CN115120588A - Eutectic crystal of rhein and sophocarpine, preparation method, composition and application thereof - Google Patents

Eutectic crystal of rhein and sophocarpine, preparation method, composition and application thereof Download PDF

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CN115120588A
CN115120588A CN202110317182.5A CN202110317182A CN115120588A CN 115120588 A CN115120588 A CN 115120588A CN 202110317182 A CN202110317182 A CN 202110317182A CN 115120588 A CN115120588 A CN 115120588A
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rhein
sophocarpine
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吕扬
杜冠华
杨德智
刘琪文
王红娟
杨世颖
宋俊科
张雯
杨海光
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Abstract

The invention discloses a rhein and sophocarpine eutectic compound, a preparation method, a composition and application thereof. Belongs to the technical field of medicine. Specifically, the invention discloses a rhein and sophocarpine eutectic compound which takes a lead compound rhein as a medicinal active ingredient and sophocarpine as a eutectic compound ligand; a preparation method of a rhein and sophocarpine eutectic compound; the rhein and sophocarpine eutectic compound is used as the active component of the medicine in preparing the medicine for resisting inflammation, infection, osteoarthritis and the like.

Description

Eutectic crystal of rhein and sophocarpine, preparation method, composition and application thereof
Technical Field
The invention discloses a rhein and sophocarpine eutectic compound, a preparation method, a composition and application thereof. Specifically, the invention discloses a eutectic compound formed by rhein and sophocarpine; a preparation method of a rhein and sophocarpine eutectic compound; a pharmaceutical composition containing rhein and sophocarpine eutectic compound or mixed solid matter containing rhein and sophocarpine eutectic compound in any non-zero proportion; the invention also relates to the application of the eutectic compound of rhein and sophocarpine as the effective component of the medicine in preparing anti-inflammatory, anti-infection and anti-osteoarthritis medicines, belonging to the technical field of medicines.
Background
Rhein belongs to anthraquinone compounds, and has wide pharmacological activities of inhibiting tumor cell metabolism and proliferation, resisting bacteria and inflammation, regulating blood lipid, suppressing immunity, etc. However, the water solubility is very poor, so far, the application in clinic is not successful. Therefore, the improvement of the water solubility of the rhein is of great significance. Chinese patent CN102603575A [ P ]]The preparation method and purification method of rhein and arginine eutectic compound (arginine) and the application thereof in preparing the medicine for treating diabetic complications are reported in [1] (ii) a Chinese patent CN10255121A [ P ]]The preparation process of eutectic compound of rhein and lysine (lysine rhein) and its application in treating tumor are reported [2] . In addition to this, no other co-crystal reports of rhein have been found so far.
The invention takes Rhein (Rhein) as an active substance with the chemical name of 1, 8-dihydroxy-3-carboxyl anthraquinone and the molecular formula of C 15 H 8 O 6 The structural formula is shown as a formula a; sophorapine (Sophorapine) is used as eutectic compound with molecular formula of C 15 H 22 N 2 The structural formula of O is shown as a formula b, and a rhein and sophocarpine eutectic compound different from the rhein and sophocarpine eutectic compound reported in the patent and a preparation method are found through a pharmaceutical eutectic screening technology, so that the rhein and sophocarpine eutectic compound has good stability, solubility and bioavailability compared with rhein bulk drugs. In addition, the rhein lysine is a rhein arginine eutectic compound reportedCompared with the eutectic compound, the eutectic compound of rhein and sophocarpine has better water solubility and obtains unexpected technical effect.
Figure BDA0002991647250000011
Figure BDA0002991647250000021
Disclosure of Invention
The technical problems to be solved by the invention are as follows:
the invention aims to solve one of the technical problems that: provides a existence state and a representation mode of a rhein and sophocarpine eutectic compound.
The second technical problem to be solved by the present invention is: a method for preparing eutectic product of rhein and sophocarpine is provided.
The invention aims to solve the third technical problem: provides a pure product containing the eutectic product of rhein and sophocarpine, or a mixed solid substance containing the eutectic product of rhein and sophocarpine in any non-zero proportion, and a pharmaceutical composition thereof.
