Ternary drug organic salt as well as preparation method and application thereof

Abstract

The invention discloses a ternary drug organic salt as well as a preparation method and application thereof, and belongs to the technical field of drug crystallization. The ternary drug organic salt is prepared from trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride in an equal molar ratio, and a crystal structure unit of the ternary drug organic salt contains protonated trimethoprim cations, p-hydroxybenzoic acid anions, chloride ions and berberine cations. The preparation method provided by the invention comprises the following steps: obtaining a single crystal of the ternary drug organic salt by a solvent slow volatilization method, or obtaining powder of the ternary drug organic salt by a grinding, suspension or rotary evaporation method. The preparation method has the advantages of simplicity and convenience in operation, high repeatability, greenness, high efficiency and the like. Experiments show that the obtained ternary drug organic salt has a synergistic antibacterial effect and can be used as a candidate drug composition for treating gastroenteritis, bacillary dysentery and other diseases caused by bacteria.

Description

Technical Field

[0001] The invention belongs to the technical field of drug crystallization, and specifically relates to a trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt and a preparation method and application thereof. Background Art

[0002] Trimethoprim belongs to the pyrimidine class of compounds and is a classic synthetic antibiotic with the advantages of broad spectrum, low toxicity, high efficiency and low price. It is commonly used in clinical practice for respiratory tract infection, urinary tract infection, intestinal infection and other diseases. It can treat sepsis, meningitis, otitis media, typhoid fever, bacillary dysentery and other diseases caused by sensitive bacteria. Its antibacterial mechanism is to reversibly inhibit dihydrofolate reductase, so that dihydrofolate cannot be reduced to tetrahydrofolate, affecting the formation of coenzyme F, thereby affecting the reproduction and growth of microorganisms. Trimethoprim has a strong antibacterial effect on various G + Bacteria and G - At present, the application of trimethoprim is limited mainly due to two reasons: first, its solubility at room temperature is only 0.4 mg / mL, which belongs to the BCS class II drug with low solubility and high permeability; second, it is easy to produce drug resistance during clinical use.

[0003] Berberine, also known as berberine, is a quaternary ammonium alkaloid isolated from the traditional Chinese medicine Coptis chinensis. It is mainly used in the form of berberine hydrochloride in clinical practice. It can be used to treat diseases such as gastroenteritis and bacillary dysentery. It also has certain effects on tuberculosis, scarlet fever, acute tonsillitis and respiratory tract infections. Clinical studies in recent years have shown that berberine hydrochloride has lipid-lowering, antioxidant, anti-tumor, and anti-diabetic effects. Many studies have shown that oral berberine hydrochloride is poorly absorbed and its efficacy is greatly affected by its pharmacokinetic properties.

[0004] Clinical studies have shown that berberine hydrochloride and trimethoprim, as a combination prescription, have a synergistic antibacterial effect. The commercially available preparation berberine trimethoprim capsule is used to treat diseases such as gastroenteritis and bacillary dysentery caused by sensitive bacteria. However, due to the different absorption processes and bioavailability of the two in the body, the efficacy of the drugs will be affected.

[0005] Drug salt formation is a common method to optimize ionizable drugs and improve the properties of candidate drugs. Specifically, the candidate drugs are converted into suitable salts based on their physicochemical properties and processability to improve the chemical, biological and physical properties of the drugs. Parahydroxybenzoic acid (PHBA) is a compound with a phenolic acid structure. It is widely found in plants such as fruits and vegetables. It has multiple pharmacological activities such as antioxidant, anti-inflammatory and antibacterial. Structurally, parahydroxybenzoic acid has both hydroxyl and carboxyl groups. While undergoing proton transfer with the weakly alkaline trimethoprim, it can also form hydrogen bonds with berberine hydrochloride. In terms of efficacy, the formation of an organic salt between the three is expected to produce a synergistic effect and has good application potential. But At present, there is no public report on the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt and its preparation method and application. Summary of the invention

[0006] The object of the present invention is to provide a trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt and its preparation method and application. The preparation method has the advantages of simple operation, high repeatability, green and high efficiency. The obtained ternary drug organic salt has excellent wet stability, thermal stability and light stability; the formation of the ternary drug organic salt helps to improve the solubility of trimethoprim, reduce the solubility difference between trimethoprim and berberine hydrochloride and parahydroxybenzoic acid, realize the rapid synchronous release of the three-component drug in a short time, and help the synchronous absorption of the drug in the body; in addition, the ternary drug organic salt has a synergistic antibacterial effect and can be used as a candidate drug composition for treating diseases such as gastroenteritis and bacillary dysentery caused by bacteria.

