CN115124420B - Rhein and matrine eutectic hydrate, preparation method, composition and application thereof - Google Patents
Rhein and matrine eutectic hydrate, preparation method, composition and application thereof Download PDFInfo
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- CN115124420B CN115124420B CN202110317201.4A CN202110317201A CN115124420B CN 115124420 B CN115124420 B CN 115124420B CN 202110317201 A CN202110317201 A CN 202110317201A CN 115124420 B CN115124420 B CN 115124420B
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- rhein
- matrine
- hydrate
- eutectic
- eutectic hydrate
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Classifications
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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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 rhein and matrine eutectic hydrate which takes a lead compound rhein as a medicinal active ingredient and matrine as a eutectic ligand; a preparation method of rhein and matrine eutectic hydrate; the application of the cocrystal hydrate of rhein and matrine as the active ingredients in preparing anti-inflammatory, anti-infection and anti-osteoarthritis medicines.
Description
Technical Field
The invention discloses rhein and matrine eutectic hydrate, a preparation method, a composition and application thereof. Specifically, the invention discloses a eutectic substance formed by rhein and matrine; a preparation method of rhein and matrine eutectic hydrate; pharmaceutical compositions comprising a hydrate of the co-crystal of rhein and matrine or a mixed solid comprising any non-zero ratio of rhein to matrine co-crystal; the invention also relates to application of rhein and matrine eutectic hydrate as active ingredients of medicines in preparation of anti-inflammatory, anti-infection and anti-osteoarthritis medicines, and belongs 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, inhibiting immunity, etc. However, the use of the water-soluble polymer has not been successfully applied to clinic until now because of extremely poor water solubility. Therefore, the improvement of rhein water solubility is of great significance. Chinese patent CN102603575a reports the preparation method, purification method and application of rhein and arginine cocrystal (rhein) in preparing medicine for treating diabetic complications [1] The method comprises the steps of carrying out a first treatment on the surface of the Chinese patent CN10255121a reports the preparation process of rhein and lysine cocrystal (lys rhein) and its application in tumor treatment [2] . In addition, other co-crystal reports of rhein have not been found so far.
The invention takes Rhein (Rhein) as active substance, the chemical name of the Rhein is 1, 8-dihydroxyl-3-carboxyanthraquinone, and the molecular formula is C 15 H 8 O 6 The structural formula is shown as formula a; matrine (Matrine) is used as eutectic substance, and molecular formula is C 15 H 24 N 2 O has a structural formula shown in a formula b, and a rhein and matrine eutectic hydrate and a preparation method thereof are discovered through a pharmaceutical eutectic screening technology, and compared with rhein bulk drugs, the rhein and matrine eutectic hydrate has obviously improved solubility. In addition, compared with the reported rhein arginine eutectic, rhein lysine eutectic, the rhein and matrine eutectic hydrate has better water solubility, and unexpected technical effect is obtained.
Disclosure of Invention
The invention aims to solve the technical problems:
one of the technical problems to be solved by the invention is as follows: provides the existence state and characterization mode of the eutectic hydrate of rhein and matrine.
The second technical problem to be solved by the invention is: provides a preparation method of a rhein and matrine eutectic hydrate.
The third technical problem to be solved by the invention is: provides a mixed solid substance containing pure rhein and matrine eutectic hydrate or any non-zero ratio rhein and matrine eutectic hydrate and a pharmaceutical composition thereof.
The invention aims to solve the fourth technical problem: a pharmaceutical composition using a cocrystal hydrate of rhein and matrine as pharmaceutically active ingredients is provided, which has a dose per administration in the range of 0.5-300 mg. The pharmaceutical composition comprises bone joint cavity injection, tablets, capsules, pills, injection and slow-release or controlled-release preparation medicines.
The invention solves the technical problems: provides the advantage of better solubility of rhein and matrine eutectic hydrate compared with rhein.
The invention solves the technical problems: provides the cocrystal hydrate of rhein and matrine which has the therapeutic effect of improving the blood concentration in the body due to the formation of cocrystal substances in the course of treating diseases.
