Daidzein co-crystal with piperazine, methods of preparation and compositions and uses thereof

Abstract

The application discloses a daidzein and piperazine co-crystal, a preparation method and a composition and application thereof, and belongs to the technical field of medicines. 15 H 10 O4)·(C4H 10 N2);a daidzein and piperazine co-crystal, a preparation method and a composition and application thereof, and belongs to the technical field of medicines. The application discloses a daidzein and piperazine co-crystal, a preparation method and a composition and application thereof, and belongs to the technical field of medicines. The application discloses a daidzein and piperazine co-crystal, a preparation method and a composition and application thereof, and belongs to the technical field of medicines. The application discloses a daidzein and piperazine co-crystal, a preparation method and a composition and application thereof, and belongs to the technical field of medicines. The application discloses a daidzein and piperazine co-crystal, a preparation method and a composition and application thereof, and belongs to the technical field of medicines.

Description

TECHNICAL FIELD

[0001] The present application relates to a daidzein and piperazine cocrystal, a preparation method and a composition and use thereof. Specifically, the present application discloses a cocrystal formed by daidzein and piperazine; a preparation method of the daidzein and piperazine cocrystal; and an application of the daidzein and piperazine cocrystal as an effective pharmaceutical ingredient in the preparation of antitumor, antioxidant, anti-inflammatory, antiarrhythmic, hypolipidemic, antihypertensive, osteoporosis, coronary heart disease, menopausal syndrome and prostatic hyperplasia treatment drugs. The present application belongs to the technical field of medicine. BACKGROUND

[0002] Daidzein (English name: Daidzein) is an isoflavone compound with a wide range of biological activities, mainly existing in leguminous plants [1] , and its structural formula is shown in Figure a. Daidzein has rich pharmacological effects, such as antitumor, antioxidant, anti-inflammatory, antiosteoporosis, antiarrhythmic, hypolipidemic and antihypertensive effects, and has good effects on osteoporosis and coronary heart disease, and has a dual effect of estrogen and antiestrogen, and has important value for new drug development [2-6] . However, daidzein belongs to flavonoids, and the C6-C3-C6 basic carbon skeleton structure in the parent nucleus forms a planar structure of a large conjugated region, which directly leads to poor water solubility and low bioavailability, which seriously affects the clinical curative effect and becomes a bottleneck problem in new drug development. In order to solve this bottleneck problem, based on the principle of crystal engineering, daidzein is used as an active pharmaceutical ingredient (Active Pharmaceutical Ingredients, API), and piperazine is used as a cocrystal former (cocrystal former, CCF), and a daidzein and piperazine cocrystal is obtained for the first time. The molecular formula of piperazine is C4H 12 N2, and its structural formula is shown in Figure b.

[0003]

[0004] Research on the polymorphs and cocrystals of daidzein: so far, four crystal forms of daidzein have been found [7-9] , of which three are anhydrous or solvent-free crystal forms, and one is a DMF solvate. The daidzein raw material used in the present application is crystal I, which is an anhydrous and solvent-free crystal form [8] . So far, there have been five reports on daidzein cocrystals, which are daidzein-4,4'-dipyridine cocrystal

[10] , daidzein-isonicotinamide cocrystal

[11] , daidzein-cytosine cocrystal

[11] , daidzein-theobromine cocrystal

[11] , and daidzein-theophylline cocrystal

[12] .

