Preparation method for licoflavone multi-component supramolecular inclusion complex and gastric retention sustained-release formulation thereof and use thereof

Abstract

The present invention provides a preparation method for a licoflavone multi-component supramolecular inclusion complex and a gastric retention sustained-release formulation thereof and use thereof, and belongs to the technical field of biopharmaceuticals. The licoflavone multi-component supramolecular inclusion complex provided by the present invention is prepared from 10 parts by weight of licoflavone, 10-30 parts by weight of poloxamer, 10-100 parts by weight of cyclodextrin, and 1-10 parts by weight of hypromellose. The licoflavone multi-component supramolecular inclusion complex and the gastric retention sustained-release formulation thereof of the present invention can significantly improve the solubility of licoflavone in water and the solubility of licoflavone in gastric juice, increase the retention time of licoflavone in the stomach, enable sustained release of the drug, increase the absorption of the drug by the stomach or duodenum, improve the bioavailability, reduce the dosage level and the frequency of administration, and have a significant therapeutic effect on stomach ulcers, etc.

Description

Preparation method and application of glycyrrhiza flavone multi-molecular inclusion compound and its gastric retention sustained-release preparation TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a preparation method and application of a glycyrrhiza flavone multi-molecular inclusion compound and its gastric retention sustained-release preparation. BACKGROUND

[0002] Glycyrrhiza flavone is an important active ingredient in licorice, and its main chemical components are glycyrrhizin, isoglycyrrhizin, glycyrrhizol A, and isoglycyrrhizin, etc. Glycyrrhiza flavone has significant pharmacological effects such as antibacterial, liver protection, antioxidant, antiviral, anti-ulcer, anti-tumor, anti-pigment deposition, and anti-arrhythmia, and can treat and repair gastric ulcer and duodenal ulcer, improve symptoms such as stomach pain, poor appetite, and abdominal distension, improve blood supply to gastric mucosa, protect and repair gastric mucosa, scavenge free radicals, inhibit the release of inflammatory factors, and reduce the occurrence of mucosal inflammation. Glycyrrhiza flavone also has an inhibitory effect on the growth of various cancer cells, and can inhibit the proliferation of tumor cells through mechanisms such as cell cycle arrest, affecting the regulation of tumor cell apoptosis genes, and inhibiting tumor cell angiogenesis.

[0003] The present application is associated with the following existing patents and documents: ①CN201110002457.2 discloses a method for preparing water-soluble glycyrrhiza flavone by using β-cyclodextrin to encapsulate glycyrrhiza flavone; ②Zhu Hongxia et al. have developed a glycyrrhiza flavone-HP-β-CD inclusion compound with a solubility of 1.6358 mg / mL (Zhu Hongxia et al., Preparation and Solubilization of Glycyrrhiza Flavone-HP-β-CD Inclusion Compound [J], Food and Drug, 2014, 16(4): 381-383); ③CN201710076778.4 discloses a method for preparing Anweiyan sustained-release dropping pills from glycyrrhiza flavone, stearic acid, polyethylene polymer, xylitol, and acacia, etc. The 1h cumulative release is about 20%, and the cumulative release rate is as high as 92%, but the cumulative release rate is low, and the drug release is incomplete; ④Lu Liemei et al., Optimization of the Prescription and Process of Glycyrrhiza Flavone Gastric Floating Tablets [J], Pharmaceutical and Clinical Research, 2018, 26(1): 22-25, selected hydroxypropyl methylcellulose, sodium carboxymethylcellulose, octadecanol, polyethylene glycol 6000, and lactose as excipients to prepare glycyrrhiza flavone gastric floating tablets, but the 1h cumulative release rate is 30-40%, and the release speed is fast. The above-mentioned documents and patents disclose that the solubility of glycyrrhiza flavone in water and gastric juice is still low, the drug concentration in the released gastric juice is very low, the drug release is incomplete, the drug is released quickly in a short time, and the drug efficacy is affected.

[0004] Therefore, it is desirable to provide a scheme to increase the solubility of glycyrrhiza flavones, improve the solubility of the drug in gastric juice, prolong the residence time of the drug in the stomach, increase the action time of the drug in the target organ of the gastrointestinal tract, expand the absorption, improve the bioavailability of the drug, improve the clinical efficacy, reduce the frequency of drug administration, and increase the compliance of patients. SUMMARY

[0005] The present application aims to provide a glycyrrhiza flavone multi-molecular supermolecular inclusion complex, which can significantly improve the water solubility and solubility in gastric juice of glycyrrhiza flavones, increase the residence time of glycyrrhiza flavones in the stomach, and improve the bioavailability of glycyrrhiza flavones.

[0006] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0007] The present application provides a glycyrrhiza flavone multi-molecular supermolecular inclusion complex, which is made of the following raw materials by weight: 10 parts of glycyrrhiza flavones, 10-30 parts of poloxamer, 10-100 parts of cyclodextrin, and 1-10 parts of hydroxypropyl methyl cellulose.

[0008] The present application provides a preparation method of the above-mentioned glycyrrhiza flavone multi-molecular supermolecular inclusion complex, which comprises the following steps:

[0009] (1) mixing glycyrrhiza flavones and poloxamer with ethanol to obtain a mixed solution 1, then adding water to the mixed solution 1 and continuing to mix, and then adding cyclodextrin and stirring to obtain a mixed solution 2;

[0010] (2) adding water to hydroxypropyl methyl cellulose and stirring to obtain a mixed solution 3, mixing the mixed solution 3 and the mixed solution 2 of step (1), and drying to obtain the glycyrrhiza flavone multi-molecular supermolecular inclusion complex.

[0011] Preferably, the glycyrrhiza flavones are glycyrrhiza flavone extracts extracted from the residue after water extraction of glycyrrhiza, and the content of flavonoids in the glycyrrhiza flavones is ≥80.0%;

[0012] Preferably, the poloxamer is poloxamer 188;

[0013] Preferably, the cyclodextrin is β-cyclodextrin or hydroxypropyl-β-cyclodextrin;

[0014] Preferably, the hydroxypropyl methyl cellulose is hydroxypropyl methyl cellulose K100M.

[0015] Preferably, in step (1), the mass ratio of glycyrrhiza flavones to ethanol is 10:40-120, the volume fraction of ethanol is 90-95%, and the mixing temperature with ethanol is 40-60°C.

