product, wash it 3 times with anhydrous ethanol solution, and vacuum dry it. Nanozyme, as an artificial enzyme, has the advantages of magnetism, good stability, and good biosafety, which makes up for the defects of urease, and obtains nanozyme;

[0085] S3, pour 60.0mg soy lecithin, 10.0mg cholesterol, and artemisinin into 30mL anhydrous ethanol solution, the amount of artemisinin added is 12.0mg, artemisinin has good antipyretic and analgesic effects, can relieve pain symptoms, and control the increase of uric acid levels, then add 5mL of the traditional Chinese medicine extract described in step S1 and 5.0mg of the nanozyme described in step S2, stir magnetically until completely dissolved, and use a micro-syringe to slowly and uniformly inject the mixed solution into 20mL of normal saline, maintaining a constant temperature of 45°C, The ethanol was removed by continuous magnetic stirring to fully hydrate the mixture, and then the ethanol was removed by reduced pressure evaporation at 35° C. using a rotary evaporator. The obtained liposome suspension was ultrasonically treated in an ice bath for 2 min at an ultrasonic power of 180 W. By encapsulating the compound Chinese medicine and nanozyme of the medicinal substance into the artemisinin liposome, the artemisinin liposome was endowed with a certain magnetic property, which could target the inflammatory site, improve the bioavailability of the medicinal substance, and promote the aggregation of anti-inflammatory macrophages at the targeted site, thereby obtaining drug-loaded magnetic artemisinin liposome.

[0086] S4, adding the drug-loaded magnetic Fe-based MOFs system to the drug-loaded magnetic artemisinin liposomes described in step S3, and ultrasonically homogenizing. During the ultrasonic homogenization process, the ultrasonic temperature is 20°C, the ultrasonic frequency is 25KHz, the ultrasonic power is 600W, and the ultrasonic time is 20min. The drug-loaded magnetic artemisinin liposomes are modified on the surface of the drug-loaded magnetic Fe-based MOFs system through electrostatic adsorption or covalent bonding, forming a double-layer separated drug-loading system, further enhancing the drug loading capacity, having a dual magnetic targeting effect, and a dual-effect combination that acts more accurately on the inflammatory site, promotes the release of the active ingredients, and improves the therapeutic efficiency to obtain the main drug;

[0087] S5. Evenly mix the main drug described in step S4 and soluble starch, dextrin and microcrystalline cellulose, and granulate them. The soluble starch, dextrin and microcrystalline cellulose act as auxiliary materials, and the granular state is beneficial to the stability of the active ingredients and the composite carrier, so as to obtain the compound granules of Chicanthus chinensis for treating gout.

[0088] Example 3

[0089] This embodiment proposes a compound granule of Artemisia selengensis for treating gout, comprising the following components in parts by weight: 7.5 parts of drug-loaded magnetic Fe-based MOFs system, 25 parts of drug-loaded magnetic artemisinin liposomes, 55 parts of soluble starch, 35 parts of dextrin, and 20 parts of microcrystalline cellulose.

[0090] The drug-loaded magnetic Fe-based MOFs system comprises the following components in parts by weight: 12 parts of catechin-functionalized Fe3O4-MIL-100 (Fe), 75 parts of red cang vine extract, and 75 parts of urease.

[0091] The drug-loaded magnetic artemisinin liposome comprises the following components in parts by weight: 13.5 parts of artemisinin, 70 parts of soybean lecithin, 15 parts of cholesterol, 7.5 parts of traditional Chinese medicine extract, and 6.5 parts of nanozyme.

[0092] The raw materials of the Chinese medicine extract include the following components in parts by weight: 2.5 parts of Smilax glabra, 2.5 parts of Phellodendron chinense, 2.5 parts of Scutellaria baicalensis, 2.5 parts of Radix Dioscoreae, 2.5 parts of Paeonia lactiflora, and 2.5 parts of Licorice.

[0093] The preparation method of the drug-loaded magnetic Fe-based MOFs system specifically comprises the following steps:

[0094] (1) Pour 10.0 g of crude powder of Caulis Atractylodes macrocephala dried to constant weight into 300 mL of 60% ethanol solution, add 3% cellulase, adjust the pH to 5.5 with acetate buffer, perform enzymolysis for 45 min, and perform enzymolysis at 45°C. After enzymolysis, boil the mixture in boiling water for 5 min to inactivate the enzyme, perform ultrasonic treatment for 25 min, and perform ultrasonic power of 700 W. Filter, concentrate, and freeze-dry. The alcohol extract of Caulis Atractylodes macrocephala contains flavonoids, phenols, alkaloids, triterpenes, and coumarin compounds, and has a strong anti-inflammatory effect. It can not only inhibit the activity of xanthine oxidase and reduce serum uric acid content, but also has a protective effect on the soothing function of vascular endothelium, and can relieve the degree of toe swelling. Thus, a Caulis Atractylodes macrocephala extract is obtained.

