Rhein and sophocarpine eutectic, preparation method, composition and use thereof

Abstract

The invention discloses a cocrystal of rhein and sophocarpine, a preparation method thereof, and a composition and use thereof. The invention belongs to the field of medical technology. Specifically, the invention discloses a cocrystal of rhein and sophocarpine with a lead compound rhein as a pharmaceutical active ingredient and sophocarpine as a cocrystal ligand; a preparation method of the cocrystal of rhein and sophocarpine; and the use of the cocrystal of rhein and sophocarpine as a pharmaceutical active ingredient in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other drugs.

Description

Technical Field

[0001] The invention discloses a cocrystal of rhein and sophocarpine, a preparation method thereof, a composition and a use thereof. Specifically, the invention discloses a cocrystal formed by rhein and sophocarpine; a preparation method of the cocrystal of rhein and sophocarpine; a pharmaceutical composition containing the cocrystal of rhein and sophocarpine or a mixed solid substance containing the cocrystal of rhein and sophocarpine in any non-zero ratio; the invention also relates to the use of the cocrystal of rhein and sophocarpine as an effective ingredient in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other drugs, belonging to the field of medical technology. Background Art

[0002] Rhein belongs to the anthraquinone class of compounds and has a wide range of pharmacological activities, including inhibition of tumor cell metabolism and proliferation, antibacterial, anti-inflammatory, lipid regulation and immunosuppression. However, due to its extremely poor water solubility, it has not been successfully applied in clinical practice. Therefore, improving the water solubility of rhein is of great significance. Chinese patent CN102603575A[P] reports the preparation method and purification method of the cocrystal of rhein and arginine (rheinic acid) and its application in the preparation of drugs for the treatment of diabetic complications. [1] ; Chinese patent CN10255121A[P] reports the preparation process of rhein and lysine eutectic (lysine rhein) and its application in tumor treatment [2] Apart from this, no other cocrystals of rhein have been reported so far.

[0003] The present invention uses rhein as the active substance, whose chemical name is 1,8-dihydroxy-3-carboxyanthraquinone and whose molecular formula is C 15 H8O6, the structural formula is shown in formula a; Sophocarpine is the eutectic forming substance, the molecular formula is C 15 H 22 N2O, with a structural formula as shown in formula b, a cocrystal of rhein and sophocarpine different from the above patent reports and a preparation method thereof were found through drug cocrystal screening technology, which has good stability, solubility and bioavailability compared with the raw material of rhein. In addition, compared with the reported cocrystal of rhein arginine and the cocrystal of rhein lysine, the cocrystal of rhein and sophocarpine has better water solubility, achieving unexpected technical effects.

[0004]

[0005] Summary of the invention

[0006] The technical problems to be solved by the present invention are:

[0007] One of the technical problems to be solved by the present invention is to provide an existence state and characterization method of a cocrystal of rhein and sophocarpine.

[0008] The second technical problem to be solved by the present invention is to provide a method for preparing a cocrystal of rhein and sophocarpine.

[0009] The third technical problem to be solved by the present invention is to provide a pure product of the cocrystal of rhein and sophocarpine, or a mixed solid material containing the cocrystal of rhein and sophocarpine in any non-zero ratio, and a pharmaceutical composition thereof.

[0010] The fourth technical problem to be solved by the present invention is to provide a pharmaceutical composition using rhein and sophocarpine cocrystal as the active ingredient, wherein the dosage of each drug is in the range of 0.5-300 mg. The pharmaceutical composition includes bone joint cavity injection, tablets, capsules, pills, injections, sustained-release or controlled-release preparations.

[0011] The fifth technical problem to be solved by the present invention is to provide a co-crystal of rhein and sophocarpine which has a better solubility advantage than the raw material of rhein.

[0012] The sixth technical problem to be solved by the present invention is to provide a method for forming a eutectic substance between rhein and sophocarpine to increase the blood drug concentration in the body during the treatment of a disease and exert a therapeutic effect.

[0013] The seventh technical problem to be solved by the present invention: Application of the cocrystal of rhein and sophocarpine as a pharmaceutical active ingredient in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other drugs.

