A mesalazine-tetrandrine hydrochloride drug cocrystal and its preparation method and application

Abstract

The present invention discloses a mesalazine-tetrandrine hydrochloride drug cocrystal and its preparation method and application, belonging to the technical field of drug crystallization. The structural unit of the drug cocrystal contains mesalazine molecules and tetrandrine hydrochloride molecules, the molar ratio of the two is 1:1, and the molecular formula is [C7H7NO3]·[C 21 H 22 ClNO4]. The present invention mixes mesalazine and tetrandrine hydrochloride hydrate in a solvent at a molar ratio of 1:1, and prepares mesalazine-tetrandrine hydrochloride drug cocrystals through evaporation, mechanical grinding, or suspension stirring. The preparation method is simple and has a high cocrystal yield. The prepared mesalazine-tetrandrine hydrochloride cocrystal has significantly reduced solubility in a pH 1.2 simulated gastric fluid medium and exhibits sustained release behavior in a pH 6.8 simulated intestinal fluid medium. It can effectively increase the contact time of mesalazine and tetrandrine hydrochloride with the inflamed intestinal mucosa and exhibits good inhibitory activity against human colon cancer cells.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug crystallization, and in particular relates to a mesalazine-tetrandrine hydrochloride drug cocrystal and a preparation method and application thereof. Background Art

[0002] Mesalazine, also known as 5-aminosalicylic acid, is a first-line medication for the treatment of ulcerative colitis and Crohn's disease, demonstrating excellent efficacy, tolerability, and safety. Mesalazine acts directly on the intestinal mucosa of the anterior gastrointestinal tract, a high-inflammation site. By inhibiting the production of various inflammatory mediators, such as prostaglandins, leukotrienes, and oxygen free radicals, it alleviates the body's inflammatory response, thereby treating inflammatory bowel disease. Studies have shown that mesalazine's pharmacological and physiological effects also include antioxidant, antibacterial, anticancer, anti-Alzheimer's, gastroprotective, and anti-diverticular effects.

[0003] Palmatine hydrochloride (also known as palmatine and palmatine hydrochloride) has demonstrated antibacterial and anti-inflammatory properties and is clinically used to treat conditions such as bacillary dysentery, enteritis, respiratory and urinary tract infections, gynecological inflammation, and conjunctivitis. In recent years, increasing research has focused on the anti-inflammatory and antioxidant properties of palmatine hydrochloride, elucidating their mechanisms of action. Furthermore, palmatine hydrochloride has demonstrated promising pharmacological activities in areas such as anticancer, hypoglycemic, and Alzheimer's disease.

[0004] Drug-drug cocrystals are a novel solid-state pharmaceutical compound, combining two or more active pharmaceutical ingredients within a single crystal lattice via non-covalent bonding. These compounds possess well-defined structures and stable physicochemical properties. The formation of cocrystals can improve drug solubility, dissolution rate, stability, and other physicochemical properties, while also enabling synchronized release and synergistic efficacy of the two drugs. Given that mesalazine and palmatine hydrochloride share many common pharmacological activities, their formation into drug-drug cocrystals is expected to produce synergistic effects, thus possessing significant clinical application value.

[0005] Patent CN109310642A discloses a unit-dose pharmaceutical product of the oral drug mesalazine, which includes a plurality of delayed immediate-release tablets and a plurality of delayed extended-release tablets. By providing a pH-dependent enteric coating, the delayed immediate-release tablets of the drug show substantially no release of mesalazine at a pH of 1.2-4.5 during an in vitro dissolution test, and selectively release mesalazine in the distal ileum at a pH of 5.5 or higher. The plurality of delayed extended-release tablets comprise a compressed matrix containing mesalazine, provided with an inner pH-independent extended-release coating and an outer pH-dependent enteric coating, wherein the delayed extended-release tablets selectively release mesalazine in the colon at a pH of 7 or higher. The patented drug achieves selective drug release through multi-layer coating technology and can be used to treat inflammatory bowel disease. However, the coating preparation process is complex and technically difficult. In addition, the drug coating occupies a large proportion of the unit-dose pharmaceutical product, and the coating components also impose a metabolic burden on other organs of the body.

