CN115124420A - Rhein and matrine co-crystal hydrate and preparation method, composition and use thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and discloses a rhein and matrine eutectic hydrate, a preparation method, a composition and application thereof. Specifically, the invention discloses a rheinic acid and matrine eutectic hydrate which takes a lead compound rheinic acid as a medicinal active ingredient and matrine as a eutectic ligand; a preparation method of rhein and matrine eutectic crystal hydrate; the rhein and matrine eutectic crystal hydrate is used as the active component of the medicine in preparing medicine for resisting inflammation, infection, osteoarthritis, etc.

Description

Rhein and matrine co-crystal hydrate and preparation method, composition and use thereof

technical field

The invention discloses a co-crystal hydrate of rhein and matrine, a preparation method, and a composition and application thereof. Specifically, the present invention discloses a co-crystal formed by rhein and matrine; a preparation method of a co-crystal hydrate of rhein and matrine; a co-crystal hydrate containing rhein and matrine A pharmaceutical composition containing any non-zero ratio of rhein and matrine co-crystal mixed solid matter; the invention also relates to rhein and matrine co-crystal hydrate as an active ingredient in the preparation of anti-inflammatory, anti-infective, The application in anti-osteoarthritis and other medicines belongs to the technical field of medicine.

Background technique

Rhein is an anthraquinone compound with extensive pharmacological activities such as inhibiting tumor cell metabolism and proliferation, antibacterial, anti-inflammatory, regulating blood lipids and immunosuppression. However, due to its extremely poor water solubility, it has not been successfully used in clinical practice so far. Therefore, it is very important to improve the water solubility of rhein. Chinese patent CN102603575A reported the preparation method of rhein and arginine co-crystal (large arginine), the purification method and its application in the preparation of medicine for treating diabetic complications ^[1] ; Chinese patent CN10255121A reported rhein and lysine Preparation process of amino acid co-crystal (lysine rhein) and its application in tumor therapy ^[2] . Apart from this, no other co-crystal reports of rhein have been found so far.

The present invention uses rhein (Rhein) as an active substance, its chemical name is 1,8-dihydroxy-3-carboxyanthraquinone, its molecular formula is C ₁₅ H ₈ O ₆ , and its structural formula is shown in formula a; Matrine) is a co-crystal former, the molecular formula is C ₁₅ H ₂₄ N ₂ O, and the structural formula is shown in formula b. A rhein and matrine co-crystal hydrate and a preparation method were found through the drug co-crystal screening technology. , Compared with the rhein API, the solubility of the rhein-matrine co-crystal hydrate was significantly improved. In addition, compared with the reported rhein arginine co-crystal and rhein lysine co-crystal, the water solubility of rhein and matrine co-crystal hydrate is better, and an unexpected technology has been achieved. Effect.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention:

One of the technical problems to be solved by the present invention is to provide a state of existence and a characterization method of a co-crystal hydrate of rhein and matrine.

The second technical problem to be solved by the present invention is to provide a preparation method of rhein and matrine co-crystal hydrate.

The third technical problem to be solved by the present invention: provide a mixed solid substance containing rhein and matrine co-crystal hydrate pure product, or containing any non-zero ratio of rhein and matrine co-crystal hydrate and its medicine combination.

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

The fifth technical problem to be solved by the present invention is to provide that the co-crystal hydrate of rhein and matrine has better solubility than rhein.

The sixth technical problem to be solved by the present invention is to provide a co-crystal hydrate of rhein and matrine to play a therapeutic effect by increasing the blood drug concentration in the body due to the formation of a co-crystal substance during the treatment of diseases.

The seventh technical problem to be solved by the present invention is the application of rhein and matrine co-crystal hydrate as an active ingredient of medicine in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other medicines.

In order to solve the above-mentioned technical problems, the present invention adopts the following technical solutions:

1. Morphological characteristics of rhein and matrine co-crystal hydrate samples:

1.1 The co-crystal hydrate of rhein and matrine designed by the present invention is a co-crystal hydrate formed by non-covalent bonds of rhein, matrine and water in a molar ratio of 4:2:1.

