A maltol iron-quercetin eutectic and its preparation method

Abstract

This invention discloses a maltol-iron-quercetin eutectic, which exhibits characteristic diffraction peaks at diffraction angles of approximately 8.6±0.2°, 11.1±0.2°, 12.1±0.2°, 15.0±0.2°, 20.1±0.2°, 22.9±0.2°, 23.4±0.2°, 25.0±0.2°, and 26.4±0.2° in X-ray powder diffraction patterns obtained using Cu-Kα radiation. The maltol-iron-quercetin eutectic of this invention exhibits good stability, showing no crystal transformation for at least 60 days under accelerated conditions (40°C, 75% RH). By introducing the cocrystallized ligand quercetin, the maltol iron-quercetin cocrystallization has relatively low solubility and a slower dissolution rate, which can ensure a more stable and sustained release rate of the drug in vivo, avoid short-term drug concentration peaks, and reduce the side effects of maltol iron gastrointestinal inflammation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to drug cocrystals, specifically to a maltol iron-quercetin cocrystal and its preparation method. Background Technology

[0002] Ferric maltol is a novel, chemically stable, non-salt complex formed by iron and maltol. It is a reddish-brown crystalline solid, and its chemical structural formula is as follows:

[0003]

[0004] Ferrous maltol provides essential iron, supplementing the body's nutritional needs and preventing or treating iron-deficiency anemia. Ferrous maltol has a unique absorption mechanism, offering significant advantages compared to similar iron supplements. Developed by Shield Therapeutics in the UK, ferrous maltol capsules were approved by the European Medicines Agency (EMA) in 2016 and the US Food and Drug Administration (FDA) in 2019 for the treatment of iron deficiency in adults (with or without anemia symptoms), under the brand names Feraccru (EU market) and Accrufer (US market), respectively. A series of clinical trials have demonstrated that ferrous maltol capsules are an oral medication for treating iron deficiency in adults with a low incidence of adverse reactions, high bioavailability, low risk of iron overload, and good tolerability. For patients who are intolerant to or do not respond well to existing oral iron supplements, ferrous maltol capsules are an ideal alternative. According to reports, the main adverse reactions of maltol iron include: gastrointestinal inflammation, flatulence, constipation, diarrhea, etc. (Khoury A, Pagan KA, Farland MZ. Ferric maltol: A new oral iron formulation for the treatment of iron deficiency in adults. Ann Pharmacother. 2021, 55(2):222-229).

[0005] Quercetin is a natural product with good biological activity. It is a dietary polyphenol with the ability to scavenge free radicals and can also induce the activation of antioxidant and detoxification enzymes, thereby protecting cells from oxidative damage caused by carcinogenic compounds. Quercetin mainly exists in the form of glycosides in vegetables, fruits, tea and wine, and its sources are wide-ranging, safe and readily available. Quercetin has been widely recognized for its effects in treating diabetes, hypertension, anti-aging and analgesia. It has been reported that quercetin has good safety and multifaceted anti-inflammatory pharmacological activities, which can relieve colitis symptoms and maintain colon length and intestinal barrier integrity (Wang X, Xie X, Li Y, et al., Quercetin ameliorates ulcerative colitis by activating aryl hydrocarbon receptor to improve intestinal barrier integrity. Phytother. Res. 2023, 38(1):253-264).

[0006] Drug cocrystals refer to crystals formed by the combination of active drug molecules and cocrystal ligands in the same lattice through nonionic and non-covalent bonds in a fixed stoichiometric ratio. They do not change the original chemical structure of the drug, but rather optimize the physicochemical properties of the drug through physical means, such as improving solubility, enhancing stability, and improving bioavailability.

[0007] There are currently no reports on maltol-iron eutectic, therefore, developing a maltol-iron eutectic product with excellent stability is of great significance. Summary of the Invention

[0008] The purpose of this invention is to provide a maltol iron-quercetin cocrystal and its preparation method. The maltol iron-quercetin cocrystal is composed of maltol iron and the pharmaceutically acceptable small-molecule excipient quercetin. The introduction of the ligand quercetin can reduce the gastrointestinal side effects of maltol iron, thereby achieving optimal clinical efficacy. The maltol iron-quercetin cocrystal can be prepared into various dosage forms such as tablets, capsules, transdermal patches, and inhalers, suitable for different routes of administration.

[0009] The objective of this invention is achieved through the following technical solution:

[0010] A maltol iron-quercetin cocrystal is formed by using maltol iron as the active pharmaceutical ingredient and quercetin as the cocrystal ligand, and by a suspension stirring method.

