CN121226301A - Robinia pseudoacacia and piperazine eutectic compound, preparation method, composition and application thereof - Google Patents

Abstract

The invention discloses a locust element and piperazine eutectic compound, a preparation method, a composition and application thereof, and belongs to the technical field of medicines. The invention particularly discloses a eutectic substance formed by locust element and piperazine, the molecular formula of the eutectic substance is (C ₁₆H₁₂O₅)·(C₄H₁₀N₂), a preparation method of the eutectic substance of the locust element and the piperazine, and application of the eutectic substance of the locust element and the piperazine as an active ingredient in preparing medicaments for resisting oxidation, inflammation, viruses, tumors, rheumatism, pain, liver protection, immunoregulation, osteoporosis and cardiovascular and cerebrovascular diseases.

Description

Robinia pseudoacacia and piperazine eutectic compound, preparation method, composition and application thereof

Technical Field

The invention relates to a locust element and piperazine eutectic compound, a preparation method, a composition and application thereof. The invention particularly discloses a eutectic substance formed by locust element and piperazine, a preparation method of the eutectic substance of the locust element and the piperazine, and application of the eutectic substance of the locust element and the piperazine as an effective component in preparing medicaments for resisting oxidation, inflammation, viruses, tumors, rheumatism, pains, liver protection, immunoregulation, osteoporosis and cardiovascular and cerebrovascular diseases. Belongs to the technical field of medicines.

Background

Robinia pseudoacacia (English name: acacetin) is a natural flavone active ingredient widely existing in nature, and has rich biological base sources and wide pharmacological actions. In recent years, the research of the pharmacological action of Guan Cihuai elements is endless, new pharmacological actions are continuously discovered, and pharmacological mechanisms are also intensively studied. Research shows that the locust element has obvious functions of resisting oxidation, inflammation, virus, tumor, osteoporosis and rheumatism. In addition, the locust element also has the functions of neuroprotection, liver protection and heart protection, can effectively relieve cardiovascular and cerebrovascular diseases, and has good effects on analgesia and immunoregulation. The locust has high medicinal value and strong medicinal effect, and has great market development potential. But its water solubility is very low and bioavailability is poor, which has a great impact on its market development and clinical application. The locust element is used as a classical flavonoid substance, a plane structure formed by a large conjugated area exists in the molecule, and a carbonyl group at a 4-position and a hydroxyl group at a 5-position easily form intramolecular hydrogen bonds, and the 4' -position is replaced by methoxy groups, so that the water solubility of the flavonoid substance is further weakened. In addition, research shows that the acacetin has higher plasma protein binding rate, poorer stability in the gastrointestinal tract, obvious first pass elimination effect in the liver and extremely low water solubility, so that the bioavailability of the acacetin is poor. Aiming at the problem of low solubility and bioavailability of the locust element, the invention uses the locust element as a medicine active component (Active Pharmaceutical Ingredients, API) and piperazine as a eutectic ligand (cocrystal former, CCF) based on the crystal engineering principle to obtain the eutectic of the locust element and the piperazine for the first time. The molecular formula of piperazine is C ₄H₁₀N₂, and the structural formula is shown as b.

A great deal of literature is consulted, and no report of the locust element eutectic crystal is found. The eutectic technology is used as an important means for improving the drug property of insoluble drugs, and has obvious advantages and great potential. The eutectic technology is adopted to improve the low solubility of the locust element and simultaneously provide a new means and a new way for optimizing the pharmacological action of the locust element.

Based on the structural characteristics of the locust element, piperazine is selected as a eutectic ligand, and the eutectic of the locust element and the piperazine is obtained for the first time. Research results show that after the locust element forms eutectic crystals, the dissolution rate and the dissolution degree of the locust element are obviously improved, unexpected effects are obtained, and the problem of patent drug bottleneck with poor water solubility and low bioavailability of the locust element is hopefully solved.

Disclosure of Invention

The research of the invention is that the novel eutectic solid substance which is different from the simple combined application of the locust element and the piperazine is formed by preparing the eutectic solid substance with specific non-covalent acting force from the locust element and the piperazine, and the application of the novel eutectic solid substance in preparing medicaments for resisting oxidation, inflammation, viruses, tumors, rheumatism, pains, liver protection, immunoregulation, osteoporosis and cardiovascular and cerebrovascular diseases is found.