[0007] To achieve the above object, the present invention adopts the following technical solution: A trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt, which is composed of trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride, and its molecular formula is [C 14 H 18 N4O3·C7H6O3·C 20 H 18 ClNO4].

[0008] Furthermore, the ternary drug organic salt is a uniform and stable solid form, and its crystal structure unit contains a protonated trimethoprim cation, a parahydroxybenzoate anion, a chloride ion and a berberine cation. Specifically, the protonated trimethoprim cation and the parahydroxybenzoate anion simultaneously form hydrogen bonds with the chloride ion of berberine hydrochloride to form an asymmetric unit of the single crystal structure of the three-component drug organic salt, and the hydrogen bonds formed are NH•••Cl − and OH•••Cl −.

[0009] Furthermore, the ternary drug organic salt belongs to the triclinic system, P-1 space group, and the unit cell parameters are: a =11.5488(5) Å, b= 12.1101(5)Å, c =14.8282(7)Å, α= 97.758(4)º, β= 101.522(4)º, γ= 104.197(4)° V =1932.67(15)Å 3 , Z=2, ρ calc =1.375 g / cm 3 .

[0010] One of the preparation methods of the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt is to add trimethoprim, parahydroxybenzoic acid and berberine hydrochloride hydrate in a molar ratio of 1:1:1 in an organic solvent, stir and heat to form a transparent clear solution, filter and cool to room temperature, and then slowly volatilize at room temperature to precipitate yellow block crystals, so as to obtain a single crystal of the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt.

[0011] The second method for preparing the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt is to mix trimethoprim, parahydroxybenzoic acid and berberine hydrochloride hydrate in a molar ratio of 1:1:1, pour the mixture into a ball mill, add an appropriate amount of organic solvent for mechanical grinding (grinding at a frequency of 25 Hz for 20 minutes), and dry the obtained product at room temperature to obtain trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

[0012] The third method for preparing the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt is to mix trimethoprim, parahydroxybenzoic acid and berberine hydrochloride hydrate in a molar ratio of 1:1:1, and add an appropriate amount of organic solvent to form a suspension, and then stir at room temperature for 24 hours and filter, and the obtained precipitate is dried and ground to obtain trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

[0013] The fourth method for preparing the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt is to mix trimethoprim, parahydroxybenzoic acid and berberine hydrochloride hydrate in a molar ratio of 1:1:1, add methanol to dissolve to form a clear and transparent solution, and then obtain a co-amorphous product of the ternary drug by reduced pressure rotary evaporation (water bath temperature is 50°C, rotation speed is 120 rpm), and then the obtained co-amorphous product is ethanol-assisted ball milling (grinding at a frequency of 30 Hz for 15 minutes) or heated at 170°C for 15 minutes. The obtained product is trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

[0014] Furthermore, in the above preparation method, the organic solvent is selected from one of ethanol, methanol or acetonitrile.

[0015] The trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt has antibacterial synergistic effect and can be used to prepare an antibacterial and anti-inflammatory drug composition.

[0016] Furthermore, the antibacterial and anti-inflammatory pharmaceutical composition is specifically a pharmaceutical composition for treating intestinal infections, such as gastroenteritis and bacillary dysentery caused by sensitive bacteria.

[0017] The specific beneficial effects are: (1) The present invention prepares the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt for the first time, and the preparation method thereof has the advantages of simple operation, high repeatability, and being green and efficient.