[0011] In the X-ray powder diffraction pattern obtained using Cu-Kα radiation measurement, the maltol iron-quercetin eutectic exhibits characteristic diffraction peaks at diffraction angles of approximately 8.6±0.2°, 11.1±0.2°, 12.1±0.2°, 15.0±0.2°, 20.1±0.2°, 22.9±0.2°, 23.4±0.2°, 25.0±0.2°, and 26.4±0.2°. The 2θ angle of the characteristic peak with a relative intensity of 100% is 20.1±0.2°.

[0012] Preferably, the maltol iron-quercetin eutectic has the following properties: Figure 1 or Figure 5 or Figure 6 The X-ray powder diffraction pattern shown is shown.

[0013] The infrared absorption spectra obtained by pressing the maltol iron-quercetin cocrystal with potassium bromide (KBr) into tablets were 3411.84, 3266.53, 1625.95, 1602.16, 1570.45, 1528.86, 1504.59, 1470.70, 1437.68, 1420.00, 1375.07, and 1326. .27, 1274.71, 1200.79, 1167.82, 1099.34, 1042.82, 1019.90, 998.39, 928.84 ,891.12,850.99,786.29,726.56,656.94,621.25,542.83,511.13,417.27cm -1 There are characteristic peaks in the vicinity.

[0014] In the differential scanning calorimetry (DSC) spectrum, the maltol iron-quercetin eutectic exhibits a single endothermic melting peak at 263.56 °C.

[0015] Another object of the present invention is to provide a method for preparing the maltol iron-quercetin cocrystal, wherein the preparation method adopts a suspension stirring method and includes the following steps: adding maltol iron and quercetin to an organic solvent to form a suspension, stirring and reacting, filtering, and drying to obtain the maltol iron-quercetin cocrystal.

[0016] The molar ratio of maltol iron to quercetin is 1:0.5 to 1:3, preferably 1:1 to 1:2, and more preferably 1:1.

[0017] The organic solvent is anhydrous ethanol, methanol, acetonitrile, acetone, ethyl acetate, or a mixture of at least two of the above organic solvents. Considering the reaction rate and the yield of the eutectic, anhydrous ethanol or methanol is preferred.

[0018] The ratio of maltol iron to organic solvent is 2:1 to 500:1 mg / mL, preferably 50 mg:1 to 200:1 mg / mL.

[0019] The reaction temperature is 15-50°C, preferably 25-35°C, and most preferably room temperature (25°C).

[0020] The reaction time is 2 to 7 days, preferably 5 to 6 days.

[0021] The stirring speed is 50-1000 rpm, preferably 200-400 rpm.

[0022] Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned maltol iron-quercetin cocrystal, and a pharmaceutically acceptable carrier.

[0023] The pharmaceutical composition is available in various dosage forms, including tablets, capsules, transdermal patches, and inhalers.

[0024] The beneficial effects of this invention are:

[0025] (1) The PXRD, DSC and IR spectra of the maltol iron-quercetin eutectic of the present invention are different from those of maltol iron crystal, quercetin crystal and physical mixture of maltol iron-quercetin. It is a new solid-state material that is completely different from existing maltol iron and quercetin.

[0026] (2) The maltol iron-quercetin cocrystal of the present invention does not undergo crystal form transformation for at least 60 days under accelerated conditions (40°C, 75% RH), exhibiting good stability. This can extend the shelf life of the cocrystal preparation, reduce the decrease in efficacy and quality problems caused by crystal form transformation, and simultaneously reduce the risks of production and quality control.

[0027] (3) Compared with ferrous maltol, the present invention introduces the co-crystallized ligand quercetin. The ferrous maltol-quercetin co-crystallization has relatively low solubility and slow dissolution rate, which can ensure that the drug release rate in the body is more stable and lasting, avoids drug concentration peak in a short period of time, provides a new solution for the design of sustained-release and long-acting drug release systems, and can reduce the side effects of ferrous maltol gastrointestinal inflammation, exert a synergistic therapeutic effect, and achieve the best clinical efficacy.

[0028] (4) Compared with amorphous solid dispersion technology, which usually requires a polymer carrier several times larger than the drug to fully disperse the drug, the maltol iron-quercetin cocrystal of the present invention has a high drug loading and better stability; compared with nanotechnology, the maltol iron-quercetin cocrystal of the present invention is easier to industrialize and the quality is easier to control.

[0029] (5) The method for preparing maltol iron-quercetin eutectic of the present invention is simple, low in cost, easy to control, and conducive to industrial production. Attached Figure Description

[0030] Figure 1 The image shows the PXRD pattern of the maltol iron-quercetin eutectic obtained in Example 1.

