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

Abstract

The invention provides a mefenamic acid-aloperine co-amorphous substance as well as a preparation method and application thereof, and belongs to the technical field of medicines. The mefenamic acid-aloperine co-amorphous substance is prepared from mefenamic acid and aloperine in a molar ratio of 1: (0.5-3), and the co-amorphous substance is prepared by a grinding method or a solution crystallization method. The mefenamic acid-aloperine co-amorphous substance provided by the invention has good stability, and the solubility of mefenamic acid in water can be remarkably improved, so that the bioavailability of mefenamic acid is improved, and the mefenamic acid-aloperine co-amorphous substance can achieve synergistic interaction.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a mefenamic acid-sophorapine co-amorphous compound, a preparation method and an application thereof. Background Art

[0002] Mefenamic acid (Mef) is a nonsteroidal anti-inflammatory drug that primarily exerts analgesic and anti-inflammatory effects by inhibiting prostaglandin synthase. Most NSAIDs have low solubility and high permeability, and mefenamic acid is no exception. Mefenamic acid, a Class II drug in the Biopharmaceutics Classification System (BCS), has poor water solubility, which limits its bioavailability. Therefore, improving the solubility of mefenamic acid is of great significance. Summary of the Invention

[0003] In view of the shortcomings of the prior art, the object of the present invention is to provide a mefenamic acid-sophorapine co-amorphous compound, which has good stability, can significantly improve the solubility of mefenamic acid in water, thereby improving the bioavailability of mefenamic acid, and can also achieve synergistic synergy.

[0004] To achieve this object, the present invention adopts the following technical solutions:

[0005] In a first aspect, the present invention provides a mefenamic acid-sophorapine co-amorphous compound, wherein the mefenamic acid-sophorapine co-amorphous compound is composed of mefenamic acid and sophorapine in a molar ratio of 1:(0.5-3).

[0006] The molar ratio of mefenamic acid to alopecurine can be, for example, 1:0.5, 1:0.6, 1:0.8, 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 invention is not limited thereto, and other values ​​not listed within this range are equally applicable.

[0007] The molecular formula of mefenamic acid is C 15 H 15 NO2, whose structural formula is shown in Formula I.

[0008]

[0009] The molecular formula of Aloperine (Alo) is C 15 H 24 N2, whose structural formula is shown in Formula II.

[0010]

[0011] Sophora flavescens is a quinoline alkaloid extracted from Sophora flavescens. It is often used in clinical practice to treat dysentery and has good anti-inflammatory, antioxidant, antiviral and analgesic effects.

[0012] The present invention uses mefenamic acid as an active pharmaceutical ingredient and alopecurine as a drug ligand to prepare a co-amorphous compound. The co-amorphous compound has good stability under high temperature (60°C), high humidity (75% relative humidity at 25°C), and light (4500lx±500lx) conditions; it can significantly increase the solubility of mefenamic acid in water, thereby improving its bioavailability; and since alopecurine itself has a certain anti-inflammatory effect, the co-amorphous compound formed by mefenamic acid and alopecurine also has a certain synergistic effect.

[0013] In some preferred embodiments of the present invention, the molar ratio of the mefenamic acid to the alopecurine is 1:1.

[0014] In some embodiments of the present invention, the equilibrium solubility of the mefenamic acid-sophorapine co-amorphous compound in water at 37° C., calculated as mefenamic acid, is 1.28 mg / mL.

[0015] In a second aspect, the present invention provides a method for preparing the mefenamic acid-sophorapine co-amorphous compound as described in the first aspect, wherein the preparation method is a grinding method or a solution crystallization method;

[0016] The grinding method comprises the following steps: soaking mefenamic acid and alopecurine in a first solvent, grinding until the first solvent is completely evaporated to obtain a mefenamic acid-alopecurine co-amorphous compound;

[0017] The solution crystallization method comprises the following steps: dissolving mefenamic acid and alopecurine in a second solvent, and drying to obtain a mefenamic acid-alopecurine co-amorphous substance.

[0018] In some embodiments of the present invention, the first solvent is a combination of 60-95 vol% ethanol aqueous solution and ethyl acetate, wherein the concentration of the ethanol aqueous solution can be, for example, 60 vol%, 65 vol%, 70 vol%, 75 vol%, 80 vol%, 85 vol%, 90 vol%, or 95 vol%.

[0019] In some embodiments of the present invention, in the first solvent, the volume ratio of 60-95 vol% ethanol aqueous solution to ethyl acetate 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.

