Flavonoid compound-meglumine co-amorphous substance and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a flavonoid compound-meglumine co-amorphous substance and a preparation method thereof. The flavonoid compounds comprise baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin and the like, and the co-amorphous substance consists of a single flavonoid compound and meglumine and is prepared by adopting a melting shock cooling method or a rotary evaporation method. The miscibility of the flavonoid compounds and the meglumine is screened through Hansen solubility. The crystal diffraction characteristics, thermodynamic properties and intermolecular interaction of the co-amorphous substance are measured through PXRD, DSC and FTIR, and it is shown that the six flavonoid compounds and meglumine successfully form a co-amorphous system. The solubility and the dissolution rate of the six flavonoid compound-meglumine co-amorphous substance are obviously superior to those of flavonoid bulk drugs, and the physical stability of the formed co-amorphous substance is obviously superior to that of a single amorphous drug, so that the co-amorphous substance shows good patent medicine performance.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a flavonoid compound-methylglucamine co-amorphous substance and a preparation method thereof. Background Art

[0002] Flavonoids are a class of naturally occurring polyphenolic secondary metabolites, mainly from fruits, vegetables, grains, herbs, flower boxes and seeds. At the same time, flavonoids have a variety of pharmacological effects, such as antimicrobial, antiviral, anticancer, anti-inflammatory, antioxidant, neuroprotective and cardiovascular protective effects. In recent years, many flavonoids with different activities have been discovered, such as quercetin, which has antioxidant and coronary artery dilation effects; baicalein, which has antibacterial and antiviral effects; genistein and soy bean extract, which have estrogen-like effects; silymarin, which has liver protection and other effects, is clinically used to treat acute and chronic hepatitis, cirrhosis and various toxic liver damage. However, flavonoids are generally poorly soluble or insoluble in water, and their low solubility / dissolution leads to slow dissolution rate and poor oral bioavailability. Therefore, it is necessary to adopt certain strategies to improve the solubility / dissolution defects of flavonoids.

[0003] To date, a variety of strategies (such as nanoparticles, liposomes, amorphous solid dispersions, inclusion compounds and self-microemulsions) aim to improve the solubility / dissolution rate of poorly soluble drugs. Among these strategies, destroying the drug lattice to amorphize the drug is an effective method to enhance the water solubility of poorly soluble compounds and their oral absorption. However, high-energy amorphous systems are severely limited in their applications due to their own thermodynamic instability during processing, storage and dissolution. Currently, amorphous solid dispersions are prepared by dispersing the drug in a crystalline solid with a high glass transition temperature (T g ) in a polymer matrix to enhance intermolecular forces and reduce molecular mobility to stabilize amorphous drugs. However, potential incompatibility or low compatibility between drugs and polymer carriers may inevitably lead to the use of more polymers to meet effective clinical doses, resulting in a large volume / mass of oral administration. In addition, most of the carriers of amorphous solid dispersions are hydrophilic materials, which have strong hygroscopicity and are prone to reduce physical stability.

[0004] In recent years, drug co-amorphous systems have attracted widespread attention as a potential alternative technology to amorphous solid dispersions, which can effectively overcome the limitations of amorphous solid dispersions. Drug co-amorphous systems (CM) are single homogeneous amorphous systems formed by combining drugs and small molecule ligands (biosafe small molecule excipients or another drug) through intermolecular non-covalent interactions using the principles and methods of crystal engineering. Co-amorphous systems have shown significant improvements in the solubility / dissolution of poorly soluble drugs and their physical stability. In addition, drug-drug co-amorphous systems can be designed to produce combined effects, such as synergistic effects, fewer side effects and pharmacological interactions. Therefore, drug co-amorphous systems are of great significance to pre-formulation research and formulation design of drug preparations, and will receive more and more attention and attention from scholars at home and abroad. However, both amorphous solid dispersions and drug co-amorphous systems are metastable drug amorphous systems, and there may still be a risk of recrystallization during production, dissolution and storage. Summary of the invention

[0005] The present invention provides a flavonoid compound-methylglucamine co-amorphous substance and a preparation method thereof. To achieve the above-mentioned object, the present invention adopts the following technical scheme:

[0006] The flavonoid compound and meglumine co-amorphous product of the present invention is prepared by a melt quenching method or a rotary evaporation method, wherein the flavonoid compound comprises baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin, chrysin, silymarin, licorice root, epicatechin, morin, nobiletin, phloretin, galangin, genistein, taxiflavone or soy isoflavones.