[0005] Through the serious research on the study of daidzein pre-cocrystal, it is found that only daidzein-4,4'-dipyridine cocrystal in these synthetic cocrystals obtains a single crystal structure, and the related single crystal data results show that the hydroxyl group of daidzein forms a hydrogen bond with the nitrogen atom of 4,4'-dipyridine

[10] The cocrystal former (CCF) involved in the present application is piperazine, and the molecular structure of the CCF is significantly different from the CCF structure of the reported daidzein cocrystal. The reported daidzein cocrystal study shows that the CCF forming a cocrystal with daidzein all contains sp 2 hybrid nitrogen atom, while the CCF piperazine involved in the present application only contains sp 3 hybrid nitrogen atom. In addition, compared with the existing published cocrystal reports, the daidzein-piperazine cocrystal involved in the present application is particularly remarkable in improving the dissolution rate, dissolution degree and bioabsorption, and unexpected effects are achieved, so as to solve the bottlenecks of daidzein in poor water solubility and low bioavailability. SUMMARY

[0006] The research of the present application is to prepare a cocrystal type solid material with specific non-covalent force by daidzein and piperazine, so as to form a new material different from daidzein and piperazine and the simple combination of the two, and then find the application of the new cocrystal solid material of the present application in preparing antitumor, antioxidant, anti-inflammatory, antiarrhythmic, hypolipidemic, antihypertensive, osteoporosis, coronary heart disease, menopausal syndrome and prostatic hyperplasia treatment drugs.

[0007] The technical problems to be solved by the present application are:

[0008] One of the technical problems to be solved by the present application is to provide the existence state and characterization method of daidzein and piperazine cocrystal.

[0009] The second technical problem to be solved by the present application is to provide a preparation method of daidzein and piperazine cocrystal.

[0010] The third technical problem to be solved by the present application is to provide a pure product containing daidzein and piperazine cocrystal, or a mixed solid material containing any non-zero proportion of daidzein and piperazine cocrystal and a pharmaceutical composition thereof.

[0011] The fourth technical problem to be solved by the present application is to provide a pharmaceutical composition using daidzein and piperazine cocrystal as a pharmaceutical active ingredient, and the dosage of each medication is in the range of 5-3000 mg. The pharmaceutical composition includes tablets, capsules, pills, injections, sustained-release or controlled-release preparation drugs.

[0012] The fifth technical problem to be solved by the present application is to provide a daidzein and piperazine co-crystal, which has better solubility and bioavailability advantages compared with daidzein raw materials.

[0013] The sixth technical problem to be solved by the present application is the application of the daidzein and piperazine co-crystal as a pharmaceutical effective component in the preparation of anti-tumor, anti-oxidation, anti-inflammatory, anti-arrhythmia, blood lipid-lowering, blood pressure-lowering, osteoporosis, coronary heart disease, menopausal syndrome and prostatic hyperplasia treatment drugs.

[0014] To solve the above technical problems, the present application adopts the following technical solutions:

[0015] 1. The sample form characteristics of the daidzein and piperazine co-crystal are as follows:

[0016] 1.1 The daidzein and piperazine co-crystal involved in the present application is formed by the combination of daidzein and piperazine through non-covalent bonds, and the molar ratio of the two is 1:1.

[0017] 1.2 The daidzein and piperazine co-crystal involved in the present application exhibits monoclinic symmetry when analyzed by single crystal X-ray diffraction, and the space group is P21 / c, and the cell parameters are as follows: β = 95.021°. The cell volume The molecular formula of the co-crystal is C 15 H 10 O4·C4H 10 N2. The Figure 1 The molecular stereoscopic structure projection diagram of the daidzein and piperazine co-crystal is given, and the Figure 2 The molecular cell packing diagram of the daidzein and piperazine co-crystal is given, and the non-hydrogen atom coordinate parameters of the daidzein and piperazine co-crystal are given in Table 1.

[0018] Table 1 Non-hydrogen atom coordinate parameters of daidzein and piperazine co-crystal

[0019]

[0020] 1.3 The daidzein and piperazine co-crystal involved in the present application does not contain crystallization solvent or crystallization water components, and when analyzed by powder X-ray diffraction under CuK α radiation experimental conditions, it exhibits diffraction peak position: 2-Theta value (°) or d value The relative intensity of the diffraction peak has the following characteristic peak values (Table 2, Figure 3 ). The powder X-ray diffraction spectrum data of the daidzein and piperazine physical mixture are shown in Table 3, Figure 4The powder X-ray diffraction patterns of the daidzein and piperazine co-crystal and the daidzein and piperazine physical mixture are obviously different in the number of diffraction peaks, diffraction peak position, diffraction peak intensity, diffraction peak topological pattern and the like, indicating that the daidzein and piperazine co-crystal and the daidzein and piperazine physical mixture are neither identical nor equivalent.

