Baicalein-piperine-resveratrol ternary co-amorphous substance as well as preparation method and application thereof

Abstract

The invention discloses a baicalein-piperine-resveratrol ternary co-amorphous substance as well as a preparation method and application of the baicalein-piperine-resveratrol ternary co-amorphous substance. The ternary co-amorphous substance is prepared from baicalein, piperine and resveratrol according to the molar ratio of 1: (1-4): 1, and powder X-ray diffraction, differential scanning calorimetry and infrared spectroscopy show that the prepared ternary co-amorphous substance is in an amorphous state different from an independent component and a physical mixture. Compared with a single component, the baicalein-piperine-resveratrol ternary co-amorphous substance has the advantages that the apparent solubility of baicalein, piperine and resveratrol in the baicalein-piperine-resveratrol ternary co-amorphous substance is remarkably improved, the physical stability of the baicalein-piperine-resveratrol ternary co-amorphous substance is superior to that of a binary co-amorphous substance, and the baicalein-piperine-resveratrol ternary co-amorphous substance has remarkably improved bacteriostatic activity, antioxidant activity and anti-inflammatory activity and shows enhanced synergistic pharmacological action.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and specifically relates to a ternary co-amorphous compound of baicalin-piperine-resveratrol and a preparation method and application thereof. Background Art

[0002] Baicalein, chemically known as 5,6,7-trihydroxyflavone, is mainly derived from the root extract of Scutellaria baicalensis of the Labiatae family. Its chemical formula is C 15 H 10 O5. Baicalein has a wide range of pharmacological effects, including anti-tumor, antibacterial, antioxidant and anti-inflammatory properties, as well as the improvement of cerebral blood circulation and anti-platelet aggregation. It also has a positive effect on obesity-related complications and non-alcoholic fatty liver disease. However, baicalein has poor water solubility and low oral bioavailability, which greatly limits its clinical application.

[0003] Resveratrol is a non-flavonoid polyphenol compound and a bioactive component in wine and grape juice. 14 H 12 O3. Resveratrol has a wide range of pharmacological activities, such as anti-oxidation, anti-inflammatory, and anti-tumor. In addition, resveratrol is considered to be one of the most effective anti-aging substances, and it also has the effect of improving metabolic syndrome, Alzheimer's disease, kidney disease, etc. However, its poor solubility, low bioavailability, and rapid metabolism limit its application.

[0004] Piperine, also known as piperamide, is extracted from the ripe fruit of pepper of the Piperaceae family. Its chemical formula is C 17 H 19 NO3. Piperine has a variety of pharmacological activities, such as anti-tumor, antibacterial, antioxidant and anti-inflammatory effects. In addition, piperine is also a natural bioavailability enhancer. When it is used in combination with other drugs, it can improve the efficacy of drugs and increase bioavailability. However, the fact that piperine itself is almost insoluble in water limits its clinical application.

[0005] A co-amorphous substance is an amorphous system composed of two or more small molecules through intermolecular interaction forces (such as hydrogen bonds, π-π stacking, van der Waals forces, etc.). Compared with crystalline substances, amorphous substances have higher Gibbs free energy and the particle surface is easily hydrated, so they are used to improve the solubility and dissolution rate of poorly soluble drugs and improve their bioavailability. In addition, a co-amorphous system composed of two or more drugs may also produce synergistic pharmacological effects or reduce adverse reactions caused by single medication. Therefore, the preparation of a variety of drugs into a co-amorphous system has also attracted much attention in the pharmaceutical industry, especially in line with the synergistic medication characteristics of traditional Chinese medicine with multiple components, multiple targets and multiple pathways. However, the co-amorphous system is in a thermodynamically unstable state, and its physical stability needs further consideration. Studies have shown that the stability of the ternary co-amorphous system is better than that of the binary system. Based on this, the present invention designs baicalein, piperine and resveratrol to be made into a ternary co-amorphous substance to improve drug solubility and dissolution rate. Summary of the invention

[0006] One of the purposes of the present invention is to provide a ternary co-amorphous compound of baicalin-piperine-resveratrol, which is prepared from baicalin, piperine and resveratrol, wherein the molar ratio of baicalin, piperine and resveratrol is 1:(1-4):1.