β＝78.773(2)°；晶胞体积

分子式为(C₁₅H₇O₆)₄·(C₁₅H₂₅N₂O)₂·H₂O。附图1给出大黄酸与苦参碱共晶物水合物的分子立体结构投影图，附图2给出大黄酸与苦参碱共晶物水合物的分子晶胞堆积图，表1给出大黄酸与苦参碱共晶物水合物非氢原子坐标参数。1.2 The co-crystal hydrate of rhein and matrine designed by the present invention, when analyzed by single crystal X-ray diffraction, exhibits triclinic symmetry, the space group is P1, and the unit cell parameter value is a=8.2593 ( 2), b=14.0254(5),

β=78.773(2)°; unit cell volume

The molecular formula is (C ₁₅ H ₇ O ₆ ) ₄ ·(C ₁₅ H ₂₅ N ₂ O) ₂ ·H ₂ O. Accompanying drawing 1 provides the molecular stereo structure projection diagram of rhein and matrine co-crystal hydrate, and accompanying drawing 2 provides the molecular unit cell stacking diagram of rhein and matrine co-crystal hydrate, and Table 1 provides Non-hydrogen atomic coordinate parameters of rhein and matrine co-crystal hydrate.

Table 1 Non-hydrogen atom coordinate parameters of rhein and matrine co-crystal hydrate

值、衍射峰相对强度：峰高值(Height％)或峰面积值(Area％)具有如下表示(表2，图3)。大黄酸与苦参碱物理混合物的粉末X射线衍射图谱及数据见表3、图4。大黄酸与苦参碱共晶物水合物与大黄酸与苦参碱物理混合物的粉末X射线衍射图谱在衍射峰数量、衍射峰位置、衍射峰强度、衍射峰拓扑图形等方面均存在明显差异，表明大黄酸与苦参碱共晶物水合物与大黄酸与苦参碱物理混合物既不相同也不等同。1.3 The rhein and matrine co-crystal hydrate involved in the present invention, when the powder X-ray diffraction analysis adopts CuK _α radiation experimental conditions, the position of the diffraction peak: 2-Theta (°) value or

Values, relative intensities of diffraction peaks: peak height values (Height %) or peak area values (Area %) have the following representations (Table 2, Figure 3). The powder X-ray diffraction pattern and data of the physical mixture of rhein and matrine are shown in Table 3 and Figure 4. The powder X-ray diffraction patterns of the co-crystal hydrate of rhein and matrine and the physical mixture of rhein and matrine have obvious differences in the number of diffraction peaks, the positions of diffraction peaks, the intensity of diffraction peaks, and the topological patterns of diffraction peaks. It is shown that the co-crystal hydrate of rhein and matrine is neither the same nor equivalent to the physical mixture of rhein and matrine.

Table 2 Rhein and matrine co-crystal hydrate powder X-ray diffraction peaks

Table 3 rhein and matrine physical mixed powder X-ray diffraction peaks

1.4 When the rhein and matrine co-crystal hydrate involved in the present invention is analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the results are 1672, 1624, 1561, 1467, 1449, 1389, 1367, 1260, 1246, 1189, 1156, 1088, 1073, 1048, 1005, 962, 932, 895, 839, 818, 799, 770, 750, 744, 722, There are characteristic infrared spectral peaks at 703 and 665 cm ^-1 (Fig. 5), wherein the allowable deviation of the characteristic infrared spectral peaks is ±2 cm ^-1 .

1.5 When the rhein and matrine co-crystal hydrate involved in the present invention is analyzed by differential scanning calorimetry, it is characterized in that, in the temperature range of 30 to 240 °C, when the heating rate is 10 °C/min, its In the DSC spectrum, there were two endothermic peaks at 74°C±3°C and 171°C±3°C ( FIG. 6 ). Figure 7 shows the superimposed DSC diagrams of rhein, matrine and co-crystal hydrate of rhein and matrine There are obvious differences in the number and position of endothermic peaks among the bases, indicating that rhein and matrine form a co-crystal hydrate.

2. Characteristics of the preparation method of rhein and matrine co-crystal hydrate and mixed solid:

2.1 The preparation method of the rhein and matrine eutectic hydrate that the present invention relates to, it is characterized in that, adopt liquid adding grinding method, feed feeding according to rhein and matrine in a 1:1 mol ratio, and the solvent addition amount is every Add 0.5 to 50 ml of gram sample; the grinding time is 0.05 to 10 h, and the drying temperature is 80 ° C; The ball mill shearing impact energy of the liquid adding 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; 20r/min～400r/min.

