Febuxostat and alopecurine co-amorphous compound and its preparation method and application

Abstract

The present invention relates to the field of biomedicine technology, and more particularly to a kind of Febuxostat and alopecurine co-amorphous substance and its preparation method and application. The Febuxostat and alopecurine co-amorphous substance has a mol ratio of Febuxostat and alopecurine of (0.5-3): 1. The Febuxostat and alopecurine co-amorphous substance provided by the present invention has excellent stability, can effectively improve the water solubility and bioavailability of Febuxostat, and can effectively improve the therapeutic effect for related diseases such as gout, gouty arthritis and hyperuricemia, and has broad application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a co-amorphous compound of febuxostat and sophora flavescens, and a preparation method and application thereof. Background Art

[0002] Gout is a disease caused by metabolic dysfunction, with elevated uric acid levels as a prominent hallmark. In recent years, with improvements in quality of life, the number of gout sufferers and the incidence of gout have both increased. Gout has become a relatively common metabolic disease, particularly among middle-aged and elderly individuals. Patients experience swelling, stiffness, and deformity in the affected joints, most commonly around the ears, toes, and fingers. Patients experience extreme pain, and in severe cases, limited mobility, requiring long-term medication.

[0003] Currently, Febuxostat is the most widely used and commonly used drug for the treatment of gout and hyperuricemia, but it belongs to the BCS Class II of the Biopharmaceutics Classification System, that is, a low solubility and high permeability drug, and its water solubility is poor, which leads to its limited bioavailability.

[0004] Therefore, it is desirable to provide a method for improving the aqueous solubility and bioavailability of febuxostat. Summary of the Invention

[0005] In order to solve the above technical problems, the present invention provides a febuxostat and alopecurine co-amorphous compound and its preparation method and application. The febuxostat and alopecurine co-amorphous compound provided by the present invention has excellent stability, can not only effectively improve the water solubility and bioavailability of febuxostat, but also can effectively improve the therapeutic effect for related diseases such as gout, gouty arthritis and hyperuricemia, and has broad application prospects.

[0006] In a first aspect, the present invention provides a co-amorphous compound of febuxostat and alopecurine, wherein the molar ratio of febuxostat to alopecurine in the co-amorphous compound of febuxostat and alopecurine is (0.5-3):1, for example, 0.5:1, 1:1, 2:1, 3:1, etc.

[0007] The febuxostat and alopecurine co-amorphous compound provided by the present invention has excellent stability, which can not only effectively improve the water solubility and bioavailability of febuxostat, but also has important significance for improving the therapeutic effect of gout, gouty arthritis, and hyperuricemia. Specifically:

[0008] The febuxostat and alopecurine co-amorphous compound provided by the present invention has febuxostat as an active pharmaceutical ingredient, and its chemical name is 2-[(3-cyano-4-isobutyloxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, and its molecular formula is C 16 H 16 N2O3S, its structural formula is:

[0009]

[0010] At the same time, alopecurine is used as a drug ligand, and its molecular formula is C 15 H 24 N2, whose structural formula is:

[0011]

[0012] The interaction between the two makes the equilibrium solubility of the febuxostat and alopecurine co-amorphous compound provided by the present invention in water 10588 times that of febuxostat, effectively improving the water solubility of febuxostat, and then effectively improving its bioavailability, and experiments under conditions of high temperature, high humidity, light, etc. have found that it has good stability. In addition, the present invention uses alopecurine and febuxostat to prepare a co-amorphous compound. Febuxostat itself has no anti-inflammatory activity, and alopecurine is an alkaloid extracted from the legume plant Sophora flavescens, which has antibacterial and anti-inflammatory effects and can be used to treat diseases such as rheumatism and rheumatoid arthritis. In addition, alopecurine has a significant inhibitory effect on acute inflammation caused by various inflammatory agents and type III and IV allergic reactions and adjuvant arthritis. Therefore, the febuxostat and alopecurine co-amorphous compound provided by the present invention has the advantages of both febuxostat and alopecurine, and can effectively improve the therapeutic effect of related diseases such as gout and gouty arthritis.

[0013] As a preferred technical solution of the present invention, the molar ratio of febuxostat to sophora flavescens in the co-amorphous product of febuxostat and sophora flavescens is 1:1.

[0014] As a preferred technical solution of the present invention, the equilibrium solubility of the amorphous compound of febuxostat and sophora flavescens in water is 180 mg / mL.