[0007] The inventors found in preliminary experiments that when the proportion of baicalein or resveratrol was increased, a pure co-amorphous solid could not be obtained.

[0008] Furthermore, the glass transition temperature of the baicalein-piperine-resveratrol ternary co-amorphous compound is 40-110°C.

[0009] Furthermore, the ternary co-amorphous compound of baicalein-piperine-resveratrol has no sharp crystal diffraction peaks in the powder X-ray diffraction pattern.

[0010] The second object of the present invention is to provide a method for preparing the above-mentioned baicalein-piperine-resveratrol ternary co-amorphous compound, which comprises dissolving baicalein, piperine and resveratrol in an organic solvent, removing the solvent by rotary evaporation and then drying to obtain the compound.

[0011] Furthermore, the organic solvent is one or a mixture of methanol, acetone or anhydrous ethanol, preferably a mixed solvent of methanol and acetone (1:2-2:1, v / v).

[0012] Furthermore, the temperature of the rotary evaporation is 50-70°C, preferably 50-60°C.

[0013] The third object of the present invention is to provide a pharmaceutical preparation, comprising the above-mentioned baicalein-piperine-resveratrol ternary co-amorphous compound, and pharmaceutically acceptable excipients and / or carriers.

[0014] The pharmaceutically acceptable excipients and / or carriers are pharmaceutically acceptable excipients and / or carriers known to those skilled in the art, for example, lactose, microcrystalline cellulose, starch, etc. The dosage form of the pharmaceutical preparation can be tablets, capsules, etc.

[0015] The beneficial effects of the present invention are:

[0016] 1. The ternary co-amorphous compound of baicalin-piperine-resveratrol provided by the present invention has a simple preparation method, no other auxiliary materials are added, and has good reproducibility.

[0017] 2. Compared with the three crystalline drugs of baicalin, piperine and resveratrol, the apparent solubility of the drugs in the baicalin-piperine-resveratrol ternary co-amorphous compound is significantly improved; compared with the baicalin-piperine and resveratrol-piperine binary co-amorphous systems, the ternary co-amorphous compound has improved physical stability during dissolution and storage.

[0018] 3. Antibacterial, anti-inflammatory and antioxidant tests show that the baicalein-piperine-resveratrol ternary co-amorphous compound has enhanced antibacterial, anti-inflammatory and antioxidant activities. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is the powder X-ray diffraction (PXRD) pattern of the ternary co-amorphous compound of baicalein-piperine-resveratrol (1:1:1) in Example 1.

[0020] Figure 2 This is the PXRD pattern of the ternary co-amorphous compound of baicalein-piperine-resveratrol (1:2:1) in Example 2.

[0021] Figure 3 This is the PXRD spectrum of the ternary co-amorphous compound of baicalein-piperine-resveratrol (1:3:1) in Example 3.

[0022] Figure 4 This is the PXRD pattern of the ternary co-amorphous compound of baicalein-piperine-resveratrol (1:4:1) in Example 4.

[0023] Figure 5 This is the PXRD spectrum of the baicalein-piperine (1:1) binary co-amorphous compound in Comparative Example 1.

[0024] Figure 6 This is the PXRD pattern of the resveratrol-piperine (1:1) binary co-amorphous compound in Comparative Example 2.

[0025] Figure 7This is the modulated differential scanning calorimetry (MDSC) spectrum of the ternary co-amorphous compound of baicalein-piperine-resveratrol (1:1:1) in Example 1.

[0026] Figure 8 This is the Fourier transform infrared spectrum (FTIR) of the ternary co-amorphous compound of baicalein-piperine-resveratrol (1:1:1) in Example 1.

[0027] Fig. 9 The supersaturated dissolution curves of baicalein in pH 6.8 phosphate buffer of baicalein-piperine-resveratrol (1:1:1) ternary co-amorphous substance, physical mixture and baicalein in Example 1.

[0028] Fig.10 The supersaturated dissolution curves of piperine in the ternary co-amorphous substance of baicalein-piperine-resveratrol (1:1:1), the physical mixture and piperine in pH 6.8 phosphate buffer in Example 1 are shown.