[0006] Patent CN115245487A discloses a cocrystal drug of mesalamine and maleic acid. This drug has significant advantages over the mesalamine in the prior art in terms of safety, stability and biological activity. However, the therapeutic effect of this drug on inflammatory diseases such as enteritis is unclear.

[0007] Currently, there is no public report on mesalazine-tetrandrine hydrochloride cocrystal and its preparation method and application. Summary of the Invention

[0008] To address technical issues in the prior art, such as the complex sustained-release coating technology for mesalazine and the unclear effects of other mesalazine cocrystals, the present invention proposes a mesalazine-tetrandrine hydrochloride drug cocrystal, its preparation method, and its application. The preparation method is simple, and the cocrystal yield is high. Containing both mesalazine and tetrandrine hydrochloride as active ingredients, the cocrystal offers enhanced inflammatory treatment efficacy. Furthermore, the mesalazine-tetrandrine hydrochloride drug cocrystal exhibits significantly reduced solubility at pH 1.2 and a slow release rate in a simulated intestinal fluid medium at pH 6.8, demonstrating a sustained-release effect.

[0009] In order to achieve the above object, the technical solution of the present invention is achieved as follows:

[0010] A mesalazine-tetrandrine hydrochloride drug cocrystal, the molecular formula of which is [C7H7NO3]·[C 21 H 22 ClNO4], which is composed of mesalazine molecules and tetrandrine hydrochloride molecules, with a molar ratio of 1:1.

[0011] Preferably, it belongs to the triclinic system, P-1 space group, and the unit cell parameters are: a= 13.5972(3) Å, b = 14.6481(4) Å, c = 15.3925(4) Å, α= 67.261(3) º, β= 66.387(2)º, γ= 81.200(2) º, V = 2590.74(13) Å 3 , Z = 4, ρ calc = 1.387 g / cm 3 .

[0012] The powder X-ray diffractometer was used to analyze the (Cu K α When the radiation is applied, the X-ray diffraction pattern of the mesalazine-tetrandrine hydrochloride drug cocrystal powder is at a diffraction angle of 2 θ ±0.3° is: 6.5, 7.5, 7.7, 8.4, 10.9, 11.9, 12.7, 13.1, 13.6, 14.3, 14.8, 15.2, 15.5, 15.7, 16.9, 17.8, 18.6, 19.4, 19.7, 20.2, 20.6, 21.0, 21.3, 22.1, 22.3, 22.6, 22.9, 23.2, 23.8, 24.4, 25.0, 25.3, 26. There are characteristic diffraction peaks at .2, 26.7, 27.1, 27.6, 27.9, 28.6, 28.9, 29.4, 29.8, 29.9, 30.3, 31.2, 31.6, 31.8, 32.9, 34.0, 35.2, 35.6, 36.3, 36.9, 37.4, 37.7, 38.4, 39.1, 39.3, 40.4, 41.7, 42.6, 44.1, 45.6, 47.1 and 49.8°.

[0013] The method for preparing the mesalazine-tetrandrine hydrochloride drug cocrystal as described above comprises the following steps: dissolving mesalazine and tetrandrine hydrochloride hydrate in a molar ratio of 1:1 in a solvent to obtain a clear solution, and evaporating the solvent from the solution to obtain the mesalazine-tetrandrine hydrochloride drug cocrystal.

[0014] The method for preparing the mesalazine-tetrandrine hydrochloride drug cocrystal as described above comprises the following steps: adding a solvent to a drug mixture of mesalazine and tetrandrine hydrochloride hydrate at a molar ratio of 1:1 to form a semi-solid state, followed by grinding, and drying the obtained product to obtain the mesalazine-tetrandrine hydrochloride drug cocrystal.

[0015] The method for preparing the mesalazine-tetrandrine hydrochloride drug cocrystal as described above comprises the following steps: dispersing mesalazine and tetrandrine hydrochloride hydrate in a molar ratio of 1:1 in a solvent to form a suspension, sealing the suspension, stirring the suspension at room temperature, and then separating and drying the suspension to obtain the mesalazine-tetrandrine hydrochloride drug cocrystal.