[0095] (2) Add catechin powder and 0.04g sodium hydroxide solid to 17.5mL pure water, then add 0.15g ferrous sulfate powder, and the amount of catechin added is 0.2g. Catechins can relieve gout by inhibiting NLRP3 inflammasome activation. Stir evenly, adjust the pH to 11.0 with 15% sulfuric acid solution, and then transfer to a 50mL autoclave, seal and keep at 155°C for 7h. After cooling to room temperature, collect the black precipitate with a magnet, wash it with ultrapure water 4 times, and dry it in an oven at 50°C for 12h. Catechins are attached to the surface of Fe3O4 nanoparticles through functionalization, and have strong magnetism and adsorption, which enhances the stability and bioavailability of the nanoparticles and specifically enhances their pharmacological effects. Thus, catechin functionalized Fe3O4 nanoparticles are obtained.

[0096] (3) 1.5 g of the catechin-functionalized Fe3O4 nanoparticles described in step (2) and 1.5 g of ferrous chloride tetrahydrate were dissolved in 42.5 mL of deionized water as solution A, and 0.7 g of trimesic acid solid and 0.4 g of sodium hydroxide solid were weighed and dissolved in 15 mL of deionized water as solution B. Solution B was then slowly dripped into solution A, stirred at room temperature for 12 h, magnetically separated, washed with deionized water and anhydrous ethanol solution for 4 times in sequence, and vacuum dried at 60° C. The magnetic nanoparticles were combined with Fe-based MOFs. The synergistic effect of the two had higher biosafety and higher drug loading capacity, and also had the advantages of targeted release to the lesion area, thereby obtaining catechin-functionalized Fe3O4-MIL-100 (Fe);

[0097] (4) Dissolve 4.0 mg of the catechin-functionalized Fe3O4-MIL-100 (Fe) described in step (3) in 500 mL of water, add 25.0 mg of the Caulis Atractylodes extract described in step (1) and 25.0 mg of urease. Urease can directly act on uric acid to promote its metabolism, and can also act on the formed uric acid stones to promote their dissolution, thereby enhancing the therapeutic effect of the Caulis Atractylodes extract on gout. After stirring evenly, transfer to a constant temperature shaker for drug loading culture. During the shaking culture process, the load temperature is controlled at 30°C and the load speed is controlled at 150 rpm. The loading time was 75 min, and shaking culture promoted the mixing of the drug and the carrier, allowing it to better enter the internal pores of the catechin-functionalized Fe3O4-MIL-100 (Fe), thereby increasing the drug loading amount and stability. The catechin-functionalized Fe3O4-MIL-100 (Fe) carrier has a high porosity and a large specific surface area. The main active substances, Caulis Cangqu extract and urease, can be loaded in the internal pores of MOFs through shaking culture to achieve sustained release of the drug, improve bioavailability and therapeutic effect, and then freeze-dry to obtain a drug-loaded magnetic Fe-based MOFs system.

[0098] This embodiment provides a method for preparing compound granules of Caulis Scutellariae for treating gout, which specifically comprises the following steps:

[0099] S1. Grind Smilax glabra, Phellodendron amurense, Scutellaria baicalensis, Radix Dioscoreae, Paeonia lactiflora and Licorice, pass through a 70-mesh sieve, mix the Chinese medicine powders evenly, add 250 mL of distilled water and boil for 2-3 times, filter while hot, combine the filtrates, and then concentrate to 1 / 4 of the original volume of the filtrate, use other Chinese medicines as secondary pharmacodynamic substances, have multi-target and multi-pathway therapeutic characteristics, down-regulate the expression of TLR4, MyD88, and NF-κB, inhibit the signal transduction carried out by them, reduce the release of factors such as TNF-α, IL-1β, IL-8, and relieve gout inflammatory response, and obtain a Chinese medicine extract;

[0100] S2. Dissolve 1081.0 mg of ferric chloride hexahydrate and 471.0 mg of sodium citrate powder in 40 mL of diethylene glycol solution, react at 75 ° C for 1.5 h, add 1314.0 mg of anhydrous sodium acetate powder, react at 55 ° C for 1 h, then transfer to a hydrothermal reactor, react at 190 ° C for 7 h, cool to room temperature, centrifuge, collect the black product, wash it 4 times with anhydrous ethanol solution, and vacuum dry it. Nanozyme, as an artificial enzyme, has the advantages of magnetism, good stability, and good biosafety, which makes up for the defects of urease, and obtains nanozyme;