[0007] The flavonoid compounds of the present invention and meglumine are calculated by Hansen solubility, and 13 flavonoid compounds with good miscibility with meglumine are screened out, including baicalin, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin or chrysin.

[0008] The flavonoid compounds of the present invention are preferably baicalein, hesperetin, naringenin, kaempferol, quercetin and isoliquiritigenin.

[0009] Meglumine (MEG), chemically known as N-methyl-D-glucosamine, is a methylamino derivative of sorbitol with a molecular formula of C7H7NO5. It is a white or off-white crystalline powder that is easily soluble in water and slightly soluble in ethanol. Its chemical structure is: The molecular structure of meglumine contains 6 hydrogen bond acceptors, 6 hydrogen bond donors (-OH) and 6 rotatable bonds, all of which can participate in the formation of intermolecular hydrogen bonds. At the same time, the molecular structure of flavonoids is complementary to that of meglumine, and usually contains multiple hydrogen bond acceptors and hydrogen bond donors, and there is a high possibility of forming intermolecular hydrogen bonds between the two. The present invention aims at the water solubility defect of flavonoids, introduces small molecule meglumine as a ligand and prepares a co-amorphous substance with flavonoid drugs, improves the solubility / dissolution of flavonoid components, and is expected to improve its oral bioavailability.

[0010] The flavonoids and meglumine are mixed in a molar ratio of 1:(0.25-4); preferably, the molar ratio of flavonoids:meglumine=1:(0.5-2); most preferably, the molar ratio of flavonoids:meglumine=1:1.

[0011] The method for preparing the flavonoid compound-methylglucamine co-amorphous substance by the melt quenching method is to uniformly mix the flavonoid compound and the methylglucamine in different stoichiometric ratios for 10 minutes using a vortex instrument to obtain a physical mixture. Then, the flavonoid compound-methylglucamine physical mixture in different stoichiometric ratios is poured into an aluminum foil weighing dish and spread in an oil bath. The melting temperature is 130-170°C and the melting time is 2-20 minutes. After complete melting, the sample is immediately taken out and quenched on liquid nitrogen (-196°C) for 2 minutes, vacuum dried and ground to obtain the flavonoid compound-methylglucamine co-amorphous substance.

[0012] The method for preparing the flavonoid compound-methylglucamine co-amorphous substance by rotary evaporation is as follows: placing the flavonoid compound and the meglucamine in a 100 mL single-mouth bottle, adding an organic solvent and ultrasonically dissolving them. The solution is subjected to reduced pressure rotary evaporation to remove the solvent, and vacuum drying is performed to obtain the flavonoid compound-methylglucamine co-amorphous substance.

[0013] The organic solvent is any one of methanol, ethanol or ethyl acetate, preferably methanol. The water bath temperature for removing the organic solvent by rotary evaporation under reduced pressure is 30-60°C and the rotation speed is 50-400 rpm. The preferred temperature is 50°C and the rotation speed is 200 rpm.

[0014] The flavonoid compound-meglumine co-amorphous prepared by the present invention is analyzed by powder X-ray diffraction (PXRD), and the spectrum shows diffuse broad diffraction rings. The spectrum shows a single glass transition temperature by differential scanning calorimetry (DSC). The spectrum of the co-amorphous is shifted to a certain extent compared with the flavonoid raw material and meglumine by Fourier transform infrared spectroscopy (FTIR).

[0015] The flavonoid compound-methylglucamine co-amorphous material of the present invention has significantly improved solubility / dissolution rate and maintained long-term supersaturated dissolution behavior under the conditions of pH 1.2 hydrochloric acid buffer and pH 6.8 phosphate buffer compared to the flavonoid compound crystals, showing good potential for improving the in vivo absorption of flavonoid drugs and their clinical application. Compared with the single amorphous material, the co-amorphous material exhibits higher physical stability.