[0016] In the above-mentioned method for preparing the mesalazine-tetrandrine hydrochloride drug cocrystal, the solvent is at least one of water, ethanol, acetonitrile, methanol and acetone.

[0017] The use of the mesalazine-tetrandrine hydrochloride drug cocrystal in the preparation of anti-inflammatory, antibacterial, antiviral and anticancer drugs.

[0018] The mesalazine-tetrandrine hydrochloride drug cocrystal is used in the preparation of drugs for treating ulcerative colitis, Crohn's disease or colorectal cancer.

[0019] The administration methods of the mesalazine-tetrandrine hydrochloride cocrystal drug include gastrointestinal administration and rectal administration; and the dosage forms include tablets, capsules, powders, granules, enemas and suppositories.

[0020] The present invention has the following beneficial effects:

[0021] (1) The present invention prepares mesalazine-tetrandrine hydrochloride drug cocrystal for the first time. The preparation method is simple and the cocrystal yield is high. The cocrystal contains two active pharmaceutical ingredients, mesalazine and tetrandrine hydrochloride.

[0022] (2) Dynamic water vapor adsorption experiments showed that the hygroscopicity of the mesalazine-tetrandrine hydrochloride drug cocrystal was significantly reduced compared to that of tetrandrine hydrochloride hydrate. At 25 °C and 95% RH, at adsorption equilibrium, the weight percentage of water adsorbed by the mesalazine-tetrandrine hydrochloride drug cocrystal was only 0.96%, indicating that the cocrystal had only weak hygroscopicity.

[0023] (3) The results of the stability test showed that the mesalazine-tetrandrine hydrochloride drug cocrystal did not undergo any crystal transformation when placed at 60°C (avoid light) for 10 days, or at 90% RH (temperature 25°C, avoid light) for 10 days, or at a light intensity of 4500 Lx (temperature 25°C) for 10 days. That is, the drug cocrystal has good thermal stability, humidity stability and light stability.

[0024] (4) The results of equilibrium solubility experiments showed that the formation of mesalazine-tetrandrine hydrochloride drug cocrystals significantly reduced the sensitivity of mesalazine solubility to the pH of the dissolution medium. In a simulated gastric fluid medium with a pH of 1.2, the solubility of mesalazine in the mesalazine-tetrandrine hydrochloride drug cocrystal was significantly lower than that of the pure API, which would reduce its release rate in the stomach and thus reduce gastric absorption, achieving an effect similar to that of an enteric-coated preparation.

[0025] (5) In vitro dissolution experiments showed that in a pH 6.8 simulated intestinal fluid medium, the dissolution rates of the two components of the mesalazine-palmitine hydrochloride drug cocrystal were significantly lower than those of the raw material, showing a sustained release behavior. Therefore, the drug cocrystal can effectively increase the contact time of mesalazine with the inflammatory intestinal mucosa, which is conducive to achieving better therapeutic effects.

[0026] (6) The results of in vitro cell experiments showed that for HCT-116 human colon cancer cells, the IC values ​​of mesalazine-tetrandrine hydrochloride drug cocrystal, tetrandrine hydrochloride and mesalazine were 50 The half-maximal inhibitory concentrations (CI50) were 49.46 μg / mL, 57.00 μg / mL, and >200 μg / mL, respectively. For HT29 human colon cancer cells, the IC values ​​of mesalazine-tetrandrine hydrochloride cocrystal, tetrandrine hydrochloride, and mesalazine were 50 The concentrations of mesalazine and palmatine hydrochloride were 60.13 μg / mL, 80.17 μg / mL and >200 μg / mL, respectively, indicating that there was a definite pharmacodynamic synergistic effect between mesalazine and palmatine hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0028] Figure 1 This is a crystal structure unit diagram of the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in Example 1.

[0029] Figure 2 This is the powder X-ray diffraction pattern of the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in Example 2.