[0101] S3, pour 70.0mg soy lecithin, 15.0mg cholesterol, and artemisinin into 40mL anhydrous ethanol solution, the amount of artemisinin added is 13.5mg, artemisinin has good antipyretic and analgesic effects, can relieve pain symptoms, and control the increase of uric acid levels, then add 7.5mL of the traditional Chinese medicine extract described in step S1 and 6.5mg of the nanozyme described in step S2, stir magnetically until completely dissolved, and use a microsyringe to slowly and uniformly inject the mixed solution into 20mL of normal saline, maintaining a constant temperature of 45°C, The ethanol was removed by continuous magnetic stirring to fully hydrate the mixture, and then the ethanol was removed by reduced pressure evaporation at 35° C. using a rotary evaporator. The obtained liposome suspension was ultrasonically treated in an ice bath for 2.5 min at an ultrasonic power of 200 W. The artemisinin liposomes were endowed with a certain magnetic property by encapsulating the compound Chinese medicine and nanozyme with the medicinal substance, so that the artemisinin liposomes could target the inflammatory site, improve the bioavailability of the medicinal substance, and promote the aggregation of anti-inflammatory macrophages at the targeted site, thereby obtaining drug-loaded magnetic artemisinin liposomes.

[0102] S4, adding the drug-loaded magnetic Fe-based MOFs system to the drug-loaded magnetic artemisinin liposomes described in step S3, and ultrasonically homogenizing. During the ultrasonic homogenization process, the ultrasonic temperature is 30°C, the ultrasonic frequency is 37.5KHz, the ultrasonic power is 800W, and the ultrasonic time is 25min. The drug-loaded magnetic artemisinin liposomes are modified on the surface of the drug-loaded magnetic Fe-based MOFs system through electrostatic adsorption or covalent bonding, forming a double-layer separated drug-loading system, further enhancing the drug loading capacity, having a dual magnetic targeting effect, and a dual-effect combination that acts more accurately on the inflammatory site, promotes the release of the active ingredients, and improves the therapeutic efficiency to obtain the main drug;

[0103] S5. Evenly mix the main drug described in step S4 and soluble starch, dextrin and microcrystalline cellulose, and granulate them. The soluble starch, dextrin and microcrystalline cellulose act as auxiliary materials, and the granular state is beneficial to the stability of the active ingredients and the composite carrier, so as to obtain the compound granules of Chicanthus chinensis for treating gout.

[0104] Example 4

[0105] This embodiment proposes a compound granule of Artemisia annua for treating gout, comprising the following components in parts by weight: 10 parts of drug-loaded magnetic Fe-based MOFs system, 20 parts of drug-loaded magnetic artemisinin liposomes, 60 parts of soluble starch, 40 parts of dextrin, and 25 parts of microcrystalline cellulose.

[0106] The drug-loaded magnetic Fe-based MOFs system comprises the following components in parts by weight: 15 parts of catechin-functionalized Fe3O4-MIL-100 (Fe), 90 parts of red cang vine extract, and 60 parts of urease.

[0107] The drug-loaded magnetic artemisinin liposome comprises the following components in parts by weight: 12 parts of artemisinin, 80 parts of soybean lecithin, 20 parts of cholesterol, 10 parts of traditional Chinese medicine extract, and 5 parts of nanozyme.

[0108] The raw materials of the Chinese medicine extract include the following components in parts by weight: 3 parts of Smilax glabra, 3 parts of Phellodendron amurense, 3 parts of Scutellaria baicalensis, 3 parts of Radix Dioscoreae, 3 parts of Paeonia lactiflora, and 3 parts of Licorice.

[0109] The preparation method of the drug-loaded magnetic Fe-based MOFs system specifically comprises the following steps:

[0110] (1) Pour 10.0 g of crude powder of Caulis Achyranthis Bidentatae medicinal material dried to constant weight into 300 mL of 60% ethanol solution, then add 4% cellulase, adjust the pH to 6.0 with acetate buffer, perform enzymolysis for 40 min, and perform enzymolysis at 50°C. After enzymolysis, boil the mixture in boiling water for 5 min to inactivate the enzyme, then perform ultrasonic treatment for 20 min at an ultrasonic power of 800 W, filter, concentrate, and freeze-dry. The alcohol extract of Caulis Achyranthis Bidentatae contains flavonoids, phenols, alkaloids, triterpenes, and coumarin compounds, and has a strong anti-inflammatory effect. It can not only inhibit the activity of xanthine oxidase and reduce serum uric acid content, but also has a protective effect on the soothing function of vascular endothelial cells, and can relieve the degree of toe swelling. Thus, a Caulis Achyranthis Bidentatae extract is obtained.