[0016] Beneficial effects of the present invention:

[0017] The present invention aims to improve the solubility, dissolution and stability of flavonoids by co-amorphizing flavonoids and meglumine to improve the oral bioavailability of flavonoids, thereby providing a new idea for the development of preparations of flavonoids and other poorly soluble drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the powder X-ray diffraction pattern of the flavonoid compound-methylglucamine co-amorphous substance prepared in Example 1;

[0019] Figure 2 is the DSC graph of the flavonoid compound-methylglucamine co-amorphous substance prepared in Example 1;

[0020] Figure 3 is the infrared spectrum of the flavonoid compound-methylglucamine co-amorphous substance prepared in Example 1;

[0021] Figure 4 It is a comparison diagram of the dissolution curves of baicalein crystals, the physical mixture of baicalein and meglumine prepared in Example 1, and the baicalein-meglumine co-amorphous substance prepared in Example 1 under non-sink conditions;

[0022] Figure 5 It is a comparison diagram of the dissolution curves of hesperetin crystals, the physical mixture of hesperetin and meglumine prepared in Example 1, and the hesperetin-meglumine co-amorphous substance prepared in Example 1 under non-sink conditions;

[0023] Figure 6 is a comparative diagram of the dissolution curves of naringenin crystals, the physical mixture of naringenin and meglumine prepared in Example 1, and the naringenin-meglumine co-amorphous substance prepared in Example 1 under non-sink conditions;

[0024] Figure 7 is a comparative diagram of the dissolution curves of kaempferol crystals, the physical mixture of kaempferol and meglumine prepared in Example 1, and the kaempferol-meglumine co-amorphous substance prepared in Example 1 under non-sink conditions;

[0025] Figure 8It is a comparison diagram of the dissolution curves of quercetin crystals, the physical mixture of quercetin and meglumine prepared in Example 1, and the quercetin-meglumine co-amorphous prepared in Example 1 under non-sink conditions;

[0026] Fig. 9 It is a comparative diagram of the dissolution curves of isoliquiritigenin crystals, the physical mixture of isoliquiritigenin and meglumine prepared in Example 1, and the isoliquiritigenin-meglumine co-amorphous substance prepared in Example 1 under non-sink conditions;

[0027] Fig.10 This is the PXRD pattern of the stability comparison of baicalein amorphous form;

[0028] Fig.11 This is the PXRD pattern of stability comparison of hesperidin amorphous;

[0029] Fig.12 This is the PXRD pattern of stability comparison of naringenin amorphous;

[0030] Fig.13 This is the PXRD pattern of stability comparison of kaempferol amorphous;

[0031] Fig.14 is the PXRD pattern of stability comparison of quercetin amorphous;

[0032] Fig.15 is the PXRD pattern of stability comparison of isoliquiritigenin amorphous;

[0033] Fig.16 is a PXRD diagram of stability comparison of baicalein-methylglucamine co-amorphous prepared in Example 1;

[0034] Fig.17 is a PXRD diagram of stability comparison of hesperetin-methylglucamine co-amorphous prepared in Example 1;

[0035] Fig.18 is a PXRD diagram of stability comparison of naringenin-methylglucamine co-amorphous compound prepared in Example 1;

[0036] Fig.19 is a PXRD diagram of stability comparison of kaempferol-methylglucamine co-amorphous material prepared in Example 1;

[0037] Fig. 20 is a PXRD diagram of stability comparison of quercetin-methylglucamine co-amorphous prepared in Example 1;

[0038] Fig.21 This is a PXRD diagram for stability comparison of the isoliquiritigenin-methylglucamine co-amorphous product prepared in Example 1. DETAILED DESCRIPTION

[0039] The present invention will be further described below in conjunction with the embodiments.

[0040] Example 1

[0041] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in EP tube, vortex mix for 10 min. Transfer the flavonoid compound-meglumine physical mixture to an aluminum foil weighing dish, heat in a 150°C electric constant temperature oil bath for 5 min, and immediately quench it with liquid nitrogen after melting completely. Then, grind and dry, and seal and store at 4°C.

[0042] Test 1: The flavonoid compound-methylglucamine co-amorphous substance of Example 1 was characterized as follows:

[0043] 1. Powder X-ray Diffraction

[0044] The analysis was performed using a SmartLab9 X-ray diffractometer (Rigaku, Japan) with Cu-Kα palladium as the emission source, with the tube voltage set to 40 KV, the tube current set to 40 mA, the step length set to 0.02°, the scanning speed set to 4° / min, and the scanning range set to 2θ, 5-40°. The crystal diffraction peaks of the co-amorphous flavonoid-methylglucamine were scanned.

[0045] like Figure 1 As shown, in Example 1, the crystal diffraction peaks of the baicalein-meglumine combination, hesperetin-meglumine combination, naringenin-meglumine combination, kaempferol-meglumine combination, quercetin-meglumine combination and isoliquiritigenin-meglumine combination in the PXRD spectrum disappeared, showing a diffuse broad diffraction halo, indicating that the 6 flavonoids (baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin) and meglumine combination coexist in an amorphous state. In Examples 2 to 16, the baicalein-meglumine combination, hesperetin-meglumine combination, naringenin-meglumine combination, kaempferol-meglumine combination, quercetin-meglumine combination and isoliquiritigenin-meglumine combination showed the same or similar PXRD patterns.