[0016] Preferably, in step (1), the mass ratio of glycyrrhiza flavones to water is 10:100-400;

[0017] The temperature of the stirring is 40-60 DEG C, and the time is 0.5-2h.

[0018] Preferably, the mass ratio of the hydroxypropyl methyl cellulose and water in step (2) is 1:40-50.

[0019] The temperature of the stirring is 30-40 DEG C, and the time is 3-5h.

[0020] Preferably, the temperature when mixing the mixed solution 3 and the mixed solution 2 in step (2) is 30-40 DEG C.

[0021] Preferably, the drying in step (2) is spray drying, the inlet air temperature is 160-180 DEG C, and the outlet air temperature is 70-80 DEG C.

[0022] The application further provides a licorice flavone multi-component supermolecular inclusion gastric retention sustained-release preparation, which is composed of the above licorice flavone multi-component supermolecular inclusion, microcrystalline cellulose and sodium bicarbonate according to a mass ratio of 100:5-15:5-10.

[0023] The application provides application of the above licorice flavone multi-component supermolecular inclusion or the licorice flavone multi-component supermolecular inclusion gastric retention sustained-release preparation in preparation of a medicine for treating gastric ulcer or resisting tumor.

[0024] The licorice flavone, cyclodextrin, poloxamer and hydroxypropyl methyl cellulose are prepared into a multi-component supermolecular inclusion, which can significantly improve water solubility and gastric juice solubility of the licorice flavone, and has high stability; the licorice flavone multi-component supermolecular inclusion prepared by the application can effectively delay the dissolution and release speed of the licorice flavone, and further delay the release speed of the licorice flavone in gastric juice, and the sustained-release effect is significantly better than that of the licorice flavone-cyclodextrin-poloxamer ternary inclusion.

[0025] The DSC (Differential Scanning Calorimetry) test result shows that the licorice flavone multi-component supermolecular inclusion prepared by the application forms a new phase; the HPLC (High Performance Liquid Chromatography) spectrum proves that the licorice flavone components are in the inclusion, and the multi-component supermolecular inclusion does not change the chemical components of the licorice flavone.

[0026] The licoricidin and isoliquiritigenin multi-molecular super-molecular inclusion gastric retention sustained-release preparation can significantly prolong the retention time of licoricidin and isoliquiritigenin in the stomach, float rapidly after being administered in gastric juice, the floating time is less than 10s, the sustained floating time is more than 12h, the release is more than 88.7% within 8h, and the highest release is up to 98.2%, the cumulative release rate within 12h is more than 95%, the gastric retention absorption effect and the bioavailability of licoricidin and isoliquiritigenin are improved; through animal research, it is found that the gastric retention time of the licoricidin and isoliquiritigenin multi-molecular super-molecular inclusion gastric retention sustained-release preparation is significantly longer than that of the common preparation of licoricidin and isoliquiritigenin, and the preparation has a significant anti-ulcer effect on the gastric ulcer animal model, and has a significant anti-ulcer and repairing effect on the gastric ulcer surface, and can significantly improve the bioavailability of licoricidin and isoliquiritigenin in rabbits.

[0027] In conclusion, the licoricidin and isoliquiritigenin multi-molecular super-molecular inclusion and the gastric retention sustained-release preparation thereof can significantly improve the water solubility and the solubility in gastric juice of licoricidin and isoliquiritigenin, delay the release speed of licoricidin and isoliquiritigenin in gastric juice, increase the retention time of licoricidin and isoliquiritigenin in the stomach, increase the absorption effect of licoricidin and isoliquiritigenin in the stomach or duodenum, improve the bioavailability, reduce the dosage and frequency of taking, and have a significant therapeutic effect on gastric ulcer and the like. BRIEF DESCRIPTION OF DRAWINGS

[0028] Fig. 1 is a DSC spectrum of licoricidin and isoliquiritigenin in the test example 1.

[0029] Fig. 2 is a DSC spectrum of hydroxypropyl-β-cyclodextrin in the test example 1.

[0030] Fig. 3 is a DSC spectrum of β-cyclodextrin in the test example 1.

[0031] Fig. 4 is a DSC spectrum of poloxamer in the test example 1.

[0032] Fig. 5 is a DSC spectrum of hydroxypropyl methyl cellulose in the test example 1.

[0033] Fig. 6 is a DSC spectrum of a physical mixture of licoricidin and isoliquiritigenin, hydroxypropyl-β-cyclodextrin, poloxamer and hydroxypropyl methyl cellulose in the test example 1.

[0034] Fig. 7 is a DSC spectrum of a physical mixture of licoricidin and isoliquiritigenin, β-cyclodextrin, poloxamer and hydroxypropyl methyl cellulose in the test example 1.

[0035] Fig. 8 is a DSC spectrum of the licoricidin and isoliquiritigenin multi-molecular super-molecular inclusion prepared in the test example 1.

[0036] Fig. 9 is a DSC spectrum of the licoricidin and isoliquiritigenin multi-molecular super-molecular inclusion prepared in the test example 2.

[0037] Fig. 10 is a liquid chromatogram of the second ethyl acetate washing liquid in the test example 2.

[0038] Figure 11 is a liquid chromatogram of the licorice flavone multi-molecular supermolecular inclusion complex after twice ethyl acetate washing in Test Example 2.

[0039] Figure 12 is a liquid chromatogram of the licorice flavone raw material in Test Example 2.

[0040] Figure 13 is a cumulative dissolution curve of the licorice flavone in Test Example 6.

[0041] Figure 14 is a cumulative release curve of the licorice flavone in Test Example 7.

[0042] Figure 15 is a blood drug concentration-time curve of the licorice chalcone A in Test Example 10. DETAILED DESCRIPTION

[0043] The technical solutions provided by the present application are described in detail below in conjunction with the examples, but they should not be understood as limiting the scope of protection of the present application.

[0044] Example 1 A licorice flavone multi-molecular supermolecular inclusion complex is prepared as follows:

[0045] (1) 10 g of licorice flavone with a flavonoid content of 80%, 10 g of poloxamer 188 and 40 g of 95% ethanol are stirred and dissolved at 50°C to obtain a mixed solution 1, 100 g of water is added and stirred uniformly, and 10 g of hydroxypropyl-β-cyclodextrin is stirred at 50°C for 1 h to obtain a mixed solution 2;

[0046] (2) 200 g of water is added to 5 g of hydroxypropyl methyl cellulose K100M, stirred at 40°C for 3 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 40°C, followed by spray drying, with an inlet air temperature of 170°C and an outlet air temperature of 70°C, to obtain the licorice flavone multi-molecular supermolecular inclusion complex.