[0111] (2) Add catechin powder and 0.04g sodium hydroxide solid to 20mL pure water, then add 0.15g ferrous sulfate powder, and the amount of catechin added is 0.2g. Catechins can relieve gout by inhibiting NLRP3 inflammasome activation. Stir evenly, adjust the pH to 11.0 with 20% sulfuric acid solution, and then transfer to a 50mL autoclave, seal and keep at 160°C for 6h. After cooling to room temperature, collect the black precipitate with a magnet, wash it with ultrapure water 5 times, and dry it in an oven at 50°C for 12h. Catechins are attached to the surface of Fe3O4 nanoparticles through functionalization, and have strong magnetism and adsorption, which enhances the stability and bioavailability of the nanoparticles and specifically enhances their pharmacological effects. Thus, catechin functionalized Fe3O4 nanoparticles are obtained.

[0112] (3) 2.0 g of the catechin-functionalized Fe3O4 nanoparticles described in step (2) and 1.5 g of ferrous chloride tetrahydrate were dissolved in 45 mL of deionized water as solution A, and 0.7 g of trimesic acid solid and 0.4 g of sodium hydroxide solid were weighed and dissolved in 15 mL of deionized water as solution B. Solution B was then slowly dripped into solution A, stirred at room temperature for 12 h, magnetically separated, washed with deionized water and anhydrous ethanol solution for 5 times in sequence, and vacuum dried at 60° C. The magnetic nanoparticles were combined with Fe-based MOFs. The synergistic effect of the two had higher biosafety and higher drug loading capacity, and also had the advantages of targeted release to the lesion area, thereby obtaining catechin-functionalized Fe3O4-MIL-100 (Fe);

[0113] (4) Dissolve 5.0 mg of the catechin-functionalized Fe3O4-MIL-100 (Fe) described in step (3) in 500 mL of water, add 30.0 mg of the Caulis Atractylodes extract described in step (1) and 20.0 mg of urease. Urease can directly act on uric acid to promote its metabolism, and can also act on the formed uric acid stones to promote their dissolution, thereby enhancing the therapeutic effect of the Caulis Atractylodes extract on gout. After stirring evenly, transfer to a constant temperature shaker for drug loading culture. During the shaking culture process, the load temperature is controlled at 35°C and the load speed is controlled at 200 rpm. The loading time was 60 min, and the shaking culture promoted the mixing of the drug and the carrier, allowing it to better enter the internal pores of the catechin-functionalized Fe3O4-MIL-100 (Fe), thereby increasing the drug loading amount and stability. The catechin-functionalized Fe3O4-MIL-100 (Fe) carrier had a high porosity and a large specific surface area. The main active substances, the extract of Caulis Cangquilla and urease, could be loaded in the internal pores of MOFs through shaking culture, thereby achieving sustained release of the drug, improving bioavailability and therapeutic effects, and then freeze-dried to obtain a drug-loaded magnetic Fe-based MOFs system.

[0114] This embodiment provides a method for preparing compound granules of Caulis Scutellariae for treating gout, which specifically comprises the following steps:

[0115] S1. Grind Smilax glabra, Phellodendron amurense, Scutellaria baicalensis, Radix Dioscoreae, Paeonia lactiflora and Licorice, pass through an 80-mesh sieve, mix the Chinese medicine powders evenly, add 300 mL of distilled water and boil for 3 times, filter while hot, combine the filtrates, and concentrate to 1 / 5 of the original volume of the filtrate. Use other Chinese medicines as secondary pharmacodynamic substances, have multi-target and multi-pathway therapeutic characteristics, down-regulate the expression of TLR4, MyD88, and NF-κB, inhibit the signal transduction carried out by them, reduce the release of factors such as TNF-α, IL-1β, IL-8, and relieve gout inflammatory response, and obtain a Chinese medicine extract;

[0116] S2. Dissolve 1081.0 mg of ferric chloride hexahydrate and 471.0 mg of sodium citrate powder in 40 mL of diethylene glycol solution, react at 80°C for 1 h, add 1314.0 mg of anhydrous sodium acetate powder, react at 60°C for 1 h, then transfer to a hydrothermal reactor, react at 200°C for 6 h, cool to room temperature, centrifuge, collect the black product, wash it 5 times with anhydrous ethanol solution, and vacuum dry it. Nanozyme, as an artificial enzyme, has the advantages of magnetism, good stability, and good biosafety, which makes up for the defects of urease, and obtains nanozyme;