[0018] (2) Dynamic water vapor adsorption experiments showed that the hygroscopicity of the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt was significantly reduced compared with berberine hydrochloride hydrate.

[0019] (3) The stability test results show that the ternary drug organic salt has good thermal stability, humidity stability and light stability.

[0020] (4) The results of equilibrium solubility experiments showed that in different pH media, the solubility of trimethoprim in the ternary drug organic salt was 1.2 to 7.5 times that of pure trimethoprim, and the solubility of berberine hydrochloride in the ternary drug organic salt was 1.2 to 5.6 times that of pure berberine hydrochloride hydrate.

[0021] (5) In vitro dissolution experiments showed that the three active ingredients of trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride in the ternary drug organic salt can be released rapidly and synchronously in a short period of time, which helps the synchronous absorption of the drugs in the body.

[0022] (6) The results of in vitro antibacterial experiments showed that compared with the use of each drug alone, the minimum inhibitory concentration of the ternary drug organic salt of trimethoprim-parahydroxybenzoic acid-berberine hydrochloride against Staphylococcus aureus was reduced, indicating that the drugs have a synergistic antibacterial effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the crystal structure unit of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt single crystal prepared in Example 1.

[0024] Figure 2 This is the powder X-ray diffraction pattern of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt and the raw material prepared in Example 2.

[0025] Figure 3 This is a differential scanning calorimetry analysis diagram of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt and the raw material prepared in Example 2.

[0026] Figure 4 This is a dynamic water vapor adsorption diagram of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in Example 3 at 25°C.

[0027] Figure 5 This is the powder X-ray diffraction pattern of the trimethoprim-p-hydroxybenzoic acid-berberine ternary co-amorphous and drug organic salt prepared in Example 4.

[0028] Figure 6 This is a graph showing the crystal stability test results of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder prepared in Example 3.

[0029] Figure 7 The dissolution curves of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in Example 3 for in vitro dissolution experiment, (a) the dissolution medium is pH 6.8 phosphate buffer; (b) the dissolution medium is purified water. DETAILED DESCRIPTION

[0030] In order to make the contents of the present invention easier to understand, the technical solution of the present invention is further described below in conjunction with specific implementation methods, but the present invention is not limited thereto.

[0031] Example 1 0.2 mmol trimethoprim, 0.2 mmol p-hydroxybenzoic acid and 0.2 mmol berberine hydrochloride hydrate were weighed and placed in 20 mL ethanol, heated and dissolved. After filtering, a yellow transparent clear solution was obtained. The solution was sealed with a sealing film and several small holes were opened on the sealing film. The solution was allowed to evaporate slowly at room temperature for 7 days to obtain a trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt single crystal.

[0032] The trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in this example was characterized by single crystal X-ray diffraction. Figure 1 . Figure 1 The results of single crystal analysis show that the crystal structure unit includes protonated trimethoprim cation, p-hydroxybenzoic acid anion, chloride ion and berberine cation. Its specific unit cell parameters are: triclinic system, P-1 space group, unit cell parameters are: a =11.5488(5) Å, b= 12.1101(5)Å, c =14.8282(7)Å, α= 97.758(4)º, β= 101.522(4)º, γ= 104.197(4)° V =1932.67(15)Å 3 , Z=2, ρ calc =1.375 g / cm 3 .

[0033] Example 2 0.5 mmol of trimethoprim, 0.5 mmol of p-hydroxybenzoic acid and 0.5 mmol of berberine hydrochloride hydrate powder were weighed and mixed evenly, and then placed in the tank of a ball mill. 100 μL of ethanol was transferred to the mixed powder using a pipette, and then the ball mill was ground at a frequency of 25 Hz for 20 min. After the grinding, the solid product was dried at room temperature to obtain trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

[0034] Figure 2 This is the powder X-ray diffraction pattern of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in this example (instrument Rigaku SmartLab, Cu Kα radiation). It can be seen from the figure that the prepared sample has a diffraction angle of 2 θThe trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in this embodiment has characteristic peaks at 8.16, 8.83, 9.48, 10.78, 11.61, 12.39, 15.01, 15.23, 15.97, 17.67, 18.62, 18.93, 20.23, 21.53, 22.13, 22.50, 24.13, 24.82, 25.34, 25.93, 26.17, 26.59, 27.04, 29.37°, etc., with an error range of ±0.3°. The trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in this embodiment has a single crystal simulated powder X-ray diffraction pattern at the same 2 θ The peaks at different angles indicate that the two have the same crystal structure.

