Febuxostat-cytisine eutectic crystal as well as preparation method and application thereof

Abstract

The invention provides a febuxostat-cytisine eutectic crystal as well as a preparation method and application thereof, and belongs to the technical field of medicines. The febuxostat-cytisine eutectic crystal provided by the invention is stable in property, the solubility of the febuxostat-cytisine eutectic crystal in water at 37 DEG C is 414 times that of a febuxostat raw material medicine in terms of febuxostat, the bioavailability of febuxostat can be remarkably improved, meanwhile, the febuxostat-cytisine eutectic crystal also has the effects of febuxostat and cytisine, and the febuxostat-cytisine eutectic crystal has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a febuxostat - sparteine cocrystal, a preparation method thereof, and an application thereof. Background Art

[0002] Gout is a genetic or acquired disease caused by reduced uric acid excretion and / or purine metabolism disorders. Its occurrence is due to excessive uric acid production in the patient's body and decreased renal clearance ability, resulting in the accumulation of uric acid in the body and the deposition of urate crystals in joints and various organs. The joints of patients with the disease will show swelling, stiffness, deformity, etc., which are more common in the ear contour, toes, and fingers. Patients suffer extremely, and those with severe cases have limited mobility and need long-term drug treatment.

[0003] Febuxostat, also known as febuxostat, is a non-purine-structured selective xanthine oxidoreductase inhibitor. By highly selectively acting on this oxidoreductase, it can reduce the uric acid level in the patient's blood, thereby achieving the purpose of treating hyperuricemia and gout caused by it. Febuxostat belongs to the Biopharmaceutics Classification System (BCS II) class of drugs, that is, drugs with low solubility and high permeability. Its low solubility leads to low bioavailability. Therefore, it is of great significance to improve the solubility of febuxostat.

[0004] CN104177308A discloses three novel febuxostat drug cocrystals, namely febuxostat - isoniazid cocrystal, febuxostat - meglumine cocrystal, and febuxostat - arginine cocrystal; CN108530382A discloses a febuxostat ligustrazine cocrystal; International Application WO2012 / 098501A1 discloses febuxostat and three cocrystal formers, namely urea, nicotinamide, and caffeine cocrystals. The above cocrystals have significantly improved the solubility of febuxostat in water.

[0005] In order to further improve the clinical and industrial application prospects of febuxostat, more cocrystals with febuxostat as the active pharmaceutical ingredient still need to be developed. Summary of the Invention

[0006] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a febuxostat - sparteine cocrystal, a preparation method thereof, and an application thereof. The febuxostat - sparteine cocrystal has stable properties, and its solubility in water at 37 °C is 414 times that of the febuxostat raw material drug, which can significantly improve the bioavailability of febuxostat. At the same time, it also has the effects of both febuxostat and sparteine, and has good application prospects.

[0007] To achieve this purpose, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a febuxostat-cytisine cocrystal, and the X-ray powder diffraction pattern of the febuxostat-cytisine cocrystal has characteristic diffraction peaks at diffraction angles 2θ of 3.54° ± 0.1°, 8.74° ± 0.1°, 10.18° ± 0.1°, and 11.63° ± 0.1°.

[0009] In the present invention, the molecular formula of febuxostat is C 16 H 16 N2O3S, and its structural formula is as shown in Formula I.

[0010]

[0011] The molecular formula of cytisine is C 11 H 14 N2O, and its structural formula is as shown in Formula II.

[0012]

[0013] Cytisine is an alkaloid present in leguminous plants. As a naturally occurring bioactive compound, it has a variety of pharmacological activities. Clinically, it is applied to smoking cessation treatment, analgesia, antidepressant, and also has pharmacological effects such as respiratory stimulant, antiarrhythmic, anti-microbial infection, anti-inflammatory, anti-ulcer, anti-cancer activity, and enhancing leukocyte activity. Cytisine has high efficiency, safety, low cost, and a wide range of pharmacological activities.