[0117] S3, pour 80.0mg soy lecithin, 20.0mg cholesterol, and artemisinin into 50mL anhydrous ethanol solution, the amount of artemisinin added is 12.0mg, artemisinin has good antipyretic and analgesic effects, can relieve pain symptoms, and control the increase of uric acid levels, then add 10mL of the traditional Chinese medicine extract described in step S1 and 5.0mg of the nanozyme described in step S2, stir magnetically until completely dissolved, and use a micro-syringe to slowly and uniformly inject the mixed solution into 20mL of normal saline, maintaining a constant temperature of 45°C, The ethanol was removed by continuous magnetic stirring to fully hydrate the mixture, and then the ethanol was removed by reduced pressure evaporation at 35° C. using a rotary evaporator. The obtained liposome suspension was ultrasonically treated in an ice bath for 2 min at an ultrasonic power of 220 W. By encapsulating the compound Chinese medicine and nanozyme of the medicinal substance into the artemisinin liposome, the artemisinin liposome was endowed with a certain magnetic property, which could target the inflammatory site, improve the bioavailability of the medicinal substance, and promote the aggregation of anti-inflammatory macrophages at the targeted site, thereby obtaining drug-loaded magnetic artemisinin liposome.

[0118] S4, adding the drug-loaded magnetic Fe-based MOFs system to the drug-loaded magnetic artemisinin liposomes described in step S3, and ultrasonically homogenizing. During the ultrasonic homogenization process, the ultrasonic temperature is 40°C, the ultrasonic frequency is 50KHz, the ultrasonic power is 1000W, and the ultrasonic time is 20min. The drug-loaded magnetic artemisinin liposomes are modified on the surface of the drug-loaded magnetic Fe-based MOFs system through electrostatic adsorption or covalent bonding, forming a double-layer separated drug-loading system, further enhancing the drug loading capacity, having a dual magnetic targeting effect, and a dual-effect combination that acts more accurately on the inflammatory site, promotes the release of the active ingredients, and improves the therapeutic efficiency to obtain the main drug;

[0119] S5. Evenly mix the main drug described in step S4 and soluble starch, dextrin and microcrystalline cellulose, and granulate them. The soluble starch, dextrin and microcrystalline cellulose act as auxiliary materials, and the granular state is beneficial to the stability of the active ingredients and the composite carrier, so as to obtain the compound granules of Chicanthus chinensis for treating gout.

[0120] Comparative Example 1

[0121] This comparative example provides a composite particle of Caulis Cangquillae for treating gout, which differs from Example 1 in that the drug-loaded magnetic Fe-based MOFs system does not contain catechin-functionalized Fe3O4 nanoparticles; the preparation method of the drug-loaded magnetic Fe-based MOFs system does not include step (2); the preparation method of the composite particle of Caulis Cangquillae for treating gout is the same as that of Example 1.

[0122] Comparative Example 2

[0123] This comparative example provides a compound granule of Caulis Cangqu for treating gout, which differs from Example 1 in that the magnetic artemisinin-loaded liposomes do not contain nanozymes and artemisinin liposomes; the preparation method of the magnetic nanowire microsphere carrier is the same as that of Example 1; the preparation method of the compound granule of Caulis Cangqu for treating gout does not include steps S2 and S3.

[0124] Comparative Example 3

[0125] This comparative example provides a composite granule of Caulis Cangqu for treating gout, which is different from Example 1 in that the composite granule of Caulis Cangqu for treating gout does not contain catechin-functionalized Fe3O4 nanoparticles, nanozymes, or artemisinin liposomes; the preparation method of the drug-loaded magnetic Fe-based MOFs system does not include step (2); and the preparation method of the composite granule of Caulis Cangqu for treating gout does not include steps S2 and S3.

[0126] Experimental Example 1

[0127] Drug loading experiment

[0128] Test sample: the compound granules of Rhizoma Coptidis for treating gout prepared in Examples 1-4 and Comparative Examples 1-3.

[0129] Test method: Weigh 1g / mL of Chinese herbal medicine ingredients such as Rhizoma Coptidis and dilute to 20mg / mL, use distilled water as blank, use UV spectrophotometer to scan in the wavelength range of 330-500nm, and have maximum absorption at 350nm; then dilute the Chinese herbal medicine ingredients into 0-20mg / mL drug solution, measure the absorbance A at 350nm, and get the standard curve equation A=0.1078C+0.0216 by regression, r 2 =0.9938, the best linear range is 2-8 mg / mL; the test sample was dissolved in 1 mL of methanol solution, vortexed for 1 h and stirred to ensure sufficient extraction of the drug, and then centrifuged at 10000 rpm for 5 min after standing for 1 h. 1 mL of the supernatant was taken and fixed to a 50 mL volumetric flask, and the absorbance was measured with distilled water as the blank to calculate the drug loading (%).