The invention solves the technical problems: the application of the rhein and matrine eutectic hydrate as the effective components in preparing anti-inflammatory, anti-infective and anti-osteoarthritis medicines.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. rhein and matrine eutectic hydrate sample morphological characteristics:
1.1 the rhein and matrine eutectic hydrate designed by the invention is a eutectic hydrate formed by rhein, matrine and water in a non-covalent bond mode according to a molar ratio of 4:2:1.
1.2 the rhein and matrine eutectic hydrate designed by the invention shows triclinic symmetry when analyzed by single crystal X-ray diffraction, the space group is P1, the unit cell parameter value is a= 8.2593 (2), b= 14.0254 (5),β= 78.773 (2) °; unit cell volume->Molecular formula (C) 15 H 7 O 6 ) 4 · (C 15 H 25 N 2 O) 2 ·H 2 O. Fig. 1 shows a projection diagram of a molecular three-dimensional structure of a rhein and matrine eutectic hydrate, fig. 2 shows a molecular unit cell stacking diagram of the rhein and matrine eutectic hydrate, and table 1 shows non-hydrogen atom coordinate parameters of the rhein and matrine eutectic hydrate.
TABLE 1 rhein and matrine eutectic hydrate non-Hydrogen atom co-ordinate parameters
1.3 Co-crystal hydrate of rhein and matrine according to the present invention, cuK was used when powder X-ray diffraction analysis was used α Diffraction peak position under radiation experimental conditions: 2-Theta (°) value orValue, diffraction peak relative intensity: the peak Height value (Height%) or the peak Area value (Area%) has the following expression (table 2, fig. 3). Powder X-ray diffraction pattern and data of physical mixture of rhein and matrine are shown in Table 3 and FIG. 4. The powder X-ray diffraction patterns of the cocrystal hydrate of rhein and matrine and the physical mixture of rhein and matrine have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topology pattern and the like, which shows that rhein and matrineThe hydrate of the eutectic of the matrine is neither identical nor equivalent to the physical mixture of rhein and matrine.
TABLE 2X-ray diffraction peak of rhein and matrine eutectic hydrate powder
TABLE 3 powder X-ray diffraction peak values of physical mixtures of rhein and matrine
。
1.4 rhein and matrine eutectic hydrate according to the present invention when analyzed by attenuated total reflection fourier infrared spectroscopy, 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, 770, 750, 744, 722, 703, 665cm -1 There is an infrared spectrum characteristic peak (FIG. 5), wherein the allowable deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
1.5 the rhein and matrine eutectic hydrate according to the present invention is characterized in that when the temperature is 10 ℃/min in the temperature range of 30 to 240 ℃ and the temperature is increased in the temperature range of 30 to 240 ℃, 2 endothermic peaks exist in the DSC pattern at 74+ -3 ℃ and 171+ -3 ℃ in the analysis by using a differential scanning calorimetric technique (FIG. 6). The DSC superposition diagram of rhein, matrine and the hydrate of the eutectics of rhein and matrine is shown in figure 7, and the obvious difference between the hydrate of the eutectics of rhein and matrine and rhein, the number and the position of endothermic peaks and the like can be seen from figure 7, which indicates that the rhein and matrine form the hydrate of the eutectics.
2. The preparation method of rhein and matrine eutectic hydrate and mixed solid is characterized in that:
2.1 the preparation method of the rhein and matrine eutectic hydrate is characterized in that a liquid adding grinding method is adopted, the rhein and matrine are added according to a molar ratio of 1:1, and the addition amount of the solvent is 0.5-50 ml per gram of sample; grinding time is 0.05-10 h, and drying temperature is 80 ℃; the comprehensive filling rate of the bowl body by 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 by the liquid adding ball milling method is 10 kw-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 rotating speed is 20 r/min-400 r/min.
2.2 the preparation method of the rhein and matrine eutectic substance is characterized in that a suspension method is adopted, rhein is added into a reaction vessel, an organic solvent is added according to the solid-to-liquid ratio of 10-500 mg/mL, the mixture is stirred uniformly at the temperature of 25-30 ℃, matrine with a certain molar ratio is slowly added into the reaction vessel, and stirring is carried out while stirring, 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 suspension, and drying the filter cake in an oven at 80 ℃ for 0.5-1 h to obtain rhein and matrine eutectic hydrate.