[0035] Figure 3 This is a differential scanning calorimetry analysis diagram of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in this example (the test was carried out on a NETZSCH DSC214 differential scanning calorimeter, with the same empty crucible as a reference, the test temperature range was 30-350 ° C, the heating rate was 10 ° C / min, nitrogen was passed as a protective gas, and the flow rate was 40 mL / min). It can be seen from the figure that the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt has a single and sharp melting endothermic peak (i.e., melting point) at 220±1 ° C, which is different from the melting endothermic peaks of trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride, indicating that the three drugs are assembled to form a new crystal structure.

[0036] Example 3 0.5 mmol trimethoprim, 0.5 mmol p-hydroxybenzoic acid and 0.5 mmol berberine hydrochloride hydrate were weighed and placed in a 20 mL glass bottle, and 10 mL ethanol and a magnetic rotor were added and sealed. The suspension was magnetically stirred at room temperature for 24 hours to form a suspension, and then filtered. The obtained product was dried and ground to obtain trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

[0037] The X-ray powder diffraction characterization results show that the powder X-ray diffraction pattern of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in this example is the same as that in Example 2 at the same θ The peaks at different angles indicate that the two have the same crystal structure.

[0038] Figure 4The dynamic water vapor adsorption diagram of the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt and the raw material prepared in this example (the experiment uses the Intrinsic Plus dynamic water vapor adsorption instrument (Surface Measurement System Ltd) to test the sample for water vapor adsorption test, the set temperature is 25 ° C, and the nitrogen flow rate is 200 mL / min. The mode selection is 0-95-0% relative humidity (RH) adsorption and desorption of water vapor full cycle, and the data is saved once every 5% RH step. The equilibrium standard for each step is dm / dt ≤ 0.002%). It can be seen from the figure that in the process of relative humidity rising from 0% RH to 95% RH, the mass change of berberine hydrochloride hydrate is about 7.68%, while the mass change of the ternary drug organic salt is only 0.65%, that is, compared with berberine hydrochloride hydrate, the hygroscopicity of the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt is significantly reduced.

[0039] Example 4 Weigh 0.5 mmol trimethoprim, 0.5 mmol p-hydroxybenzoic acid and 0.5 mmol berberine hydrochloride hydrate, dissolve in 80 mL methanol, filter and transfer the filtrate to a 250 mL round-bottom flask for vacuum rotary evaporation (water bath temperature is 50 ° C, speed is 120 rpm), after the solvent in the bottle is evaporated, put it in an oven to dry, scrape out the product as a co-amorphous, then grind the prepared co-amorphous sample in a ball mill at a frequency of 30 Hz for 15 min or heat it in an oven at 170 ° C for 15 min to obtain trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

[0040] Figure 5 The powder X-ray diffraction pattern of the trimethoprim-p-hydroxybenzoic acid-berberine ternary co-amorphous and organic salt prepared in this example. As can be seen from the figure, the sample prepared in this example is the same as that in Example 2. θ The peaks at different angles indicate that the two have the same crystal structure.

[0041] Example 5 According to the standards of the Chinese Pharmacopoeia, the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder prepared in Example 3 was stored under high temperature (60 ° C), high humidity (90% RH) and strong light (4500 lx) conditions for 10 days, and then the sample was characterized by powder X-ray diffraction to evaluate its stability. The results are shown in Figure 6 .

[0042] Figure 6 The results showed that the crystal form of the ternary drug organic salt did not change under different conditions, indicating that it has good thermal stability, humidity stability and light stability.

[0043] Example 6 Equilibrium solubility experiment of trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt.

