CN115124532A - Rhein and matrine co-crystal and preparation method, composition and use thereof - Google Patents

Abstract

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

Description

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

technical field

The invention discloses a co-crystal 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 of rhein and matrine; a co-crystal containing rhein and matrine or containing any non-zero co-crystal The pharmaceutical composition of the mixed solid substance of the ratio of rhein and matrine co-crystal; the invention also relates to rhein and matrine co-crystal as active ingredients in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other medicines It belongs to the field of medical technology.

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 has 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 has 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. Through the drug co-crystal screening technology, a co-crystal of rhein and matrine and a preparation method were found. Compared with the crude drug of rhein, the solubility of the co-crystal of rhein and matrine was significantly improved. In addition, compared with the reported rhein arginine co-crystal and rhein lysine co-crystal, the rhein-matrine co-crystal has better water solubility, and an unexpected technical effect has been achieved.

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 co-crystal of rhein and matrine, and a characterization method.

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

The third technical problem to be solved by the present invention is to provide a mixed solid substance containing pure rhein and matrine co-crystal, or a mixed solid substance containing any non-zero ratio rhein and matrine co-crystal and its pharmaceutical composition.

The fourth technical problem to be solved by the present invention is to provide a pharmaceutical composition using the co-crystal of rhein and matrine 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 rhein has better solubility than matrine co-crystal material rhein.

The sixth technical problem to be solved by the present invention is to provide that rhein and matrine can 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 the co-crystal of rhein and matrine 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 co-crystal samples of rhein and matrine:

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

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与大黄酸与苦参碱物理混合物既不相同也不等同。1.2 The co-crystal of rhein and matrine involved in the present invention, when using powder X-ray diffraction analysis using CuK _α radiation experimental conditions, the position of the diffraction peak: 2-Theta (°) value or d

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 of rhein and matrine and the physical mixture of rhein and matrine have obvious differences in the number of diffraction peaks, the position of diffraction peaks, the intensity of diffraction peaks, and the topology of diffraction peaks, indicating that rhubarb Acid and matrine co-crystals are neither identical nor equivalent to physical mixtures of rhein and matrine.

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

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

1.4 The co-crystals of rhein and matrine involved in the present invention, when analyzed by attenuated total reflection Fourier transform infrared spectroscopy, were found to be There are characteristic infrared spectral peaks at 1060, 1006, 932, 896, 839, 799, 750, 724, and 704 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 involved in the present invention is analyzed using differential scanning calorimetry, it is characterized in that, in the temperature range of 30 to 250 ° C, when the heating rate is 10 ° C/min, its DSC spectrum is There was an endothermic peak at 173±3°C (Fig. 6). Figure 7 shows the superimposed DSC diagrams of rhein, matrine and co-crystal of rhein and matrine. There were obvious differences in the number and position of peaks, indicating that rhein and matrine formed a co-crystal.

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

2.1 the preparation method of the rhein and matrine eutectic that the present invention relates to, it is characterized in that, adopt liquid adding grinding method, feed feeding according to rhein and matrine in 1:1 mol ratio, and the solvent addition amount is every gram sample. Add 0.5-50ml; the grinding time is 0.05-10h, the drying temperature is 100°C, and the drying time is 0.5-1h; the comprehensive filling rate of the pot body of the liquid-adding grinding method is 10%-50%, and the reciprocating speed is 20-20%. 70m/min; the ball mill shearing impact energy of the liquid adding 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; ball milling speed 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 is filtered, and the filter cake is placed in a 100° C. oven for drying for 0.5 to 1 hour to obtain a eutectic of rhein and matrine; the organic solvent is selected from ethanol, ethyl acetate, acetonitrile, and acetone. Any single solvent or multiple mixed solvents made of different proportioning combinations; the rhein and matrine mol ratio is 1:1.5.

2.3 The mixed solid matter of the rhein and matrine eutectic material involved in the present invention is the rhein and matrine eutectic material components prepared by the above method, and other chemical substances are carried out according to any non-zero ratio and conventional methods. obtained by mixing.

3. The pharmaceutical preparation composition containing the co-crystal components of rhein and matrine, dosage characteristics and pharmaceutical use:

3.1 The pharmaceutical composition involved in the present invention comprises a co-crystal 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 a co-crystal of rhein and matrine 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-crystals, mixed solids or pharmaceutical compositions of rhein-matrine co-crystals in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other medicines.

