1. An aspirin medicine cocrystal is characterized in that the aspirin medicine cocrystal comprises aspirin and ligustrazine in a molar ratio of 1: 1.

2. An aspirin drug co-crystal according to claim 1, characterized in that it has characteristic diffraction peaks at 2 Θ ± 12.5 ° ± 0.2 °, 13.0 ° ± 0.2 °, 14.0 ° ± 0.2 °, 14.37 ° ± 0.2 °, 17.3 ° ± 0.2 °, 20.0 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.5 ° ± 0.2 °, 26.4 ° ± 0.2 °.

3. An aspirin drug co-crystal according to claim 1, characterized in that it also has characteristic diffraction peaks at 2 Θ ° ± 0.2 °, 9.9 ° ± 0.2 °, 11.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.6 ° ± 0.2 °, 18.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.9 ° ± 0.2 °, 22.5 ° ± 0.2 °, 25.1 ° ± 0.2 °, 27.8 ° ± 0.2 °, 28.3 ° ± 0.2 °, 29.7 ° ± 0.2 °, 30.0 ° ± 0.2 °, 33.5 ° ± 0.2 °, 34.6 ° ± 0.2 °.

4. An aspirin drug cocrystal according to claim 1, wherein said aspirin drug cocrystal is monoclinic I2/a space group and has unit cell parameters of α＝γ＝90°，β＝102.143°。

5. A process for the preparation of an aspirin drug cocrystal according to any one of claims 1-4, characterized in that it comprises the following steps: adding aspirin and ligustrazine into a solvent, stirring and mixing uniformly, filtering, collecting powder, and drying to obtain the aspirin medicine cocrystal.

6. The process for preparing an aspirin pharmaceutical co-crystal according to claim 5, characterized in that 360mg-721mg aspirin and 272mg-545mg ligustrazine are added to each ml of solvent; and/or

The stirring temperature is 15-30 ℃, the stirring speed is 200-300 rpm, and the stirring time is 8-30 h.

7. A process for the preparation of an aspirin drug cocrystal according to claim 5 or 6, characterized in that the solvent is acetonitrile.

8. A pharmaceutical composition comprising an effective amount of the aspirin drug cocrystal of any of claims 1-4 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a pill, an injectable formulation, a sustained release formulation, or a controlled release formulation.

10. Use of the aspirin medicament co-crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 8 to 9 for the preparation of an anti-platelet aggregation drug, an antithrombotic drug, and a drug for the prevention or treatment of cardiovascular diseases.

Background

Aspirin (asarin, ASA), a class of nonsteroidal anti-inflammatory drugs, was originally widely used for antipyretic, analgesic, anti-inflammatory, with significant efficacy. After research by scientists, aspirin can also inhibit platelet aggregation, and therefore, can be used as an antithrombotic drug. Low doses of aspirin play a crucial role in preventing the occurrence of adverse cardiovascular events, especially in patients with cardiovascular disease. However, since the dissolution of aspirin is hindered due to the low pH of gastric juice, aspirin has poor solubility in gastric juice conditions, resulting in the aggregation of insoluble particles in the stomach, which may cause damage to the gastric mucosa, leading to the problems of gastritis and peptic ulcer, and resulting in the decrease in bioavailability of aspirin.

Pharmaceutical co-crystals are crystals of a pharmaceutically active ingredient (API) and a co-crystal former (CCF) in a certain ratio formed by intermolecular non-covalent interactions. The proper eutectic formation substance is selected to form a eutectic with the active pharmaceutical ingredient API, so that various physicochemical properties and pharmaceutical properties of the medicament can be improved to a great extent. However, not any drug can form a co-crystal, the choice of co-crystal former is crucial, and the preparation method of the co-crystal can also have a significant impact on the physicochemical and pharmaceutical properties of the API. At present, no aspirin cocrystal medicine and a corresponding preparation method thereof are disclosed.

Disclosure of Invention

Aiming at the problems that aspirin medicine in the prior art has poor solubility in stomach, the efficacy can not be fully exerted, gastric mucosa is damaged and the like, the invention provides an aspirin medicine eutectic and a preparation method and application thereof.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

an aspirin medicinal cocrystal comprises aspirin and ligustrazine at a molar ratio of 1: 1.