2.3 the mixed solid matter of the rhein and matrine eutectic hydrate, which is prepared by the method, is obtained by mixing rhein and matrine eutectic hydrate components prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.
3. Pharmaceutical preparation composition containing rhein and matrine eutectic hydrate component, administration dosage characteristics and pharmaceutical application:
3.1 the pharmaceutical composition of the invention comprises rhein and matrine eutectic hydrate and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition of the invention comprises mixed solid matters of rhein and matrine eutectic hydrate and pharmaceutically acceptable carriers.
3.3 the pharmaceutical composition related by the invention has the daily dosage of rhein within the range of 0.5-300 mg.
3.4 the pharmaceutical composition of the invention is characterized in that the pharmaceutical composition is various tablets, capsules, pills, injection, sustained release preparation or controlled release preparation and bone joint cavity injection.
3.5 the invention relates to the application of rhein and matrine eutectic hydrate, and the mixed solid or pharmaceutical composition of rhein and matrine eutectic in preparing anti-inflammatory, anti-infection, anti-osteoarthritis and other drugs.
The present invention relates to a pharmaceutical composition with rhein and matrine eutectic hydrate as active ingredients. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be made 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. The content of the mixed solid of the rhein and matrine eutectic hydrate and the rhein and matrine eutectic hydrate in the pharmaceutical composition is within the range of 10-90% by weight.
The mixed solid of rhein and matrine eutectic hydrate can be administered in unit dosage form, and the administration route can be oral administration, bone joint cavity injection, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung, respiratory tract, skin, vagina, rectum and the like.
The administration form of the present invention is preferably a solid preparation and an osteoarticular cavity injection form. The solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and spray.
The mixed solid of rhein and matrine eutectic hydrate can be prepared into common preparations, slow-release preparations, controlled-release preparations and targeting preparations, various microparticle administration systems and bone joint cavity injection.
In order to prepare the rhein and matrine eutectic hydrate and rhein and matrine eutectic mixed solid into tablets, 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 wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, 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 bilayer and multilayer tablets.
In order to prepare the administration unit into a capsule, active ingredient rhein and matrine eutectic hydrate can be mixed with a diluent and a glidant, the mixture is directly placed into a hard capsule or a soft capsule, or the active ingredient rhein and matrine eutectic hydrate can be firstly prepared into particles or pellets with the diluent, an adhesive and a disintegrating agent, and then placed into the hard capsule or the soft capsule. The various diluents, adhesives, wetting agents, disintegrants and glidants used for preparing the rhein and matrine eutectic tablet of the invention can also be used for preparing capsules of the rhein and matrine eutectic hydrate mixed solid.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The administration dosage of the pharmaceutical composition of the co-crystal hydrate of rhein and matrine of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the administration route and dosage form, etc. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The rhein and matrine eutectic hydrate or composition can be taken alone or combined with other therapeutic drugs or symptomatic drugs. When the rhein and matrine eutectic hydrate of the invention have synergistic effect with other therapeutic drugs, the dosage of the rhein and matrine eutectic hydrate should be adjusted according to actual conditions.
4. The beneficial technical effects of the invention are as follows: safety and solubility characteristic advantages of rhein and matrine eutectic
4.1 the crystal solvent contained in the rhein and matrine eutectic hydrate is water, so that the rhein and matrine eutectic hydrate has the advantage of good safety and patent medicine.
4.2 the rhein and matrine eutectic hydrate of the invention has the pharmacological activity of rhein, has great improvement on solubility, and is far superior to rhein. In addition, the water solubility was better and unexpected technical effects were obtained compared to the reported rhein arginine cocrystal (fig. 8).
Drawings
FIG. 1 shows a projection of molecular stereographic structure of a hydrate of rhein eutectic matrine
FIG. 2 unit cell stacking diagram of rhein and matrine eutectic hydrate molecules
FIG. 3 powder X-ray diffraction pattern of rhein and matrine eutectic hydrate
FIG. 4 powder X-ray diffraction pattern of physical mixture of rhein and matrine
FIG. 5 Infrared absorption spectrum of rhein and matrine eutectic hydrate
FIG. 6 differential scanning calorimetric diagram of rhein and matrine eutectic hydrate
FIG. 7 differential scanning calorimetric contrast map of rhein, matrine and rhein eutectic hydrate
FIG. 8 solubility curves of rhein and matrine eutectic hydrate, rhein and arginine eutectic and rhein
Detailed Description
The following examples are given for better illustration of the technical solution of the present invention, but the present invention is not limited thereto.