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

The co-crystal of rhein and matrine, and the mixed solid of co-crystal of rhein and matrine of the present invention can be administered in the form of a unit dose, and the route of administration can be oral, intra-articular injection, intravenous injection, intramuscular injection, subcutaneous injection 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 mixed solid of rhein and matrine co-crystal, rhein and matrine co-crystal of the present invention can be made into common preparations, slow-release preparations, controlled-release preparations, targeted preparations, and various microparticles for administration Drug system and bone and joint cavity injection.

In order to prepare a tablet from the mixed solid of rhein and matrine co-crystal, rhein and matrine co-crystal of the present invention, various excipients known in the art can be widely used, including diluents, binders , 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 can be mixed with diluent and glidant, and the mixture can be directly placed in a hard capsule or soft capsule, or the active ingredient rhubarb can be mixed The acid and matrine co-crystal is first made into granules or pellets with diluents, binders and disintegrating agents, and then placed in hard capsules 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. Capsules of crystalline mixed solids.

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 of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form. 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 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 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 co-crystal of rhein and matrine of the present invention does not contain any solvent and has the advantages of good safety as a medicine.

4.2 The co-crystal of rhein and matrine of the present invention has the pharmacological activity of rhein, has great improvement in solubility, and 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).

4.3 After oral administration of the rhein and matrine co-crystal of the present invention, the predominant role and application (Fig. 7) played in the prevention and treatment of diseases by rapidly reaching the maximum concentration value in the gastrointestinal tract or in the blood are embodied in The co-crystal of rhein and matrine has the advantages of fast absorption, high blood concentration and prolonged action platform.

Description of drawings

Fig.1 Powder X-ray diffraction pattern of co-crystal of rhein and matrine

Fig.2 Powder X-ray diffraction pattern of physical mixture of rhein and matrine

Fig. 3 Infrared absorption spectrum of co-crystal of rhein and matrine

Fig.4 Differential scanning calorimetry of co-crystal of rhein and matrine

Fig. 5 Differential scanning calorimetry comparison of rhein, matrine and co-crystals of rhein and matrine

Fig.6 Solubility curves of rhein-matrine co-crystal, rhein-arginine co-crystal and rhein

Fig.7 The drug-time curve of rhein and rhein-matrine co-crystals in rhesus monkeys orally absorbed for 0-24h

Fig. 8 Stability investigation of sodium hyaluronate solution of co-crystal of rhein and matrine

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, put it into a mortar, add an appropriate amount of organic solvent, grind until the solvent evaporates, and place it in a 100°C oven 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 the co-crystal of rhein and matrine. The details are shown in Table 4:

Preparation method 2 of rhein and matrine co-crystal:

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 a 100 °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 a co-crystal of rhein and matrine. The details are shown in Table 5:

Preparation method 3 of rhein and matrine co-crystal:

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 100°C. The powder X-ray diffraction analysis was carried out, and the diffraction pattern was consistent with Fig. 1, and the obtained sample was a co-crystal of rhein and matrine. The details are shown in Table 6:

Example 2

The solubility characteristics of rhein, rhein-matrine co-crystal, 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 curves were compared using the model-independent similarity factor (f2) method, and the co-crystals of rhein and matrine, rhein and arginine were compared through the calculation of f2. Similarity of the dissolution curves of acid co-crystal (large arginic acid) and rhein API 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 and rhein in pure water

It can be seen from the in vitro dissolution data that, compared with the raw material of rhein, the dissolution amount of the rhein and matrine co-crystal disclosed in the present invention in the pure water system is increased by nearly 40 times, and the dissolution rate is also significantly improved, which is easy to use. The faster absorption to reach the effective blood drug concentration can better realize the disease treatment effect of the drug.

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-crystals 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 technical support for the subsequent research and development of rhein .

Example 3

Absorption characteristics and plasma concentration characteristics of rhein-matrine co-crystal in rhesus monkeys:

The rhesus monkeys with body weight in the range of 3.3～4.2kg were selected as experimental animals, the dosage of rhein crude drug was 15mg/kg, and the dosage of rhein-matrine co-crystal was 28.1mg/kg (converted into The dose of rhein was also 15 mg/kg). Blood was collected before administration and at 0.333, 0.667, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours after administration, respectively, placed in a heparinized centrifuge tube, centrifuged at 4000 r/min for 10 min, and the supernatant was taken. , stored in a -40°C refrigerator. To 100 μL of plasma sample, 20 μL of 1 μg/mL 7-hydroxyisoflavone (internal standard), 20 μL of 2M HCl and 1000 μL of ethyl acetate were added successively, vortexed for 3 min, centrifuged at 13400 rpm for 10 min, and all the supernatant was transferred to 1.5 mL In the EP tube, nitrogen was blown dry, reconstituted with 100 μL of 30% acetonitrile solution, vortexed for 3 min, centrifuged at 13400 rpm for 10 min, and the supernatant was taken for injection.