The invention provides a pharmaceutical cocrystal formed by combining two active components of aspirin and ligustrazine through hydrogen bond acting force, which not only improves the solubility and dissolution rate of aspirin raw material medicine under acidic condition and reduces the formation of aspirin aggregates in stomach, thereby reducing the contact of aspirin raw material medicine with gastric mucosa and reducing the damage to stomach, but also obviously reducing the sublimation of ligustrazine and improving the absorption and utilization rate of ligustrazine in the body. The aspirin-ligustrazine eutectic provided by the invention not only retains the pharmacological properties of the two active components, but also can improve the physicochemical properties such as the stability, the solubility and the like of the medicine, has more stable physicochemical properties, can effectively promote the medicine absorption, thereby improving the bioavailability, obviously enhancing the anticoagulation and antithrombotic effects, and being a novel medicine with higher application prospect for resisting platelet aggregation and thrombosis and preventing and treating cardiovascular diseases.

Ligustrazine (Ligustrazine, TMP) is the main active alkaloid in the rhizome of Ligusticum wallichii belonging to Artemisia of Umbelliferae, has the functions of promoting blood circulation, removing blood stasis, dilating blood vessel, increasing blood flow of coronary artery and cerebral vessels, improving microcirculation, resisting platelet aggregation and thrombosis, and is a common medicine for domestic ischemic cerebrovascular diseases. But the ligustrazine is easy to sublimate and insoluble in water, and the oral dosage form has large stimulation to gastric mucosa, obvious first-pass effect, low bioavailability and poor compliance of clinical patients. The invention forms eutectic by aspirin (ASA) and ligustrazine (TMP), simultaneously solves the problems of poor solubility and slow dissolution rate in aspirin stomach and easy sublimation of ligustrazine, solves the problem of large stimulation of aspirin and ligustrazine to gastric mucosa, and improves the bioavailability of the aspirin and the ligustrazine.

Preferably, the aspirin medicament co-crystal has characteristic diffraction peaks at 2 θ ═ 12.5 ° ± 0.2 °, 13.0 ° ± 0.2 °, 14.0 ° ± 0.2 °, 14.37 ° ± 0.2 °, 17.3 ° ± 0.2 °, 20.0 ° ± 0.2 °, 23.5 ° ± 0.2 °, 24.7 ° ± 0.2 °, 25.5 ° ± 0.2 °, 26.4 ° ± 0.2 °.

Preferably, the aspirin medicament co-crystal also has characteristic diffraction peaks at 2 θ ═ 7.2 ° ± 0.2 °, 9.9 ° ± 0.2 °, 11.2 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.6 ° ± 0.2 °, 18.7 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.9 ° ± 0.2 °, 22.5 ° ± 0.2 °, 25.1 ° ± 0.2 °, 27.8 ° ± 0.2 °, 28.3 ° ± 0.2 °, 29.7 ° ± 0.2 °, 30.0 ° ± 0.2 °, 33.5 ° ± 0.2 °, and 34.6 ° ± 0.2 °.

Preferably, the aspirin drug cocrystal is monoclinic I2/a space group, and the unit cell parameter isα＝γ＝90°，β＝102.143°。

The invention also provides a preparation method of the aspirin medicine eutectic, which comprises the following steps: adding aspirin and ligustrazine into a solvent, stirring and mixing uniformly, filtering, collecting powder, and drying to obtain the aspirin medicine cocrystal.

The preparation method of the aspirin-ligustrazine eutectic provided by the invention is simple, the operation condition is mild, hydrate and solvate are not easy to form, and the preparation method is suitable for large-scale industrial production and has high popularization value.

Preferably, 360mg to 721mg of aspirin and 272mg to 545mg of ligustrazine are added to each milliliter of solvent.

Preferably, the stirring temperature is 15-30 ℃, the stirring speed is 200-300 rpm, and the stirring time is 8-24 h.

Preferably, the solvent is acetonitrile.

Alternatively, the drying method is to put the filtered solid powder in a fume hood and naturally place the solid powder in a volatile solvent.