[0029] Fig.11 The supersaturated dissolution curves of resveratrol in pH 6.8 phosphate buffer of baicalein-piperine-resveratrol (1:1:1) ternary co-amorphous substance, physical mixture and resveratrol in Example 1.

[0030] Fig.12 The PXRD patterns of the ternary co-amorphous compound of baicalein-piperine-resveratrol (1:1:1), the binary co-amorphous compound of baicalein-piperine (1:1) and the binary co-amorphous compound of resveratrol-piperine (1:1) in Example 1 after being placed at 40°C for a certain period of time.

[0031] Fig.13 The inhibition zone diagrams of baicalein-piperine-resveratrol (1:1:1) ternary co-amorphous compound, baicalein-piperine (1:1) co-amorphous compound, baicalein, piperine, and resveratrol against (A) Escherichia coli (E. coli) and (B) methicillin-resistant Staphylococcus aureus (MRSA) in Example 1 are shown.

[0032] Fig.14 This is a graph showing the antioxidant capacity of the baicalein-piperine-resveratrol (1:1:1) ternary co-amorphous compound and the baicalein, piperine and resveratrol raw materials in Example 1 tested by the ABTS method.

[0033] Fig.15 This is a graph showing the antioxidant capacity of the baicalein-piperine-resveratrol (1:1:1) ternary co-amorphous compound and the baicalein, piperine and resveratrol raw materials in Example 1 tested by the DPPH method.

[0034] Fig.16This is a graph showing the anti-inflammatory ability of the baicalin-piperine-resveratrol (1:1:1) ternary co-amorphous compound and baicalin, piperine and resveratrol raw materials in Example 1 tested by the NO method. DETAILED DESCRIPTION

[0035] The preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0036] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0037] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0038] Example 1

[0039] 108.1 mg baicalein (0.4 mmol), 114.1 mg piperine (0.4 mmol) and 91.3 mg resveratrol (0.4 mmol) were weighed and placed in a 100 mL round-bottom flask, and 50 mL acetone-methanol (1:1, v / v) mixed solvent was added, and the solution was ultrasonicated at room temperature until it was clear. The resulting solution was evaporated under reduced pressure at 55 ° C to remove the solvent to obtain the corresponding solid powder. It was placed in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. The obtained powder was crushed through an 80-mesh sieve, placed in a desiccator containing calcium chloride, and stored at 4 ° C.

[0040] Example 2

[0041] 54.0 mg baicalein (0.2 mmol), 114.1 mg piperine (0.4 mmol) and 45.6 mg resveratrol (0.2 mmol) were weighed and placed in a 100 mL round-bottom flask, and 30 mL acetone-methanol (1:1, v / v) mixed solvent was added, and the solution was ultrasonicated at room temperature until it was clear. The obtained solution was evaporated under reduced pressure at 55 ° C to remove the solvent to obtain the corresponding solid powder. It was placed in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. The obtained powder was crushed through an 80-mesh sieve, placed in a desiccator containing calcium chloride, and stored at 4 ° C.

[0042] Example 3

[0043] 54.0 mg baicalein (0.2 mmol), 171.2 mg piperine (0.6 mmol) and 45.6 mg resveratrol (0.2 mmol) were weighed and placed in a 100 mL round-bottom flask, and 30 mL acetone-methanol (1:1, v / v) mixed solvent was added, and the solution was ultrasonicated at room temperature until it was clear. The obtained solution was evaporated under reduced pressure at 55 ° C to remove the solvent to obtain the corresponding solid powder. It was placed in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. The obtained powder was crushed through an 80-mesh sieve, placed in a desiccator containing calcium chloride, and stored at 4 ° C.

[0044] Example 4

[0045] 54.0 mg baicalein (0.2 mmol), 228.2 mg piperine (0.8 mmol) and 45.6 mg resveratrol (0.2 mmol) were weighed and placed in a 100 mL round-bottom flask, and 30 mL acetone-methanol (1:1, v / v) mixed solvent was added, and the solution was ultrasonicated at room temperature until it was clear. The obtained solution was evaporated under reduced pressure at 55 ° C to remove the solvent to obtain the corresponding solid powder. It was placed in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. The obtained powder was crushed through an 80-mesh sieve, placed in a desiccator containing calcium chloride, and stored at 4 ° C.