[0046] 2. Differential Scanning Calorimetry

[0047] About 5 mg of each flavonoid-methylglucamine co-amorphous complex was placed in an aluminum crucible and analyzed using a HITACHIDSC 7020 differential scanning calorimeter (Hitachi Profile, Japan). The temperature was increased from 25°C to 200°C at a heating rate of 10°C / min, and dry nitrogen was used as the carrier gas at a flow rate of 80 mL / min.

[0048] like Figure 2 As shown, in Example 1, the DSC spectra of baicalein-methylglucamine co-amorphous, kaempferol-methylglucamine co-amorphous, hesperetin-methylglucamine co-amorphous, naringenin-methylglucamine co-amorphous, quercetin-methylglucamine co-amorphous and isoliquiritigenin-methylglucamine co-amorphous showed that the endothermic melting peak of the flavonoid compound crystals disappeared and had a single glass transition temperature, which were 56.2°C, 63.7°C, 58.4°C, 57.5°C, 69.9°C and 59.4°C, respectively. In Examples 2 to 16, baicalein-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous showed similar DSC spectra, showing the disappearance of the crystalline melting peak and a single glass transition temperature, and the glass transition temperature was slightly different with the change of the molar ratio.

[0049] 3. Infrared spectroscopy

[0050] The interaction between the co-amorphous products was analyzed using a Thermo Scientific Nicolet iS50 Fourier transform infrared spectrometer (Thermo Fisher Scientific, America). The flavonoid compound-methylglucamine co-amorphous products were fully ground with potassium bromide and pressed into a 3 mm thick sheet under a pressure of about 1000 pis. The scanning range was 4000-400 cm -1 , with 4cm -1 The resolution was scanned 64 times.

[0051] like Figure 3 As shown in Example 1, the FTIR spectrum wave number (cm -1 ) are: 3385.42, 2926.50, 1659.82, 1605.87, 1578.40, 1447.41, 1374.21, 1288.12, 1242.71, 1179.11, 1080.80, 1033.66, 917.12, 897.81, 838.81, 764.27, 719.58, 687.25, 646.00, 578.41, 517.40 and 433.39cm-1 .

[0052] FTIR spectrum of hesperetin-methylglucamine co-amorphous compound (cm -1 ) are: 3404.75, 2931.00, 1640.08, 1514.34, 1442.74, 1347.22, 1273.89, 1181.82, 1130.82, 1081.74, 1025.90, 865.40, 807.05, 763.08, 743.57, 553.55 and 429.26 cm -1 .

[0053] FTIR spectrum of naringenin-methylglucamine co-amorphous compound (cm -1 ) are: 3404.74, 2931.00, 1640.09, 1514.36, 1442.76, 1347.22, 1273.91, 1181.82, 1130.85, 1081.89, 1025.88, 865.47, 807.20, 763.10, 743.63, 555.20 and 429.34cm -1 .

[0054] FTIR spectrum of kaempferol-methylglucamine co-amorphous compound (cm -1 ) are: 3404.97, 2920.20, 1651.86, 1609.36, 1560.71, 1496.72, 1369.14, 1312.11, 1257.76, 1173.06, 1081.43, 971.90, 880.76, 838.88, 692.78, 634.31, 587.52 and 516.26cm -1 .

[0055] FTIR spectrum of quercetin-methylglucamine co-amorphous compound (cm -1 ) are: 3384.96, 1601.07, 1566.69, 1507.84, 1458.66, 1361.81, 1319.55, 1247.48, 1207.98, 1169.65, 1108.99, 1004.46, 933.94, 878.63, 828.53, 796.74, 704.42, 643.86 and 464.27cm -1 .

[0058] FTIR spectrum of isoliquiritigenin-methylglucamine co-amorphous compound (cm -1) are: 3385.38, 2929.89, 1617.21, 1493.66, 1464.66, 1464.97, 1386.53, 1362.95, 1288.12, 1232.38, 1166.10, 1084.28, 839.86, 626.52 and 541.53cm -1 .