[0015] In a second aspect, the present invention provides a method for preparing the amorphous compound of febuxostat and sophora flavescens described in the first aspect, the preparation method comprising:

[0016] Place the formulated amount of febuxostat and alopecurine in a mortar, add a first solvent, and grind until the solvent is completely evaporated to obtain a co-amorphous substance of febuxostat and alopecurine;

[0017] Or, the preparation method comprises:

[0018] The febuxostat and alopecurine in the formulated amounts are mixed with a second solvent, stirred, and dried to obtain the febuxostat and alopecurine co-amorphous compound.

[0019] The febuxostat and alopecurine co-amorphous compound provided by the present invention is prepared by a grinding method or a solution crystallization method. The preparation method is simple in process and has good industrial application prospects.

[0020] As a preferred technical solution of the present invention, the first solvent includes any one or more of anhydrous ethanol, ethyl acetate and water.

[0021] As a preferred technical solution of the present invention, the mass ratio of the febuxostat and alopecurine to the volume of the first solvent is 27 mg: (1-4) mL, for example, 27 mg: 1 mL, 27 mg: 2 mL, 27 mg: 3 mL, 27 mg: 4 mL, etc.

[0022] As a preferred technical solution of the present invention, the second solvent includes any one or more of ethanol, methanol, acetonitrile, acetone and ethyl acetate.

[0023] As a preferred technical solution of the present invention, the mass ratio of the febuxostat and alopecurine to the volume of the second solvent is 27 mg: (1-4) mL, for example, 27 mg: 1 mL, 27 mg: 2 mL, 27 mg: 3 mL, 27 mg: 4 mL, etc.

[0024] As a preferred technical solution of the present invention, the stirring time is 8-16 hours, for example, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, etc.

[0025] As a preferred technical solution of the present invention, the stirring speed is 500-1000 rpm / min, for example, 500 rpm / min, 600 rpm / min, 700 rpm / min, 800 rpm / min, 900 rpm / min, 1000 rpm / min, etc.

[0026] As a preferred technical solution of the present invention, the drying is vacuum drying, the vacuum drying temperature is 50-60°C, for example, 50°C, 52°C, 54°C, 56°C, 58°C, 60°C, etc., and the vacuum drying time is 1-3h, for example, 1h, 1.5h, 2h, 2.5h, 3h, etc.

[0027] In a third aspect, the present invention provides the use of the febuxostat and alopecurine co-amorphous compound described in the first aspect or the febuxostat and alopecurine co-amorphous compound prepared by the preparation method described in the second aspect in the preparation of a drug for treating gout, gouty arthritis or hyperuricemia.

[0028] The technical solution provided by the embodiment of the present invention has the following advantages compared with the prior art:

[0029] The febuxostat and alopecurine co-amorphous compound provided by the present invention has excellent stability, can not only effectively improve the water solubility and bioavailability of febuxostat, but also can effectively improve the therapeutic effect for related diseases such as gout, gouty arthritis and hyperuricemia, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention.

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative labor.

[0032] Figure 1 XRD patterns of the co-amorphous product of febuxostat and aloperine (Feb-Alo), febuxostat (Feb), aloperine (Alo), and the mixture of febuxostat and aloperine (Feb+Alo) prepared in Example 1 of the present invention;

[0033] Figure 2 The DSC graphs of the co-amorphous product of febuxostat and aloperine (Feb-Alo), febuxostat (Feb), and aloperine (Alo) prepared in Example 1 of the present invention are shown;

[0034] Figure 3 The infrared spectra of the amorphous compound of febuxostat and alopecurine (Feb-Alo), febuxostat (Feb), and alopecurine (Alo) prepared in Example 1 of the present invention are shown;

[0035] Figure 4 X-RAY images of the amorphous compound of febuxostat and alopecurine prepared in Example 1 of the present invention after being stored at high temperature for 0 days and 10 days;

[0036] Figure 5 X-RAY images of the amorphous compound of febuxostat and alopecurine prepared in Example 1 of the present invention after storage under high humidity conditions for 0 days and 10 days;

[0037] Figure 6 These are X-RAY images of the amorphous compound of febuxostat and sophora flavescens prepared in Example 1 of the present invention stored under light conditions for 0 days and 10 days. DETAILED DESCRIPTION

[0038] In order to more clearly understand the above-mentioned objectives, features and advantages of the present invention, the scheme of the present invention will be further described below. It should be noted that, in the absence of conflict, the embodiments of the present invention and the features therein can be combined with each other.