[0047] Example 2 A licorice flavone multi-molecular supermolecular inclusion complex is prepared as follows:

[0048] (1) 10 g of licorice flavone with a flavonoid content of 90%, 20 g of poloxamer 188 and 75 g of 95% ethanol are stirred and dissolved at 60°C to obtain a mixed solution 1, 180 g of water is added and stirred uniformly, and 20 g of β-cyclodextrin is stirred at 60°C for 1.5 h to obtain a mixed solution 2;

[0049] (2) 126 g of water is added to 3 g of hydroxypropyl methyl cellulose K100M, stirred at 40°C for 4 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 40°C, followed by spray drying, with an inlet air temperature of 180°C and an outlet air temperature of 75°C, to obtain the licorice flavone multi-molecular supermolecular inclusion complex.

[0050] Example 3 A licorice flavone multi-molecular supermolecular inclusion complex is prepared as follows:

[0051] (1) 10 g of glycyrrhiza flavones with a flavone content of 83%, 30 g of poloxamer 188, and 120 g of 95% ethanol were dissolved by stirring at 40°C to obtain a mixed solution 1, 280 g of water was added and stirred uniformly, 30 g of hydroxypropyl-β-cyclodextrin was added and stirred at 40°C for 2 h to obtain a mixed solution 2;

[0052] (2) 40 g of water was added to 1 g of hydroxypropyl methyl cellulose K100M, and stirred at 30°C for 5 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 30°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular super-molecular inclusion compound.

[0053] Example 4 A glycyrrhiza flavone multi-molecular super-molecular inclusion compound was prepared as follows:

[0054] (1) 10 g of glycyrrhiza flavones with a flavone content of 85%, 10 g of poloxamer 188, and 40 g of 95% ethanol were dissolved by stirring at 55°C to obtain a mixed solution 1, 160 g of water was added and stirred uniformly, 40 g of β-cyclodextrin was added and stirred at 55°C for 0.5 h to obtain a mixed solution 2;

[0055] (2) 322 g of water was added to 7 g of hydroxypropyl methyl cellulose K100M, and stirred at 30°C for 3 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 30°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular super-molecular inclusion compound.

[0056] Example 5 A glycyrrhiza flavone multi-molecular super-molecular inclusion compound was prepared as follows:

[0057] (1) 10 g of glycyrrhiza flavones with a flavone content of 95%, 20 g of poloxamer 188, and 75 g of 95% ethanol were dissolved by stirring at 45°C to obtain a mixed solution 1, 270 g of water was added and stirred uniformly, 50 g of hydroxypropyl-β-cyclodextrin was added and stirred at 45°C for 1.5 h to obtain a mixed solution 2;

[0058] (2) 432 g of water was added to 9 g of hydroxypropyl methyl cellulose K100M, and stirred at 35°C for 4 h, and then mixed with the solution of step (1) and stirred uniformly at 35°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular super-molecular inclusion compound.

[0059] Example 6 A glycyrrhiza flavone multi-molecular super-molecular inclusion compound was prepared as follows:

[0060] (1) 10 g of glycyrrhiza flavones with a flavone content of 85%, 30 g of poloxamer 188, and 120 g of 95% ethanol were dissolved by stirring at 50°C to obtain a mixed solution 1, 320 g of water was added and stirred uniformly, and 60 g of β-cyclodextrin was added and stirred at 50°C for 2 h to obtain a mixed solution 2;

[0061] (2) 500 g of water was added to 10 g of hydroxypropyl methyl cellulose K100M, and stirred at 35°C for 5 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 35°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular inclusion complex.

[0062] Example 7 A glycyrrhiza flavone multi-molecular inclusion complex was prepared as follows:

[0063] (1) 10 g of glycyrrhiza flavones with a flavone content of 99%, 20 g of poloxamer 188, and 60 g of 95% ethanol were dissolved by stirring at 60°C to obtain a mixed solution 1, 300 g of water was added and stirred uniformly, and 70 g of hydroxypropyl-β-cyclodextrin was added and stirred at 60°C for 0.5 h to obtain a mixed solution 2;

[0064] (2) 392 g of water was added to 8 g of hydroxypropyl methyl cellulose K100M, and stirred at 40°C for 3 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 40°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular inclusion complex.

[0065] Example 8 A glycyrrhiza flavone multi-molecular inclusion complex was prepared as follows:

[0066] (1) 10 g of glycyrrhiza flavones with a flavone content of 82%, 20 g of poloxamer 188, and 75 g of 95% ethanol were dissolved by stirring at 40°C to obtain a mixed solution 1, 270 g of water was added and stirred uniformly, and 80 g of β-cyclodextrin was added and stirred at 40°C for 1 h to obtain a mixed solution 2;

[0067] (2) 282 g of water was added to 6 g of hydroxypropyl methyl cellulose K100M, and stirred at 40°C for 4 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 40°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular inclusion complex.

[0068] Example 9 A glycyrrhiza flavone multi-molecular inclusion complex was prepared as follows:

[0069] (1) 10 g of glycyrrhiza flavones with a flavone content of 88%, 30 g of poloxamer 188, and 120 g of 95% ethanol were dissolved by stirring at 55°C to obtain a mixed solution 1, 320 g of water was added and stirred uniformly, 90 g of hydroxypropyl-β-cyclodextrin was added and stirred at 55°C for 2 h to obtain a mixed solution 2;

[0070] (2) 4 g of hydroxypropyl methyl cellulose K100M was added with 180 g of water, stirred at 30°C for 5 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 30°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular super-molecular inclusion compound.

[0071] Example 10 A glycyrrhiza flavone multi-molecular super-molecular inclusion compound was prepared by the following method:

[0072] (1) 10 g of glycyrrhiza flavones with a flavone content of 87%, 30 g of poloxamer 188, and 80 g of 95% ethanol were dissolved by stirring at 45°C to obtain a mixed solution 1, 400 g of water was added and stirred uniformly, 100 g of β-cyclodextrin was added and stirred at 45°C for 1.5 h to obtain a mixed solution 2;

[0073] (2) 2 g of hydroxypropyl methyl cellulose K100M was added with 96 g of water, stirred at 30°C for 3 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 30°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular super-molecular inclusion compound.