[0031] Figure 2 The image shows a comparison of the PXRD values ​​of the maltol iron-quercetin eutectic obtained in Example 1 with those of maltol iron and quercetin.

[0032] Figure 3 The image shows a DSC comparison of the maltol iron-quercetin eutectic, maltol iron, and quercetin obtained in Example 1.

[0033] Figure 4 The image shows a comparison of the infrared spectra of the maltol iron-quercetin eutectic, the maltol iron-quercetin physical mixture, and quercetin and maltol iron prepared in Example 1.

[0034] Figure 5 The image shows the PXRD pattern of the maltol iron-quercetin eutectic obtained in Example 2.

[0035] Figure 6 The image shows the PXRD pattern of the maltol iron-quercetin eutectic obtained in Example 3.

[0036] Figure 7 The image shows a comparison of the PXRD values ​​of the maltol iron-quercetin eutectic crystals from Example 1 after 60 days and 0 days of storage under accelerated conditions (40°C, 75% RH).

[0037] Figure 8 The image shows the PXRD pattern of the product prepared by slurrying maltol iron and L-histidine in ethanol, acetonitrile, ethyl acetate and acetone in Comparative Example 1.

[0038] Figure 9 The image shows the PXRD pattern of the product prepared by slurrying maltol iron and nicotinamide in ethanol, acetonitrile, ethyl acetate and acetone in Comparative Example 2. Detailed Implementation

[0039] The maltol iron used in the preparation of the maltol iron-quercetin eutectic is maltol iron crystal form II; the maltol iron (crystal) used for comparison with the maltol iron-quercetin eutectic is maltol iron crystal form II.

[0040] Example 1

[0041] Preparation of maltol iron-quercetin eutectic

[0042] Weigh 100 mg of maltol iron and 70.1 mg of quercetin according to a molar ratio of 1:1, add 0.5 mL of anhydrous ethanol, and magnetically stir (400 rpm) at room temperature (25°C) for 6 days. Filter, and vacuum dry the filter cake at 40°C for 24 hours to obtain maltol iron-quercetin eutectic, which is a dark red solid.

[0043] The maltol-ferric-quercetin eutectic was characterized using X-ray powder diffraction (PXRD) with Cu-Kα radiation. The PXRD pattern is shown below. Figure 1 As shown.

[0044] Compare the PXRD patterns of maltol iron-quercetin eutectic with those of maltol iron crystals and quercetin crystals, such as... Figure 2 As shown, the PXRD pattern of the maltol iron-quercetin cocrystal is significantly different from that of maltol iron and quercetin alone. Further comparison of the characteristic peaks of the three is shown in Table 1. The cocrystal exhibits characteristic diffraction peaks at diffraction angles of approximately 2θ of 8.64°, 11.14°, 12.14°, 14.96°, 20.13°, 22.88°, 23.40°, 24.99°, and 26.43°, which are distinct from those of maltol iron and quercetin.

[0045] Table 1. Comparison of PXRD characteristic diffraction peak positions of maltol iron-quercetin eutectic and maltol iron and quercetin.

[0046]

[0047]

[0048] The thermal properties of maltol iron, quercetin, and the maltol iron-quercetin eutectic prepared in this example were analyzed using differential scanning calorimetry (DSC). The method was as follows: approximately 3 mg of sample was taken, the nitrogen purge gas flow rate in the sample chamber was set to 100 mL / min, equilibration was achieved at 25 °C, and the sample was heated to 400 °C at a heating rate of 10 °C / min. The results are as follows. Figure 3 As shown. By Figure 3 It can be seen that the thermal behavior of maltol iron-quercetin eutectic, maltol iron, and quercetin are significantly different. The melting point of maltol iron is 288.87℃, the melting point of quercetin is 318.05℃, and the melting point of maltol iron-quercetin eutectic is 263.56℃.

[0049] Comparison of infrared spectra of maltol iron-quercetin cocrystal: Fourier transform infrared spectroscopy was used to characterize maltol iron, quercetin, and the maltol iron-quercetin cocrystal prepared in this example. The spectral acquisition range was 4000–400 cm⁻¹. -1Before recording the spectrum of each sample, measurements were performed using air as a blank. The infrared spectra of ferric maltol, quercetin, a physical mixture of ferric maltol and quercetin (the molar ratio of ferric maltol to quercetin was 1:1), and the ferric maltol-quercetin cocrystal prepared in this example are compared as follows: Figure 4 As shown. From Figure 4 It can be seen that the maltol iron-quercetin eutectic has a range of values ​​at 3411.84, 3266.53, 1625.95, 1602.16, 1570.45, 1528.86, 1504.59, 1470.70, 1437.68, 1420.00, 1375.07, 1326.27, 1274.71, 1200.79, 1167.82, 1099.34, 1042.82, 1019.90, 998.39, 928.84, 891.12, 850.99, 786.29, 726.56, 656.94, 621.25, 542.83, 511.13, and 417.27 cm. -1 It exhibits characteristic peaks in the vicinity, which are significantly different from those of maltol iron and quercetin, as well as physical mixtures of maltol iron and quercetin.

