Artemisinic acid and dihydroartemisinic acid berberine salt, preparation method and application thereof

Abstract

The application discloses artemisinic acid and dihydroartemisinic acid berberine salt, a preparation method and application thereof, and the preparation method comprises the following steps: S1, artemisinic acid or dihydroartemisinic acid is reacted with an inorganic base to generate artemisinic acid salt or dihydroartemisinic acid salt; S2, the artemisinic acid salt or dihydroartemisinic acid salt is reacted with hydrochloric acid berberine to generate artemisinic acid or dihydroartemisinic acid berberine salt crude product; and S3, the artemisinic acid or dihydroartemisinic acid berberine salt crude product is beaten and purified to obtain artemisinic acid or dihydroartemisinic acid berberine salt pure product. The application synthesizes artemisinic acid berberine salt and dihydroartemisinic acid berberine salt two novel ionic compounds for the first time, the acidic artemisinic acid / dihydroartemisinic acid is combined with the alkaline berberine through an acid-base ionic salt formation reaction, water solubility, stability and bioavailability of the compounds can be remarkably improved, and pharmacological synergistic effects of two active ingredients are realized.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to an artemisinic acid and dihydroartemisinic acid berberine salt, their preparation method and application. Background Technology

[0002] Artemisinic acid and dihydroartemisinic acid are important sesquiterpene carboxylic acid natural products isolated from Artemisia annua, and are also key precursors in the biosynthesis of artemisinin. Neither has significant direct antimalarial efficacy. In vitro studies show that artemisinic acid possesses very low-intensity anti-inflammatory or immunomodulatory signals, but has no clear therapeutic value. Dihydroartemisinic acid has potential biological activities such as inhibiting melanin production, inhibiting mesenchymal stem cell adipogenesis, anti-inflammatory effects, and anti-glycation, but it is currently mainly in the research or cosmetic application exploration stage.

[0003] Berberine, commonly known as berberine salt, is a core active alkaloid found in traditional Chinese medicinal herbs such as Coptis chinensis and Phellodendron amurense. Belonging to the isoquinoline derivative class, it possesses broad-spectrum antibacterial, anti-inflammatory, antiviral, antitumor, and metabolic-regulating pharmacological effects. Clinically, berberine is usually formulated as a hydrochloride salt, but this form suffers from poor water solubility, low oral absorption efficiency, and a short half-life in vivo. Single-drug use has limited efficacy and significant limitations. Furthermore, both berberine and its hydrochloride salt formulations can potentially induce hemolytic anemia, leading to jaundice. This risk is related to the drug's damaging effect on red blood cell membranes.

[0004] There are currently no reports on novel ionic salt compounds and specific preparation processes for the salt formation of artemisinin, dihydroartemisinin, and berberine, nor have there been any salt derivatives with dual activities, high stability, and high bioavailability been developed. Based on this, this invention designs and synthesizes two novel compounds: artemisinin-berberine salt and dihydroartemisinin-berberine salt. These compounds achieve molecular-level complexation through an acid-base salt formation reaction, overcoming the technical deficiencies of existing natural products. Compared to berberine hydrochloride, artemisinin and dihydroartemisinin-berberine exhibit better water solubility, higher bioavailability, and superior biological activity, particularly in antibacterial and other aspects. Summary of the Invention

[0005] This invention aims to overcome the shortcomings of existing technologies and provide two novel natural product salt compounds: artemisinic acid berberine salt and dihydroartemisinic acid berberine salt. It also provides a simple, high-conversion preparation method suitable for industrial production, as well as new applications of these compounds in antibacterial drugs. This invention utilizes an acid-base ion salt formation reaction to combine acidic artemisinic acid / dihydroartemisinic acid with basic berberine, significantly improving the compound's water solubility, stability, and bioavailability, achieving a synergistic pharmacological effect between the two active ingredients.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In its first aspect, the present invention provides artemisinin and dihydroartemisinin berberine salt, which have the following chemical structural formula shown in Formula I: ; Wherein, R = CH2 or CH3; when R = CH2, the compound shown in Formula I is berberine artemisinic acid salt; when R = CH3, the compound shown in Formula I is dihydroberberine artemisinic acid salt.