2.2 The preparation method of the rhein and matrine co-crystals involved in the present invention is characterized in that, adopting a suspension method, adding rhein into the reaction vessel, adding an organic solvent at a ratio of solid-liquid ratio of 10 to 500 mg/mL, Put it at a temperature of 25～30℃ and stir evenly, then slowly add a certain molar ratio of matrine to the reaction flask, and stir while adding, and the stirring speed is 100r/min～1000r/min, until the bright yellow solution completely turns into red brown. The stirring time is 24-72h. The suspension obtained above was filtered, and the filter cake was dried in an oven at 80° C. for 0.5-1 h to obtain a eutectic hydrate of rhein and matrine.

2.3 The mixed solid substance of rhein and matrine eutectic hydrate involved in the present invention is the composition of rhein and matrine eutectic hydrate prepared by the above method, and other chemical substances according to any non-zero ratio. It is obtained by mixing with conventional methods.

3. A pharmaceutical preparation composition containing rhein and matrine co-crystal hydrate components, dosage characteristics and pharmaceutical use:

3.1 The pharmaceutical composition involved in the present invention comprises a co-crystal hydrate of rhein and matrine and a pharmaceutically acceptable carrier.

3.2 The pharmaceutical composition involved in the present invention comprises a mixed solid substance of rhein and matrine co-crystal hydrate and a pharmaceutically acceptable carrier.

3.3 In the pharmaceutical composition of the present invention, the daily dosage of rhein is in the range of 0.5-300 mg.

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

3.5 The present invention relates to the application of rhein and matrine co-crystal hydrate, mixed solid or pharmaceutical composition of rhein and matrine co-crystal in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other medicines .

The present invention relates to a pharmaceutical composition with co-crystal hydrate of rhein and matrine as active ingredients. The pharmaceutical composition can be prepared according to methods known in the art. Any formulation suitable for human or animal use can be prepared by combining the rhein and matrine co-crystal hydrate of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. dosage form. The content of rhein and matrine co-crystal hydrate, rhein and matrine co-crystal mixed solid of the present invention is in the range of 10% to 90% by weight in the pharmaceutical composition.

The hydrate of rhein and matrine co-crystal, and the mixed solid of rhein and matrine co-crystal can be administered in unit dosage form, and the route of administration can be oral, intra-articular injection, intravenous injection, intramuscular injection , subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

The dosage forms for administration of the present invention are preferably solid preparations and bone-articular cavity injection dosage forms. Solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules medicines, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.

The rhein and matrine co-crystal hydrate, the mixed solid of the rhein and matrine co-crystal can be made into common preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations, various Microparticulate drug delivery systems and intra-articular injections.

In order to prepare a tablet from the mixed solid of rhein and matrine co-crystal hydrate, rhein and matrine co-crystal of the present invention, various excipients known in the art can be widely used, including diluents, Binder, wetting agent, disintegrant, lubricant, glidant. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polymer Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and flow aids The agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

The tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.

In order to make the dosing unit into capsules, the active ingredient rhein and matrine co-crystal hydrate can be mixed with diluent and glidant, and the mixture can be directly placed in hard capsule or soft capsule. Ingredients: The co-crystal of rhein and matrine is first made into granules or pellets with diluents, binders and disintegrants, and then placed in hard or soft capsules. Various diluents, binders, wetting agents, disintegrating agents and glidants used for preparing the rhein and matrine co-crystal tablets of the present invention can also be used for preparing the rhein and matrine co-crystals of the present invention. Crystal hydrate mixed solid capsule.

In addition, colorants, preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.

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

The dosage of the pharmaceutical composition of the rhein and matrine co-crystal hydrate of the present invention can be in a wide range according to 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. Variety. The above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing regimen including the use of other therapeutic means.

The co-crystal hydrate or composition of rhein and matrine of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the co-crystal hydrate of rhein and matrine of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

4. Beneficial technical effect of the present invention: advantages of safety and solubility characteristics of rhein and matrine co-crystal

4.1 The crystallization solvent contained in the rhein and matrine co-crystal hydrate of the present invention is water, which has the advantage of good safety as a medicine.