[0130] Figure 3It is a drug loading result diagram of Examples 1-4 and Comparative Examples 1-3; as shown in the figure, the drug loading of Examples 1-4 is 39.7-45.6%, indicating that the drug loading is large; the drug loading of Comparative Examples 1-3 is 18.1-30.2%, indicating that the drug loading is small; the drug-loaded magnetic Fe-based MOFs system of Comparative Example 1 does not contain catechin-functionalized Fe3O4 nanoparticles, which is not conducive to improving the drug loading performance of Fe-based MOFs, resulting in a small drug loading; the drug-loaded magnetic artemisinin liposomes of Comparative Example 2 do not contain nanozymes and artemisinin liposomes, and can neither encapsulate traditional Chinese medicine ingredients to improve the drug loading capacity, nor lack the auxiliary pharmacological ingredient nanozyme, resulting in a small drug loading; the compound granules of Chicanthus truncatula for the treatment of gout in Comparative Example 3 do not contain catechin-functionalized Fe3O4 nanoparticles, nanozymes, and artemisinin liposomes, and cannot form a drug loading system similar to an inner and outer double layer, and only rely on Fe-based MOFs to load the pharmacological ingredients, resulting in a small drug loading.

[0131] Experimental Example 2

[0132] Magnetic properties experiment

[0133] Test sample: the compound granules of Rhizoma Coptidis for treating gout prepared in Examples 1-4 and Comparative Examples 1-3.

[0134] Test method: The vibrating sample magnetometer (VSM) measures the magnetic parameters of the test sample by observing the tiny vibrations generated by the test sample in the magnetic field and inducing the change of electromotive force at a position close to the coil; the saturation magnetization intensity of the test sample is tested using a vibrating sample magnetometer model Quantum Design PPMS DynaCool. At room temperature, the frequency is set to 12 Hz and the magnetic field range is -20,000 to 20,000 Oe.

[0135] Figure 4 It is a saturation magnetization intensity result diagram of Examples 1-4 and Comparative Examples 1-3; as shown in the figure, the saturation magnetization intensity of Examples 1-4 is 70.3-78.5emu / g, indicating that the magnetic performance is strong; the saturation magnetization intensity of Comparative Examples 1-3 is 30.4-60.5emu / g, indicating that the magnetic performance is weak; the drug-loaded magnetic Fe-based MOFs system of Comparative Example 1 does not contain catechin-functionalized Fe3O4 nanoparticles, which weakens the magnetism and only has the magnetic targeting effect of liposomes, resulting in weak magnetic performance; the drug-loaded magnetic artemisinin liposomes of Comparative Example 2 do not contain nanozymes and artemisinin liposomes, and only rely on the drug-loaded magnetic Fe-based MOFs system to exert the magnetic targeting effect, resulting in weak magnetic performance; the composite particles of Chicanthus truncatula for the treatment of gout in Comparative Example 3 do not contain catechin-functionalized Fe3O4 nanoparticles, nanozymes, and artemisinin liposomes, and cannot form a dual high-efficiency magnetic targeting effect, resulting in weak magnetic performance.

[0136] Experimental Example 3

[0137] Treatment efficacy experiment

[0138] Test sample: the compound granules of Rhizoma Coptidis for treating gout prepared in Examples 1-4 and Comparative Examples 1-3.

[0139] Test method: 140 patients with gout of varying degrees were selected, with symptoms such as joint pain, joint swelling, skin changes, fever, uric acid stones, etc., with an age distribution of 25-65 years old. They were enrolled using a random number table method and divided into 7 groups, 20 in each group, with each group using the corresponding test sample. The method of administration was oral administration, 3 times a day, and the effect was observed after 14 days. At the same time, the treatment effect was determined according to the following standards, and the treatment effectiveness (%) was calculated, specifically:

[0140] Effective: Gout symptoms completely disappeared, gout symptoms changed from severe to moderate, from moderate to mild, and from mild to normal;

[0141] Ineffective: There was no significant improvement in gout symptoms.

