Flufenamic acid-aloperine co-amorphous substance as well as preparation method and application thereof

Abstract

The invention provides a flufenamic acid-aloperine co-amorphous substance as well as a preparation method and application thereof, and belongs to the technical field of medicines. The flufenamic acid-aloperine co-amorphous substance is prepared from flufenamic acid and aloperine in a molar ratio of (3: 1)-(1: 3), and the co-amorphous substance is prepared by a grinding method or a solution crystallization method. The flufenamic acid-aloperine co-amorphous substance provided by the invention has good stability, and the solubility of flufenamic acid in water can be remarkably improved, so that the bioavailability of the flufenamic acid is improved, and the flufenamic acid-aloperine co-amorphous substance can achieve synergistic interaction.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a flufenamic acid-oxymatrine co-amorphous substance and a preparation method and application thereof. BACKGROUND

[0002] Flufenamic acid (Flu) is a non-steroidal anti-inflammatory drug, which plays an anti-inflammatory, analgesic and antipyretic role by inhibiting the activity of cyclooxygenase (COX) and reducing the synthesis of inflammatory mediators (prostaglandins). Flufenamic acid is mainly used for short-term symptom relief of inflammation-related diseases such as osteoarthritis, rheumatoid arthritis and soft tissue injury.

[0003] According to the biopharmaceutics classification system (BCS), flufenamic acid belongs to BCSII class drugs, which is characterized by poor water solubility, which leads to low oral bioavailability. Therefore, it is of great significance to improve the solubility of flufenamic acid. SUMMARY

[0004] In view of the deficiencies in the prior art, the purpose of the present application is to provide a flufenamic acid-oxymatrine co-amorphous substance and a preparation method and application thereof. The co-amorphous substance has good stability, can significantly improve the solubility of flufenamic acid in water, thereby improving the bioavailability of flufenamic acid, and can also have synergistic effect.

[0005] To achieve this purpose, the following technical solutions are adopted in the present application:

[0006] In a first aspect, the present application provides a flufenamic acid-oxymatrine co-amorphous substance, which is composed of flufenamic acid and oxymatrine in a molar ratio of 3:1-1:3.

[0007] For example, the molar ratio of flufenamic acid to oxymatrine can be 3:1, 2.8:1, 2.6:1, 2.5:1, 2.3:1, 2.2:1, 2:1, 1.8:1, 1.6:1, 1.5:1, 1.3:1, 1.2:1, 1:1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.3, 1:2.5, 1:2.6, 1:2.8 or 1:3, etc. However, the present application is not limited thereto, and other unlisted values within this range are also applicable.

[0008] The molecular formula of flufenamic acid is C 14 H 10 F3NO2, and its structural formula is shown as formula I.

[0009]

[0010] Aloperine (Alo) has a molecular formula of C 15 H 24 N2, as shown in Formula II.

[0011]

[0012] Aloperine is a quinoline alkaloid extracted from Sophora alopecuroides L. and is commonly used in clinic for treating dysentery and has good anti-inflammatory, antioxidant, antiviral and analgesic effects.

[0013] The present application discloses a kind of co-amorphous substances prepared by using flufenamic acid as active pharmaceutical ingredient and aloperine as drug ligand.The co-amorphous substance has good stability under high temperature (60 DEG C), high humidity (75% relative humidity at 25 DEG C), light (4500 lx ± 500 lx) conditions;Its solubility in water at 37 DEG C (calculated as flufenamic acid) is more than 100 times of flufenamic acid raw material, which can significantly improve the bioavailability of flufenamic acid;In addition, aloperine itself also has certain anti-inflammatory effect, so flufenamic acid and aloperine form co-amorphous substance, which also plays a certain synergistic effect.

[0014] In some preferred embodiments of the present application, the molar ratio of flufenamic acid to aloperine is 1:1.

[0015] In some embodiments of the present application, the equilibrium solubility of the flufenamic acid-aloperine co-amorphous substance in water at 37 DEG C is 1.01 mg / mL, calculated as flufenamic acid.

[0016] In a second aspect, the present application provides a preparation method of the flufenamic acid-aloperine co-amorphous substance according to the first aspect, which is a grinding method or a solution crystallization method.

