A mefenamic acid-physostigmine co-amorphous substance, a preparation method and application thereof

Abstract

The application provides mefenamic acid-oxymatrine co-amorphous substance and a preparation method and application thereof, and belongs to the technical field of medicines. The mefenamic acid-oxymatrine co-amorphous substance is composed of mefenamic acid and oxymatrine with 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-oxymatrine co-amorphous substance provided by the application has good stability, can significantly improve the solubility of mefenamic acid in water, thereby improving the bioavailability of mefenamic acid, and can also have synergistic effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a mefenamic acid-sticky alkaloid co-amorphous compound, its preparation method, and its application. Background Technology

[0002] Mefenamic acid (Mef) is a nonsteroidal anti-inflammatory drug (NSAID) that primarily exerts its analgesic and anti-inflammatory effects by inhibiting prostaglandin synthase. Like most NSAIDs, mefenamic acid exhibits low solubility and high permeability. Classified as a Group II drug in the Biopharmaceutical Classification System (BCS), mefenamic acid has poor water solubility, which limits its bioavailability. Therefore, improving its solubility is of great importance. Summary of the Invention

[0003] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a mefenamic acid-matrine 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 have a synergistic effect.

[0004] To achieve this objective, the present invention adopts the following technical solution:

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

[0006] The molar ratio of mefenamic acid to picrophylline 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. However, the invention is not limited to this, and other unlisted values ​​within this range are also applicable.

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

[0008]

[0009] Aloperine (Alo) has the molecular formula C0. 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 clinically to treat dysentery and has good anti-inflammatory, antioxidant, antiviral and analgesic effects.

[0012] This invention uses mefenamic acid as the active pharmaceutical ingredient and picrine as the drug ligand to prepare a co-amorphous compound. This co-amorphous compound exhibits good stability under high temperature (60℃), high humidity (75% relative humidity at 25℃), and light exposure (4500 lx ± 500 lx); it also significantly improves the solubility of mefenamic acid in water, thereby enhancing its bioavailability; furthermore, since picrine itself also has certain anti-inflammatory effects, the formation of the co-amorphous compound between mefenamic acid and picrine also has a certain synergistic effect.

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

[0014] In some embodiments of the present invention, the equilibrium solubility of the mefenamic acid-stigmaine 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-matrine 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 includes the following steps: soaking mefenamic acid and physostigmine in a first solvent and grinding until the first solvent is completely evaporated to obtain mefenamic acid-physostigmine co-amorphous product;

[0017] The solution crystallization method includes the following steps: dissolving mefenamic acid and physostigmine in a second solvent, drying, and obtaining a mefenamic acid-physostigmine co-amorphous compound.

[0018] In some embodiments of the present invention, the first solvent is a combination of a 60-95 vol% aqueous ethanol solution and ethyl acetate. The concentration of the aqueous ethanol solution may 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, the volume ratio of 60-95 vol% aqueous ethanol 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.

[0020] In some embodiments of the present invention, the volume ratio of the first solvent to the total mass of mefenamic acid and picrophylline 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 2.5-5 mL / g.

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

[0022] In some embodiments of the present invention, the ratio of the total mass of mefenamic acid and strychnine 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 physostigmine in a second solvent includes: mixing mefenamic acid with physostigmine and a second solvent, and stirring at a speed of 500-1000 rpm (e.g., 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 hours (e.g., 8 hours, 8.2 hours, 8.5 hours, 8.8 hours, 9 hours, 9.2 hours, 9.5 hours, 9.8 hours, or 10 hours, etc.). However, the present invention is not limited thereto, and other unlisted values ​​within this range are also 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, etc. However, the present invention is not limited thereto, and other unlisted values ​​within this range are also applicable.

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

[0026] Fourthly, an analgesic and / or anti-inflammatory drug comprising mefenamic acid-grossine co-amorphous compound as described in the first aspect or mefenamic acid-grossine co-amorphous compound prepared by the method 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] This invention uses mefenamic acid as the active pharmaceutical ingredient and picrophylline as the drug ligand to prepare a co-amorphous compound. This co-amorphous compound exhibits good stability under high temperature (60℃), high humidity (75% relative humidity at 25℃), and light exposure (4500 lx ± 500 lx); it also significantly improves the solubility of mefenamic acid in water, thereby enhancing its bioavailability; furthermore, since picrophylline itself also has certain anti-inflammatory effects, the formation of the co-amorphous compound between mefenamic acid and picrophylline also has a certain synergistic effect. Therefore, the mefenamic acid-picrophylline co-amorphous compound provided by this invention has good application prospects. Attached Figure Description

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

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

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

[0032] Figure 3 Infrared spectra of mefenamic acid, physostigmine, and the mefenamic acid-physostigmine co-amorphous compound provided in Example 2;

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

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

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

[0036] Figure 5 Solubility curves of fenamic acid and the mefenamic acid-misocyanate co-amorphous compound provided in Example 2. Detailed Implementation

[0037] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. Those skilled in the art should understand that the specific embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention.