[0014] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0015] 1. Morphological characteristics of rhein and sophocarpine eutectic samples:

[0016] 1.1 Cocrystal of rhein and sophocarpine, characterized in that the cocrystal is formed by rhein and sophocarpine in a molar ratio of 1:1.

[0017] 1.2 The cocrystal of rhein and sophocarpine of the present invention is analyzed by powder X-ray diffraction using CuK α Under radiation experimental conditions, diffraction peak position: 2-Theta (°) value or Value, diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) has the following representation (Table 1, Figure 1 The powder X-ray diffraction pattern and data of the physical mixture of rhein and sophocarpine are shown in Table 2. Figure 2The powder X-ray diffraction patterns of the cocrystal of rhein and sophocarpine and the physical mixture of rhein and sophocarpine are significantly different in terms of the number of diffraction peaks, the positions of the diffraction peaks, the intensities of the diffraction peaks, and the topological patterns of the diffraction peaks, indicating that the cocrystal of rhein and sophocarpine and the physical mixture of rhein and sophocarpine are neither the same nor identical.

[0018] Table 1 Powder X-ray diffraction peaks of rhein and sophocarpine cocrystal

[0019]

[0020] Table 2 X-ray diffraction peak values ​​of physical mixed powder of rhein and sophocarpine

[0021]

[0022] 1.3 The cocrystal of rhein and sophocarpine of the present invention was analyzed by attenuated total reflection Fourier transform infrared spectroscopy at 3077, 2937, 2899, 2857, 2309, 2104, 1664, 1627, 1608, 1558, 1472, 1450, 1435, 1424, 1391, 1367, 1346, 1336, 1256, 1195, 1176, 1156, 1112, 1087, 1076, 1059, 1033, 1004, 982, 953, 940, 920, 901, 888, 854, 837, 831, 820, 809, 796, 767, 747, 733, 709, 661 cm -1 There is a characteristic peak of infrared spectrum ( Figure 3 ), where the allowable deviation of the characteristic peak of the infrared spectrum is ±2cm -1 .

[0023] 1.4 The cocrystal of rhein and sophocarpine of the present invention is characterized in that, when analyzed by differential scanning calorimetry, within the temperature range of 30 to 220°C and at a heating rate of 10°C / min, its DSC spectrum has an endothermic peak at 182°C±3°C ( Figure 4 ). The DSC superposition of rhein, sophocarpine and the cocrystal of rhein and sophocarpine is shown in Figure 5 ,Depend on Figure 5 It can be seen that there are obvious differences between the cocrystal of rhein and sophocarpine and that of rhein and sophocarpine in terms of the number and position of endothermic peaks, which indicates that rhein and sophocarpine form a cocrystal.

[0024] 2. Characteristics of the preparation method of the cocrystal of rhein and sophocarpine and the mixed solid material:

[0025] 2.1 The preparation method of rhein and sophocarpine eutectic of the present invention is characterized in that a liquid grinding method is adopted, rhein and sophocarpine are added in a molar ratio of 1:1, and the amount of solvent added is 0.5-50 ml per gram of sample; the grinding time is 0.05-10 h, the drying temperature is 80-100° C., and the drying time is 0.5-1 h; the comprehensive filling rate of the bowl of the liquid grinding method is 10%-50%, and the reciprocating speed is 20-70 m / min; the shear impact energy of the ball mill of the liquid ball milling method is 10kw-800kw, and the comprehensive filling rate is 20-60%; the ball-to-material ratio is 1:1-10:1, preferably 6:1-10:1; the ball milling speed is 20r / min-400r / min.

[0026] 2.2 The preparation method of the cocrystal of rhein and sophocarpine involved in the present invention is characterized in that, by using a suspension method, rhein is added to a reaction container, an organic solvent is added at a solid-liquid ratio of 10 to 500 mg / mL, and the mixture is stirred evenly at a temperature of 25 to 30°C, and then a certain molar ratio of sophocarpine is slowly added to the reaction bottle while stirring, and the stirring speed is 100 r / min to 1000 r / min, until the bright yellow solution is completely transformed into reddish brown. The stirring time is 24 to 72 hours. The suspension obtained above is filtered, and the filter cake is placed in an oven at 80 to 100°C and dried for 0.5 to 1 hour to obtain the cocrystal of rhein and sophocarpine.