[0014] In the present invention, febuxostat is used as the active pharmaceutical ingredient, and cytisine is used as the drug ligand to prepare a cocrystal. The solubility of the cocrystal in water at 37°C (about 7.04 mg / mL in terms of febuxostat) is about 414 times that of the febuxostat raw material drug (0.017 mg / mL), which can significantly improve the bioavailability of febuxostat; and the cocrystal has good stability under high temperature (60°C), high humidity (relative humidity 75% at 25°C), and light conditions. In addition, in addition to the efficacy of febuxostat, the cocrystal also has the efficacy of cytisine.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of the febuxostat-cytisine cocrystal also has characteristic diffraction peaks at diffraction angles 2θ of 5.63° ± 0.1°, 6.40° ± 0.1°, and 12.18° ± 0.1°.

[0016] In some embodiments of the present invention, the infrared spectrum of the febuxostat-cytisine cocrystal has characteristic peaks at 3400 cm -1 、2402 cm -1 and 1650 cm -1 .

[0017] In some embodiments of the present invention, the differential scanning calorimetry spectrum of the febuxostat - cytisine cocrystal has an endothermic peak at 82.67 °C.

[0018] In some embodiments of the present invention, in water at 37 °C, the solubility of the febuxostat - cytisine cocrystal, calculated as febuxostat, is 7.04 mg / mL.

[0019] In some embodiments of the present invention, in the febuxostat - cytisine cocrystal, the molar ratio of febuxostat to cytisine is 1:1.

[0020] In a second aspect, the present invention provides a method for preparing the febuxostat - cytisine cocrystal as described in the first aspect, the preparation method comprising the following steps:

[0021] Dissolve febuxostat and cytisine in ethanol, and after drying the solution, obtain febuxostat - cytisine cocrystal powder.

[0022] In some embodiments of the present invention, the molar ratio of febuxostat to cytisine is 1:1.

[0023] In some embodiments of the present invention, the ratio of the total mass of febuxostat and cytisine to the volume of ethanol is 25 - 35 mg / mL; for example, it can be 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL or 35 mg / mL, etc.

[0024] In some embodiments of the present invention, the dissolving method is: at 20 - 25 °C (for example, it can be 20 °C, 21 °C, 22 °C, 23 °C, 24 °C or 25 °C, etc.), stir at a speed of 500 - 1000 rpm (for example, it can be 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm or 1000 rpm, etc.) for 8 - 16 h (for example, it can be 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h or 16 h, etc.).

[0025] In some embodiments of the present invention, the drying is carried out under the condition that the temperature is 50 - 60 °C (for example, it can be 50 °C, 51 °C, 52 °C, 53 °C, 54 °C, 55 °C, 56 °C, 57 °C, 58 °C, 59 °C or 60 °C, etc.).

[0026] In a third aspect, the present invention provides an application of the febuxostat - cytisine cocrystal as described in the first aspect or the febuxostat - cytisine cocrystal prepared by the preparation method as described in the second aspect in the preparation of a drug for treating gout or hyperuricemia.

[0027] In a fourth aspect, the present invention provides a pharmaceutical composition, which comprises the febuxostat-sparteine cocrystal as described in the first aspect or the febuxostat-sparteine cocrystal prepared by the preparation method as described in the second aspect, and a pharmaceutically acceptable carrier, diluent or excipient.

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

[0029] In the present invention, febuxostat is used as the active pharmaceutical ingredient and sparteine is used as the drug ligand to prepare a cocrystal. The solubility of the cocrystal in water at 37 °C (about 7.04 mg / mL calculated as febuxostat) is about 414 times that of the febuxostat raw material drug (0.017 mg / mL), which can significantly improve the bioavailability of febuxostat; and the cocrystal has good stability under the conditions of high temperature (60 °C), high humidity (relative humidity 75% at 25 °C), and light (4500 lx ± 500 lx). In addition, in addition to the efficacy of febuxostat, the cocrystal also has the efficacy of sparteine and has good application prospects. Description of the Drawings

[0030] Figure 1 It is the PXRD pattern of the febuxostat-sparteine cocrystal powder provided in Example 1;