Detection conditions: Agilent Poroshell 120SB-C18 (2.7μm, 2.1×50mm) column; injection volume 20μL; mobile phase: formic acid 0.02% aqueous solution and acetonitrile; flow rate 0.3mL/min; running time: 10min; mass spectrometry Signal: ESI source (negative ion detection mode), ions for quantitative analysis m/z=283 (rhein), m/z=237 (7-hydroxyisoflavone), fragmentation voltages are 100V (rhein), respectively, 140V (7-hydroxyisoflavone), the gain factor is 1.5, the drying gas flow is 11.0L/min, the spray chamber voltage is 35psig, the dryer temperature is 350°C, and the capillary voltages are 3000V (positive) and 3000V (negative).

Table 8 provides the blood concentration of rhesus monkeys at each time point after oral administration of rhein and rhein-matrine co-crystal samples; The pharmacokinetic parameters of the crystal samples from 0 to 24 hours show that the rhein-matrine co-crystal has the advantages of fast absorption, high blood concentration and prolonged action platform (Fig. 7).

)Table 8 Plasma concentrations at each time point (n=6,

)

Table 9 Pharmacokinetic parameters of SD rhesus monkeys after oral administration of rhein and rhein-matrine co-crystal

Example 4

Preparation method 1 (tablet) of combined pharmaceutical preparation:

A preparation method of a combination drug tablet, which is characterized in that a co-crystal of rhein and matrine, or a mixed solid substance containing a co-crystal of rhein and matrine in any proportion is used as the raw material drug of the combination drug, and several The excipients are used as auxiliary ingredients for the preparation of combined drug tablets, and are formulated into tablet samples with a drug content of 0.5 to 150 mg per tablet according to a certain proportion. Table 10 gives the tablet formulation ratio:

The preparation formula of table 10 rhein and matrine co-crystal combination drug tablet

The method for preparing a tablet preparation with a co-crystal of rhein and matrine as a raw material drug is as follows: mixing several excipients and the raw material drug uniformly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution to prepare a soft material , sieving and granulating, drying the wet granules, sieving and granulating, adding magnesium stearate and talc, mixing evenly, and pressing into tablets.

Preparation method 2 (capsule) of combined pharmaceutical preparation:

A preparation method of a combined medicine capsule, which is characterized in that a co-crystal of rhein and matrine, or a mixed solid substance containing a co-crystal of rhein and matrine in any proportion is used as the raw material of the combined medicine, and several kinds of co-crystals are used. The excipient is used as an auxiliary ingredient for the preparation of the combined drug capsule, and is formulated into a capsule sample with a drug content of 0.5 to 150 mg per tablet according to a certain proportion. Table 10 gives the capsule formula ratio:

Table 11. API and auxiliary formulations of rhein and matrine co-crystal combination drug capsule formulation

The method for preparing rhein and matrine co-crystals into tablet preparations is as follows: mixing several excipients and raw materials evenly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution, making wet granules and drying them Sieve and granulate, add magnesium stearate, mix evenly, and insert into capsules; , directly into capsules.

Preparation method 3 of combined pharmaceutical preparation (bone joint cavity injection)

A method for preparing a combined drug bone joint cavity injection, characterized in that a co-crystal of rhein and matrine, or a mixed solid substance containing a co-crystal of rhein and matrine in any proportion is used as the raw material drug of the combined drug , Sodium hyaluronate with a molecular weight of 5000 was used as an auxiliary ingredient for the preparation of the combined drug bone and joint cavity injection, and the bone and joint cavity injection samples were prepared according to a certain proportion. Stability test results at room temperature of 25°C.

Table 12 Stability of rhein and matrine hyaluronic acid solutions with different concentrations at room temperature of 25°C

time 0.5% 0.6% 0.7% 0.8% 1.0% 5 days Stablize Stablize Stablize Stablize Stablize 10 days Stablize Stablize Stablize Stablize Stablize

The method for preparing the osteogenic joint cavity injection preparation from the co-crystal of rhein and matrine is as follows: take a certain amount of sodium hyaluronate, and prepare it into mass concentrations of 0.5%, 0.6%, 0.7%, 0.8% respectively. % and 1.0% (g/100ml) sodium hyaluronate solution, accurately weigh the rhein and matrine eutectic that is equivalent to 5mg of rhein crude drug, and add to 5ml of the above-mentioned sodium hyaluronate solutions of different concentrations respectively , after continuous stirring for 12h, the concentration of 1 mg/mL rhein and matrine co-crystal sodium hyaluronate bone joint cavity injection was obtained.