Example 1
Preparation method 1 of rhein and matrine eutectic substance:
weighing rhein and matrine samples with a molar ratio of 1:1, placing the rhein and matrine samples into a mortar, adding a proper amount of organic solvent, grinding the rhein and matrine samples until the solvent is volatilized, drying the rhein and matrine samples in an oven at 80 ℃ for a certain time, and carrying out powder X-ray diffraction analysis on the rhein and matrine samples, wherein a diffraction pattern of the rhein and matrine samples is consistent with that of figure 1, and the obtained rhein and matrine eutectic hydrate is obtained. As shown in table 4:
preparation method 2 of rhein and matrine eutectic hydrate:
weighing rhein and matrine samples with a molar ratio of 1:1, putting the rhein and matrine samples 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 for a certain time in an oven at 80 ℃. Powder X-ray diffraction analysis is carried out on the rhein, the diffraction pattern of the rhein is consistent with that of figure 1, and the obtained sample is rhein and matrine eutectic hydrate. As shown in table 5:
preparation method 3 of rhein and matrine eutectic hydrate:
weighing a proper amount of rhein, putting the rhein into a clean container, adding a proper amount of organic solvent, uniformly stirring at 25-30 ℃, slowly adding matrine with a molar ratio of 1:1.5 into a reaction bottle, filtering the obtained suspension, and drying a filter cake in an oven at 80 ℃. Powder X-ray diffraction analysis is carried out on the rhein, the diffraction pattern of the rhein is consistent with that of figure 1, and the obtained sample is rhein and matrine eutectic hydrate. As shown in table 6:
example 2
The solubility characteristics of rhein, rhein and matrine eutectic hydrate, rhein and arginine eutectic (rhein) in a pure water system were examined. According to the measurement of common oral solid preparation dissolution test technical guidelines, the dissolution curve comparison adopts a model independent similarity factor (f 2) method, and the similarity of dissolution curves of the eutectic hydrate of the rhein and matrine, the eutectic hydrate of the rhein and arginine (rhein) and rhein bulk drugs in pure water with the pH value of 7.0 is compared through the calculation of f 2. When f2 is higher than 50, the two curves are considered similar, and when f2 is lower than 50, the two curves are considered to be different. The experiment uses rhein bulk drug as reference, and calculates model independent similarity factor f2 value. The dissolution amount is calculated by an external standard method by measuring the rhein content at 254nm wavelength by adopting a high performance liquid phase method. Dissolution curves were drawn with time as the abscissa and dissolution amount as the ordinate (fig. 8). The specific data are shown in Table 7:
TABLE 7 dissolution profile data of rhein eutectic hydrate and rhein in pure water
Compared with rhein raw materials, the dissolution rate of the rhein and matrine eutectic hydrate in a pure water system is improved by about 40 times, the dissolution rate is obviously improved, the rhein and matrine eutectic hydrate is easy to be absorbed more rapidly to achieve effective blood concentration, and the disease treatment effect of the medicine can be better realized.
In addition, the water solubility of rhein and matrine co-crystals was improved by about 10-fold compared to the already reported rhein arginine co-crystals (fig. 8). Therefore, the preparation process of the rhein and matrine eutectic hydrate adopted by the invention well improves the technical problem of poor rhein water solubility, has simple production process, is beneficial to mass production, and provides technical support for subsequent research and development of rhein.