[0030] Figure 3 This is the powder X-ray diffraction pattern of the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in Example 3.

[0031] Figure 4This is a dynamic water vapor adsorption graph of the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in Example 3 at 25°C.

[0032] Figure 5 This is the crystal stability test result of the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in Example 3.

[0033] Figure 6 It is the powder X-ray diffraction pattern of the product prepared by mesalazine and tetrandrine hydrochloride hydrate at different molar ratios.

[0034] Figure 7 These are the results of the equilibrium solubility experiment of mesalazine-tetrandrine hydrochloride drug cocrystal.

[0035] Figure 8 These are the results of the in vitro dissolution test of mesalazine-tetrandrine hydrochloride drug co-crystal. DETAILED DESCRIPTION

[0036] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without creative work are within the scope of protection of the present invention.

[0037] Example 1

[0038] This embodiment provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, comprising the following steps:

[0039] 0.5 mmol of mesalazine and 0.5 mmol of tetrandrine hydrochloride hydrate were dissolved in 50 mL of ethanol to prepare a clear solution, which was then air-dried at room temperature to prepare mesalazine-tetrandrine hydrochloride drug cocrystal.

[0040] The mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example was characterized by single crystal X-ray diffraction. The single crystal analysis results showed that the structural unit of the drug cocrystal contained mesalazine molecules and tetrandrine hydrochloride molecules, and its molecular formula was [C7H7NO3]·[C 21 H 22 ClNO4], the eutectic belongs to the triclinic system, P-1 space group, and the unit cell parameters are: a =13.5972(3) Å, b = 14.6481(4) Å, c = 15.3925(4) Å, α= 67.261(3) º, β= 66.387(2)º, γ= 81.200(2) º, V = 2590.74(13) Å 3 , Z = 4, ρ calc = 1.387 g / cm 3 .

[0041] Figure 1 This is the crystal structure unit of the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example (obtained from analysis of single crystal X-ray diffraction data). As can be seen from the figure, the structural unit of this mesalazine-tetrandrine hydrochloride drug cocrystal consists of two mesalazine molecules, two tetrandrine hydrochloride cations, and two chloride ions.

[0042] Example 2

[0043] This embodiment provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, comprising the following steps:

[0044] 0.5 mmol of mesalazine and 0.5 mmol of tetrandrine hydrochloride hydrate powder were mixed evenly and placed in the tank of a grinder. 10 μL of ethanol was transferred to the powder using a micropipette. The mixture was ground at a frequency of 1500 Hz for 15 min. After the product was air-dried, the mesalazine-tetrandrine hydrochloride drug cocrystal was obtained.

[0045] Figure 2 This is the powder X-ray diffraction pattern of the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example (instrument Rigaku SmartLab, Cu Kα radiation). As can be seen from the figure, the prepared mesalazine-tetrandrine hydrochloride drug cocrystal has a diffraction angle of 2 θ± 0.3° is: 6.5, 7.5, 7.7, 8.4, 10.9, 11.9, 12.7, 13.1, 13.6, 14.3, 14.8, 15.2, 15.5, 15.7, 16.9, 17.8, 18.6, 19.4, 19.7, 20.2, 20.6, 21.0, 21.3, 22.1, 22.3, 22.6, 22.9, 23.2, 23.8, 24.4, 25.0, 25.3, 26. 2, 26.7, 27.1, 27.6, 27.9, 28.6, 28.9, 29.4, 29.8, 29.9, 30.3, 31.2, 31.6, 31.8, 32.9, 34.0, 35.2, 35.6, 36.3, 36.9, 37.4, 37.7, 38.4, 39.1, 39.3, 40.4, 41.7, 42.6, 44.1, 45.6, 47.1, 49.8 ° and other places have characteristic diffraction peaks. The mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example has the same XRD pattern as the single crystal simulated powder of Example 1 at 2 θ The peaks at different angles indicate that the crystal structures of the two are the same.