The invention aims to solve the technical problems:

the invention provides the existence state and the characterization mode of the eutectic substance of the locust element and the piperazine.

The second technical problem to be solved by the invention is to provide a preparation method of a locust element and piperazine eutectic substance.

The third technical problem to be solved by the invention is to provide a pure product containing the eutectic substance of the locust element and the piperazine or a mixed solid substance containing the eutectic substance of the locust element and the piperazine with any non-zero proportion and a pharmaceutical composition thereof.

The invention provides a pharmaceutical composition using a locust element and piperazine eutectic as pharmaceutical active ingredients, wherein the dosage of each administration is 5-3000 mg. The medicine composition comprises tablets, capsules, pills, injection, slow release or controlled release preparation medicines.

The invention provides a locust element and piperazine eutectic substance, which has better solubility and bioavailability advantages compared with locust element bulk drugs.

The invention aims to solve the technical problem that the application of the locust element and piperazine eutectic as the active ingredients of the medicine in preparing medicines for resisting oxidation, inflammation, virus, tumor, rheumatism, pain, liver protection, immunoregulation, osteoporosis and cardiovascular and cerebrovascular diseases.

In order to solve the technical problems, the invention adopts the following technical scheme:

1. Morphological characteristics of the locust element and piperazine eutectic sample:

1.1 the co-crystal substance of the locust element and the piperazine is formed by combining the locust element and the piperazine through non-covalent bonds, and the molar ratio of the two is 1:1.

1.2 The Robinia's and piperazine Co-crystals of the present invention, which do not contain crystallization solvent or crystallization water component, exhibit diffraction peak position of 2-Theta value (°) or d value when analyzed by powder X-ray diffraction under the experimental conditions of CuK _α irradiationThe diffraction peak has a solid matter (table 1, fig. 1) having the following characteristic peak with respect to the peak Height value (Height%) or the peak Area value (Area%). Powder X-ray diffraction pattern data for physical mixtures of locust element and piperazine are shown in table 2, fig. 2. The powder X-ray diffraction patterns of the eutectic of the locust element and the piperazine and the physical mixture of the locust element and the piperazine have obvious differences in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological graph and the like, which indicates that the eutectic of the locust element and the piperazine and the physical mixture of the locust element and the piperazine are neither identical nor equivalent.

TABLE 1 powder X-ray diffraction peak data for the co-crystals of Robinia pseudoacacia and piperazine

TABLE 2 powder X-ray diffraction peak data for physical mixtures of Robinia pseudoacacia and piperazine

1.3 The co-crystals of locust element and piperazine according to the present invention, when analyzed by attenuated total reflection fourier infrared spectroscopy, had an infrared spectrum characteristic peak at 3291、3077、2998、2951、2914、2839、2745、2464、1916、1643、1608、1573、1509、1474、1433、1422、1355、1327、1308、1296、1262、1240、1157、1116、1093、1031、1008、1002、979、953、904、857、820、794、775、747、690、680、660、641、631、609、580、560、517、499、477、443、414cm^-1, wherein the allowable deviation of the infrared spectrum characteristic peak was ±2cm ^-1 (fig. 3).

1.4 The inventive co-crystal of locust element and piperazine, when analyzed by differential scanning calorimetry, has 1 endothermic peak at 189 ℃ +/-3 ℃ in DSC spectrum when the temperature rising rate is 10 ℃ per minute (figure 4). The DSC spectra of the locust element and the piperazine eutectic substance and the locust element and the piperazine have obvious difference in the absorption/release peak positions, which shows that the locust element and the piperazine eutectic substance and the locust element are novel substances which are neither identical nor equivalent to the raw materials of the locust element and the piperazine (figure 5).

