A febuxostat-berberine co-crystal, and a preparation method and application thereof

Abstract

The application provides a non-busheite-optimine co-crystal as well as a preparation method and application thereof, and belongs to the technical field of medicines. The non-busheite-optimine co-crystal provided by the application is stable in property, and the solubility of the non-busheite-optimine co-crystal in water at 37 DEG C is 414 times that of non-busheite raw medicine, so that the bioavailability of non-busheite can be significantly improved, and the non-busheite-optimine co-crystal also has the effects of non-busheite and optimine, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a febuxostat-cytisine cocrystal, its preparation method, and its application. Background Technology

[0002] Gout is a hereditary or acquired disease caused by decreased uric acid excretion and / or purine metabolism disorders. It occurs because the body produces excessive uric acid and the kidneys' ability to clear it is impaired, leading to the accumulation of uric acid and the deposition of urate crystals in the joints and organs. Affected joints may exhibit swelling, stiffness, and deformity, most commonly around the ears, toes, and between the fingers. Patients experience severe pain, and in severe cases, mobility is limited, requiring long-term medication.

[0003] Febuxostat, also known as febuxostat, is a non-purine selective xanthine oxidoreductase inhibitor. It works by selectively targeting this oxidoreductase to lower uric acid levels in the blood, thereby treating hyperuricemia and gout. Febuxostat belongs to the Biopharmaceutical Classification System (BCS II), meaning it is a drug with low solubility and high permeability. Its low solubility leads to low bioavailability; therefore, improving the solubility of febuxostat is of great importance.

[0004] CN104177308A discloses three novel febuxostat drug cocrystals: febuxostat-isonicotinic acid cocrystal, febuxostat-meglumine cocrystal, and febuxostat-arginine cocrystal; CN108530382A discloses a febuxostat-ligustrazine cocrystal; and international application WO2012 / 098501A1 discloses febuxostat and three cocrystal formations: a cocrystal formed from urea, nicotinamide, and caffeine. All of these cocrystals significantly improve the solubility of febuxostat in water.

[0005] To further enhance the clinical and industrial applications of febuxostat, more cocrystals using febuxostat as the active pharmaceutical ingredient still need to be developed. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a febuxostat-cytisine cocrystal, its preparation method, and its applications. This febuxostat-cytisine cocrystal is stable, and its solubility in water at 37°C is 414 times that of the febuxostat raw material, significantly improving the bioavailability of febuxostat. It also possesses the efficacy of both febuxostat and cytisine, demonstrating promising application prospects.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides a febuxostat-cytisine eutectic, wherein the X-ray powder diffraction pattern of the febuxostat-cytisine eutectic 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 this invention, the molecular formula of febuxostat is C 16 H 16 N2O3S has the structural formula shown in Formula I.

[0010]

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

[0012]

[0013] Cyperine is an alkaloid found in legumes. As a naturally occurring bioactive compound, it possesses a variety of pharmacological activities. Clinically, it is used in smoking cessation treatment, analgesia, and antidepressant therapy. It also exhibits respiratory stimulant, antiarrhythmic, antimicrobial, anti-inflammatory, anti-ulcer, and anticancer activities, as well as leukocyte-enhancing effects. Cyperine is highly effective, safe, low-cost, and possesses a wide range of pharmacological activities.

[0014] This invention uses febuxostat as the active pharmaceutical ingredient and cytisine as the drug ligand to prepare a co-crystal. The solubility of this co-crystal in water at 37°C (approximately 7.04 mg / mL for febuxostat) is about 414 times that of the febuxostat raw material (0.017 mg / mL), significantly improving the bioavailability of febuxostat. Furthermore, the co-crystal exhibits good stability under high temperature (60°C), high humidity (75% relative humidity at 25°C), and light conditions. In addition to the efficacy of febuxostat, this co-crystal also possesses the efficacy of cytisine.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of the febuxostat-cytisine eutectic 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 eutectic is at 3400 cm⁻¹. -1 2402cm -1 and 1650cm -1 It has a characteristic peak.

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

[0018] In some embodiments of the present invention, the febuxostat-cytisine eutectic has a solubility of 7.04 mg / mL in water at 37°C, based on febuxostat.

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

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

[0021] Febuxostat and cytisine were dissolved in ethanol, and the solution was dried to obtain a febuxostat-cytisine eutectic 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 dissolution method is as follows: stirring at 20-25°C (e.g., 20°C, 21°C, 22°C, 23°C, 24°C, or 25°C, etc.) at a speed of 500-1000 rpm (e.g., 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, or 1000 rpm, etc.) for 8-16 hours (e.g., 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, or 16 hours, etc.).