[0039] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; it is obvious that the embodiments in the specification are only part of the embodiments of the present invention, rather than all the embodiments.

[0040] Example 1

[0041] This embodiment provides a co-amorphous compound of febuxostat and sophora flavescens and a preparation method thereof, wherein the preparation method comprises the following steps:

[0042] Accurately weigh 31.64 mg of febuxostat (Feb) and 23.23 mg of alopecurine (Alo) and place them in a mortar. Add 2 mL of anhydrous ethanol and 1 drop of ethyl acetate and grind. After the solvent evaporates, an amorphous powder of febuxostat and alopecurine is obtained.

[0043] Example 2

[0044] This embodiment provides a co-amorphous compound of febuxostat and sophora flavescens and a preparation method thereof, wherein the preparation method comprises the following steps:

[0045] Accurately weigh 31.64 mg of febuxostat and 23.23 mg of alopecurine in a penicillin bottle. After adding 2 mL of 95% ethanol, the solution becomes clear and transparent. Wrap the clear and transparent solution with sealing film, leaving a hole to evaporate the solvent, add a magnetic bar (5 mm), and place it on a magnetic stirrer and stir continuously for 8 hours at a speed of 500 rpm. The solution remains clear and transparent. Then, dry the solution in vacuum at 60°C for 1 hour to obtain amorphous powder of febuxostat and alopecurine.

[0046] Example 3

[0047] This example provides a co-amorphous compound of febuxostat and alopecurine and a preparation method thereof. The preparation method is the same as that in Example 1, except that the amount of febuxostat used in this example is 31.64 mg, the amount of alopecurine used is 46.46 mg, and the amount of anhydrous ethanol used is 3 mL.

[0048] Example 4

[0049] This example provides a co-amorphous compound of febuxostat and alopecurine and a preparation method thereof. The preparation method is the same as that in Example 1, except that the amount of febuxostat used in this example is 63.28 mg, the amount of alopecurine used is 23.23 mg, and the amount of anhydrous ethanol used is 4 mL.

[0050] Example 5

[0051] This example provides a co-amorphous compound of febuxostat and alopecurine and a preparation method thereof. The preparation method is the same as that in Example 1, except that the amount of febuxostat used in this example is 94.92 mg, the amount of alopecurine used is 23.23 mg, and the amount of anhydrous ethanol used is 5 mL.

[0052] Example 6

[0053] This embodiment provides a co-amorphous compound of febuxostat and sophora flavescens and a preparation method thereof, wherein the preparation method comprises the following steps:

[0054] Accurately weigh 31.64 mg of febuxostat (Feb) and 23.23 mg of alopecurine (Alo) and place them in a mortar. Add 2 mL of ethanol and grind. After the solvent evaporates, an amorphous powder of febuxostat and alopecurine is obtained.

[0055] Example 7

[0056] This embodiment provides a co-amorphous compound of febuxostat and sophora flavescens and a preparation method thereof, wherein the preparation method comprises the following steps:

[0057] Accurately weigh 31.64 mg of febuxostat and 23.23 mg of alopecurine and place them in a penicillin bottle. After adding 2 mL of acetone, the solution becomes clear and transparent. Wrap the clear and transparent solution with sealing film, leaving a hole to evaporate the solvent, add a magnetic bar (5 mm), and place it on a magnetic stirrer and stir continuously for 8 hours at a speed of 500 rpm. The solution remains clear and transparent. Then, dry the solution in vacuum at 60°C for 3 hours to obtain amorphous powder of febuxostat and alopecurine.

[0058] Comparative Example 1

[0059] This comparative example provides a mixture of febuxostat and alopecurine, wherein the amount of febuxostat (Feb) is 31.64 mg and the amount of alopecurine (Alo) is 23.23 mg. The two are directly stirred evenly to obtain a mixture of febuxostat and alopecurine (Feb+Alo).

[0060] Performance Test 1

[0061] XRD tests were performed on the amorphous product of febuxostat and alopecurine (Feb-Alo) prepared in the example, febuxostat (Feb), alopecurine (Alo), and the mixture of febuxostat and alopecurine (Feb+Alo) obtained in comparative example 1.

[0062] Detection instrument: Rigaku D / max-2550 X-ray powder diffractometer.

[0063] Measurement conditions and method: Cu / Ka 1 pha 1, 40 kV-200 mA, I(max)=2244, 2θ=4-40°, λ=1.54056.