2. The preparation method of the locust element and piperazine eutectic is characterized in that:

2.1 the preparation method of the eutectic of the locust element and the piperazine comprises the steps of feeding the locust element and the piperazine according to a molar ratio of 1:1, and preparing the eutectic of the locust element and the pyrazole tam by adopting a mechanochemical method of controlling pressure and temperature. The mechanochemical method can be selected from a liquid adding grinding method or a liquid adding ball milling method, wherein the types of organic solvents added are mixed solvents prepared by combining any one or more of methanol, ethanol, ethyl acetate, acetone, acetonitrile, dioxane, n-hexane and cyclohexane according to different proportions, the dripping amount of the organic solvents is 50 uL-500 uL of solvent volume in each gram of solid sample, the grinding time is 0.1-10 hours, the drying mode is selected from natural drying or vacuum drying, the comprehensive pot filling rate of the liquid adding grinding method is 10% -50%, the reciprocating motion speed is 20-70 m/min, the shearing impact energy of the ball mill of the liquid adding ball milling method is 10 kw-800 kw, the comprehensive filling rate is 20-60%, the ball material ratio is 1:1-10:1, preferably 6:1-10:1, and the ball milling rotating speed is 20 r/min-400 r/min, preferably 300 r/min.

2.2 The mixed solid substance containing the locust element and piperazine eutectic substance is prepared by mixing the locust element and piperazine eutectic substance prepared by the method with other chemical substances according to any non-zero proportion and a conventional method.

3. Contains the components of the co-crystal of the locust element and the piperazine, the characteristic of the administration dosage and the characteristic of the pharmaceutical preparation composition:

3.1 pharmaceutical compositions of the invention comprise an effective dose of a co-crystal of locust element and piperazine and a pharmaceutically acceptable carrier.

3.2 The pharmaceutical composition of the invention has the administration dosage of the co-crystal of the locust element and the piperazine within the range of 5mg to 3000mg per day.

3.3 The pharmaceutical composition of the invention is in the form of tablet, capsule, pill, injection, sustained release preparation or controlled release preparation.

3.4 The application of the locust element and piperazine eutectic substance in preparing the medicines for resisting oxidation, inflammation, virus, tumor, rheumatism, pain, liver protection, immunoregulation, osteoporosis and cardiovascular and cerebrovascular diseases.

The invention relates to a pharmaceutical composition taking the locust element and piperazine eutectic compound 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 inventive co-crystals of locust element and piperazine with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compositions of the co-crystals of locust element and piperazine of the present invention are generally in the range of 10 to 90% by weight.

The co-crystals of the locust element and the piperazine of the present invention can be administered in unit dosage form by intestinal or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

The administration form of the present invention is preferably a solid dosage 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 substance of the locust element and piperazine eutectic substance and the mixed solid substance of the locust element and piperazine eutectic substance can be prepared into common preparations, and also can be prepared into sustained release preparations, controlled release preparations, targeted preparations and various microparticle drug delivery systems.

For tableting the co-crystals of locust element and piperazine of the present invention, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrophosphate, calcium carbonate and the like, the wetting agent can be water, ethanol, isopropanol and the like, the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol and the like, the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate, citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate and the like, and the lubricant and the glidant can be talcum powder, 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, the active ingredient of the pharmaceutical composition of the present invention, i.e., the co-crystal of the locust element and the piperazine, may be mixed with a diluent and a glidant, and the mixture may be directly placed into a hard capsule or a soft capsule. The active ingredients of the invention, i.e. the eutectic mixture of the locust element and the piperazine, can be made into granules or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants and glidants used for preparing the tablet of the present invention's locust element and piperazine eutectic compound can also be used for preparing the capsule of the present invention's locust element and piperazine eutectic compound.

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 amount of the co-crystal of locust element and piperazine 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 co-crystal of the locust element and the piperazine can be taken alone or combined with other therapeutic drugs or symptomatic drugs. When the co-crystal of the locust element and the piperazine and other therapeutic drugs have a synergistic effect, the dosage of the co-crystal of the locust element and the piperazine should be adjusted according to the actual situation.

4. The technical scheme of the invention has the following beneficial technical effects:

4.1 the Robinia pseudoacacia and piperazine eutectic substance does not contain any crystallization solvent, and has good safety patent medicine advantages.

4.2 The locust element and piperazine eutectic compound of the invention is stable under high temperature, high humidity and illumination conditions, and has good stability and advantages of patent medicine.