[0074] Example 11 A glycyrrhiza flavone multi-molecular super-molecular inclusion compound was prepared by the following method:

[0075] (1) 10 g of glycyrrhiza flavones with a flavone content of 80%, 20 g of poloxamer 188, and 75 g of 95% ethanol were dissolved by stirring at 50°C to obtain a mixed solution 1, 210 g of water was added and stirred uniformly, 30 g of hydroxypropyl-β-cyclodextrin was added and stirred at 50°C for 1 h to obtain a mixed solution 2;

[0076] (2) 3 g of hydroxypropyl methyl cellulose K100M was added with 123 g of water, stirred at 35°C for 4 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 35°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular super-molecular inclusion compound.

[0077] Example 12 A glycyrrhiza flavone multi-molecular super-molecular inclusion compound was prepared by the following method:

[0078] (1) 10 g of glycyrrhiza flavones with a flavone content of 96%, 10 g of poloxamer 188 and 60 g of 95% ethanol were dissolved by stirring at 60°C to obtain a mixed solution 1, 180 g of water was added and stirred uniformly, and then 50 g of β-cyclodextrin was stirred at 60°C for 0.5 h to obtain a mixed solution 2;

[0079] (2) 200 g of water was added to 4 g of hydroxypropyl methyl cellulose K100M, stirred at 35°C for 5 h, and then stirred uniformly with the mixed solution 2 of step (1) at 35°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular inclusion complex.

[0080] Example 13 A glycyrrhiza flavone multi-molecular inclusion complex was prepared as follows:

[0081] (1) 10 g of glycyrrhiza flavones with a flavone content of 92%, 10 g of poloxamer 188 and 40 g of 95% ethanol were dissolved by stirring at 40°C to obtain a mixed solution 1, 100 g of water was added and stirred uniformly, and then 20 g of hydroxypropyl-β-cyclodextrin was stirred at 40°C for 1 h to obtain a mixed solution 2;

[0082] (2) 240 g of water was added to 6 g of hydroxypropyl methyl cellulose K100M, stirred at 40°C for 3 h, and then stirred uniformly with the mixed solution 2 of step (1) at 40°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular inclusion complex.

[0083] Example 14 A glycyrrhiza flavone multi-molecular inclusion complex was prepared as follows:

[0084] (1) 10 g of glycyrrhiza flavones with a flavone content of 81%, 20 g of poloxamer 188 and 75 g of 95% ethanol were dissolved by stirring at 55°C to obtain a mixed solution 1, 180 g of water was added and stirred uniformly, and then 10 g of β-cyclodextrin was stirred at 55°C for 1.5 h to obtain a mixed solution 2;

[0085] (2) 215 g of water was added to 5 g of hydroxypropyl methyl cellulose K100M, stirred at 40°C for 4 h, and then stirred uniformly with the mixed solution 2 of step (1) at 40°C, and then spray dried to obtain a glycyrrhiza flavone multi-molecular inclusion complex.

[0086] Example 15 A glycyrrhiza flavone multi-molecular inclusion complex was prepared as follows:

[0087] (1) 10 g of glycyrrhiza flavones with a flavone content of 86%, 30 g of poloxamer 188 and 120 g of 95% ethanol were dissolved by stirring at 45°C to obtain a mixed solution 1, 280 g of water was added and stirred uniformly, 40 g of hydroxypropyl-β-cyclodextrin was added and stirred at 45°C for 0.5 h to obtain a mixed solution 2;

[0088] (2) 90 g of water was added to 2 g of hydroxypropyl methyl cellulose K100M, stirred at 40°C for 5 h, and then mixed with the mixed solution 2 of step (1) and stirred uniformly at 40°C, and then spray dried, with an inlet temperature of 160°C and an outlet temperature of 75°C, to obtain a glycyrrhiza flavone multi-component supermolecular inclusion complex.

[0089] Examples 16-30

[0090] After the raw materials were mixed uniformly according to the formula, dry granulation was performed, and the tablets were obtained, to obtain a glycyrrhiza flavone multi-component supermolecular inclusion complex gastric retention sustained-release preparation. The formula of examples 16-30 is shown in table 1 respectively:

[0091] Table 1 Formula of examples 16-30

[0092] A glycyrrhiza flavone-hydroxypropyl-β-cyclodextrin binary inclusion complex was prepared by the following method: 10 g of glycyrrhiza flavones with a flavone content of 80%, 10 g of hydroxypropyl-β-cyclodextrin and 10 g of water were ground for 1 h, dried at 70°C and finely ground to obtain a glycyrrhiza flavone-hydroxypropyl-β-cyclodextrin binary inclusion complex.

[0093] A glycyrrhiza flavone-β-cyclodextrin binary inclusion complex was prepared by the following method: 10 g of glycyrrhiza flavones with a flavone content of 90%, 20 g of β-cyclodextrin and 30 g of water were ground for 1 h, dried at 70°C and finely ground to obtain a glycyrrhiza flavone-β-cyclodextrin binary inclusion complex.

[0094] A glycyrrhiza flavone-hydroxypropyl-β-cyclodextrin-poloxamer ternary inclusion complex was prepared by the following method: 10 g of glycyrrhiza flavones with a flavone content of 80%, 10 g of poloxamer 188 and 40 g of 95% ethanol were dissolved by stirring at 50°C, 100 g of water was added and stirred uniformly, 10 g of hydroxypropyl-β-cyclodextrin was added and stirred at 50°C for 1 h, and then spray dried, with an inlet temperature of 170°C and an outlet temperature of 70°C, to obtain a glycyrrhiza flavone-hydroxypropyl-β-cyclodextrin-poloxamer ternary inclusion complex.

[0095] Comparative Example 4 A glycyrrhizin flavone-β-cyclodextrin-polyoxamer ternary inclusion complex was prepared by stirring and dissolving 10 g of glycyrrhizin flavones having a flavone content of 90% and 20 g of polyoxamer 188 in 75 g of 95% ethanol at 60°C, then stirring uniformly with 180 g of water, and then stirring for 1.5 h at 60°C after adding 20 g of β-cyclodextrin, followed by spray drying at an inlet temperature of 180°C and an outlet temperature of 75°C to obtain the glycyrrhizin flavone-β-cyclodextrin-polyoxamer ternary inclusion complex.

