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

Abstract

The invention relates to the technical field of biological medicines, in particular to a febuxostat and aloperine co-amorphous substance as well as a preparation method and application thereof. The molar ratio of the febuxostat to the aloperine in the co-amorphous substance of the febuxostat and the aloperine is (0.5-3): 1. The febuxostat and aloperine co-amorphous substance provided by the invention has excellent stability, not only can effectively improve the water solubility and bioavailability of febuxostat, but also can effectively improve the treatment effect on related diseases such as gout, gouty arthritis, hyperuricemia and the like, and has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the field of biological medicine technology, and particularly relates to a febuxostat and sophoridine co-amorphous substance, a preparation method thereof, and an application thereof. Background Art

[0002] Gout is a disease caused by the dysfunction of the metabolic system, and the increase of uric acid is one of the significant signs. In recent years, with the improvement of the quality of life, the number and incidence of gout patients have shown a gradually increasing trend. Especially for middle-aged and elderly people, gout has become a relatively common metabolic disease. The joints of patients will show swelling, stiffness, deformity, etc., which are mostly seen in the ear contour, toes, and fingers. Patients suffer extremely, and in severe cases, their mobility is limited and they need long-term medication for treatment.

[0004] Currently, febuxostat is the most widely used and common drug for the treatment of gout and hyperuricemia. However, it belongs to the BCS Class II of the biopharmaceutics classification system, that is, drugs with low solubility and high permeability. Its water solubility is poor, which leads to limited bioavailability.

[0005] Therefore, it is desired to provide a method that can improve the water solubility and bioavailability of febuxostat. Summary of the Invention

[0006] In order to solve the above technical problems, the present invention provides a febuxostat and sophoridine co-amorphous substance, a preparation method thereof, and an application thereof. The febuxostat and sophoridine co-amorphous substance provided by the present invention has excellent stability, can not only effectively improve the water solubility and bioavailability of febuxostat, but also effectively improve the treatment effect on related diseases such as gout, gouty arthritis, and hyperuricemia, and has broad application prospects.

[0007] In the first aspect, the present invention provides a febuxostat and sophoridine co-amorphous substance, and the molar ratio of febuxostat to sophoridine in the febuxostat and sophoridine co-amorphous substance is (0.5 - 3):1, such as 0.5:1, 1:1, 2:1, 3:1, etc.

[0008] The febuxostat and sophoridine co-amorphous substance provided by the present invention has excellent stability, can not only effectively improve the water solubility and bioavailability of febuxostat, but also is of great significance for improving the treatment effect on gout, gouty arthritis, hyperuricemia, etc. Specifically:

[0009] The febuxostat and sophoridine co-amorphous substance provided by the present invention uses febuxostat as the active pharmaceutical ingredient, and its chemical name is 2-[(3-cyano-4-isobutoxyphenyl)]-4-methyl-5-thiazolecarboxylic acid, and the molecular formula is C 16 H 16N2O3S, whose structural formula is:

[0010]

[0011] Meanwhile, taking matrine as a drug ligand, its molecular formula is C 15 H 24 N2, whose structural formula is:

[0012]

[0013] The interaction between the two makes the equilibrium solubility of the febuxostat and matrine co-amorphous substance provided by the present invention in water 10,588 times that of febuxostat, effectively improving the water solubility of febuxostat, and then effectively improving its bioavailability. Moreover, it is found to have good stability under conditions such as high temperature, high humidity, and light. In addition, the present invention uses matrine and febuxostat to prepare a co-amorphous substance. Febuxostat itself has no anti-inflammatory activity, while matrine is an alkaloid extracted from Sophora alopecuroides L., which has antibacterial, anti-inflammatory and other effects and can be used to treat diseases such as rheumatism and rheumatoid arthritis. In addition, matrine has significant inhibitory effects on acute inflammation caused by various inflammatory agents, type III and type IV allergic reactions, and adjuvant arthritis. Therefore, the febuxostat and matrine co-amorphous substance provided by the present invention combines the advantages of febuxostat and matrine and can effectively improve the treatment effect of related diseases such as gout and gouty arthritis.