The fourth technical problem to be solved by the invention is: a pharmaceutical composition using a co-crystal of rhein and sophocarpine as a pharmaceutically active ingredient is provided, wherein the dosage of each administration is in the range of 0.5-300 mg. The pharmaceutical composition comprises bone joint cavity injection, tablets, capsules, pills, injection and sustained-release or controlled-release preparation drugs.
The invention aims to solve the fifth technical problem: compared with rhein raw materials, the rhein and sophocarpine eutectic substance has better solubility advantage.
The invention aims to solve the technical problems of six: the rhein and sophocarpine can form eutectic substance to raise blood medicine concentration in body and to take effect in treating diseases.
The invention solves the technical problems that: a eutectic compound of rhein and sophocarpine is used as effective component of medicine for preparing anti-inflammatory, anti-infection and anti-osteoarthritis medicines.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. morphological characteristics of a sample of the rhein and sophocarpine eutectic crystal:
1.1A eutectic compound of rhein and sophocarpine, which is characterized in that the rhein and sophocarpine form the eutectic compound with a molar ratio of 1:1.
1.2 Rhein and sophocarpine cocrystal, when analyzed by powder X-ray diffraction, CuK is adopted α Diffraction peak position under irradiation test conditions: 2-Theta (°) value or
Figure BDA0002991647250000022
Value, diffraction peak relative intensity: the peak Height value (Height%) or peak Area value (Area%) is shown below (table 1, fig. 1). The powder X-ray diffraction pattern and data of the physical mixture of rhein and sophocarpine are shown in Table 2 and FIG. 2. The powder X-ray diffraction patterns of the rhein and sophocarpine eutectic compound and the physical mixture of the rhein and sophocarpine have obvious differences in the number of diffraction peaks, the positions of the diffraction peaks, the intensity of the diffraction peaks, the topological patterns of the diffraction peaks and the like, and the rhein and sophocarpine eutectic compound is different from or identical to the rhein and sophocarpine physical mixture.
TABLE 1 Rhein and sophocarpine eutectic powder X-ray diffraction peak
Figure BDA0002991647250000031
TABLE 2X-ray diffraction Peak values of physically mixed powder of rhein and sophocarpine
Figure BDA0002991647250000032
1.3 the rhein and sophocarpine eutectic compound of the invention is analyzed by attenuated total reflection Fourier infrared spectroscopy, and the analysis result shows that the rhein and sophocarpine eutectic compound has the characteristics of 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、661cm -1 There is a characteristic peak of the infrared spectrum (FIG. 3) which has an allowable deviation of. + -.2 cm -1 。
1.4 the rhein and sophocarpine eutectic compound is characterized in that 1 endothermic peak exists in a DSC (differential scanning calorimetry) spectrum at 182 +/-3 ℃ when the temperature rise rate is 10 ℃/min within the temperature range of 30-220 ℃ (figure 4). The DSC superposition of rhein, sophocarpine and rhein and sophocarpine eutectic is shown in figure 5. from figure 5, it can be seen that rhein and sophocarpine eutectic and rhein and sophocarpine have obvious difference in number and position of endothermic peaks, thus indicating that rhein and sophocarpine form eutectic.
2. The preparation method of the eutectic compound and the mixed solid substance of the rhein and the sophocarpine is characterized by comprising the following steps:
2.1 the invention relates to a preparation method of a rhein and sophocarpine eutectic compound, which is characterized in that a liquid adding grinding method is adopted, the rhein and sophocarpine are fed according to a molar ratio of 1:1, and the addition amount of a solvent is 0.5-50 ml per gram of a sample; the grinding time is 0.05-10 h, the drying temperature is 80-100 ℃, and the drying time is 0.5-1 h; the comprehensive pot filling rate of the liquid adding grinding method is 10-50%, and the reciprocating speed is 20-70 m/min; the shearing impact energy of the ball mill of the liquid adding ball milling method is 10-800 kw, and the comprehensive filling rate is 20-60%; the ball-material ratio is 1: 1-10: 1, preferably 6: 1-10: 1; the ball milling speed is 20r/min to 400 r/min.