[0096] Comparative Example 5 A glycyrrhizin flavone-polyoxamer suspension was prepared by stirring and dissolving 10 g of glycyrrhizin flavones having a flavone content of 80%, 10 g of polyoxamer 188, and 40 g of 95% ethanol at 50°C, followed by drying under reduced pressure to obtain the glycyrrhizin flavone-polyoxamer suspension.

[0097] Comparative Examples 6 to 9

[0098] Each of the raw materials was mixed uniformly according to the following formulation, dry granulation was performed, and the tablet was obtained.

[0099] Table 2 Formulation of Comparative Examples 6 to 9

[0100] Comparative Example 10 A glycyrrhizin flavone-polyoxamer suspension tablet was prepared by mixing 60 g of the glycyrrhizin flavone-polyoxamer suspension prepared according to the preparation method of Comparative Example 5, 30 g of hydroxypropyl-β-cyclodextrin, 15 g of hydroxypropyl methylcellulose K100M, 5.25 g of microcrystalline cellulose, and 5.25 g of sodium bicarbonate uniformly, followed by dry granulation and tabletting to obtain the glycyrrhizin flavone-polyoxamer suspension tablet.

[0101] Comparative Example 11 A glycyrrhizin flavone physical mixture tablet was prepared by mixing 30 g of glycyrrhizin flavones having a flavone content of 80%, 30 g of polyoxamer 188, 30 g of hydroxypropyl-β-cyclodextrin, 15 g of hydroxypropyl methylcellulose K100M, 5.25 g of microcrystalline cellulose, and 5.25 g of sodium bicarbonate uniformly, followed by dry granulation and tabletting to obtain the glycyrrhizin flavone physical mixture tablet.

[0102] Test Example 1 Thermal analysis (DSC) measurement

[0103] Each of 3 to 5 mg of glycyrrhizin flavones, hydroxypropyl-β-cyclodextrin, β-cyclodextrin, polyoxamer, hydroxypropyl methylcellulose, and two physical mixtures thereof, and the glycyrrhizin flavone multi-component supramolecular inclusion complex prepared in Examples 1 and 2 of the present application (after washing with ethyl acetate and drying) was tabletted, and thermal analysis (DSC) measurement was performed, and the results are shown in FIGS. 1 to 9.

[0104] As shown in Figures 1-9: licorice flavone has characteristic peaks at 491.42℃, 528.31℃, etc., poloxamer has characteristic peaks at 54.22℃, etc., and hydroxypropyl methyl cellulose has characteristic peaks at 481.17℃, etc.; the licorice flavone-hydroxypropyl-β-cyclodextrin-poloxamer-hydroxypropyl methyl cellulose multi-component supramolecular inclusion compound has characteristic peaks at 539.38℃, etc., while the physical mixture thereof has characteristic peaks at 52.9℃, 512.24℃, etc.; the licorice flavone-β-cyclodextrin-poloxamer-hydroxypropyl methyl cellulose multi-component supramolecular inclusion compound has characteristic peaks at 444.23℃, 537.5℃, etc., while the physical mixture thereof has characteristic peaks at 52.34℃, 393.58℃, 530.66℃, etc.; it is shown that the DSC spectrum of the licorice flavone multi-component supramolecular inclusion compound is different from that of the physical mixture, and the characteristic peaks of DSC of licorice flavone, poloxamer and hydroxypropyl methyl cellulose in the multi-component supramolecular inclusion compound disappear, proving that a new phase is formed.

[0105] Test Example 2: Determination by high performance liquid chromatography

[0106] 1. 0.4 g of the licorice flavone multi-component supramolecular inclusion compound prepared in Example 1 was taken, washed with 20 mL of ethyl acetate, shaken for 2 min, filtered, and the filtrate was discarded. The residue was added with 20 mL of ethyl acetate, shaken for 2 min, filtered, and the second ethyl acetate washing liquid was collected. After being evaporated to dryness, it was dissolved in anhydrous ethanol, made up to 25 mL, filtered, and injected. The liquid chromatogram of the second ethyl acetate washing liquid is shown in Figure 10.

[0107] 2. At the same time, 0.2 g of the multi-component supramolecular inclusion compound after being washed with ethyl acetate twice and dried was taken, added with 80% ethanol, ultrasonically dissolved for 20 min, made up to 50 mL, filtered, and injected. The liquid chromatogram of the licorice flavone multi-component supramolecular inclusion compound after being washed with ethyl acetate twice is shown in Figure 11.

[0108] 3. 0.1 g of licorice flavone crude drug was taken, added with anhydrous ethanol, ultrasonically dissolved, made up to 50 mL, filtered, and injected. The liquid chromatogram of the licorice flavone crude drug is shown in Figure 12.

[0109] The liquid chromatography conditions were as follows: C18 column, detection wavelength 300 nm, flow rate 1.0 mL / min, with acetonitrile and 0.1% phosphoric acid solution as the mobile phase, and the gradient being acetonitrile 19%→45% for 60 min, acetonitrile 45%→62% for 20 min, and acetonitrile 62%→90% for 12 min.

[0110] As shown in FIGS. 10-12, the glycyrrhizin flavone multi-molecular super-molecular inclusion prepared by the present application is washed by ethyl acetate, and there is no chromatographic peak in the second ethyl acetate washing liquid. The retention time of each component peak of the glycyrrhizin flavone multi-molecular super-molecular inclusion after being extracted by 80% ethanol is consistent with that of the glycyrrhizin flavone original medicine, which indicates that the glycyrrhizin flavone component contained in the multi-molecular super-molecular inclusion is consistent with that of the glycyrrhizin flavone original medicine, proves that the glycyrrhizin flavone component is included in the inclusion, and the multi-molecular super-molecular inclusion does not change the chemical components of the glycyrrhizin flavone.