[0014] As a preferred technical solution of the present invention, the molar ratio of febuxostat to matrine in the febuxostat and matrine co-amorphous substance is 1:1.

[0015] As a preferred technical solution of the present invention, the equilibrium solubility of the febuxostat and matrine co-amorphous substance in water is 180 mg / mL.

[0016] In a second aspect, the present invention provides a preparation method of the febuxostat and matrine co-amorphous substance described in the first aspect, and the preparation method includes:

[0017] Put the formulated amounts of febuxostat and matrine into a mortar, add a first solvent, and grind until the solvent completely volatilizes to obtain the febuxostat and matrine co-amorphous substance;

[0018] Or, the preparation method includes:

[0019] Mix the formulated amounts of febuxostat and matrine with a second solvent, stir and dry to obtain the febuxostat and matrine co-amorphous substance.

[0020] The febuxostat and matrine co-amorphous substance provided by the present invention is prepared by a grinding method or a solution crystallization method. The preparation method has a simple process and has good industrial application prospects.

[0021] As a preferred technical solution of the present invention, the first solvent includes any one or more of absolute ethanol, ethyl acetate, and water.

[0022] As a preferred technical solution of the present invention, the ratio of the sum of the masses of febuxostat and sophocarpine to the volume of the first solvent is 27 mg:(1 - 4) mL, such as 27 mg:1 mL, 27 mg:2 mL, 27 mg:3 mL, 27 mg:4 mL, etc.

[0023] 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.

[0024] As a preferred technical solution of the present invention, the ratio of the sum of the masses of febuxostat and sophocarpine to the volume of the second solvent is 27 mg:(1 - 4) mL, such as 27 mg:1 mL, 27 mg:2 mL, 27 mg:3 mL, 27 mg:4 mL, etc.

[0025] As a preferred technical solution of the present invention, the stirring time is 8 - 16 h, such as 8 h, 10 h, 12 h, 14 h, 16 h, etc.

[0026] As a preferred technical solution of the present invention, the stirring speed is 500 - 1000 rpm / min, such as 500 rpm / min, 600 rpm / min, 700 rpm / min, 800 rpm / min, 900 rpm / min, 1000 rpm / min, etc.

[0027] As a preferred technical solution of the present invention, the drying is vacuum drying, the temperature of the vacuum drying is 50 - 60 °C, such as 50 °C, 52 °C, 54 °C, 56 °C, 58 °C, 60 °C, etc., and the time of the vacuum drying is 1 - 3 h, such as 1 h, 1.5 h, 2 h, 2.5 h, 3 h, etc.

[0028] In the third aspect, the present invention provides the use of the febuxostat and sophocarpine co - amorphous substance described in the first aspect or the febuxostat and sophocarpine co - amorphous substance prepared by the preparation method described in the second aspect in the preparation of a medicament for treating gout, gouty arthritis, or hyperuricemia.

[0029] The technical solutions provided by the embodiments of the present invention have the following advantages compared with the prior art:

[0030] The febuxostat and sophocarpine co - amorphous substance provided by the present invention has excellent stability, can not only effectively improve the water solubility and bioavailability of febuxostat, but also effectively improve the therapeutic effect on related diseases such as gout, gouty arthritis, and hyperuricemia, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The drawings herein are incorporated into and constitute a part of this specification, showing embodiments in accordance with the present invention and, together with the specification, are used to explain the principles of the present invention.

[0032] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, for those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0033] Figure 1 XRD diagrams of the febuxostat-aloperine co-amorphous (Feb-Alo), febuxostat (Feb), aloperine (Alo), and the mixture of febuxostat and aloperine (Feb+Alo) prepared in Example 1 of the present invention;

[0034] Figure 2 DSC diagrams of the febuxostat-aloperine co-amorphous (Feb-Alo), febuxostat (Feb), aloperine (Alo) prepared in Example 1 of the present invention;

[0035] Figure 3 Infrared spectra of the febuxostat-aloperine co-amorphous (Feb-Alo), febuxostat (Feb), aloperine (Alo) prepared in Example 1 of the present invention;