[0021] Table 2 Powder X-ray diffraction peak data of daidzein and piperazine co-crystal

[0022]

[0023] Table 3 Powder X-ray diffraction peak data of daidzein and piperazine physical mixture

[0024]

[0025]

[0026] 1.4 The daidzein and piperazine co-crystal involved in the present application has infrared spectral characteristic peaks at 3283, 3217, 3069, 3034, 2967, 2930, 2889, 2862, 2779, 2673, 2580, 2495, 1896, 1807, 1679, 1620, 1615, 1578, 1539, 1514, 1494, 1471, 1455, 1433, 1377, 1328, 1311, 1282, 1255, 1220, 1195, 1176, 1153, 1103, 1045, 983, 948, 905, 881, 843, 827, 794, 785, 724, 694, 666, 641, 623, 607, 543, 530, 496, 466, 463, 418, 411, 407 cm -1 wherein the allowable deviation of the infrared spectral characteristic peaks is ±2 cm -1 ( Figure 5 )。

[0027] 1.5 The daidzein and piperazine co-crystal involved in the present application has an endothermic peak at 235℃±3℃ in the DSC spectrum when analyzed using differential scanning calorimetry technology at a temperature increase rate of 10℃ per minute in the range of 30-300℃ ( Figure 6 ). The DSC spectra of the daidzein and piperazine co-crystal and daidzein and piperazine are obviously different in the number and position of endothermic / exothermic peaks, indicating that the daidzein and piperazine co-crystal and daidzein and piperazine are neither identical nor equivalent ( Figure 7 )。

[0028] 2. The preparation method of the daidzein and piperazine co-crystal is characterized in that

[0029] 2.1 The solvent assisted milling method for preparing the daidzein and piperazine co-crystal according to the present application comprises the following steps:

[0030] (1) Put daidzein and piperazine in a mortar in a molar ratio of 1:1, grind uniformly to obtain a mixture;

[0031] (2) Grind the mixture obtained in step (1) in a clockwise direction, and add a certain volume of organic solvent to it every 5 min, and grind for 10 min to 10 h. The organic solvent is preferably selected from any one or more of methanol, ethanol, ethyl acetate, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane, or a mixed solvent prepared by different proportions of the above-mentioned solvents; the amount of organic solvent added is 50 uL to 500 uL per gram of solid sample; and the drying method is selected from natural drying or vacuum drying to obtain daidzein and piperazine co-crystal.

[0032] (3) Dry the product obtained in step (2) to obtain a solid product of daidzein and piperazine co-crystal.

[0033] 2.2 The solvent assisted milling method for preparing the daidzein and piperazine co-crystal according to the present application can use mechanical ball milling method, wherein the ball-to-material ratio of the ball milling method is 1:1 to 10:1, preferably 6:1 to 10:1; the ball milling speed is 20 r / min to 400 r / min, preferably 200 r / min to 400 r / min.

[0034] 2.3 The mixed solid material containing daidzein and piperazine co-crystal according to the present application is prepared by mixing daidzein and piperazine co-crystal obtained by the above-mentioned method with other chemical substances in any non-zero proportion and by a conventional method.

[0035] 3. Daidzein and piperazine co-crystal composition, dosage characteristics, and pharmaceutical formulation composition characteristics:

[0036] 3.1 The pharmaceutical composition according to the present application contains an effective dose of daidzein and piperazine co-crystal and a pharmaceutically acceptable carrier.