[0007] Preferably, the synthetic route for artemisinic acid and dihydroartemisinic acid berberine salt is as follows: .

[0008] A second aspect of the present invention provides a method for preparing artemisinic acid and dihydroartemisinic acid berberine salt as described above, comprising the following steps: S1. Artemisinic acid or dihydroartemisinic acid is reacted with an inorganic base to produce artemisinate or dihydroartemisinate; S2. Artemisinin salt or dihydroartemisinin salt is reacted with berberine hydrochloride to produce crude artemisinin acid or dihydroartemisinin berberine salt. S3. Purify the crude artemisinin acid or dihydroartemisinin berberine salt by pulping to obtain pure artemisinin acid or dihydroartemisinin berberine salt.

[0009] Preferably, the method for preparing artemisinic acid and dihydroartemisinic acid berberine salt is characterized by comprising the following steps: S1. Dissolve an inorganic base in deionized water, add artemisinin or dihydroartemisinin, and stir until the reaction system is clear, generating a product containing artemisinin or dihydroartemisinin. S2. Add berberine hydrochloride to the product obtained in step S1, heat and stir to react, cool down after the reaction is completed, filter, wash and dry the filter cake to obtain crude artemisinic acid or dihydroartemisinic acid berberine salt. S3. Mix crude artemisinic acid or dihydroartemisinic acid berberine salt with an organic solvent, heat and stir, cool down after the reaction is complete, filter, wash and dry the filter cake to obtain pure artemisinic acid or dihydroartemisinic acid berberine salt.

[0010] Preferably, the inorganic base in step S1 is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate, more preferably sodium hydroxide or potassium carbonate.

[0011] Preferably, the equivalent ratio of artemisinic acid or dihydroartemisinic acid to inorganic base in step S1 is 1:1 to 1.8; for example, the ratio is 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8 or any value formed by any two of them, more preferably 1:1.4.

[0012] Preferably, the ratio of the mass of artemisinin or dihydroartemisinin used in step S1 to the volume of deionized water is 1:3 to 9, in volume units of mL and weight units of g; for example, the ratio is 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or any value formed by any two of them, more preferably 1:5.

[0013] Preferably, the equivalent ratio of berberine hydrochloride to artemisinic acid or dihydroartemisinic acid in step S2 is 1:1.1 to 1.5; for example, the ratio is 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or any value formed by any two of them, more preferably 1:1.3.

[0014] Preferably, the reaction temperature in step S2 is 50~90°C, for example, the reaction temperature is 50, 60, 70, 80, 90°C or any value formed by any two of them, more preferably 70°C.

[0015] Preferably, the reaction time in step S2 is 10 to 20 hours, for example, 10, 12, 14, 16, 18, 20 hours or any value between any two of them, more preferably 16 hours.

[0016] Preferably, the organic solvent in step S3 is one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and chloroform, and more preferably ethyl acetate.

[0017] Preferably, the ratio of the volume of the organic solvent to the mass of the crude artemisinin acid or dihydroartemisinin berberine salt in step S3 is 3 to 8:1, in volume units of mL and weight units of g; for example, the ratio is 3, 4, 5, 6, 7, 8 or any value formed by any pair thereof, more preferably 5.

[0018] Preferably, the heating and stirring temperature in step S3 is 40~80°C, for example, 40, 50, 60, 70, 80°C or any value formed by any two of them, more preferably 60°C.

[0019] Preferably, the heating and stirring time in step S3 is 2 to 6 hours, for example, 2, 3, 4, 5, 6 hours or any value between any two of them, more preferably 3 hours.

[0020] Preferably, the method for preparing artemisinic acid and dihydroartemisinic acid berberine salt is characterized by comprising the following steps: S1. Dissolve the inorganic base in deionized water, add artemisinin or dihydroartemisinin, and stir until the reaction system is clear, generating a product containing artemisinin or dihydroartemisinin, which can be directly used in the next step of the reaction. S2. Add berberine hydrochloride to the product obtained in step S1, heat and stir at 50~90℃ for 10~20h, cool down after the reaction is completed, filter, rinse the filter cake with deionized water and dry to obtain crude artemisinic acid or dihydroartemisinic acid berberine salt. S3. Mix crude artemisinic acid or dihydroartemisinic acid berberine salt with an organic solvent, heat and stir at 40~80℃ for 2~6h, cool down after the reaction is complete, filter, wash the filter cake with an organic solvent and dry it to obtain pure artemisinic acid or dihydroartemisinic acid berberine salt.