The optimized reaction condition is favorable for forming aspirin-ligustrazine eutectic with high crystallinity and good crystal form stability.

The invention also provides a pharmaceutical composition comprising an effective amount of an aspirin drug cocrystal according to any one of the above and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers include carriers, diluents, wetting agents, emulsifiers, binders, coating agents, fillers, glidants, lubricants, disintegrants, pH buffers and the like known in the art to be useful in pharmaceutical formulations.

Preferably, the dosage form of the pharmaceutical composition is tablets, capsules, pills, injection preparations, sustained-release preparations or controlled-release preparations.

The aspirin-ligustrazine cocrystal provided by the invention can be prepared into various dosage forms, such as tablets (including common tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets and orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric-coated capsules), granules, powder, pellets, dropping pills and the like, and can also be prepared into sustained-release preparations and controlled-release preparations. It is prepared according to the conventional method of the preparation in the field.

The invention also provides application of the aspirin medicament cocrystal or the pharmaceutical composition in preparation of anti-platelet aggregation medicaments, antithrombotic medicaments and medicaments for preventing or treating cardiovascular diseases.

The aspirin-ligustrazine eutectic provided by the invention has good stability and high solubility, can be developed into various preparations, is used as a novel medicament for resisting coagulation and thrombosis and preventing or treating cardiovascular diseases, and has a relatively high application prospect.

Drawings

FIG. 1 is a powder X-ray diffraction pattern of an aspirin-ligustrazine cocrystal prepared in example 1 of the present invention;

FIG. 2 is a powder X-ray diffraction pattern of aspirin;

FIG. 3 is a powder X-ray diffraction pattern of ligustrazine;

FIG. 4 is a Scanning Electron Microscope (SEM) picture of an aspirin-ligustrazine cocrystal prepared in example 1 of the present invention;

FIG. 5 is a Scanning Electron Microscope (SEM) image of aspirin;

FIG. 6 is a Scanning Electron Microscope (SEM) image of ligustrazine;

FIG. 7 is a schematic view showing the structure of an asymmetric unit of an aspirin-ligustrazine cocrystal prepared in example 1 of the present invention;

FIG. 8 is a schematic view showing a one-dimensional chain structure formed by an asymmetric unit structure of an aspirin-ligustrazine cocrystal prepared in example 1 of the present invention;

FIG. 9 is a schematic diagram of a two-dimensional structure formed by a one-dimensional chain structure of an aspirin-ligustrazine cocrystal prepared in example 1 of the present invention;

FIG. 10 is a schematic diagram of a three-dimensional structure formed by a one-dimensional chain structure of an aspirin-ligustrazine cocrystal prepared in example 1 of the present invention;

FIG. 11 is a Differential Scanning Calorimetry (DSC) chart of the aspirin-ligustrazine cocrystal, aspirin, and ligustrazine prepared in example 1 of the present invention;

FIG. 12 is a thermogravimetric analysis (TG) plot of aspirin-ligustrazine cocrystal, aspirin, and ligustrazine prepared in example 1 of the present invention;

FIG. 13 is a graph of infrared spectroscopic analysis (FT-IR) of an aspirin-ligustrazine cocrystal, aspirin, and ligustrazine prepared in example 1 of the present invention;

FIG. 14 is a weight sublimation drawing of an aspirin-ligustrazine cocrystal, aspirin, and ligustrazine prepared in example 1 of the present invention;

FIG. 15 is a graph showing the intrinsic dissolution rates of aspirin-ligustrazine cocrystal, aspirin, and ligustrazine prepared in example 1 of the present invention in hydrochloric acid buffer solution at pH 1.2.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

In order to better illustrate the invention, the following examples are given by way of further illustration.

Example 1

The embodiment provides an aspirin-ligustrazine eutectic, and the preparation method comprises the following steps:

720.6mg of aspirin (molecular weight 180.16) and 544.8mg of ligustrazine (molecular weight 136.2) are weighed, added into a test tube, 1mL of acetonitrile is added, stirred for 24h at 25 ℃ and 200r/min, then filtered by using filter paper, and the obtained solid powder is placed in a fume hood to volatilize the solvent, thus obtaining the aspirin-ligustrazine eutectic.