4.2 The co-crystal hydrate of rhein and matrine 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 co-crystal, the water solubility is better, and an unexpected technical effect is achieved (Fig. 8).

Description of drawings

Figure 1. Projection diagram of molecular stereo structure of co-crystal hydrate of rhein and matrine

Figure 2. The unit cell packing diagram of rhein and matrine co-crystal hydrate molecules

Fig.3 Powder X-ray diffraction pattern of rhein and matrine co-crystal hydrate

Fig.4 Powder X-ray diffraction pattern of physical mixture of rhein and matrine

Fig.5 Infrared absorption spectrum of rhein and matrine co-crystal hydrate

Fig.6 Differential scanning calorimetry of rhein and matrine co-crystal hydrate

Fig. 7 Differential scanning calorimetry comparison of rhein, matrine and co-crystal hydrate of rhein and matrine

Fig.8 Solubility curves of rhein-matrine co-crystal hydrate, rhein-arginine co-crystal and rhein

Detailed ways

In order to better illustrate the technical solutions of the present invention, the following examples are given, but the present invention is not limited thereto.

Example 1

Preparation method of rhein and matrine co-crystal 1:

Weigh a sample of rhein and matrine with a molar ratio of 1:1, add an appropriate amount of organic solvent into a mortar, grind until the solvent evaporates, and place it in an oven at 80 °C to dry for a certain period of time, and conduct powder X-ray diffraction on it. Analysis, the diffraction pattern is consistent with Figure 1, the obtained sample is rhein and matrine co-crystal hydrate. The details are shown in Table 4:

Preparation method 2 of rhein and matrine co-crystal hydrate:

Weigh a sample of rhein and matrine with 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 rotation speed, grind for an appropriate time, and place it in an 80°C oven to dry. a certain time. The powder X-ray diffraction analysis was carried out, and the diffraction pattern was consistent with Fig. 1, and the obtained sample was the co-crystal hydrate of rhein and matrine. The details are shown in Table 5:

Preparation method 3 of rhein and matrine co-crystal hydrate:

Weigh an appropriate amount of rhein, put it into a clean container, add an appropriate amount of organic solvent, stir evenly at a temperature of 25 to 30 °C, and then slowly add matrine with a molar ratio of 1:1.5 to the reaction flask. The suspension was filtered, and the filter cake was oven-dried at 80°C. The powder X-ray diffraction analysis was carried out, and the diffraction pattern was consistent with Fig. 1, and the obtained sample was the co-crystal hydrate of rhein and matrine. The details are shown in Table 6:

Example 2

The solubility characteristics of rhein, rhein-matrine co-crystal hydrate, rhein-arginine co-crystal (large arginine) in pure water system were investigated. Referring to the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Preparations", the dissolution curve was compared using the model-independent similarity factor (f2) method, and the co-crystal hydrate of rhein and matrine, and the Similarity of the dissolution curves of arginine co-crystal (large arginine) and rhein bulk drug in pure water at pH=7.0. When f2 is higher than 50, the two curves are considered to be similar, and when f2 is lower than 50, the two curves are considered to be different. In the experiment, the rhein raw material drug was used as a reference to calculate the model-independent similarity factor f2 value. The content of rhein was measured at the wavelength of 254 nm by high performance liquid phase method, and the dissolved amount was calculated by external standard method. Taking the time as the abscissa and the dissolution amount as the ordinate, the dissolution curves were drawn respectively (Fig. 8). The specific data are shown in Table 7:

Table 7 Dissolution curve data of rhein co-crystal hydrate and rhein in pure water

It can be seen from the in vitro dissolution data that, compared with the raw material of rhein, the dissolved amount of the rhein and matrine cocrystal hydrate disclosed in the present invention in the pure water system is increased by nearly 40 times, and the dissolution rate is also significantly improved. , it is easy to be absorbed more quickly to reach the effective blood drug concentration, and the disease treatment effect of the drug can be better realized.

In addition, the water solubility of the rhein-matrine co-crystal was approximately 10-fold improved compared to the reported rhein-arginine co-crystal (Figure 8). Therefore, the preparation process of rhein and matrine co-crystal hydrate adopted in the present invention well improves the technical problem of poor water solubility of rhein, and the production process is simple, which is conducive to mass production, and provides a good solution for the subsequent research and development of rhein. Technical Support.