[0037] 3.2 The pharmaceutical composition according to the present application has a daily dosage of daidzein and piperazine co-crystal in the range of 5 mg to 3000 mg.

[0038] 3.3 The pharmaceutical composition according to the present application has a dosage form of tablet, capsule, pill, injection, sustained-release preparation, or controlled-release preparation.

[0039] 3.4 The application relates to the use of the daidzein-piperazine co-crystal in the preparation of antitumor, antioxidant, anti-inflammatory, antiarrhythmic, hypolipidemic, hypotensive, osteoporosis, coronary heart disease, menopausal syndrome and prostatic hyperplasia drugs.

[0040] The application relates to a pharmaceutical composition containing the daidzein-piperazine co-crystal as an active ingredient. The pharmaceutical composition can be prepared according to the methods known in the art. The daidzein-piperazine co-crystal can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to form any dosage form suitable for human or animal use. The daidzein-piperazine co-crystal is generally present in an amount of 10-90% by weight.

[0041] The daidzein-piperazine co-crystal can be administered in unit dosage form and the administration route can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0042] The administration dosage form of the application is preferably a solid dosage form. The solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, chewable tablets, dispersible tablets, effervescent tablets, oral disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosol (powder) sprays, sprays, etc.

[0043] The daidzein-piperazine co-crystal and the mixed solid substance of the daidzein-piperazine co-crystal can be prepared into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0044] In order to prepare the daidzein-piperazine co-crystal into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0045] The tablets can be further prepared into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0046] To prepare the administration unit into a capsule, the effective component, the daidzein-piperazine co-crystal of the present application, can be mixed with diluents, glidants, and the mixture is directly placed into a hard capsule or a soft capsule. The effective component, the daidzein-piperazine co-crystal of the present application, can also be mixed with diluents, binders, and disintegrants to prepare granules or pellets, and then placed into a hard capsule or a soft capsule. The various diluents, binders, wetting agents, disintegrants, and glidants used for preparing the daidzein-piperazine co-crystal component tablets of the present application can also be used for preparing the daidzein-piperazine co-crystal capsules of the present application.

[0047] In addition, if necessary, coloring agents, preservatives, flavors, taste correctors, or other additives can also be added to the pharmaceutical preparation.

[0048] To achieve the purpose of medication and enhance the therapeutic effect, the pharmaceutical or pharmaceutical composition of the present application can be administered by any known administration method.

[0049] The administration dose of the daidzein-piperazine co-crystal of the present application can vary greatly 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 dose can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the administration regimen including the use of other therapeutic methods.

[0050] The daidzein-piperazine co-crystal of the present application can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the daidzein-piperazine co-crystal of the present application has a synergistic effect with other therapeutic drugs, the dose thereof should be adjusted according to the actual situation.

[0051] 4. The technical solution of the present application has the following beneficial technical effects:

[0052] 4.1 The daidzein-piperazine co-crystal of the present application does not contain any crystallization solvent, and has the advantages of good safety and drug preparation.

[0053] 4.2 The daidzein-piperazine co-crystal of the present application is stable under high temperature, high humidity, and light conditions, and has the advantages of good stability and drug preparation.

[0054] 4.3 The daidzein and piperazine co-crystal involved in the present application has significant advantages in solubility compared with daidzein raw material, which is embodied in that it shows significant solubility and dissolution rate advantages in hydrochloride buffer (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8), pure water (pH 7.0) and other dissolution systems. Its solubility in the four media is 2.4, 2.0, 2.5 and 11.7 times higher than that of daidzein raw material, respectively.