[0038] Example 1

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

[0040] Accurately weigh 29.62 mg (0.1 mol) mefenamic acid and 23.23 mg (0.1 mol) picrine, 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 has evaporated, obtain mefenamic acid-picrine co-amorphous powder.

[0041] Example 2

[0042] This embodiment provides a mefenamic acid-grossroots alkaloid 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 picrine, place them in a vial, add 2 mL of 95 vol% ethanol aqueous solution, the solution is transparent, add a magnetic stir bar and place on a magnetic stirrer and stir continuously for 8 hours at a speed of 800 rpm, the solution is still transparent, place the solution in a vacuum drying oven and vacuum dry at 60℃ for 2 hours to obtain mefenamic acid-picrine co-amorphous powder.

[0044] Example 3

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

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

[0047] Example 4

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

[0049] Accurately weigh 59.24 mg (0.2 mol) mefenamic acid and 23.23 mg (0.1 mol) picrine, 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 has evaporated, obtain mefenamic acid-picrine co-amorphous powder.

[0050] Example 5

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

[0052] Accurately weigh 29.62 mg (0.1 mol) mefenamic acid and 46.46 mg (0.2 mol) picrine, place them in a vial, add 1 mL of acetone, the solution is transparent, add a magnetic stir bar and place on a magnetic stirrer and stir continuously for 9 hours at a speed of 500 rpm, the solution is still transparent, place the solution in a vacuum drying oven and vacuum dry at 40℃ for 3 hours to obtain mefenamic acid-picrine co-amorphous powder.

[0053] Example 6

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

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

[0056] Comparative Example 1

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

[0058] Comparative Example 2

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

[0060] Characterization of mefenamic acid-matrine co-amorphous compounds

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

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

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

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

[0065] The comparison diagram of the PXRD spectra of Mef, Alo, Mef+Alo, and Mef-Alo provided in Example 2 is shown below. Figure 1A As 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 picroline 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-picroline amorphous compound provided in Example 2 is diffuse, with the characteristic peaks of mefenamic acid and picroline disappearing, forming a typical amorphous powder X-ray diffraction pattern. The X-ray diffraction patterns of the mefenamic acid-picroline amorphous compounds provided in Examples 1 and 3-6 are similar, also 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 peaks are not diffuse and characteristic peaks have appeared, indicating that the powders prepared in Comparative Example 1 and Comparative Example 2 did not form co-amorphous substances.

[0068] 2. Differential Scanning Calorimetry (DSC)

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

[0070] Detection conditions and methods: Weigh approximately 3 mg of mefenamic acid (Mef), physostigmine (Alo), and the mefenamic acid-physostigmine co-amorphous compound (Mef-Alo) provided in Example 2, and detect them by heating from 30°C to 290°C at a heating rate of 10°C / min.

[0071] A comparison chart of the DSC spectra of Mef, Alo, and Mef-Alo provided in Example 2 is shown below. Figure 2 As shown. From Figure 2 It can be seen that mefenamic acid (Mef) has an endothermic peak at 231.33℃, and physostigmine (Alo) has an endothermic peak at 73℃, while the endothermic peak of the mefenamic acid-physostigmine co-amorphous compound (Mef-Alo) provided in Example 2 is at 60.50℃. The endothermic peak temperatures of the mefenamic acid-physostigmine co-amorphous compound differ from those of mefenamic acid and physostigmine alone, indicating the formation of a new phase.

[0072] 3. Fourier Transform Infrared Spectroscopy (IR)

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

[0074] Determination conditions and methods: Appropriate amounts of mefenamic acid (Mef), physostigmine (Alo), and the mefenamic acid-physostigmine co-amorphous powder (Mef-Alo) provided in Example 2 were taken and analyzed using infrared absorption spectroscopy at 4000–400 cm⁻¹. -1 Scan within the range and record the infrared absorption spectrum.

[0075] Test results as follows Figure 3 As shown. From Figure 3 It can be seen that the stretching vibration of NH in mefenamic acid (Mef) is at 3311 cm⁻¹. -1 Characteristic absorption is present at 1577 cm⁻¹, and bending vibration occurs at this point. -1 Characteristic absorption is present at 1653 cm⁻¹, and the stretching vibration of C=O occurs at this point. -1 Characteristic absorptions are present at [location missing]. However, when mefenamic acid forms a co-amorphous compound with picrophylline, these vibrational modes change significantly: the stretching vibration absorption peak of NH shifts to 2928 cm⁻¹. -1 The bending vibration absorption peak appears at 1581 cm⁻¹. -1 At that point, the absorption peak of the stretching vibration of C=O shifted to 1473 cm⁻¹. -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] Detection conditions and methods:

[0079] 4.1 High temperature: Take a small amount of mefenamic acid-matrine co-amorphous compound (Mef-Alo) provided in Example 2, place it in a weighing bottle, place the weighing bottle in a drying oven at 60°C, and perform PXRD detection after 0, 5 and 10 days respectively.