2.2 the invention relates to a preparation method of rhein and sophocarpine eutectic compound, which is characterized in that rhein is added into a reaction vessel by adopting a suspension method, an organic solvent is added according to the solid-liquid ratio of 10-500 mg/mL, the mixture is stirred uniformly at the temperature of 25-30 ℃, sophocarpine with a certain molar ratio is slowly added into a reaction bottle while stirring, and the stirring speed is 100 r/min-1000 r/min until the bright yellow solution is completely changed into reddish brown. The stirring time is 24-72 h. Filtering the obtained suspension, and drying the filter cake in an oven at 80-100 ℃ for 0.5-1 h to obtain the rhein and sophocarpine eutectic compound.
2.3 the mixed solid matter of rhein and sophocarpine eutectic compound related by the invention is obtained by mixing the rhein and sophocarpine eutectic compound component prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. The pharmaceutical preparation composition containing the rhein eutectic component has the following characteristics of administration dosage and pharmaceutical application:
3.1 the pharmaceutical composition comprises a eutectic compound of rhein and sophocarpine and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition comprises a mixed solid matter of rhein and sophocarpine eutectic compound and a pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition of the invention has a daily dosage of rhein within the range of 0.5-300 mg.
3.4 the invention relates to a pharmaceutical composition, which is characterized by being various bone and joint cavity injections, tablets, capsules, pills, injections, sustained-release preparations or controlled-release preparations.
3.5 the application of the eutectic crystal of rhein and sophocarpine, the mixed solid of rhein and sophocarpine or the pharmaceutical composition in preparing anti-inflammatory, anti-infection and anti-osteoarthritis medicines.
The invention relates to a pharmaceutical composition taking rhein and sophocarpine eutectic crystal as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The rhein and sophocarpine eutectic compound can be combined with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliary agents to prepare any preparation formulation suitable for human or animal use. The content of the rhein and sophocarpine eutectic compound and the mixed solid of the rhein and the sophocarpine eutectic compound in the pharmaceutical composition is within the range of 10 to 90 percent by weight.
The rheinic acid and sophocarpine eutectic compound and the mixed solid of rheinic acid and sophocarpine eutectic compound can be administrated in unit dosage form, and the administration route can be intestinal tract or non-intestinal tract, such as oral administration, bone joint cavity injection, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.
The administration forms of the invention are preferably solid preparations and osteoarticular cavity injection forms. The solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.
The rheinic acid and sophocarpine eutectic compound and the mixed solid of rheinic acid and sophocarpine eutectic compound can be prepared into common preparation, slow release preparation, controlled release preparation, target preparation, various particle drug delivery systems and bone joint cavity injection.
In order to prepare tablets from the rhein and sophocarpine eutectic compound and the mixed solid of rhein and sophocarpine eutectic compound, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants and glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to make the administration unit into a capsule, the eutectic crystal of the effective components rhein and sophocarpine can be mixed with a diluent and a glidant, and the mixture is directly placed into a hard capsule or a soft capsule. Or mixing the eutectic mixture of rhein and sophocarpine with diluent, binder, and disintegrating agent, granulating or making into pellet, and placing into hard capsule or soft capsule. Various diluents, adhesives, wetting agents, disintegrating agents and glidants for preparing the rhein and sophocarpine eutectic compound tablet can also be used for preparing capsules of mixed solid of the rhein and sophocarpine eutectic compound.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The administration dosage of the pharmaceutical composition of the eutectic crystal of rhein and sophocarpine can be widely changed according to the nature and severity of diseases to be prevented or treated, individual conditions of patients or animals, administration routes, dosage forms and the like. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The rhein and sophocarpine eutectic crystal or the composition can be taken alone or combined with other treatment medicines or symptomatic medicines. When the rhein and sophocarpine eutectic compound has synergistic effect with other therapeutic drugs, the dosage of the rhein and sophocarpine eutectic compound is adjusted according to actual conditions.
4. The invention has the beneficial technical effects that: the rhein and sophocarpine eutectic compound has the advantages of safety and solubility
4.1 the rhein and sophocarpine eutectic compound does not contain any crystallization solvent, and has good safety and patent medicine advantages.
4.2 the rhein and sophocarpine eutectic crystal has pharmacological activity of rhein, greatly improves the solubility and is far superior to rhein. In addition, compared with the reported rhein arginine eutectic compound and rhein lysine eutectic compound, the rhein and sophocarpine eutectic compound has better water solubility and unexpected technical effect (figure 6).