[0044] Weigh 100 mg of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in Example 3 and the same amount of the raw material drug in a 10 mL centrifuge tube, add 2 mL of different solution media (pH 1.2 hydrochloric acid aqueous solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and pure water), and oscillate continuously in a 37 ° C constant temperature oscillator for 48 hours. Take the upper clear liquid through a 0.45 μm membrane and then immediately dilute it with pure water to a certain concentration. The saturated equilibrium solubility of the sample was determined by high performance liquid chromatography (HPLC), and the parallel samples were 3 groups (n=3). The results are shown in Table 1, and the solubility unit is mg / mL.

[0045] Table 1 Equilibrium solubility test results (solubility unit is mg / mL, n=3)

[0046] As can be seen from Table 1, after trimethoprim forms salt, its solubility is improved to different degrees in different pH media, and the best is 7.5 times that of pure trimethoprim in water. Similarly, due to the common ion effect, the solubility of pure berberine hydrochloride in pH1.2 medium is very small, but the formation of ternary drug organic salt makes the solubility of berberine hydrochloride in pH1.2 medium increase to 5.6 times that of pure berberine hydrochloride. It can be seen that the formation of ternary drug organic salt reduces the solubility difference between different drugs and creates conditions for the synergistic absorption of drugs.

[0047] Example 7 In vitro dissolution study of trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt.

[0048] Weigh the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt prepared in Example 3 and the raw material powder of the same amount of substance, use the small cup paddle method, the propeller speed is 75 rpm / min, pH 6.8 phosphate buffer (simulated intestinal fluid) and pure water as the dissolution medium, respectively, and the medium temperature is 37 ° C. The experiment was sampled at 5, 10, 15, 30, 45, 60, 90, and 120 min. The extraction solutions used were all passed through a 0.45 μm membrane, and their concentrations were measured by HPLC. The parallel samples were 3 groups (n = 3). The results are as follows Figure 7 .

[0049] As can be seen from the figure, in the pH 6.8 simulated intestinal fluid dissolution medium and pure water medium, the formation of the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt increased the dissolution rate of trimethoprim and berberine hydrochloride, so that the three active ingredients of the drug were all dissolved synchronously within 20 minutes, which has a positive effect on the synergistic effect of the drugs and is conducive to achieving better therapeutic effects.

[0050] Example 8 In vitro antibacterial experiment of trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt.

[0051] The experiment measured the minimum inhibitory concentration (MIC) of the trimethoprim-parahydroxybenzoic acid-berberine hydrochloride ternary drug organic salt and the raw material drug prepared in Example 3, and compared the in vitro antibacterial effect of the organic salt and the corresponding raw material drug on Staphylococcus aureus. The specific experimental steps include: (1) Strain recovery: Take 0.1 mL of the frozen stock solution of Staphylococcus aureus and inoculate it into a test tube containing 5 mL of nutrient broth (NB) and culture it in a shaking incubator at 37 °C for 12 h.

[0052] (2) Bacterial solution dilution: Determine OD using a spectrophotometer 600 To determine the original bacterial solution concentration, and then dilute the bacterial solution to a certain concentration with nutrient broth.

[0053] (3) Preparation of drug solution and gradient dilution: Take equal volumes of drug stock solution and double concentrated nutrient broth, mix well and set aside. Add 100 µL of nutrient broth to each well of a 96-well cell culture plate. Use a pipette to take 100 µL of drug solution and add it to the first column of a sterilized 96-well plate. Mix well and then pipette 100 µL from the first column to the second column. Continue diluting to the tenth column and pipette 100 µL of solution from the tenth column and discard.

[0054] (4) Add bacterial solution: Add 100 µL of diluted bacterial solution to the first 10 columns, add 200 µL of nutrient broth medium to the 11th column as a negative control, and add the same concentration of bacterial solution to the 12th column as a positive control.