[0017] The grinding method comprises the following steps: soaking flufenamic acid and aloperine in a first solvent, grinding until the first solvent is completely volatilized, to obtain flufenamic acid-aloperine co-amorphous substance.

[0018] The solution crystallization method comprises the following steps: dissolving flufenamic acid and aloperine in a second solvent, and drying to obtain flufenamic acid-aloperine co-amorphous substance.

[0019] In some embodiments of the present application, the first solvent is a combination of 60-95 vol% ethanol aqueous solution and ethyl acetate. For example, the concentration of 60-95 vol% ethanol aqueous solution can be 60 vol%, 65 vol%, 70 vol%, 75 vol%, 80 vol%, 85 vol%, 90 vol% or 95 vol%, etc. However, the present application is not limited to this, and other unlisted values within this range are also applicable.

[0020] In some embodiments of the present application, the volume ratio of 60-95 vol% aqueous ethanol solution to ethyl acetate in the first solvent is 2-3:1; for example, it can be 2:1, 2.2:1, 2.3:1, 2.5:1, 2.6:1, 2.8:1 or 3:1. However, the present application is not limited thereto, and other unlisted values within the range are also applicable.

[0021] In some embodiments of the present application, the ratio of the volume of the first solvent to the total mass of flufenamic acid and fangchinoline is 1.8-5 mL / g; for example, it can be 1.8 mL / g, 2 mL / g, 2.2 mL / g, 2.5 mL / g, 2.8 mL / g, 3 mL / g, 3.2 mL / g, 3.5 mL / g, 3.8 mL / g, 4 mL / g, 4.2 mL / g, 4.5 mL / g, 4.8 mL / g or 5 mL / g, etc. However, the present application is not limited thereto, and other unlisted values within the range are also applicable.

[0022] In some embodiments of the present application, the second solvent is a combination of one or more of 60-95 vol% aqueous ethanol solution, ethyl acetate, acetonitrile, acetone and methanol. Among them, the concentration of 60-95 vol% aqueous ethanol solution can be, for example, 60 vol%, 65 vol%, 70 vol%, 75 vol%, 80 vol%, 85 vol%, 90 vol% or 95 vol%, etc. However, the present application is not limited thereto, and other unlisted values within the range are also applicable.

[0023] In some embodiments of the present application, the ratio of the total mass of flufenamic acid and fangchinoline to the volume of the second solvent is 1-80 mg / mL; for example, it can be 1 mg / mL, 3 mg / mL, 5 mg / mL, 8 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL or 80 mg / mL, etc. However, the present application is not limited thereto, and other unlisted values within the range are also applicable.

[0024] In some embodiments of the present application, the step of dissolving flufenamic acid and roemerine in the second solvent comprises mixing flufenamic acid and roemerine with the second solvent, and stirring at a rotation speed of 500-1000 rpm (for example, it can be 500 rpm, 550 rpm, 600 rpm, 650 rpm, 700 rpm, 750 rpm, 800 rpm, 850 rpm, 900 rpm, 950 rpm or 1000 rpm, etc.) for 8-10 h (for example, it can be 8 h, 8.2 h, 8.5 h, 8.8 h, 9 h, 9.2 h, 9.5 h, 9.8 h or 10 h, etc.). However, the present application is not limited to this, and other unlisted values within the range are also applicable.

[0025] In some embodiments of the present application, the drying method is vacuum drying, and the temperature during drying is 50-70℃; for example, it can be 50℃, 52℃, 55℃, 58℃, 60℃, 62℃, 65℃, 68℃ or 70℃, etc. However, the present application is not limited to this, and other unlisted values within the range are also applicable.

[0026] In a third aspect, the present application provides a flufenamic acid-roemerine co-amorphous material as described in the first aspect or prepared by the preparation method described in the second aspect, for use in the preparation of a medicament for analgesia and / or anti-inflammation.

[0027] In a fourth aspect, a medicament for analgesia and / or anti-inflammation comprises a flufenamic acid-roemerine co-amorphous material as described in the first aspect or prepared by the preparation method described in the second aspect, and a pharmaceutically acceptable carrier, diluent or excipient.