[0142] The formula for calculating the treatment effectiveness is as follows:

[0143] Treatment effectiveness (%) = effective number of people / 20×100%

[0144] Figure 5 It is a therapeutic efficacy result diagram of Examples 1-4 and Comparative Examples 1-3; as shown in the figure, the therapeutic efficacy of Examples 1-4 is 80-95%, indicating that the effect of treating gout is better; the therapeutic efficacy of Comparative Examples 1-3 is 45-65%, indicating that the effect of treating gout is poor; the drug-loaded magnetic Fe-based MOFs system of Comparative Example 1 does not contain catechin-functionalized Fe3O4 nanoparticles, which not only reduces the drug loading amount, but also weakens the magnetic targeting, resulting in poor gout treatment effect; the drug-loaded magnetic artemisinin liposomes of Comparative Example 2 do not contain nanozymes and artemisinin liposomes, and magnetic liposomes that can encapsulate drugs cannot be formed and attached to the drug-loaded magnetic Fe-based MOFs system, which reduces the drug loading performance and weakens the magnetic targeting, resulting in poor gout treatment effect; the compound particles of Chi Cang Teng for treating gout in Comparative Example 3 do not contain catechin-functionalized Fe3O4 nanoparticles, nanozymes, and artemisinin liposomes, and cannot form a drug-loading system similar to an inner and outer double layer, and do not have a dual high-efficiency magnetic targeting effect, resulting in poor gout treatment effect.

[0145] The above experimental results show that the drug loading capacity, magnetic properties and therapeutic efficacy of Examples 1-4 of the present invention are significantly better than those of the samples in Comparative Examples 1-3. Among them, Example 1 using a drug-loaded magnetic Fe-based MOFs system and a drug-loaded magnetic artemisinin liposome has a larger drug loading capacity, stronger magnetic properties and better therapeutic efficacy. In the drug-loaded magnetic Fe-based MOFs system, catechin-functionalized Fe3O4 nanoparticles are combined with Fe-based MOFs to increase the drug loading capacity and can also target the release of effective substances to the lesion area. In the drug-loaded magnetic artemisinin liposomes, the addition of nanozymes gives the liposomes a certain magnetic effect. The drug-loaded magnetic artemisinin liposomes are attached to the drug-loaded magnetic Fe-based MOFs system to form a drug-loading system similar to an inner and outer double layer, which not only increases the drug loading capacity, but also enhances the stability of the system drug loading, reduces drug leakage caused by fusion and rupture of liposomes during storage, and also has a dual high-efficiency magnetic targeting effect, which significantly improves the precise release of effective substances in the lesion area, improves bioavailability, and improves the therapeutic effect of gout.

[0146] While the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that many changes, modifications, substitutions and variations can be made to the embodiments without departing from the principles and spirit of the invention.

[0147] The present invention and its implementation methods are described above, which is not restrictive. The drawings are only one of the implementation methods of the present invention, and the actual application is not limited thereto. In short, if ordinary technicians in the field are inspired by it and design methods and embodiments similar to the technical solution without creativity without departing from the purpose of the invention, they should all fall within the protection scope of the present invention.

Claims

1. A compound granule of Rhizoma Coptidis for treating gout, characterized in that: The compound granules of red cang vine for treating gout include the following components in parts by weight: 5-10 parts of drug-loaded magnetic Fe-based MOFs system, 20-30 parts of drug-loaded magnetic artemisinin liposomes, 50-60 parts of soluble starch, 30-40 parts of dextrin, and 15-25 parts of microcrystalline cellulose; the drug-loaded magnetic Fe-based MOFs system includes the following components in parts by weight: 9-15 parts of catechin functionalized Fe3O4-MIL-100 (Fe), 9-15 parts of red cang vine extract, 9-15 parts of catechin functionalized Fe3O4-MIL-100 (Fe), ... The drug-loaded magnetic artemisinin liposomes include the following components in parts by weight: 12-15 parts of artemisinin, 60-80 parts of soybean lecithin, 10-20 parts of cholesterol, 5-10 parts of traditional Chinese medicine extract, and 5-8 parts of nanozyme; the raw materials of the traditional Chinese medicine extract include the following components in parts by weight: 2-3 parts of Smilax glabra, 2-3 parts of Phellodendron chinense, 2-3 parts of Scutellaria baicalensis, 2-3 parts of Radix Dipterocarpifolia, 2-3 parts of Paeonia lactiflora, and 2-3 parts of Licorice.