[0020] In some embodiments of the present invention, the ratio of the volume of the first solvent to the total mass of mefenamic acid and alopecurine is 1 mL / g or more, for example, it can be 1 mL / g, 1.5 mL / g, 2 mL / g, 2.5 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, 5 mL / g, 5.5 mL / g, 6 mL / g, 6.5 mL / g or 7 mL / g, etc.; preferably, it can be 2.5-5 mL / g.

[0021] In some embodiments of the present invention, the second solvent is a combination of one or more of 60-95 vol% ethanol aqueous solution, acetone and methanol.

[0022] In some embodiments of the present invention, the ratio of the total mass of mefenamic acid and alopecurine 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.

[0023] In some embodiments of the present invention, the step of dissolving mefenamic acid and alopecurine in a second solvent comprises: mixing mefenamic acid with alopecurine and a second solvent, and stirring at a speed of 500-1000 rpm (for example, 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, 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 invention is not limited thereto, and other unlisted values ​​within this range are equally applicable.

[0024] In some embodiments of the present invention, the drying method is vacuum drying, and the drying temperature is 40-60°C; for example, it can be 40°C, 42°C, 45°C, 48°C, 50°C, 52°C, 55°C, 58°C, or 60°C. However, the present invention is not limited thereto, and other values ​​not listed within this range are also applicable.

[0025] In a third aspect, the present invention provides a mefenamic acid-sophorapine co-amorphous compound as described in the first aspect or a mefenamic acid-sophorapine co-amorphous compound prepared by the preparation method as described in the second aspect, and its use in the preparation of analgesic and / or anti-inflammatory drugs.

[0026] In a fourth aspect, an analgesic and / or anti-inflammatory drug comprises the mefenamic acid-sophorapine co-amorphous compound as described in the first aspect or the mefenamic acid-sophorapine co-amorphous compound prepared by the preparation method as described in the second aspect, and a pharmaceutically acceptable carrier, diluent or excipient.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The present invention uses mefenamic acid as an active pharmaceutical ingredient and aloperine as a drug ligand to prepare a co-amorphous compound. The co-amorphous compound has good stability under high temperature (60°C), high humidity (75% relative humidity at 25°C), and light (4500lx±500lx) conditions; it can significantly increase the solubility of mefenamic acid in water, thereby improving its bioavailability; in addition, since aloperine itself also has a certain anti-inflammatory effect, the co-amorphous compound formed by mefenamic acid and aloperine also has a certain synergistic effect. Therefore, the mefenamic acid-aloperine co-amorphous compound provided by the present invention has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1A A comparison of PXRD spectra of mefenamic acid, alopecurine, a mixture of mefenamic acid powder and alopecurine powder, and the mefenamic acid-alopecurine co-amorphous compound provided in Example 2;

[0030] Figure 1B The PXRD spectra of the powders prepared in Comparative Example 1 and Comparative Example 2 are shown;

[0031] Figure 2 A comparison of the DSC spectra of mefenamic acid, alopecurine, and the mefenamic acid-alopecurine co-amorphous compound provided in Example 2;

[0032] Figure 3 The infrared spectra of mefenamic acid, sophora flavescens and the mefenamic acid-sophora flavescens co-amorphous compound provided in Example 2;

[0033] Figure 4A The PXRD spectra of the mefenamic acid-sophorapine co-amorphous compound provided in Example 2 after being placed under high temperature conditions for 0, 5, and 10 days;

[0034] Figure 4B The PXRD spectra of the mefenamic acid-sophorapine co-amorphous compound provided in Example 2 after being placed under high humidity conditions for 0, 5, and 10 days;

[0035] Figure 4C The PXRD spectra of the mefenamic acid-sophorapine co-amorphous compound provided in Example 2 after being placed under light conditions for 0, 5, and 10 days;

[0036] Figure 5 This is a dissolution curve diagram of fenamic acid and the mefenamic acid-sophorapine co-amorphous compound provided in Example 2. DETAILED DESCRIPTION

[0037] The technical solution of the present invention will be further described below with reference to the accompanying drawings and through specific embodiments. It should be understood by those skilled in the art that the specific embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0038] Example 1

[0039] This embodiment provides a mefenamic acid-sophorapine co-amorphous compound, the preparation method of which is as follows:

[0040] Accurately weigh 29.62 mg (0.1 mol) of mefenamic acid and 23.23 mg (0.1 mol) of alopecurine, place them in a mortar, add 0.1 mL of 95 vol% ethanol aqueous solution and 0.05 mL of ethyl acetate, grind for 15 min, and after the solvent evaporates, obtain a mefenamic acid-alopecurine co-amorphous powder.