[0021] A third aspect of the present invention provides the use of artemisinic acid and dihydroartemisinic acid berberine salt as described above in the preparation of antibacterial drugs.

[0022] In a fourth aspect, the present invention provides a pharmaceutical composition comprising artemisinic acid and berberine dihydroartemisinic acid as described above, and pharmaceutically acceptable excipients.

[0023] Preferably, the pharmaceutical composition is used for antibacterial purposes.

[0024] Preferably, the pharmaceutical composition is formulated into commonly used preparations, such as tablets, capsules, granules, oral solutions, oral suspensions, syrups, pills, topical preparations, injections, etc.

[0025] The beneficial effects of this invention are: This invention is the first to synthesize two novel ionic compounds, artemisinic acid berberine salt and dihydroartemisinic acid berberine salt. By using intermolecular ionic bonds to replace traditional physical mixing, it solves the technical problems of component separation and poor stability in existing compound formulations. This invention also provides a method for preparing artemisinic acid berberine salt and dihydroartemisinic acid berberine salt. This method features mild reaction conditions, simple operation, no high-temperature and high-pressure reaction, high raw material conversion rate, high product purity, recyclable and reusable solvent, low production cost, and is environmentally friendly, making it suitable for large-scale industrial production.

[0026] Compared to berberine hydrochloride, the dihydroartemisinic acid berberine and artemisinic acid berberine prepared in this invention can form aqueous solutions of 100 mg / 10 mL and 80 mg / 10 mL, respectively, which is at least 8-10 times higher than that of berberine hydrochloride (<10 mg / mL). This is because the chloride ion in berberine hydrochloride has a small radius and forms a dense crystal with a high lattice energy with the berberine quaternary ammonium cation, resulting in poor water solubility. On the other hand, the dihydroartemisinic acid and artemisinic acid anions have large molecular volumes, and the size mismatch between the anions and cations reduces the lattice energy of the salt. At the same time, the polar groups on the organic acid anions can form hydrogen bonds with water molecules, weakening the crystal stacking effect. Therefore, the dihydroartemisinic acid and artemisinic acid berberine salts exhibit better water solubility than berberine hydrochloride. The improved water solubility of dihydroartemisinic acid and artemisinic berberine is beneficial to improving the in vivo absorption efficiency and bioavailability during administration, effectively solving the defects of poor water solubility, rapid metabolism and weak efficacy of berberine hydrochloride. Attached Figure Description

[0027] Figure 1 The 1H NMR spectrum of the dihydroartemisinic acid berberine salt prepared in Example 1; Figure 2 The 1H NMR spectrum of the artemisinic acid berberine salt prepared in Example 2; Figure 3 This is a photograph of the actual samples used in Example 3 to test the solubility of berberine dihydroartemisinic acid salt, berberine artemisinic acid salt, and berberine hydrochloride in water. Detailed Implementation

[0028] The present invention will be further described in detail below with reference to embodiments, so that those skilled in the art can implement it based on the description.

[0029] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0030] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available. For examples where specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer are followed. For reagents or instruments whose manufacturers are not specified, they are all commercially available products.

[0031] Example 1 This example provides a berberine dihydroartemisinic acid salt, the preparation method of which includes the following steps: S1. Add 19.5 g (488.2 mmol) of sodium hydroxide and 412 mL of deionized water to a 1 L three-necked flask, stir until dissolved, add 82.4 g (348.7 mmol) of dihydroartemisinic acid in portions, and stir until dissolved. This solution can be used directly in the next reaction.

[0032] S2. Add 100 g (268.2 mmol) of berberine hydrochloride to the above reaction solution in portions, then heat to 70°C and stir for 16 h. After the reaction solution is cooled to room temperature, filter it, rinse the filter cake with deionized water, collect the filter cake, and dry it at 60°C to obtain 148.2 g of crude berberine dihydroartemisinic acid.