[0059] Test 2: The saturated solubility test of the flavonoid compound-methylglucamine co-amorphous substance of Example 1 was carried out as follows:

[0060] Weigh the excess flavonoid crystals, flavonoid-meglumine physical mixture, and flavonoid-meglumine co-amorphous substance and dissolve them in 5 mL of HCl buffer (pH 1.2) and phosphate buffer solution (pH 6.8), place them in a constant temperature shaker at 37℃±0.5℃ for 24 hours to achieve solubility equilibrium, centrifuge them at a speed of 12000rpm for 10 minutes, take the supernatant and filter it through a 0.45μm microporous membrane and dilute it with methanol. Take the filtrate for HPLC analysis to determine the concentration of flavonoids in each sample. The chromatographic column used in this study is Ultimate XB-C18 (4.6mm×250mm, 5μm), the mobile phase is acetonitrile-0.3% phosphoric acid water = 60:40 (V / V), the injection volume is 10μL, the flow rate is 1.0mL / min, and each sample is measured in parallel 3 times.

[0061] From Table 1, it can be seen that there is no significant difference in the solubility of flavonoids and physical mixtures in the two media. However, the solubility of flavonoid-meglumine co-amorphous compound in pH 1.2 HCl buffer solution increased by 2.25 to 17.86 times and the solubility in pH 6.8 phosphate buffer solution increased by 2.46 to 14.92 times. Therefore, by co-amorphizing flavonoids and meglumine, the solubility of flavonoids is significantly increased. The flavonoid-meglumine co-amorphous complex in Examples 2 and 8 also showed significantly improved solubility.

[0062] From Table 2, it can be seen that the solubility of other flavonoids (chrysin, fisetin) and their melt-quenched products with meglumine in the two pH media did not show a significant increase.

[0063] Table 1 Solubility of flavonoid crystals, flavonoid-meglumine physical mixture and flavonoid-meglumine co-amorphous

[0064]

[0065]

[0066] Table 2 Solubility of other flavonoid crystals and flavonoid-methylglucamine preparation products (preparation method is the same as above)

[0067]

[0068] Test 3: A non-sink dissolution test was performed on the flavonoid compound-methylglucamine co-amorphous substance in Example 1, as follows:

[0069] Take excess flavonoid crystals, flavonoid-glucamine physical mixture (molar ratio 1:1), and flavonoid-glucamine co-amorphous (molar ratio 1:1), and use the slurry method for non-leakage tank dissolution evaluation according to the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia. The dissolution medium is pH 1.2 HCl buffer and pH 6.8 phosphate buffer solution. The medium temperature is 37℃±0.5℃ and stirred at 100rpm. Take 2mL of samples in EP tubes at different times, and add isothermal and equal volumes of dissolution medium at the same time. Take out the liquid through a 0.45μm microporous filter membrane and dilute it by half with methanol. Take the filtrate for HPLC analysis and record the peak area respectively. Each sample is measured in parallel 3 times.

[0070] like Figures 4 to 9 As shown in Tables 3 and 5, in Example 1, the flavonoid raw material and the physical mixture showed similar dissolution curves, and the dissolution concentration was low, while the dissolution of baicalein-meglumine co-amorphous, hesperidin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous was significantly improved compared with the corresponding crystalline drug and reached the maximum supersaturation concentration maintained at 12h. The flavonoid-meglumine co-amorphous complex in Examples 2 and 8 also showed significantly improved dissolution concentrations at different time points. From Tables 4 and 6, it can be compared that other flavonoid raw materials (chrysin, fisetin) and their quenched products with meglumine melt in different pH media showed similar dissolution curves, which were not significantly improved.

[0071] At 12 h, under the condition of hydrochloric acid buffer solution of pH 1.2, the baicalein-methylglucamine co-amorphous in Example 1 was increased by 6.17 times compared with baicalein; the hesperidin-methylglucamine co-amorphous in Example 1 was increased by 5.79 times compared with hesperidin; the naringenin-methylglucamine co-amorphous in Example 1 was increased by 4.33 times compared with naringenin; the kaempferol-methylglucamine co-amorphous in Example 1 was increased by 4.14 times compared with kaempferol; the quercetin-methylglucamine co-amorphous in Example 1 was increased by 15.15 times compared with quercetin; and the isoliquiritigenin-methylglucamine co-amorphous in Example 1 was increased by 2.25 times compared with isoliquiritigenin.