[0046] Example 5

[0047] Weigh 135.1 mg baicalein (0.5 mmol), 142.7 mg piperine (0.5 mmol) and 114.1 mg resveratrol (0.5 mmol) respectively into a 250 mL round-bottom flask, add 80 mL methanol, and ultrasonicate at room temperature until the solution is clear. The resulting solution is evaporated under reduced pressure at 50 ° C to remove the solvent to obtain the corresponding solid powder. Place it in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. After the obtained powder is crushed through an 80-mesh sieve, it is placed in a desiccator filled with calcium chloride and stored at 4 ° C.

[0048] Example 6

[0049] Weigh 162.1 mg baicalein (0.6 mmol), 171.2 mg piperine (0.6 mmol) and 136.9 mg resveratrol (0.6 mmol) respectively into a 250 mL round-bottom flask, add 80 mL acetone, and ultrasonicate at room temperature until the solution is clear. The resulting solution is evaporated under reduced pressure at 50 ° C to remove the solvent to obtain the corresponding solid powder. Place it in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. After the obtained powder is crushed through an 80-mesh sieve, it is placed in a desiccator filled with calcium chloride and stored at 4 ° C.

[0050] Example 7

[0051] 108.1 mg baicalein (0.4 mmol), 114.1 mg piperine (0.4 mmol) and 91.3 mg resveratrol (0.4 mmol) were weighed and placed in a 100 mL round-bottom flask, and 50 mL acetone-methanol (50:50, v / v) mixed solvent was added, and the solution was ultrasonicated at room temperature until it was clear. The obtained solution was evaporated under reduced pressure at 60 ° C to remove the solvent to obtain the corresponding solid powder. It was placed in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. The obtained powder was crushed through an 80-mesh sieve, placed in a desiccator containing calcium chloride, and stored at 4 ° C.

[0052] Comparative Example 1

[0053] Weigh 108.1 mg of baicalein (0.4 mmol) and 114.1 mg of piperine (0.4 mmol) respectively into a 100 mL round-bottom flask, add 50 mL of acetone-methanol (1:1, v / v) mixed solvent, and ultrasonicate at room temperature until the solution is clear. The resulting solution is evaporated under reduced pressure at 55 ° C to remove the solvent to obtain the corresponding solid powder. Place it in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. After the obtained powder is crushed through an 80-mesh sieve, it is placed in a desiccator containing calcium chloride and stored at 4 ° C.

[0054] Comparative Example 2

[0055] Weigh 91.3 mg of resveratrol (0.4 mmol) and 114.1 mg of piperine (0.4 mmol) respectively into a 100 mL round-bottom flask, add 50 mL of acetone-methanol (1:1, v / v) mixed solvent, and ultrasonicate at room temperature until the solution is clear. The resulting solution is evaporated under reduced pressure at 55 ° C to remove the solvent to obtain the corresponding solid powder. Place it in a vacuum drying oven at room temperature for 24 hours to remove the residual solvent in the rotary evaporation product. After the obtained powder is crushed through an 80-mesh sieve, it is placed in a desiccator containing calcium chloride and stored at 4 ° C.

[0056] The samples prepared in the above embodiments and comparative examples are tested below.

[0057] Test Example 1

[0058] The PXRD spectra of the samples were collected using an X-ray diffractometer (Malvern Panalytical, United Kingdom) in the range of 2θ 5°-40°. The radiation source of the equipment was Cu-Kα The tube voltage and tube current were set to 45 kV and 40 mA, respectively, the scanning speed was 4° / min, and the step size was 0.02°.

[0059] like Figure 1-Figure 4 As shown, in the PXRD spectrum of the ternary co-amorphous compound of baicalein-piperine-resveratrol prepared by rotary evaporation, the crystalline peak of the raw material completely disappeared, presenting a single diffuse diffraction ring, proving that a new amorphous solid form was successfully prepared.