Example 3

Preparation method 1 (tablet) of combined pharmaceutical preparation:

A preparation method of a combination drug tablet, which is characterized by using rhein and matrine eutectic hydrate, or a mixed solid substance containing any ratio of rhein and matrine eutectic hydrate as the raw material of the combination drug For the medicine, several excipients are used as the auxiliary ingredients for the preparation of the combined medicine tablets, and the tablet samples containing each tablet with a drug content of 0.5 to 150 mg are prepared according to a certain proportion. Table 8 shows the tablet formulation ratio:

The preparation formula of table 8 rhein and matrine co-crystal hydrate combination drug tablet

The method for preparing a tablet preparation by using rhein and matrine co-crystal hydrate as a bulk drug is as follows: mixing several excipients and bulk drug uniformly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution to prepare The soft material is sieved and granulated, the wet granules are dried, sieved and granulated, and magnesium stearate and talc are added to mix evenly, and press into tablets.

Preparation method 2 (capsule) of combined pharmaceutical preparation:

A preparation method of a combined medicine capsule, which is characterized by using rhein and matrine eutectic hydrate, or a mixed solid substance containing any ratio of rhein and matrine eutectic hydrate as the raw material drug of the combination medicine , using several excipients as the adjuvant ingredients for the preparation of the combined drug capsules, according to a certain proportion to make capsule samples with a drug content of 0.5 to 150 mg per tablet, Table 9 gives the capsule formula ratio:

Table 9 Raw materials and auxiliary material formulations of rhein and matrine co-crystal hydrate combination drug capsule preparation

The method of preparing rhein and matrine co-crystal hydrate into tablet preparation is as follows: mix several excipients and raw materials evenly, add 1% sodium hydroxymethyl cellulose solution in an appropriate amount, and prepare wet granule baking Dry sieve and granulate, add magnesium stearate and mix evenly, insert into capsules; , after sieving, directly into capsules.

Example 4

Dosage 1 (tablet) of the combination drug of rhein and matrine co-crystal:

Use rhein and matrine co-crystal hydrate sample as a pharmaceutical active ingredient to prepare and develop a pharmaceutical composition, characterized in that rhein and matrine co-crystal hydrate is used as the active ingredient of the drug, and the daily dosage It is 0.5-300mg, and can be prepared into 1-6 ordinary tablet types containing 10, 100, 200, 300, 500 mg of active ingredient each time.

Dosage 2 (capsule) of the combination drug of rhein and matrine co-crystal hydrate:

Use rhein and matrine co-crystal hydrate sample as a pharmaceutical active ingredient to prepare and develop a pharmaceutical composition, characterized in that rhein and matrine co-crystal hydrate is used as the active ingredient of the drug, and the daily dosage For 10-3000mg, it can be prepared into 1-6 capsules each containing 10, 100, 200, 300, 500mg of active ingredients.

Problems that need to be explained: the pharmaceutical composition of rhein and matrine co-crystal hydrate involved in the present invention is affected by many factors on the dosage of active ingredients, for example: the age of patients, the difference in body surface area, the route of administration , the number of administrations, and the purpose of treatment are different, resulting in different dosages each time; the absorption and blood concentration of rhein and matrine co-crystal hydrate samples are different, which also causes the present invention to use rhein and bittern. Each suitable dosage range of the ginsenoside co-crystal hydrate ingredient is 0.01-300 mg/kg body weight, preferably 10-100 mg/kg body weight. When using, different total dosage regimens of active ingredients of rhein and matrine co-crystal hydrate should be formulated according to the actual needs of treatment, and it can be divided into multiple or one-time administration methods.

references

1. Chinese patent CN102603575A.

2. Chinese patent CN10255121A.

Claims (15)

1. A rhein and matrine co-crystal hydrate, characterized in that rhein, matrine and water form a co-crystal hydrate in a molar ratio of 4:2:1. 2. The rhein and matrine eutectic hydrate according to claim 1, when using single crystal X-ray diffraction analysis, shows triclinic symmetry, the space group is P1, and the unit cell parameter value is