[0111] Test Example 3: Determination of total flavone content by UV spectrophotometry

[0112] Take 50 mg of the sample, add 0.5 mL of water, and then add 20 mL of anhydrous ethanol after being dissolved. After ultrasonic treatment for 20 min, add anhydrous ethanol to constant volume, shake well, filter, and dilute 10 times with anhydrous ethanol. Take glycyrrhizin as a control, and determine the absorbance at 280 nm wavelength to calculate the total flavone content in the glycyrrhizin flavone. The same method is used for blank auxiliary material test, and it is found that the auxiliary material does not interfere with the determination of total flavone.

[0113] Test Example 4: Determination of encapsulation efficiency

[0114] Take 50 mg of the glycyrrhizin flavone multi-molecular super-molecular inclusion prepared by the present application, glycyrrhizin flavone-cyclodextrin binary inclusion (comparative examples 1-2), and glycyrrhizin flavone-cyclodextrin-poloxamer ternary inclusion (comparative examples 3-4) respectively, wash with ethyl acetate, collect the ethyl acetate solution, and then add anhydrous ethanol to dissolve and constant volume to 25 mL after being dried. Filter, dilute 10 times with anhydrous ethanol, take glycyrrhizin as a control, determine the absorbance at 280 nm wavelength, determine the total flavone content in the un-included glycyrrhizin flavone, and calculate the encapsulation efficiency by referring to the method of Test Example 3. The results are shown in Table 3.

[0115] Encapsulation efficiency (%) = (1-amount of un-included drug / total amount of drug in inclusion) x 100%

[0116] As shown in Table 3, the encapsulation efficiency of the glycyrrhizin flavone multi-molecular super-molecular inclusion prepared by the present application is significantly higher than that of the glycyrrhizin flavone-cyclodextrin binary inclusion (comparative examples 1-2).

[0117] Test Example 5: Solubility test

[0118] The glycyrrhizic flavone multi-molecular super-molecular inclusion prepared in the examples 1-15 of the present application, the glycyrrhizic flavone-cyclodextrin binary inclusion (comparative examples 1-2), the glycyrrhizic flavone-cyclodextrin-poloxamer ternary inclusion (comparative examples 3-4), the glycyrrhizic flavone-poloxamer suspension (comparative example 5), and the glycyrrhizic flavone raw drug were respectively taken, added into 10 mL of artificial gastric juice to prepare supersaturated solution, stirred in 37°C water bath for 24 h, filtered, 1 mL of the filtrate was taken, diluted with appropriate amount of anhydrous ethanol, and the absorbance was determined at 280 nm wavelength with glycyrrhizin as a control to calculate the solubility of total flavones in the glycyrrhizic flavone, and the results are shown in Table 3.

[0119] Table 3 solubility and encapsulation efficiency of glycyrrhizic flavone

[0120] As shown in Table 3, the water solubility of the glycyrrhizic flavone multi-molecular super-molecular inclusion prepared in the present application is significantly better than that of the glycyrrhizic flavone raw drug, the glycyrrhizic flavone-cyclodextrin binary inclusion (comparative examples 1-2), and the glycyrrhizic flavone-poloxamer suspension (comparative example 5).

[0121] Test example 6 dissolution test

[0122] The glycyrrhizic flavone multi-molecular super-molecular inclusion prepared in the examples 1-15 of the present application, the glycyrrhizic flavone-cyclodextrin binary inclusion (comparative examples 1-2), the glycyrrhizic flavone-cyclodextrin-poloxamer ternary inclusion (comparative examples 3-4), the glycyrrhizic flavone-poloxamer suspension (comparative example 5), and the glycyrrhizic flavone raw drug were respectively taken to determine the drug dissolution at different times. The dissolution medium was artificial gastric juice, 100 r / min, temperature (37°C±0.5), 5 mL was taken at a fixed time, filtered, diluted 10 times with anhydrous ethanol, the absorbance was determined at 280 nm wavelength with glycyrrhizin as a control to calculate the cumulative dissolution percentage, and the results are shown in Table 4 and Fig. 13.

[0123] Table 4 dissolution test of glycyrrhizic flavone

[0124] The results show that the cumulative dissolution percentage of the glycyrrhizic flavone multi-molecular super-molecular inclusion prepared in the present application is significantly higher than that of the glycyrrhizic flavone raw drug, the glycyrrhizic flavone-poloxamer suspension (comparative example 5), and the glycyrrhizic flavone-cyclodextrin binary inclusion (comparative examples 1-2). Compared with comparative examples 1-5, the time for the glycyrrhizic flavone multi-molecular super-molecular inclusion prepared in the present application to reach the maximum cumulative dissolution percentage is significantly prolonged, which can delay the dissolution and release speed of the glycyrrhizic flavone.

[0125] Test example 7 release test

[0126] The licoricidin-multicomponent supramolecular inclusion gastric retention sustained-release preparation prepared in Examples 16-30 of the present application, the licoricidin-cyclodextrin binary inclusion tablet (Comparative Examples 6-7), the licoricidin-cyclodextrin-poloxamer ternary inclusion tablet (Comparative Examples 8-9), the licoricidin-poloxamer suspension tablet (Comparative Example 10), the licoricidin physical mixture tablet (Comparative Example 11), and Examples 1-2 (dry granulation and tabletting) were respectively taken to determine the drug release at different times. The release medium was artificial gastric juice, 100 r / min, and the temperature was (37±0.5) °C. The time was counted by a stopwatch, the time when the tablet floated to the liquid surface was set as the floating start time, and the time from the floating start to the end of the experiment was set as the continuous floating time. The results are shown in Table 5 and FIG. 14.

[0127] Table 5 Release rate test of licoricidin

[0128] The release rate test results show that the cumulative release percentage of the licoricidin-multicomponent supramolecular inclusion gastric retention sustained-release preparation prepared in the present application is significantly higher than that of the licoricidin physical mixture tablet (Comparative Example 11), the licoricidin-poloxamer suspension tablet (Comparative Example 10), and the licoricidin-cyclodextrin binary inclusion tablet (Comparative Examples 6-7). Compared with Comparative Examples 6-11, the time to reach the maximum cumulative release percentage of the licoricidin-multicomponent supramolecular inclusion gastric retention sustained-release preparation prepared in the present application is significantly prolonged, which can delay the dissolution rate of licoricidin and prolong the retention time of licoricidin in the stomach.