[0027] 2.3 The mixed solid material of rhein and sophocarpine eutectic substance of the present invention is obtained by mixing the rhein and sophocarpine eutectic substance components prepared by the above method with other chemical substances in any non-zero ratio and in a conventional manner.

[0028] 3. Compositions of pharmaceutical preparations containing rhein eutectic components, dosage characteristics and pharmaceutical uses:

[0029] 3.1 The pharmaceutical composition of the present invention comprises a cocrystal of rhein and sophocarpine and a pharmaceutically acceptable carrier.

[0030] 3.2 The pharmaceutical composition of the present invention comprises a mixed solid substance of rhein and sophocarpine cocrystal and a pharmaceutically acceptable carrier.

[0031] 3.3 In the pharmaceutical composition of the present invention, the daily dosage of rhein is in the range of 0.5 to 300 mg.

[0032] 3.4 The pharmaceutical composition involved in the present invention is characterized in that the pharmaceutical composition is various bone and joint cavity injections, tablets, capsules, pills, injections, sustained-release preparations or controlled-release preparations.

[0033] 3.5 Use of the cocrystal of rhein and sophocarpine, the mixed solid of the cocrystal of rhein and sophocarpine or the pharmaceutical composition of the present invention in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other drugs.

[0034] The present invention relates to a pharmaceutical composition with the cocrystal of rhein and sophocarpine of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to a method known in the art. The cocrystal of rhein and sophocarpine of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare any dosage form suitable for human or animal use. The content of the cocrystal of rhein and sophocarpine and the mixed solid of the cocrystal of rhein and sophocarpine of the present invention in the pharmaceutical composition is in the range of 10% to 90% by weight.

[0035] The cocrystal of rhein and sophocarpine and the mixed solid of the cocrystal of rhein and sophocarpine of the present invention can be administered in the form of unit dosage, and the administration route can be enteral or parenteral, such as oral administration, bone joint cavity injection, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0036] The dosage form of the present invention is preferably a solid preparation and a bone joint cavity injection dosage form. The solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols (powders), sprays, etc.

[0037] The rhein and sophocarpine cocrystal and the mixed solid of rhein and sophocarpine cocrystal can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations, various microparticle drug delivery systems and bone-joint cavity injections.

[0038] In order to prepare tablets of the cocrystal of rhein and sophocarpine or the mixed solid of rhein and sophocarpine cocrystal of the present invention, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0039] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0040] In order to prepare the dosing unit into a capsule, the active ingredient rhein and sophocarpine cocrystal can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient rhein and sophocarpine cocrystal can also be first made into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the rhein and sophocarpine cocrystal tablets of the present invention can also be used to prepare the capsules of the mixed solid of rhein and sophocarpine cocrystal of the present invention.

[0041] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

[0042] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0043] The dosage of the pharmaceutical composition of rhein and sophocarpine cocrystal of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form, etc. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other treatment means.

[0044] The cocrystal of rhein and sophocarpine or the composition of the present invention can be taken alone or used in combination with other therapeutic drugs or symptomatic drugs. When the cocrystal of rhein and sophocarpine of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0045] 4. Beneficial technical effects of the present invention: Safety and solubility characteristics of the cocrystal of rhein and sophocarpine

[0046] 4.1 The rhein and sophocarpine cocrystal of the present invention does not contain any crystallization solvent and has good safety and drug-making advantages.

[0047] 4.2 The rhein and sophocarpine cocrystal of the present invention has the pharmacological activity of rhein, and has a great improvement in solubility, which is far superior to rhein. In addition, compared with the reported rhein arginine cocrystal and rhein lysine cocrystal, the rhein and sophocarpine cocrystal has better water solubility, achieving unexpected technical effects ( Figure 6 ). BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Powder X-ray diffraction pattern of cocrystal of rhein and sophocarpine

[0049] Figure 2 Powder X-ray diffraction pattern of physical mixture of rhein and sophocarpine

[0050] Figure 3 Infrared absorption spectrum of rhein and sophocarpine cocrystal

[0051] Figure 4 Differential scanning calorimetry of cocrystal of rhein and sophocarpine

[0052] Figure 5 Differential scanning calorimetry of rhein, sophocarpine and cocrystal of rhein and sophocarpine

[0053] Figure 6 Solubility curves of rhein and sophocarpine cocrystals, rhein and arginine cocrystals, and rhein DETAILED DESCRIPTION

[0054] In order to better illustrate the technical solution of the present invention, the following embodiments are given, but the present invention is not limited thereto.