4.3 Compared with the raw material medicine of the locust element and piperazine, the eutectic substance of the locust element and piperazine has obvious advantages in terms of solubility, and particularly shows obvious advantages of solubility and dissolution rate in dissolution systems such as hydrochloride buffer (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8), pure water (pH 7.0) and the like. The solubility of the compound in 4 mediums is respectively improved by 5.3 times, 4.3 times, 13.3 times and 327.8 times compared with that of the locust element bulk drug.

Drawings

FIG. 1 powder X-ray diffraction pattern of a co-crystal of locust element and piperazine

FIG. 2 powder X-ray diffraction pattern of physical mixture of locust element and piperazine

FIG. 3 is an infrared absorption spectrum of a co-crystal of locust element and piperazine

FIG. 4 differential scanning calorimetric diagram of the co-crystal of locust element and piperazine

FIG. 5 differential scanning calorimetric superposition Spectrum of Robinia pseudoacacia and piperazine Co-crystals, robinia pseudoacacia and piperazine

FIG. 6 stability profile of Robinia pseudoacacia and piperazine eutectic at high temperature, high humidity and high light

FIG. 7 solubility curves of piperazine co-crystals and locust element at different pH conditions

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 locust element and piperazine eutectic

And respectively weighing a proper amount of locust element and piperazine according to a molar ratio of 1:1, putting the materials into a clean mortar, uniformly grinding to obtain a physical mixture of the locust element and the piperazine, dropwise adding a certain volume of organic solvent into the mixture every 5min, grinding the obtained mixture in a clockwise direction for a certain time, and drying the obtained product. Powder X-ray diffraction analysis is carried out on the sample, the diffraction pattern of the sample is consistent with that of fig. 1, and the obtained sample is a locust element and piperazine eutectic.

TABLE 3 preparation method 1 specific examples

Preparation method 2 of locust element and piperazine eutectic

And (3) weighing a proper amount of locust element and piperazine according to a molar ratio of 1:1, respectively, putting into a clean ball milling tank, dropwise adding a certain volume of organic solvent into the ball milling tank at intervals of 15min by adopting a specific ball-to-material ratio, and grinding the mixture according to a certain rotating speed. After grinding for a certain period of time, the resulting product is dried. Powder X-ray diffraction analysis is carried out on the sample, the diffraction pattern of the sample is consistent with that of fig. 1, and the obtained sample is a locust element and piperazine eutectic.

Table 4 preparation method 2 specific examples

Example 2

In vitro dissolution and release characteristics of locust element and piperazine eutectic compound

The solubility characteristics of the co-crystals of locust element and piperazine and the raw material of locust element in a solution system of hydrochloride buffer (ph 1.2), acetate buffer (ph 4.5), phosphate buffer (ph 6.8) and pure water (ph 7.0) were examined. The experiment is carried out by referring to the common oral solid preparation dissolution test technical guidelines. And calculating the sample dissolution concentration by adopting a high-performance liquid phase method and an external standard method. Dissolution curves were plotted on the abscissa for time (min) and on the ordinate for sample concentration (μg/mL) (FIG. 7). The data are shown in Table 5.

The detection conditions include a detection system of alignment 1260, a chromatographic column of Odyssil C < 18 > (4.6X105 mm,5 μm), a mobile phase of methanol-0.1% acetic acid water (85:15, v/v), a flow rate of 1mL min ^-1, a column temperature of 30 ℃, a detection wavelength of locust element of 268nm, and a sample injection amount of 10. Mu.l.

TABLE 5 dissolution profile data

The experimental data show that the dissolution behavior of the eutectic of the locust element and the piperazine in a hydrochloride buffer solution, an acetate buffer solution, a phosphate buffer solution and a pure water system is obviously superior to that of the raw material of the locust element, and the dissolution rate of the eutectic of the locust element and the piperazine in 4 media is respectively improved by 30.6 times, 15.4 times, 44.7 times and 2600.2 times after the eutectic of the locust element and the piperazine is formed in the aspect of improving the dissolution rate, and the solubility of the eutectic of the locust element and the piperazine in 4 media is respectively improved by 5.3 times, 4.3 times, 13.3 times and 327.8 times. The formation of the eutectic enables the locust element to have a faster dissolution rate and a higher dissolution amount, which is of great importance for the subsequent improvement of the speed and extent of the biological absorption of the locust element.