[0129] From the floating start time and the continuous floating time, it can be seen that the licoricidin-multicomponent supramolecular inclusion gastric retention sustained-release preparation prepared in the present application has a floating start time <10 s and a continuous floating time >12 h, and has good floating performance, which is significantly better than other preparations.

[0130] Test Example 8 Stability test

[0131] The licoricidin-multicomponent supramolecular inclusion gastric retention sustained-release preparation prepared in Examples 16-30 of the present application and Comparative Examples 6-11 were taken, packaged with aluminum foil, and placed in an accelerated test condition of temperature 37±1 °C and relative humidity 75%, and sampled at 0, 1, 2, and 3 months, respectively. The total flavonoid content of licoricidin was determined according to the method of Test Example 3, and the cumulative release percentages at 2 h and 8 h were determined according to the method of Test Example 7. The results are shown in Table 6.

[0132] Table 6 Stability test

[0133] The results show that with the prolongation of the storage time of the accelerated test, the total flavone content and the cumulative release percentage of the licoroflavone multi-molecular super-molecular inclusion gastric retention sustained-release preparation and the licoroflavone-cyclodextrin-poloxamer ternary inclusion tablet (comparative examples 8-9) prepared by the present application do not change obviously, while the cumulative release percentage of the licoroflavone binary inclusion tablet (comparative examples 6-7) and the licoroflavone poloxamer suspension tablet (comparative example 10) decreases obviously, which is probably caused by the separation of part of the licoroflavone from the system due to the instability of the system. The cumulative release percentage of the licoroflavone multi-molecular super-molecular inclusion gastric retention sustained-release preparation is significantly better than that of comparative examples 6-7, comparative example 10 and comparative example 11, indicating that the licoroflavone multi-molecular super-molecular inclusion gastric retention sustained-release preparation prepared by the present application has good stability and can effectively prevent phase separation of the system.

[0134] Test example 9 Anti-peptic ulcer animal test

[0135] 1. Test animals: rabbits, male, weighing 2.3-2.7 kg, 30, provided by the animal experiment center of Shenyang Medical College.

[0136] 2. Establishment of animal model: anesthetized by intraperitoneal injection of 10% chloral hydrate 3.5 ml / kg, fixed on the operating table, cut the skin under the xiphoid process, open the abdomen about 10 cm, separate the stomach and place it on the gauze soaked with physiological saline and antibiotics. A glass tube with an inner diameter of 5 mm is vertically placed on the serosal surface of the anterior wall of the stomach about 5 mm below the lesser curvature notch, and 0.1 mL of acetic acid is injected into the tube, continuously stimulating the gastric serosal surface for 60 s. The acetic acid in the glass tube is absorbed with a cotton swab and then lightly wiped twice with a cotton swab dipped in physiological saline, the greater omentum is pulled to cover the acetic acid damaged site and the stomach is returned to the abdominal cavity, then layered sutured (note: water is given on the day of modeling, and free diet is given from the next day), and a gastric ulcer model is obtained.

[0137] 3. Grouping and drug administration scheme: divided into ulcer control group, licoroflavone ordinary tablet group (prepared according to comparative example 11), licoroflavone multi-molecular super-molecular inclusion gastric retention sustained-release tablet group (prepared according to example 16, specification 50 mg / tablet), 10 in each group. On the third day after the operation, drug treatment was started, the dose was 100 mg / kg, once a day, and the ulcer control group was given the same volume of physiological saline. Course of treatment: 30 days.

[0138] 4. Therapeutic effect evaluation

[0139] (1) B-ultrasound observation: B-ultrasound was used to observe the process of tablet retention, movement and disintegration in the stomach.

[0140] (2) Ulcer area change: The stomach was cut along the greater curvature, and the gastric contents were collected and slowly rinsed with 4℃ physiological saline. The ulcer area (S) was used as the evaluation index for curative effect, and the longest diameter and the widest diameter perpendicular to the longest diameter of the ulcer were measured with a vernier caliper. S = π x longest diameter x widest diameter x 1 / 4.

[0141] 5. Statistical processing of test data: SPSS 17.0 statistical software was used for data analysis, and measurement data were expressed as (x ± s). Single-factor variance analysis was used for comparison among multiple sample means, and t-test was used for comparison between two groups. P < 0.05 was considered to be a significant difference, which was statistically significant.

[0142] Test results: The B-ultrasound observation results of the rabbits showed that the licorice flavone raw drug ordinary tablet was retained in the stomach of the rabbits for about 2 h, and the licorice flavone multi-molecular inclusion complex gastric retention sustained-release preparation was retained in the stomach of the rabbits for about 6 h. The sustained-release preparation significantly prolonged the retention time of licorice flavone in the stomach.

[0143] The gastric ulcer curative effect test results are shown in Table 7. Compared with the licorice flavone raw drug ordinary tablet, the licorice flavone multi-molecular inclusion complex gastric retention sustained-release preparation prepared in the application has a significant anti-ulcer effect on the gastric ulcer of the rabbits and has a significant anti-ulcer and repair effect on the gastric ulcer surface.

[0144] Table 7. Curative effect of licorice flavone on gastric ulcer of rabbits

[0145] *: Compared with the control group; **: Compared with the ordinary tablet group.

[0146] Test Example 10 Pharmacokinetic test

[0147] 1. Administration method and blood sample collection: Rabbits, 2.5-3.0 kg, male, were provided by the Animal Experiment Center of Shenyang Medical College. They were divided into two groups and were respectively administered with licorice flavone multi-molecular inclusion complex gastric retention sustained-release tablets (prepared according to Example 16, specification 50 mg / tablet) or licorice flavone ordinary tablets (prepared according to Comparative Example 11) by gavage, 6 tablets per rabbit. Licorice chalcone A is one of the main active components of licorice flavone. The blood sampling time was 1, 2, 3, 4, 5, 6, 7, and 8 h. The blood was collected from the ear margin vein and placed in a heparinized centrifuge tube, which was frozen for later use.

[0148] 2. Blood sample processing method: 1 mL of the blood sample was taken, 1 mL of methanol was added, and the mixture was ultrasonicated in ice water for 2 min, centrifuged for 5 min, and the supernatant was taken for HPLC analysis to determine the mass concentration of licorice chalcone A.

[0149] 3. Liquid chromatography conditions: chromatographic column: C18 column; mobile phase: methanol: water (9:1, v:v); flow rate: 1 mL / min; detection wavelength: 372 nm.