[0033] S3. 148.2 g (258.8 mmol) of crude berberine dihydroartemisinic acid was mixed with 740 mL of ethyl acetate and heated to 60 °C and stirred for 3 h. Then the mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filter cake was collected and dried at 60 °C to obtain 140.1 g of pure berberine dihydroartemisinic acid, with a total yield of 91.2%.

[0034] The 1H NMR spectrum of berberine dihydroartemisinic acid prepared in this embodiment is as follows: Figure 1 As shown, the NMR data are as follows: 1 H NMR (400 MHz, DMSO): δ 9.90 (s, 1H), 8.95 (s, 1H), 8.20 (d, J = 9.1Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.80 (s, 1H), 7.08 (s, 1H), 6.17 (s, 2H), 6.16-5.99 (m, 1H), 5.15 (s, 1H), 4.94 (t, J = 6.3 Hz, 2H), 4.09 (s, 3H), 4.07 (s, 3H), 3.79 (d, J = 1.8 Hz, 1H), 3.20 (t, J = 6.2 Hz, 2H), 2.34 (s, 1H), 2.09-2.02(m, 1H), 1.89-1.70 (m, 2H), 1.58 (s, 3H), 1.50-1.39 (m, 4H), 1.33-1.29 (m, 1H), 1.16-1.12 (m, 1H), 0.87 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H), 0.84-0.78(m, 1H).

[0035] Example 2 This example provides an artemisinic acid berberine salt, the preparation method of which includes the following steps: S1. Add 51.9 g (375.5 mmol) of potassium carbonate and 530 mL of deionized water to a 1 L three-necked flask, stir until dissolved, add 88.0 g (375.5 mmol) of artemisinin in portions, and stir until dissolved. This solution can be used directly in the next step of the reaction.

[0036] S2. Add 100 g (268.2 mmol) of berberine hydrochloride to the above reaction solution in portions, then heat to 70 °C and stir for 16 h. Cool the reaction solution, filter, rinse the filter cake with deionized water, collect the filter cake, and dry it at 60 °C to obtain 146.5 g of crude berberine artemisinic acid.

[0037] S3. 146.5 g of crude artemisinin berberine and 880 mL of tetrahydrofuran were mixed and heated to 60 °C and stirred for 3 h. Then the mixture was cooled to room temperature, filtered, and the filter cake was washed with tetrahydrofuran. The filter cake was collected and dried at 60 °C to obtain 136.3 g of pure artemisinin berberine, with a total yield of 89.0%.

[0038] The 1H NMR spectrum of artemisinin berberine prepared in this embodiment is as follows: Figure 2 As shown, the NMR data are as follows: 1 H NMR (400 MHz, DMSO): δ 9.91 (s, 1H), 8.96 (s, 1H), 8.19 (d, J = 9.1Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.80 (s, 1H), 7.08 (s, 1H), 6.17 (s, 2H), 5.78(dd, J = 2.9, 1.0 Hz, 1H), 4.99 (s, 1H), 4.96-4.93 (m, 2H), 4.88 (s, 1H), 4.09 (s, 3H), 4.07 (s, 3H), 3.20 (t, J= 6.2 Hz, 2H), 2.62-2.58 (m, 1H), 2.56-2.52 (m,1H), 1.87-1.75 (m, 2H), 1.72-1.65 (m, 1H), 1.64-1.57 (m, 1H), 1.52 (s, 3H), 1.45-1.39 (m, 1H), 1.38-1.22 (m, 3H), 1.21-1.11 (m, 1H), 1.01-0.91 (m, 1H), 0.84 (d, J = 6.1 Hz, 3H).

[0039] Example 3 Solubility test: Tests showed that the dihydroartemisinic acid berberine salt and artemisinic acid berberine salt prepared in Examples 1 and 2 both had good water solubility, and could form clear and transparent aqueous solutions of 100 mg / 10 mL and 80 mg / 10 mL with water, respectively. Under the same conditions, the 10 mg / 10 mL aqueous solution of berberine hydrochloride clearly formed a suspension.