Example 2

The embodiment provides an aspirin-ligustrazine eutectic, and the preparation method comprises the following steps:

1441.2mg of aspirin (molecular weight 180.16) and 1089.6mg of ligustrazine (molecular weight 136.2) are weighed, added into a test tube, 2mL of acetonitrile is added, stirred for 24h at 20 ℃ and 250r/min, then filtered by using filter paper, and the obtained solid powder is placed in a fume hood to volatilize the solvent, thus obtaining the aspirin-ligustrazine eutectic.

Example 3

The embodiment provides an aspirin-ligustrazine eutectic, and the preparation method comprises the following steps:

720.6mg of aspirin (molecular weight 180.16) and 544.8mg of ligustrazine (molecular weight 136.2) are weighed, added into a test tube, 1mL of acetonitrile is added, stirred for 24h at 30 ℃ and 300r/min, then filtered by using filter paper, and the obtained solid powder is placed in a fume hood to volatilize the solvent, thus obtaining the aspirin-ligustrazine eutectic.

Example 4

The embodiment provides an aspirin-ligustrazine eutectic, and the preparation method comprises the following steps:

720.6mg of aspirin (molecular weight 180.16) and 544.8mg of ligustrazine (molecular weight 136.2) are weighed, added into a test tube, 1mL of acetonitrile is added, stirred for 30h at the temperature of 15 ℃ and at the speed of 200r/min, then filtered by using filter paper, and the obtained solid powder is placed in a fume hood to volatilize the solvent, thus obtaining the aspirin-ligustrazine eutectic.

Example 5

The embodiment provides an aspirin-ligustrazine eutectic, and the preparation method comprises the following steps:

weighing 360mg of aspirin (molecular weight 180.16) and 272mg of ligustrazine (molecular weight 136.2), adding into a test tube, adding 1mL of acetonitrile, stirring at 30 ℃ and 300r/min for 8h, filtering with filter paper, and placing the obtained solid powder in a fume hood to volatilize the solvent to obtain the aspirin-ligustrazine eutectic.

Comparative example 1

Weighing 180.2mg of aspirin (molecular weight 180.16) and 136.2mg of ligustrazine (molecular weight 136.2), adding into a test tube, adding 1mL of acetonitrile, stirring at 25 deg.C and 200r/min for 24h, and clarifying the solution without white solid powder, i.e. obtaining the aspirin-ligustrazine eutectic.

Test examples

1. Sample determination and structural characterization

The aspirin-ligustrazine eutectic (ASA-TMP) prepared in example 1 is determined and structurally characterized by the following specific method:

1.1 powder X-ray diffraction

Powder X-ray diffraction (PXRD) a german bruker D8 Advance X-ray diffractometer was used. The measurement conditions were as follows: the light source is Cu Ka (wavelength)) The voltage of the instrument is controlled to be 40kV, the current is 40mA, the test step length is set to be 0.02 degrees, the test speed is 0.1s per step, the scanning range is 3-35 degrees, and the test temperature is room temperature.

The powder X-ray diffraction pattern of the aspirin-ligustrazine cocrystal obtained in example 1 is shown in FIG. 1. The X-ray powder diffraction of the aspirin-ligustrazine eutectic has diffraction peaks at diffraction angles of 7.2 +/-0.2 degrees, 9.9 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.5 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.0 +/-0.2 degrees, 14.37 +/-0.2 degrees, 15.7 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.3 +/-0.2 degrees, 18.7 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.0 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.5 +/-0.2 degrees, 23.5 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.1 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.4 +/-0.2 degrees, 27.8 +/-0.2.3 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.1 +/-0.2 degrees, 25.5 +/-0.2 degrees, 26.4 degrees, 27.8 +/-0.2 degrees, 3 +/-0.3 degrees, 33 degrees, 2 degrees.

The powder X-ray diffraction pattern of aspirin (ASA) tested using the same conditions is shown in fig. 2.

The powder X-ray diffraction pattern of ligustrazine (TMP) tested using the same conditions is shown in fig. 3.

As can be seen from a comparison of FIGS. 1, 2 and 3, the product obtained in example 1 is a new crystalline substance, namely, aspirin-ligustrazine eutectic.