Example 3

Preparation method of combination pharmaceutical formulation 1 (tablet):

A preparation method of a combined medicine tablet is characterized in that a pure product of a locust and piperazine eutectic substance 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 tablet, a tablet sample with 5-500 mg of medicine content per tablet is prepared according to a certain proportion, and the formula proportion of the tablet is given in table 6:

table 6 formulation of pharmaceutical tablets of the Robinia pseudoacacia and piperazine co-crystals

The method for preparing the pure crude drugs of the locust element and piperazine eutectic into the tablet preparation comprises the steps of uniformly mixing a plurality of excipients with the crude drugs, directly tabletting, or uniformly mixing the excipients with the crude drugs after dry granulating, tabletting.

Preparation method of combination pharmaceutical formulation 2 (tablet):

A preparation method of a combined medicine tablet is characterized in that a pure product of a locust and piperazine eutectic substance 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 tablet, a tablet sample with 5-500 mg of medicine content per tablet is prepared according to a certain proportion, and the formula proportion of the tablet is given in table 7:

Table 7 formulation for preparing pharmaceutical tablet of locust element and piperazine co-crystal compound

The preparation method of the tablet preparation from pure crude drugs of the locust and piperazine eutectic substance comprises the steps of uniformly mixing a plurality of excipients and crude drugs, adding a proper amount of 1% hydroxymethyl cellulose sodium solution, preparing soft materials, sieving, granulating, drying wet granules, sieving, granulating, adding magnesium stearate and talcum powder, uniformly mixing, and tabletting.

Preparation method 3 of the combined pharmaceutical preparation (capsule):

a preparation method of a combination drug capsule is characterized in that a pure product of a locust element and piperazine eutectic is used as a raw material medicine of the combination drug, a plurality of excipients are used as auxiliary material components for preparing the combination drug capsule, a capsule sample with 5-500 mg of drug content per tablet is prepared according to a certain proportion, and the formula proportion of the capsule is shown in a table 8:

Table 8 pharmaceutical raw material and auxiliary material formulation of pharmaceutical capsule preparation of locust element and piperazine eutectic compound

The preparation method of the tablet preparation from the pharmaceutical raw materials of the eutectic mixture of the locust and the piperazine comprises the steps of uniformly mixing a plurality of excipients and the pharmaceutical raw materials, adding a proper amount of 1% hydroxymethyl cellulose sodium solution, preparing wet granules, drying, sieving, granulating, adding magnesium stearate, uniformly mixing, and inserting into capsules, or directly mixing the pharmaceutical raw materials of the eutectic mixture of the soybean aglycone and the piperazine with a plurality of excipient excipients uniformly without a granulating step, sieving, and directly encapsulating.

Example 4

Dosage 1 (tablet) of the combination drug of the locust element and piperazine co-crystal:

the pharmaceutical composition is characterized in that the pharmaceutical composition is prepared by taking a locust element and piperazine eutectic substance sample as pharmaceutical active ingredients, wherein the administration dosage of the pharmaceutical composition is 300mg per day, and the pharmaceutical composition can be prepared into 100 common tablets of 3 times per day or 1 tablet of 100mg per time or 300mg tablets of 1 time per day.

Administration dose 2 (capsule) of the combination drug of the locust element and piperazine co-crystal:

the pharmaceutical composition is prepared and developed by using a locust element and piperazine eutectic substance sample as a pharmaceutical active ingredient, and is characterized in that the locust element and piperazine eutectic substance is used as the pharmaceutical active ingredient, and the daily administration dosage is 500mg, and the pharmaceutical composition can be prepared into capsules of 250mg for 2 times a day/1 granule a day or capsules of 500mg for 1 time a day/1 granule a day respectively. The administration dosage of the pharmaceutical composition of the co-crystal of locust element and piperazine according to the present invention is affected by many factors, such as the difference of daily administration dosage due to the different use for prevention and treatment, the difference of daily administration dosage due to the different disease property and disease severity, the difference of daily administration dosage due to the different sex, age and body surface area of patients, the difference of administration route, administration times and treatment purpose, and the difference of absorption and blood concentration between crystal forms, and the daily suitable dosage range of the pharmaceutical composition of the co-crystal of locust element and piperazine according to the present invention is 0.002-20mg/kg body weight, preferably 0.01-10mg/kg body weight. When in use, different total dosage schemes of the active ingredients of the co-crystal of the locust element and the piperazine should be formulated according to the actual requirements of prevention and treatment under different conditions, and the administration can be completed in a mode of multiple times or one time.