[0072] At 12 h, under the conditions of pH 6.8 phosphate buffer, the baicalein-meglumine co-amorphous in Example 1 was 3.52 times higher than that of baicalein; the hesperidin-meglumine co-amorphous in Example 1 was 9.17 times higher than that of hesperidin; the naringenin-meglumine co-amorphous in Example 1 was 4.72 times higher than that of naringenin; the kaempferol-meglumine co-amorphous in Example 1 was 25.42 times higher than that of kaempferol; the quercetin-meglumine co-amorphous in Example 1 was 8.58 times higher than that of quercetin; and the isoliquiritigenin-meglumine co-amorphous in Example 1 was 2.48 times higher than that of isoliquiritigenin.

[0073] Table 3 Dissolution concentrations of flavonoid crystals and flavonoid-meglumine co-amorphous at different time points under pH 1.2 (μg / mL)

[0074]

[0075]

[0076]

[0077] Table 4 Dissolution concentrations (μg / mL) of other flavonoid crystals and flavonoid-methylglucamine preparation products (preparation method is the same as above) at different time points under pH 1.2 conditions

[0078]

[0079] Table 5 Dissolution concentrations of flavonoid crystals and flavonoid-methylglucamine co-amorphous at different time points under pH 6.8 (μg / mL)

[0080]

[0081]

[0082] Table 6 Dissolution concentrations (μg / mL) of other flavonoid crystals and flavonoid-methylglucamine preparation products (preparation method is the same as above) at different time points under pH 6.8

[0083]

[0084] Test 4: The stability test of the flavonoid compound-methylglucamine co-amorphous substance in Example 1 was carried out as follows:

[0085] Baicalein amorphous, hesperidin amorphous, naringenin amorphous, kaempferol amorphous, quercetin amorphous and isoliquiritigenin amorphous were prepared by melt quenching method, firstly, 1g of the above flavonoid compounds were weighed and placed in an aluminum foil pan, floated in an oil bath, and heated to 5°C above the melting point to melt the crystalline drug. Then, it was immediately placed in a liquid nitrogen environment for quenching, and the obtained product was dried and ground and stored for later use.

[0086] In order to comprehensively evaluate the stability of the co-amorphous preparations during storage, baicalein amorphous, hesperetin amorphous, naringenin amorphous, kaempferol amorphous, quercetin amorphous, isoliquiritigenin amorphous, baicalein-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous were placed in a drug stability test chamber at 25°C and 40°C, and the powder X-ray diffraction (PXRD) was used to evaluate the physical stability at different time points.

[0087] like Figures 10 to 15 As shown in the figure, baicalein amorphous, hesperidin amorphous, naringenin amorphous, kaempferol amorphous, quercetin amorphous and isoliquiritigenin amorphous were stored at 25°C and 40°C, and the PXRD diffraction patterns showed characteristic diffraction peaks of crystals. The results showed that baicalein amorphous, hesperidin amorphous, naringenin amorphous and quercetin amorphous had recrystallized within 14 days, and kaempferol amorphous had recrystallized within 30 days. Isoliquiritigenin amorphous did not show characteristic diffraction peaks in the PXRD diffraction pattern within 90 days, indicating that isoliquiritigenin amorphous has high physical stability.

[0088] like Figures 16 to 21 As shown, the baicalein-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous in Example 1 were stored at 25°C and 40°C for 90 days, and no characteristic diffraction peaks were shown in the PXRD diffraction patterns. The results indicate that the baicalein-meglumine co-amorphous has a high physical stability.

[0089] Example 2

[0090] Weigh baicalein (204.52 mg)-meglumine (295.45 mg), hesperidin (218.19 mg)-meglumine (281.81 mg), naringenin (205.42 mg)-meglumine (294.58 mg), kaempferol (211.50 mg)-meglumine (288.49 mg), quercetin (218.17 mg)-meglumine (281.83 mg), isoliquiritigenin (198.13 mg)-meglumine (301.87 mg) respectively, place in EP tube, vortex mix for 10 min. Transfer the flavonoid compound-meglumine physical mixture to an aluminum foil weighing dish, heat in a 150°C electric constant temperature oil bath for 5 min, and immediately quench it with liquid nitrogen after melting completely. Then, grind and dry, and seal and store at 4°C.

[0091] Example 3

[0092] Weigh approximately baicalein (367.33 mg)-meglumine (132.67 mg), hesperidin (377.96 mg)-meglumine (122.04 mg), naringenin (368.05 mg)-meglumine (131.95 mg), kaempferol (373.86 mg)-meglumine (127.14 mg), quercetin (377.94 mg)-meglumine (122.06 mg), and isoliquiritigenin (362.08 mg)-meglumine (137.92 mg) respectively, place in an EP tube, and vortex mix for 10 minutes. Transfer the flavonoid compound-meglumine physical mixture to an aluminum foil weighing dish, heat it in a 150°C electric constant temperature oil bath for 5 minutes, and immediately quench it with liquid nitrogen after it is completely melted. Subsequently, grind and dry, and seal it and store it dry at 4°C.