[0060] like Figure 5 and Figure 6 As shown, baicalein-piperine binary co-amorphous compound and resveratrol-piperine binary co-amorphous compound were also prepared.

[0061] Test Example 2

[0062] The MDSC spectra of the samples were detected by modulated differential scanning calorimetry (DSC 250, TA Instruments, USA). 3-5 mg of the sample was heated in the temperature range of 5°C to 300°C at a heating rate of 2°C / min, and the total heat flow, reversible heat flow, and irreversible heat flow versus temperature curves were recorded.

[0063] like Figure 7 As shown, in the MDSC spectrum of the ternary co-amorphous compound of baicalein-piperine-resveratrol, a single glass transition temperature was observed, which was different from the melting peak of the crystalline component, proving the successful formation of the ternary co-amorphous compound.

[0064] Test Example 3

[0065] About 2 mg of sample was pressed into a pellet with 200 mg of KBr and the samples were analyzed by Fourier transform infrared spectrometer (Nicolet iS5, Thermo Fisher Scientific Inc., USA) at 4000-500 cm -1 The sample is measured within the range with a resolution of 4.0cm -1 , the number of scans is 64 times.

[0066] like Figure 8 As shown in the figure, compared with the API and the ternary physical mixture of baicalin-piperine-resveratrol (1:1:1), the stretching vibration peak of the phenolic hydroxyl group of baicalin (3409.5 cm -1 ) disappeared, and the stretching vibration peak of the piperine carbonyl group (1633.9 cm -1 ) disappears, and the in-plane bending vibration of the phenolic hydroxyl group of resveratrol decreases from 1384.2 cm -1 Move to 1369.2cm -1 , and the benzene rings of the three components also underwent peak shifts, indicating that there was an interaction between the molecules of baicalein, piperine, and resveratrol in the ternary co-amorphous compound, further proving the formation of a new solid form.

[0067] Test Example 4

[0068] Use a dissolution tester to determine the supersaturated dissolution of the sample in a pH 6.8 phosphate buffer solution. Add the sample to 200 mL of phosphate buffer (pH = 6.8), the medium temperature is 25°C, and the stirring paddle speed is 100 rpm. Take 3 mL of samples at 1, 2, 4, 8, 12, 16, and 24 hours, and immediately add an equal volume of dissolution medium at the same temperature. The removed solution is filtered with a 0.22 μm microporous filter membrane, and then appropriately diluted with a methanol solution, and the drug concentration is determined by HPLC. Each sample is measured in parallel 3 times.

[0069] HPLC determination conditions: the detection system is Shimadzu LC-2050, the chromatographic column is Ultimate XB-C18 (250mm×4.6mm, 5μm), the mobile phase is acetonitrile-0.1% phosphoric acid aqueous solution (50:50, v / v), the flow rate is 1mL / min, the column temperature is 30℃, the detection wavelengths of baicalein, piperine and resveratrol are 280nm, 342nm and 306nm respectively; the injection volume is 10μL.

[0070] like Figure 9-11 As shown, compared with baicalin, piperine and resveratrol crystals, the apparent solubilities of the three components in the baicalin-piperine-resveratrol (1:1:1) ternary co-amorphous compound were 26.0 μg / mL, 22.6 μg / mL and 53.3 μg / mL, respectively, which were 3.2 times, 5.3 times and 4.3 times that of their corresponding crystals, and maintained high supersaturation for at least 24 hours.

[0071] Test Example 5

[0072] The newly prepared ternary amorphous compound of baicalin-piperine-resveratrol was placed in a high temperature environment of 40°C for stability testing, and samples were taken at fixed time points to test the crystallization of the samples by PXRD.

[0073] like Fig.12 As shown, compared with the baicalein-piperine binary co-amorphous compound and the resveratrol-piperine binary co-amorphous compound, the baicalein-piperine-resveratrol ternary co-amorphous compound remained amorphous for at least 30 days, showing a single diffuse diffraction ring and having good physical stability.