[0050] Example 2

[0051] Preparation of maltol iron-quercetin eutectic

[0052] Weigh 100 mg of maltol ferric and 140.2 mg of quercetin according to a molar ratio of 1:2. Add 0.5 mL of anhydrous ethanol and stir magnetically (400 rpm) for 6 days at room temperature (25°C). Filter, and vacuum dry the filter cake at 40°C for 24 hours to obtain a dark red solid. Characterize it using PXRD. The PXRD pattern obtained using Cu-Kα radiation is shown below. Figure 5 As shown. From Figure 5 It can be seen that the characteristic diffraction peaks of this product are basically the same as those of the product in Example 1, and maltol iron-quercetin cocrystal was also obtained.

[0053] Example 3

[0054] Preparation of maltol iron-quercetin eutectic

[0055] Weigh 100 mg of maltol ferric and 70.1 mg of quercetin according to a 1:1 molar ratio of maltol ferric and quercetin, add 0.5 mL of anhydrous ethanol, and magnetically stir (200 rpm) for 6 days at room temperature (25℃). Filter, and vacuum dry the filter cake at 40℃ for 24 hours to obtain a dark red solid. Characterize it using PXRD. The PXRD pattern obtained using Cu-Kα radiation is shown below. Figure 6 As shown. From Figure 6It can be seen that the characteristic diffraction peaks of this product are basically the same as those of the product in Example 1, and maltol iron-quercetin cocrystal was also obtained.

[0056] Example 4

[0057] Stability Study of Maltol Iron-Quercetin Cocrystal

[0058] The maltol-ferric-quercetin eutectic obtained in Example 1 was placed in a constant temperature and humidity chamber under accelerated conditions (40°C, 75% RH), and samples were taken on day 60 and characterized using X-ray powder diffraction (PXRD). The results are as follows: Figure 7 As shown. From Figure 7 It is known that maltol iron-quercetin eutectic does not undergo crystal transformation for at least 60 days under accelerated conditions.

[0059] Table 2. Comparison of PXRD characteristic diffraction peak positions of maltol iron-quercetin eutectic at 40℃ and 75%RH for 0 days and 60 days.

[0060]

[0061] Example 5

[0062] Solubility determination

[0063] Test solution: Measure 5 mL of water into a vial, add excess maltol iron or maltol iron-quercetin eutectic (Example 1), seal the vial, place it at 25 °C and stir magnetically until equilibrium is reached (24 h), then filter through a 0.22 μm microporous membrane to obtain the test solution.

[0064] Reference solution: Weigh 5.0 mg of maltol iron reference standard accurately, place it in a 100 mL volumetric flask, dissolve and dilute with water to the mark, shake well, and filter through a 0.22 μm microporous membrane to obtain the solution.

[0065] The content of maltol iron was determined by ultraviolet spectrophotometry at a wavelength of 411 nm.

[0066] The results showed that at 25°C, the solubility of maltol iron-quercetin cocrystal in water was 7.08 mg / mL, lower than that of maltol iron crystals (9.03 mg / mL). Maltol iron-quercetin cocrystals with relatively low solubility generally dissolve slowly. From a formulation perspective, the maltol iron-quercetin cocrystal of this invention has some unique advantages, especially in the design and development of sustained-release and controlled-release drug formulations. The low-solubility cocrystal can be used to design long-acting drug release systems, ensuring a more stable and sustained rate of drug release in vivo, and avoiding short-term peak drug concentrations.

[0067] Comparative Example 1

[0068] Preparation of maltol iron and L-histidine cocrystallization

[0069] Weigh 100 mg of maltol ferric and 35.98 mg of L-histidine according to a 1:1 molar ratio of maltol ferric to L-histidine. Add 0.5 mL of anhydrous ethanol (or acetone, ethyl acetate, or acetonitrile). Stir magnetically at room temperature (25°C) for 6 days (400 rpm). Filter, and vacuum dry the filter cake at 40°C for 24 hours to obtain a deep red solid. Characterize it using X-ray powder diffraction (PXRD). The results are as follows: Figure 8 As shown. From Figure 8 It can be seen that the characteristic diffraction peaks of the obtained product are basically consistent with those of maltol iron and L-histidine, that is, maltol iron and L-histidine cannot form a eutectic.