[0093] Example 4

[0094] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in EP tube, and vortex mix for 10 min. Transfer the flavonoid compound-meglumine physical mixture to an aluminum foil weighing dish, heat in a 130°C electric constant temperature oil bath for 5 min, and immediately quench it with liquid nitrogen after melting completely. Then, grind and dry, and seal and store at 4°C.

[0095] Example 5

[0096] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperetin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in EP tube, vortex mix for 10 min. Transfer the flavonoid compound-meglumine physical mixture to an aluminum foil weighing dish, heat in a 170°C electric constant temperature oil bath for 5 min, and immediately quench it with liquid nitrogen after melting completely. Then, grind and dry, and seal and store at 4°C.

[0097] Example 6

[0098] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in EP tube, vortex mix for 10 min. Transfer the flavonoid compound-meglumine physical mixture to an aluminum foil weighing dish, heat in a 150°C electric constant temperature oil bath for 2 min, and immediately quench it with liquid nitrogen after melting completely. Then, grind and dry, and seal and store at 4°C.

[0099] Example 7

[0100] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in EP tube, vortex mix for 10 min. Transfer the flavonoid compound-meglumine physical mixture to an aluminum foil weighing dish, heat in a 150°C electric constant temperature oil bath for 20 min, and immediately quench it with liquid nitrogen after melting completely. Then, grind and dry, and seal and store at 4°C.

[0101] Example 8

[0102] Baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) were weighed respectively, placed in a 100 mL single-mouth bottle, 50 mL of methanol was added, and ultrasonically dissolved to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50°C water bath, and the speed was set to 200 rpm. After the methanol was completely volatilized, the corresponding solid sample was obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0103] Example 9

[0104] Baicalein (204.52 mg)-meglumine (295.45 mg), hesperidin (218.19 mg)-meglumine (281.81 mg), naringenin (205.42 mg)-meglumine (294.58 mg), kaempferol (211.50 mg)-meglumine (288.49 mg), quercetin (218.17 mg)-meglumine (281.83 mg), isoliquiritigenin (198.13 mg)-meglumine (301.87 mg) were weighed respectively, placed in a 100 mL single-mouth bottle, 50 mL of methanol was added, and ultrasonically dissolved to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50°C water bath, and the speed was set to 200 rpm. After the methanol was completely volatilized, the corresponding solid sample was obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0105] Example 10

[0106] Weigh about baicalein (367.33 mg)-meglumine (132.67 mg), hesperidin (377.96 mg)-meglumine (122.04 mg), naringenin (368.05 mg)-meglumine (131.95 mg), kaempferol (373.86 mg)-meglumine (127.14 mg), quercetin (377.94 mg)-meglumine (122.06 mg), isoliquiritigenin (362.08 mg)-meglumine (137.92 mg), place in a 100 mL single-mouth bottle, add 50 mL of methanol, and ultrasonically dissolve to obtain a clear and transparent solution. The solution is placed on a reduced pressure rotary evaporator in a 50°C water bath, and the speed is set to 200 rpm. After the methanol is completely volatilized, the corresponding solid sample is obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0107] Embodiment 11

[0108] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in a 100 mL single-mouth bottle, add 50 mL of methanol, and ultrasonically dissolve to obtain a clear and transparent solution. The solution is placed on a reduced pressure rotary evaporator in a 40°C water bath, and the speed is set to 200 rpm. After the methanol is completely volatilized, the corresponding solid sample is obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0109] Example 12

[0110] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in a 100 mL single-mouth bottle, add 50 mL of methanol, and ultrasonically dissolve to obtain a clear and transparent solution. The solution is placed on a reduced pressure rotary evaporator in a 60°C water bath, and the speed is set to 200 rpm. After the methanol is completely volatilized, the corresponding solid sample is obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0111] Embodiment 13

[0112] Baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) were weighed respectively, placed in a 100 mL single-mouth bottle, 50 mL of ethanol was added, and ultrasonically dissolved to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50°C water bath, and the speed was set to 200 rpm. After the ethanol was completely evaporated, the corresponding solid sample was obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0113] Embodiment 14