Example 5

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

A pharmaceutical composition prepared and developed using a rhein and matrine co-crystal sample as a pharmaceutical active ingredient, characterized in that the rhein and matrine co-crystal is used as the active ingredient of the drug, and the daily dosage is 0.5-300 mg , can be prepared into 1-6 ordinary tablets each containing 10, 100, 200, 300, 500 mg of active ingredients.

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

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

Problems that need to be explained: the pharmaceutical composition of rhein and matrine co-crystals involved in the present invention has many influences on the administration dosage of the active ingredients, for example: the age of the patient, the difference in body surface area, the route of administration, the dosage of The different times of medication and the purpose of treatment result in different dosages each time; the absorption and blood concentration of the rhein and matrine co-crystal samples are different, etc., which also causes the present invention to use rhein and matrine co-crystals in the present invention. Each suitable dosage range of the biological 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 cocrystal 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 (14)

1. A rhein and matrine co-crystal, characterized in that, rhein and matrine form a co-crystal with a mol ratio of 2:1. 2. rhein according to claim 1 and matrine eutectic, 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:

3. rhein and matrine co-crystal according to claim 1, is characterized in that, when using attenuated total reflection Fourier transform infrared spectroscopy to analyze, at 2928, 2743, 1717, 1672, 1626, 1562, 1452, There are characteristic infrared spectral peaks at 1367, 1262, 1192, 1159, 1060, 1006, 932, 896, 839, 799, 750, 724, 704 cm ^-1 , and the deviation of the characteristic infrared spectral peaks is ±2 cm ^-1 . 4. The co-crystal of rhein and matrine according to claim 1, characterized in that, when analyzed using differential scanning calorimetry, it is shown that in the temperature range of 30 to 250 °C, the heating rate is 10 °C/ min, there is an endothermic peak at 173℃±3℃ in the DSC spectrum. 5. the preparation method of the described rhein and matrine eutectic in any one of claim 1-4, it is characterized in that, adopt liquid adding grinding method, rhein and matrine feed intake with 1:1 mol ratio , after adding an appropriate amount of organic solvent, grinding continuously until the solvent evaporates to dryness, and drying in a high temperature oven at 100°C to obtain a eutectic of rhein and matrine. 6. preparation method according to claim 5, 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 drying temperature is 100 ° C, and the drying time is 0.5-1h; %, the reciprocating speed is 20~70m/min; the ball mill shearing impact energy of the ball mill with liquid addition method is 10kw~800kw, the comprehensive filling rate is 20~60%; the ball-to-material ratio is 1:1~10:1, Preferably it is 6:1～10:1; the ball milling speed is 20r/min～400r/min. 7. the preparation method of the rhein and matrine co-crystal described in any one of claim 1-4, it is characterized in that, adopt suspension method, add rhein in reaction vessel, by solid-liquid ratio 10～ Add organic solvent at a ratio of 500 mg/mL, stir evenly at a temperature of 25-30 °C, 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 reddish-brown. The stirring time is 24-72h. The suspension obtained above was filtered, and the filter cake was dried in an oven at 100° C. for 0.5 to 1 hour to obtain a co-crystal of rhein and matrine. 8. preparation method according to claim 7, 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. 9. A mixed solid material containing rhein and matrine eutectic, characterized in that the content of the rhein and matrine eutectic according to any one of claims 1-4 is 1-99.9 %, preferably 50-99.9%, most preferably 85-99.9%. 10. A pharmaceutical composition, characterized in that it comprises an effective dose of the co-crystal of rhein and matrine according to any one of claims 1-4 and a pharmaceutically acceptable carrier. 11. A pharmaceutical composition, characterized in that it comprises an effective dose of the mixed solid substance containing the co-crystal of rhein and matrine according to claim 9 and a pharmaceutically acceptable carrier. 12. The pharmaceutical composition according to any one of claims 10 or 11, wherein the daily dosage of rhein is in the range of 0.5-300 mg. 13. The pharmaceutical composition according to any one of claims 10 or 11, wherein the dosage form of the pharmaceutical composition is bone joint cavity injection, injection, tablet, capsule, powder, sustained-release preparation or controlled-release preparation . 14. The co-crystal of rhein and matrine according to any one of claims 1-4 or the mixed solid substance of claim 9 containing co-crystal of rhein and matrine or claim 10 or 11 Application of any one of the pharmaceutical compositions in the preparation of anti-inflammatory, anti-infective, anti-osteoarthritis and other medicines.

Images