1.2 scanning Electron microscopy analysis (SEM)

A sample of the aspirin-ligustrazine eutectic prepared in example 1 was attached to a conductive tape and subjected to gold spraying, and a scanning electron microscope photograph taken at 5kV with a magnification of 5000 times is shown in FIG. 4.

A scanning electron micrograph of aspirin taken under the same conditions at 2000 x magnification is shown in fig. 5.

Scanning electron micrographs of ligustrazine taken under the same conditions at 500 x magnification are shown in fig. 6.

Comparing fig. 4, fig. 5 and fig. 6, it can be seen that aspirin is in the form of strip-shaped aggregation, ligustrazine is in the form of irregular block, and aspirin-ligustrazine eutectic crystal is in the form of block with clear edges and corners.

1.3 Single Crystal X-ray diffraction (SXRD)

The aspirin-ligustrazine eutectic sample prepared in example 1 is placed at a sample device of a single crystal X-ray diffractometer, and the test temperature is 150K, and Cu K alpha ray diffraction is carried outThe tube voltage is 20kV and the current is5 mA. The single crystal data collected was subject to cell refinement and data reduction using the CrysAlisPRO program. The structure was resolved and refined using the Olex2 program, optimized on F2 using full matrix least squares, and all non-hydrogen atoms were refined using anisotropic displacement parameters. All hydrogen atoms were placed in the calculated positions with fixed isotropic thermal parameters. Finally, the crystal structure is drawn by Mercury 4.2.0 software.

The single crystal structure analysis of ASA-TMP shows that the eutectic belongs to the I2/a space group of monoclinic system and the unit cell parameter isα ═ γ ═ 90 °, β ═ 102.143 °. FIG. 7 is a schematic diagram of the structure of asymmetric units of aspirin-ligustrazine cocrystalThe asymmetric units comprise an aspirin molecule and a ligustrazine molecule, and the aspirin molecule and the ligustrazine molecule are connected into a dimer structure by strong hydrogen bond (O4-H4 … N1) acting force. The adjacent dimers form a one-dimensional chain structure by pi-pi stacking and van der waals forces, as shown in fig. 8. One-dimensional chains are packed into two-dimensional and three-dimensional structures by van der waals forces, as shown in fig. 9 and 10.

1.4 Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) was performed on aspirin, ligustrazine, and the aspirin-ligustrazine co-crystal prepared in example 1.

The differential scanning calorimetry (SDT Q600, TA of USA) was used to measure, and about 5mg of sample was placed in an aluminum pan, covered with an aluminum lid, and heated from 40 deg.C to 250 deg.C at a nitrogen flow rate of 50mL/min under the protection of nitrogen, and at a temperature rise rate of 10 deg.C/min, respectively, to obtain a Differential Scanning Calorimetry (DSC) chart as shown in FIG. 11.

The results from fig. 11 show that: aspirin has an endothermic peak at 144.2 deg.C, indicating a melting point of about 144.2 deg.C. Ligustrazine has a sharp endothermic peak at 88.3 ℃, indicating that its melting point is about 88.3 ℃. The aspirin-ligustrazine eutectic has a sharp endothermic peak at 95.3 ℃, which indicates that the melting point is 95.3 ℃, and further indicates that the substance is a single crystalline phase.

1.5 thermogravimetric analysis (TG)

Thermogravimetric analysis (TG) was performed on aspirin, ligustrazine, and the aspirin-ligustrazine co-crystal prepared in example 1.

Using a thermogravimetric analyzer (SDT Q600, TA, USA), about 5mg of the sample was placed in an aluminum pan, covered with an aluminum lid, and heated from 40 ℃ to 250 ℃ at a rate of 10 ℃/min under nitrogen protection at a flow rate of 50 mL/min. The resulting thermogravimetric analysis is shown in FIG. 12.

The TG diagram of fig. 12 shows that ligustrazine has a certain degree of weight loss before the melting point due to sublimation, and the weight loss accelerates until complete weight loss when the melting point is reached. The aspirin begins to lose weight after the melting point, and the aspirin-ligustrazine eutectic crystal has no weight loss before the melting point, which shows that the defect that the ligustrazine is easy to sublimate is improved, and the weight loss begins after the temperature reaches the melting point.