[0041] Example 2

[0042] This embodiment provides a mefenamic acid-sophorapine co-amorphous compound, the preparation method of which is as follows:

[0043] Accurately weigh 29.62 mg (0.1 mol) of mefenamic acid and 23.23 mg (0.1 mol) of alopecurine and place them in a cillin bottle. Add 2 mL of 95 vol% ethanol aqueous solution until the solution becomes transparent. Add a magnet and place it on a magnetic stirrer and stir continuously for 8 h at a speed of 800 rpm. The solution remains transparent. Place the solution in a vacuum drying oven and vacuum dry it at 60°C for 2 h to obtain a mefenamic acid-alopecurine co-amorphous powder.

[0044] Example 3

[0045] This embodiment provides a mefenamic acid-sophorapine co-amorphous compound, the preparation method of which is as follows:

[0046] Accurately weigh 29.62 mg (0.1 mol) of mefenamic acid and 69.69 mg (0.3 mol) of alopecurine, place them in a mortar, add 0.2 mL of a 60 vol% ethanol aqueous solution and 0.1 mL of ethyl acetate, grind for 15 min, and after the solvent evaporates, obtain a mefenamic acid-alopecurine co-amorphous powder.

[0047] Example 4

[0048] This embodiment provides a mefenamic acid-sophorapine co-amorphous compound, the preparation method of which is as follows:

[0049] Accurately weigh 59.24 mg (0.2 mol) of mefenamic acid and 23.23 mg (0.1 mol) of alopecurine, place them in a mortar, add 0.3 mL of 85 vol% ethanol aqueous solution and 0.1 mL of ethyl acetate, grind for 15 min, and after the solvent evaporates, obtain a mefenamic acid-alopecurine co-amorphous powder.

[0050] Example 5

[0051] This embodiment provides a mefenamic acid-sophorapine co-amorphous compound, the preparation method of which is as follows:

[0052] Accurately weigh 29.62 mg (0.1 mol) of mefenamic acid and 46.46 mg (0.2 mol) of alopecurine, place them in a cillin bottle, add 1 mL of acetone, the solution becomes transparent, add a magnet and place it on a magnetic stirrer and stir continuously for 9 h at a speed of 500 rpm. The solution remains transparent. Place the solution in a vacuum drying oven and vacuum dry it at 40 ° C for 3 h to obtain a mefenamic acid-alopecurine co-amorphous powder.

[0053] Example 6

[0054] This embodiment provides a mefenamic acid-sophorapine co-amorphous compound, the preparation method of which is as follows:

[0055] Accurately weigh 29.62 mg (0.1 mol) of mefenamic acid and 34.85 mg (0.15 mol) of alopecurine, place them in a cillin bottle, add 6 mL of methanol, the solution becomes transparent, add a magnet and place it on a magnetic stirrer and stir continuously for 10 h at a speed of 1000 rpm. The solution remains transparent, place the solution in a vacuum drying oven and vacuum dry it at 50 ° C for 1 h to obtain a co-amorphous powder of mefenamic acid-alopecurine.

[0056] Comparative Example 1

[0057] The difference between this comparative example and Example 1 is that the solvent is replaced by ethyl acetate, and the total volume of the solvent remains unchanged.

[0058] Comparative Example 2

[0059] The difference between this comparative example and Example 2 is that the amounts of raw materials used are 35.54 mg (0.12 mol) of mefenamic acid and 9.29 mg (0.04 mol) of alopecurine.

[0060] Characterization of Mefenamic Acid-Alopecurine Co-amorphous Compound

[0061] 1. Powder X-ray diffraction (PXRD)

[0062] PXRD analysis was performed on mefenamic acid (Mef), alopecurine (Alo), a mixture of mefenamic acid powder and alopecurine powder in a molar ratio of 1:1 (Mef+Alo), the mefenamic acid-alopecurine co-amorphous powder (Mef-Alo) provided in the examples, and the powder prepared in the comparative example.

[0063] Detection instrument: Rigaku D / max-2550 X-ray powder diffractometer.

[0064] Detection conditions: Cu / K-alpha 1, 40 kV-200 mA, I(max)=2244, 2θ=4°-40°, λ=1.54056 nm.

[0065] Among them, the comparison of the PXRD spectra of Mef, Alo, Mef+Alo and Mef-Alo provided in Example 2 is shown in FIG. Figure 1A shown.