Drawings
FIG. 1 powder X-ray diffraction pattern of eutectic product of rhein and sophocarpine
FIG. 2 powder X-ray diffraction Pattern of a physical mixture of rhein and sophocarpine
FIG. 3 is an infrared absorption spectrum of eutectic compound of rhein and sophocarpine
FIG. 4 differential scanning calorimetry pattern of eutectic of rhein and sophocarpine
FIG. 5 Differential Scanning Calorimetry (DSC) spectra of rhein, sophocarpine and rhein-sophocarpine eutectic compound
FIG. 6 shows the solubility curves of eutectic compound of rhein and sophocarpine, eutectic compound of rhein and arginine, and rhein
Detailed Description
The following examples are given to better illustrate the technical aspects of the present invention, but the present invention is not limited thereto.
Example 1
The preparation method of the rhein and sophocarpine eutectic compound comprises the following steps:
weighing a rheinic acid and sophocarpine sample with a molar ratio of 1:1, putting the sample into a mortar, adding a proper amount of organic solvent, grinding for a certain time, grinding until the solvent is volatilized, putting the sample into an oven at 80-100 ℃ for drying for a certain time, and carrying out powder X-ray diffraction analysis on the sample, wherein the diffraction spectrum of the sample is consistent with that of a figure 1, and the obtained sample is the rheinic acid and sophocarpine eutectic crystal. The details are shown in table 3:
Figure BDA0002991647250000071
preparation method of rhein and sophocarpine eutectic compound 2:
weighing a rhein and sophocarpine sample with a molar ratio of 1:1, putting the rhein and sophocarpine sample into a ball milling tank, adding a proper amount of organic solvent, selecting a proper ball-material ratio, setting a proper rotating speed, grinding for a proper time, and drying in an oven at 80-100 ℃ for a certain time. Performing powder X-ray diffraction analysis on the product, wherein the diffraction pattern is consistent with that shown in figure 1, and the obtained sample is rhein and sophocarpine eutectic compound. Specifically, as shown in table 4:
Figure BDA0002991647250000072
Figure BDA0002991647250000081
preparation method of rhein and sophocarpine eutectic compound 3:
weighing a proper amount of rhein, putting the rhein into a clean container, adding a proper amount of organic solvent, uniformly stirring at the temperature of 25-30 ℃, slowly adding sophocarpine with the molar ratio of 1:1.5 into a reaction bottle, filtering the obtained suspension, and drying the filter cake in an oven at the temperature of 80-100 ℃. Performing powder X-ray diffraction analysis on the product, wherein the diffraction pattern is consistent with that of figure 1, and the obtained sample is the eutectic compound of rhein and sophocarpine. Specifically, as shown in table 5:
Figure BDA0002991647250000082
example 2
The solubility characteristics of rhein, a rhein and sophocarpine eutectic compound and a rhein and arginine eutectic compound (arginine) in a pure water system are examined. According to the determination of the general oral solid preparation dissolution test technical guideline, a model independent similarity factor (f2) method is adopted for the dissolution curve comparison, and the similarity of the dissolution curves of the rhein and sophocarpine eutectic compound and the rhein and arginine eutectic compound and rhein bulk drug in pure water with the pH value of 7.0 is compared through the calculation of the f2 value. When f2 is higher than 50, the two curves are considered similar, and when f2 is lower than 50, the two curves are considered different. In the experiment, rhein bulk drug is used as reference, and the value of the model independent similarity factor f2 is calculated. The content of rhein is measured at 254nm wavelength by high performance liquid chromatography, and the dissolution amount is calculated by external standard method. Dissolution curves were respectively plotted with time as abscissa and% dissolution as ordinate (fig. 6). Specific data are shown in table 6:
TABLE 6 dissolution curve data of eutectic rhein and rhein in pure water
Figure BDA0002991647250000083
In vitro dissolution data show that compared with rhein raw materials, the rhein and sophocarpine eutectic compound disclosed by the invention has the advantages that the dissolution amount of the rhein and sophocarpine eutectic compound in a pure water system is increased by about 55 times, the dissolution rate is obviously improved, the rhein and sophocarpine eutectic compound is easy to absorb more quickly to reach effective blood concentration, and the disease treatment effect of the medicine can be better realized.