1.6 Infrared Spectroscopy (FT-IR)

Infrared spectroscopic analysis (FT-IR) was performed on aspirin, ligustrazine, and the aspirin-ligustrazine co-crystal prepared in example 1.

An infrared spectrometer Nicolet iS5 (American Samerfei Nile high-force iS5 infrared spectrometer) iS used for infrared spectrum collection, and the collection range iS 400-4000cm^-1Resolution of 2cm^-1Each sample was scanned 64 times. The results of infrared spectroscopy are shown in FIG. 13, where aspirin was at 3487.04cm^-1The absorption peak of hydroxyl on carboxyl is shown, and the absorption peak of ligustrazine is 1411.34cm^-1The peak is C-N absorption peak, and the absorption peaks of aspirin-ligustrazine eutectic at the two positions disappear, which indicates that O4-H4 … N1 is formed.

1.7 sublimation study

Sublimation studies were conducted on aspirin, ligustrazine, and the aspirin-ligustrazine co-crystal prepared in example 1.

This study compared the sublimation characteristics of aspirin, ligustrazine, and the aspirin-ligustrazine co-crystal prepared in example 1. Firstly, cutting the tinfoil paper into several parts with similar weight, stacking the parts into tinfoil paper discs with uniform size, weighing and recording the empty tinfoil paper discs. Then respectively weighing 6 parts of proper aspirin, ligustrazine and aspirin-ligustrazine eutectic, spreading the aspirin, the ligustrazine and the aspirin-ligustrazine eutectic in a tin foil paper disc, respectively weighing the weight of each sample at 0h, 1h, 2h, 3h, 4h and 24h under the condition of normal pressure and constant humidity at 25 ℃, recording the weight loss condition of the samples, calculating the weight loss percentage, and evaluating the percentage of the weight loss of the samples in the original weight at the time point by using the average value of the weight loss percentage.

The result is shown in fig. 14, aspirin does not reduce weight loss substantially at 24h, ligustrazine reduces weight by 50.24% at 24h, and aspirin-ligustrazine eutectic reduces weight by only 8.50% at 24h, which shows that at normal temperature, aspirin-ligustrazine eutectic significantly improves the sublimation-prone property of ligustrazine.

1.8 measurement of intrinsic dissolution Rate

The inherent dissolution rate was measured for aspirin, ligustrazine, and the aspirin-ligustrazine co-crystal prepared in example 1.

Approximately 300mg samples of aspirin (ASA), ligustrazine (TMP), aspirin-ligustrazine cocrystal (ASA-TMP) were tabletted separately. Placing each tablet in 500mL hydrochloric acid buffer solution with pH of 1.2 at 100rpm and 37 deg.C, respectively, taking out 1mL dissolution medium at 2min, 5min, 10min, 15min, 20min, 30min and 45min, and supplementing with equal volume of fresh medium. The drug concentration was determined separately and each set of experiments was run in triplicate.

The results are shown in table 1 and fig. 15, the dissolution rate of TMP drug substance in hydrochloric acid buffer solution with ph1.2 is high, and the linearity is good within 20 min; the co-crystal of ASA starting material and ASA-TMP was well linear within 45 min. Compared with the raw material drug ASA, the intrinsic dissolution rate of the ASA in the eutectic is improved by about 28%. The dissolution rate of ASA in the stomach is increased, so that the contact of drug particles with the gastric mucosa can be reduced, and the gastric injury can be reduced.

TABLE 1

1.9 pharmacokinetic testing

Pharmacokinetic experiments were performed on aspirin, ligustrazine, and the aspirin-ligustrazine cocrystal prepared in example 1.