[0055] 4.4 The daidzein and piperazine co-crystal involved in the present application has significant advantages in bioabsorption and utilization compared with daidzein raw material, which is embodied in that the formation of daidzein and piperazine co-crystal makes the maximum blood concentration Cmax of daidzein increase by 2.0 times, and the area under the curve AUC value increase by 3.2 times. max BRIEF DESCRIPTION OF DRAWINGS

[0056] Figure 1 Molecular stereoscopic structure projection diagram of daidzein and piperazine co-crystal

[0057] Figure 2 Molecular crystal cell accumulation diagram of daidzein and piperazine co-crystal

[0058] Figure 3 Powder X-ray diffraction pattern of daidzein and piperazine co-crystal

[0059] Figure 4 Powder X-ray diffraction pattern of daidzein and piperazine physical mixture

[0060] Figure 5 Infrared absorption spectrum of daidzein and piperazine co-crystal

[0061] Figure 6 Differential scanning calorimetry pattern of daidzein and piperazine co-crystal

[0062] Figure 7 Differential scanning calorimetry superimposed pattern of daidzein and piperazine co-crystal, daidzein and piperazine

[0063] Figure 8 Stability spectrum of daidzein and piperazine co-crystal under high temperature, high humidity and strong light

[0064] Figure 9 Dissolution curves of daidzein and piperazine co-crystal and daidzein under different PH conditions

[0065] Figure 10 Pharmacokinetic curves of daidzein and piperazine co-crystal and daidzein DETAILED DESCRIPTION

[0066] ​In order to better illustrate the technical solutions of the present application, the following examples are given, but the present application is not limited to them.

[0067] Example 1

[0068] Preparation method 1 of daidzein and piperazine co-crystal

[0069] An appropriate amount of daidzein and piperazine were weighed according to a 1:1 molar ratio and placed in a clean mortar. After grinding uniformly, a physical mixture of daidzein and piperazine was obtained. A certain volume of organic solvent was added dropwise every 5 min, and the obtained mixture was ground in a clockwise direction. After grinding for a certain period of time, the obtained product was dried. Powder X-ray diffraction analysis was performed on it, and the diffraction pattern thereof was consistent with that of Figure 3 , indicating that the obtained sample was a daidzein and piperazine co-crystal.

[0070] Table 4 Specific examples of preparation method 1

[0071]

[0072] Preparation method 2 of daidzein and piperazine co-crystal

[0073] An appropriate amount of daidzein and piperazine was weighed according to a 1:1 molar ratio and placed in a clean ball mill tank. A specific ball-to-material ratio was used, and a certain volume of organic solvent was added dropwise every 15 min. The mixture was ground at a certain speed. After grinding for a certain period of time, the obtained product was dried. Powder X-ray diffraction analysis was performed on it, and the diffraction pattern thereof was consistent with that of Figure 3 , indicating that the obtained sample was a daidzein and piperazine co-crystal.

[0074] Table 5 Specific examples of preparation method 2

[0075]

[0076] Example 2

[0077] In-vitro dissolution release characteristics of daidzein and piperazine co-crystal

[0078] The solubility characteristics of daidzein and piperazine co-crystal and daidzein raw material in hydrochloride buffer solution (pH 1.2), acetate buffer solution (pH 4.5), phosphate buffer solution (pH 6.8), and pure water (pH 7.0) solution systems were investigated. The experiment was carried out in accordance with the “Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations”. The sample dissolution concentration was calculated by the external standard method using high performance liquid chromatography. The dissolution curves were drawn with time (min) as the abscissa and sample concentration (μg / mL) as the ordinate Figure 9 . The data are shown in Table 5.

[0079] Detection condition: detection system: Aligent 1260, column: Odyssil C18 (4.6x250mm, 5um); mobile phase: methanol-0.1% acetic acid water (70:30, v / v); flow rate: 1 mL·min -1 ; column temperature: 30℃; detection wavelength: daidzein: 250nm; injection volume: 10ul.

