CN113214209B - Hesperetin and carbamazepine co-crystal and its preparation method and its composition and use - Google Patents

Abstract

The invention discloses a hesperetin and carbamazepine eutectic, a preparation method, a composition and application thereof, and belongs to the technical field of medicines. Specifically, the invention discloses a eutectic substance formed by hesperetin and carbamazepine, which has a molecular formula of (C ₁₆ H ₁₄ O ₆ )·(C ₁₅ H ₁₂ N ₂ O); a preparation method of hesperetin and carbamazepine eutectic; the hesperetin and carbamazepine eutectic is used as the effective components of the medicine, and is applied to preparing the medicines for resisting tumor, oxidation, inflammation, epilepsy, trigeminal neuralgia, manic depression and preventing atherosclerosis, arrhythmia diseases and complications.

Description

Hesperetin and carbamazepine co-crystal and its preparation method and its composition and use

Technical field

The invention relates to a eutectic product formed by hesperetin and carbamazepine; a preparation method of the eutectic product of hesperetin and carbamazepine; and the eutectic product of hesperetin and carbamazepine is used as an active ingredient of medicine in the preparation of anti-inflammatory drugs. The application of drugs in tumors, antioxidants, anti-inflammation, epilepsy, trigeminal neuralgia, mania and depression, prevention of atherosclerosis, arrhythmia diseases and complications; belongs to the field of medical technology.

Background technique

Hesperetin (English name: Hesperetin) is a dihydroflavonoid compound widely found in citrus fruits. It is the hydrolyzate of hesperidin. Its structural formula is shown in a. It can play an anti-tumor, antioxidant, and anti-inflammatory role. , prevent atherosclerosis ^[1-3] .

Carbamazepine (English name: Carbamazepine) is a common and highly fat-soluble calcium channel blocker. It is the drug of choice for clinical treatment of epilepsy. It is often used to treat trigeminal neuralgia, manic depression, arrhythmia and other conditions. Structural formula As shown in b. Some progress has been made in the research on co-crystals of carbamazepine, such as co-crystals of carbamazepine and nicotinamide ^[4] , co-crystals of carbamazepine and saccharin ^[5] , and co-crystals of carbamazepine and aspirin ^{[6] ]} , co-crystal of carbamazepine and 2-hydroxybenzoic acid ^[7] , etc.

Research on the polymorphic forms of hesperetin: The currently discovered hesperetin has two crystal forms ^[8-9] . Among them, the studied crystal type A is hesperetin containing a molecule of water, and the crystal type B does not contain crystals. type. There are essential differences in material composition between these two crystal forms and the present invention. The hesperetin raw material used in this patent is crystal form B.

To sum up, so far there are no research reports on the formation of a eutectic between hesperetin and carbamazepine, and there are no similar or conflicting research contents with the present invention in terms of material form, combination ratio, preparation method and use.

Contents of the invention

The research of the present invention is to prepare hesperetin and carbamazepine into a eutectic solid substance with specific non-covalent interaction force, thereby forming a product that is different from hesperetin and carbamazepine and their simple combined application. New substances, and further discover the usefulness of the new eutectic solid material of the present invention in the preparation of drugs for anti-tumor, antioxidant, anti-inflammation, epilepsy, trigeminal neuralgia, manic depression, prevention of atherosclerosis, arrhythmia diseases and complications. Special advantages.

Technical problems to be solved by this invention:

One of the technical problems to be solved by the present invention is to provide the existence state and characterization method of the co-crystal of hesperetin and carbamazepine.

The second technical problem to be solved by the present invention is to provide a method for preparing a cocrystal of hesperetin and carbamazepine.

The third technical problem to be solved by the present invention is to provide a pharmaceutical composition using a co-crystal of hesperetin and carbamazepine as active pharmaceutical ingredients, with a dosage in the range of 10-1000 mg per time. The pharmaceutical compositions include tablets, capsules, pills, injections, and sustained-release or controlled-release preparations.

The fourth technical problem to be solved by the present invention is to provide a co-crystal of hesperetin and carbamazepine. In the process of treating diseases, the combination of the two co-crystals increases the blood drug concentration in the organism and exerts an effective therapeutic effect.