[0031] Figure 2 It is a comparison diagram of the PXRD patterns of febuxostat, sparteine, the powder mixture of febuxostat and sparteine, and the febuxostat-sparteine cocrystal powder provided in Example 1;

[0032] Figure 3 It is the DSC pattern of febuxostat, sparteine and the febuxostat-sparteine cocrystal powder provided in Example 1;

[0033] Figure 4 It is the infrared spectrum of febuxostat, sparteine and the febuxostat-sparteine cocrystal powder provided in Example 1;

[0034] Figure 5 It is the PXRD pattern of the febuxostat-sparteine cocrystal powder provided in Example 1 placed at high temperature for 0, 5, and 10 days;

[0035] Figure 6 It is the PXRD pattern of the febuxostat-sparteine cocrystal powder provided in Example 1 placed at high humidity for 0, 5, and 10 days;

[0036] Figure 7 It is the PXRD pattern of the febuxostat-sparteine cocrystal powder provided in Example 1 placed under light for 0, 5, and 10 days;

[0037] Figure 8 Dissolution curves of febuxostat and the febuxostat - cytisine cocrystal powder provided in Example 1. Detailed implementation manners

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

[0039] Example 1

[0040] This example provides a febuxostat - cytisine cocrystal, and its preparation method is as follows:

[0041] Precisely weigh 31.64 mg (0.1 mmol) of febuxostat (Feb) and 19.02 mg (0.1 mmol) of cytisine (Cyt) and place them in a vial. Add 2 mL of ethanol, and the solution is in a suspension state. Wrap the above suspension with a sealing film, leave holes to volatilize the solvent, add a magnetic stir bar (5 mm), place it on a magnetic stirrer, and continuously stir at room temperature for 8 h at a rotation speed of 500 rpm to form a homogeneous and clear solution. Dry the solution at 60 °C for 1 h to obtain the febuxostat - cytisine cocrystal powder.

[0042] Example 2

[0043] This example provides a febuxostat - cytisine cocrystal, and its preparation method is as follows:

[0044] Precisely weigh 41.13 mg (0.13 mmol) of febuxostat (Feb) and 24.73 mg (0.13 mmol) of cytisine (Cyt) and place them in a vial. Add 2 mL of ethanol, and the solution is in a suspension state. Wrap the above suspension with a sealing film, leave holes to volatilize the solvent, add a magnetic stir bar (5 mm), place it on a magnetic stirrer, and continuously stir at room temperature for 12 h at a rotation speed of 800 rpm to form a homogeneous and clear solution. Dry the solution at 50 °C for 2 h to obtain the febuxostat - cytisine cocrystal powder.

[0045] Example 3

[0046] This example provides a febuxostat - cytisine cocrystal, and its preparation method is as follows:

[0047] Accurately weigh 63.28 mg (0.2 mmol) of febuxostat (Feb) and 38.04 mg (0.2 mmol) of cytisine (Cyt) and place them in a vial. Add 4 mL of ethanol, and the solution is in a suspension state. Wrap the above suspension with a sealing film, leave a hole to volatilize the solvent, add a magnetic stir bar (5 mm), and continuously stir at room temperature for 16 h on a magnetic stirrer at a rotation speed of 1000 rpm to form a homogeneous and clear solution. Dry the solution at 55 °C for 3 h to obtain the febuxostat-cytisine cocrystal powder.

[0048] Characterization of Febuxostat-Cytisine Cocrystal

[0049] 1. Powder X-ray Diffraction Pattern (PXRD)

[0050] Perform PXRD detection on febuxostat (Feb), cytisine (Cyt), a mixture of febuxostat powder and cytisine powder with a molar ratio of 1:1 (Feb + Cyt), and the febuxostat-cytisine cocrystal powder (Feb-Cyt) provided in Examples 1-3 respectively.

[0051] Detection instrument: Rigaku D / max-2550 type X-ray powder diffractometer.

[0052] Detection conditions: Cu / K-α1, 40 kV - 200 mA, I(max) = 2244, 2θ = 4° - 40°, λ = 1.54056 nm.