[0080] Table 5 dissolution curve data

[0081]

[0082] From the experimental data, it can be seen that the solubility behavior of daidzein-piperazine co-crystal in hydrochloride buffer solution, acetate buffer solution, phosphate buffer solution and pure water system is significantly better than that of daidzein raw material, which is specifically reflected in: in terms of dissolution rate improvement, after daidzein and piperazine form co-crystal, the dissolution rate of daidzein in the first 30 minutes in the four media is increased by 3.6, 6.4, 13.7 and 11.1 times respectively; in terms of solubility improvement, after daidzein and piperazine form co-crystal, the solubility of daidzein in the four media is increased by 2.4, 2.0, 2.5 and 11.7 times respectively. Daidzein-piperazine co-crystal significantly improves the dissolution rate and amount of API, which is of great significance to improve the speed and extent of daidzein bioabsorption.

[0083] Example 3

[0084] Daidzein-piperazine co-crystal in vivo bioabsorption advantage

[0085] Based on SD rat animal model, the pharmacokinetic behavior of daidzein raw material and daidzein-piperazine co-crystal in rats was investigated by solid gavage administration. The related pharmacokinetic parameters obtained by experiment are shown in Table 6, and the blood sampling time (min) is taken as the abscissa and the blood concentration (ng / mL) is taken as the ordinate to draw the drug-time curve of daidzein raw material and daidzein-piperazine co-crystal respectively. Figure 7 .

[0086] Table 6 pharmacokinetic parameters

[0087]

[0088] Note: "**" represents P<0.01, "*" represents P<0.05

[0089] By comparing the pharmacokinetic parameters of daidzein raw material and daidzein-piperazine co-crystal, it can be seen that the formation of daidzein-piperazine co-crystal makes the peak time T max of daidzein prolonged from 3.8h to 8.2h, and the maximum blood drug concentration C maxThe increase was 2.0 times the original, and the area under the curve (AUC) value was 3.2 times the original. This shows that the formation of the co-crystal enhances the absorption of daidzein and improves the bioavailability, which is of great significance to solve the problem of poor bioabsorption and low bioavailability of daidzein raw material.

[0090] Example 4

[0091] Preparation method 1 (tablet) of the combined drug preparation:

[0092] A preparation method of a combined drug tablet, characterized in that daidzein and piperazine co-crystal pure product is used as the raw material of the combined drug, several excipients are used as the auxiliary ingredient for preparing the combined drug tablet, and the tablet samples containing 5-500 mg of drug per tablet are prepared according to a certain proportion, and the tablet formulation proportion is shown in Table 7:

[0093] Table 7 Preparation formulation of daidzein and piperazine co-crystal combined drug tablet

[0094]

[0095] The method for preparing daidzein and piperazine co-crystal pure product raw material into a tablet preparation is to mix several excipients and the raw material uniformly, directly compress the tablet, or granulate the excipients by dry method, then mix the granules with the raw material uniformly, and compress the tablet.

[0096] Preparation method 2 (tablet) of the combined drug preparation:

[0097] A preparation method of a combined drug tablet, characterized in that daidzein and piperazine co-crystal pure product is used as the raw material of the combined drug, several excipients are used as the auxiliary ingredient for preparing the combined drug tablet, and the tablet samples containing 5-500 mg of drug per tablet are prepared according to a certain proportion, and the tablet formulation proportion is shown in Table 8:

[0098] Table 8 Preparation formulation of daidzein and piperazine co-crystal combined drug tablet

[0099]

[0100] The method for preparing daidzein and piperazine co-crystal pure product raw material into a tablet preparation is to mix several excipients and the raw material uniformly, add an appropriate amount of 1% sodium hydroxymethyl cellulose solution, make soft material, sieve and granulate, dry the wet granules, sieve and size the granules, mix with magnesium stearate and talc powder uniformly, and compress the tablet.