[0070] Comparative Example 2

[0071] Preparation of maltol iron and nicotinamide cocrystal

[0072] Weigh 100 mg of maltol ferric and 28.33 mg of nicotinamide according to a 1:1 molar ratio of maltol ferric and nicotinamide. Add 0.5 mL of anhydrous ethanol (or acetone, ethyl acetate, or acetonitrile). Stir magnetically at room temperature (25°C) (400 rpm) for 6 days. Filter, and vacuum dry the filter cake at 40°C for 24 hours to obtain a deep red solid. Characterize it using X-ray powder diffraction (PXRD). The results are as follows: Figure 9 As shown. From Figure 9 It can be seen that the characteristic diffraction peaks of the obtained product are basically consistent with those of maltol iron and nicotinamide, that is, maltol iron and nicotinamide cannot form a eutectic.

Claims

1. A maltol iron-quercetin eutectic, characterized in that: In the X-ray powder diffraction pattern obtained using Cu-Kα radiation measurements, the diffraction angle 2θ is 8.6 ± 0.

2. o 11.1±0.2 o 12.1±0.2 o 15.0±0.2 o 20.1±0.2 o 22.9±0.2 o 23.4±0.2 o 25.0±0.2 o 26.4±0.2 o It has characteristic diffraction peaks.

2. The maltol iron-quercetin eutectic according to claim 1, characterized in that: The maltol iron-quercetin eutectic has an X-ray powder diffraction pattern as shown in Figure 1, Figure 5, or Figure 6.

3. The maltol iron-quercetin eutectic according to claim 1, characterized in that: The infrared absorption spectra of maltol iron-quercetin cocrystals were at 3411.84, 3266.53, 1625.95, 1602.16, 1570.45, 1528.86, 1504.59, 1470.70, 1437.68, 1420.00, 1375.07, 1326.27, 1274.71, 1200.79, 1167.82, 1099.34, 1042.82, 1019.90, 998.39, 928.84, 891.12, 850.99, 786.29, 726.56, 656.94, 621.25, 542.83, 511.13, and 417.27 cm⁻¹. -1 Characteristic peaks are present in the vicinity; in the differential scanning calorimetry spectrum, the melting point of the maltol iron-quercetin eutectic is 263.56 ℃.

4. The maltol iron-quercetin eutectic according to claim 1, characterized in that: It is a co-crystal formed by using maltol iron as the active pharmaceutical ingredient and quercetin as the co-crystal ligand, and by a suspension stirring method.

5. A method for preparing the maltol iron-quercetin eutectic according to claim 1, characterized in that: include: Ferric maltol and quercetin were added to an organic solvent, stirred and reacted, filtered, and dried to obtain ferric maltol-quercetin eutectic crystals.

6. The method for preparing maltol iron-quercetin eutectic according to claim 5, characterized in that: The molar ratio of maltol iron to quercetin is 1:0.5 to 1:

3.

7. The method for preparing maltol iron-quercetin eutectic according to claim 6, characterized in that: The molar ratio of maltol iron and quercetin is 1:1 to 1:

2.

8. The method for preparing maltol iron-quercetin eutectic according to claim 7, characterized in that: The molar ratio of maltol iron to quercetin is 1:

1.

9. The method for preparing maltol iron-quercetin eutectic according to claim 5, characterized in that: The organic solvent is ethanol, methanol, acetonitrile, acetone, ethyl acetate, or a mixture of at least two of the above organic solvents.

10. The method for preparing maltol iron-quercetin eutectic according to claim 5 or 9, characterized in that: The ratio of maltol iron to organic solvent is 2:1 to 500:1 mg / mL.

11. The method for preparing maltol iron-quercetin eutectic according to claim 10, characterized in that: The ratio of maltol iron to organic solvent is 50 mg: 1 to 200: 1 mg / mL.

12. The method for preparing maltol iron-quercetin eutectic according to claim 5, characterized in that: The reaction temperature is 15–50°C; the reaction time is 2–7 days.

13. The method for preparing maltol iron-quercetin eutectic according to claim 12, characterized in that: The reaction temperature is 25℃~35℃; the reaction time is 5~6 days.

14. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the maltol iron-quercetin cocrystal of claim 1, and a pharmaceutically acceptable carrier.

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