[0053] The detection results are as Figure 1 and Figure 2 shown. Among them, Figure 1 is the PXRD pattern of the febuxostat-cytisine cocrystal powder (Feb-Cyt) provided in Example 1. The PXRD patterns of the febuxostat-cytisine cocrystal powders provided in Examples 2 and 3 are the same as that in Example 1; Figure 2 is the comparison chart of the PXRD patterns of Feb, Cyt, Feb + Cyt, and Feb-Cyt.

[0054] From Figure 1 and Figure 2It can be seen that compared with the febuxostat-cytisine cocrystal (Feb-Cyt), the characteristic diffraction peaks of the X-ray powder diffraction spectrum of febuxostat (Feb) at 2θ=6.79°, 7.37°, 16.68°, 26.06°, and 26.87° disappeared; the characteristic diffraction peaks of the X-ray powder diffraction spectrum of cytisine (Cyt) at 2θ=9.5°, 15.29°, 18.24°, 21.99°, 22.38°, and 29.67° disappeared. The febuxostat-cytisine cocrystal (Feb-Cyt) has new characteristic peaks at 3.55°, 6.89°, 10.41°, and 11.74°, indicating that it is a new cocrystal.

[0055] 2. Differential Scanning Calorimetry (DSC)

[0056] Detection instrument: Mettler Toledo DSC3 / 700 / 200 differential scanning calorimeter.

[0057] Detection conditions and methods: Weigh about 3 mg of febuxostat (Feb), cytisine (Cyt), and febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1, respectively, and heat the mixture from 30°C to 220°C at a heating rate of 10°C / min for detection.

[0058] Test results such as Figure 3 As shown. Figure 3 It can be seen that Febuxostat (Feb) has an exothermic peak at 204.1°C, and endothermic peaks at 202.6°C and 210.4°C. The transitions at 204.1°C (exothermic) and 210.4°C (endothermic) can be attributed to the crystallization and melting of the crystalline form, respectively. Cytisine (Cyt) has an endothermic peak at 156.83°C. Febuxostat-Cytisine cocrystal (Feb-Cyt) has an endothermic peak at about 82.67°C. This indicates that a new crystalline phase has been formed, which may be a cocrystal.

[0059] 3. Infrared spectroscopy

[0060] Detection instrument: Perkin Elmer Spectrum 400 infrared spectrometer.

[0061] Detection conditions and methods: Febuxostat (Feb), cytisine (Cyt), and the febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1 were analyzed and detected by infrared absorption spectroscopy at 4000-400 cm -1 Scan within the range and record the infrared absorption spectrum.

[0062] Test results such as Figure 4 As shown. Figure 4It can be seen that the infrared absorption spectra of the three substances are different. The carbonyl peak in Febuxostat (Feb) is from 1678cm -1 The 1650 cm- -1 , this shift indicates the possible existence of hydrogen bonding. The infrared spectrum of cytisine (Cyt) is at 3281cm -1 The -NH stretching vibration peak at 240 nm becomes a large broad peak in the infrared spectrum of febuxostat-cytisine cocrystal (Feb-Cyt), which may be due to hydrogen bonding.

[0063] 4. Stability test

[0064] Testing instruments: HPP260 constant temperature and humidity incubator, Rigaku D / max-2550 X-ray powder diffractometer.

[0065] Testing conditions and methods:

[0066] 4.1. High temperature: Take a small amount of the febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1, place it in a weighing bottle, place the weighing bottle in a drying oven at a temperature of 60° C., and perform PXRD detection after 5 and 10 days, respectively.

[0067] 4.2. High humidity: Take a small amount of the febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1, 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 humidity of 75%, and perform PXRD detection after 5 and 10 days, respectively.

[0068] 4.3. Illumination: Take a small amount of the febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1, place it in a weighing bottle, place the weighing bottle under a white light source with a temperature of 25° C. and a light intensity of 4500 lx±500 lx, and perform PXRD detection after 5 and 10 days, respectively.