[0025] In some embodiments of the present invention, the drying is carried out at a temperature of 50-60°C (e.g., 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C).

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

[0027] Fourthly, the present invention provides a pharmaceutical composition comprising a febuxostat-cytisine cocrystal as described in the first aspect or a febuxostat-cytisine cocrystal prepared by the preparation method 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] This invention utilizes febuxostat as the active pharmaceutical ingredient and cytisine as the drug ligand to prepare a co-crystal. The solubility of this co-crystal in water at 37°C (approximately 7.04 mg / mL for febuxostat) is approximately 414 times that of the febuxostat raw material (0.017 mg / mL), significantly improving the bioavailability of febuxostat. Furthermore, the co-crystal exhibits good stability under high temperature (60°C), high humidity (75% relative humidity at 25°C), and light exposure (4500 lx ± 500 lx). In addition to possessing the efficacy of febuxostat, this co-crystal also exhibits the efficacy of cytisine, demonstrating promising application prospects. Attached Figure Description

[0030] Figure 1 The PXRD pattern of the febuxostat-cytisine eutectic powder provided in Example 1;

[0031] Figure 2 A comparison of the PXRD spectra of febuxostat, cytisine, a powder mixture of febuxostat and cytisine, and the febuxostat-cytisine eutectic powder provided in Example 1.

[0032] Figure 3 DSC spectra of febuxostat, cytisine, and the febuxostat-cytisine eutectic powder provided in Example 1;

[0033] Figure 4 Infrared spectra of febuxostat, cytisine, and the febuxostat-cytisine eutectic powder provided in Example 1;

[0034] Figure 5 PXRD spectra of the febuxostat-cytisine eutectic powder provided in Example 1 after being placed at high temperature for 0, 5, and 10 days;

[0035] Figure 6 PXRD spectra of the febuxostat-cytisine eutectic powder provided in Example 1 after being placed under high humidity conditions for 0, 5, and 10 days;

[0036] Figure 7 PXRD spectra of the febuxostat-cytisine eutectic powder provided in Example 1 after being placed under light for 0, 5, and 10 days;

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

[0038] 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.

[0039] Example 1

[0040] This embodiment provides a febuxostat-cypermethrin eutectic, the preparation method of which is as follows:

[0041] Accurately 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 sealing film, leaving a hole to evaporate the solvent. Add a magnetic stir bar (5 mm) and place it on a magnetic stirrer and stir continuously at room temperature for 8 hours at a speed of 500 rpm to form a homogeneous and clear solution. Dry the solution at 60 °C for 1 hour to obtain febuxostat-cytisine eutectic powder.

[0042] Example 2

[0043] This embodiment provides a febuxostat-cypermethrin eutectic, the preparation method of which is as follows:

[0044] Accurately 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 sealing film, leaving a hole to evaporate the solvent. Add a magnetic stir bar (5 mm) and place it on a magnetic stirrer and stir continuously at room temperature for 12 h at a speed of 800 rpm to form a homogeneous and clear solution. Dry the solution at 50 °C for 2 h to obtain febuxostat-cytisine eutectic powder.

[0045] Example 3

[0046] This embodiment provides a febuxostat-cypermethrin eutectic, the preparation method of which 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 sealing film, leaving a hole to evaporate the solvent. Add a magnetic stir bar (5 mm) and place it on a magnetic stirrer and stir continuously at room temperature for 16 h at a speed of 1000 rpm to form a homogeneous and clear solution. Dry the solution at 55 °C for 3 h to obtain febuxostat-cytisine eutectic powder.

[0048] Characterization of Febuxostat-cytisine eutectic

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

[0050] Febuxostat (Feb), cytisine (Cyt), a mixture of Febuxostat powder and cytisine powder in a molar ratio of 1:1 (Feb+Cyt), and the Febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Examples 1-3 were subjected to PXRD analysis.

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

[0052] Detection conditions: Cu / Ka l pha 1, 40kV-200mA, I(max)=2244, 2θ=4°-40°, λ=1.54056nm.

[0053] Test results as follows Figure 1 and Figure 2 As shown. Among them, Figure 1 The PXRD spectrum of the febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1 is shown. The PXRD spectra of the febuxostat-cytisine eutectic powders provided in Examples 2 and 3 are the same as those in Example 1. Figure 2 A comparison of the PXRD spectra of Feb, Cyt, Feb+Cyt, and Feb-Cyt.