[0036] Figure 4 X-RAY diagrams of the febuxostat-aloperine co-amorphous prepared in Example 1 of the present invention stored at high temperature for 0 days and 10 days;

[0037] Figure 5 X-RAY diagrams of the febuxostat-aloperine co-amorphous prepared in Example 1 of the present invention stored under high humidity conditions for 0 days and 10 days;

[0038] Figure 6 X-RAY diagrams of the febuxostat-aloperine co-amorphous prepared in Example 1 of the present invention stored under light conditions for 0 days and 10 days. DETAILED DESCRIPTION OF THE INVENTION

[0039] In order to more clearly understand the above objects, features, and advantages of the present invention, the following will further describe the solutions of the present invention. It should be noted that, without conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other.

[0040] In the following description, many specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; obviously, the embodiments in the specification are only a part of the embodiments of the present invention, rather than all of the embodiments.

[0041] Example 1

[0042] This example provides a febuxostat and aloperine co-amorphous substance and a preparation method thereof. The preparation method includes the following steps:

[0043] Precisely weigh 31.64 mg of febuxostat (Feb) and 23.23 mg of aloperine (Alo) and place them in a mortar. Add 2 mL of absolute ethanol and 1 drop of ethyl acetate, and grind. After the solvent has evaporated completely, a febuxostat and aloperine co-amorphous substance powder is obtained.

[0044] Example 2

[0045] This example provides a febuxostat and aloperine co-amorphous substance and a preparation method thereof. The preparation method includes the following steps:

[0046] Precisely weigh 31.64 mg of febuxostat and 23.23 mg of aloperine and place them in a vial. After adding 2 mL of 95% ethanol, the solution is clear and transparent. Wrap the clear and transparent solution with a sealing film, leave a hole to volatilize the solvent, add a magnetic stir bar (5 mm), place it on a magnetic stirrer and stir continuously for 8 hours at a rotation speed of 500 rpm. The solution remains clear and transparent. Then, dry the solution in a vacuum at 60 °C for 1 h to obtain a febuxostat and aloperine co-amorphous substance powder.

[0047] Example 3

[0048] This example provides a febuxostat and aloperine co-amorphous substance and a preparation method thereof. The preparation method is the same as that of Example 1. The difference from Example 1 is that in this example, the dosage of febuxostat is 31.64 mg, the dosage of aloperine is 46.46 mg, and the dosage of absolute ethanol is 3 mL.

[0049] Example 4

[0050] This example provides a febuxostat and aloperine co-amorphous substance and a preparation method thereof. The preparation method is the same as that of Example 1. The difference from Example 1 is that in this example, the dosage of febuxostat is 63.28 mg, the dosage of aloperine is 23.23 mg, and the dosage of absolute ethanol is 4 mL.

[0051] Example 5

[0052] This example provides a febuxostat and aloperine co-amorphous substance and a preparation method thereof. The preparation method is the same as that of Example 1. The difference from Example 1 is that in this example, the dosage of febuxostat is 94.92 mg, the dosage of aloperine is 23.23 mg, and the dosage of absolute ethanol is 5 mL.

[0053] Example 6

[0054] This example provides a febuxostat and aloperine co-amorphous substance and a preparation method thereof. The preparation method includes the following steps:

[0055] Precisely weigh 31.64 mg of febuxostat (Feb) and 23.23 mg of aloperine (Alo) and place them in a mortar. Add 2 mL of ethanol and grind. After the solvent has completely evaporated, a febuxostat and aloperine co-amorphous substance powder is obtained.

[0056] Example 7

[0057] This example provides a febuxostat and aloperine co-amorphous substance and a preparation method thereof. The preparation method includes the following steps:

[0058] Precisely weigh 31.64 mg of febuxostat and 23.23 mg of aloperine and place them in a vial. After adding 2 mL of acetone, the solution becomes clear and transparent. Wrap the clear and transparent solution with a sealing film, leave holes for solvent evaporation, add a magnetic stir bar (5 mm), place it on a magnetic stirrer and continuously stir for 8 hours at a speed of 500 rpm. The solution remains clear and transparent. Then, dry the solution in a vacuum at 60 °C for 3 h to obtain a febuxostat and aloperine co-amorphous substance powder.