[0055] Example 1

[0056] Preparation method 1 of cocrystal of rhein and sophocarpine:

[0057] Weigh a sample of rhein and sophocarpine in a molar ratio of 1:1, put it into a mortar, add an appropriate amount of organic solvent, grind it for a certain time, grind it until the solvent evaporates, place it in an oven at 80-100°C for a certain time, and perform powder X-ray diffraction analysis on it. The diffraction pattern is the same as Figure 1 The obtained sample is the eutectic of rhein and sophocarpine. The details are shown in Table 3:

[0058]

[0059] Preparation method 2 of cocrystal of rhein and sophocarpine:

[0060] Weigh a sample of rhein and sophocarpine in a molar ratio of 1:1, put it into a ball mill, add an appropriate amount of organic solvent, select an appropriate ball-to-material ratio, set an appropriate speed, grind for an appropriate time, and place it in an oven at 80-100°C to dry for a certain period of time. Perform powder X-ray diffraction analysis on it, and its diffraction pattern is consistent with Figure 1 The obtained sample is a cocrystal of rhein and sophocarpine. The details are shown in Table 4:

[0061]

[0062]

[0063] Preparation method 3 of rhein and sophocarpine cocrystal:

[0064] Weigh an appropriate amount of rhein, put it into a clean container, add an appropriate amount of organic solvent, stir it at 25-30°C, and then slowly add sophocarpine at a molar ratio of 1:1.5 to the reaction bottle. The obtained suspension is filtered and the filter cake is placed in an oven at 80-100°C for drying. The powder X-ray diffraction analysis is performed on it, and its diffraction pattern is consistent with Figure 1. The obtained sample is a cocrystal of rhein and sophocarpine. The specific details are shown in Table 5:

[0065]

[0066] Example 2

[0067] The solubility characteristics of rhein, rhein and sophocarpine cocrystals, and rhein and arginine cocrystals (rhein) in pure water systems were investigated. The dissolution curves were compared using the model-independent similarity factor (f2) method in accordance with the "Technical Guidelines for Dissolution Tests of Ordinary Oral Solid Preparations". The similarity of the dissolution curves of rhein and sophocarpine cocrystals, rhein and arginine cocrystals, and rhein API in pure water at pH = 7.0 was compared by calculating the f2 value. When f2 is higher than 50, the two curves are considered similar, and when f2 is lower than 50, it is considered that there is a difference between the two. The experiment used rhein API as a reference to calculate the model-independent similarity factor f2 value. The content of rhein was determined by HPLC at a wavelength of 254 nm, and its dissolved amount was calculated by the external standard method. The dissolution curves were plotted with time as the horizontal axis and the percentage of dissolved content as the vertical axis ( Figure 6 ). The specific data are shown in Table 6:

[0068] Table 6 Dissolution curve data of rhein eutectic and rhein in pure water

[0069]

[0070] It can be seen from the in vitro dissolution data that, compared with the raw material of rhein, the solubility of the rhein and sophocarpine cocrystal disclosed in the present invention in the pure water system is increased by nearly 55 times, and the dissolution rate is also significantly improved, which is easy to be absorbed more quickly to reach an effective blood drug concentration, and can better achieve the disease treatment effect of the drug.

[0071] In addition, compared with the reported rhein-arginine cocrystal, the water solubility of the rhein-sophorocarpine cocrystal was increased by about 10 times ( Figure 6 ). Therefore, the preparation process of the cocrystal of rhein and sophocarpine adopted in the present invention has greatly improved the technical problem of poor water solubility of rhein, and the production process is simple, which is conducive to mass production, and provides technical support for the subsequent research and development of rhein.