[0055] (5)Culture and results: Gently shake and mix the 96-well cell culture plate and place it in an incubator at 37 °C for 18 - 24 h. Put the 96-well cell culture plate into a microplate reader and measure the absorbance (optical density, OD) at 600 nm. The concentration with a final bacteriostatic rate of 90% is defined as the minimum inhibitory concentration (MIC90). The bacteriostatic rate = [ (OD value of positive control - OD value of experiment) / (OD value of positive control - OD value of negative control) ] × 100%. Calculate the fractional inhibitory concentration index (FICI) to determine whether the drugs have a synergistic antibacterial effect. FICI = (MIC of drug A in combination / MIC of drug A alone) + (MIC of drug B in combination / MIC of drug B alone); when FICI < 1, there is a synergistic effect between the drugs; when FICI = 1, there is an additive effect between the drugs; when 1 < FICI ≤ 4, there is an irrelevant effect between the drugs; when FICI > 4, there is an antagonistic effect between the drugs. The experimental results are shown in Table 2, and the parallel samples of the experiment are set to 3 groups (n = 3).

[0056] Table 2 MIC90 values of different samples (unit: μg / mL, n = 3)

[0057] As shown in the results of Table 2, the MIC90 of trimethoprim - p-hydroxybenzoic acid - berberine hydrochloride ternary drug organic salt against Staphylococcus aureus is 4 μg / mL, the MIC90 of trimethoprim is 2 μg / mL, the MIC90 of p-hydroxybenzoic acid is 1024 μg / mL, and the MIC90 of berberine hydrochloride is 64 μg / mL. Finally, the calculated FICI value is 0.754, determining that there is a synergistic antibacterial effect among the three components of the drug salt.

[0058] The above are only the preferred embodiments of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope covered by the present invention.

Claims

1. A trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt, characterized in that: The ternary drug organic salt is prepared from trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride in a molar ratio of 1:1:1, and its molecular formula is [C 14 H 18 N4O3·C7H6O3·C 20 H 18 ClNO4].

2. The trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt according to claim 1, characterized in that: The ternary drug organic salt belongs to the triclinic system, P-1 space group, and the unit cell parameters are: a =11.5488(5) Å, b= 12.1101(5)Å, c =14.8282(7)Å, α= 97.758(4)º, β= 101.522(4)º, γ= 104.197(4)° V =1932.67(15)Å 3 , Z=2, ρ calc =1.375 g / cm 3 .

3. A method for preparing the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt as claimed in claim 1, characterized in that: Add trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride hydrate to an organic solvent in proportion, stir and heat to form a transparent clear solution, filter and cool to room temperature, and then slowly evaporate at room temperature to precipitate yellow block crystals to obtain single crystals of trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt.

4. A method for preparing the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt as claimed in claim 1, characterized in that: The trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride hydrate are mixed evenly in proportion and poured into a ball mill, and an organic solvent is added for mechanical grinding. The obtained product is dried at room temperature to obtain trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

5. A method for preparing the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt as claimed in claim 1, characterized in that: The trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride hydrate are mixed in proportion, and an organic solvent is added to form a suspension, which is then stirred at room temperature for 24 hours and filtered. The obtained precipitate is dried and ground to obtain a trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

6. A method for preparing the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt as claimed in claim 1, characterized in that: After trimethoprim, p-hydroxybenzoic acid and berberine hydrochloride hydrate are mixed in proportion, methanol is added to dissolve to form a clear and transparent solution, and then the co-amorphous product of the ternary drug is obtained by reduced pressure rotary evaporation. The obtained co-amorphous product is then ball-milled with the assistance of ethanol or heated at 170°C for 15 minutes. The obtained product is trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt powder.

7. The preparation method according to claims 3 to 6, characterized in that: The organic solvent is selected from ethanol, methanol or acetonitrile.

8. Use of the trimethoprim-p-hydroxybenzoic acid-berberine hydrochloride ternary drug organic salt as claimed in claim 1 in the preparation of an antibacterial and anti-inflammatory pharmaceutical composition.

9. The use according to claim 8, characterized in that: The antibacterial and anti-inflammatory pharmaceutical composition is specifically a pharmaceutical composition for treating intestinal infection.

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