In addition, the water solubility of rhein and sophocarpine co-crystals was increased by about 10 times compared to rhein and arginine co-crystals that have been reported (fig. 6). Therefore, the preparation process of the eutectic product of rhein and sophocarpine well solves the technical problem of poor water solubility of rhein, is simple in production process, is beneficial to batch production, and provides technical support for subsequent research and development of rhein.
Example 3
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined drug tablet is characterized in that rhein and sophocarpine eutectic compounds or mixed solid substances containing rhein and sophocarpine eutectic compounds in any proportion are used as raw material drugs of the combined drug, a plurality of excipients are used as auxiliary material components for preparing the combined drug tablet, tablet samples with drug content of 0.5-150 mg are prepared according to a certain proportion, and the formula proportion of the tablet is given in table 7:
TABLE 7 preparation formula of eutectic compound combined pharmaceutical tablet of rhein and sophocarpine
Figure BDA0002991647250000091
The method for preparing the tablet preparation by taking the rhein and sophocarpine eutectic compound as the raw material medicine comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into soft material, sieving, granulating, oven drying, sieving, grading, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Method 2 of preparation of the combined pharmaceutical preparation (capsule):
a preparation method of a combined medicine capsule is characterized in that rhein and sophocarpine eutectic compounds or mixed solid substances containing rhein and sophocarpine eutectic compounds in any proportion are used as raw material medicines of the combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine capsule, capsule samples with the medicine content of 0.5-150 mg are prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 8:
table 8 formula of pharmaceutical raw materials and adjuvants for rhein and sophocarpine eutectic compound combined pharmaceutical capsule preparation
Figure BDA0002991647250000101
The method for preparing the rhein and sophocarpine eutectic crystal into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the eutectic substance of the sophocarpine rheum and a plurality of excipient auxiliary materials without using a granulating step, sieving and directly encapsulating to obtain the pharmaceutical composition.
Example 4
The administration dosage of the rhein and sophocarpine eutectic compound combined medicine is 1 (tablet):
the pharmaceutical composition is prepared and developed by using a rhein and sophocarpine eutectic sample as a pharmaceutical active ingredient, and is characterized in that the rhein and sophocarpine eutectic is used as the pharmaceutical active ingredient, the daily administration dose is 100mg, and the rhein and sophocarpine eutectic can be respectively prepared into 150mg common tablet for 2 times a day or 1 tablet for 1 time a day, or 100mg tablet.
The administration dosage of the rhein and sophocarpine eutectic compound combined medicine is 2 (capsules):
the pharmaceutical composition is prepared and developed by using a rhein and sophocarpine eutectic sample as a pharmaceutical active ingredient, and is characterized in that the rhein and sophocarpine eutectic is used as the pharmaceutical active ingredient, the daily administration dose is 150mg, and the rhein and sophocarpine eutectic can be respectively prepared into 1 common tablet with 50mg for 3 times a day or 1 capsule with 150mg for 1 time a day.
Problems to be explained are: the rhein and sophocarpine cocrystal drug composition has many factors on the administration dosage of the effective components, such as: the age and the body surface area of patients are different, and the administration route, the administration frequency and the treatment purpose are different, so that the dosage of each administration is different; the difference of absorption and blood concentration between the rhein and sophocarpine cocrystal samples also causes that the suitable dosage range of each time when the rhein and sophocarpine cocrystal components are used in the invention is 0.01-5mg/kg of body weight, preferably 0.02-3mg/kg of body weight. When in use, different total dosage schemes of the rhein and sophocarpine eutectic crystal active ingredients are made according to different actual requirements of treatment, and the total dosage can be completed in a multi-time or one-time administration mode.
Reference to the literature
1. Chinese patent CN 102603575A.
2. Chinese patent CN 10255121A.

Claims (14)

1. A rhein and sophocarpine eutectic compound is characterized in that rhein and sophocarpine form the eutectic compound at a molar ratio of 1:1.