[0072] Example 3

[0073] Preparation method 1 of combined pharmaceutical preparation (tablets):

[0074] A method for preparing a combination drug tablet, characterized in that a cocrystal of rhein and sophocarpine, or a mixed solid material containing a cocrystal of rhein and sophocarpine in any proportion is used as a raw material of the combination drug, and several excipients are used as auxiliary material components for preparing the combination drug tablet, and a tablet sample containing 0.5 to 150 mg of drug per tablet is prepared according to a certain ratio. Table 7 shows the tablet formula ratio:

[0075] Table 7 Preparation formula of rhein and sophocarpine cocrystal combination drug tablets

[0076]

[0077] The method for preparing a tablet preparation using the cocrystal of rhein and sophocarpine as a raw material is as follows: several excipients are mixed evenly with the raw material, an appropriate amount of 1% sodium hydroxymethylcellulose solution is added to make a soft material, sieve granules, dry the wet granules, sieve whole granules, add magnesium stearate and talcum powder, mix evenly, and press into tablets.

[0078] Preparation method 2 of combined pharmaceutical preparation (capsules):

[0079] A method for preparing a combined drug capsule, characterized in that a cocrystal of rhein and sophocarpine, or a mixed solid material containing a cocrystal of rhein and sophocarpine in any proportion is used as a raw material of the combined drug, and several excipients are used as auxiliary material components for preparing the combined drug capsule, and capsule samples with a drug content of 0.5 to 150 mg per tablet are prepared according to a certain ratio. Table 8 shows the capsule formula ratio:

[0080] Table 8 The raw materials and excipients formula of the capsule preparation of the combination drug of rhein and sophocarpine cocrystal

[0081]

[0082] The method for preparing the rhein and sophocarpine cocrystal into a tablet preparation is as follows: several excipients are mixed with the raw material drug evenly, an appropriate amount of 1% sodium hydroxymethylcellulose solution is added to prepare wet granules, the wet granules are dried and sieved, magnesium stearate is added to mix evenly, and the tablets are inserted into capsules; or the granulation step is not used, and the rhein and sophocarpine cocrystal raw material drug is directly mixed with several excipients and auxiliary materials, the tablets are sieved, and the tablets are directly loaded into capsules.

[0083] Example 4

[0084] Dosage of the combination drug of rhein and sophocarpine cocrystal 1 (tablets):

[0085] The pharmaceutical composition is developed using a sample of rhein and sophocarpine cocrystal as the active ingredient of the drug. The pharmaceutical composition is characterized in that the cocrystal of rhein and sophocarpine is used as the active ingredient of the drug, and the daily dosage is 100 mg. It can be prepared into a 50 mg ordinary tablet twice a day / one tablet each time, or a 100 mg tablet once a day / one tablet each time.

[0086] Dosage of the combination drug of rhein and sophocarpine cocrystal 2 (capsule):

[0087] A pharmaceutical composition is developed using a sample of rhein and sophocarpine cocrystal as a drug active ingredient. The pharmaceutical composition is characterized in that a sample of rhein and sophocarpine cocrystal is used as a drug active ingredient. The daily dosage is 150 mg and the composition can be prepared into a 50 mg ordinary tablet, one tablet three times a day, or a 150 mg capsule, one tablet once a day.

[0088] Issues that need to be explained: There are many factors that affect the dosage of the active ingredients of the pharmaceutical composition of rhein and sophocarpine cocrystals of the present invention, such as: differences in patient age, body surface area, administration routes, administration times, and treatment purposes, resulting in different dosages for each dose; different absorption and blood drug concentrations between samples of rhein and sophocarpine cocrystals, etc., also result in the invention using rhein and sophocarpine cocrystals The appropriate dosage range for each dose is 0.01-5 mg / kg body weight, preferably 0.02-3 mg / kg body weight. When used, different total dosage plans of the active ingredients of rhein and sophocarpine cocrystals should be formulated according to the actual treatment requirements of different situations, and can be completed in multiple or one-time administration.

[0089] References

[0090] 1. Chinese patent CN102603575A.

[0091] 2. Chinese patent CN10255121A.