[0066] from Figure 1A It can be seen that the powder X-ray diffraction pattern of mefenamic acid has characteristic diffraction peaks at 2θ = 6.27°, 15.80°, 21.35°, and 26.34°; the powder X-ray diffraction pattern of alopecurine has characteristic diffraction peaks at 2θ = 9.5°, 15.29°, 18.24°, 21.99°, 22.38°, and 29.67°. The powder X-ray diffraction pattern of the mefenamic acid-alopecurine co-amorphous compound provided in Example 2 is diffuse, and the characteristic peaks of mefenamic acid and alopecurine disappear, forming a typical amorphous powder X-ray diffraction pattern. The X-ray diffraction patterns of the mefenamic acid-alopecurine co-amorphous compounds provided in Examples 1, 3-6 are similar to this and are diffuse.

[0067] The X-ray diffraction patterns of the powders prepared in Comparative Example 1 and Comparative Example 2 are as follows: Figure 1B As shown, from Figure 1B It can be seen that the diffraction peak is not diffuse, and characteristic peaks appear, indicating that the powders prepared in Comparative Examples 1 and 2 do not form co-amorphous materials.

[0068] 2. Differential Scanning Calorimetry (DSC)

[0069] Detection instrument: Mettler Toledo DSC3 / 700 / 200 differential scanning calorimeter.

[0070] Detection conditions and methods: About 3 mg of mefenamic acid (Mef), alopecurine (Alo), and the mefenamic acid-alopecurine co-amorphous compound (Mef-Alo) provided in Example 2 were weighed respectively, and the temperature was raised from 30°C to 290°C at a heating rate of 10°C / min for detection.

[0071] The comparison of the DSC spectra of Mef, Alo and Mef-Alo provided in Example 2 is shown in FIG. Figure 2 As shown. Figure 2 It can be seen that mefenamic acid (Mef) has an endothermic peak at 231.33°C, aloperine (Alo) has an endothermic peak at 73°C, and the endothermic peak of the mefenamic acid-aloperine co-amorphous compound (Mef-Alo) provided in Example 2 is at 60.50°C. The endothermic peak temperatures of the mefenamic acid-aloperine co-amorphous compound are different from those of mefenamic acid and aloperine, indicating the formation of a new phase.

[0072] 3. Fourier transform infrared spectroscopy (IR)

[0073] Detection instrument: Perkin Elmer Spectrum 400 infrared spectrometer.

[0074] Determination conditions and methods: Take appropriate amounts of mefenamic acid (Mef), alopecurine (Alo), and the amorphous powder of mefenamic acid-alopecurine co-form (Mef-Alo) provided in Example 2, and analyze and detect them by infrared absorption spectroscopy at 4000-400 cm -1 Scan within the range and record the infrared absorption spectrum.

[0075] Test results such as Figure 3 As shown. Figure 3 It can be seen that the stretching vibration of NH of mefenamic acid (Mef) is at 3311 cm -1 There is characteristic absorption at 1577cm -1 There is a characteristic absorption at 1653cm -1 However, when mefenamic acid and alopecurine form a co-amorphous compound, these vibration modes undergo significant changes: the NH stretching vibration absorption peak moves to 2928 cm -1 , the bending vibration absorption peak appears at 1581cm -1 The C=O stretching vibration absorption peak moves to 1473 cm -1 These changes may be due to hydrogen bonding.

[0076] 4. Stability test

[0077] Testing instruments: HPP260 constant temperature and humidity incubator, Rigaku D / max-2550 X-ray powder diffractometer.

[0078] Testing conditions and methods:

[0079] 4.1. High Temperature: A small amount of the mefenamic acid-sophorapine co-amorphous compound (Mef-Alo) provided in Example 2 was placed in a weighing bottle. The weighing bottle was placed in a drying oven at 60° C. and PXRD analysis was performed after 0, 5, and 10 days.

[0080] 4.2. High Humidity: Take a small amount of the mefenamic acid-sophorapine co-amorphous compound (Mef-Alo) provided in Example 2 and place it in a weighing bottle. Place the weighing bottle in a constant temperature and humidity incubator at a temperature of 25°C and a relative humidity of 75%. Perform PXRD analysis after 0, 5, and 10 days, respectively.

[0081] 4.3. Illumination: A small amount of the mefenamic acid-sophorapine co-amorphous compound (Mef-Alo) provided in Example 2 was placed in a weighing bottle. The weighing bottle was placed under a white light source at a temperature of 25° C. and an illumination intensity of 4500 lx±500 lx. PXRD detection was performed after 0, 5, and 10 days.