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

[0055] 2. Differential Scanning Calorimetry (DSC)

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

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

[0058] Test results as follows Figure 3 As shown. From Figure 3 It can be seen that febuxostat (Feb) has an exothermic peak at 204.1℃ and endothermic peaks at 202.6℃ and 210.4℃, respectively. The transformations at 204.1℃ (exothermic) and 210.4℃ (endothermic) can be attributed to crystallization and melting of the crystal form, respectively. Cytisine (Cyt) has an endothermic peak at 156.83℃. The febuxostat-cytisine eutectic (Feb-Cyt) has an endothermic peak at approximately 82.67℃. This indicates the formation of a new crystalline phase, possibly a eutectic.

[0059] 3. Infrared spectroscopy

[0060] Testing 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. -1 Scan within the range and record the infrared absorption spectrum.

[0062] Test results as follows Figure 4 As shown. From Figure 4It can be seen that the infrared absorption spectra of the three substances are different. The carbonyl peak in febuxostat (Feb) is lower than that at 1678 cm⁻¹. -1 The 1650 cm⁻¹ region transforms into a febuxostat-cytisine eutectic (Feb-Cyt). -1 This transformation suggests the possible presence of hydrogen bonds. The infrared spectrum of cytisine (Cyt) is at 3281 cm⁻¹. -1 The -NH stretching vibration peak at the position becomes a broad peak in the infrared spectrum of febuxostat-cytisine eutectic (Feb-Cyt), possibly 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] Detection conditions and methods:

[0066] 4.1 High temperature: Take a small amount of 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 60°C, and perform PXRD detection after 5 and 10 days respectively.

[0067] 4.2 High humidity: Take a small amount of febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1, place it in a weighing bottle, and place the weighing bottle in a constant temperature and humidity incubator at 25°C and 75% humidity. Perform PXRD detection after 5 and 10 days, respectively.

[0068] 4.3 Irradiation: Take a small amount of febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1, 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 4500lx±500lx. Perform PXRD detection after 5 and 10 days, respectively.

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

[0070] 5. Equilibrium solubility determination

[0071] Using the shake-flask method and water as the solvent, the equilibrium solubility of febuxostat (Feb) and the febuxostat-cytisine eutectic powder (Feb-Cyt) provided in Example 1 was determined. 5 mL of deionized water was placed in a 15 mL centrifuge tube, an excess of powder sample was added, the tube was sealed, and the mixture was stirred on a shaker at 37°C at 120 rpm. The supernatant was collected at 0.5 h, 1 h, 2 h, 20 h, 22 h, and 24 h, filtered, and the content was detected by high-performance liquid chromatography (HPLC). The equilibrium solubility was then calculated.

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

[0073] 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 febuxostat-cytisine eutectic, characterized in that, The X-ray powder diffraction pattern of the febuxostat-cytisine eutectic exhibits 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-cytisine eutectic according to claim 1, characterized in that, The X-ray powder diffraction pattern of the febuxostat-cytisine eutectic also exhibits characteristic diffraction peaks at diffraction angles 2θ of 5.63°±0.1°, 6.40°±0.1°, and 12.18°±0.1°.

3. The febuxostat-cytisine eutectic according to claim 1 or 2, characterized in that, The infrared spectrum of the febuxostat-cytisine eutectic at 3400 cm⁻¹ -1 2402cm -1 and 1650cm -1 It has a characteristic peak.

4. The febuxostat-cytisine eutectic according to claim 1 or 2, characterized in that, The differential scanning calorimetry (DSC) spectrum of the Febuxostat-cytisine eutectic showed an endothermic peak at 82.67 °C.

5. The febuxostat-cytisine eutectic according to claim 1 or 2, characterized in that, The febuxostat-cytisine eutectic has a solubility of 7.04 mg / mL in water at 37°C, calculated as febuxostat.

6. A method for preparing the febuxostat-cytisine eutectic as described in any one of claims 1-5, characterized in that, The preparation method includes the following steps: Febuxostat and cytisine were dissolved in ethanol, and the solution was dried to obtain a febuxostat-cytisine eutectic powder.

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

8. The preparation method according to claim 6, characterized in that, The dissolution method is as follows: stirring at 500-1000 rpm for 8-16 hours at 20-25℃; And / or, the drying is carried out at a temperature of 50-60°C.

9. The use of a febuxostat-cytisine cocrystal as described in any one of claims 1-5 or a febuxostat-cytisine cocrystal prepared by the preparation method as described in any one of claims 6-8 in the preparation of a medicament for treating gout or hyperuricemia.

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

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