[0069] Among them, the test results under high temperature, high humidity and light conditions are as follows: Figure 5 , Figure 6 , Figure 7 As shown. Figures 5 to 7 It can be seen that after the febuxostat-cytisine cocrystal (Feb-Cyt) was placed under high temperature, high humidity or light conditions for 10 days, the PXRD spectrum did not change, indicating that the febuxostat-cytisine cocrystal provided by the present invention has good stability.

[0070] 5. Equilibrium solubility determination

[0071] According to the shake-flask method, using water as the solvent, the equilibrium solubilities of febuxostat (Feb) and the febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1 were determined respectively. 5 mL of deionized water was taken and placed in a 15 mL centrifuge tube. An excessive amount of powder sample was added, sealed, and placed on a shaker at 37 °C and stirred at a rotation speed of 120 r / min. The supernatant was taken at 0.5 h, 1 h, 2 h, 20 h, 22 h, and 24 h respectively, filtered, and the content was detected by high performance liquid chromatography (HPLC) method, and the equilibrium solubility was calculated.

[0072] The measurement results are as Figure 8 shown. The equilibrium solubility of the febuxostat raw material in water at 37 °C is 0.017 mg / mL, and the equilibrium solubility of the febuxostat-cytisine eutectic in water at 37 °C (calculated as febuxostat) is 7.04 mg / mL, which is 414 times that of the febuxostat raw material. This obviously helps to improve the bioavailability of febuxostat.

[0073] The above are only specific embodiments of the present disclosure, enabling those skilled in the art to understand or implement the present disclosure. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present disclosure. Therefore, the present disclosure will not be limited to these embodiments described herein, but rather will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An febuxostat - sparteine cocrystal, characterized in that, The X-ray powder diffraction pattern of the febuxostat-sparteine cocrystal has characteristic diffraction peaks at diffraction angles 2θ of 3.54° ± 0.1°, 8.74° ± 0.1°, 10.18° ± 0.1°, and 11.63° ± 0.1°.

2. The febuxostat - sparteine cocrystal according to claim 1, characterized in that, The X-ray powder diffraction pattern of the febuxostat-sparteine cocrystal also has characteristic diffraction peaks at diffraction angles 2θ of 5.63° ± 0.1°, 6.40° ± 0.1°, and 12.18° ± 0.1°.

3. The febuxostat-sparteine cocrystal according to claim 1 or 2, wherein The infrared spectrum of the febuxostat-sparteine cocrystal has characteristic peaks at 3400 cm -1 , 2402 cm -1 and 1650 cm -1 .

4. The febuxostat - sparteine cocrystal according to claim 1 or 2, characterized in that, The differential scanning calorimetry thermogram of the febuxostat-sparteine cocrystal has an endothermic peak at 82.67 °C.

5. The febuxostat - sparteine eutectic according to claim 1 or 2, characterized in that, In water at 37 °C, the solubility of the febuxostat-sparteine cocrystal, calculated as febuxostat, is 7.04 mg / mL.

6. A preparation method of febuxostat - sparteine eutectic as described in any one of claims 1 - 5, characterized in that, The preparation method includes the following steps: Dissolve febuxostat and sparteine in ethanol, and after drying the solution, obtain febuxostat-sparteine cocrystal powder.

7. The preparation method according to claim 6, wherein The molar ratio of the febuxostat to the sparteine is 1:1; and / or, the ratio of the total mass of the febuxostat and sparteine to the volume of the ethanol is 25 - 35 mg / mL.

8. The preparation method according to claim 6, characterized in that, The dissolving method is: stir at a speed of 500 - 1000 rpm for 8 - 16 h at 20 - 25 °C; and / or, the drying is carried out under the condition that the temperature is 50 - 60 °C.

9. Use of a febuxostat-sparteine cocrystal as described in any one of claims 1 - 5 or a febuxostat-sparteine cocrystal prepared by the preparation method as described in any one of claims 6 - 8 in the preparation of a drug for treating gout or hyperuricemia.

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition includes a febuxostat-sparteine cocrystal as described in any one of claims 1 - 5 or a febuxostat-sparteine cocrystal prepared by the preparation method as described in any one of claims 6 - 8, and a pharmaceutically acceptable carrier, diluent, or excipient.

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