[0064] Among them, the XRD test results of the febuxostat and alopecurine co-amorphous compound (Feb-Alo), febuxostat (Feb), alopecurine (Alo), and the mixture of febuxostat and alopecurine (Feb+Alo) prepared in Example 1 are as follows: Figure 1 As shown. Figure 1 It can be found that the X-ray powder diffraction pattern of febuxostat has characteristic diffraction peaks at 2θ=6.79°, 7.37°, 16.68°, 26.06°, and 26.87°; the X-ray powder diffraction pattern of alopecurine has characteristic diffraction peaks at 2θ=9.5°, 15.29°, 18.24°, 21.99°, 22.38°, and 29.67°; and the above-mentioned characteristic peaks of the amorphous compound of febuxostat and alopecurine disappear, and the diffraction pattern becomes diffuse, forming a typical amorphous powder X-ray diffraction pattern.

[0065] Performance Test 2

[0066] DSC tests were performed on the febuxostat and alopecurine co-amorphous compound (Feb-Alo), febuxostat (Feb), and alopecurine (Alo) prepared in the examples.

[0067] Detection instrument: Mettler Toledo DSC3 / 700 / 200 differential scanning calorimeter.

[0068] Determination conditions and methods: Weigh approximately 3 mg of febuxostat, alopecurine, and amorphous product of febuxostat and alopecurine, respectively, and test at a heating rate of 10°C / min from 30 to 220°C.

[0069] The DSC test results of the febuxostat and alopecurine co-amorphous compound (Feb-Alo), febuxostat (Feb), and alopecurine (Alo) prepared in Example 1 are as follows: Figure 2 As shown by Figure 2 It can be found that the amorphous compound of febuxostat and sophora flavescens has only one endothermic peak at 61.17°C, and the onset temperature is significantly different from that of the two monomers of febuxostat and sophora flavescens, indicating that the two have formed a new phase.

[0070] Performance Test 3

[0071] Infrared tests were performed on the febuxostat and alopecurine co-amorphous compound (Feb-Alo), febuxostat (Feb), and alopecurine (Alo) prepared in the examples.

[0072] Detection instrument: Perkin Elmer Spectrum 400 infrared spectrometer.

[0073] Determination conditions and methods: Febuxostat, alopecurine, and amorphous substance of Febuxostat and alopecurine were analyzed and detected by infrared absorption spectroscopy at 4000-400 cm -1 Scan within the range and record the infrared absorption spectrum.

[0074] Among them, the infrared detection results of the febuxostat and alopecurine co-amorphous compound (Feb-Alo), febuxostat (Feb), and alopecurine (Alo) prepared in Example 1 are as follows: Figure 3 As shown by Figure 3 It can be found that the infrared spectrum of Febuxostat is at 2952 cm -1 , 2232cm -1 、1517cm -1 Peaks are shown at 2920 cm-1, which correspond to the OH stretching of the carboxyl group, the C≡N stretching of the carboxyl group, and the C=N stretching of the thiazole ring. In the amorphous compound of febuxostat and alopecurine, these bands shift to 2920 cm-1, -1 , 2227cm -1 、1510cm -1 In addition, the 1678 cm -1 The peak shifted to 1606 cm -1 .

[0075] Performance Test 4

[0076] The febuxostat and sophora flavescens co-amorphous product prepared in Example 1 was subjected to high temperature, high humidity and light experiments.

[0077] 1. High temperature experiment

[0078] Testing instrument: HPP260 constant temperature and humidity incubator

[0079] Determination conditions and methods: Take a small amount of sample and place it in a weighing bottle. Place the weighing bottle in a drying oven at 60°C and measure the X-RAY spectrum after 5 and 10 days respectively.

[0080] Test results such as Figure 4 As shown, Figure 4 These are the X-RAY images of the amorphous compound of febuxostat and alopecurine stored at high temperature for 0 days and 10 days. It can be found that the X-RAY spectrum of the amorphous compound of febuxostat and alopecurine did not change after 10 days of high temperature storage.

[0081] 2. High humidity experiment

[0082] Take a small amount of sample and place it in a weighing bottle, then place the weighing bottle in a high temperature and high humidity incubator at a temperature of 25°C and a humidity of 75%, and measure the X-RAY spectrum after 5 and 10 days respectively.

[0083] Test results such as Figure 5 As shown, Figure 5 These are the X-RAY images of the amorphous compound of febuxostat and alopecurine stored under high humidity conditions for 0 days and 10 days. It can be found that after being stored under high humidity conditions with a humidity of 75% for 10 days, the X-RAY spectrum of the amorphous compound of febuxostat and alopecurine did not change.