[0101] Preparation method 3 (capsule) of the combined drug preparation:

[0102] A preparation method of a combination drug capsule, characterized by using a pure daidzein and piperazine co-crystal as a raw material of the combination drug, using several excipients as auxiliary components for preparing the combination drug capsule, and preparing capsule samples containing 5-500 mg of the drug per tablet according to a certain proportion, and Table 9 shows the capsule formulation proportion:

[0103] Table 9 Formulation of raw materials and auxiliary materials of daidzein and piperazine co-crystal combination drug capsule

[0104]

[0105] The method for preparing daidzein and piperazine co-crystal raw materials into tablet formulations is as follows: several excipients are mixed with the raw materials, an appropriate amount of 1% sodium hydroxymethyl cellulose solution is added, the wet granules are dried, sieved, and granulated, magnesium stearate is added and mixed uniformly, and then inserted into a capsule to obtain the tablet; or the granulation step is not used, and the daidzein and piperazine co-crystal raw materials are directly mixed with several excipients, sieved, and then directly loaded into a capsule to obtain the tablet.

[0106] Example 5

[0107] Dosing of daidzein and piperazine co-crystal combination drug 1 (tablet):

[0108] A pharmaceutical composition prepared using daidzein and piperazine co-crystal samples as active pharmaceutical ingredients, characterized by using daidzein and piperazine co-crystal as active ingredients of the drug, with a daily dosing of 300 mg, which can be prepared into 100 mg ordinary tablets, 1 tablet per time, 3 times a day, or 300 mg tablets, 1 tablet per time, once a day.

[0109] Dosing of daidzein and piperazine co-crystal combination drug 2 (capsule):

[0110] A pharmaceutical composition prepared using daidzein and piperazine co-crystal samples as active pharmaceutical ingredients, characterized by using daidzein and piperazine co-crystal as active ingredients of the drug, with a daily dosing of 500 mg, which can be prepared into 250 mg capsules, 1 capsule per time, 2 times a day, or 500 mg capsules, 1 capsule per time, once a day.

[0111] It should be noted that the soy isoflavone and piperazine co-crystal pharmaceutical composition of the present application has many factors affecting the dosage of the active ingredient, such as: different uses for prevention and treatment cause different daily medication dosages; different disease nature and severity cause different daily medication dosages; different patient gender, age, body surface area, different administration routes, administration times, treatment purposes cause different daily medication dosages; in addition, the absorption and blood concentration between different crystal samples also cause the present application to have a suitable daily dosage range of 0.002-20 mg / kg body weight, preferably 0.01-10 mg / kg body weight, when using soy isoflavone and piperazine co-crystal components. When used, different total dosage schemes of soy isoflavone and piperazine co-crystal active ingredients should be formulated according to the actual needs of different prevention and treatment situations, and can be completed in multiple or one-time administration modes.

[0112] References

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Claims

1. A daidzein co-crystal with piperazine, characterized by daidzein and piperazine form a co-crystal with non-covalent bond in a 1:1 molar ratio, When using powder X-ray diffraction analysis with Cu K α The diffraction peak positions: 2-Theta values (°) or d values (A) and diffraction peak relative intensities: peak height values (Height %) or peak area values (Area %) have the following characteristics when the experimental conditions of radiation are as follows: 。 2. The daidzein co-crystal with piperazine according to claim 1, characterized in that, When analyzed using single crystal X-ray diffraction, it exhibits monoclinic symmetry, space group P21 / c, with cell parameters: a = 12.162 A, b = 6.385 A, c = 21.224 A, β = 95.021°, cell volume V = 1641.85 A3. 3 .

3. The daidzein co-crystal with piperazine according to claim 1, characterized in that, when analyzed using attenuated total reflectance Fourier transform infrared spectroscopy, exhibit infrared spectral characteristic peaks at 3283, 3217, 3069, 3034, 2967, 2930, 2889, 2862, 2779, 2673, 2580, 2495, 1896, 1807, 1679, 1620, 1615, 1578, 1539, 1514, 1494, 1471, 1455, 1433, 1377, 1328, 1311, 1282, 1255, 1220, 1195, 1176, 1153, 1103, 1045, 983, 948, 905, 881, 843, 827, 794, 785, 724, 694, 666, 641, 623, 607, 543, 530, 496, 466, 463, 418, 411, 407 cm -1 wherein the infrared spectral characteristic peaks have a permissible deviation of ± 2 cm -1 .