2. A method for preparing the compound granules of Caulis Cangqu for treating gout according to claim 1, characterized in that: The specific steps include: S1. Grind Smilax glabra, Phellodendron amurense, Scutellaria baicalensis, Radix Dioscoreae, Radix Paeoniae Rubra and Radix Glycyrrhizae, pass through a 60-80 mesh sieve, mix the Chinese medicine powders evenly, add 200-300 mL of distilled water and boil for 2-3 times, filter while hot, combine the filtrate, and then concentrate to 1 / 5 to 1 / 4 of the original volume of the filtrate to obtain a Chinese medicine extract; S2, dissolve 1081.0 mg of ferric chloride hexahydrate and 471.0 mg of sodium citrate powder in 40 mL of diethylene glycol solution, react at 70-80 ° C for 1-2 h, add 1314.0 mg of anhydrous sodium acetate powder, react at 50-60 ° C for 1 h, then transfer to a hydrothermal reactor, react at 180-200 ° C for 6-8 h, cool to room temperature, centrifuge, collect the black product, wash with anhydrous ethanol solution 3-5 times, and vacuum dry to obtain nanozyme; S3, pour 60.0-80.0mg soy lecithin, 10.0-20.0mg cholesterol, and artemisinin into 30-50mL anhydrous ethanol solution, then add 5-10mL of the traditional Chinese medicine extract described in step S1 and 5.0-8.0mg of the nanozyme described in step S2, stir magnetically until completely dissolved, and use a microsyringe to slowly and uniformly inject the mixed solution into 20mL of normal saline, maintain a constant temperature of 45°C, and continuously stir magnetically to remove ethanol to fully hydrate it, then use a rotary evaporator to evaporate the ethanol under reduced pressure at 35°C, and the obtained liposome suspension is ultrasonically treated in an ice bath, the ultrasonic time is 2-3min, and the ultrasonic power is 180-220W to obtain drug-loaded magnetic artemisinin liposomes; S4, adding the drug-loaded magnetic Fe-based MOFs system to the drug-loaded magnetic artemisinin liposomes described in step S3, and ultrasonically homogenizing, during which the ultrasonic temperature is 20-40°C, the ultrasonic frequency is 25-50KHz, the ultrasonic power is 600-1000W, and the ultrasonic time is 20-30min to obtain the main drug; S5. Evenly mix the main drug described in step S4 with soluble starch, dextrin and microcrystalline cellulose, and granulate to obtain compound granules of Caulis Cangquillae for treating gout.

3. The method for preparing the compound granules of Caulis Cangcunii for treating gout according to claim 2, characterized in that: In step S3, the amount of artemisinin added is 12.0-15.0 mg.

4. The method for preparing the compound granules of Caulis Cangcunii for treating gout according to claim 3, characterized in that: The preparation method of the drug-loaded magnetic Fe-based MOFs system specifically comprises the following steps: (1) Pour 10.0 g of crude powder of the medicinal material of the red cang tung oil plant dried to a constant weight into 300 mL of an ethanol solution with a mass fraction of 60%, then add 2-4% of cellulase, adjust the pH to 5.0-6.0 with acetate buffer, and perform enzymolysis for 40-50 min at a temperature of 40-50°C. After enzymolysis, boil the mixture in boiling water for 5 min to inactivate the enzyme, then perform ultrasonic treatment for 20-30 min at an ultrasonic power of 600-800 W, filter, concentrate, and freeze-dry to obtain a red cang tung oil plant extract; (2) Add catechin powder and 0.04 g sodium hydroxide solid to 15-20 mL pure water, then add 0.15 g ferrous sulfate powder, stir evenly, adjust the pH to 11.0 with 10-20% sulfuric acid solution, then transfer to a 50 mL autoclave, seal and keep at 150-160 ° C for 6-8 h, cool to room temperature, collect the black precipitate with a magnet, wash with ultrapure water 3-5 times, and dry in an oven at 50 ° C for 12 h to obtain catechin functionalized Fe3O4 nanoparticles; (3) Dissolve 1.0-2.0 g of the catechin-functionalized Fe3O4 nanoparticles described in step (2) and 1.5 g of ferrous chloride tetrahydrate in 40-45 mL of deionized water as solution A, and then weigh 0.7 g of trimesic acid solid and 0.4 g of sodium hydroxide solid and dissolve them in 15 mL of deionized water as solution B, then slowly drip solution B into solution A, stir at room temperature for 12 h, separate by magnetic separation, wash with deionized water and anhydrous ethanol solution for 3-5 times in sequence, and dry under vacuum at 60° C. to obtain catechin-functionalized Fe3O4-MIL-100 (Fe); (4) Dissolve 3.0-5.0 mg of the catechin-functionalized Fe3O4-MIL-100 (Fe) described in step (3) in 500 mL of water, add 20.0-30.0 mg of the Caulis Sinensis extract described in step (1) and 20.0-30.0 mg of urease, stir evenly and transfer to a constant temperature shaker for drug loading culture, and then freeze-dry to obtain a drug-loaded magnetic Fe-based MOFs system.

5. The method for preparing the compound granules of Caulis Cangcunii for treating gout according to claim 4, characterized in that: In step (2), the amount of catechin added is 0.2 g.

6. The method for preparing the compound granules of Caulis Cangcunii for treating gout according to claim 5, characterized in that: In step (4), during the shaking incubation process, the load temperature is controlled at 25-35°C, the load speed is controlled at 100-200 rpm, and the load time is controlled at 60-90 min.

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