[0028] Compared with the prior art, the present application has the following beneficial effects:

[0029] In the present application, flufenamic acid is used as an active pharmaceutical ingredient, and roemerine is used as a drug ligand, to prepare a co-amorphous material. The co-amorphous material has good stability under high temperature (60℃), high humidity (relative humidity of 75% at 25℃), and light (4500 lx±500 lx) conditions; its solubility in water at 37℃ (calculated based on flufenamic acid) is more than 100 times that of flufenamic acid raw material, which can significantly improve the bioavailability of flufenamic acid; in addition, since roemerine itself also has certain anti-inflammatory effect, the formation of a co-amorphous material of flufenamic acid and roemerine also plays a certain synergistic effect. Therefore, the flufenamic acid-roemerine co-amorphous material provided by the present application has good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1AA comparison chart of PXRD patterns of flufenamic acid, robustin, a mixture of flufenamic acid powder and robustin powder, and the flufenamic acid-robustin co-amorphous provided in Example 2;

[0031] Figure 1A A PXRD pattern of the powder prepared for Comparative Example 1;

[0032] Figure 2 A comparison chart of DSC patterns of flufenamic acid, robustin, and the flufenamic acid-robustin co-amorphous provided in Example 2;

[0033] Figure 3 An infrared spectrum of flufenamic acid, robustin, and the flufenamic acid-robustin co-amorphous provided in Example 2;

[0034] Figure 4A PXRD patterns of the flufenamic acid-robustin co-amorphous provided in Example 2 placed under high temperature conditions for 0, 5, 10 days;

[0035] Figure 4B PXRD patterns of the flufenamic acid-robustin co-amorphous provided in Example 2 placed under high humidity conditions for 0, 5, 10 days;

[0036] Figure 4C PXRD patterns of the flufenamic acid-robustin co-amorphous provided in Example 2 placed under light conditions for 0, 5, 10 days;

[0037] Figure 5 A dissolution curve of flufenamic acid and the flufenamic acid-robustin co-amorphous provided in Example 2. DETAILED DESCRIPTION

[0038] The technical solutions of the present application will be further described below in conjunction with the accompanying drawings and through specific embodiments. Those skilled in the art should understand that the specific embodiments are only to help understand the present application and should not be regarded as specific limitations of the present application.

[0039] Example 1

[0040] This example provides a flufenamic acid-robustin co-amorphous substance, and the preparation method is as follows:

[0041] 28.12 mg (0.1 mol) of flufenamic acid and 23.23 mg (0.1 mol) of robustin were precisely weighed and placed in a mortar, 100 μL of 95 vol% ethanol aqueous solution and 50 μL of ethyl acetate were added, and grinding was performed for 15 min. After the solvent was completely volatilized, a flufenamic acid-robustin co-amorphous substance powder was obtained.

[0042] Example 2

[0043] The present example provides a flufenamic acid-oxymatrine co-amorphous material, which is prepared according to the following method:

[0044] Accurately weigh 28.12 mg (0.1 mol) of flufenamic acid and 23.23 mg (0.1 mol) of oxymatrine, and place them in a Schlenk flask. Add 2 mL of 95 vol% ethanol aqueous solution. The solution is transparent. Stir continuously at 800 rpm using a magnetic stirrer. The solution remains transparent after 8 h. Place the solution in a vacuum drying oven and dry at 60°C for 2 h. Flufenamic acid-oxymatrine co-amorphous material powder is obtained.

[0045] Example 3

[0046] The present example provides a flufenamic acid-oxymatrine co-amorphous material, which is prepared according to the following method:

[0047] Accurately weigh 28.12 mg (0.1 mol) of flufenamic acid and 23.23 mg (0.1 mol) of oxymatrine, and place them in a Schlenk flask. Add 2 mL of 95 vol% ethanol aqueous solution. The solution is transparent. Stir continuously at 800 rpm using a magnetic stirrer. The solution remains transparent after 8 h. Place the solution in a vacuum drying oven and dry at 60°C for 2 h. Flufenamic acid-oxymatrine co-amorphous material powder is obtained.