[0114] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in a 100 mL single-mouth bottle, add 50 mL of ethyl acetate, and dissolve by ultrasonication to obtain a clear and transparent solution. The solution is placed on a reduced pressure rotary evaporator in a 50°C water bath, and the speed is set to 200 rpm. After the ethyl acetate is completely volatilized, the corresponding solid sample is obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0115] Embodiment 15

[0116] Weigh baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) respectively, place in a 100 mL single-mouth bottle, add 50 mL of methanol, and ultrasonically dissolve to obtain a clear and transparent solution. The solution is placed on a reduced pressure rotary evaporator in a 50°C water bath, and the speed is set to 50 rpm. After the methanol is completely volatilized, the corresponding solid sample is obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0117] Example 16

[0118] Baicalein (290.30 mg)-meglumine (209.70 mg), hesperidin (303.80 mg)-meglumine (196.20 mg), naringenin (291.20 mg)-meglumine (208.80 mg), kaempferol (297.26 mg)-meglumine (202.74 mg), quercetin (303.78 mg)-meglumine (196.22 mg), isoliquiritigenin (283.80 mg)-meglumine (216.20 mg) were weighed respectively, placed in a 100 mL single-mouth bottle, 50 mL of methanol was added, and ultrasonically dissolved to obtain a clear and transparent solution. The solution was placed on a reduced pressure rotary evaporator in a 50°C water bath, and the speed was set to 400 rpm. After the methanol was completely volatilized, the corresponding solid sample was obtained. The sample was removed from the rotary evaporator and placed in a vacuum drying oven to dry at room temperature for 24 h to remove the residual organic solvent and pass through an 80-mesh sieve. The sieved powder was sealed and stored dry at 4°C.

[0119] Test 5: The Hansen solubility calculation of the flavonoid-meglumine co-amorphous was performed as follows:

[0120] The Hansen solubility parameter (δ) was calculated by Molecular Modeling Pro software, and the flavonoid drugs with good miscibility with meglumine were screened out according to the solubility parameter difference (Δδ). It can be seen from Table 7 that 13 flavonoid compounds (baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin, chrysin) have good miscibility with meglumine. However, rotenone, chalcone, galangin, taxifolin, etc. have poor miscibility with meglumine.

[0121] Table 7 Hansen solubility parameters (δ) of flavonoid crystals and meglumine crystals

[0122]

[0123]

[0124] In Examples 2 to 16, baicalein-meglumine co-amorphous, hesperetin-meglumine co-amorphous, naringenin-meglumine co-amorphous, kaempferol-meglumine co-amorphous, quercetin-meglumine co-amorphous and isoliquiritigenin-meglumine co-amorphous showed the same or similar FTIR spectra.

Claims

1. A flavonoid compound-methylglucamine co-amorphous substance, characterized in that: The co-amorphous material is prepared from flavonoids and meglumine by melt quenching or rotary evaporation; wherein the flavonoids include baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin, chrysin, silymarin, licorice, epicatechin, morin, nobiletin, phloretin, galangin, genistein, taxiflavone or soy isoflavones.

2. The flavonoid compound-methylglucamine co-amorphous substance according to claim 1, characterized in that: The flavonoid compound is: baicalein, hesperetin, naringenin, kaempferol, quercetin, isoliquiritigenin, daidzein, genistein, luteolin, apigenin, fisetin, myricetin or chrysin.

3. The flavonoid compound-methylglucamine co-amorphous substance according to claim 1, characterized in that: The flavonoid compounds are baicalein, hesperetin, naringenin, kaempferol, quercetin and isoliquiritigenin.

4. The flavonoid compound-methylglucamine co-amorphous substance according to claim 1, characterized in that: The molar ratio of the flavonoid compound to meglumine is 1:0.25-4.

5. The flavonoid compound-methylglucamine co-amorphous substance according to claim 1, characterized in that: The molar ratio of the flavonoid compound to meglumine is 1:0.5-2.

6. The flavonoid compound-methylglucamine co-amorphous substance according to claim 1, characterized in that: The melting temperature of the melt quenching method is 130 to 170° C., and the melting time is 2 to 20 minutes.

7. The flavonoid compound-methylglucamine co-amorphous substance according to claim 1, characterized in that: The water bath temperature of the rotary evaporation method is 30-60° C., and the rotation speed is 50-400 rpm.

8. The flavonoid compound-methylglucamine co-amorphous substance according to claim 1, characterized in that: The organic solvent used in the rotary evaporation method is any one of methanol, ethanol or ethyl acetate.

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