[0046] Example 3

[0047] This embodiment provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, comprising the following steps:

[0048] 0.5 mmol of mesalazine, 0.5 mmol of tetrandrine hydrochloride hydrate, and 5 mL of ethanol were placed in a glass bottle with a lid. A magnetic rotor was added and the glass bottle was sealed. The suspension was formed by magnetic stirring at room temperature. After 24 hours, the resulting precipitate was filtered and dried to obtain mesalazine-tetrandrine hydrochloride drug cocrystal.

[0049] Figure 3 This is the powder X-ray diffraction pattern of the mesalazine-tetrandrine hydrochloride cocrystal prepared in this example. As can be seen from the figure, the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example is the same as that in Example 2. θ The peaks at different angles indicate that the crystal structures of the two are the same.

[0050] Figure 4The following is a dynamic water vapor sorption graph of tetrandrine hydrochloride hydrate and the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example at 25°C (SMS DVS Intrinsic instrument). As shown, as the relative humidity increases from 0% RH to 95% RH, the mass of tetrandrine hydrochloride hydrate changes by approximately 14%, while the mass of the mesalazine-tetrandrine hydrochloride cocrystal changes by only 0.96%. This indicates that the mesalazine-tetrandrine hydrochloride drug cocrystal exhibits significantly lower hygroscopicity than tetrandrine hydrochloride hydrate.

[0051] Figure 5 These are the crystal form stability test results for the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example. The mesalazine-tetrandrine hydrochloride drug cocrystal did not undergo crystal form transformation after being stored at 60°C (protected from light) for 10 days, at 90% RH (25°C, protected from light) for 10 days, or at a light intensity of 4500 Lx (25°C) for 10 days. This indicates that the drug cocrystal exhibits excellent thermal, light, and humidity stability.

[0052] Example 4

[0053] This embodiment provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, comprising the following steps:

[0054] 0.5 mmol of mesalazine, 0.5 mmol of tetrandrine hydrochloride hydrate, and 5 mL of water were placed in a glass bottle with a lid. A magnetic rotor was added and the glass bottle was sealed. The suspension was formed by magnetic stirring at room temperature. After 24 hours, the resulting precipitate was filtered and dried to obtain mesalazine-tetrandrine hydrochloride drug cocrystal.

[0055] The X-ray powder diffraction characterization results show that the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example is the same as that in Example 2. θ The peaks at different angles indicate that the crystal structures of the two are the same.

[0056] Example 5

[0057] This embodiment provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, comprising the following steps:

[0058] 0.5 mmol of mesalazine, 0.5 mmol of tetrandrine hydrochloride hydrate, and 5 mL of acetonitrile were placed in a glass bottle with a lid. A magnetic rotor was added and the glass bottle was sealed. The suspension was formed by magnetic stirring at room temperature. After 24 hours, the resulting precipitate was filtered and dried to obtain mesalazine-tetrandrine hydrochloride drug cocrystal.

[0059] The X-ray powder diffraction characterization results show that the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example is the same as that in Example 2. θ The peaks at different angles indicate that the crystal structures of the two are the same.

[0060] Example 6

[0061] This embodiment provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, comprising the following steps:

[0062] 0.5 mmol of mesalazine, 0.5 mmol of tetrandrine hydrochloride hydrate, 2.5 mL of methanol, and 2.5 mL of acetone were placed in a glass bottle with a lid. A magnetic rotor was added and the glass bottle was sealed. The suspension was formed by magnetic stirring at room temperature. After 24 hours, the resulting precipitate was filtered and dried to obtain mesalazine-tetrandrine hydrochloride drug cocrystal.

[0063] The X-ray powder diffraction characterization results show that the mesalazine-tetrandrine hydrochloride drug cocrystal prepared in this example is the same as that in Example 2. θ The peaks at different angles indicate that the crystal structures of the two are the same.

[0064] Comparative Example 1

[0065] This comparative example provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, which differs from Example 2 in that the molar ratio of mesalazine to tetrandrine hydrochloride hydrate is 3:1, and specifically comprises the following steps:

[0066] 0.75 mmol of mesalazine and 0.25 mmol of tetrandrine hydrochloride hydrate powder were mixed evenly and placed in the tank of a grinder. 10 μL of ethanol was transferred to the powder using a micropipette. The grinder was ground at a frequency of 1500 Hz for 15 min. After the product was air-dried, a solid product was obtained.