[0059] Comparative Example 1

[0060] This comparative example provides a mixture of febuxostat and aloperine. Among them, the dosage of febuxostat (Feb) is 31.64 mg and the dosage of aloperine (Alo) is 23.23 mg. Stir the two directly until evenly mixed to obtain a mixture of febuxostat and aloperine (Feb + Alo).

[0061] Performance Test 1

[0062] Perform XRD tests on the febuxostat and aloperine co-amorphous substance (Feb - Alo), febuxostat (Feb), aloperine (Alo), and the mixture of febuxostat and aloperine (Feb + Alo) obtained in the examples respectively.

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

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

[0065] Among them, the XRD test results of the febuxostat-aloperine co-amorphous (Feb-Alo), febuxostat (Feb), aloperine (Alo), and the mixture of febuxostat and aloperine (Feb + Alo) prepared in Example 1 are as Figure 1 shown. From 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 aloperine has characteristic diffraction peaks at 2θ = 9.5°, 15.29°, 18.24°, 21.99°, 22.38°, and 29.67°; while the above characteristic peaks of the febuxostat-aloperine co-amorphous disappear, and the diffraction pattern is diffused, forming a typical X-ray diffraction pattern of amorphous powder.

[0066] Performance Test 2

[0067] DSC tests were respectively carried out on the febuxostat-aloperine co-amorphous (Feb-Alo), febuxostat (Feb), and aloperine (Alo) prepared in the examples.

[0068] Detection instrument: Mettler Toledo DSC3 / 700 / 200 type differential scanning calorimeter.

[0069] Determination conditions and methods: Weigh about 3 mg of febuxostat, aloperine, and febuxostat-aloperine co-amorphous respectively, and detect them from 30 - 220 °C at a heating rate of 10 °C / min.

[0070] Among them, the DSC test results of the febuxostat-aloperine co-amorphous (Feb-Alo), febuxostat (Feb), and aloperine (Alo) prepared in Example 1 are as Figure 2 shown. From Figure 2 it can be found that the febuxostat-aloperine co-amorphous 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 aloperine, indicating that a new phase is formed between them.

[0071] Performance Test 3

[0072] Infrared tests were respectively carried out on the febuxostat-aloperine co-amorphous (Feb-Alo), febuxostat (Feb), and aloperine (Alo) prepared in the examples.

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

[0074] Determination conditions and method: Take febuxostat, aloperine, and the co-amorphous product of febuxostat and aloperine, and analyze and detect them by infrared absorption spectrometry. Scan in the range of 4000 - 400 cm -1 and record the infrared absorption spectrum.

[0075] Among them, the infrared detection results of the co-amorphous product of febuxostat and aloperine (Feb-Alo), febuxostat (Feb), and aloperine (Alo) prepared in Example 1 are as Figure 3 shown. It can be found from Figure 3 that the infrared spectrum of febuxostat shows peaks at 2952 cm -1 , 2232 cm -1 , and 1517 cm -1 , which correspond to the O-H stretching of the carboxyl group, C≡N stretching, and C=N stretching of the thiazole ring respectively. In the co-amorphous product of febuxostat and aloperine, these bands are shifted to 2920 cm -1 , 2227 cm -1 , and 1510 cm -1 respectively. In addition, the peak at 1678 cm -1 corresponding to the C=O stretching of febuxostat moves to 1606 cm -1 .

[0076] Performance test 4

[0077] Conduct high-temperature, high-humidity, and light experiments on the co-amorphous product of febuxostat and aloperine prepared in Example 1.

[0078] 1. High-temperature experiment

[0079] Detection instrument: HPP260 constant temperature and humidity incubator

[0080] Determination conditions and method: Take a small amount of sample and place it in a weighing bottle. Put the weighing bottle in a drying oven at 60 °C and measure the X-RAY pattern after 5 and 10 days respectively.

[0081] The detection results are as Figure 4 shown. Figure 4 are the X-RAY patterns of the co-amorphous product of febuxostat and aloperine stored at high temperature for 0 days and 10 days. It can be found that after storing at high temperature for 10 days, the X-RAY pattern of the co-amorphous product of febuxostat and aloperine has not changed.