Example 3
Preparation method of combination pharmaceutical formulation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that a rhein and matrine eutectic hydrate or mixed solid substances containing rhein and matrine eutectic hydrate in any proportion are used as raw material medicines of the combined medicine, several excipients are used as auxiliary material components for preparing the combined medicine tablet, and tablet samples with the drug content of 0.5-150 mg per tablet are prepared according to a certain proportion, and the formula proportion of the tablets is shown in table 8:
preparation formula of table 8 rhein and matrine eutectic hydrate combined pharmaceutical tablet
The method for preparing the tablet preparation by taking rhein and matrine eutectic hydrate as raw material medicines comprises the following steps: mixing several excipients and raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into soft material, sieving, granulating, oven drying, sieving, granulating, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Preparation method 2 (capsule) of the combined pharmaceutical preparation:
a preparation method of a combined medicine capsule is characterized in that a rhein and matrine eutectic hydrate or a mixed solid substance containing rhein and matrine eutectic hydrate in any proportion is used as a raw material medicine of the combined medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine capsule, a capsule sample with the dosage of 0.5-150 mg per tablet is prepared according to a certain proportion, and the formula proportion of the capsule is shown in a table 9:
table 9 pharmaceutical raw material and auxiliary material formulation of rhein and matrine eutectic hydrate combined pharmaceutical capsule preparation
The method for preparing the rhein and matrine eutectic hydrate into the tablet preparation comprises the following steps: mixing several excipients with the raw materials, adding 1% sodium hydroxymethyl cellulose solution, making into wet granule, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the large Huang Suangu alkaloid eutectic hydrate raw material with several excipient adjuvants without granulating, sieving, and directly encapsulating.
Example 4
Dosage 1 (tablet) of rhein and matrine cocrystal combination drug:
the pharmaceutical composition is prepared and developed by using a rhein and matrine eutectic hydrate sample as a pharmaceutical active ingredient, and is characterized in that the rhein and matrine eutectic hydrate is used as the pharmaceutical active ingredient, the daily administration dosage is 0.5-300mg, and 1-6 tablets each time containing 10, 100, 200, 300 and 500mg of the active ingredient can be prepared into common tablet types.
Rhein and matrine eutectic hydrate combined drug administration dosage 2 (capsule):
the pharmaceutical composition is prepared and developed by using a rhein and matrine eutectic hydrate sample as a pharmaceutical active ingredient, and is characterized in that the rhein and matrine eutectic hydrate is used as the pharmaceutical active ingredient, the daily administration dosage is 10-3000mg, and 1-6 capsules containing 10, 100, 200, 300 and 500mg of the active ingredient can be prepared respectively.
Problems to be described: the pharmaceutical composition of the rhein and matrine eutectic hydrate has a plurality of factors on the administration dosage of the active ingredients, such as: the age and body surface area of patients are different, and the dosage of each administration is different due to the different administration routes, administration times and treatment purposes; the absorption and blood concentration differences between the rhein and matrine eutectic hydrate samples also result in the proper dosage range of 0.01-300mg/kg body weight, preferably 10-100mg/kg body weight, of rhein and matrine eutectic hydrate components used in the present invention. When in use, different total dosage schemes of active ingredients of the eutectics hydrate of rhein and matrine are formulated according to the actual requirements of different treatment conditions, and the administration can be completed in a mode of multiple times or one time.
Reference to the literature
1. Chinese patent CN102603575a.
2. Chinese patent CN10255121a.
Claims (14)
1. A rhein and matrine eutectic hydrate, which is characterized in that rhein, matrine and water form the eutectic hydrate in a molar ratio of 4:2:1.
2. The rhein and matrine eutectic hydrate according to claim 1, which exhibits triclinic symmetry when analyzed by single crystal X-ray diffraction, and has a space group of P1 and a unit cell parameter value of β= 78.773 °; unit cell volume->Molecular formula (C) 15 H 7 O 6 ) 4 ·(C 15 H 25 N 2 O) 2 ·H 2 O。
3. According to claim 1The rhein and matrine eutectic hydrate is characterized in that CuK is adopted when powder X-ray diffraction analysis is used α Diffraction peak position under radiation experimental conditions: 2-Theta (°),Diffraction peak relative intensity: peak Height value (Height%), peak Area value (Area%) has the following characteristics:
。
4. the co-crystal hydrate of rhein and matrine according to claim 1, wherein when analyzed using attenuated total reflectance fourier infrared spectroscopy, 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, 770, 750, 744, 722, 703, 665cm -1 There is an infrared spectrum characteristic peak, wherein the deviation of the infrared spectrum characteristic peak is + -2 cm -1 。
5. The rhein and matrine eutectic hydrate according to claim 1, wherein the rhein and matrine eutectic hydrate is characterized by having 2 endothermic peaks in a DSC profile at 74±3 ℃ and 171±3 ℃ when analyzed by differential scanning calorimetry at a temperature ranging from 30 ℃ to 240 ℃ and a heating rate of 10 ℃/min.