The fifth technical problem to be solved by the present invention is to provide raw materials for using hesperetin and carbamazepine co-crystals and their mixed crystalline solid materials as active ingredients of medicines. , trigeminal neuralgia, manic depression, application in preventing atherosclerosis, arrhythmia diseases and complications.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

1. Morphological characteristics of hesperetin and carbamazepine eutectic sample:

1.1 The present invention relates to the eutectic substance of hesperetin and carbamazepine. Hesperetin and carbamazepine are combined by non-covalent bonds to form a eutectic substance. The molar ratio of the two is 1:1.

1.2 The cocrystal of hesperetin and carbamazepine involved in the present invention does not contain crystallization solvent or crystal water components. When powder X-ray diffraction analysis is used and CuK _α radiation experimental conditions are used, the diffraction peak position is: 2-Theta value (°) or d value The relative intensity peak height value (Height%) or peak area value (Area%) of the diffraction peak has the following characteristic peaks for a solid material (Table 1, Figure 1). The powder X-ray diffraction pattern data of the physical mixture of hesperetin and carbamazepine are shown in Figure 2 and Table 2. There are obvious differences in the powder X-ray diffraction patterns of the cocrystal of hesperetin and carbamazepine and the physical mixture of hesperetin and carbamazepine in terms of the number of diffraction peaks, the position of the diffraction peaks, the intensity of the diffraction peaks, and the topology of the diffraction peaks. It is shown that the hesperetin and carbamazepine cocrystals and the hesperetin and carbamazepine physical mixtures are neither the same nor the same.

Table 1 Powder X-ray diffraction peak data of hesperetin and carbamazepine cocrystal

Table 2 Powder X-ray diffraction peak data of physical mixture of hesperetin and carbamazepine

1.3 When the hesperetin and carbamazepine eutectic involved in the present invention is analyzed using attenuated total reflection Fourier transform infrared spectroscopy, the values at 3430, 3348, 3206, 3057, 3025, 2969, 2941, 2845, 2605, 2252, 2155 ,2053,1969,1677,1644,1604,1583,1514,1491,1447,1418,1401,1386,1343,1289,1273,1237,1220,1193,1160,1132,1114,1080,1067,1042,10 28 , 1016, 985, 971, 957, 878, 867, 860, 841, 827, 801, 789, 772, 764, 741, 716, 663cm ^-1 There are infrared spectrum characteristic peaks, among which the allowable deviation of the infrared spectrum characteristic peak is ±2cm ^-1 (Fig. 3).

1.4 When the hesperetin and carbamazepine eutectic involved in the present invention is analyzed using differential scanning calorimetry technology, when the temperature rise rate is 10°C per minute in the range of 30 to 250°C, its DSC spectrum is at 176°C. There is an endothermic peak at ±3°C (Figure 4). There are obvious differences in the number and position of the endothermic/exothermic peaks between the DSC spectra of hesperetin and carbamazepine cocrystals and hesperetin and carbamazepine, indicating that the hesperetin and carbamazepine cocrystals are different from hesperetin and carbamazepine. The raw materials of cortisol and carbamazepine are neither the same nor the same (Figure 5).

2. Preparation method characteristics of hesperetin and carbamazepine co-crystal:

2.1 The preparation method of the hesperetin and carbamazepine co-crystal involved in the present invention adopts the solvent suspension method to mix hesperetin and carbamazepine in a molar ratio of 1:1, add an organic solvent, and at room temperature, The stirring speed is 20r/min ~ 400r/min, and the mixture is stirred for 1 hour to 96 hours. The obtained suspension is dried by solvent evaporation, natural drying by filtration or vacuum drying by filtration to obtain a co-crystal of hesperetin and carbamazepine. The organic solvent is preferably any one or more mixed solvents made from methanol, ethanol, acetonitrile, acetone, ethyl acetate, dioxane, n-hexane, and cyclohexane in different proportions; keep The total mass of hesperetin and carbamazepine and the solid-liquid ratio of the organic solvent are in the range of 1mg/ml-500mg/ml.

2.2 The mixed solid material containing hesperetin and carbamazepine eutectic of the present invention is the hesperetin and carbamazepine eutectic prepared by the above method, and other chemical substances according to any non-zero ratio and conventional Methods are mixed.

3. Ingredients, dosage characteristics and pharmaceutical preparation composition characteristics of hesperetin and carbamazepine co-crystals:

3.1 The pharmaceutical composition involved in the present invention contains an effective dose of hesperetin and carbamazepine co-crystal and a pharmaceutically acceptable carrier.