[0040] Reference Figure 3 The images, from left to right, show the dissolution of 100 mg of berberine dihydroartemisinic acid, 80 mg of berberine artemisinic acid, and 10 mg of berberine hydrochloride in 10 mL of water. It can be seen that when 100 mg of berberine dihydroartemisinic acid and 80 mg of berberine artemisinic acid are dissolved in 10 mL of water, the solutions are clear and completely dissolved. However, when 10 mg of berberine hydrochloride is dissolved in 10 mL of water, a large amount of insoluble matter appears.

[0041] Example 4 Antibacterial properties tests of berberine hydrochloride, dihydroartemisinic acid, artemisinic acid, artemisinic acid, or a 1:1 physical mixture of dihydroartemisinic acid and berberine hydrochloride, berberine dihydroartemisinic acid salt, and berberine artemisinic acid salt: Methods: Samples were dissolved in water to prepare solutions of different concentrations. Bacterial suspensions of *Escherichia coli* [strain number CMCC(B) 44102 (ATCC 25922)], *Staphylococcus aureus* [strain number CMCC(B) 26003 (ATCC 25923)], and *Salmonella* [strain number CMCC(B) 50115 (ATCC 14028)] were added and incubated for 1 hour. Colony counts were obtained using the plate counting method. 0.5 wt% DMSO (dimethyl sulfoxide) was added to the dihydroartemisinic acid and artemisinic acid solutions to aid dissolution.

[0042] The test results are shown in Tables 1-3 below. Each item was tested in two parallel experiments. The colony count in the table represents the number of colonies after 1 hour of incubation in the two parallel experiments. The survival rate is the ratio of the colony count of each group after 1 hour of incubation to the control group (aqueous solution). The survival rate result in the table is the average of the results of the two parallel experiments.

[0043] Table 1 Results of Escherichia coli antibacterial experiment Results Analysis: Berberine hydrochloride, dihydroartemisinin, and artemisinin showed no significant inhibitory effect on Escherichia coli at low / high concentrations. The antibacterial effect of a physical mixture of artemisinin or dihydroartemisinin with berberine hydrochloride in a 1:1 molar ratio was not improved compared to berberine hydrochloride alone. However, the dihydroartemisinin-berberine salt group achieved an inhibition rate of 99% at a low concentration of 0.5 mg / mL and completely inhibited bacterial growth at a high concentration of 2 mg / mL. The artemisinin-berberine salt group also achieved an inhibition rate of 97.0% at a low concentration of 0.5 mg / mL and completely inhibited bacterial growth at a high concentration of 2 mg / mL. This demonstrates that the antibacterial effects of dihydroartemisinin-berberine salt and artemisinin-berberine salt on Escherichia coli are significantly better than those of berberine hydrochloride, dihydroartemisinin, and artemisinin alone, and are also significantly better than those of artemisinin or a physical mixture of dihydroartemisinin and berberine hydrochloride.

[0044] Table 2 Results of Staphylococcus aureus antibacterial experiment Results Analysis: Berberine hydrochloride showed weak antibacterial effects against Staphylococcus aureus at both low and high concentrations. Dihydroartemisinin and artemisinin groups showed no significant antibacterial effects at either high or low concentrations. The antibacterial effect of a physical mixture of artemisinin or dihydroartemisinin with berberine hydrochloride in a 1:1 molar ratio was not significantly different from that of berberine hydrochloride alone. However, both dihydroartemisinin berberine salt and artemisinin berberine salt completely inhibited bacterial growth at both low concentrations of 0.5 mg / mL and high concentrations of 2 mg / mL. This demonstrates that the antibacterial effects of dihydroartemisinin berberine salt and artemisinin berberine salt against Staphylococcus aureus are significantly better than those of berberine hydrochloride, dihydroartemisinin, and artemisinin alone, and also significantly better than artemisinin or the physical mixture of dihydroartemisinin and berberine hydrochloride.