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

[0081] 4.3 Irradiation: Take a small amount of the mefenamic acid-matrine co-amorphous compound (Mef-Alo) provided in Example 2, place it in a weighing bottle, and place the weighing bottle under a white light source with a temperature of 25°C and an irradiation intensity of 4500 lx ± 500 lx. Perform PXRD detection after 0, 5, and 10 days.

[0082] 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-matrine co-amorphous compound provided in Example 2 after 5 days and 10 days of storage showed no significant changes compared with the initial (day 0) PXRD spectra, indicating that the mefenamic acid-matrine co-amorphous compound has good stability.

[0083] 5. Equilibrium solubility determination

[0084] The equilibrium solubility of mefenamic acid (Mef) and the mefenamic acid-matrine co-amorphous compound (Mef-Alo) provided in Example 2 were determined by the shake flask method.

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

[0086] The solubility curves of mefenamic acid (Mef) and the mefenamic acid-matrine co-amorphous compound (Mef-Alo) provided in Example 2 are shown in the figure. Figure 5 As shown.

[0087] Figure 5The results showed that the equilibrium solubility of mefenamic acid (Mef) raw material in water at 37°C was 0.005 mg / mL, while the equilibrium solubility (based on mefenamic acid) of the mefenamic acid-matrine co-amorphous compound (Mef-Alo) provided in Example 2 was 1.28 mg / mL. The water solubility of mefenamic acid was significantly improved, which obviously helps to improve the bioavailability of mefenamic acid.

[0088] The above description is merely a specific embodiment of this disclosure, enabling those skilled in the art to understand or implement it. 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 this disclosure. Therefore, this disclosure is not to be limited to the embodiments described herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A mefenamic acid-picric acid co-amorphous compound, characterized in that, The mefenamic acid-matrine co-amorphous compound is composed of mefenamic acid and matrine in a molar ratio of 1:1; The preparation method of the mefenamic acid-grossroots co-amorphous compound includes the following steps: Mefenamic acid and phytic acid were soaked in a first solvent and ground until the first solvent was completely evaporated to obtain a mefenamic acid-phytic acid co-amorphous product. Alternatively, mefenamic acid and physostigmine can be dissolved in a second solvent and dried to obtain a mefenamic acid-physostigmine co-amorphous product. The first solvent is a combination of 60-95 vol% aqueous ethanol solution and ethyl acetate, and the second solvent is one or more of 60-95 vol% aqueous ethanol solution, acetone and methanol.

2. The mefenamic acid-picric acid co-amorphous compound according to claim 1, characterized in that, The equilibrium solubility of the mefenamic acid-misocyanate co-amorphous compound in water at 37°C, calculated as mefenamic acid, is 1.28 mg / mL.

3. A method for preparing the mefenamic acid-matrine co-amorphous compound as described in claim 1 or 2, characterized in that, The preparation method includes the following steps: Mefenamic acid and phytic acid were soaked in a first solvent and ground until the first solvent was completely evaporated to obtain a mefenamic acid-phytic acid co-amorphous product. Alternatively, mefenamic acid and physostigmine can be dissolved in a second solvent and dried to obtain a mefenamic acid-physostigmine co-amorphous product. The first solvent is a combination of 60-95 vol% aqueous ethanol solution and ethyl acetate, and the second solvent is one or more of 60-95 vol% aqueous ethanol solution, acetone and methanol.

4. The preparation method according to claim 3, characterized in that, In the first solvent, the volume ratio of 60-95 vol% aqueous ethanol to ethyl acetate is 2-3:

1.

5. The preparation method according to claim 3 or 4, characterized in that, The volume ratio of the first solvent to the total mass of mefenamic acid and picrine is 1 mL / g or more.

6. The preparation method according to claim 5, characterized in that, The volume ratio of the first solvent to the total mass of mefenamic acid and picrine is 2.5-5 mL / g.

7. The preparation method according to claim 3, characterized in that, The ratio of the total mass of mefenamic acid and strychnine to the volume of the second solvent is 1-80 mg / mL.

8. The preparation method according to claim 3 or 7, characterized in that, The step of dissolving mefenamic acid and physostigmine in a second solvent includes: mixing mefenamic acid with physostigmine and the second solvent, and stirring at a speed of 500-1000 rpm for 8-10 hours.

9. The preparation method according to claim 3, characterized in that, The drying method is vacuum drying, and the drying temperature is 40-60℃.

10. The use of a mefenamic acid-grossine co-amorphous compound as described in claim 1 or 2, or a mefenamic acid-grossine co-amorphous compound prepared by any one of the preparation methods described in claims 3-9, in the preparation of analgesic and / or anti-inflammatory medicaments.

11. A pain-relieving and / or anti-inflammatory drug, characterized in that, The drug comprises the mefenamic acid-stearin co-amorphous compound as described in claim 1 or 2, or the mefenamic acid-stearin co-amorphous compound prepared by the preparation method described in any one of claims 3-9, as well as a pharmaceutically acceptable carrier, diluent, or excipient.

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