[0067] Comparative Example 2

[0068] This comparative example provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, which differs from Example 2 in that the molar ratio of mesalazine to tetrandrine hydrochloride hydrate is 2:1, and specifically comprises the following steps:

[0069] 0.67 mmol of mesalazine and 0.33 mmol of tetrandrine hydrochloride hydrate powder were mixed evenly and placed in the tank of a grinder. 10 μL of ethanol was transferred to the powder using a micropipette. The grinder was ground at a frequency of 1500 Hz for 15 min. After the product was air-dried, a solid product was obtained.

[0070] Comparative Example 3

[0071] This comparative example provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, which differs from Example 2 in that the molar ratio of mesalazine to tetrandrine hydrochloride hydrate is 1:2, and specifically comprises the following steps:

[0072] 0.33 mmol of mesalazine and 0.67 mmol of tetrandrine hydrochloride hydrate powder were mixed evenly and placed in the tank of a grinder. 10 μL of ethanol was transferred to the powder using a micropipette. The grinder was ground at a frequency of 1500 Hz for 15 min. After the product was air-dried, a solid product was obtained.

[0073] Comparative Example 4

[0074] This comparative example provides a method for preparing a mesalazine-tetrandrine hydrochloride drug cocrystal, which differs from Example 2 in that the molar ratio of mesalazine to tetrandrine hydrochloride hydrate is 1:3, and specifically comprises the following steps:

[0075] 0.25 mmol of mesalazine and 0.75 mmol of tetrandrine hydrochloride hydrate powder were mixed evenly and placed in the tank of a grinder. 10 μL of ethanol was transferred to the powder using a micropipette. The grinder was ground at a frequency of 1500 Hz for 15 min. After the product was air-dried, a solid product was obtained.

[0076] The effect of the molar ratio of mesalazine to tetrandrine hydrochloride hydrate on the crystalline form of the product was investigated: the powder X-ray diffraction patterns of the solid products obtained in Example 2 and Comparative Examples 1-4 are shown in FIG. Figure 6 As shown in the figure, pure mesalazine-tetrandrine hydrochloride drug cocrystals (i.e., Example 2) can only be prepared when the molar ratio of mesalazine to tetrandrine hydrochloride hydrate is 1:1. When the molar ratios of mesalazine to tetrandrine hydrochloride hydrate are 1:2 and 1:3, the product contains not only mesalazine-tetrandrine hydrochloride drug cocrystals but also tetrandrine hydrochloride hydrate crystals. When the molar ratios of mesalazine to tetrandrine hydrochloride hydrate are 3:1 and 2:1, the product contains not only mesalazine-tetrandrine hydrochloride cocrystals but also mesalazine crystals.

[0077] Experimental Example 1 Equilibrium Solubility Experiment of Mesalazine-Tetrandrine Hydrochloride Cocrystal

[0078] 100 mg of the mesalazine-tetrandrine hydrochloride cocrystal powder and mesalazine powder from Example 3 were weighed separately and placed in 10 mL centrifuge tubes. 2 mL of different media (pure water, pH 1.2, pH 4.5, and pH 6.8) were added to obtain supersaturated solutions. The supernatant was continuously shaken in a 37°C air bath for 48 h. The supernatant was filtered through a 0.45 μm membrane and then immediately diluted with pure water to a specific concentration. The saturated equilibrium solubility of the samples was determined by high-performance liquid chromatography (HPLC). Three replicates (n = 3) were used. The results are shown in Figure 2. Figure 7 As shown in the figure, the solubility of pure mesalamine is sensitive to the pH of the medium, with the highest solubility in a medium with a pH of 1.2. The formation of a mesalamine-tetrandrine hydrochloride cocrystal significantly reduces the sensitivity of mesalamine solubility to the pH of the dissolution medium. In particular, in a medium with a pH of 1.2, the solubility of mesalamine in the mesalamine-tetrandrine hydrochloride cocrystal is significantly lower than that of pure mesalamine, which helps reduce the decomposition and absorption of mesalamine in the stomach, achieving an effect similar to that of mesalamine enteric-coated preparations.