Claims (12)

1. A robinin-piperazine cocrystal, characterized in that robinin and piperazine form a cocrystal by non-covalent bonds in a 1:1 molar ratio. 2. The robinin-piperazine cocrystal according to claim 1, characterized in that, when powder X-ray diffraction analysis is performed under CuK _α radiation experimental conditions, the diffraction peak position is: 2-Theta value. or d value The relative intensity of the diffraction peaks: peak height (Height%) or peak area (Area%) has the following characteristics: 3. The robinin-piperazine cocrystal according to claim 1, characterized in that, when analyzed using attenuated total reflectance Fourier transform infrared spectroscopy, the following parameters are observed: 3291, 3077, 2998, 2951, 2914, 2839, 2745, 2464, 1916, 1643, 1608, 1573, 1509, 1474, 1433, 1422, 1355, 13 Infrared spectral characteristic peaks exist at 27, 1308, 1296, 1262, 1240, 1157, 1116, 1093, 1031, 1008, 1002, 979, 953, 904, 857, 820, 794, 775, 747, 690, 680, ⁶⁶⁰ , 641, 631, 609, 580, 560, 517, 499, 477, 443, and 414 cm⁻¹, with an allowable deviation of ±2 ^cm⁻¹ for the infrared spectral characteristic peaks. 4. The robinin-piperazine cocrystal according to claim 1, characterized in that, when analyzed by differential scanning calorimetry, it exhibits an endothermic peak at 189℃±3℃ in its DSC spectrum within the range of 30～280℃ at a heating rate of 10℃ per minute. 5. The method for preparing the robinin and piperazine cocrystal as described in any one of claims 1-4, characterized in that robinin and piperazine are fed in a 1:1 molar ratio, and the robinin and piperazine cocrystal is prepared by a mechanochemical method that controls pressure and temperature. 6. The preparation method according to claim 5, characterized in that the mechanochemical method can be selected from liquid-addition milling or liquid-addition ball milling, wherein the organic solvent added is any one or more mixed solvents prepared by different proportions; the organic solvent is selected from any one or more mixed solvents prepared by different proportions from methanol, ethanol, ethyl acetate, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane; the amount of organic solvent added is 50 μL to 500 μL of solvent volume per gram of solid sample; during milling... The drying time is 0.1 to 10 hours, and the drying method is selected from natural drying or vacuum drying. The overall filling rate of the bowl in the liquid-addition grinding method is 10% to 50%, and the reciprocating speed is 20 to 70 m/min. The shear impact energy of the ball mill in the liquid-addition ball milling method is 10 kW to 800 kW, and the overall filling rate is 20% to 60%. The ball-to-material ratio 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 300 r/min to 400 r/min. 7. A mixed solid substance containing robinin and piperazine cocrystal, characterized in that the amount of robinin and piperazine cocrystal as described in any one of claims 1-4 is 1-99.9%, preferably 10-99.9%, more preferably 50-99.9%, and most preferably 85-99.9%. 8. A pharmaceutical composition, characterized in that it comprises an effective dose of the robinin-piperazine cocrystal of any one of claims 1-4 and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition characterized by comprising an effective dose of a mixed solid substance of robinin and piperazine cocrystal as described in claim 7 and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition according to claim 8 or 9, characterized in that the daily dose of the robinin-piperazine cocrystal is in the range of 5 mg to 3000 mg. 11. The pharmaceutical composition according to claim 8 or 9, characterized in that the dosage form of the pharmaceutical composition is a tablet, capsule, pill, powder for injection, sustained-release formulation or controlled-release formulation. 12. The use of the robinin and piperazine cocrystal of any one of claims 1-4, or the mixed solid substance containing the robinin and piperazine cocrystal of claim 7, or the pharmaceutical composition of claim 8 or 9, in the preparation of medicaments for the treatment of antioxidant, anti-inflammatory, antiviral, antitumor, antirheumatic, analgesic, hepatoprotective, immunomodulatory, osteoporosis, and cardiovascular and cerebrovascular diseases.