[0048] Example 4

[0049] The present example provides a flufenamic acid-oxymatrine co-amorphous material, which is prepared according to the following method:

[0050] Accurately weigh 28.12 mg (0.1 mol) of flufenamic acid and 23.23 mg (0.1 mol) of oxymatrine, and place them in a Schlenk flask. Add 2 mL of 95 vol% ethanol aqueous solution. The solution is transparent. Stir continuously at 800 rpm using a magnetic stirrer. The solution remains transparent after 8 h. Place the solution in a vacuum drying oven and dry at 60°C for 2 h. Flufenamic acid-oxymatrine co-amorphous material powder is obtained.

[0051] Example 5

[0052] The present example provides a flufenamic acid-oxymatrine co-amorphous material, which is prepared according to the following method:

[0053] Accurately weigh 28.12 mg (0.1 mol) of flufenamic acid and 23.23 mg (0.1 mol) of oxymatrine, and place them in a Schlenk flask. Add 2 mL of 95 vol% ethanol aqueous solution. The solution is transparent. Stir continuously at 800 rpm using a magnetic stirrer. The solution remains transparent after 8 h. Place the solution in a vacuum drying oven and dry at 60°C for 2 h. Flufenamic acid-oxymatrine co-amorphous material powder is obtained.

[0054] Example 6

[0055] The present example provides a flufenamic acid-alopecurarine co-amorphous material, which is prepared by the following method:

[0056] 56.24 mg (0.2 mol) of flufenamic acid and 23.23 mg (0.1 mol) of alopecurarine were accurately weighed and placed in a Schlenk flask, 8 mL of methanol was added, the solution was transparent, a magnet was added and placed on a magnetic stirrer for continuous stirring at 1000 rpm for 10 h, the solution was still transparent, and the solution was placed in a vacuum drying oven at 70°C for 1 h, to obtain flufenamic acid-alopecurarine co-amorphous material powder.

[0057] Example 7

[0058] The present example provides a flufenamic acid-alopecurarine co-amorphous material, which is prepared by the following method, and the difference from Example 2 is that the solvent 95 vol% ethanol aqueous solution is replaced by ethyl acetate.

[0059] Example 8

[0060] The present example provides a flufenamic acid-alopecurarine co-amorphous material, which is prepared by the following method, and the difference from Example 2 is that the solvent 95 vol% ethanol aqueous solution is replaced by acetonitrile.

[0061] Comparative Example 1

[0062] The difference between the present comparative example and Example 1 is that the solvent is water, and the total volume of the solvent is unchanged.

[0063] Characterization of flufenamic acid-alopecurarine co-amorphous material

[0064] 1. Powder X-ray diffraction spectrum (PXRD)

[0065] PXRD detection was performed on flufenamic acid (Flu), alopecurarine (Alo), a mixture of flufenamic acid powder and alopecurarine powder with a molar ratio of 1:1 (Flu+Alo), flufenamic acid-alopecurarine co-amorphous material powder provided by the present example (Flu-Alo), and the powder prepared in the comparative example.

[0066] Detection instrument: Rigaku D / max-2550 type X-ray powder diffractometer.

[0067] Detection conditions: Cu / K-alpha 1, 40 kV-200 mA, I(max) = 2244, 2θ = 4°-40°, λ = 1.54056 nm.

[0068] The PXRD spectra of Flu, Alo, Flu+Alo, and Flu-Alo provided by Example 2 are shown in the following figure: Figure 1A

[0069] From​Figure 1A It can be seen that the powder X-ray diffraction pattern of flufenamic acid has characteristic diffraction peaks at 2Θ = 13.23°, 17.869°, 18.930°, 19.749°, 24.342°, 26.700°; the powder X-ray diffraction pattern of aloin has characteristic diffraction peaks at 2Θ = 9.5°, 15.29°, 18.24°, 21.99°, 22.38°, 29.67°. The flufenamic acid-aloin co-amorphous material provided in Example 2 only has one larger diffraction ring observed, the powder X-ray diffraction pattern is diffuse, and the characteristic peaks of flufenamic acid and aloin disappear, indicating that the product is in a co-amorphous state. The X-ray diffraction patterns of the flufenamic acid-aloin co-amorphous materials provided in Examples 1, 3-8 are similar to this, and are diffuse.