[0045] Table 3. Results of Salmonella inhibition test Results analysis: Berberine hydrochloride and dihydroartemisinin, artemisinin, and physical mixtures of artemisinin and dihydroartemisinin with berberine hydrochloride in a 1:1 molar ratio showed no significant inhibitory effect on Salmonella at low / high concentrations. However, the dihydroartemisinin berberine salt group achieved an inhibition rate of 96.3% at a low concentration of 0.5 mg / mL and completely inhibited bacterial growth at a high concentration of 2 mg / mL. The artemisinin berberine salt group achieved an inhibition rate of 98.1% at a low concentration of 0.5 mg / mL and completely inhibited bacterial growth at a high concentration of 2 mg / mL. This demonstrates that the inhibitory effects of dihydroartemisinin berberine salt and artemisinin berberine salt on Salmonella are significantly better than those of berberine hydrochloride, dihydroartemisinin, and artemisinin alone, and are also significantly better than artemisinin or physical mixtures of dihydroartemisinin and berberine hydrochloride.

[0046] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details.

Claims

1. A berberine salt containing artemisinic acid and dihydroartemisinic acid, characterized in that, It has the chemical structural formula shown in Formula I: ； Wherein, R = CH2 or CH3; when R = CH2, the compound shown in Formula I is berberine artemisinic acid salt; when R = CH3, the compound shown in Formula I is dihydroberberine artemisinic acid salt.

2. A method for preparing artemisinic acid and dihydroartemisinic acid berberine salt as described in claim 1, characterized in that, Includes the following steps: S1. Artemisinic acid or dihydroartemisinic acid is reacted with an inorganic base to produce artemisinate or dihydroartemisinate; S2. Artemisinin salt or dihydroartemisinin salt is reacted with berberine hydrochloride to produce crude artemisinin acid or dihydroartemisinin berberine salt. S3. Purify the crude artemisinin acid or dihydroartemisinin berberine salt by pulping to obtain pure artemisinin acid or dihydroartemisinin berberine salt.

3. The method for preparing artemisinic acid and dihydroartemisinic acid berberine salt according to claim 2, characterized in that, Includes the following steps: S1. Dissolve an inorganic base in deionized water, add artemisinin or dihydroartemisinin, and stir until the reaction system is clear, generating a product containing artemisinin or dihydroartemisinin. S2. Add berberine hydrochloride to the product obtained in step S1, heat and stir to react, cool down after the reaction is completed, filter, wash and dry the filter cake to obtain crude artemisinic acid or dihydroartemisinic acid berberine salt. S3. Mix crude artemisinic acid or dihydroartemisinic acid berberine salt with an organic solvent, heat and stir, cool down after the reaction is complete, filter, wash and dry the filter cake to obtain pure artemisinic acid or dihydroartemisinic acid berberine salt.

4. The method for preparing artemisinic acid and dihydroartemisinic acid berberine salt according to claim 2 or 3, characterized in that, The inorganic base in step S1 is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.

5. The method for preparing artemisinic acid and dihydroartemisinic acid berberine salt according to claim 3, characterized in that, In step S1, the equivalence ratio of artemisinic acid or dihydroartemisinic acid to inorganic base is 1:1~1.8; The ratio of the mass of artemisinin or dihydroartemisinin used in step S1 to the volume of deionized water is 1:3~9, expressed in mL and g respectively.

6. The method for preparing artemisinic acid and dihydroartemisinic acid berberine salt according to claim 2 or 3, characterized in that, In step S2, the equivalence ratio of berberine hydrochloride to artemisinic acid or dihydroartemisinic acid is 1:1.1~1.5; The reaction temperature in step S2 is 50~90℃ and the reaction time is 10~20h.

7. The method for preparing artemisinic acid and dihydroartemisinic acid berberine salt according to claim 2 or 3, characterized in that, The organic solvent in step S3 is one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and chloroform.

8. The method for preparing artemisinic acid and dihydroartemisinic acid berberine salt according to claim 2 or 3, characterized in that, The ratio of the volume of the organic solvent to the mass of the crude artemisinin acid or dihydroartemisinin berberine salt in step S3 is 3~8:1, expressed in mL and g. In step S3, the heating and stirring temperature is 40~80℃ and the time is 2~6h.

9. The use of artemisinic acid and dihydroartemisinic acid berberine salt as described in claim 1 in the preparation of antibacterial drugs.

10. A pharmaceutical composition, characterized in that, It includes artemisinic acid and dihydroartemisinic acid berberine salt as described in claim 1, as well as pharmaceutically acceptable excipients.

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