3.2 For the pharmaceutical composition involved in the present invention, the daily dosage of the cocrystal of hesperetin and carbamazepine is in the range of 10 mg to 1000 mg.

3.3 The pharmaceutical composition related to the present invention, the dosage form of the pharmaceutical composition is tablet, capsule, pill, injection, sustained-release preparation or controlled-release preparation.

3.4 The cocrystal of hesperetin and carbamazepine involved in the present invention can be used in the preparation of anti-tumor, antioxidant, anti-inflammatory, epilepsy, trigeminal neuralgia, manic depression, prevention of atherosclerosis, arrhythmia diseases and complications drugs. Applications.

The present invention relates to a pharmaceutical composition using the cocrystal of hesperetin and carbamazepine of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining the cocrystal of hesperetin and carbamazepine of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or auxiliaries. . The composition of the cocrystal of hesperetin and carbamazepine of the present invention is usually in the range of 10-90% by weight.

The cocrystal of hesperetin and carbamazepine of the present invention can be administered in unit dose form, and the route of administration can be intestinal or non-intestinal, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, Lungs and respiratory tract, skin, vagina, rectum, etc.

The dosage form of the present invention is preferably a solid dosage form. Solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), and granules. Preparations, powders, pellets, dropping pills, suppositories, films, patches, aerosols (powder), sprays, etc.

The hesperetin and carbamazepine eutectic of the present invention and the mixed solid material of the hesperetin and carbamazepine eutectic of the present invention can be made into ordinary preparations, sustained-release preparations, controlled-release preparations, and targeted preparations. and various particulate drug delivery systems.

In order to make the hesperetin and carbamazepine eutectic of the present invention into tablets, 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 hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropyl Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia glue, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyethylene glycol, etc. Vinyl pyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and flow aids The agent can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

Tablets can also be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bi-layer and multi-layer tablets.

In order to make the dosage unit into a capsule, the active ingredient hesperetin-carbamazepine cocrystal of the present invention can be mixed with a diluent and a glidant, and the mixture can be placed directly into a hard capsule or soft capsule. The active ingredient hesperetin and carbamazepine eutectic of the present invention can also be made into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or soft capsule. The various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the hesperetin and carbamazepine eutectic tablets of the present invention can also be used to prepare the hesperetin and carbamazepine eutectic tablets of the present invention. Capsules of marzepine cocrystal.

In addition, if necessary, colorants, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations.

4. Uses of co-crystals containing hesperetin and carbamazepine:

The present invention finds that hesperetin and carbamazepine co-crystals are useful in preparing and/or treating anti-tumor, antioxidant, anti-inflammation, epilepsy, trigeminal neuralgia, manic depression, prevention of atherosclerosis, arrhythmia diseases and complications. Application in disease medicine.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the cocrystal of hesperetin and carbamazepine of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and dosage form, etc. The above dosage may be administered as a single dosage unit or divided into several dosage units, depending on the physician's clinical experience and the dosage regimen including the use of other therapeutic modalities.

The cocrystal of hesperetin and carbamazepine of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the cocrystal of hesperetin and carbamazepine of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

The technical solution of the present invention has the following beneficial technical effects:

The co-crystal of hesperetin and carbamazepine of the present invention has significant advantages over hesperetin in the prior art in terms of safety, solubility, stability and biological activity.

The co-crystal of hesperetin and carbamazepine of the present invention does not contain any crystallization solvent and has good safety and pharmaceutical advantages.

Compared with hesperetin, the co-crystal of hesperetin and carbamazepine involved in the present invention has unexpected solubility advantages, which are specifically reflected in: in hydrochloride buffer (pH 1.2), acetate Buffer (pH4.5), phosphate buffer (pH6.8), pure water (pH7.0) and other dissolution systems show significant solubility and dissolution rate advantages (Figure 6).

The hesperetin and carbamazepine eutectic involved in the present invention can be stable under high temperature (60°C), high humidity (25°C), relative humidity (90%±5%), and light (4500lx±500lx) conditions. It has the advantage of good stability as a pharmaceutical (Figure 7).