[0070] The X-ray diffraction pattern of the powder prepared in Comparative Example 1 is shown in Figure 1B It can be seen from Figure 1B that the diffraction peaks are not diffuse, and characteristic peaks appear, indicating that the powder prepared in Comparative Example 1 does not form a co-amorphous material.

[0071] 2. Differential scanning calorimetry detection (DSC)

[0072] Detection instrument: Mettler Toledo DSC3 / 700 / 200 type differential scanning calorimeter.

[0073] Detection conditions and methods: About 3 mg of flufenamic acid (Flu), aloin (Alo), and the flufenamic acid-aloin co-amorphous material (Flu-Alo) provided in Example 2 were weighed, respectively, and detected at a temperature rise rate of 10 ℃ / min from 30 ℃ to 140 ℃.

[0074] The comparison chart of the DSC spectra of Flu, Alo, and the Flu-Alo provided in Example 2 is shown in Figure 2 It can be seen from Figure 2 that flufenamic acid (Flu) has an endothermic peak at 135.07 ℃, aloin (Alo) has an endothermic peak at 73 ℃, and the flufenamic acid-aloin co-amorphous material (Flu-Alo) provided in Example 2 has an endothermic peak at 65.17 ℃. The endothermic peak temperature of the flufenamic acid-aloin co-amorphous material is different from that of flufenamic acid and aloin, which indicates that a new phase is formed.

[0075] 3. Fourier infrared spectrum (IR)

[0076] Detection instrument: Perkin Elmer Spectrum 400 type infrared spectrum detector.

[0077] Determination conditions and methods: Take a proper amount of flu fenamic acid (Flu), aloperine (Alo), the flu fenamic acid-aloperine co-amorphous powder provided in Example 2 (Flu-Alo), and analyze and detect by infrared absorption spectroscopy, scan in the range of 4000-400 cm -1 -1, and record the infrared absorption spectrum.

[0078] The detection results are shown in Figure 3 From Figure 3 it can be seen that the N-H stretching vibration peak of flu fenamic acid (Flu) appears at 3322 cm -1 , and the C=O stretching vibration peak appears at 1652 cm -1 ; the N-H stretching vibration peak of aloperine (Alo) appears at 2920 cm -1 . When flu fenamic acid and aloperine form a co-amorphous substance, the C=O stretching vibration peak of flu fenamic acid and the N-H stretching vibration peak of aloperine move to 1582 cm -1 and 2931 cm -1 , respectively. The above changes may be caused by the formation of hydrogen bonds.

[0079] 4. Stability test

[0080] Detection instrument: HPP260 type constant temperature and humidity incubator, Rigaku D / max-2550 type X-ray powder diffractometer.

[0081] Detection conditions and methods:

[0082] 4.1. High temperature: Take a small amount of flu fenamic acid-aloperine co-amorphous substance (Flu-Alo) provided in Example 2, place it in a weighing bottle, and place the weighing bottle in a drying oven with a temperature of 60°C. Perform PXRD detection at 0, 5, 10 days, respectively.

[0083] 4.2. High humidity: Take a small amount of flu fenamic acid-aloperine co-amorphous substance (Flu-Alo) provided in Example 2, place it in a weighing bottle, and place the weighing bottle in a constant temperature and humidity incubator with a temperature of 25°C and a relative humidity of 75%. Perform PXRD detection at 0, 5, 10 days, respectively.

[0084] 4.3. Light: Take a small amount of flu fenamic acid-aloperine co-amorphous substance (Flu-Alo) provided in Example 2, place it in a weighing bottle, and place the weighing bottle in a white light source with a temperature of 25°C and a light intensity of 4500 lx±500 lx. Perform PXRD detection at 0, 5, 10 days, respectively.

[0085] The detection results under the conditions of high temperature, high humidity, and light are shown in Figure 4A , Figure 4B , respectively.Figure 4C As shown in the figure, under the conditions of high temperature, high humidity and light, the PXRD patterns of the flufenamic acid-allophane co-amorphous substance provided in Example 2 after 5 days and 10 days of storage are still diffuse, and no obvious changes are observed compared with the initial (0 day) PXRD pattern, indicating that the flufenamic acid-allophane co-amorphous substance has good stability.