[0074] Test Example 6

[0075] The antibacterial activity of baicalein-piperine-resveratrol ternary co-amorphous was evaluated by disk diffusion method. 6CFU / mL) of E. coli and MRSA bacterial solutions were evenly coated on the surface of LB agar plates. 15 μL of sample solution (concentration of 7.4 mM) was dripped on a circular sterilized paper sheet with a diameter of 6 mm and a thickness of 0.7 mm, and placed on the surface of the LB agar plate and cultured in a constant temperature incubator at 37°C for 16 hours. DMSO solution was used as the negative control group. The antibacterial activity of the sample was evaluated by measuring the diameter (mm) of the inhibition zone formed around the sample. The experiment was repeated three times.

[0076] like Fig.13 As shown, the ternary co-amorphous compound of baicalin-piperine-resveratrol has a synergistically enhanced antibacterial effect compared with baicalin, piperine and resveratrol crystals.

[0077] Test Example 7

[0078] The antioxidant capacity of baicalein-piperine-resveratrol ternary co-amorphous was evaluated by ABTS method and DPPH method. The test method of ABTS test is to take 10μL of sample solution with a series of concentrations and mix it with 190μL ABTS working solution in a 96-well plate, react for 6 minutes, and measure the absorption at 734nm by microplate reader. The test method of DPPH test is to take 400μL of sample solution with a series of concentrations and mix it with 600μL DPPH working solution in a 96-well plate, react for 30 minutes, and measure the absorption at 517nm by microplate reader. Each group of experiments was repeated three times.

[0079] like Fig.14 and Fig.15 As shown, compared with baicalin, piperine and resveratrol crystals, the baicalin-piperine-resveratrol ternary co-amorphous compound has superior antioxidant capacity than each raw material.

[0080] Test Case 8

[0081] Mouse mononuclear macrophage Raw 264.7 cells in the logarithmic growth phase were cultured at 2×10 5 / mL density was inoculated in a 24-well plate. After incubation for 24 hours, the cells were pretreated with samples of different concentrations for 2 hours, and lipopolysaccharide (1μg / mL) was added to treat the cells for 24 hours. The culture supernatant was collected and tested with Griess reagent according to the instructions of the detection kit to determine NO. Each sample was tested in parallel 3 times.

[0082] like Fig.16 As shown, the baicalin-piperine-resveratrol ternary co-amorphous compound has increased anti-inflammatory activity within a certain concentration range compared with baicalin, piperine and resveratrol crystals.

Claims

1. A ternary co-amorphous compound of baicalin, piperine and resveratrol, characterized in that: It is prepared from baicalein, piperine and resveratrol, and the molar ratio of baicalein, piperine and resveratrol is 1: (1-4):

1.

2. The ternary co-amorphous compound of baicalein, piperine and resveratrol according to claim 1, characterized in that: The glass transition temperature of the baicalein-piperine-resveratrol ternary co-amorphous compound is 40-110°C.

3. The ternary co-amorphous compound of baicalein, piperine and resveratrol according to claim 1, characterized in that: The ternary co-amorphous compound of baicalein, piperine and resveratrol has no sharp crystal diffraction peak in the powder X-ray diffraction spectrum.

4. The method for preparing the ternary co-amorphous compound of baicalein, piperine and resveratrol according to claim 1, characterized in that: The baicalein, piperine and resveratrol are mixed and dissolved in an organic solvent, the solvent is removed by rotary evaporation and then dried to obtain the product.

5. The preparation method according to claim 4, characterized in that: The organic solvent is one or a mixture of methanol, acetone or anhydrous ethanol.

6. The preparation method according to claim 5, characterized in that: The organic solvent is a mixed solvent of methanol and acetone.

7. The preparation method according to claim 6, characterized in that: The volume ratio of methanol to acetone in the mixed solvent is 1:2-2:

1.

8. The preparation method according to claim 4, characterized in that The temperature of the rotary evaporation is 50-70°C.

9. The preparation method according to claim 8, characterized in that The temperature of the rotary evaporation is 50-60°C.

10. A pharmaceutical preparation, characterized in that The invention comprises the ternary co-amorphous substance of baicalin-piperine-resveratrol as claimed in claim 1, and pharmaceutically acceptable auxiliary materials and / or carriers.

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