Description of the drawings

Figure 1 Powder X-ray diffraction pattern of hesperetin and carbamazepine cocrystal

Figure 2 Powder X-ray diffraction pattern of the physical mixture of hesperetin and carbamazepine

Figure 3 Infrared absorption spectrum of hesperetin and carbamazepine co-crystal

Figure 4 Differential scanning calorimetry spectrum of the cocrystal of hesperetin and carbamazepine

Figure 5 Differential scanning calorimetry spectra of hesperetin and carbamazepine cocrystals and raw materials

Figure 6 Solubility curves of samples under different conditions

Figure 7 Stability chart of hesperetin and carbamazepine co-crystal

Detailed ways

In order to better illustrate the technical solution of the present invention, the following examples are given, but the present invention is not limited thereto.

Example 1

Preparation method of hesperetin and carbamazepine co-crystal 1

Take an appropriate amount of hesperetin and carbamazepine, the molar ratio of the two is 1:1, use the solvent suspension method to add the sample to a suitable container at room temperature, add an appropriate amount of organic solvent, stir at room temperature for an appropriate time, and mix the resulting mixture The suspension solvent is evaporated to dryness, filtered to natural drying, or filtered to vacuum drying. See Table 3 for condition parameters. Powder X-ray diffraction analysis was performed on it, and the diffraction pattern was consistent with Figure 1, indicating that the obtained sample was a cocrystal of hesperetin and carbamazepine.

Table 3 Specific examples of preparation method 1 of hesperetin and carbamazepine co-crystals

Example 2

In vitro dissolution and release characteristics of hesperetin and carbamazepine cocrystals

The solubility characteristics of hesperetin and carbamazepine co-crystals and hesperetin API in pure water solution systems with pH value of 1.2, pH value of 4.5 and pH value of 6.8 were investigated. The experiment was carried out with reference to the "Technical Guiding Principles for Dissolution Test of General Oral Solid Preparations". The dissolved percentage was calculated using high performance liquid phase method and external standard method. Draw dissolution curves with time as the abscissa and dissolution percentage as the ordinate (Figure 6). The data are shown in Table 4.

Detection conditions: Detection system: Aligent 1200, chromatographic column: Agilent Eclipse XDB-C18 (4.6×150mm, 5μm); mobile phase: methanol-water (70:30, v/v); flow rate: 1mL·min ^-1 ; column Temperature: 30°C; detection wavelength: hesperetin: 280nm; injection volume: 10 μl.

Table 4 Dissolution curve data

It can be seen from the experimental data that the dissolution behavior of hesperetin and carbamazepine co-crystals in hydrochloride buffer solution, acetate buffer solution, phosphate buffer solution and pure water system is better than that of hesperetin raw material. Specifically, the cocrystal of hesperetin and carbamazepine has a faster dissolution rate and a higher dissolution amount, and is easier to absorb more quickly to reach an effective blood concentration. The total amount of absorption also increases significantly, and the dissolved amount is about 1.5 times that of hesperetin, which can better realize the disease treatment effect of the drug; the solubility curve of the hesperetin and carbamazepine co-crystal has a stable release platform, which can ensure that the blood drug remains stable during the disease treatment process. concentration.

Example 3

Stability advantages of hesperetin and carbamazepine cocrystals

High temperature test: Place a sample of hesperetin and carbamazepine eutectic in an open clean watch glass, place it at 60°C for 10 days, and take samples on the 0th day, the 5th day and the 10th day. The samples obtained from the above sampling points were subjected to powder X-ray diffraction analysis. The results showed that the hesperetin and carbamazepine eutectic was stable under the test of high temperature influencing factors.

High humidity test: Place the sample of hesperetin and carbamazepine eutectic in an open clean watch glass, place it at 25°C for 10 days at a relative humidity of 90% ± 5%, and test it on the 0th day, the 5th day and Samples were taken on the 10th day. The samples obtained from the above sampling points were subjected to powder X-ray diffraction analysis. The results showed that the hesperetin and carbamazepine eutectic was stable under high humidity conditions.