[0086] 5. Equilibrium solubility determination

[0087] According to the shake flask method, the equilibrium solubility of flufenamic acid (Flu) and the flufenamic acid-allophane co-amorphous substance (Flu-Alo) provided in Example was determined, respectively.

[0088] 5 mL of deionized water was taken in a 15 mL centrifuge tube, an excess of the powder sample was added, sealed, placed on a 37°C shaking bed for stirring, the rotation speed was 120 r / min, and the supernatant was taken at 2 h, 4 h, 8 h, 24 h, 48 h and 60 h, respectively, filtered with a filter membrane, and the content was detected by high performance liquid chromatography (HPLC) method to calculate the equilibrium solubility.

[0089] The dissolution curve of flufenamic acid (Flu) and the flufenamic acid-allophane co-amorphous substance (Flu-Alo) provided in Example 2 is shown in Figure 5 .

[0090] Figure 5 As shown in the figure, under the conditions of high temperature, high humidity and light, the PXRD patterns of the flufenamic acid-allophane co-amorphous substance provided in Example 2 after 5 days and 10 days of storage are still diffuse, and no obvious changes are observed compared with the initial (0 day) PXRD pattern, indicating that the flufenamic acid-allophane co-amorphous substance has good stability.

[0091] The above description is merely a specific implementation of the present disclosure, enabling those skilled in the art to understand or implement the present disclosure. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present disclosure. Therefore, the present disclosure will not be limited to these embodiments described herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A co-amorphous flufenamic acid- picrinine, characterized in that, The flufenamic acid-oxymatrine co-amorphous material is composed of flufenamic acid and oxymatrine in a molar ratio of 3:1-1:

3.

2. The co-amorphous fenamic acid-olivil of claim 1, wherein, The molar ratio of the flufenamic acid to the oxymatrine is 1:

1.

3. The co-amorphous fenamic acid-olivil of claim 1 or 2, characterized in that, The equilibrium solubility of the flufenamic acid-oxymatrine co-amorphous material in water at 37℃ is 1.01 mg / mL in terms of flufenamic acid.

4. A process for the preparation of a co-amorphous flufenamic acid- picraflavine according to any one of claims 1 to 3, characterized in that, The preparation method comprises the following steps: The flufenamic acid and the oxymatrine are infiltrated with a first solvent, and are ground until the first solvent is completely volatilized to obtain the flufenamic acid-oxymatrine co-amorphous material; Or, the flufenamic acid and the oxymatrine are dissolved in a second solvent, and after drying, the flufenamic acid-oxymatrine co-amorphous material is obtained.

5. The preparation method according to claim 4, characterized in that, The first solvent is a combination of 60-95 vol% of an ethanol aqueous solution and ethyl acetate; Preferably, in the first solvent, the volume ratio of the 60-95 vol% of the ethanol aqueous solution to the ethyl acetate is 2-3:

1.

6. The production method according to claim 4 or 5, characterized by, The ratio of the volume of the first solvent to the total mass of the flufenamic acid and the oxymatrine is 1.8-5 mL / g.

7. The preparation method according to claim 4, characterized in that, The second solvent is a combination of one or more of 60-95 vol% of an ethanol aqueous solution, ethyl acetate, acetonitrile, acetone and methanol; Preferably, the ratio of the total mass of the flufenamic acid and the oxymatrine to the volume of the second solvent is 1-80 mg / mL.

8. The production method according to claim 4 or 7, characterized by, The step of dissolving the flufenamic acid and the oxymatrine in the second solvent comprises mixing the flufenamic acid and the oxymatrine with the second solvent, and stirring at a rotation speed of 500-1000 rpm for 8-10 h; Preferably, the drying method is vacuum drying, and the temperature during drying is 50-70℃.

9. The flufenamic acid-oxymatrine co-amorphous material of any one of claims 1-3 or prepared by the preparation method of any one of claims 4-8 for use in the preparation of a medicament for analgesia and / or anti-inflammation.

10. An analgesic and / or anti-inflammatory medicament, characterized in that, The medicament comprises the flufenamic acid-oxymatrine co-amorphous material of any one of claims 1-3 or prepared by the preparation method of any one of claims 4-8, and a pharmaceutically acceptable carrier, diluent or excipient.

Images