6. The method for preparing rhein and matrine eutectic hydrate according to any one of claims 1-5, characterized in that rhein and matrine are added according to a molar ratio of 1:1 by adopting a liquid adding grinding method or a liquid adding ball milling method, and then are continuously ground until solvent volatilizes, and the rhein and matrine eutectic hydrate is obtained by drying in a high-temperature oven at 80 ℃, wherein the organic solvent is selected from any one single solvent of ethanol, ethyl acetate, acetonitrile and acetone or a mixed solvent prepared by combining a plurality of solvents according to different proportions; the addition amount of the solvent is 0.5-50 ml per gram of sample; grinding time is 0.05-10 hours; the comprehensive filling rate of the bowl body by 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 by the liquid adding ball milling method is 10 kw-800 kw, and the comprehensive filling rate is 20-60%; the ball-material ratio is 1:1-10:1; the ball milling rotating speed is 20 r/min-400 r/min.
7. The method for preparing rhein and matrine eutectic hydrate according to any one of claims 1-5, characterized in that a suspension method is adopted, rhein is added into a reaction vessel, an organic solvent is added according to the solid-to-liquid ratio of 10-500 mg/mL, the mixture is stirred uniformly at the temperature of 25-30 ℃, matrine with a certain molar ratio is slowly added into the reaction vessel, stirring is carried out while adding, 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, the obtained suspension is filtered, a filter cake is put into an oven at 80 ℃ and dried for 0.5-1 h, and the rhein and matrine eutectic hydrate is obtained, wherein the organic solvent is any one single solvent selected from ethanol, ethyl acetate, acetonitrile and acetone or a mixed solvent prepared by combining a plurality of solvents with different proportions; the mol ratio of rhein to matrine is 1:1.5.
8. A mixed solid material containing rhein and matrine eutectic hydrate, characterized in that the content of rhein and matrine eutectic hydrate is 1-99.9% according to any one of claims 1-5.
9. A mixed solid material containing rhein and matrine eutectic hydrate, characterized in that the content of rhein and matrine eutectic hydrate is 50-99.9% according to any one of claims 1-5.
10. A mixed solid material containing rhein and matrine eutectic hydrate, characterized in that the content of rhein and matrine eutectic hydrate is 85-99.9% according to any one of claims 1-5.
11. A pharmaceutical composition comprising an effective amount of a co-crystal hydrate of rhein and matrine according to any one of claims 1-5 and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising an effective amount of a mixed solid comprising a co-crystal hydrate of rhein and matrine according to any one of claims 8-10 and a pharmaceutically acceptable carrier.
13. Pharmaceutical composition according to any of claims 11 or 12, characterized in that the pharmaceutical composition is in the form of an osteoarticular cavity injection, an injection, a tablet, a capsule, a powder, a slow release formulation or a controlled release formulation.
14. Use of a co-crystal hydrate of rhein and matrine according to any one of claims 1-5 or a mixed solid substance comprising a co-crystal of rhein and matrine according to any one of claims 8-10 or a pharmaceutical composition according to any one of claims 11 or 12 for the preparation of an anti-inflammatory, anti-infective medicament.
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| CN101898960A (en) * | 2009-05-31 | 2010-12-01 | 中国医学科学院药物研究所 | Rheinic acid crystal type A solid substance and preparation method and application thereof |
| CN102603575A (en) * | 2012-01-04 | 2012-07-25 | 丛晓东 | Rhein-arginine eutectic compound, and preparation method, purification method and application thereof in preparation of medicines for treating diabetic complications |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
| CN107286035A (en) * | 2017-05-19 | 2017-10-24 | 华东师范大学 | A kind of 5 aminosalicylic acid pharmaceutical co-crystals and preparation method thereof |
| CN109810013A (en) * | 2017-11-22 | 2019-05-28 | 盘锦格林凯默科技有限公司 | A kind of preparation method of Rhein-amino acid conjugate |
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