Illumination test: Place the hesperetin and carbamazepine eutectic sample in a clean watch glass with an opening, place it in a light box equipped with a fluorescent lamp, and place it for 10 days at an illumination of 4500lx±500lx. Samples were taken on days 5 and 10. The samples obtained from the above sampling points were subjected to powder X-ray diffraction analysis. The results showed that the hesperetin and carbamazepine eutectic was stable under high humidity conditions. (Figure 7)

Example 4

Preparation method of combination pharmaceutical preparation 1 (tablet):

A method for preparing a combination drug tablet, which is characterized by using pure hesperetin and carbamazepine eutectic as the raw material of the combination drug, and using several excipients as auxiliary ingredients for preparing the combination drug tablet, according to Tablet samples containing 10 to 500 mg of drug per tablet are prepared in a certain proportion. Table 5 gives the tablet formula proportions:

Table 5 Preparation formula of hesperetin and carbamazepine cocrystal combination pharmaceutical tablets

The method of preparing the pure raw material drug of hesperetin and carbamazepine co-crystal into tablet preparations is: mix several excipients and the raw drug evenly, and directly compress the tablet; or mix the excipients and dry granulate and then mix it with the raw drug Mix evenly and press into tablets.

Preparation method 2 of combination pharmaceutical preparation (tablet):

A method for preparing a combination drug tablet, which is characterized by using the pure co-crystal of hesperetin and carbamazepine as the raw material of the combination drug, and using several excipients as auxiliary ingredients for preparing the combination drug tablet, according to Tablet samples containing 10 to 500 mg of drug per tablet are prepared in a certain proportion. Table 6 gives the tablet formula proportions:

Table 6 Preparation formula of hesperetin and carbamazepine cocrystal combination pharmaceutical tablets

The method of preparing pure raw materials of hesperetin and carbamazepine co-crystal into tablet preparations is: mix several excipients and raw materials evenly, add an appropriate amount of 1% sodium hydroxymethylcellulose solution, and prepare Soft material, sieve and granulate, dry the wet granules, sieve and make whole granules, add magnesium stearate and talcum powder, mix evenly, and press into tablets to obtain.

Preparation method 3 of combined pharmaceutical preparation (capsule):

A method for preparing a combination drug capsule, which is characterized by using the pure co-crystal of hesperetin and carbamazepine as the raw material of the combination drug, and using several excipients as auxiliary ingredients for preparing the combination drug capsule, according to a certain proportion The proportions are used to make capsule samples with a drug content of 10 to 500 mg per tablet. Table 7 shows the capsule formula proportions:

Table 7 Raw materials and excipient formulas of hesperetin and carbamazepine cocrystal combination pharmaceutical capsule preparations

The method of preparing the raw material drug of hesperetin and carbamazepine co-crystal into tablet preparations is: mix several excipients and the raw material drug evenly, add an appropriate amount of 1% sodium hydroxymethylcellulose solution to prepare wet tablets Dry and sieve the granules, add magnesium stearate, mix evenly, and insert into capsules; or directly mix the hesperetin and carbamazepine co-crystal API with several excipients without using the granulation step. Evenly, after sieving, it is directly put into capsules.

Example 5

Dosage 1 (tablet) of the combination drug of hesperetin and carbamazepine cocrystal:

A pharmaceutical composition prepared and developed using a co-crystal sample of hesperetin and carbamazepine as the active ingredient of the drug. It is characterized by using a co-crystal of hesperetin and carbamazepine as the active ingredient of the drug. The daily dosage is 300 mg. , can be prepared into ordinary tablets of 100 mg 3 times a day / one time each time, or 300 mg tablets once a day / one time each time.

Dosage of hesperetin and carbamazepine cocrystal combination drug 2 (capsules):

A pharmaceutical composition prepared and developed using a co-crystal sample of hesperetin and carbamazepine as the active ingredient of the drug. It is characterized by using a co-crystal of hesperetin and carbamazepine as the active ingredient of the drug. The daily dosage is 500 mg. , can be prepared into one 250mg capsule twice a day/one time, or one 500mg capsule once a day/one time.

Problems that need to be explained: The dosage of the active ingredients of the hesperetin and carbamazepine co-crystal pharmaceutical composition involved in the present invention is affected by many factors, such as: different uses for prevention and treatment, resulting in daily Differences in medication dosage; differences in the nature and severity of the disease resulting in differences in daily medication dosage; differences in gender, age, body surface area of patients, and differences in administration routes, frequency of administration, and treatment purposes resulting in differences in daily medication dosage Differences; in addition, the differences in absorption and blood concentration between crystalline samples also cause the appropriate daily dosage range of the present invention to use the hesperetin and carbamazepine co-crystal component to be 0.002-20mg/kg body weight. Preferably it is 0.01-10 mg/kg body weight. During use, different total dosage plans of the active ingredients of the hesperetin and carbamazepine cocrystal should be formulated according to the actual needs for prevention and treatment of different situations, and can be completed in multiple or one-time administration.