15 SPF rats (250 + -10 g) were randomly divided into three groups (n-5) and fasted prior to the experiment, and each group was administered by intragastric administration in a homogeneous suspension in sodium carboxymethylcellulose at the dose of ASA group (66.14mg/kg), TMP group (50mg/kg), ASA-TMP cocrystal group (116.14 mg/kg). Blood was collected from the orbit at 400-. The blood sample is centrifuged at 6000rpm for 10min, the supernatant is taken and treated by protein precipitation, centrifuged at 12000rpm for 10min, the supernatant is taken, filtered and analyzed by high performance liquid chromatography. Since ASA is rapidly metabolized to Salicylic Acid (SA) after entering the body, plasma levels of SA are used to reflect ASA levels. The pharmacokinetic parameters are shown in table 2. The results show that the peak reaching time of SA in the cocrystal is obviously prolonged, the area under the curve of the drug time is increased by 14.73 percent, and the peak reaching concentration of TMP in the cocrystal and the area under the curve of the drug time are respectively 4.15 times and 5.09 times of that of the TMP group. The results show that the bioavailability of ASA and TMP is improved to different degrees after the eutectic is prepared.

TABLE 2 pharmacokinetic parameters of ASA, TMP, ASA-TMP

Note: comparison between SA,. P <0.01 indicated that the difference was very significant; the comparison between the TMP and the TMP,^#p <0.01 indicates that the difference is very significant.

2. Pharmacodynamic test

Pharmacodynamic tests were performed on aspirin, ligustrazine, and the aspirin-ligustrazine co-crystal prepared in example 1.

Animal grouping and administration: 36 male SPF rats (250 ± 10g) were randomly divided into six groups of 6 rats: 0.5% of CMC-Na group; ② ASA group (20.83mg kg)^-1) (ii) a ③ TMP group (15.75mg kg)^-1) (ii) a (36.58mg kg) of a physical mixture of ASA and TMP^-1) (ii) a Low dosage group of ASA-TMP eutectic (18.29mg kg)^-1) (ii) a Sixthly, ASA-TMP eutectic high-dose group (36.58mg kg)^-1). Rats were dosed orally once daily for seven consecutive days.

Effect on clotting time in rats: after the last intragastric administration is finished for 1h, blood is collected by the eyepit of the micro blood collection tube, the blood is dripped on a glass slide, a stopwatch is used immediately for recording, a pin is used for slightly picking from the edge of the blood drop to the middle once every 20s, and when blood streak is picked up, the recording is stopped, and the blood coagulation time is recorded. The results are shown in table 3, and the experimental results show that: the coagulation time of the physical mixture group and the two eutectic groups is obviously prolonged (P is less than 0.01) compared with that of the ASA group and the TMP group, the coagulation time of the eutectic group at the same dosage is prolonged by 34.66% compared with that of the physical mixture group, and the coagulation time of the eutectic group at a low dosage is prolonged by 17.22% compared with that of the physical mixture group, so that the anticoagulation effect of the eutectic group is good, and the anticoagulation effect is obviously better than that of the physical mixture group.

TABLE 3 Effect of ASA, TMP, ASA-TMP on clotting time in rats

Group of	Administration dose (mg/kg)	Clotting time(s)
			CMC-Na group	-	50.25±9.32#
ASA group	20.83	86.25±22.91*#
			TMP group	15.75	91.00±14.49*#
Group of physical mixtures	36.58	113.25±28.14*
			Eutectic low dose group	18.29	132.75±12.25*
Eutectic high dose group	36.58	152.5±28.97*#

Note: comparison with the CMC-Na group: represents significant difference (P < 0.05); comparison with physical mixture group: # represents significant difference (P < 0.05).

Effect on tail thrombosis in rats:

immediately after the completion of orbital hemospasia in rats, kappa-carrageenan (20mg/kg) was injected into the abdominal cavity of rats. And measuring the tail thrombus length of the rat by using a steel ruler after injecting the kappa-carrageenan for 24h and 48h, recording, counting the number of black tails of the rat and calculating the black tail rate.

The results are shown in table 4, and the experimental results show that: when the mold is molded for 24h and 48h, the black tail rate of the CMC-Na group and the ASA group reach 100 percent, the black tail rate of the TMP group and the physical mixture group is 83 percent, and the black tail rate of the eutectic group is only 50 percent and is reduced by 33 percent compared with the black tail rate of the physical mixture, which shows that the ASA-TMP eutectic has obviously better effect of inhibiting tail thrombus than the physical mixture group of the single-use group and the two medicines.

TABLE 4 influence of ASA, TMP, ASA-TMP on the black tail rate in rats

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.