[0084] 3. Lighting Experiment

[0085] Take a small amount of sample and place it in a weighing bottle. Place the weighing bottle under a light source with an illumination of 4500±500lx, and measure the X-RAY spectrum after 5 and 10 days respectively.

[0086] Test results such as Figure 6 As shown, Figure 6 These are X-RAY images of the amorphous compound of febuxostat and alopecurine stored under light conditions for 0 days and 10 days. It can be found that the X-RAY spectrum of the amorphous compound of febuxostat and alopecurine did not change after being stored under light for 10 days.

[0087] High temperature, high humidity and light experiments show that the febuxostat and sophora flavescens co-amorphous compound prepared by the present invention has good stability.

[0088] Performance Test 5

[0089] The equilibrium solubility of the co-amorphous product of febuxostat and sophora flavescens prepared in the examples and febuxostat was measured.

[0090] According to the shake flask method recommended by WHO, 5 mL of water was measured and placed in a 15 mL centrifuge tube. An excess of solid sample (amorphous product of febuxostat and sophora flavescens or febuxostat) was added. The tube was sealed and placed on a shaker at 37°C with a stirring speed of 120 r / min. Samples were taken at 0.5 h, 1 h, 2 h, 20 h, and 24 h, and the content was measured by HPLC to calculate the equilibrium solubility.

[0091] The test found that the equilibrium solubility of the amorphous compound of Febuxostat and Sophora flavescens in water was 180 mg / mL, and the equilibrium solubility of the Febuxostat raw material was 0.017 mg / mL. The equilibrium solubility of the amorphous compound in water was 10,588 times that of the raw material.

[0092] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article, or device comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or device. In the absence of further limitations, an element defined by the phrase "comprising a ..." does not exclude the presence of other identical elements in the process, method, article, or device comprising the element.

[0093] The foregoing description is intended only to provide specific embodiments of the present invention, which will enable those skilled in the art to understand and implement the present invention. 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 invention. Therefore, the present invention is not intended to be limited to the embodiments described herein, but is to be construed in the widest manner consistent with the principles and novel features disclosed herein.

Claims

1. A co-amorphous compound of febuxostat and sophora flavescens, characterized in that: The molar ratio of febuxostat to sophoravine in the febuxostat and sophoravine co-amorphous compound is (0.5-3):

1.

2. The febuxostat and sophora flavescens co-amorphous compound according to claim 1, characterized in that: The molar ratio of febuxostat to sophora flavescens in the febuxostat and sophora flavescens co-amorphous compound is 1:

1.

3. The febuxostat and sophora flavescens co-amorphous compound according to claim 1 or 2, characterized in that: The equilibrium solubility of the amorphous compound of febuxostat and sophora flavescens in water is 180 mg / mL.

4. The method for preparing the amorphous compound of febuxostat and sophora flavescens according to any one of claims 1 to 3, characterized in that: The preparation method comprises: Place the formulated amount of febuxostat and alopecurine in a mortar, add a first solvent, and grind until the solvent is completely evaporated to obtain a co-amorphous substance of febuxostat and alopecurine; Or, the preparation method comprises: The febuxostat and alopecurine in the formulated amounts are mixed with a second solvent, stirred, and dried to obtain the febuxostat and alopecurine co-amorphous compound.

5. The preparation method according to claim 4, characterized in that The first solvent includes any one or more of anhydrous ethanol, ethyl acetate and water; And / or, the ratio of the mass of the febuxostat and alopecurine to the volume of the first solvent is 27 mg:(1-4) mL.

6. The preparation method according to claim 4, characterized in that The second solvent includes any one or more of ethanol, methanol, acetonitrile, acetone and ethyl acetate.

7. The preparation method according to claim 4 or 6, characterized in that: The ratio of the mass of the febuxostat and alopecurine to the volume of the second solvent is 27 mg:(1-4) mL.

8. The preparation method according to claim 4, characterized in that The stirring time is 8-16h; And / or, the stirring speed is 500-1000 rpm / min.

9. The preparation method according to claim 4, characterized in that The drying is vacuum drying, the vacuum drying temperature is 50-60° C., and the vacuum drying time is 1-3 hours.

10. Use of the febuxostat and aloperine co-amorphous compound according to any one of claims 1 to 3 or the febuxostat and aloperine co-amorphous compound prepared by the preparation method according to any one of claims 4 to 9 in the preparation of a medicament for treating gout, gouty arthritis or hyperuricemia.

Images