[0082] Among them, the test results under high temperature, high humidity and light conditions are as follows: Figure 4A 、 Figure 4B 、 Figure 4C As shown in the figure, under the three conditions of high temperature, high humidity and light, the PXRD spectra of the mefenamic acid-sophorapine co-amorphous compound provided in Example 2 after 5 and 10 days of storage did not show obvious changes compared with the initial (day 0) PXRD spectra, indicating that the mefenamic acid-sophorapine co-amorphous compound has good stability.

[0083] 5. Equilibrium solubility determination

[0084] According to the shake flask method, the equilibrium solubility of mefenamic acid (Mef) and the mefenamic acid-aloperine co-amorphous compound (Mef-Alo) provided in Example 2 were measured.

[0085] Take 5 mL of deionized water and place it in a 15 mL centrifuge tube. Add an excess of powder sample, seal it, and place it on a shaker at 37°C with a stirring speed of 120 r / min. Take the supernatant at 2 h, 4 h, 8 h, 24 h, 48 h, and 60 h, filter it with a filter membrane, detect the content by high performance liquid chromatography (HPLC), and calculate the equilibrium solubility.

[0086] The dissolution curves of mefenamic acid (Mef) and the mefenamic acid-sophane co-amorphous compound (Mef-Alo) provided in Example 2 are shown in FIG. Figure 5 shown.

[0087] Figure 5It is shown that in water at 37°C, the equilibrium solubility of the mefenamic acid (Mef) raw material is 0.005 mg / mL, while the equilibrium solubility (calculated as mefenamic acid) of the mefenamic acid-sophorapine co-amorphous compound (Mef-Alo) provided in Example 2 is 1.28 mg / mL. The water solubility of mefenamic acid is greatly improved, which obviously helps to improve the bioavailability of mefenamic acid.

[0088] The foregoing description is intended only to provide specific embodiments of the present disclosure, intended to enable those skilled in the art to understand and implement the present disclosure. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present disclosure. Therefore, the present disclosure is not intended to be limited to the embodiments described herein, but rather to be construed in the broadest manner consistent with the principles and novel features disclosed herein.

Claims

1. A mefenamic acid-sophane co-amorphous compound, characterized in that: The mefenamic acid-sophorapine co-amorphous material consists of mefenamic acid and sophorapine in a molar ratio of 1:(0.5-3).

2. The mefenamic acid-sophane co-amorphous compound according to claim 1, characterized in that The molar ratio of the mefenamic acid to the alopecurine is 1:

1.

3. The mefenamic acid-sophane co-amorphous compound according to claim 2, characterized in that The equilibrium solubility of the mefenamic acid-sophorapine co-amorphous compound in water at 37° C., calculated as mefenamic acid, is 1.28 mg / mL.

4. A method for preparing the mefenamic acid-sophorapine co-amorphous compound according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: soaking mefenamic acid and alopecurine with a first solvent, and grinding until the first solvent is completely evaporated to obtain a mefenamic acid-alopecurine co-amorphous compound; Alternatively, mefenamic acid and alopecurine are dissolved in a second solvent and dried to obtain a mefenamic acid-alopecurine co-amorphous compound.

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

1.

6. The preparation method according to claim 4 or 5, characterized in that The ratio of the volume of the first solvent to the total mass of mefenamic acid and alopecurine is 1 mL / g or more, preferably 2.5-5 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% ethanol aqueous solution, acetone and methanol; Preferably, the ratio of the total mass of mefenamic acid and alopecurine to the volume of the second solvent is 1-80 mg / mL.

8. The preparation method according to claim 4 or 7, characterized in that The step of dissolving mefenamic acid and alopecurine in a second solvent comprises: mixing mefenamic acid, alopecurine and a second solvent, and stirring at a speed of 500-1000 rpm for 8-10 hours; Preferably, the drying method is vacuum drying, and the drying temperature is 40-60°C.

9. Use of the mefenamic acid-sophorapine co-amorphous compound according to any one of claims 1 to 3 or the mefenamic acid-sophorapine co-amorphous compound prepared by the preparation method according to any one of claims 4 to 8 in the preparation of analgesic and / or anti-inflammatory drugs.

10. An analgesic and / or anti-inflammatory drug, characterized in that: The drug comprises the mefenamic acid-sophorapine co-amorphous compound according to any one of claims 1 to 3 or the mefenamic acid-sophorapine co-amorphous compound prepared by the preparation method according to any one of claims 4 to 8, and a pharmaceutically acceptable carrier, diluent or excipient.

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