Claims

1. A eutectic of rhein and sophocarpine, characterized in that: Rhein and sophocarpine form a eutectic in a 1:1 molar ratio, characterized in that when analyzed by powder X-ray diffraction using CuK α Under radiation experimental conditions, diffraction peak position: 2-Theta (°), The relative intensity of the diffraction peak: the peak height value (Height%) and the peak area value (Area%) have the following characteristics:

2. The eutectic compound of rhein and sophocarpine according to claim 1, characterized in that: When analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the peaks were 3077, 2937, 2899, 2857, 2309, 2104, 1664, 1627, 1608, 1558, 1472, 1450, 1435, 1424, 1391, 1367, 1346, 1336, 1256, 1195, 1176, 1156, 1112, 1087, 1076, 1059, 1033, 1004, 982, 953, 940, 920, 901, 888, 854, 837, 831, 820, 809, 796, 767, 747, 733, 709, 661 cm -1 There is a characteristic peak of infrared spectrum at the position, and the deviation of the characteristic peak of infrared spectrum is ±2cm -1 .

3. The eutectic compound of rhein and sophocarpine according to claim 1, characterized in that: When using differential scanning calorimetry analysis, it is shown that when the temperature range is 30-220°C and the heating rate is 10°C / min, there is an endothermic peak at 182°C±3°C in the DSC spectrum.

4. The method for preparing the cocrystal of rhein and sophocarpine according to any one of claims 1 to 3, characterized in that: The method comprises adopting a liquid addition grinding method or a liquid addition ball milling method, feeding rhein and sophocarpine in a molar ratio of 1:1, adding an appropriate amount of an organic solvent, continuously grinding until the solvent evaporates, and drying in a high-temperature oven at 80 to 100° C. to obtain a cocrystal of rhein and sophocarpine; The organic solvent is selected from any single solvent of methanol, ethanol, ethyl acetate, acetonitrile and acetone or a mixed solvent prepared by combining multiple solvents in different proportions; the amount of solvent added is 0.5 to 50 ml per gram of sample; the grinding time is 0.05 to 10 hours, the drying temperature is 80 to 100°C, and the drying time is 0.5 to 1 hour; the comprehensive filling rate of the bowl of the liquid-adding grinding method is 10% to 50%, and the reciprocating motion speed is 20 to 70 m / min; the shear impact energy of the ball mill of the liquid-adding ball milling method is 10kw to 800kw, and the comprehensive filling rate is 20 to 60%; the ball-to-material ratio is 1:1 to 10:1; and the ball milling speed is 20r / min to 400r / min.

5. The method for preparing the cocrystal of rhein and sophocarpine according to any one of claims 1 to 3, characterized in that: The suspension method is adopted, rhein is added to a reaction container, an organic solvent is added at a solid-liquid ratio of 10 to 500 mg / mL, and the mixture is stirred evenly at a temperature of 25 to 30° C., and then a certain molar ratio of sophocarpine is slowly added to the reaction bottle while stirring, and the stirring speed is 100 r / min to 1000 r / min, until the bright yellow solution completely turns into reddish brown, and the stirring time is 24 to 72 hours. The obtained suspension is filtered, and the filter cake is placed in an oven at 80 to 100° C. and dried for 0.5 to 1 hour to obtain a eutectic of rhein and sophocarpine, wherein the organic solvent is selected from a mixed solvent prepared by combining any one or more of methanol, ethanol, acetone, ethyl acetate, and acetonitrile in different proportions; and the molar ratio of rhein to sophocarpine is 1:1 to 1:1.

5.

6. A mixed solid material containing a cocrystal of rhein and sophocarpine, characterized in that: The content of the eutectic compound of rhein and sophocarpine according to any one of claims 1 to 3 is 1-99.9%.

7. A pharmaceutical composition, characterized in that The invention comprises an effective dose of the co-crystal of rhein and sophocarpine according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition, characterized in that A mixed solid material containing an effective dose of the co-crystal of rhein and sophocarpine as claimed in claim 6 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition according to any one of claims 7 or 8, characterized in that The dosage form of the pharmaceutical composition is a bone-articular cavity injection, tablet, capsule, powder, injection, sustained-release preparation or controlled-release preparation.

10. Use of the cocrystal of rhein and sophocarpine according to any one of claims 1 to 3, the mixed solid material containing the cocrystal of rhein and sophocarpine according to claim 6, or the pharmaceutical composition according to any one of claims 7 or 8 in the preparation of anti-inflammatory and anti-infective drugs.

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