4. The daidzein co-crystal with piperazine according to claim 1, characterized in that, when analyzed using differential scanning calorimetry technique, it shows that there is an endothermic peak at 235°C ± 3°C in the DSC spectrum at a temperature range of 30-300°C and a temperature rate of 10°C per minute.

5. The process for preparing a daidzein co-crystal with piperazine as claimed in any one of claims 1 to 4, characterized in that, Prepared by solvent assisted grinding method, comprising the following steps: (1) placing daidzein and piperazine in a mortar in a 1:1 molar ratio, grinding uniformly to obtain a mixture; (2) taking the mixture obtained in step (1) and grinding in a clockwise direction, and adding a certain volume of organic solvent every 5 minutes, grinding for 10 minutes to 10 hours; (3) drying the product obtained in step (2) to obtain a solid product of daidzein and piperazine co-crystal; wherein the organic solvent is selected from any one or more of methanol, ethanol, ethyl acetate, acetone, acetonitrile, dioxane, n-hexane, cyclohexane or a mixed solvent prepared by different proportioning combinations.

6. The preparation method according to claim 5, wherein the solvent assisted grinding method is selected from manual grinding method or mechanical ball milling method, the volume of organic solvent added is 50 uL to 500 uL per gram of solid sample; and the drying method is selected from natural drying or vacuum drying to prepare daidzein and piperazine co-crystal.

7. The mechanical ball milling method according to claim 6, wherein the ball-to-material ratio of the ball milling method is 1:1 to 10:1, and the ball milling rotation speed is 20 r / min to 400 r / min.

8. The mechanical ball milling method according to claim 6, wherein the ball-to-material ratio of the ball milling method is 6:1 to 10:1, and the ball milling rotation speed is 200 r / min to 400 r / min.

9. A mixed solid material comprising a daidzein and piperazine co-crystal, characterized in that, The amount of daidzein and piperazine co-crystal according to any one of claims 1-4 is 1-99.9%.

10. The mixed solid material of daidzein and piperazine co-crystal according to claim 9, characterized in that, The amount of daidzein and piperazine co-crystal according to any one of claims 1-4 is 10-99.9%.

11. The mixed solid material of daidzein and piperazine co-crystal of claim 9, characterized in that, The amount of daidzein and piperazine co-crystal according to any one of claims 1-4 is 50-99.9%.

12. The mixed solid material of daidzein and piperazine co-crystal of claim 9, characterized in that, The amount of daidzein and piperazine co-crystal according to any one of claims 1-4 is 85-99.9%.

13. A pharmaceutical composition, characterized by, An effective dose of daidzein and piperazine co-crystal according to any one of claims 1-4 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition, characterized by, An effective dose of daidzein and piperazine co-crystal according to any one of claims 9-12 and a pharmaceutically acceptable carrier.

15. Pharmaceutical composition according to claim 13 or 14, characterized in that, The daily dose of daidzein and piperazine co-crystal is in the range of 5 mg to 3000 mg.

16. Pharmaceutical composition according to claim 13 or 14, characterized in that The dosage form of the pharmaceutical composition is tablet, capsule, pill, powder injection, sustained-release preparation or controlled-release preparation.

17. Use of daidzein and piperazine co-crystal according to any one of claims 1-4 or daidzein and piperazine co-crystal-containing mixed solid substance according to any one of claims 9-12 or the pharmaceutical composition according to claim 13 or 14 in the preparation of antitumor, antioxidant, anti-inflammatory, antiarrhythmic, hypolipidemic, antihypertensive, osteoporosis, coronary heart disease, menopausal syndrome and prostatic hyperplasia therapeutic drugs.

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