[0079] Experimental Example 2 In vitro dissolution test of mesalazine-tetrandrine hydrochloride drug cocrystal

[0080] The mesalazine-tetrandrine hydrochloride cocrystal and mesalazine powder from Example 3 were sieved through a 100-mesh sieve to ensure uniform particle size and reduce the effect of particle size on dissolution. The experiment used a small cup paddle method, the paddle speed was set at 50 rpm / min, and 250 mL of pure water was used as the dissolution medium. 100 mg of mesalazine-tetrandrine hydrochloride cocrystal, 50 mg of mesalazine, and 50 mg of tetrandrine hydrochloride hydrate were weighed separately. When the pure water temperature stabilized at 37 °C, the samples were put into a pH 6.8 simulated intestinal fluid dissolution medium. In the experiment, 1 mL of solution was taken at a specific time, and 1 mL of medium solution was immediately added. All the extracted solutions were passed through a 0.45 μm membrane, and their concentrations were measured by HPLC. There were 3 parallel samples (n = 3), and the results are as follows. Figure 8 shown.

[0081] Depend on Figure 8 As shown, in the simulated intestinal fluid (pH 6.8), the two active ingredients in the mesalazine-tetrandrine hydrochloride cocrystal dissolve nearly synchronously, contributing to a synergistic enhancement of the efficacy of the two drugs. Furthermore, compared with pure mesalazine and tetrandrine hydrochloride hydrate, the dissolution rate of the two components in the mesalazine-tetrandrine hydrochloride cocrystal was significantly reduced, with complete release occurring after 24 hours. This suggests that the mesalazine-tetrandrine hydrochloride cocrystal exhibits synchronous sustained release in simulated intestinal fluid, potentially increasing the contact time of mesalazine and tetrandrine hydrochloride with the inflamed intestinal mucosa and promoting a better therapeutic effect.

[0082] Experimental Example 3: Inhibitory Effect of Mesalazine-Tetrandrine Hydrochloride Cocrystal on Proliferation of Human Colorectal Cancer Cells

[0083] Tumor cells in the logarithmic growth phase were seeded onto 96-well culture plates. After 24 hours of culture, 100 μL of sample solution at different concentrations was added to the experimental groups, with triplicate wells for each concentration. The negative control group received 100 μL of nutrient solution, and the blank control well received 100 μL of nutrient solution for instrument zeroing. After 72 hours of incubation, the culture medium was removed and 100 μL of 10% trichloroacetic acid (TCA) was added to each well. The plates were fixed overnight at 4°C. After removing the TCA, the plates were washed five times with double-distilled water. Sulforhodamine B (SRB) staining solution (100 μL / well) was added. After 0.5 hours, the plates were washed three to four times with 0.01% acetic acid. After air drying, 100 μL of 0.1 M Tris solution was added to each well. The plates were shaken on a shaker for approximately 5 minutes until the crystals in the cells were fully dissolved. The absorbance of each well was measured at 550 nm using a microplate reader. The average value of each group was taken, and the cell viability of the negative control group was set as 100%. The proliferation inhibition rate (IR) of each group of cells was calculated according to the formula: Proliferation inhibition rate = (1-experimental group A 550 Value / control group A 550 The dose-effect curves of different samples were drawn with the logarithmic concentration as the horizontal axis and the inhibition rate as the vertical axis. The inhibition rate was linearly regressed at each point between 20% and 80% to calculate the half inhibition concentration IC. 50 .

[0084] Table 1 IC values ​​of mesalazine, tetrandrine hydrochloride hydrate and mesalazine-tetrandrine hydrochloride cocrystal prepared in Example 3 against HT29 and HCT116 human colorectal cancer cells 50

[0085]

[0086] As shown in Table 1, the IC values ​​of mesalazine-tetrandrine hydrochloride cocrystal against HCT116 and HT29 human colorectal cancer cells are 50 Both were higher than those of palmatine hydrochloride hydrate and aspirin alone, indicating that mesalazine and palmatine hydrochloride in the cocrystal produced a clear synergistic inhibitory effect on HCT116 and HT29 human colorectal cancer cells.