2. The co-crystal of rhein and sophocarpine according to claim 1, wherein CuK is used when powder X-ray diffraction analysis is used α Diffraction peak position under irradiation test conditions: 2-Theta (°) or
Figure FDA0002991647240000012
Diffraction peak relative intensity: peak Height (Height%) or peakThe Area value (Area%) has the following characteristics:
Figure FDA0002991647240000011
3. rhein and sophocarpine cocrystals according to claim 1, characterized in that they are found in 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, 661cm infrared spectroscopy when analyzed using attenuated total reflection Fourier infrared spectroscopy -1 The characteristic peaks of infrared spectrum exist, wherein the deviation of the characteristic peaks of infrared spectrum is +/-2 cm -1 。
4. The rhein-sophocarpine eutectic compound of claim 1, wherein 1 endothermic peak exists at 182 ℃ ± 3 ℃ in a DSC spectrum when the temperature is increased at 10 ℃/min within a temperature range of 30-220 ℃ as analyzed by differential scanning calorimetry.
5. The process for preparing the co-crystal of rhein and sophocarpine according to any one of claims 1 to 4, wherein rhein and sophocarpine are added in a molar ratio of 1:1 by a liquid-adding grinding method. Adding a proper amount of organic solvent, continuously grinding until the solvent is volatilized, and drying by a high-temperature oven at 80-100 ℃ to obtain the rhein and sophocarpine eutectic crystal.
6. The preparation method according to claim 5, wherein the organic solvent is selected from one of methanol, ethanol, ethyl acetate, acetonitrile and acetone, or a mixture thereof; the adding amount of the solvent is 0.5-50 ml per gram of the sample; grinding for 0.05-10 hours, drying at 80-100 ℃ for 0.5-1 hour; the comprehensive pot filling rate of the liquid adding grinding method is 10-50%, and the reciprocating speed is 20-70 m/min; the shearing impact energy of the ball mill of the liquid adding ball milling method is 10-800 kw, and the comprehensive filling rate is 20-60%; the ball material ratio is 1: 1-10: 1, preferably 6: 1-10: 1; the ball milling speed is 20r/min to 400 r/min.
7. The preparation method of the rhein-sophocarpine eutectic compound as claimed in any one of claims 1 to 4, wherein a suspension method is adopted, rhein is added into a reaction vessel, an organic solvent is added according to a solid-to-liquid ratio of 10-500 mg/mL, the mixture is stirred uniformly at a temperature of 25-30 ℃, and then sophocarpine with a certain molar ratio is slowly added into a reaction bottle while stirring, and the stirring speed is 100-1000 r/min until the bright yellow solution is completely converted into reddish brown. The stirring time is 24-72 h. Filtering the obtained suspension, and drying the filter cake in an oven at 80-100 ℃ for 0.5-1 h to obtain the rhein and sophocarpine eutectic compound.
8. The method for preparing the rhein-sophocarpine eutectic crystal according to claim 7, wherein the organic solvent is selected from one or more of methanol, ethanol, acetone, ethyl acetate, acetonitrile and the like, and is a mixed solvent prepared by combining the solvents in different proportions; the mole ratio of the rhein to the sophocarpine is 1: 1-1: 1.5.
9. A mixed solid matter of eutectic product of rhein and sophocarpine, which contains rhein and sophocarpine of any one of claims 1 to 4 in an amount of 1 to 99.9%, preferably 50 to 99.9%, and most preferably 85 to 99.9%.
10. A pharmaceutical composition comprising an effective amount of the co-crystal of rhein and sophocarpine according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition comprising an effective amount of the rhein and sophocarpine cocrystal mixed solid of claim 9 and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition according to any of claims 10 or 11, wherein rhein is administered in a daily dose in the range of 0.5 to 300 mg.
13. The pharmaceutical composition according to any one of claims 10 or 11, wherein the pharmaceutical composition is in the form of an osteoarticular cavity injection, tablet, capsule, powder, injection, sustained-release preparation or controlled-release preparation.
14. Use of the co-crystal of rhein and sophocarpine as defined in any one of claims 1 to 4, or the mixed solid matter of rhein and sophocarpine as defined in claim 9, or the combination drug as defined in any one of claims 10 or 11 for preparing anti-inflammatory, anti-infective, anti-osteoarthritis drugs.
CN202110317182.5A 2021-03-25 2021-03-25 Eutectic crystal of rhein and sophocarpine, preparation method, composition and application thereof Pending CN115120588A (en)

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