β=78.773°; unit cell volume

The molecular formula is (C ₁₅ H ₇ O ₆ ) ₄ ·(C ₁₅ H ₂₅ N ₂ O) ₂ ·H ₂ O. 3. rhein according to claim 1 and matrine eutectic hydrate, is characterized in that, when using powder X-ray diffraction analysis to adopt CuK _alpha radiation experimental condition, diffraction peak position: 2-Theta (°) or

Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) has the following characteristics:

4. rhein and matrine co-crystal hydrate according to claim 1, is characterized in that, when using attenuated total reflection Fourier transform infrared spectroscopy to analyze, at 3323, 3091, 2971, 2932, 2878, 2703, 2537, 2067, 1922, 1717, 1672, 1624, 1561, 1467, 1449, 1389, 1367, 1260, 1246, 1189, 1156, 1088, 1073, 1048, 1005, 962, 932, 895, 839, 818, 799, There are characteristic peaks of infrared spectrum at 770, 750, 744, 722, 703, and 665 cm ^-1 , and the deviation of the characteristic peaks of infrared spectrum is ±2 cm ^-1 . 5. The rhein and matrine co-crystal hydrate according to claim 1, characterized in that, when analyzed using differential scanning calorimetry, it is shown that in the temperature range of 30 to 240 °C, the heating rate is 10 At ℃/min, there are two endothermic peaks at 74±3℃ and 171℃±3℃ in the DSC spectrum. 6. the preparation method of rhein and matrine eutectic hydrate described in any one of claim 1-5, it is characterized in that, adopt liquid adding grinding method, rhein and matrine are 1: 1 mole Rhein and matrine eutectic hydrate is obtained by drying in a high temperature oven at 80° C. 7. preparation method according to claim 6, described organic solvent is selected from any single solvent in ethanol, ethyl acetate, acetonitrile, acetone or the mixed solvent made through different proportioning combination; Solvent The addition amount is 0.5-50ml per gram of sample; the grinding time is 0.05-10 hours; the comprehensive filling rate of the pot body of the liquid-adding grinding method is 10%-50%, and the reciprocating speed is 20-70m/min; The ball mill shearing impact energy of the liquid addition ball milling method is 10kw ~ 800kw, the comprehensive filling rate is 20 ~ 60%; the ball to material ratio is 1: 1 ~ 10: 1, preferably 6: 1 ~ 10: 1; /min～400r/min. 8. the preparation method of the rhein according to any one of claims 1-5 and matrine eutectic hydrate, it is characterized in that, adopt suspension method, in reaction vessel, add rhein, by solid-liquid ratio Add organic solvent at a ratio of 10～500mg/mL, stir evenly at 25～30℃, then slowly add matrine in a certain molar ratio into the reaction flask, and stir while adding, and the stirring speed is 100r/min～1000r /min until the bright yellow solution completely turns reddish-brown. The stirring time is 24-72h. The suspension obtained above was filtered, and the filter cake was dried in an oven at 80° C. for 0.5-1 h to obtain a eutectic hydrate of rhein and matrine. 9. preparation method according to claim 8, described organic solvent is any single solvent selected from ethanol, ethyl acetate, acetonitrile, acetone or the mixed solvent made through different proportioning combinations; The molar ratio of rhein to matrine is 1:1.5. 10. A mixed solid substance containing rhein and matrine eutectic hydrate, characterized in that it contains the content of the rhein and matrine eutectic hydrate according to any one of claims 1-5 1-99.9%, preferably 50-99.9%, most preferably 85-99.9%. 11. A pharmaceutical composition, characterized in that it comprises an effective dose of the co-crystal hydrate of rhein and matrine according to any one of claims 1-5 and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition, characterized in that it comprises an effective dose of the mixed solid substance containing rhein and matrine co-crystal hydrate according to claim 10 and a pharmaceutically acceptable carrier. 13. The pharmaceutical composition according to any one of claims 11 or 12, wherein the daily dosage of rhein is in the range of 0.5-300 mg. 14. The pharmaceutical composition according to any one of claims 11 or 12, wherein the dosage form of the pharmaceutical composition is bone joint cavity injection, injection, tablet, capsule, powder, sustained-release preparation or controlled-release preparation . 15. The rhein and matrine eutectic hydrate according to any one of claims 1-5 or the mixed solid substance containing rhein and matrine eutectic according to claim 10 or claim 11 Or the application of the pharmaceutical composition of any one of 12 in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other medicines.

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