[0087] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A mesalazine-tetrandrine hydrochloride drug cocrystal, characterized by: The molecular formula is [C7H7NO3]·[C 21 H 22 ClNO4], which is composed of mesalazine molecules and tetrandrine hydrochloride molecules, with a molar ratio of 1:1; The mesalazine-tetrandrine hydrochloride drug cocrystal belongs to the triclinic system, P-1 space group, and the unit cell parameters are: a =13.5972(3) Å, b = 14.6481(4) Å, c = 15.3925(4) Å, α = 67.261(3) º, β = 66.387(2)º, γ = 81.200(2) º, V = 2590.74(13) Å 3 , Z = 4, ρ calc = 1.387 g / cm 3 .

2. The mesalazine-tetrandrine hydrochloride pharmaceutical cocrystal according to claim 1, characterized in that The X-ray diffraction pattern of mesalazine-tetrandrine hydrochloride cocrystal powder at a diffraction angle of 2 θ ±0.3° is: 6.5, 7.5, 7.7, 8.4, 10.9, 11.9, 12.7, 13.1, 13.6, 14.3, 14.8, 15.2, 15.5, 15.7, 16.9, 17.8, 18.6, 19.4, 19.7, 20.2, 20.6, 21.0, 21.3, 22.1, 22.3, 22.6, 22.9, 23.2, 23.8, 24.4, 25.0, 25.3, 26. There are characteristic diffraction peaks at .2, 26.7, 27.1, 27.6, 27.9, 28.6, 28.9, 29.4, 29.8, 29.9, 30.3, 31.2, 31.6, 31.8, 32.9, 34.0, 35.2, 35.6, 36.3, 36.9, 37.4, 37.7, 38.4, 39.1, 39.3, 40.4, 41.7, 42.6, 44.1, 45.6, 47.1 and 49.8°.

3. The method for preparing the mesalazine-tetrandrine hydrochloride pharmaceutical cocrystal according to any one of claims 1 to 2, characterized in that: The method comprises the following steps: dissolving mesalazine and tetrandrine hydrochloride hydrate in a molar ratio of 1:1 in a solvent to obtain a clear solution, and evaporating the solvent from the solution to obtain the mesalazine-tetrandrine hydrochloride drug cocrystal; The solvent is at least one of water, ethanol, acetonitrile, methanol and acetone.

4. The method for preparing the mesalazine-tetrandrine hydrochloride pharmaceutical cocrystal according to any one of claims 1 to 2, characterized in that: The following steps are involved: A solvent is added to a drug mixture of mesalazine and tetrandrine hydrochloride hydrate in a molar ratio of 1:1 to form a semi-solid state, followed by grinding, and the resulting product is dried to obtain a mesalazine-tetrandrine hydrochloride drug cocrystal; The solvent is at least one of water, ethanol, acetonitrile, methanol and acetone.

5. The method for preparing the mesalazine-tetrandrine hydrochloride pharmaceutical cocrystal according to any one of claims 1 to 2, characterized in that: The method comprises the following steps: dispersing mesalazine and tetrandrine hydrochloride hydrate at a molar ratio of 1:1 in a solvent to form a suspension, sealing the suspension, stirring the suspension at room temperature, and then separating and drying the suspension to obtain a mesalazine-tetrandrine hydrochloride drug cocrystal; The solvent is at least one of water, ethanol, acetonitrile, methanol and acetone.

6. Use of the mesalazine-tetrandrine hydrochloride drug cocrystal according to claim 1 in the preparation of a drug for treating ulcerative colitis, Crohn's disease or colorectal cancer.

7. The use according to claim 6, characterized in that: The administration method of the mesalazine-tetrandrine hydrochloride cocrystal drug includes gastrointestinal administration and rectal administration; the dosage form is any one of tablets, capsules, powders, granules, enemas and suppositories.

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