[0082] 2. High-humidity experiment

[0083] Take a small amount of the sample and place it in a weighing bottle. Put 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 patterns after 5 and 10 days respectively.

[0084] The test results are as Figure 5 shown. Figure 5 Figures for the X-RAY of the amorphous co-form of febuxostat and sophoridine stored for 0 and 10 days under high humidity conditions. It can be found that after storage for 10 days under high humidity conditions of 75%, the X-RAY pattern of the amorphous co-form of febuxostat and sophoridine did not change.

[0085] 3. Light exposure experiment

[0086] Take a small amount of the sample and place it in a weighing bottle. Put the weighing bottle under a light source with an illuminance of 4500 ± 500 lx, and measure the X-RAY patterns after 5 and 10 days respectively.

[0087] The test results are as Figure 6 shown. Figure 6 Figures for the X-RAY of the amorphous co-form of febuxostat and sophoridine stored for 0 and 10 days under light exposure conditions. It can be found that after storage for 10 days under light exposure, the X-RAY pattern of the amorphous co-form of febuxostat and sophoridine did not change.

[0088] The high-temperature, high-humidity, and light exposure experiments show that the amorphous co-form of febuxostat and sophoridine prepared by the present invention has good stability.

[0089] Performance test 5

[0090] Determine the equilibrium solubility of the amorphous co-form of febuxostat and sophoridine and febuxostat prepared in the examples.

[0091] According to the shaking flask method recommended by the WHO, measure 5 mL of water and place it in a 15 mL centrifuge tube. Add an excessive amount of solid sample (amorphous co-form of febuxostat and sophoridine or febuxostat), seal it, place it on a shaker at 37°C and stir at a speed of 120 r / min. Take samples at 0.5 h, 1 h, 2 h, 20 h, and 24 h respectively, measure the content by HPLC method, and calculate the equilibrium solubility.

[0092] The detection found that the equilibrium solubility of the amorphous co-form of febuxostat and sophoridine in water is 180 mg / mL, and the equilibrium solubility of the febuxostat raw material is 0.017 mg / mL. The equilibrium solubility of the amorphous co-form in water is 10588 times that of the raw drug.

[0093] It should be noted that, in this document, relational terms such as "first" and "second" are only used 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 "comprising", "including" or any other variation thereof are intended to cover non-exclusive inclusion, such that a process, method, article or device comprising a series of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising an..." does not exclude the presence of additional identical elements in the process, method, article or device comprising the said element.

[0094] The above are only specific embodiments of the present invention, enabling those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be obvious 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 invention. Therefore, the present invention will not be limited to these embodiments described herein, but rather to the broadest scope consistent with the principles and novel features disclosed herein.

Claims

1. An amorphous co-form of febuxostat and albiflorine, characterized in that, The molar ratio of febuxostat to sophoramine in the febuxostat and sophoramine co-amorphous substance is (0.5 - 3):

1.

2. The febuxostat and sophoridine co-amorphous substance according to claim 1, wherein The molar ratio of febuxostat to sophoramine in the febuxostat and sophoramine co-amorphous substance is 1:

1.

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

4. The preparation method of the amorphous solid dispersion of febuxostat and aloperine according to any one of claims 1-3, characterized in that, The preparation method includes: Placing the formula amounts of febuxostat and sophoramine in a mortar, adding a first solvent, and grinding until the solvent completely volatilizes to obtain the febuxostat and sophoramine co-amorphous substance; Or, the preparation method includes: Mixing the formula amounts of febuxostat and sophoramine with a second solvent, stirring, and drying to obtain the febuxostat and sophoramine co-amorphous substance.

5. The preparation method according to claim 4, wherein, The first solvent includes any one or more of absolute ethanol, ethyl acetate, and water; And / or, the mass sum of febuxostat and sophoramine and the volume ratio 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 mass sum of febuxostat and sophoramine and the volume ratio 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 - 16 h; 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 temperature of the vacuum drying is 50 - 60 °C, and the time of the vacuum drying is 1 - 3 h.

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

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