[0150] 4. Standard curve: 3.6 mg of glycyrrhiza chalcone A standard was weighed, and 50 mL of mobile phase solution was prepared. The mobile phase was diluted to the same volume to obtain a series of glycyrrhiza chalcone A solutions with different concentrations, which were stored in a refrigerator. One rabbit was taken, and blood was collected from the ear vein into a heparinized 2 mL centrifuge tube, 1 mL of blood per tube, a total of twelve tubes. 0.1 mL of glycyrrhiza chalcone A standard solution was added to each tube and shaken, and then dried at room temperature under reduced pressure. 1 mL of methanol was added to each tube, which was ultrasonically treated in ice water for 2 min, centrifuged for 5 min, and the supernatant was analyzed by HPLC. The concentration of glycyrrhiza chalcone A in the blood sample was taken as the abscissa, and the peak area was taken as the ordinate. Linear regression was performed, and the linear regression equation was Y = 460.35X + 69.553, R = 0.9975, which had a good linear relationship in the concentration range of 0.05-7.20 μg / mL. 2

[0151] 5. Blood concentration and time curve: The mass concentration of glycyrrhiza chalcone A in blood samples collected at different times was determined, and the blood concentration-time curve of glycyrrhiza chalcone A was plotted, as shown in Figure 15. The blood concentration data of glycyrrhiza flavone multi-molecular inclusion complex gastric retention sustained-release tablets and glycyrrhiza flavone ordinary tablets were processed by Drug And Statistics 1.0 Chinese version of pharmacokinetic software, and the AUC of the two was calculated, as shown in Table 8.

[0152] RF (relative bioavailability) = (AUC1 / AUC2) x 100%

[0153] Table 8 Main pharmacokinetic parameters of glycyrrhiza chalcone A in rabbits after administration of each group

[0154] The test results show that the peak time of glycyrrhiza flavone ordinary tablets is 1 h, and the peak time of glycyrrhiza flavone multi-molecular inclusion complex gastric retention sustained-release tablets is 5 h. Compared with glycyrrhiza flavone ordinary tablets, the relative bioavailability (RF) of glycyrrhiza flavone multi-molecular inclusion complex gastric retention sustained-release tablets is 276.1%, and the glycyrrhiza flavone multi-molecular inclusion complex gastric retention sustained-release preparation prepared by the present application significantly improves the bioavailability of glycyrrhiza chalcone A.

[0155] The above only describes the preferred embodiments of the present application, and it should be noted that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered within the protection scope of the present application.​

Claims

1. Licorice flavone polycomponent supramolecular inclusion complex, characterized in that, The preparation is made from the following raw materials by weight: 10 parts of glycyrrhiza flavones, 10-30 parts of poloxamer, 10-100 parts of cyclodextrin and 1-10 parts of hydroxypropyl methyl cellulose.

2. The method for preparing the licorice flavone poly-molecular inclusion complex of claim 1, characterized in that, The method comprises the following steps: (1) mixing glycyrrhiza flavones and poloxamer with ethanol to obtain a mixed solution 1, then adding water to the mixed solution 1 and continuing to mix, and then adding cyclodextrin and stirring to obtain a mixed solution 2; (2) adding water to hydroxypropyl methyl cellulose and stirring to obtain a mixed solution 3, mixing the mixed solution 3 and the mixed solution 2 of step (1), and drying to obtain a glycyrrhiza flavones multi-component supramolecular inclusion compound.

3. The method for preparing the glycyrrhizin flavonoid multi-component supramolecular inclusion complex as described in claim 2, characterized in that, The glycyrrhiza flavones are glycyrrhiza flavones extract obtained from residues after water extraction of glycyrrhiza, and the content of flavonoids in the glycyrrhiza flavones is ≥80.0%; The poloxamer is poloxamer 188; The cyclodextrin is β-cyclodextrin or hydroxypropyl-β-cyclodextrin; The hydroxypropyl methyl cellulose is hydroxypropyl methyl cellulose K100M.

4. The method for preparing the glycyrrhizin flavonoid multi-component supramolecular inclusion complex as described in claim 3, characterized in that, In step (1), the mass ratio of the glycyrrhiza flavones to ethanol is 10:40-120, the volume fraction of the ethanol is 90-95%, and the mixing temperature is 40-60°C.

5. The method of claim 4, wherein the licofelone polyplex is prepared by the steps of: a) dissolving licofelone in a solvent; b) adding a cyclodextrin to the solution; c) evaporating the solvent; and d) drying the mixture. In step (1), the mass ratio of the glycyrrhiza flavones to water is 10:100-400. The stirring temperature is 40-60°C, and the stirring time is 0.5-2h.

6. The method of claim 5, wherein the licofelone polyplex is prepared by the steps of: a) dissolving licofelone in a solvent; b) adding a cyclodextrin to the solution; c) evaporating the solvent; and d) drying the mixture. In step (2), the mass ratio of the hydroxypropyl methyl cellulose to water is 1:40-50. The stirring temperature is 30-40°C, and the stirring time is 3-5h.

7. The method of claim 6, wherein the licofelone polyplex is prepared by the steps of: a) dissolving licofelone in a solvent; b) adding a cyclodextrin to the solution; c) evaporating the solvent; and d) drying the mixture. In step (2), the mixing temperature of the mixed solution 3 and the mixed solution 2 is 30-40°C.

8. The method of claim 7, wherein the licofelone polyplex is prepared by the steps of: a) dissolving licofelone in a solvent; b) adding a cyclodextrin to the solution; c) evaporating the solvent; and d) drying the mixture. The drying in step (2) is spray drying, the inlet air temperature is 160-180°C, and the outlet air temperature is 70-80°C.

9. A gastric residence sustained release formulation of licorice flavonoid polymeric supramolecular inclusion complex, characterized in that, The glycyrrhiza flavones multi-component supramolecular inclusion compound of claim 1, microcrystalline cellulose and sodium bicarbonate are composed according to a mass ratio of 100:5-15:5-10.

10. Use of the glycyrrhiza flavones multi-component supramolecular inclusion compound of claim 1 or the gastric retention sustained-release preparation of the glycyrrhiza flavones multi-component supramolecular inclusion compound of claim 9 in the preparation of a medicament for treating gastric ulcer or resisting tumors.

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