references

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Claims (14)

1. A co-crystal of hesperetin and carbamazepine, characterized in that hesperetin and carbamazepine form a co-crystal with a non-covalent bond according to a molar ratio of 1:1. When powder X-ray diffraction analysis is used, Under CuK _alpha radiation experimental conditions, the diffraction peak position: 2-Theta value (°) or d value And the relative intensity of the diffraction peak: the peak height value (Height%) or the peak area value (Area%) has the following characteristics: 2. Hesperetin and carbamazepine eutectic according to claim 1, characterized in that, when analyzed using attenuated total reflection Fourier transform infrared spectroscopy, at 3430, 3348, 3206, 3057, 3025, 2969, 2941 ,2845,2605,2252,2155,2053,1969,1677,1644,1604,1583,1514,1491,1447,1418,1401,1386,1343,1289,1273,1237,1220,1193,1160,1132,11 14 , 1080, 1067, 1042, 1028, 1016, 985, 971, 957, 878, 867, 860, 841, 827, 801, 789, 772, 764, 741, 716, 663cm ^-1 There are characteristic peaks in the infrared spectrum, among which The allowable deviation of the characteristic peaks of the infrared spectrum is ±2cm ^-1 . 3. Hesperetin and carbamazepine eutectic according to claim 1, characterized in that, when analyzed using differential scanning calorimetry technology, the temperature rise rate is in the range of 30 to 250°C and the temperature rise rate is 10 per minute. ℃, there is an endothermic peak at 176℃±3℃ in its DSC spectrum. 4. A method for preparing the hesperetin and carbamazepine eutectic as claimed in any one of claims 1 to 3, characterized in that hesperetin and carbamazepine are fed in a molar ratio of 1:1, using The co-crystal of hesperetin and carbamazepine was prepared by the chemical method of solvent suspension. 5. The preparation method according to claim 4, the solvent suspension method, wherein the solvent is selected from methanol, ethanol, ethyl acetate, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane; the stirring speed is 20r/min ~ 400r/min; stirring time is 1 hour ~ 96 hours. The obtained suspension is prepared by solvent evaporation and drying, filtration and natural drying or filtration and vacuum drying to obtain hesperetin and carbamazepine co-crystal. 6. A mixed solid material containing hesperetin and carbamazepine eutectic, characterized in that the amount of hesperetin and carbamazepine eutectic described in any one of claims 1-3 is 1 -99.9%. 7. A mixed solid material containing hesperetin and carbamazepine eutectic, characterized in that the amount of hesperetin and carbamazepine eutectic described in any one of claims 1-3 is 10 -99.9%. 8. A mixed solid material containing hesperetin and carbamazepine eutectic, characterized in that the amount of hesperetin and carbamazepine eutectic described in any one of claims 1 to 3 is 50 -99.9%. 9. A mixed solid material containing hesperetin and carbamazepine eutectic, characterized in that the amount of hesperetin and carbamazepine eutectic described in any one of claims 1-3 is 85 -99.9%. 10. A pharmaceutical composition, characterized by containing an effective dose of the cocrystal of hesperetin and carbamazepine according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier. 11. A pharmaceutical composition, characterized in that it contains an effective dose of a mixed solid material of the cocrystal of hesperetin and carbamazepine according to any one of claims 6 to 9 and a pharmaceutically acceptable carrier. 12. The pharmaceutical composition according to claim 10 or 11, characterized in that the daily dosage of the cocrystal of hesperetin and carbamazepine is in the range of 10 mg to 1000 mg. 13. The pharmaceutical composition according to claim 10 or 11, characterized in that the dosage form of the pharmaceutical composition is a tablet, capsule, pill, powder injection, sustained release preparation or controlled release preparation. 14. The hesperetin and carbamazepine eutectic product according to any one of claims 1 to 3 or the mixed solid containing hesperetin and carbamazepine eutectic product according to any one of claims 6 to 9 Substances or pharmaceutical compositions according to claim 10 or 11 are used in the preparation of anti-tumor, antioxidant, anti-inflammatory, anti-epileptic, anti-trigeminal neuralgia, anti-manic depression, prevention of atherosclerosis, anti-arrhythmic diseases and complications. Applications in medicine.